WO2012085169A1 - Amido-borates métalliques destinés à la fonctionnalisation de composés organiques - Google Patents

Amido-borates métalliques destinés à la fonctionnalisation de composés organiques Download PDF

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WO2012085169A1
WO2012085169A1 PCT/EP2011/073715 EP2011073715W WO2012085169A1 WO 2012085169 A1 WO2012085169 A1 WO 2012085169A1 EP 2011073715 W EP2011073715 W EP 2011073715W WO 2012085169 A1 WO2012085169 A1 WO 2012085169A1
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atom
group
independently represents
groups
atoms
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Benjamin HAAG
Paul Knochel
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Haag Benjamin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to the field of reactive organometallic adducts for making functionalized organic compounds.
  • Organometallic reagents are of increasing importance in organic chemistry especially for the synthesis of pharmaceutical drugs as well as organic materials. Since organomagnesium and organolithium reagents possess an unnecessary high reactivity, organic chemists focused during the last decades on more selective organometallic reagents such as zinc, silicon, tin and boron derived compounds in order to achieve higher tolerance towards a wide range of functional groups.
  • organoboron compounds have proven to be of distinguished usefulness in transition-metal catalyzed reactions.
  • organoboranes in the Pd-catalyzed Suzuki-Miyaura cross-couplings has emerged as highly practical straightforward C-C-bond formation.
  • This reaction has been frequently applied in academic institutions and industry.
  • Organoboron compounds such as boronic acids, boronic esters and, in particular, organotrifluoroborates have been found to have a relatively high tolerance towards functional groups and improved thermal stability.
  • the direct synthesis of such compounds has been difficult, has had a low atom-economy and has required transition-metal catalyzed C-H-activation reactions. Thermal instability at ambient temperatures has remained an issue.
  • organoboron compounds for the synthesis of functionalized organic compounds is currently not sufficient to reduce or eliminate costly and time-consuming purification of the resulting products. Therefore, there continues to be a need for direct, practical and inexpensive synthesis of organoborates via metalation reactions to facilitate the synthesis of functionalized organic compounds, particularly synthesis via cross-coupling reactions.
  • the present invention relates to metallic amidoborate adducts for making metalated compounds that enable a direct, practical and inexpensive functionalization of organic compounds.
  • the metallic amidoborate adducts comprise at least one metallic cation or cationic complex and an anion comprising the moiety represented by formula (I):
  • each R 1 independently represents Z 1 (Z 1A ) P - , wherein each Z 1 and Z 1A independently represents a carbon atom or a silicon atom and each p independently represents the integer 2 or 3 and
  • each R 2 independently represents a fluorine atom or Z 2 (Z 2A - , wherein each Z 2 independently represents a carbon atom, nitrogen atom or a silicon atom, each Z 2A represents a hydrogen atom, a carbon atom or a silicon atom, and "k" is a positive integer equal to the valence of Z 2 minus 1, wherein at least one, preferably two, and more preferably three, of the R 2 substituents is/are Z 2 (Z 2A -.
  • the present invention also relates to a process for making metallic amidoborate adducts comprising reacting:
  • R 1 and R 2 have the same meaning as defined above and Met represents at least one metallic cation or cationic complex.
  • the present invention also relates to methods for making a metalated organic compound comprising reacting (A) at least one organic compound with
  • each Q independently represents an organic compound comprising at least two carbon atoms
  • w represents an integer having a value of at least 1.
  • the present invention relates to methods for functionalizing organic compounds comprising reacting at least one metalated organic compound according to this invention with at least one compound comprising at least one atom, or group of atoms, that is electrophilic relative to the metalated position(s).
  • Fig. 1 shows the mass spectrometric analysis spectrum of a metalated 2-chloro- pyridyltrialkylborate prepared according to Example 8 of the present invention in dry tetrahydrofuran (THF) which was not previously exposed to hydrolytic conditions.
  • Fig. 2 shows the mass spectrometric analysis spectrum of the metalated 2- chloropyridyltrialkylborate of Fig. 1 after treating the metalated 2- chloropyridyltrialkylborate with water (50 vol%) at 25°C for one hour.
