WO2009068284A2 - Process for the stereoselective reduction of ketoimines catalysed by trichlorosilane - Google Patents

Process for the stereoselective reduction of ketoimines catalysed by trichlorosilane Download PDF

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WO2009068284A2
WO2009068284A2 PCT/EP2008/010079 EP2008010079W WO2009068284A2 WO 2009068284 A2 WO2009068284 A2 WO 2009068284A2 EP 2008010079 W EP2008010079 W EP 2008010079W WO 2009068284 A2 WO2009068284 A2 WO 2009068284A2
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alkyl
branched
straight
formula
halogen
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PCT/EP2008/010079
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WO2009068284A3 (en
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Maurizio Benaglia
Stefania Guizzetti
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Universita Degli Studi Di Milano
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Priority claimed from EP08016622A external-priority patent/EP2166002A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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

Definitions

  • the present invention relates to a process for the preparation of enantiomerically enriched amines from ketoimines catalysed by picolinic acid derivatives.
  • N-picolinoyl aminoalcohols as metal-free catalysts for the enantioselective reduction of N-aryl ketoimines with trichlorosilane. Zheng et al /tetrahedron Lett.
  • N-aryl ketoimines with trichlorosilane in the presence of a picolinic acid derivative as catalyst can be carried out in one-pot forming the ketoimine in situ from suitable precursors, i.e. a primary aromatic amine and a ketone.
  • suitable precursors i.e. a primary aromatic amine and a ketone.
  • formed in situ or “prepared in situ” means that the amine, the ketone, trichlorosilane and the solvent are mixed together in suitable amounts and allowed to react at a suitable temperature for a suitable time; the resulting ketoimine is not isolated, but the catalyst is directly added to the mixture in order to promote the reduction reaction which leads to the desired N-aryl substituted chiral amine.
  • the picolinic acid derivative used as catalyst in the one-pot process is a compound of general formula (I):
  • R 1 is H, halogen, preferably Cl, Br, I or straight or branched
  • R 2 is H or halogen, preferably Cl or Br
  • R 3 is H or halogen, preferably Cl
  • R 4 is H or halogen, preferably Cl
  • R 5 is straight or branched (C 1 -C 4 )alkyl, preferably Me or n-Pr, or benzyl, optionally substituted with one or more halogens or straight or branched (C 1 -C 4 )alkyl groups, which can be the same or different from one another;
  • R 6 is straight or branched (Ci-C 4 )alkyl, preferably Me or /-Pr, or R 6 can be linked to the adjacent 1 -phenyl group to form a ring of formula A:
  • R 7 is H, straight or branched (C 1 -C 4 )alkyl, preferably Me, or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl and is preferably 2-pyridyl.
  • Examples of compounds of formula (I) are those wherein R 5 and R 6 are methyl and R 7 is hydrogen, such as compounds (Ia) - (Ih) below:
  • the compounds of formula (I) can be prepared by reaction of a picolinic acid derivative of formula (II)
  • R- 1 -R 4 are as defined above and X is a carboxy-activating group, such as chlorine or bromine and an aminoalcohol of formula (III)
  • the compound of formula (II) can also be prepared in situ from a picolinic acid of formula (IV)
  • R 1 -R 4 are as defined above, by reaction with a halogenating agent in the presence of a dehydrating agent.
  • the catalyst compounds of formula (I) can also be prepared by reaction of the picolinic acid (IV) with the amino-alcohol (III) in the presence of a dehydrating agent.
  • N-aryl ketoimines which can be reduced with the catalysts of formula (I) have formula (V)
  • Ar is phenyl, optionally substituted with one or more straight or branched (C r C 4 )alkyl or (CrC 4 )alkoxy groups, which can be the same or different from one another;
  • R 8 is selected from straight or branched (C r C 4 )alkyl, straight or branched (CrC 4 )alkoxy and COOR 1O wherein Rio is straight or branched (C r C 4 )alkyl; R 9 is selected from straight or branched (C 1 -C 4 )alkyl, phenyl and naphthyl optionally substituted with one or more straight or branched
  • the imine of formula (V) is prepared in situ from a ketone of formula R 8 COR 9 and a primary aromatic amine of formula
  • the process is usually carried out dissolving a suitable molar ratio of aromatic amine and ketone, usually an amineiketone ratio of 1.5 - 2.5, and 1.5 to 3 mol/eq of trichlorosilane in a chlorinated organic solvent, preferably dichloromethane or chloroform, more preferably chloroform, then stirring at a temperature ranging from room temperature to -20 0 C until formation of the imine; thereafter, 1 to 10% (molar percentage) of catalyst (I) is added and the mixture is stirred at the same temperature until the reduction reaction is complete (TLC analysis).
  • the reduction reaction occurs with high yields and high enantiomeric excess also in the presence of only 1% of compound (I); mixtures of compounds (I) can also be used.
  • R 1 is H, halogen, preferably Cl, Br, I or straight or branched
  • R 2 is H or halogen, preferably Cl or Br;
  • R 3 is H or halogen, preferably Cl
  • R 4 is H or halogen, preferably Cl;
  • R 5 is straight or branched (C r C 4 )alkyl, preferably Me or «-Pr, or benzyl, optionally substituted with one or more halogens or straight or branched (CrC 4 )alkyl groups, which can be the same or different from one another;
  • R 6 is straight or branched (C 1 -C 4 )alkyl, preferably Me or /-Pr, or R 6 can be linked to the adjacent 1 -phenyl group to form a ring of formula A: and R 7 is H,- straight or branched (Ci-C 4 )alkyl, preferably Me, or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl and is preferably 2-pyridyl are also able to catalyse enantioselective reduction of N-alkyl ketoimines in the presence of trichlorosilane. In particular, they promote the reduction of N-alkyl ketoimines of formula (VII)
  • R' is phenyl or naphthyl optionally substituted with one or more halogens, alkyl or alkoxy groups as defined above, which may be the same or different from one another; or R' is straight or branched (C 1 -C 4 )alkyl wherein the carbon chain is optionally interrupted by an oxygen atom or a COOR group in which R is as defined above
  • R" is optionally substituted alkyl or alkyl benzyl in which alkyl is as defined herein before.
