Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B31/00—Reduction in general
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B55/00—Racemisation; Complete or partial inversion
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the invention concerns a process for the de-enrichment of enantiomerically enriched substrates, especially alcohols and sulphides.
• a process for the de-enrichment of enantiomerically enriched compositions which comprises reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group Vl heteroatom, in the presence of a catalyst system and optionally a reaction promoter to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a carbon-heteroatom bond, the ratio of second to first enantiomer or diastereomer in the product composition being greater than the ratio of second to first enantiomer or diastereomer in the enantiomerically enriched composition.
• the product composition is a racemic mixture of the first and second enantiomers of the substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre.
• Substrates which may be enantiomerically de-enriched by the process of the present invention include alcohols at a chiral secondary carbon atom and sulphides chiral at a secondary carbon atom.
• the substrate comprising a carbon-heteroatom bond, the carbon atom being a chiral centre is a compound of formula (1 ):
• X represents O, S; R 1 , R 2 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R 1 & R 2 are optionally linked in such a way as to form an optionally substituted ring(s); provided that R 1 and R 2 are selected such that * is a chiral centre.
• Hydrocarbyl groups which may be represented by R 1'2 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
• Alkyl groups which may be represented by R 1"2 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprising up to 10 branch chain carbon atoms, preferably up to 4 branch chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R 1'4 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.
• Alkenyl groups which may be represented by R 1"2 include C 2-20 , and preferably C 2-6 alkenyl groups. One or more carbon - carbon double bonds may be present.
• the alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups. When either of R 1 or R 2 represents an alkenyl group, a carbon - carbon double bond is preferably located at the position ⁇ to the C-heteroatom moiety.
• Aryl groups which may be represented by R 1"2 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
• aryl groups which may be represented by R 1"2 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
• Perhalogenated hydrocarbyl groups which may be represented by R 1'2 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups.
• Examples of perhalogenated alkyl groups which may be represented by R 1'2 include -CF 3 and -C 2 F 5 .
• Heterocyclic groups which may be represented by R 1"2 independently include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
• the heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P.
• R 1 or R 2 represents or comprises a heterocyclic group
• the atom in R 1 or R 2 bonded to the C-heteroatom group is preferably a carbon atom.
• heterocyclic groups which may be represented by R 1'2 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.
• R 1"2 When any of R 1"2 is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivety of the reaction.
• Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di- hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R 1 above.
• One or more substituents may be present.
• R 1 & R 2 are linked in such a way that when taken together with either the carbon atom and/or atom X of the compound of formula (1) that a ring is formed, it is preferred that these be 5, 6 or 7 membered rings and optionally containing one or more ring heteroatoms, preferably O, S or N ring atoms.
• examples of such compounds of formula (1) include 2-methylcyclohexanol.
• R 1 and R 2 are both different and selected to both be different C 1-6 alkyl groups, both be different aryl groups, particularly where one is a phenyl group, or are selected such that one is aryl, particularly phenyl and one is C 1-6 alkyl. Substituents may be present, particularly substituents para to the C-X group when one or both of R 1 and R 2 is a substituted phenyl group.
• Examples of compounds of formula (1) include 1-phenylethan-1-ol, 1-(2- naphthyl)ethan-1-ol, 1-(1-naphthyl)ethan-1-ol 1-phenylethan-1 -thiol, 1-(2-naphthyl)ethan- 1 -thiol, and 1-(1-naphthyl)ethan-1 -thiol.
• the catalyst system preferably comprises a transition metal catalyst and optionally a ligand.
• Ligands which optionally may be present include amines, alcohols and sulphides.
• the ligand and the transition metal catalyst may be pre-mixed or pre-coordinated prior to the reaction with the substrate.
• Examples of such pre-coordinated ligand and the transition metal catalysts include those catalysts disclosed in the International patent applications with publication numbers WO97/20789, WO98/42643, and WO02/44111 , each of which is incorporated herein by reference.
