WO2009019469A2 - Composés catalyseurs - Google Patents

Composés catalyseurs Download PDF

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Publication number
WO2009019469A2
WO2009019469A2 PCT/GB2008/002663 GB2008002663W WO2009019469A2 WO 2009019469 A2 WO2009019469 A2 WO 2009019469A2 GB 2008002663 W GB2008002663 W GB 2008002663W WO 2009019469 A2 WO2009019469 A2 WO 2009019469A2
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Prior art keywords
compound
group
around
formula
reducing agent
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PCT/GB2008/002663
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WO2009019469A9 (fr
WO2009019469A3 (fr
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Simon Jones
François-Moana GAUTIER
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The University Of Sheffield
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Publication of WO2009019469A3 publication Critical patent/WO2009019469A3/fr
Publication of WO2009019469A9 publication Critical patent/WO2009019469A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
    • C07C211/48—N-alkylated amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to compounds for use as catalysts, methods for producing said compounds and the use of said compounds as catalysts in catalytic processes including, but not limited to, the asymmetric reduction of imine compounds and/or the reductive animation of aldehyde or ketone compounds.
  • compounds containing imine groups can also be used, whereby the imine group is reduced to the corresponding chiral amine group.
  • the three most widely adopted methods developed to date are transition metal catalysed high pressure hydrogenation, hydrosilylation (typically using trichlorosilane) and transfer hydrogenation. Methods employing metal catalysts, however, suffer from disadvantages associated with metal leaching and catalyst regeneration and so the development of improved catalysts for the generation of chiral amines is of significant commercial interest.
  • An object of the present invention is to obviate or mitigate one or more of the above problems.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each separately selected from the group consisting of hydrogen, alkyl and aryl; X is oxygen or sulfur; and Z has the formula (II)
  • R 6 and R 7 are each separately selected from the group consisting of hydrogen, alkoxy, nitro, halogen, alkyl and aryl, or R 6 and R 7 are linked to form a cyclic group; and Y is oxygen, sulfur or NR in which R 10 is selected from the group consisting of hydrogen, alkyl and aryl.
  • Examples 8 to 11 demonstrate the applicability of compounds according to the first aspect of the present invention to the direct asymmetric reductive amination of aldehydes and ketones to corresponding chiral amine compounds.
  • Example 12 illlustrates the ability for compounds according to the first aspect of the present invention to catalyse the asymmetric reduction of enamines to corresponding chiral amine compounds, for example amino acids by selection of appropriate carboxyl/carboxylate group containing substrates.
  • R 8 and R 9 are each separately selected from the group consisting of hydrogen, alkoxy, nitro, halogen, alkyl and aryl; and Y is oxygen, sulfur or NR 1 in which R 10 is selected from the group consisting of hydrogen, alkyl and aryl.
  • a second aspect of the present invention provides a process for the production of a compound according the first aspect of the present invention, the process comprising reacting a compound of formula (IX) with a compound of formula (X) in the presence of a base
  • R 11 is a substituted or unsubstituted alkyl group.
  • a related aspect of the present invention provides a process for the production of a compound according formula (I) in which Z is formula (III), the process comprising reacting a compound of formula (IX) with a compound of formula (XI) in the presence of a base
  • R 1 ' is a substituted or unsubstituted alkyl group.
  • Examples 1 and 2 below describe preferred methods for the production of compounds (Villa) and (XVIa), which represent preferred embodiments of the first aspect of the present invention.
  • a process for effecting catalytic reduction of an imine compound to provide a corresponding amine compound comprising reacting said imine compound with a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention.
  • a fourth aspect of the present invention provides use of a compound having a formula according to the first aspect of the present invention to catalyse the reduction of an imine compound to provide a corresponding amine compound.
  • a process for effecting the direct asymmetric reductive amination of a first compound including an aldehyde or ketone group with a second compound including a first amine group to provide a third compound including a second amine group comprising reacting said first compound with said second compound and a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention.
  • a sixth aspect of the present invention provides use of a compound having a formula according to the first aspect of the present invention to catalyse the direct asymmetric reductive amination of an aldehyde or ketone compound to provide an amine compound.
