WO2012016147A2 - Ligands for selective asymmetric hydroformylation - Google Patents

Ligands for selective asymmetric hydroformylation Download PDF

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Publication number
WO2012016147A2
WO2012016147A2 PCT/US2011/045897 US2011045897W WO2012016147A2 WO 2012016147 A2 WO2012016147 A2 WO 2012016147A2 US 2011045897 W US2011045897 W US 2011045897W WO 2012016147 A2 WO2012016147 A2 WO 2012016147A2
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Prior art keywords
alkyl
crc
amino
hydroxyl
amido
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PCT/US2011/045897
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English (en)
French (fr)
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WO2012016147A3 (en
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Christopher James Cobley
Gary Noonan
Matthew Clarke
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Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
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Priority to EP11813250.5A priority Critical patent/EP2598510A4/en
Priority to JP2013522001A priority patent/JP2013532691A/ja
Publication of WO2012016147A2 publication Critical patent/WO2012016147A2/en
Publication of WO2012016147A3 publication Critical patent/WO2012016147A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
    • C07C45/50—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
    • C07C45/505—Asymmetric hydroformylation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
    • B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65683—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/321—Hydroformylation, metalformylation, carbonylation or hydroaminomethylation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/822—Rhodium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to phosphine-phosphite ligands with a chiral phospholane (S,S)-diphenylphospholane and chiral or achiral biaryl phenols linked by a hydroxym ethyl bridge.
  • the invention provides compounds of the formula 4:
  • Olefin hydroformylation has been practiced industrially for decades for the production of commodity aldehyde intermediates. Since linear regioisomers are desired often, a major industrial focus has been the development of highly linear- selective ligands for rhodium-catalyzed hydroformylation. Several phosphorous- based ligands have been developed which exhibit sufficiently high regioselectivity for linear aldehydes for this methodology to be industrially applicable. Linear regioisomers are desired most often in the commodity chemicals sector. However, in organic synthesis of the more complex molecules used in the fine chemicals and pharmaceutical sector, there are demands for both linear and branched aldehyde regioisomers.
  • the branched regioisomers of the aldehydes are also frequently preferred in optically active form; thus such products can be prepared by regioselective and enantioselective hydroformylation of olefins.
  • the current state-of-the-art catalysts for enantioselective hydroformylation only deliver the branched aldehyde regioisomer for a select number of carefully chosen olefinic substrates.
  • Ph-BPE has shown high activity and enantioselectivity for the asymmetric hydroformylation of selected olefins.
  • Kelliphite a bisphosphite ligand was discovered to be effective for enantioselective hydroformylation after a comprehensive screen of novel ligands of this class.
  • Binaphos an atropisomeric biaryl-based phosphine-phosphite has proven to be a prominent ligand for enantioselective hydroformylation with arguably the widest applicability demonstrated to date with high enantioselectivies observed with a range of terminal olefins bearing aryl, heteroaryl, alkenyl, heteroatom substituted groups, and a range of internal olefins. High enantioselectivity is a common feature in these reactions, with olefinic substrates chosen for their tendency to preferentially form the desired branched isomer giving regioselectivities of between 75% and in exceptional cases 99%.
  • Rh catalysts derived from phosphine-phosphites give similar regioselectivity in the hydroformylation of olefins to simple achiral ligands such as triphenylphosphine or 1 ,2-bis-(diphenylphosphino)ethane.
  • Phosphine-phosphites have been reported lacking the diphenylphospholane moiety.
  • the invention provides compounds of the formula 4:
  • the invention provides compounds of the formula 4:
  • n and m are each independently an integer from 1 to 3;
  • Ar are both independently C-6-Ci 4 aryl or Ci-Cgheteroaryl, which can be unsubstituted or substituted with one or more of the following groups: CrC 6 alkyl-, halogen, CrCehaloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, (C C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, HO2C-, (CrC 6 alkoxy)carbonyl-, (d- C 6 alkyl)carboxyl-, di(CrC 6 alkyl)amido-, H 2 NC(0)-, (CrC 6 alkyl)amido-, or 0 2 N-; -Ar ⁇ -Ar 2 - is a bi(C 6 -Ci 4 aryl), bi(Ci-C 9 heteroaryl), or -(C 6 -Ci 4 aryl)-(Ci-
  • the invention provides compound 3b (Fig. 3 crystal structure and Fig.4).