• Transition metal catalysts include transition metal halides, transition metal halide complexes and transition metal complexes wherein the transition metal is optionally complexed by a displaceable ligand.
• Displaceable ligands include phosphines, such as tri-hydrocarbyl phosphines for example Ph 3 P, carbenes such as imidazole carbene, nitriles such as acetonitrile, carbon monoxide, triflate, alkenes and dienes.
• phosphines such as tri-hydrocarbyl phosphines for example Ph 3 P
• carbenes such as imidazole carbene
• nitriles such as acetonitrile
• carbon monoxide triflate
• alkenes and dienes alkenes and dienes.
• transition metal complexes wherein the transition metal is optionally complexed by a displaceable ligand include complexes of the formula M n L 0 X p Y r Wherein
• M is a transition metal
• L is a displaceable ligand
• X is a halide
• Y is a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n is an integer; and each of o, p, and r is 0 or an integer provided that o+p+r is an integer.
• the transition metal catalyst is a transition metal halide or transition metal halide complex based on the transition metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. More preferably, the transition metal catalyst is a transition metal halide complex of the formula M n X p Y r Wherein
• M is a transition metal
• X is a halide
• Y is a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n, p and r are integers.
• transition metal catalyst is believed to be substantially as represented in the above formula, in some circumstances the transition metal catalyst may also exist as a dimer, trimer or some other polymeric species.
• Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation.
• Preferred metals include transition metals, more preferably the metals in Group VIII of the Periodic Table, (iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium and platinum), more preferably ruthenium, rhodium or iridium, most preferably iridium.
• the integers n, p, r are selected such that the transition metal halide complex is overall a neutral species. Therefore, the selection of n, p, r are directly related to the valance state of the metal and the number of halides present and the nature of the complexing group Y. For example, where Y is a negatively charged cyclopentadienyl complexing group, the number of negatively charged halides required to balance the valence state of the metal will be less than when Y is a neutral hydrocarbyl complexing group. When the metal is ruthenium it is preferably present in valence state II.
• the metal When the metal is rhodium or iridium it is preferably present in valence state I when Y is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and preferably present in valence state III when Y is an optionally substituted cyclopentadienyl ligand.
• An especially preferred metal is iridium.
• the neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl complexing group which may be represented by Y includes optionally substituted aryl and alkenyl complexing group.
• Optionally substituted aryl complexing groups which may be represented by Y may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings.
• the complexing group comprises a 6 membered aromatic ring.
• the ring or rings of the aryl complexing group are often substituted with hydrocarbyl groups.
• the substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 substituents are present.
• Substituents may include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R 1 above.
• the 1 to 6 substituents are each independently hydrocarbyl groups, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups.
• Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl.
• the complexing group is preferably benzene or a substituted benzene.
• the complexing group is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne.
• the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used.
• Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred complexing group.
• Optionally substituted alkenyl complexing groups which may be represented by Y include C 2-30 , and preferably C 6-12 , alkenes or cycloalkenes with preferably two or more carbon-carbon double bonds, preferably only two carbon-carbon double bonds.
• the carbon-carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other.
• the alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents.
• the optionally substituted alkenyl complexing group may comprise two separate alkenes.
• Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl.
• optionally substituted alkenyl complexing groups include cyclo-octa-1 ,5-diene and 2,5-norbornadiene. Cyclo-octa-1 ,5-diene is especially preferred.
• Optionally substituted cyclopentadienyl complexing groups which may be represented by Y includes cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 substituents.
• Substituents may include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R 1 above.
• the cyclopentadienyl group is substituted with 1 to 5 hydrocarbyl groups, more preferably with 3 to 5 hydrocarbyl groups and most preferably with 5 hydrocarbyl groups.
• hydrocarbyl substituents include methyl, ethyl and phenyl.
• hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it may be advantageous that the enantiomerically and/or diastereomerically purified forms of these are used.
• cyclopentadienyl complexing groups include cyclopentadienyl, pentamethyl-cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl- tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred.