  • metalated means that the compound that is the subject of this adjective is bonded, coordinated or complexed with Met.
  • hetero atoms as used herein preferably refers to the atoms N, O, S, and P.
  • each R 1 independently represents a moiety represented by the formula Z 1 (Z 1A ) P - , wherein each Z 1 and Z 1A independently represents a carbon atom or a silicon atom and each p independently represents the integer 2 or 3.
  • Z 1 is a silicon atom
  • Z 1A is preferably a carbon atom
  • Z 1 is preferably a carbon atom.
  • Z 1 (Z 1A )p- more preferably R 1 , contains bonds selected solely from C-C bonds and C- Si bonds.
  • R 1 is preferably represented by the formula (R 3 )3 -p - Z 1 (Z 1A ) P -, wherein each R 3 is independently selected from H, a methyl group, an alkyl group such as a C2-8 alkyl group, a cycloalkyl group such as a C 5- i 0 cycloalkyl group, an aryl group such as a C 5- io aryl group, an aralkyl group such as a Ce-is aralkyl group, or a silyl group which is preferably mono-, di- or tri-substituted with a methyl group an alkyl group such as a C 2- 8 alkyl group, a cycloalkyl group such as a C 5- i 0 cycloalkyl group, an aryl group such as a Cs-io aryl group, an aralkyl group such as a Ce-is aralkyl group or, when each R 1 is represented
  • the multivalent group covalently bonded to each Z 1 group is a divalent alkylene group, such as a C2-3 alkylene group, which is optionally substituted with one or more methyl groups, alkyl groups such as C2-8 alkyl groups, cycloalkyl groups such as Cs-io cycloalkyl groups, aryl groups such as Cs-io aryl groups, aralkyl groups such as Ce-is aralkyl groups, or silyl groups mono-, di- or tri- substituted with a methyl group or an alkyl group, such as a C2-8 alkyl group.
  • the multivalent group is ethylene, propylene or isopropylene, more preferably propylene.
  • Each Z 1A of R 1 is preferably independently a methyl group, an alkyl group, such as a C2-8 alkyl group, a cycloalkyl group, such as a Cs-io cycloalkyl group, an aryl group, such as a Cs-io aryl group, an aralkyl group, such as a Ce-is aralkyl group, or a silyl group tri-substituted with a methyl group or an alkyl group, such as a C2-8 alkyl group.
  • each Z 1A group is a methyl group.
  • each and every Z 1A and R 3 of R 1 represents a methyl group.
  • R 3 is preferably a hydrogen atom, so that R 1 preferably represents zPr, for example.
  • Z 1 is a silicon atom
  • R 3 is preferably a methyl group, so that R 1 preferably represents a trimethylsilyl group, for example.
  • each R 2 independently represents a fluorine atom or Z 2 (Z 2A )k-, wherein each Z 2 independently represents a carbon atom, nitrogen atom or a silicon atom, each Z 2A represents a hydrogen atom, a fluorine atom, a carbon atom or a silicon atom, and "k" represents an integer equal to the valence of Z 2 minus 1, wherein at least one, preferably two, and more preferably three, of the R 2 substituents is/are Z 2 (Z 2A ) k -.
  • each Z 2 (Z 2A )k- independently represents
  • Z 2 (Z 2A (R 2A ) 3 ) k - wherein Z 2 and "k" have the same meaning as in Z 2 (Z 2A ) k -, Z 2A represents a carbon or silicon atom, and each R 2A independently represents an hydrogen atom, a fluorine atom, a carbon atom, a nitrogen atom, or silicon atom.
  • Z (Z (R ) 3 )k-, Z (Z and/or R , contains bonds selected solely from C-C bonds, C-N bonds and C-Si bonds.
