WO2015131100A1 - Ligand-controlled c(sp3)-h arylation and olefination in synthesis of unnatural chiral alpha amino acids - Google Patents
Ligand-controlled c(sp3)-h arylation and olefination in synthesis of unnatural chiral alpha amino acids Download PDFInfo
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- WO2015131100A1 WO2015131100A1 PCT/US2015/018103 US2015018103W WO2015131100A1 WO 2015131100 A1 WO2015131100 A1 WO 2015131100A1 US 2015018103 W US2015018103 W US 2015018103W WO 2015131100 A1 WO2015131100 A1 WO 2015131100A1
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- 0 CCOC(C=CC[C@@](*)NC(OC(C)(C)C)=O)=O Chemical compound CCOC(C=CC[C@@](*)NC(OC(C)(C)C)=O)=O 0.000 description 23
- VSZBYPXHHDNXJJ-UHFFFAOYSA-N CC(C)COc1nc2ccccc2cc1 Chemical compound CC(C)COc1nc2ccccc2cc1 VSZBYPXHHDNXJJ-UHFFFAOYSA-N 0.000 description 2
- CKWLBLYSBFEADS-QMMMGPOBSA-N N[C@@H](Cc1ccccc1)C(Nc(c(F)c(c(C(F)(F)F)c1F)F)c1F)=O Chemical compound N[C@@H](Cc1ccccc1)C(Nc(c(F)c(c(C(F)(F)F)c1F)F)c1F)=O CKWLBLYSBFEADS-QMMMGPOBSA-N 0.000 description 2
- VHHFHLGLZMWTBV-UHFFFAOYSA-N CC(CC1)Oc2c1c(C)c(ccc(C(F)(F)F)c1)c1n2 Chemical compound CC(CC1)Oc2c1c(C)c(ccc(C(F)(F)F)c1)c1n2 VHHFHLGLZMWTBV-UHFFFAOYSA-N 0.000 description 1
- RLTMYZPTDSFMFM-UHFFFAOYSA-N CC(CCc1c(C)c2ccc3)Oc1nc2c3F Chemical compound CC(CCc1c(C)c2ccc3)Oc1nc2c3F RLTMYZPTDSFMFM-UHFFFAOYSA-N 0.000 description 1
- FQMFYRHAXSQCLZ-UOTNVTSPSA-N CC([C@@H](C(Nc(c(F)c(c(C(F)(F)F)c1F)F)c1F)=O)N)c1ccc(C)cc1 Chemical compound CC([C@@H](C(Nc(c(F)c(c(C(F)(F)F)c1F)F)c1F)=O)N)c1ccc(C)cc1 FQMFYRHAXSQCLZ-UOTNVTSPSA-N 0.000 description 1
- QZXHIKYQZVQPSP-UHFFFAOYSA-N CC1(C#N)NC(C#N)=CC=C1 Chemical compound CC1(C#N)NC(C#N)=CC=C1 QZXHIKYQZVQPSP-UHFFFAOYSA-N 0.000 description 1
- UWGGYFZFVQWFDO-UHFFFAOYSA-N CC1(NC(OC)=CC=C1)OC Chemical compound CC1(NC(OC)=CC=C1)OC UWGGYFZFVQWFDO-UHFFFAOYSA-N 0.000 description 1
- ZENOEMLZOZWVRD-UHFFFAOYSA-N CC1Oc2nc(cccc3)c3c(C)c2CC1 Chemical compound CC1Oc2nc(cccc3)c3c(C)c2CC1 ZENOEMLZOZWVRD-UHFFFAOYSA-N 0.000 description 1
- UTQFVBHZYHBFPP-UHFFFAOYSA-N CCC(C)Oc1nc(cccc2)c2cc1 Chemical compound CCC(C)Oc1nc(cccc2)c2cc1 UTQFVBHZYHBFPP-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N CN(C)c1ccncc1 Chemical compound CN(C)c1ccncc1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- CDOHJPOEPKSHBM-UHFFFAOYSA-N COC(C(C1)NCc(cc2)c1cc2OC)=O Chemical compound COC(C(C1)NCc(cc2)c1cc2OC)=O CDOHJPOEPKSHBM-UHFFFAOYSA-N 0.000 description 1
- GPTXVLYILNSSRN-UHFFFAOYSA-N COC(CCc1ccc2[nH]ccc2c1)=O Chemical compound COC(CCc1ccc2[nH]ccc2c1)=O GPTXVLYILNSSRN-UHFFFAOYSA-N 0.000 description 1
- QAXMGTIPCITBRF-ZETCQYMHSA-N COC([C@H](Cc1cc(Cl)ncc1)N)=O Chemical compound COC([C@H](Cc1cc(Cl)ncc1)N)=O QAXMGTIPCITBRF-ZETCQYMHSA-N 0.000 description 1
- UUNRBALABMXLGK-RCCKNPSSSA-N COC(c(cc1)ccc1/C(/c1cc(OC)ccc1)=C(/C(Nc(c(F)c(c(C(F)(F)F)c1F)F)c1F)=O)\N)=O Chemical compound COC(c(cc1)ccc1/C(/c1cc(OC)ccc1)=C(/C(Nc(c(F)c(c(C(F)(F)F)c1F)F)c1F)=O)\N)=O UUNRBALABMXLGK-RCCKNPSSSA-N 0.000 description 1
- RUKRSUTZMIMFGF-QMMMGPOBSA-N COc1c(C[C@@H](C(Nc(c(F)c(c(C(F)(F)F)c2F)F)c2F)=O)N)cccc1 Chemical compound COc1c(C[C@@H](C(Nc(c(F)c(c(C(F)(F)F)c2F)F)c2F)=O)N)cccc1 RUKRSUTZMIMFGF-QMMMGPOBSA-N 0.000 description 1
- IBTGEEMBZJBBSH-UHFFFAOYSA-N COc1cccc(OC)n1 Chemical compound COc1cccc(OC)n1 IBTGEEMBZJBBSH-UHFFFAOYSA-N 0.000 description 1
- XSDGFKOHFNMTKZ-NNJIEVJOSA-N C[C@H](C(c1ccc(C)cc1)c1cc(C)cc(C)c1)N Chemical compound C[C@H](C(c1ccc(C)cc1)c1cc(C)cc(C)c1)N XSDGFKOHFNMTKZ-NNJIEVJOSA-N 0.000 description 1
- MBTGBRYMJKYYOE-UHFFFAOYSA-N Fc1cccc(F)n1 Chemical compound Fc1cccc(F)n1 MBTGBRYMJKYYOE-UHFFFAOYSA-N 0.000 description 1
- OEIUMLSCWINLBB-UHFFFAOYSA-N OC(CCc1ccc(C(F)(F)F)cc1)=O Chemical compound OC(CCc1ccc(C(F)(F)F)cc1)=O OEIUMLSCWINLBB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Definitions
- the present invention relates to a method for the preparation of mono- and di-p-arylated and ⁇ -heteroarylated amino acid derivatives, and more particularly to a method for the Pd-catalyzed insertion of one or two of the same or different aryl or heteroaryl substituents or ethylenic unsaturation at the ⁇ -carbon of a protected amino acid substrate in a high yield and with high diastereoselectivity.
- the auxiliary (CONHOMe) group displayed excellent efficiency in directing ⁇ -C-tt activation. For example, ?-arylation of the amide derived from pivalic acid with Ph-I using this auxiliary proceeds at room temperature. Numerous applications of this powerful auxiliary in directed C(sp 2 )-H activation have also been reported with Pd(II), Rh(III), and Ru(II) catalysts. Unfortunately, C(sp 3 )-H activation of aliphatic acids using this auxiliary has been limited to substrates containing a-quaternary centers under current conditions. Apart from the known Thorpe-Ingold effect in cyclopalladation, it was thought that the acidic a-hydrogen of aliphatic acid substrates could be responsible for the lack of reactivity.
- arylations are carried out preferably using a simple N-methoxyamide auxiliary or perfluoro- 4-tolylamide as the directing group.
- a 2-picoline ligand (L7) promotes the selective mono-arylation of primary C(sp 3 )-H bonds and 2,6- lutidine ligand (L13) enables the subsequent arylation of secondary C(sp 3 )-H bonds in one pot.
- Sequential arylation of alanine derivatives with two different aryl iodides using these ligands enables the introduction of two distinct aryl groups to produce a variety of -Rr ' - ⁇ -amino acids with excellent levels of diastereoselectivity .
- KAT aminotransferase II inhibitor
- the present invention contemplates method for the preparation of aryl or heteroaryl mono- or disubstituted protected amino acid molecules, as well as the beta-olefination of such molecules.
- both the amine and carboxyl groups are protected, usually with selectively removable protecting groups, although a contemplated method can also be carried out in the absence of a carboxyl protecting group.
- This method is carried out via a ligand- controlled catalytic arylation or heteroarylation of a primary and secondary C(sp 3 )-H bonds of a protected amino acid substrate molecule.
- the catalyst utilized herein is a Pd(II) catalyst that is paired with a pyridine-type ligand to provide selectively to the activation of primary and secondary C-H bonds for the addition of an aromatic or heteroaromatic
- a reaction mixture contains (a) a protected amino acid substrate molecule A (below) , whose substituents are discussed below, (b) an excess of an aromatic or heteroaromatic iodide reactant, (c) a Pd(II) catalyst, (d) a pyridine ligand, and (e) a silver compound oxidant dissolved or dispersed in a solvent.
- the reaction mixture is sealed in an appropriate vessel and the contents heated to a temperature of about 80 to about 120° C for a time period sufficient for the reaction to progress to a desired extent of formation of an arylated or heteroarylated product. That product can be recovered, or maintained in the reacted reaction mixture and further reacted at a later time.
- N-BPG is a protected amino group in which B is hydrogen or a further bond between the nitrogen atom and the protecting group (PG) ;
- R is hydrogen (hydrido) , a 3 ⁇ 4-C]_2 hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubsttuted or substituted with a NBPG protected amino group that is the same or different from that previously defined, or a Cg-C ⁇ Q aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen (fluoro, chloro and bromo; i.e., other than iodo) , C ] _-Cg hydrocarbyl, C ⁇ -Cg hydrocarbyloxy, carboxy C ] _-Cg hydrocarbyl, trifluoromethyl , C ⁇ -Cg hydrocar
- a substrate molecule of Formula A where R is hydrido is reacted as above using a ligand such as a member of those compounds defined by Formula L, hereinafter, like Ligands L10, Lll , L12, or L18, preferably Ligands and L18, and a reactive olefin in place of the iodinated aromatic or heteroaromatic reactant along with the other reaction mixture components recited above.
- ligand such as a member of those compounds defined by Formula L, hereinafter, like Ligands L10, Lll , L12, or L18, preferably Ligands and L18, and a reactive olefin in place of the iodinated aromatic or heteroaromatic reactant along with the other reaction mixture components recited above.
- Those ingredients are dissolved or dispersed in a solvent as above.
- the reaction mixture is sealed in an appropriate vessel and the contents heated to a temperature of about 80 to about 120° C for a time period sufficient for the reaction to progress
- the resulting reaction product is a lactam that is typically recovered and the lactam ring can be opened by reaction with a strong base such as lithium bis (trimethylsilyl) amide (LiHMDS) to form the corresponding olefin.
- a strong base such as lithium bis (trimethylsilyl) amide (LiHMDS)
- the amine-protecting group such as the phthalimido group can be cleaved using standard procedures such as ethylene diamine reaction followed by the addition of another amine-protecting group that is more usually used in peptide synthesis like a t-BOC group prior to opening the lactam to form a N-t-BOC-protected lactam whose ring can be subsequently opened as discussed above. This is illustrated hereinafter in conjunction with Table 7.
- the present invention has several benefits and advantages.
- One benefit is the insertion of a substituted or unsubstituted aryl or heteroaryl substituent into the beta-carbon of an amine- protected amino acid.
- An advantage of the invention is that that insertin reaction proceeds with high yields.
- Another benefit of the invention is that two of the same or different aryl or heteroaryl groups can be inserted into the beta carbon, again in high yield.
- Another advantage of the invention is that the two aryl or heteroaryl groups can be added in either orientation by use of particular ligands in a particular order of reaction.
- an element means one element or more than one element.
- hydrocarbyl is used herein as a short hand term for a non-aromatic group that includes straight and branched chain aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen.
- alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking are also hydrocarbyl groups, are separately referred to herein as aryl groups or radicals, as discussed hereinafter.
- hydrocarbyl groups contain a chain of 1 to about 7 carbon atoms, and preferably 1 to about 4 carbon atoms (C1-C4) .
- hydrocarbyl group is an alkyl group.
- a generalized, but more preferred substituent can be recited by replacing the descriptor "hydrocarbyl” with “alkyl” in any of the substituent groups enumerated herein.
- alkyl radicals examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
- suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4- pentadienyl, 1, -butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.
- alkynyl radicals examples include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
- hydrocarbyl ether is referred to as a "hydrocarbyloxy” group rather than a “hydrocarboxy” group as may possibly be more proper when following the usual rules of chemical nomenclature.
- Illustrative hydrocarbyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclohexenyloxy groups and the like.
- a hydrocarbyloxy group include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclohexenyloxy groups and the like.
- hydrocarbyl group containing a -C(0)- functionality is referred to as a hydrocarboyl (acyl) group inasmuch as there is no ambiguity in using that suffix.
- exemplary hydrocarboyl and hydrocarboyloxy groups include acyl and acyloxy groups, respectively, such as acetyl and acetoxy, acryloyl and acryloyloxy.
- aryl or "aromatic”, alone or in combination, means an aromatic hydrocarbyl ring system.
- a ring system includes a phenyl, naphthyl and biphenyl ring system.
- the heterocyclyl is a single 5- or 6-membered ring or a fused or linked 5,5- 5,6- 6, 6-ring system that contains 1 to 4 hetero atoms (non-carbons) in the ring that independently are nitrogen, oxygen or sulfur atoms in a saturated or partially unsaturated ring.
- heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, oxathiazolyl, 1, 2 , 3-triazolyl, 1, 2 , 4-triazolyl, pyrazolyl, 1, 2 , 4-oxadiazinyl and azepinyl groups and a bipiperidinyl group.
- a “heteroaryl” group is an aromatic heterocyclic ring that preferably contains one, or two, or three or four atoms in the ring other than carbon. Those heteroatoms can independently be nitrogen, sulfur or oxygen.
- a heteroaryl group can contain a single 5- or 6-membered ring or a fused ring system having two 6-membered rings or a 5- and a 6-membered ring, or a linked 5,5-, 5,6- or 6,6- membered rings as in a bipyridinyl group.
- Exemplary additional heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1, 2, 3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl groups; 6-/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1- benzopyronyl, quin
- amino-protecting group refers to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality.
- protected (monosubstituted) amino means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
- protected carboxamide means there is an amino-protecting group present replacing the proton of the amido nitrogen so that there is no N-alkylation .
- amino-protecting groups include the formyl ("For") group, the trityl group (Trt) , the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups.
- Orethane blocking groups such as t-butoxy-carbonyl ("Boc"), 2- ( 4-biphenylyl) propyl (2 ) oxycarbonyl ("Bpoc”), 2- phenylpropyl (2 ) oxycarbonyl ("Poc”), 2- (4- xenyl ) isopropoxycarbonyl , 1 , 1-diphenylethyl ( 1 ) - oxycarbonyl, 1.1-diphenylpropyl (1) oxycarbonyl, 2- ( 3, 5-dimethoxyphenyl) propyl (2) oxycarbonyl ("Ddz”), 2- (p- 5 toluyl ) propyl (2 ) oxycarbonyl , cyclopentanyl- oxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl , 1-methylcyclohexanyl- oxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4- tolu
- benzyloxycarbonyl (“Z”), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy-carbonyl, a-2 ,4,5, -tetramethyl- benzyloxycarbonyl ("Tmz”), 4-methoxybenzyl- oxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chloro- benz loxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, -cyanobenzyIoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, and the like, the benzoylirtethylsulfonyl group, dithiasuccinoyl ("Dts 1 ) group, the 2- (nitro) henylsul
- amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the compound.
- Preferred amino-protecting groups are Boc and Fmoc.
- protected amino defines an amino group substituted with an amino-protecting group discussed above.
- C1-C4 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, -butylsulfonyl , t-butylsulfonyl, and the like.
- the present invention contemplates the ligand-controlled catalytic arylation or
- the catalyst utilized herein is a mixed Pd(II) catalyst that is paired with a pyridine-type ligand to provide the selectively to promote the activation of primary and secondary C-H bonds. That C-H bond activation can lead to a wide range of ⁇ -Ar-amino acids and ⁇ -Ar-p-A 1 -cc-amino acids with excellent levels of diastereoselectivity (d.r. > 20:1). Both configurations of the ⁇ -chiral center can be accessed by choosing the order in which the aryl groups are installed.
- a contemplated protected amino acid substrate molecule is designated A (below) , wherein
- N-BPG is a protected amino group in which B is hydrogen or a further bond between the nitrogen atom and the protecting group;
- R is hydrogen
- hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubsttuted or substituted with a NBPG protected amino group that is the same or different from that previously defined, or a Cg-C ] _o aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen (fluoro, chloro and bromo) , C]_-Cg hydrocarbyl, C ] _-Cg hydrocarbyloxy, carboxy C ] _-Cg hydrocarbyl, trifluoromethyl, 3 ⁇ 4-Cg hydrocarboyl, nitro, 3 ⁇ 4-Cg hydrocarbylthiooxy, cyano and 1,2-(C]_-Cg
- hydrocarbylene dioxide such as 1, 2-methylenedioxide
- X is NHR 1 in which R 1 is a Ci-C 12 hydrocarbyl aliphatic or aromatic group that is unsubstituted or substituted with fluorine atoms, can also be a hydroxyl (OH) , 0-C]_-C]_2 hydrocarbyl, or NH-0-C2-C]_2 hydrocarbyl group, so that the substrate molecule is a protected amino amide, acid, ester or hydrocarbyloxyamide, respectively.
- the oc-carbon of a substrate molecule A is a chiral center and a contemplated substrate molecule A can exist as one or the other of the two enantiomers, substrate molecules A-1 and. A-2, below.
- Illustrative protecting groups (PG) for the a-amine include what may be referred to as monodentate and bidentate protecting groups.
- a monodentate protecting group bonds to only one of the possible valances of the nitrogen atom, leaving the other available to bond to a hydrogen (hydrido group) .
- Illustrative monodentate protecting groups include amine group-protecting moieties typically utilized in peptide synthesis such as t-BOC, f-MOC, CBZ, as well as ]_-C]_2 hydrocarboyl (acyl) and C 7 -Ci2 sulfamido group.
- Bidentate amine protecting groups utilize both of the valances of the nitrogen atom, and with that nitrogen atom form cyclic imides such as succinimido, maleimido, ortho-benzoic sulfimido and phthalimido, which is most preferred.
- a particularly preferred NHR ⁇ substituent contains a R group that is a perfluorinated p-tolyl group that is usually abbreviated Ar F and has the chemical formula 4-(CF 3 )CgF 4 , so that X is NH [4- (CF3) C5F4] .
- R group that is a perfluorinated p-tolyl group that is usually abbreviated Ar F and has the chemical formula 4-(CF 3 )CgF 4 , so that X is NH [4- (CF3) C5F4] .
- Yields are also good when X is a ⁇ - ⁇ -0]_-3 ⁇ 42 hydrocarbyl group, and particularly a NH-O-C ⁇ -Cg hydrocarbyl group, such as a methyl or t-butyl group, with X being NH-0-CH3 also being particularly preferred.
- Arylation product yields using other amides and esters are minimal, and use of those X groups is less preferred.
- Aromatic and heteroaromatic iodides are the coreactants in a contemplated arylation or heteroarylation reaction.
- the iodide reactant is typically utilized in excess over the molar amount of the protected amino acid substrate molecule
- the molar ratio of iodide reactant to substrate is about 1.1 to about 4 to 1. More specifically, where a single aromatic or heteroaromatic group is added to a substrate where R is hydrido, the molar ratio is about 1.1 to about 2 to 1, and preferably about 1.5:1 (iodide: substrate) . Where the substrate R group is other than hydrido, a larger quantity of iodide is typically utilized and the iodide to substrate molar ratio is about 2 to about 4 to 1, and preferably about 3:1
- a contemplated aromatic or heteroaromatic iodide can be otherwise unsubstituted, or contain up to three substituents in addition to the iodo group.
- Contemplated substituents are independently selected from one or more of the group consisting of halogen
- Illustrative iodide-substituted aryl rings are phenyl and naphthyl that is optionally substituted as discussed above.
- Illustrative iodide- substituted heteroaryl ring compound includes an aromatic monocyclic or bicyclic heterocycle that contains one or more ring atoms that are other than carbon and is optionally substituted as defined above .
- a “heteroaryl” group preferably contains one, two, three or four (up to four) ring atoms other than carbon (heteroatoms) . Those heteroatoms can be nitrogen, sulfur or oxygen.
- a heteroaryl group can contain a single 5- or 6-membered ring or a fused ring system having two 6-membered rings or a combination of two 5- and 6-membered rings.
- heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1, 2, 3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl groups; 6-/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1- benzopyronyl, quinolinyl
- R of a protected amino acid substrate molecule A is hydrido
- carrying out an arylation or heteroarylation reaction can provide a second substrate molecule A in which R is a substituted or unsubstituted aryl or heteroaryl substituent.
- that second substrate molecule A can be reacted again with another aryl iodide to form an a-amine-protected p-Ar-p-Ar ' -cc amino acid, for example .
- the product a-amine-protected ⁇ - ⁇ - ⁇ - Ar'-a-amino acid or ⁇ -Ar-p- (hydrocarbyl) -a-amino acid made in a method of this invention contains a new chiral center at the ⁇ -carbon so that the product can contain two chiral centers and thereby diastereomers.
- a product of a contemplated method is prepared with high diastereoselectivity that typically exceeds a diastereomeric ratio (d.r.) of about 15. A more usually deviserved d.r. exceeds about 20, and can be very large where only one diastereomer was produced.
- Pd(II) catalysts are well known in the art.
- Exemplary catalysts include PdCl 2 , Pd(TFA) 2 , Pd(Piv) 2 , [PdCl(C 3 H 5 ) ] 2 , PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , [PdCl 2 (MeCN) 2 ] , [Pd (OTf) 2 ⁇ 4MeCN] , and
- Pd(BF 4 ) 2 -4MeCN [Pd(BF 4 ) 2 -4MeCN] .
- Pd(TFA) 2 Pd(Piv) 2 and Pd(0Ac) 2 are presently preferred.
- a contemplated catalyst is utilized in a catalytic amount. That amount is typically about 5 to about 40 mole percent based on the moles of reactive substrate, and more preferably about 10 to about 20 mole percent.
- the reaction mixture preferably contains about 20 mole percent trifluorpacetic acid (TFA) to assist in inhibiting degradation of the substrate .
- a contemplated ligand is a pyridine compound that is preferably substituted at one or both of the 2- and 6-positions. Pyridine itself and
- pyridine compounds substituted at one or both of the 2- and 6-positions such as acridine, 2, 6-difluoropyridine,
- a group of preferred pyridine-type ligands is defined by Formula P, below, where R 2 and R 3 are
- R 2 and R 3 forms a saturated or unsaturated 5- or 6-membered carbocyclic or oxa-substituted carbocyclic ring with the depicted ring at ring positions 3- and 5-, respectively, and R4 is independently hydrido or Cj-Cg alkyl, with the proviso that at least one of and is other than hydrido.
- a ligand that is particularly preferred for use in inserting a second aryl or heteroaryl group as discussed hereinafter corresponds in structure to Formula L, below, where "n" is 1 or zero such that
- R5 is hydrido or a substituent selected from the group consisting of halogen other than iodo
- R ⁇ is preferably t-butyl.
- L17 and L18 are within the ambit of Formula L.
- 2-picoline is particularly useful at providing mono-arylation or
- a second ligand that is a member of those compounds defined by Formula L, is 2, 5-dimethyl-3, 4-dihydro-2H-pyrano [2, 3-b] quinoline that is also often referred to as ligand L10, was used to prepare desired ⁇ -Ar-p-Ar ' -oc-amino acids in high yield with high diaselectivity.
- 2, 6-Lutidine, L6 is also quite useful in preparation of ⁇ -Ar-p- Ar ' -a-amino acids in high yield with high
- Ligands L6, L7 and L10 are particularly preferred.
- a ligand is typically present in the reaction composition at about 10 to about 30 mole percent based on the moles of substrate. Preferably, the ligand is present at about 20 mole percent.
- a contemplated method utilizes an excess, about 1.1 to about 4 equivalents of an oxidant per mole of reactive substrate, and preferably about 1.5 to about 2 equivalents of oxidant.
- a silver oxidant is typically used, although oxygen and other mild oxidants can also be used.
- Illustrative catalysts include Ag(Piv), Ag(OAc), Ag 2 0, AgTFA, AgOTf, Ag 2 C0 3 ,
- a contemplated reaction is carried out with the ingredients dissolved or dispersed in a solvent and with agitation as can be provided by the use of a magnetic stir bar. Additional means of agitation such as shaking can also be utilized.
- exemplary solvents include ⁇ uCC ⁇ Me, hexafluoro-isopropanol
- DCE 2-dichloroethane
- a contemplated method is preferably carried out under anhydrous conditions.
- a bench-scale reaction using about 0.05 to about 0.10 mmoles of reactive substrate and appropriate amounts of other ingredients is typically carried out in about 0.5 to about 1 mL of solvent. Larger quantities can be readily scaled from those proportions.
- a reaction mixture formed in carrying out a method of the invention is maintained at a temperature of about 70° to about 120° C for a time period sufficient to carry out the electrophilic insertion and form a reaction product. More preferably, that temperature is about 80° to about 100° C. Reaction times are typically about 15 to about 50 hours, with times of about 18-36 hours being usual .
- a contemplated reaction is preferably carried out in a sealed reaction vessel, so the pressure under which the ingredients are maintained is mostly that created by the solvent used, with some contribution from the reactants, at the reaction temperature .
- an activated reactive olefin is inserted to the beta-carbon of a substrate molecule A, whose R group is hydrido and whose X group is an amido nitrogen atom [-C (0) -NHRI] .
- the reaction conditions are similar to those discussed above except that (i) the ligand of choice is a member of those compounds defined by Formula L such as Ligands L10, Lll or L12 , and preferably L10, and (ii) an excess of a reactive olefin is used in place of the excess of iodinated aryl or heteroaryl reactant.
- An illustrative activated reactant olefin is present at about 1.1 to about 5 equivalents relative to substrate molecule A, and preferably at about 3 to about 4 equivalents.
- a contemplated activated olefin reactant is typically an ⁇ , ⁇ -unsaturated ester or ketone, such as an acrylate or methacrylate C ⁇ -Cg-hydrocarbyl ester.
- the ethyl and methyl (C]_-Cg-hydrocarbyl) esters of c 3 _c 12 olefins are preferred.
- C ⁇ -Cg- hydrocarbyl esters of cinnamic acid, of butenoic acid, octanoic acid, dodec-2-enoic acid, fumaric and maleic acids, ethyl 2- ( 1 , 3-dioxoisoindolin-2- yl) acrylate, C]_-Cg-hydrocarbyl) esters of C3-C12 olefins and the like can also be reactants.
- Another typical olefin is a C4-C]_2 ⁇ olefinic ketone.
- ketones include but-3-en-2-one, pent-3- en-2-one, methyl cyclohex-l-enecarboxylate, isopropyl cyclopent-l-enecarboxylate, pent-4-en-3-one, cyclopent-2-en-l-one, cyclohex-2-en-l-one, naphthalen-1 ( 4H) -one, and the like.
- an olefinic sulfone or sulfoxide such as a C ⁇ -C ⁇ - olefinic sulfone or sulfoxide is contemplated like ethyl vinyl sulfone.
- hydrocarbyl diester of an olefinic phosphonate such as an ( 3 ⁇ 4-Cg-hydrocarbyl-diesters of C2-C12 olefinic phosphonates such as diethyl vinyl phosphonate
- the product of this reaction is a 5-membered lactam whose ring members include one carbon from the olefin, the beta- and alpha-carbons of the starting derivatized amino acid, the amido group carbon atom and its amido nitrogen atom.
- the lactam product can be and usually is isolated.
- a ligand for monoarylation A ligand for monoarylation .
- a first challenge in the development of a versatile method for the preparation of stereo- defined ⁇ -Ar-p-Ar ' -a-amino acids from alanine was to achieve selective monoarylation of primary C(sp 3 )-H bonds without further arylating the secondary C(sp 3 )-H bonds.
- the Yu research group has recently focused on the development of simple auxiliaries, such as W-methoxyamides and perfluorinated arylamides, to direct a wide range of C(sp 3 )-H activation reactions [Wang et al., J. Am. Chem. Soc. 130:7190-7191 (2008); Wasa et al., J. Am. Chem. Soc.
- monodentate pyridine-derived ligands for their ability to selectively promote primary C(sp 3 )-H activation, thereby permitting for highly mono- selective arylation of illustrative alanine-derxved amide Compound 1.
- pyridine-related (pyridine and substituted pyridines including quinolones) ligands was studied for their efficiency in promoting mono-arylation in the presence of TFA.
- Pyridine and 4-dimethylaminopyridine (Ligands LI and L2) are highly selective for monoarylation, but neither enhances conversion significantly relative to the ligand-free catalyst.
- 2 , 6-dimethoxypyridine, acridine, 2,6-lutidine and 2-picoline (Ligands L4-L7) promote substantially higher conversion, though use of Ligands L4-L6 leads to appreciable quantities of the undesired diarylated product Compound 3 as well.
- the 2-picoline Ligand L7 seems to possess an optimal balance of steric and electronic properties to provide Compound 2 in high yield with an excellent level of selectivity for mono-arylation (NMR yield of 94%) .
- the monoarylation reaction also proceeded in the presence of 5 mol% of Pd(TFA) 2 and 10 mol% of Ligand L7 to give the desired product
- Arylation with 4-methylthiophenyl iodide also proceeds to give the arylated product (Compound 2p) in a synthetically useful yield, indicating that the pyridine ligand is able to out-compete the methylthio group for coordination at Pd(II).
- the reaction of Compound 1 with 2-iodonaphthalene to give Compound 2q is particularly useful, as the resulting product can be applied to synthesis of bioactive peptides that block cell cycle progression in HeLa cells [Wildemann et al., J. Med. Chem. 49:2147-2150
- auxiliary 2 , 3, 5, 6-tetrafluoro-4- (trifluoromethyl) aniline is readily prepared from octafluorotoluene (currently about $0.47/g) on 100- gram scale or purchased directly from Aldrich. Due to these practical advantages, a variety of mono- arylated alanines were prepared on 10-mmol scale to facilitate peptide drug discovery in collaboration with Bristol-Myers Squibb Co. (Compounds 2c-2e, 2g, 2h, 2j, 21, and 2r) .
- R as defined previously in regard to Formula A, is hydrogen (hydrido) , a C]_-C]_2 hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubsttuted or substituted with a NBPG protected amino group that is the same or different from that previously defined, or a Cg-C]_o aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen (fluoro, chloro and bromo) , c l _c 6 hydrocarbyl, 3 ⁇ 4-C hydrocarbyloxy, carboxy C]_- Cg hydrocarbyl, trifluoromethyl, C ⁇ -Cg hydrocarboyl, nitro, 3 ⁇ 4-Cg hydrocarbylthiooxy, cyano and 1,2-(C ] _-Cg hydro
- phenylalanine-derived amide Compound 2 can be arylated with a broad range of electron-rich and electron-poor aryl iodides in high yields (Table 3, below) .
- ortho-Substituted aryl iodides are also compatible with this reaction despite the known steric hindrance associated with the arylation of secondary C(sp 3 )-H bonds (Compound 3j).
- Ligands L7 and L10 which enable the arylation of primary and secondary p-C(sp 3 )-H bonds, respectively, can be employed for the sequential one- pot incorporation of two distinct aryl groups onto the ⁇ -carbon of alanine-derivative Compound 1 (Table 5) .
- Ligand L10 and a second aryl iodide can be added to provide a ⁇ -Ar-p-Ar ' -oc-amino acid.
- the aryl iodide (1.5 equiv) used in the first step is mostly incorporated into the product with small amount being converted to the biaryl
- Lactam Compound 8 is converted to W-Boc- protected product Compound 10 using established procedures (Table 7, below) .
- Compound 10 can be subjected to cross metathesis to afford olefinated product Compounds 11 and 12 with high levels of ElZ selectivity or hydrogenated to provide the corresponding alkylated product Compound 13 (Table 8, below) .
- N-hydrocarbyloxyamide auxiliary such as the illustrative itf-methoxyamide group, with the assistance of a ligand, can accommodate substrates derived from carboxylic acids containing a-hydrogen atoms .
- phthaloyl alanine amide Compound 25 was reacted with 1.5 equiv. of p-Tol-I using Pd(OAc) 2 and ligand L18 under various conditions. It was found that the mono-arylation proceeded under the conditions shown in the Scheme below to give the arylated products as a mixture of amide Compound 28a and the corresponding ester in 45% yield. A substantial amount of the starting material was converted to corresponding unreactive ester. The conversion of the N-methoxyamide to the corresponding ester via a radical process is known to be promoted by silver salts [(a) Crawford et al . , J. Org. Chem.
- a broad range of variously substituted aryl iodides are compatible with this ligand-promoted ⁇ -C- H arylation reaction (Table 19).
- Aryl iodides containing methyl, phenyl and methoxy groups react with substrate Compound 28 under the standard conditions to give the desired products in good to excellent yields (28a-f) .
- aryl iodides display similar reactivity to the mono-substituted ones (28q-t) .
- aryl iodides containing well-known directing groups such as acetamide, phosphonate and hydroxyls are also reactive coupling partners (28u-x) , thus overcoming some limitations of previous protocols [ (a) Wang et al., Chem. Sci. 5:3952 (2014); (b) Chen et al., Chem. Comm. 50:13924 (2014); (c) He et al., Science
- heteroaryl iodides Arylation with heteroaryl iodides
- Pd(II) catalysts usually coordinate strongly to Pd(II) catalysts and result in catalyst poisoning. This detrimental effect often prevents the use of heteroaryl iodides as coupling partners in C-H activation reactions. It was reasoned that the acidic solvent HFIP used in this protocol could weaken the coordinating ability of the heterocycles. Furthermore, the pyridine-type ligand picoline could potentially also out-compete the coordination of the heteroaryl iodides.
- N, N-Bis-heteroatom-substituted amides formed from W-alkoxyamides can thermally decompose to give the corresponding esters .
- a wide range of metal oxidants including silver oxide (Ag 2 0) , nickel (IV) peroxide hydrate (Ni0 2 'H 2 0), eerie ammonium nitrate (CAN), and lead(IV) acetate [Pb(OAc) ] have been used to convert silver oxide (Ag 2 0) , nickel (IV) peroxide hydrate (Ni0 2 'H 2 0), eerie ammonium nitrate (CAN), and lead(IV) acetate [Pb(OAc) ] have been used to convert silver oxide (Ag 2 0) , nickel (IV) peroxide hydrate (Ni0 2 'H 2 0), eerie ammonium nitrate (CAN), and lead(IV) acetate [Pb(OAc) ] have been used to convert silver oxide (Ag 2 0) , nickel (IV) peroxide hydrate (Ni0 2 'H 2 0), eerie ammonium nitrate (CAN
- AT-alkoxyamides can be converted to the esters by treating with sodium azide via Heron rearrangement (Eq 5) [ Glover et al., J. Chem. Soc, Perkin Trans 2002, 1728].
- Lewis acid boron trifluoride diethyl etherate (Et 2 0"BF 3 ) was also identified as an efficient reagent to convert Itf-methoxyamides into esters in methanol at 90 °C. This latter protocol is also compatible with the indole-containing amides. Importantly, no racemization of the a-chiral center was observed during the C-H arylation and the subsequent removal of the auxiliary (Scheme) .
- This reaction is also compatible with aryl iodides containing electron- withdrawing groups (Compounds 31j-m) .
- Arylation with naphthalene iodide and di-substituted aryl iodides also afforded synthetically useful yields (Compounds 31n-p) .
- this arylation reaction affords excellent diastereoselectivity which can be explained by a previously isolated C-H cleavage intermediate from a related amide substrate [He et al., Science 343:1216 (2014)].
- cyclopropyl C-H bond in Compound 32h is less reactive under these conditions and requires the use of ligand L18 to permit the arylation to proceed in moderate yield (45%) .
- alanine substrate 25 was coupled with fluorinated and trifluoromethylated aryl iodides (20 mmol scale) using 2-picoline as the ligand to give the mono-arylated products in excellent yields (Scheme below) .
- Af-methoxyamide auxiliary is further demonstrated by its versatile transformations to various biologically active compounds (Scheme below) . Radical cyclization of 28e with [bis (trifluoroacetoxy) iodo]benzene (PIFA) led to a lactam [Amano et al . , Synlett (2008) 134] and subsequent deprotection of the phthalamide using ethylenediamine afforded Compound 41 as a key intermediate for the synthesis of glycogen
- the AT-methoxyamide auxiliary also gives access to I ⁇ ?-hydroxy-3-amino-3, 4-dihydroquinolinone class of compounds.
- Davis and coworkers over thirty years ago, they were shown to exhibit antibacterial activity [(a) Davis et al . , J. Med. Chem. 7:632 (1964); (b) Davis et al., J. Med. Chem. 18:752 (1972)].
- similar scaffolds have been identified as potent inhibitors of ⁇ II, an enzyme currently being investigated as a therapeutic target for cognitive impairment associated with schizophrenia, among other disorders [(a) McAllister et al., J. Org. Chem. 76:3484 (2011);
- Chiral amino alcohols derived from chiral amino acids are essential building blocks for the preparation of chiral ligands.
- the sterically hindered chiral amino alcohol derived from tert-leucine is a key precursor for the synthesis of one of the most effective chiral oxazoline ligands in asymmetric catalysis.
- ⁇ - ⁇ - ⁇ - ⁇ ' - ⁇ -amino acids prepared via the recently developed procedure can be readily reduced to the corresponding chiral amino alcohols containing two chiral centers that are previously difficult to make (Scheme) .
- Scheme Scheme
- Compound 31z was obtained in moderate yields via a two steps, one-pot procedure on a 10 mmol scale. Hydrolysis of the amide group to ester followed by removal of the phthalimide protecting group led to the amino ester 51, which was reduced to the amino alcohol 52 in 75% yield.
- 2,6-lutidine enables the subsequent arylation of secondary C(sp 3 )-H bonds in one pot.
- This new method is extensively applied to gram-scale synthesis of novel, unnatural amino acids, as well as bioactive compounds and chiral bis (oxazoline) ligands.
- the starting material Compound 25 (0.1 mmol, 24.8 mg) , Pd(OAc) 2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol), 2-picoline (20 mol%, 2 ⁇ ,) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent.
- the starting material 25 (0.1 mmol, 24.8 mg) , Pd(OAc) 2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol) , 2-picoline (20 mol%, 2 L) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room
- reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent.
- the starting material 25 (0.1 mmol, 24.8 mg), Pd(OAc) 2 (15 mol%, 3.3 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol),
- the substrate Compound 28 (O.lmmol, 32.4 mg) , Pd(OAc) 2 (10 mol%, 2.2 mg) , NaH 2 P0 4 -H 2 0 (0.3 mmol, 42 mg) and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.3 mmol), 2,6-lutidine (20 mol%, 2 pL) , and HFIP (1 mil ) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring.
- reaction mixture Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
- the starting material 25 (10.0 mmol, 2.48 g) , Pd(0Ac) 2 (1.50 mmol, 337 mg) , and AgOAc (20.0 mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar.
- aryl iodide (15 mmol) , ligand (3.00 mmol), and HFIP (100 mL) were added.
- the reaction mixture was first stirred at room temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and recovered for next time use.
- the starting material (0.1 mmol, 24.8 mg) , Pd(OAc) 2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, the first aryl iodide (0.12 mmol),
- reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
- Solvents were obtained from Sigma-Aldrich, Alfa-Aesar and Acros and used directly without further purification.
- Carboxylic acids and carboxylic acid chlorides were obtained from the commercial sources or synthesized following literature procedures, and used to prepare the corresponding amides.
- Amino acids and 2,3,5,6- tetrafluoro-4- (trifluoromethyl) aniline were obtained from the commercial sources or synthesized following literature procedures, and used to prepare the corresponding amides.
- HRMS High-resolution mass spectra
- Enantiomeric excesses values were determined on a Hitachi LaChrom Elite® HPLC system using commercially available chiral columns. Optical rotation data were obtained on a Perkin-Elmer 341 polarimeter. Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus .
- Phthalimido-protected amino acid (10 mmol) , thionyl chloride (25 mmol) and several drops of DMF were added in toluene at 80 °C for 3 hours.
- the excess of thionyl chloride was removed in vacuo, and the crude acid chloride was added to a vigorously stirring solution of 2,3,5,6- tetrafluoro-4- (trifluoromethlyl) aniline (10 mmol) in toluene (8 mL) .
- the reaction mixture was stirred for 12 hours under reflux, and then stirred at room temperature for 0.5 hours.
- the product mixture was concentrated in vacuo and was recrystallized from ethyl acetate/hexane to provide the amide.
- ee value was determined by HPLC analysis on a Chiralcel OD-H column (20% isopropanol/hexanes , 0.5 mL/min) with t r 30.5 min (major), 56.1 min (minor): 97% ee.
- Substrate Compound 1 (0.1 mmol, 43.4 mg) , Pd(TFA) 2 (0.01 mmol, 3.3 mg) , and Ag 2 C0 3 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar.
- the aryl iodide (0.15 mmol), 2-picoline (0.02 mmol, 2 ⁇ , TFA (0.02 mmol, 2 ⁇ ) , and DCE (0.5 mL) were added.
- the reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/EtOAc or hexane/EtOAc as the eluent.
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 E NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc mixtures (30/1) as the eluent, Compound 2 was obtained as a white solid (45.2 mg, 89%, 97% ee) . The ee value was determined by HPLC analysis on a Chiralcel OD-H column (20% isopropanol/hexanes, 0.5 mL/min) with t r 51.4 min (major), 64.1 min (minor).
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 ⁇ 2 NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2a was obtained as a white solid (48.1 mg, 92%).
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by X H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2b was obtained as a white solid (48.2 mg, 89%).
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2c was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 3 ⁇ 4 NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2d was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by X H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) mixtures as the eluent, Compound 2e was obtained as a white solid (47.4 mg, 90%).
- Substrate Compound 1 was arylated following the general arylatxon procedure A. Analysis of crude reaction mixture by 3 ⁇ 4 NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2f was obtained as a white solid (44.1 mg, 84%).
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2g was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 3 ⁇ 4 NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2h was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2i was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2j was obtained as a white solid (49.5 mg, 86%).
- Substrate Compound 1 was arylated followin the general arylation procedure A. Analysis of crud reaction mixture by 3 ⁇ 4 NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2k was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by X H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 21 was obtained as a white solid
- Substrate 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by J H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 2m was obtained as a white solid
- Substrate 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2n was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by X H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 2o was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2p was obtained as a white solid (39.8 mg, 72%).
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a 14:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2q was obtained as a light yellow solid (50.7 mg, 91%).
- Substrate 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by X H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2r was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2s was obtained as a white solid (47.3 mg, 85%).
- Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1 ⁇ 2 NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2t was obtained as a white solid (55.4 mg, 86%) .
- Ar F 4-(CF 3 )C 6 F 4
- Substrate Compound 2 or Compounds 5a-5d (0.1 mmol) , Pd(T A) 2 (0.01 mmol, 3.3 mg) , Ligand L10 (0.02 mmol, 4.3 mg) and Ag 2 C0 3 (0.2 mmol, 55.0 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. The aryl iodide (0.3 mmol), TFA (0.02 mmol, 2 ⁇ ,) , and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon
- reaction mixture was cooled to room temperature.
- solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/EtOAc or hexane/EtOAc as the eluent.
- Substrate Compound 2 was arylated following the general arylation procedure B. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3 was obtained as a white solid (52.7 mg, 90%).
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by X H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was /arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 3 ⁇ 4 NMR showed a 19:1 diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3k was obtained as a white solid (54.2 mg, 88%) .
- Substrate Compound 5a was arylated following the general arylation procedure B.
- Substrate Compound 5b was arylated following the general arylation procedure B.
- Substrate Compound 5c was arylated following the general arylation procedure B. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 6c-mono was obtained as a white solid (35.6 mg, 60%).
- Substrate Compound 5d was arylated following the general arylation procedure B.
- Substrate Compound 1 (0.1 mmol, 43.4 mg) , Pd(TFA) 2 (0.01 mmol, 3.3 mg) , and Ag 2 C0 3 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar.
- Ar 1 -! (0.15 mmol)
- 2-picoline (0.02 mmol, 2 pL)
- TFA 0.02 mmol, 2 pL)
- DCE 0.5 mL
- reaction mixture was cooled to room temperature.
- Pd(TFA) 2 (0.01 mmol, 3.3 mg)
- Ligand L10 (0.02 mmol, 4.3 mg)
- Ag 2 C0 3 0.2 mmol, 55.0 mg) were weighed open to air and added in the reaction mixture.
- Ar 2 -I 0.3 mmol
- TFA 0.2 mmol, 2 pL
- reaction mixture was cooled to room temperature.
- solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/EtOAc or hexane/EtOAc as the eluent.
- Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1 H NMR showed a 19:1 diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 7a was obtained as a white solid (42.9 mg, 68%). 3 ⁇ 4 NMR
- Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by X H NMR showed a 19:1 diastereomer ratio. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 7b was obtained as a white solid (39.7 mg, 62%). 1 NMR
- Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1 NMR showed a > 20:1
- Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1
- Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1 ⁇ 2 NMR showed a 16:1 diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 7f was obtained as a white solid (38.8 mg, 60%).
- Ar F 4-(CF 3 )C 6 F 4
- Substrate Compound 1 (0.1 mmol) , Pd(TFA) 2 (0.015 mmol, 5.0 mg) , igand L10 (0.03 mmol, 6.5 mg) and Ag 2 CC (0.2 mmol, 55 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. The heteroaryl iodide (0.15 mmol) and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon
- reaction mixture was cooled to room temperature.
- solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexane/EtOAc as the eluent .
- Substrate Compound 1 was arylated following the general arylation procedure D. Analysis of crude reaction mixture by 1 H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2u was obtained as a white solid (29.8 mg, 55%).
- Substrate Compound 1 was arylated following the general arylation procedure D. Analysis of crude reaction mixture by X H NMR showed a 12:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 2v was obtained as a white solid
- Substrate Compound 1 was arylated following the general arylation procedure D. Analysis of crude reaction mixture by 1 H NMR showed > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2w was obtained as a white solid (38.3 mg, 72%).
- Ar F 4-(CF 3 )C 6 F 4
- Substrate 1 (0.1 mmol, 43.4 mg) [ Fu et al. r Bioorg. Med. Chem. Lett. 17:1102-1106 (2007)], Pd(OAc) 2 (0.01 mmol, 2.3 mg) , Ligand L10 (0.02 mmol, 4.3 mg) , and Ag 2 C0 3 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. Ethyl acrylate (0.33 mmol, 35 ⁇ , TFA (0.01 mmol, 1 ⁇ ) , and toluene (0.5 mL) were added.
- reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/Et 2 0 (5/1) as the eluent .
- Substrate Compound 8 (0.5 mmol, 266 mg) was weighed and placed in a round-bottom flask (25 mL) with a magnetic stir bar. DCM (1.5 mL) , EtOH (1.5 mL) , and ethylenediamine (2.5 mmol, 0.17 mL) were added. The reaction vessel was capped and the mixture was heated to 40 °C for 3 hours with vigorous stirring. Opon completion, the solvents were removed under reduced pressure. CuCl 2 (1.25 mmol, 168 mg) and deionized water (15 mL) were added into the resulting mixture. The aqueous solution was extracted with EtOAc (3 x 20 mL) .
- amide Compound 1 (43.4 mg, 0.10 mmol) , Pd(TFA) 2 (33.2 mg, 0.10 mmol) , 2-picoline (18.6 mg, 0.2 mmol), and CsF (30.4 mg, 0.20 mmol) were dissolved in DCE (2 mL) .
- the reaction mixture was then tightly capped and stirred for 10 minutes at room temperature, and then heated up to 100 °C with vigorous stirring for 20 hours.
- the reaction mixture was then cooled to room temperature, and filtered through a small pad of Celite.
- the residue was purified by preparative TLC using hexane/EtOAc (1/2) as the eluent to afford
- Substrate Compound 1 (0.1 mmol, 43.4 mg) , Intermediate A (0.01 mmol, 7.2 mg) , and Ag 2 C0 3 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. Iodobenzene (30.6 mg, 0.15 mmol), TFA (0.02 mmol, 2 ⁇ ) , and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature.
- Phthalimido-protected amino ester Compound 17 (4.60 mmol, 1.56 g) was dissolved in MeOH (88 mL) , and N 2 H 4 ⁇ 3 ⁇ 40 (4 equiv) was added. The reaction was stirred at room temperature for 20 hours, after which, the solvent was removed in vacuo. Saturated aqueous NaHC0 3 was added, and the solution extracted with EtOAc (3 x 50 mL) . The organic layer was washed with brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated.
- Amino ester Compound 18 (3.54 mmol, 0.74 g) was taken up in 1,4-dioxane (18 mL) , and 10% aqueous NaHC0 3 (11 mli) was added. The mixture was cooled to 0 °C in an ice bath and FmocCl (3.54 mmol, 1 equiv) was added. The ice bath was permitted to warm to room temperature overnight (about 18 hours) , after which H 2 0 and EtOAc were added to the reaction mixture. The aqueous layer was then extracted with EtOAc (3 x 50 mL) and the combined organic layer was washed with brine, dried over anhydrous Na 2 SC filtered and concentrated.
- Methyl ester Compound 19 (2.55 mmol, 1.10 g) was dissolved in THF (18 mL) . The solution was cooled to 0 °C, and a cold solution of LiOH ⁇ 2 0 (5.10 mmol, 2 equiv) in H 2 0 (18 mL) were added. The reaction was maintained at 0 °C and monitored by TLC.
- Substrate Compound 21 (0.1 mmol, 30.6 mg) , Pd(TFA) 2 (0.01 mmol, 3.3 mg) , and Ag 2 C0 3 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar.
- Substrate 25 (4 mmol, 1 g) , Pd(OAc) 2 (0.6 mmol, 134 mg) , and AgOAc (8 mmol, 1.34 g) were weighed in air and placed in a microwave tube (200 mL) with a magnetic stir bar.
- the aryl iodide (10 mmol), ligand (1.2 mmol, 323mg) , TFA (0.8 mmol, 0.1 mL) , and DCE (40 mL) were added.
- the reaction mixture was first stirred at room temperature for 10 minutes and then heated to 80 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature.
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Abstract
The use of ligands to tune the reactivity and selectivity of transition metal-catalysts for C(-sp3)-H bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a rare example of catalyst-controlled C(sp3)-H arylation using pyridine and quinoline derivatives: the former promotes exclusive monoarylation, whereas the latter activates the catalyst further to achieve diarylation. Successive application of these ligands enables the sequential diarylation of a methyl group in an alanine derivative with two different aryl iodides, affording a wide range of β-Ar-p-Ar ' -cc-amino acids with excellent levels of diastereoselectivity (d.r. > 20:1). Both configurations of the β-chiral center can be accessed by choosing the order in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables C(sp3)-H olefination of a protected alanine.
Description
LIGAND-CONTROLLED C(sp3)-H ARYLATION
AND OLEFINATION IN SYNTHESIS OF UNNATURAL CHIRAL -AMINO ACIDS
GOVERNMENTAL SUPPORT
The present invention was made with governmental support pursuant to grant NIGMS
2R01GM084019 from the National Institutes of Health. The government has certain rights in the invention.
TECHNICAL FIELD
The present invention relates to a method for the preparation of mono- and di-p-arylated and β-heteroarylated amino acid derivatives, and more particularly to a method for the Pd-catalyzed insertion of one or two of the same or different aryl or heteroaryl substituents or ethylenic unsaturation at the β-carbon of a protected amino acid substrate in a high yield and with high diastereoselectivity.
BACKGROUND ART
Over the past decade substantial progress has been achieved in the palladium-catalyzed activation of the inert β-0(3ρ3)-Η bonds of aliphatic carboxylic acids derivatives using chiral oxazolines [Giri et al., Angew. Chem. Int. Ed. 44:2112-2115 (2005) ] , the 8-aminoquinoline auxiliary [Zaitsev et al., J. Am. Chem. Soc. 127:13154-13155 (2005); Zhang et al., J. Am. Chem. Soc. 135:12135-12141 (2013)], and a variety of weakly coordinating amide directing groups [Wang et al., J. Am. Chem. Soc. 130:7190-7191
(2008) ; Wasa et al., J. Am. Chem. Soc. 131:9886-9887
(2009) . In particular, the synthesis of unnatural amino acids via the direct β-functionalization of
α-amino acids has been an area of extensive research since a seminal report by Corey [Reddy et al., Org. Lett. 8:3391-3394 (2006)].
The stereochemistry obtained in the C-H insertion step was used to deduce the pre-transition state structure of directed C-H insertions using chiral oxazoline auxiliaries. With hindsight and recent in-depth computational and kinetic studies [Giri et al., J. Am. Chem. Soc. 134:14118 (2012)], the primitive, but important insights obtained from these studies regarding the conformation and structure of the C-H insertion precursors paved the way for subsequent design of more efficient auxiliaries. In the past decade, while Daugulis' bidentate
8-aminoquinoline auxiliary has emerged as a powerful directing group using several different metals, the present work is focused on the development of mono- dendate simple amide auxiliaries, hoping to achieve ligand-accelerated and -controlled β-C-H
functionalization reactions.
Due to the moderate reactivity of sodium or potassium carboxylates in β-C-R arylation [Giri et al., J. Am. Chem. Soc. 129:3510 (2007)], an auxiliary group such as a N-methoxyamide or perfluoro-p-tolyl group [ 4- (CF3 ) C5F4 ] to mimic the carboxylate while allowing improved coordination with Pd(II) [Wang et al., J. Am. Chem. Soc. 130:7190 (2008)]. The simple rationale behind this design was to best mimic the conformation of the coordination structure of Pd(II) with carboxylates, while at the same time slightly increase the binding strength.
The auxiliary (CONHOMe) group displayed excellent efficiency in directing β-C-tt activation.
For example, ?-arylation of the amide derived from pivalic acid with Ph-I using this auxiliary proceeds at room temperature. Numerous applications of this powerful auxiliary in directed C(sp2)-H activation have also been reported with Pd(II), Rh(III), and Ru(II) catalysts. Unfortunately, C(sp3)-H activation of aliphatic acids using this auxiliary has been limited to substrates containing a-quaternary centers under current conditions. Apart from the known Thorpe-Ingold effect in cyclopalladation, it was thought that the acidic a-hydrogen of aliphatic acid substrates could be responsible for the lack of reactivity.