  • ketoimines (VII) are prepared by reaction of a ketone RCOR' and an amine R" ⁇ H 2 wherein R, R' and R" are as defined herein before. It has also been found that the compounds of formula (I)
  • R is H, halogen, preferably Cl, Br, I or straight or branched
  • R 2 is H or halogen, preferably Cl or Br;
  • R 3 is H or halogen, preferably Cl
  • R 4 is H or halogen, preferably Cl;
  • R 5 is straight or branched (C r C 4 )alkyl, preferably Me or n-P ⁇ , or benzyl, optionally substituted with one or more halogens or straight or branched (CrC 4 )alkyl groups, which can be the same or different from one another;
  • R 6 is straight or branched (Ci-C 4 )alkyl, preferably Me or /-Pr, or R 6 can be linked to the adjacent 1-phenyl group to form a ring of formula A:
  • R 7 is H, straight or branched (C r C 4 )alkyl, preferably Me, or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl and is preferably
  • 2-pyridyl are also able to catalyse enantioselective reduction of cyclic imines to cyclic amines, in particular of cyclic imines of formula (IX) to cyclic chiral amines of formula (X)
  • R 4 -R 8 are independently selected from hydrogen, straight or branched (C r C 4 )alkyl or optionally substituted phenyl, or any two adjacent R 4 -R 8 groups can be mutually linked to form a six-membered aromatic ring, in particular a benzyl ring and the remaining groups are as defined hereinbefore.
  • Ketoimines (IX) are prepared by cyclization of a ⁇ -amino-ketone of formula (XI):
  • the reduction of a ketoimine of formula (VII) and (IX) with trichlorosilane is carried out dissolving the imine in a suitable organic solvent in the presence of 0.1-0.01 mol/eq of catalyst of formula (I) and 3.5 mol/eq of trichlorosilane.
  • Suitable organic solvents are, for example acetonitrile, toluene, tetrahydrofuran, dioxane, and in particular chlorinated solvents, namely dichloromethane and trichloromethane.
  • the reaction is carried out in the cold, usually at temperatures ranging from -45°C to +5°C. Although usually one compound of formula (I) is used, mixtures of two or more of them can be used to optimise the reaction.
  • the compounds of formula (I) provide remarkable advantages on an industrial scale: the reduction process occurs under mild conditions and the resulting chiral amine can be isolated from the reaction mixture by a simple aqueous workup; at the end of the reaction the catalyst of formula (I) can be recovered by flash chromatography on silica gel.
  • the catalysts of formula (I) can be easily prepared from commercially available products, i.e. ephedrine or a derivative thereof and picolinic acid and are stable in comparison with organometallic catalysts which are often employed with trichlorosilane.
  • N-aryl ketoimines are usually difficult to prepare and isolate, so synthesizing them in situ allows to avoid troublesome recovery procedures which cause yield losses; therefore, the process is particularly suitable for industrial scale, as it decreases reaction times and costs.
  • N-aryl chiral amines can be synthesized in situ starting from a mixture of aryl amine and ketone in the presence of trichlorosilane is surprising, because trichlorosilane usually reduces ketones to alcohols, so a skilled person would not expect that the desired amine would form.
  • This compound was prepared following the procedure of example 1, using (IS, 2R) ephedrine.
  • 13 C-NMR 1 ( ⁇ 55.5, 1C); 2 ( ⁇ 86.1, 1C); 3 ( ⁇ 31.3, 1C); 4 ( ⁇ 148, 1C); 5 ( ⁇ 124, 1C); 6 ( ⁇ 136, 1C); 7 ( ⁇ 122.5, 1C); 8 ( ⁇ 154, 1C); 9 ( ⁇ 168.5, 1C); 10 ( ⁇ 1 1.7, 1C); 12 ( ⁇ 127.1, 2C); 13 ( ⁇ 128.4, 2C); 14 ( ⁇ 127.7 1C); 11 ( ⁇ 140 1C); 15 ( ⁇ 57.1 1C).
  • Amine (Via) was prepared according to the one-pot procedure from 0.75 mmol aniline and 0.3 mmol acetophenone using 0.03 mmol catalyst (Ia) and either dichloromethane or chloroform as solvent. The results are reported in table 2 below.
  • N-(2-methoxyphenyl) imine of acetophenone (Vb) and N-(4-methoxyphenyl) imine of acetophenone (Vc) were successfully reduced in very high yields and enantioselectivity of 90% and 80% respectively.
  • Amines (VIb) and (VIc) were also prepared according to the one-pot procedure from acetophenone and 2-methoxy- or 4-methoxy aniline with the following yield and enantiomeric excess:
  • amines (VIb) and (VIc) are potential precursors of primary amine groups, since the both the ⁇ rt/zo-methoxyphenyl ring and the /> ⁇ r ⁇ 2-methoxyphenyl moiety can be removed.
  • the S isomer of amine (VIe) was prepared using the enantiomer of catalyst (Ia) obtained from (IS, 2R)-(+)-ephedrine, under the conditions reported in table 5.
  • Table 8 reports the results of the reduction of imine (Va) with other compounds of formula (I).

Abstract

The invention relates to a process for the preparation of enantiomerically enriched amines from ketoimines with trichlorosilane in the presence of picolinic acid derivatives of general formula (I) wherein R1-R7 are as defined in the description as catalysts.

Description

PROCESS FOR THE STEREOSELECTIVE REDUCTION OF KETOIMINES CATALYSED BY TRICHLOROSILANE
Field of the invention
The present invention relates to a process for the preparation of enantiomerically enriched amines from ketoimines catalysed by picolinic acid derivatives. State of the art
The stereoselective reduction of carbon-nitrogen double bonds is of remarkable interest in the preparation of pharmaceutical products, agrochemicals, fragrances and precursors of biologically active molecules.