  • Z 2 (Z 2A - independently represent(s) a methyl group; an alkyl group, such as a C2-8 alkyl group; a cycloalkyl group, such as a Cs-io cycloalkyl group; an aryl group, such as a Cs-io aryl group; an aralkyl group, such as a Ce-is aralkyl group; a silyl group; -N(R 4 )2 wherein each R 4 independently represents -C(Z 3A ) 3 , wherein Z 3A represents a hydrogen atom, a carbon atom or a silicon atom or the two R 4 groups are j oined to each other to form a divalent group attached to the nitrogen atom of -N(R 4 ) 2 to form a nitrogen-containing ring structure, wherein the divalent group preferably comprises two or more carbon atoms and, optionally
  • Each R 4 preferably independently represents any one of the R 1 and R 2 groups as previously defined other than -N(R 4 )2.
  • no more than one R 2 substituent is a fluorine atom.
  • none of the R 2 substituents is a fluorine atom.
  • no more than two, more preferably no more than one, and even more preferably none, of the R 2 substituents are halogen atoms.
  • R 2 substituent(s) represent Me, Et, zPr, nBu, sBu, tBu, c- hexyl, Ph, HMDS, -Nz ' Pr 2 , N-pyrrolidyl, and N-piperidinyl, which may optionally be substituted with one or more fluorine atoms.
  • the N-pyrrolidyl, and N-piperidinyl may also be optionally substituted with one or more groups comprising one or more carbon atoms and, optionally, one or more hetero atoms preferably selected from nitrogen atoms, oxygen atoms, sulfur atoms, or silicon atoms, such as Me, methoxy, methoxymethylene, Et, ethoxy, ethoxyethylene, zPr, «Bu, sBu, tBu, ohexyl, Ph, HMDS, and -Nz ' Pr 2 .
  • Particularly preferred R 2 substituents are those having at least 2 carbon atoms up to 6, more preferably up to 4, carbon atoms.
  • the R 2 substituents are preferably alkyl groups, such as Et and sBu.
  • R 2 is an aryl ring, more preferably a phenyl ring, fully substituted by fluorine atoms (e.g., -CeF 5 ).
  • Met is preferably selected from the group consisting of Li, MgX, Na, ZnX, CaX, A1X 2 , MnX q , FeX r , CuX s , LaX 2 or ZrX 3 , or a mixture thereof, wherein X represents CI, Br or I and p, q, and r represent the number of "X" atoms.
  • the number of "X" atoms is less than the valence of the metal atom with which it is associated, so that the metal complex has a positive (i.e., cationic) charge.
  • Each of the values of "q”, “r”, and “s” are therefore an integer that is equal to the valence of the corresponding metal atom Mn, Fe and Cu, respectively, minus 1.
  • the value of "q” and “r” is therefore preferably 1 or 2 and the value of "s” is therefore preferably zero or 1, the selection of each depending on the valence of Mn, Fe and Cu, respectively.
  • MgCl is preferred.
  • metals such as Li
  • metal complexes such as LiCl
  • MgCl is preferably present as well.
  • Particularly preferred metal amide bases of Formula (II) for making the amidoborate bases according to the invention described herein include: Li or MgX or Na or
  • R1 H, alkyl, aryl, heteroaryl,
  • suitable metal amides include lithium diisopropylamide, magnesium chloride diisopropylamide, tmpLi, tmpMgCl LiCl, LiHMDS,
  • the above metal amides are either commercially available or may be prepared by the skilled chemist without undue effort.
  • the metal amides tmpMgCl LiCl, LiHMDS and zPr 2 NLi are commercially available from sources such as Sigma Aldrich and Acros Organics.
  • the following table provides examples of citations describing procedures for making additional metal amides. The citations are incorporated herein by reference for their relevant disclosure.
  • amidoborate bases according to the invention described herein include:
  • R H, alkyl, aryl, heteroaryl
  • R H, halogen, alkyl, aryl, heteroaryl
  • R H, halogen, alkyl, aryl, heteroaryl
  • R H, halogen, alkyl, aryl, heteroaryl, alkenyl, cycloalkyl, alkenyl, cycloalkyl,
  • Suitable borane compounds include BMe 3 (la), BEt 3 (lb),
  • the metal amidoborate base obtained by reacting the metal amide and the borane compound preferably have a decomposition temperature greater than 30°C.
