US20030181319A1 - Process for preparing nonracemic chiral alcohols - Google Patents

Process for preparing nonracemic chiral alcohols Download PDF

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US20030181319A1
US20030181319A1 US10/158,560 US15856002A US2003181319A1 US 20030181319 A1 US20030181319 A1 US 20030181319A1 US 15856002 A US15856002 A US 15856002A US 2003181319 A1 US2003181319 A1 US 2003181319A1
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ligand
catalyst system
nonracemic
diphosphine
chiral
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Charles Tucker
Qiongzhong Jiang
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DSM IP Assets BV
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DSM NV
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Priority to PCT/NL2002/000827 priority patent/WO2003061826A1/en
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    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
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    • 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
    • B01J31/1805—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 nitrogen
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    • 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
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    • 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
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C07F9/3813—N-Phosphonomethylglycine; Salts or complexes thereof
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
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Definitions

  • This invention relates generally to preparing nonracemic chiral alcohols. It more particularly relates to preparing nonracemic chiral alcohols by hydrogenation of ketones using transition metal catalysts comprising nonracemic chiral ligands. Nonracemic chiral alcohols are useful as pharmaceuticals and other bioactive products and as intermediates for the preparation of such products.
  • Ketones can be converted to racemic chiral alcohols by hydrogenation using certain catalyst systems of ruthenium, a phosphine ligand, a 1,2-diamine, and an alkaline base.
  • Aromatic and heteroaromatic ketones can be hydrogenated to nonracemic chiral alcohols by using certain catalyst systems of ruthenium, an appropriate enantiomeric diphosphine ligand, an enantiomeric 1,2-diamine, and a base.
  • M 2 is an alkali metal or an alkaline earth metal
  • Y is a hydroxy group, alkoxy group, mercapto group or naphthyl group
  • applicable ones include KOH, KOCH 3 , KOCH(CH 3 ) 2 , KC 10 H 8 , KOC(CH 3 ) 3 , LiOH, LiOCH 3 , LiOCH(CH 3 ) 2 , NaOH, NaOCH 3 , NaOCH(CH 3 ) 2 , as well as quaternary ammonium salt.”
  • solvent “Since the product is alcohol, alcohol type solvents are preferable.
  • 2-propanol may be preferably used.”
  • the Examples of U.S. Pat. No. 5,763,688 exemplify only KOH as the base and only 2-propanol as the solvent. J. Am. Chem. Soc., vol. 117 (1995), 2675-2676, whose authors are inventors of U.S. Pat. No. 5,763,688, further discusses this process of U.S. Pat. No. 5,763,688 and states, “2-propanol is the solvent of choice. The reaction in methanol, ethanol, or tert-butylalcohol is much slower, while THF, dichoromethane, and toluene are not useable.”
  • ketones can be hydrogenated to nonracemic chiral alcohols using related catalyst systems formed with a racemic chiral 1,2-diamine.
  • the active diastereomeric ruthenium catalyst is formed with the enantiomeric diphosphine ligand and the “matched” enantiomer of the racemic chiral 1,2-diamine.
  • an inorganic or a quaternary ammonium salt can be exemplified, preferably an alkali metal compound or an alkaline earth metal compound and a quaternary ammonium salt, more preferably an alkali metal or alkaline earth metal hydroxide or a salt thereof and a quaternary ammonium salt.
  • Its illustrative examples include LiOH, LiOMe, LiOEt, LiOCH(CH 3 ) 2 , LiOC(CH 3 ) 3 , NaOH, NaOMe, NaOEt, NaOCH(CH 3 ) 2 , NaOC(CH 3 ) 3 , KOH, KOCH 3 , KOCH(CH 3 ) 2 , KOC(CH 3 ) 3 , KC 10 H 8 , and the like.
  • a quaternary ammonium salt can also be used.” It further states that, for solvent, “Because the product is an alcohol, alcohol solvents most preferred, and 2-propanol is particularly preferred.”
  • the Examples of European Patent Application 901 997 exemplify only KOH and KOC(CH 3 ) 3 as the base and only 2-propanol as main solvent.
  • the other references cited above in this Background of the Invention section similarly use KOH or KOC(CH 3 ) 3 as the base and 2-propanol as main solvent.
  • a catalyst system of ruthenium, the atropisomeric diphosphine (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), achiral ethylenediamine, and potassium hydroxide in 2-propanol is reported to hydrogenate 1′-acetonaphthone to (R)-1-(1-naphthyl)ethanol in 57% enantiomeric excess.
  • the present invention provides a catalyst system and a process for the preparation of a nonracemic chiral alcohol by hydrogenation of a ketone using the catalyst system, wherein the catalyst system comprises ruthenium, a nonracemic chiral diphosphine ligand, a bidentate amine ligand, and an organic base selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes, with the proviso that when the nonracemic chiral diphosphine is an atropisomeric diphosphine and the organic base is selected from alkylamidines, the catalyst system is essentially free of alkali metal salt.
  • the organic base is selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes, and is most preferably selected from alkylguanidines.
  • these organic bases often provide greater enantioselectivity for the hydrogenation of a ketone to a nonracemic chiral alcohol as compared to the basic salts preferred in the teachings of the background references.
  • these organic bases allow the inventive process to be conducted with solvents other than the alcohol solvent preferred in the background references, including solvents such as dichloromethane and toluene and solvents in which the basic salts preferred in the background references are not soluble.
  • the chirality of the dominant enantiomer of the nonracemic alcohol product can be opposite that obtained with the otherwise identical catalyst system comprising a basic salt.
  • the term “treating”, “contacting” or “reacting” refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. “Side-reaction” is a reaction that does not ultimately lead to a production of a desired product.
  • Alkyl means a linear saturated monovalent hydrocarbon radical or a branched saturated monovalent hydrocarbon radical or a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms indicated in the prefix.
  • (C 1 -C 6 )alkyl is meant to include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl and the like.
  • a divalent alkyl radical refers to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix.
  • a divalent (C 1 -C 6 )alkyl is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond.
  • (C 2 -C 6 )alkenyl is meant to include, ethenyl, propenyl, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix.
  • (C 2 -C 6 )alkynyl is meant to include ethynyl, propynyl, and the like.
  • Alkoxy means a radical —OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
  • Aryl means a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms which is substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and heteroalkyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted derivatives thereof.
  • Aralkyl refers to a radical wherein an aryl group is attached to an alkyl group, the combination being attached to the remainder of the molecule through the alkyl portion.
  • aralkyl groups are benzyl, phenylethyl, and the like.
  • Heteroalkyl means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano, alkoxy, amino, mono- or di-alkylamino, thioalkoxy, and the like, with the understanding that the point of attachment of the heteroalkyl radical to the remainder of the molecule is through a carbon atom of the heteroalkyl radical.
  • Heteroaryl means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • the heteroaryl ring is optionally substituted independently with one to four substituents, preferably one or two substituents, selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and heteroalkyl.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzo furanyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and the substituted derivatives thereof.
  • Hydrophobicarbyl is used herein to refer to an organic radical, that can be an alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroalkyl or heteroaryl radical, or a combination thereof which is optionally substituted with one or more substituents generally selected from the groups noted above.
  • the present invention provides a method for the preparation of a chiral alcohol of formula II (shown without stereochemistry) from a ketone of formula I.
  • Suitable ketones for use in the present invention are those wherein R 1 and R 2 are different, and optionally, one or both of R 1 and R 2 have a chiral center.
  • R 1 and R 2 in formulas I and II each independently represent a hydrocarbyl group that can be an acyclic, cyclic, or heterocyclic hydrocarbyl group, or a combination thereof.
  • each of the hydrocarbyl groups R 1 and R 2 can be saturated or unsaturated, including components defined above as alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, as well as combinations thereof.
  • each of R 1 and R 2 can be optionally substituted with one or more substituents that do not interfere with the reaction chemistry of the invention.
  • R 1 and R 2 are linked together in a cyclic structure.
  • R 1 is an optionally substituted alkyl group and R 2 is an optionally substituted aryl or heteroaryl group.
  • R 1 and R 2 can also be, independently, chiral or achiral.
  • the ruthenium, nonracemic chiral diphosphine ligand, and bidentate amine ligand components of the catalyst system can be provided to the reaction mixture individually to form the reactive catalyst complex in situ or they can be provided as preformed complexes. Preformed complexes of ruthenium with the diphosphine ligand, or the bidentate amine ligand, or both can be used.
  • Examples of preformed complexes of the ruthenium with the diphosphine ligand include complexes represented by the formula RuX 2 LY n , wherein X represents a halogen atom or pseudo-halide group, preferably chloride or bromide, L represents the diphosphine ligand, Y represents a weakly coordinating neutral ligand, and n is an integer from 1 to 5.
  • Examples of Y include trialkylamines, for examples triethylamine and tetramethylethylenediamine, and tertiary amides, for example dimethylformamide.
  • Such complexes can be prepared by the reaction of the diphosphine ligand with a complex of the formula [RuX 2 (arene)] 2 , wherein examples of the arene include benzene, p-cymene, 1,3,5-trimethylbenzene, and hexamethylbenzene, in a solvent comprising Y.
  • Examples of preformed complexes of the ruthenium with both the diphosphine ligand and bidentate amine ligand include complexes represented by the formula RuX 2 LA, wherein A represents the bidentate amine ligand.
  • Such complexes can be prepared by the reaction of the bidentate amine with a complex of the formula RuX 2 LY n as described above.
  • the ruthenium component of the catalyst system can be provided by any ruthenium salt or complex capable of forming the active catalyst system in combination with the diphosphine ligand, the bidentate amine ligand, and the base. This can be determined by routine functional testing for ketone hydrogenation activity and enantioselectivity in the manner shown in the Examples.
  • a preferred source of the ruthenium component is a complex of the formula [RuX 2 (arene)] 2 as defined above.
  • Suitable nonracemic chiral diphosphine ligands for the present invention are bis-tertiary phosphines of the general formula R 3 R 4 PR a PR 5 R 6 , wherein R 3 , R 4 , R 5 , and R 6 are hydrocarbyl radicals, which may be the same or different, and R a is a hydrocarbyl diradical, any of which may be optionally linked in one or more cyclic structures.
  • Suitable hydrocarbyl groups R 3 , R 4 , R 5 , R 6 , and diradicals thereof for R a include acyclic, cyclic, or heterocyclic hydrocarbyl groups, or combinations thereof.
  • each of the hydrocarbyl groups R 3 , R 4 R 5 , R 6 and R a can be saturated or unsaturated, including components defined above as alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, as well as combinations thereof. Still further, each of R 3 , R 4 , R 5 , R 6 and R a can be optionally substituted with one or more substituents that do not undesirably affect the reaction chemistry of the invention.
  • the chirality of the diphosphine ligand may reside in one or more of the hydrocarbyl groups R 3 , R 4 , R 5 , R 6 , in the bridging hydrocarbyl radical R a , at phosphorus when two hydrocarbyl radicals on phosphorus are different (R 3 ⁇ R 4 , or R 5 ⁇ R 6 , or both), or combinations thereof.
  • Chirality in the bridging hydrocarbyl diradical R a may be due to the presence of one or more stereogenic carbon atoms, or due to atropoisomerism.
  • Atropisomers do not comprise a stereogenic atom, but are chiral because of greatly hindered or prevented rotation about a single bond.
  • Atropisomeric biaryl diphosphine ligands comprise a 1,1′-biaryl bond in the bridge between the phosphorus atoms, about which rotation is sterically prohibited and which are thereby chiral although lacking a stereogenic carbon or phosphorus atom.
  • Atropisomeric biaryl diphosphine ligands include, among others, the enantiomers of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), BINAP derivatives having one or more alkyl or aryl groups connected to one or both naphthyl rings, BINAP derivatives having one to five alkyl substituents on the phenyl rings bonded to phosphorus, for example 2,2′-bis-(di-p-tolylphosphino)-1,1′-binaphthyl (TolBINAP), 5,6,7,8,5′,6′,7′,8′-octahydro-BINAP (H 8 BINAP), 2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl (BICHEP), 2,2′-bis(diphenylphosphino)-6,6′-
  • alkylene methylene, 1,2-ethylene, 1,3-propylene, . . . , respectively), 5,5′-bis(diphenylphosphino)-4,4′-bi(benzodioxolyl) (SEGPHOS), and 2,2′-bis(diphenylphosphino)-3,3′-bi(benzo[b]thiophene) (BITIANP).
  • the nonracemic chiral diphosphine ligand is selected from nonracemic nonatropisomeric chiral diphosphine ligands, and more preferably, atropisomeric chiral substructures are not present in the nonracemic nonatropisomeric chiral diphosphine ligand.
  • the nonracemic nonatropisomeric chiral diphosphine ligand comprises one or more stereogenic carbon atoms.
  • nonracemic nonatropisomeric chiral diphosphine ligands are the enantiomers of 1,2-bis-(diphenylphosphino)propane (PROPHOS), 2,3-bis(diphenylphosphino)butane (CHIRAPHOS), 2,4-bis(diphenylphosphino)pentane (SKEWPHOS), 1-cyclohexyl-1,2-bis(diphenylphosphino)ethane (CYCPHOS), 1-substituted 3,4-bis(diphenyl-phosphino)pyrolidine (DEGPHOS), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP), 3,4-O-isopropylidene-3,4-dihydroxy-2,5-bis-(diphenylphosphino)hexane (DIOP*
  • Certain preferred nonracemic nonatropisomeric chiral diphosphine ligands comprise at least one, preferably at least two, and most preferably four, stereogenic carbon atoms in the hydrocarbyl diradical that connects the two phosphorus atoms (R a in the formula above.).
  • Illustrative examples of nonracemic nonatropisomeric chiral diphosphine ligands wherein the bridging hydrocarbyl diradical comprises a stereogenic carbon atom are the enantiomers of PROPHOS, CHIRAPHOS, SKEWPHOS, DIOP, DIOP*, and BICP ligands.
  • nonracemic nonatropisomeric chiral diphosphine ligands wherein the bridging hydrocarbyl diradical comprises a stereogenic carbon atom, comprise a 2,2′-bis-(diorgano-phosphino)-1,1′-bis(cyclic) structure, wherein each cycle of the bridging bis(cyclic) diradical comprises three to eight carbon atoms, and wherein the 1, 1′, 2, and 2′ carbon atoms in the bis(cyclic) diradical are saturated.
  • ligands are described in detail in U.S. Pat. No. 6,037,500, incorporated herein by reference.
  • nonracemic nonatropisomeric diphosphine ligands comprising a 2,2′-bis-(diorgano-phosphino)-1,1′-bis(cyclic) structure are of the formula V and its enantiomer, wherein Ar is an aryl group.
  • Preferred aryl groups in formula V are phenyl (the BICP ligand) and mono-, di-, and trialkyl-phenyl, particularly wherein alkyl is methyl, for example 2,2′-bis[di(3,5-dimethylphenyl)phosphino]-1,1′-dicyclopentane (3,5-Me 8 BICP).
  • Suitable bidentate amine ligands comprise a primary amino group and another heteroatom-containing group that is capable of ligating to the ruthenium.