This reasoning led to the development of another acidic amide auxiliary (CONHArF, ArF = p- CF3C6F4) that is compatible with aliphatic acid substrates containing α-hydrogen atoms [ (a) Wasa et al., J. Am. Chem. Soc. 131:9886 (2009); (b) Wasa et al., J. Am. Chem. Soc. 132:3680 (2010); (c) Wasa et al., J. Am. Chem. Soc. 133:19598 (2011); (d) Wasa et al., J. Am. Chem. Soc. 134:18570 (2012); (e) Zhu et al., J. Am. Chem. Soc. 136:13194 (2014)]. Despite the broad utility of this new directing group, the simplicity of CONHOMe and similar compounds in terms of installation and removal prompted development of new conditions that may overcome the limitation of this potentially broadly useful auxiliary.
It was envisioned that a sequential diarylation of alanine with two different aryl iodides could potentially provide an efficient route for the preparation of β-ΑΓ-β-ΑΓ 1 -α-amino acids containing a β-chiral center. Although the more strongly coordinating 8-aminoquinoline auxiliary
developed by Daugulis is a powerful directing group for the β-arylation of alanine, this auxiliary provides predominantly β,β-homo-diarylated products, which prevents the sequential installation of two different aryl groups.
It is possible to use a specifically designed 2-methylthioaniline auxiliary to achieve mono-arylation of alanine in moderate yield and then use a different auxiliary to perform the secondary C(sp3)-H arylation with a distinct aryl iodide (below) [Tran et al., Angew. Chem. Int. Ed. 51:5188-5191 (2012) ] . However, this hypothetical route has not Arylation)
omo-diarylation yet been used for preparing β-ΑΓ-β-Ar 1 -a-amino acids because the removal and installation of the second auxiliary would add three synthetic steps to the sequence. In addition, the basic reaction conditions used in the arylation step partially racemize the amino acid to 90% enantiomeric excess (ee) .
It was reasoned that a ligand-controlled strategy could provide an ideal solution for the synthesis of β-Ar-p-Ar ' -cc-amino acids. Specifically, the application of two different ligands was envisioned. One would selectively promote primary β- C(sp3)-H arylation (without further arylating the remaining, now secondary, β-( (Ξρ3)-Η bonds), and another would enable further secondary β-ϋ(3ρ3)-Η
arylation, thereby introducing both aryl substituents successively onto a single substrate in one pot, as is shown schematically below. This reaction sequence
Ligand-Controlled C(sp3)-H Arylation ψβ Ligand A
H H S:ONHArF
H "" P"d("ll"), "Ar ?~
readily available hetero-diarylation
Direct Construction of β-Stereogenic Center provides an alternative synthetic disconnection to the existing asymmetric hydrogenation method for the synthesis of chiral β-Ar-p-Ar ' - -amino acids
[Ferreira et al., Eur. J. Org. Chem. 4676-4683 (2008); Noyori et al., Acc. Chem. Res. 23:345-350 (1990); Tang et al., Chem. Rev. 103:3029-3069 (2003); Roseblade et al . , Acc. Chem. Res. 40:1402-1411 (2007)] that is shown retrosynthetically in the scheme below. asymmetric
hydrogenation
I
Fundamentally, the development of appropriate ligands to confer selectivity for primary or secondary -C(sp3)-H bonds on a weakly coordinating substrate can greatly improve C(sp )-H activation reactions [Rodriguez et al., Chem. Sci. 4:175-179 (2013); Shang et al., J. Am. Chem. Soc. 135:6030-6032 (2013); Simmons et al., Nature 483:70-73 (2012); Gutekunst et al., J. Am. Chem. Soc. 133:19076-19079 (2011); Hasegawa et al., J. Am. Chem. Soc. 133:8070-
8073 (2011); Baudoin, Chem. Soc . Rev. 40:4902-4911 (2011); Lyons et al., Chem. Rev. 110:1147-1169 (2010); Jazzar et al., Chem. Eur. J. 16:2654-2672 (2010); and Wasa et al., Isr. J. Chem. 50:605-616 (2010) ] .
The discussion hereinafter discloses the discovery that a pyridine-based ligand promotes mono- arylation of primary p-C(sp3)-H bonds exclusively and that a second, quinoline-based ligand (a substituted pyridine) enables introduction of a distinct aryl group via subsequent secondary p-C(sp3)-H activation in one pot. The reactions proceed with excellent levels of diastereoselectivity with respect to the starting configuration at the -carbon as is set out in the ligand-controlled C(sp3)-H arylation shown above. As such, both configurations at the new β-stereogenic center can be constructed by simply choosing the order of aryl group installation. It is further demonstrated that the use of a quinoline- based ligand enables the C(sp3)-H olefination of an alanine-derived substrate to afford olefin- substituted chiral amino acids.
These arylations are carried out preferably using a simple N-methoxyamide auxiliary or perfluoro- 4-tolylamide as the directing group. As will be seen, a 2-picoline ligand (L7) promotes the selective mono-arylation of primary C(sp3)-H bonds and 2,6- lutidine ligand (L13) enables the subsequent arylation of secondary C(sp3)-H bonds in one pot. Sequential arylation of alanine derivatives with two different aryl iodides using these ligands enables the introduction of two distinct aryl groups to
produce a variety of -Rr ' -α-amino acids with excellent levels of diastereoselectivity .
Arylation of the N-methoxyamide derived from alanine with a variety of heterocyclic aryl iodides on gram scales to make various unnatural amino acids is also demonstrated. These unnatural amino acid intermediates were further transformed to drug molecules such as a human kynurenine
aminotransferase (KAT) II inhibitor [ (a) McAllister et al., J. Org. Chem. 76:3484 (2011); (b) Dounay et al., ACS Med. Chem. Lett. 3:187 (2012); (c) Tuttle et al., ACS Med. Chem. Lett. 4:37 (2013)] and
Doxanthrine [(a) Cueva et al . , J. Med. Chem. 49:6848 (2006); (b) Przybyla et al., Eur. Neuropsycho- pharmacol. 19:138 (2009); (c) Cueva et al., Eur. J. Med. Chem. 48:97 (2012)], as well as chiral hydroxa-mic acid ligands [Xiao et al . , J. Am. Chem. Soc. 136:8138 (2014)] and a variety of new chiral pyridine-2, 6-bis (oxazolines) (PyBOX) ligands [Desimoni et al., Chem. Rev. (2003) 103:3119 (2003)] (below).
'"fSS "
BRIEF SUMARY OF THE INVENTION
The present invention contemplates method for the preparation of aryl or heteroaryl mono- or disubstituted protected amino acid molecules, as well as the beta-olefination of such molecules.
Typically, both the amine and carboxyl groups are protected, usually with selectively removable
protecting groups, although a contemplated method can also be carried out in the absence of a carboxyl protecting group.
This method is carried out via a ligand- controlled catalytic arylation or heteroarylation of a primary and secondary C(sp3)-H bonds of a protected amino acid substrate molecule. The catalyst utilized herein is a Pd(II) catalyst that is paired with a pyridine-type ligand to provide selectively to the activation of primary and secondary C-H bonds for the addition of an aromatic or heteroaromatic
substituent. That C-H bond activation can lead to a wide range of β-Ar-amino acids and β-Ar-p-Ar ' -a-amino acids with excellent levels of diastereoselectivity (d.r. > 20:1). Both configurations of the β-chiral center can be accessed by choosing the order in which the aryl groups are installed.
In accordance with a contemplated method, a reaction mixture is provided that contains (a) a protected amino acid substrate molecule A (below) ,
whose substituents are discussed below, (b) an excess of an aromatic or heteroaromatic iodide reactant, (c) a Pd(II) catalyst, (d) a pyridine ligand, and (e) a silver compound oxidant dissolved or dispersed in a solvent. The reaction mixture is sealed in an appropriate vessel and the contents heated to a temperature of about 80 to about 120° C for a time period sufficient for the reaction to progress to a desired extent of formation of an arylated or
heteroarylated product. That product can be recovered, or maintained in the reacted reaction mixture and further reacted at a later time.
Where R in substrate A was hydrido and after the reacted reaction mixture has cooled sufficiently for safety, a second amount of each of the same or different iodide reactant, catalyst, pyridine ligand and silver oxidant can be added, the vessel resealed and again heated and maintained at an elevated temperature as before to provide a second product that contains two of the same or different aryl or heteroaryl substituents . That second product is typically purified and recovered.
In a substrate molecule of Formula A, (i) N-BPG is a protected amino group in which B is hydrogen or a further bond between the nitrogen atom and the protecting group (PG) ; (ii) R is hydrogen (hydrido) , a ¾-C]_2 hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubsttuted or substituted with a NBPG protected amino group that is the same or different from that previously defined, or a Cg-C^Q aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen (fluoro, chloro and bromo; i.e., other than iodo) , C]_-Cg hydrocarbyl, C^-Cg hydrocarbyloxy, carboxy C]_-Cg hydrocarbyl, trifluoromethyl , C^-Cg hydrocarboyl, nitro, C ~Cg hydrocarbylthiooxy, cyano and 1,2-(C]_-Cg hydrocarbylene) dioxide such as 1, 2-methylenedioxide; and (iii) X is NHR1 in which R1 is a <¾-0]_2 hydrocarbyl aliphatic or aromatic group that is unsubstituted or substituted with fluorine atoms, R^
can also be a hydroxyl (OH) , O-Cj-C]^ hydrocarbyl, or NH-0-C]_-C]_2 hydrocarbyl group, so that the substrate molecule is a protected amino amide, acid, ester or hydrocarbyloxyamide, respectively.
In another contemplated method, a substrate molecule of Formula A where R is hydrido is reacted as above using a ligand such as a member of those compounds defined by Formula L, hereinafter, like Ligands L10, Lll , L12, or L18, preferably Ligands and L18, and a reactive olefin in place of the iodinated aromatic or heteroaromatic reactant along with the other reaction mixture components recited above. Those ingredients are dissolved or dispersed in a solvent as above. The reaction mixture is sealed in an appropriate vessel and the contents heated to a temperature of about 80 to about 120° C for a time period sufficient for the reaction to progress to a desired extent of formation of an arylated or heteroarylated product. That product can be recovered, or maintained in the reacted reaction mixture and further reacted at a later time.
The resulting reaction product is a lactam that is typically recovered and the lactam ring can be opened by reaction with a strong base such as lithium bis (trimethylsilyl) amide (LiHMDS) to form the corresponding olefin. The amine-protecting group such as the phthalimido group can be cleaved using standard procedures such as ethylene diamine reaction followed by the addition of another amine-protecting group that is more usually used in peptide synthesis like a t-BOC group prior to opening the lactam to form a N-t-BOC-protected lactam whose ring can be subsequently opened as discussed above. This is illustrated hereinafter in conjunction with Table 7.
The present invention has several benefits and advantages.
One benefit is the insertion of a substituted or unsubstituted aryl or heteroaryl substituent into the beta-carbon of an amine- protected amino acid.
An advantage of the invention is that that insertin reaction proceeds with high yields.
Another benefit of the invention is that two of the same or different aryl or heteroaryl groups can be inserted into the beta carbon, again in high yield.
Another advantage of the invention is that the two aryl or heteroaryl groups can be added in either orientation by use of particular ligands in a particular order of reaction.
Still further benefits and advantages of the invention will be apparent to workers of ordinary skill from the disclosure that follows.
DEFINITIONS
In the context of the present invention and the associated claims, the following terms have the following meanings :
The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
The word "hydrocarbyl" is used herein as a short hand term for a non-aromatic group that includes straight and branched chain aliphatic as well as alicyclic groups or radicals that contain
only carbon and hydrogen. Thus, alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking are also hydrocarbyl groups, are separately referred to herein as aryl groups or radicals, as discussed hereinafter.
Where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited; i.e., C1-C4 alkyl, methyl or hexenyl. Exemplary hydrocarbyl groups contain a chain of 1 to about 7 carbon atoms, and preferably 1 to about 4 carbon atoms (C1-C4) .
A particularly preferred hydrocarbyl group is an alkyl group. As a consequence, a generalized, but more preferred substituent can be recited by replacing the descriptor "hydrocarbyl" with "alkyl" in any of the substituent groups enumerated herein.
Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4- pentadienyl, 1, -butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
Usual chemical suffix nomenclature is followed when using the word "hydrocarbyl" except that the usual practice of removing the terminal "yl" and adding an appropriate suffix is not always followed because of the possible similarity of a resulting name to one or more substituents . Thus, a hydrocarbyl ether is referred to as a
"hydrocarbyloxy" group rather than a "hydrocarboxy" group as may possibly be more proper when following the usual rules of chemical nomenclature.
Illustrative hydrocarbyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclohexenyloxy groups and the like. On the other hand, a
hydrocarbyl group containing a -C(0)- functionality is referred to as a hydrocarboyl (acyl) group inasmuch as there is no ambiguity in using that suffix. Exemplary hydrocarboyl and hydrocarboyloxy groups include acyl and acyloxy groups, respectively, such as acetyl and acetoxy, acryloyl and acryloyloxy.
As a skilled worker will understand, a substituent that cannot exist such as a C]_ alkenyl group is not intended to be encompassed by the word "hydrocarbyl", although such substituents with two or more carbon atoms are intended.
The term "aryl" or "aromatic", alone or in combination, means an aromatic hydrocarbyl ring system. Such a ring system includes a phenyl, naphthyl and biphenyl ring system.
The heterocyclyl (heterocyclo) is a single 5- or 6-membered ring or a fused or linked 5,5- 5,6- 6, 6-ring system that contains 1 to 4 hetero atoms (non-carbons) in the ring that independently are nitrogen, oxygen or sulfur atoms in a saturated or partially unsaturated ring. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, oxathiazolyl, 1, 2 , 3-triazolyl, 1, 2 , 4-triazolyl, pyrazolyl, 1, 2 , 4-oxadiazinyl and azepinyl groups and a bipiperidinyl group.
A "heteroaryl" group is an aromatic heterocyclic ring that preferably contains one, or two, or three or four atoms in the ring other than carbon. Those heteroatoms can independently be nitrogen, sulfur or oxygen. A heteroaryl group can contain a single 5- or 6-membered ring or a fused ring system having two 6-membered rings or a 5- and a 6-membered ring, or a linked 5,5-, 5,6- or 6,6- membered rings as in a bipyridinyl group.. Exemplary additional heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1, 2, 3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl groups; 6-/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1- benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-benzoxazinyl groups.
The term "amino-protecting group" as used herein refers to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality. The term "protected (monosubstituted) amino" means there is an amino-protecting group on the monosubstituted amino nitrogen atom. In addition, the term "protected carboxamide" means there is an amino-protecting group present replacing the proton of the amido nitrogen so that there is no N-alkylation . Examples of such amino-protecting groups include the formyl ("For") group, the trityl group (Trt) , the phthalimido group,
the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups. Orethane blocking groups, such as t-butoxy-carbonyl ("Boc"), 2- ( 4-biphenylyl) propyl (2 ) oxycarbonyl ("Bpoc"), 2- phenylpropyl (2 ) oxycarbonyl ("Poc"), 2- (4- xenyl ) isopropoxycarbonyl , 1 , 1-diphenylethyl ( 1 ) - oxycarbonyl, 1.1-diphenylpropyl (1) oxycarbonyl, 2- ( 3, 5-dimethoxyphenyl) propyl (2) oxycarbonyl ("Ddz"), 2- (p- 5 toluyl ) propyl (2 ) oxycarbonyl , cyclopentanyl- oxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl , 1-methylcyclohexanyl- oxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4- toluylsulfonyl ) ethoxycarbonyl, 2- (methylsulfonyl) - ethoxycarbonyl, 2- (triphenylphosphino) -ethoxycarbonyl, 9-fluoroenylmethoxycarbonyl ("Fmoc"), 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-l-enyloxycarbonyl, 5-benz- isoxalylmethoxycarbonyl , 4-acetoxybenzyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2-ethynyl(2) propoxy- carbonyl, cyclopropylmethoxycarbonyl, isobornyl- oxycarbonyl, 1-piperidyloxycarbonyl,
benzyloxycarbonyl ("Z"), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy-carbonyl, a-2 ,4,5, -tetramethyl- benzyloxycarbonyl ("Tmz"), 4-methoxybenzyl- oxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chloro- benz loxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, -cyanobenzyIoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, and the like, the benzoylirtethylsulfonyl group, dithiasuccinoyl ("Dts1) group, the 2- (nitro) henylsulfenyl group ("Nps'), the diphenylphosphine oxide group, and like amino- protecting groups. The species of amino-protecting
group employed is usually not critical so long as the derivatized amino group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the compound. Preferred amino-protecting groups are Boc and Fmoc.
Further examples of amino-protecting groups embraced to by the above term are well known in organic synthesis and the peptide art and are described by, for example: T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, New York. N.Y., Chapter 7, 1991; M. Bodanzsky, Principles of Peptide Synthesis, 1st and 2nd revised ed. , Springer-Verlag, New York, N.Y., 1984 and 1993; and Stewart and Young, Solid Phase Peptide Synthesis, 2nd ed. , Pierce Chemical Co, Rockford, IL 1984.
The related term "protected amino" defines an amino group substituted with an amino-protecting group discussed above.
The term "C1-C4 alkylsulfonyl" encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, -butylsulfonyl , t-butylsulfonyl, and the like.
DETAILED DESCRIPTION OF THE INVENTION
The present invention contemplates the ligand-controlled catalytic arylation or
heteroarylation of a primary and secondary C(sp3)-H bonds of a protected amino acid substrate molecule. The catalyst utilized herein is a mixed Pd(II) catalyst that is paired with a pyridine-type ligand to provide the selectively to promote the activation
of primary and secondary C-H bonds. That C-H bond activation can lead to a wide range of β-Ar-amino acids and β-Ar-p-A 1 -cc-amino acids with excellent levels of diastereoselectivity (d.r. > 20:1). Both configurations of the β-chiral center can be accessed by choosing the order in which the aryl groups are installed.
(i) N-BPG is a protected amino group in which B is hydrogen or a further bond between the nitrogen atom and the protecting group; (ii) R is hydrogen
(hydrido) , a C]_-C]_2 hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubsttuted or substituted with a NBPG protected amino group that is the same or different from that previously defined, or a Cg-C]_o aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen (fluoro, chloro and bromo) , C]_-Cg hydrocarbyl, C]_-Cg hydrocarbyloxy, carboxy C]_-Cg hydrocarbyl, trifluoromethyl, ¾-Cg hydrocarboyl, nitro, ¾-Cg hydrocarbylthiooxy, cyano and 1,2-(C]_-Cg
hydrocarbylene) dioxide such as 1, 2-methylenedioxide; and (iii) X is NHR1 in which R1 is a Ci-C12 hydrocarbyl aliphatic or aromatic group that is
unsubstituted or substituted with fluorine atoms, can also be a hydroxyl (OH) , 0-C]_-C]_2 hydrocarbyl, or NH-0-C2-C]_2 hydrocarbyl group, so that the substrate molecule is a protected amino amide, acid, ester or hydrocarbyloxyamide, respectively. The oc-carbon of a substrate molecule A is a chiral center and a contemplated substrate molecule A can exist as one or the other of the two enantiomers, substrate molecules A-1 and. A-2, below.
Illustrative protecting groups (PG) for the a-amine include what may be referred to as monodentate and bidentate protecting groups. A monodentate protecting group bonds to only one of the possible valances of the nitrogen atom, leaving the other available to bond to a hydrogen (hydrido group) . Illustrative monodentate protecting groups include amine group-protecting moieties typically utilized in peptide synthesis such as t-BOC, f-MOC, CBZ, as well as ]_-C]_2 hydrocarboyl (acyl) and C7-Ci2 sulfamido group. Bidentate amine protecting groups utilize both of the valances of the nitrogen atom, and with that nitrogen atom form cyclic imides such as succinimido, maleimido, ortho-benzoic sulfimido and phthalimido, which is most preferred.
Turning more specifically to the "X" group, a particularly preferred NHR^ substituent contains a R group that is a perfluorinated p-tolyl group that is usually abbreviated ArF and has the chemical
formula 4-(CF3)CgF4, so that X is NH [4- (CF3) C5F4] . When X is OH, yields of the desired arylated product are satisfactory as is illustrated hereinafter.
Yields are also good when X is a ΝΗ-Ο-0]_-¾2 hydrocarbyl group, and particularly a NH-O-C^-Cg hydrocarbyl group, such as a methyl or t-butyl group, with X being NH-0-CH3 also being particularly preferred. Arylation product yields using other amides and esters are minimal, and use of those X groups is less preferred.
Aromatic and heteroaromatic iodides are the coreactants in a contemplated arylation or heteroarylation reaction. The iodide reactant is typically utilized in excess over the molar amount of the protected amino acid substrate molecule
(substrate) . Broadly, the molar ratio of iodide reactant to substrate is about 1.1 to about 4 to 1. More specifically, where a single aromatic or heteroaromatic group is added to a substrate where R is hydrido, the molar ratio is about 1.1 to about 2 to 1, and preferably about 1.5:1 (iodide: substrate) . Where the substrate R group is other than hydrido, a larger quantity of iodide is typically utilized and the iodide to substrate molar ratio is about 2 to about 4 to 1, and preferably about 3:1
(iodide : substrate) .
A contemplated aromatic or heteroaromatic iodide can be otherwise unsubstituted, or contain up to three substituents in addition to the iodo group. Contemplated substituents are independently selected from one or more of the group consisting of halogen
(fluoro, chloro and bromo) , C^-Cg hydrocarbyl, C^-Cg hydrocarbyloxy, carboxy C]_-Cg hydrocarbyl,
trifluoromethyl, C]_-Cg hydrocarboyl, nitro, C]_-Cg hydrocarbylthiooxy, cyano and 1, 2-hydrocarbylene- dioxide such as 1, 2-methylenedioxide .
Illustrative iodide-substituted aryl rings are phenyl and naphthyl that is optionally substituted as discussed above. Illustrative iodide- substituted heteroaryl ring compound includes an aromatic monocyclic or bicyclic heterocycle that contains one or more ring atoms that are other than carbon and is optionally substituted as defined above .
A "heteroaryl" group preferably contains one, two, three or four (up to four) ring atoms other than carbon (heteroatoms) . Those heteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group can contain a single 5- or 6-membered ring or a fused ring system having two 6-membered rings or a combination of two 5- and 6-membered rings.
Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1, 2, 3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl groups; 6-/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1- benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1 , 4-benzoxazinyl groups. When an iodide-sustituted heteroaryl group contains a ring -NH- group, it is preferred that that nitrogen atom
be present as a C]_-Cg carboxamide or C]_-Cg
sulfonamide.
It is thus to be understood that where R of a protected amino acid substrate molecule A is hydrido, carrying out an arylation or heteroarylation reaction can provide a second substrate molecule A in which R is a substituted or unsubstituted aryl or heteroaryl substituent. Where the first reaction added an aryl group, that second substrate molecule A can be reacted again with another aryl iodide to form an a-amine-protected p-Ar-p-Ar ' -cc amino acid, for example .
It is to be noted that inasmuch as the substrate molecule A can be one or the other enantiomers, the product a-amine-protected β-ΑΓ-β- Ar'-a-amino acid or β-Ar-p- (hydrocarbyl) -a-amino acid made in a method of this invention contains a new chiral center at the β-carbon so that the product can contain two chiral centers and thereby diastereomers. As is seen from the data reported hereinafter, a product of a contemplated method is prepared with high diastereoselectivity that typically exceeds a diastereomeric ratio (d.r.) of about 15. A more usually obererved d.r. exceeds about 20, and can be very large where only one diastereomer was produced.
Useful Pd(II) catalysts are well known in the art. Exemplary catalysts include PdCl2, Pd(TFA)2, Pd(Piv)2, [PdCl(C3H5) ]2, PdCl2(PPh3)2, Pd(PPh3)4, Pd2(dba)3, [PdCl2 (MeCN) 2] , [Pd (OTf) 2 ■ 4MeCN] , and
[Pd(BF4)2 -4MeCN] . Of these catalysts, Pd(TFA)2, Pd(Piv)2 and Pd(0Ac)2 are presently preferred. A contemplated catalyst is utilized in a catalytic amount. That amount is typically about 5 to about 40
mole percent based on the moles of reactive substrate, and more preferably about 10 to about 20 mole percent. The reaction mixture preferably contains about 20 mole percent trifluorpacetic acid (TFA) to assist in inhibiting degradation of the substrate .
A contemplated ligand is a pyridine compound that is preferably substituted at one or both of the 2- and 6-positions. Pyridine itself and
4-dimethylamino-pyridine did not provide a
substantial enhancement in yield compared to use of no ligand. On the other hand, pyridine compounds substituted at one or both of the 2- and 6-positions such as acridine, 2, 6-difluoropyridine,
2 , 6-dimethoxypyridine, 2, 6-lutidine, 2-picoline (also sometimes referred to as ligand L7) , quinoline, a 2- C]_-Cg-hydrocarbyloxy-substituted quinoline and the ligands defined by Formula L, below, are particularly useful .
A group of preferred pyridine-type ligands is defined by Formula P, below, where R2 and R3 are
independently selected from the group consisting of hydrido, halogen other than iodo (fluoro, chloro or bromo) , Cj-Cg alkyl, C]_-Cg alkyloxy, and
trifluoromethyl, or one or both of R2 and R3 forms a saturated or unsaturated 5- or 6-membered carbocyclic or oxa-substituted carbocyclic ring with the depicted ring at ring positions 3- and 5-, respectively, and
R4 is independently hydrido or Cj-Cg alkyl, with the proviso that at least one of and is other than hydrido. These and other useful pyridine-type ligands are illustrated in Tables 1 and 3
hereinafte .
A ligand that is particularly preferred for use in inserting a second aryl or heteroaryl group as discussed hereinafter corresponds in structure to Formula L, below, where "n" is 1 or zero such that
when n is zero, the bracketed methylene is absent, and R5 is hydrido or a substituent selected from the group consisting of halogen other than iodo
(fluoride, chloride, or bromide), C^-Cg alkyl, C^-Cg alkyloxy, and trifluoromethyl . R^ is preferably t-butyl. Ligands L10, Lll, L12 , L13, L14, L15, L16,
L17 and L18 are within the ambit of Formula L.
Additional useful ligands within the ambit of Formula L are described in Zhang et al., Org. Lett. 9:3651- 3653 (2007).
Of these ligands, 2-picoline is particularly useful at providing mono-arylation or
monoheteroarylation . A second ligand, that is a member of those compounds defined by Formula L, is 2, 5-dimethyl-3, 4-dihydro-2H-pyrano [2, 3-b] quinoline that is also often referred to as ligand L10, was used to prepare desired β-Ar-p-Ar ' -oc-amino acids in high yield with high diaselectivity. 2, 6-Lutidine,
L6, is also quite useful in preparation of β-Ar-p- Ar ' -a-amino acids in high yield with high
diaselectivity. Ligands L6, L7 and L10 are particularly preferred.
A ligand is typically present in the reaction composition at about 10 to about 30 mole percent based on the moles of substrate. Preferably, the ligand is present at about 20 mole percent.
A contemplated method utilizes an excess, about 1.1 to about 4 equivalents of an oxidant per mole of reactive substrate, and preferably about 1.5 to about 2 equivalents of oxidant. A silver oxidant is typically used, although oxygen and other mild oxidants can also be used. Illustrative catalysts include Ag(Piv), Ag(OAc), Ag20, AgTFA, AgOTf, Ag2C03,
Me Me Me
Et-^—C02Ag, Et^—C02Ag, Et-^—C02Ag, and Cu(OAc)2. Ag2C03 is Me Me Me
a preferred oxidant.
A contemplated reaction is carried out with the ingredients dissolved or dispersed in a solvent and with agitation as can be provided by the use of a magnetic stir bar. Additional means of agitation such as shaking can also be utilized. Exemplary solvents include ^uCC^Me, hexafluoro-isopropanol
C6F6, DCM, and 1 , 2-dichloroethane (DCE) . DCE, t-amylOH and HFIP are preferred among these materials .
A contemplated method is preferably carried out under anhydrous conditions. A bench-scale reaction using about 0.05 to about 0.10 mmoles of reactive substrate and appropriate amounts of other ingredients is typically carried out in about 0.5 to
about 1 mL of solvent. Larger quantities can be readily scaled from those proportions.
A reaction mixture formed in carrying out a method of the invention is maintained at a temperature of about 70° to about 120° C for a time period sufficient to carry out the electrophilic insertion and form a reaction product. More preferably, that temperature is about 80° to about 100° C. Reaction times are typically about 15 to about 50 hours, with times of about 18-36 hours being usual .
It has also been found that the presence of 1 to about 3 equivlents of sodium dihydrogen phosophate in the reaction mixture enhances the yield. The presence of the hydrated form of the salt is more preferred.
A contemplated reaction is preferably carried out in a sealed reaction vessel, so the pressure under which the ingredients are maintained is mostly that created by the solvent used, with some contribution from the reactants, at the reaction temperature .
Another, similar reaction is also contemplated in which an activated reactive olefin is inserted to the beta-carbon of a substrate molecule A, whose R group is hydrido and whose X group is an amido nitrogen atom [-C (0) -NHRI] . The reaction conditions are similar to those discussed above except that (i) the ligand of choice is a member of those compounds defined by Formula L such as Ligands L10, Lll or L12 , and preferably L10, and (ii) an excess of a reactive olefin is used in place of the excess of iodinated aryl or heteroaryl reactant. An
illustrative activated reactant olefin is present at about 1.1 to about 5 equivalents relative to substrate molecule A, and preferably at about 3 to about 4 equivalents.
A contemplated activated olefin reactant is typically an α,β-unsaturated ester or ketone, such as an acrylate or methacrylate C^-Cg-hydrocarbyl ester. The ethyl and methyl (C]_-Cg-hydrocarbyl) esters of c3_c12 olefins are preferred. Thus, C^-Cg- hydrocarbyl esters of cinnamic acid, of butenoic acid, octanoic acid, dodec-2-enoic acid, fumaric and maleic acids, ethyl 2- ( 1 , 3-dioxoisoindolin-2- yl) acrylate, C]_-Cg-hydrocarbyl) esters of C3-C12 olefins and the like can also be reactants. Another typical olefin is a C4-C]_2~olefinic ketone.
Illustrative ketones include but-3-en-2-one, pent-3- en-2-one, methyl cyclohex-l-enecarboxylate, isopropyl cyclopent-l-enecarboxylate, pent-4-en-3-one, cyclopent-2-en-l-one, cyclohex-2-en-l-one, naphthalen-1 ( 4H) -one, and the like. Similarly, an olefinic sulfone or sulfoxide such as a C^-C^- olefinic sulfone or sulfoxide is contemplated like ethyl vinyl sulfone. Also contemplated is a hydrocarbyl diester of an olefinic phosphonate such as an (¾-Cg-hydrocarbyl-diesters of C2-C12 olefinic phosphonates such as diethyl vinyl phosphonate
[H2C=CH-P(0) (0Et)2l, or a Ci-Cg-hydrocarbyl ester of a C2-C]_2-°lefi-n:>-c sulfonate such as ethyl vinyl sulfonate [H2C=CH-S (0) 2 (OEt ) ] .
The product of this reaction is a 5-membered lactam whose ring members include one carbon from the olefin, the beta- and alpha-carbons
of the starting derivatized amino acid, the amido group carbon atom and its amido nitrogen atom. The lactam product can be and usually is isolated.
Where it is desired to obtain an olefinic amino acid derivative as where one desires to incorporate an olefinic amino acid residue into a peptide, the lactam ring can be readily opened to form the corresponding unsaturated amino-protected amino acid amide. Such reactions are illustrated in conjunction with the discussion of Table 7.
RESULTS
Arylation Directed by A Perfluorinated
Anilide
A ligand for monoarylation .
A first challenge in the development of a versatile method for the preparation of stereo- defined β-Ar-p-Ar ' -a-amino acids from alanine was to achieve selective monoarylation of primary C(sp3)-H bonds without further arylating the secondary C(sp3)-H bonds. The Yu research group has recently focused on the development of simple auxiliaries, such as W-methoxyamides and perfluorinated arylamides, to direct a wide range of C(sp3)-H activation reactions [Wang et al., J. Am. Chem. Soc. 130:7190-7191 (2008); Wasa et al., J. Am. Chem. Soc. 131:9886-9887 (2009)] by weak coordination to Pd catalysts. However, to date, these auxiliaries have been found to be incompatible with the functionalization of the C(sp3)-H bonds of a-amino acids [Wang et al., J. Am. Chem. Soc. 130:7190-7191 (2008); Wasa et al., J. Am. Chem. Soc. 131:9886-9887 (2009)].
The use of an alkoxypyridine ligand that can match the weak coordination of the amide
auxiliary (CONHArF) and facilitate secondary C(sp3)-H activation (albeit with only simple aliphatic amides) was recently reported [ asa et al . , J. Am. Chem. Soc. 134:18570-18572 (2012)], indicating that pyridine- based ligands are capable of lowering the transition state energy of C(sp3)-H activation. This finding prompted examination of a diverse array of
monodentate pyridine-derived ligands for their ability to selectively promote primary C(sp3)-H activation, thereby permitting for highly mono- selective arylation of illustrative alanine-derxved amide Compound 1.
NPhth
HyS;ONHArF ArF = 4-(CF3)C6F4 H
1
To obtain preliminary information regarding the reactivity of the CONHArF amide auxiliary with amino acid substrates, efforts were initiated by studying C(sp3)-H arylation of Compound 1 under a variety of different reaction conditions in the absence of an ancillary ligand. Through extensive screening, it was found that the use of about 20 mol% trifluoroacetic acid (TFA) prevented substrate decomposition, which had been observed with Compound 1 under previously developed basic conditions [Wasa et al., J. Am. Chem. Soc. 134:18570-18572 (2012)].
Under the best conditions from this initial screen, monoarylated product Compound 2 (below) could
be obtained in 47% yield, along with full recovery of the remaining starting material. Additional attempts to fine-tune various reaction parameters, including increasing the catalyst loading to 30 mol%, failed to improve the reaction conversion. The low conversion was found to result primarily from product
inhibition. [Table 14, entry 16.]
Alternative aryl iodide coupling partners reacted in even lower yields (Compounds 2m-2p, below) . These findings pointed to the need for the identification of a ligand that promotes the activation of primary p-C(sp )-H bonds exclusively, but not the secondary p-C(sp3)-H bonds in the product.
Hence, a library of pyridine-related (pyridine and substituted pyridines including quinolones) ligands was studied for their efficiency in promoting mono-arylation in the presence of TFA. Pyridine and 4-dimethylaminopyridine (Ligands LI and L2) are highly selective for monoarylation, but neither enhances conversion significantly relative to the ligand-free catalyst. In contrast, we found that 2 , 6-dimethoxypyridine, acridine, 2,6-lutidine and 2-picoline (Ligands L4-L7) promote substantially higher conversion, though use of Ligands L4-L6 leads to appreciable quantities of the undesired diarylated product Compound 3 as well.
The 2-picoline Ligand L7 seems to possess an optimal balance of steric and electronic properties to provide Compound 2 in high yield with an excellent level of selectivity for mono-arylation (NMR yield of 94%) . The monoarylation reaction also proceeded in the presence of 5 mol% of Pd(TFA)2 and 10 mol% of Ligand L7 to give the desired product
Compound 2 in 79% yield.
The applicability of this ligand-controlled monoarylation protocol in the preparation of diverse chiral β-Ar-p-Ar ' -oc-amino acids is shown in Table 1, bellow. It is seen that phenylalanine derivatives with electron-rich or electron poor-groups in the ortho-, meta-, or para-positions can be synthesized in high yields. This reaction is tolerant of halide substituents and a wide range of polar functional groups .
Table 1
Arylation with 4-methylthiophenyl iodide also proceeds to give the arylated product (Compound 2p) in a synthetically useful yield, indicating that the pyridine ligand is able to out-compete the methylthio group for coordination at Pd(II). The reaction of Compound 1 with 2-iodonaphthalene to give Compound 2q is particularly useful, as the resulting product can be applied to synthesis of bioactive peptides that block cell cycle progression in HeLa cells [Wildemann et al., J. Med. Chem. 49:2147-2150
(2006) ] . Arylation with disubstituted aryl iodides is also efficient, giving Compounds 2r-2t in >85% yields. Deprotection of Compound 2s affords L-DOPA, which is widely used in the treatment of Parkinson' s disease [Cotzias et al., N. Engl. J. Med. 276:374-379
(1967) ] , indicating the potential bioactivity of this type of unnatural amino acids .
When conducted at 100 °C, these reactions are typically complete within 20 hours, and no racemization of the stereogenic center is observed. Subsequent removal of the auxiliary can be
accomplished under mild conditions without loss of enantiomeric purity (Table 2, below) and the
resultant compounds are readily converted to the corresponding Fmoc-protected unnatural amino acids following literature procedures as is illustrated hereinafter .
The auxiliary 2 , 3, 5, 6-tetrafluoro-4- (trifluoromethyl) aniline is readily prepared from octafluorotoluene (currently about $0.47/g) on 100- gram scale or purchased directly from Aldrich. Due to these practical advantages, a variety of mono- arylated alanines were prepared on 10-mmol scale to facilitate peptide drug discovery in collaboration with Bristol-Myers Squibb Co. (Compounds 2c-2e, 2g, 2h, 2j, 21, and 2r) .
Illustrative arylation and heteroarylation of a protected amino acid of Formula A where R, as defined previously in regard to Formula A, is hydrogen (hydrido) , a C]_-C]_2 hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubsttuted or substituted with a NBPG protected amino group that is the same or different from that previously defined, or a Cg-C]_o aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen (fluoro, chloro and bromo) , cl_c6 hydrocarbyl, ¾-C hydrocarbyloxy, carboxy C]_- Cg hydrocarbyl, trifluoromethyl, C^-Cg hydrocarboyl, nitro, ¾-Cg hydrocarbylthiooxy, cyano and 1,2-(C]_-Cg hydrocarbylene) dioxide such as 1, 2-methylenedioxide is illustrated below.
53% yield (crude NMR)
75% yield (mono:dl = 1.5:1) (crude NMR) 57% y'eld (monoidi = 2:1) (crude NMR)
An illustrative arylation or
NPhth
•COOH
58% yield (crude NMR)
A ligand for diarylation
Work was carried out to identify a second ligand that can promote the subsequent arylation of the secondary p-C(sp3)-H bonds. As previously mentioned, the recently disclosed procedure for the ligand-promoted arylation of secondary C(sp3)-H bonds under basic reaction conditions [ asa et al., J. Am. Chem. Soc. 134:18570-18572 (2012)] is not compatible with amino acid substrates. However, the formation of minor amounts of the diarylated product Compound 3 from amide Compound 1 with Ligand L4 (13% yield, Table 1) suggested that these new conditions could be effective for secondary p-C(sp3)-H bond arylation with an appropriate ligand.
It was pleasing to find that the arylation of phenylalanine-derived amide Compound 2, in the presence of Ligand L4, afforded the desired product Compound 3 in 47% yield. The modest success of this ligand and the previously reported 2-alkoxylquinoline Ligand L9 [Wasa et al . , J. Am. Chem. Soc. 134:18570- 18572 (2012) ] led to exploration of a variety of electron-rich 2-alkoxylpyridine and
2-alkoxylquinoline ligands for this secondary C(sp3)-H
bond arylation. A significant improvement in reaction efficiency using Ligand L8 or L9 suggested that the 2-substituted quinoline motif possesses favorable steric and electronic properties that promote C(sp3)-H activation.
The impact of further increasing the electron-donating ability of the alkoxyl group was next examined by synthesizing the tricyclic Ligand L10, in which the conformation of the lone pairs on the oxygen atom is rigidified to favor π-conjugation with the pyridine ring. The use of this new ligand led to a dramatic improvement in reaction efficiency, affording product Compound 3 in 92% yield (90% isolated yield) . Further modifications of Ligand L10 to weaken or strengthen the coordinating ability of the quinoline led to a decrease in product yield (Ligands Lll and L12) .
Under these optimized reaction conditions phenylalanine-derived amide Compound 2 can be arylated with a broad range of electron-rich and electron-poor aryl iodides in high yields (Table 3, below) . ortho-Substituted aryl iodides are also compatible with this reaction despite the known steric hindrance associated with the arylation of secondary C(sp3)-H bonds (Compound 3j).
Table 3
To demonstrate the generality of this ligand effect for secondary C(sp3)-H activation, arylation of four representative open chain and cyclic alkyl amino acids was also carried out. Amide substrates derived from lysine, L-2-aminobutyric acid, l-aminocyclobutane-l-carboxylic acid and
1-aminocyclopropane-l-carboxylic acid were
successfully arylated using Ligand L10 to give the corresponding p-alkyl-p-aryl-a-amino acid derivatives in good to excellent yields (Table 4, below) . These arylation reactions all proceeded with high levels of diastereoselectivity. These aliphatic secondary C(sp3)-H bonds are less reactive than benzylic C(sp3)-
H bonds and the use of Ligand L10 is important to achieve this reactivity.
Table 4
I
One pot diarylation
Ligands L7 and L10, which enable the arylation of primary and secondary p-C(sp3)-H bonds, respectively, can be employed for the sequential one- pot incorporation of two distinct aryl groups onto the β-carbon of alanine-derivative Compound 1 (Table 5) . Thus, following the completion of the monoarylation of Compound 1 with an aryl iodide using Ligand L7, one can add Ligand L10 and a second aryl iodide to provide a β-Ar-p-Ar ' -oc-amino acid.
Table 5
The aryl iodide (1.5 equiv) used in the first step is mostly incorporated into the product with small amount being converted to the biaryl
[Wang, Org. Lett. 11:1079-1082 (2009)]. The remaining aryl iodide is outcompeted by a large excess of the second aryl iodide (3 equiv) , thus avoiding participation in a second arylation event. This one-pot procedure is successfully applied with both electron-rich and electron-deficient aryl iodides to prepare a variety of diarylated amino acids (Compounds 7a-7f) in good yields with excellent levels of diastereoselectivity . Small amounts of unreacted monoarylated products (15-25%) from the first step are also isolated as a byproduct of this transformation .
By simply switching the order of the addition of the two different aryl iodides, the inverse configuration at the β-stereogenic center can be obtained, as shown with Compounds 7e and 7f
(absolute configuration of Compound 7f was confirmed by X-ray crystallography) . When the sequential hetero-diarylation of Compound 1 was conducted in one pot on a 5-mmol scale (2.2 g) , the desired product, Compound 7b, was isolated in 60% yield.
The superior reactivity of Ligand L10 prompted revisiting the previously unsuccessful arylation with heteroaryl iodides. Although secondary C(sp3)-H arylation of Compound 2 with heteroaryl iodides proved inefficient, primary C(sp3)-H arylation of Compound 1 with pyridyl, indolyl and thiophenyl iodides afforded synthetically useful yields (Table 6, below) . These heteroaryl-containing unnatural amino acids are especially desirable for developing peptide drug molecules.
Table 6
NPhth 1^rn°l%,o,diT n A)2 NPhth
H X 30 mol% L10 . ,μ .. =
H^CONHArF + Ar(Het)-l > Ar(Het) -^CONHArF 1 (1.5 equiv) l00 °C, 20 h 2u_2w
Olefination with ligand LIO
The feasibility of using Ligand LIO to effect the olefination of alanine-derived substrate
Compound 1 was examined. Efficient reactivity under slightly modified reaction conditions was observed. The subsequent lactamization in situ also ensured the mono-selectivity of the reaction.
Lactam Compound 8 is converted to W-Boc- protected product Compound 10 using established procedures (Table 7, below) . The olefinated product
Table 7
Compound 10 can be subjected to cross metathesis to afford olefinated product Compounds 11 and 12 with high levels of ElZ selectivity or hydrogenated to provide the corresponding alkylated product Compound 13 (Table 8, below) .
Table 8
NHBoc NHBoc
-CgHi3s
^Hl3 #fs^CONHArF CONHArF 11, 86% (11.5/1 ©Z ratio) 14, 95%
n-C6H3 ^i-
NHBoc NHBoc
CONHArF ^CONHArp
95%
12, 69% (> 20/1 E/Z ratio) 15, 97%
Mechanistic studies
Whereas C(sp3)-H arylation with aryl iodides likely proceeds via a Pd (II) /Pd (IV) catalytic cycle, olefination likely proceeds via a Pd(II)/Pd(0) redox manifold. The significant ligand effect consistently observed in these distinct reaction pathways implicates the intimate involvement of the ligand in the C(sp3)-H cleavage step as the common step. This is further substantiated by the intramolecular kinetic isotope effect observed in the arylation reaction, which showed a noticeable and consistent dependence on the ligand (without ligand, ^H/D = 6.0; with Ligand L7, kH/D = 8.1; with Ligand HO, ]¾/D = 10.7, see supplementary materials).
To obtain further insights into the coordination of the substrate and ligands at the Pd(II) centers, the C-H insertion intermediates
(Intermediate A and Intermediate B) were successfully
characterized, formed via primary and secondary C(sp3)-H activation, respectively (Table 9). The formation of these C(sp3)-H insertion intermediates in the absence of Arl also rules out the involvement of a Pd(0)/Pd(II) catalytic cycle initiated with aryl iodides .
Intermediate B
75%
It is found that Intermediate A reacts with iodobenzene stoichiometrically to provide Compound 2. However, the addition of TFA is required for this transformation, presumably to facilitate the dissociation of one of the pyridine ligands. These intermediates are viable pre-catalysts for primary and secondary C(sp3)-H arylation, respectively (Table 10, below). These rare and valuable C(sp3)-H insertion intermediates provide a promising platform for further kinetic and computational study of elementary steps in a well-defined manner.
Table 10
Arylation Directed by a N-Hydrocarbyloxyamide
^- ono-arylation directed by N-methoxyamide p-C-H functionalizations of amino acid derivatives using various auxiliaries have been extensively studied since the first report from the Corey group [(a) Reddy et al . , J. Org. Lett. 8:3391 (2006); (b) Feng et al., Angew. Chem. Int. Ed. 49:958 (2010); (c) Tran et al. , Angew. Chem., Int. Ed.
51:5188 (2012); (d) Zhang et al., Angew. Chem., Int. Ed. 52:13588 (2013); (e) Wang et al . , Chem. Sci. 5:3952 (2014); (f) Chen et al., Chem. Comm. 50:13924 (2014)]. It was established in this early study that the use of the phthalimide protecting group was important for achieving β-C-H activation [Reddy et al., J. Org. Lett. 8:3391 (2006)].
The above-discussed work using pyridine- and quinoline-based ligands promote activation of the C(sp3)-H bonds in alanine using CONHArF (ArF = p- CF3C6F4) auxiliary as the directing group has now been published [He et al., Science 343:1216 (2014)]-.
Although the precise mechanistic origin of the ligand effects remains to be elucidated, a recent
computational study suggests that the ligand is involved in every step of the catalytic cycle including the C-H activation step [Dang et al., J. Am. Chem. Soc. 137:2006 (2015)]. This development
encouraged revisitation of whether a simpler
N-hydrocarbyloxyamide auxiliary such as the illustrative itf-methoxyamide group, with the assistance of a ligand, can accommodate substrates derived from carboxylic acids containing a-hydrogen atoms .
Thus, phthaloyl alanine amide Compound 25 was reacted with 1.5 equiv. of p-Tol-I using Pd(OAc)2 and ligand L18 under various conditions. It was found that the mono-arylation proceeded under the conditions shown in the Scheme below to give the arylated products as a mixture of amide Compound 28a and the corresponding ester in 45% yield. A substantial amount of the starting material was converted to corresponding unreactive ester. The conversion of the N-methoxyamide to the corresponding ester via a radical process is known to be promoted by silver salts [(a) Crawford et al . , J. Org. Chem. 28:2419 (1963) (b) Cooley et al., J. Am. Chem. Soc. 90:1867 (1968); (c) De Almeida et al., J. Am. Chem. Soc. 117:4870 (1995); (d) Glover et al., Tetrahedron 55:3413 (1999); (e) Kawase et al., J. Org. Chem. 54:3394 (1989); (f) Yus et al., Org. Lett. 14:5518 (2006) ; (g) For itf-methoxyamide as orfcho-lithiation directing group, see: Fisher et al., J. Org. Chem. 58:3643 (1993)]. A control experiment showed that ligand L18 was required for the formation of the arylated product.
Prior to undertaking further ligand screening, conditions under which the known decomposition of the W-methoxyamide to the unreactive ester via a radical process [(a) Crawford et al., J. Org. Chem. 28:2419 (1963) (b) Cooley et al., J. Am. Chem. Soc. 90:1867 (1968); (c) De Almeida et al . , J. Am. Chem. Soc. 117:4870 (1995)] was minimized needed to be identified (Table 17). The use of (2,2,6,6- tetramethylpiperidin-l-yl) oxy (TEMPO) to inhibit the radical process led to a slight drop in product yield (Table 1, entry 2) . The reaction did not proceed at a lower temperature of 60 °C (Table 17, entry 3) . Switching to a range of commonly used solvents did not reduce the decomposition or improve the yields (Table 17, entries 4-8) .
It was pleasing to find that the decomposition of the ii-methoxyainide was effectively prevented by using acidic solvents, such as 2,2,2- trifluoroethanol (CF3CH2OH) or hexafluoro-2-propanol (HFIP) (Table 17, entries 9-10) . Arylation proceeded in HFIP to give the mono-arylated product in 76% yield and the di-arylated product in 10% yield (Table 17, entry 10). Running the reaction in 1,2- dichloroethene (DCE) in the presence of 20 mol% trifluoroacetic acid (TFA) also significantly improved the yield to 75% (Table 17, entry 11).
Table 17
Evaluation of Reaction Condit
Entry Solvent Additive % Yield of 28a"
1 r-AmylOH no 45
2 f-AmylOH TEMPO 40
3C f-AmylOH no N.R.
4 Toluene no 30
5 CH3CN no 35
6 1 ,4-Dioxane no 50
7 DCE no 43
8 D F no 40
9 CF3CH2OH no 60
10 HFIP no 76(86)<i
11 DCE TFA 75 a Conditions: Substrate 25 (0.1 mmol) , Pd(0Ac)2 (10 mol%) , AgOAc (0.2 mmol), p-Tol-I (0.15 mmol), Ligand L18 (20 mol%), solvent (1.0 mL) , 75 °C, 24 hours. b Determined by 1HNMR analysis of the crude product using CH2Br2 as an internal standard, and the yield is based on the amide and ester. c Reaction run at 60 °C. d Combined 76% mono- and 10% di-arylated products determined by crude 1HNMR.
Although further ligand screening using DCE/TFA solvent system did not provide noticeable improvement, dramatic ligand effects were observed for this reaction in HFIP (Table 18) . A variety of pyridine-based ligands, including quinolones that can
be viewed as substituted pyridines, afforded moderate to good yields (up to 83%) . Further optimizations of quinoline-based ligands were not fruitful.
A wide range of monocyclic substituted pyridines were found to be suitable ligands for this reaction. 2-Picoline ligand (L7) was found to be highly effective affording both excellent yield (90%) and mono-selectivity (99%). Replacing the 2-methyl group by other substituents in 2-substituted pyridines (L21-L25) resulted in lower yields. Among the di-substituted and tri-substituted pyridines (L13-L31) , L26 and L27 containing a 2-methyl group performed well with good yields (84% and 83%) and mono-selectivity. Interestingly, the use of 2,6- lutidine (L13) resulted in some loss of mono- selectivity affording the mono-arylated product 28a in 70% yield and the di-arylated product Compound 31r in 10% yield.
Arylation in the absence of ligand under these new conditions gave the desired product in 36% yield, thus confirming the significant ligand acceleration effect. Mechanistically, the comparison of the most effective ligand L7 with the less effective ligands L23 and L24 is informative. The decrease in binding strength of the ligands via either electronic or steric effects reduces the efficiency of the catalysts.
Table 18
Ligand Screening with N-methoxyamide a,b
a Conditions: Substrate 25 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), p-Tol-I (0.15 mmol), Ligand (20 mol%), HFIP (1.0 mL) , 75 °C, 24 hours. b The yields were determined by ¾ NMR analysis of the crude product using C¾Br2 as an internal standard. The mono:di ratio was determined by ¾ NMR.
A broad range of variously substituted aryl iodides are compatible with this ligand-promoted β-C- H arylation reaction (Table 19). Aryl iodides containing methyl, phenyl and methoxy groups react with substrate Compound 28 under the standard
conditions to give the desired products in good to excellent yields (28a-f) . Aryl iodides further containing fluoro, chloro, bromo and iodo
substituents are all tolerated and moderate to good yields are obtained (28g-k) . Aryl iodides containing highly electron-withdrawing groups including acetyl and methoxycarbonyl are excellent coupling partners affording the arylation products in 71-82% yields (Compounds 281-p) .
Di- and tri-substituted aryl iodides display similar reactivity to the mono-substituted ones (28q-t) . Most importantly, aryl iodides containing well-known directing groups such as acetamide, phosphonate and hydroxyls are also reactive coupling partners (28u-x) , thus overcoming some limitations of previous protocols [ (a) Wang et al., Chem. Sci. 5:3952 (2014); (b) Chen et al., Chem. Comm. 50:13924 (2014); (c) He et al., Science
343:1216 (2014) ] .
These resulting unnatural amino acids have been widely used as building blocks for the preparation of bioactive peptides [ (a) Garbay- Jaureguiberry et al., Int. J. Pept. Prot. Res. 39:523 (1992); (b) Kim et al., Int. J. Pept. Prot. Res. 44:457 (1994)]. For example, the corresponding amino acid of Compound 28v was used to replace tyrosine in a peptide to afford an improved β2 adrenergic receptor [Garbay-Jaureguiberry et al., Int. J. Pept. Prot. Res. 39:523 (1992)], whereas a tetrapeptide containing the corresponding amino acid of Compound 28w has been evaluated as a tyrosine kinase inhibitor [Kim et al., Int. J. Pept. Prot. Res. 44:457 (1994)].
Table 19
Substrate Scope of Aryl Iodides of Mono-Arylationa,jb
a Conditions: Substrate 25 (0.1 mmol), Pd(OAc)2 (10 mol %), AgOAc (0.2 mmol), Ar-I (0.15 mmol),
2-picoline (20 mol%), HFIP (1.0 mL) , 75 °C, 24 hours. b Isolated yields are shown. c Ar-I (0.3 mmol). d After C-H activation, the reaction mixture was subjected to PhI(OAc)2 (0.1 mmol), MeOH (1 mL) , 80 °C, 3 hours. Yields are for two steps.
Arylation with heteroaryl iodides
Heteroatoms in heterocycles usually coordinate strongly to Pd(II) catalysts and result in catalyst poisoning. This detrimental effect often prevents the use of heteroaryl iodides as coupling partners in C-H activation reactions. It was reasoned that the acidic solvent HFIP used in this protocol could weaken the coordinating ability of the heterocycles. Furthermore, the pyridine-type ligand picoline could potentially also out-compete the coordination of the heteroaryl iodides.