  • a seventh aspect of the present invention there is provided a process for effecting catalytic reduction of an enamine compound to provide a corresponding amine compound, the process comprising reacting said enamine compound with a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention.
  • a eighth aspect of the present invention provides use of a compound having a formula according to the first aspect of the present invention to catalyse the reduction of an enamine compound to provide a corresponding amine compound.
  • reduction of the enamine compound is effected using a chiral catalytic compound according to the first aspect of the present invention such that the process provides a chiral amine compound.
  • a chiral catalytic compound such that the process provides a chiral amine compound.
  • alkyl or “alkyl group” is used herein without any further qualification it is to be interpreted as encompassing both substituted and unsubstituted alkyl groups. Moreover, where the term “alkyl” or “alkyl group” is used herein without any further qualification it will be understood to encompass linear, branched and cyclic alkyl groups.
  • aryl or "aryl group” is used herein without any further qualification it is to be interpreted as encompassing both substituted and unsubstituted aryl groups. Any substitution may be provided as an appendage to the carbocyclic ring structure and/or within the carbocyclic ring structure wherein at least one carbon atom forming part of the aryl ring structure is replaced with a non- carbon atom so as to provide a heteroaryl ring structure, e.g. a pyridinyl group.
  • a Roman reference numeral will be used and where a formula is used to depict a specific enantiomer of that compound the Roman reference numeral will be suffixed by a letter 'a' or 'b'.
  • a preferred compound according to the first aspect of the present invention has a generic formula denoted '(VIII)' and the (S)- enantiomer of this preferred compound is denoted '(VIIIa)'.
  • X may be oxygen or sulfur
  • X is oxygen such that compound (I) incorporates a central carbonyl moiety.
  • the preferred embodiment of compound (I), wherein X is oxygen incorporates an amide functional group. Since the nitrogen atom bonded to the carbonyl carbon atom forms part of a 5-membered heterocyclic ring, the amide functional group is a cyclic amide.
  • substituent Y may be oxygen, sulfur or NR 10 , in which R 10 is hydrogen, alkyl or aryl. It is preferred that Y is NR 10 such that group Z is an imidazole of formula (XXVII) or (XXVIII).
  • R 10 is an alkyl group, more preferably a C 1 -C 6 linear or branched alkyl group, such as a methyl, ethyl or propyl group. Most preferably, R 10 is a methyl group.
  • each of these substituents may be individually selected from the group consisting of hydrogen, alkoxy (e.g. methoxy, ethoxy), nitro (-NO 2 ), halogen (e.g. F, Cl, Br, I), alkyl (e.g. Ci- C 6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl). It is preferred that at least one of R 6 and R 7 is hydrogen, more preferably, both of R 6 and R 7 are hydrogen.
  • group Z has a formula (V)
  • R 6 and R 7 may be linked to form a cyclic group, which may be substituted with one or more substituent selected from the group consisting of hydrogen, alkoxy (e.g. methoxy, ethoxy), nitro (-NO 2 ), halogen (e.g. F, Cl, Br, I), alkyl (e.g. Ci-C 6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl). It is particularly preferred that the cyclic group, which may be substituted or unsubstituted, is a cycloalkyl group or an aromatic group.
  • substituent selected from the group consisting of hydrogen, alkoxy (e.g. methoxy, ethoxy), nitro (-NO 2 ), halogen (e.g. F, Cl, Br, I), alkyl (e.g. Ci-C 6 linear or branched alkyl group, such as methyl, ethyl
  • R and R are individually selected from the group consisting of hydrogen, alkoxy (e.g. methoxy, ethoxy), nitro (-NO 2 ), halogen (e.g. F, Cl, Br, I), alkyl (e.g. C 1 -C 6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl).
  • At least one of R 8 and R 9 may be hydrogen and it is preferred that both R 8 and R 9 are hydrogen.
  • a preferred embodiment of the compound having formula (I) incorporates group Z having the formula (VII)
  • R 1 and R 2 are each separately selected from the group consisting of hydrogen, alkyl (e.g. C 1 -C 6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl).