For this purpose, many reducing agents have been studied; in particular, trichlorosilane proved effective for the reduction of ketoimines under mild conditions; however, trichlorosilane requires the presence of a catalyst to generate a hexacoordinated hydridosilicate, which is the actual reducing species.
Onomura et al. (Tetrahedron Letters, 48 (2007) 7934-7937) disclosed some
N-picolinoyl aminoalcohols as metal-free catalysts for the enantioselective reduction of N-aryl ketoimines with trichlorosilane. Zheng et al /tetrahedron Lett.
(2007) 7934-7937) disclosed the following N-picolinoyl aminoalcohols:
Figure imgf000002_0001
for the enantioselective reduction of N-aryl and N-benzyl ketoimines. Disclosure of the invention
It has now been found that the reduction of N-aryl ketoimines with trichlorosilane in the presence of a picolinic acid derivative as catalyst can be carried out in one-pot forming the ketoimine in situ from suitable precursors, i.e. a primary aromatic amine and a ketone. In the present description, "formed in situ " or "prepared in situ " means that the amine, the ketone, trichlorosilane and the solvent are mixed together in suitable amounts and allowed to react at a suitable temperature for a suitable time; the resulting ketoimine is not isolated, but the catalyst is directly added to the mixture in order to promote the reduction reaction which leads to the desired N-aryl substituted chiral amine.
The picolinic acid derivative used as catalyst in the one-pot process is a compound of general formula (I):
Figure imgf000003_0001
wherein:
R1 is H, halogen, preferably Cl, Br, I or straight or branched
(Ci-C4)alkyl, preferably Me;
R2 is H or halogen, preferably Cl or Br; R3 is H or halogen, preferably Cl;
R4 is H or halogen, preferably Cl;
R5 is straight or branched (C1-C4)alkyl, preferably Me or n-Pr, or benzyl, optionally substituted with one or more halogens or straight or branched (C1-C4)alkyl groups, which can be the same or different from one another;
R6 is straight or branched (Ci-C4)alkyl, preferably Me or /-Pr, or R6 can be linked to the adjacent 1 -phenyl group to form a ring of formula A:
Figure imgf000003_0002
and R7 is H, straight or branched (C1-C4)alkyl, preferably Me, or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl and is preferably 2-pyridyl.
Examples of compounds of formula (I) are those wherein R5 and R6 are methyl and R7 is hydrogen, such as compounds (Ia) - (Ih) below:
Figure imgf000004_0001
Further examples of compounds of formula (I) are compounds (Ii) - (Iq) below:
Figure imgf000004_0002
Compounds (Ib) - (Im) and (In) - (Iq) are novel and are a further object of the invention. These compounds, in particular compound (If) can also reduce N-aryl and N-benzyl ketoimines which are not formed in situ; therefore, the present invention also relates to a process for the reduction of N-aryl ketoimines which comprises reacting a N-aryl ketoimine with trichlorosilane in the presence of compounds (Ib) - (Im) and (In) - (Iq) as catalysts.
The compounds of formula (I) can be prepared by reaction of a picolinic acid derivative of formula (II)
Figure imgf000005_0001
wherein R-1-R4 are as defined above and X is a carboxy-activating group, such as chlorine or bromine and an aminoalcohol of formula (III)
Figure imgf000005_0002
("I) wherein R5-R7 are as defined above in the presence of a suitable organic solvent, preferably dichloromethane or chloroform, more preferably chloroform, usually at room temperature.
The compound of formula (II) can also be prepared in situ from a picolinic acid of formula (IV)
Figure imgf000005_0003
wherein R1-R4 are as defined above, by reaction with a halogenating agent in the presence of a dehydrating agent.
The catalyst compounds of formula (I) can also be prepared by reaction of the picolinic acid (IV) with the amino-alcohol (III) in the presence of a dehydrating agent.
In one embodiment, the N-aryl ketoimines which can be reduced with the catalysts of formula (I) have formula (V)
Figure imgf000006_0001
(V) thus affording amines of formula (VI)
/Ar HN
R9 R8
(Vl) in which:
Ar is phenyl, optionally substituted with one or more straight or branched (CrC4)alkyl or (CrC4)alkoxy groups, which can be the same or different from one another;
R8 is selected from straight or branched (CrC4)alkyl, straight or branched (CrC4)alkoxy and COOR1O wherein Rio is straight or branched (CrC4)alkyl; R9 is selected from straight or branched (C1-C4)alkyl, phenyl and naphthyl optionally substituted with one or more straight or branched
(CrCOalkyl or (C]-C4)haloalkyl groups, which can be the same or different from one another.
In the one-pot process, the imine of formula (V) is prepared in situ from a ketone of formula R8COR9 and a primary aromatic amine of formula
Ar-NH2, wherein Ar is as defined above. The process is usually carried out dissolving a suitable molar ratio of aromatic amine and ketone, usually an amineiketone ratio of 1.5 - 2.5, and 1.5 to 3 mol/eq of trichlorosilane in a chlorinated organic solvent, preferably dichloromethane or chloroform, more preferably chloroform, then stirring at a temperature ranging from room temperature to -200C until formation of the imine; thereafter, 1 to 10% (molar percentage) of catalyst (I) is added and the mixture is stirred at the same temperature until the reduction reaction is complete (TLC analysis). The reduction reaction occurs with high yields and high enantiomeric excess also in the presence of only 1% of compound (I); mixtures of compounds (I) can also be used.