The reactivity of a wide range of heterocyclic iodides under the standard conditions was therefore examined. It was found that aryl iodides containing dioxane and chromonyl moieties were coupled with alanine substrate 25 successfully to give the desired products 30a and 30b in 76% and 70% yields respectively (Table 20) . Tosyl-protected indolyl and indazolyl iodides also afforded 30c-f in synthetically useful yields (58-65%) . These unnatural amino acids containing heteroaryls are not readily accessible via other methods [Tang et al., Chem. Rev. 103:3029 (2003)] and are often desirable in medicinal chemistry.
Table 20
Scope of Heteroaryl Iodide Couplings"4
"
3 Conditions: Substrate 25 (0.1 imol), Pd(0Ac)2 (10 mol%), AgOAc (0.2 mmol), Ar-I (0.15 mmol) , 2-picoline
(20 mol%), HFIP (1.0 mL) , 80 °C, 24 hours. b Isolated yields are shown. c Pd(OAc)2 (15 mol %) , 2-picoline
(30 mol%) . d Yields based on the amide and ester.
However, arylation with the more coordinative pyridyl iodide gave poor yields (less than 10%) . Considering that a halogen substituent at the 2-position of a pyridine can be readily removed or transformed to other functional groups, the reactivity of 2-fluoro, 2-chloro and 2-bromopyridyl iodides was tested. These coupling partners reacted with substrate 25 to give the desired products in approximately 20% yields under the standard conditions .
Through further ligand screening, 2,6-lutidine was identified as a more efficient ligand. Thus, arylations with a range of pyridyl iodides were carried out under the optimized conditions (Table 21) . Although 4-pyridyl iodide
gave poor yield (Compound 30g' ) , all 2-halo-pyridyl iodides afford synthetically useful yields (Compound 30h'-30m'). The arylated products were obtained as a mixture of amides and esters which are treated with PhI(0Ac)2 in one pot to provide the pure esters as the isolated products.
Arylation with pyridyl iodides containing 2-CF3, 2-Me and 2-OMe substituents proceeded to give the desired products in 42-66% yields. The presence of 3-CH2OH group reduced the yield to 32% (30r' ) · Various quinolinyl and quinoxalinyl iodides are also compatible with the protocol affording heterocycle- containing amino acids (30s'-30v') in moderate yields .
Table 21
Expanding the Scope of Heteroaryl Iodide Couplings3'*
Y L^,
"co2Me
304'
a Conditions: Substrate 25 (0.1 ramol) , Pd(OAc)2 (15 mol%), AgOAc (0.2 mmol), Ar-I (0.15 mmol) , Ligand (30 mol%), HFIP (1.0 mL) , 85 °C, 36 hours, and then PhI(OAc)2 (0.1 mmol), MeOH (1 mL) , 80 °C, 3 hours. * Isolated yields are shown. ° Substrate 25 (0.2 mmol), Ar-I (0.1 mmol), yield based on the Ar-I. d Lactone was first formed, then was converted to 30r' with MeS03H. For details, see supporting information.
Removal of the Auxilliary
Because N-alkoxyamides are used as masked esters, a number of deprotection procedures based on radical pathways have been developed (Eq 1) [ (a) Crawford et al., J. Org. Chem. 28:2419 (1963) (b) Cooley et al., J. Am. Chem. Soc. 90:1867 (1968); (c) De Almeida et al., J. Am. Chem. Soc. 117:4870 (1995); (d) Glover et al., Tetrahedron 55:3413 (1999); (e) Ka ase et al., J. Org. Chem. 54:3394 (1989); (f) Yus et al., Org. Lett. 14:5518 (2006); (g) For
N-methoxyamide as orfcho-lithiation directing group, see: Fisher et al., J. Org. Chem. 58:3643 (1993); (h) Zhang et al., J. Org. Chem. 78:8705 (2013)].
N, N-Bis-heteroatom-substituted amides formed from W-alkoxyamides can thermally decompose to give the corresponding esters .
A wide range of metal oxidants including silver oxide (Ag20) , nickel (IV) peroxide hydrate (Ni02'H20), eerie ammonium nitrate (CAN), and lead(IV) acetate [Pb(OAc) ] have been used to convert
W-alkoxyamides into esters [(a) Crawford et al . , J. Org. Chem. 28:2419 (1963) (b) Cooley et al., J. Am. Chem. Soc. 90:1867 (1968); (c) De Almeida et al., J. Am. Chem. Soc. 117:4870 (1995); (d) Glover et al., Tetrahedron 55:3413 (1999); (e) Kawase et al., J. Org. Chem. 54:3394 (1989); (f) Yus et al., Org. Lett. 14:5518 (2006); (g) For W-methoxyamide as ortho-
lithiation directing group, see: Fisher et al., J. Org. Chem. 58:3643 (1993)]. One-step conversion o N-alkoxyamides to esters by reaction with
W-bromosuccinimide (NBS) in toluene has also been reported [Zhang et al., J. Org. Chem. 78:8705 (2013) ] . W-Chlorohydroxamates generated from
AT-alkoxyamides can be converted to the esters by treating with sodium azide via Heron rearrangement (Eq 5) [ Glover et al., J. Chem. Soc, Perkin Trans 2002, 1728].
However, all of these protocols convert the amino acid-derived amides to esters in only moderate yields. It was found that reacting W-methoxyamides with iodosobenzene diacetate [PhI(OAc)2] in methanol at 80 °C afforded esters in excellent yields excluding indole-containing amides (Compounds 30c, 30d) , which suffered from partial intramolecular radical lactamization .
Lewis acid boron trifluoride diethyl etherate (Et20"BF3) was also identified as an efficient reagent to convert Itf-methoxyamides into esters in methanol at 90 °C. This latter protocol is also compatible with the indole-containing amides. Importantly, no racemization of the a-chiral center was observed during the C-H arylation and the subsequent removal of the auxiliary (Scheme) .
Following the development of mono-arylation of the primary C(sp3)-H bonds directed by
itf-methoxyamide, a search was begun for ligands that would promote further arylation of the methylene C-H bonds. The formation of 10% of the di-arylated product with the quinoline ligand L18 (Table 17) led to investigation of whether these conditions can be optimized for arylation of methylene C-H bonds (Table 22) .
Considering the previously observed significant effects of inorganic bases on the β-C-E functionalizations of itf-methoxyamides arylation with a wide range of base additives was investigated. Among the various potassium, sodium and lithium salts, monohydrogen phosphate (Table 22, entries 5 and 8) and dihydrogen phosphate (Table -22, entries 6, 9-11) significantly improved the yields of the arylation. Sodium dihydrogen phosphate was especially effective, affording the arylated product in 50% yield (Table 22, entries 9, 10) . Increasing the amount of sodium dihydrogen phosphate monohydrate (NaH2P04 · H20) to three equivalents improved the yield to 72% (Table 22, entry 15) .
Table 22
Additive Screening in the Arylation
28 HFIP, 100 °C, air, 36 h
Entry Additives (equiv) % Yield
1 no 10
2 K2C03 0
3 KHC03 8
4 K3PO4(0.5) 14
5 K2HP04 40
6 KH2P04 30
7 KF 16
8 Na2HP04 32
9 NaH2P0 -H20 50
10 NaH2P0 49
11 LiHzP04 36
12 LiOAc 0
13 NaH2P04-H20 (1.5) 56
14 NaH2P04-H20 (2) 66
15 NaH2P04-H20 (3) 72
16 NaH2P04-H20 (4) 70
Conditions : Substrate 28 (0. .1 itimol) , Pd(OAc)2 ( mol%), AgOAc (0.2 mmol) , p-Tol-I (0.3 mmol) , L18 (20 mol%), HFIP (1.0 mL) , 100 °C, 36 hours. b Determined by 1 NMR analysis of the crude product using CH2Br2 as an internal standard.
With this promising result in hand, screening of ligands (Table 22) began to further improve the arylation of phenylalanine 28. The dependence of this reaction on ligand was confirmed
by the complete loss of reactivity in the absence of a ligand. Whereas other quinoline-based ligands (L5, L19, L20) were all inferior to L18, 2,6-lutidine (L6) and 2 , , 6-trimethylpyridine (L28) proved to be superior ligands, affording the desired product in 92% and 86% yields respectively.
Table 22
Ligand Screening3'*
a Conditions: Substrate 28 (0.1 mmol) , Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), p-Tol-I (0.3 mmol), Ligand (20 mol%), HFIP (1.0 mL) , 100 °C, 36 hours. b Determined by 1H NMR analysis of the crude product using CH2Br2 as an internal standard.
The scope of this newly developed methylene C-H arylation was examined with a broad range of electron-rich and electron-poor aryl iodides (Table
23) . Aryl iodides containing electron-donating substituents at the ortho-, meta- and para-positions served as efficient coupling partners, affording the /?-arylated phenylalanine products in good to excellent yields (Compounds 31a-f) . Arylation of 28 with fluoro- and chloro-substituted aryl iodides proceeded to afford the desired products in 70-75% yields (Compounds 31g-i) . This reaction is also compatible with aryl iodides containing electron- withdrawing groups (Compounds 31j-m) . Arylation with naphthalene iodide and di-substituted aryl iodides also afforded synthetically useful yields (Compounds 31n-p) . In all cases, this arylation reaction affords excellent diastereoselectivity which can be explained by a previously isolated C-H cleavage intermediate from a related amide substrate [He et al., Science 343:1216 (2014)].
Table 23
Substrate Scope of Aryl Iodides in the Arylation of
Phenylalanine3
a Conditions: Substrate 28 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar-I (0.3 mmol), 2,6- lutidine (20 mol%), NaH2P04-H20 (0.3 mmol), HFIP (1.0 mL) , 100 °C, 36 hours. b Isolated yields are shown.
The removal of the auxiliary from the3-diaryl alanine products using PhI(OAc)2 often
resulted in the formation of a substantial amount of a lactamization side product. The use of Lewis acid Et20'BF3 proved to be effective in removing the auxiliary in high yields. Importantly, the enantiopurity of the a-chiral center was retained during both the C-H arylation step and the subsequent conversion of the amide to the corresponding ester (Scheme) .
Homo-diarylation of alanine
The recently identified 2,6-lutidine ligand was also applied to the arylation of alanine substrate 25 to obtain homo-diarylation products in one pot (Table 24) . Various 3-diaryl-a-araino acids (Compounds 31q-t) were synthesized in 63-75% yields. Considering the steric hindrance on the /3-carbon of these diarylated amino acids, it is believed that the corresponding chiral amino alcohols are highly valuable for the synthesis of bulky chiral bis (oxazoline) ligands.
Table 24
Homo-Diarylation of Alanine Substrate'
a Conditions: Substrate 25 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar-I (0.3 mmol), 2,6- lutidine (20 mol%), NaH2P04'H20 (0.3 mmol), HFIP (1.0 mL) , 100 °C, 36 hours. h Isolated yields are shown.
One-Pot Sequential Hetero-diarylation of Alanine
The exclusive mono-selectivity of 2-picoline-promoted /?-arylation of primary C-H bonds provides a possibility for achieving sequential arylation of alanine substrate Compound 25 with two different aryl iodides in one pot. Thus, Compound 25 was subjected to the mono-arylation conditions with 1.2 equiv. of 4-iodotoluene . After Compound 25 was completely arylated as shown by thin layer chromatography (TLC) , 3 equiv. of phenyl iodide (Phil as well as other reagents (2,6-lutidine, AgOAc, NaH2P0 «H20) required for the methylene C-H activation were added to the reaction to initiate the second arylation (Table 25) . This one-pot procedure afforded the hetero-diarylated product 31u in 71% yield.
The formation of homo-arylated product with 4-i'odotoluene was not observed suggesting that the
remaining aryl iodide from the first step was outcompeted by the excess phenyl iodide introduced in the second step. This protocol is also compatible with other combinations of a variety of aryl iodides, affording diverse range of hetero-diarylated products in 43-71% yields with excellent diastereoselectivity (Compounds 31u-ab) . The switching of the arylation order to access different diastereomers was also demonstrated with the preparation of Compounds 31w and 31x.
Given the availability of both enantiomers of the starting amino acids, all four diasteromeric products can be obtained by switching the order of addition of the two different aryl iodides. Overall, this protocol offers a highly versatile approach for the preparation of chiral β-Ατ-β-Ar ' -a-amino acids.
A sequential hetero-diarylation using a strongly coordinating bidentate directing group has also been demonstrated [Wang et al., Chem. Sci.
5:3952 (2014)], although the mono-arylated product needs to be isolated and subjected to different conditions to perform the second arylation. A recent report [Molinaro et al., J. Am. Chem. Soc. 137:999 (2015) ] on an improved synthesis of differentially substituted dehydro-/3, /3-diarylalanine derivatives and subsequent asymmetric hydrogenation also speaks to the need for efficient methods for preparing chiral β-Ατ-β-Ar ' -a-amino acids.
Table 25
Hetero-Diarylation of Alanine Substratea Hs1 γ ίΟΝΗΟΜβ
a Conditions: Substrate 25 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar^I (0.12 mmol), 2-picoline (20 mol%), HFIP (1.0 mL) , 75 °C, 24 hours. Then Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar2-I (0.3 mmol), 2,6-lutidine (20 mol%) , NaH2P04-H20 (0.3 mmol), 100 °C, 36 hours. b Isolated yields are shown.
Arylation of Other Carboxylic Acids
To demonstrate the generality of Ji-methoxyamide as a directing group for the arylation of C(sp3)-H bond, the arylation of other aliphatic acid substrates was also examined. Under the conditions for the /9-arylation of primary C-H bonds using 2-picoline as the ligand, amides derived from 2-methyl butyric acid, /^-hydroxy acid, /3-amino acid, and 2-aminoisobutyric acid afforded the arylated products in 53-72% yields (Table 26, Compounds 33a-
d) . Interestingly, arylation of the cyclobutyl C-H bonds in the amide substrate derived from 1-amino- cyclobutane-l-carboxylic acid afforded 86% yield under these conditions (Compound 33g) .
As expected, ?-arylation of amide substrates derived from tyrosine and L-2-aminobutyric acid only proceeded under the conditions developed for methylene C-H bonds (Compounds 33e-f) .
Surprizingly, cyclopropyl C-H bond in Compound 32h is less reactive under these conditions and requires the use of ligand L18 to permit the arylation to proceed in moderate yield (45%) .
Table 26
Arylation of Other Amino Acids and Carboxylic Acids3
a Isolated yields are shown. b Conditions: Substrate (0.2 mmol) , Pd(OAc)2 (10 mol%) , AgOAc (0.4 mmol) ,
p-Tol-I (0.3 mmol), 2-picoline (20 mol%) , HFIP (2.0 mL) , 80 °C, 24 hours. ° Conditions: Substrate (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), p-Tol-I
(0.3 mmol), 2,6-lutidine (20 mol%), NaH2P04'H20 (0.3 mmol), HFIP (1.0 mL) , 90 °C, 36 hours. d Substrate
(0.1 mmol), Pd(OAc)2 (15 mol%), AgOAc (0.2 mmol), p-Tol-I (0.3 mmol), L18 (30 mol %), TFA (20 mol %), DCE (1.0 mL), 85 °C, 36 hours.
Gram-scale syntheses of unnatural amino acids
The use of N-methoxyamide auxiliary has important advantages for gram-scale preparation of unnatural amino acids. Firstly, methoxyamine hydrochloride is inexpensive and has a low molecular weight. Secondly, the installation involves treatment of a carboxylic acid with oxalyl chloride and methoxyamine hydrochloride at room temperature to afford the itf-methoxyamides in nearly quantitative yields. Notably, the installation of other amide directing groups such as CONHArF (Arr = p-CF3C often requires refluxing conditions or proceeds in low yields. Furthermore, the removal of this auxiliary using Et2OBF3 or PhI(OAc)2 is highly reliable and high yielding with retention of stereochemistry at the acidic a-carbon center.
In response to needs for bioactive peptides from Bristol-Myers Squibb Co., alanine substrate 25 was coupled with fluorinated and trifluoromethylated aryl iodides (20 mmol scale) using 2-picoline as the ligand to give the mono-arylated products in excellent yields (Scheme below) .
The resulting crude products were treated with PhI(OAc)2 in methanol to afford the esters in 85- 98% yields over two steps. The phthalimide group was
removed in presence of ethylenediamine to generate the free amines that were subsequently converted to Fmoc-protected amino esters. Finally, the esters were hydrolyzed in presence of lithium hydroxide to give 7.5-9.0 grams of the desired amino acids (Compounds 34-36) in 50-55% overall yields.
The less reactive heteroaryl iodides and trifluoro-aryl iodide were also successfully coupled with alanine 25 using 2 , 6-lutidine. Following a similar procedure, 1.1-6.0 grams of these desired Fmoc-protected amino acids were prepared (Compounds 37-40)
34, 35, 36,
Diverse Synthetic Applications
The practical advantage of the
Af-methoxyamide auxiliary is further demonstrated by its versatile transformations to various biologically active compounds (Scheme below) . Radical cyclization of 28e with [bis (trifluoroacetoxy) iodo]benzene (PIFA) led to a lactam [Amano et al . , Synlett (2008) 134] and subsequent deprotection of the phthalamide using ethylenediamine afforded Compound 41 as a key intermediate for the synthesis of glycogen
phosphorylase inhibitors [Birch et al., Bioorg. Med. Chem. Lett. 17:394 (2007)].
Conversion of Compound 28e to carboxylic acid and subsequent treatment with oxalyl chloride and aluminum trichloride gave the 2-amino-l-indanone 42 [McClure et al . , J. Org. Chem. 48:2675 (1983)], a key intermediate of αχ-adrenoceptor antagonists [Li et al., Chem Biol Drug Des (2007) 70:461 (2007)]. The amino ester 43 derived from 28e was readily converted
to Fmoc-protected unnatural amino acid 44 as a useful building block for peptide synthesis. Through the Pictet-Spengler reaction, Compound 43 could be also converted to a chiral tetrahydroisoquinoline Compound 45, a known Itf-methyl-D-aspartate (NMDA) agonist
[Ortwine et al., J. Med. Chem. 35:1345 (1992)]. A chiral bioactive indoline 46 [Stoddart et al., J. Chem. Biol. (2012) 19:1105 (2012)] could also be synthesized via the previously-developed
intramolecular C-H amination reaction of sulfonyl protected Compound 44 [Mei et al., Org. Lett. 15:3058
The AT-methoxyamide auxiliary also gives access to I\?-hydroxy-3-amino-3, 4-dihydroquinolinone class of compounds. First reported by Davis and coworkers over thirty years ago, they were shown to exhibit antibacterial activity [(a) Davis et al . , J.
Med. Chem. 7:632 (1964); (b) Davis et al., J. Med. Chem. 18:752 (1972)]. More recently, similar scaffolds have been identified as potent inhibitors of ΚΆΤ II, an enzyme currently being investigated as a therapeutic target for cognitive impairment associated with schizophrenia, among other disorders [(a) McAllister et al., J. Org. Chem. 76:3484 (2011);
(b) Dounay et al., ACS Med. Chem. Lett. 3:187 (2012);
(c) Tuttle et al., ACS Med. Chem. Lett. 4:37 (2013)]. Using the above protocols, arylation followed by a known radical cyclization, provided medicinally important analogues of W-methoxy-3-amino-3, 4- dihydroquinolines 41', and Compounds 47-49 were prepared in a straightforward manner (Table 27).
Table 27
3 Conditions for cyclization: Substrate, PIFA (2 equiv.), DCM, 0 °C to r.t. b Isolated yields are shown .
Chiral amino alcohols derived from chiral amino acids are essential building blocks for the preparation of chiral ligands. For example, the
sterically hindered chiral amino alcohol derived from tert-leucine is a key precursor for the synthesis of one of the most effective chiral oxazoline ligands in asymmetric catalysis. β-Αΐ-β-Άτ ' -α-amino acids prepared via the recently developed procedure can be readily reduced to the corresponding chiral amino alcohols containing two chiral centers that are previously difficult to make (Scheme) . Thus, employing the hetero-diarylation protocol above, Compound 31z was obtained in moderate yields via a two steps, one-pot procedure on a 10 mmol scale. Hydrolysis of the amide group to ester followed by removal of the phthalimide protecting group led to the amino ester 51, which was reduced to the amino alcohol 52 in 75% yield.
From this common intermediate, Compound 52, PyBox ligand Compound 53 and Box ligand Compound 54 were successfully prepared [Cornejo et al., Synlett 2321 (2005)]. It is believed that these novel chiral bis (oxazoline) ligands will display interesting and useful properties in asymmetric catalysis. The potential impact of the additional chiral centers of ligand Compounds 53 and 54 on asymmetric catalysis is also intriguing.
Scheme
Conclusion
During the past decade-long efforts to develop a simple and practical auxiliary or directing group for β-C-R functionalizations of carboxylic acids, research focus has been on the use of relatively weak coordination from the substrates to direct metalation, and to match that weak
coordination with ligand development to enhance the reactivity. The simple ff-methoxyamide group, initially used as a masked ester, has been reinvented as a broadly useful directing group for β-C-R
arylation with the assistance of pyridine-type ligands. 2-Picoline promotes the mono-selective arylation of primary C(sp3)-H bonds, whereas
2,6-lutidine enables the subsequent arylation of secondary C(sp3)-H bonds in one pot. This new method is extensively applied to gram-scale synthesis of novel, unnatural amino acids, as well as bioactive compounds and chiral bis (oxazoline) ligands.
Experimental Section
General procedure for monoarylation with aryl iodides
The starting material Compound 25 (0.1 mmol, 24.8 mg) , Pd(OAc)2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol), 2-picoline (20 mol%, 2 μΐ,) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent.
General procedure for monoarylation with heterocyclic iodides:
Method A
The starting material 25 (0.1 mmol, 24.8 mg) , Pd(OAc)2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol,
33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol) , 2-picoline (20 mol%, 2 L) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room
temperature for 10 minutes and then heated to 80 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent.
Method B
The starting material 25 (0.1 mmol, 24.8 mg), Pd(OAc)2 (15 mol%, 3.3 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol),
2,6-lutidine (30 mol%, 3 pL) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 80 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was added PhI(OAc)2 (0.1 mmol, 32.2 mg) and MeOH (1 mL) in a sealed tube (10 mL) with a magnetic stir bar. The reaction mixture was heated to 80 °C for 3 hours. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced
pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent.
Method C
The starting material Compound 25 (0.2 mmol, 49.6 mg) , Pd(0Ac)2 (15 mol%, 3.3 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.1 mmol),
2,6-lutidine (30 mol%, 3 pL) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 80 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was added Phi (OAc) 2 (0.1 mmol, 32.2 mg) and MeOH (1 mL) in a sealed tube (10 mL) with a magnetic stir bar. The reaction mixture was heated to 80 °C for 3 hours. Upon completion, the reaction mixture was cooled to room temperature^ filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent.
General procedure for arylation of phenylalanine:
The substrate Compound 28 (O.lmmol, 32.4 mg) , Pd(OAc)2 (10 mol%, 2.2 mg) , NaH2P04-H20 (0.3 mmol, 42 mg) and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl
iodide (0.3 mmol), 2,6-lutidine (20 mol%, 2 pL) , and HFIP (1 mil ) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
General procedure for large scale of mono- arylation step:
The starting material 25 (10.0 mmol, 2.48 g) , Pd(0Ac)2 (1.50 mmol, 337 mg) , and AgOAc (20.0 mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (15 mmol) , ligand (3.00 mmol), and HFIP (100 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and recovered for next time use. The resulting mixture was added PhI(OAc)2 (10 mmol, 3.22 g) and MeOH (100 mL) in a sealed tube (350 mL) with a magnetic stir bar. The reaction mixture was heated to 80 °C for 3 hours. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash
chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent.
General procedure for one pot synthesis of /3-Ar-/3-Ar ' -a-amino acids:
The starting material (0.1 mmol, 24.8 mg) , Pd(OAc)2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, the first aryl iodide (0.12 mmol),
2-picoline (20 mol%, 2 L) , HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, to the reaction mixture, Pd(OAc)2 (0.01 mmol, 2.2 mg) , NaH2P04'H20 (0.3 mmol, 42 mg) , AgOAc (0.2 mmol, 33.4 mg) , the second aryl iodide (0.3 mmol) and 2,6-lutidine (0.2 mmol, 2 μΐι) , were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
MATERIALS AND METHODS
General Information
Solvents were obtained from Sigma-Aldrich, Alfa-Aesar and Acros and used directly without
further purification. Carboxylic acids and carboxylic acid chlorides were obtained from the commercial sources or synthesized following literature procedures, and used to prepare the corresponding amides. Amino acids and 2,3,5,6- tetrafluoro-4- (trifluoromethyl) aniline were obtained from the commercial sources or synthesized following literature procedures, and used to prepare the corresponding amides.
Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254.
Visualization was carried out with UV light and Vogel's permanganate.
1H NMR spectra were recorded on Bruker AMX- 400 instrument (400 MHz) or Bruker DRX-600 instrument
(600 MHz) . When the ½ NMR solvent was CDC13, chemical shifts were quoted in parts per million
(ppm) referenced to 0.00 ppm for tetramethylsilane; When the 1U NMR solvent was MeOD, chemical shifts were quoted in parts per million (ppm) referenced to 3.31 ppm for solvent MeOD; When the XH NMR solvent was Acetone-d-6, chemical shifts were quoted in parts per million (ppm) referenced to 2.05 ppm for solvent Acetone-d-6. The following abbreviations (or combinations thereof) were used to explain
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constants, J, were reported in Hertz unit
(Hz) .
13C NMR spectra were recorded on Bruker AMX- 400 instrument (100 MHz) or Bruker DRX-600 instrument (150 MHz), and were fully decoupled by broad band proton decoupling. Chemical shifts were reported in parts per million (ppm) referenced to the center line
of a triplet at 77.0 ppm of chloroform-d. When the 13C NMR solvent was MeOD, chemical shifts were quoted in ppm referenced to 49.1 ppm for solvent MeOD; When the 13C NMR solvent was Acetone-d-6, chemical shifts were quoted in parts per million (ppm) referenced to 29.9 ppm for solvent Acetone-d-6. In the 13C NMR analysis, peaks that correspond to those of the polyfluoroarylaniide auxiliary appeared as nearly invisible, complex sets of multiplets; they are omitted in the following spectroscopic analysis.
High-resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI- TOF (electrospray ionization-time of flight) .
Enantiomeric excesses values were determined on a Hitachi LaChrom Elite® HPLC system using commercially available chiral columns. Optical rotation data were obtained on a Perkin-Elmer 341 polarimeter. Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus .
Experimental Section
A. Substrate Preparation
General Procedure for the Preparation of Amide Substrates
To a 100 mL round-bottom flask were added the appropriate amino acid (20 mmol) , finely ground phthalic anhydride (20 mmol or 40 mmol in the
synthesis of lysine derivatives), toluene (45 mL) , and triethylamine (20 mmol, 2.8 mL) . After refluxing the reaction mixture overnight (about 18 hours), the crude product was evacuated and dissolved in DCM. After adding concentrated hydrochloric acid (0.4 mL) , the mixture was washed by water (50 mL) and dried over anhydrous Na2SC . The organic solvent was removed to give the phthalimido-protected amino acid.
Phthalimido-protected amino acid (10 mmol) , thionyl chloride (25 mmol) and several drops of DMF were added in toluene at 80 °C for 3 hours. After the reaction, the excess of thionyl chloride was removed in vacuo, and the crude acid chloride was added to a vigorously stirring solution of 2,3,5,6- tetrafluoro-4- (trifluoromethlyl) aniline (10 mmol) in toluene (8 mL) . The reaction mixture was stirred for 12 hours under reflux, and then stirred at room temperature for 0.5 hours. The product mixture was concentrated in vacuo and was recrystallized from ethyl acetate/hexane to provide the amide.
(S) -2-Phthalimido-Zi- (2,3,5, 6-tetrafluoro-4- ( rifluoromethy1) henyl) ropanamide (1)
½ NMR (600 MHz, CDC13) δ 8.39 (br s, 1H) , 7.87-7.84 (m, 2H) , 7.78-7.75 (m, 2H) , 5.15 (q, J = 7.2 Hz, 1H) , 1.79 (d, J= 7.2 Hz, 3H) ; 13C NMR (150 MHz, CDC13) 8167.7, 167.5, 134.6, 131.4, 123.8, 49.9, 15.5; HRMS (ESI-TOF) Calcd for C18HioF7 203 [M+H] + : 435.0574;
found: 435.0574. The ee value was determined by HPLC analysis on a Chiralcel OD-H column (20%
isopropanol/hexanes , 0.5 mL/min) with tr 30.5 min (major), 56.1 min (minor): 97% ee.
(S) -3-Phenyl-2-phthalimxdo-N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) henyl) propanamxde (2)
1H NMR (400 MHz , CDC13) δ 8.50 (br s, 1H) , 7.83-7.78 (m, 2H) , 7.75-7.71 (m, 2H) , 7.23-7.13 (m, 5H) , 5.34 (dd, Ji = 6.4 Hz, J2 = 10.4 Hz, 1H) , 3.64 (ABqd, Jx = 6.4 Hz, J2 = 14.2 Hz, 1H) , 3.58 (ABqd, Ji = 10.4 Hz, J2 = 14.2 Hz, 1H) ; 13C NMR (100 MHz, CDC13) 5168.0, 166.6, 135.4, 134.7, 131.0, 128.9, 128.8, 127.4, 123.8, 56.6, 35.3; HRMS (ESI-TOF) Calcd for C24Hi4F7 203 [M+H]+: 511.0887; found: 511.0883.
(S) -2 , 6-Bis (phthalimido) -N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) hexanamide (5a)
¾ NMR (400 MHz, CDCI3) δ 8.68 (br s, 1H) , 7.91-7.87 (m, 2H) , 7.82-7.77 (m, 4H) , 7.73-7.70 (m, 2H) , 5.04 (dd, Jx = 6.4 Hz, J2 = 9.6 Hz, 1H) , 3.70 (t, J= 7.0 Hz, 2H) , 2.49-2.32 (m, 2H) , 1.82-1.74 (m, 2H) , 1.50- 1.38 (m, 2H) ; 13C NMR (150 MHz, CDC13) 5168.5, 168.2, 166.8, 134.7, 134.0, 131.9, 131.3, 124.0, 123.2, 55.3, 36.9, 28.6, 27.5, 23.2; HRMS (ESI-TOF) Calcd for C29Hi9F7N305 [M+H]+: 622.1207; found: 622.1203.
(S) -2-Phthalimido-N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) butanamide (5b)
¾ NMR (400 MHz, CDC13) δ 8.68 (br s, 1H) , 7.95-7.91 (m, 2H) , 7.83-7.79 (m, 2H) , 5.00 (dd, Jx = 6.8 Hz, J2 = 9.6 Hz, 1H) , 2.42-2.25 (m, 2H) , 1.02 (t, J= 7.4 Hz, 3H) ; 13C NMR (100 MHz, CDC13) δ 168.3, 167.1, 134.8, 131.2, 123.9, 57.1, 22.9, 10.6; HRMS (ESI-TOF) Calcd for C19Hi2F7N203 [M+H] +: 449.0731; found: 449.0733.
l-Phthalimido-tf- (2,3,5, 6-tetrafluoro-4-
(trifluoromethyl) phenyl) cyclobutaneoarboxamide (5c)
JH NMR (400 MHz, CDC13) δ 8.23 (br s, 1H) , 7.89-7.85 (m, 2H) , 7.79-7.76 (m, 2H) , 3.14-3.09 (m, 2H) , 2.84- 2.75 (m, 2H) , 2.19-2.00 (m, 2H) ; 13C NMR (100 MHz, CDCI3) 8169.1, 168.0, 134.6, 131.5, 123.5, 60.8, 31.6, 17.3; HRMS (ESI-TOF) Calcd for C2oHi2F7N203
[M+H]+: 461.0731; found: 461.0727.
1-Phthalimido-W- (2,3,5, 6-tetrafluoro-4-
(trifluoromethyl) henyl) cyclopropanecarboxamide (5d)
*H NMR (600 MHz, CDC13) δ 7.94-7.91 (m, 2H) , 7.84-7. (m, 2H) , 7.50 (br s, 1H) , 1.97 (dd, Jx = 5.4 Hz, J2 9.0 Hz, 2H) , 1.50 (dd, Ji = 5.4 Hz, J2 = 9.0 Hz, 2H) 13C NMR (150 MHz, CDCI3) 6168.0, 135.0, 131.2, 124.0 33.5, 17.3; HRMS (ESI-TOF) Calcd for Ci9H9F7N203Na [M+Na]+: 469.0394; found: 469.0389.
3,3, 3-Trideuterio-2-methyl-W~ (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) henyl) ropionamide (21)
½ NMR (600 MHz, CDCI3) δ 7.00 (br s, 1H) , 2.67 (q, J = 7.2 Hz, 1H) , 1.31 (d, J= 7.2 Hz, 3H) ; 13C NMR (150 MHz, CDCI3) 5174.6, 35.6, 19.3; HRMS (ESI-TOF) Calcd for CuH6D3F7N0 [M+H]+: 307.0752; found: 307.0754.
Me
N O Me
L10
2 , 5-Dimethyl-3 , 4-dihydro-2H-pyrano [2 , 3-£>] quinoline (L10)
L10 was synthesized according to the literature procedure [Zhang et al., Org. Lett.
9:3651-3653 (2007)]. ¾ NMR (400 MHz, CDC13) δ 7.89 (d, J = 8.4 Hz, 1H) , 7.83 (d, J= 8.4 Hz, 1H) , 7.59- 7.55 (m, 1H), 7.39-7.35 (m, 1H) , 4.42-4.35 (m, 1H) , 3.04-2.98 (m, 1H) , 2.92-2.83 (m, 1H) , 2.56 (s, 3H) , 2.18-2.12 (m, 1H) , 1.90-1.76 (m, 1H) , 1.52 (d, J = 6.4 Hz, 3H) .
9-Fluoro-2 ,5-dimethyl-3 , 4-dihydro-2H-pyrano [2 , 3- b]quinoline (Lll)
Lll was synthesized according to the literature procedure [Zhang et al., Org. Lett.
9:3651-3653 (2007)]. *H NMR (400 MHz, CDC13) δ 7.69- 7.61 (m, 1H) , 7.31-7.25 (m, 2H) , 4.44-4.36 (m, 1H) , 3.04-2.98 (m, 1H) , 2.92-2.84 (m, 1H) , 2.55 (s, 3H) , 2.19-2.13 (m, 1H) , 1.91-1.76 (m, 1H) , 1.52 (d, J = 6.4 Hz, 3H) .
L12
7-Methoxy-2 , 5-dimethyl-3 , 4-dihydro-2H-pyrano [2 , 3- b]quinoline (L12)
L12 was synthesized according to the literature procedure [Zhang et al., Org. Lett.
9:3651-3653 (2007)]. ¾ NMR (400 MHz, CDC13) δ 7.74 (d, J = 8.8 Hz, 1H) , 7.24 (d, J = 8.8 Hz, 1H) , 7.12 (s, 1H) , 4.40-4.34 (m, 1H) , 3.93 (s, 3H) , 3.02-2.96 (m, 1H) , 2.90-2.82 (m, 1H) , 2.53 (s, 3H) , 2.18-2.11 (m, 1H), 1.90-1.75 (m, 1H) , 1.52 (d, J= 6.4 Hz, 3H) .
B. Ligand-Promoted Primary C(sp3)-H Arylation
Screening studies were carried out using (S) -2-phthalimido-W- (2, 3, 5, 6-tetrafluoro-4- (trifluoromethyl ) henyl) propanamide (Compound 1) (43.4 mg, 0.1 mmol) as the substrate and iodobenzene. The conditions for each trial are specified in Tables 13 and 14 below. All yields were determined by analysis of the crude 1E NMR (CDCI3) spectrum using CH2Br2 as the internal standard after filtration of the reaction mixture through a pad of silica gel.
Table 13
2: 47% 29% 52% 65% 87%
2: 88% 94% 76%
2: 77% 79% 91%
2: 59% 83% 66%
3: 1% 17% 3%
Table 14
Entry Pd catalyst (mol%) (mol%) Ag salt (equiv) Temp. (°C) 1 H NMR yleld (%)
1 none 20 Ag2C03(1.5) 100 0 0
2 Pd(TFA)2 (10) 20 Ag2C03(1.5) 100 94 2
3 Pd(TFA)2(10) 40 Ag2C03(1.5) 100 60 0
4 Pd(TFA)2 (5) 10 Ag2C03(1.5) 100 79 2
5 Pd(OAo)2 (10) 20 Ag2C03(1.5) 100 80 10
6 Pd(TFA)2(10) 20 Ag3PO,(1.5) 100 82 2
7 Pd(TFA)2(10) 20 Ag2C03(1) 100 75 2
8 Pd(TFA)2( 0) 20 AgOAc (3) 100 45 1
9 Pd(TFA)2 ( 0) 20 AgTFA (3) 100 0 0
10 Pd(TFA)2(10) 20 none 100 0 0
11 Pd(TFA)2(10) 20 Ag2C03(1.5) 90 53 1
12 Pd(TFA)2(10) 20 Ag2C03(1.5) 80 32 0
13 Pd(TFA)2(10) 0 Ag2C03(1.5) 100 47 1
14 Pd(TFA)2 (20) 0 Ag2C03(1.5) 100 55 1
15 Pd(TFA)2 (30) 0 Ag2C03(1.5) 100 52 1
16 Pd(TFA)2(10) 0 Ag2C03(1,5) 100 32* N/A
General Procedure Scheme A
General Arylation Procedure A
Substrate Compound 1 (0.1 mmol, 43.4 mg) , Pd(TFA)2 (0.01 mmol, 3.3 mg) , and Ag2C03 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. The aryl iodide (0.15 mmol), 2-picoline (0.02 mmol, 2
μΙ , TFA (0.02 mmol, 2 μΐ) , and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/EtOAc or hexane/EtOAc as the eluent.
(S) -3-Phenyl-2-phthalimido-N- (2 , 3 , 5, 6-tetrafluoro-4- { rifluoromethyl) henyl) ropanamide (2 )
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1E NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc mixtures (30/1) as the eluent, Compound 2 was obtained as a white solid (45.2 mg, 89%, 97% ee) . The ee value was determined by HPLC analysis on a Chiralcel OD-H column (20% isopropanol/hexanes, 0.5 mL/min) with tr 51.4 min (major), 64.1 min (minor). ¾ NMR (600 MHz, CDC13) δ 8.48 (br s, 1H) , 7.84-7.81 (m, 2H) , 7.76-7.73 (m, 2H), 7.23-7.18 (m, 4H) , 7.17-7.15 (m, 1H) , 5.35 (dd, Ji = 6.6 Hz, J2 = 10.8 Hz, 1H) , 3.64 (ABqd, Ji = 6.6 Hz, J2 = 14.2 Hz, 1H) , 3.59 (ABqd, J = 10.8 Hz, J2 = 14.2 Hz, 1H) .
(S) -2-Pht alimido-2i- (2 , 3 , 5 , 6-tetrafluoro-4-
(trifluoromethyl) henyl) -3- (p-tolyl) propanamide (2a)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by ½ NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2a was obtained as a white solid (48.1 mg, 92%). 1H NMR (600 MHz, CDC13) δ 8.46 (br s, 1H) , 7.83-7.81 (m, 2H) , 7.76-7.73 (m, 2H) , 7.09 (d, J = 7.8 Hz, 2H) , 7.02 (d, J= 7.8 Hz, 2H) , 5.32 (dd, ^ = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.60 (ABqd, Ji = 6.6 Hz, j2 = 14.4 Hz, 1H) , 3.54 (ABqd, <¾ = 10.2 Hz, J2 = 14.4 Hz, 1H) , 2.23 (s, 3H) ; 13C NMR (150 MHz, CDC13) 5168.1, 166.7, 137.1, 134.7, 132.2, 131.1, 129.6, 128.7, 123.8, 56.7, 34.9, 21.0; HRMS (ESI-TOF) Calcd for C25Hi6F7N203 [M+H]+: 525.1044; found: 525.1049.
(S) -3- (4-Methoxyphenyl) -2-phthalimido-IT- (2,3,5,6- te rafluoro- - (trifluoromethyl) phenyl) ropanamide (2b)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by XH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by
column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2b was obtained as a white solid (48.2 mg, 89%). ¾ NMR (600 MHz, CDC13) δ 8.52 (br s, 1H) , 7.81-7.80 (m, 2H) , 7.74-7.72 (m, 2H) , 7.11 (d, J = 7.8 Hz, 2H) , 6.73 (d, J = 7.8 Hz, 2H) , 5.29 (dd, J2 = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.71 (s, 3H) , 3.57 (ABqd, Ji = 6.6 Hz, J2 = 14.4 Hz, 1H) , 3.52 (ABqd, Ji = 10.2 Hz, J2 = 14.4 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 5168.1, 166.7, 158.7, 134.7, 131.1, 129.9, 127.3, 123.8, 114.2, 56.7, 55.1, 34.5; HRMS (ESI-TOF) Calcd for C25Hi6F7N204 [M+H]+: 541.0993; found: 541.0994.
(S) -3- (3-Methoxyphenyl) -2-phthalimido-Ii- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (2c)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2c was obtained as a white solid
(46.6 mg, 86%). ¾ NMR (600 MHz, CDC13) δ 8.49 (br s, 1H) , 7.82-7.79 (m, 2H) , 7.75-7.73 (m, 2H) , 7.12-7.09
(m, 1H), 6.77 (d, J = 7.2 Hz, 1H) , 6.73-6.72 (m, 1H) , 6.70-6.68 (m, 1H) , 5.35 (dd, Ji = 6.3 Hz, J2 = 10.5 Hz, 1H) , 3.67 (s, 3H), 3.61 (ABqd, Ji = 6.3 Hz, J2 = 14.4 Hz, 1H) , 3.56 (ABqd, Jx = 10.5 Hz, J2 = 14.4 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 5168.0, 166.6, 159.8, 137.0, 134.7, 131.1, 129.9, 123.8, 121.1, 114.1,
113.3, 56.4, 55.1, 35.3; HRMS (ESI-TOF) Calcd for C25H16F7 2O4 [M+H] + : 541.0993; found: 541.0989.
Large scale reaction: Substrate Compound 1
(10 mmol, 4.34 g) , Pd(TFA)2 (1.0 mmol, 0.33 g) , and Ag2C03 (15 mmol, 4.14 g) were weighed in air and placed in a round-bottom flask (100 mL) with a magnetic stir bar. 3-Iodoanisole (15 mmol, 3.51 g) , 2-picoline (2.0 mmol, 0.19 g) , TFA (2.0 mmol, 0.23 g) , and DCE (35 mL) were added. The pressure vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C. Upon completion, the reaction mixture was purified by a silica gel-packed flash chromatography column, and Compound 2c was obtained in 87% yield
(4.69 g) .
(S) -3- (2-Methoxyphenyl) -2-phthalimido-W- (2,3,5,6- tetrafluoro- - (trifluoromethyl) henyl) ropanamide (2d)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by ¾ NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2d was obtained as a white solid
(47.3 mg, 88%). JH NMR (600 MHz, CDCI3) δ 8.53 (br s, 1H), 7.80-7.78 (m, 2H) , 7.73-7.70 (m, 2H) , 7.17-7.14
(m, 1H) , 7.08-7.06 (m, 1H) , 6.78 (d, J = 7.8 Hz, 1H) , 6.76-6.74 (m, 1H) , 5.47 (dd, Ji = 5.7 Hz, J2 = 9.9 Hz, 1H) , 3.77 (s, 3H) , 3.65 (ABqd, Ji = 5.7 Hz, J2 = 14.1
Hz, 1H) , 3.50 (ABqd, Ji = 9.9 Hz, J2 = 14.1 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 5167.9, 166.9, 157.3, 134.4, 131.3, 130.9, 128.9, 124.0, 123.6, 120.7, 110.4, 55.2, 54.6, 30.9; HRMS (ESI-TOF) Calcd for C25Hi6F7ISI204 [M+H]+: 541.0993; found: 541.0993.
Large scale reaction: Substrate Compound 1 (15 mmol, 6.51 g) , Pd(TFA)2 (1.5 mmol, 0.50 g) , and Ag2C03 (22.5 mmol, 6.12 g) were weighed in air and placed in a round-bottom flask (100 mL) with a magnetic stir bar. 2-Iodoanisole (22.5 mmol, 5.27 g) , 2-picoline (3.0 mmol, 0.28 g) , TFA (3.0 mmol, 0.34 g) , and DCE (50 mL) were added. The pressure vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C. Upon completion, the reaction mixture was purified by a silica gel-packed flash chromatography column, and Compound 2d was obtained in 80% yield (6.48 g) .
(S) -3- (4-Fluorophenyl) -2-phthalimido-W- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) ropanamide (2e)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by XH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) mixtures as the eluent, Compound 2e was obtained as a white solid (47.4 mg, 90%). XH NMR (600 MHz, CDC13) δ
8.54 (br s, 1H) , 7.82-7.79 (m, 2H) , 7.76-7.73 (m, 2H) , 7.16-7.13 (m, 2H) , 6.90-6.86 (m, 2H) , 5.29 (dd, Ji = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.60 (ABqd, Jx = 6.6 Hz, J2 = 14.4 Hz, 1H) , 3.56 (ABqd, Ji = 10.2 Hz, J2 = 14.4 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 8168.0, 166.5, 162.0 (d, JFC = 244.5 Hz), 134.8, 131.1 (d, JFC = 3.3 Hz), 130.9, 130.5 (d, J" FC = 8.0 Hz), 123.9, 115.7 (d, JFC = 21.2 Hz), 56.4, 34.4; HRMS (ESI-TOF) Calcd for C24H13 8N2O3 [M+H] + : 529.0793; found: 529.0793.
(S) -3- (3-Fluorophenyl) -2-phthalimido-N- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (2f)
Substrate Compound 1 was arylated following the general arylatxon procedure A. Analysis of crude reaction mixture by ¾ NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2f was obtained as a white solid (44.1 mg, 84%). ¾ NMR (600 MHz, CDC13) δ 8.51 (br s, 1H), 7.82-7.79 (m, 2H) , 7.76-7.73 (m, 2H) , 7.19-7.15 (m, 1H) , 6.97 (d, J= 7.2 Hz, 1H) , 6.91-6.89 (m, 1H) , 6.87-6.83 (m, 1H) , 5-32 (dd, Ji = 6.0 Hz, J2 = 10.8 Hz, 1H) , 3.63 (ABqd, Ji = 6.0 Hz, J2 = 14.4 Hz, 1H) , 3.58 (ABqd, Ji = 10.8 Hz, J2 = 14.4 Hz, 1H) ; 13C NMR (150 MHz, CDCI3) 8167.9, 166.4, 162.8 (d, JFC = 245.4 Hz), 138.0 (d, JFC = 7.4 Hz), 134.8, 130.9, 130.3 (d, JFC = 8.3 Hz), 124.6 (d, JFC = 2.9 Hz), 123.9, 115.9 (d, J" FC = 21.3 Hz), 114.4 (d, JFC = 20.7 Hz), 56.1,
34.8; HRMS (ESI-TOF) Calcd for C24Hi3F8N203 [M+H]+: 529.0793; found: 529.0794.
(S) -3- (2-Fluorophenyl) -2-phthalimido-N- (2,3,5,6- tetrafluoro-4- (trxfluoromethyl) henyl) propanamide (2g)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2g was obtained as a white solid
(45.0 mg, 85%). ¾ NMR (600 MHz, CDC13) δ 8.46 (br s, 1H), 7.81-7.78 (m, 2H) , 7.74-7.71 (m, 2H) , 7.18-7.13
(m, 2H), 6.96-6.93 (m, 2H) , 5.36 (dd, Jx = 5.7 Hz, J2 = 10.5 Hz, 1H)\ 3.67 (ABqd, Jj = 5.7 Hz, J2 = 14.1 Hz, 1H) , 3.60 (ABqd, J = 10.5 Hz, J2 = 14.1 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 5167.8, 166.3, 161.3 (d, JFC = 244.7 Hz), 134.7, 131.3 (d, JFC = 4.5 Hz), 131.0, 129.4 (d, JFC = 8.1 Hz), 124.4 (d, JFC = 3.5 Hz), 123.8, 122.7 (d, JFC = 15.5 Hz), 115.5 (d, JFC = 21.6 Hz), 54.8, 29.2 (d, JFC = 2.1 Hz); HRMS (ESI-TOF) Calcd for C24Hi3F8N203 [M+H] + : 529.0793; found:
529.0789.
Large scale reaction: Substrate Compound 1
(10 mmol, 4.34 g) , Pd(TFA)2 (1.0 mmol, 0.33 g) , and Ag2C03 (15 mmol, 4.14 g) were weighed in air and placed in a round-bottom flask (100 mL) with a magnetic stir bar. l-Fluoro-2-iodobenzene (15 mmol,
3.33 g) , 2-picoline (2.0 mmol, 0.19 g) , TFA (2.0 mmol, 0.23 g) , and DCE (35 mL) were added. The pressure vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C. Upon completion, the reaction mixture was purified by a silica gel-packed flash chromatography column, and Compound 2g was obtained in 78% yield (4.11 g) .
(S) -3- (4-Chlorophenyl) -2-phthalimido-iT- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (2h)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by ¾ NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2h was obtained as a white solid
(46.1 mg, 85%). XH NMR (600 MHz, CDC13) δ 8.51 (br s, 1H) , 7.82-7.79 (m, 2H) , 7.76-7.73 (m, 2H) , 7.17 (d, J = 8.4 Hz, 2H) , 7.12 (d, J = 7.8 Hz, 2H) , 5.30 (dd, Jx = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.61-3.54 (m, 2H) ; 13C NMR (150 MHz, CDC13) 5168.0, 166.4, 134.8, 133.9, 133.3, 130.9, 130.2, 129.0, 123.9, 56.1, 34.5; HRMS
(ESI-TOF) Calcd for C24H13C1F7N203 [M+H]+: 545.0497; found: 545.0496.
Large scale reaction: Substrate Compound 1
(10 mmol, 4.34 g) , Pd(TFA)2 (1.0 mmol, 0.33 g) , and Ag2C03 (15 mmol, 4.14 g) were weighed in air and
placed in a round-bottom flask (100 mL) with a magnetic stir bar. l-Chloro-2-iodobenzene (15 mmol, 3.58 g) , 2-picoline (2.0 mmol, 0.19 g) , TFA (2.0 mmol, 0.23 g) , and DCE (35 mL) were added. The pressure vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C. Upon completion, the reaction mixture was purified by a silica gel-packed flash chromatography column, and Compound 2h was obtained in 78% yield (4.24 g) .
(S) -3- (4-Bromophenyl) -2~phthaliniido-ir- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) ropanamide (2i)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2i was obtained as a white solid
(50.7 mg, 86%). ¾ NMR (600 MHz, CDC13) δ 8.50 (br s, 1H), 7.82-7.80 (m, 2H) , 7.76-7.74 (m, 2H) , 7.32 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H) , 5.30 (dd, Ji = 6.9 Hz, J2 = 9.9 Hz, 1H) , 3.60-3.53 (m, 2H) ; 13C NMR
(150 MHz, CDC13) 5167.9, 166.4, 134.9, 134.4, 131.9, 130.9, 130.6, 123.9, 121.4, 56.1, 34.6; HRMS (ESI- TOF) Calcd for C24Hi3BrF7 203 [M+H] + : 588.9992; found: 588.9999.
(S) -2-Phthalimido-N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) -3- (4- (trifluoromethyl) - pheny1) ropanamide (2j)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2j was obtained as a white solid (49.5 mg, 86%). λΗ NMR (600 MHz, CDC13) δ 8.45 (br s, 1H) , 7.83-7.81 (m, 2H) , 7.77-7.75 (m, 2H) , 7.47 (d, J = 8.4 Hz, 2H) , 7.32 (d, J = 8.4 Hz, 2H) , 5.30 (dd, Ji = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.72-3.64 (m, 2H) ; 13C NMR (150 MHz, CDC13) 5167.9, 166.2, 139.6, 134.9, 130.8, 129.7 (q, JFC = 32.3 Hz), 129.3, 125.7 (q, JFC = 3.8 Hz), 124.0, 123.9 (q, JFC = 270.5 Hz), 55.9, 34.9; HRMS (ESI-TOF) Calcd for C25H13 F10N2O3 [M+H] + : 579.0761; found: 579.0767.
(S) -Methyl 4- (3-oxo-2-phthalimido-3- ( (2,3,5,6- tetrafluoro-4- (trifluoromethyl)phenyl) amino) - propyl) benzoate (2k)
Substrate Compound 1 was arylated followin the general arylation procedure A. Analysis of crud reaction mixture by ¾ NMR showed a > 20:1 ratio of
mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2k was obtained as a white solid
(49.5 mg, 87%). ½ NMR (600 MHz, CDC13) δ 8.50 (br s, 1H) , 7.86 (d, J= 7.8 Hz, 2H) , 7.81-7.79 (m, 2H) , 7.74-7.73 (m, 2H) , 7.27 (d, J = 7.8 Hz, 2H) , 5.36
(dd, Ji = 7.5 Hz, J2 = 9.3 Hz, 1H) , 3.85 (s, 3H) , 3.72-3.64 (m, 2H) ; 13C NMR (150 MHz, CDC13) 5167.9, 166.7, 166.3, 140.8, 134.9, 130.9, 130.1 , 129.2 , 129.0, 124.0, 56.0, 52.1, 35.1; HRMS (ESI-TOF) Calcd for C26Hi6F7N205 [M+H]+: 569.0942; found: 569.0940.
(S)-Methyl 3- (3-oxo-2-phthalimido-3- ( (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) amino) - propyl) benzoate (21)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by XH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 21 was obtained as a white solid
(50.0 mg, 88%). JH NMR (400 MHz, CDC13) δ 8.58 (br s, 1H) , 7.85-7.77 (m, 4H) , 7.75-7.70 (m, 2H) , 7.41-7.38
(m, 1H) , 7.30-7.26 (m, 1H) , 5.34 (dd, Ji = 6.0 Hz, J2 = 10.4 Hz, 1H), 3.80 (s, 3H) , 3.69 (ABqd, Jx = 6.2 Hz, J2 = 14.3 Hz, 1H) , 3.63 (ABqd, Ji = 10.4 Hz, J2 = 14.3 Hz, 1H) ; 13C NMR (100 MHz, CDC13) δ 167.9, 166.6, 166.4, 136.0, 134.7, 133.5, 131.0, 130.5, 130.0, 128.9, 128.6, 123.9, 56.2, 52.1, 34.9; HRMS (ESI-TOF)
Calcd for C26Hi6F7N205 [M+H]+: 569.0942; found:
569.0941.
Large scale reaction: Substrate Compound 1 (10 mmol, 4.34 g) , Pd(TFA)2 (1.0 mmol, 0.33 g) , and Ag2C03 (15 mmol, 4.14 g) were weighed in air and placed in a round-bottom flask (100 mL) with a magnetic stir bar. Methyl 3-iodobenzoate (15 mmol, 3.93 g) , 2-picoline (2.0 mmol, 0.19 g) , TFA (2.0 mmol, 0.23 g) , and DCE (35 mL) were added. The pressure vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minuters and then heated to 100 °C. Upon completion, the reaction mixture was purified by a silica gel-packed flash chromatography column, and Compound 21 was obtained in 78% yield (4.43 g) .
