WO2006046056A1

WO2006046056A1 - Process for the transfer hydrogenation of an organic compound in the presence of a catalyst regenerator

Info

Publication number: WO2006046056A1
Application number: PCT/GB2005/004171
Authority: WO
Inventors: George Robert Hodges; Matthew John Stirling
Original assignee: Avecia Pharmaceuticals Limited
Priority date: 2004-10-29
Filing date: 2005-10-27
Publication date: 2006-05-04
Also published as: GB0424004D0

Abstract

There is provided a process for the transfer hydrogenation of an organic compound having a carbon-carbon or carbon-heteroatom double bond wherein an organic compound of formula (I): wherein: X represents CR3R4, NR5, (NR5R6)+Q-, O or S; Q- represents an anion; R1, R2 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group; R3, R4, and R6 each independently represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group; R5 independently represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group or a removable group; or one or more of R1 & R2, R1 & R3, R2 & R4, R3 & R4, R1 & R5, R2 & R6 and R5 & R6 optionally being linked in such a way as to form an optionally substituted ring(s), is reacted with a hydrogen donor in the presence of a transfer hydrogenation catalyst, and substantially in the presence of a catalyst regenerator. Catalyst regenerators include oxidants, for example KMnO4, oxygen and oxygen/inert gas mixtures.

Description

PROCESS FOR THE TRANSFER HYDROGENATION OF AN ORGANIC COMPOUND IN THE PRESENCE OF A CATALYST REGENERATOR

The invention concerns a process for the catalytic transfer hydrogenation of substrates, particularly imines, aldehydes and ketones.

According to a first aspect of the present invention there is provided a process for the transfer hydrogenation of an organic compound having a carbon-carbon or carbon- heteroatom double bond wherein a) the organic compound is reacted with a hydrogen donor in trie presence of a transfer hydrogenation catalyst, and b) substantially in the presence of a catalyst regenerator.

Preferably, in the process of the present invention, the organic compound having a carbon-carbon or carbon-heteroatom double bond is a compound of formula (1 ):

(D wherein:

X represents CR³R⁴, NR⁵, (NR⁵RTQ/, O or S;

Q^" represents an anion;

R¹ , R² each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group;

R³, R⁴, and R⁶ each independently represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group;

R⁵ independently represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group or a removable group; or one or more of R¹ & R², R¹ & R³, R² & R⁴, R³ & R⁴, R¹ & R⁵, R² & R⁶ and R⁵ & R⁶ optionally being linked in such a way as to form an optionally substituted ring(s). Preferably, R¹, R², R³, R⁴, R⁵ and R⁶ are selected such that the carbon atom to which R¹ and R² are attached is pro-chiral.

Preferably the transfer hydrogenation catalyst is a catalyst of general formula (2):

<^E>

M

Y' V

(2) wherein:

R⁷ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand; A represents -NR⁸-, -NR⁹-, -NHR⁸, -NR⁸R⁹ or -NR⁹R¹⁰ where R⁸ is H, C(O)R¹⁰, SO₂R¹⁰, C(O)NR¹⁰R¹⁴, C(S)NR¹⁰R¹⁴, C(=NR¹⁴)SR¹⁵ or C(=NR¹⁴)OR¹⁵, R⁹ and R¹⁰ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹⁴ and R¹⁵ are each independently hydrogen or a group as defined for R¹⁰; B represents -O-, -OH, OR¹¹, -S-, -SH, SR¹¹, -NR¹¹-, -NR¹²-, -NHR¹², -NR¹¹R.¹², -NR¹¹R¹³, -PR¹¹- or -PR¹¹R¹³ where R¹² is H, C(O)R¹³, SO₂R¹³, C(O)NR¹³R.¹⁶, C(S)NR¹³R¹⁶, C(=NR¹⁶)SR¹⁷ or C(=NR¹⁶)OR¹⁷, R¹¹and R¹³ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹⁶ and R¹⁷ are each independently hydrogen or a group as defined for R¹³; E represents a linking group;

M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site; provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

Preferably, A-E-B, M, R⁷ and Y are chosen such that the catalyst is chiral. When such is the case, an enantiomerically and/or diastereomerically purified form is preferably employed. In many embodiments, the chirality of the catalyst is derived from the natu re of A-E-B.

