WO2006003194A1 - Process for preparing amines and a carboxamide thereof - Google Patents

Process for preparing amines and a carboxamide thereof Download PDF

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Publication number
WO2006003194A1
WO2006003194A1 PCT/EP2005/053168 EP2005053168W WO2006003194A1 WO 2006003194 A1 WO2006003194 A1 WO 2006003194A1 EP 2005053168 W EP2005053168 W EP 2005053168W WO 2006003194 A1 WO2006003194 A1 WO 2006003194A1
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alkyl
process according
crc
alkoxy
methyl
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PCT/EP2005/053168
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French (fr)
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Benoît PUGIN
Xiang Dong Feng
Felix Spindler
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Solvias Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • 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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines

Definitions

  • the present invention relates to a process for the enantioselective hydrogenation of prochiral aromatic imines in the presence of iridium complexes having chiral ferrocene tetraphosphines as ligands, and a process for the enantioselective preparation of chloroacetamides of prochiral aromatic imines.
  • Optically active N-chloroacetanilides have been found to be very good and selective herbicides, cf., for example, EP-A-O 077 755 and EP-A-O 115470. They are prepared in a simple manner by chloroacetylation of corresponding optically active anilines which can be obtained, for example, by enantioselective hydrogenation of imines using iridium catalysts containing chiral ferrocene diphosphines as ligands (US patents 5,463,097, 5,466,844 and 5,583,241).
  • Catalysts are auxiliaries, remain as impurities in the reaction product and have to be removed. Efforts are therefore made to use very small amounts, with the molecular weight and the amount of metal being important factors. However, ferrocene diphosphines have not only a high iron content but also a relatively high molecular weight.
  • the invention provides a process for preparing secondary amines of the formula I or II,
  • Roi, Ro 2 and R 03 are each, independently of one another, C r C 4 -alkyl, R 04 is C r C 4 -alkyl,
  • R 0 and R 00 are each, independently of one another, hydrogen, Ci-C 20 -alkyl, C 3 -C 8 -cycloalkyl,
  • Ri and R 2 are each, independently of one another, a hydrogen atom, a halogen atom or a substituent bound to the cyclopentadienyl rings via a C atom, S atom, Si atom, a P(O) or
  • the two indices m are each, independently of one another, 1, 2 or 3;
  • Xi, X 2 and X 3 are each, independently of one another, a secondary phosphine group.
  • Alkyl radicals R O i, R 02 and R 03 can be, for example, methyl, ethyl, n- or i-propyl, n-, i- or t- butyl.
  • R 01 , R 02 and R 03 are preferably methyl or ethyl.
  • An alkyl radical R 04 can be methyl, ethyl, n- or i-propyl, n-, i- or t-butyl.
  • the alkoxy group in C r C 4 -alkoxymethyl or d-C 4 -alkoxyethyl radicals R 04 can be methoxy, ethoxy, n- or i- propoxy, n-, i- or t-butoxy.
  • R 04 is preferably methoxyethyl or methoxy methyl.
  • Preferred compounds of the formulae I and Il are ones in which R O i is methyl, R 02 is methyl or ethyl, R 03 is methyl and R 04 is methoxy methyl.
  • the symbol * indicates predominantly one configurational isomer, which means that the enantiomeric excess (ee) is at least 50%, preferably at least 60% and particularly preferably at least 70%.
  • the configurational isomer is preferably the S enantiomer.
  • R 1 and R 2 can each be present from one to three times in the cyclopentadienyl rings.
  • Hydrocarbon radicals as or in substituents Ri and R 2 can in turn bear one or more, for example from one to three, preferably one or two, substituents such as halogen (F, Cl or Br, in particular F), -OH, -SH, -CH(O) 1 -CN 1 -NR 07 R 08 , -C(O)-O-R 05 , -S(O)-O-R 05 , -S(O) 2 -O-R 05 , -P(OR 05 ) 2j -P(O)(OR 05 ) 2 , -C(O)-NR 07 R 08 , -S(O)-NR 07 R 08 , -S(O) 2 -NR 07 R 08 , -0-(O)C-R 06 , -R 07 N-(O)C-R 06 , -R 07 N-S(O)-R 06 , -R 07 N-S(O)-R 06 , -R 07 N
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, Ci-Ci 2 -alkyl, preferably CrCa-alkyl and particularly preferably Ci-C 4 -alkyl. Examples are methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, pentyl, hexyl, heptyl, octyl, decyl and dodecyl.