  • groups are known in the art, and include groups having a heteroatom selected from oxygen, nitrogen, sulfur, and phosphorus.
  • Preferred bidentate amine ligands include diamines and amino-thioethers.
  • the bidentate amine ligand may be achiral, racemic chiral, or nonracemic chiral. In certain inventive embodiments of the invention, the bidentate amine ligand is an achiral diamine.
  • Suitable diamine ligands for the present invention are of the general formula H 2 NR b NH 2 , wherein R b is an hydrocarbyl diradical.
  • the hydrocarbyl diradical comprises at least two to fifty carbon atoms, more preferably at least three to fifty carbon atoms, still more preferably at least four to fifty carbon atoms, and most preferably at least six to fifty carbon atoms
  • Suitable hydrocarbyl diradicals for R b include acyclic, cyclic, and heterocyclic hydrocarbyl diradicals, include saturated and unsaturated hydrocarbyl diradicals, include alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl diradicals, and can be optionally substituted with one or more substituents that do not interfere with the reaction chemistry of the invention.
  • Suitable chiral diamine ligands include the enantiomers and mixtures thereof of chiral derivatives of ethylenediamine, propylenediamines, butanediamines, cycloalkanediamines, and phenylenediamines.
  • Illustrative examples include chiral stereoisomers of 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-isobutyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-methyl-2,2-dinaphthylethylenediamine, 1-isobutyl-2,2-dinaphthylethylenediamine, 1-isopropyl-2,2-dinap
  • Suitable achiral diamines may be achiral by comprising neither atropisomerism nor stereogenic carbon atoms or it may be achiral comprising a meso compound. That is, the achiral hydrocarbyl diradical may contain one or more pairs of stereogenic carbon atoms that are related in at least one of its conformations by a plane of symmetry. For example, while (S,S)- and (R,R)-1,2-diphenylethylenediamine are chiral enantiomers, (S,R)-1,2-diphenylethylenediamine is an achiral meso compound.
  • Illustrative examples of achiral diamines include ethylenediamine, 1,3-propylenediamine, 2-methyl-1,2-propylene-diamine, meso-2,3-butanediamine, meso-1,2-cyclopentanediamine, meso-1,2-cyclo-hexane-diamine, meso-1,2-cyclo-heptane-diamine, meso-1,2-diphenylethylenediamine, meso-2,3-dimethyl-butane-1,2-diamine, 1,2-phenylenediamine, 2-aminobenzyl-amine, 1,8-diaminonaphthalene, and equivalents thereto that are recognized by those skilled in the art, any of which may be substituted with one or more substituents that do not interfere with the reaction chemistry of the invention, and provided such substitution preserves the achirality of the diamine.
  • Preferred achiral diamines are selected from 1,2-alkylenediamine compounds, 1,2-phenylenediamine compounds and 1,8-diamino-naphthalene compounds, which may be substituted or unsubstituted.
  • Suitable substituents include alkyl (e.g. 4,5-dimethyl-1,2-phenylene-diamine), benzo (e.g. 9,10-diaminophenanthrene), and alkoxy (e.g, 1,3-benzodioxole-5,6-diamine).
  • Suitable amino-thioether ligands for the present invention are of the general formula H 2 NR c SR 7 , wherein R 7 is a hydrocarbyl radical and R c is a hydrocarbyl diradical and which may be optionally linked in a cyclic structure.
  • Suitable hydrocarbyl groups R 7 and diradicals thereof for R c include acyclic, cyclic, and heterocyclic hydrocarbyl groups, include saturated and unsaturated hydrocarbyl groups, include alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, and can be optionally substituted with one or more substituents that do not undesirably the reaction chemistry of the invention.
  • the amino-thioether ligand may be achiral, racemic chiral, or nonracemic chiral, preferably achiral.
  • Preferred amino-thioether ligands are selected from 2-(alkylthio)ethylamines, 2-(alkylthio)anilines, and equivalents thereto that are recognized by those skilled in the art. Most preferred are 2-(alkylthio)anilines. Preferably the alkyl group therein is selected from C 1 to C 4 alkyl groups. Most preferred are methyl and ethyl. Illustrative examples include 2-(methylthio)aniline and 2-(ethylthio)aniline.
  • Suitable alkylguanidines have the general formula VI, wherein R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected from hydrogen and alkyl groups, with the proviso that at least one of R 8 , R 9 , R 10 , R 11 , and R 12 is an alkyl group.
  • the alkylguanidine comprises two alkyl groups, more preferably three alkyl groups, even more preferably four alkyl groups, and most preferably five alkyl groups. Any of the alkyl groups R 8 , R 9 , R 10 , R 11 , and R 12 may be optionally linked in one or more cyclic structures.
  • An illustrative example of a suitable tetraalkylguanidine base is 1,5,7-triazabicyclo[4.4.0]dec-5-ene and tetramethylguanidine.
  • suitable pentalkylguanidines are 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and tetramethyl-2-t-butylguanidine.
  • Suitable aminophosphazenes have the general formula VII, wherein R 13 is selected from hydrogen and alkyl groups, R 14 is an alkyl group and the two R 14 groups on each —NR 14 2 group may optionally be linked in a cyclic structure, and x is an integer from zero to three, preferably 3.
  • Suitable proazaphosphatranes are described in U.S. Pat. No. 5,051,533 and have the general formula VIII, wherein R 15 , R 16 , and R 17 are independently selected from hydrogen and alkyl groups.
  • R 15 , R 16 , and R 17 are selected from C 1 to C 8 alkyl groups, most preferably methyl.
  • Suitable alkylamidines have the general formula IX wherein R 18 , R 19 , and R 20 are independently selected from alkyl groups and R 21 is selected from hydrogen and alkyl groups. Preferably, R 21 is selected from alkyl groups.
  • any of the alkyl groups R 18 , R 19 , R 20 , and R 21 may be optionally linked in one or more cyclic structures.
  • An illustrative example of a suitable alkylamidine base is 1,5-diazabicyclo[4.3.0]non-5-ene.
  • the organic base is selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes. More preferably, the organic base is an alkylguanidine, most preferably selected from tetraalkylguanidines and pentaalkylguanidines.
  • the catalyst system is essentially free of alkali metal salt.
  • the invention includes the proviso that for embodiments wherein an alkylamidine base is used in combination with a nonracemic atropisomeric diphosphine ligand, the catalyst system is essentially free of alkali metal salt.
  • the phrase “essentially free of alkali metal salt” means that the concentration of the alkali metal salt is not sufficient to significantly increase the activity of the catalyst system. This can be readily determined experimentally.
  • the catalyst system is free of alkali metal salt.
  • the components of the catalyst system are each present in a catalytic amount, meaning less than stoichiometric relative to the ketone reactants.
  • the minimum amount of the catalyst system relative to the ketone reactant may depend on the activity of the specific catalyst system composition, the specific ketone to be reacted, the hydrogen pressure, the gas-liquid mixing characteristics of the reaction vessel, the reaction temperature, the concentrations of the reactants and catalyst system components in the solution, and the maximum time allowed for completion of the reaction, and can be readily determined by routine experimentation.
  • the mole ratio of the ruthenium component of the catalyst system to the ketone reactant is in the range from about 1/100 to about 1/100,000, preferably in the range from about 1/500 to about 1/10,000.
  • the mole ratio of the nonracemic diphosphine ligand to the ruthenium in the catalyst system is typically in the range from about 0.5 to about 2.0, preferably from about 0.8 to about 1.2, and most preferably is about 1.
  • the mole ratio of the bidentate amine ligand to the ruthenium in the catalyst system is typically in the range from about 1 to about 50, and preferably from about 5 to about 20.
  • the mole ratio of the base to the ruthenium in the catalyst system is typically in the range from about 1 to about 100, and preferably from about 5 to about 50.
  • the hydrogenation reaction may be conducted without solvent when the ketone itself is a liquid at the reaction temperature and capable of dissolving the catalyst system. More typically, the hydrogenation reaction is conducted in a solvent system that is capable of dissolving the catalyst system and is reaction-inert.
  • solvent system is used to indicate that a single solvent or a mixture of two or more solvents can be used.
  • reaction-inert it used to mean that the solvent system does not react unfavorably with the reactants, products, or the catalyst system.
  • reaction-inert does not mean that the solvent does not participate productively in the desired reaction.
  • alcohol solvents level organic bases selected from the preferred alkylguanidines, aminophosphazenes, or proazaphosphatranes. That is, these bases deprotonate the alcohol to form an alkoxide base in the reaction solution.
  • organic bases of the present invention allow the inventive process to be conducted using solvents other than alcohol solvents, including solvents in which the basic alkoxide salts preferred in the background references are not soluble.
  • the solvent system need not bring about complete solution of the ketone reactant or the chiral alcohol product.
  • the ketone reactant may be incompletely dissolved at the beginning of the reaction or the chiral alcohol product may be incompletely dissolved at the end of the reaction, or both.
  • Representative solvents are aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic hydrocarbons such as pentane, hexane, heptane; halogen-containing hydrocarbon solvents such as dichloromethane and chlorobenzene; alkyl ethers, polyethers, and cyclic ethers such as methyl-t-butyl-ether, dibutylether, diethoxymethane, 1,2-dimethoxyethane, and tetrahydrofuran; ester solvents such as ethyl acetate, organic solvents containing heteroatoms such as acetonitrile, DMF and DMSO; and alcohol solvents such as methanol, ethanol, 2-propanol, t-butanol, benzyl alcohol and the like; and mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene
  • aliphatic hydrocarbons such as pen
  • the reaction is suitably conducted at a temperature from about ⁇ 30° C. to about 100° C., more typically from about 0° C. to about 50° C., and most typically from about 20° C. to about 40° C.
  • hydrogenating and “hydrogenation” refer to reacting the ketone with a source of hydrogen atoms under appropriate conditions so that two hydrogen atoms are added to the carbonyl group of the ketone to produce the hydroxyl group of the chiral alcohol.
  • the source of hydrogen atoms may be molecular hydrogen (H 2 ), a hydrogen donating organic or inorganic compound, or mixtures thereof.
  • the source of hydrogen atoms includes molecular hydrogen.
  • Hydrogen donating compounds are compounds capable of donating hydrogen atoms via the action of the catalyst system.
  • Compounds capable of donating hydrogen atoms for transfer hydrogenation reactions using ruthenium catalysts include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol, formic acid and salts thereof, unsaturated hydrocarbons and heterocyclic compounds having in part a saturated C—C bond such as tetralin, cyclohexane, and cyclohexadiene, hydroquinone, phosphorous acid, and the like.
  • alcohols are preferred and isopropanol is most preferred.
  • the hydrogen pressure in the reaction is typically at least about 1 atm, and typically in the range from about 1 atm to about 100 atm. More typically, the hydrogen pressure is in the range from about 5 atm to about 20 atm.
  • reaction rate and time to completion are dependent on the identities of the ketone reactant and the catalyst components, their absolute concentrations and relative ratios, the temperature, the hydrogen pressure, the gas-liquid mixing provided, and the other reaction conditions. Typically, the reaction is allowed to continue for sufficient time to complete the conversion of the ketone reactant. For typical ketone reactants, using the preferred catalyst systems described and the preferred reaction conditions described herein, the reaction is typically completed in a period of time in the range from about a few minutes to about 24 hours, more typically in the range from about 1 hour to about 10 hours.
  • the nonracemic chiral alcohol product has, by definition, a stereomeric excess greater than zero.
  • the nonracemic chiral alcohol is formed in at least about 50% stereomeric excess, more preferably at least about 60%, still more preferably at least about 70%, still again more preferably at least about 80%, and most preferably at least about 90%.
  • These stereomeric excesses refer to the chirality at the hydroxyl-bearing carbon of the alcohol group generated by the hydrogenation of the ketone group.
  • the chiral alcohol can be one of two enantiomers, and the enantiomer excess (e.e.) is the measure of stereomeric excess.
  • nonracemic diastereomer when used to refer to a nonracemic chiral alcohol product, refers to a product with an excess of one diastereomer vs. its diastereomer with the opposite chirality at the hydroxyl-bearing carbon.
  • the nonracemic diastereomer is produced in at least about 50% d.e., more preferably at least about 60% d.e., still more preferably at least about 70% d.e., still again more preferably at least about 80% d.e., and most preferably at least about 90% d.e.
  • the resulting orange-red solid residue comprising [RuCl 2 (R,R,R,R-BICP)(DMF)n] was further dried at 80° C. under vacuum for at least an additional hour.
  • a stock solution of 250 micromolar [RuCl 2 ((R,R,R,R-BICP)(DMF)n] in isopropanol was prepared by dissolving the solid residue in 120 mL anhydrous, deaerated isopropanol and stored under nitrogen.
  • This Example illustrates the process of the invention wherein acetophenone is hydrogenated to nonracemic 1-phenethanol using a ruthenium catalyst system comprising a nonracemic diphosphine ligand, a bidentate amine ligand and a pentaalkylguanidine base.
  • the glass reaction vial containing the resulting mixture was sealed in an autoclave, which was then removed from the glovebox.
  • the gas phase in the autoclave was replaced by hydrogen at 18 bar and the reaction mixture was stirred at room temperature for 6 hours under 17-18 bar hydrogen.
  • 1 ml of the resulting reaction solution was eluted through a short column of silica gel with 9 mL methanol. Chiral gas chromatographic analysis of the eluate showed 100% conversion of the acetophenone to give S-1-phenethanol with 77% e.e.
  • This Comparative Example shows the result substituting an alkoxide salt for the alkylguanidine base exemplified in Examples 1.
  • Example 1 shows that the enantioselectivity for hydrogenation of acetophenone is substantially greater with the otherwise identical catalyst comprising an alkylguanidine base.
  • diamine base (hrs) (%) 1 ethylenediamine tetramethyl-2-t-butylguanidine 6 77 Comp. 1 ethylenediamine sodium isopropoxide 6 51 2 1,3-propylenediamine tetramethyl-2-t-butylguanidine 4 78 Comp. 2 1,3-propylenediamine sodium isopropoxide 6 77 3 4,5-dimethyl-1,2-phenylenediamine tetramethyl-2-t-butylguanidine 10 77 Comp. 3 4,5-dimethyl-1,2-phenylenediamine sodium isopropoxide 6 71 4 1,8-naphthalenediamine tetramethyl-2-t-butylguanidine 4 86 Comp.
  • Example diamine base (hrs) (%) 8 ethylenediamine tetramethyl-2-t-butylguanidine 4 86 Comp. 8 ethylenediamine sodium isopropoxide 4 56 9 1,3-propylenediamine tetramethyl-2-t-butylguanidine 4 85 Comp. 9 1,3-propylenediamine sodium isopropoxide 4 82 10 4,5-dimethyl-1,2-phenylenediamine tetramethyl-2-t-butylguanidine 4 84 Comp.
  • This Example illustrates the process of the invention wherein acetophenone is hydrogenated to nonracemic 1-phenethanol using a ruthenium catalyst system comprising a nonracemic diphosphine ligand, a bidentate amine ligand and a tetraaalkylguanidine base.