• Transition metal halide complexes of the formula M n X p Y r wherein M is Rh or Ir, and Y is an optionally substituted cyclopentadienyl group are preferred. Transition metal halide complexes of the formula M n X p Y r wherein M is Ir and Y is an optionally substituted cyclopentadienyl group are most preferred.
• transition metal halide complexes include Ru 2 CI 4 (CyITIyI) 2 , Rh 2 CI 4 (Cp * ) 2 , Rh 2 Br 4 (Cp * );, , Rh 2 l 4 (Cp * ) 2 ⁇ lr 2 CI 4 (Cp * ) 2i Ru 2 l 4 (cymyl) 2, RhCI 2 Cp * , RhBr 2 Cp * , RhI 2 Cp * , and lr 2 l 4 (Cp * ) 2 wherein Cp * is a pentamethylcyclopentadienyl group.
• the catalyst system is preferably a composition obtainable by contacting a transition metal halide complex of the formula M n X p Y r wherein M is a transition metal; X is a halide; Y is a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n, p and r are integers with an alcohol or sulphide ligand of formula (1).
• the catalytic system may advantageously be introduced, at least in part, on a solid support or as an encapsulated system.
• a solid support or as an encapsulated system such supported catalyst systems may be of assistance in performing separation operations which may be required, and may facilitate the ease of cycling of materials between steps, especially when repetitions are envisaged.
• solid support or encapsulation technology that may be employed to support or encapsulate the catalytic system are described in WO03/006151 and WO05/016510.
• Reaction promoters include halide salts, for example metal halides.
• Preferred reaction promoters include bromide and especially iodide salts. Highly preferred are potassium iodide and caesium iodide.
• the process of the present invention is carried out in the presence of a base.
• bases include potassium carbonate and sodium carbonate.
• X represents O, S
• R 1 , R 2 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or
• R 1 & R 2 are optionally linked in such a way as to form an optionally substituted ring(s); provided that R 1 and R 2 are different, derived by deprotonation of the starting alcohols or sulphides of formula (1) may be produced.
• Hydrogen acceptors which may be present in the process of the present invention include the proton from an acid, oxygen, aldehydes and ketones, imines and imminium salts, readily hydrogenatable hydrocarbons, dyes, clean oxidising agents, carbonates, bicarbonates and any combination thereof.
• the proton may emanate from any convenient and compatible acid such as formic acid, acetic acid, hydrogen carbonate, hydrogen sulfate, ammonium salt or alkyl ammonium salt. Conveniently the proton may emanate from the substrate itself.
• Aldehydes and ketones which may be employed as hydrogen acceptors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, and more preferably 3 to 5 carbon atoms.
• Aldehydes and ketones include alkyl, aryl, hetroaryl aldehydes and ketones, and ketones with mixed alkyl, aryl or hetroaryl groups.
• aldehydes and ketones which may be represented as hydrogen acceptors include formaldehyde, acetone, methylethylketone and benzophenone.
• the hydrogen donor is an aldehyde or ketone, acetone is especially preferred.
• Readily hydrogenatable hydrocarbons which may be employed as hydrogen acceptors comprise hydrocarbons which have a propensity to accept hydrogen or hydrocarbons which have a propensity to form reduced systems.
• Examples of readily hydrogenatable hydrocarbons which may be employed by as hydrogen donors include quinones, dihydroarenes and tetrahydroarenes.
• Clean oxidising agents which may be represented as hydrogen acceptors comprise reducing agents with a high reduction potential, particularly those having an oxidation potential relative to the standard hydrogen electrode of greater than about 0.1eV, often greater than about 0.5eV, and preferably greater than about 1eV.
• Examples of clean oxidising agents which may be represented as hydrogen acceptors include oxidising metals and oxygen.
• Dyes include Rose Bengal, Proflavin, Ethidium Bromide, Eosin and Phenolphthalein.
• Carbonates and bicarbonates include alkali metal, alkaline earth metal, ammonium and quaternary amine salts of carbonate and bicarbonate.