  • substituted alkyl examples include alkyl-CH(OH)-, cycloalkyl-CH(OH)-, aryl-CH(OH)-, heteroaryl-CH(OH)-, alkyl 2 C(OH)-, cycloalkyl 2 C(OH)-, aryl 2 -CH(OH)-, heteroaryl 2 CH(OH)-, alkyl-phenylC(OH)-.
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, C 5 -C 8 - cycloalkyl, preferably C 5 -C 6 -cycloalkyl. Examples are cyclopentyl, cyclohexyl and cyclooctyl. - A -
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, C 5 -C 8 - cycloalkyl-alkyl, preferably Cs-Ce-cycloalkyl-alkyl. Examples are cyclopentylmethyl, cyclohexyl methyl or cyclohexylethyl and cyclooctyl methyl.
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, C 6 -C 18 -aryl, preferably C 6 -Ci 0 -aryl. Examples are phenyl or naphthyl.
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, C 7 -Ci 2 -arylalkyl (for example benzyl or 1-phenyleth-2-yl).
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, W(CrC 4 - alkyl)Si or triphenylsilyl.
  • Examples of trial kylsilyl are trimethylsilyl, triethylsilyl, tri-n-propylsilyl, tri-n-butylsilyl and dimethyl-t-butylsilyl.
  • the substituents Ri and R 2 can, for example, be halogen. Examples are F, Cl and Br.
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, a thio radical or sulphoxide radical or a sulphone radical of the formulae -SR 09 , -S(O)R 0 9 and -S(O) 2 R 09 , where R 09 is d-C ⁇ -alkyl, preferably CrC 8 -alkyl and particularly preferably Ci-C 4 -alkyl; C 5 -C 8 - cycloalkyl, preferably C 5 -C 6 -cycloalkyl; C 6 -Ci 8 -aryl and preferably C 6 -Ci 0 -aryl; or C 7 -C 12 - aralkyl. Examples of these hydrocarbon radicals have been mentioned above for Ri.
  • the substituents Ri and R 2 can be, for example, -CH(O), -C(O)-C r C 4 -alkyl Or-C(O)-C 6 -C 10 - aryl.
  • the substituted or unsubstituted substituents R 1 and R 2 can be, for example, radicals - CO 2 R 05 or -C(O)-NR 07 R 08 , where R 07 , R 08 and R 05 have the abovementioned meanings, including the preferences.
  • the substituted or unsubstituted substituents Ri and R 2 can be, for example, radicals - S(O)-O-R 05 , -S(O) 2 -O-R 05 , -S(O)-NR 07 R 08 and -S(O) 2 -NR 07 R 08 , where R 07 , R 08 and R 05 have the abovementioned meanings, including the preferences.
  • the substituted or unsubstituted substituents R 1 and R 2 can be, for example, radicals - P(ORo ⁇ ) 2 or -P(0)(ORo 5 ) 2 , where R 05 has the abovementioned meanings, including the preferences.
  • the substituted or unsubstituted substituents R 1 and R 2 can be, for example, radicals - P(0)(Ro 5 ) 2 or -P(S)(ORo 5 ) 2 , where R 05 has the abovementioned meanings, including the preferences.
  • An R 1 in the first cyclopentadienyl ring together with an R 2 in the second cyclopentadienyl ring can form a C 2 -C 4 chain, preferably a C 2 -Ce chain, for example as 1 ,2-ethylene, 1,2- and 1 ,3-propylene.
  • substituents R 1 and R 2 are selected from among C 1 -C 4 - alkyl, substituted or unsubstituted phenyl, tri(CrC 4 -alkyl)Si, triphenylsilyl, halogen (in particular F, Cl and Br), -SR aj -CH 2 OH, -CH 2 O-R 3 , -CH(O), -CO 2 H, -CO 2 R 3 , where R 3 is a hydrocarbon radical having from 1 to 10 carbon atoms. Ri is preferably a hydrogen atom.