  • Fig. 3 Crystal structure of diphenyl-phospholane-phosphite ligand 3b
  • the invention provides compounds of the formulae 1 , 2a, 2b, and 3b.
  • the invention provides a synthesis of 2-phenylpropanal from styrene and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
  • the invention provides a synthesis of 3-methyl-4- oxobutanenitrile from allyl cyanide and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
  • the invention provides a synthesis of 1 -oxopropan-2-yl acetate from vinyl acetate and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
  • Table 1 are shown the results for the above hydroformylation of styrene using catalysts derived from ligands of type 4, which identified ligand 3b as the most enantioselective ligand.
  • Table 1 Rh catalyzed hydroformylation of styrene
  • Iigand1-3b (0.5%) , 1 mmol styrene, 3.5 ml_ toluene.
  • the invention provides a regioselective synthesis of 2-methyl- 3-phenylpropan-1 -al from allyl benzene and Syngas in the presence of an Rh catalyst derived from ligands of type 4, under conditions where ligands outside the phospholane-phosphite class give no selectivity as shown in Table 2.
  • BH 3 DMS is borane dimethyl sulfide complex ((CH 3 ) 2 S BH 3 ), DABCO is 1 ,4-diazabicyclo[2.2.2]octane, r. t. is room temperature, TMS-I is iodotrimethylsilane.
  • % e. e means the enantiomeric excess of a substance, which is defined as the absolute difference between the mole fraction of each enantiomer.
  • the number of carbon atoms present in a given group is designated "C x -C y ", where x and y are the lower and upper limits, respectively.
  • a group designated as " ⁇ - ⁇ - ⁇ ” contains from 1 to 6 carbon atoms.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • arylalkyloxycabonyl refers to the group (C 6 -Ci 4 aryl)-(Ci-C 6 alkyl)-O- C(O)-. It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
  • (Alkoxy)carbonyl refers to the group alkyl-O-C(O)-.
  • Exemplary (Cr C 6 alkoxy)carbonyl groups include but are not limited to methoxy, ethoxy, n- propoxy, 1 -propoxy, n-butoxy, and t-butoxy.
  • An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, -NH 2 , (C C 6 alkyl)N-, (Ci-C 6 alkyl)(Ci-C 6 alkyl)N-, -N(C C 3 alkyl)C(0)(Ci- Cealkyl), -NHC(0)(Ci-C 6 alkyl), -NHC(0)H, -C(0)NH 2 , -C(0)NH(CrC 6 alkyl), - C(0)N(Ci-C 6 alkyl)(Ci-C 6 alkyl), -CN, C C 6 alkoxy, -C(0)OH, -C(0)0(C C 6 alkyl), - C(O)(d-C 6 alkyl), C 6 -C 14 aryl, C C 9 heteroaryl, C 3 -C 8 cycloalkyl, Ci-C 6 haloalkyl
  • Alkyl- refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C-
  • C C 6 alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (Ci-C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (C C- 6 alkyl)C(0)N(Cr C 3 alkyl)-, (C C 6 alkyl)carboxyamido-, HC(0)NH-, H 2 NC(O)-, (Ci-C 6 alkyl)NHC(0)-, di(Ci-C 6 alkyl)NC(O)-, NC-, hydroxyl, CrC 6 alkoxy-, CrC 6 alkyl-, HO 2 C-, (C C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(0)-, C 6 -C aryl-, C-i-Cgheteroaryl-, C 3 - Cscycloalkyl-, CrC 6 haloalkyl-, amino
  • (Alkyl)amido- refers to a -C(0)NH- group in which the nitrogen atom of said group is attached to an alkyl group, as defined above.