  • this Example shows that the enantioselectivity for hydrogenation of acetophenone is substantially greater with the catalyst system comprising the tetraalkylguanidine base compared to the otherwise identical catalyst system comprising an the alkoxide salt for the base.
  • Example 14 The procedure was identical to Example 14 with the exceptions that an equal molar amount of the base shown in Table 4 was substituted for the tetramethyl-2-t-butyl-guanidine and the reaction mixtures were stirred under hydrogen for the time shown in Table 4.
  • Table 4 gives the base, the reaction time, the conversion of the 2-acetylthiophene, and the enantiomeric excess of the S-1-(2-thienyl)ethanol product. TABLE 4 Time Conv. e.e. Example base (hrs) (%) (%) Comp.
  • the chirality of the dominant enantiomer of the nonracemic alcohol product is the same, S, showing that it is controlled by the chirality of the diphosphine enantiomer.
  • the chirality of the 1,2-cyclohexanediamine affects only the degree of enantioselectivity toward the S-alcohol. Comparisons between the results that use the same base consistently show that that the R,R-1,2-cyclohexanediamine is matched to the chirality of the R,R,R,R-BICP, their combination giving higher enantioselectivities than the combination of the S,S-1,2-cyclohexanediamine with R,R,R,R-BICP.
  • Example 35 shows that the unmatched combination of S,S-1,2-cyclohexanediamine with R,R,R,R-BICP when used with an alkylguanidine base can provide in an enantioselectivity on par with the matched combination of R,R-1,2-cyclohexanediamine with R,R,R,R-BICP when used with the alkoxide salt base (Comparative Example 2).
  • the chirality of the dominant enantiomer of the nonracemic alcohol product is the same, S, showing that it is controlled by the chirality of the diphosphine enantiomer.
  • the chirality of the 1,2-propylenediamine affects only the degree of enantioselectivity toward the S-alcohol. Comparisons between the results that use the same base consistently show that that the R-1,2-propylenediamine is matched to the chirality of the R,R,R,R-BICP, their combination giving higher enantioselectivities than the combination of the S-1,2-propylenediamine with R,R,R,R-BICP.
  • Example 38 shows that the unmatched combination of S-1,2-propylenediamine with R,R,R,R-BICP when used with an alkylguanidine base can provide in an enantioselectivity comparable with the matched combination of R-1,2-propylenediamine with R,R,R,R-BICP when used with the alkoxide salt base (Comparative Example 15).
  • Example ketone base (hrs) (%) 2 acetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 83 Comp. 1 acetophenone sodium isopropoxide 6 51 8 2-acetylthiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 88 Comp. 8 2-acetylthiophene sodium isopropoxide 4 56 46 2′-acetonaphthone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 83 Comp.
  • Table 8 gives the ketone base, the reaction time, and the enantiomeric excess of the S-alcohol product. TABLE 8 Time e.e. Example ketone base (hrs) (%) 51 acetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 87 Comp. 23 acetophenone sodium isopropoxide 9 68 52 2-acetylthiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 93 Comp. 15 2-acetylthiophene sodium isopropoxide 6 77 53 2′-acetonaphthone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 87 Comp.
  • Example ketone base (hrs) (%) (%) 57 acetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 73 7 acetophenone tetramethyl-2-t-butylguanidine 12 100 71 Comp. 7 acetophenone sodium isopropoxide 6 100 67 26 2-acetylthiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 56 90 14 2-acetylthiophene tetramethyl-2-t-butylguanidine 4 84 90 Comp.
  • Table 10 gives the diphosphine, the base, the reaction time, the conversion of the 2-acetylthiophene, the absolute configuration of the 1-(2-thienyl)ethanol, and its e.e. TABLE 10 Time Conv. e.e. (%)
  • Example diphosphine base (hrs) (%) (R/S) 8 R,R,R,R-BICP tetramethyl-2-t-butylguanidine 4 100 86 (S) Comp. 8 R,R,R,R-BICP sodium isopropoxide 4 100 56 (S) 68 S,S-CHIRAPHOS tetramethyl-2-t-butylguanidine 8 17 64 (S) Comp.
  • Examples 68 and Comparative Example 34, using CHIRAPHOS show the surprising result of the chirality of the dominant enantiomer of the nonracemic alcohol being switched upon using the tetramethyl-2-t-butylguanidine instead of sodium isopropoxide.
  • Example 14 and 74 show substantial improvements in enantioselectivity using tetramethyl-2-t-butylguanidine as compared to using sodium isopropoxide.
  • Example 74 and Comparative Example 40, using CHIRAPHOS show the surprising result of the chirality of the dominant enantiomer of the nonracemic alcohol being switched upon using the tetramethyl-2-t-butylguanidine instead of sodium isopropoxide. A similar switch in chirality, though lesser in e.e.
  • R,R-SKEWPHOS sodium isopropoxide 12 90 56 (S) 76 R,R-Me-PennPhos tetramethyl-2-t-butylguanidine 8 63 77 (S) Comp. 42 R,R-Me-PennPhos sodium isopropoxide 12 100 76 (S) 77 R,R-DIOP tetramethyl-2-t-butylguanidine 8 5 52 (R) Comp. 43 R,R-DIOP sodium isopropoxide 12 94 57 (R) 78 R-BINAP tetramethyl-2-t-butylguanidine 6 12 34 (S) Comp.
  • R-C4-TunaPhos sodium isopropoxide 6 100 33 (S) 80 S-MeOBIPHEP tetramethyl-2-t-butylguanidine 12 20 34 (R)
  • S-MeOBIPHEP sodium isopropoxide 10 100 41 (R)
  • alkylguanidine base can provide significantly greater enantioselectivity than a basic salt like sodium isopropoxide in the process of the invention. They also show that the degree of the relative improvement can also depend on the identity of the diamine ligand, and appears greatest with a simpler and smaller achiral diamine, especially with ethylene diamine.
  • Table 13 gives the solvent, the conversion of the 3′,5′-bis-(trifluoromethyl)acetophenone, and the e.e of the (S)-3′,5′-bis(trifluoromethyl)-1-phenethanol product.
  • Examples 84 and 86 may be compared to the report in J. Am. Chem. Soc., vol. 117 (1995), 2675-2676 that toluene and dichloromethane are not useable in the disclosed process using KOH or (CH 3 ) 2 CHOK as the base.
  • the reaction mixture was analyzed by chiral HPLC.
  • Table 14 gives the base, the conversion of the ketone and the chemical yield of the (1S,2S)-diastereomer of 1-(4-benzoxy-phenyl)2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol.
  • Conv. yield Example base (%) (%) Comp. 50 guanidine 1.4 1.4 Comp. 51 4,7,13,16,21-pentaoxa-1,10-diazabicyclo 0.1 0.1 [8.8.5]tricosane Comp.
  • Examples 91-99 show that organic bases selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes provide high activity and diastereoselectivity in the process of the invention. Comparative Examples 50 and 51 show that certain other organic bases provide insignificant catalytic activity. By comparison to Comparative Example 50 using guanidine, Examples 98 and 99 show that the N-alkyl substitution in the alkylguanidine bases is required for catalyst system activity. Comparative Example 50 shows that a trialkylamine base does not provide any significant catalyst activity.

Abstract

The present invention provides a catalyst system and a process for the preparation of a nonracemic chiral alcohol by hydrogenation of a ketone using the catalyst system, wherein the catalyst system comprises ruthenium, a nonracemic chiral diphosphine ligand, a bidentate amine ligand, and an organic base selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes.

Description

    CROSS-REFERENCES TO RELATED APPLICATIONS
  • This application is a continuation-in-part of U.S. patent application Ser. No. 10/057,826, filed Jan. 24, 2002, incorporated herein by reference in its entirety. This application is also related to co-filed U.S. patent applications Ser. No. ______ (Attorney Docket No. 021153-001600US, “Process for Preparing Nonracemic Chiral Alcohols”), and Ser. No. ______ (Attorney Docket No. 021153-001700US, “Process for Preparing Nonracemic Chiral Alcohols”), incorporated herein by reference in their entireties.[0001]
    • STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
  • NOT APPLICABLE [0002]
    • REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK
  • NOT APPLICABLE [0003]
    • FIELD OF THE INVENTION
  • This invention relates generally to preparing nonracemic chiral alcohols. It more particularly relates to preparing nonracemic chiral alcohols by hydrogenation of ketones using transition metal catalysts comprising nonracemic chiral ligands. Nonracemic chiral alcohols are useful as pharmaceuticals and other bioactive products and as intermediates for the preparation of such products. [0004]
    • BACKGROUND OF THE INVENTION
  • Ketones can be converted to racemic chiral alcohols by hydrogenation using certain catalyst systems of ruthenium, a phosphine ligand, a 1,2-diamine, and an alkaline base. Aromatic and heteroaromatic ketones can be hydrogenated to nonracemic chiral alcohols by using certain catalyst systems of ruthenium, an appropriate enantiomeric diphosphine ligand, an enantiomeric 1,2-diamine, and a base. [0005] Angew. Chem. Int. Ed., vol. 40, (2001), 40-73 (a review with 211 references); U.S. Pat. No. 5,763,688; J. Am. Chem. Soc., vol. 117 (1995), 2675-2676; J. Org. Chem., vol. 64 (1999), 2127-2129. U.S. Pat. No. 5,763,688 states, “In the bases expressed by the general formula M2Y, for example, M2 is an alkali metal or an alkaline earth metal, and Y is a hydroxy group, alkoxy group, mercapto group or naphthyl group, and more specifically, applicable ones include KOH, KOCH3, KOCH(CH3)2, KC10H8, KOC(CH3)3, LiOH, LiOCH3, LiOCH(CH3)2, NaOH, NaOCH3, NaOCH(CH3)2, as well as quaternary ammonium salt.” It further states that, for solvent, “Since the product is alcohol, alcohol type solvents are preferable. More preferably, 2-propanol may be preferably used.” The Examples of U.S. Pat. No. 5,763,688 exemplify only KOH as the base and only 2-propanol as the solvent. J. Am. Chem. Soc., vol. 117 (1995), 2675-2676, whose authors are inventors of U.S. Pat. No. 5,763,688, further discusses this process of U.S. Pat. No. 5,763,688 and states, “2-propanol is the solvent of choice. The reaction in methanol, ethanol, or tert-butylalcohol is much slower, while THF, dichoromethane, and toluene are not useable.”
  • Others have noted that ketones can be hydrogenated to nonracemic chiral alcohols using related catalyst systems formed with a racemic chiral 1,2-diamine. In their catalyst system, the active diastereomeric ruthenium catalyst is formed with the enantiomeric diphosphine ligand and the “matched” enantiomer of the racemic chiral 1,2-diamine. Interestingly, the diastereomeric ruthenium complex with the “unmatched” enantiomer of the racemic chiral 1,2-diamine, if it is formed, is relatively inactive. [0006] Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; European Patent Application 901 997; J. Am. Chem. Soc., vol. 120 (1998), 1086-1087. European Patent Application 901 997, having inventors in common with U.S. Pat. No. 5,763,688 states, “With regard to the base, an inorganic or a quaternary ammonium salt can be exemplified, preferably an alkali metal compound or an alkaline earth metal compound and a quaternary ammonium salt, more preferably an alkali metal or alkaline earth metal hydroxide or a salt thereof and a quaternary ammonium salt. Its illustrative examples include LiOH, LiOMe, LiOEt, LiOCH(CH3)2, LiOC(CH3)3, NaOH, NaOMe, NaOEt, NaOCH(CH3)2, NaOC(CH3)3, KOH, KOCH3, KOCH(CH3)2, KOC(CH3)3, KC10H8, and the like. A quaternary ammonium salt can also be used.” It further states that, for solvent, “Because the product is an alcohol, alcohol solvents most preferred, and 2-propanol is particularly preferred.” The Examples of European Patent Application 901 997 exemplify only KOH and KOC(CH3)3 as the base and only 2-propanol as main solvent. The other references cited above in this Background of the Invention section similarly use KOH or KOC(CH3)3 as the base and 2-propanol as main solvent.
  • A catalyst system of ruthenium, the atropisomeric diphosphine (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), achiral ethylenediamine, and potassium hydroxide in 2-propanol is reported to hydrogenate 1′-acetonaphthone to (R)-1-(1-naphthyl)ethanol in 57% enantiomeric excess. The corresponding catalyst system having enantiomeric (S,S)-1,2-diphenylethylenediamine instead of achiral ethylene diamine is reported to hydrogenate 1′-acetonaphthone under the same conditions to (R)-1-(1-naphthyl)ethanol in 97% enantiomeric excess. [0007] Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; J. Am. Chem. Soc., vol. 117 (1995), 2675-2676.
  • An attempt to provide a catalyst system of ruthenium, the atropisomeric diphosphine S-BINAP, enantiomeric (S,S)-1,2-diphenylethylenediamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene as the base (in the place of the alkali base used in the references discussed above) in 2-propanol gave no catalytic activity for the hydrogenation of acetophenone. The addition of selected alkali metal salts of tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate to this attempted catalyst system provided catalytic activity for the hydrogenation of acetophenone to nonracemic 1-phenethanol. The investigators conclude that alkali metal cations are required for the activity of this catalyst system. [0008] Angew. Chem. Int. Ed., vol. 40, (2001), 3581-3585.
    • BRIEF SUMMARY OF THE INVENTION
  • The present invention provides a catalyst system and a process for the preparation of a nonracemic chiral alcohol by hydrogenation of a ketone using the catalyst system, wherein the catalyst system comprises ruthenium, a nonracemic chiral diphosphine ligand, a bidentate amine ligand, and an organic base selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes, with the proviso that when the nonracemic chiral diphosphine is an atropisomeric diphosphine and the organic base is selected from alkylamidines, the catalyst system is essentially free of alkali metal salt. Preferably, the organic base is selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes, and is most preferably selected from alkylguanidines. Surprisingly, these organic bases often provide greater enantioselectivity for the hydrogenation of a ketone to a nonracemic chiral alcohol as compared to the basic salts preferred in the teachings of the background references. Additionally, these organic bases allow the inventive process to be conducted with solvents other than the alcohol solvent preferred in the background references, including solvents such as dichloromethane and toluene and solvents in which the basic salts preferred in the background references are not soluble. Even more surprisingly, by using these organic bases to conduct the process in solvents other than alcohol solvents, increased enantioselectivities are often provided compared to those obtained when the process is conducted using alcohol solvents. Still more surprisingly, in certain embodiments, the chirality of the dominant enantiomer of the nonracemic alcohol product can be opposite that obtained with the otherwise identical catalyst system comprising a basic salt. [0009]
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • Not applicable [0010]
    • DETAILED DESCRIPTION OF THE INVENTION
  • Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: [0011]
  • As used herein, the term “treating”, “contacting” or “reacting” refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. “Side-reaction” is a reaction that does not ultimately lead to a production of a desired product. [0012]
  • “Alkyl” means a linear saturated monovalent hydrocarbon radical or a branched saturated monovalent hydrocarbon radical or a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms indicated in the prefix. For example, (C[0013] 1-C6)alkyl is meant to include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl and the like. For each of the definitions herein (e.g., alkyl, alkenyl, alkoxy, aralkyloxy), when a prefix is not included to indicate the number of main chain carbon atoms in an alkyl portion, the radical or portion thereof will have twelve or fewer main chain carbon atoms. A divalent alkyl radical refers to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. For example, a divalent (C1-C6)alkyl is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • “Alkenyl” means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, (C[0014] 2-C6)alkenyl is meant to include, ethenyl, propenyl, and the like.