  • substituted or unsubstituted substituents R 1 and R 2 are methyl, ethyl, n- and i- propyl, n-, i- and t-butyl, pentyl, hexyl, cyclohexyl, cyclohexyl methyl, phenyl, benzyl, trimethylsilyl, F, Cl, Br, methylthio, methylsulphonyl, methylsulphoxyl, phenylthio, phenylsulphonyl, phenylsulphoxyl, -CH(O), -C(O)OH, -C(O)-OCH 3 , -C(O)-OC 2 H 5 , -C(O)-NH 2 , -C(O)-NHCH 3 , -C(O)-N(CHg) 2 , -SO 3 H, -S(O)-OCH 3 , -S(O)-OC
  • Alky I radicals R 0 and R 00 can be linear or branched and the alkyl preferably contains from 1 to 14, more preferably from 1 to 8 and particularly preferably from 1 to 6, carbon atoms.
  • Cycloalkyl radicals Ro and Roo are preferably Cs-C ⁇ -cycloalkyl, particularly preferably Cs-C ⁇ - cycloalkyl.
  • Aryl radicals R 0 and R 00 can be, for example, phenyl, naphthyl or anthracenyl, with phenyl being preferred.
  • Heteroaryl radicals R 0 and R O o are preferably C 3 -C 8 -heteroaryl.
  • Substituents for R 0 and R O o can be, for example, F, trifluoromethyl, methyl, ethyl, n- or i- propyl, n-, i- or t-butyl, pentyl, hexyl, methoxy, ethoxy, n- or i-propoxy, n-, i- ort-butoxy, pentoxy, hexoxy, cyclopentyl, cyclohexyl, cyclopentoxy, cyclohexoxy, phenyl, methylphenyl, dimethyl phenyl, methoxyphenyl, furyl, thienyl or pyrrolyl.
  • R 0 and R O o are methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cyclooctyl, phenyl, benzyl, methylphenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, methoxybenzyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, pyridyl, pyrimidyl, quinolyl, furylmethyl, thienylmethyl and pyrrolylmethyl.
  • R 0 and R O o are identical radicals.
  • R 0 and R O o are identical radicals selected from the group consisting of C r C 8 - alkyl, C 5 -C 8 -cycloalkyl, phenyl and benzyl, which are unsubstituted or substituted as defined above.
  • the secondary phosphine groups Xi, X 2 and X 3 can contain two identical hydrocarbon radicals or two different hydrocarbon radicals.
  • the secondary phosphine groups Xi, X 2 and X 3 preferably each contain two identical hydrocarbon radicals.
  • the secondary phosphine groups Xi and X 2 , Xi and X 3 , X 2 and X 3 and also Xi, X 2 and X 3 can be identical or different.
  • the hydrocarbon radicals can be unsubstituted or substituted and/or contain heteroatoms selected from the group consisting of O, S and N. They can contain from 1 to 22, preferably from 1 to 12 and particularly preferably from 1 to 8, carbon atoms.
  • a preferred secondary phosphine is one in which the phosphine group contains two identical or different radicals selected from the group consisting of linear or branched CrCi 2 -alkyl; unsubstituted or CrC ⁇ - alkyl- or C r C 6 -alkoxy-substituted C 5 -Ci 2 -cycloalkyl or C 5 -Ci 2 -cycloalkyl-CH 2 -; phenyl, naphthyl, furyl or benzyl; and phenyl or benzyl substituted by halogen (for example F, Cl and Br), CrC 6 -alkyl, CrC 6 -haloalkyl (for example trifluoromethyl), CrC 6
  • alkyl substituents on P which preferably contain from 1 to 6 carbon atoms, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the isomers of pentyl and hexyl.
  • alkyl substituents on P are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the isomers of pentyl and hexyl.