• the most preferred hydrogen acceptors are protons from acids, acetone, oxygen, the substrate amine and carbonate and bicarbonate salts.
• Hydrogen donors include hydrogen, primary and secondary alcohols, primary , secondary and tertiary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons, clean reducing agents, and any combination thereof.
• Primary and secondary alcohols which may be employed as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 2 to 7 carbon atoms, and more preferably 3 or 4 carbon atoms.
• Examples of primary and secondary alcohols which may be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan- 2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cyclohexanol, benzylalcohol, and menthol.
• secondary alcohols are preferred, especially propan-2-ol and butan-2-ol.
• Primary secondary and tertiary amines which may be employed as hydrogen donors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 14 carbon atoms, and more preferably 3 or 8 carbon atoms.
• Examples of primary, secondary and tertiary amines which may be represented as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, hexylamine, diethylamine, dipropylamine, di-isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine, piperidine, (R) or (S) 6,7-dimethoxy-1- methyldihydroisoquinoline, triethylamine.
• the hydrogen donor is an amine
• primary amines are preferred, especially primary amines comprising a secondary alkyl group, particularly isopropylamine and isobutylamine.
• Carboxylic acids or their esters or salts which may be employed as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms.
• the carboxylic acid is advantageously a beta-hydroxy- carboxylic acid.
• Esters may be derived from the carboxylic acid and a C 1-10 alcohol. Examples of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid.
• carboxylic acid When a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as a salt.
• Amine salts may be formed.
• Amines which may be used to form such salts include both aromatic and non-aromatic amines, also primary, secondary and tertiary amines and comprise typically from 1 to 20 carbon atoms. Tertiary amines, especially trialkylamines, are preferred.
• Examples of amines which may be used to form salts include trimethylamine, triethylamine, di-isopropylethylamine and pyridine. The most preferred amine is triethylamine.
• the mole ratio of acid to amine is commonly about 5 : 2. This ratio may be maintained during the course of the reaction by the addition of either component, but usually by the addition of the carboxylic acid.
• Other preferred salts include sodium, potassium, magnesium
• Readily dehydrogenatable hydrocarbons which may be employed as hydrogen donors comprise hydrocarbons which have a propensity to aromatise or hydrocarbons which have a propensity to form highly conjugated systems.
• Examples of readily dehydrogenatable hydrocarbons which may be employed by as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpenes.
• Clean reducing agents which may be represented as hydrogen donors comprise reducing agents with a high reduction potential, particularly those having a reduction potential relative to the standard hydrogen electrode of greater than about -0.1 eV, often greater than about -0.5eV, and preferably greater than about -1eV.
• Examples of clean reducing agents which may be represented as hydrogen donors include hydrazine and hydroxylamine.
• the most preferred hydrogen donors are (R) or (S) 6,7-dimethoxy-1- methyldihydroisoquinoline propan-2-ol, butan-2-ol, triethylammonium formate, sodium formate, potassium formate and a mixture of triethylammonium formate and formic acid.
• gaseous hydrogen may be present, the process is normally operated in the absence of gaseous hydrogen since it appears to be unnecessary.
• inert gas sparging may be employed.
• the process is carried out at temperatures in the range of from minus 78 to plus 150 0 C, preferably from minus 20 to plus 110 0 C and more preferably from minus 10 to plus 4O 0 C.
• the initial concentration of the substrate, a compound of formula (1 ), is suitably in the range 0.05 to 1.0 and, for convenient larger scale operation, can be for example up to 6.0 more especially 0.75 to 2.0, on a molar basis.
• the molar ratio of the substrate to the catalyst system is suitably no less than 50:1 and can be up to 50000:1 , preferably between 250:1 and 5000:1 and more preferably between 500:1 and 2500:1.
• reaction promoter is preferably employed in a molar excess over the substrate, especially from 1 to 5 fold or, if convenience permits, greater, for example up to 20 fold.
• the hydrogen donor and/or acceptor is preferably employed in a molar excess over the substrate, especially from 5 to 20 fold or, if convenience permits, greater, for example up to 500 fold.