It has also been found that the compounds of formula (I)
Figure imgf000007_0001
wherein: R1 is H, halogen, preferably Cl, Br, I or straight or branched
(Ci-C4)alkyl, preferably Me;
R2 is H or halogen, preferably Cl or Br;
R3 is H or halogen, preferably Cl;
R4 is H or halogen, preferably Cl; R5 is straight or branched (CrC4)alkyl, preferably Me or «-Pr, or benzyl, optionally substituted with one or more halogens or straight or branched (CrC4)alkyl groups, which can be the same or different from one another;
R6 is straight or branched (C1-C4)alkyl, preferably Me or /-Pr, or R6 can be linked to the adjacent 1 -phenyl group to form a ring of formula A:
Figure imgf000008_0001
and R7 is H,- straight or branched (Ci-C4)alkyl, preferably Me, or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl and is preferably 2-pyridyl are also able to catalyse enantioselective reduction of N-alkyl ketoimines in the presence of trichlorosilane. In particular, they promote the reduction of N-alkyl ketoimines of formula (VII)
,R"
Ν'
R1^ R (VIi) to N-alkyl amines (VIII)
Figure imgf000008_0002
(VIII) in which R is straight or branched (CrC4)alkyl;
R' is phenyl or naphthyl optionally substituted with one or more halogens, alkyl or alkoxy groups as defined above, which may be the same or different from one another; or R' is straight or branched (C1-C4)alkyl wherein the carbon chain is optionally interrupted by an oxygen atom or a COOR group in which R is as defined above
R" is optionally substituted alkyl or alkyl benzyl in which alkyl is as defined herein before.
The ketoimines (VII) are prepared by reaction of a ketone RCOR' and an amine R"ΝH2 wherein R, R' and R" are as defined herein before. It has also been found that the compounds of formula (I)
Figure imgf000009_0001
wherein: R) is H, halogen, preferably Cl, Br, I or straight or branched
(CrC4)alkyl, preferably Me;
R2 is H or halogen, preferably Cl or Br;
R3 is H or halogen, preferably Cl;
R4 is H or halogen, preferably Cl; R5 is straight or branched (CrC4)alkyl, preferably Me or n-Pτ, or benzyl, optionally substituted with one or more halogens or straight or branched (CrC4)alkyl groups, which can be the same or different from one another;
R6 is straight or branched (Ci-C4)alkyl, preferably Me or /-Pr, or R6 can be linked to the adjacent 1-phenyl group to form a ring of formula A:
Figure imgf000009_0002
and R7 is H, straight or branched (CrC4)alkyl, preferably Me, or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl and is preferably
2-pyridyl are also able to catalyse enantioselective reduction of cyclic imines to cyclic amines, in particular of cyclic imines of formula (IX)
Figure imgf000010_0001
to cyclic chiral amines of formula (X)
Figure imgf000010_0002
in which R4-R8 are independently selected from hydrogen, straight or branched (CrC4)alkyl or optionally substituted phenyl, or any two adjacent R4-R8 groups can be mutually linked to form a six-membered aromatic ring, in particular a benzyl ring and the remaining groups are as defined hereinbefore.
Ketoimines (IX) are prepared by cyclization of a γ-amino-ketone of formula (XI):
Figure imgf000010_0003
(Xl) in which R4-R8 are as defined herein before.
The reduction of a ketoimine of formula (VII) and (IX) with trichlorosilane is carried out dissolving the imine in a suitable organic solvent in the presence of 0.1-0.01 mol/eq of catalyst of formula (I) and 3.5 mol/eq of trichlorosilane. Suitable organic solvents are, for example acetonitrile, toluene, tetrahydrofuran, dioxane, and in particular chlorinated solvents, namely dichloromethane and trichloromethane. The reaction is carried out in the cold, usually at temperatures ranging from -45°C to +5°C. Although usually one compound of formula (I) is used, mixtures of two or more of them can be used to optimise the reaction.
The compounds of formula (I) provide remarkable advantages on an industrial scale: the reduction process occurs under mild conditions and the resulting chiral amine can be isolated from the reaction mixture by a simple aqueous workup; at the end of the reaction the catalyst of formula (I) can be recovered by flash chromatography on silica gel. The catalysts of formula (I) can be easily prepared from commercially available products, i.e. ephedrine or a derivative thereof and picolinic acid and are stable in comparison with organometallic catalysts which are often employed with trichlorosilane. The one- pot reduction of N-aryl ketoimines is advantageous in that N-aryl ketoimines are usually difficult to prepare and isolate, so synthesizing them in situ allows to avoid troublesome recovery procedures which cause yield losses; therefore, the process is particularly suitable for industrial scale, as it decreases reaction times and costs. Furthermore, the fact that N-aryl chiral amines can be synthesized in situ starting from a mixture of aryl amine and ketone in the presence of trichlorosilane is surprising, because trichlorosilane usually reduces ketones to alcohols, so a skilled person would not expect that the desired amine would form.
These advantages will be clearer from the following experimental section, which illustrates the invention in greater detail. EXPERIMENTAL SECTION
1. Preparation of the catalysts
Example 1.1 - Synthesis of diastereoisomer (1R,2S) of compound (Ia) (comparative example)
Figure imgf000011_0001
Picolinic acid, EDC (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide) and HOBt (1 -hydroxy lH-benzotriazole) were dissolved in CHCI3 under dry atmosphere and stirred; after 15 minutes ephedrine was added. Table 1 below indicates the amount of each reagent.
Table 1
Figure imgf000012_0002
After stirring for 24 hours at 25°C the solvent was evaporated under reduced pressure and the product was purified by flash chromatography (d = 2.5 cm, h = 18 cm, eluant: CH2Cl2 MeOH 98:2).
Yield = 70%
MW = 270.33 g/mol
Figure imgf000012_0001
Rotamer 1 :
1H-NMR (300 MHz, CDClQ: 1 (δ 4.35, IH); 2 (5 4.81, IH); 3 (δ 2.80, 3H); 4 (δ 8.5, IH); 5 (δ 7.36, IH); 6 (δ 7.75, IH); 7 (δ 7.49, IH); 10 (δ 1.33, 3H); 12,13,14 (δ 7.25-7.30, 5H).