(S) -3- (4-Acetylphenyl) -2-phthalimido-W- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (2m)
Substrate 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by JH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 2m was obtained as a white solid
(45.8 mg, 83%). ¾ NMR (600 MHz, CDC13) δ 8.59 (br s, 1H) , 7.81-7.73 (m, 6H) , 7.29 (d, J = 7.8 Hz, 2H) , 5.37 (dd, Ji = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.72-3.65
(m, 2H) , 2.50 (s, 3H) ; 13C NMR (150 MHz, CDC13)
6197.8, 167.9, 166.3, 141.2, 136.0, 134.8, 130.9, 129.2, 128.8, 123.9, 55.8, 35.0, 26.5; HRMS (ESI-TOF) Calcd for C26H16F7N2O4 [M+H]+: 553.0993; found:
553.0992.
(S) -3- (4-Nitrophenyl) -2-phthalimido-li- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl)propanamide (2n)
Substrate 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2n was obtained as a white solid
(45.6 mg, 82%). *H NMR (600 MHz, CDC13) δ 8.41 (br s, 1H) , 8.06 (d, J= 7.8 Hz, 2H) , 7.83-7.81 (m, 2H) , 7.78-7.76 (m, 2H) , 7.38 (d, J= 7.8 Hz, 2H) , 5.37
(dd, Jx = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.76-3.69 (m, 2H) ; 1C NMR (150 MHz, CDC13) 6167.7, 166.0, 147.2, 143.3, 135.1, 130.7, 129.9, 124.1, 124.0, 55.4, 34.8; HRMS (ESI-TOF) Calcd for C24H13F7N3O5 [M+H]+: 556.0738; found: 556.0732.
(S) -3- (4-Cyanophenyl) -2-phthalimido-W- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (2o)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by XH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 2o was obtained as a white solid
(45.9 mg, 86%). ¾ NMR (600 MHz, CDC13) δ 8.42 (br s, 1H) , 7.84-7.81 (m, 2H) , 7.78-7.75 (m, 2H) , 7.48 (d, J = 7.8 Hz, 2H) , 7.32 (d, J = 7.8 Hz, 2H) , 5.33 (dd, Jx = 6.0 Hz, J2 = 10.8 Hz, 1H) , 3.70 (ABqd, Jj = 6.0 Hz, J2 = 14.3 Hz, 1H) , 3.65 (ABqd, Jx = 10.8 Hz, J2 = 14.3 Hz, 1H) ; 13C NMR (150 MHz, CDCI3) 5167.7, 166.0, 141.3, 135.0, 132.5, 130.8, 129.8, 124.0, 118.4, 111.2, 55.4, 35.1; HRMS (ESI-TOF) Calcd for C25H13F7N3O3
[M+H]+: 536.0840; found: 536.0838.
(S) - (4- (Methylthio) phenyl) -2-phthalimido-3-N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) - phenyl) propanamide (2p)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2p was obtained as a white solid (39.8 mg, 72%). 1H NMR (400 MHz, CDC13) δ 8.53 (br s,
1H) , 7.83-7.79 (m, 2H) , 7.76-7.71 (m, 2H) , 7.12-7.06 (m, 4H) , 5.31 (dd, ϋΎ = 6.8 Hz, J2 = 10.0 Hz, 1H) , 3.62-3.52 (m, 2H) , 2.39 (s, 3H) ; 13C NMR (100 MHz, CDC13) δ168.0, 166.6, 137.6, 134.7, 132.0, 131.0, 129.3, 126.7, 123.9, 56.3, 34.7, 15.6; HRMS ( ESI-TOF) Calcd for C25Hi6F7I l203S [M+H]+: 557.0764; found:
557.0765.
(S) -3- (Naphthalen-2-yl) -2-phthalimido-N- (2,3,5,6- tetra luoro-4- (trifluoromethyl)phenyl) propanamide (2q)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a 14:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2q was obtained as a light yellow solid (50.7 mg, 91%). ¾ NMR (600 MHz, CDC13) δ 8.52 (br s, 1H) , 7.77-7.71 (m, 4H) , 7.68-7.62 (m, 4H) , 7.41-7.37 (m, 2H) , 7.36-7.34 (m, 1H) , 5.47 (dd, Ji = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.82-3.74 (m, 2H) ; 13C NMR (150 MHz, CDC13) 6168.1, 166.7, 134.6, 133.3, 132.9, 132.5, 131.0, 128.7, 127.9, 127.6, 127.5, 126.5, 126.2, 125.9, 123.8, 56.3, 35.4; HRMS (ESI- TOF) Calcd for C28Hi6F7N203 [M+H] + : 561.1044; found: 561.1048.
(S) -3- (3,4-Dimethylphenyl) -2-phthalimido-N- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (2r)
Substrate 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by XH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2r was obtained as a white solid
(47.0 mg, 87%). 1H NMR (600 MHz, CDC13) δ 8.44 (br s, 1H) , 7.83-7.80 (m, 2H) , 7.75-7.72 (m, 2H) , 6.97-6.96
(m, 2H) , 6.94-6.92 (m, 1H) , 5.31 (dd, σ = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.58 (ABqd, J = 6.6 Hz, J2 = 14.4 Hz, 1H) , 3.48 (ABqd, Jj. = 10.2 Hz, J2 = 14.4 Hz, 1H) , 2.14
(s, 3H) , 2.11 (s, 3H) ; 13C NMR (150 MHz, CDC13) 5168.1, 166.7, 137.2, 135.7, 134.6, 132.7, 131.2, 130.13, 130.09, 126.1, 123.8, 56.6, 34.9, 19.5, 19.3; HRMS (ESI-TOF) Calcd for C26HIBF7N203 [M+H] + : 539.1200; found: 539.1195.
Large scale reaction: Substrate Compound 1
(15 mmol, 6.51 g) , Pd(TFA)2 (1.5 mmol, 0.50 g) , and Ag2C03 (22.5 mmol, 6.12 g) were weighed in air and placed in a round-bottom flask (100 inL) with a magnetic stir bar. 4-Iodo-o-xylene (22.5 mmol, 5.22 g), 2-picoline (3.0 mmol, 0.28 g) , TFA (3.0 mmol, 0.34 g) , and DCE (50 mL) were added. The pressure vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C. Upon completion, the reaction
mixture was purified by a silica gel-packed flash chromatography column, and Compound 2r was obtained in 79% yield (6.38 g) .
(S) -3- (3 , 4-Methylenedioxyphenyl) -2-phthalimido- N- (2 , 3 , 5 , 6-tetrafluoro-4- (trifluoromethyl) phenyl) - propanamide (2s)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2s was obtained as a white solid (47.3 mg, 85%). XH NMR (600 MHz, CDC13) δ 8.50 (br s, 1H) , 7.85-7.81 (m, 2H) , 7.77-7.73 (m, 2H) , 6.70 (s, 1H) , 6.63-6.60 (m, 2H) , 5.88 (ABq, J = 1.5 Hz, 1H) , 5.86 (ABq, J = 1.5 Hz, 1H) , 5.27 (dd, Jx = 6.0 Hz, J2 = 10.2 Hz, 1H) , 3.55 (ABqd, Ji = 6.0 Hz, J2 = 14.4 Hz, 1H) , 3.49 (ABqd, Ji = 10.2 Hz, J2 = 14.4 Hz, 1H) ; 13C NMR (150 MHz, CDCI3) 8168.1, 166.6, 148.0, 146.8, 134.7, 131.1, 129.0, 123.9, 122.1, 109.1, 108.5, 101.0, 56.6, 35.0; HRMS (ESI-TOF) Calcd for C25H1 F7N2O5 [M+H]+: 555.0785; found: 555.0776.
(S) -3- (3,5-Bis (trifluoromethyl)phenyl) -2-phthalimido- N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) - propanamide (2t)
Substrate Compound 1 was arylated following the general arylation procedure A. Analysis of crude reaction mixture by ½ NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 2t was obtained as a white solid (55.4 mg, 86%) . LH NMR (400 MHz, CDC13) δ 8.44 (br s, 1H), 7.83-7.73 (m, 4H) , 7.68 (s, 1H) , 7.63 (s, 2H) , 5.31 (dd, Ji = 6.0 Hz, Jz = 10.4 Hz, 1H) , 3.78 (ABqd, Ji = 6.0 Hz, J2 = 14.4 Hz, 1H) , 3.68 (ABqd, Ji = 10.4 Hz, J2 = 14.4 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 5167.8, 165.8, 138.3, 135.1, 132.0 (q, JFC = 33.3 Hz), 130.7, 129.3 (q, JFC = 3.6 Hz), 124.0, 122.9 (q, JFC = 271.2 Hz), 121.4-121.3, 55.4, 34.6; HRMS (ESI-TOF) Calcd for C26H12F13N2O3 [M+H] + : 647.0635; found:
647.0630.
C. Ligand-Promoted Secondary C(sp3)-H Arylation Condition Screening Scheme
NPhth Conditions NPhth
PhYACONHArF + Ph"" »" Ρή ΟΟΝΗΑΓΡ
H (3 equiv) Ph
2 3
ArF = 4-(CF3)C6F4
Condition Screening Table
Screening studies were carried out using (S) -3-phenyl-2-phthalimido-W- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (Compound 2) (51.0 mg, 0.1 mmol) as the substrate and iodobenzene. The conditions for each trial are specified in the
tables below. All yields were determined by analysis of the crude 1H NMR (CDC13) spectrum using CH2Br2 as the internal standard after filtration of the reaction mixture through a pad of silica gel.
Ligand Screening
Table 15
Pd (TFA) 2 (10 mol%), ligand (20 mol ), TFA (20 mol%), AgzC03 (2 equlv) , DCE, 100 °C, 20 h
General Procedure Scheme B
= 4-(CF3)C6F4
General Arylation Procedure B
Substrate Compound 2 or Compounds 5a-5d (0.1 mmol) , Pd(T A)2 (0.01 mmol, 3.3 mg) , Ligand L10 (0.02 mmol, 4.3 mg) and Ag2C03 (0.2 mmol, 55.0 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. The aryl iodide (0.3 mmol), TFA (0.02 mmol, 2 μΐ,) , and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon
completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/EtOAc or hexane/EtOAc as the eluent.
(S) -3 , 3-Diphenyl-2-phthalimido-N- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) ropanamide (3)
Substrate Compound 2 was arylated following the general arylation procedure B. After
purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3 was obtained as a white solid (52.7 mg, 90%). 1H NMR (600 MHz, CDC13) δ 8.70 (br s, 1H) , 7.78-7.76 (m, 2H) , 7.70-7.67 (m, 2H) , 7.57 (d, J = 7.2 Hz, 2H) , 7.38- 7.36 (m, 2H) , 7.32-7.26 (m, 3H) , 7.16-7.14 (m, 2H) , 7.06-7.04 (m, 1H) , 5.90 (d, J= 12.6 Hz, 1H) , 5.33 (d, J = 12.6 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 165.3 , 139.3, 138.8, 134.6, 130.9, 129.3, 128.8, 128.0, 127.5, 127.4, 123.8, 59.1, 50.9; HRMS (ESI-TOF) Calcd for C3oHieF7N203 [M+H] + : 587.1200; found: 587.1193.
3a
(2S , 3R) -3-Phenyl-2-phthalimido-W- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) henyl) -3- (p-tolyl) ropanamide (3a)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a 20:1 diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3a was obtained as a white solid (53.5 mg, 89%). ¾ NMR (400 MHz, CDCI3) δ 8.65 (br s, 1H) , 7.78-7.74 (m, 2H) , 7.70-7.67 (m, 2H) , 7.57 (d, J = 8.0 Hz, 2H) , 7.31-
7.29 (m, 2H) , 7.19-7.12 (m, 4H) , 7.06-7.02 (m, 1H) , 5.89 (d, J = 12.8 Hz, 1H) , 5.28 (d, J = 12.8 Hz, 1H) ,
2.30 (s, 3H) ; 13C NMR (100 MHz, CDCI3) 5165.4, 139.6, 137.8, 135.8, 134.5, 130.9, 130.0, 128.8, 127.8, 127.4, 127.3, 123.7, 59.0, 50.6, 21.1; HRMS (ESI-TOF)
Calcd for C31H2oF7N203 [M+H]+: 601.1357; found:
601.1349.
(2S , 3R) -3-Phenyl-2-phthalimido-N- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) henyl) -3- (zn-tolyl) propanamide (3b)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3b was obtained as a white solid (51.5 mg, 86%). 1H NMR (600 MHz , CDC13) δ 8.54 (br s, 1H) , 7.78-7.75 (m, 2H) , 7.69-7.66 (m, 2H) , 7.39-7.36 (m, 2H) , 7.31 (d, J= 7.8 Hz, 2H) , 7.28-7.25 (m, 1H) , 7.16-7.14 (m, 2H) , 7.09 (d, J = 7.8 Hz, 1H) , 7.06- 7.03 (m, 1H) , 5.89 (d, J= 12.6 Hz, 1H) , 5.29 (d, J = 12.6 Hz, 1H) , 2.35 (s, 3H) ; 13C NMR (150 MHz, CDC13) 5165.3, 139.5, 139.1, 138.8, 134.5, 130.9, 129.2, 128.83, 128.80, 128.76, 127.5, 127.3, 124.9, 123.7, 58.9, 50.8, 21.5; HRMS (ESI-TOF) Calcd for C31H20F7N2O3 [M+H]+: 601.1357; found: 601.1355.
3c
(2S,3R) -3- (4-Methoxyphenyl) -3-phenyl-2-phthalimido- N- (2 , 3 ,5 , 6-tetrafluoro-4- (trifluoromethyl) henyl) - propanamide (3c)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by XH NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3c was obtained as a white solid
(52.5 mg, 85%). ½ NMR (400 MHz, CDC13) δ 8.70 (br s, 1H) , 7.80-7.75 (m, 2H) , 7.71-7.66 (m, 2H) , 7.50-7.47
(m, 2H), 7.30-7.28 (m, 2H) , 7.17-7.13 (m, 2H) , 7.06- 7.02 (m, 1H), 6.92-6.88 (m, 2H) , 5.85 (d, J = 12.8 Hz, 1H), 5.28 (d, J= 12.8 Hz, 1H) , 3.77 (s, 3H) 13C NMR (100 MHz, CDC13) 6165.4, 159.2, 139.7, 134.6, 130.9, 130.8, 129.1, 128.8, 127.4, 127.3, 123.8, 114.7, 59.2, 55.2, 50.2; HRMS (ESI-TOF) Calcd for C31H20F7N2O4 [M+H] + : 617.1306; found: 617.1295.
(2S,3R) -3- (3-Me hoxyphenyl) -3-phenyl-2-phthalimido-N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (3d)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3d was obtained as a white solid (49.6 mg, 81%). 1H NMR (600 MHz, CDC13) δ 8.56 (br s,
1H) , 7.78-7.76 (m, 2H) , 7.70-7.67 (m, 2H) , 7.32-7.29 (m, 3H) , 7.18-7.14 (m, 3H) , 7.09-7.08 (m, 1H) , 7.07- 7.04 (m, 1H) , 6.82-6.80 (m, 1H) , 5.89 (d, J = 12.6 Hz, 1H) , 5.30 (d, J= 12.6 Hz, 1H) , 3.80 (s, 3H) ; 13C NMR (150 MHz, CDC13 ) δ 165.2 , 160.1, 140.5, 139.3, 134.6, 130.9, 130.4, 128.8, 127.5, 127.4, 123.8, 120.0, 114.1, 113.1, 58.8, 55.2, 50.8; HRMS (ESI-TOF) Calcd for C31H2oF7 204 [M+H]+: 617.1306; found:
617.1300.
3e
(2S,3R) -3- (4-Fluorophenyl) -3-phenyl-2-phthalimido-N- (2 , 3 , 5 , 6-tetrafluoro-4- (trifluoromethyl) henyl) - propanamide (3e)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3e was obtained as a white solid
(46.2 mg, 76%). 1H NMR (600 MHz, CDC13) δ 8.93 (br s, 1H), 7.80-7.77 (m, 2H) , 7.72-7.69 (m, 2H) , 7.53-7.51
(m, 2H) , 7.29-7.26 (m, 2H) , 7.18-7.15 (m, 2H) , 7.08- 7.03 (m, 3H), 5.83 (d, J = 12.6 Hz, 1H) , 5.32 (d, J = 12.6 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 5165.2, 162.2
(d, JFC = 245.7 Hz), 139.0, 134.7, 134.5 (d, JFC = 3.2 Hz), 130.7, 129.7 (d, JFC = 8.1 Hz), 128.9, 127.6, 127.4, 123.9, 116.1 (d, JFC = 21.5 Hz), 59.4, 50.2;
( ESI-TOF) Calcd for C3 DHnFe 203 [M+H]+: 605.1106; : 605.1097.
3f
(2S , 3R) -3- (4-Chlorophenyl) -3-phenyl-2-phthalimido-2f- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) henyl) - propanamide (3f)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3f was obtained as a white solid (45.7 mg, 74%). ¾ NMR (600 MHz, CDC13) δ 8.92 (br s, 1H) , 7.79-7.76 (m, 2H) , 7.72-7.69 (m, 2H) , 7.48 (d, J = 8.4 Hz, 2H) , 7.32 (d, J = 8.4 Hz, 2H) , 7.27-7.26 (m, 2H) , 7.17-7.14 (m, 2H) , 7.08-7.05 (m, 1H) , 5.84 (d, J = 12.6 Hz, 1H), 5.31 (d, J = 12.6 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 6165.2, 138.7, 137.3, 134.8,
133.8, 130.7, 129.4, 129.3, 129.0, 127.7, 127.5,
123.9, 59.2, 50.3; HRMS (ESI-TOF) Calcd for
C3oHi7ClF7 203 [M+H] + : 621.0810; found: 621.0803.
39
(2S,3R) -3- (4-Broitiophenyl) -3-phenyl-2-phthalimido- N- (2 , 3 , 5 , 6-tetrafluoro-4- (trifluoromethyl) henyl) - propanamide (3g)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3g was obtained as a white solid (47.7 mg, 72%). ¾ NMR (600 MHz, CDC13) δ 8.91 (br s, 1H) , 7.79-7.77 (m, 2H) , 7.72-7.70 (m, 2H) , 7.48 (d, J = 8.4 Hz, 2H) , 7.42 (d, J= 8.4 Hz, 2H) , 7.27-7.26 (m, 2H) , 7.17-7.14 (m, 2H) , 7.08-7.06 (m, 1H) , 5.83 (d, J = 12.6 Hz, 1H), 5.30 (d, J = 12.6 Hz, 1H) ; 13C NMR (150 MHz, CDC13) 8165.1, 138.6, 137.8, 134.8, 132.2, 130.7, 129.7, 129.0, 127.7, 127.5, 123.9, 121.9, 59.1, 50.4; HRMS (ESI-TOF) Calcd for
C3oHi7BrF7N203 [M+H]+: 665.0305; found: 665.0290.
3h
Methyl 4- ( (1R,2S) -3-oxo-l-phenyl-2-phthalimido-3- ((2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) - amino) ropyl) benzoate (3h)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 3h was obtained as a white solid
(52.8 mg, 82%). 1H NMR (600 MHz, CDC13> δ 8.92 (br s, 1H) , 8.02 (d, J= 7.8 Hz, 2H) , 7.79-7.77 (m, 2H) , 7.71-7.69 (m, 2H) , 7.63 (d, J = 8.4 Hz, 2H) , 7.30- 7.28 (m, 2H), 7.17-7.15 (m, 2H) , 7.08-7.06 (m, 1H) , 5.91 (d, J = 12.6 Hz, 1H) , 5.40 (d, J= 12.6 Hz, 1H) , 3.89 (s, 3H) ; 1 C NMR (150 MHz, CDC13) 8166.6, 165.1, 143.9, 138.4, 134.8, 130.7, 130.4, 129.6, 129.0, 128.1, 127.7, 127.6, 123.9, 58.9, 52.1, 50.8; HRMS (ESI-TOF) Calcd for C32H20F7N2O5 [M+H] + : 645.1255;
found: 645.1246.
Methyl 3- { (1R,2S) -3-oxo-l-phenyl-2-phthalimido-3- ((2,3,5, 6-tetrafluoro-4- (trifluoromethyl) henyl) - amino) propyl)benzoate (3i)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 3i was obtained as a white solid
(50.2 mg, 78%). ¾ NMR (600 MHz, CDC13) 58.97 (br s, 1H) , 8.21-8.20 (m, 1H) , 7.95-7.93 (m, 1H) , 7.80-7.77
(m, 3H) , 7.72-7.69 (m, 2H) , 7.46-7.44 (m, 1H) , 7.33- 7.31 (m, 2H), 7.18-7.15 (m, 2H) , 7.09-7.06 (m, 1H) , 5.92 (d, J= 12.6 Hz, 1H) , 5.42 (d, J= 12.6 Hz, 1H) , 3.90 (s, 3H) ; 13C NMR (150 MHz, CDCI3) 5166.6, 165.1, 139.3, 138.6, 134.7, 132.5, 130.9, 130.8, 129.25, 129.23, 129.1, 129.0, 127.7, 127.6, 123.9, 59.1,
52.2, 50.6; HRMS (ESI-TOF) Calcd for C32H20F7N2O5
[M+H] + : 645.1255; found: 645.1264.
Methyl 2- ( (1R, 2S) -3-oxo-l-phenyl-2-phthalimido-3- ( (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) - amino) propyl) benzoate (3j)
Substrate Compound 2 was /arylated following the general arylation procedure B. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 3j was obtained as a white solid (43.8 mg, 68%). ¾ NMR (600 MHz, CDC13) δ 9.76 (br s, 1H) , 7.90 (d, J = 7.8 Hz, 1H) , 7.84-7.80 (m, 3H) , 7.72-7.69 (m, 2H) , 7.62-7.59 (m, 1H) , 7.35-7.33 (m, 3H) , 7.17-7.14 (m, 2H) , 7.08-7.06 (m, 1H) , 6.75 (d, J = 12.6 Hz, 1H) , 6.01 (d, J= 12.6 Hz, 1H) , 4.01 (s, 3H) ; 13C NMR (150 MHz, CDC13) 5169.5, 165.2, 140.0, 138.9, 134.5, 132.8, 131.0, 130.9, 129.6, 128.9, 128.0, 127.6, 127.52, 127.49, 123.8, 58.9, 52.9, 42.6; HRMS (ESI-TOF) Calcd for C32H20 F7N2O5 [M+H]+: 645.1255; found: 645.1248.
3k
(2S , 3R) -3- (3 , 4-Dimethylphenyl) -3-phenyl-2~
phthalimido-K'- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) henyl) -propanamide (3k)
Substrate Compound 2 was arylated following the general arylation procedure B. Analysis of crude reaction mixture by ¾ NMR showed a 19:1 diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 3k was obtained as a white solid (54.2 mg, 88%) . 1H NMR (600 MHz, CDC13) δ 8.48 (br s, 1H) , 7.77-7.75 (m, 2H) , 7.69-7.66 (m, 2H) , 7.32-7.30 (m, 4H) , 7.15-7.13 (m, 3H) , 7.04-7.02 (m, 1H) , 5.88 (d, J = 12.6 Hz, 1H) , 5.25 (d, J = 12.6 Hz, 1H) , 2.25 (s, 3H) , 2.21 (s, 3H) ; 13C NMR (150 MHz, CDC13) 8165.4, 139.8, 137.8, 136.5, 136.3, 134.5, 131.0, 130.6, 129.2, 128.8, 127.4, 127.2, 125.1, 123.7, 58.8, 50.6, 19.9, 19.4; HRMS (ESI-TOF) Calcd for C32H22F7N2O3 [M+H]+: 615.1513; found: 615.1512.
6a
(2S , 3R) -3- (3 , 4-Dimethylphenyl) -2 , 6-bis (phthalimido) - N- (2 , 3 , 5 , 6-tetrafluoro-4- (trifluoromethyl) henyl) - hexanamide (6a)
Substrate Compound 5a was arylated following the general arylation procedure B.
Analysis of crude reaction mixture by 1H NMR showed a > 20:1 diastereomer ratio. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 6a was obtained as a white solid
(47.8 mg, 66%). ¾ NMR (600 MHz, CDC13) δ 8.30 (br s, 1H) , 7.92-7.89 (m, 2H) , 7.82-7.79 (m, 2H) , 7.73-7.70
(m, 2H) , 7.68-7.65 (m, 2H) , 7.14-7.11 (m, 3H) , 5.24
(d, J= 11.4 Hz, 1H) , 3.87-3.83 (m, 1H) , 3.51 (t, J = 7.5 Hz, 2H) , 2.25 (s, 3H) , 2.22 (s, 3H) , 1.68-1.56
(m, 2H) , 1.46-1.41 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ168.1, 165.3, 137.8, 136.7, 135.3, 134.7, 133.8, 131.9, 131.3, 130.6, 129.4, 125.6, 124.0, 123.1, 60.6, 43.9, 37.3, 30.1, 25.6, 19.8, 19.5; HRMS (ESI- TOF) Calcd for C37H27F7N305 [M+H]+: 726.1833; found: 726.1826.
6b
(2S , 3R) -2-Phthalimido-N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) -3- (p-tolyl) butanamide (6b)
Substrate Compound 5b was arylated following the general arylation procedure B.
Analysis of crude reaction mixture by 1H NMR showed a 15:1 diastereomer ratio. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, 6b was obtained as a white solid (47.6 mg, 88%). XH NMR (400 MHz, CDC13) δ 8.39 (br s, 1H) , 7.98-7.93 (m, 2H) , 7.84-7.80 (m, 2H) , 7.33 (d, J= 8.0 Hz, 2H) , 7.21 (d, J = 8.0 Hz, 2H) , 5.22 (d, J = 12.0 Hz, 1H), 4.07-3.99 (m, 1H) , 2.34 (s, 3H) , 1.26 (d, J= 6.8 Hz, 3H) ; 13C NMR (100 MHz, CDC13) 6168.4, 165.5, 137.79, 137.77, 134.8, 131.2, 130.0, 127.4, 124.0, 61.4, 39.0, 21.1, 20.0; HRMS (ESI-TOF) Calcd for C26HIBF7N203 [M+H]+: 539.1200; found: 539.1196.
6c-mono
Methyl 4- (2-phthalimido-2- ( (2 , 3 , 5 , 6-tetrafluoro-4- (trifluoromethyl) henyl) carbamoyl) cyclobutyl)benzoate (6c-mono)
Substrate Compound 5c was arylated following the general arylation procedure B. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 6c-mono was obtained as a white solid (35.6 mg, 60%). τΕ NMR (600 MHz, CDC13) δ 7.97 (d, J = 8.4 Hz, 2H) , 7.91-7.87 (m, 2H), 7.81-7.78 (m, 2H) , 7.57 (d, J = 8.4 Hz, 2H) , 7.29 (br s, 1H) , 4.75 (t, J = 9.9 Hz, 1H) , 3.84 (s, 3H) , 3.45-3.42 (m, ΊΗ) , 2.64-2.57 (m, 1H) , 2.55-2.50 (m, 1H) , 2.43-2.38 (m, 1H) ; 13C NMR (150 MHz, CDC13) 5Π168.0, 167.0, 166.9, 143.2, 134.8, 131.5, 129.42, 129.39, 129.0, 123.7, 67.5, 52.0, 47.4, 28.3, 23.1; HRMS (ESI-TOF) Calcd for C28Hi8F7N205 [M+H] + : 595.1098; found: 595.1101.
6c -di
Dimethyl 4,4'- (2-phthalimido-2- ((2,3,5, 6-tetrafluoro- 4- (trifluoromethyl) henyl) carbamoyl) cyclobutane-
1 , 3-diyl) dibenzoate (6c-di)
Compound 6c-di was obtained as a yellow solid (22.0 mg, 30%). ½ NMR (600 MHz, CDC13) δ 7.97- 7.92 (m, 6H), 7.83-7.81 (m, 2H) , 7.56 (d, J = 8.4 Hz, 4H) , 7.36 (br s, 1H) , 4.90-4.87 (m, 2H) , 3.84 (s, 6H), 3.24-3.19 (m, 1H) , 2.80-2.75 (m, 1H) ; 13C NMR (150 MHz, CDCI3) 5168.4, 167.0, 164.6, 142.6, 135.0, 131.4, 129.2, 129.0, 128.9, 123.9, 72.6, 52.0, 45.7, 26.8; HRMS (ESI-TOF) Calcd for C36H24F7 207 [M+H]+: 729.1466; found: 729.1453.
Methyl 3- (2-phthalimido-2- ( (2 , 3 ,5, 6-tetrafluoro- 4- (trifluoromethyl) phenyl) carbamoyl) cyclopropyl) - benzoate (6d)
Substrate Compound 5d was arylated following the general arylation procedure B.
Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (2/1) as the eluent, Compound 6d was obtained as a yellow solid (40.5 mg, 70%). ¾ NMR (400 MHz, CDCI3) δ 8.14 (br s, 1H) , 7.95-7.91 (m, 3H) , 7.84-7.78 (m, 4H) , 7.45 (t, J = 7.6 Hz, 1H) , 3.90 (s, 3H) , 3.08 (t, J= 9.6 Hz, 1H) , 2.76 (dd, Jx = 7.2 Hz, J2 = 9.2 Hz, 1H) , 2.05 (dd, Ji = 7.2 Hz, J2 = 10.0 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 166.8, 164.3, 135.0, 133.8, 131.2, 130.4, 130.1, 129.2, 128.7, 124.0, 52.2, 40.5, 33.8, 17.4; HRMS (ESI-TOF) Calcd for C27Hi6F7N205 [M+H] + : 581.0942; found: 581.0943.
D. Sequential C(sp )-H Arylation Reactions
General Procedure Scheme C
Pd(TFA)2 (10 mol%) Me
General Arylation Procedure C:
Substrate Compound 1 (0.1 mmol, 43.4 mg) , Pd(TFA)2 (0.01 mmol, 3.3 mg) , and Ag2C03 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. Ar1-! (0.15 mmol), 2-picoline (0.02 mmol, 2 pL) , TFA (0.02 mmol, 2 pL) , and DCE (0.5 mL) were added and the reaction vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring .
Upon completion, the reaction mixture was cooled to room temperature. Pd(TFA)2 (0.01 mmol, 3.3 mg) , Ligand L10 (0.02 mmol, 4.3 mg) , and Ag2C03 (0.2 mmol, 55.0 mg) were weighed open to air and added in the reaction mixture. Ar2-I (0.3 mmol) and TFA (0.02 mmol, 2 pL) were then added. The reaction vessel was sealed. The mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon
completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a
silica gel-packed flash chromatography column using toluene/EtOAc or hexane/EtOAc as the eluent.
7a
(2S , 3R) -3- (4-Methoxyphenyl) -2-phthalimido-ST- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) henyl) -3- (p-tolyl)propanamide (7a)
Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1H NMR showed a 19:1 diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 7a was obtained as a white solid (42.9 mg, 68%). ¾ NMR
(600 MHz, CDC13) δ 8.68 (br s, 1H) , 7.79-7.78 (m, 2H) , 7.70-7.69 (m, 2H) , 7.46 (d, J = 7.8 Hz, 2H) , 7.17 (d, J= 7.8 Hz, 2H) , 6.95 (d, J = 7.8 Hz, 2H) , 6.89 (d, J = 7.8 Hz, 2H), 5.83 (d, J = 12.6 Hz, 1H) , 5.24 (d, J = 12.6 Hz, 1H) , 3.77 (s, 3H) , 2.14 (s, 3H) ; 13C NMR
(150 MHz, CDCI3) 5165.5, 159.1, 136.9, 136.7, 134.5, 131.1, 131.0, 129.5, 129.0, 127.2, 123.8, 114.7, 59.2, 55.2, 49.8, 20.9; HRMS (ESI-TOF) Calcd for C32H22F7N2O4 [M+H]+: 631.1462; found: 631.1460.
7b
(2S , 3S) -3- (4-Acetylphenyl) -2-phthalimido-Xf- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) -3- (p-tolyl) - propanamide (7b)
Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by XH NMR showed a 19:1 diastereomer ratio. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 7b was obtained as a white solid (39.7 mg, 62%). 1 NMR
(600 MHz , CDC13) δ 8.54 (br s, 1H) , 7.76-7.73 (m, 4H) , 7.69-7.66 (m, 2H) , 7.44-7.40 (m, 4H) , 7.17 (d, J = 7.8 Hz, 2H), 5.91 (d, J = 12.6 Hz, 1H) , 5.41 (d, J= 12.6 Hz, 1H) , 2.43 (s, 3H) , 2.29 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 197.5, 165.0, 145.1, 138.2, 136.0, 135.1, 134.7, 130.8, 130.2, 128.9, 127.8, 127.7, 123.9, 58.4, 50.3, 26.5, 21.0; HRMS (ESI-TOF) Calcd for C33H22F7N2O4 [M+H] + : 643.1462; found: 643.1458.
Large scale reaction: Substrate Compound 1
(5 mmol, 2.17 g) , Pd(TFA)2 (0.5 mmol, 0.17 g) , and Ag2CC (7.5 mmol, 2.07 g) were weighed out open to air and added in a round-bottom flask (100 mL) with a magnetic stir bar. ' -Iodoacetophenone (7.5 mmol, 1.85 g), 2-picoline (1 mmol, 100 pL) , TFA (1 mmol, 0.11 g) , and DCE (25 mL) were added and the pressure vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. Pd(TFA)2 (0.5 mmol, 0.17 g) , Ligand L10 (1 mmol, 0.21 g) , Ag2C03 (10 mmol, 2.75 g) , and 4-iodotoluene (15 mmol, 3.27 g) were weighed out open to air and added in the reaction vessel, and TFA (1 mmol, 0.11 g) was then added. The vessel was sealed. The reaction mixture was first stirred at
room temperature for 10 minutes and then heated to 100 °C for 20 hours under vigorous stirring. Upon completion, the resulting mixture was purified by a silica gel-packed flash chromatography column, and Compound 7b was obtained in 60% yield (1.92 g) .
Methyl 4- ( (1R,2S) -1- (3-methoxyphenyl) -3-oxo-2- phthalimido-3- ((2,3,5, 6-tetrafluoro-4- ( rifluoromethyl) henyl) amino) propyl) benzoate (7c)
Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1 NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using hexane/EtOAc (5/1) as the eluent, Compound 7c was obtained as a white solid
(43.5 mg, 65%). XH NMR (600 MHz, CDC13) δ 8.45 (br s, 1H) , 7.84 (d, J = 7.8 Hz, 2H) , 7.78-7.77 (m, 2H) , 7.71-7.69 (m, 2H) , 7.40 (d, J = 7.8 Hz, 2H) , 7.33- 7.30 (m, 1H) , 7.16 (d, J = 7.8 Hz, 1H) , 7.07 (s, 1H) , 6.83 (d, J = 7.8 Hz, 1H) , 5.90 (d, J = 12.6 Hz, 1H) , 5.41 (d, J= 12.6 Hz, 1H) , 3.80 (s, 6H) ; 13C NMR (150 MHz, CDCI3) 5166.5, 164.9, 160.2, 144.5, 139.7, 134.7, 130.8, 130.6, 130.2, 129.3, 127.6, 123.9, 120.0, 114.2, 113.3, 58.3, 55.3, 52.1, 50.6; HRMS
(ESI-TOF) Calcd for C33H22 F7 2O6 [M+H]+: 675.1361;
, found: 675.1358.
7d
Methyl 3- ( (1S,2S) -1- (3,4-dimethylphenyl) -3-oxo-2- phthalimido-3- ((2,3,5, 6-tetrafluoro-4- (trifluoromethyl)phenyl) amino)propyl) benzoate (7d)
Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 7d was obtained as a white solid
(44.1 mg, 66%). 'H NMR {600 MHz, CDC13) δ 8.42 (br s, 1H) , 7.97 (s, 1H) , 7.79-7.76 (m, 2H) , 7.75-7.73 (m, 1H) , 7.70-7.67 (m, 2H) , 7.55-7.53 (m, 1H) , 7.33-7.31
(m, 2H) , 7.27-7.24 (m, 1H) , 7.15 (d, J= 7.8 Hz, 1H) , 5.90 (d, J = 12.6 Hz, 1H) , 5.34 (d, J= 12.6 Hz, 1H) , 3.84 (s, 3H) , 2.26 (s, 3H) , 2.21 (s, 3H) ; 13C NMR (150 MHz, CDCI3) 5166.5, 165.2, 140.3, 138.0, 136.8, 135.8, 134.6, 131.6, 130.9, 130.7, 130.6, 129.2, 129.0, 128.9, 128.6, 125.1, 123.8, 58.6, 52.1, 50.3, 19.9, 19.4; HRMS (ESI-TOF) Calcd for C34H24F7 205
[M+H]+: 673.1568; found: 673.1566.
7e
(2S , 3S) -3- (3 , 4-Dimethylp enyl) -3- (4-methoxyphenyl) -2- phthalimido-Ii- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) -phenyl) propanamide (7e)
Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent. Compound 7e was obtained as a white solid
(37.8 mg, 59%). ¾ NMR (600 MHz, CDC13) 5 8.69 (br s, 1H), 7.80-7.78 (m, 2H) , 7.70-7.69 (m, 2H) , 7.46 (d, J = 7.8 Hz, 2H), 7.02-7.01 (m, 2H) , 6.90-6.87 (m, 3H) , 5.82 (d, J = 12.6 Hz, 1H) , 5.20 (d, J= 12.6 Hz, 1H) , 3.76 (s, 3H) , 2.07 (s, 3H) , 2.04 (s, 3H) ; 13C NMR (150 MHz, CDC13) 8165.6, 159.1, 137.03, 136.99, 135.5, 134.5, 131.2, 131.0, 130.0, 129.0, 128.8, 124.3, 123.8, 114.6, 59.3, 55.2, 49.7, 19.7, 19.2; HRMS
(ESI-TOF) Calcd for C33H24 F7N2O4 [M+H] + : 645.1619;
found: 645.1618.
7f
(2S , 3R) -3- (3 , -Dimethylphenyl) -3- (4-methoxyphenyl) -2- phthalimido-W- (2,3,5, 6-tetrafluoro-4- ( rifluoromethyl) -phenyl) propanamide (7f)
Substrate Compound 1 was arylated following the general arylation procedure C. Analysis of crude reaction mixture by ½ NMR showed a 16:1 diastereomer ratio. After purification by column chromatography using toluene/EtOAc (30/1) as the eluent, Compound 7f
was obtained as a white solid (38.8 mg, 60%).
Compound 7f was recrystallized in EtOAc/hexane, and the structure was determined by X-ray diffraction.
[a] 2D° = -31.5 (c = 1.00, CHC13) ; m.p. 192-193 °C (EtOAc/hexane) ; 1H NMR (400 MHz, CDC13) δ 8.46 (br s, 1H) , 7.81-7.76 (m, 2H) , 7.71-7.69 (m, 2H) , 7.30-7.28 (m, 2H) , 7.23-7.20 (m, 2H) , 7.14-7.12 (m, 1H) , 6.69- 6.65 (m, 2H), 5.83 (d, J = 12.4 Hz, 1H) , 5.19 (d, J = 12.4 Hz, 1H), 3.63 (s, 3H) , 2.25 (s, 3H) , 2.20 (s, 3H) ; 1 C NMR (150 MHz, CDC13) 5165.5, 158.5, 137.7, 136.7, 136.4, 134.5, 131.9, 131.0, 130.6, 129.1, 128.5, 125.0, 123.8, 114.2, 58.9, 55.1, 49.8, 19.9, 19.4; HRMS (ESI-TOF) Calcd for ¾Η24 7Ν204 [M+H]+: 645.1619; found: 645.1622.
Metrical parameters for the structure of Compound 7f are available free of charge from the Cambridge Crystallographic Data Centre under reference number CCDC-985675.
General Procedure Scheme D
Pd(TFA)2 (15 mol%)
Me
N 0 Me
NPhth NPhth
(30 mol%)
Ar(Het)-l Ar(Het)
CONHAi-p CONHArp
(1.5 equiv) Ag2C03 (2 equiv)
DCE, 100 °C, air, 20 h
2u-2w
ArF = 4-(CF3)C6F4
General Arylation Procedure D :
Substrate Compound 1 (0.1 mmol) , Pd(TFA)2 (0.015 mmol, 5.0 mg) , igand L10 (0.03 mmol, 6.5 mg) and Ag2CC (0.2 mmol, 55 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a
magnetic stir bar. The heteroaryl iodide (0.15 mmol) and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon
completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexane/EtOAc as the eluent .
(S) -3- (2-Chloropyridin-4-yl) -2-pht.halimido-N- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl) - phenyl)propanamide (2u)
Substrate Compound 1 was arylated following the general arylation procedure D. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2u was obtained as a white solid (29.8 mg, 55%). 1H NMR (400 MHz, CDC13) δ 8.54 (br s, 1H), 8.21-8.20 (m, 1H) , 7.85-7.80 (m, 2H) , 7.79-7.74 (m, 2H), 7.17-7.16 (m, 1H) , 7.09-7.07 (m, 1H) , 5.35 (dd, Ji = 6.4 Hz, J2 = 10.4 Hz, 1H) , 3.66 (ABqd, J = 6.4 Hz, J2 = 14.4 Hz, 1H) , 3.59 (ABqd, Ji = 10.4 Hz, J2 = 14.4 Hz, 1H) ; 13C NMR (100 MHz, CDC13) 5167.6, 165.8, 152.0, 149.9, 148.4, 135.0, 130.8, 124.7, 124.1, 122.8, 54.5, 34.0; HRMS (ESI-TOF) Calcd for C23H12C1F7N303 [M+H]+: 546.0450; found: 546.0451.
(S) -2-Phthalimido-Ii- (2,3,5, 6-tetrafluoro-4- (trifluoromethyl)phenyl) -3- (l-tosyl-lH-indol-5-yl) - propanamide (2v)
Substrate Compound 1 was arylated following the general arylation procedure D. Analysis of crude reaction mixture by XH NMR showed a 12:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (3/1) as the eluent, Compound 2v was obtained as a white solid
(45.5 mg, 65%). XH NMR (600 MHz, CDC13) δ 8.40 (br s, 1H) , 7.81 (d, J= 8.4 Hz, 1H) , 7.79-7.76 (m, 2H) , 7.72-7.70 (m, 2H) , 7.68 (d, J = 8.4 Hz, 2H) , 7.46 (d, J = 3.6 Hz, 1H) , 7.37-7.36 (m, 1H) , 7.18 (d, J = 7.8 Hz, 2H) , 7.14-7.13 (m, 1H) , 6.50 (d, J= 3.6 Hz, 1H) , 5.35 (dd, Ji = 6.6 Hz, J2 = 10.2 Hz, 1H) , 3.70 (ABqd, Ji = 6.6 Hz, J2 = 14.4 Hz, 1H) , 3.61 (ABqd, Jx = 10.2 Hz, J2 = 14.4 Hz, 1H) , 2.32 (s, 3H) ; 13C NMR (150 MHz, CDCI3) 5168.1, 166.6, 145.0, 135.1, 134.7, 134.0, 131.2, 131.0, 130.5, 129.8, 126.9, 126.7, 125.3, 123.9, 121.7, 113.9, 108.8, 56.7, 35.1, 21.5; HRMS
(ESI-TOF) Calcd for C33H21F7N3O5S [M+H]+: 704.1085; found: 704.1085.
(trifluoromethyl) henyl) ropanamide (2w)
Substrate Compound 1 was arylated following the general arylation procedure D. Analysis of crude reaction mixture by 1H NMR showed > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using hexane/EtOAc (4/1) as the eluent, Compound 2w was obtained as a white solid (38.3 mg, 72%). XH NMR (400 MHz, CDC13) δ 8.37 (br s, 1H) , 7.88-7.84 (m, 2H) , 7.79-7.74 (m, 2H) , 6.63 (d, J = 3.6 Hz, 1H) , 6.47-6.46 (m, 1H) , 5.35 (t, J= 8.0 Hz, 1H) , 3.66 (d, J = 8.0 Hz, 2H) , 2.34 (s, 3H) ; 13C NMR (100 MHz, CDC13) 6168.0, 166.2, 139.9, 135.0, 134.7, 131.2, 126.8, 125.1, 123.9, 56.4, 29.7, 15.3; HRMS (ESI-TOF) Calcd for C23Hi4F7 203S [M+H] + : 531.0608; found: 531.0606.
The mono-arylated product Compound 2 (153 mg, 0.3 mmol) was dissolved in the mixed solvents (3 mL, AcOH/Ac20 = 1/2), and then cooled to 0 °C. NaN02 (414 mg, 6 mmol) was slowly added into the reaction mixture in portions. The reaction mixture was first stirred at 0 °C for 3 hours and then at room temperature for 17 hours. Upon completion, the solvents were removed under reduced pressure, and the mixture was neutralized by slow addition of saturated
aHC03 solution to pH 8. The aqueous phase was extracted with ether (4 χ 10 mL) , and then carefully acidified with cold HC1 solution (I N) to pH 2, and then extracted with ether (4 χ 20 mL) . The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the desired product Compound 4 (84.5 mg, 95%) (31) . ½ NMR (400 MHz, CDC13) δ 8.11 (br s, 1H) , 7.80-7.75 (m, 2H) , 7.70-7.65 (m, 2H) , 7.21-7.11 (m, 5H) , 5.22 (dd, Ji = 7.6 Hz, J2 = 8.8 Hz, 1H) , 3.60- 3.58 (m, 2H) .
To a solution of Compound 4 (29.5 mg, 0.1 mmol) in anhydrous methanol (5 mL) was added thionyl chloride (44 L, 0.6 mmol) dropwise at 0 °C. The solution was stirred overnight (about 18 hours) at room temperature. After concentration, the mixture was purified by column chromatography using hexane/EtOAc (5/1) as the eluent, and the product Compound 16 was obtained as white solid (27.8 mg, 90%, 97% ee) [Fu et al., Bioorg. Med. Chem. Lett. 17:1102-1106 (2007)]. The ee value was determined by HPLC analysis on a Chiralcel OJ column (25% isopropanol/hexanes, 0.5 mL/min) with tr = 28.1 min (major), 43.3 min (minor) . XH NMR (400 MHz, CDC13) δ 7.80-7.76 (m, 2H) , 7.71-7.66 (m, 2H) , 7.21-7.11 (m, 5H) , 5.16 (dd, Ji = 5.2 Hz, J2 = 11.2 Hz, 1H) , 3.78 (s, 3H) , 3.60 (ABqd, Ji = 5.2 Hz, J2 = 14.4 Hz, 1H) , 3.54 (ABqd, Ji = 11.2 Hz, J2 = 14.4 Hz, 1H) .
G. Synthesis of Boc-Protected Unnatural Amino Acid Derivatives via C(sp3)-H Olefination
NPhth 10 mol% Pd(OAc)2 Nphth ί 20 mol% L10 S^0
H^C0NHArF + ^C02Et 10 moW TFA » -N
1 (3.3 equiv) Ag2C03, toluene B02C-^ ArF
100 °C, 20 h 8, 93%
ArF = 4-(CF3)C6F4
Substrate 1 (0.1 mmol, 43.4 mg) [ Fu et al.r Bioorg. Med. Chem. Lett. 17:1102-1106 (2007)], Pd(OAc)2 (0.01 mmol, 2.3 mg) , Ligand L10 (0.02 mmol, 4.3 mg) , and Ag2C03 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. Ethyl acrylate (0.33 mmol, 35 μΙ , TFA (0.01 mmol, 1 μΐ) , and toluene (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/Et20 (5/1) as the eluent .
Ethyl 2- ( (4S) -5-oxo-4-phthalimido-l- (2,3,5,6- tetrafluoro-4- (trifluoromethyl) henyl) pyrrolidin-2- yl) -acetate (8)
Analysis of crude reaction mixture by 1H NMR showed a 2.2:1 average diastereomer ratio. After purification, Compound 8 was obtained as a white
solid (49.6 mg, 93%). XH NMR (400 MHz, CDC13) δ 7.91- 7.85 (m, 2H) , 7.79-7.75 (m, 2H) , 5.36-5.20 (m, 1H) , 4.80-4.60 (m, 1H) , 4.13-4.04 (m, 2H) , 3.06-2.93 (m, 1H), 2.77-2.63 (m, 2H) , 2.60-2.41 (m, 1H) , 1.25-1.19 (m, 3H) ; 13C NMR (100 MHz , CDCI3) 5169.4, 169.2, 169.1, 168.9, 167.1, 167.0, 134.4, 131.6, 123.7, 61.2, 54.1, 53.2, 48.6, 47.7, 39.2, 38.6, 31.2, 30.3, 13.91, 13.89; HRMS (ESI-TOF) Calcd for C23Hi6F7N205 [M+H]+: 533.0942; found: 533.0941.
Substrate Compound 8 (0.5 mmol, 266 mg) was weighed and placed in a round-bottom flask (25 mL) with a magnetic stir bar. DCM (1.5 mL) , EtOH (1.5 mL) , and ethylenediamine (2.5 mmol, 0.17 mL) were added. The reaction vessel was capped and the mixture was heated to 40 °C for 3 hours with vigorous stirring. Opon completion, the solvents were removed under reduced pressure. CuCl2 (1.25 mmol, 168 mg) and deionized water (15 mL) were added into the resulting mixture. The aqueous solution was extracted with EtOAc (3 x 20 mL) . The organic layer was washed with brine, dried over anhydrous Na2S04, filtered, and concentrated. The residue was dissolved in DCM (1.5 mL) without purification, and di-t-butyl dicarbonate (1.5 mmol, 0.35 mL) was added in the solution. The solvent was removed after one-hour reaction, and the mixture was purified by a silica gel-packed flash chromatography column using hexane/EtOAc (4/1 to 3/1) as the eluent.
Ethyl 2- ( (4S) -4- ( ( fc-butoxycarbonyl) amino) -5-oxo-l- (2 , 3 , 5 , 6-tetrafluoro-4- (trifluoromethyl) henyl) - pyrrolidin-2-yl) acetate (9)
After purification, Compound 9 was obtained as a white solid (181 mg, 72%). XH NMR (400 MHz, CDC13) δ 5.27-5.16 (m, 1H) , 4.62-4.44 (m, 2H) , 4.08- 4.00 (m, 2H) , 3.15-3.07 and 2.72-2.66 (m, 1H) , 2.63- 2.60 (m, 1H), 2.57-2.43 and 2.00-1.92 (m, 2H) , 1.471- 1.465 (m, 9H) , 1.22-1.17 (m, 3H) ; 13C NMR (150 MHz, CDCI3) 8171.9, 169.6, 169.1, 155.6, 155.5, 80.5,
80.4, 61.24, 61.22, 54.2, 53.4, 51.7, 50.1, 38.8,
38.5, 35.1, 34.2, 28.2, 13.9; HRMS (ESI-TOF) Calcd for C20H22F7N2O5 [M+H]+: 503.1411; found: 503.1415.
NHBoc
^,ο LiHMDS ^ NHBoc η / ^ THF,-78°C to Et°2C^v^CONHArF Et02C- ArF .20 »c 1 h
9 10, 90%, 95% ee
To a dried Schlenk tube (50 mL) equipped with a magnetic stir bar were added lactam Compound 9 (50.2 mg, O.lmmol) and 1 mL of anhydrous THF. After cooling to -78 °C, LiHMDS (0.5 M in 2- methyltetrahydrofuran, 0.5 mL, 0.5 mmol) was added dropwise within 5 minutes. The mixture was warmed up to -20 °C naturally in one hour. The reaction was then quenched with saturated NH4Cl/AcOH (v/v = 20/1) at -78 °C and exacted with EtOAc (3 x 6 mL) . The combined organic layer was washed with brine and
dried over anhydrous MgSC , filtered and concentrated. The crude product was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (10/1) as the eluent.
Ethyl (S ,E) -5- ( ( t-butoxycarbonyl) amino) -6-oxo-6~ ((2,3,5, 6-tetrafluoro-4- (trifluoromefchyl) henyl) - amino) hex-2-enoate (10)
After purification, Compound 10 was obtained as a white solid (45.2 mg, 90%, 95% ee) . The ee value was determined by HPLC analysis on a Chiralpak AD-H column (20% isopropanol/hexanes , 0.2 mL/min) with tr = 28.1 min (minor), 34.5 min (major). ¾ NMR (400 MHz, CDC13) δ 8.92 (br s, 1H) , 6.97-6.89 (m, 1H), 5.98 (d, J = 16.0 Hz, 1H) , 5.25-5.12 (m, 1H) , 4.56-4.44 (m, 1H) , 4.20 (q, J = 7.2 Hz, 2H) , 2.86-2.79 (m, 1H) , 2.76-2.68 (m, 1H) , 1.47 (s, 9H) , 1.29 (t, J = 7.2 Hz, 3H) ; 13C NMR (150 MHz, CDC13) 5169.1, 165.8, 156.5, 141.9, 125.5, 81.8, 60.6, 53.3, 33.5, 28.2, 14.2; HRMS (ESI-TOF) Calcd for
To a dried Schlenk tube (25 mL) were added Grubbs Catalyst, 2nd Generation (2.8 mg, 0.0035 mmol) , amide Compound 10 (35.1mg, 0.07 mmol) , DCM (1.5 mL) , and 1-octene (71.5 mg, d = 0.715 g/mL, 0.1
ml, 0.64 mmol) . The mixture refluxed under N2 atmosphere (oil bath, 50 °C) for 16 hours. The mixture was filtered through a small pad of Celite. The solvents were removed under reduced pressure and the resulting mixture was purified by preparative TLC using hexane/EtOAc (5/1) as the eluent to afford product Compound 11 as colorless oil (31.0 mg, 86%) .
t-Butyl (S) - (1-oxo-l- ( (2 , 3 ,5, 6-tetrafluoro-4- (trifluoromethyl) henyl) amino) undec-4-en-2- yl) carbamate (11)
JH NMR (400 MHz, CDC13) δ 8.85 (br s, 1H) , 5.96-5.89 and 5.66-5.59 (m, 1H) , 5.51-5.34 (m, 1H) , 5.22-5.04
(m, 1H), 4.38 (br s, 1H) , 2.74-2.49 (m, 2H) , 2.09- 1.97 (m, 2H), 1.46 (s, 9H) , 1.35-1.27 (m, 8H) , 0.88
(t, J= 6.6 Hz, 3H) ; 13C NMR (150 MHz, CDC13) δ169.9, 156.5, 136.4, 123.2, 81.3, 54.1, 34.5, 32.5, 31.7, 29.2, 28.8, 28.2, 22.6, 14.1; HRMS (ESI-TOF) Calcd for C23H30F7N2O3 [M+H]+: 515.2139; found: 515.2137.