  • Representative examples of a (CrC 6 alkyl)amido group include, but are not limited to, - C(O)NHCH 3 , -C(0)NHCH 2 CH 3 , -C(0)NHCH 2 CH 2 CH 3 , -C(0)NHCH 2 CH 2 CH 2 CH 3l - C(0)NHCH 2 CH 2 CH 2 CH 2 CH 3 , -C(O)NHCH(CH 3 ) 2 , -C(0)NHCH 2 CH(CH 3 ) 2l - C(0)NHCH(CH 3 )CH 2 CH 3 , -C(O)NH-C(CH 3 ) 3 and -C(0)NHCH 2 C(CH 3 ) 3 .
  • (Alkyl)amino- refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above.
  • Representative examples of an (Ci-C 6 alkyl)amino- group include, but are not limited to CH 3 NH-, CH 3 CH 2 NH-, CH 3 CH 2 CH 2 NH-, CH 3 CH 2 CH 2 CH 2 NH-, (CH 3 ) 2 CHNH-, (CH 3 ) 2 CHCH 2 NH-, CH 3 CH 2 CH(CH 3 )NH- and (CH 3 ) 3 CNH-.
  • An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, ⁇ 2 ⁇ -, (CrC 6 alkyl)amino-, di(CrC 6 alkyl)amino-, (Ci-C 6 alkyl)C(0)N(CrC 3 alkyl)-, (CrC 6 alkyl)carboxyamido-, HC(0)NH-, H 2 NC(0)-, (d-C 6 alkyl)NHC(0)-, di(C C 6 alkyl)NC(0)-, NC-, hydroxyl, C C 6 alkoxy-, C C 6 alkyl-, H0 2 C-, (C C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(0)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, C 3 - Cscycloalkyl-, CrC 6 haloalkyl-, amino(
  • Alkylcarboxy refers to an alkyl group, defined above, attached to the parent structure through the oxygen atom of a carboxyl (C(O)-O-) functionality.
  • Examples of (CrC 6 alkyl)carboxy include acetoxy, ethylcarboxy, propylcarboxy, and isopentylcarboxy.
  • Aryl- refers to an aromatic hydrocarbon group.
  • Examples of an C 6 - Ci 4 aryl- group include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, 3- biphen-1 -yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl.
  • An aryl group can be unsubstituted or substituted with one or more of the following groups: CrC 6 alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, amino(C C 6 alkyl)-, di(CrC 6 alkyl)amino-, H0 2 C-, (Ci- C 6 alkoxy)carbonyl-, (C C 6 alkyl)carboxyl-, di(Ci-C 6 alkyl)amido-, H 2 NC(0)-, (C C 6 alkyl)amido-, or 0 2 N-.
  • Di(alkyl)amido- refers to a -NC(O)- group in which the nitrogen atom of said group is attached to two alkyl groups, as defined above. Each alkyl group can be independently selected.
  • Representative examples of a di(C C 6 alkyl)amido- group include, but are not limited to, -C(O)N(CH 3 ) 2 , - C(O)N(CH 2 CH 3 ) 2 , -C(O)N(CH 3 )CH 2 CH 3) -C(0)N(CH 2 CH 2 CH 2 CH 3 ) 2 , -C(0)N(CH 2 CH 3 )CH 2 CH 2 CH 3 , -C(0)N(CH 3 )CH(CH 3 ) 2l -C(O)N(CH 2 CH 3 )CH 2 CH(CH 3 ) 2 , - C(0)N(CH(CH 3 )CH 2 CH 3 ) 2> -C(O)N(CH 2 CH 3 )C(CH 3
  • Di(alkyl)amino- refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected.