13C-NMR (300 MHz. CDCM: 1 (δ 58.3, 1C); 2 (δ 76.1, 1C); 3 (δ 29.7, 1C); 4 (δ 147.3, 1C); 5 (δ 124.5, 1C); 6 (δ 137.4, 1C); 7 (δ 123.1, 1C); 8 (δ 154.2, 1C); 9 (δ 169, 1C); 10 (δ 14.5, 1C); 11 (δ 141.5, 1C); 12 (δ 126.7, 2C); 13 (δ 128.2, 2C); 14 (δ 127.4, 1C).
Rotamer 2:
1H-NMR (300 MHz, CDCh): 1 (δ 4.57, IH); (2 δ 5.09,1H); 3 (δ 2.87, 3H); 4 (δ 8.5, IH); 5 (δ 7.36, IH); 6 (δ 7.75, IH); 7 (δ 7.49, IH); 10 (δ 1.28, 3H); 12,13,14 (δ 7.25-7.30, 5H).
13C-NMR (300 MHz, CDCl1): 1 (δ 58.6, 1C); 2 (δ 76.4, 1C); 3 (δ 35.0, 1C); 4 (δ 148.3, 1C); 5 (δ 124.5, 1C); 6 (δ 137.1, 1C); 7 (δ 124.3, 1C); 8 (δ 154.8, 1C); 9 (δ 169.8, 1C); 10 (δ 11.2, 1C); 11 (δ 142.1, 1C); 12 (δ 126.3, 2C); 13 (δ 128.2, 2C); 14 (δ 127.1, 1C).
MS-ESI+: m/z 271 [M+H]+, m/z = 293 [M+Na]+.
[α]23 -i9 (c O.55 in DCM);
IR (DCM): vc=o = 1725.01 cm"1
Example 1.2 - Synthesis of diastereoisomer (IS, 2S) of compound (Ia) (comparative example)
Figure imgf000013_0001
This compound was prepared following the procedure of example 1, using (IS, 2R) ephedrine.
Figure imgf000013_0002
1H-NMR: l(δ 4.21, IH); 2 (δ 4.60, IH); 3 (δ 3.18, 3H); 4 (δ 8.70, IH); 5 (δ 7.50, IH); 6 (δ 7.94, IH); 7 (δ 7.89, IH); 10 (δ 0.95, 3H); 12 (δ 7.28, 2H); 13 (δ 7.34, 2H); 14 (δ 7.28, IH). 13C-NMR: 1 (δ 59.0, 1C); 2 (δ 75.4, 1C); 3 (δ 27.3, 1C); 4 (δ 148.4, 1C); 5 (δ 125.2, 1C); 6 (δ 138.4, 1C); 7 (δ 125.7, 1C); 8 (δ 153.9, 1C); 9 (δ 168.6, 1C); 10 (δ 16.4, 1C); 1 1 (δ 143.2, 1C); 12 (δ 126.8, 2C); 13 (δ 128.5, 2C); 14 (δ 127.8, 1C). m.p..: 108-1100C
MS-ESI+: m/z 271 [M+H]+, m/z = 293 [M+Na]+.
[α]23 240 (c 0.16 in DCM);
Example 1.3 - Synthesis of compound (Id)
This compound was prepared following the procedure of example 1.
Figure imgf000014_0001
Rotamer 1:
1H-NMR: 1 (δ 4.2, IH); 2 (δ 4.93, IH); 3 (δ 3.0, 3H); 5 (δ 7.38, IH); 6 (δ 7.68, IH); 7 (δ 7.15, IH); 10 (δ 1.33, 3H); 12 (δ 7.26, 2H); 13 (δ 7.31, 2H); 14 (δ 7.31, IH).
13C-NMR: 1 (δ 58.9, 1C); 2 (δ 76.3, 1C); 3 (δ 29.3, 1C); 4 (δ 150.2, 1C); 5 (δ 125.1, 1C); 6 (δ 139.7, 1C); 7 (δ 122.5, 1C); 8 (δ 154.8, 1C); 9 (δ 167.8, 1C); 10 (δ 13.7, 1C); 12 (δ 126.35, 2C); 13 (δ 128.3, 2C); 14 (δ 127.65, 1C); 11 (δ 141.6, 1C). Rotamer 2:
1H-NMR: 1 (δ 4.54, IH); 2 (δ 5.08,1H); 3 (δ 2.9, 3H); 5 (δ 7.38, IH); 6 (δ 7.75, IH); 7 (δ 7.41, IH); 10 (δ 1.35, 3H); 12 (δ 7.47, 2H); 13 (δ 7.38, 2H); 14 (δ 7.31, IH).
13C-NMR: 1 (δ 59, 1C); 2 (δ 77, 1C); 3 (δ 35.2, 1C); 4 (δ 149.6, 1C); 5 (δ 125.1, 1C); 6 (δ 139.7, 1C); 7 (δ 121.9, 1C); 8 (δ 154.9, 1C); 9 (δ 167.4, 1C); 10 (δ 11.4, 1C); 12 (δ 126.3, 2C); 13 (δ 128.4, 2C); 14 (δ 128 1C); 11 (δ 141.8, 1C). MS-ESI+: m/z = 327 [M+Na]+. [α]23 -13 (c 0.55 in DCM); Example 1.4 - Synthesis of compound (Ib) This compound was prepared following the procedure of example 1.
Figure imgf000015_0001
Rotamer 1 :
1H-NMR: 1 (δ 4.75, IH ); 2 (δ 5.05, 1H); 3 (δ 2.67,3H); 4 (δ 8.29, IH); 5 (δ 7.17, IH); 6 (δ 7.50, IH); 10 (δ 1.28, 3H); 12 (δ 7.47, 2H); 13 (δ 7.34, 2H); 14 (δ 7.25, IH); 7 (δ 2.09,3H).