The reaction of Grubbs Catalyst, 2nd Generation (2.8 mg, 0.0035 mmol), amide Compound 10 (35.3 mg, 0.07 mmol), DCM (1.5 ml), and 4- fluorostyrene (153.6 mg, d = 1.024 g/mL, 0.15 mL,
mmol) afforded Compound 12 as a white solid 3 mg, 69%) .
t-Butyl (S,E) - (5- (4-fluorophenyl) -1-oxo-l- ( (2, 3,5,6- tetrafluoro-4- (trifluoromethyl) henyl) amino) ent-4- en-2-yl) carbamate (12)
¾ NMR (600 MHz, CDC13) δ 8.87 (br s, 1H) , 7.34-7.29 (m, 2H) , 7.02-6.97 (m, 2H) , 6.50 (d, J = 15.6 Hz, 1H) , 6.11 (dt, Ji = 7.2 Hz, J2 = 15.6 Hz, 1H) , 5.19 (d, J = 7.8 Hz, 1H), 4.51 (br s, 1H) , 2.79-2.72 (m, 2H) , 1.43 (s, 9H) ; 13C NMR (150 MHz, CDC13) 6169.7, 162.4 (d, JFC = 245.7 Hz), 156.5, 133.5, 132.7, 127.8 (d, JFC = 8.0 Hz), 123.1, 115.5 (d, JFC = 21.5 Hz), 81.6, 54.1, 34.8, 28.2; HRMS (ESI-TOF) Calcd for C23H2oF8N203Na [M+Na]+: 547.1238; found: 547.1234.
13, 95%
To a round-bottom flask (25 mL) was added
Pd/C (10 wt. % loading on carbon, 5.0 mg) , amide Compound 10 (35.2 mg, 0.07 mmol), and EtOAc (1 mL) . The reaction tube was evacuated and back-filled with H2 (3 times, balloon) . After stirring at room temperature for 24 hours, the mixture was filtered through a small pad of Celite. The solvents were removed under reduced pressure and the resulting mixture was purified by preparative TLC using hexane/EtOAc (3/1) as the eluent to afford Compound 13 as colorless oil (33.4 mg, 95%).
Ethyl (S) -5- ( ( t-butoxycarbonyl) amino) -6-0x0-6- ( (2 , 3 , 5 , 6-tetrafluoro-4- (trifluoromethyl) henyl) - amino) hexanoate (13)
aH NMR (400 MHz, CDC13) δ 8.96 (br s, 1H) , 5.24 (br s, 1H) , 4.33 (br s, 1H) , 4.15 (q, J= 7.2 Hz, 2H) , 2.48- 2.35 (m, 2H), 2.04-1.93 (m, 1H) , 1.87-1.76 (m, 3H) , 1.47 (s, 9H) , 1.27 (t, J = 7.2 Hz, 3H) ; 13C NMR (150 MHz, CDCI3) 8173.5, 170.0, 156.6, 81.3, 60.7, 54.1, 33.4, 30.4, 28.2, 20.7, 14.2; HRMS (ESI-TOF) Calcd for C20H24F7N2O5 [M+H]+: 505.1568; found: 505.1567.
The reaction of Pd/C (10 wt. % loading on carbon, 5.0 mg) , amide Compound 11 (31.0 mg) , and
EtOAc (1 mL) afforded Compound 14 as colorless oil
(29.5 mg, 95%) .
t-Butyl (S) - (1-oxo-l- ((2,3,5, 6-tetrafluoro-4- (trifluoromethyl) phenyl) amino) undecan-2-yl) carbamate (14)
¾ NMR (600 MHz, CDC13) δ 9.00 (br s, 1H) , 5.22-5.20 (m, 1H) , 4.38-4.37 (m, 1H) , 1.95-1.89 (m, 1H) , 1.75-
1.66 (m, 1H) , 1.45-1.40 (m, 11H) , 1.34-1.26 (m, 12H) , 0.88 (t, J = 6.9 Hz, 3H) ; 13C NMR (150 MHz, CDC13) 5170.6, 156.6, 81.2, 54.6, 31.8, 31.5, 29.44, 29.38, 29.2, 28.2, 25.6, 22.7, 14.1; HRMS (ESI-TOF) Calcd for C23H31F7N203 a [M+Na]+: 539.2115; found: 539.2111.
IslHBoc Pd/c, H2 (1 atm) ' ^HB°C
CONHArp ^ „„ * ^^^^CONHArp EtOAc, rt, 40 mm
12 15, 97%
The reaction of Pd/C (10 wt. % loading on carbon, 5.0 mg) , amide Compound 12 (25.3 mg) , and EtOAc (1 mL) afforded Compound 15 as colorless oil (24.6 mg, 97%) .
t-Butyl (S) - (5- (4-fluorophenyl) -1-oxo-l- ((2,3,5,6- tetrafluoro-4- (trifluoromethyl) phenyl) amino) pentan-2- 1) carbamate (15)
1H NMR (600 MHz, CDC13) δ 8.88 (br s, 1H) , 7.13-7.10 (m, 2H) , 6.98-6.94 (m, 2H) , 5.14-5.12 (m, 1H) , 4.36 (br s, 1H) , 2.69-2.59 (m, 2H) , 2.00-1.94 (m, 1H) ,
1.76-1.70 (m, 3H) , 1.44 (s, 9H) ; 13C NMR (150 MHz,
CDC13) 5170.2, 161.3 (d, JFC = 242.3 Hz), 156.6, 136.9 (d, JFC = 3.5 Hz), 129.6 (d, JFC = 7.7 Hz), 115.2 (d,
JFC = 21.0 Hz), 81.4, 54.4, 34.5, 30.6, 28.2, 27.5;
HRMS (ESI-TOF) Calcd for C23H22F8N203Na [M+Na] + :
549.1395; found: 549.1394.
H. Synthesis and Reactivity of Palladacycle
Intermediates in C(sp3)-H Arylation
Intermediate A
72% (with CsF) 60% (with Ag2C03)
In a sealable tube (20 mL) , amide Compound 1 (43.4 mg, 0.10 mmol) , Pd(TFA)2 (33.2 mg, 0.10 mmol) , 2-picoline (18.6 mg, 0.2 mmol), and CsF (30.4 mg, 0.20 mmol) were dissolved in DCE (2 mL) . The reaction mixture was then tightly capped and stirred for 10 minutes at room temperature, and then heated up to 100 °C with vigorous stirring for 20 hours. The reaction mixture was then cooled to room temperature, and filtered through a small pad of Celite. The residue was purified by preparative TLC using hexane/EtOAc (1/2) as the eluent to afford
Intermediate A as a yellow solid (52.0 mg, 72%). HRMS (ESI-TOF) Calcd for C3oH22F7N403Pd [M+H]+: 725.0609; found: 725.0621. Intermediate A was recrystallized in DCM/hexane, and the structure was determined by X- ray diffraction.
Crystal Data and Structure Refinement for Intermediate A
CCDC-985676
Identification code Intermediate A
Empirical formula C31H23Cl2F7 403Pd
Molecular formula C30H2iF7N4O3Pd, C¾C12
Formula weight 809.83
Temperature 200(2) K
Wavelength 0^71073 A
Crystal system Triclinic
Space group PI
Unit cell dimensions a ^ 100..9436(12) A a = 110.701(3) b = 122..9351(14) A β = 108.032(3) c = 133..8591(16) A γ = 103.155(3)
Volume 1614.9(3) A3
Z 2
Density (calculated) 1.665 Mg/m3
Absorption coefficient 0.820 mm"1
F(000) 808
Crystal size 0.28 x 0.12 x 0.10 mm3 Crystal color, habit COLORLESS BLOCK
Theta range for data collectio■nn 1.74 to 26.43°.
Index ranges --113<=h<=13, -16<=k<=16, -17<=1<= Reflections collected 14965
Independent reflections 9256 [R(int) = 0.0366] Completeness to theta = 25.00° 99.9 % Absorption correction multi-scan / sadabs Max. and min. transmission 0.9225 and 0.8029 Refinement method FFuull-matrix least-squares on F2 Data / restraints / parameters 9256 / 94 / 876
Goodness-of-fit on F2 1.038
Final R indices [I>2sigma (I ) ] Rl = 0.0417, wR2 = 0.0927 R indices Call data) Rl = 0.0592, wR2 = 0.0986 Absolute structure parameter -0.01(2)
Largest diff . peak and hole 1.240 and -0.704 e.A"3
Intermediate B
In a sealable tube (20 mL) , amide Compound 1 (43.4 mg, 0.10 mmol) , Pd(TFA)2 (49.8 mg, 0.15 mmol) , L10 (42.6 mg, 0.20 mmol), and CsF (30.4 mg, 0.20 mmol) were dissolved in DCE (2 mL) . The reaction mixture was then tightly capped and stirred for 10 minutes at room temperature, and then heated up to 60 °C with vigorous stirring for 12 hours. The reaction mixture was then cooled to room temperature, and filtered through a small pad of Celite. The residue was purified by preparative TLC using hexane/EtOAc (1/2) as the eluent to afford Intermediate B as a yellow solid (78.0 mg, 75%). HRMS (ESI-TOF) Calcd for C52H42 7N405Pd [M+H]+: 1041.2073; found: 1041.2070. Intermediate B was recrystallized in DCM/hexane, and the structure was determined by X-ray diffraction.
Crystal Data and Structure Refii Lent for Intermediate B
CCDC-985677
Identification code Intermediate B
Empirical formula C ,2ClF,N4O5Pd
Molecular formula C52H4iF7N4OsPd, 0.5(C¾C12) Formula weight 1083.75
Temperature 150(2) K
Wavelength 0.71073 A
Crystal system onoclinic
Space group C2
Unit cell dimensions a 34.9648(19) A a = 90°.
b 15.3694(7) A β = 125.823(3)°. c 23.2457 (13) A γ = 90°.
Volume 10128.8(9) A3
Z 8
Density (calculated) 1.421 Mg/m3
Absorption coefficient 0.495 mm"1
F(000) 4408
Crystal size 0.20 χ 0.16 x 0.12 mm3
Crystal color, habit orange / block
Theta range for data collection 1.76 to 26.45° .
Index ranges -43<=h<=35, -19<=k<=19, 0<=1<=28
Reflections collected 20613
Independent reflections 20613 [R(int) = 0.0000]
Completeness to theta = 25.00° 99.9 %
Absorption correction multi-scan / sadabs
Max. and min. transmission 0.9430 and 0.9075
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 20613 / 82 / 1227
Goodness-of-fit on F2 1.049
Final R indices [I>2sigma (I) ] Rl = 0.0459, wR2 = 0.1080
R indices (all data) Rl = 0.0652, wR2 = 0.1137
Absolute structure parameter 0.043(18)
Largest diff. peak and hole 0.522 and -0.652 e.A"3
Metrical parameters for the structures of Intermediates A and Intermediate B are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers CCDC-985676, and CCDC- 985677, respectively.
Intermediate A (0.1 mmol, 72.4 mg) , and
Ag2C03 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a sealable tube (50 mL) with a magnetic stir bar. Iodobenzene (30.6 mg, 0.15 mmol), TFA (0.2 mmol, 22.8 mg) , and DCE (2 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was
cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexane/EtOAc mixtures (3/1) as the eluent to afford Compound 2 (24.6 mg,
Substrate Compound 1 (0.1 mmol, 43.4 mg) , Intermediate A (0.01 mmol, 7.2 mg) , and Ag2C03 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. Iodobenzene (30.6 mg, 0.15 mmol), TFA (0.02 mmol, 2 μΤ) , and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/EtOAc mixtures (30/1) as the eluent to afford Compound 2 (53.1 mg, 95% based on Compound 1 and Intermediate A) .
3a, 60%, d.r. > 20:1
Substrate Compound 2 (0.1 mmol, 51.0 mg) , Intermediate E (0.01 mmol, 10.4 mg) , 4-iodotoluene
(0.3 mmol, 65.4 mg) , and Ag2C03 (0.2 mmol, 55.0 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar. TFA
(0.02 mmol, 2 pL) and DCE (0.5 mL) were added. The reaction vessel was sealed and the mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 20 hours with vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using toluene/EtOAc mixtures (30/1) as the eluent to afford Compound 3a (39.8 mg, 60% based on Compound 2 and Intermediate B) . Analysis of crude reaction mixture by 1H NMR showed a > 20:1
diastereomer ratio.
A sealable pressure flask was charged with MeOH (99 mL) and the amide Compound 2d (6.46 mmol, 3.49 g) . BF3 -Et20 (6 equiv) was added dropwise via syringe, and the reaction vessel sealed. The mixture was heated to 100 °C for 20 hours, and then cooled to room temperature. Triethylamine (6 equiv) was then carefully added via syringe, and stirred for 10 minutes. The solvent was removed in vacuo, and the residue purified by column chromatography using
hexane/EtOAc (5/1) as the eluent to afford the desired product Compound 17 (87%, 1.91 g) . 1H NMR (400 MHz, CDC13) δ 7.76-7.74 (m, 2H) , 7.67-7.66 (m, 2H) , 7.12-7.09 (m, 1H) , 6.99-6.98 (m, 1H) , 6.76-6.75 (m, 1H), 6.70-6.67 ( , 1H) , 5.39-5.36 (m, 1H) , 3.78 (s, 3H) , 3.76 (s, 3H) , 3.66-3.63 (m, 1H) , 3.44-3.40 (m, 1H) .
NPhth N2H4-H20 NH2
C02Me MeOH, RT ¾02Me
OMe 20 h OMe
17 18, 77%
Phthalimido-protected amino ester Compound 17 (4.60 mmol, 1.56 g) was dissolved in MeOH (88 mL) , and N2H4 ·¾0 (4 equiv) was added. The reaction was stirred at room temperature for 20 hours, after which, the solvent was removed in vacuo. Saturated aqueous NaHC03 was added, and the solution extracted with EtOAc (3 x 50 mL) . The organic layer was washed with brine, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography using hexane/EtOAc (1/1) as the eluent to afford the desired product Compound 18 (77%, 0.74 g) (33). ¾ NMR (500 MHz, CDC13) δ 7.24-7.21 (m, 1H) , 7.13-7.11 (m, 1H) , 6.91-6.85 (m, 2H) , 3.83-3.79 (m, 4H) , 3.70 (s, 3H) , 3.12 (dd, Ji = 5.6 Hz, J2 = 13.3 Hz, 1H), 2.85 (dd, Ji = 8.2 Hz, J2 = 13.3 Hz, 1H) , 1.64 (br s, 2H) .
FmocCI
r* l] H2 10% aq. NaHC03 f^ jl NHFmoc
I¾ JL A^ *>» ^J^^k
] C02Me 1,4-dioxane, 0 °C to RT | C02Me
OMe 22 h OMe
18 19, 75%
Amino ester Compound 18 (3.54 mmol, 0.74 g) was taken up in 1,4-dioxane (18 mL) , and 10% aqueous
NaHC03 (11 mli) was added. The mixture was cooled to 0 °C in an ice bath and FmocCl (3.54 mmol, 1 equiv) was added. The ice bath was permitted to warm to room temperature overnight (about 18 hours) , after which H20 and EtOAc were added to the reaction mixture. The aqueous layer was then extracted with EtOAc (3 x 50 mL) and the combined organic layer was washed with brine, dried over anhydrous Na2SC filtered and concentrated. The residue was purified by column chromatography using hexane/EtOAc (5/1) as the eluent to afford the desired product Compound 19 (75%, 1.15 g) . ¾ NMR (400 MHz , CDC13) δ 7.75 (d, J = 7.6 Hz, 2H) , 7.56-7.51 (m, 2H) , 7.41-7.37 (m, 2H) , 7.31-7.22 (m, 3H) , 7.10-7.08 (m, 1H) , 6.92-6.86 (m, 2H) , 5.61 (d, J = 7.8 Hz, 1H) , 4.61-4.56 (m, 1H) , 4.32 (d, J= 6.7 Hz, 2H) , 4.18 (t, J = 7.1 Hz, 1H) , 3.82 (s, 3H) , 3.73 (s, 3H) , 3.17-3.08 (m, 2H) .
19 20, 70%
Methyl ester Compound 19 (2.55 mmol, 1.10 g) was dissolved in THF (18 mL) . The solution was cooled to 0 °C, and a cold solution of LiOH ·Η20 (5.10 mmol, 2 equiv) in H20 (18 mL) were added. The reaction was maintained at 0 °C and monitored by TLC.
After consumption of starting material, the reaction was acidified with HC1 (2 N) and extracted with EtOAc
(4 x 50 mL) . The combined organic layers were dried over anhydrous Na2SO¾ and concentrated. The residue was purified by column chromatography using hexane/EtOAc/MeOH (3/2/0.1) as the eluent to afford the desired product Compound (70%, 0.74 g) .
Spectral data agree with literature [Myers et al . , J.
Jim. Chem. Soc. 117:8488-8489 (1995)]. 1H NMR (400 MHz, CDC13) δ 7.75 (d, J= 7.6 Hz, 2H) , 7.54-7.49 (m, 2H) , 7.41-7.37 (m, 2H) , 7.31-7.24 (m, 3H) , 7.14 (d, J = 7.2 Hz, 1H) , 6.93-6.87 (m, 2H) , 5.68 (d, J= 7.3 Hz, 1H) , 4.60-4.54 (m, 1H) , 4.34 (d, J = 7.0 Hz, 2H) , 4.18 (t, J = 7.1 Hz, 1H) , 3.80 (s, 3H) , 3.23-3.13 (m, 2H) .
Intramolecular Isotope Effect and Ligand Acceleration
General Procedure
Substrate Compound 21 (0.1 mmol, 30.6 mg) , Pd(TFA)2 (0.01 mmol, 3.3 mg) , and Ag2C03 (0.15 mmol, 41.4 mg) were weighed out open to air and placed in a microwave tube (5 mL) with a magnetic stir bar.
4-Iodotoluene (0.15 mmol, 32.7 mg) , ligand (0.02 mmol), TFA (0.02 mmol, 2 μΐ,) , and DCE (0.5 mL) were added. The reaction vessel was sealed. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C under vigorous stirring. After a certain amount of time, the reaction mixture was cooled to room temperature . The solvents were removed under reduced pressure. All conversions were determined by analysis of the crude ¾ NMR (CDCI3) spectrum using CH2Br2 as the internal standard. The ratio of the arylated products was determined by ¾ NMR (CDC13) spectrum after the reaction mixture was purified by a silica gel-packed flash chromatography column using hexane/EtOAc (5/1) as the eluent. The results are shown below in Table 16.
Table 16
Pd(TFA)2 (10 mol%)
ligand (20 mol%)
CD3 TFA(20mol%) CD3 Me
Me-^CONHArF p-Tol-l (1.5 equiv* P"T°l ^CONHArF + Ρ"ΤθΙ ΟΟΝΗΑΓΡ
Ag2C03(1.5eq_iv) D D 21 DCE, 100 °C, time 22 22
Entry Ligand Time (h) Conversion (%)" Ratio (22/22')* 1 — 10 13 6.0
2 L7 10 45 8.1
3 L7 24 80 8.1
4 L10 5 100 10.7
^Conversions and ratios are the averaged results of three reproducible studies
NPhth
(l-tosyl-lH-indol-5-yl) propanamide
Substrate 25 (4 mmol, 1 g) , Pd(OAc)2 (0.6 mmol, 134 mg) , and AgOAc (8 mmol, 1.34 g) were weighed in air and placed in a microwave tube (200 mL) with a magnetic stir bar. The aryl iodide (10 mmol), ligand (1.2 mmol, 323mg) , TFA (0.8 mmol, 0.1 mL) , and DCE (40 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 80 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc as the eluent. Brown solid (1.28g, 62%). 1H NMR (400 MHz, CDC13) 89.12 (br, s,lH), 7.79 (d, J = 8 Hz, 1H) , 7.76-7.72 (m, 2H), 7.71-7.67 (m, 2H) , 7.46 (d, J = 4 Hz, 1H) , 7.33 (s, 1H) , 7.18 (d, J = 8 Hz, 2H) , 7.10 (d, J = 8 Hz, 1H) , 6.50 (d, J = 4 Hz, 1H) , 5.11(br, s,lH), 3.73 (s, 3H), 3.73-3.54 (m, 2H) , 2.33 (s, 3H) ;
Synthesis of Quinoline Ligands
The quinolone ligands were prepared according to the literature with small modifications by following the general reaction scheme shown below.
A mixture of aniline (30 mmol) , dioxinone (42 mmol), and NaOAc (30 mmol) in THF (6 mL) were heated under reflux for 24 hours. After cooling to room temperature, the mixture was diluted with AcOEt, washed with H20 and brine. The organic phase was dried with anhydrous Na2S04, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, hexane/EtOAc 5/1 to 2/1) .
2. Synthesis of Compound 8 [Zhang et al.. Org. Lett. 2007, 9:3651.]
To a 250 mL of round bottle flask were added Compound 7 (20 mmol) and K2C03 (46 mmol) and DMF (50 mL) . After stirring for 1 hour,
1 , 4-dibromobutane (22 mmol) was added. The reaction was stirred for additional 12 hours (monitored by TLC) before it was poured into water (150 mL) . The mixture was extracted with EtOAc (40 mL * 3). The combined organic layers was washed with HC1 (3 M, 40 mL x 2) and brine, dried with Na2S04, filtrated and concentrated under vacuum affording the crude product that could be used without further purification.
3. Synthesis of Quinoline Ligands [Zhang et al.. Org. Lett. 2007, 9:3651.]
To a 100 mL of round bottle were added Compound 8 (about 20 mmol) and 15 mL of H2S0 . The
mixture was stirred at 50 °C until full conversion of Compound 8 (about 1.5 hours) was noted. The reaction mixture was carefully poured into ammonia/ice (ammonia: 28%, 50 mL; ice: ~ 100 ml) . The mixture was extracted with EtOAc (60 ml 3) . The combined organic layers was washed with brine, dried with MgS04, filtrated and concentrated affording the crude product which was purified by flash column
chromatography (silica gel, hexane/EtOAc 4/1 to 1/1) .
2 , 5-Dimethyl~3 , 4-dihydro-2H-pyrano [2 , 3-b] uinoline (L10)
½ NMR (400 MHz, CDC13) δ 7.89 (d, J = 8.4 Hz, 1H) , 7.83 (d, J = 8.4 Hz, 1H) , 7.59-7.55 (m, 1H) , 7.39- 7.35 (m, 1H), 4.42-4.35 (m, 1H) , 3.04-2.98 (m, 1H) , 2.92-2.83 (m, 1H) , 2.56 (s, 3H) , 2.18-2.12 (m, 1H) , 1.90-1.76 (m, 1H) , 1.52 (d, J= 6.4 Hz, 3H) .
XH NMR (400 MHz, CDC13) δ 7.74 (d, J = 8.8 Hz, 1H) , 7.24 (d, J= 8.8 Hz, 1H) , 7.12 (s, 1H) , 4.40-4.34 (m, 1H) , 3.93 (s, 3H) , 3.02-2.96 (m, 1H) , 2.90-2.82 (m, 1H) , 2.53 (s, 3H), 2.18-2.11 (m, 1H) , 1.90-1.75 (m, 1H) , 1.52 (d, J = 6.4 Hz, 3H) .
L13
8-methoxy-2 , 5-dimethyl-3 , 4-dihydro-2H-pyrano [2 , 3-bJ - quinoline (L13 )
JH NMR (600 MHz, CDCI3) δ 7.74 (d, J = 9.6 Hz, 1 H) , 7.18 (d, J = 2.4 Hz, 1 H) , 7.00 (dd, Ji = 9.0 Hz, J2 = 2.4 Hz, 1 H) , 4.38-4.31 (m, 1 H) , 3.89 (s, 3 H) , 2.93 (ddd, Ji = 16.4 Hz, J2 = 3.9 Hz, J3 = 2.6 Hz, 1 H) , 2.85-2.76 (m, 1 H) , 2.48 (s, 3 H) , 2.15-2.08 (m, 1 H) , 1.82-1.73 (m, 1 H) , 1.50 (d, J= 6.6 Hz, 3 H) ; 13C NMR (150 MHz, CDC13) δ 160.4, 160.2, 147.4, 144.1, 124.4, 120.0, 116.0, 113.4, 106.5, 73.0, 55.3, 29.0, 23.2, 21.3, 13.9; HRMS (ESI-TOF) Calcd for Ci5H18N02 [M+H]+: 244.1338; found: 244.1340.
L14
2 , 5-dimethyl-7- (trifluoromethyl) -3 , 4-dihydro-2H- pyrano [2 , 3-i>] quinolone (L14)
½ NMR (400 MHz, CDC13) δ 8.18 (s, 1 H) , 7.91 (d, J = 8.8 Hz, 1 H) , 7.74 (d, J = 8.8 Hz, 1 H) , 4.48-4.37
(m, 1 H), 3.08-2.82 (m, 2 H) , 2.60 (s, 3 H) , 2.23- 2.13 (m, 1 H) , 1.90-1.76 (m, 1 H) , 1.54 (d, J = 6.4 Hz, 3 H) ; 13C NMR (150 MHz, CDC13) δ 161.4, 147.2, 145.0, 128.9, 125.5 (q, J= 32.1 Hz), 124.6 (q, J= 3.0 Hz), 124.5 (q, J= 270.3 Hz), 124.1, 121.3 (q, J = 4.4 Hz), 117.7, 73.6, 28.7, 23.5, 21.3, 14.0; HRMS
(ESI-TOF) Calcd for Ci5H15F3NO [M+H]+: 282.1106; found: 282.1113.
9-fluoro-2 , 5-dimethyl-3 , 4-dihydro-2H-pyrano [2 , 3-b] - quinolone (L15)
1H NMR (400 MHz, CDC13) δ 7.69-7.62 (m, 1 H) , 7.30- 7.25 (m, 2 H), 4.45-4.35 (m, 1 H) , 3.01 (ddd, J = 16.9 Hz, J2 = 5.3 Hz, J3 = 2.9 Hz, 1 H) , 2.94-2.83 (m, 1 H) , 2.56 (s, 3 H) , 2.20-2.12 (m, 1 H) , 1.88-1.76 (m, 1 H) , 1.52 (d, J = 6.4 Hz, 3 H) ; 13C NMR (150 MHz, CDCI3) δ 160.1, 157.0 (d, J= 252.6 Hz), 144.3 (d, J = 2.7 Hz), 135.9 (d, J= 11.4 Hz), 126.9 (d, J = 2.6 Hz), 123.0 (d, J = 7.7 Hz), 118.8 (d, J = 4.5 Hz), 117.3, 112.9 (d, J = 18.5 Hz), 73.3, 28.7, 23.6, 21.3, 14.2; HRMS (ESI-TOF) Calcd for C14H15FNO [M+H]+: 232.1138; found: 232.1140.
L16
2 , 5-dimethyl-8- (trifluoromethyl) -3 , 4-dihydro-2H- pyrano [2 , 3-i] quinolone (L16)
1H NMR (400 MHz , CDC13) δ 8.09 (s, 1 H) , 7.97 (d, J = 8.8 Hz, 1 H) , 7.53 (d, J = 8.8 Hz, 1 H) , 4.48-4.34 (m, 1 H), 3.10-2.80 (m, 2 H) , 2.56 (s, 3 H) , 2.24- 2.10 (m, 1 H), 1.90-1.76 (m, 1 H) , 1.53 (d, J = 6.4 Hz, 3 H) ; 13C NMR (150 MHz, CDC13) δ 160.8, 144.9, 144.1, 130.5 (q, J = 32.3 Hz), 126.7, 125.5 (q, J= 4.2 Hz), 124.4, 124.1 (q, J = 270.6 Hz), 119.3 (q, J = 2.9 Hz), 118.5, 73.5, 28.6, 23.6, 21.3, 14.0; Calcd for C15H15F3NO [M+H] + : 282.1106; found: 282.1105.
L17
8- ( text-butyl) -2 , 5-dimethyl-3 , 4-dihydro-2H- pyrano [2 , 3-b] uinolone (L17)
1H NMR (400 MHz, CDC13) δ 7.83-7.77 (m, 2 H) , 7.45 (dd, Ji = 9.0 Hz, J2 = 1.8 Hz, 1 H) , 4.42-4.28 (m, 1 H) , 2.96 (ddd, Ji = 16.8 Hz, J2 = 5.6 Hz, J3 = 2.8 Hz, 1 H) , 2.90-2.78 (m, 1 H) , 2.51 (s, 3 H) , 2.16-2.07 (m, 1 H) , 1.86-1.72 (m, 1 H) , 1.50 (d, J= 6.0 Hz, 3 H) , 1.39 (s, 9 H) ; 13C NMR (150 MHz, CDC13) δ 160.0, 151.9, 145.7, 143.7, 123.5, 123.0, 122.7, 122.3, 115.3, 73.0, 34.8, 31.1, 29.0, 23.3, 21.3, 13.7; HRMS (ESI-TOF) Calcd for Ci8H2 O [M+H]+: 270.1858; found: 270.1861.
L18
7- ( tert-butyl) -2 , 5-dimethyl-3 , 4-dihydro-2H- pyrano[2,3-Jb]quinoline (L18)
¾ NMR (400 MHz, CDC13) δ 7.80 (d, J = 2.4 Hz, 1 H) , 7.77 (d, J= 8.8 Hz, 1 H) , 7.66 (dd, J = 9.0 Hz, J2 = 1.8 Hz, 1 H) , 4.41-4.31 (m, 1 H) , 2.99 (ddd, Jx = 16.8 Hz, J2 = 5.6 Hz, J3 = 2.8 Hz, 1 H) , 2.92-2.80 (m, 1 H), 2.56 (s, 3 H), 2.18-2.09 (m, 1 H) , 1.87-1.74 (m, 1 H), 1.51 (d, J = 6.4 Hz, 3 H) , 1.41 (s, 9 H) ; 13C NMR (150 MHz, CDC13) δ 159.6, 146.3, 143.97, 143.95, 127.5, 124.5, 118.1, 115.9, 73.0, 34.9, 31.4, 29.0, 23.6, 21.4, 13.8; HRMS (ESI-TOF) Calcd for Ci8H24NO [M+H]+: 270.1858; found: 270.1856.
Structures of Additional Illustrative Substrates
Structures of Heterocyclic Iodides prepared for coupling laboratory
A. Preparation of Substrates General Method A (Amino Acid Substrates) :
Synthesis of phthalimide-protected amino acids: [Zhang et al., Angew. Chem. , Int. Ed. 52:13588
(2013) ]
Amino acid {1 equiv) and a2C03 (1 equiv) were dissolved in water (1M) at room temperature and W-ethoxy-carbonylphthalimide (1 equiv) was added to. the solution in small portions. The reaction was stirred for 3 hours at room temperature, and then the aqueous solution was cooled to °C and slowly acidified with aqueous HC1 (6 M) until pH of 1-2 was attained and white precipitate was observed. The precipitate was collected and washed with aqueous HC1 (20 mL, 1M) and EtOAc/hexanes = 1/5 (20 mL) to give phthalimide- protected amino acid in high yields.
Synthesis of W-methoxy amides from acids :
To a 250 mL round-bottom flask were added the acid (50 mmol, 1 equiv), DCM (100 mL) , and 0.05 mL DMF, oxalyl chloride (100 mmol, 8.5 mL, 2 equiv) was added slowly to the mixture, the above mixture were reacted for 3 hours at room temperature (rt) . Then, the excess of oxalyl chloride and DCM were removed in vacuo, and the crude acid chloride in DCM
(60 mL) was added slowly to a vigorously stirring solution of ¾N0Me-HCl (60 mmol, 5.0 g, 1.2 equiv) and NaHC03 (120 mmol, 2.4 equiv), in DCM (60 mL) and water
(60 mL) in ice cooled bath. The reaction mixture was stirred for 3 hours at 0 °C (monitored by TLC) , after which H20 and DCM was added to the reaction mixture. The aqueous layer was then extracted with DCM (3 χ ) and the combined organics were washed with brine, dried over Na2S04, filtered and concentrated. The product was recrystallized in DCM/hexanes to give the pure amide (over 90% yield) . Phth
H3C^CONHOMe
25
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -W-methoxypropanamide (25)
White solid, m.p. = 126-127 °C. ΧΗ NMR (400 MHz, CDC13) δ 8.93 (s, 1H) , 7.89-7.86 (m, 2H) , 7.78-7.75 (m, 2H), 4.97 (m, 1H) , 3.77 (s, 3H) , 1.70 (d, J = 7.4
Hz, 3H) . The ee value was determined by HPLC analysis on a Chiralcel OD-H column (20% isopropanol in hexanes, 0.4 mL/min) with tr = 32.2 minutes (minor), 37.8 minutes (major): 99% ee.
28
(S) -2- (l,3-Dioxoisoindolin-2-yl) -N-methoxy-3- phenylpropanamide (28)
1H NMR (600 MHz, CDC13) δ 9.31 (s, 1H) , 7.78-7.75 (m, 2H), 7.71-7.68 (m, 2H) , 7.18-7.11 (m, 5H) , 5.08 (m, 1H) , 3.75 (s, 3H) , 3.54-3.40 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.90, 166.58, 136.07, 134.40, 131.25, 128.89, 128.67, 127.10, 123.60, 64.52, 54.57, 34.75; HRMS (ESI-TOF) Calcd for C1BHnN20 [M+H] + : 325.1183; found: 325.1185. The ee value was determined by HPLC analysis on a Chiralcel® OD-H column (20% isopropanol in hexanes, 0.4 mL/min) with tr = 39.4 minutes (minor), 48.3 minutes (major) : 99% ee.
CH3
H3C CONHOMe
27a
N-Methoxy- -methylbutanamide (27 )
½ NMR (600 MHz, CDCI3) δ 8.38 (s, 1H) , 3.77 (s, 3H) , 1.99 (m, 1H), 1.73-1.66 (m, 1H) , 1.49-1.42 (m, 1H) , 1.15 (d, J = 7.2 Hz, 3H) , 0.92 (t, J = 7.8 Hz, 3H) ; 13C NMR (150 MHz, CDC13) δ 174.32, 64.47, 39.92, 27.00, 17.26, 11.78; HRMS (ESI-TOF) Calcd for C6Hi4N02 [M+H]+: 132.1019; found: 132.1020.
CH3
BnO^GONHOMe
27b
(S) -3- (Benzyloxy) -N-methoxy-2-methylpropanamide (27b)
1H NMR (600 MHz , CDC13) δ 8.83 (s, 1H) , 7.37-7.30 (in, 5H), 4.55-4.50 (m, 2H) , 3.73 (s, 3H) , 3.53-3.50 (m, 2H) , 2.49 (m, 1H) , 1.15 (d, J= 7.2 Hz, 3H) ; 13C NMR (150 MHz, CDCI3) δ 172.91, 137.44, 128.54, 127.97, 127.77, 73.48, 71.82, 64.31, 38.84, 13.36; HRMS (ESI- TOF) Calcd for Ci2Hi8N03 [M+H]+: 224.1281; found:
27c
3- (l,3-Dioxoisoindolin-2-yl) -U-methoxy-2- methylpropanamide (27c)
White solid, m.p. = 182-184 °C. ½ NMR (600 MHz,
CDCI3) δ 8.45 (s, 1H) , 7.86-7.85 (m, 2H) , 7.74-7.72
(m, 2H), 3.93 (dd, J = 13.5, 7.5 Hz, 1H) , 3.77 (dd, J = 14.1, 6.5 Hz, 1H) , 3.70 (s, 3H) , 2.73 (m, 1H) , 1.23
(d, J = 7.2 Hz, 3H) ; 13C NMR (150 MHz, CDC13) δ 171.23, 168.26, 134.19, 131.82, 123.44, 64.43, 40.88, 37.36, 15.31; HRMS (ESI-TOF) Calcd for C13Hi5N204
27d
2- (1 , 3-Dioxoisoindolin-2-yl) -W-methoxy-2- methylpropanamide ( 7d)
White solid, m.p. = 172-175 °C. H NMR (600 MHz, CDC13) δ 8.57 (s, 1H) , 7.81-7.78 (m, 2H) , 7.73-7.70 (ra, 2H) , 3.81 (s, 3H) , 1.84 (s, 6H) , 1.67 (m, 1H) ; 13C NMR (150 MHz, CDC13) δ 171.35, 168.44, 134.19, 131.77, 123.19, 64.15, 60.26, 24.51; HRMS (ESI-TOF) Calcd for C13H15N2O4 [M+H]+: 263.1026; found: 263.1022.
27e
(S) -3- (4- ( ( tert-Butyldimathylsilyl) oxy) henyl) -2- (l,3-dioxoisoindolin-2-yl) -W-methoxy propanamide (27e)
¾ NMR (600 MHz, CDC13) δ 9.30 (s, 1H) , 7.77-7.74 (m, 2H) , 7.70-7.67 (m, 2H) , 6.99 (d, J= 8.0 Hz, 2H) , 6.63 (d, J = 8.4 Hz, 2H) , 5.05 (m, 1H) , 3.75 (s, 3H) , 3.43-3.41 (m, 2H) , 0.89 (s, 9H) , 0.06 (s, 3H) , 0.05 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.90, 166.70, 154.60, 134.33, 131.24, 129.90, 128.65, 123.54, 120.37, 64.50, 54.76, 34.05, 25.62, 18.15, -4.55; HRMS (ESI-TOF) Calcd for C24H3iN205Si [M+H]+: 455.1997;
found: 455.2000.
NPhth
H3C< / .CONHOMe
27f
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxybutanamide (27f)
White solid, m.p. = 153-155 °C. ¾ NMR (600 MHz,
CDCI3) δ 9.22 (s, 1H), 7.89-7.88 (m, 2H) , 7.78-7.76 (m, 2H) , 4.76 (m, 1H) , 3.76 (s, 3H) , 2.23-2.18 (m, 2H) , 0.94 (t, J= 7.5 Hz, 3H) ; 1C NMR (150 MHz,
CDCI3) δ 168.15, 161.93, 134.54, 131.44, 123.75, 64.57, 55.29, 22.43, 10.77; HRMS (ESI-TOF) Calcd for Ci3H15N204 [M+H] + : 263.1026; found: 263.1023.
NPhth
i
CONHOMe
27g
1- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxycyclobutane-1- carboxamlde (27g)
White solid, m.p. = 196-200 °C. XH NMR (600 MHz, CDC13) δ 8.93 (s, 1H) , 7.85-7.82 (m, 2H) , 7.76-7.73 (m, 2H) , 3.76 (s, 3H) , 3.02-2.98 (m, 2H) , 2.74-2.68 (m, 2H) , 2.13-2.10 (m, 1H) , 1.98-1.95 (m, 1H) ; 13C NMR (150 MHz, CDCI3) δ 169.35, 167.87, 134.42, 131.77, 123.46, 64.45, 59.19, 31.78, 17.58; HRMS (ESI-TOF) Calcd for C14H15 2O [ +H] + : 275.1026; found: 275.1029.
27h
1- (1 , 3-Dioxoisoindolin-2-yl) -li-methoxycyclopropane-1- carboxamide (27h)
White solid, m.p. = 208-212 °C. ½ NMR (600 MHz,
CDCI3) δ 8.52 (s, 1H) , 7.90-7.88 (m, 2H) , 7.80-7.79 (m, 2H) , 3.70 (s, 3H) , 1.87-1.85 (m, 2H) , 1.33-1.31 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 168.56, 167.81, 134.74, 131.29, 123.78, 64.53, 31.86, 16.25; HRMS (ESI-TOF) Calcd for C13H13N20 [M+H]+: 261.0870; found: 261.0871.
B. Preparation of Heterocyclic Iodides
Sodium hydride (60% dispersion in mineral oil, 2.4 g, 60.0 mmol) was suspended in 50 ml N,N- dimethylformamide (DMF) and the mixture was cooled in an ice-bath. A solution of 5-iodo-lff-indole (9.72 g, 40.0 mmol) in 25 ml DMF was added dropwise over 10 minutes and the mixture was stirred for 30 minutes. A solution of 4-methylbenzene-l-sulfonyl chloride (9.17 g, 48.0 mmol) in 25 ml DMF was added dropwise and the mixture was stirred for 2 hours, warming to room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous NaHC03, dried over MgS04, filtered and evaporated. The residue was purified using the hexanes/EtOAc as eluent (100: 0 to 90:10) to give 14.69 g (93%) of the title compound as a white solid.
5-Iodo-l-tosyl-lH-indole
1H NMR (400 MHz, CDC13) δ 7.87 (d, J = 1.2 Hz, 1H) , 7.76-7.72 (m, 3H) , 7.68-7.56 (m, 1H) , 7.52 (d, J = 3.6 Hz, 1H) , 7.23 (d, J = 8.4 Hz, 2H) , 6.57 (d, J = 3.6 Hz, 1H) , 2.35 (s, 3H) .
An oven dried, sealable glass tube was charged with a magnetic stir bar, 6-bromoindole (0.98 g, 5.0 mmol), freshly ground sodium iodide (1.52 g, 10.0 mmol), and copper (I) iodide (100 mg, 0.5 mmol). The vessel was then fitted with a rubber septum, evacuated under vacuum and backfilled with argon. This process was repeated three times. The vessel was then charged with 1,4-dioxane (5 mL) followed by N, N' -dimethylethylenediamine (0.12 mL, 1.0 mmol) via
syringe . The rubber septum was removed and the reaction vessel immediately sealed tightly with a Teflon screw cap and heated to 110 °C for 22 hours. After cooling to room temperature, the reaction was diluted with saturated aqueous NH4C1 (30 mL) and extracted with DCM (4 χ 25 mL) . The combined organic layers were washed with brine (30 mL) and dried over Na2S04, then concentrated to a brown residue. The residue was triturated in hexanes and concentrated to provide 6-iodo-lJT-indole as a crude product.
[Anzalone et al., Angew. Chem. , Int. Ed. 52:650
(2013) . ]
Sodium hydride (60% dispersion in mineral oil, 0.3 g, 7.5 mmol) was suspended in 5 ml DMF and the mixture was cooled in an ice-bath. A solution of 6-iodo-lH-indole in 1 ml DMF was added dropwise over 5 minutes and the mixture was stirred for 30 minutes. A solution of 4-methylbenzene-l-sulfonyl chloride (1.18 g, 6.0 mmol) in 2 ml DMF was added dropwise and the mixture was stirred for 2 hours, warming to room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous NaHC03, dried over MgS04, filtered and evaporated. The residue was purified using the hexanes/EtOAc as eluent (100/0 to 90/10) to give 1.51 g (76%) of the title compound as a gray solid.
6-Iodo-l-tosyl-lH-indole
XH NMR (400 MHz, CDCI3) δ 8.36 (s, 1H) , 7.76 (d, J = 8.4 Hz, 2H) , 7.52 (dd, J = 8.4, 1.2 Hz, 1H) , 7.48 (d, J = 3.6 Hz, 1H) , 7.28-7.25 (m, 4H) , 6.60 (d, J = 3.6 Hz, 1H) , 2.36 (s, 3H) .
Sodium hydroxide (0.3 g, 6 mmol) was suspended in 10 ml DCM. 5-iodo-lfi-indazole (448 mg, 2 mmol) was added, and the mixture was stirred for 30 minutes. A solution of 4-methyl-benzene-l-sulfonyl chloride (456 mg, 2.4 mmol) in 2 mL DCM was added dropwise and the mixture was stirred for several hours. The mixture was partitioned with water. The organic layer was washed with saturated aqueous NaHC03, dried over MgS04, filtered and evaporated. The residue was purified via column chromatography on silica gel using the hexanes/EtOAc as eluent (100/0 to 90/10) to give 517 mg (65%) of the title compound as a gray solid.
5-Iod.o-l-tosyl-lff-indazole
¾ NMR (600 MHz, CDC13) δ 8.09 (d, J= 1.2 Hz, 1H) , 8.05-8.04 (m, 1H) , 8.00-7.99 (m, 1H) , 7.86-7.84 (m, 2H) , 7.81-7.79 (m, 1H) , 7.26-7.25 (m, 2H) , 2.37 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 145.72, 139.85, 139.53, 137.64, 134.28, 130.22, 129.95, 128.01, 127.60, 114.90," 87.92, 21.67; HRMS (ESI-TOF) Calcd for C14Hi2lN202S [M+H] + : 398.9659; found: 398.9663.
Sodium hydroxide (0.3 g, 6 mmol) was suspended in 10 ml DCM. 5-iodo-lif-indazole (448 mg, 2 mmol) was added, and the mixture was stirred for 30 minutes. A solution of 4-methyl-benzene-l-sulfonyl chloride (456 mg, 2.4 mmol) in 2 mL DCM was added
dropwise and the mixture was stirred for several hours. The mixture was partitioned with water. The organic layer was washed with saturated aqueous NaHC03, dried over MgS04, filtered and evaporated. The residue was purified via column chromatography on silica gel using the hexanes/EtOAc as eluent (100/0 to 90/10) to give 358 mg (45%) of the title compound as a gray solid.
6-Iodo-l-tosyl-lii-indazol
½ NMR (600 MHz , CDC13) δ 8.64 (d, J = 0.6 Hz, 1H) , 8.12 (d, J= 0.6 Hz, 1H), 7.89-7.87 (m, 2H) , 7.64- 7.62 (m, 1H), 7.43-7.41 (m, 1H) , 7.29-7.27 (m, 2H) , 2.38 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 145.73, 141.06, 140.90, 134.34, 133.33, 129.98, 127.68, 125.00, 122.37, 122.18, 95.55, 21.68; HRMS (ESI-TOF) Calcd for C14H12IN202S [M+H]+: 398.9659; found:
An oven dried, sealable glass tube was charged with a magnetic stir bar, 3-bromoqunoline (1.04 g, 5.0 mmol), freshly ground sodium iodide (1.52 g, 10.0 mmol), and copper (I) iodide (100 mg, 0.5 mmol). The vessel was fitted with a rubber septum, evacuated under vacuum and backfilled with argon. This process was repeated three times. The vessel was then charged with 1,4-dioxane (5 mL) followed by N, N' -dimethylethylenediamine (0.12 mL, 1.0 mmol) via syringe. The rubber septum was removed and the reaction vessel immediately sealed tightly with a Teflon screw cap and heated to 110 °C for 22 hours. After cooling to room temperature, the
reaction was diluted with saturated aqueous NH4C1 (30 mli) and extracted with DCM (4 χ 25 mL) . The combined organic layers were washed with brine (30 mL) and dried over Na2S04, then concentrated to a brown residue. The residue was recrystallized in
hexanes/EtOAc to provide 3-iodoqunoline (1.15g, 90%). 3-Iodoquinoline
H NMR (600 MHz, CDC13) δ 9.04 (d, J = 1.8 Hz, 1H) , 8.55-8.54 (m, 1H) , 8.08-8.06 (m, 1H) , 7.75-7.71 (m, 2H) , 7.58-7.56 (m, 1H) ; 13C NMR (150 MHz, CDC13) δ 155.57, 146.34, 143.71, 130.03, 130.01, 129.50, 127.41, 126.79, 89.77; HRMS (ESI-TOF) Calcd for C9H7IN [M+H]+: 255.9618; found: 255.9623.
The starting material (638 mg, 2.5 mmol) was dissolved in methanol (20 mL) , and the methanol solution was transferred to a 250 mL pressure vessel containing Cul (47.6 mg, 0.25 mmol, 10.0 mol%) , phenanthroline (90.0 mg, 0.5 mmol, 20.0 mol%) and KI (0.622 g, 3.76 mmol, 1.50 equiv) . The mixture was stirred at room temperature, and water (5 mL) was added. The flask was sealed under air, and the mixture was heated at 80 °C for 1 hour, over which time the reaction was monitored by TLC. The reaction was cooled to room temperature, water (25 mL) was added, and the mixture was extracted with Et20 (3 χ 25 mL) . The combined organic phases were washed with brine (25 mL) , dried with MgSO^, and concentrated in vacuo. After purification by column chromatography using hexanes/EtOAc (20/1) as the eluent, the product was obtained as a white solid (593 mg, 93%)
[Partridge et al., Org. Lett. 15:140 (2013)].
Partridge et al., Org. Lett. 15:140 (2013)
7-Iodoquinoline
1H NMR (600 MHz, CDC13) δ 8.91 (dd, J= 4.2, 1.8 Hz, 1H) , 8.55-8.54 (m, 1H) , 8.13-8.11 (m, 1H) , 7.81 (dd, J = 8.4, 1.8 Hz, 1H) , 7.54 (d, J = 8.4 Hz, 1H) , 7.42 (dd, J" = 8.4, 4.2 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 151.07, 148.94, 138.53, 135.99, 135.30, 128.90, 127.25, 121.60, 95.47; HRMS (ESI-TOF) Calcd for C9H7IN [M+H]+: 255.9618; found: 255.9621.
(2-Chloro-4-iodopyridin-3-yl) methanol
¾ NMR (600 MHz, CDC13) δ 7.91 (d, J = 4.8 Hz, 1H) , 7.75 (d, J = 5.4 Hz, 1H) , 5.00-4.99 (m, 2H) , 2.22 (br, 1H) ; 13C NMR (150 MHz, CDC13) δ 150.89, 149.05, 136.86, 134.34, 113.30, 66.94; HRMS (ESI-TOF) Calcd for C6H6C1IN0 [M+H]+: 269.9177; found: 269.9181.
General Reaction Scheme :
General procedure for monoarylation with aryl iodides :
The starting material Compound 25 (0.1 mmol, 24.8 mg) , Pd(OAc)2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in
a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol) , 2- picoline (20 mol%, 2 pL) , hexafluoro-2-propanol (HFIP) (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent.
28
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -W-methoxy-3- phenylpropanamide (28)
Substrate Compound 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28 was obtained as a white solid (29.8 mg, 90%). (For the NMR data, see the substrate preparation section.)
28a
(S) -2- (l,3-Dioxoisoindolin-2-yl) -li-methoxy-3- (p-tolyl) ropanamide (28a)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28a was obtained as a white solid (31.0 mg, 92%). XH NMR (600 MHz, CDC13) δ 9.34 (s, 1H) , 7.78-7.75 (m, 2H) , 7.70-7.68 (m, 2H) , 7.03 (d, J = 7.8 Hz, 2H) , 6.97 (d, J = 7.8 Hz, 2H) , 5.06 (m, 1H), 3.74 (s, 3H) , 3.47 (m, 2H) , 2.21 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 167.93, 166.64, 136.63, 134.34, 132.90, 131.31, 129.35, 128.71, 123.57, 64.49, 54.62, 34.34, 20.99; HRMS (ESI-TOF) Calcd for ¾9Η19 2θ [M+H]+: 339.1339; found: 339.1338. The ee value was determined by HPLC analysis on a Chiralcel OD-H column (20% isopropanol in hexanes, 0.4 mL/min) with tr = 42.5 minutes (minor), 45.6 minutes (major): 99% ee.
28b
(S) -2- (l,3-Dioxoisoindolin-2-yl) -AT-methoxy-3- (m-tolyl) propanamide (28b)
Substrate. 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by "Ή NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28b was obtained as a white solid (22.1 mg, 65%). 1H NMR (600 MHz, CDC13) δ 9.29 (s, 1H) , 7.78-7.75 (m, 2H) , 7.70-7.67 (m, 2H) ,
7.05 (t, J = 7.5 Hz, 1H) , 6.95-6.92 (m, 3H) , 5.06 (m, 1H) , 3.74 (s, 3H), 3.52-3.44 (m, 2H) , 2.17 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.92, 166.59, 138.28, 135.98, 134.36, 131.31, 129.69, 128.53, 127.81, 125.85, 123.56, 64.50, 54.65, 34.70, 21.19; HRMS (ESI-TOF) Calcd for C19H19N2O4 [M+H] + : 339.1339; found: 339.1337.
28c
(S) -3- ( [1, 1 ' -Biphenyl] -4-yl) -2- (1,3-dioxoisoindolin- 2-yl) -N-methoxypropanamide (28c)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28c was obtained as a yellow solid (25.4 mg, 64%). m.p. = 107-110 °C. 1R NMR (600 MHz, CDCI3) δ 9.32 (s, 1H) , 7.79-7.76 (m, 2H) , 7.70-7.67 (m, 2H) , 7.47 (d, J = 7.2 Hz, 2H) , 7.41 (d, J = 8.4 Hz, 2H) , 7.40-7.36 (m, 2H) , 7.31-7.28 (m, 1H) , 7.23 (d, J = 7.8 Hz, 2H) , 5.13 (m, 1H) , 3.76 (s, 3H) , 3.57 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.93, 166.56, 140.44, 139.81, 135.09, 134.41, 131.25, 129.30, 128.68, 127.29, 127.25, 126.87, 123.63, 64.54, 54.46, 34.40; HRMS (ESI-TOF) Calcd for
C24H21 2O4 [M+H]+: 401.1496; found 401.1497.
NPhth
CONHOMe
28d
(S) -2- (l,3-Dioxoiso ndolin-2-yl) -Ii-methoxy-3- (4-methoxyphenyl) propanam de (28d)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, 28d was obtained as a white solid
(25.3 mg, 72%). XH NMR (600 MHz, CDC13) δ 9.32 (s, 1H) , 7.79-7.76 (m, 2H) , 7.71-7.68 (m, 2H) , 7.06 (d, J = 8.4 Hz, 2H) , 6.70 (d, J= 8.4 Hz, 2H) , 5.05 (m, 1H), 3.75 (s, 3H) , 3.69 (s, 3H) , 3.45 (m, 2H) ; 13C NMR
(150MHz, CDC13) δ 167.94, 166.67, 158.51, 134.37, 131.27, 129.90, 127.93, 123.60, 114.06, 64.51, 55.15, 54.75, 33.94; HRMS (ESI-TOF) Calcd for Ci9Hi9N205
28e
(S) -2- (1 ,3-Dioxoisoindolin-2-yl) -N-methoxy-3- (3-methoxyphenyl) propanamxde (28e)
Substrate 1 was arylated following the general arylation procedure. Analysis of crude reaction mixture by XH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28e was obtained as a white solid (29.3 mg, 83%). ¾ NMR (600 MHz, CDC13) δ
9.36 (s, 1H) , 7.79-7.76 (m, 2H) , 7.71-7.68 (m, 2H) , 7.07 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H) , 6.69 (s, 1H) , 6.67-6.65 (m, 1H) , 5.10 (m, 1H) , 3.75 (s, 3H) , 3.66 (s, 3H), 3.55-3.41 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.89, 166.52, 159.66, 137.61, 134.38, 131.29, 129.66, 123.58, 121.18, 114.07, 113.02, 64.50, 55.08, 54.43, 34.75; HRMS (ESI-TOF) Calcd for C19Hi9 205 [M+H] + : 355.1288; found: 355.1291.
28f
(S) -2- (1 , 3-dioxoisoindolin-2-yl) -W-methoxy-3- (2-methoxyphenyl)propanamids (28f)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28f was obtained as a white solid (27.0 mg, 76%). ½ NMR (600 MHz, CDC13) δ 9.23 (s, 1H), 7.77-7.75 (m, 2H) , 7.70-7.67 (m, 2H) , 7.14-7.13 (m, 1H) , 7.03 (dd, 3 = 7.2, 1.8 Hz, 1H) , 6.76-6.74 (m, 1H) , 6.73-6.70 (m, 1H) , 5.26 (m, 1H) , 3.76 (s, 3H) , 3.74 (s, 3H) , 3.54-3.40 (m, 2H) ; 13C NMR (150 MHz, CDCI3) δ 167.83, 166.89, 157.47, 134.18, 131.47, 131.01, 128.62, 124.44, 123.42, 120.54, 110.28, 64.49, 55.18, 52.75, 30.40; HRMS (ESI-TOF) Calcd for C19Hi9 205 [M+H]+: 355.1288; found: 355.1291.