  • “Alkynyl” means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. For example, (C[0015] 2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.
  • “Alkoxy”, “aryloxy”, “aralkyloxy”, or “heteroaralkyloxy” means a radical —OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like. [0016]
  • “Aryl” means a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms which is substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and heteroalkyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted derivatives thereof. [0017]
  • “Aralkyl” refers to a radical wherein an aryl group is attached to an alkyl group, the combination being attached to the remainder of the molecule through the alkyl portion. Examples of aralkyl groups are benzyl, phenylethyl, and the like. [0018]
  • “Heteroalkyl” means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano, alkoxy, amino, mono- or di-alkylamino, thioalkoxy, and the like, with the understanding that the point of attachment of the heteroalkyl radical to the remainder of the molecule is through a carbon atom of the heteroalkyl radical. [0019]
  • “Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one to four substituents, preferably one or two substituents, selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and heteroalkyl. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzo furanyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and the substituted derivatives thereof. [0020]
  • “Hydrocarbyl” is used herein to refer to an organic radical, that can be an alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroalkyl or heteroaryl radical, or a combination thereof which is optionally substituted with one or more substituents generally selected from the groups noted above. [0021]
  • In a general sense, the present invention provides a method for the preparation of a chiral alcohol of formula II (shown without stereochemistry) from a ketone of formula I. Suitable ketones for use in the present invention are those wherein R[0022] 1 and R2 are different, and optionally, one or both of R1 and R2 have a chiral center.
    Figure US20030181319A1-20030925-C00001
  • The symbols R[0023] 1 and R2 in formulas I and II each independently represent a hydrocarbyl group that can be an acyclic, cyclic, or heterocyclic hydrocarbyl group, or a combination thereof. Additionally, each of the hydrocarbyl groups R1 and R2 can be saturated or unsaturated, including components defined above as alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, as well as combinations thereof. Still further, each of R1 and R2 can be optionally substituted with one or more substituents that do not interfere with the reaction chemistry of the invention. In some embodiments, R1 and R2 are linked together in a cyclic structure. In a preferred combination of R1 and R2, R1 is an optionally substituted alkyl group and R2 is an optionally substituted aryl or heteroaryl group.
  • R[0024] 1 and R2 can also be, independently, chiral or achiral. As used herein, however, the adjective “chiral” in the term “chiral alcohol”, specifically refers to the chirality at the carbon atom bearing each of R1 and R2, which chirality is produced by the hydrogenation of the keto group at that center. The term is not meant to refer to the chirality that may be present in either R1 or R2.
  • The ruthenium, nonracemic chiral diphosphine ligand, and bidentate amine ligand components of the catalyst system can be provided to the reaction mixture individually to form the reactive catalyst complex in situ or they can be provided as preformed complexes. Preformed complexes of ruthenium with the diphosphine ligand, or the bidentate amine ligand, or both can be used. [0025]
  • Examples of preformed complexes of the ruthenium with the diphosphine ligand include complexes represented by the formula RuX[0026] 2LYn, wherein X represents a halogen atom or pseudo-halide group, preferably chloride or bromide, L represents the diphosphine ligand, Y represents a weakly coordinating neutral ligand, and n is an integer from 1 to 5. Examples of Y include trialkylamines, for examples triethylamine and tetramethylethylenediamine, and tertiary amides, for example dimethylformamide. Such complexes can be prepared by the reaction of the diphosphine ligand with a complex of the formula [RuX2(arene)]2, wherein examples of the arene include benzene, p-cymene, 1,3,5-trimethylbenzene, and hexamethylbenzene, in a solvent comprising Y.
  • Examples of preformed complexes of the ruthenium with both the diphosphine ligand and bidentate amine ligand include complexes represented by the formula RuX[0027] 2LA, wherein A represents the bidentate amine ligand. Such complexes can be prepared by the reaction of the bidentate amine with a complex of the formula RuX2LYn as described above.
  • The ruthenium component of the catalyst system, whether provided to the reaction mixture separately from the other components or used to form a preformed complex with the diphosphine ligand, the bidentate amine ligand, or both, can be provided by any ruthenium salt or complex capable of forming the active catalyst system in combination with the diphosphine ligand, the bidentate amine ligand, and the base. This can be determined by routine functional testing for ketone hydrogenation activity and enantioselectivity in the manner shown in the Examples. A preferred source of the ruthenium component is a complex of the formula [RuX[0028] 2(arene)]2 as defined above.
  • Suitable nonracemic chiral diphosphine ligands for the present invention are bis-tertiary phosphines of the general formula R[0029] 3R4PRaPR5R6, wherein R3, R4, R5, and R6 are hydrocarbyl radicals, which may be the same or different, and Ra is a hydrocarbyl diradical, any of which may be optionally linked in one or more cyclic structures. Suitable hydrocarbyl groups R3, R4, R5, R6, and diradicals thereof for Ra, include acyclic, cyclic, or heterocyclic hydrocarbyl groups, or combinations thereof. Additionally, each of the hydrocarbyl groups R3, R4 R5, R6 and Ra can be saturated or unsaturated, including components defined above as alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, as well as combinations thereof. Still further, each of R3, R4, R5, R6 and Ra can be optionally substituted with one or more substituents that do not undesirably affect the reaction chemistry of the invention.
  • The chirality of the diphosphine ligand may reside in one or more of the hydrocarbyl groups R[0030] 3, R4, R5, R6, in the bridging hydrocarbyl radical Ra, at phosphorus when two hydrocarbyl radicals on phosphorus are different (R3≠R4, or R5≠R6, or both), or combinations thereof. Chirality in the bridging hydrocarbyl diradical Ra may be due to the presence of one or more stereogenic carbon atoms, or due to atropoisomerism.
  • Atropisomers do not comprise a stereogenic atom, but are chiral because of greatly hindered or prevented rotation about a single bond. Atropisomeric biaryl diphosphine ligands comprise a 1,1′-biaryl bond in the bridge between the phosphorus atoms, about which rotation is sterically prohibited and which are thereby chiral although lacking a stereogenic carbon or phosphorus atom. Examples of atropisomeric biaryl diphosphine ligands include, among others, the enantiomers of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), BINAP derivatives having one or more alkyl or aryl groups connected to one or both naphthyl rings, BINAP derivatives having one to five alkyl substituents on the phenyl rings bonded to phosphorus, for example 2,2′-bis-(di-p-tolylphosphino)-1,1′-binaphthyl (TolBINAP), 5,6,7,8,5′,6′,7′,8′-octahydro-BINAP (H[0031] 8BINAP), 2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl (BICHEP), 2,2′-bis(diphenylphosphino)-6,6′-dimethyl-1,1′-biphenyl (BIPHEMP), 2,2′-bis(diphenylphosphino)-6,6′-di-methoxy-1,1′-biphenyl (MeOBIPHEP), [6,6′-(alkylene-α,ω-dioxy)biphenyl-2,2′-diyl]bis-(diphenylphosphine) (Cn-TunaPhos; n=1, 2, 3, . . . for alkylene=methylene, 1,2-ethylene, 1,3-propylene, . . . , respectively), 5,5′-bis(diphenylphosphino)-4,4′-bi(benzodioxolyl) (SEGPHOS), and 2,2′-bis(diphenylphosphino)-3,3′-bi(benzo[b]thiophene) (BITIANP).
  • Preferably, the nonracemic chiral diphosphine ligand is selected from nonracemic nonatropisomeric chiral diphosphine ligands, and more preferably, atropisomeric chiral substructures are not present in the nonracemic nonatropisomeric chiral diphosphine ligand. Most preferably, the nonracemic nonatropisomeric chiral diphosphine ligand comprises one or more stereogenic carbon atoms. [0032]
  • Illustrative examples of nonracemic nonatropisomeric chiral diphosphine ligands are the enantiomers of 1,2-bis-(diphenylphosphino)propane (PROPHOS), 2,3-bis(diphenylphosphino)butane (CHIRAPHOS), 2,4-bis(diphenylphosphino)pentane (SKEWPHOS), 1-cyclohexyl-1,2-bis(diphenylphosphino)ethane (CYCPHOS), 1-substituted 3,4-bis(diphenyl-phosphino)pyrolidine (DEGPHOS), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP), 3,4-O-isopropylidene-3,4-dihydroxy-2,5-bis-(diphenylphosphino)hexane (DIOP*), 1-[1,2-bis-(diphenylphosphino)ferrocenyl]ethyl-dimethylamine (BPPFA), 1,2-bis[(o-methoxyphenyl)phenylphosphino]ethane (DIPAMP), 2,5-disubstituted 1,2-bis(phospholano)benzenes (DuPHOS), for example 1,2-bis(2,5-dimethylphospholano)benzene (Me-DuPHOS), substituted 1,2-bis(phospholano)ethylenes (BPE), for example 1,2-bis(2,5-dimethylphospholano)ethylene (Me-BPE), 1,2-bis-[3,4-benzoxy-2,5-dimethylphospholanyl]benzene (RoPhos), 1,2-bis-[3,4-O-isopropyl-idene-3,4-dihydroxy-2,5-dimethylphospholanyl]benzene (Me-KetalPhos), 1,1′-bis[3,4-O-iso-propylidene-3,4-dihydroxy-2,5-dimethyl-phospholanyl]ferrocene (Me-f-KetalPhos), 5,6-bis(diphenylphosphino)-2-norbornene (NORPHOS), N,N′-bis-(diphenylphosphino)-N,N′-bis(1-phenylethyl)ethylenediamine (PNNP), 2,2′-bis(diphenylphosphino)-1,1′-dicyclo-pentane (BICP), 1,2-bis-{2,5-disubstituted-7-phosphabicyclo[2.2.1]hept-7-yl}-benzenes (PennPhos), for example 1,2-bis-{2,5-dimethyl-7-phosphabicyclo[2.2.1]hept-7-yl}-benzene (Me-PennPhos) and 1,2-bis-{2,5-diisopropyl-7-phosphabicyclo[2.2.1]hept-7-yl}-benzene (iPr-PennPhos), and 1,2-bis{1-phosphatricyclo[3.3.0.0]undecan-1-yl}benzene (C5-Tricyclophos), and equivalents thereto that are recognized by those skilled in the art. [0033]
  • Certain preferred nonracemic nonatropisomeric chiral diphosphine ligands comprise at least one, preferably at least two, and most preferably four, stereogenic carbon atoms in the hydrocarbyl diradical that connects the two phosphorus atoms (R[0034] a in the formula above.). Illustrative examples of nonracemic nonatropisomeric chiral diphosphine ligands wherein the bridging hydrocarbyl diradical comprises a stereogenic carbon atom are the enantiomers of PROPHOS, CHIRAPHOS, SKEWPHOS, DIOP, DIOP*, and BICP ligands.
  • Particularly preferred nonracemic nonatropisomeric chiral diphosphine ligands, wherein the bridging hydrocarbyl diradical comprises a stereogenic carbon atom, comprise a 2,2′-bis-(diorgano-phosphino)-1,1′-bis(cyclic) structure, wherein each cycle of the bridging bis(cyclic) diradical comprises three to eight carbon atoms, and wherein the 1, 1′, 2, and 2′ carbon atoms in the bis(cyclic) diradical are saturated. These ligands are described in detail in U.S. Pat. No. 6,037,500, incorporated herein by reference. The preferred nonracemic diphosphine ligands comprising a 2,2′-bis-(diorgano-phosphino)-1,1′-bis(cyclic) structure are of the formulas III and IV and their enantiomers, in which m=1 to 6 and wherein each cycle of the bis(cyclic) structure may be unsubstituted as shown in formulas III and IV or further substituted with one or more substituents chosen from hydrocarbyl substituents and heteroatom containing substituents that do not interfere with the ketone hydrogenation chemistry, and wherein R′ is a substituted or unsubstituted hydrocarbyl group selected from alkyl groups and aryl groups. [0035]
    Figure US20030181319A1-20030925-C00002
  • Particularly preferred nonracemic nonatropisomeric diphosphine ligands comprising a 2,2′-bis-(diorgano-phosphino)-1,1′-bis(cyclic) structure are of the formula V and its enantiomer, wherein Ar is an aryl group. [0036]
    Figure US20030181319A1-20030925-C00003
  • Preferred aryl groups in formula V are phenyl (the BICP ligand) and mono-, di-, and trialkyl-phenyl, particularly wherein alkyl is methyl, for example 2,2′-bis[di(3,5-dimethylphenyl)phosphino]-1,1′-dicyclopentane (3,5-Me[0037] 8BICP).
  • Suitable bidentate amine ligands comprise a primary amino group and another heteroatom-containing group that is capable of ligating to the ruthenium. Such groups are known in the art, and include groups having a heteroatom selected from oxygen, nitrogen, sulfur, and phosphorus. Preferred bidentate amine ligands include diamines and amino-thioethers. [0038]
  • The bidentate amine ligand may be achiral, racemic chiral, or nonracemic chiral. In certain inventive embodiments of the invention, the bidentate amine ligand is an achiral diamine. [0039]
  • Suitable diamine ligands for the present invention are of the general formula H[0040] 2NRbNH2, wherein Rb is an hydrocarbyl diradical. Preferably, the hydrocarbyl diradical comprises at least two to fifty carbon atoms, more preferably at least three to fifty carbon atoms, still more preferably at least four to fifty carbon atoms, and most preferably at least six to fifty carbon atoms, Suitable hydrocarbyl diradicals for Rb include acyclic, cyclic, and heterocyclic hydrocarbyl diradicals, include saturated and unsaturated hydrocarbyl diradicals, include alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl diradicals, and can be optionally substituted with one or more substituents that do not interfere with the reaction chemistry of the invention.