  • unsubstituted or alkyl-substituted cycloalkyl substituents on P are cyclopentyl, cyclohexyl, methylcyclopentyl and ethylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl and ethylcyclohexyl and dimethylcyclohex
  • alkyl-, alkoxy-, haloalkyl-, haloalkoxy- and halogen-substituted phenyl and benzyl substituents on P are o-, m- or p- fluorophenyl, o-, m- or p-chlorophenyl, difluorophenyl or dichlorophenyl, pentafluorophenyl, methylphenyl, dimethylphenyl, trimethylphenyl, ethylphenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, trifluoromethylphenyl, bistrifluoromethylphenyl, tristrifluoromethylphenyl, trifluoromethoxyphenyl, bistrifluoromethoxyphenyl, 3,5-dimethyl-4- methoxyphenyl and 3,5-di-t-butyl-4-methoxyphenyl.
  • Preferred secondary phosphine groups are ones in which the identical radicals are selected from the group consisting of CrC 6 -alkyl, unsubstituted cyclopentyl or cyclohexyl, cyclopentyl or cyclohexyl substituted by from 1 to 3 C r C 4 -alkyl or C r C 4 -alkoxy radicals, benzyl and in particular phenyl which are unsubstituted or substituted by from 1 to 3 Ci-C 4 -alkyl, CrC 4 - alkoxy, F, Cl, Ci-C 4 -fluoroalkyl or Ci-C 4 -fluoroalkoxy radicals.
  • the secondary phosphino group preferably corresponds to the formula -PR 3 R 4 , where R 3 and R 4 are each, independently of one another, a hydrocarbon radical having from 1 to 18 carbon atoms which is unsubstituted or substituted by halogen, Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, CrCe-alkoxy, CrC 6 -haloalkoxy, (Ci-C 4 -alkyl) 2 amino, (C 6 H 5 ) 3 Si, (C r Ci 2 -alkyl) 3 Si or- CO 2 -CrC 6 -alkyl and/or contains heteroatoms O.
  • R 3 and R 4 are each, independently of one another, a hydrocarbon radical having from 1 to 18 carbon atoms which is unsubstituted or substituted by halogen, Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, CrCe-alkoxy, CrC 6 -haloal
  • R 3 and R 4 are preferably identical radicals selected from the group consisting of linear or branched C r C 6 -alkyl, unsubstituted cyclopentyl or cyclohexyl, cyclopentyl or cyclohexyl substituted by from one to three CrC 4 -alkyl or Ci-C 4 -alkoxy radicals, furyl, unsubstitued benzyl or benzyl substituted by from one to three Ci-C4-alkyl or CrC 4 -alkoxy radicals, and in particular unsubstituted phenyl or phenyl substituted by from one to three CrC4-alkyl, CrC 4 - alkoxy, -NH 2 , -N(Ci-C 6 -alkyl) 2 , OH, F, Cl 1 Ci-C 4 -fluoroalkyl or d-C 4 -fluoroalkoxy radicals.
  • R 3 and R 4 are particularly preferably identical radicals selected from the group consisting of CrC 6 -alkyl, cyclopentyl, cyclohexyl, furyl and unsubstituted phenyl or phenyl substituted by from one to three d-C 4 -alkyl, CrC 4 -alkoxy and/or CrC 4 -fluoroalkyl radicals.
  • the secondary phosphine groups Xi, X 2 and X 3 can be cyclic secondary phosphino, for example groups of the formulae
  • the substituents can be bound to the P atom in one or both ⁇ positions in order to introduce chiral C atoms.
  • the substituents in one or both ⁇ positions are preferably d-C 4 -alkyl or benzyl, for example methyl, ethyl, n- or i-propyl, benzyl or-CH 2 -O-Ci-C 4 -alkyl or-
  • Substituents in the ⁇ , ⁇ positions can be, for example, Ci-C 4 -alkyl, CrC 4 -alkoxy, benzyloxy or -0-CH 2 -O-, -O-CH(C r C 4 -alkyl)-O- and -O-C(C r C 4 -alkyl) 2 -O-.
  • Some examples are methyl, ethyl, methoxy, ethoxy, -O-CH(phenyl)-O-, -O-CH(methyl)-O- and -O-C(methyl) 2 -O-.
  • an aliphatic 5- or 6-membered ring or benzene can be fused onto two adjacent carbon atoms.