13C-NMR: 1 (δ 56.5, 1C); 2 (δ 76, 1C); 3 (δ 33, 1C); 4 (δ 146.3, 1C); 5 (δ 123.6, 1C); 6 (δ 138.6, 1C); 7 (δ 130, 1C); 8 (δ 154, 1C); 9 (δ 169, 1C); 10 (δ 11.3, 1C); 12 (δ 126.4, 2C); 13 (δ 128.2, 2C); 14 (δ 127.4, 1C); 11 (δ 142, 1C); 7 (δ 17.1 , 1C). Rotamer 2:
1H-NMR: 1 (δ 3.75, 1C); 2 (δ 4.84, 1H); 3 (δ 2.98, 3H); 4 (δ 8.33, IH); 5 (δ 7.2, IH); 6 (δ 7.50, IH); 10 (δ 1.2, 3H); 12 (δ 7.07, 2H); 13 (δ 7.2, 2H); 14 (δ 7.25, IH); 7 (δ 2.06, 3H). 13C-NMR: 1 (δ 58.9, 1C); 2 (δ 76, 1C); 3 (δ 28.5, 1C); 4 (δ 145.7, 1C);
5 (δ 123.7, 1C); 6 (δ 138.8, 1C); 7 (δ 132, 1C); 8 (δ 154, 1C); 9 (δ 169, 1C); 10 (δ 13.1, 1C); 12 (δ 126.1 , 2C); 13 (δ 128.2, 2C); 14 (δ 127.5, 1C); 1 1 (δ 142, lC) 7 (δ 18, 1C).
MS-ESI+: m/z 285 [M+H]+, [α]23 -23.7 (c 0.4 in DCM). Example 1.5 - Synthesis of compound (Ii) (comparative example)
This compound was prepared following the procedure of example 1.
Figure imgf000016_0001
Rotamer 1 :
1H-NMR: 1 (δ 4.18, IH); 2 (δ 4.36, IH); 3 (δ 3.12, 3H); 4 (δ 8.59, IH); 5 (δ 7.29, IH); 6 (δ 7.68, IH); 7 (δ 7.08, IH); 10 (δ 1.36, 3H); 12 (δ 7.43, 2H); 13 (δ 7.3, 2H); 14 (δ 7.38, IH); 15 (δ 3.27, 3H).
13C-NMR: 1 (δ 58.6, 1C); 2 (δ 86.1, 1C); 3 (δ 28.6, 1C); 4 (δ 148, 1C); 5 (δ 124, 1C); 6 (δ 136, 1C); 7 (δ 124, 1C); 8 (δ 154, 1C); 9 (δ 169, 1C); 10 (δ 13.5, 1C); 12 (δ 126.8, 2C); 13 (δ 128.4, 2C); 14 (δ 127.9, 1C); 1 1 (δ 139.5, 1C); 15 (δ 57.1 1C). Rotamer 2:
1H-NMR: 1 (δ 4.75, IH); 2 (δ 4.57, 1H); 3 (δ 2.92, 3H); 4 (δ 8.59, IH); 5 (δ 7.29, IH); 6 (δ 7.75, IH); 7 (δ 7.29, IH); 10 (δ 1.36, 3H); 12 (δ 7.08, 2H); 13 (δ 7.3, 2H); 14 (δ 7.38, IH); 15 (δ 3.32, 3H).
13C-NMR: 1 (δ 55.5, 1C); 2 (δ 86.1, 1C); 3 (δ 31.3, 1C); 4 (δ 148, 1C); 5 (δ 124, 1C); 6 (δ 136, 1C); 7 (δ 122.5, 1C); 8 (δ 154, 1C); 9 (δ 168.5, 1C); 10 (δ 1 1.7, 1C); 12 (δ 127.1, 2C); 13 (δ 128.4, 2C); 14 (δ 127.7 1C); 11 (δ 140 1C); 15 (δ 57.1 1C).
MS-ESI+: m/z 285 [M+H]+, [α]23 -35.3 (c 0.3 in DCM); 2. Reduction reactions
General procedure for the reduction of imines The catalyst (0.1-0.01% mol/eq) and the imine (1 mol/eq) are dissolved in the selected solvent under dry atmosphere and stirred at the proper reaction temperature. Trichlorosilane (typically 3.5 mol/eq) is then added and the reaction mixture is stirred until completion of the reaction. Then NaHCO3 (sat. sol.) is added, the organic phase is separated, dried over sodium sulphate and evaporated under reduced pressure. If necessary, the product is purified by flash chromatography.
General procedure for the one-pot reduction of N-aryl ketoimines
A solution of aromatic amine (0.75 mmol), ketone (0.3 mmol) and trichlorosilane (0.75 mmol) in 1 - 2 ml solvent is stirred under nitrogen at 00C for about 30 minutes. Then a solution of the catalyst (0.03 mmol in 1-2 ml solvent) is added by means of a syringe. After stirring at 00C for about 20-72 hours the reaction is quenched by addition of a saturated aqueous solution of NaHCO3 (1 ml). The mixture is allowed to warm-up to room temperature and water (2 ml) and dichloromethane (5 ml) are added. The organic phase is separated and the combined organic phases are dried over Na2SO4, filtered, and concentrated under vacuum at room temperature to afford a crude product. Example 2.1 - Synthesis of amine (Via)
Figure imgf000017_0001
from imine (Va)
Figure imgf000017_0002
Amine (Via) was prepared according to the one-pot procedure from 0.75 mmol aniline and 0.3 mmol acetophenone using 0.03 mmol catalyst (Ia) and either dichloromethane or chloroform as solvent. The results are reported in table 2 below.
Table 2
e.e. aniline (eq) time (h) solvent Yield (%) alcohol (%
(%)
1 48 CH2Cl2 50 10 78
1 72 CH2Cl2 67 29 78
1.5 72 CH2Cl2 78 12 76
2.5 72 CHCl3 96 / 73
2.5 15 CHCl 94 / 80
2.2 Synthesis of amines (VIb) and (VIc) with catalyst (Ia) comparative example
Figure imgf000018_0001
Amines (VIb) and (VIc) were prepared using 10% compound (Ia) as catalyst, under the best reaction conditions, in chloroform at 00C. The results are reported in table 3 below.