  • Suitable chiral diamine ligands include the enantiomers and mixtures thereof of chiral derivatives of ethylenediamine, propylenediamines, butanediamines, cycloalkanediamines, and phenylenediamines. Illustrative examples include chiral stereoisomers of 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-isobutyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-methyl-2,2-dinaphthylethylenediamine, 1-isobutyl-2,2-dinaphthylethylenediamine, 1-isopropyl-2,2-dinaphthylethylenediamine, and equivalents thereto that are recognized by those skilled in the art, any of which may be substituted with one or more substituents that do not interfere with the reaction chemistry of the invention, and provided such substitution preserves the achirality of the diamine. Preferred chiral diamines are chiral stereoisomers of 1,2-diphenylethylenediamine and 1,2-cyclohexanediamine. [0041]
  • Suitable achiral diamines may be achiral by comprising neither atropisomerism nor stereogenic carbon atoms or it may be achiral comprising a meso compound. That is, the achiral hydrocarbyl diradical may contain one or more pairs of stereogenic carbon atoms that are related in at least one of its conformations by a plane of symmetry. For example, while (S,S)- and (R,R)-1,2-diphenylethylenediamine are chiral enantiomers, (S,R)-1,2-diphenylethylenediamine is an achiral meso compound. [0042]
  • Illustrative examples of achiral diamines include ethylenediamine, 1,3-propylenediamine, 2-methyl-1,2-propylene-diamine, meso-2,3-butanediamine, meso-1,2-cyclopentanediamine, meso-1,2-cyclo-hexane-diamine, meso-1,2-cyclo-heptane-diamine, meso-1,2-diphenylethylenediamine, meso-2,3-dimethyl-butane-1,2-diamine, 1,2-phenylenediamine, 2-aminobenzyl-amine, 1,8-diaminonaphthalene, and equivalents thereto that are recognized by those skilled in the art, any of which may be substituted with one or more substituents that do not interfere with the reaction chemistry of the invention, and provided such substitution preserves the achirality of the diamine. [0043]
  • Preferred achiral diamines are selected from 1,2-alkylenediamine compounds, 1,2-phenylenediamine compounds and 1,8-diamino-naphthalene compounds, which may be substituted or unsubstituted. Suitable substituents include alkyl (e.g. 4,5-dimethyl-1,2-phenylene-diamine), benzo (e.g. 9,10-diaminophenanthrene), and alkoxy (e.g, 1,3-benzodioxole-5,6-diamine). [0044]
  • Suitable amino-thioether ligands for the present invention are of the general formula H[0045] 2NRcSR7, wherein R7 is a hydrocarbyl radical and Rc is a hydrocarbyl diradical and which may be optionally linked in a cyclic structure. Suitable hydrocarbyl groups R7 and diradicals thereof for Rc include acyclic, cyclic, and heterocyclic hydrocarbyl groups, include saturated and unsaturated hydrocarbyl groups, include alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, and can be optionally substituted with one or more substituents that do not undesirably the reaction chemistry of the invention. The amino-thioether ligand may be achiral, racemic chiral, or nonracemic chiral, preferably achiral.
  • Preferred amino-thioether ligands are selected from 2-(alkylthio)ethylamines, 2-(alkylthio)anilines, and equivalents thereto that are recognized by those skilled in the art. Most preferred are 2-(alkylthio)anilines. Preferably the alkyl group therein is selected from C[0046] 1 to C4 alkyl groups. Most preferred are methyl and ethyl. Illustrative examples include 2-(methylthio)aniline and 2-(ethylthio)aniline.
  • Turning next to the organic bases suitable for use in the present methods, those bases selected from alkylamidines, alkylguanidines, aminophosphazenes and proazaphosphatranes have been found particularly attractive as providing, in some instances, greater enantioselectivity and utility with solvent systems other than the alcohols used in related processes. [0047]
  • Suitable alkylguanidines have the general formula VI, wherein R[0048] 8, R9, R10, R11, and R12 are independently selected from hydrogen and alkyl groups, with the proviso that at least one of R8, R9, R10, R11, and R12 is an alkyl group.
    Figure US20030181319A1-20030925-C00004
  • Preferably the alkylguanidine comprises two alkyl groups, more preferably three alkyl groups, even more preferably four alkyl groups, and most preferably five alkyl groups. Any of the alkyl groups R[0049] 8, R9, R10, R11, and R12 may be optionally linked in one or more cyclic structures. An illustrative example of a suitable tetraalkylguanidine base is 1,5,7-triazabicyclo[4.4.0]dec-5-ene and tetramethylguanidine. Illustrative examples of suitable pentalkylguanidines are 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and tetramethyl-2-t-butylguanidine.
  • Suitable aminophosphazenes have the general formula VII, wherein R[0050] 13 is selected from hydrogen and alkyl groups, R14 is an alkyl group and the two R14 groups on each —NR14 2 group may optionally be linked in a cyclic structure, and x is an integer from zero to three, preferably 3.
  • R13N═P(—NR 14 2)x[—N═P(NR14 2)3](3-x)  VII
  • Illustrative examples of suitable aminophosphazenes include N,N,N′,N′,N″,N″-hexa-methyl-phosphorimidic triamide (R[0051] 13=H, R14=methyl, x=3), N′″-t-butyl-N,N,N′,N′,N″,N″-hexamethyl-phosphorimidic triamide (R13=t-butyl, R14=methyl, x=3), (t-butyl-imino)-tris(pyrrolidino)-phosphorane (R13=t-butyl, —NR14 2=pyrrolidino, x=3), N′″-[N-ethyl-P,P-bis-(dimethyl-amino)phosphinimyl]-N,N,N′,N′,N″,N″-hexamethyl-phosphorimidic triamide (R13=ethyl, R14=methyl, x=2), and t-butyl-tris[tris(dimethyl-amino)-phosphoranylidene]phosphorimidic triamide (R13=t-butyl, R14=methyl, x=0).
  • Suitable proazaphosphatranes are described in U.S. Pat. No. 5,051,533 and have the general formula VIII, wherein R[0052] 15, R16, and R17 are independently selected from hydrogen and alkyl groups.
    Figure US20030181319A1-20030925-C00005
  • Preferably R[0053] 15, R16, and R17 are selected from C1 to C8 alkyl groups, most preferably methyl. An illustrative preferred proazaphosphatrane is 2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (R15=R16=R17=methyl).
  • Suitable alkylamidines have the general formula IX wherein R[0054] 18, R19, and R20 are independently selected from alkyl groups and R21 is selected from hydrogen and alkyl groups. Preferably, R21 is selected from alkyl groups.
    Figure US20030181319A1-20030925-C00006
  • Any of the alkyl groups R[0055] 18, R19, R20, and R21 may be optionally linked in one or more cyclic structures. An illustrative example of a suitable alkylamidine base is 1,5-diazabicyclo[4.3.0]non-5-ene.
  • Preferably, the organic base is selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes. More preferably, the organic base is an alkylguanidine, most preferably selected from tetraalkylguanidines and pentaalkylguanidines. [0056]
  • Preferably, the catalyst system is essentially free of alkali metal salt. The invention includes the proviso that for embodiments wherein an alkylamidine base is used in combination with a nonracemic atropisomeric diphosphine ligand, the catalyst system is essentially free of alkali metal salt. The phrase “essentially free of alkali metal salt” means that the concentration of the alkali metal salt is not sufficient to significantly increase the activity of the catalyst system. This can be readily determined experimentally. Preferably the catalyst system is free of alkali metal salt. [0057]
  • The components of the catalyst system are each present in a catalytic amount, meaning less than stoichiometric relative to the ketone reactants. The minimum amount of the catalyst system relative to the ketone reactant may depend on the activity of the specific catalyst system composition, the specific ketone to be reacted, the hydrogen pressure, the gas-liquid mixing characteristics of the reaction vessel, the reaction temperature, the concentrations of the reactants and catalyst system components in the solution, and the maximum time allowed for completion of the reaction, and can be readily determined by routine experimentation. In typical embodiments, the mole ratio of the ruthenium component of the catalyst system to the ketone reactant is in the range from about 1/100 to about 1/100,000, preferably in the range from about 1/500 to about 1/10,000. [0058]
  • The mole ratio of the nonracemic diphosphine ligand to the ruthenium in the catalyst system is typically in the range from about 0.5 to about 2.0, preferably from about 0.8 to about 1.2, and most preferably is about 1. The mole ratio of the bidentate amine ligand to the ruthenium in the catalyst system is typically in the range from about 1 to about 50, and preferably from about 5 to about 20. The mole ratio of the base to the ruthenium in the catalyst system is typically in the range from about 1 to about 100, and preferably from about 5 to about 50. [0059]
  • The hydrogenation reaction may be conducted without solvent when the ketone itself is a liquid at the reaction temperature and capable of dissolving the catalyst system. More typically, the hydrogenation reaction is conducted in a solvent system that is capable of dissolving the catalyst system and is reaction-inert. The term solvent system is used to indicate that a single solvent or a mixture of two or more solvents can be used. The term reaction-inert it used to mean that the solvent system does not react unfavorably with the reactants, products, or the catalyst system. [0060]
  • The term reaction-inert does not mean that the solvent does not participate productively in the desired reaction. For example, while not wishing to be bound by theory, it is believed that alcohol solvents level organic bases selected from the preferred alkylguanidines, aminophosphazenes, or proazaphosphatranes. That is, these bases deprotonate the alcohol to form an alkoxide base in the reaction solution. However, the mere formation of an alkoxide base in situ cannot explain the often greater enantioselectivity in the ketone hydrogenation reaction that is provided by the organic bases of the present invention compared to the basic alkoxide salts preferred in the teachings of the background references. Also, the organic bases of the present invention allow the inventive process to be conducted using solvents other than alcohol solvents, including solvents in which the basic alkoxide salts preferred in the background references are not soluble. [0061]
  • The solvent system need not bring about complete solution of the ketone reactant or the chiral alcohol product. The ketone reactant may be incompletely dissolved at the beginning of the reaction or the chiral alcohol product may be incompletely dissolved at the end of the reaction, or both. [0062]
  • Representative solvents are aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic hydrocarbons such as pentane, hexane, heptane; halogen-containing hydrocarbon solvents such as dichloromethane and chlorobenzene; alkyl ethers, polyethers, and cyclic ethers such as methyl-t-butyl-ether, dibutylether, diethoxymethane, 1,2-dimethoxyethane, and tetrahydrofuran; ester solvents such as ethyl acetate, organic solvents containing heteroatoms such as acetonitrile, DMF and DMSO; and alcohol solvents such as methanol, ethanol, 2-propanol, t-butanol, benzyl alcohol and the like; and mixtures thereof. [0063]
  • In typical embodiments, the reaction is suitably conducted at a temperature from about −30° C. to about 100° C., more typically from about 0° C. to about 50° C., and most typically from about 20° C. to about 40° C. [0064]
  • The terms “hydrogenating” and “hydrogenation” refer to reacting the ketone with a source of hydrogen atoms under appropriate conditions so that two hydrogen atoms are added to the carbonyl group of the ketone to produce the hydroxyl group of the chiral alcohol. The source of hydrogen atoms may be molecular hydrogen (H[0065] 2), a hydrogen donating organic or inorganic compound, or mixtures thereof. Preferably the source of hydrogen atoms includes molecular hydrogen. Hydrogen donating compounds are compounds capable of donating hydrogen atoms via the action of the catalyst system. Compounds capable of donating hydrogen atoms for transfer hydrogenation reactions using ruthenium catalysts are known in the art, and include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol, formic acid and salts thereof, unsaturated hydrocarbons and heterocyclic compounds having in part a saturated C—C bond such as tetralin, cyclohexane, and cyclohexadiene, hydroquinone, phosphorous acid, and the like. Among hydrogen donating compounds, alcohols are preferred and isopropanol is most preferred.
  • The hydrogen pressure in the reaction is typically at least about 1 atm, and typically in the range from about 1 atm to about 100 atm. More typically, the hydrogen pressure is in the range from about 5 atm to about 20 atm. [0066]
  • The reaction rate and time to completion are dependent on the identities of the ketone reactant and the catalyst components, their absolute concentrations and relative ratios, the temperature, the hydrogen pressure, the gas-liquid mixing provided, and the other reaction conditions. Typically, the reaction is allowed to continue for sufficient time to complete the conversion of the ketone reactant. For typical ketone reactants, using the preferred catalyst systems described and the preferred reaction conditions described herein, the reaction is typically completed in a period of time in the range from about a few minutes to about 24 hours, more typically in the range from about 1 hour to about 10 hours. [0067]
  • The nonracemic chiral alcohol product has, by definition, a stereomeric excess greater than zero. In preferred embodiments, the nonracemic chiral alcohol is formed in at least about 50% stereomeric excess, more preferably at least about 60%, still more preferably at least about 70%, still again more preferably at least about 80%, and most preferably at least about 90%. These stereomeric excesses refer to the chirality at the hydroxyl-bearing carbon of the alcohol group generated by the hydrogenation of the ketone group. When the ketone is achiral, the chiral alcohol can be one of two enantiomers, and the enantiomer excess (e.e.) is the measure of stereomeric excess. When the ketone reactant is already chiral, the chiral alcohol product is a diastereomer, and diastereomeric excess (d.e.) is the formally appropriate measure of stereomeric excess. Accordingly, the term “nonracemic diastereomer” when used to refer to a nonracemic chiral alcohol product, refers to a product with an excess of one diastereomer vs. its diastereomer with the opposite chirality at the hydroxyl-bearing carbon. Preferably, the nonracemic diastereomer is produced in at least about 50% d.e., more preferably at least about 60% d.e., still more preferably at least about 70% d.e., still again more preferably at least about 80% d.e., and most preferably at least about 90% d.e.[0068]
    • EXAMPLES OF THE INVENTION
  • Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following specific examples are intended merely to illustrate the invention and not to limit the scope of the disclosure or the scope of the claims in any way whatsoever. [0069]
    • Preparation 1
  • Preparation of [RuCl[0070] 2(R,R,R,R-BICP)(DMF)n]: To 7.5 mg (30 microgram-atom Ru) [RuCl2(benzene)]2 and 16.2 mg (32 micromole) (R,R,R)-2,2′-bis-(diphenylphosphino)-1,1′-dicyclopentane (R,R,R,R-BICP) in a 200 mL Schlenk flask under nitrogen was added 10 mL anhydrous, deaerated dimethylformamide (DMF). The resulting orange solution was heated at 130° C. for 30 minutes, then evaporated to dryness at 130° C. under vacuum (10 mmHg). The resulting orange-red solid residue, comprising [RuCl2(R,R,R,R-BICP)(DMF)n], was further dried at 80° C. under vacuum for at least an additional hour. A stock solution of 250 micromolar [RuCl2((R,R,R,R-BICP)(DMF)n] in isopropanol was prepared by dissolving the solid residue in 120 mL anhydrous, deaerated isopropanol and stored under nitrogen.
  • This general procedure was used for the preparation of the other [RuCl[0071] 2(diphosphine)(DMF)n] complexes and the solutions thereof used in the following Examples.
    • Example 1
  • This Example illustrates the process of the invention wherein acetophenone is hydrogenated to nonracemic 1-phenethanol using a ruthenium catalyst system comprising a nonracemic diphosphine ligand, a bidentate amine ligand and a pentaalkylguanidine base. [0072]
  • In a dry nitrogen-filled glovebox, a 20-ml glass reaction vial was charged with 5 mL 250 micromolar (1.25 micromole) [RuCl[0073] 2((R,R,R,R-BICP)(DMF)n] in isopropanol, 5 mL isopropanol, and 125 microliter 0.1M (12.5 micromole) ethylenediamine in isopropanol. After stirring for several minutes, 73 microliter (625 micromole) acetophenone was added, followed by 0.50 mL 0.1 M (50 micromoles) tetramethyl-2-t-butylguanidine in isopropanol. The glass reaction vial containing the resulting mixture was sealed in an autoclave, which was then removed from the glovebox. The gas phase in the autoclave was replaced by hydrogen at 18 bar and the reaction mixture was stirred at room temperature for 6 hours under 17-18 bar hydrogen. After releasing the hydrogen pressure, 1 ml of the resulting reaction solution was eluted through a short column of silica gel with 9 mL methanol. Chiral gas chromatographic analysis of the eluate showed 100% conversion of the acetophenone to give S-1-phenethanol with 77% e.e.