Whilst the catalytic species is believed to be substantially as represented in tine above formula, the catalytic species may advantageously be introduced on a so lid support.

Where the catalytic species is present on a solid support, such supported catalysts 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.

In certain preferred catalysts of formula (2) at least one of said groups R⁹ to R¹¹ or R¹³ to R¹⁷ is present in the form of an optionally substituted sulphonated hydrocarbyl group, a sulphonated perhalogenated hydrocarbyl group, or an optionally substituted sulphonated heterocyclyl group. The term "sulphonated" is intended to cover tine presence of the sulphonic acid moiety (-SO₃H) and salts thereof.

Hydrocarbyl groups which may be represented by R^1"6, R⁹, R¹⁰, R¹¹ and R^13"17 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"6, R⁹, R¹⁰, R¹¹ and R^13"17 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"6, R⁹, R¹⁰, R¹¹ and R^13"17 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.

Alkenyl groups which may be represented by R^1"6, R⁹, R¹⁰, R¹¹ and R^13"17 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 R¹ or R² represents an alkenyl group, a carbon - carbon double bond is preferably located at the position β to the C=X moiety. When either of R¹ or R² represents an alkenyl g roup, the compound of formula (1) is preferably an α,β-unsaturated ketone.

Aryl groups which may be represented by R^1'6, R⁹, R¹⁰, R¹¹ and R^13'17 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R^{1 S}, R⁹, R¹⁰, R¹¹ and R^13"17 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.

Perhalogenated hydrocarbyl groups which may be represented by R^1"6, R⁹, R¹⁰, R¹¹ and R^13"17 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"6, R⁹, R¹⁰, R¹¹ and R^13"17 include -CF₃ and -C₂F₅.

Heterocyclic groups which may be represented t>y R^1"6, R⁹, R¹⁰, R¹¹ and R^13"17 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. When either of R¹ or R² represents or comprises a heterocyclic group, the atom in R¹ or R² bonded to the C=X group is preferably a carbon atom. Examples of heterocyclic groups which may be represented by R^1"6, R⁹, R¹⁰, R¹¹ and R^13'17 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.

Removable groups which may be represented by R⁵ include -P(O)R¹⁸R¹⁹, -P(O)OR²⁰OR²¹, -P(O)OR²⁰OH, -P(O)(OH)₂, -P(O)SR²²SR²³, -P(O)SR²²SH, -P(O)(SH)₂, -P(O)NR²⁴R²⁵NR²⁶R²⁷, -P(O)NR²⁴R²⁵NHR²⁶, -P(O)NHR²⁴NHR²⁶, -P(O)NR²⁴R²⁵NH₂, -P(O)NHR²⁴NH₂, -P(O)(NH₂J₂, -P(O)R¹⁸OR²⁰, -P(O)R¹⁸OH, -P(O)R¹⁸SR²², -P(O)R¹⁸SH, -P(O)R¹⁸NR²⁴R²⁵, -P(O)R¹⁸NHR²⁴, -P(O)R¹⁸NH₂, -P(O)OR²⁰SR²², -P(O)OR²⁰SH, -P(O)OHSR²², -P(O)OHSH, -P(O)OR²⁰NR²⁴R²⁵, -P(O)OR²⁰NHR²⁴, -P(O)OR²⁰NH₂, -P(O)OHNR²⁴R²⁵, -P(O)OHNHR²⁴, -P(O)OHNH₂, -P(O)SR²²NR²⁴R²⁵, -P(O)SR²²NHR²⁴, -P(O)SR²²NH₂, -P(O)SHNR²⁴R²⁵, -P(O)SHNHR²⁴, -PCO)SHNH₂, -P(S)R¹⁸R¹⁹, -P(S)OR²⁰OR²¹, -P(S)OR²⁰OH, -P(S)(OH)₂, -P(S)SR²²SR²³, -P(S)SR²²SH, -P(S)(SH)₂, -P(S)NR²⁴R²⁵NR²⁶R²⁷, -P(S)NR²⁴R²⁵NHR²⁶, -P(S)NHR²⁴N HR²⁶, -P(S)NR²⁴R²⁵NH₂, -P(S)NHR²⁴NH₂, -P(S)(NHa)₂, -P(S)R¹⁸OR²⁰, -P(S)R¹⁸OH, -P(S)R¹⁸SR²², -P(S)R⁸SH, -P(S)R¹⁸NR²⁴R²⁵, -P(S)R¹⁸NHR²⁴, -P(S)R¹⁸NH₂, -P(S)OR²⁰SR²², -P(S)OHSR²², -P(S)OR²⁰SH, -P(S)OHSH, -P(S)OR²⁰NR²⁴R²⁵, -P(S)OR²⁰NHR²⁴, -P(S)OR²⁰NH₂,