  • aromatic rings may be substituted by CrC 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -alkoxy- Ci-C 2 -alkyl, phenyl, benzyl, benzyloxy or Ci-C 4 -alkylicienedioxyl or Ci-C 4 -alkylenedioxyl (cf. US 2003/0073868 A1 and WO 02/048161).
  • the cyclic phosphine radicals can be C-chiral, P-chiral or C- and P-chiral.
  • the cyclic secondary phosphino can, for example, correspond to the formulae (only one of the possible diastereomers is indicated),
  • radicals R' and R" are each Ci-C 4 -alkyl, for example methyl, ethyl, n- or i-propyl, benzyl, or-CH 2 -O-Ci-C 4 -alkyl or-CH 2 -0-C 6 -Cio-aryl, and R' and R" are identical or dfferent.
  • R' and R" are bound to the same carbon atom, they can together form a C 4 -C 5 -alkylene group.
  • the radicals Xi are preferably identical and the radicals X 2 and X 3 are identical or different and Xi, X 2 and X 3 are preferably noncyclic secondary phosphine selected from the group consisting of -PCCrCe-alkyl) ⁇ -P(C 5 -C 8 -cycloalkyl) 2j -P(C 7 -C 12 -bicycloalkyl) 2 , -P(o-furyl) 2j -P(C 6 Hs) 2 , -P[2-(C r C 6 - alkyl)C 6 H 4 ] 2 , -P ⁇ -fd-Ce-alkyOCel-Uk -P[4-(Ci-C ⁇ -alM)C ⁇ Hd 2 , -P[2-(CrC 6 -alkoxy)C 6 H 4 ] 2 , -P[3-(C r C 6 -
  • Ci-C 4 -alkoxy C 1 -C4- alkoxy-Ci-C 2 -alkyl, phenyl, benzyl, benzyloxy, d-C 4 -alkylidenedioxyl or unsubstituted or phenyl-substituted methylenedioxyl groups.
  • Some specific examples are -P(CH 3 J 2 , -P(J-C 3 Hr) 2 , -P(n-C 4 H 9 ) 2) -P(i-C 4 H 9 ) 2 , -P(C 6 Hn) 2 , -P(norbornyl) 2l -P(o-furyl) 2 , -P(C 6 Hg) 2 , -P[2-(methyl)C 6 H 4 ] 2 , -P[3-(methyl)C 6 H 4 ] 2) -P[4- (methyl)C 6 H 4 ] 2j -P[2-(methoxy)C 6 H 4 ] 2 , -P[3-(methoxy)C 6 H 4 ] 2j -P[4-(methoxy)C 6 H 4 ] 2 , -P[3- (trifluoromethyl)C 6 H 4 ] 2 , -P[4-(trifluoromethyl)C 6 H 4 ]
  • R' is methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, methoxy methyl, ethoxymethyl or benzyloxymethyl and R" has the same meaning as R'.
  • the compounds of the formula V are preferably present as diastereomers of the formula Va (R,S,R',S' configuration) or Vd (S,R,S',R' configuration) or mixtures thereof, or as diastereomers of the formula Vc (R,R,R',R' configuration) or Vb (S,S,S',S' configuration) or mixtures thereof,
  • the compounds of the formula V and diastereomers or mixtures of diastereomers can be prepared by methods known per se or analogous methods, as are described, for example, in US-A-5,463,097, by T. Hayashi et al. in J. of Organometallic Chemistry, 370 (1989), pages 229-139 or in WO 96/16971.
  • Ferrocenes having -CHR 0 -O-acyl Or-CHR 0 -NR 2 groups or-CHR 00 -O-acyl or -CHR 0 O-NR 2 groups on each cyclopentadienyl ring are known. Reaction of these compounds with two equivalents of alkylLi (butylLi, methylLi) and addition of two equivalents of a monochloro- phosphine enables the secondary phosphine groups X 2 and X 3 to be introduced. The diphosphines obtained have become known as ferriphos when they contain a -CHR-NR 2 group.
  • the two -O-acyl Or-NR 2 groups are then substituted in a known manner using two equivalents of the secondary phosphine XrH.