    • Comparative Example 1
  • This Comparative Example shows the result substituting an alkoxide salt for the alkylguanidine base exemplified in Examples 1. [0074]
  • The procedure was the identical to Example 1 with the exemption that 0.50 mL 0.1 M (50 micromoles) sodium isopropoxide was used instead of the tetramethyl-2-t-butylguanidine solution. The analysis showed 100% conversion of the acetophenone to give S-1-phenethanol with 51% e.e. [0075]
  • By comparison, Example 1 shows that the enantioselectivity for hydrogenation of acetophenone is substantially greater with the otherwise identical catalyst comprising an alkylguanidine base. [0076]
    • Examples 2-7 and Comparative Examples 2-7
  • These Examples illustrate the process of the invention wherein acetophenone is hydrogenated to nonracemic 1-phenethanol using catalysts systems comprising various diamine ligands, including achiral diamines and enantiomers of chiral diamines, in combination with a pentaalkylguanidine base. The Comparative Examples show the corresponding results obtained by substituting an alkoxide salt for the alkylguanidine base. [0077]
  • The procedure was identical to Example 1 with the exemptions that an equimolar amount of the diamine ligand listed in Table 1 was substituted for the ethylene-diamine, the reaction mixture was stirred under hydrogen for the time shown in Table 1, and for the Comparative Examples, an equimolar amount of sodium isopropoxide was substituted for the tetramethyl-2-t-butylguanidine. In each example, the analysis showed the conversion of the acetophenone was 100%. Table 1 gives the diamine ligand, the base, the reaction time, and the enantiomeric excess of the S-1-phenethanol product. [0078]
    TABLE 1
    Time e.e.
    Example. diamine base (hrs) (%)
    1 ethylenediamine tetramethyl-2-t-butylguanidine 6 77
    Comp. 1 ethylenediamine sodium isopropoxide 6 51
    2 1,3-propylenediamine tetramethyl-2-t-butylguanidine 4 78
    Comp. 2 1,3-propylenediamine sodium isopropoxide 6 77
    3 4,5-dimethyl-1,2-phenylenediamine tetramethyl-2-t-butylguanidine 10 77
    Comp. 3 4,5-dimethyl-1,2-phenylenediamine sodium isopropoxide 6 71
    4 1,8-naphthalenediamine tetramethyl-2-t-butylguanidine 4 86
    Comp. 4 1,8-naphthalenediamine sodium isopropoxide 8 86
    5 R,R-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 6 68
    Comp. 5 R,R-1,2-cyclohexanediamine sodium isopropoxide 6 62
    6 S,S-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 6 14
    Comp. 6 S,S-1,2-cyclohexanediamine sodium isopropoxide 6 3
    7 meso-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 12 71
    Comp. 7 meso-1,2-cyclohexanediamine sodium isopropoxide 6 67
  • The results in Table 1 show that the enantioselectivity for hydrogenation of acetophenone is at least as good as and in many cases better for the catalyst system comprising the pentaalkylguanidine base compared to the otherwise identical catalyst system comprising an the alkoxide salt for the base. [0079]
    • Examples 8-16 and Comparative Examples 8-16
  • These Examples illustrate the process of the invention wherein 2-acetylthiophene to nonracemic 1-(2-thienyl)ethanol using catalysts systems comprising various diamine ligands, including achiral diamines and enantiomers of chiral diamines, in combination with a pentaalkylguanidine base. The Comparative Examples show the corresponding results obtained by substituting an alkoxide salt for the alkylguanidine base. [0080]
  • The procedure was identical to Example 1, with the exceptions that 68 microliter (625 micromole) 2-acetylthiophene was reacted instead of the acetophenone, an equimolar amount of the diamine ligand listed in Table 2 was substituted for the ethylenediamine, the reaction mixture was stirred under hydrogen for the time shown in Table 2, and for the Comparative Examples, an equimolar amount of sodium isopropoxide was substituted for the tetramethyl-2-t-butylguanidine. In each example, the analysis showed the conversion of the acetophenone was 100%. Table 2 gives the diamine ligand, the base, the reaction time, and the enantiomeric excess of the 1-(2-thienyl)ethanol product. [0081]
    TABLE 2
    Time e.e.
    Example diamine base (hrs) (%)
     8 ethylenediamine tetramethyl-2-t-butylguanidine 4 86
    Comp. 8 ethylenediamine sodium isopropoxide 4 56
     9 1,3-propylenediamine tetramethyl-2-t-butylguanidine 4 85
    Comp. 9 1,3-propylenediamine sodium isopropoxide 4 82
    10 4,5-dimethyl-1,2-phenylenediamine tetramethyl-2-t-butylguanidine 4 84
    Comp. 10 4,5-dimethyl-1,2-phenylenediamine sodium isopropoxide 4 84
    11 1,8-naphthalenediamine tetramethyl-2-t-butylguanidine 4 86
    Comp. 11 1,8-naphthalenediamine sodium isopropoxide 4 85
    12 R,R-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 4 87
    Comp. 12 R,R-1,2-cyclohexanediamine sodium isopropoxide 4 72
    13 S,S-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 6 62
    Comp. 13 S,S-1,2-cyclohexanediamine sodium isopropoxide 6 16
    14 meso-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 4 90
    Comp. 14 meso-1,2-cyclohexanediamine sodium isopropoxide 4 81
    15 R-1,2-propylenediamine tetramethyl-2-t-butylguanidine 6 89
    Comp. 15 R-1,2-propylenediamine sodium isopropoxide 6 77
    16 2-aminobenzylamine tetramethyl-2-t-butylguanidine 6 57
    Comp. 16 2-aminobenzylamine sodium isopropoxide 6 54
  • The results in Table 2 show that the enantioselectivity for hydrogenation of 2-acetylthiophene is at least comparable and in many cases significantly better for the catalyst system comprising the pentaalkylguanidine base compared to the otherwise identical catalyst system comprising an the alkoxide salt for the base. [0082]
    • Example 17
  • This Example illustrates the process of the invention wherein acetophenone is hydrogenated to nonracemic 1-phenethanol using a ruthenium catalyst system comprising a nonracemic diphosphine ligand, a bidentate amine ligand and a tetraaalkylguanidine base. [0083]
  • The procedure was the identical to Example 1 with the exemptions that 0.50 mL 0.1 M (50 micromoles) 1,5,7-triazabicyclo[4.4.0]dec-5-ene was used instead of the tetramethyl-2-t-butylguanidine solution and the reaction time was 12 hours. The analysis showed 100% conversion of the acetophenone to give S-1-phenethanol with 83% e.e. [0084]
  • By comparison with Comparative Example 1, this Example shows that the enantioselectivity for hydrogenation of acetophenone is substantially greater with the catalyst system comprising the tetraalkylguanidine base compared to the otherwise identical catalyst system comprising an the alkoxide salt for the base. [0085]
    • Examples 18-25
  • These Examples show the process of the invention for hydrogenation of 2-acetylthiophene to nonracemic 1-(2-thienyl)ethanol using a various bases selected from alkylamidines, alkylguanidines and aminophosphazenes with ethylenediamine as the bidentate amine ligand. [0086]
  • The procedure was identical to Examples 8 with the exceptions that an equal molar amount of the base shown in Table 3 was substituted for the tetramethyl-2-t-butyl-guanidine and the reaction mixtures were stirred under hydrogen for the time shown in Table 2. Table 2 gives the base, the reaction time, the conversion of the 2-acetylthiophene, and the enantiomeric excess of the S-1-(2-thienyl)ethanol product. [0087]
    TABLE 3
    Time Conv. e.e.
    Example base (hrs) (%) (%)
    Comp. 8 sodium isopropoxide 4 100 56
     8 tetramethyl-2-t-butylguanidine 6 100 86
    18 1,5-diazabicyclo[4.3.0]non-5-ene 12 8 89
    19 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 100 88
    20 7-methyl-1,5,7-triazabicyclo[4.4.0] 6 95 90
    dec-5-ene
    21 N,N,N′,N′,N″,N″-hexamethyl- 6 88 89
    phosphorimidic triamide
    22 N′′′-t-butyl-N,N,N′,N′,N″,N″- 12 100 81
    hexamethyl-phosphorimidic
    triamide
    23 (t-butyl-imino)-tris(pyrrolidino) 12 100 61
    phosphorane
    24 N′′′-[N-ethyl-P,P-bis(dimethylamino) 12 100 51
    phosphinimyl]-N,N,N′,N′,N″,N″-
    hexamethyl-phosphorimidic
    triamide
    25 t-butyl-tris[tris(dimethylamino) 6 100 51
    phosphoranylidene]-
    phosphorimidic triamide
  • By comparison to Comparative Example 8, these Examples demonstrate that a variety of bases selected from alkylamidines, alkylguanidines and aminophosphazenes provide enantioselectivities at least comparable, and in some instances substantially superior to that provided by a basic salt (sodium isopropoxide) as the base in the inventive catalyst systems using ethylene diamine as the achiral diamine ligand. [0088]
    • Examples 26-32
  • These Examples show the process of the invention for hydrogenation of 2-acetylthiophene to nonracemic 1-(2-thienyl)ethanol using a various bases selected from alkylguanidines and aminophosphazenes with meso-1,2-cyclohexanediamine as the bidentate amine ligand. [0089]
  • The procedure was identical to Example 14 with the exceptions that an equal molar amount of the base shown in Table 4 was substituted for the tetramethyl-2-t-butyl-guanidine and the reaction mixtures were stirred under hydrogen for the time shown in Table 4. Table 4 gives the base, the reaction time, the conversion of the 2-acetylthiophene, and the enantiomeric excess of the S-1-(2-thienyl)ethanol product. [0090]
    TABLE 4
    Time Conv. e.e.
    Example base (hrs) (%) (%)
    Comp. 14 sodium isopropoxide 4 100 81
    14 tetramethyl-2-t-butylguanidine 4 84 90
    26 1,5,7-triazabicyclo[4.4.0] 6 56 90
    dec-5-ene
    27 7-methyl-1,5,7-triazabicyclo[4.4.0] 6 34 91
    dec-5-ene
    28 N,N,N′,N′,N″,N″-hexamethyl- 6 30 90
    phosphorimidic triamide
    29 N′′′-t-butyl-N,N,N′,N′,N″,N″- 12 100 90
    hexamethyl-phosphorimidic
    triamide
    30 (t-butyl-imino)-tris(pyrrolidino) 12 100 85
    phosphorane
    31 N′′′-[N-ethyl-P,P-bis 12 100 79
    (dimethylamino)phosphinimyl]-
    N,N,N′,N′,N″,N″-hexamethyl-
    phosphorimidic triamide
    32 t-butyl-tris[tris(dimethylamino) 12 100 80
    phosphoranylidene]-
    phosphorimidic triamide
  • By comparison to Comparative Example 14, these Examples demonstrate that a variety of bases selected from alkylguanidines and aminophosphazenes provide enantioselectivities at least comparable, and in some superior, to that provided by a basic salt (sodium isopropoxide) as the base in the inventive catalyst systems. [0091]
    • Examples 33-36
  • These Examples show the process of the invention for hydrogenation of 2-acetylthiophene to nonracemic 1-(2-thienyl)ethanol using various bases selected from alkylguanidines and aminophosphazenes in combinations with enantiomers of chiral 1,2-cyclohexanediamine as the bidentate amine ligand. [0092]
  • The procedure was identical to Examples 12 and 13, for R,R- and S,S-1,2-cyclohexanediamine respectively, with the exceptions that an equal molar amount of the base shown in Table 5 was substituted for the tetramethyl-2-t-butylguanidine and the reaction mixtures were stirred under hydrogen for the time shown in Table 5. Table 5 gives the chirality of the 1,2-cyclohexane diamine, the base, the reaction time, the conversion of the 2-acetylthiophene, and the enantiomeric excess of the S-1-(2-thienyl)ethanol product. [0093]
    TABLE 5
    c-hexane Time Conv. e.e.
    Example diamine base (hrs) (%) (%)
    Comp. 12 R,R- sodium isopropoxide 4 100 72
    12 R,R- tetramethyl-2-t- 4 100 87
    butylguanidine
    33 R,R- 7-methyl-1,5,7- 12 99 92
    triazabicyclo[4.4.0]
    dec-5-ene
    34 R,R- N′′′-t-butyl- 12 100 85
    N,N,N′,N′,N″,N″,-
    hexamethyl-
    phosphorimidic triamide
    Comp. 13 S,S- sodium isopropoxide 6 100 16
    13 S,S- tetramethyl-2-t- 6 100 62
    butylguanidine
    35 S,S- 7-methyl-1,5,7- 12 92 72
    triazabicyclo[4.4.0]
    dec-5-ene
    36 S,S- N′′′-t-butyl- 12 100 56
    N,N,N′,N′,N″,N″-
    hexamethyl-
    phosphorimidic triamide
  • The results in Table 5 demonstrate, for each enantiomer of chiral 1,2-cyclohexanediamine, that bases selected from alkylguanidines and aminophosphazenes can provide substantially greater enantioselectivities to that provided by an alkoxide salt. [0094]
  • In all these Examples, the chirality of the dominant enantiomer of the nonracemic alcohol product is the same, S, showing that it is controlled by the chirality of the diphosphine enantiomer. Among these results, the chirality of the 1,2-cyclohexanediamine affects only the degree of enantioselectivity toward the S-alcohol. Comparisons between the results that use the same base consistently show that that the R,R-1,2-cyclohexanediamine is matched to the chirality of the R,R,R,R-BICP, their combination giving higher enantioselectivities than the combination of the S,S-1,2-cyclohexanediamine with R,R,R,R-BICP. [0095]
  • Surprisingly, Example 35 shows that the unmatched combination of S,S-1,2-cyclohexanediamine with R,R,R,R-BICP when used with an alkylguanidine base can provide in an enantioselectivity on par with the matched combination of R,R-1,2-cyclohexanediamine with R,R,R,R-BICP when used with the alkoxide salt base (Comparative Example 2). [0096]
    • Examples 37-45 and Comparative Examples 15 and 17
  • These Examples show the process of the invention for hydrogenation of 2-acetylthiophene to nonracemic 1-(2-thienyl)ethanol using various bases selected from alkylguanidines and aminophosphazenes in combinations with the enantiomers of 1,2-propylenediamine as the bidentate amine ligand. [0097]
  • The procedure was identical to Example 15 with the exceptions that S-1,2-propylenediamine was substituted for R-1,2-propylenediamine in some of the Examples, an equal molar amount of the base shown in Table 6 was substituted for the tetramethyl-2-t-butylguanidine, and the reaction mixtures were stirred under hydrogen for the time shown in Table 6. Table 6 gives the chirality of the 1,2-propylenediamine, the base, the reaction time, the conversion of the 2-acetylthiophene, and the enantiomeric excess of the S-1-(2-thienyl)ethanol product. [0098]
    TABLE 6
    diamine Time Conv. e.e.