-P(S)OHNR²⁴R²⁵, -P(S)OHNHR²⁴, -P(S)OHNH₂, -P(S)SR²²MR²⁴R²⁵, -P(S)SR²²NHR²⁴, -P(S)SR²²NH₂, -P(S)SHNR²⁴R²⁵, -P(S)SHNHR²⁴, -P(S)SHNH₂, -PR¹⁸R¹⁹, -POR²⁰OR²¹, -PSR²²SR²³, -PNR²⁴R²⁵NR²⁶R²⁷, -PR¹⁸OR²⁰, -PR¹⁸SR²¹, -PR¹⁹NR²⁴R²⁵, -POR²⁰SR²², -POR²⁰NR²⁴R²⁵, -PSR²²NR²⁴R²⁵, -S(O)R²⁸, -S(O)₂R²⁹, -COR³⁰, -CO₂R³¹, or SiR³²R³³R³⁴ wherein R¹⁸ and R¹⁹ independently represent an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group or -N=CR³⁵R³⁶ where R³⁵ and R³⁶ are as defined for R¹; and R²⁰ to R³⁴ each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group.

When any of R^1'6, R⁹, R¹⁰, R¹¹ and R^13'34 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 R¹ above. One or more substituents may be present.

When any of R¹ & R², R¹ & R³, R² & R⁴, R³ & R⁴, R¹ & R⁵, R² & R⁶, and R⁵ & R⁶ 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. Examples of such compounds of formula (1 ) include 1-methyl-3,4- dihydroisoquinoline, 1-phenyl-3,4-dihydroisoquinoline, 1 -tetralone, 2-tetralone, 4- chromanone, 1-methyl-6,7-dirnethoxy-3,4-dihydroisoquinoline, 1-benzosubarone, 2- indanone and 1-indanone.

Compounds of formula (1 ) where X is represented by NR⁵ or (NR⁵R⁶)⁺Q^", include imines or immonium salts. Where a compound of formula (1) is an imine, it may optionally be converted to an immonium salt. Immonium salts are preferred over imines. Preferred immonium salts are represented by compounds of formula (1 ) in which X is (NR⁵R⁶)⁺Q- such that either R⁵ or R⁶ are hydrogen but that R⁵ or R⁶ are not identical. When the compound of formula (1 ) is an immonium salt, an anion represented by Q^" is present. Examples of anions which may be present are halide, sulphate, hydrogen sulphate, tosylate, formate, acetate, tetrafluoroborate, trifluoromethanesulphonate and trifluoroacetate.

X is preferably O, NR⁵ or (NR⁵R⁶)⁺Q. X is most preferably O. In certain preferred embodiments, R¹ and R² 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 R¹ and R² is a substituted phenyl group.

Examples of compounds of formula (1 ) include 1-phenylethan-1-one, 1-(4-chlorophenyl)ethan-1-one, 1-(4-methoxyphenyl)ethan-1-one, 1-(4- trifluoromethylphenyl)ethan-1 -one, 1 -(4-nitrophenyl)ethan-1 -one, 1 -(2-chlorophenyl)ethan- 1-one and N-benzyl-1-phenylethylimine.

The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R⁷ includes optionally substituted aryl and alkenyl ligands.