  • this process it is possible to block an ortho position in the cyclopentadienyl ring by means of an auxiliary substituent such as trimethylsilyl which can be eliminated, thus enabling diastereomers of the formulae Vc and Vd to be prepared in a targeted manner.
  • intermediates can be purified, for example by means of distillation, crystallization or chromatography, before they are used in subsequent steps.
  • the intermediates are obtained in high optical purity in the known processes.
  • the compounds of the formula I are obtained in good yields and purities.
  • iridium complexes from 1 to 2 equivalents, for example, of iridium can be bound to a compound of the formula V.
  • the amount of bound iridium is preferably from 1.2 to 2 equivalents, particularly preferably from 1.5 to 2 equivalents and very particularly preferably from 1.7 to 2 equivalents.
  • the iridium complexes can be catalyst precursors or catalytically active complexes.
  • the iridium complexes can correspond to the formulae Vl, VII and VIII,
  • a 1 is one of the compounds of the formula V, preferably of one of the formulae Va to Vb;
  • Me is iridium
  • Y is two olefins or one diene
  • Z is Cl, Br or I
  • E 1 ' or E 2 2' is the anion or dianion of an oxo acid or complex acid.
  • Olefins Y can be C 2 -C 12 -, preferably C 2 -C 6 - and particularly preferably C 2 -C 4 -olefins. Examples are propene, 1-butene and in particular ethylene.
  • the diene can contain from 5 to 12 carbon atoms, preferably from 5 to 8 carbon atoms, and can be an open-chain, cyclic or polycyclic diene.
  • the two olefin groups of the diene are preferably connected by one or two CH 2 groups.
  • Examples are 1,4-pentadiene, cyclopentadiene, 1,5-hexadiene, 1,4- cyclohexadiene, 1,4- or 1,5-heptadiene, 1,4- or 1 ,5-cycloheptadiene, 1,4- or 1,5-octadiene, 1,4- or 1,5-cyclooctadiene and norbomadiene.
  • Y is preferably two ethylene molecules or 1,5- hexadiene, 1 ,5-cyclooctadiene or norbomadiene.
  • E can be -Cr, -Bf 1 -I “ , CIO 4 " , CF 3 SO 3 ' , CH 3 SO 3 -, HSO 4 " , SO 4 2" , oxalate, (CF 3 SOz) 2 N “ , (CF 3 SO 2 ) 3 C “ , tetraaryl borates such as B(phenyl) 4 " , B[bis(3,5-trifluoromethyl)phenyl] 4 " , B[bis(3,5-dimethyl)phenyl] 4 " , B(C 6 F 5 J 4 " and B(4-methylphenyl) 4 “ , BF 4 " , PF 6 “ , SbCI 6 “ , AsF 6 “ or SbF 6 “ .
  • Z is preferably Cl or Br.
  • E 1 are BF 4 " , CIO 4 “ , CF 3 SO 3 “ , CH 3 SO 3 “ , HSO 4 " , B(phenyl) 4 “ , B[bis(3,5-trifluoromethyl)phenyl] 4 " , PF 6 “ , SbCI 6 “ , AsF 6 “ or SbF 6 “ .
  • the metal complexes are prepared by methods known from the literature (see also US-A-5,371,256, US-A-5,446,844, US-A-5,583,241 and E. Jacobsen, A. Pfalte, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, Berlin, 1999, and references cited therein).
  • the process of the invention can be carried out at low or elevated temperatures, for example temperatures of from -20 to 150 0 C, preferably from -10 to 10O 0 C and particularly preferably from 10 to 80 0 C.
  • the optical yields are generally better at relatively low temperature than at higher temperatures, while a more rapid conversion can be achieved at higher temperatures.
  • the process of the invention can be carried out at atmospheric pressure or super- atmospheric pressure.
  • the pressure can be, for example, from 10 5 to 2 x 10 7 Pa (pascal).
  • Catalysts are preferably used in amounts of from 0.00001 to 10 mol%, particularly preferably from 0.00001 to 50 mol% and very particularly preferably from 0.00001 to 1 mol%, based on the compound to be hydrogenated.
  • the hydrogenation can be carried out in the presence or absence of an inert solvent, with one solvent or mixtures of solvents being able to be used.