  • the reaction between the metal amide and the borane compound is preferably conducted at a temperature in the range from 25°C up to, but not including, the decomposition temperature of the reactant having the lowest decomposition temperature.
  • the reaction is generally conducted under the exclusion of oxygen or air in an inert nonprotic solvent under an inert atmosphere, such as argon gas, until conversion of at least one starting material is complete.
  • Suitable inert nonprotic solvents include, but are not limited to, cyclic ethers, such as THF and Me-THF, aliphatic ethers, such as dimethoxyethane, toluene, benzene, dimethylsulfoxide, dimethylformamide, dichloromethane, tetrachloromethane, hexachloromethane, and acetonitrile.
  • cyclic and aliphatic ethers are preferred.
  • THF and Me-THF are particularly preferred solvents.
  • reaction should be carried out in the substantial absence of protic solvents, such as water.
  • the reaction vessel, reactants and solvent should be dried or distilled before use to ensure that water is not present during the reaction.
  • the metal amidoborate bases described above may be reacted with a substrate to form a metalated organic compound.
  • the substrate is an organic compound having at least one C-H bond.
  • the organic compound preferably comprises at least one ring comprising at least one carbon atom having at least one C-H bond and, optionally, one or more hetero atoms as ring members.
  • the ring may be substituted or unsubstituted, saturated or unsaturated, carbocyclic or heterocyclic ring or ring structure.
  • the ring structure may comprise multiple rings that may be fused or non-fused.
  • the rings and ring systems preferably comprise unsaturated rings.
  • the unsaturated rings are preferably carbocyclic or heterocyclic aryl or aralkyl rings.
  • the carbocyclic aromatic ring is preferably optionally substituted Ph, more preferably substituted Ph.
  • the carbocyclic aromatic ring system is preferably a naphthalene ring system.
  • the heterocyclic and carbocyclic aryl or aralkyl rings are further described below.
  • the substituents are preferably halogen atoms F, CI, Br, or I), nitro groups, sulfoxy groups, ether groups, thioether groups, and ester groups, methyl groups, alkyl goups, an alkyl group such as a C2-8 alkyl group, a cycloalkyl group such as a Cs-io cycloalkyl group, an aryl group such as a Cs-io aryl group, an aralkyl group such as a C6-is aralkyl group, or a silyl group which is preferably mono-, di- or tri-substituted with a methyl group an alkyl group such as a C2-8 alkyl group, a cycloalkyl group such as a Cs-io cycloalkyl group, an aryl group such as a Cs-io aryl group, and an aralkyl
  • each substituent independently represents an electronegative group, such as a halogen atom or an aromatic ring or ring system.
  • the halogen atoms are preferably selected from F, CI, Br and I.
  • the ring preferably comprises 1, 2, or 3 hetero atoms as ring members.
  • the hetero atoms are preferably selected from N, S, and O.
  • the ring preferably comprises at least one nitrogen atom as a ring-member. Examples include the organic compounds used as substrates in the examples which follow.
  • reaction conditions such as solvent and temperature conditions, are substantially the same as those used to prepare the metal amidoborate bases.
  • the reaction is conducted at a temperature in the ranges previously specified for making the metal amidoborate bases, except that the decomposition temperature below which the reaction should be conducted is now the decomposition temperature of the metal amidoborate base or the metalated organic compound, whichever is lower.
  • the decomposition temperature is often greater than the lowest decomposition temperature for making the metal amidoborate bases. It is preferably at least 30°C, more preferably at least 40°C, so that the reaction may preferably be conducted at room temperature (25°C).
  • the reaction proceeds rapidly, so that the reaction time may be less than one hour, preferably less than half an hour, when conducting the reaction as a batch.
  • the amidoborate bases zPr 2 NBEt 3 MgCl LiCl, zPr 2 NBEt 3 MgCl and zPr 2 NBsBu 3 MgCl were found to be particularly suitable.