  • alkyl e.g. C 1 -C 6 linear or branched alkyl group, such as methyl, ethyl or propyl
  • aryl e.g. phenyl
  • At least one of R 1 and R 2 is a relatively bulky group, i.e. possessing an atomic radius greater than hydrogen. It is thus preferred that at least one of R 1 and R 2 is an alkyl group or an aryl group. Suitable alkyl groups incorporate at least one to six carbon atoms and possibly more, and include linear or branched alkyl groups, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • At least one of R 1 and R 2 is preferably an aryl group, preferably both of R 1 and R are the same or different aryl groups, such as phenyl, benzyl, tolyl or xylyl groups. It is particularly preferred that both R 1 and R 2 are phenyl groups, such that formula (XXIX) below represents a preferred structure for the compound according to the first aspect of the present invention.
  • R 3 , R 4 and R 5 are each separately selected from the group consisting of hydrogen, alkyl (e.g. Ci-C 6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl). It is preferred that at least one of R 3 , R 4 and R 5 is hydrogen, more preferably at least two of R 3 , R 4 and R 5 is hydrogen, and most preferably R 3 , R 4 and R 5 are all hydrogen.
  • alkyl e.g. Ci-C 6 linear or branched alkyl group, such as methyl, ethyl or propyl
  • aryl e.g. phenyl
  • R 1 and R 2 are phenyl
  • R 3 , R 4 and R 5 are hydrogen
  • X is oxygen
  • a particularly preferred embodiment of the first aspect of the present invention has the formula (VIII)
  • Another preferred embodiment of the first aspect of the present invention has the formula (XIXa)
  • a still further preferred embodiment of the first aspect of the present invention has the formula (XXXXVIa)
  • R 11 is a substituted or unsubstituted alkyl group.
  • Preferred embodiments of the compound of formula (I) incorporate a central carbonyl moiety, i.e. where X is oxygen, and so preferred processes for producing these preferred embodiments of compound (I) utilise an ester derivative of compounds (X) and (XI).
  • a preferred method for producing preferred compound (Villa) is set out below in Example 1, wherein a preferred embodiment of compound (X), ester compound (XII), is reacted with a preferred embodiment of compound (IX), compound (XIIIa), to produce compound (Villa).
  • a further preferred method for producing a different preferred compound (XVIa) is set out below in Example 2, wherein a preferred embodiment of compound (X), ester compound (XIV), is reacted with a preferred embodiment of compound (IX), compound (XVa), to produce compound (XVIa).
  • the base is sodium hydride.
  • reaction of compound (IX) with compound (X) or (XI) may be effected at any suitable temperature. It is preferred that the reaction is carried out at an elevated temperature, that is, a temperature above room temperature. Preferably, the reaction is effected at a temperature of at least around 40 °C, more preferably at least around 50 °C, more preferably at least around 60 0 C, and most preferably at a temperature of around 70 °C.
  • Compound (IX) may be reacted with compound (X) or (XI) over any appropriate time period. It is desirable that the reaction time should be sufficiently long to ensure that as much of starting material as possible has been converted to product. Preferably the reaction is effected over a time period of at least around 10 hours, more preferably at least around 20 hours and still more preferably at least around 30 hours. Most preferably the reaction is effected over a time period of around 40 hours.
  • the third aspect of the present invention relates to a process for effecting catalytic reduction of an imine compound to provide a corresponding amine compound, the process comprising reacting said imine compound with a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention, that is, a compound of formula (I).
  • the imine nitrogen atom is bonded to an electron-withdrawing group.
  • the imine nitrogen atom is bonded to an atom or group of atoms of higher electronegativity than the imine nitrogen atom.
  • the imine nitrogen atom may be bonded to an atom or group of atoms which polarises the bond connecting said atom or group of atoms to the imine nitrogen atom.
  • said polarisation produces a dipole across the bond such that a partial positive charge (sometimes referred to as a "delta positive” charge) resides on the imine nitrogen atom and a partial negative charge (sometimes referred to as a "delta negative” charge) resides on the atom or group of atoms bonded to the imine nitrogen atom.
  • the imine nitrogen atom is bonded to an electron-donating group, which is of lower electronegativity than the imine nitrogen atom, such that a partial negative charge resides on the imine nitrogen atom and a partial positive charge resides on the atom or group of atoms bonded to the imine nitrogen atom.
  • the imine nitrogen atom is bonded directly to a cyclic group, such as a carbocyclic or heterocyclic group which may be aromatic or non- aromatic.