    Example chirality base (hrs) (%) (%)
    Comp. 17 S- sodium isopropoxide 6 100 35
    37 S- tetramethyl-2-t-butylguanidine 6 85 70
    38 S- 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 88 75
    Comp. 15 R- sodium isopropoxide 6 100 77
    15 R- tetramethyl-2-t-butylguanidine 6 100 89
    39 R- 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 100 94
    40 R- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 100 93
    41 R- N,N,N′,N′,N″,N″-hexamethyl-phosphorimidic 6 96 94
    triamide
    42 R- N′′′-t-butyl-N,N,N′,N′,N″,N″-hexamethyl- 12 100 89
    phosphorimidic triamide
    43 R- (t-butyl-imino)-tris(pyrrolidino)phosphorane 12 100 81
    44 R- N′′′-[N-ethyl-P,P-bis(dimethylamino)- 12 100 76
    phosphinimyl]-N,N,N′,N′,N″,N″-hexamethyl-
    phosphorimidic triamide
    45 R- t-butyl-tris[tris(dimethylamino)- 6 100 76
    phosphoranylidene]phosphorimidic triamide
  • The results in Table 6 demonstrate, for each enantiomer of 1,2-propylenediamine, that bases selected from alkylguanidines and aminophosphazenes can provide substantially greater enantioselectivities to that provided by an alkoxide salt. [0099]
  • In all these Examples, the chirality of the dominant enantiomer of the nonracemic alcohol product is the same, S, showing that it is controlled by the chirality of the diphosphine enantiomer. Among these results, the chirality of the 1,2-propylenediamine affects only the degree of enantioselectivity toward the S-alcohol. Comparisons between the results that use the same base consistently show that that the R-1,2-propylenediamine is matched to the chirality of the R,R,R,R-BICP, their combination giving higher enantioselectivities than the combination of the S-1,2-propylenediamine with R,R,R,R-BICP. [0100]
  • Surprisingly, Example 38 shows that the unmatched combination of S-1,2-propylenediamine with R,R,R,R-BICP when used with an alkylguanidine base can provide in an enantioselectivity comparable with the matched combination of R-1,2-propylenediamine with R,R,R,R-BICP when used with the alkoxide salt base (Comparative Example 15). [0101]
    • Examples 46-50 and Comparative Examples 18-22
  • These Examples show the hydrogenation of various ketones using either the tetraalkylguanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene (the Examples) or sodium isopropoxide (the Comparative Examples) in combination with ethylenediamine as the bidentate amine ligand. [0102]
  • The procedure was identical to Example 1 with the exceptions that 625 micromole of the ketone shown in Table 7 was reacted instead of the acetophenone, an equimolar amount of either 1,5,7-triazabicyclo[4.4.0]dec-5-ene or sodium isopropoxide was substituted for the tetramethyl-2-t-butylguanidine, and the reaction mixture was stirred under hydrogen for the time shown in Table 7. In each example, the analysis showed the conversion of the ketone was 100% and that the chirality of the product alcohol was predominantly S. Table 7 gives the ketone, the base, the reaction time, and the enantiomeric excess of the S-alcohol product. [0103]
    TABLE 7
    Time e.e.
    Example ketone base (hrs) (%)
     2 acetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 83
    Comp. 1 acetophenone sodium isopropoxide 6 51
     8 2-acetylthiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 88
    Comp. 8 2-acetylthiophene sodium isopropoxide 4 56
    46 2′-acetonaphthone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 83
    Comp. 18 2′-acetonaphthone sodium isopropoxide 9 64
    47 2-acetylbenzothiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 82
    Comp. 19 2-acetylbenzothiophene sodium isopropoxide 12 68
    48 2-acetylfuran 1,5,7-triazabicyclo[4.4.0]dec-5-ene 9 82
    Comp. 20 2-acetylfuran sodium isopropoxide 9 60
    49 2-methoxyacetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 9 75
    Comp. 21 2-methoxyacetophenone sodium isopropoxide 9 51
    50 3′,5′-bis(trifluoromethyl)- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 9 76
    acetophenone
    Comp. 22 3′,5′-bis(trifluoromethyl)- sodium isopropoxide 12 78
    acetophenone
  • These Examples show that for many ketones, when using ethylene diamine as the achiral diamine ligand, an alkylguanidine base can provide significantly greater enantioselectivity than a basic salt like sodium isopropoxide. They also show that the degree of the relative improvement can also depend on the identity of the ketone. [0104]
    • Examples 51-56 and Comparative Examples 23-28
  • These Examples show the hydrogenation of various ketones using either 1,5,7-triabicyclo[4.4.0]dec-5-ene (the Examples) or sodium isopropoxide (the Comparative Examples) in combination with R-propylenediamine as the bidentate amine ligand. [0105]
  • The procedure was identical to Example 1 with the exceptions that 625 micromole of the ketone shown in Table 8 was reacted instead of the acetophenone, an equimolar amount R-propylenediamine was substituted for the ethylenediamine, an equimolar amount of either 1,5,7-triazabicyclo[4.4.0]dec-5-ene or sodium isopropoxide was substituted for the tetramethyl-2-t-butylguanidine, and the reaction mixture was stirred under hydrogen for the time shown in Table 8. In each example, the analysis showed the conversion of the ketone was 100% and that the chirality of the product alcohol was predominantly S. Table 8 gives the ketone base, the reaction time, and the enantiomeric excess of the S-alcohol product. [0106]
    TABLE 8
    Time e.e.
    Example ketone base (hrs) (%)
    51 acetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 87
    Comp. 23 acetophenone sodium isopropoxide 9 68
    52 2-acetylthiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 93
    Comp. 15 2-acetylthiophene sodium isopropoxide 6 77
    53 2′-acetonaphthone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 87
    Comp. 24 2′-acetonaphthone sodium isopropoxide 9 77
    54 2-acetylbenzothiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 88
    Comp. 25 2-acetylbenzothiophene sodium isopropoxide 12 81
    55 2-acetylfuran 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 87
    Comp. 26 2-acetylfuran sodium isopropoxide 9 74
    55 2-methoxyacetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 81
    Comp. 27 2-methoxyacetophenone sodium isopropoxide 9 60
    56 3′,5′-bis(trifluoromethyl)- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 79
    acetophenone
    Comp. 28 3′,5′-bis(trifluoromethyl)- sodium isopropoxide 12 78
    acetophenone
  • These Examples show that for many ketones, when using R-propylenediamine as the achiral diamine ligand, an alkylguanidine base can provide significantly greater enantioselectivity than a basic salt like sodium isopropoxide. They also show that the degree of the relative improvement can also depend on the identity of the ketone. [0107]
    • Examples 57-67 and Comparative Examples 29-33
  • These Examples show the hydrogenation of various ketones using either an alkylguanidine base (the Examples) or sodium isopropoxide (the Comparative Examples) in combination with meso-cyclohexanediamine as the bidentate amine ligand. [0108]
  • The procedure was identical to Example 7 with the exceptions that 625 micromole of the ketone shown in Table 9 was reacted instead of the acetophenone, in some reactions an equimolar amount of either 1,5,7-triazabicyclo[4.4.0]dec-5-ene or sodium isopropoxide was substituted for the tetramethyl-2-t-butylguanidine, and the reaction mixture was stirred under hydrogen for the time shown in Table 9. In each example, the chirality of the product alcohol was predominantly S. Table 9 gives the ketone base, the reaction time, the conversion of the ketone and the enantiomeric excess of the S-alcohol product. [0109]
    TABLE 9
    Time Conv. e.e.
    Example ketone base (hrs) (%) (%)
    57 acetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 73
     7 acetophenone tetramethyl-2-t-butylguanidine 12 100 71
    Comp. 7 acetophenone sodium isopropoxide 6 100 67
    26 2-acetylthiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 56 90
    14 2-acetylthiophene tetramethyl-2-t-butylguanidine 4 84 90
    Comp. 14 2-acetylthiophene sodium isopropoxide 4 100 81
    58 2-acetonaphthone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 81
    59 2-acetonaphthone tetramethyl-2-t-butylguanidine 12 100 80
    Comp. 29 2-acetonaphthone sodium isopropoxide 9 100 78
    60 2-acetylbenzothiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 93
    61 2-acetylbenzothiophene tetramethyl-2-t-butylguanidine 12 100 92
    Comp. 30 2-acetylbenzothiophene sodium isopropoxide 12 100 89
    62 2-acetylfuran 1,5,7-triazabicyclo[4.4.0]dec-5-ene 9 84 83
    63 2-acetylfuran tetramethyl-2-t-butylguanidine 12 100 83
    Comp. 31 2-acetylfuran sodium isopropoxide 9 100 79
    64 2-methoxyacetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 71
    65 2-methoxyacetophenone tetramethyl-2-t-butylguanidine 8 84 67
    Comp. 32 2-methoxyacetophenone sodium isopropoxide 9 100 55
    66 3′,5′-bis(trifluoromethyl)- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 64
    acetophenone
    67 3′,5′-bis(trifluoromethyl)- tetramethyl-2-t-butylguanidine 12 100 64
    acetophenone
    Comp. 33 3′,5′-bis(trifluoromethyl)- sodium isopropoxide 12 100 70
    acetophenone
  • These Examples show that for many ketones, when using meso-cyclohexanediamine as the achiral diamine ligand, an alkylguanidine base can provide greater enantioselectivity than a basic salt like sodium isopropoxide. They also show that the relative improvement can also depend on the identity of the ketone. [0110]
    • Examples 68-73 and Comparative Examples 34-39
  • These Examples illustrate the hydrogenation of 2-acetylthiophene to 1-(2-thienyl)ethanol using various chiral diphosphine ligands in combinations with ethylendiamine as the bidentate amine ligand and either tetramethyl-2-t-butylguanidine (the Examples) or sodium isopropoxide (the Comparative Examples) as the base. [0111]
  • Stock solutions of [RuCl[0112] 2(diphosphine)(DMF)n] complexes were prepared by the procedure described for [RuCl2(R,R,R,R-BICP)(DMF)n] in Preparation 1. The procedure for the hydrogenation reactions was identical to Example 8 with the exceptions that an equal molar amount the [RuCl2(diphosphine)(DMF)n] having the diphosphine shown in Table 10 (abbreviations are given in the Detailed Description of the Invention) was substituted for [RuCl2(R,R,R,R-BICP)(DMF)n], for the Comparative Examples an equimolar amount of sodium isopropoxide was substituted for the tetramethyl-2-t-butylguanidine and the reaction mixtures were stirred for the time shown in Table 10. Table 10 gives the diphosphine, the base, the reaction time, the conversion of the 2-acetylthiophene, the absolute configuration of the 1-(2-thienyl)ethanol, and its e.e.
    TABLE 10
    Time Conv. e.e. (%)
    Example diphosphine base (hrs) (%) (R/S)
     8 R,R,R,R-BICP tetramethyl-2-t-butylguanidine 4 100 86 (S)
    Comp. 8 R,R,R,R-BICP sodium isopropoxide 4 100 56 (S)
    68 S,S-CHIRAPHOS tetramethyl-2-t-butylguanidine 8 17 64 (S)
    Comp. 34 S,S-CHIRAPHOS sodium isopropoxide 12 100 43 (R)
    69 R,R-SKEWPHOS tetramethyl-2-t-butylguanidine 8 29 55 (S)
    Comp. 35 R,R-SKEWPHOS sodium isopropoxide 6 100 53 (S)
    70 R,R-Me-PennPhos tetramethyl-2-t-butylguanidine 8 49 61 (S)
    Comp. 36 R,R-Me-PennPhos sodium isopropoxide 12 100 36 (S)
    71 R-BINAP tetramethyl-2-t-butylguanidine 6 21 23 (S)
    Comp. 37 R-BINAP sodium isopropoxide 4 100 23 (S)
    72 R-C4-TunaPhos tetramethyl-2-t-butylguanidine 12 69 12 (R)
    Comp. 38 R-C4-TunaPhos sodium isopropoxide 6 100  3 (R)
    73 S-MeOBIPHEP tetramethyl-2-t-butylguanidine 12 54 <1 (R)
    Comp. 39 S-MeOBIPHEP sodium isopropoxide 6 100 <1 (R)
  • These Examples show that for many chiral diphosphines, when using ethylenediamine as the bidentate amine ligand, an alkylguanidine base can provide greater enantioselectivity than a basic salt like sodium isopropoxide. They also show that the improvement can also depend on the identity of the chiral diphosphine. Among these chiral diphosphines, the greater such improvements as well as the greater absolute enantioselectivities are obtained among the nonatropisomeric chiral diphosphines (Examples 8, 69, and 70), while the lesser such improvements and lesser absolute enantioselectivities are obtained among the atropisomeric chiral diphosphines (Examples 71, 72, and 73). [0113]
  • Examples 68 and Comparative Example 34, using CHIRAPHOS show the surprising result of the chirality of the dominant enantiomer of the nonracemic alcohol being switched upon using the tetramethyl-2-t-butylguanidine instead of sodium isopropoxide. [0114]
    • Examples 74-80 and Comparative Examples 40-46
  • These Examples illustrate the hydrogenation of 2-acetylthiophene to 1-(2-thienyl)ethanol using various chiral diphosphine ligands in combinations with meso-cyclohexanediamine as the bidentate amine ligand and either tetramethyl-2-t-butyl-guanidine (the Examples) or sodium isopropoxide (the Comparative Examples) as the base. [0115]
  • The procedure was identical to Example 14 with the exceptions that an equal molar amount the [RuCl[0116] 2(diphosphine)(DMF)n] having the diphosphine shown in Table 10 (abbreviations are given in the Detailed Description of the Invention) was substituted for [RuCl2(R,R,R,R-BICP)(DMF)n], for the Comparative Examples an equimolar amount of sodium isopropoxide was substituted for the tetramethyl-2-t-butylguanidine and the reaction mixtures were stirred for the time shown in Table 11. Table 11 gives the diphosphine, the base, the reaction time, the conversion of the 2-acetylthiophene, the absolute configuration of the 1-(2-thienyl)ethanol, and its e.e.