  • each Q independently represents a substrate as defined above covalently bonded to each boron atom via a C-B bond
  • R 2 and Met have the same meanings as defined above
  • w represents an integer having a value of at least 1.
  • the value of w is preferably not greater than 3, more preferably not greater than 2, and even more preferably 1.
  • Q comprises 5 to 7 ring members, more preferably 6 ring members, not including atoms in a fused ring system outside each heterocyclic ring Q.
  • the ring members preferably comprise at least four carbon atoms.
  • the ring members preferably comprise up to three, more preferably up to two, and yet more preferably one, nitrogen atom.
  • the heterocyclic ring may comprise other hetero atoms, such as oxygen or sulfur atoms.
  • the heterocyclic ring preferably comprises solely carbon atoms and one or more nitrogen atoms.
  • the substitution may be regioselective.
  • Regioselectivity may be determined when, for example, at least one heterocyclic ring has at least one nonreactive electronegative substituent, such as a halogen atom or an aromatic ring, and/or at least one heterocyclic ring is part of a fused ring system.
  • regioselectivity is preferably at least greater than 95: 1, more preferably at least greater than 99: 1, based on GC-analysis of iodolyzed reaction aliquots relative to the total yield of metalated organic compound.
  • the metalated organoborate compound is reacted with an electrophile, E + , which is a compound comprising an electrophilic atom or group with respect to the nucleophilic organoborate.
  • E + an electrophile
  • Electrophilic atom such as CI, Br, and I, are preferred.
  • the compound may, for example, be X 2 , wherein X represents CI, Br, or I.
  • the electrophile, E is an organic compound having a halogen or a nucleophilic leaving group substituent.
  • Each nucleophilic leaving group is preferably selected from the group consisting
  • R A , R c , R D , R E , and R F each independently represents an hydrocarbyl group or a fluorocarbyl group, wherein the hydrocarbyl or fluorocarbyl group preferably has
  • Preferred hydrocarbyl groups include methyl, branched-chain and straight-chain aliphatic hydrocarbons such as ethyl, propyl, isopropyl, w-butyl, sec -butyl and /-butyl, and aromatic hydrocarbons such as phenyl and benzyl.
  • Preferred fluorocarbyl groups include -(CF 2 ) m CF 3 , wherein "m" represents an integer in the range from zero to 4 and fluorinated aryl groups, such as fluorinated benzyl groups.
  • Preferred nucleophilic leaving groups include triflates (-OS(0) 2 CF 3 ); mesylates (-OS(0) 2 CH 3 ); nonaflates (-OS(0)2(CF 2 )3CF 3 ); tosylates (-OS(0) 2 C 6 H5CH 3 );
  • diazonium salts such as ArN 2 BF 4 , wherein Ar represents an aryl group such as phenyl, benzyl, tolyl, xylyl, or naphthyl; acetate; pivalate; thiomethyl; and thioaryl, such as thiobenzyl.
  • Preferred organic compounds may be represented by formula (V):
  • R 5 represents an organic residue comprising one or more carbon atoms and, optionally, one or more hetero atoms
  • L represents CI, Br, I, or a nucleophilic leaving group
  • j represents an integer in the range from 1 up to 10, preferably up to 4, more preferably up to 2, and even more preferably up to 1.
  • the organic residue, R 5 preferably does not comprise protonated hetero atoms such as, for example, OH, NH, or SH and preferably comprises one or more cyclic groups and/or one or more aliphatic groups.
  • the cyclic groups may comprise carbocyclic groups, such as cycloalkyl groups and aryl groups, and heterocyclic groups, such as heteroaryl groups and partially or fully saturated heterocyclic compounds.
  • Preferred cyclic groups have at least 4, more preferably at least 5, and even more preferably at least 6, up to 20, more preferably up to 15, and even more preferably up to 10, carbon atoms and optionally from 1 preferably up to a number of hetero atoms equal to the number of carbon atoms in the cyclic group.
  • the heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S.
  • the cyclic group may comprise a monocyclic or polycyclic ring system.