  • Representative examples of an di(CrC 6 alkyl)amino- group include, but are not limited to, - N(CH 3 ) 2 , -N(CH 2 CH 3 )(CH 3 ), -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , N(CH 2 CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 ) 2 ) 2 , -N(CH(CH 3 ) 2 )(CH 3 ), -N(CH 2 CH(CH 3 ) 2 ) 2 , - NH(CH(CH 3 )CH 2 CH 3 ) 2 , -N(C(CH 3 ) 3 ) 2, -N(C(CH 3 ) 3 )(CH 3 ), and -N(CH 3 )(CH 2
  • the two alkyl groups on the nitrogen atom when taken together with the nitrogen to which they are attached, can form a 3- to 7- membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with -N(H)-, -N(CrC 6 alkyl)-, -N(C 3 -C 8 cycloalkyl)-, -N(C 6 -C 4 aryl)-, -N(d- Cgheteroaryl)-, -N(amino(Ci-C 6 alkyl))-, -N(C 6 -Ci 4 arylamino)-, -O-, -S-, -S(O)-, or - S(0) 2 -.
  • Halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • Haloalkyl- refers to an alkyl group, as defined above, wherein one or more of the Ci-C 6 alkyl group's hydrogen atoms has been replaced with -F, -CI, - Br, or -I. Each substitution can be independently selected from -F, -CI, -Br, or -I.
  • Ci-C 6 haloalkyl- group include, but are not limited to, -CH 2 F, -CCI 3 , -CF 3 , CH 2 CF 3 , -CH 2 CI, -CH 2 CH 2 Br, -CH 2 CH 2 I, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CH 2 CI, -CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH CH 2 CH 2 CH 2 CH 2 Br, - CH 2 CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH(Br)CH 3 , -CH 2 CH(CI)CH 2 CH 3 , -CH(F)CH 2 CH 3 and - C(CH 3 ) 2 (CH 2 CI).
  • Heteroaryl- refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur, and nitrogen.
  • monocyclic Ci -Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyi, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
  • bicyclic C Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl.
  • the contemplated heteroaryl- rings or ring systems have a minimum of 5 members.
  • Ci heteroaryl- radicals would include but are not limited to tetrazolyl
  • C 2 heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyi, and tetrazinyl
  • Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl.
  • a heteroaryl group can be unsubstituted or substituted with one or more of the following groups: C-i-C 6 alkyl-, halogen, CrC 6 haloalkyl-, hydroxyl, Ci-C 6 hydroxylalkyl-, H 2 N-, amino(Ci-C 6 alkyl), di(Ci-C 6 alkyl)amino-, -COOH, (CrC 6 alkoxy)carbonyl-, (CrC 6 alkyl)carboxyl-, di(CrC 6 alkyl)ainnido-, H 2 NC(0)-, (Ci-C 6 alkyl)amido-, or 0 2 N-.
  • “Hydroxylalkyl-” refers to an alkyl group, as defined above, wherein one or more of the C-i-Cealkyl group's hydrogen atoms have been replaced with hydroxyl groups.
  • Examples of hydroxyl (C Cealkyl)- moieties include, for example, - CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH 2 CH(OH)CH 3 , - CH(CH 3 )CH 2 OH and higher homologs.
  • leaving group refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction.
  • the leaving group is bromide.
  • the leaving group is trimethylamine.
  • the electrophilic nitration of benzene it is H + .
  • the term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates ⁇ i.e.
  • EXAMPLE 6 Regioselective and enantioselective hydroformylation of Vinyl acetate. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO) 2 ] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes.
  • the pressure was then vented and the apparatus cooled to room temperature.
  • the require substrate (vinyl acetate 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 ml_ volume.
  • the apparatus was then purged three times with Syngas, placed at 2.5 bar pressure and heated to 60 °C at constant pressure for 4 hours, after which time no further Syngas uptake was used up (>99% conversion).
  • the AE was then cooled and the reaction mixture analyzed by GC in the standard protocol using a beta- Dex 225 chiral column. This along with NMR revealed that the only product present was the branched aldehyde (B / L >99:1 ) and with an e. e.. of 83 %.
  • EXAMPLE 7 Regioselective and enantioselective hydroformylation of styrene. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO) 2 ] and ligand 3a were prepared as 1 mg per mL solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes.
  • the pressure was then vented and the apparatus cooled to room temperature.
  • the require substrate (styrene 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume.
  • the apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 60 °C at constant pressure for 6 hours, after which time no further Syngas uptake was used up (>99% conversion).