Table 3
Figure imgf000018_0002
N-(2-methoxyphenyl) imine of acetophenone (Vb) and N-(4-methoxyphenyl) imine of acetophenone (Vc) were successfully reduced in very high yields and enantioselectivity of 90% and 80% respectively. Amines (VIb) and (VIc) were also prepared according to the one-pot procedure from acetophenone and 2-methoxy- or 4-methoxy aniline with the following yield and enantiomeric excess:
(VIb): yield 87%, enantiomeric excess 90% (VIc): yield 90%, enantiomeric excess 81%
It is worth noting that amines (VIb) and (VIc) are potential precursors of primary amine groups, since the both the ørt/zo-methoxyphenyl ring and the />αr<2-methoxyphenyl moiety can be removed.
Example 2.3 - Comparative example - Synthesis of amine (VIe)
Figure imgf000019_0001
Imine (Ve)
Figure imgf000019_0002
(Ve) was prepared by reaction of methoxyacetone and 2,6-dimethylaniline and then reduced to amine (VIe) (R enantiomer) with trichlorosilane in the presence of 0.1 eq. of compound (Ia) derived from (IR, 2S)-(-)-ephedrine, for about 15 hours. Table 4 below shows that the reaction proceeds with high yield and enantioselectivity. Table 4
Figure imgf000020_0001
The S isomer of amine (VIe) was prepared using the enantiomer of catalyst (Ia) obtained from (IS, 2R)-(+)-ephedrine, under the conditions reported in table 5.
Table 5
Figure imgf000020_0002
Both isomers of amine (VIe) were also synthesised with 86% yield and 70% ee following the one pot procedure at 00C in chloroform. 2.4 Synthesis of amine (Via) with different compounds (I)
3 -methyl picolinic acid was condensed with (-) ephedrine to afford compound (Ib), which promoted the reduction of imine (Va) in 98% yield and 77% e.e. in dichloromethane at 00C (reaction time 15 hours; 0.1 eq of compound (Ib)). 3-chloro picolinic acid was condensed with (-) ephedrine to afford compound (Ic), which promoted the reduction of imine (Va) in 77% yield and 71% e.e. in dichloromethane at 00C; stereoselectivity was higher at -200C, using chloroform as solvent. The results are resumed in table 6 below (reaction time: 15 hours; 0.1 equivalents of compound (Ic), except for entry 5, wherein 0.01 equivalents were used). Table 6
Figure imgf000021_0001
4-chloropicolinic acid was condensed with (-) ephedrine to afford compound (If), which promoted the reduction of imine (Va) in 98% yield and 83% e.e. in dichloromethane. The best results were obtained in chloroform at - 200C; the yield was basically quantitative and the enantiomeric excess was 93%. The results are resumed in table 7 below (reaction time: 15 hours; 0.1 equivalents of compound (If)).
Table 7
Figure imgf000021_0002
Table 8 reports the results of the reduction of imine (Va) with other compounds of formula (I). Table 8
Figure imgf000022_0002
Table 9 below reports the results obtained after reduction of imine (Va) with catalysts (Ia) and (If) respectively. Table 9
Cataly Cat. Temp Yield
Entry Time e.e. (%) st Load.
1 Ia 10% 15 h O0C 97 82 (R)
2 If 10% 15 h 00C 98 87 (R)
3 Ia 1% 15 h 00C 89 78 (R)
4 If 5% 2 h 00C 93 88 (R)
5 If 1% 2 h 00C 91 88 (R)
6 Ia 10% 15 h -200C 98 88 (R)
7 If 10% 15 h -200C 98 93 (R)
These results show that the compound (If) provides higher enantioselectivity than compound (Ia) both at 00C (entries 1-2) and at -200C (entries 6-7); when 1% compound (If) is used, the amine is obtained with 91% yield in only 2 hours. Moreover, using 5% or 1% (If) at 00C, the same enantioselectivity is obtained, while in the case of compound (Ia) enantioselectivity decreases when the amount of catalyst is lowered from 5% to 1%.
Example 2.5 - Synthesis of amines (VIf) and (VIg)
Figure imgf000022_0001
The reduction of N-phenyl imine of 4-trifluoromethylphenyl-methyl ketone (Vf)
Figure imgf000023_0001
and N-phenyl imine of 2-naphthyl-methyl ketone (Vg)
Figure imgf000023_0002
at -200C in CHCl3 was also successfully performed with catalyst (If) afforded the corresponding amines in 85% yield, 91% e.e. and 87% yield, 94% e.e. respectively. Preparation of ^-(l-phenylethy^-butylainine
The reduction of N-butylimine of acetophenone was performed in the presence of trichlorosilane (1.5 - 3 mol/eq) and of a catalytic amount (1%) of N-methyl, N-picolinoyl-(lR, 2S)-ephedrine, under different experimental conditions; the best results were obtained in chlorinated solvents (Table 10). N-methyl, N-picolinoyl-(lR, 2S)-ephedrine, was able to promote the reduction in dichloromethane at 00C in quantitative yield and 77% ee. Lowering the reaction temperature to 200C, enantioselectivity increased to 82% without decrease of the chemical yield. Working in chloroform, a further improvement in enantioselection was observed (97% yield and 90% ee). Table 10
Entry t Solvent T (0C) Yield e.e.