28g
(S) -2- (1 , 3-Dioxoisoindolin~2-yl) -3- (4-fluorophenyl) - N-iuethoxypropanamide (28g)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28g was obtained as a white solid (27.8 mg, 81%). m.p. = 135-137 °C. ¾ NMR
(600 MHz, CDC13) δ 9.44 (s, 1H) , 7.80-7.76 (m, 2H) , 7.72-7.68 (m, 2H) , 7.12-7.10 (m, 2H) , 6.85 (t, J= 8.4 Hz, 2H) , 5.04 (m, 1H) , 3.74 (s, 3H) , 3.56-3.40
(m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.84, 166.40, 161.80 (d, Jjrc = 243.9 Hz), 134.47, 131.80, 131.17, 130.43 (d, JFC = 8.0 Hz), 123.63, 115.52 (d, JFC = 21.3 Hz), 64.50, 54.39, 33.88; HRMS (ESI-TOF) Calcd for Ci8HiGFN204 [M+H]+: 343.1089; found:. 343.1086.
28h
(S) -2- (l,3-dioxoisoindolin-2-yl) -3- (3-fluorophenyl) - N-methoxypropanamide (28h)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28h was obtained as a
white solid (24.3 mg, 71%). m.p. = 125-127 °C. 1H NMR (600 MHz, CDC13) δ 9.47 (s, 1H) , 7.78-7.77 (m, 2H) , 7.71-7.70 (m, 2H) , 7.15-7.12 (m, 1H) , 6.94 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 10.2 Hz, 1H) , 6.82 (t, J = 8.4 Hz, 1H), 5.05 (m, 1H) , 3.74 (s, 3H) , 3.52 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.80, 166.25, 162.72 (d, JFC = 245.1 Hz), 138.69, 134.47, 131.19, 130.14 (d, J" FC = 8.4 Hz), 124.57 (d, J" FC = 2.9 Hz), 123.64, 115.89 (d, JFc = 20.7 Hz), 114.04 (d, JFC = 20.9 Hz), 64.48, 54.03, 34.34; HRMS (ESI-TOF) Calcd for
28i
(S) -3- (4-Chlorophenyl) -2- (1 , 3-dioxoisoindolin-2-yl) - N-methoxypropanamide (281)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28i was obtained as a white solid (22.6 mg, 63%). ½ NMR (600 MHz, CDC13) δ 9.33 (s, 1H), 7.80-7.77 (m, 2H) , 7.73-7.70 (m, 2H) , 7.14 (d, J = 8.4 Hz, 2H) , 7.09 (d, J = 8.4 Hz, 2H) , 5.04 (m, 1H) , 3.75 (s, 3H) , 3.49 (m, 2H) ; 13C NMR (150 MHz, CDCI3) δ 167.82, 166.33, 134.53, 132.92, 131.14, 130.24, 128.81, 123.70, 64.55, 54.19, 34.00; HRMS (ESI-TOF) Calcd for Ci8H16ClN204 [M+H] + : 359.0793; found: 359.0791.
28j
(S) -3- (4-Bromophenyl) -2- (1 , 3-dioxoisoindolin-2-yl) -N- methoxypropanamide (28j)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28j was obtained as a white solid (28.6 mg, 71%). 1H NMR (600 MHz , CDC13) δ 9.27 (s, 1H), 7.80-7.77 (m, 2H) , 7.73-7.70 (m, 2H) , 7.30 (d, J" = 8.4 Hz, 2H) , 7.03 (d, J = 7.2 Hz, 2H) , 5.06 (m, 1H) , 3.75 (s, 3H) , 3.48 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.82, 166.31, 135.06, 134.55, 131.77, 131.12, 130.60, 123.72, 121.05, 64.57, 54.15, 34.08; HRMS (ESI-TOF) Calcd for CiBHi6BrN204 [M+H] + : 403.0288; found: 403.0284.
28k
(S) -2- (l,3-dioxoisoindolin-2-yl) -3- (3-iodophenyl) - W-methoxypropanamide (28k)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28k was obtained as a white solid (22.1 mg, 49%). ¾ NMR (600 MHz, CDC13) δ 9.27 (s, 1H), 7.82-7.79 (m, 2H) , 7.74-7.72 (m, 2H) ,
7.47-7.45 (m, 2H) , 7.14 (d, J= 7.2 Hz, 1H) , 6.93 (t, J = 7.8 Hz, 1H) , 5.01 (m, 1H) , 3.75 (s, 3H) , 3.47- 3.45 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.82, 166.14, 138.53, 137.98, 136.18, 134.55, 131.15, 130.36, 128.16, 123.73, 94.39, 64.58, 54.25, 34.23; HRMS (ESI-TOF) Calcd for Ci8Hi6I 204 [M+H]+: 451.0149; found: 451.0143.
281
(S) -2- (l,3-Dioxoisoindolin-2-yl) -Ii-methoxy-3- (4- (trifluoromethyl) henyl) ropanamide (281)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 281 was obtained as a white solid (28.0 mg, 71%) . m.p. = 137-139 °C. 1H NMR (600 MHz, CDC13) δ 9.43 (s, 1H) , 7.79-7.76 (m, 2H) , 7.73-7.70 (m, 2H) , 7.43 (d, J= 7.8 Hz, 2H) , 7.28 (d, J = 7.2 Hz, 2H) , 5.10 (m, 1H) , 3.75 (s, 3H) , 3.59 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.78, 166.16, 140.33, 134.57, 131.12, 129.67-129.03, 125.57 (q, JFC = 3.5 Hz) 123.98 (q, JFC = 270.4 Hz), 123.70, 64.53, 53.84, 34.41; HRMS (ESI-TOF) Calcd for
28m
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy-3- (4- (trifluoromethoxy) henyl) propanamide (28m)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28m was obtained as a white solid (33.6 mg, 82%) . JH NMR (600 MHz, CDC13) δ 9.41 (s, 1H), 7.79-7.76 (m, 2H) , 7.72-7.69 (m, 2H) , 7.18 (d, J = 7.8 Hz, 2H) , 7.02 (d, J = 7.8 Hz, 2H) , 5.07 (m, 1H) , 3.74 (s, 3H) , 3.53 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.83, 166.34, 148.19, 134.88, 134.53, 131.15, 130.34, 123.65, 121.11, 120.32 (q, JFC = 255.5 Hz), 64.51, 54.14, 33.99; HRMS (ESI-TOF) Calcd for Ci9Hi6F3N205 [M+H]+: 409.1006; found: 409.1013.
28n
Methyl (S) -4- (2- (1 , 3-dioxoisoindolin-2-yl) -3- (methoxyamino) -3-oxopropyl)benzoate (28n)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products . After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent. Compound 28n was obtained as a white solid (31.3 mg, 82%) . 1H NMR (600 MHz , CDC13) δ 9.49 (s, 1H) , 7.82 (d, J = 8.4 Hz, 2H) , 7.76-7.63 (m, 2H), 7.70-7.66 (m, 2H) , 7.22 (d, J = 7.8 Hz, 2H) , 5.10 (m, 1H) , 3.83 (s, 3H) , 3.58 (m, 2H) ; 13C NMR (150 MHz, CDCI3) δ 167.72, 166.82, 166.18, 141.64, 134.48,
131.12, 129.91, 128.97, 128.89, 123.65, 64.50, 53.83, 52.07, 34.56; HRMS (ESI-TOF) Calcd for C2oHi9 205
28o
methyl (S) -3- (2- (1 , 3-dioxoisoindolin-2-yl) -3- (methoxyamino) -3-oxopropyl)benzoate (28o)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28o was obtained as a white solid (30.9 mg, 81%). XH NMR (600 MHz, CDC13) δ 9.40 (s, 1H) , 7.82-7.79 (m, 2H) , 7.78-7.76 (m, 2H) , 7.71-7.69 (m, 2H) , 7.37 (d, J= 7.2 Hz, 1H) , 7.26- 7.25 (m, 1H) , 5.10 (m, 1H) , 3.82 (s, 3H) , 3.76 (s, 3H) , 3.59-3.57 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.78, 166.72, 166.14, 136.64, 134.44, 133.50, 131.21, 130.44, 130.06, 128.76, 128.37, 123.65, 64.51, 54.27, 52.10, 34.42; HRMS (ESI-TOF) Calcd for Ο20Ηι9Κΐ2θ6 [M+H] + : 383.1238; found: 383.1240.
28p
(S) -3- (4-Ace ylphenyl) -2- (1 , 3-dioxoisoindolin-2-yl) - N-methoxypropanamide ( 8p)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude
reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28p was obtained as a white solid (26.3 mg, 72%). ¾ NMR (600 MHz, CDC13) δ 9.55 (s, 1H) , 7.76-7.74 (m, 4H) , 7.71-7.68 (m, 2H) , 7.25 (d, J = 7.8 Hz, 2H) , 5.11 (m, 1H) , 3.75 (s, 4H) , 3.59 (m, 2H) , 2.49 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 197.90, 167.72, 166.11, 141.94, 135.84, 134.51, 131.14, 129.17, 128.70, 123.67, 64.49, 53.80, 34.54, 26.52; HRMS (ESI-TOF) Calcd for C2oH19 205 [M+H]+: 367.1288; found: 367.1286.
28q
(S) -3- (2 , 3-Dimethoxyphenyl) -2- (1 , 3-dioxoisoindolin- 2-yl) -W-methoxypropanamide (28q)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28q was obtained as a white solid (22.8 mg, 60%). ½ NMR (600 MHz, CDC13) δ 9.27 (s, 1H), 7.79-7.76 (m, 2H) , 7.71-7.69 (m, 2H) , 6.68-6.63 (m, 3H) , 5.08 (m, 1H) , 3.76 (s, 6H) , 3.70 (s, 3H) , 3.47-3.44 (m, 2H) . 13C NMR (150 MHz, CDC13) δ 167.95, 166.70, 148.79, 147.89, 134.45, 131.24, 128.33, 123.59, 121.06, 111.68, 111.19, 64.56, 55.72, 55.66, 54.75, 34.37; HRMS (ESI-TOF) Calcd for C2oH2iN206 [M+H]+: 385.1394; found: 385.140
28r
(S) -3- (3,5-Dimethylphenyl) -2- (1 , 3-dioxoisoindolin- 2-yl) -Jf-methoxypropanamide (28r)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent. Compound 28r was obtained as a white solid (36.4 mg, 75%). XH NMR (600 MHz, CDC13) δ 9.26 (s, 1H) , 7.80-7.77 (m, 2H) , 7.71-7.69 (m, 2H) , 6.75 (s, 3H) , 5.04 (m, 1H) , 3.74 (s, 3H) , 3.46-3.36 (m, 2H) , 2.13 (s, 6H) ; 13C NMR (150 MHz, CDC13) δ 167.95, 166.60, 138.15, 135.92, 134.32, 131.38, 128.68, 126.70, 123.52, 64.48, 54.70, 34.66, 21.04; HRMS (ESI-TOF) Calcd for C20H21 2O4 [M+H]+: 353.1496; found: 353.1498.
28s'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (3,4, 5-trifluorophenyl) propanoate (28s ' )
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. The solvents were removed under reduced pressure and the resulting mixture was added PhI(OAc)2 (0.1 mmol, 32.2 mg) and MeOH (1 mL) in a sealed tube (10 mL) with a magneti
stir bar, the reaction mixture was heated to 80 °C for 3 hours. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent.
Compound 28s' was obtained as a white solid (22.5 mg, 62%). 1H NMR (600 MHz, CDC13) δ 7.85-7.82 (m, 2H) , 7.76-7.73 (m, 2H) , 6.83-6.78 (m, 2H) , 5.09-5.07 (m, 1H) , 3.78 (s, 3H), 3.56-3.46 (m, 2H) ; 1C NMR (150 MHz, CDCI3) δ 168.67, 167.39, 151.06 (ddd, JFC = 248.8 Hz, 9.8 Hz, 4.0 Hz), 138.76 (dt, JFC = 249.0 Hz, 15.1 Hz), 134.43, 133.11-132.98, 131.39, 123.73, 112.96 (dd, J" FC = 16.4 Hz, 4.4 Hz), 53.12, 52.59, 34.16; HRMS (ESI-TOF) Calcd for C1BHi3F3 04 [M+H]+: 364.0791; found: 364.0794.
28f
Methyl (S) -3- (3 ,5-bis (trifluoromethyl) phenyl) -2- (1 , 3-dioxoisoindolin-2-yl) propanoate (28f )
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by ½ NMR showed a > 20:1 ratio of mono- and diarylated products. The solvents . were removed under reduced pressure and the resulting mixture was added PhI{OAc)2 (0.1 mmol, 32.2 mg) and MeOH (1 mL) in a sealed tube (10 mL) with a magnetic stir bar. The reaction mixture was heated to 80 °C for 3 hours. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite
using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using Hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent.
Compound 28t' was obtained as a white solid (23.6 mg, 53%). H NMR (600 MHz, CDC13) δ 7.83-7.80 (m, 2H) , 7.75-7.72 (m, 2H) , 7.68 (s, 1H) , 7.63 (s, 2H) , 5.15 (dd, J = 10.8, 5.4 Hz, 1H) , 3.80 (s, 3H) , 3.73 (dd, J = 14.4, 5.4 Hz, 1H) , 3.64 (dd, J= 14.4, 10.6 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 168.57, 167.31, 139.40, 134.48, 131.83 (q, JFC = 33.2 Hz), 131.31, 129.24 (q, JFC = 4.3 Hz), 123.69, 123.26 (q, JFC = 271.2 Hz), 121.14-120.97, 53.17, 52.42, 34.56; HRMS (ESI-TOF) Calcd for C20H1 F6NO4 [M+H]+: 446.0822; found: 446.0820.
23u
(S) -3- (4-Acetamidophenyl) -2- (1,3-dioxoisoindolin- 2-yl) -N-methoxypropanamide (28u)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (4/1 to 2/1 to 0/1) as the eluent, Compound 28u was obtained as a white solid" (20.2 mg, 53%). JH NMR (600 MHz, MeOD) δ 7.82-7.79 (m, 4H) , 7.35 (d, J= 8.4 Hz, 2H) , 7.09 (d, J= 7.8 Hz, 2H) , 5.08 (dd, J = 11.4, 5.4 Hz, 1H) , 4.63 (br, 1H), 3.72 (s, 3H) , 3.52-3.43 (m, 2H) , 2.07 (s, 3H) ; 13C NMR (150 MHz, MeOD) δ 171.60, 169.10, 168.09, 138.78, 135.68, 133.73, 132.97, 130.51,
124.36, 121.13, 64.47, 54.31, 34.62, 23.83; HRMS (ESI-TOF) Calcd for C20H20 3O5 [M+H]+: 382.1397; found: 382.1401.
28v
Diethyl (S) - (4- (2- (1 , 3-dioxoisoindolin-2-yl) -3- (methoxyamino) -3-oxopropyl) benzyl) phosphonate (28v)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (4/1· to 2/1 to 0/1) as the eluent, Compound 28v was obtained as a white solid (44.4 mg, 94%). 1H NMR (600 MHz, CDC13) δ 10.20 (s, 1H), 7.76-7.73 (m, 2H) , 7.69-7.67 (m, 2H) , 7.07 (m, 4H) , 5.05 (m, 1H) , 3.89-3.82 (m, 4H) , 3.72 (s, 3H), 3.57-3.45 (m, 2H) , 3.05-2.89 (m, 2H) , 1.15- 1.12 (m, 6H) ; 13C NMR (150 MHz, CDC13) δ 167.79, 166.27, 135.26, 134.17, 131.48, 129.99, 129.95, 129.10, 123.42, 64.20, 62.21-62.11, 54.09, 34.20, 33.16 (d, Jpc = 137.4 Hz), 16.28-16.23; HRMS (ESI-TOF) Calcd for C23H28N207P [M+H]+: 475.1629; found: 475.1630.
28w
(S) -2- (1, 3-Dioxoisoindolin-2-yl) -3- (4- (hydroxymethyl) henyl) -If-methoxypropanamide (28w)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude
reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products . After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28w was obtained as a white solid (22.1 mg, 62%). JH NMR (600 MHz, CDC13) δ 9.41 (s, 1H) , 7.78-7.75 (m, 2H) , 7.71-7.68 (m, 2H) , 7.17-7.12 (m, 4H) , 5.05 (m, 1H) , 4.55 (s, 2H) , 3.73
(s, 3H) , 3.53-3.43 (m, 2H) , 2.02-1.78 (br, 1H) ; 13C NMR (150 MHz, CDC13) δ 167.90, 166.51, 139.68, 135.44, 134.43, 131.23, 129.03, 127.28, 123.63, 64.82, 64.48, 54.44, 34.40; HRMS (ESI-TOF) Calcd for C19H19N205
28x
(S) -2- (l,3-Dioxoisoindolin-2-yl) -3- (2- (hydroxymethyl) henyl) -N-methoxypropanamide (28x)
Substrate 25 was arylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 28x was obtained as a white solid (15.0 mg, 42%). m.p. = 122-124 °C. ■ 1H NMR (600 MHz, CDC13) δ 9.71 (s, 1H) , 7.79-7.76 (dm, 2H) , 7.71-7.68 (m, 2H) , 7.30 (d, J= 7.5 Hz, 1H) , 7.15-7.14 (m, 1H) , 7.07-7.06 (m, 2H) , 5.22 (m, 1H) , 4.84 (d, J = 12.6 Hz, 1H) , 4.69 (d, J" = 12.0 Hz, 1H) , 3.69 (s, 3H) , 3.69-3.64 (m, 1H) , 3.53 (dd, J= 14.4, 10.0 Hz, 1H) , 1.85 (br, 1H) ; 13C NMR (150 MHz, CDC13) δ 168.04, 166.45, 138.58, 135.53, 134.33, 131.38, 130.09, 129.95, 128.34, 127.48, 123.58, 64.37, 63.67,
53.67, 31.85; HRMS (ESI-TOF) Calcd for C19H19N2O5
[M+H]+: 355.1288; found: 355.1287.
Removal of the directing grou :
Methyl (S) -2- <1 , 3-dioxoisoindolin-2-yl) -
3-phenylpropanoate (28'')
The substrate 28 (0.1 mmol, 32.8 mg) was dissolved in MeOH (1 mL) , followed by the addition of PhI(0Ac)2 (0.1 mmol, 32.2 mg) . The reaction mixture was heated to 80 °C for 3 hours. The reaction mixture was cooled to room temperature and then saturated aq. Na2S03 and saturated aq. NaHC03 were added. The formed aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over MgS04, filtered and concentrated. The compound was purified by column chromatography (hexanes/ EtOAc = 2:1 to 1:1) to provide product Compound 28'', (29.4 mg. 95%). ¾ NMR (600 MHz, CDC13) δ 7.79-7.77 (m, 2H) , 7.70-7.68 (m, 2H) , 7.19-7.13 (m, 5H) , 5.16 (dd, J= 11.4, 5.4 Hz, 1H), 3.78 (s, 3H) , 3.61-3.52 (m, 2H) . The ee value was determined by HPLC analysis on a Chiralcel® OJ column (25% isopropanol in hexanes, 0.4 mL/min) with tr = 42.7 minutes (major), 63.0 minutes (minor) : 99% ee.
A sealable pressure flask was charged with MeOH (1 mL) and amide Compound 28 (0.1 mmol, 32.8 mg) . BF3«OEt2 (5 equiv.) was added and the reaction vessel sealed. The reaction mixture was heated to 90
°C for 8 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and H20 and EtOAc were added, organic layers were removed, the aqueous layer was extracted with EtOAc, and the combined organics washed with brine, dried over MgS04, filtered and concentrated. The compound was purified by column chromatography
(hexanes/ EtOAc = 2:1 to 1:1) to provide Compound 28' ' white solid (30.9 mg, >99%) . The ee value was determined by HPLC analysis on a Chiralcel® OJ column (25% isopropanol in hexanes, 0.4 mL/min) with tr = 42.6 minutes (major), 60.7 minutes (minor): 99% ee.
Arylation with heteroaryl iodides
"y oNHOIto
General procedure for monoarylation of 25 with a heterocyclic iodide [Ar(Het)-I]:
The starting material Compound 25 (0.1 mmol, 24.8 mg) , Pd(OAc)2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To
the reaction mixture, aryl iodide (0.15 mmol) , 2- picoline (20 mol%, 2 μΐ,) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 80 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent.
30a
(S) -3- (2 , 3-Dihydrobenzo [b] [1 , 4] dioxin-6-yl) -2- (1 , 3-dioxoisoindolin-2-yl) ~2V-methoxy propanamide (30a)
Substrate 25 was heteroarylated following the general arylation procedure. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 30a was obtained as a white solid (29.0 mg, 76%) . XH NMR (600 MHz, CDC13) δ 9.23 (s, 1H) , 7.81-7.78 (m, 2H) , 7.72-7.70 (m, 2H) , 6.68 (s, 1H) , 6.65 (d, J = 7.8 Hz, 1H) , 6.60 (d, J = 7.8 Hz, 1H) , 5.02 (m, 1H) , 4.16-4.14 (m, 4H) , 3.74
(s, 3H) , 3.40 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 167.93, 166.58, 143.49, 142.54, 134.36, 131.34, 129.16, 123.63, 121.75, 117.68, 117.35, 64.51, 64.16, 54.64, 34.10; HRMS (ESI-TOF) Calcd for C20H19 2O6
[M+H]+: 383.1238; found: 383.1244.
EtOaC^ i.
NPhth
"CONHO e
O
30b
Ethyl (S) -6- (2- (1 , 3-dioxoisoindolin-2-yl) -3- (methoxyamino) -3-oxopropyl) -4-oxo-4H-chromene-3- carboxylate (30b)
Substrate 25 was heteroarylated following the general arylation procedure. Analysis of crude reaction mixture by JH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 30b was obtained as a white solid (31.5 mg, 70%) . 1H NMR (600 MHz, CDC13) δ 10.03 (s, 1H) , 7.95 (s, 1H) , 7.76-7.74 (m, 2H) , 7.69- 7.67 (m, 2H) , 7.60 (dd, J = 8.7, 2.1 Hz, 1H) , 7.44 (d, J = 8.7 Hz, 1H) , 6.96 (s, 1H) , 5.13 (m, 1H) , 4.43 (q, J = 7.2 Hz, 2H) , 3.77 (s, 3H) , 3.68-3.67 (m, 2H) , 1.41 (t, J = 7.2 Hz, 3H) ; 13C NMR (150 MHz, CDCl3) δ 178.24, 167.67, 166.00, 160.38, 154.92, 152.19, 135.79, 134.86, 134.43, 131.23, 125.68, 124.12, 123.66, 119.18, 114.50, 64.45, 63.05, 53.83, 34.04, 14.07; HRMS (ESI-TOF) Calcd for C2 H2i 208 [M+H]+: 465.1292; found: 465.1295.
30c
(S) -2- (l,3-Dioxoisoindolin-2-yl) -li-methoxy- 3- (l-tosyl-lH-indol-5-yl)propanamide (30c)
Substrate 25 was heteroarylated following the general arylation procedure. Analysis of crude
reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 30c was obtained as a white solid (25.6 mg, 62%). m.p. = 194-196 °C. H NMR (600 MHz, CDC13) δ 9.12 (s, 1H) , 7.79 (d, J = 9.0 Hz, 1H), 7.75-7.73 (m, 2H) , 7.69-7.67 (m, 4H) , 7.46 (d, J = 3.6 Hz, 1H) , 7.33 (s, 1H) , 7.18 (d, J = 8.4 Hz, 2H) , 7.10 (d, J = 8.4 Hz, 1H) , 6.50 (d, J = 3.6 Hz, 1H) , 5.10 (m, 1H) , 3.72 (s, 3H) , 3.59-3.55 (m, 2H) , 2.33 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 167.90, 166.71, 144.92, 135.16, 134.41, 133.88, 131.20, 131.08, 129.87, 126.73, 126.71, 125.37, 123.62, 121.67, 113.67, 108.82, 64.52, 54.80, 34.63, 21.55; HRMS (ESI-TOF) Calcd for C27H24N306S [M+H]+: 518.1380; found 518.1386.
^T^j] -Phth
Ts
30d
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -W-methoxy-3- (1- osyl-lH-indol-6-yl) ropanamide (3Od)
Substrate 25 was heteroarylated following the general arylation procedure. Analysis of crude reaction mixture by XH NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 30d was obtained as a white solid (33.7 mg, 65%). JH NMR (600 MHz, CDC13) δ 9.24 (s, 1H), 7.83 (s, 1H) , 7.77-7.75 (m, 2H) , 7.72- 7.68 (m, 4H) , 7.42 (d, J = 3.6 Hz, 1H) , 7.33 (d, J = 7.8 Hz, 1H) , 7.21 (d, J = 8.4 Hz, 2H) , 7.05 (d, J = 7.8 Hz, 1H), 6.51 (d, J= 3.0 Hz, 1H) , 5.16 (m, 1H) ,
3.78 (s, 3H), 3.67-3.66 (m, 2H) , 2.33 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.92, 166.51, 144.87, 135.19, 135.04, 134.36, 132.82, 131.29, 129.94, 129.71, 126.80, 126.37, 124.33, 123.64, 121.54, 113.81, 108.73, 64.56, 54.94, 35.11, 21.55; H MS (ESI-TOF) Calcd for C27H2,iN306S [M+H]+: 518.1380; found: 518.1386.
30e'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (1-tosyl- lH-indazol-5-yl) ropanoate (30e ' )
(S) -2- (l,3-Dioxoisoindolin-2-yl) -W-methoxy-3- (1- tosyl-lH-indazol-5-yl) ropanamide (30e)
Substrate 25 was heteroarylated following the general arylation procedure except Pd(OAc)2 (15 mol%, 3.3 mg) and 2-picoline (30 mol%, 3 μL) were used. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column
chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 30e' was obtained as a white solid (8.5 mg, 16%). 1H NMR (600 MHz, CDC13) δ 8.05- 8.03 (m, 2H), 7.82-7.80 (m, 2H) , 7.78-7.75 (m, 2H) , 7.71-7.67 (m, 2H) , 7.48 (s, 1H) , 7.38 (dd, J = 8.4, 1.8 Hz, 1H) , 7.21 (d, J = 8.4 Hz, 2H) , 5.18 (dd, J = 10.8, 5.4 Hz, 1H) , 3.78 (s, 3H) , 3.72-3.63 (m, 2H) , 2.35 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 169.09, 167.45, 145.36, 140.97, 139.41, 134.52, 134.27, 132.96, 131.43, 130.28, 129.81, 127.55, 126.11, 123.58, 121.24, 113.34, 53.15, 53.02, 34.40, 21.63; HRMS (ESI-TOF) Calcd for C26H22N306S [M+H]+: 504.1224;
found: 504.1225. Compound 30e was obtained as a white solid (21.8 mg, 42%). ¾ NMR (600 MHz, CDC13) δ 9.28 (s, 1H) , 8.03-8.01 (m, 2H) , 7.80-7.79 (m, 2H) , 7.75-
7.73 (m, 2H) , 7.69-7.68 (m, 2H) , 7.48 (s, 1H) , 7.38 (d, J = 8.4 Hz, 1H) , 7.22-7.20 (m, 2H) , 5.12 (m, 1H) ,
3.74 (s, 3H) , 3.64 (m, 2H) , 2.34 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.81, 166.25, 145.44, 140.94, 139.40, 134.56, 134.42, 132.38, 131.07, 130.26, 129.83, 127.52, 126.10, 123.69, 121.43, 113.39, 64.57, 54.35, 34.38, 21.63; HRMS (ESI-TOF) Calcd for C26H23 406S [M+H]+: 519.1333; found: 519.1339.
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (l-tosyl-lH-indazol-6-yl)propanoate (30f ' )
(S) -2- (1 ,3-Dioxoisoindolin-2-yl) -li-methoxy-3- (l-tosyl-lH-indazol-6-yl)propanamide (30f)
Substrate 25 was heteroarylated following the general arylation procedure except Pd(OAc)2 (15 mol%, 3.3 mg) and 2-picoline (30 mol%, 3 pL) were used. Analysis of crude reaction mixture by 1H NMR showed a > 20:1 ratio of mono- and diarylated products. After purification by column
chromatography using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent, Compound 30f 1 was obtained as a white solid (11.6 mg, 22%). JH NMR (600 MHz, CDC13) δ 8.04 (m, 2H) , 7.80-7.76 (m, 4H) , 7.72-7.70 (m, 2H) , 7.51 (dd, J= 8.2, 0.7 Hz, 1H) , 7.19-7.15 (m, 3H) , 5.24 (dd, J = 11.4, 5.4 Hz, 1H) , 3.82 (s, 3H) , 3.80-3.75 (m, 2H) , 2.34 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ
168.98, 167.38, 145.22, 141.02, 140.63, 138.82, 134.53, 134.23, 131.52, 129.81, 127.53, 125.44, 124.84, 123.61, 121.41, 113.28, 53.33, 53.08, 35.13, 21.64; HRMS (ESI-TOF) Calcd for C26H22N306S [M+H] + : 504.1224; found: 504.1225. Compound 30f was obtained as a white solid (23.0 mg, 44%). 1H NMR (600 MHz, CDC13) δ 9.40 (s, 1H) , 8.03 (s, 1H) , 7.80 (s, 1H) , 7.78-7.76 (m, 4H) , 7.71-7.69 (m, 2H) , 7.51 (d, J = 7.8 Hz, 1H) , 7.20 (d, J = 7.8 Hz, 2H) , 7.17 (d, J = 8.4 Hz, 1H), 5.21 (m, 1H) , 3.80 (s, 3H) , 3.77-3.68 (m, 2H), 2.34 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 167.81, 165.93, 145.33, 140.96, 140.50, 138.28, 134.52, 134.43, 131.16, 129.85, 127.51, 125.50, 124.88, 123.73, 121.56, 113.24, 64.69, 54.44, 35.13, 21.64; HRMS (ESI-TOF) Calcd for C26H23 4O6S [M+H]+: 519.1333; found: 519.1340.
General procedure for monoheteroarylation of Compound 25 with a heterocyclic iodide [Ar (Het) -I] :
Method A.
The starting material 25 (0.1 mmol, 24.8 mg) , Pd(0Ac)2 (15 mol%, 3.3 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 ml) with a magnetic stir bar. To the reaction mixture, heteroaryl iodide (0.15 mmol), 2,6-lutidine (30 mol%, 3 pL) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 80 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room
temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was added Phi (OAc) 2 (0.1 mmol, 32.2 mg) and MeOH (1 mL) in a sealed tube (10 mL) with a magnetic stir bar. The reaction mixture was heated to 80 °C for 3 hours. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent .
Method B.
The starting material 25 (0.2 mmol, 49.6 mg) , Pd(OAc)2 (15 mol%, 3.3 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, heteroaryl iodide (0.1 mmol), 2,6-lutidine (30 mol%, 3 pL) , and HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 80 °C for 36 hours under vigorous stirring. Opon completion, the reaction mixture was cooled to room temperature, filtered with celite "using DCM. The solvents were removed under reduced pressure and the resulting mixture was added with Phi (OAc) 2 (0.2 mmol, 64.4 mg) and MeOH (1 mL) in a sealed tube (10 mL) with a magnetic stir bar. The reaction mixture was heated to 80 °C for 3 hours. Dpon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash
chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent.
301V
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3- (2-fluoropyridin-4-yl)propanoate (30h' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30h' was obtained as a white solid (16.0 mg, 47%). JH NMR (600 MHz, CDC13) δ 8.07 (d, J= 5.4 Hz, 1H) , 7.82-7.81 (m, 2H) , 7.75-7.73 (m, 2H) , 7.03 (d, J= 5.4 Hz, 1H) , 6.77 (m, 1H) , 5.20 (dd, J= 10.5, 5.7 Hz, 1H) , 3.79 (s, 3H) , 3.64-3.62 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 168.58, 167.34, 163.98 (d, JFC = 87.6 Hz), 151.79 (d, Jwc = 7.8 Hz), 147.85 (d, JFC = 15.2 Hz), 134.48, 131.34, 123.77, 121.69 (d, JFC = 4.1 Hz), 109.85 (d, JFC = 37.1 Hz), 53.22, 51.80, 34.03 (d, JFC = 2.9 Hz); HRMS (ESI-TOF) Calcd for C17H14 F 2O4 [M+H] + : 329.0932; found: 329.0929.
3or
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3- (6-fluoropyridin-3-yl) propanoate (30i ' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using
hexanes/EtOAc (3/1) as the eluent. Compound 30i' was obtained as a white solid (18.5mg, 56%). XH NMR (600 MHz, CDC13) δ 7.98-7.97 (m, 1H) , 7.81-7.80 (m, 2H) , 7.74-7.72 (m, 2H) , 7.68-7.65 (m, 1H) , 6.82 (dd, J = 8.4, 3.0 Hz, 1H), 5.09 (dd, J = 10.2, 6.6 Hz, 1H) , 3.80 (s, 3H) , 3.58-3.56 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 168.73, 167.35, 162.80 (d, JFC = 237.3 Hz), 147.79 (d, JFC = 14.1 Hz), 141.50 (d, JFC = 6.3 Hz), 134.43, 131.36, 129.94 (d, JFC = 4.2 Hz), 123.75, 109.56 (d, JFC = 37.5 Hz), 53.13, 52.62, 31.40; HRMS (ESI-TOF) Calcd for C17H14FN2O [M+H]+: 329.0932; found: 329.0942.
30
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3- (2-fluoropyridin-3-yl)propanoate (30 ' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent. Compound 30j ' was obtained as a white solid (9.8 mg, 30%). ¾ NMR (600 MHz, CDCI3) δ 8.05-8.04 (m, 1H) , 7.82-7.81 (m, 2H) , 7.73-7.72 (m, 2H) , 7.62-7.59 (m, 1H) , 7.05-7.02 (m, 1H) , 5.19 (dd, J = 10.8, 4.8 Hz, 1H) , 3.79 (s, 3H) , 3.64 (dd, J = 14.7, 5.1 Hz, 1H) , 3.55 (dd, J= 14.4, 10.8 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 168.76, 167.26, 162.15 (d, JFC = 88.4 Hz), 146.50 (d, JFC = 14.7 Hz), 141.82 (d, JFC = 5.6 Hz), 134.32, 131.47, 123.67, 121.53 (d, JFC = 4.8 Hz), 118.88 (d, JFC = 30.5 Hz), 53.09, 51.34, 28.80 (d, JFC = 3.2 Hz); HRMS (ESI-
TOF) Calcd for C17H14 FN2O4 [M+H] + : 329.0932; found: 329.0940.
30k1
Methyl (S) -3- (2-chloropyridin-4-yl) -2- (1 ,3-dioxoisoindolin-2-yl)propanoate (30k' >
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30k' was obtained as a white solid (19.8 mg, 57%). H NMR (600 MHz, CDC13) δ 8.23 (d, J= 4.8 Hz, 1H) , 7.83-7.82 (m, 2H) , 7.75-7.73 (m, 2H) , 7.18 (s, 1H) , 7.07 (dd, J = 5.1, 1.5 Hz, 1H) , 5.18 (dd, J = 10.8, 5.4 Hz, 1H) , 3.79 (s, 3H) , 3.62-3.54 (m, 2H) ; 13C NMR (150 MHz, CDCI3) δ 168.54, 167.34, 151.90, 149.81, 149.23, 134.49, 131.33, 124.66, 123.77, 122.70, 53.22, 51.72, 33.93; HRMS (ESI-TOF) Calcd for C17H14CIN2O4 [M+H]+: 345.0637; found: 345.0635.
30Γ
Methyl (S) -3- (6-chloropyridin-3-yl) -2- (l,3-dioxoisoindolin-2-yl)propanoate (301' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 301' was obtained as a white solid (21.0 mg, 61%). XH NMR (600
MHz, CDCI3) δ 8.16 (dd, J = 2.4, 0.6 Hz, 1H) , 7.82- 7.80 (m, 2H), 7.74-7.73 (m, 2H) , 7.54 (dd, J = 8.2, 2.5 Hz, 1H) , 7.21 (dd, J= 8.2, 0.7 Hz, 1H) , 5.09 (dd, J= 10.0, 6.4 Hz, 1H) , 3.79 (s, 3H) , 3.57-3.55 (m, 2H) ; 1C NMR (150 MHz, CDC13) δ 168.66, 167.35, 150.28, 150.03, 139.14, 134.45, 131.35, 131.27, 124.23, 123.76, 53.16, 52.47, 31.35; HRMS (ESI-TOF) Calcd for Ci7Hi4ClN204 [M+H]+: 345.0637; found:
30m'
Methyl (S) -3- (2-bromopyridin-4-yl) -2- (1 , 3-dioxoisoindolin-2-yl) ropanoate (30m' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30m' was obtained as a white solid (18.3 mg, 47%). 1H NMR (600 MHz, CDCI3) δ 8.21 (d, J= 5.4 Hz, 1H) , 7.83-7.82 (m, 2H), 7.75-7.74 (m, 2H) , 7.34 (s, 1H) , 7.11 (d, J = 4.8 Hz, 1H) , 5.17 (dd, J = 10.8, 5.4 Hz, 1H) , 3.79 (s, 3H) , 3.60-3.51 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 168.52, 167.33, 150.22, 148.95, 142.60, 134.49, 131.33, 128.47, 123.78, 123.06, 53.22, 51.70, 33.85; HRMS (ESI-TOF) Calcd for CnHiBrN204 [M+H] + : 389.0131; found: 389.0132.
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (2- (trifluoromethyl)pyridin-4-yl)propanoate (30η' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30n' was obtained as a white solid (25.0 mg, 66%). XH NMR (600 MHz, CDC13) δ 8.57 (d, J = 4.8 Hz, 1H) , 7.84-7.81 (m, 2H) , 7.76-7.72 (m, 2H) , 7.52 (s, 1H) , 7.35 (d, J = 4.8 Hz, 1H) , 5.21 (dd, J = 11.1, 5.7 Hz, 1H) , 3.79
(s, 3H) , 3.73-3.63 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 168.48, 167.32, 150.21, 148.57 (q, JFC = 34.0 Hz), 148.02, 134.54, 131.30, 126.66, 123.78, 121.32 (q, JFC = 272.5 Hz), 121.00-120.95, 53.26, 51.70, 34.33; HRMS
(ESI-TOF) Calcd for C18Hi4F3N204 [M+H] + : 379.0900;
30o'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (6- (trifluoromethyl) pyridin-2-yl) ropanoate (30o ' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30o' was obtained as a white solid (17.6 mg, 47%). 1H NMR (600 MHz, CDCI3) δ 7.82-7.79 (m, 2H) , 7.74-7.70 (m, 3H) ,
7.45 (d, J = 7.2 Hz, 1H) , 7.38 (d, J= 7.8 Hz, 1H) ,
5.46 (dd, J = 8.4, 7.2 Hz, 1H) , 3.79-3.78 (m, 2H) , 3.78 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 169.31, 167.39, 158.02, 147.82 (q, JFC = 34.5 Hz), 137.82, 134.07, 131.76, 126.44, 123.46, 121.14 (q, JFC = 272.7
Hz), 118.48-118.40, 52.98, 51.23, 36.11; HRMS (ESI- TOF) Calcd for dsH^^C^ [M+H]+: 379.0900; found: 379.0898.
30p'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (2-methylpyridin-4-yl)propanoate (30ρ' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method B) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30p' was obtained as a white solid (13.7 mg, 42%). ¾ NMR (600 MHz, CDC13) δ 8.31 (d, J = 4.8 Hz, 1H) , 7.81-7.80 (m, 2H) , 7.73-7.71 (m, 2H) , 6.99 (s, 1H) , 6.92 (dd, J= 5.4, 1.2 Hz, 1H) , 5.20 (dd, J = 10.8, 6.0 Hz, 1H) , 3.79 (s, 3H) , 3.56-3.53 (m, 2H) , 2.43 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 168.92, 167.40, 158.66, 149.24, 146.08, 134.33, 131.43, 123.69, 123.63, 121.07, 53.10, 52.05, 34.04, 24.24; HRMS (ESI-TOF) Calcd for Ci8Hi7N204 [M+H] + : 325.1183; found: 325.1184.
30q"
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (2-methoxypyridin-4-yl) propanoate (30q' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method B) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30q' was
obtained as a white solid (17.1 mg, 50%). :H NMR (600 MHz, CDC13) δ 7.99 (d, J = 5.4 Hz, 1H) , 7.82-7.79 (m, 2H), 7.73-7.70 (m, 2H) , 6.71 (dd, J = 5.1, 1.5 Hz, 1H) , 6.56 (s, 1H), 5.18 (dd, J= 10.2, 6.0 Hz, 1H) , 3.84 (s, 3H), 3.78 (s, 3H) , 3.55-3.53 (m, 2H) ; 13C NMR (150 MHz, CDCI3) δ 168.92, 167.38, 164.51, 148.56, 147.02, 134.28, 131.49, 123.66, 117.21, 110.91, 53.34, 53.09, 52.07, 33.96; HRMS (ESI-TOF) Calcd for 018Ηι7Ν2θ5 [M+H]+: 341.1132; found 341.1134.
CONHOMe
(S) -2- (9-chloro-3-oxo-l , 3 , 4 , 5-tetrahydrooxepino [3,4- c]pyridin-4-yl) isoindoline-1 , 3-dione (30r)
Substrate 25 was heteroarylated following the general arylation (method A) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30r was obtained as a white solid (11.0 mg, 32%). ¾ NMR (600 MHz, CDC13) δ 8.36
(d, J = 4.8 Hz, 1H), 7.92-7.91 (m, 2H) , 7.80-7.79 (m, 2H) , 7.17 (d, J= 5.4 Hz, 1H) , 5.81 (d, J= 15.6 Hz, 1H) , 5.63 (d, J= 15.0 Hz, 1H) , 5.56 (dd, J= 12.6, 4.8 Hz, 1H) , 4.32 (dd, J = 16.5, 12.9 Hz, 1H) , 3.25
(dd, J = 16.8, 4.8 Hz, 1H) ; 13C NMR (151 MHz, CDC13) δ 168.26, 167.20, 150.72, 149.68, 147.86, 134.66, 131.61, 128.16, 123.95, 123.94, 65.52, 49.10, 33.87; HRMS (ESI-TOF) Calcd for C17H12CIN2O4 [M+H]+: 343.0480; found: 343.0482.
Methyl (S) -3- (2-chloro-3- (hydroxymethyl)pyridin-4- yl) -2- (1 , 3-dioxoisoindolin-2-yl) ropanoate (30r ' )
To a solution of Compound 30r (0.032 mmol, 11.0 mg) in MeOH (1 mL) was added MeS03H (1.5 equiv) . After the mixture was heated to reflux for one to two hours, the reaction was cooled to room temperature. The solvents were removed under reduced pressure and the resulting mixture was purified by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30r' was obtained as a white solid (11.5 mg, >99%). ¾ NMR (600 MHz, CDC13) δ 8.12 (d, J = 4.8 Hz, 1H) , 7.82-7.81 (m, 2H) , 7.75-7.73 (m, 2H) , 7.02 (d, J= 4.8 Hz, 1H) , 5.35 (dd, J = 11.1, 5.1 Hz, 1H) , 4.95 (d, J = 12.6 Hz, 1H) , 4.88 (d, J = 12.6 Hz, 1H) , 3.81 (dd, J= 14.4, 5.4 Hz, 1H) , 3.79 (s, 3H) , 3.61 (dd, J = 14.7, 11.1 Hz, 1H) , 2.49 (br, 1H) ; 1C NMR (150 MHz, CDC13) δ 168.62, 167.52, 152.81, 148.72, 148.70, 134.49, 133.06, 131.35, 124.46, 123.80, 59.01, 53.23, 52.15, 32.24; HRMS (ESI-TOF) Calcd for C18H15C1N205 [M+H]+: 375.0742; found: 375.0743.
30s'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3- (quinolin-6-yl) propanoate (30s' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method B) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30s' was
obtained as a white solid (15.6 mg, 43%). 1H NMR (600 MHz , CDC13) δ 8.82 (dd, J = 3.6, 1.2 Hz, 1H) , 8.03-
8.01 (m, 1H) , 7.96 (d, J = 8.4 Hz, 1H) , 7.76-7.74 (m, 2H) , 7.67-7.62 (m, 2H) , 7.62 (d, J = 1.2 Hz, 1H) , 7.56 (dd, J = 8.7, 2.0 Hz, 1H) , 7.32 (dd, J= 8.4,
4.2 Hz, 1H) , 5.30 (dd, J = 10.8, 5.4 Hz, 1H) , 3.83 (s, 3H) , 3.82-3.74 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ
169.18, 167.47, 150.10, 147.24, 135.85, 135.24,
134.19, 131.45, 130.53, 129.64, 128.21, 127.50, 123.56, 121.25, 53.04, 52.93, 34.67; HRMS (ESI-TOF) Calcd for C2iHnN204 [M+H]+: 361.1183; found: 361.1185.
30t'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -
3- (guinolin-7-yl) ropanoate (30f )
Substrate 25 was heteroarylated following the general arylation and deprotection (method B) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent. Compound 30t' was obtained as a white solid (14.9 mg, 42%). 1H NMR (600 MHz, CDCI3) δ 8.82 (dd, J = 4.2, 1.8 Hz, 1H) , 8.07- 8.05 (m, 1H), 7.87 (s, 1H) , 7.76-7.73 (m, 2H) , 7.71 (d, J = 8.4 Hz, 1H) , 7.67-7.64 (m, 2H) , 7.44 (dd, J = 8.4, 1.8 Hz, 1H) , 7.31 (dd, J = 8.4, 4.2 Hz, 1H) , 5.29 (dd, J = 11.1, 5.1 Hz, 1H) , 3.84-3.74 (m, 2H) , 3.80 (s, 3H) ; 1C NMR (150 MHz, CDC13) δ 169.17, 167.41, 150.52, 148.21, 138.51, 135.80, 134.12, 131.52, 129.29, 128.15, 127.53, 127.11, 123.58, 120.87, 53.06, 53.03, 35.01; HRMS (ESI-TOF) Calcd for C21H17N204 [M+H]+: 361.1183; found: 361.1188.
30u'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3- (quinolin-3-yl) ropanoate (30u ' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method B) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 30u' was obtained as a white solid (11.0 mg, 31%). ¾ NMR (600 MHz, CDC13) δ 8.75 (d, J = 2.4 Hz, 1H) , 8.02-8.00 (m, 2H) , 7.79-7.76 (m, 2H) , 7.72-7.71 (m, 1H) , 7.70-767 (m, 2H) , 7.66-7.63 (m, 1H) , 7.50-7.47 (m, 1H) , 5.27 (dd, J= 10.8, 5.4 Hz, 1H) , 3.86-3.73 (m, 2H) , 3.81 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 168.93, 167.47, 151.45, 147.21, 135.53, 134.30, 131.44, 129.63, 129.23, 129.15, 127.84, 127.53, 126.78, 123.68, 53.11, 52.83, 32.23; HRMS (ESI-TOF) Calcd for
30V
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3- (quinoxalin-6-yl) propanoate (30ν' )
Substrate 25 was heteroarylated following the general arylation and deprotection (method B) . After purification by column chromatography using hexanes/EtOAc (3/1) as the eluent, Compound 4v' was obtained as a white solid (16.2 mg, 45%). ½ NMR (600 MHz, CDCI3) δ 8.76 (s, 2H) , 7.99 (d, J = 8.4 Hz, 1H) , 7.90-7.89 (m, 1H) , 7.77-7.76 (m, 2H) , 7.69-7.65 (m, 3H) , 5.30 (dd, J = 10.8, 5.4 Hz, 1H) , 3.88-3.75 (m.
2H) , 3.81 (s, 3H) ; 13C NMR (150 MHz , CDC13) δ 168. 167.39, 145.12, 144.73, 142.89, 142.04, 139.41, 134.23, 131.44, 131.17, 129.75, 129.22, 123.64, 53.10, 52.86, 34.89; HR S (ESI-TOF) Calcd for
C20H16 3O4 [M+H]+: 362.1135; found: 362.1139.
General procedure :
The substrate 28 (0.1 mmol, 24.8 mg) , Pd(OAc)2 (0.01 mmol, 2.2 mg) , NaH2P0 'H20 (0.3 mmol, 42 mg) and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.3 mmol), 2,6-lutidine (0.02 mmol, 2 pL) , and HFIP (1 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column.
31 q
(S) -2- (l,3-Dioxoisoindolin-2-yl) - N-methoxy-3 , 3-diphenylpropanamide (31q)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31q was obtained as a white solid (30.7 mg, 77%). m.p. = 220-222 °C. 1H NMR (600 MHz, CDC13) δ 9.14 (s, 1H) , 7.73-7.71 (m, 2H) , 7.66- 7.63 (m, 2H) , 7.52-7.50 (m, 2H) , 7.34 (t, J= 7.8 Hz, 2H) , 7.28-7.26 (m, 2H) , 7.24 (t, J= 7.2 Hz, 1H) , 7.13 (t, J = 7.8 Hz, 2H) , 7.03 (t, J= 7.2 Hz, 1H) , 5.57 (d, J= 12.6 Hz, 1H) , 5.32 (t, J= 12.6 Hz, 1H) , 3.48 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.90, 164.99, 139.78, 139.73, 134.30, 131.07, 129.07, 128.73, 128.16, 127.63, 127.54, 127.13, 123.55, 64.14, 56.91, 50.20; HRMS (ESI-TOF) Calcd for
C24H21N2O4 [M+H]+: 401.1496; found: 401.1493. The ee value was determined by HPLC analysis on a Chiralcel OD-H column (20% isopropanol in hexanes, 0.4 mL/min) with tr = 28.9 minutes (minor), 31.0 minutes (major): 99% ee.
31 q'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3 , 3-diphenylpropanoate (31q' )
A sealable pressure flask was charged with MeOH (1 ml) and amide 31q (0.1 mmol, 40 mg) . BF3 «OEt2 (5 equiv.) was added and the reaction vessel sealed. The reaction mixture was heated to 90 °C for 8 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and H20 and EtOAc was added, organic layers were removed, the aqueous layer was then extracted with EtOAc and the combined organics washed with brine, dried over MgS04, filtered and concentrated. The concentrated organics were purified by column chromatography (hexanes/EtOAc = 2/1 to 1/1) to provide Compound 31q' as a white solid (34.7 mg, 90%). XH NMR (600 MHz, CDC13) δ 7.74- 7.72 (m, 2H), 7.66-7.64 (m, 2H) , 7.49 (d, J= 7.8 Hz, 2H) , 7.33 (t, J= 7.8 Hz, 2H) , 7.26-7.20 (m, 3H) , 7.09 (t, J = 7.8 Hz, 2H) , 6.98 (t, J= 7.2 Hz, 1H) , 5.75 (d, J = 12.0 Hz, 1H) , 5.27 (d, J = 12.0 Hz, IH) , 3.57 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 168.67, 167.29, 141.49, 140.35, 134.07, 131.31, 128.73, 128.49, 127.98, 127.70, 126.89, 126.87, 123.41, 54.81, 52.63, 50.56. The ee value was determined by HPLC analysis on a Chiralcel® ADH column (10% isopropanol in hexanes, 0.5 mL/min) with tr = 37.9 minutes (minor), 45.6 minutes (major): 98% ee.
31a
(2S, 3E) -2- (1 , 3-Dioxoisoindolin-2-yl) -ίί-methoxy- 3-phenyl-3- (p-tolyl)propanamide (31a)
Substrate 28 was arylated followxng the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31a was obtained as a white solid (33.6 mg, 81%). m.p. = 215-218 °C. XH NMR (600 MHz, CDCI3) δ 9.09 (s, 1H) , 7.73-7.71 (m, 2H) , 7.65- 7.63 (m, 2H) , 7.41-7.39 (m, 2H) , 7.25 (d, J = 7.8 Hz, 2H) , 7.15-7.11 (m, 4H) , 7.03-7.00 (m, 1H) , 5.56 (d, J = 12.6 Hz, 1H) , 5.25 (d, J= 12.6 Hz, 1H) , 3.52 (s, 3H) , 2.29 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.92, 165.12, 140.05, 137.37, 136.68, 134.27, 131.09, 129.81, 128.70, 127.95, 127.45, 127.04, 123.53, 64.20, 56.95, 49.92, 21.04; HRMS (ESI-TOF) Calcd for C25H23N2O4 [M+H] + : 415.1652; found: 415.1649.
31b
(2S, 3R) -2- (1 , 3-Dioxoisoindolin-2-yl) -2i-methoxy- 3-phenyl-3- (m-tolyl)propanamide (31b)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31b was obtained as a white solid (33.6 mg, 82%). 1H NMR (600 MHz, CDC13) δ 9.07 (s, 1H), 7.74 (m, 2H), 7.66-7.63 (m, 2H) , 7.32-7.26 (m, 4H), 7.22 (t, J= 7.8 Hz, 1H) , 7.13 (t, J = 7.8 Hz, 2H) , 7.05-7.01 (m, 2H) , 5.56 (d, J= 12.6 Hz, 1H) , 5.27 (d, J = 12.6 Hz, 1H) , 3.52 (s, 3H) , 2.35 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 167.88, 165.03,
139.92, 139.66, 138.76, 134.25, 131.09, 128.98,
128.93, 128.69, 128.43, 127.53, 127.06, 125.00,
123.51, 64.12, 56.79, 50.14, 45.20, 21.49; HRMS (ESI- TOF) Calcd for ¾5Η23Ν2θ4 [M+H]+: 415.-1652; found: 415.1651.
(2S, 3JR) -3- ([1,1' -Biphenyl] -4-yl) -2- (1 , 3-dioxo- isoindolin-2-yl) -N-methoxy-3-phenyl propanamide (31c)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31c was obtained as a yellow solid (27.6 mg, 61%). :H NMR (600 MHz, CDC13) δ 9.28 (s, 1H) , 7.73-7.71 (m, 2H) , 7.65-7.62 (m, 2H) , 7.60- 7.55 (m, 4H) , 7.54-7.52 (m, 2H) , 7.41 (t, J = 7.8 Hz, 2H) , 7.33-7.30 (m, 3H) , 7.15 (t, J = 7.8 Hz, 2H) , 7.04 (t, J = 7.2 Hz, 1H) , 5.61 (d, J= 12.6 Hz, 1H) , 5.39 (d, J = 12.6 Hz, 1H) , 3.51 (s, 3H) . 13C NMR (150 MHz, CDC13) δ 167.92, 165.01, 140.41, 139.73, 138.73, 134.32, 134.26, 131.05, 128.82, 128.79, 128.75, 128.57, 127.69, 127.58, 127.36, 127.20, 126.98, 123.55, 64.18, 56.83, 49.85; HRMS (ESI-TOF) Calcd for C30H25 2O4 [M+H] + : 477.1809; found: 477.1809.