  • the imine nitrogen atom may be bonded to a cyclic group (e.g. an aryl group) via a bivalent alkyl group, such as a Ci-C 6 bivalent alkyl group, e.g. methylene.
  • the imine nitrogen atom is bonded directly to an aromatic group, which is preferably substituted with one or more atoms or groups of atoms which are other than hydrogen atoms. It is particularly preferred that the aromatic group is substituted with one or more electron donating group, for example an alkoxide group, such as a methoxy group. Most preferably the or each electron donating group is provided at the position on the aromatic group which maximises the electron donating ability of that group.
  • a six-membered aryl group e.g.
  • aryl group is substituted with a methoxy group at the carbon atom of the aryl group that is para to the carbon bonded to the imine nitrogen atom.
  • each of R 12 , R 13 and R 14 is a chemical group, for example but not limited to, hydrogen, alkyl or aryl, moreover, R 12 and R 13 may be linked to form a carbocyclic or heterocyclic ring structure.
  • R 14 is an electron withdrawing group, although in other preferred embodiments R 14 may be an electron donating group. It will be appreciated that the electronegativity of the imine nitrogen atom will be affected to some extent by the nature of the other two atoms or groups (R 12 and R 13 ) bonded to the imine nitrogen. Accordingly, the electron donating/withdrawing ability of a particular R 14 group relative to the imine nitrogen atom may also be affected by the nature of R 12 and/or R 13 .
  • compound (XXX) is not an oxime.
  • R 14 is preferably any chemical group, subject to the proviso that it is other than a hydroxide group or alkoxide group bonded to the imine nitrogen atom via the alkoxide oxygen atom.
  • compound (XXX) is other than an enamide and/or phosphinoylimine.
  • the third aspect of the present invention therefore provides a means by which an imine, preferably a ketimine, functional group present in a compound can be 1 /
  • the achiral imine functionality can be converted to a chiral amine possessing the desired stereochemistry in high enantiomeric excess.
  • the catalyst is provided in an amount of around 0.01 mol % to around 10 mol % of the amount of the reducing agent.
  • the catalyst loading may be lowered further, such that the catalyst may be provided in an amount of around 0.01 mol % to around 5 mol % of the amount of the reducing agent, or an amount of around 0.01 mol % to around 2 mol % of the amount of the reducing agent. More preferably still lower catalyst loadings may be employed, such as around 1 mol % of the amount of the reducing agent.
  • the catalyst is provided in an amount of around 0.01 mol % to around 1 mol % of the amount of the reducing agent.
  • Any suitable reducing agent may be used provided it shows the potential to reduce a carbon-nitrogen double bond to a carbon-nitrogen single bond, that is, reduce an imine to a corresponding amine.
  • Preferred reducing agents are silanes and a particularly preferred reducing agent is trichlorosilane, not least because it is known to be a cheap, versatile reducing agent.
  • the initial molar amount of the reducing agent is in excess of the initial molar amount of the imine that is to undergo asymmetric reduction to a corresponding amine.
  • the initial molar ratio of the reducing agent compared to the imine may lie in the range around 1 : 1 (reducing agent : imine) to around 5 : 1. That is, the reducing agent and imine may be provided initially in approximately equal molar amounts or up to an amount whereby the reducing agent is provided in a fivefold excess compared to the amount of the imine starting material.
  • the initial molar ratio of the reducing agent compared to the imine may be in the range around 1.5 : 1 (reducing agent : imine) to around 4 : 1, and may lie in the range around 1.5 : 1 to around 2 : 1.
  • the reducing agent is provided in about two-fold excess compared to the initial amount of imine, i.e. a molar ratio of around 2 : 1 (reducing agent : imine).
  • the asymmetric reduction reaction may be effected over a wide range of reaction temperatures without detriment to the enantiomeric excess obtained.
  • the process may be effected at a reaction temperature in the range around -20 °C to around 30 °C, more preferably at a reaction temperature in the range around 0 °C to around 25 °C. Still more preferably, the process is effected at a reaction temperature in the range around 0 °C to around 15 0 C.
  • reaction solvent Any appropriate reaction solvent or mixture of solvents may be employed in the asymmetric reduction reaction.