Optionally substituted aryl ligands which may be represented by R⁷ may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings. Preferably, 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. Particularly when the aryl ligand is a single ring, the ligand is preferably benzene or a substituted benzene. When the ligand is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When 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 R⁷ 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. When the alkene has only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl ligands include cyclo-octa-1 ,5- diene and 2,5-norbornadiene. Cyclo-octa-1 ,5-diene is especially preferred.

Optionally substituted cyclopentadϊenyl groups which may be represented by R⁷ includes 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. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Examples of optionally substituted cyclopentadienyl groups include cyclopentadienyl, pentamethyl- cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadϊenyl, menthyltetraphenylcyclopentadienyl, neomenthyl- tetraphenylcyclopentad ienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred.

Transfer hydrogenation catalysts of formula (2) wherein R⁷ is an optionally substituted cyclopentadienyl groups are most preferred.

When either A or B is an amide group represented by -NR⁸-, -NHR⁸, NR⁸R⁹, -NR¹²-, -NHR¹² or NR¹¹ R¹² wherein R⁹ and R¹¹ are as hereinbefore defined, and where R⁸ or R¹² is an acyl group represented by -C(O)R¹⁰ or -C(O)R¹³, R¹⁰ and R¹³ independently are often linear or branched C_1-7alkyl, C_1-8-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R⁸ or R¹³ include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl, groups.

When either A or B is present as a sulphonamide group represented by -NR⁸-, -NHR⁸, NR⁸R⁹, -NR¹²-, -NHR¹² or NR¹¹R¹² wherein R⁹ and R¹¹ are as hereinbefore defined, and where R⁸ or R¹² is a sulphonyl group represented by -S(O)₂R¹⁰ or -S(O)₂R¹³, R¹⁰ and R¹³ independently are often linear or branched C_1-8alkyl, C.,_₈cycloalkyl or aryl, for example phenyl. Preferred sulphonyl groups include methanesulphonyl, trifluoromethanesulphonyl and especially p-toluenesulphonyl groups and naphthylsulphonyl groups.

When either of A or B is present as a group represented by -NR⁸-, -NHR⁸, NR⁸R⁹, -NR¹²-, -NHR¹² or NR¹¹ R¹² wherein R⁹ and R¹¹ are as hereinbefore defined, and where R⁸ or R¹² is a group represented by C(O)NR¹⁰R¹⁴, C(S)NR¹⁰R¹⁴, C(=NR¹⁴)SR¹⁵, C(=NR¹⁴)OR¹⁵, C(O)NR¹³R¹⁶, C(S)NR¹³R¹⁶, C(=NR¹⁶)SR¹⁷ or C(=NR¹⁶)OR¹⁷, R¹⁰ and R¹³ independently are often linear or branched C_1-8alkyl, such as methyl, ethyl, isopropyl, C_1-8cycloalkyl or aryl, for example phenyl, groups and R^14"17 are often each independently hydrogen or linear or branched C_1-8alkyl, such as methyl, ethyl, isopropyl, C_1-8cycloalkyl or aryl, for example phenyl, groups.

When B is present as a group represented by -OR¹¹, -SR¹¹, -PR¹¹- or -PR¹¹R¹³, R¹¹ and R¹³ independently are often linear or branched (Ξ_1-8alkyl, such as methyl, ethyl, isopropyl,

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. Often the atoms linking A and B will be carbon atoms. Preferably, 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 R¹ as defined above. Substituent groups may also include sulphanted groups such as those defined for R⁹ above. Advantageously, 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. Most preferably, A and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety. When A and B are linked by two carbon atoms, 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. Particularly preferred are embodiments in which 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. Where 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. When at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state.

When 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, i-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. Further 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. When a diamine is represented by A-E-B, preferably at least one amino group is N-tosylated. The aminoalcohols or diamines sare 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.