  • EXAMPLE 8 Regioselective and enantioselective hydroformylation of allyl cyanide. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO)2] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes.
  • the pressure was then vented and the apparatus cooled to room temperature.
  • the require substrate (allyl cyanide, 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume.
  • the apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 30 °C at constant pressure for 14 hours, after which time no further Syngas uptake was used up (>99% conversion).

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PCT/US2011/045897 2010-07-30 2011-07-29 Ligands for selective asymmetric hydroformylation WO2012016147A2 (en)

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EP11813250.5A EP2598510A4 (en) 2010-07-30 2011-07-29 LIGANDS FOR SELECTIVE ASYMMETRIC HYDROFORMYLATION
JP2013522001A JP2013532691A (ja) 2010-07-30 2011-07-29 選択的非対称ヒドロホルミル化のための配位子

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US9308527B2 (en) 2014-03-17 2016-04-12 Eastman Chemical Company Phosphorous compounds useful as ligands and compositions and methods regarding them
CN104744514B (zh) * 2013-12-27 2018-03-23 中国科学院上海药物研究所 一种手性磷烯配体、合成方法及其在不对称反应中的应用
WO2019108501A1 (en) * 2017-11-28 2019-06-06 Eastman Chemical Company Highly isoselective catalyst for alkene hydroformylation
US10351583B2 (en) 2017-11-28 2019-07-16 Eastman Chemical Company Highly isoselective catalyst for alkene hydroformylation
WO2022046420A1 (en) * 2020-08-25 2022-03-03 Eastman Chemical Company Phospholane-phosphite ligands for alkene hydroformylation catalysts
WO2022046421A1 (en) * 2020-08-25 2022-03-03 Eastman Chemical Company Olefin hydroformylation processes using hydrocarbon solvents and fluorinated solvents in the presence of phospholane-phosphite ligands
US11542278B1 (en) 2020-05-05 2023-01-03 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
US11667649B2 (en) 2020-05-05 2023-06-06 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
US12043626B2 (en) 2021-10-01 2024-07-23 Nuvalent, Inc. Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compounds

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104744514B (zh) * 2013-12-27 2018-03-23 中国科学院上海药物研究所 一种手性磷烯配体、合成方法及其在不对称反应中的应用
US9308527B2 (en) 2014-03-17 2016-04-12 Eastman Chemical Company Phosphorous compounds useful as ligands and compositions and methods regarding them
WO2019108501A1 (en) * 2017-11-28 2019-06-06 Eastman Chemical Company Highly isoselective catalyst for alkene hydroformylation
US10351583B2 (en) 2017-11-28 2019-07-16 Eastman Chemical Company Highly isoselective catalyst for alkene hydroformylation
CN111315483A (zh) * 2017-11-28 2020-06-19 伊士曼化工公司 用于烯烃加氢甲酰化的高异构选择性催化剂
CN111315755A (zh) * 2017-11-28 2020-06-19 伊士曼化工公司 用于烯烃加氢甲酰化的高异构选择性催化剂
CN111315755B (zh) * 2017-11-28 2024-03-01 伊士曼化工公司 用于烯烃加氢甲酰化的高异构选择性催化剂
US11667649B2 (en) 2020-05-05 2023-06-06 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
US11542278B1 (en) 2020-05-05 2023-01-03 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
US12054498B2 (en) 2020-05-05 2024-08-06 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
WO2022046421A1 (en) * 2020-08-25 2022-03-03 Eastman Chemical Company Olefin hydroformylation processes using hydrocarbon solvents and fluorinated solvents in the presence of phospholane-phosphite ligands
WO2022046420A1 (en) * 2020-08-25 2022-03-03 Eastman Chemical Company Phospholane-phosphite ligands for alkene hydroformylation catalysts
US12043626B2 (en) 2021-10-01 2024-07-23 Nuvalent, Inc. Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compounds

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WO2012016147A3 (en) 2012-04-19
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EP2598510A4 (en) 2014-02-26

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