  • Preferred solvents are selected from the group consisting of trichloromethane, dichloromethane and toluene.
  • Any suitable reaction time may be adopted in order to obtain the optimum yield.
  • the process may be effected over a time period of up to around 15 hours, more preferably a time period in the range around 1 hour to around 13 hours, or most preferably a time period of around 4 hours.
  • the fifth aspect of the present invention provides a process for effecting the direct, i.e. single-step or 'one-pot', asymmetric reductive animation of a first compound including an aldehyde or ketone group with a second compound including a first amine group to provide a third compound including a second amine group, the process comprising reacting said first compound with said second compound and a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention.
  • the basis of the reductive animation process is to couple compound (XXXII) to compound (XXXIII) by linking the carbonyl carbon atom of compound (XXXII) to the amine nitrogen atom of compound (XXXIII).
  • the new amine compound (XXXIV) is generated in which groups R 15 , R 16 and R 17 are linked via a new carbon-nitrogen bond and resulting in that carbon atom being a chiral centre when R 16 and R 17 are different chemical groups.
  • each of R 15 , R 16 and R 17 is any chemical group, for example but not limited to, hydrogen, alkyl or aryl.
  • R 15 and R 16 can also be linked to form a carbocyclic or heterocyclic ring.
  • the reducing agent may be a silane, and is preferably trichlorosilane.
  • the catalyst is provided in an amount of around 0.01 mol % to around 10 mol % of the amount of the reducing agent.
  • the catalyst loading may be lower, for example 0.01 mol % to around 5 mol %, or around 0.01 mol % to around 2 mol % of the amount of the reducing agent. Yet more preferably even lower catalyst loadings may be employed, such as around 1 mol % of the amount of the reducing agent.
  • the catalyst is provided in an amount of around 0.01 mol % to around 1 mol % of the amount of the reducing agent.
  • the first compound i.e. the aldehyde or ketone starting material
  • the second compound i.e. the amine starting material
  • the initial molar amount of the reducing agent is preferably in excess of the initial molar amount of the aldehyde or ketone that is to undergo reductive amination to the third compound (i.e. the product incorporating the second amine group).
  • the initial molar ratio of the reducing agent compared to the aldehyde or ketone may lie in the range around 1 : 1 to around 5 : 1.
  • the reducing agent and aldehyde/ketone may be provided initially in approximately equal molar amounts or up to an amount whereby the reducing agent is provided in a five-fold excess compared to the amount of the aldehyde/ketone starting material.
  • the initial molar ratio of the reducing agent compared to the aldehyde/ketone may be in the range around 1.5 : 1 (first compound : second compound) to around 4 : 1, and may lie in the range around 1.5 : 1 to around 2 : 1.
  • the reducing agent is provided in about two-fold excess compared to the initial amount of aldehyde/ketone, i.e. a molar ratio of around 2 : 1.
  • the solvent in which the reductive amination process is carried out may be any appropriate solvent. It is preferred that the process in carried out in a non-polar solvent.
  • a preferred reaction solvent is dichloromethane.
  • the reductive amination can be conducted at any suitable temperature, for example, a temperature in the range around 0 0 C to around 50 °C.
  • the reaction is more preferably carried out at a temperature in the range around 10 0 C to around 40 °C, still more preferably around 20 0 C to around 30 0 C.
  • the reaction is most preferably carried out at around room temperature.
  • reaction time period may be adopted to provide optimum generation of the chiral amine product, that is, a satisfactory yield over a realistic and economically viable time period. It is preferred that the reaction is carried out over a time period of up to around 30 hours, more preferably around 1 hour to around 20 hours, and still more preferably around 5 hours to around 20 hours. It is most preferred that the process is carried out over a time period of around 15 hours.
  • a further related aspect of the present invention relates to a compound for use as a catalyst, said compound comprising a catalytic moiety linked to a polymer support, wherein said compound has the formula (XXXV)
  • R 18 is alkyl or alkoxy;
  • A is alkyl, aryl or -(CH 2 O) 01 -CH 2 - in which m is an integer that may be zero or higher;
  • p is a non-zero integer;
  • n is a non-zero integer representing the number of repeating units of the structure shown comprised in the backbone of the polymer support.