• Reaction times are typically in the range of from 1.0 min to 24h, especially up to 8h and conveniently about 3h. After reaction, the mixture is worked up by standard procedures.
• a reaction solvent may be present, for example dimethylformamide, acetonitrile, tetrahydrofuran, toluene, chloroform, dichloromethane or, conveniently, the substrate alcohol or sulphide when the substrate alcohol or sulphide is liquid at the reaction temperature. Usually it is preferred to operate in substantial absence of water, but water does not appear to unduly inhibit the reaction. If the substrate amine or the reaction solvent is not miscible with water and the desired product is water soluble, it may be desirable to have water present as a second phase.
• the concentration of substrate may be chosen to optimise reaction time, yield and de-enrichment of enantiomeric excess.
• a composition comprising the ketones or thioketones of formula (2) resulting from reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group Vl heteroatom, in the presence of a catalyst system and optionally a reaction promoter is then contacted with a transfer hydrogenation catalyst and a hydrogen donor to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a carbon-heteroatom bond, the ratio of second to first enantiomer or diastereomer in the product composition being greater than the ratio of second to first enantiomer or diastereomer in the enantiomerically enriched composition.
• Hydrogen donors are as defined hereinbefore above.
• the reduction of compounds of Formula 2 is preferably accomplished employing a stereoselective reduction system. It is most preferred that the stereoselective reduction employs a chiral coordinated transition metal catalysed transfer hydrogenation process. Examples of such processes, and the catalysts, reagents and conditions employed therein include those disclosed in International patent application publication numbers WO97/20789, WO98/42643, and WO02/44111 each of which is incorporated herein by reference.
• Preferred transfer hydrogenation catalysts for use in the process of the present invention have the general formula (a):
• R 3 represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;
• A represents an optionally substituted nitrogen
• B represents an optionally substituted nitrogen, oxygen, sulphur or phosphorous
• E represents a linking group
• M represents a metal capable of catalysing transfer hydrogenation
• Y represents an anionic group, a basic ligand or a vacant site; provided that at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.
• Particularly preferred transfer hydrogenation catalysts are those Ru, Rh or Ir catalysts of the type described in WO97/20789, WO98/42643, and WO02/44111 which comprise an optionally substituted diamine ligand, for example an optionally substituted ethylene diamine ligand, wherein at least one nitrogen atom of the optionally substituted diamine ligand is substituted, preferably with a group containing a chiral centre, and a neutral aromatic ligand, for example p-cymene, or an optionally substituted cyclopentadiene ligand, for example pentamethylcyclopentadiene.
• an optionally substituted diamine ligand for example an optionally substituted ethylene diamine ligand, wherein at least one nitrogen atom of the optionally substituted diamine ligand is substituted, preferably with a group containing a chiral centre, and a neutral aromatic ligand, for example p-cymene, or an optionally substituted cyclopentad
• Highly preferred transfer hydrogenation catalysts for use in the process of the present invention are of general Formula (A):
• R 3 represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;
• B represents -O-, -OH, OR 7 , -S-, -SH, SR 7 , -NR 7 -, -NR 8 -, -NHR 8 , -NR 7 R 8 , -NR 7 R 9 , -PR 7 - or -PR 7 R 9
• R 7 and R 9 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R 12 and R 13 are each independently hydrogen or a group as defined for R 9
• E represents a linking group
• M represents a metal capable of catalysing transfer hydrogenation
• Y represents an anionic group, a basic ligand or a vacant site; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.
• the catalytic species is believed to be substantially as represented in the above formula. It may be introduced on a solid support.
• Optionally substituted hydrocarbyl groups represented by R 5"7 or R 9'11 include alkyl, alkenyl, alkynyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
• Alkyl groups which may be represented by R 5"7 or R 9"11 include linear and branched alkyl groups comprising 1 to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms.
• the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings.
• Examples of alkyl groups which may be represented by R 5"7 or R 9"11 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.