Specific examples of compounds which can be represented by A-E-B and the protonated equivalents from which they may be derived are:

These compounds are used in their enantiomerically and/or diastereomerically purified forms. Examples include (1 S,2R)-(+)-norephedrine, (1 R,2S)-(+)-cis-1-amino-2-indariol, (1 S,2R)-2-amino-1 ,2-diphenyl ethanol, (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-tosyl-(1 S,2S)-1 ,2-diphenylethyIenediamI ne, (1 R,2S)-cis-1 ,2-indandiamine, (1 S,2R)-cis-1 ,2-indandiamine, (R)-(-)-2-pyrrolidinemethanol and (S)-(+)-2-pyrrolidinemethanol.

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. When the metal is ruthenium it is preferably present in valence state II. Wlhen the metal is rhodium or iridium it is preferably present in valence state I when R⁷ i s a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl lϊgand, and preferably present in valence state III when R⁷ is an optionally substituted cyclopentadienyl ligand.

Anionic groups which may be represented by Y include hydride, hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when a halogen is represented by Y, the halogen is chloride. When a hydrocarbyloxy or hydrocarbylannino 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.

Examples of catalysts which may be employed in the process of the present invention include

Hydrogen donors include hydrogen, primary and secondary alcohols, primary and secondary 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. When the hydrogen donor is an alcohol, secondary alcohols are preferred, especially propan-2-ol and butan-2-ol.

Primary and secondary 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 and secondary 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 and piperidine. When the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising a secondary alkyl grou p, particularly isopropylamine and isobutylamine.

Carboxylic acids or their esters which may be employed as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid is advantageously a beta-hydroxy-carboxylic acid. Esters may be derived from the carboxylic acid and a C_1-10 alcohol. Exampl es of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid. When a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as an amine salt or ammonium salt. Amines which may be used to form such salts include both aromatic and non-aromatic amines, also primary, secondary and tertiary amines and comprise typ>ically 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. When at least some of the carboxylic acid is present as an amine salt, particularly when a mixture of formic acid and triethylamine is employed, 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.

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 in elude 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 propan-2-ol, butan-2-ol, triethylammonium formate and a mixture of triethylammonium formate and formic acid.

The process is carried out preferably in the presence of a base, especially wrien Y is not a vacant site. The pK_a of the base is preferably at least 8.0, especially at least 10.0. Convenient bases are the hydroxides, alkoxides and carbonates of alkali metals; tertiary amines and quaternary ammonium compounds. Preferred bases are sodium 2-propoxide and triethylamine. When the hydrogen donor is not an acid, the quantity of base used can be up to 5.0, commonly up to 3.0, often up to 2.5 and especially in the range 1.0 to 3.5, by moles of the catalyst. When the hydrogen donor is an acid, the catalyst is preferably contacted with a base prior to the introduction of the hydrogen donor. In such a case, the mole ratio of base to catalyst prior to the introduction of the hydrogen donor is often from 1 : 1 to 3 : 1 , and preferably about 1 : 1.

The organic compound is reacted substantially in the presence of a catalysts regenerator. Substantially in the presence of, means that the catalysts regenerators may be present for the duration of the reaction or may be present intermittently during the reaction, for example being intermittently added as the reaction progresses. The speed and rate of addition of catalysts regenerators to the reaction may be varied in order to optimise yield and optical purity of the product. Advantageously, slow release agents may be employed to control the addition of the catalysts regenerators.

Advantageously, the use of the catalysts regenerators may allow for smaller amounts of catalyst to be used.

Catalyst regenerators which may be present include oxidants, for example KMnO₄, oxygen and oxygen/inert gas mixtures. Preferred catalysts regenerators include oxygen and oxygen/inert gas mixtures, for example air or oxygen/nitrogen mixtures.

Although pure oxygen may be used, often for safety and organic solvent compatibility reasons it is preferred that oxygen/inert gas mixtures are used. When oxygen/inert gas mixtures are used, the concentration of oxygen is often up to 30% (v/v), preferably up to 25% (v/v) and most preferably less than 10% (v/v), and typically from 0.01 to 10%(v/v), and often 0.05 to 5%(v/v) in the inert gas. Preferred inert gases are nitrogen and argon.