  • the catalytic moiety is the oxazaborolidine functional group and the polymer support is the bracketed portion of formula (XXXV) incorporating the cyclopentane ring.
  • the poly ether containing chain incorporating the group A may be considered as a linking group which connects the catalytic moiety to the polymer support.
  • Reducing agent e.g. BH 3
  • R . 19 , R >20 and R >21 may be any chemical group, such as but not limited to, hydrogen, alkyl or aryl.
  • R ,22 may be an alkyl group.
  • R and R ,20 may be linked to form a carbocyclic or heterocyclic ring.
  • a further related aspect of the present invention relates to a process for the reduction of an imine or oxime functional group present in a molecule to provide an amine functional group, wherein the process comprises reacting the molecule containing the imine or oxime functional group with a reducing agent in the presence of a compound of formula (XXXV).
  • Another aspect of the present invention relates to use of a compound of formula (XXXV) to catalyse the reduction of an imine or oxime functional group present in a molecule to provide an amine functional group in said molecule.
  • the compound of general formula (XXXV) may be used to catalyse the reduction of a ketone functional group within a molecule to an alcohol, typically chiral alcohol, functional group, as depicted generically below.
  • Reducing agent e.g. BH 3 UH »
  • R 19 and R 20 may be alkyl or aryl. Moreover, R 19 and R 20 may be linked to form a carbocyclic or heterocyclic ring.
  • a still further related aspect of the present invention relates to a process for the reduction of a ketone functional group present in a molecule to provide an alcohol functional group, wherein the process comprises reacting the molecule containing the ketone functional group with a reducing agent in the presence of a compound of formula (XXXV).
  • Another aspect of the present invention relates to use of a compound of formula (XXXV) to catalyse the reduction of a ketone functional group present in a molecule to provide an alcohol functional group in said molecule.
  • Any appropriate reducing agent may be used, such as a borane, e.g. BH 3 .
  • the reducing agent may be provided in any suitable amount to provide the desired yield of the amine or alcohol.
  • the reaction time and temperature may each be selected to suit a particular application. While the reduction reaction may be carried out in any suitable solvent, it is preferred that the reaction is carried out in tetrahydrofuran.
  • the catalyst compound (XXXV) may be provided in any desirable amount.
  • a catalyst loading of around 10 % compared to the molar amount of the imine/oxime/ketone starting material may be used. More preferably a catalyst loading of around 0.1 % to around 10 % is used, more preferably from around 0.1 % to around 5 %. Most preferably a lower catalyst loading of around 0.1 % to around 2 % is used. Most preferably a catalyst loading of around 1 % compared to the molar amount of the imine/oxime/ketone starting material is used.
  • R may be an alkyl group or an alkoxy group. It is preferred that R 18 is a Ci-C 6 linear or branched alkyl group. More preferably R 18 is a Ci-C 3 linear alkyl group, most preferably a methyl group.
  • Group A which forms part of the linker connecting the catalytic moiety to the polymer support may be an alkyl, aryl or -(CH 2 O) 1n -CH 2 - group.
  • the alkyl group is preferably a Ci-C 6 linear or branched alkyl group, such as methyl, ethyl or propyl group.
  • group A may be an aryl group, such as a phenyl, benzyl, tolyl or xylyl group.
  • m is an integer from 1 to 6, more preferably 1 to 4 and most preferably 1 to 2.
  • integer m is zero, the -(CH 2 O)- repeating unit is not present such that a methylene group connects the oxygen atom bonded to the benzene ring of the catalytic moiety to the oxygen atom linked via a methylene group to the cyclopentane ring forming part of the backbone of the polymer support.
  • the polymer support may incorporate any appropriate number of cyclopentane- containing repeating units, in other words, n may take any appropriate value.
  • n may take any appropriate value. The provision of the polymer support significantly eases separation of the catalytic moiety from the reaction mixture once the reaction has run to completion or reached the desired end point.
  • Another aspect of the present invention provides a process for the production of compound (XXXV). It is preferred that the process comprises ring opening metathesis polymerisation (ROMP) of appropriate starting materials.
  • REP ring opening metathesis polymerisation
  • a generalised scheme for the production of the compound (XXXV) is set out below.