  • These Examples show that, when using meso-cyclohexanediamine as the bidentate amine ligand, the greater enantioselectivities are obtained when using the preferred nonatropisomeric chiral diphosphine ligands (Examples 14, 74-77) as compared to the atropisomeric chiral diphosphine ligands (Examples 78-80). The Examples using the most preferred chiral diphosphine ligands, comprising four stereogenic carbon atoms in the hydrocarbyl diradical that connects the two phosphorus atoms (Examples 14 and 74) show substantial improvements in enantioselectivity using tetramethyl-2-t-butylguanidine as compared to using sodium isopropoxide. Examples 74 and Comparative Example 40, using CHIRAPHOS show the surprising result of the chirality of the dominant enantiomer of the nonracemic alcohol being switched upon using the tetramethyl-2-t-butylguanidine instead of sodium isopropoxide. A similar switch in chirality, though lesser in e.e. points, is shown by Examples 79 and Comparative Example 45, using R-C4-TunaPhos. For a number of the other chiral diphosphines, the enantioselectivity with tetramethyl-2-t-butylguanidine was no better than that with sodium isopropoxide. The data in Tables 10 and 11, collectively, show that the enantioselectivity advantages which may be provided by the alkylguanidine bases in the present invention is dependent on both the diphosphine ligand and the bidentate amine ligand, and can be determined by routing experimentation. [0117]
    TABLE 11
    Time Conv. e.e. (%)
    Example diphosphine base (hrs) (%) (R/S)
    14 R,R,R,R-BICP tetramethyl-2-t-butylguanidine 4 84 90 (S)
    Comp. 14 R,R,R,R-BICP sodium isopropoxide 4 100 81 (S)
    74 S,S-CHIRAPHOS tetramethyl-2-t-butylguanidine 8 18 64 (S)
    Comp. 40 S,S-CHIRAPHOS sodium isopropoxide 10 100 58 (R)
    75 R,R-SKEWPHOS tetramethyl-2-t-butylguanidine 8 10 52 (S)
    Comp. 41 R,R-SKEWPHOS sodium isopropoxide 12 90 56 (S)
    76 R,R-Me-PennPhos tetramethyl-2-t-butylguanidine 8 63 77 (S)
    Comp. 42 R,R-Me-PennPhos sodium isopropoxide 12 100 76 (S)
    77 R,R-DIOP tetramethyl-2-t-butylguanidine 8 5 52 (R)
    Comp. 43 R,R-DIOP sodium isopropoxide 12 94 57 (R)
    78 R-BINAP tetramethyl-2-t-butylguanidine 6 12 34 (S)
    Comp. 44 R-BINAP sodium isopropoxide 4 100 45 (S)
    79 R-C4-TunaPhos tetramethyl-2-t-butylguanidine 12 25 24 (R)
    Comp. 45 R-C4-TunaPhos sodium isopropoxide 6 100 33 (S)
    80 S-MeOBIPHEP tetramethyl-2-t-butylguanidine 12 20 34 (R)
    Comp. 46 S-MeOBIPHEP sodium isopropoxide 10 100 41 (R)
    • Examples 81-83 and Comparative Examples 47-49
  • These Examples show the hydrogenation of 3-(dimethylamino)-1-(2-thienyl)-1-propanone to nonracemic 3-(dimethylamino)-1-(2-thienyl)-1-propanol using various diamine ligands and either tetramethyl-2-t-butylguanidine (the Examples) or sodium isopropoxide (the Comparative Examples) as the base. [0118]
  • A 1.47 mM solution of [RuCl[0119] 2((R,R,R,R-BICP)(DMF)n] in isopropanol was prepared from [RuCl2(benzene)]2 and 1.1 equivalents R,R,R,R-BICP following the general procedure given in Preparation 1. For each example, in a dry nitrogen-filled glovebox, a 20 ml glass reaction vial was charged with 2 mL 1.47 mM (2.9 micromole) [RuCl2((R,R,R,R-BICP)(DMF)n] in isopropanol, 3 mL isopropanol, 0.58 mL 0.1M (0.58 mmole) diamine ligand in isopropanol, 0.25 g (1.43 mmole) 3-(dimethylamino)-1-(2-thienyl)1-propanone (free base), and 0.29 mL 0.2M (0.58 mmole) base in isopropanol. The glass reaction vial containing the resulting mixture was sealed in an autoclave, which was then removed from the glovebox. The gas phase in the autoclave was replaced by hydrogen and the reaction mixture was stirred under 6.8 bar (gauge) hydrogen at room temperature for 18 hours. The reaction mixture was sampled and analyzed by chiral HPLC. was 100%. Table 12 gives the achiral diamine ligand, the base, the conversion of the ketone, and the enantiomeric excess of the resulting S-3-(dimethylamino)-1-(2-thienyl) 1-propanol product.
    Conv. e.e.
    Example diamine ligand base (%) (%)
    81 ethylene diamine tetramethyl-2-t- 89 79
    butylguanidine
    Comp. 47 ethylene diamine sodium isopropoxide 96 24
    82 2-methyl-1,2- tetramethyl-2-t- 85 85
    propylenediamine butylguanidine
    Comp. 48 2-methyl-1,2- sodium isopropoxide 97 68
    propylenediamine
    83 meso-1,2- tetramethyl-2-t- 77 88
    cyclohexanediamine butylguanidine
    Comp. 49 meso-1,2- sodium isopropoxide 96 83
    cyclohexanediamine
  • These Examples further show that an alkylguanidine base can provide significantly greater enantioselectivity than a basic salt like sodium isopropoxide in the process of the invention. They also show that the degree of the relative improvement can also depend on the identity of the diamine ligand, and appears greatest with a simpler and smaller achiral diamine, especially with ethylene diamine. [0120]
    • Examples 83-90
  • These Examples illustrate the inventive process for hydrogenation of 3′,5′-bis-(trifluoromethyl)acetophenone to nonracemic 3′,5′-bis(trifluoromethyl)-1-phenethanol in various solvents using tetramethyl-2-t-butylguanidine as the base. They also illustrate the use of an amino-thioether as the bidentate amine ligand in the present invention. [0121]
  • Stock solutions of 556 micromolar [RuCl[0122] 2((R,R,R,R-BICP)(DMF)n] in various anhydrous, deaerated solvents were prepared analogous to the procedure in Preparation 1 by dissolving the solid residue comprising [RuCl2(R,R,R,R-BICP)(DMF)n] in the desired solvent instead of isopropanol. In the same manner as described in Example 1, solutions prepared from 0.2843 g (1.11 mmol) 3′,5′-bis(trifluoromethyl)acetophenone, 10 mL 556 micromolar (5.56 micromoles) [RuCl2(R,R,R,R-BICP)(DMF)n] in the solvent, 0.22 mL 0.1 M (22 micromole) 2-(ethylthio)aniline in the solvent, and 0.20 mL 0.1 M (20 micromoles) tetramethyl-2-t-butylguanidine in the solvent were stirred under 100 psi hydrogen for 19 hours at room temperature. Table 13 gives the solvent, the conversion of the 3′,5′-bis-(trifluoromethyl)acetophenone, and the e.e of the (S)-3′,5′-bis(trifluoromethyl)-1-phenethanol product.
    TABLE 13
    Conv.
    Example solvent (%) % e.e.
    83 isopropanol 100 72
    84 toluene 100 77
    85 dibutyl ether 100 75
    86 dichloromethane 100 75
    87 chlorobenzene 100 78
    88 ethylacetate 37 74
    89 1,2-dimethoxy ethane 58 78
    90 methyl t-butyl ether 24 70
  • These results show that that an organic base selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes allows the inventive process to be conducted using solvents other than alcohol solvents and in which basic salts such as sodium isopropoxide are not soluble, and that many solvents provide for higher enantioselectivities than the alcohol solvent. [0123]
  • Examples 84 and 86 may be compared to the report in [0124] J. Am. Chem. Soc., vol. 117 (1995), 2675-2676 that toluene and dichloromethane are not useable in the disclosed process using KOH or (CH3)2CHOK as the base.
    • Examples 91-99 and Comparative Examples 50-52
  • These Examples illustrate the process of the invention for the hydrogenation of a enantiomeric chiral ketone to a diastereomeric chiral alcohol. The Comparative Examples show results obtained using certain organic bases that are not selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes. [0125]
  • For each example, (2S)-1-(4-benzyl-oxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanone was hydrogenated in isopropanol solution at room temperature under 18 bar hydrogen for four hours using [RuCl[0126] 2((S,S,S,S-BICP)(DMF)n], 4,5-dimethyl-1,2-diamino-benzene and a base in the mole ratios ketone:RuBICP:diamine:base=500:1:5:20. The reaction mixture was analyzed by chiral HPLC. Table 14 gives the base, the conversion of the ketone and the chemical yield of the (1S,2S)-diastereomer of 1-(4-benzoxy-phenyl)2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol.
    Conv. yield
    Example base (%) (%)
    Comp. 50 guanidine 1.4 1.4
    Comp. 51 4,7,13,16,21-pentaoxa-1,10-diazabicyclo 0.1 0.1
    [8.8.5]tricosane
    Comp. 52 sodium isopropoxide 98.6 93.2
    91 N′′′-[N-ethyl-P,P-bis(dimethylamino) 99.5 95.1
    phosphinimyl]-N,N,N′,N′,N″,N″-
    hexamethyl-phosphorimidic triamide
    92 N′′′-t-butyl-N,N,N′,N′,N″,N″- 99.5 96.5
    hexamethyl-phosphorimidic triamide
    93 N,N,N′,N′,N″,N″-hexamethyl- 99.6 95.2
    phosphorimidic triamide
    94 t-butyl-tris[tris(dimethylamino) 99.6 96.4
    phosphoranylidene]-phosphorimidic triamide
    95 2,8,9-trimethyl-2,5,8,9-tetraaza-1- 98.6 93.2
    phosphabicyclo[3.3 .3]undecane
    96 1,5,7-triazabicyclo[4.4.0]dec-5-ene 99.6 96.2
    97 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene 99.5 96.7
    98 tetramethyl-2-t-butylguanidine 99.5 97.1
    99 tetramethylguanidine 60.7 58.8
  • Examples 91-99 show that organic bases selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes provide high activity and diastereoselectivity in the process of the invention. Comparative Examples 50 and 51 show that certain other organic bases provide insignificant catalytic activity. By comparison to Comparative Example 50 using guanidine, Examples 98 and 99 show that the N-alkyl substitution in the alkylguanidine bases is required for catalyst system activity. Comparative Example 50 shows that a trialkylamine base does not provide any significant catalyst activity. [0127]
  • All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. [0128]

Claims (35)

What is claimed is:
1. A catalyst system useful for the hydrogenation of a ketone to a nonracemic chiral alcohol comprising ruthenium, a nonracemic chiral diphosphine ligand, a bidentate amine ligand, and an organic base selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes, with the proviso that when said nonracemic chiral diphosphine is an atropisomeric diphosphine and the organic base is selected from alkylamidines, said catalyst system is essentially free of alkali metal salt.
2. The catalyst system of claim 1 wherein the nonracemic chiral diphosphine ligand is a nonracemic nonatropisomeric chiral diphosphine ligand.
3. The catalyst system of claim 2 wherein the nonracemic nonatropisomeric chiral diphosphine ligand comprises at least one stereogenic carbon atom.
4. The catalyst system of claim 3 wherein the nonracemic nonatropisomeric chiral diphosphine ligand comprises at least one stereogenic carbon atom in a hydrocarbyl diradical that connects the two phosphorus atoms.
5. The catalyst system of claim 4 wherein the nonracemic nonatropisomeric diphosphine ligand comprises a 2,2′-bis(diorganophosphino)-1,1′-bis(cyclic) structure.
6. The catalyst system of claim 5 wherein the nonracemic nonatropisomeric diphosphine ligand is selected from enantiomers of diphosphine ligands having the structural formula
Figure US20030181319A1-20030925-C00007
wherein Ar is an aryl group.
7. The catalyst system of claim 6 wherein Ar is selected from phenyl, monoalkylphenyl, dialkylphenyl, and trialkylphenyl.
8. The catalyst system of claim 1 wherein the bidentate amine ligand is a diamine ligand.
9. The catalyst system of claim 8 wherein the diamine amine ligand is a bis-primary amine ligand.
10. The catalyst system of claim 8 wherein the diamine ligand is an achiral diamine ligand.
11. The catalyst system of claim 10 wherein the achiral diamine ligand is selected from meso-1,2-alkylenediamine compounds, 1,2-phenylenediamine compounds and 1,8-diaminonaphthalene compounds.
12. The catalyst system of claim 1 wherein the bidentate amine ligand is an amino-thioether ligand.
13. The catalyst system of claim 12 wherein the amino-thioether ligand is selected from 2-(alkylthio)ethylamines and 2-(alkylthio)anilines.
14. The catalyst system of claim 13 wherein the amino-thioether is a 2-(alkylthio)aniline.
15. The catalyst system of claim 1 wherein the organic base is selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes.
16. The catalyst system of claim 15 wherein the organic base is an alkylguanidine.
17. The catalyst system of claim 16 wherein the base is selected from tetraalkylguanidines and pentaalkylguanidines.
18. A process for the preparation of a nonracemic chiral alcohol comprising hydrogenating a ketone in the presence of a catalyst system, wherein the catalyst system comprises ruthenium, a nonracemic chiral diphosphine ligand, a bidentate amine ligand, and an organic base selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes, with the proviso that when said nonracemic chiral diphosphine is an atropisomeric diphosphine and said organic base is selected from alkylamidines, said catalyst system is essentially free of alkali metal salt.
19. The process of claim 18 wherein the nonracemic chiral diphosphine ligand is a nonracemic nonatropisomeric chiral diphosphine ligand.
20. The process of claim 21 wherein the nonracemic nonatropisomeric chiral diphosphine ligand comprises at least one stereogenic carbon atom.
21. The process of claim 20 wherein the nonracemic nonatropisomeric chiral diphosphine ligand comprises at least one stereogenic carbon atom in a hydrocarbyl diradical that connects the two phosphorus atoms.
22. The process of claim 21 wherein the nonracemic nonatropisomeric diphosphine ligand comprises a 2,2′-bis(diorganophosphino)-1,1′-bis(cyclic) structure.
23. The process of claim 22 wherein the nonracemic nonatropisomeric diphosphine ligand is selected from enantiomers of diphosphine ligands having the structural formula
Figure US20030181319A1-20030925-C00008
wherein Ar is an aryl group.
24. The process of claim 23 wherein Ar is selected from phenyl, monoalkylphenyl, dialkylphenyl, and trialkylphenyl.
25. The process of claim 18 wherein the bidentate amine ligand is a diamine ligand.
26. The process of claim 25 wherein the diamine amine ligand is a bis-primary amine ligand.
27. The process of claim 25 wherein the diamine ligand is an achiral diamine ligand.
28. The process of claim 27 wherein the achiral diamine ligand is selected from meso-1,2-alkylenediamine compounds, 1,2-phenylenediamine compounds and 1,8-diaminonaphthalene compounds.
29. The process of claim 18 wherein the bidentate amine ligand is an amino-thioether ligand.
30. The process of claim 29 wherein the amino-thioether ligand is selected from 2-(alkylthio)ethylamines and 2-(alkylthio)anilines.
31. The process of claim 30 wherein the amino-thioether is a 2-(alkylthio)aniline.
32. The process of claim 18 wherein the organic base is selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes.
33. The process of claim 32 wherein the organic base is an alkylguanidine.
34. The process of claim 33 wherein the base is selected from tetraalkylguanidines and pentaalkylguanidines.
35 The process of claim 18 wherein the nonracemic chiral alcohol is formed in at least about 60% stereomeric excess.
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