• Alkenyl groups which may be represented by one or more of R 5"7 or R 9'11 include C 2-20 , and preferably C 2-6 alkenyl groups. One or more carbon - carbon double bonds may be present.
• the alkenyl group may carry one or more substituents, particularly phenyl substituents.
• Alkynyl groups which may be represented by one or more of R 5"7 or R 9'11 include
• alkynyl group may carry one or more substituents, particularly phenyl substituents.
• alkynyl groups include ethynyl, propyl and phenylethynyl groups.
• Aryl groups which may be represented by one or more of R 5"7 or R 9'11 may contain
• aryl groups which may be represented by R 5"7 or R 9"11 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
• Perhalogenated hydrocarbyl groups which may be represented by one or more of
• R 57 or R 9"11 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups.
• perhalogenated alkyl groups which may be represented by R 5'7 or R 9'11 include -CF 3 and -C 2 F 5 .
• Heterocyclic groups which may be represented by one or more of R 5'7 or R 9'11 independently include aromatic, saturated and partially unsaturated ring systems and may comprise 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
• the heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P.
• heterocyclic groups which may be represented by R 5"7 or R 9'11 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazolyl groups.
• R 5'7 or R 9'11 is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivity of the reaction.
• Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carboxy, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R 5'7 or R 9"11 above.
• R 5"7 or R 9"11 may each contain one or more chiral centres.
• the neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R 3 includes optionally substituted aryl and alkenyl ligands.
• Optionally substituted aryl ligands which may be represented by R 3 may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings.
• the ligand comprises a 6 membered aromatic ring.
• the ring or rings of the aryl ligand are often substituted with hydrocarbyl groups.
• the substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 hydrocarbyl substituent groups are present, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups.
• Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl.
• the ligand is preferably benzene or a substituted benzene.
• the ligand is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne.
• the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used.
• Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred ligands.
• Optionally substituted alkenyl ligands which may be represented by R 3 include C 2-30 , and preferably C 6 ⁇ 2 , alkenes or cycloalkenes with preferably two or more carbon- carbon double bonds, preferably only two carbon-carbon double bonds.
• the carbon- carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other.
• the alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents.
• the optionally substituted alkenyl ligand may comprise two separate alkenes.
• Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl.
• optionally substituted alkenyl ligands include cyclo-octa-1 ,5- diene and 2,5-norbomadiene. Cyclo-octa-1 ,5-diene is especially preferred.
• Optionally substituted cyclopentadienyl groups which may be represented by R 3 include cyclopentadienyl groups capable of eta-5 bonding.
• the cyclopentadienyl group is often substituted with from 1 to 5 hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and more preferably with 5 hydrocarbyl groups.
• Preferred hydrocarbyl substituents include methyl, ethyl and phenyl.
• cyclopentadienyl groups include cyclopentadienyl, pentamethyl- cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl- tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred.
• a or B is an amide group represented by -NR 4 -, -NHR 4 , NR 4 R 5 , -NR 8 - , -NHR 8 or NR 7 R 8 wherein R 5 and R 7 are as hereinbefore defined, and where R 4 or R 8 is an acyl group represented by -C(O)R 6 or -C(O)R 9 , R 6 and R 9 independently are often linear or branched C 1-7 alkyl, C 1-8 -cycloalkyl or aryl, for example phenyl.
• acyl groups which may be represented by R 6 or R 10 include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl groups.
• a or B is present as a sulphonamide group represented by -NR 4 -, -NHR 4 , NR 4 R 4 , -NR 8 -, -NHR 8 or NR 7 R 8 wherein R 5 and R 7 are as hereinbefore defined, and where R 4 or R 8 is a sulphonyl group represented by -S(O) 2 R 6 or -S(O) 2 R 9 , R 6 and R 9 independently are often linear or branched C 1-12 alkyl, C 1-12 cycloalkyl or aryl, for example phenyl.