(2S, 3R) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy- 3- (4-methoxyphenyl) -3-phenyl propanamide (31d)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent. Compound 31d was obtained as a white solid (35.2 mg, 80%) . m.p. = 175-178 °C. 1H NMR (600 MHz, CDC13) δ 9.15 (s, 1H) , 7.74-7.71 (m, 2H) , 7.66- 7.63 (m, 2H) , 7.44-7.41 (m, 2H) , 7.27-7.24 (m, 2H) , 7.14-7.12 (m, 2H) , 7.04-7.01 (m, 1H) , 6.89-6.88 (m, 2H) , 5.52 (d, J = 12.6 Hz, 1H) , 5.25 (d, J = 12.6 Hz, 1H) , 3.76 (s, 3H) , 3.53 (s, 3H) ; 13C NMR (150 MHz, CDCI3 ) δ 167.94, 165.16, 158.94, 140.12, 134.30, 131.70, 131.08, 129.24, 129.21, 128.72, 127.40, 127.03, 123.54, 114.46, 64.23, 57.09, 55.24, 49.46; HRMS (ESI-TOF) Calcd for C25H23N2O:; [M+H]+: 431.1601; found: 431.1601.
31e
(2S, 3R) -2- (1 , 3-Dioxoisoindolin-2-yl) -li-methoxy- 3- (3-methoxyphenyl) -3-phenylpropanamide (31e)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31e was obtained as a white solid (32.1 mg, 75%). 1H NMR (600 MHz, CDC13) δ 9.08 (s, 1H) , 7.73-7.70 (m, 2H) , 7.65-7.62 (m, 2H) , 7.27- 7.24 (m, 3H) , 7.14-7.10 (m, 3H) , 7.04-7.01 (m, 2H) , 6.783-6.77 (m, 1H) , 5.54 (d, J = 12.6 Hz, 1H) , 5.30 (d, J = 12.6 Hz, 1H) , 3.79 (s, 3H) , 3.52 (s, 3H) ; 13C
NMR (150 MHz, CDC13) δ 167.87, 165.00, 159.96, 141 139.70, 134.27, 131.09, 130.13, 128.72, 127.55, 127.15, 123.53, 120.23, 114.21, 112.81, 64.17, 56. 55.26, 50.10; HRMS (ESI-TOF) Calcd for C25H23N2O5
[M+H]+: 431.1601; found: 431.1606.
31 f
(2S, 3R) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy- 3- (2-methoxyphenyl) -3-phenyl propanamide (31f)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31f was obtained as a yellow solid (25.5 mg, 59%). 1H NMR (600 MHz, CDC13) δ 9.33 (s, 1H) , 7.75-7.72 (m, 2H) , 7.66-7.63 (m, 2H) , 7.59- 7.58 (m, 1H) , 7.31-7.29 (m, 2H) , 7.23-7.21 (m, 1H) , 7.10 (t, J = 7.8 Hz, 2H) , 7.01-6.98 (m, 2H) , 6.88- 6.87 (m, 1H) , 5.80 (d, J = 13.2 Hz, 1H) , 5.68 (d, J = 13.2 Hz, 1H) , 3.90 (s, 3H) , 3.46 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 168.21, 165.08, 156.76, 139.62, 134.23, 131.15, 128.70, 128.40, 128.34, 127.93, 126.87, 123.49, 121.25, 111.32, 110.02, 63.95, 56.61, 55.71, 42.80; HRMS (ESI-TOF) Calcd for C25H23N2O5 [M+H] + : 431.1601; found: 431.1597.
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31g was obtained as a white solid (30.1 mg, 72%). Η NMR (600 MHz , CDC13) δ 9.37 (s, 1H) , 7.73-7.70 (m, 2H) , 7.67-7.64 (m, 2H) , 7.49- 7.47 (m, 2H) , 7.24 (d, J = 7.8 Hz, 2H) , 7.14 (t, J = 7.8 Hz, 2H), 7.06-7.00 (m, 3H) , 5.51 (d, J= 12.6 Hz, 1H) , 5.34 (d, J = 12.6 Hz, 1H) , 3.52 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.90, 164.92, 162.02 (d, JFC = 245.1 Hz), 139.51, 135.51, 134.40, 130.98, 129.84 (d, Jrc = 8.0 Hz), 128.83, 127.47, 127.28, 123.60, 115.83 (d, JFC = 21.2 Hz), 64.20, 56.98, 49.35; HRMS (ESI- TOF) Calcd for C24H20F 2O4 [M+H] + : 419.1402; found: 419.1402.
31 h
(2S, 3R) -2- (l,3-Dioxoisoindolin-2-yl) -3- (3- fluorophenyl) -N-methoxy-3-phenylpropanamide (31h)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31h was obtained as a white solid (29.2 mg, 70%). ¾ NMR (600 MHz, CDC13) δ 9.33 (s, 1H), 7.73-7.71 (m, 2H) , 7.67-7.64 (m, 2H) , 7.32- 7.29 (m, 2H) , 7.27-7.25 (m, 2H) , 7.21 (d, J = 10.2 Hz, 1H) , 7.15 (t, J= 7.5 Hz, 2H) , 7.06 (t, J = 7.2 Hz, 1H) , 6.93 (t, J= 7.2 Hz, 1H) , 5.51 (d, J = 12.6
Hz, 1H), 5.37 (d, J= 12.6 Hz, 1H) , 3.53 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.83, 164.79, 162.91 (d, JFC = 245.4 Hz), 142.28, 139.10, 134.39, 130.98, 130.48 (d, JFC = 7.5 Hz), 128.85, 127.59, 127.39, 123.87, 123.60, 115.30 (d, JFC = 21.8 Hz), 114.51 (d, JFC = 20.7 Hz), 64.19, 56.60, 49.74; HRMS (ESI-TOF) Calcd for C24H20F 2O [M+H]+: 419.1402; found: 419.1402.
31i
(2S, 3R) -3- (4-chlorophenyl) -2- (1 , 3-dioxoisoindolin-2- yl) -Ii-methoxy-3-phenylpropanamide (31i)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31i was obtained as a white solid (32.6 mg, 75%). XH NMR (600 MHz, CDC13) δ 9.40 (s, 1H) , 7.72-7.70 (m, 2H) , 7.66-7.64 (m, 2H) , 7.45- 7.44 (m, 2H) , 7.30-7.28 (m, 2H) , 7.24-7.23 (m, 2H) , 7.14 (t, J= 7.5 Hz, 2H) , 7.06-7.03 (m, 1H) , 5.51 (d, J = 12.6 Hz, 1H) , 5.33 (d, J= 12.6 Hz, 1H) , 3.53 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.86, 164.84, 139.25, 138.24, 134.41, 133.38, 130.95, 129.56, 129.08, 128.85, 127.49, 127.35, 123.60, 64.22, 56.71, 49.46; HRMS (ESI-TOF) Calcd for C24H20CIN2O4 [M+H]+: 435.1106; found: 435.1107.
31j
<2S, 3E) -2- (l,3-dioxoisoindolin-2-yl) -N-methoxy-3- phenyl-3- (4- (t ifluoromethyl) henyl) propanamide (31j)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31j was obtained as a white solid (34.9 mg, 75%). m.p. = 120-123 °C. ½ NMR (600 MHz, CDC13) δ 9.48 (s, 1H) , 7.73-7.71 (m, 2H) , 7.67- 7.64 (m, 4H) , 7.58 (d, J = 8.4 Hz, 2H) , 7.26-7.25 (m, 2H) , 7.15 (t, J = 7.5 Hz, 2H) , 7.07-7.05 (m, 1H) , 5.58 (d, J = 12.6 Hz, 1H) , 5.45 (d, J = 12.6 Hz, 1H) , 3.49 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.86, 164.75, 143.81, 138.81, 134.48, 130.93, 129.67 (q, JF( = 32.4 Hz), 128.94, 128.64, 127.62, 127.54, 125.93- 125.75, 123.97 (q, JFC = 270.5 Hz), 123.65, 64.17, 56.47, 49.82; HRMS (ESI-TOF) Calcd for C25H20F3N2O4 [M+H]+: 469.1370; found: 469.1372.
31k
Methyl 4-((lR, 2S) -2- (1 , 3-dioxoisoindolin-2-yl) -
3- (methoxyamino) -3-oxo-l-phenylpropyl) benzoate (31k)
Substrate 28 was arylated following the general arylation procedure. After purification by
column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31k was obtained as a white solid (34.7 mg, 76%). XH NMR (600 MHz, CDC13) δ 9.49
(s, 1H) , 7.99 (d, J = 8.4 Hz, 2H) , 7.72-7.69 (m, 2H) , 7.66-7.63 (m, 2H) , 7.60 (d, J = 8.4 Hz, 2H) , 7.26 (d, J = 7.2 Hz, 3H) , 7.14 (t, J= 7.8 Hz, 3H) , 7.05 (t, J = 7.2 Hz, 1H), 5.58 (d, J = 12.6 Hz, 1H) , 5.45 (d, J = 12.6 Hz, 1H) , 3.88 (s, 3H) , 3.48 (s, 3H) ; 13C NMR
(150 MHz, CDC13) δ 167.83, 166.71, 164.74, 144.99, 138.98, 134.40, 130.97, 130.20, 129.24, 128.86, 128.28, 127.66, 127.42, 123.59, 64.15, 56.39, 52.13, 49.94; HRMS (ESI-TOF) Calcd for 3Ν206 [M+H]+:
459.1551; found: 459.1554.
Methyl 3-((LR, 2S) -2- (1 , 3-dioxoisoindolin-2-yl) -
3- (methoxyamino) -3-oxo-l-phenylpropyl) benzoate (311)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 311 was obtained as a white solid (37.8 mg, 83%). m.p. = 107-109 °C. ¾ NMR (600 MHz, CDCI3) δ 9.42 (s, 1H) , 8.17 (s, 1H) , 7.91 (d, J = 7.2 Hz, 1H) , 7.75-7.72 (m, 3H) , 7.67-7.64 (m, 2H) , 7.42 (t, J = 7.8 Hz, 1H) , 7.29 (d, J = 7.2 Hz, 2H) , 7.15 (t, J = 7.2 Hz, 2H) , 7.05 (t, J = 7.5 Hz, 1H) , 5.59 (d, J = 12.6 Hz, 1H) , 5.43 (d, J = 12.6 Hz, 1H) , 3.89 (s, 3H) , 3.49 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ
167.87, 166.77, 164.72, 140.24, 139.15, 134.41,
132.88, 130.98, 130.69, 129.27, 129.11, 128.89,
128.76, 127.60, 127.38, 123.62, 64.18, 56.73, 52.21, 49.88; HRMS (ESI-TOF) Calcd for C26H23 206 [M+H] + : 459.1551; found: 459.1550.
31m
(2S, 3R) -3- (4-Acetylp enyl) -2- (1 , 3-dioxoisoindolin-2- yl) -N-methoxy-3-phenylpropanamide (31m)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31m was obtained as a white solid (24.3 mg, 55%) . ¾ NMR (600 MHz, CDC13) δ 9.44 (s, 1H) , 7.92 (d, J = 8.4 Hz, 2H) , 7.75-7.72 (m, 2H) , 7.68-7.66 (m, 2H) , 7.62 (d, J = 8.4 Hz, 2H) , 7.29- 7.27 (m, 2H) , 7.14 (t, J = 7.2 Hz, 2H) , 7.08-7.05 (m, 1H) , 5.59 (d, J = 12.6 Hz, 1H) , 5.41 (d, J = 12.6 Hz, 1H) , 3.51 (s, 3H) , 2.56 (s, 3H) ; 13C NMR (151 MHz, CDC13) δ 197.61, 167.86, 164.79, 145.08, 138.84, 136.17, 134.47, 130.93, 128.99, 128.90, 128.41, 127.61, 127.49, 123.65, 64.23, 56.51, 50.04, 26.60; HRMS (ESI-TOF) Calcd for C26H23N2O5 [M+H]+: 443.1601; found: 443.1601.
(2S, 3R) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy-3- (naphthalen-2-yl) -3-phenyl propanami.de (31n)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31n was obtained as a yellow solid (27.6 mg, 61%) . 1H NMR (600 MHz, CDC13) δ 9.20 (s, 1H) , 8.01 (s, 1H) , 7.85-7.76 (m, 3H) , 7.75-7.72 (m, 2H) , 7.66-7.63 (m, 2H) , 7.58 (dd, J = 8.4, 1.8 Hz, 1H) , 7.47-7.43 (m, 2H) , 7.33 (d, J = 7.8 Hz, 2H) , 7.14 (t, J = 7.8 Hz, 2H) , 7.04-7.01 (m, 1H) , 5.71 (d, J = 12.6 Hz, 1H) , 5.50 (d, J = 12.6 Hz, 1H) , 3.39 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.96, 165.03, 139.69, 137.12, 134.32, 133.48, 132.63, 131.08, 128.92, 128.76, 127.95, 127.67, 127.60, 127.19, 126.87, 126.37, 126.14, 126.01, 123.58, 64.13, 56.74, 50.20; HRMS (ESI-TOF) Calcd for C28H23N2O [M+H]+: 451.1652; found: 451.1651.
31o
(2S, 3E) -3- (3 , 5-Dimethylphenyl) -2- (1 , 3-dioxo- isoindolin-2-yl) -Itf-methoxy-3-phenyl propanamide (31o)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31o was obtained as a white solid (32.2 mg, 75%) . m.p. = 108-110 °C. 1H NMR (600 MHz, CDCI3) δ 8.91 (s, 1H) , 7.73-7.71 (m, 2H) , 7.65- 7.63 (m, 2H) , 7.27-7.25 (m, 2H) , 7.14-7.11 (m, 4H) , 7.03-7.01 (m, 1H) , 6.87 (s, 1H) , 5.55 (d, J = 12.6
Hz, 1H) , 5.19 (d, J= 12.6 Hz, 1H) , 3.52 (s, 3H) , 2.29 (s, 6H) ; 13C NMR (150 MHz, CDC13) δ 167.90, 165.10, 140.05, 139.59, 138.70, 134.21, 131.14, 129.43, 128.67, 127.51, 127.02, 125.80, 123.50, 64.14, 56.74, 50.13, 21.38; HRMS (ESI-TOF) Calcd for C26H25 2O4 [M+H]+: 429.1809; found: 429.1806.
31p
(2S, 3R) -3- (3, 4-Dimethoxyphenyl) -2- (1 , 3-dioxo- isoindolin-2-yl) -W-methoxy-3-phenyl propanamide (31p)
Substrate 28 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31p was obtained as a yellow solid (31.6 mg, 69%). ¾ NMR (600 MHz, CDC13) δ 9.10 (s, 1H), 7.73-7.71 (m, 2H) , 7.66-7.63 (m, 2H) , 7.27- 7.25 (m, 2H) , 7.15-7.13 (m, 2H) , 7.07 (dd, J = 8.1, 2.1 Hz, 1H), 7.05-7.02 (m, 1H) , 6.98 (d, J= 2.4 Hz, 1H) , 6.84 (d, J = 8.4 Hz, 1H) , 5.51 (d, J = 12.6 Hz, 1H) , 5.26 (d, J = 12.6 Hz, 1H) , 3.89 (s, 3H) , 3.83 (s, 3H) , 3.53 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.92, 165.20, 149.21, 148.41, 140.054, 134.30, 132.21, 131.08, 128.73, 127.41, 127.11, 123.54, 119.95, 111.61, 111.52, 64.24, 56.94, 56.02, 55.85, 49.69; HRMS (ESI-TOF) Calcd for C26H 206 [M+H]+: 461.1707; found: 461.1708.
Homo-diarylation of Alanine
General procedure:
The substrate 25 (0.1 mmol, 24.8 mg) , Pd(OAc)2 (0.01 mmol, 2.2 mg) , NaH2P04'H20 (0.3 mmol, 42 mg) and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.3 mmol), 2,6-lutidine (0.2 mmol, 2 μΐ,) , and HFIP (1 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
31q
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy- 3 , 3-diphenylpropanamide (31q)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31q was obtained as a white solid (26.7 mg, 67%). (The NMR data are above.)
31 r
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy- 3 , 3-di-p-tolylpropanamide (31r)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31r was obtained as a white solid (26.8 mg, 63%). m.p. = 120-122 °C. ½ NMR (600 MHz , CDC13) δ 9.08 (s, 1H) , 7.75-7.72 (m, 2H) , 7.66- 7.63 (m, 2H) , 7.38 (d, J = 7.8 Hz, 2H) , 7.14 (dd, J = 7.8, 1.8 Hz, 4H) , 6.92 (d, J = 7.8 Hz, 2H) , 5.53 (d, J = 12.6 Hz, 1H) , 5.21 (d, J = 12.6 Hz, 1H) , 3.51 (s, 3H) , 2.28 (s, 3H) , 2.12 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.94, 165.20, 137.24, 137.05, 137.00, 136.57, 134.23, 131.16, 129.78, 129.40, 127.89, 127.23, 123.54, 64.17, 57.01, 49.50, 21.03, 20.88; HRMS (ESI-TOF) Calcd for C26H25N2O4 [M+H] + : 429.1809; found: 429.1803.
31s
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -3, 3-bis (4- fluorophenyl) -W-methoxypropanamide (31s)
Substrate 25 was arylated following thi general arylation procedure. After purification
column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31s was obtained as a white solid (31.4 mg, 72%). m.p. = 102-104 °C. ¾ NMR (600 MHz, CDC13) δ 9.33 (s, 1H) , 7.75-7.72 (m, 2H) , 7.69- 7.67 (m, 2H), 7.47-7.45 ( , 2H) , 7.23-7.21 (m, 2H) ,
7.03 (t, J = 8.4 Hz, 2H) , 6.84 (t, J" = 8.4 Hz, 2H) ,
5.45 (d, J = 12.6 Hz, 1H) , 5.35 (d, J = 12.6 Hz , 1H) , 3.51 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.86, 164.74, 162.07 (d, JFC = 245.4 Hz), 161.74 (d, JFC = 245.0 Hz), 135.40, 135.30, 134.53, 130.91, 129.75 (d, = 8.0 Hz), 129.09 (d, = 17.7 Hz), 123.68, 116.00-115.71, 64.21, 56.90, 48.56; HRMS (ESI-TOF) Calcd for [M+H] + : 437.1307; found:
437.1308.
311
(S) -3 , 3-Bis (3 , 5-Dime hylphenyl) -2- (1 , 3- dioxoisoindolin-2-yl) -Iff-methoxypropanamide (31t)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, 3t was obtained as a white solid (34.4 mg, 75%) . m.p. = 100-102 °C. 1H NMR (600 MHz, CDC13) δ 8.95 (s, 1H), 7.75-7.72 (m, 2H) , 7.65-7.53 (m, 2H) , 7.10 (s, 2H) , 6.86 (s, 1H),6.84 (s, 2H) , 6.63 (s, 1H) , 5.53 (d, J = 12.6 Hz, 1H) , 5.10 (d, J= 12.6 Hz, 1H) , 3.51 (s, 3H) , 2.30 (s, 6H) , 2.11 (s, 6H) ; 13C NMR (150 MHz, CDCI3) δ 167.91, 165.22, 139.80, 139.76, 138.60, 137.99, 134.17, 131.26, 129.34, 128.71,
125.83, 125.26, 123.44, 64.09, 56.87, 49.97, 21 21.21; HRMS (ESI-TOF) Calcd for C28H29N2O4 [M+H] + 457.2122; found: 457.2118.
General procedure :
The starting material 25 (0.1 mmol, 24.8 mg), Pd(0Ac)2 (10 mol%, 2.2 mg) , and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, the first aryl iodide (0.12 mmol), 2-picoline (20 mol%, 2 pL) , HFIP (1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, to the reaction mixture, Pd(0Ac)2 (O.Olmmol, 2.2mg), NaH2P04 «H20 (0.3 mmol, 42 mg) , AgOAc (0.2 mmol, 33.4mg), the second aryl iodide (0.3 mmol) and 2,6-lutidine (0.02 mmol, 2 μΐ.) , were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
31 u
(2S) -2- (l,3-Dioxoisoindolin-2-yl) -N-met.hoxy-3- phenyl-3- (p-tolyl) ropanamide (31u)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31u was obtained as a white solid (29.4 mg, 71%). 1H NMR (600 MHz , CDC13) δ 9.07
(s, 1H), 7.75-7.73 (m, 2H) , 7.67-7.65 (m, 2H) , 7.50- 7.49 (m, 2H) , 7.33 (t, J = 7.8 Hz, 2H) , 7.23 (t, J = 7.2 Hz, 1H) , 7.15 (d, J = 7.8 Hz, 2H) , 6.94 (d, J = 7.8 Hz, 2H) , 5.54 (d, J = 12.6 Hz, 1H) , 5.27 (d, J = 12.6 Hz, 1H) , 3.47 (s, 3H) , 2.13 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.93, 165.08, 140.01, 136.75, 136.71, 134.28, 131.14, 129.45, 129.06, 128.10, 127.55, 127.31, 123.59, 64.14, 57.02, 49.81, 20.90; HRMS
(ESI-TOF) Calcd for C25¾3N204 [M+H]+: 415.1652; found: 415.1656.
31v
(2S) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy-3- (p- tolyl) -3- (4- (trifluoromethyl) phenyl) propanamide (31v)
Substrate 25 was arylated following the general arylation procedure. After purification by
column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31v was obtained as a white solid (23.1 mg, 48%). m.p. = 111-113 °C. ½ NMR (600 MHz, CDC13) δ 9.35 (s, 1H) , 7.77-7.74 (m, 2H) , 7.69- 7.67 (m, 2H) , 7.62-7.59 ( m, 2H) , 7.13 (d, J = 7.8 Hz, 2H) , 6.96 (d, J = 7.8 Hz, 2H) , 5.54 (d, J = 12.6 Hz, 1H) , 5.37 (d, J= 12.6 Hz, 1H) , 3.50 (s, 3H) , 2.14 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.89, 164.82, 144.04, 137.24, 135.74, 134.48, 130.98, 129.96-129.30, 129.66, 128.53, 127.37, 125.85-125.83, 123.97 (q, JFC = 270.5 Hz), 123.71, 64.21, 56.69, 49.50, 20.91; HRMS (ESI-TOF) Calcd for C26H22 F3N2O4 [M+H]+: 483.1526; found 483.1523.
31 w
(2S) -3- (3 ,5-Dimethylphenyl) -2- (1,3-dioxoisoindolin- 2-yl) -i/-methoxy-3- (p-tolyl) propanamide (31w)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31w was obtained as a white solid (29.9 mg, 67%). ½ NMR (600 MHz, CDC13) δ 8.88 (s, 1H) , 7.74-7.72 (m, 2H) , 7.66-7.63 (m, 2H) , 7.14 (d, J = 8.4, 2H) , 7.10 (s, 2H) , 6.92 (d, J= 8.4 Hz, 2H) , 6.86 (s, 1H) , 5.53 (d, J= 12.6 Hz, 1H) , 5.16 (d, J = 12.6 Hz, 1H) , 3.51 (s, 3H) , 2.28 (s, 6H) , 2.13 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.92, 165.18, 139.89, 138.66, 137.04, 136.56, 134.18, 131.22, 129.39, 129.34, 127.29, 125.74, 123.53,
64.12, 56.81, 49.73, 21.38, 20.90; HRMS (ESI-TOF) Calcd for C27H27N204 [M+H]+: 443.1965; found: 443.1962.
31 x
(2S) -3- (3,5-Dimethylphenyl) -2- (1 , 3-dioxoisoindolin- 2-yl) -If-methoxy-3- (p-tolyl) propanamide (31x)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31x was obtained as a white solid (22.5 mg, 51%) . 1H NMR (600 MHz, CDC13) δ 9.08 (s, 1H), 7.76-7.73 (m, 2H) , 7.67-7.64 (m, 2H) , 7.38 (d, J = 7.8 Hz, 2H) , 7.14 (d, J = 7.8 Hz, 2H) , 6.84 (s, 2H) , 6.63 (s, 1H), 5.53 (d, J= 12.6 Hz, 1H) , 5.13 (d, J = 12.6 Hz, 1H) , 3.51 (s, 3H) , 2.29 (s, 3H) , 2.10 (s, 6H) ; 13C NMR (150 MHz, CDC13) δ 167.98, 165.25, 139.81, 138.03, 137.25, 136.85, 134.22, 131.22, 129.77, 128.70, 127.97, 125.20, 123.48, 64.17, 57.14, 49.81, 21.19, 21.05; HRMS (ESI-TOF) Calcd for C27H27N204 [M+H]+: 443.1965; found: 443.1962.
31y
Methyl 3- { (2S) -1- (3 , 5-dimeth lphenyl) - dioxoisoindolin-2-yl) -3- (methoxyamino)
oxopropyl) benzoate (31y)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31y was obtained as a white solid (23.2 mg, 48%). ¾ NMR (600 MHz, CDC13) δ 9.39 (s, 1H) , 8.15 (s, 1H) , 7.92-7.90 (m, 1H) , 7.76-7.73 (m, 3H) , 7.69-7.66 (m, 2H) , 7.42 (t, J= 7.8 Hz, 1H) , 6.86 (s, 2H) , 6.66 (s, 1H) , 5.56 (d, J = 12.6 Hz, 1H) , 5.29 (d, J= 12.6 Hz, 1H) , 3.91 (s, 3H) , 3.48 (s, 3H) , 2.12 (s, 6H) ; 13C NMR (150 MHz, CDCI3) δ 167.94, 166.82, 164.85, 140.35, 138.91, 138.29, 134.38, 132.77, 131.09, 130.62, 129.39, 129.05, 128.67, 125.32, 123.58, 64.16, 56.96, 52.20, 49.81, 21.19; HRMS (ESI-TOF) Calcd for ¾ΒΗ27Ν205 [M+H]+: 487.1864; found: 487.1862.
31z
(2S,2S) -3- (3 , 5-Dimethylphenyl) -2- (1 , 3-dioxo- isoindolin-2-yl) -li-methoxy-3- (3-methoxyphenyl) propanamide (31z)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31z was obtained as a white solid (25.1 mg, 55%). ¾ NMR (600 MHz, CDC13) δ 8.88 (s, 1H), 7.77-7.73 (m, 2H) , 7.67-7.64 (m, 2H) , 7.10 (s, 2H) , 7.04 (t, J= 8.1 Hz, 1H) , 6.88 (s, 1H) , 6.85 (d, J= 7.8 Hz, 1H) , 6.80 (t, J= 1.8 Hz, 1H) , 6.57 (dd, J= 8.4, 2.4 Hz, 1H) , 5.54 (d, J= 12.6 Hz, 1H) ,
5.15 (d, J = 12.6 Hz, 1H) , 3.67 (s, 3H) , 3.52 (s, 3H) , 2.30 (s, 6H) ; 13C NMR (150 MHz, CDC13) δ 167.94, 165.07, 159.54, 141.54, 139.46, 138.70, 134.25, 131.21, 129.67, 129.49, 125.79, 123.56, 119.73, 113.07, 112.76, 64.16, 56.73, 55.10, 50.12, 21.40; HRMS (ESI-TOF) Calcd for C27H27N2O5 [M+H] + : 459.1914; found: 459.1917.
31 aa
Methyl 3- ( (2S) -2- (1 , 3-dioxoisoindolin-2-yl) -1- (4- fluorophenyl) -3- (methoxyamino) -3-oxopropyl) benzoate
(31aa)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 31aa was obtained as a white solid (25.1 mg, 53%). ½ NMR (600 MHz, CDC13) δ 9.33 (s, 1H) , 8.14 (s, 1H) , 7.93 (d, J = 7.2 Hz, 1H) , 7.77-7.74 (m, 2H) , 7.77-7.68 (m, 3H) , 7.43 (t, J = 7.8 Hz, 1H), 7.27-7.25 (m, 2H) , 6.84 (t, J = 8.4 Hz, 2H) , 5.53 (d, J= 12.6 Hz, 1H) , 5.43 (d, J = 12.6 Hz, 1H) , 3.91 (s, 3H) , 3.49 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 167.85, 166.70, 164.54, 161.80 (d, JFC = 245.0 Hz), 140.02, 135.02, 134.55, 132.75, 130.85 (d, Jfc = 17.3 Hz), 129.25, 129.19, 129.11, 128.87, 123.71, 115.86 (d, C = 21.3 Hz), 64.21, 56.70, 52.26, 49.09; HRMS (ESI-TOF) Calcd for
31ab
Methyl 4- ( (2S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (methoxyamino) -3-oxo-l- (p-tolyl) ropyl) benzoate (31ab)
Substrate 25 was arylated following the general arylation procedure. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 3ab was obtained as a white solid (22.3 mg, 47%). ½ NMR (600 MHz, CDC13) δ 8.99 (s, 1H), 7.81 (d, J= 8.4 Hz, 2H) , 7.74-7.71 (m, 2H) , 7.67-7.65 (m, 2H) , 7.38 (d, J = 7.8 Hz, 2H) , 7.35 (d, J= 8.4 Hz, 2H) , 7.15 (d, J = 7.8 Hz, 2H) , 5.55 (d, J = 12.6 Hz, 1H) , 5.37 (d, J = 12.6 Hz, 1H) , 3.79 (s, 3H) , 3.52 (s, 3H) , 2.30 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 167.86, 166.64, 164.78, 145.32, 137.77, 135.91, 134.43, 130.98, 130.08, 129.97, 128.91, 127.98, 127.55, 123.67, 64.24, 56.50, 52.02, 49.76, 21.05; HRMS (ESI-TOF) Calcd for C27H25 206 [M+H] + : 473.1707; found: 473.1710.
General procedure for arylation with aryl iodides:
Method A:
The starting material (0.2 mmol) , Pd(OAc) (10 mol%, 4.4 mg) , and AgOAc (0.4 mmol, 66.8 mg) we
weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.3 mmol) , 2-picoline (20 mol%, 4 pL) , and HFIP (2.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column.
Method B:
The substrate (0.1 mmol), Pd(OAc)2 (0.01 mmol, 2.2 mg) , NaH2P04'H20 (0.3 mmol, 42 mg) and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.3 mmol), 2,6- lutidine (0.02 mmol, 2 pL) , and HFIP (1 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using.
Method C:
The substrate (0.1 mmol, 24.8 mg) , Pd(OAc)2 (0.015 mmol, 3.3 mg) and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (0.3 mmol), L18 (0.03 mmol, 8.1
mg) , TFA (2 pL) and DCE (1 mL) were added. The reaction mixture was first stirred at room
temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column.
33a
ff-Methoxy-2- (4-methylbenzyl)butanamide (33a)
Substrate 33a was arylated following the general arylation procedure of Method A. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 33a was obtained as a white solid (26.5 mg, 60%). ¾ NMR (600 MHz, CDC13) δ 7.99 (s, 1H) , 7.08-7.05 (m, 4H) , 3.58
(s, 3H) , 2.87 (dd, J= 13.2, 9.6 Hz, 1H) , 2.71 (dd, J = 13.2, 5.4 Hz, 1H), 2.32 (s, 3H) , 2.01-2.00 (m, 1H) , 1.78-1.74 (m, 1H) , 1.57-1.53 (m, 1H) , 0.93 (t, J = 7.4 Hz, 3H) ; 13C NMR (150 MHz, CDC13) δ 172.78, 136.35, 135.91, 129.15, 128.80, 64.32, 48.72, 38.43, 25.46, 21.02, 11.96; HRMS (ESI-TOF) Calcd for C13H2oN02
[M+H]+: 222.1489; found: 222.1489.
33b
(S) -O- (3- (Benzyloxy) -2- (4-methylbenzyl) -112-propyl) - N-methoxyhydroxylamine (33b)
Substrate 32b was arylated following the general arylation procedure of Method A. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 33b was obtained as a white solid (16.6 mg, 53%). ¾ NMR (600 MHz, CDC13) δ 8.47 (s, 1H) , 7.36-7.29 (m, mH) , 7.10- 7.04 (m, 4H) , 4.51-4.46 (m, 2H) , 3.65 (s, 3H) , 3.59- 3.53 (m, 2H) , 2.97 (dd, J = 13.6, 7.8 Hz, 1H) , 2.73 (dd, J = 13.6, 7.5 Hz, 1H) , 2.54 (m, 1H) , 2.31 (s, 3H).; 13C NMR (150 MHz, CDC13) δ 171.75, 137.50, 136.08, 135.54, 129.23, 128.83, 128.53, 127.95, 127.81, 73.53, 69.66, 64.32, 47.16, 34.17, 21.03; HRMS (ESI-TOF) Calcd for C19H24NO3 [M+H]+: 314.1751; found: 314.1747.
33c
2- (3- ( (Me hoxyamino) oxy) -2- (4-me hylbenzyl) -312- propyl) isoindoline-1 , 3-dione (33c)
Substrate 32c was arylated following the general arylation procedure of Method A. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 33c was
obtained as a white solid (25.3 mg, 72%). 1H NMR (600 MHz, CDC13) δ 8.18 (s, 1H) , 7.82-7.81 (m, 2H) , 7.71- 7.70 (m, 2H) , 7.06-7.01 (m, 4H) , 4.00 (dd, J= 14.4, 7.8 Hz, 1H) , 3.87 (dd, J= 14.4, 7.2 Hz, 1H) , 3.49 (s, 3H) , 3.03-2.99 (m, 1H) , 2.91-2.86 (m, 1H) , 2.79 (dd, J = 13.2, 5.4 Hz, 1H) , 2.24 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 169.83, 168.18, 136.22, 134.90, 134.13, 131.78, 129.24, 128.74, 123.38, 64.21, 44.78, 39.88, 35.96, 20.97; HRMS (ESI-TOF) Calcd for C20H21N2O4
[M+H]+: 353.1496; found: 353.1493.
2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy-2-methyl-Sip-tolyl) ropanamide (33d)
2- (1 , 3-Dioxoisoindolin-2-yl) -W-methoxy-2- (4- methylbenzyl) -3- (p-tolyl)propanamide (33d' )
Substrate 32d was arylated following the general arylation procedure of Method A. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent. Compound 33d was obtained as a white solid (20.3 mg, 29%). ¾ NMR (600 MHz, CDCI3) δ 8.42 (s, 1H) , 7.78-7.75 (m, 2H) , 7.77- 7.69 (m, 2H) , 7.02-6.93 (m, 4H) , 3.79 (d, J = 13.2 Hz, 1H) , 3.75 (s, 3H) , 3.25 (d, J= 13.2 Hz, 1H) , 2.26 (s, 3H) , 1.83 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 170.76, 168.57, 136.80, 134.23, 131.79, 135.53, 130.50, 128.98, 123.22, 64.26, 64.15, 40.24, 21.84, 21.05; HRMS (ESI-TOF) Calcd for C20H21N2O4 [M+H]+: 353.1496; found: 353.1497. Compound 33d' was obtained as a white solid (30.4 mg, 35%). ½ NMR (600 MHz,
CDCI3) δ 8.09 (s, 1H) , 7.72 -7.67 (m, 4H) , 7.15-7.14 (m, 4H) , 7.05-7.02 (m, 4H) , 3.71 (d, J = 13.8 Hz, 2H) , 3.65 (s, 3H) , 3.44 (d, J = 13.8 Hz, 2H) , 2.27 (s, 6H) ; 13C NMR (150 MHz, CDC13) δ 169.24, 168.70, 136.92, 134.09, 131.83, 131.39, 130.71, 129.12, 123.14, 68.86, 63.97, 37.47, 21.05; HRMS (ESI-TOF)
(2S, 3S) -3- (4- ( (Tert-butyldimethylsilyl) oxy) phenyl) - 2- (1 , 3-dioxoisoindolin-2-yl) -N-methoxy-3- (p-tolyl) - propanamide (33e)
Substrate 32e was arylated following the general arylation procedure of Method B. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 33e was obtained as a white solid (31.6 mg, 58%). ½ NMR (600 MHz, CDCI3) δ 9.15 (s, 1H) , 7.73-7.71 (m, 2H) , 7.66- 7.63 (m, 2H) , 7.42-7.40(m, 2H) , 7.15 (d, J= 7.8 Hz, 2H) , 7.09 (d, J = 8.4 Hz, 2H) , 6.58-6.56 (m, 2H) , 5.49 (d, J= 12.6 Hz, 1H) , 5.12 (d, J= 12.6 Hz, 1H) , 3.53 (s, 3H), 2.30 (s, 3H) , 0.82 (s, 9H) , -0.031 (s, 3H) , -0.034 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.92, 165.20, 154.47, 137.26, 136.84, 134.24, 132.82, 131.09, 129.76, 128.53, 127.90, 123.50, 120.31, 64.19, 57.30, 49.36, 25.55, 21.05, 18.08, - 4.62; HRMS (ESI-TOF) Calcd for C31H37N205Si [M+H] + : 545.2466; found: 545.2464.
(2S, 3R) -2- (l,3-Dioxoisoindolin-2-yl) -IT-methoxy- 3- (p-tolyl) butanamide (33f)
Substrate 32f was arylated following the general arylation procedure of Method B. After purification by column chromatography using hexanes/EtOAc (2/1) as the eluent, Compound 33f was obtained as a white solid (19.2 mg, 55%) . m.p. = 152- 154 °C. ¾ NMR (600 MHz, CDC13) δ 8.86 (s, 1H) , 7.91- 7.88 (m, 2H) , 7.79-7.76 (m, 2H) , 7.28 (d, J = 7.8 Hz, 2H) , 7.18 (d, J = 7.8 Hz, 2H) , 4.86 (d, J = 12.0 Hz, 1H) , 3.98-3.97 (m, 1H) , 3.48 (s, 3H) , 2.34 (s, 3H) , 1.20 (d, J = 6.6 Hz, 3H) ; 13C NMR (150 MHz, CDC13) δ 168.26, 165.34, 138.59, 137.34, 134.50, 131.42, 129.75, 127.57, 123.76, 64.12, 59.55, 38.44, 21.09, 19.74; HRMS (ESI-TOF) Calcd for C2oH21N204 [M+H] + : 353.1496; found: 353.1495.
(IS, 2R) -1- (l,3-Dioxoisoindolin-2-yl) -W-methoxy-2- (p-tolyl) cyclobutane-l-carboxamide (33g)
(IS, 2K) -1- (l,3-Dioxoisoindolin-2-yl) -W-methoxy-2 , 4- di-p-tolylcyclobutane-l-carboxamide (33g' )
Substrate 32g was arylated following the general arylation procedure of Method A. After
purification by column chromatography using hexanes/EtOAc (2/1) as the eluent. Compound 33g was obtained as a white solid (16.8 mg, 23%) . m.p. = 209- 211 °C. 1H NMR (600 MHz, CDC13) δ 7.96 (s, 1H) , 7.86- 7.83 (m, 2H), 7.77-7.74 (m, 2H) , 7.42 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H) , 4.48 (t, J = 10.2 Hz, 1H) , 3.39-3.36 (m, 4H) , 2.56-2.49 (m, 1H) , 2.43-2.36 (m, 1H) , 2.33 (s, 3H) , 2.32-2.26 (m, 1H) . 13C NMR (150 MHz, CDCI3) δ 167.90, 167.85, 137.23, 135.37, 134.45, 131.69, 129.13, 128.76, 123.45, 65.49, 63.98, 47.41, 27.98, 23.56, 21.10; HRMS (ESI-TOF) Calcd for
C21H21N2O4 [M+H] + : 365.1496; found: 365.1491. Compound 33g' was obtained as a white solid (57.3 mg, 63%). 1H NMR (600 MHz, CDC13) δ 7.92 (s, 1H) , 7.88-7.85 (m, 2H) , 7.77-7.74 (m, 2H) , 7.38 (d, J = 8.4 Hz, 4H) , 7.15 (d, J = 7.8 Hz, 4H) , 4.85-4.82 (m, 2H) , 3.28 (s, 3H) , 3.03-2.97 (m, 1H) , 2.63-2.59 (m, 1H) , 2.33 (s, 6H) ; 13C NMR (150 MHz, CDC13) δ 168.65, 165.86, 136.99, 134.60, 134.41, 131.63, 128.89, 128.61, 123.46, 71.61, 63.78, 44.41, 25.91, 21.11; HRMS (ESI- TOF) Calcd for ¾8Η27 2θ4 [M+H]+: 455.1965; found: 455.1962.
33h
2- ( (IS, 2R) -1- ( ( (Methoxyamino) oxy) -12-methyl) -2- (p-tolyl) cyclopropyl) isoindoline-1 , 3-dione (33h)
Substrate 32h was arylated following the general arylation procedure of Method C. After purification by column chromatography using
hexanes/EtOAc (2/1) as the eluent, Compound 33h was obtained as a white solid 15.8 mg (45%). m.p. = 203- 206 °C. ¾ NMR {600 MHz, CDC13) δ 8.29 (s, 1H) , 7.927.89 (m, 2H) , 7.80-7.77 (m, 2H) , 7.38 (d, J= 7.8 Hz, 2H) , 7.17 (d, J = 7.8 Hz, 2H) , 3.26 (s, 3H) , 2.84 (t, J = 9.6 Hz, 1H) , 2.50 (dd, J = 8.4, 6.6 Hz, 1H) , 2.33 (s, 3H), 1.83 (dd, J = 9.6, 7.2 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 168.30, 164.66, 137.40, 134.67, 131.41, 130.80, 129.21, 128.90, 123.76, 63.96, 38.50, 32.19, 21.15, 16.14; HRMS (ESI-TOF) Calcd for C2oHi9N204 [M+H] + : 351.1339; found: 351.1339
Gram-Scale Synthesis of Unnatural Amino Acids
yields for two steps:
28g', Ar = 4-F-C6H4 92%
28h-, Ar = 3-F-C6H4 85%
281', Ar = 4-CF3-CeH4 98%
Fmoc-CI
1Q% aq.NaHCO^ NHFmoc LiOH-H20 NHFmoc
Ar^ .
1 ,4-dioxane, 0 °C to r.t 'C02Me 1:1 THF/H20, 0°C C02H
2-3.5 h
yields for three steps
34, Ar = 4-F-C6H4 50%
35, Ar = 3-F-CeH 55%
36, Ar = 4-CF3-CeH4 50%
|| HFmoc
34, 7.5 g 35, 7.6 g 36, 9.0 g total yields: 46% 47% 49%
Gerenal procedure for scale-up synthesis of unnatural amino acid
Nphth Pd(OAc)2 (10 mol%)
2-picoline (20 mol%) Phth
CONHOMe Ύ A
AgOAc (2.0 eq.) CONHOMe
HFIP, 75 °C, air, 24 h
20 mmol scale
The starting material (20.0 mmol, 4.96 g) , Pd(OAc)2 (3.0 mmol, 674 mg) , and AgOAc (40.0 mmol, 6.68 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (30 mmol), 2-picoline (6.00 mmol, 0.6 mL) , and HFIP (150 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, and HFIP was recovered by distillation. The residue was filtered with DCM and concentrated as crude product.
The above crude product substrate was dissolved in MeOH (120 ml) , followed by the addition of PhI(OAc)2 (20 mmol, 6.44.g). The reaction mixture was heated to 80 °C for 3 hours. The reaction mixture was then cooled to room temperature, saturated aq. Na2S03 and saturated aq. NaHC03 were added. The aqueous layer was then extracted with EtOAc and the combined organic layers washed with brine, dried over MgSC filtered and concentrated. Purification by column chromatography (hexanes/ EtOAc = 2/1) provided product.
Fmoo-CI
NPhth 10% aq.NaHCO3 NHFmoc
Α ~' -∞2Μβ DCM/MeOH 1 ,4-dioxane, 0"C to*. A ^C02Me
The substrate (5 mmol) was dissolved in a 1:1 mixture of DCM/MeOH (50 mL total), and
ethylenediamine (5-6 equiv. ) was added. The reaction mixture was heated to 40 °C for 3 hours, and then cooled to room temperature. The reaction mixture was stirred at room temperature for 7 hours (monitored by TLC) . The reaction mixture (with solvent) was then transferred to a column with silica gel and purified by column chromatography (DCM/MeOH =10/1) . Crude amino ester product was obtained as oil (yield 85- 95%) and used directly for next step.
The amino ester was dissolved in 1,4- dioxane, and 10% aq. NaHC03 was added. The mixture was cooled to 0 °C and Fmoc-Cl (1.2 equiv) was added. The ice bath was allowed to warm to room temperature overnight (about 18 hours), after which H20 and EtOAc was added to the reaction mixture. The aqueous layer was then extracted with EtOAc twice and the combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. Purification was carried out by column chromatography (hexanes/EtOAc = 3/1 to 2/1) .
NHFmoc LiOH.H20 NHFmoc
Ar\^C02Me THF/H20, 0°C Ar\^C02H
The substrate was dissolved in THF. The solution was cooled to 0 °C, and a cold solution of LiOH'H20 (2 equiv) in ¾0 was added. The reaction was maintained at 0 °C for 1 hour. The reaction was acidified with 2N HC1 and extracted with EtOAc. The combined organic layers were dried over MgS04, and
concentrated. The residue was purified by column chromatography (hexanes/EtOAc/AcOH= 10/10/1) .
34
(S) -2- ( ( ( (9ff-Fluoren-9-yl) methoxy) carbonyl) amino) - 3- (4-fluorophenyl) ropanoic acid (34)
Total yield (46%), white solid (7.5 g) . m.p. = 162-165 °C. ¾ NMR (600 MHz, Acetone d-6) δ 7.85 (d, J= 7.8 Hz, 2H), 7.65 (t, J = 7.8 Hz, 2H) , 7.40 (t, J = 7.8 Hz, 2H) , 7.35-7.29 (m, 4H) , 7.04 (t, J = 9.0 Hz, 2H) , 4.49 (dd, J= 9.0, 4.8 Hz, 1H) , 4.32-4.25 (m, 2H) , 4.19 <t, J = 7.8 Hz, 1H) , 3.24 (dd, J= 13.8, 4.8 Hz, 1H) , 3.03 (dd, J = 13.8, 9.6 Hz, 1H) ; 13C NMR (150 MHz, Acetone d-6) δ 173.19, 162.69 (d, JFC = 241.1 Hz), 156.81, 145.08, 145.02, 142.14, 134.58, 132.05 (d, JFC = 8.0 Hz), 128.57, 127.96, 126.21, 126.17, 120.85, 115.82 (d, JFC = 21.3 Hz), 67.17, 56.13, 48.00, 37.34; HRMS (ESI-TOF) Calcd for C24H2iFN04 [M+H]+: 406.1449; found: 406.1446.
35
(S) -2- ( ( ( (9H-Fluoren-9-yl) methoxy) carbonyl) amino) -3- (3-fluorophenyl) propanoic acid (35)
Total yield (47%), white solid (7.6 g) . m.p. = 145- 148 °C. ¾ NMR (600 MHz, Acetone d-6) δ 7.84 (d, J = 7.2 Hz, 2H) , 7.65 (t, J= 7.5 Hz, 2H) , 7.40 (t, J = 7.5 Hz, 2H) , 7.34-7.29 (m, 3H) , 7.16-7.12 (m, 2H) , 6.99 (dt, J = 8.5, 2.4 Hz, 1H) , 4.57-4.53 (m, 1H) , 4.31-4.24 (m, 2H) , 4.19 (t, J = 7.2 Hz, 1H) , 3.29
(dd, J = 13.8, 4.8 Hz, 1H) , 3.08 (dd, J = 13.8, 9.6 Hz, 1H); 13C NMR (150 MHz, Acetone d-6) δ 173.13, 163.66 (d, JFC = 242.0 Hz) , 156.88, 145.04, 145.01, 142.11, 141.47, 141.42, 130.94 (d, JFC = 8.4 Hz), 128.57, 127.97, 126.26 (d, JTC = 2.6 Hz), 126.22, 126.16, 120.84, 116.98 (d, JFC = 21.3 Hz), 114.24 (d, JFC = 21.0 Hz), 67.26, 55.99, 47.97, 37.86; HRMS (ESI- TOF) Calcd for C24H21FNO4 [M+H]+: 406.1449; found:
36
(S) -2- ( ( ( (9H-Fluoren-9-yl)me hoxy) carbonyl) mino) -3- (4- (trifluoromethyl) henyl) propanoic acid (36)
Total yield (49%), white solid (9.0 g) . m.p. = 170-174 °C. ½ NMR (600 MHz, MeOD) δ 7.78 (d, J = 7.8 Hz, 2H) , 7.59-7.52 (m, 4H) , 7.40-7.36 (m, 4H) , 7.29-7.25 (m, 2H) , 4.40 (dd, J= 9.0, 4.8 Hz, 1H) , 4.36-4.31 (m, 1H) , 4.23 (dd, J= 10.8, 6.6 Hz, 1H) , 4.14 (t, J = 6.6 Hz, 1H) , 3.31-3.28 (m, 1H) , 3.02 (dd, J = 13.8, 9.0 Hz, 1H) ; 13C NMR (150 MHz, MeOD) δ 176.16, 158.36, 145.33, 145.26, 143.86, 142.65, 131.16, 130.47- 129.80, 128.84, 128.20, 126.32, 126.27-126.20, 125.91(q, JFC = 269.3 Hz), 120.98, 120.97, 67.91, 57.13, 48.42, 38.61; HRMS (ESI-TOF) Calcd for C25H21F3NO4 [M+H]+: 456.1417; found: 456.1415.
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -3- (6-fluoropyridin- 3-yl) -W-methoxypropanamide (30i)
The starting material 25 (10.0 mmol, 2.48 g) , Pd(OAc)2 (1.50 mmol, 337 mg) , and AgOAc (20.0 mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (15 mmol), 2,6- lutidine (3.00 mmol, 0.3 mL) , and HFIP (100 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, and HFIP was recovered by distillation. The residue was filtered with DCM and concentrated as
crude product. ¾ NMR (600 MHz, CDC13) δ 9.16 (s, 1H) , 7.96 (s, 1H), 7.82-7.79 (m, 2H) , 7.5-7.74 (m, 2H) , 7.70-7.67 (m, 1H) , 6.81 (dd, J = 8.4, 2.4 Hz, 1H) , 5.04 (m, 1H) , 3.76 (s, 3H) , 3.58-3.49 (m, 2H) ; 13C NMR (150 MHz, CDCI3) δ 167.71, 165.97, 162.87 (d, JFC = 237.9 Hz), 147.78 (d, JFC = 14.4 Hz), 141.68 (d, JFC = 8.0 Hz), 134.78, 131.01, 129.49, 123.89, 109.69 (d, JFC = 37.2 Hz), 64.66, 53.84, 30.98; HRMS (ESI-TOF) Calcd for Ci7Hi5FN304 [M+H]+: 343.0968; found: 343.1047.
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (6-fluoropyridin-3-yl)propanoate (30i' )
The above crude product substrate was dissolved in MeOH (100 mL) , followed by the addition of PhI(OAc)2 (10 mmol, 3.22 g) . The reaction mixture was heated to 80 °C for 3 hours. The reaction mixture was cooled to room temperature and then saturated aq. a2S03 and saturated aq. NaHC03 were added. The aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over MgS04, filtered and concentrated. After purification by column chromatography (hexanes/ EtOAc = 2/1 to 1/1), the product was obtained as white solid
Compound 30i' (1.81g, 55%). (The NMR data are provided above.) H2N Fmoc-CI F
Nphth ^ 10% ag.NaHC03 NHFrnoc
N¾^ -^C02IVIe DC /MeOH 1 ,4-dioxane, 0°C to r.t. N'¾^ ^^C02Me 30i' 37·
Methyl (S) -2- ( ( ( ( 9ff-fluoren-9-yl) methoxy) carbonyl) - amino) -3- (6-fluoropyridin-3-yl) propanoate (3V)
The substrate 30i' (3.63 mmol, 1.19 g) was dissolved in a 1:1 mixture of DCM/MeOH (25 mL total), and ethylenediamine (18.2 mmol, 1.09 g) was added. The reaction mixture was heated to 40 °C for 3 hours, and then cooled to room temperature. After removing the solvent in vacuo, the residue was purified by column chromatography (DCM/MeOH = 20:1 to 10:1). The resulting amino ester was dissolved in 1,4-dioxane
(22 mL) , and 10% aq. NaHC03 (14 mL) was added. The mixture was cooled to 0 °C and Fmoc-Cl (3.99 mmol, 1.03 g) was added. The ice bath was allowed to warm to room temperature overnight (about 18 hours) , after which H20 and EtOAc were added. The aqueous layer was then extracted with EtOAc (2 x) and the combined organic layers were washed with brine, dried over MgSO^, filtered and concentrated. After purification by column chromatography (hexanes/EtOAc = 3/1 to 2/1 to 1/1), the Compound 37' product was a white solid
(1.42 g, 93%). ¾ NMR (600 MHz, CDC13) δ 7.95 (s, 1H) , 7.78 (d, J = 7.2 Hz, 2H) , 7.57 (d, J = 7.8 Hz, 2H) , 7.47 (t, J = 7.2 Hz, lH), 7.42-7.40 (m, 2H) , 7.35- 7.31 (m, 2H) , 6.85 (d, J= 6.0 Hz, 1H) , 5.31 (d, J = 6.6 Hz, 1H), 4.64 (dd, J = 13.2, 6.0 Hz, 1H) , 4.49
(dd, J = 10.8, 6.6 Hz, 1H) , 4.42-4.39 (m, 1H) , 4.21
(t, J = 6.6 Hz, 1H) , 3.75 (s, 3H) , 3.16 (dd, J = 14.4, 6.0 Hz, 1H) , 3.07 (dd, J = 14.4, 6.0 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 171.21, 162.96 (d, JFC = 237.5 Hz), 155.46, 147.92 (d, JFC = 14.3 Hz), 143.70, 143.54, 141.93 (d, JFC = 8.0 Hz), 141.38, 141.32, 129.12 (d, JFC = 4.4 Hz), 127.79, 127.12, 127.08, 124.99, 124.90, 120.05, 120.02, 109.42 (d, JFC = 37.2 Hz), 66.91, 54.48, 52.68, 47.16, 34.51; HRMS (ESI- TOF) Calcd for C24H22FN2O4 [M+H]+: 421.1558; found: 421.1562.
F.
NHFmoc LiOH.H20 F.
NHFmoc
THF/H20, 0°C
"C02Me "C02H
37' 37
(S) -2- ( ( ( (9H-Fluoren-9-yl)methoxy) carbonyl) amino) - 3- (6-fluoropyridin-3-yl)propanoic acid (37)
The substrate 37' (4.02 mmol, 1.69 g) was dissolved in THF (20 mL) . The solution was cooled to 0 °C, and a cold solution of LiOH«H20 (8.04 mmol, 0.338 g) in H20 (20 mL) was added. The reaction was maintained at 0 °C for 1 hour. The reaction was acidified with 2N HC1 and extracted with EtOAc. The combined organic layers were dried over MgSO^ and concentrated. The residue was purified by column chromatography (hexanes/EtOAc/AcOH = 10/10/1) . Pale yellow solid Compound 37 (1.10 g, 67%). m.p. = 136- 138 °C. ½ NMR (600 MHz, MeOD) δ 8.06 (d, J = 2.4 Hz, 1H) , 7.81-7.77 (m, 3H) , 7.60-7.57 (m, 2H) , 7.38 (t, J = 7.2 Hz, 2H) , 7.29 (t, J = 7.2 Hz, 2H) , 6.97 (dd, J = 8.4, 2.4 Hz, 1H) , 4.43 (dd, J = 9.6, 4.8 Hz, 1H) , 4.34-4.27 (m, 2H) , 4.17 (t, J = 7.2 Hz, 1H) , 3.24 (dd, J= 14.4, 4.8 Hz, 1H) , 2.98 (dd, J = 14.4, 9.6 Hz, 1H) 13C NMR (150 MHz, MeOD) δ 174.48, 164.14 (JFC = 236.9 Hz), 158.47, 148.82 (JFC = 13.4 Hz), 145.32, 145.19, 144.15 (JFC = 8.6 Hz), 142.65, 132.81 (JFC = 5.4 Hz), 128.86, 128.24, 126.29, 126.24, 121.00, 120.99, 110.37 (JFC = 36.8 Hz), 67.99, 56.29, 48.42, 34.76; HRMS (ESI-TOF) Calcd for C23H20FN2O4 [M+H]+: 407.1402; found: 407.1401.