  • the polycyclic ring system may comprise fused ring systems, bridged ring systems and rings having one atom in common.
  • Preferred carbocyclic groups are aryl cycloalkyl groups,and cycloalkenyl groups, such as phenyl groups, napththalene rings, cyclohexyl groups, cyclohexenyl groups, cyclopentyl groups, cyclopentenyl groups, etc.
  • heterocyclic groups include heteroaryl groups having 5, 6, or 7 ring members and 1, 2, or 3 hetero atoms.
  • heterocyclic groups containing one or more nitrogen atoms as ring members include pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isothiazolyl, isoxazolyl, furazanyl, pyridinyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, morpholinyl or mo holino, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxal
  • oxygen-containing heterocyclic groups other than those previously mentioned among nitrogen atom-containing heterocyclic groups include furyl, pyranyl, isobenzofuranyl, chromenyl, chromanyl, iaochromanyl, and xanthenyl.
  • the aliphatic group preferably comprises at least 2, more preferably at least 3, and even more preferably at least 4, up to 20, more preferably up to 12, and even more preferably up to 8, and even more preferably up to 6, carbon atoms.
  • the aliphatic group may be straight-chained or branched, may comprise one or more heteroatoms representing up to half, more preferably up to one-fourth, the total number of atoms in the aliphatic group, and may comprise one or more unsaturated bonds.
  • the heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S.
  • the unsaturated bonds are preferably double bonds and triple bonds.
  • Preferred aliphatic groups include alkyl groups, alkenyl groups and alkynyl groups.
  • the aliphatic groups are preferably saturated (i.e., do not contain unsaturated bonds).
  • the electrophile may be represented by the formula:
  • R 5 , L and "j" have the same meaning, including preferred meanings, as defined above in Formula (V) and Y represents O or S.
  • Preferred substituents also include fluorine atoms and nonprotic functional groups.
  • the substituents may include halogen atoms that are less electrophilic than the L group(s), nitro groups, sulfoxy groups, ether groups, thioether groups, acyl groups, and ester groups.
  • Preferred functional group substituents are nitrile, nitro, ester, amide, protected alcohol, protected amine and protected amide.
  • the ester group is preferably represented by the formula -C(0)OR 6 , wherein R 6 is an organic moiety, which may be selected from a wide range of moieties having at least 1, preferably at least 2, more preferably at least 3, and even more preferably at least 4 up to 15, more preferably up to 10, and even more preferably up to 8, carbon atoms and, optionally, one or more hetero atoms.
  • R 6 is preferably selected from a methyl group, an alkyl group, such as a C 2- 8 alkyl group, a cycloalkyl group, such as a C 5- i 0 cycloalkyl group, an aryl group, such as a Cs-io aryl group, an aralkyl group, such as a Ce-is aralkyl group, or a silyl group tri-substituted with a methyl group or an alkyl group, such as a C2-8 alkyl group.
  • Protected alcohol, protected amine and protected amide are alcohol, amine and amide groups in which each proton bonded to an oxygen atom or nitrogen atom has been replaced with a group that is less reactive than the proton and yet capable of being removed to permit reactions to take place on the respective groups.
  • Suitable protecting groups for those functionalities are well known in the state of the art. A description of suitable protective groups is provided, for example, in "Protective groups in organic synthesis" T. W. Greene, P. G. M: Wuts, Wiley.
  • An example is TIPS to protect alcoholic and phenolic OH groups.
  • thermodynamically favored to proceed quickly e.g., at least 70 percent yield within 1 hour
  • mild conditions e.g., at 25°C
  • E + When the electrophile, E + , is not a halogen molecule, but rather an organic compound having a halogen substituent, such as a compound represented by formula (V), it is often desirable to promote the reaction using a catalyst.
  • Catalysts appropriate for conducting nucleophilic-electrophilic cross-coupling, acylation, or allylation are well-known in the organic chemistry literature. Examples include Pd- catalyzed Suzuki cross-coupling and Cu-catalyzed acylation.
  • the Pd is preferably complexed with dba.