  • Suitable solvents are, for example, aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (methylene chloride, chloroform, dichloroethane and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol monomethyl or mono
  • the reaction can be carried out in the presence of cocatalysts, for example alkali metal halides (Li, K, Na) or ammonium halides, in particular quaternary ammonium halides, with halide preferably being Br or I and particularly preferably being I. Tetrabutylammonium iodide has been found to be particularly useful.
  • the amount of cocatalysts can be, for example, from 0.1 to 100 equivalents, preferably from 1 to 80 equivalents, based on the iridium complex.
  • the hydrogenation can also be carried out in the presence of cocatalysts and protic acids, for example mineral acids, carboxylic acids or sulphonic acids (for cocatalysts and acids, see, for example, US-A-5,371,256, US-A-5,446,844, US-A-5,583,241 and EP-A-O 691 949).
  • the acid can, for example, be used as solvent or in amounts of from 0.001 to 50% by weight, preferably from 0.1 to 50% by weight, based on the amount of imine.
  • fluorinated alcohols such as 1,1,1-trifluoroethanol can likewise promote the catalytic reaction.
  • Hydroiodic acid can be generated in situ from an ammonium iodide and an acid.
  • the metal complexes used as catalysts can be added as separately prepared, isolated compounds, or they can be formed in situ prior to the reaction and then mixed with the substrate to be hydrogenated. It can be advantageous in the case of a reaction using isolated metal complexes to add additional ligands or, in the in situ preparation, to use an excess of ligands. The excess can be, for example, up to 6 mol and preferably up to 2 mol, based on the iridium compound used for the preparation.
  • the process of the invention is generally carried out by placing the catalyst in a reaction vessel and then adding the substrate, if desired reaction auxiliaries, pressurizing the vessel with hydrogen and then starting the reaction. The process can be carried out continuously or batchwise in various types of reactor.
  • the preparative process of the invention gives the amines of the formulae I and Il in high yields and very good optical purity.
  • the optical purity can be up to 80% ee and more.
  • the optical purity can be improved further by purification or separation methods known per se, for example preparative chromatography or recrystallization.
  • the amines of the formulae I and Il are highly suitable for the preparation of enriched or optically pure chloroacetamides in the form of the desired S configuration, for example (S)-N-(I '-methyl-2'-ethoxymethyl)-N- chloroacetyl-2,6-dimethylaniline.
  • the invention further provides a process for preparing compounds of the formulae
  • Roi ⁇ Ro 2 and R0 3 are each, independently of one another, CrC 4 -alkyl, R 04 is Ci-C4-alkyl, CrC 4 -alkoxymethyl or C 1 -C 4 -alkoxyethyl l and * indicates predominantly an S enantiomer, by hydrogenation of a ketimine of the formula III or IV,
  • R 0 and R 00 are each, independently of one another, hydrogen, Ci-C 2 o-alkyl, C 3 -C 8 -cycloalkyI,
  • Ri and R 2 are each, independently of one another, a hydrogen atom, a halogen atom or a substituent bound to the cyclopentadienyl rings via a C atom, S atom, Si atom, a P(O) or
  • the two indices m are each, independently of one another, 1 , 2 or 3;
  • X 1 , X 2 and X 3 are each, independently of one another, a secondary phosphine group.
  • the chloroacetylation is carried out in a manner known per se, for example as described in EP-A-O 115470.
  • the enantiomeric excess (ee) of the S enantiomer is preferably at least 70%, more preferably at least 75% and particularly preferably at least 80%.
  • Me is methyl
  • Bu is butyl
  • Ph is phenyl
  • XyI is 3,5-dimethylphen-i-yl
  • Cy is cyclohexyl
  • MOD is
  • the mixture is slowly admixed with water and extracted with water/TBME, the organic phases are collected, dried over sodium sulphate and the solvent is distilled off under reduced pressure on a rotary evaporator.
  • the crude product is prepurified by chromatography on a column (silica gel 60; eluent: ethanol). Recrystallization from ethanol gives 7.03 g of pure product as a yellow, crystalline material (yield: 46%).
  • the aqueous phase is ex ⁇ tracted two times with 100 ml of hexane.