When oxygen or oxygen/inert gas mixtures are used, the flow rate of gas through the reaction mixture employed depends on factors such as the volume of reactor, ease of gas dispersion and volume of the reaction mixture. Preferably, the volume/min flow rate is from 0.01 to 20 times the volume of the reaction mixture, more preferably from 1 to 10 times the volume of the reaction mixture, and typically 5 to 8 times the volume of the reaction mixture.

When solid oxidants, for example KMnO₄, are used, the molar ratio of the catalyst regenerator to catalyst is preferably from 0.01 :1 up to 200: 1 , more preferably between 0.1 :1 and 20:1 and most preferably between 0.5:1 and 5:1.

Although gaseous hydrogen may be present, the process is normally operated in the absence of gaseous hydrogen since it appears to be unnecessary.

Suitably the process is carried out at temperatures in the range of from minus 78 to plus 150⁰C, preferably from minus 20 to plus 110⁰C and more preferably from minus 10 to plus 40⁰C. 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 catalyst 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. The hydrogen donor 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, dichloromethane or, conveniently, tine hydrogen donor when the hydrogen donor is liquid at the reaction temperature, particularly when the hydrogen donor is a primary or secondary alcohol or a primary or secondary amine. Usually it is preferred to operate in substantial absence of water, but water does not appear to inhibit the reaction. If the hydrogen donor, the substrate, the product and/or the reaction solvent are not miscible with water, it may be desirable to have water present as a second phase. Multi-phase systems may be advantageous when some components of the reaction reside in one phase and the other components of the reaction reside in another phase.

The invention is illustrated by the following Examples.

Example 1 : Reduction of 4-fluoroacetaphenone with and without KMnO₄ present

Rhodium Cp* chloride dimer (269.5mg, 4.4 x 10^"4 mol, 2 x 10^~3 moleq) and RRR- CsDPhen ligand (375.6mg, 8.8 x 10^"4 mol, 4 x 10^"3 moleq) were dissolved in acetonitrile (70ml) and stirred for 15 minutes. 4-fluoroacetophenone (3Og, 0.22 mbl, 1.0 moleq) and biphenyl (5g, as internal standard) were dissolved in acetonitrile (40ml) and added to the catalyst solution. An initial sample was taken before adding TEAF (43ml, 5:2 formic acid : TEA, 0.48 mol, 2.2 moleq of formic acid) over 150 minutes with continual sampling. Samples of 0.25ml were removed and quenched into 2ml DCM/2ml 10% NaOH solution. The DCM phase was separated, dried over magnesium sulphiate and diluted before chiral GC analysis.

The reaction was then repeated but with the addition of KMnO₄ (140mg, 2eq based on catalyst) every 50 minutes.

GC Method

Initial temperature 80⁰C

Initial time 5 minutes

Rate 10°C/minute

Final temperature 180⁰C

Final time 10 minutes

Front inlet temperature 250⁰C

Column head pressure 12 PSI

Column Chrompack CP7502 CP-Chirasil-Dex-CB

Maximum temperature 200⁰C

Dimensions 25.0m x 250.0μm x 0.25μm

Retention times

4-fluoroacetophenone 9.4 minutes Biphenyl (internal standard) 1 4.6 minutes R-1 -(4-fluorophenyl)ethanol 1 2.2 minutes S-1 -(4-fluorophenyl)ethanol 1 2.4 minutes

Example 2 : Reduction of 4-fluoroacetaphenone under nitrogen sparging and under air sparging.

Rhodium Cp^* chloride dimer (269.5mg, 4.4 x 10^"4 mol, 2 x 10^"3 moleq) and RRR- CsDPhen ligand (375.6mg, 8.8 x 10^"4 mol, 4 x 10^"3 moleq) were dissolved in acetonitrile (70ml) and stirred for 15 minutes. 4-fluoroacetophenone (3Og, 0.22 mol, 1.0 moleq) and biphenyl (5g, as internal standard) were dissolved in acetonitrile (40ml) and added to the catalyst solution. An initial sample was taken before adding TEAF (43ml, 5:2 formic acid : TEA, 0.48 mol, 2.2 moleq of formic acid) over 150 minutes with continual sampling. Samples of 0.25ml were removed and quenched into 2ml DCM/2ml 1O% NaOH solution. The DCM phase was separated, dried over magnesium sulphate and diluted before chiral GC analysis.