(S) -2- (l,3-Dioxoisoindolin-2-yl) -N-iaet oxy-3- (l-tosyl-lH-indol-5-yl) ropanamide (30c)
Substrate 25 (25 mmol, 6.2 g) , Pd(OAc)2 (3.75 mmol, 844 mg) , and AgOAc (50 mmol, 8.35 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (37.5 mmol, 14.9 g) , 2,6-lutidine (7.5 mmol, 0.75 mL) , and HFIP (130 mL) were added. The reaction mixture was first stirred at room
temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and recovered for next use, and the
resulting mixture of crude amide was used directly for next step.
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) -3- (l-tosyl-lH-indol-5-yl)propanoate (30 ' )
A sealable pressure flask was charged with MeOH (120 mL) and crude amide 30c. Et2OBF3 (105 mmol, 14 mL) was added and the reaction vessel sealed. The reaction mixture was heated to 100 °C for 12 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and H20 and EtOAc was added, organic layers were removed, the aqueous layer was then extracted with EtOAc (3 x) and the combined organics washed with brine, dried over MgS04, filtered and concentrated. After purification by column chromatography (hexanes/ EtOAc = 2/1 to 1/1) , the product Compound 30c' was provided as a white solid (5.53 g, 44%). Η NMR (600 MHz, CDC13) δ 7.79 (d, J= 8.4 Hz, 1H) , 7.76-7.73 (m, 2H) , 7.69- 7.66 (m, 3H) , 7.45 (d, J = 3.6 Hz, 1H) , 7.33-7.30 (m, 1H) , 7.18 (d, J= 8.4 Hz, 2H) , 7.10 (dd, J= 8.4, 1.2 Hz, 1H) , 6.50 (d, J = 3.6 Hz, 1H) , 5.17 (dd, J = 10.8, 5.4 Hz, 1H) , 3.77 (s, 3H) , 3.66-3.58 (m, 3H) , 2.33 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 169.36, 167.49, 144.84, 135.23, 134.10, 133.86, 131.79, 131.56, 131.01, 129.82, 126.73, 126.56, 125.41, 123.49, 121.54, 113.56, 108.89, 53.46, 52.92, 34.46, 21.56; HRMS (ESI-TOF) Calcd for C27H23N206S [M+H]+: 503.1271; found: 503.1271.
Methyl (S) -2- ( ( ( <9H-fluoren-9-yl)methoxy) carbonyl) - amino) -3- (l-tosyl-lH-indol-5-yl) propanoate (38-1)
Compound 30c' (15 mmol, 7.5 g) was dissolved in a 1:1 mixture of DCM/MeOH (80 mL total), followed by the addition of ethylenediamine (75 mmol, 5 mL) . The reaction mixture was heated to 40 °C for 3 hours, and then cooled to room temperature. Then reaction mixture (with solvent) was transferred to a column with silica gel, and purified by column chromatography (DCM/MeOH =10/1) . The amino ester was dissolved in 1,4-dioxane (60 mL) , and 10% aq. NaHC03 (45 mL) was added. The mixture was cooled to 0 °C and Fmoc-CI (16.5 mmol, 4.3 g) was added. The ice bath was allowed to warm to room temperature overnight (about 18 hours) , after which H20 and EtOAc were added to the reaction mixture. The aqueous layer was then extracted with EtOAc (3 x) and the combined organics washed with brine, dried over MgSO/i, filtered and concentrated. After being purified by column chromatography (hexanes/EtOAc = 3/1 to 2/1 to 1/1), the Itf-Ts methyl ester Compound 38-1 was obtained as white solid (8.1 g, 88%). 1H NMR (600 MHz, CDC13) δ 7.89 (d, J = 8.4 Hz, 1H) , 7.77 (d, J= 7.2 Hz, 1H) , 7.74 (d, J = 8.4 Hz, 2H) , 7.56-7.52 (m, 4H) , 7.41-7.39 (m, 2H) , 7.31-7.28 (m, 2H) , 7.18 (d, J = 8.4 Hz, 1H) , 7.02 (d, J= 8.4 Hz, 1H) , 6.58 (d, J = 3.6 Hz, 1H), 5.22 (d, J= 7.8 Hz, 1H) , 4.67 (dd, J = 13.8, 6.0 Hz, 1H), 4.43-4.41 (m, 1H) , 4.32 (dd, J = 10.2, 6.6 Hz, 1H) , 4.19 (t, J= 6.6 Hz, 1H) , 3.71 (s, 3H) , 3.20-3.13 (m, 2H) , 2.30 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 171.91, 155.54, 144.99, 143.81, 143.71,
141.31, 135.28, 133.99, 131.06, 130.73, 129.91, 127.76, 127.09, 126.79, 126.75, 125.88, 125.10, 125.03, 121.92, 120.02, 120.00, 113.56, 108.77, 66.95, 54.97, 52.39, 47.15, 38.07, 21.54; HRMS (ESI- TOF) Calcd for C34H3iN206S [M+H] + : 595.1897; found: 595.1897.
Methyl (S) -2- ( ( ( ( 9H-fluoren-9-yl) methoxy) carbonyl) - amino) -3- (lH-indol-5-yl)propanoate (38-2)
A solution of the N-Ts methyl ester (12 mmol, 7.13g) and NH4C1 (120 mmol, 6.5g) in MeOH (240 mL) was cooled to 0 °C, Mg powder (325 mesh) (240 mmol, 5.8g) was added in small portions under vigorous stirring. Upon completion (about 4 hours) , a solution of AcOH (30 mL) in ethyl acetate (150 mL) was added at 0 °C and the resulting mixture stirred for 30 minutes. After filtration by celite, the filtrate was concentrated. The residue was dissolved in ethyl acetate and water (400 mL/150 mL) . The aq. layer was extracted with EtOAc (100 mL 2) . The combined ethyl acetate phase was dried over a2S04, filtered and concentrated. After purified by column chromatography (EtOAc/hexanes/DCM = 1/10/10 to 2/10/10), Compound 38-2 was obtained as white solid
(4.4 g, 83%) . JH NMR (600 MHz, CDC13) δ 8.14 (s, 1H) , 7.76 (d, J = 7.2 Hz, 2H) , 7.55 (dd, J = 13.8, 7.2 Hz, 2H) , 7.40-7.38 (m, 2H) , 7.33-7.28 (m, 3H) , 7.21 (t, J = 3.0 Hz, 1H) , 6.94 (d, J = 8.4 Hz, 1H) , 6.51 (s, 1H) , 5.26 (d, J = 8.4 Hz, 1H) , 4.71 (dd, J = 13.8, 6.0 Hz, 1H) , 4.41 (dd, J = 10.2, 7.2 Hz, 1H) , 4.31
(dd, J = 10.8, 7.2 Hz, 1H) , 4.21 (t, J = 7.2 Hz, 1H) ,
3.74 (s, 3H) , 3.23 (dd, J = 5.4, 3.6 Hz, 2H) ; C NMR (150 MHz, CDC13) δ 172.29, 170.66, 155.66, 143.90, 143.84, 141.29, 135.03, 128.20, 127.67, 127.05, 126.81, 125.21, 125.13, 124.62, 123.35, 121.29, 119.96, 119.94, 111.21, 102.56, 67.01, 55.19, 52.30, 47.17, 38.32; HRMS (ESI-TOF) Calcd for C27H25 204
(S) -2- ( ( ( (9H-Fluoren-9-yl) methoxy) carbonyl) amino) - 3- (lH-indol-5-yl)propanoic acid (38)
The substrate 38-2 (21.3 mmol, 9.4 g) was dissolved in THF (100 mL) . The solution was cooled to 0 °C, and a cold solution of LiOH-H20 (42.6 itimol, 1.79 g) in ¾0 (100 mL) was added. The reaction was maintained at 0 °C for 1 hour. The reaction was acidified with 2N HC1 and extracted with EtOAc. The combined organic layers were dried over gS04, and concentrated. The residue was purified by column chromatography (hexanes/EtOAc/AcOH = 10/10/1) .
Compound 38 was obtained as white solid (5.7 g, 63%). m.p. = 119-121 °C. 1H NMR (600 MHz, MeOD) δ 7.75 (d, J = 7.2 Hz, 2H), 7.53 (t, J= 8.4 Hz, 2H) , 7.44 (s, 1H), 7.34 (dd, J = 13.8, 6.6 Hz, 2H) , 7.29 (d, J = 8.4 Hz, 1H) , 7.23 (t, J = 7.2 Hz, 1H) , 7.19-7.16 (m, 2H) , 7.01 (d, J = 8.4 Hz, 1H) , 6.36 (d, J = 3.0 Hz, 1H), 4.46 (dd, J = 9.0, 4.8 Hz, 1H) , 4.27 (dd, J = 9.6, 6.6 Hz, 1H) , 4.16-4.11 (m, 2H) , 3.28 (dd, J = 13.8, 4.8 Hz, 1H) , 3.02 (dd, J = 13.8, 9.6 Hz, 1H) ; 13C NMR (150 MHz, MeOD) δ 175.77, 158.49, 145.30, 142.58, 136.86, 129.74, 128.79, 128.23, 126.48, 126.32, 125.92, 123.75, 121.84, 120.92, 112.22,
102.28, 68.10, 57.60, 48.39, 39.03; HRMS (ESI-TOF) Calcd for 3N [M+H]+: 427.1652; found: 427.16.
(S) -3- (2-Chloropyridin-4-yl) -2- (1 , 3-dioxoisoindolin- 2-yl) -2i-methoxypropanamide (301)
The starting material 25 (10.0 mmol, 2.48 g) , Pd(OAc)2 (1.50 mmol, 337 mg) , and AgOAc (20.0 mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (15 mmol), 2,6- lutidine (3.00 mmol, 0.3 mL) , and HFIP (100 mL) were added. The reaction mixture was first stirred at room ' temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, and HFIP was recovered by distillation.
The residue was filtered with DCM and concentrated as crude product 301.
Methyl (S) -3- (2-chloropyridin-4-yl) -2- (1 , 3-dioxoisoindolin-2-yl)propanoate (3011 )
The above crude product substrate was dissolved in MeOH (100 mL) , followed by the addition of PhI(0Ac)2 (10 mmol, 3.22 g) . The reaction mixture was heated to 80 °C for 3 hours. The reaction mixture was cooled to room temperature and then saturated aq. Na2S03 and saturated aq. NaHC03 were added. The aqueous layer was extracted with EtOAc, and the combined organic layers washed with brine, dried over MgSOi; filtered and concentrated. The residue was purified by column chromatography (hexanes/ EtOAc = 2/1 to 1/1) to provide product Compound 301' (2.00 g,
301' 39'
Methyl (S) -2- ( ( ( (9H-fluoren-9-yl)methoxy) carbonyl) - amino) -3- (2-chloropyridin-4-yl) propanoate (39')
The substrate 301' (24.6 mmol, 8.5 g) was dissolved in a 1:1 mixture of DCM/MeOH (100 mL total), and ethylenediamine (123 mmol, 7.36 g) was added. The reaction mixture was heated to 40 °C for 3 hours, and then cooled to room temperature. Then reaction mixture (with solvent) was transferred to a column with silica gel directly and purified by
column chromatography (DCM/MeOH = 10/1) . The resulting amino ester was dissolved in 1,4-dioxane
(100 mL) , and 10% aq. NaHC03 (75 inL) was added. The mixture was cooled to 0 °C and Fmoc-Cl (30 mmol, 7.69 g) was added. The ice bath was allowed to warm to room temperature overnight (about 18 hours) , after which H20 and EtOAc was added to the reaction mixture. The aqueous layer was then extracted with EtOAc and the combined organic layers were washed with brine, dried over MgS0,j, filtered and concentrated. After being purified by column chromatography
39' 39
(S) -2- ( ( ( (9H-Fluoren-9-yl)methoxy) carbonyl) amino) - 3- (2-chloropyridin-4-yl)propanoic acid (39)
The substrate 39' (18.3 mmol, 8.0 g) was dissolved in THF (100 mL) . The solution was cooled to 0 °C, and a cold solution of LiOH»¾0 (36.6 mmol, 1.53 g) in H20 (100 mL) was added. The reaction was maintained at 0 °C for 1 hour. The reaction was acidified with 2N HC1 and extracted with EtOAc. The combined organic layers were dried over MgS0i and concentrated. The residue was purified by column chromatography (hexanes/EtOAc/AcOH = 10/10/1).
Compound 39 was obtained as white solid (6.0 g, 78%). m.p. = 202-204 °C. 1H NMR (600 MHz, MeOD) δ 8.17 (d, J = 4.8 Hz, 1H) , 7.78 (d, J = 7.8 Hz, 2H) , 7.60 (dd, J = 12.0, 7.8 Hz, 2H) , 7.39-7.35 (m, 3H) , 7.31- 7.28 (m, 2H) , 7.23 (d, J = 4.8 Hz, 1H) , 4.38 (dd, J =
10.2, 6.6 Hz, 1H), 4.30 (dd, J= 7.8, 4.8 Hz, 1H) , 4.21 (dd, J= 10.2, 6.6 Hz, 1H) , 4.17-4.15 (m, 1H) , 3.23 (dd, J = 13.2, 4.8 Hz, 1H) , 2.99 (dd, J= 13.8, 8.4 Hz, 1H); 13C NMR (150 MHz, MeOD) δ 176.85, 158.00, 153.94, 152.04, 150.01, 145.40, 145.29, 142.64, 128.84, 128.25, 128.23, 126.75, 126.35, 126.22, 125.53, 120.98, 120.96, 67.85, 57.82, 48.47, 38.91; HRMS (ESI-TOF) Calcd for C23H20CIN2O4 [M+H] + : 423.1106; found: 423.1107.
(S) -2- (1 ,3-Dioxoisoindolin-2-yl) -Itf-methoxy- 3- (3 , 4 , 5-trifluorophenyl) ropanamide (28s)
The starting material 25 (10.0 mmol, 2.48 g) , Pd(OAc)2 (1.50 mmol, 337 mg) , and AgOAc (20.0
mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (15 mmol), 2,6- lutidine (3.00 mmol, 0.3 mL) , and HFIP (100 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 90 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, and HFIP was recovered by distillation. The residue was filtered with DCM and concentrated as crude product 28s.
28s 28s'
Methyl (S) -2- (1 , 3-Dioxoisoindolin-2-yl) - 3- (3 , 4 , 5-trifluorophenyl) ropanoate (28s ' )
The above crude product substrate 28s was dissolved in MeOH (100 mL) , followed by the addition of PhI(0Ac)2 (10 mmol, 3.22 g) . The reaction mixture was heated to 80 °C for 3 hours. The reaction mixture was cooled to room temperature and then saturated aq. Na2S03 and saturated aq. NaHC03 were added. The aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over MgS04, filtered and concentrated. After being purified by column chromatography (hexanes/ EtOAc = 2/1 to 1/1), product 28s' 2.49 g (66%) was obtained. (The NMR Data are provided above.)
Methyl (S) -2- ( ( ( (9H-fluoren-9-yl)methoxy) carbonyl) - amino) -3- (3 , 4 ,5-trifluorophenyl) propanoate (40')
The substrate 28s' (5.11 mmol, 1.86 g) was dissolved in a 1:1 mixture of DCM/MeOH (40 mL total), and ethylenediamine (25 mmol, 1.47 g) was added. The reaction mixture was heated to 40 °C for 3 hours, and then cooled to room temperature. The reaction mixture (with solvent) was transferred to a column with silica gel, and purified by column
chromatography (DCM/MeOH = 10/1) . The resulting amino ester was dissolved in 1,4-dioxane (20 mL) , and 10% aq. NaHC03 (15 mL) was added. The mixture was cooled to 0 °C and Fmoc-Cl (6.22 mmol, 0.94 g) was added. The ice bath was allowed to warm to room temperature overnight, after which ¾0 and EtOAc was added to the reaction mixture. The aqueous layer was extracted with EtOAc (2 x) and the combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. The residue was purified by column chromatography (hexanes/EtOAc = 3/1 to 2/1 to 1/1) to provide Compound 40' as white solid (3.43 g, 67%). 1H NMR (600 MHz, CDC13) δ 7.77 (d, J = 7.2 Hz, 2H) , 7.56 (t, J = 6.6 Hz, 2H) , 7.40 (dd, J = 13.2, 7.2 Hz, 2H) , 7.33-7.30 (m, 2H) , 6.69 (t, J = 6.6 Hz, 2H) , 5.33 (d, J = 6.6 Hz, 1H) , 4.61 (dd, J = 13.2, 6.0 Hz, 1H), 4.50 (dd, J = 10.2, 7.2 Hz, 1H) , 4.39 (dd, J= 10.8, 6.6 Hz, 1H) , 4.20 (t, J= 6.6 Hz, 1H) , 3.74 (s, 3H) , 3.06 (dd, J = 13.8, 5.4 Hz, 1H) , 2.98 (dd, J= 13.8, 6.0 Hz, 1H) ; 13C NMR (150 MHz, CDCI3) δ 171.19, 155.45, 151.03 (ddd, JFC = 249.0, 9.6, 3.2 Hz), 143.74, 143.48, 141.51, 141.35, 141.33, 138.98 (dt, JFC = 249.9, 14.7 Hz), 132.22-132.10, 127.79, 127.10, 127.07, 127.04, 124.97, 124.87, 120.06, 113.36 (dd, JFC = 16.6, 3.9 Hz), 66.92, 54.44,
52.64, 47.16, 37.60; HRMS (ESI-TOF) Calcd for
[M+H] + : 456.1417; found: 456.1419.
(S) -2- ( < ( (9ff-Fluoren-9-yl)methoxy) carbonyl) amino) - 3- (3 , 4 , 5-trifluorophenyl) ropanoic acid (40)
The substrate 40' (3.43 mmol, 1.56 g) was dissolved in THF (20 mL) . The solution was cooled to 0 °C, and a cold solution of LiOH"H20 (6.86 mmol, 0.288 g) in ¾0 (20 mL) were added. The reaction was maintained at 0 °C for 1 hour. The reaction was acidified with 2N HC1 and extracted with EtOAc. The combined organic layers were dried over MgS04i and concentrated. The residue was purified by column chromatography (hexanes/EtOAc/AcOH = 10/10/1) .
Compound 40 was obtained as white solid (1.23 g, 81%). m.p. = 165-168 °C. 1H NMR (600 MHz, MeOD) δ 7.78 (d, J = 7.2 Hz, 2H) , 7.62-7.56 (m, 2H) , 7.39- 7.36 (m, 2H), 7.28 (t, J= 7.8 Hz, 2H) , 6.98 (t, J = 7.8 Hz, 2H) , 4.39-4.33 (m, 2H) , 4.26 (dd, J = 10.8, 6.6 Hz, 1H) , 4.19 (t, J = 6.6 Hz , 1H) , 3.17 (dd, J = 13.8, 4.2 Hz, 1H) , 2.90 (dd, J = 13.2, 9.6 Hz, 1H) ; 13C NMR (150 MHz, MeOD) δ 175.88, 158.34, 152.16 (ddd, JEC = 246.5, 9.8, 3.9 Hz), 145.37, 145.21, 142.67, 139.79 (dt, = 246.2, 10.5 Hz), 136.51-136.37, 128.85, 128.20, 126.29, 126.19, 121.00, 120.98, 114.71 (dd, JFC = 16.7, 4.2 Hz), 67.91, 57.10, 48.45, 38.26; HRMS (ESI-TOF) Calcd for C24Hi9F3N04 [M+H]+: 442.1261; found: 442.1264.
Diverse Synthetic Applications :
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -N-methoxy- 3- (3-methoxyphenyl)propanamide (28e)
The starting material 25 (10.0 mmol, 2.48 g) , Pd(OAc)2 (1.0 mmol, 220 mg) , and AgOAc (20.0 mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide (15 mmol), 2-picoline (2.00 mmol, 0.2 mL) , HFIP (100 mL) were added. The reaction mixture was first stirred at room
temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The
solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent. Compound 28e was obtained as yellow oil (2.90 g, 82%).
28e 1'
(S) -2- (1 , 6-Dimethoxy-2-oxo-l , 2,3, 4-tetrahydro- quinolin-3-yl) isoindoline-1 , 3-dione (41 ' )
Amide 28e (0.3 mmol, 106.2 mg) was dissolved in DCM (2 mL) , in an ice-cooled flask. Phenyliodine (III) bis (trifluoroacetate) (PIFA, 0.45 mmol) was added in one portion and the reaction mixture was stirred at 0 °C, and monitored by TLC. After completion of the reaction (about 3 hours), the mixture was diluted with DCM (4 mL) and washed with a saturated aqueous NaHC03 solution, then with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was purified by silica gel chromatography using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent. Compound 41' was obtained as white solid (79.2 mg, 75%) [Birch et al., Bioorg. Med. Chem. Lett. 17:394 (2007)]. 1H NMR (600 MHz, CDC13) δ 7.90-7.89 (m, 2H) , 7.77-7.75 (m, 2H) , 7.19 (d, J = 9.0 Hz, 1H) , 6.86 (dd, J= 9.0, 3.0 Hz, 1H) , 6.76 (dd, J = 3.0, 1.2 Hz, 1H) , 5.14 (dd, J= 15.0, 6.0 Hz, 1H), 4.03-3.93 (m, 4H) , 3.81 (s, 3H) , 2.92 (dd, J = 15.0, 6.3 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 167.59, 161.03, 156.33, 134.25, 131.91, 130.75, 123.64, 122.54, 114.23, 113.90, 112.92, 62.73, 55.64,
48.86, 29.92; HRMS (ESI-TOF) Calcd Ci9Hi7N205 [M+H]+: 353.1132; found: 353.1135.
(S) -3-Amino-l , 6-dimethoxy-3 , 4-dihydroquinolin-2 (1H) - one (41)
The substrate 41' (0.2 mmol, 70.4 mg) was dissolved in a 1:1 mixture of DCM/MeOH (2 ml total), and ethylenediamine (0.4 mmol) was added. The reaction mixture was heated to 40 °C for 3 hours, and then cooled to room temperature. After removing the solvent in vacuo, the residue was purified by column chromatography (DCM/MeOH = 20/1 to 10/1) . Compound 41 was obtained as gray solid (42.8 mg, 96%). ¾ NMR (600 MHz, CDC13) δ 7.13 (d, J = 8.8 Hz, 1H) , 6.83 (dd, J = 8.7, 2.7, Hz, 1H) , 6.77 (d, J = 9.0 Hz, 1H) , 3.91 (s, 3H) , 3.80 (s, 3H) , 3.63 (dd, J= 13.2, 6.0 Hz, 1H) , 3.05 (dd, J= 15.6, 6.0 Hz, 1H) , 2.86-2.81 (m, 1H) ; 13C NMR (150 MHz, CDCI3) δ 167.17, 156.20, 130.74, 123.82, 114.34, 113.75, 112.69, 62.37, 55.60, 51.06, 34.21; HRMS (ESI-TOF) Calcd for CUH14N203 [M+H]+:
222.1004; found: 223.1079. hth
(S) -2- (1 , 3-Dioxoisoindolin-2-yl) -3- (3-methoxyphenyl) ropanoic acid (42')
The mono-arylated product 28e (0.3 mmol, 106mg) was dissolved in the mixed solvents (3 mL, AcOH/Ac20 = 1/2), and then cooled to 0 °C. NaN02 (414
mg, 6 mmol) was slowly added into the reaction mixture in portions. The reaction mixture was first stirred at 0 °C for 3 hours and then at room temperature for 17 hours. Upon completion, the solvents were removed under reduced pressure, and the mixture was neutralized by slow addition of saturated NaHC03 solution to pH 8. The aqueous phase was extracted with ether (4 « 10 mL) , carefully acidified with cold HC1 solution (I N) to pH 2, and then extracted with ether (4 χ 20 mL) . The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the desired product Compound 42' as yellow oil (66.3 mg, 68%) [He et al . , Science 343:1216 (2014)]. ¾ NMR (600 MHz, CDC13) δ 7.78-7.76 (m, 2H) , 7.68-7.67 (m, 2H) , 7.09 (t, J = 7.8 Hz, 1H) , 6.75 (d, J = 7.8 Hz, 1H) , 6.69-6.67 (m, 2H) , 5.23-5.20 (m, 1H) , 3.67 (s, 3H) , 3.56-3.54 (m, 2H) ; 13C NMR (150 MHz, CDC13) δ 173.71, 167.41, 159.61, 138.01, 134.15, 131.52, 129.57, 123.53, 121.12, 114.03, 112.80, 60.48, 55.08, 34.44; HRMS (ESI-TOF) Calcd for CiaH14N05 [M-H] ~: 324.0877; found: 324.0880.
42' 42
(S) -2- (5-Methoxy-l-oxo-2 ,3-dihydro-lH-inden-2-yl) - isoindoline-1 , 3-dione (42)
To a solution of 42 ' (0.2 mmol, 65 mg) in DCM (2 mL) was added a drop of DMF and oxalyl chloride (0.6 mmol) at room temperature. Stirring was continued for 3 hours at that temperature. After concentration of the mixture in vacuo, the residue was dissolved in DCM (2 mL) and added dropwise
rapidly to a suspension of AICI3 (0.6 mol, 79.7 mg) in DCM (2 mL) . Stirring was continued for 1-2 hours after the addition had been completed. The mixture was poured into ice-cold dilute HC1 with vigorous stirring which was continued for 1 hour. The layers were separated, and the aqueous phase was extracted several times with DCM. The combined organic phase was dried by adding Na2SC>4 and silica gel, filtered, and concentrated to give Compound 42 as a white solid (47.9 mg, 78%) [McClure et al., J. Org. Chem. 48:2675 (1983]. ¾ NMR (600 MHz, CDC13) δ 7.86-7.85 (m, 2H) , 7.78 (d, J = 9.0 Hz, 1H) , 7.75-7.72 (m, 2H) , 6.98- 6.97 (m, 1H) , 6.93-6.92 (m, 1H) , 5.08 (dd, J= 8.7, 5.7 Hz, 1H) , 3.91 (s, 3H) , 3.57-3.52 (m, 1H) , 3.39- 3.36 (m, 1H) .13C NMR (150 MHz, CDC13) δ 198.02, 167.55, 165.95, 153.86, 134.16, 132.02, 128.14, 126.27, 123.50, 115.94, 109.77, 55.74, 53.68, 31.89; HRMS (ESI-TOF) Calcd for CleHi4N04 [M+H]+: 308.0917; found: 308.0917.
28e 28e'
Methyl (S) -2- (1 , 3-dioxoisoindolin-2-yl) - 3- (3-methoxyphenyl) ropanoate (28e ' )
The scale-up procedure followed. ½ NMR (600 MHz, CDCI3) δ 7.80-7.77 (m, 2H) , 7.71-7.67 (m, 2H) , 7.09
(t, J = 8.0 Hz, 1H) , 6.75 (d, J = 7.8 Hz, 1H) , 6.70- 6.66 (m, 2H) , 5.17 (dd, J = 11.4, 5.4 Hz, 1H) , 3.78
(s, 3H), 3.67 (s, 3H) , 3.60-3.50 (m, 2H) ; 13C NMR (150 MHz, CDCI3) δ 169.33, 167.42, 159.60, 138.23, 134.10, 131.61, 129.54, 123.47, 121.13, 114.08, 112.70,
55.06, 53.13, 52.91, 34.64; HRMS (ESI-TOF) Calcd for C19Hi8NO [M+H] + : 340.1179; found: 340.1177.
Methyl (S) -2-amino-3- (3-methoxyphenyl)propanoate (43)
The scale-up procedure followed. 1H NMR (600 MHz, CDC13) δ 7.22 (t, J = 7.8 Hz, 1H) , 6.80-6.77 (m, 2H) , 6.74 (t, J= 1.8 Hz, 1H) , 3.79 (s, 3H) , 3.75-3.73 (m, 1H) , 3.73 (s, 3H) , 3.08 (dd, J = 13.2, 5.1 Hz, 1H) , 2.83 (dd, J= 13.5, 8.0 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 175.38, 159.72, 138.78, 129.56, 121.60, 114.96, 112.19, 55.77, 55.16, 52.01, 41.13; HRMS (ESI-TOF) Calcd for CuHi5N03 [M+H]+: 209.1052; found: 210.1125.
45
Similarly, Compound 43 can be transformed into Compound 46 as described in McClure et al . , J.
(S) -2- ( ( ( (9H-Fluoren-9-yl)methoxy) carbonyl) amino) - 3- (3-methoxyphenyl) propanoic acid (44)
The scale-up procedure followed. ¾ NMR (600 MHz, MeOD) δ 7.74 (d, J = 7.8 Hz, 2H) , 7.55 (d, J= 6.6 Hz, 2H) , 7.35 (t, J = 7.5 Hz, 2H) , 7.27-7.23 (m, 2H) , 7.16 (t, J= 7.8 Hz, 1H) , 6.83-6.81 (m, 2H) , 6.74 (dd, J= 8.1, 2.7 Hz, 1H) , 4.44 (dd, J = 9.6, 4.8 Hz, 1H) , 4.27 (dd, J = 10.8, 7.2 Hz, 1H) , 4.17 (dd, J = 10.2, 7.2 Hz, 1H) , 4.12-4.10 (m, 1H) , 3.71 (s, 3H) , 3.19 (dd, J = 13.9, 4.5 Hz, 1H) , 2.91 (dd, J = 13.8, 9.6 Hz, 1H) ; 13C NMR (150 MHz, MeOD) δ 175.46, 161.19, 158.41, 145.25, 142.56, 142.54, 140.25, 130.47, 128.80, 128.21, 126.41, 126.29, 122.67, 120.95, 120.92, 115.99, 113.30, 68.10, 56.91, 55.63, 48.35, 38.72; HRMS (ESI-TOF) Calcd for C25H24N05 [M+H] + :
418.1649; found: 418.1647.
General procedure :
ftmide (0.1 mmol) was dissolved in DCM (2 mL) , in an ice-cooled flask. Phenyliodine (III) bis (trifluoroacetate) (PIFA, 0.15 mmol) was added in one portion and the reaction mixture was stirred at 0 °C, and monitored by TLC. After completion of the reaction (about 3 hours) , the mixture was diluted
with DCM (4 mL) and washed with a saturated aqueous NaHC03 solution, then with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was purified by silica gel chromatography using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent .
41'
(S) -2- (1 , 6-Dimethoxy-2-oxo-l ,2,3, 4-tetrahydro- quinolin-3-yl) isoindoline-1 , 3-dione (41 ' )
White solid, 75% yield. (The NMR data are provided above . )
(S) -2- (1 , 6-Dimethoxy-2-oxo-l ,2,3,4- tetrahydroquinolin-3-yl) -isoindoline-1 , 3-dione compound with 2- { (3S, 423) -1 , 6-dimethoxy-2-oxo-4- phenyl-1 ,2,3, 4-tetrahydroquinolin-3-yl) isoindoline- 1, 3-dione (1:1) (47)
White solid, 82% yield. 1ti NMR (600 MHz, CDC13) δ 7.76-7.73 (m, 2H) , 7.67-7.64 (m, 2H) , 7.31-7.22 (m, 6H) , 6.86 (dd, J= 8.7, 2.7 Hz, 1H) , 6.18-6.17 (m, 1H) , 5.36 (d, J= 14.4 Hz, 1H) , 5.20 (d, J= 14.4 Hz, 1H) , 4.01 (s, 3H), 3.66 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.48, 160.67, 156.41, 136.46, 134.02,
131.59, 130.29, 129.16, 129.04, 128.08, 127.67, 123.49, 114.95, 113.82, 112.44, 62.84, 55.47, 54. 44.90; HRMS (ESI-TOF) Calcd for C25H21N2O5 [M+H] + :
429.1445; found: 429.1449.
2- ( (3S, 4K) -l-Methoxy-4- (3-methoxyphenyl) -6 , 8- dimethyl-2-oxo-l , 2,3, 4-tetrahydroquinolin-3- yl) isoindoline-1 , 3-dione (48)
White solid, 94% yield. ½ NMR (600 MHz, CDC13) δ 7.75-7.73 (m, 2H) , 7.65-7.63 (m, 2H) , 7.20 (t, J= 7.8 Hz, 1H) , 6.96 (s, 1H) , 6.81-6.80 (m, 1H) , 6.77- 6.75 (m, 2H), 6.21 (s, 1H) , 5.36 (d, J= 13.8 Hz, 1H) , 5.21 (d, J= 14.4 Hz, 1H) , 3.84 (s, 3H) , 3.72 (s, 3H) , 2.45 (s, 3H) , 2.16 (s, 3H) ; 13C NMR (150 MHz, CDCI3) δ 167.53, 162.41, 159.83, 138.15, 135.05, 133.99, 132.66, 132.39, 131.59, 130.17, 129.93, 127.60, 125.88, 123.45, 121.62, 113.99, 61.95, 55.22, 54.20, 45.33, 20.79, 20.73; HRMS (ESI-TOF) Calcd for C27H25N2O5 [M+H]+: 457.1758; found: 457.1756.
49
2- ( (3S) -l-Methoxy-4, 7-dimethyl-2-oxo-l ,2,3,4- tetrahydroquinolin-3-yl) isoindoline-1 , 3-dione (49)
White solid, 39% yield. ¾ NMR (600 MHz, CDC13) δ 7.92-7.89 (m, 2H) , 7.78-7.76 (m, 2H) , 7.18 (d, J =
7.8 Hz, 1H) , 7.13 (s, 1H) , 6.97 (d, J= 7.8 Hz, 1H) , 4.72 (d, J = 13.8 Hz, 1H) , 3.98 (s, 3H) , 3.95-3.89 (m, 1H) , 2.41 (s, 3H) , 1.34 (d, J = 6.6 Hz, 3H) ; 13C NMR (150 MHz, CDC13) δ 167.85, 161.80, 138.45, 136.59, 134.27, 131.86, 125.46, 124.95, 123.66, 122.90, 113.12, 62.90, 55.27, 31.71, 21.39, 14.35; HRMS (ESI- TOF) Calcd for C20H19N2O4 [M+H] +: 351.1339; found:
351.1340.
Synthesis of PyBOX and BOX ligands .
(2R, 3S) -3- (3 , 5-Dimethylphenyl) -2- (1 , 3-dioxo-2 , 3- dihydro-lH-inden-2-yl) -N-methoxy-3- (3-methoxyphenyl) - propanamide (31z)
The starting material 25 (10.0 mmol, 2.48 g) , Pd(OAc)2 (1.0 miriol, 220 mg) , and AgOAc (20.0 mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mli) with a magnetic stir bar. To that reaction mixture, aryl iodide (12 mmol), 2-picoline (2.00 mmol, 0.2 mL) , HFIP (100 mL) were added. The reaction mixture was first stirred at room
temperature for 10 minutes and then heated to 75 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature .
To that cooled reaction mixture, Pd(OAc)2
(1.0 mmol, 220 mg) , NaH2P04'H20 (30 mmol, 4.2 g) , AgOAc (20 mmol, 3.34 g) , the second aryl iodide (30 mmol) and 2,6-lutidine (2 mmol, 0.2 mL) were added. The reaction mixture was first stirred at room temperature for 10 minutes and then heated to 100 °C for another 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite using DCM. The solvents were removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent to afford Compound 31z
(2.1 g, 46% overall yield). (The NMR data for this compound are provided above.)
(2R, 3S)- ethyl 3- (3 , 5-dimethylphenyl) -2- (1 , 3-dioxo- 2 , 3-dihydro-lH-inden-2-yl) -3- (3-methoxyphenyl) - propanoate (50)
A sealable pressure flask was charged with MeOH (120 mL) and crude amide 31z (4.57 mmol, 2.1 g) . Et20"BF3 (27.4 mmol) was added and the reaction vessel sealed. The reaction mixture was heated to 100 °C for 12 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure and ¾0 and EtOAc was added, organic layers were removed and the aqueous layer was then extracted with EtOAc and the combined organics washed with brine, dried over MgS04, filtered and concentrated.
(2S, 3S) -Methyl 2-amino-3- (3 , 5-dimethylphenyl) - 3- (3-methoxyphenyl) propanoate (51)
The crude 50 was dissolved in a 1:1 mixture of DCM/MeOH (40 mL total), and ethylenediamine (22.9 mmol) was added. The reaction mixture was heated to 40 °C for 6 hours, and then cooled to room
temperature. After removing the solvent in vacuo, the residue was purified by column chromatography
(DCM/MeOH = 20/1 to 10/1) . Compound 51 was obtained as gray solid (1.1 g, 77% yield for two steps) . XH NMR
(600 MHz, CDC13) δ 7.24 (t, J = 7.8 Hz, 1H) , 6.90-6.89
(m, 3H) , 6.85 (t, J = 2.1 Hz, 1H) , 6.81 (s, 1H) , 6.77 (dd, J = 8.1, 2.1 Hz, 1H), 4.19-4.14 (m, 2H) , 3.78 (s, 3H) , 3.54 (s, 3H) , 2.25 (s, 6H) ; 13C NMR (150 MHz, CDC13) δ 174.84, 159.75, 142.20, 140.98, 137.81, 129.69, 128.49, 125.82, 120.98, 114.97, 111.84, 58.84, 56.36, 55.15, 51.80, 21.37; HRMS (ESI-TOF) Calcd for C19H24NO3 [M+H]+: 314.1751; found: 314.1749.
(2S, 3S) -2-Amino-3- (3 , 5-dimethylphenyl) -3- (3-methoxyphenyl) -propan-l-ol (52
To a suspension of LAH (5 mL, 1M in THF) in THF (10 mL) at 0 °C was added dropwise a solution of the ester 51 (535 mg, 1.70 mmol) in THF (10 mL) . The mixture was reacted less than 15 minutes and then cooled to 0 °C. The mixture was then treated dropwise with water (3 mL) and 10% aqueous sodium hydroxide (3 mL) . Note: extreme care should be practiced during the quenching process. As this process is exothermic and produces flammable hydrogen gas, it is highly advisable to cool the reaction mixture to 0 °C prior to quenching and to add the water and aqueous solution of sodium hydroxide cautiously. The mixture was filtered over Na2S04, and the filtrate was evaporated under reduced pressure, purified by column chromatography (DCM/MeOH = 20/1 to 10/1) . Compound 52 was obtained as white solid (363 mg, 75%). 1H NMR (600 MHz, CDC13) δ 7.24 (t, J = 7.8 Hz, 1H) , 6.95 (d, J = 7.8 Hz, 1H) , 6.90-6.88 (m, 2H) , 6.81 (s,lH), 6.75-6.73 (m, 1H) , 3.79 (s, 3H) , 3.65-
3.63 (m, 2H) , 3.57-3.55 (m, 1H) , 3.30-3.27 (m, 1H) , 2.25 (s, 6H) , 1.93 (br, 3H) ; 13C NMR (150 MHz, CDC13) δ 159.91, 143.95, 141.67, 138.16, 129.94, 128.45, 125.55, 120.43, 114.54, 111.51, 64.76, 56.58, 55.58, 55.18, 21.38; HRMS (ESI-TOF) Calcd for C18H24N02
[M+H]+: 286.1802; found: 286.1803.
2 , 6-Bis ( (S) -4- ( (S) - (3 , 5-dimethylp eny1) (3-methoxy- phenyl) methyl) -4, 5-dihydrooxazol-2-yl) yridine (53)
A 10-mL two-necked round-bottomed flask fitted with a reflux condenser was charged pyridine- 2 , 6-dicarbonitrile (13 mg, 0.1 mmol) and the adequate amount of zinc triflate (40 mg, 0.1 mmol). The system was purged with argon and dry toluene (1 mL) was added. The solution was stirred for 5 minutes and a solution of the /3-amino alcohol 52 (62 mg, 0.1 mmol) in dry toluene (1.5 mL) was added. The solution was heated under reflux for 48 hours. The system was allowed to cool, and the cooled reaction was diluted with 25 mL of EtOAc. The solution was then washed with brine (3 χ 25 mL) and saturated aq. NaHC03 (3 x 25 mL) , dried with MgS0 and the solvent evaporated, and the crude product was purified by silica gel chromatography with EtOAc/hexanes (1/5 to 1/3) as the eluent, producing a yellow solid Compound 53 (32.0 mg, 48%) [Cornejo et al . , Synlett 2321 (2005)]. *H NMR (600 MHz, CDC13) δ 8.16 (d, J= 7.8 Hz, 2H) , 7.78 (t, J = 8.1 Hz, 1H) , 7.22 (t, J = 7.8 Hz, 2H) , 6.96-6.94 (m, 2H) , 6.90 (t, J= 2.1 Hz, 2H) ,
6.87 (s, 4H) , 6.83 (s, 2H) , 6.75-6.73 (m, 2H) , 5.13- 5.11 (m, 2H) , 4.51 (t, J= 9.3 Hz, 2H) , 4.17 (t, J = 8.4 Hz, 2H) , 3.91 (d, J = 9.6 Hz, 2H) , 3.77 (s, 6H) , 2.26 (s, 12H) ; 13C NMR (150 MHz, CDC13) δ 162.81, 159.44, 146.73, 143.96, 141.42, 138.17, 137.07,
129.26, 128.61, 126.22, 126.19, 120.92, 114.94,
111.27, 72.35, 70.36, 57.10, 55.12, 21.39; HRMS (ESI- TOF) Calcd for C43H44N3O4 [M+H] + : 666.3326; found 666.3326.
(S, 4S, 4'S)-2,2'-(propane-2,2-diyl)bis(4-((S)-(3,5- dimethyl-phenyl) (3-methoxyphenyl) methyl) -4 , 5- dihydrooxazole) (54)
A 10-mli two-necked round-bottomed flask fitted with a reflux condenser was charged with 2,2- dimethyl malononitrile (10 mg, 0.1 mmol) and zinc triflate (40 mg, 0.1 mmol) . The system was purged with argon and dry toluene (1 mL) was added. The solution was stirred during 5 minutes and a solution of the /3-amino alcohol 52 (57 mg, 0.2 mmol) in dry toluene (1 mL) was added. The solution was heated under reflux for 48 hours. The system was allowed to cool. The cooled reaction was then washed with brine (3 * 25 mL) and saturated aq. NaHC03 (3 20 mL) , dried with MgSC and the solvent evaporated, and the crude product was purified by silica gel
chromatography, with EtOAc/hexanes (1/5 to 1/3) as the eluent, producing a yellow solid Compound 54
(45.9 mg, 73%). 1H NMR (600 MHz, CDC13) δ 7.26 (d, J= 2.4 Hz, 1H) , 7.18-7.15 (m, 2H) , 6.84-6.80 (m, 9H) , 6.72-6.71 (m, 2H) , 4.84-4.80 (m, 2H) , 4.27-4.24 (m, 2H) , 4.00-3.97 (m, 2H) , 3.89 (d, J = 7.8 Hz, 2H) , 3.74 (s, 6H), 2.25 (s, 12H) , 1.32 (s, 6H) ; 13C NMR
(150 MHz, CDC13) δ 169.25, 159.26, 143.81, 141.32, 137.74, 128.99, 128.33, 126.72, 121.31, 115.27, 111.13, 71.50, 69.28, 56.20, 55.07, 38.60, 23.93, 21.38; HRMS (ESI-TOF) Calcd for C4iH47N204 [M+H] + : 631.3530; found: 631.3527.
Each of the patents, patent applications and articles cited herein is incorporated by reference .
The foregoing description and the examples are intended as illustrative and are not to be taken as limiting. Still other variations within the spirit and scope of this invention are possible and will readily present themselves to those skilled in the art.
Claims
CLAIMS : method for forming a substituted protected amino acid molecule having one or two aryl or heteroaryl substituent groups bonded to the beta- carbon atom comprising the steps of:
i) providing a reaction mixture in a sealable vessel that contains (a) a protected amino acid substrate molecule of Formula A,
whose substituents are defined below, (b) an excess of an aromatic or heteroaromatic iodide reactant, (c) a catalytic amount of Pd(II) catalyst, (d) a pyridine ligand, and (e) an excess of a silver compound oxidant dissolved or dispersed in a solvent;
wherein (i) N-BPG is a protected amino group in which B is hydrogen or a further bond between the nitrogen atom and the protecting group (PG) ; (ii) R is hydrido, a C]_-C]_2 hydrocarbyl
straight or branched chain or cyclic aliphatic group that is unsubstituted or substituted with a NBPG protected amino group that is the same or different from that previously defined, or is a Cg-C_g aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen, Ο -Cg hydrocarbyl, C]_-Cg hydrocarbyloxy, carboxy C]_-Cg hydrocarbyl,
trifluoromethyl, C]_-Cg hydrocarboyl, nitro, C]_-Cg
hydrocarbylthiooxy, cyano and 1,2-(C]_-Cg
hydrocarbylene) dioxide; and (iii) X is NHR.1 in which R1 is a C]_-C]_2 hydrocarbyl aliphatic or aromatic group that is unsubstituted or substituted with fluorine atoms, a hydroxyl, 0-C]_-C]_2 hydrocarbyl, or NH-O-C1-C22 hydrocarbyl group; and
ii) sealing said vessel and heating the contents thereof to a temperature of about 70° to about 120° C for a time period sufficient for the reaction to progress to a desired extent of formation of a product that is arylated or heteroarylated at the β-carbon atom.
2. The method according to claim 1, wherein said aromatic or heteroaromatic iodide reactant is otherwise unsubstituted or contains up to three substituents in addition to the iodo group that are independently selected from one or more of the group consisting of halogen (fluoro, chloro and bromo) , C_-Cg hydrocarbyl, C^-Cg hydrocarbyloxy, carboxy C]_-Cg hydrocarbyl, trifluoromethyl , C_-Cg hydrocarboyl, nitro, C]_-Cg hydrocarbylthiooxy, cyano and 1 , 2-hydrocarbylene-dioxide .
3. The method according to claim 1, wherein the molar ratio of said aromatic or
heteroaromatic iodide reactant to said substrate molecule of Formula A is about 1.1 to about 4 to 1.
4. The method according to claim 1, wherein said aromatic iodide reactant is a phenyl iodide or a naphthyl iodide.
5. The method according to claim 1, wherein said heteroaryl iodide reactant contains up to four ring atoms other than carbon that are nitrogen, sulfur or oxygen.
6. The method according to claim 5, wherein said heteroaryl iodide reactant contains a single 5- or 6-membered ring or a fused ring system having two 6-membered rings or a combination of 5- and 6-membered rings .
7. The method according to claim 1, wherein X of said substrate molecule of Formula A is OH, NH[4- (CF3) C6F4] , or a NH-0-C1-C12 hydrocarbyl group .
8. The method according to claim 1, wherein R of said substrate molecule of Formula A is hydrido .
9. The method according to claim 1, wherein R of said substrate molecule of Formula A is a C]_-C]_2 hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubstituted or substituted with a NBPG protected amino group.
10. The method according to claim 1, wherein R of said substrate molecule of Formula A is a Cg-C]_Q aromatic or heteroaromatic group that is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen, C]_-Cg
hydrocarbyl, C]_-Cg hydrocarbyloxy, carboxy C^-Cg hydrocarbyl, trifluoromethyl, C]_-Cg hydrocarboyl , nitro, C]_-Cg hydrocarbylthiooxy, cyano and 1,2-(C]_-Cg hydrocarbylene) dioxide .
11. The method according to claim 1, wherein R of said substrate molecule of Formula A is hydrido, including the further steps of
iii) providing a second reaction mixture that contains (a) the β-carbon-arylated or
-heteroarylated product in place of said substrate molecule of Formula A, (b) an excess of the same or different aromatic or heteroaromatic iodide reactant, (c) a Pd(II) catalyst, (d) the same or different pyridine ligand, and (e) an excess of a silver compound oxidant dissolved or dispersed in a solvent;
iv) sealing said vessel and heating the contents thereof to a temperature of about 70° to about 120° C for a time period sufficient for the reaction to progress to a desired extent of formation of a product that contains two of the same or
different aryl or heteroaryl substituents bonded to the β-carbon atom; and
v) recovering said product.
12. The method according to claim 11, wherein the pyridine ligand present in step iii) is different from the pyridine ligand present in step i) ·
13. The method according to claim 12, wherein the pyridine ligand present in step iii) corresponds in structure to Formula L, below
where "n" is 1 or zero such that when n is zero, the bracketed methylene is absent, and is hydrido or a substituent selected from the group consisting of halogen, C^-Cg alkyl, C]_-Cg alkyloxy, and
trifluoromethyl .
14. The method according to claim 13, wherein "n" in Formula L is one.
15. The method according to claim 13, wherein said second ligand corresponds in structure to the formula
16. The method according to claim 11, wherein the pyridine ligand of step i) corresponds ih structure to Formula P , below, where and are
independently selected from the group consisting of hydrido, halogen other than iodo (fluoro, chloro or bromo) , C^-Cg alkyl, C^-Cg alkyloxy, and
trifluoromethyl, or one or both of and R^ forms a saturated or unsaturated 5- or 6-membered carbocyclic or oxa-substituted carbocyclic ring with the depicted ring at ring positions 3- and 5-, respectively, and is independently hydrido or C]_-Cg alkyl, with the proviso that at least one of and R^ is other than hydrido .
16. The method according to claim 15, wherein said first-named ligand is 2-picoline.
17. The method according to claim 11, wherein an excess of a different aromatic or
heteroaromatic iodide reactant is present in step iii) .
18. The method according to claim 17, wherein said product of step v) is present in a diastereomeric ratio in excess of about 15.
19. The method according to claim 17, wherein the different aromatic or heteroaromatic iodide reactants of steps i) and iii) are reversed.
20. The method according to claim 1, wherein R of said substrate molecule of Formula A is a C]_-C]_2 hydrocarbyl straight or branched chain or cyclic aliphatic group that is unsubstituted or substituted with a NBPG protected amino group that is the same or different from that previously defined,
and the pyridine ligand present in step i)
corresponds in structure to Formula L , below
where "n" is 1 or zero such that when n is zero, the bracketed methylene is absent, and R^ is hydrido or a substituent selected from the group consisting of halogen, Ο -Cg alkyl, C]_-Cg alkyloxy, and
trifluoromethyl .
21. The method according to claim 20, wherein "n" in Formula L is one.
22. A method for forming a protected amino acid lactam comprising the steps of:
i) providing a reaction mixture in a sealable vessel that contains
(a) a protected amino acid substrate molecule of Formula A, wherein (i) N -B PG is a
protected amino group in which B is hydrogen or a further bond between the nitrogen atom and the protecting group ( PG ) , (ii) R is hydrido, and (iii) X is NHRI in which R1 is a C ]_ -C]_2 hydrocarbyl aliphatic or aromatic group that is unsubstituted or
substituted with fluorine atoms, a hydroxy!, 0-C]_-C]_2 hydrocarbyl, or NH-0-C]_-C]_2 hydrocarbyl group;
(b) an excess of activated reactive olefin,
(c) a catalytic amount of Pd(II) catalyst,
(d) a pyridine ligand where "n" is 1 or zero
such that when n is zero, the bracketed methylene is absent, and is hydrido or a substituent selected from the group consisting of halogen, C^-Cg alkyl,
C]_-Cg alkyloxy, and trifluoromethyl, and
(e) an excess of a silver compound oxidant dissolved or dispersed in a solvent;
ii) sealing said vessel and heating the contents thereof to a temperature of about 70° to about 120° C for a time period sufficient for the reaction to progress to a desired extent of formation of a product lactam; and
iii) recovering said product lactam.
23. The method according to claim 22, wherein said activated reactant olefin is present at about 1.1 to about 5 equivalents relative to
substrate molecule A .
24. The method according to claim 22, wherein said activated reactant olefin is selected from the group consisting of an α,β-unsaturated ester
or ketone, an olefinic sulfone or sulfoxide or a hydrocarbyl diester of an olefinic phosphonate.
25. The method according to claim 22 including the further step of reacting said lactam with a strong, non-nucleophilic base to form the corresponding β-olefin-substituted derivative of the protected amino acid substrate molecule of Formula A.
26. A pre-catalyst C-H insertion intermediate that corresponds in structure to the formula wherein (i) N-BPG is a protected amino
n Pyr / ^pyr group in which B is hydrogen or a further bond between the nitrogen atom and the protecting group
(PG) ; (ii) R1 is a C]_-C]_2 hydrocarbyl aliphatic or aromatic group that is unsubstituted or substituted with fluorine atoms, a hydroxyl, 0-C]_-C;]_2
hydrocarbyl, or NH-0-C]_-C]_2 hydrocarbyl group; and (iii) Pyr is a pyridine ligand.
27. The pre-catalyst C-H insertion intermediate according to claim 26, wherein said pyridine ligand of step corresponds in structure to
Formula P , below, where and are independently
selected from the group consisting of hydrido, halogen other than iodo, C -C5 alkyl, C]_-Cg alkyloxy, and trifluoromethyl, or one or both of and R-3 forms a saturated or unsaturated 5- or 6-membered carbocyclic or oxa-substituted carbocyclic ring with the depicted ring at ring positions 3- and 5-, respectively, and is independently hydrido or C^- Cg alkyl, with the proviso that at least one of and R^ is other than hydrido.
28. The method according to claim 27, wherein said first-named ligand is 2-picoline.
29. The pre-catalyst C-H insertion intermediate according to claim 26, wherein said pyridine ligand corresponds in structure to Formula L , below, where "n" is 1 or zero such that when n is
30. The pre-catalyst C-H insertion
intermediate according to claim 29, wherein wherein "n" in Formula L is one.
31. The pre-catalyst C-H insertion
intermediate according to claim 30, wherein said wherein said pyridine ligand corresponds in structure to the formula
32. The pre-catalyst C-H insertion
intermediate according to claim 26, wherein said N-BPG group is a monodentate or a bidentate
protecting group.
33. The pre-catalyst C-H insertion
intermediate according to claim 32, wherein said N-BPG group is a monodentate protecting group
selected from the group consisting of t-BOC, f-MOC, CBZ, C]_-C]_2 hydrocarboyl and C -C]_2 sulfamido groups,
34. The pre-catalyst C-H insertion
intermediate according to claim 32, wherein said N-BPG group is a bidentate protecting group selected from the group consisting of succinimido, maleimido, ortho-benzoic sulfimido and phthalimido groups.
35. The pre-catalyst C-H insertion
intermediate according to claim 26 that is
crystalline .
36. A compound that corresponds in structure to the formula shown below
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