• Preferred sulphonyl groups include methanesulphonyl, trifluoromethanesulphonyl, more preferably p-toluenesulphonyl groups and naphthylsulphonyl groups and especially camphorsulphonyl.
• R 6 and R 9 independently are often linear or branched C 1-8 alkyl, such as methyl, ethyl, isopropyl, C 1-8 cycloalkyl or aryl, for example phenyl, groups and R 10'13 are often each independently hydrogen or linear or branched C 1-8 alkyl, such as methyl, ethyl
• R 7 and R 9 independently are often linear or branched C 1-8 alkyl, such as methyl, ethyl, isopropyl, C 1-8 cycloalkyl or aryl, for example phenyl. It will be recognised that the precise nature of A and B will be determined by whether A and/or B are formally bonded to the metal or are coordinated to the metal via a lone pair of electrons.
• the groups A and B are connected by a linking group E.
• the linking group E achieves a suitable conformation of A and B so as to allow both A and B to bond or coordinate to the metal, M.
• a and B are commonly linked through 2, 3 or 4 atoms.
• the atoms in E linking A and B may carry one or more substituents.
• the atoms in E, especially the atoms alpha to A or B, may be linked to A and B, in such a way as to form a heterocyclic ring, preferably a saturated ring, and particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other rings.
• the atoms linking A and B will be carbon atoms.
• one or more of the carbon atoms linking A and B will carry substituents in' addition to A or B.
• Substituent groups include those which may substitute R 5 - 7 or R 9 - ii as defined above.
• any such substituent groups are selected to be groups which do not coordinate with the metal, M.
• Preferred substituents include halogen, cyano, nitro, sulphonyl, hydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups as defined above.
• Most preferred substituents are C 1-6 alkyl groups, and phenyl groups.
• a and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety.
• the two carbon atoms linking A and B may comprise part of an aromatic or aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other such rings.
• E represents a 2 carbon atom separation and one or both of the carbon atoms carries an optionally substituted aryl group as defined above or E represents, a 2 carbon atom separation which comprises a cyclopentane or cyclohexane ring, optionally fused to a phenyl ring.
• E preferably comprises part of a compound having at least one stereospecific centre.
• any or all of the 2, 3 or 4 atoms linking A and B are substituted so as to define at least one stereospecific centre on one or more of these atoms, it is preferred that at least one of the stereospecific centres be located at the atom adjacent to either group A or B.
• at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state.
• B represents -O- or -OH, and the adjacent atom in E is carbon, it is preferred that B does not form part of a carboxylic group.
• Compounds which may be represented by A-E-B, or from which A-E-B may be derived by deprotonation, are often aminoalcohols, including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols, 1 ⁇ aminoalkan-3-ols, and especially 2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, and particularly 2-aminoethanols or 3-aminopropanols, or are diamines, including 1 ,4-diaminoalkanes, 1 ,3-diaminoalkanes, especially 1 ,2- or 2,3- diaminoalkanes and particularly ethylenediamines.
• aminoalcohols including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols
• aminoalcohols that may be represented by A-E-B are 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused to a phenyl ring.
• Further diamines that may be represented by A-E-B are 1 ,2-diaminocyclopentanes and 1 ,2-diaminocyclohexanes, preferably fused to a phenyl ring.
• the amino groups may advantageously be N-tosylated.
• a diamine is represented by A-E-B, preferably at least one amino group is N-tosylated.
• the aminoalcohols or diamines are advantageously substituted, especially on the linking group, E, by at least one alkyl group, such as a C 1-4 -alkyl, and particularly a methyl, group or at least one aryl group, particularly a phenyl group.
• the enantiomerically and/or diastereomerically purified forms of these are used.
• Examples include (1S,2R)-(+)-norephedrine, (1R,2S)-(+)-cis-1-amino-2- indanol, (1 S,2R)-2-amino-1 ,2-diphenylethanol, (1 S,2R)-(-)-cis-1 -amino-2-indanol, (1 R,2S)-(-)-norephedrine, (S)-(+)-2-amino-1 -phenylethanol, (1 R,2S)-2-amino-1 ,2- diphenylethanol, N-tosyl-(1 R,2R)-1 ,2-diphenylethylenediamine, N-tosylr(1 S,2S)-1 ,2- diphenylethylenediamine, (1 R,2S)-cis-1 ,2-indandiamine, (1
• Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation.