  • Compound (Villa) which represents a preferred embodiment of the first aspect of the present invention, was prepared by reacting compound XII with compound XIIIa in the presence of a base as follows
  • Compound (XVIa) which represents a further preferred embodiment of the first aspect of the present invention, was prepared by reacting compound XIV with compound XVa in the presence of a base as follows:
  • a compound having the formula (Villa) in accordance with a preferred embodiment of the present invention was tested as a catalyst in the asymmetric reduction of the ketimine, N-phenyl acetophenone (XVII), to the corresponding chiral amine
  • the asymmetric reduction reaction was carried out by addition of trichlorosilane to a stirred solution of the ketimine (XVII) and catalyst (Villa) in dry dichloromethane under an atmosphere of nitrogen at 0 °C. After 4 hours, the reaction was quenched with 1 M hydrochloric acid and subjected to standard work-up procedures.
  • the asymmetric reduction reaction was carried out by addition of trichlorosilane to a stirred solution of the ketimine (XVII) and catalyst (XIXa) in dry dichloromethane under an atmosphere of nitrogen at 0 0 C. After 4 hours, the reaction was quenched with 1 M hydrochloric acid and subjected to standard work-up procedures.
  • the asymmetric reduction reaction was carried out by addition of trichlorosilane to a stirred solution of the ketimine (XVII) and catalyst (XIXa) in dry dichloromethane under an atmosphere of nitrogen at 0 °C. After 4 hours, the reaction was quenched with 1 M hydrochloric acid and subjected to standard work-up procedures.
  • Each asymmetric reduction reaction was carried out by addition of trichlorosilane to a stirred solution of the ketimine (XVII) and catalyst (Villa) in a dry solvent under an atmosphere of nitrogen at a predefined temperature. After a predetermined amount of time (indicated in Table 1 below) each reaction was quenched with 1 M hydrochloric acid and subjected to standard work-up procedures.
  • the starting ketone was 1-cyclohexylethanone.
  • the amine starting material and the reducing agent were the same as in Example 8, that is, p- methoxyaniline and trichlorosilane respectively.
  • the reaction was again carried out in dichloromethane, at room temperature but over a longer time period of 24 hours. A catalyst loading of 10 % was again used.
  • the starting ketone was 1 -(4-nitrophenyl)ethanone.
  • the amine starting material and the reducing agent were again the same as in Example 8, i.e. p- methoxyaniline and trichlorosilane respectively.
  • the reaction was carried out in dichloromethane, at room temperature over 24 hours. A catalyst loading of 10 % was used.
  • reaction shown below was carried out by addition of trichlorosilane (2 eq.) to a stirred solution of a /? ⁇ r ⁇ -methoxyphenyl protected enamine and catalyst (Villa) (10 mol %) in dry CH 2 Cl 2 under an atmosphere of nitrogen at 0 °C. After 4 hours the reaction was quenched with 1 M hydrochloric acid and subjected to standard work-up procedures.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention porte sur des composés destinés à être utilisés comme catalyseurs, sur des procédés de fabrication desdits composés, et sur l'utilisation desdits composés comme catalyseurs dans des procédés catalytiques, comprenant mais sans y être limités, la réduction asymétrique de composés imines et énamines et/ou l'animation réductrice de composés cétones. Un composé destiné à être utilisé comme catalyseur est représenté par la formule (I) dans laquelle chacun parmi R1, R2, R3, R4 et R5 est choisi séparément du groupe constitué par hydrogène, alkyle et aryle; X représente oxygène ou soufre; et Z a la formule (II) dans laquelle chacun parmi R6 et R7 est choisi séparément dans le groupe constitué par hydrogène, alcoxy, nitro, halogène, alkyle et aryle, ou R6 et R7 sont liés pour former un groupe cyclique; et Y représente oxygène, soufre ou NR10 dans lequel R10 est choisi dans le groupe constitué par hydrogène, alkyle et aryle.
PCT/GB2008/002663 2007-08-06 2008-08-05 Composés catalyseurs WO2009019469A2 (fr)

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GB0715206.9 2007-08-06
GB0715206A GB2451629A (en) 2007-08-06 2007-08-06 1-(Azolylcarbonyl)-2-(hydroxymethyl)pyrrolidine derivatives for use as catalysts for asymmetric reduction of imines & reductive amination of ketones

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