(h) (%)
1 15 DCM 0 98 77
2 15 CHCl3 0 97 90
3 15 DCM -20 98 82
4 15 CHCl3 -20 98 83
5a 40 CHCl, 0 77 71

Claims

1. A process for the stereoselective reduction of N-aryl ketoimines with trichlorosilane in the presence of a catalyst of general formula (I):
Figure imgf000025_0001
wherein:
R1 is H, halogen or straight or branched (CrC4)alkyl;
R2 is H or halogen;
R3 is H or halogen;
R4 is H or halogen;
R5 is straight or branched (Ci-C4)alkyl or benzyl optionally substituted with one or more halogens or straight or branched (C1-C4)alkyl groups, which can be the same or different from one another;
R6 is straight or branched (Ci-C4)alkyl, or R6 can be linked to the adjacent 1-phenyl group to form a ring of formula A:
Figure imgf000025_0002
wherein R7 is H, straight or branched (C]-C4)alkyl or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl characterised in that the N-aryl ketoimine is prepared in situ.
2. A process according to claim 1 in which the N-aryl ketoimine has formula (V):
Figure imgf000026_0001
(V) in which:
Ar is phenyl, optionally substituted with one or more straight or branched (CrC4)alkyl or (C1-C4^IkOXy groups, which can be the same or different from one another;
R8 is selected from straight or branched (CrC4)alkyl, straight or branched (CrC4)alkoxy and COORi0 wherein R]0 is straight or branched (CrC4)alkyl;
R9 is selected from straight or branched (CrC4)alkyl, phenyl and naphthyl optionally substituted with one or more straight or branched
(Ci-C4)alkyl or (CrC4)haloalkyl groups, which can be the same or different from one another.
3. A process according to claim 1 or 2 in which the catalyst of formula (I) is selected from:
Figure imgf000026_0002
Figure imgf000027_0001
4. A process according to claim 3 in which the catalyst is compound (If).
5. A process for the stereoselective reduction of N-alkyl or N-alkyl-benzyl ketoimines of formula (VII)
Ν
FT R
(VIl) in which:
R is straight or branched
Figure imgf000027_0002
R' is phenyl or naphthyl optionally substituted with one or more halogens, alkyl or alkoxy groups as defined above, which may be the same or different from one another; or R' is straight or branched (Ci-C4)alkyl wherein the carbon chain is optionally interrupted by an oxygen atom; or R is COOR in which R is as defined herein before R' ' is optionally substituted alkyl or benzyl as defined above the process comprising subjecting an amine of formula (VII) to reduction with trichlorosilane in the presence of a catalyst of formula
Figure imgf000027_0003
in which:
R1 is H, halogen or straight or branched (C1-C4) alkyl; R2 is H or halogen; R3 is H or halogen; R4 is H or halogen;
R5 is straight or branched (C1-C4) alkyl or benzyl optionally substituted with one or more halogens or straight or branched (CrC4)alkyl groups, which can be the same or different from one another; R6 is straight or branched (Ci-C4)alkyl, or R6 can be linked to the adjacent 1 -phenyl group to form a ring of formula A:
Figure imgf000028_0001
wherein R7 is H, straight or branched (CrC4)alkyl or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl
6. A process for the stereoselective reduction of cyclic ketoimine of formula (IX)
Figure imgf000028_0002
(IX) in which:
R4-R8 are independently selected from hydrogen, straight or branched (CrC4)alkyl or optionally substituted phenyl, or any two adjacent R4-R8 groups can be reciprocally linked to form a six-membered aromatic ring, in particular a benzyl ring and the remaining groups are as defined hereinbefore the process comprising subjecting a cyclic amine of formula (IX) to reduction with trichlorosilane in the presence of a catalyst of formula
Figure imgf000029_0001
in which:
R1 is H, halogen or straight or branched (C1-C4) alkyl; R2 is H or halogen; R3 is H or halogen; R4 is H or halogen; R5 is straight or branched (CrC4)alkyl or benzyl optionally substituted with one or more halogens or straight or branched (CrC4)alkyl groups, which can be the same or different from one another; R6 is straight or branched (C1-C4)BIlCyI, or R6 can be linked to the adjacent 1 -phenyl group to form a ring of formula A:
Figure imgf000029_0002
wherein R7 is H, straight or branched (C!-C4)alkyl or a CO-aryl group, wherein aryl is selected from phenyl, naphthyl, thiophenyl, furyl, oxazolyl, thiazolyl and pyridyl.
7. A process according to claim 5 or 6 in which the catalyst of formula (I) is selected from:
Figure imgf000030_0001
8. A process according to claim 7 in which the catalyst is compound (If) 9. A compound selected from:
Figure imgf000031_0001
10. Compound (If) according to claim 9.
11. A process for the enantioselective reduction of N-aryl or N-benzyl ketoimines which comprises subjecting a N-aryl or N-benzyl ketoimine to reduction with trichlorosilane in the presence of a compound of formula of claim 9) or 10).
12. The process according to claim 11 in which N-aryl ketoimine has formula (V):
.Ar
Ν'
< R8 00 in which:
Ar is phenyl, optionally substituted with one or more straight or branched (CrC4)alkyl or (CrC4)alkoxy groups, which can be the same or different from one another; R8 is selected from straight or branched (Ci-C4)alkyl, straight or branched (Ci-C4)alkoxy and COORi0 wherein R]0 is straight or branched (CrC4)alkyl;
R9 is selected from straight or branched (Cj-C4)alkyl, phenyl and naphthyl optionally substituted with one or more straight or branched (CrC4)alkyl or (CrC4)haloalkyl groups, which can be the same or different from one another.
PCT/EP2008/010079 2007-11-30 2008-11-27 Process for the stereoselective reduction of ketoimines catalysed by trichlorosilane WO2009068284A2 (en)

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EP07023240A EP2065371A1 (en) 2007-11-30 2007-11-30 Chiral organic catalysts for the stereoselective reduction of carbon-nitrogen double bonds for the preparation of enantiomerically enriched amines
EP08016622A EP2166002A1 (en) 2008-09-22 2008-09-22 Chiral organic catalysts for the enantioselective reduction of n-alkyl and n-benzyl-substituted alicyclic and cyclic imines
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