• Preferred metals include transition metals, more preferably the metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium.
• the metal is ruthenium it is preferably present in valence state II.
• the metal is rhodium or iridium it is preferably present in valence state I when R 3 is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and preferably present in valence state III when R 3 is an optionally substituted cyclopentadienyl ligand.
• M the metal
• R 3 is an optionally substituted cyclopentadienyl ligand.
• Anionic groups which may be represented by Y include hydride, hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups.
• a halogen is represented by Y
• the halogen is chloride.
• a hydrocarbyloxy or hydrocarbylamino group is represented by Y, the group may be derived from the deprotonation of the hydrogen donor utilised in the reaction.
• Basic ligands which may be represented by Y include water, C 1-4 alcohols, C 1-8 primary or secondary amines, or the hydrogen donor which is present in the reaction system.
• a preferred basic ligand represented by Y is water.
• A-E-B, R 3 and Y are chosen so that the catalyst is chiral.
• an enantiomerically and/or diastereomerically purified form is preferably employed.
• Such catalysts are most advantageously employed in asymmetric transfer hydrogenation processes.
• the chirality of the catalyst is derived from the nature of A-E-B.
• the transfer hydrogenation catalysts may be prepared in advance or in-situ by combining a ligand, preferably a chiral bidentate nitrogen ligand, with a metal complex, for example a Ru, Rh or Ir metal complex containing a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group.
• a solvent is present in this operation.
• the solvent used may be anyone which does not adversely effect the formation of the catalyst.
• These solvents include acetonitrile, ethylacetate, toluene, methanol, tetrahydrofuran, ethylmethyl ketone.
• the solvent is methanol.
• the process of the present invention may find use in recycling unwanted isomers obtained from chiral processes, such as chiral separations, chemical and enzymic chiral resolutions and the likes.
• chiral separations or resolutions racemic mixtures are subjected to physical, chemical or biochemical treatments which result in the separation of a desired enantiomer or enatiomeric product while often leaving behind an unreacted or unwanted enatiomers or enatiomeric bi- products.
• the process of the present invention provides a method for converting the unreacted enatiomers to usable feedstocks containing wanted enatiomers.
• the (+)-norephedrine and rhodium compound were weighed out into a clean dry Schlenk flask.
• the flask was stoppered with a 'Suba-seal' (RTM). Its contents were evacuated, then purged at room temperature by 15 changes of nitrogen. Then 2- propanol (20ml) was added by cannula.
• the flask tap was closed and the flask swirled until the starting solids dissolved. The result was an orange-coloured supernatant and a dark solid.
• the flask tap was re-opened, a current of nitrogen fed in, and the flask contents heated at 60 0 C for 2h 5min.
• the catalyst was checked at 30 min intervals. At each interval it was a dark brown solution, with a black solid at the bottom.
• the rhodium compound was suspended in 50ml of 2-propanol and degassed by 3 cycles of vacuum and nitrogen flush. The mixture was heated to gentle reflux until the solid dissolved, then cooled to ambient temperature. (1S,2R)-(-)-cis-1-amino-2-indanol was added to the solution with stirring. The mixture was degassed by cycles of vacuum and nitrogen flush and warmed at 30 0 C for 30min. The resulting orange-red solution of the catalyst was passed to the next stage but could be stored under argon or nitrogen.
• Acetophenone (2ml, 17mmol) was dissolved in 2-propanol (80ml) and purged with nitrogen. Then the catalyst solution was added followed by potassium hydroxide solution (3.3ml of 0.1 M solution in 2-propanol). The mixture was stirred at ambient temperature under nitrogen for 10h. This gave 1-phenylethanol. Yield 68%, ee 49%.

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