  • a N-heterocyclic compound is metalated with a metallic amidoborate base described herein to form a metallic organoborate base having a -BR 2 3 » Met group derived from the metallic amidoborate base.
  • the electrophile E is reacted with the metallic organoborate base, the -BR 2 3 » Met group on the metallic organoborate base is replaced by the electrophile E + .
  • electrophile residues E, s after attachment to a substrate
  • electrophile residues E, s after attachment to a substrate
  • the method described herein may be used to acylate an organic compound, serving as the substrate, with an aldehyde group in the absence of a transition metal catalyst.
  • R 1 , R 2 CMe2-(CH 2 )3-CMe 2i Si(Me 3 ), / ' Pr
  • the borate bases described herein display high stability towards decomposition at room temperature for at least several weeks without loss of reactivity or significant decrease in
  • 3-halopyridines (4) were used as test-substrates for regioselective metalation reactions with tmp-derived borate bases affording organoboron compounds of type 5 (Scheme 2).
  • tmp- derived bases of the type tmpBR 2 3 ⁇ MgCl (type 3) were utilized for the preparation of organoborates via C-H activations and subsequent functionalizations (Scheme 4).
  • E represents the positively charged synthon reacting with the nucleophilic organoborate affording a neutral product.
  • E + defines the carbon- or halogen-based electrophile for C-C- or C-Hal-bond forming reactions.
  • the substrate is reacted with the base in THF to form a metallic organoborate intermediate under the temperature and time conditions specified in Table 3.
  • the metallic organoborate intermediate is then reacted with the electrophile, E, in THF to form the functionalized products 6a to 6g under the following conditions:
  • Products 6a and 6d are obtained by cross-coupling the metallic organoborate intermediate with ZnC ⁇ (10 mol%) ) at a temperature of 25°C for 10 minutes followed by reacting the product of the cross-coupling reaction with Ar-I (0.8 equiv) in the presence of Pd(dba) 2 (2 mol%), P(2-furyl) 3 (4 mol%) at 25°C for 12 hours.
  • trialkylborane and aminoborane derived bases is highly beneficial due to the high reaction rates obtained.
  • Example 8 Functionalization of carbocycles using tmp-derived borate bases
  • the substrate is reacted with the base in THF to form a metallic organoborate intermediate under the temperature and time conditions specified in Table 3A.
  • the metallic organoborate intermediate is then reacted with the electrophile, E, in THF to form the functionalized products lib to llg under the following conditions:
  • 3-fluorobenzonitrile (10a) was metalated using tmpBEt 3 MgCl LiCl (2b; 25 °C, 30 min) furnishing after a Suzuki -type cross-coupling (ZnCl 2 (10 mol%), Pd(OAc) 2 (3 mol%), S-Phos (6 mol%), 65 °C, 1 h) with ethyl 4-iodobenzoate (12; 0.8 equiv) the functionalized biphenyl 11a in 83% yield (Table 3 A, entry 1).
  • tmpBEtyMgCl LiCl (2.2 mL, 1.0 M in THF, 2.2 mmol) was added dropwise at 25 °C to a solution of 3-fluorobenzonitrile (10a; 242 mg, 2.0 mmol) in THF (2 mL) in a flame-dried and Argon-flushed Schlenk-tube equipped with septum and magnetic stirring bar.
  • tmpBEtyMgCl LiCl (2.2 mL, 1.0 M in THF, 2.2 mmol) was added dropwise at 25 °C to a solution of 3,5-(trifluoromethyl)anisole (10b; 352 mg, 2.0 mmol) in THF (2 mL) in a flame-dried and Argon-flushed Schlenk-tube equipped with septum and magnetic stirring bar.
  • disubsituted anisole derivative such as lOf lead after metalation using 2b (25 °C, 0.5 h) followed by cross-coupling (ZnCl 2 (10 mol%), Pd(OAc) 2 (3 mol%), S-Phos (6 mol%), 65 °C, 1 h) with 12 (0.8 equiv) to the functionalized anisole llf in 96% yield (Table 3A, entry 6).