The gas sparge experiments were then conducted with a sparge tube submersed within the reaction medium, the flow rate of gas throughout the reaction was 300ml/min (2 volumes of gas per volume of reaction).

Example 3: Comparison of low percentages of oxygen in nitrogen

Sparging reactions using 1 % and 0.1 % oxygen in nitrogen were conducted as described in Example 2 the flow rate of gas was 300ml/min (2 volumes of gas per volume of reaction) and the reactions were compared against a control reaction using a nitrogen sparge.

Example 4: Comparison of nitrogen and air sparging for acetophenone.

The reactions were conducted as described in Example 2 but using DMF as solvent in place of acetonitrile and acetophenone as the substrate in place of A- fluoroacetophenone.

Retention time

Acetophenone 9.7 min

R-1-phenylethanol 11.8 min

S-1-phenylethanol 11.9 min

Claims

1. A process for the transfer hydrogenation of an organic compound having a carbon-carbon or carbon-heteroatom double bond wherein a) the organic compound is reacted with a hydrogen donor in the presence of a transfer hydrogenation catalyst, and b) substantially in the presence of a catalyst regenerator.

2. A process according to claim 1 wherein the organic compound having a carbon- carbon or carbon-heteroatom double bond is a compound of formula (1):

(1 ) wherein:

X represents CR³R⁴, NR⁵, (NR⁵R⁶)⁺Q/, O or S;

Q^" represents an anion;

R¹, R² each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group;

R⁵ independently represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group or a removable group; or one or more of R¹ & R², R¹ & R³, R² & R⁴, R³ & R⁴, R¹ & R⁵, R² & R⁶ and R⁵ & R⁶ optionally being linked in such a way as to form an optionally substituted ring(s).

3. A process according to Claim 1 or 2 wherein the transfer hydrogenation catalyst is a catalyst of general formula (2):

A \ M .^B Y R⁷

(2) wherein:

R⁷ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;

A represents -NR⁸-, -NR⁹-, -NHR⁸, -NR⁸R⁹ or -NR⁹R¹⁰ where R⁸ is H, C(O)R¹⁰, SO₂R¹⁰, C(O)NR¹⁰R¹⁴, C(S)NR¹⁰R¹⁴, C(=NR¹⁴)SR¹⁵ or C(=NR¹⁴)OR¹⁵, R⁹ and R¹⁰ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and

R¹⁴ and R¹⁵ are each independently hydrogen or a group as defined for R¹⁰;

B represents -O-, -OH, OR¹¹ , -S-, -SH, SR¹¹, -NR¹¹-, -NR¹²-, -MHR¹², -NR¹¹R¹²,

-NR¹¹R¹³, -PR¹¹- or -PR¹¹R¹³ where R¹² is H, C(O)R¹³, SO₂R^{1 3}, C(O)NR¹³R¹⁶,

C(S)NR¹³R¹⁶, C(=NR¹⁶)SR¹⁷ or C(=NR¹⁶)OR¹⁷, R¹¹and R¹³ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹⁶ and R¹⁷ are each independently hydrogen or a group as defined for R¹³;

E represents a linking group;

M represents a metal capable of catalysing transfer hydrogenation ; and

Y represents an anionic group, a basic ligand or a vacant site; provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

4. A process according to any one of Claims 1 to 3 wherein the catalyst regenerator is present for the duration of the reaction or is present intermittently during the reaction.

5. A process according to any one of Claims 1 to 4 wherein the catalyst regenerator is an oxidant.

6. A process according to Claim 5 wherein the catalyst regenerator is KMnO₄, oxygen or an oxygen inert gas mixture.

7. A process according to Claim 6 wherein the catalyst regenerator is an oxygen inert gas mixture.

8. A process according to Claim 7 wherein the oxygen inert gas mixture is a mixture of oxygen in nitrogen or oxygen in argon, wherein the concentration of oxygen is up to 30% (v/v).