  • tmpBEtyMgCl LiCl (2.2 mL, 1.0 M in THF, 2.2 mmol) was added dropwise at 25 °C to a solution of 3- bis(trifluoromethyl)anisole (lOf; 488 mg, 2.0 mmol) in THF (2 mL) in a flame-dried and Argon-flushed Schlenk-tube equipped with septum and magnetic stirring bar.
  • Example 10 Stability of pyridyltrialkylborate towards water
  • Example 11 Functionalization of iV-heterocycles using iPr 2 NBEt 3 -derived bases
  • N-heterocycles such as thiomethylpyrazine and isoquinoline were reacted with iPr 2 NBEt 3 ⁇ Met bases generating the organoborate intermediates which were subsequently reacted in Suzuki type cross-coupling reactions furnishing the corresponding substituted N-heterocycles 6h-j as shown in Scheme 8a and Table 4.
  • the substrate is reacted with the base to form a metallic organoborate intermediate.
  • the metallic organoborate intermediate is reacted with the electrophile identified in Table 4 to form the respective products by cross-coupling the metallic organoborate intermediate with the Ar-Br electrophile (0.8 equiv) and ZnCl 2 (10 mol%) in the presence of Pd(OAc) 2 (3 mol%) and S-Phos (6 mol%) at 50°C for 12 hours. All reactions were conducted in THF. The results are shown in Table 4 below. Table 4: Functionalization of N-heterocycles using iPr 2 NBEt 3 -derived bases
  • structurally diverse amidoborates (2a- w) can be prepared which react rapidly with a wide range of heterocyclic and carbocyclic compounds to produce metalated borate compounds in high yield and selectivity.
  • the metalated borate compounds can be further functionalized, such as by means of Suzuki -type cross-couplings.

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Abstract

L'invention concerne des amido-borates métalliques, leur anions et le traitement pour les fabriquer, qui comprennent au moins un cation métallique ou un complexe cationique et un anion comprenant le groupe fonctionnel (R1)2N -B(R2)3, dans lequel chaque R1 représente indépendamment Z1(Z1A)p-, Z1 et Z1A représentant indépendamment un atome de carbone ou un atome de silicium et chaque p représente indépendamment l'entier 2 ou 3 et chaque R2 représente indépendamment un atome de fluor ou Z2(Z2A)k -, chaque Z2 représentant indépendamment un atome de carbone, un atome d'azote ou un atome de silicium, chaque Z2A représentant indépendamment un atome d'hydrogène, un atome de carbone ou un atome de silicium, et k représente un entier positif égal à la valence de Z2, au moins un des substitutifs de R2 étant Z2(Z2A)k -. Les composés à base d'amido-borates métalliques peuvent s'utiliser pour produire des composés organiques métallisés qui à leur tour peuvent réagir avec un electrophile afin de fonctionnaliser les composés organiques par le résidu électrophile. Les bases d'amido-borates métalliques décrites ici sont exceptionnellement stables, et de cette manière la fonctionnalisation du composé organique peut être effectuée rapidement et avec un rendement élevé à température ambiante.
PCT/EP2011/073715 2010-12-22 2011-12-22 Amido-borates métalliques destinés à la fonctionnalisation de composés organiques WO2012085169A1 (fr)

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KR20140127249A (ko) * 2012-02-17 2014-11-03 바이엘 인텔렉쳐 프로퍼티 게엠베하 알칼리 토금속-착물화된 금속 아미드
CN108586508A (zh) * 2018-06-26 2018-09-28 烟台显华光电材料研究院有限公司 一类用作电致发光材料的多芳香环化合物及其发光装置
CN108690060A (zh) * 2018-05-24 2018-10-23 烟台显华光电材料研究院有限公司 一类用作电致发光材料的多芳香环化合物及其发光装置
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CN113527079A (zh) * 2020-04-21 2021-10-22 信越化学工业株式会社 制备2-异丙烯基-5-甲基-4-己烯酸及衍生醇及其羧酸酯的方法

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