  • the combined organic phases are washed with 100 ml of water, dried over sodium sulphate and concentrated in a rotary evaporator.
  • the crude product is purified by fractional distillation. B.p. 0 1 135-140 0 C, ee 76.5.

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Abstract

Chiral, secondary amines of the formula (I) or (II), where R01, R02 and R03 are each, independently of one another, C1-C4-alkyl, R04 is C1-C4-alkyl, C1-C4-alkoxymethyl or C1-C4-alkoxyethyl, and * indicates predominantly one configurational isomer, can be obtained by hydrogenation of corresponding ketimines in the presence of iridium complexes with chiral ferrocene tetraphosphines in which a secondary phosphine group and 1-secondary phosphinalk-1-yl are bound to each cyclopentadienyl ring in ortho positions.

Description

Process for preparing amines and a carboxamide thereof
The present invention relates to a process for the enantioselective hydrogenation of prochiral aromatic imines in the presence of iridium complexes having chiral ferrocene tetraphosphines as ligands, and a process for the enantioselective preparation of chloroacetamides of prochiral aromatic imines.
Optically active N-chloroacetanilides have been found to be very good and selective herbicides, cf., for example, EP-A-O 077 755 and EP-A-O 115470. They are prepared in a simple manner by chloroacetylation of corresponding optically active anilines which can be obtained, for example, by enantioselective hydrogenation of imines using iridium catalysts containing chiral ferrocene diphosphines as ligands (US patents 5,463,097, 5,466,844 and 5,583,241).
Catalysts are auxiliaries, remain as impurities in the reaction product and have to be removed. Efforts are therefore made to use very small amounts, with the molecular weight and the amount of metal being important factors. However, ferrocene diphosphines have not only a high iron content but also a relatively high molecular weight.
It has now been found that the problem of the excessively high iron content and the excessively high molecular weight can be solved without loss of the valuable catalytic properties in the enantioselective hydrogenation of particular aromatic ketimines when the diphosphine structure of the first cyclopentadienyl ring is also present in the second cyclopentadienyl ring so as to form a tetradentate ligand.
The invention provides a process for preparing secondary amines of the formula I or II,
Figure imgf000002_0001
where Roi, Ro2 and R03 are each, independently of one another, CrC4-alkyl, R04 is CrC4-alkyl,
CrC4-alkoxymethyl or Ci-C4-alkoxyethyl, and * indicates predominantly one configurational isomer, by hydrogenation of a ketimine of the formula III or IV,
Figure imgf000003_0001
in the presence of catalytic amounts of an enantioselective iridium complex with chiral ferrocene phosphines, which is characterized in that the ferrocene phosphine is a compound of the formula V,
Figure imgf000003_0002
where
R0 and R00 are each, independently of one another, hydrogen, Ci-C20-alkyl, C3-C8-cycloalkyl,
C6-Ci4-aryl or C3-Ci2-heteroaryl having heteroatoms selected from the group consisting of O,
S and N, which are unsubstituted or substituted by CrC6-alkyl, CrC6-alkoxy, C5-C8- cycloalkyl, C5-C8-cycloalkoxy, phenyl, d-C6-alkylphenyl, C1 -C6-alkoxy phenyl, C3-C8- heteroaryl, F or trifluoromethyl;
Ri and R2 are each, independently of one another, a hydrogen atom, a halogen atom or a substituent bound to the cyclopentadienyl rings via a C atom, S atom, Si atom, a P(O) or
P(S) group; the two indices m are each, independently of one another, 1, 2 or 3; and
Xi, X2 and X3 are each, independently of one another, a secondary phosphine group.
Alkyl radicals ROi, R02 and R03 can be, for example, methyl, ethyl, n- or i-propyl, n-, i- or t- butyl. R01, R02 and R03 are preferably methyl or ethyl. An alkyl radical R04 can be methyl, ethyl, n- or i-propyl, n-, i- or t-butyl. The alkoxy group in CrC4-alkoxymethyl or d-C4-alkoxyethyl radicals R04 can be methoxy, ethoxy, n- or i- propoxy, n-, i- or t-butoxy. R04 is preferably methoxyethyl or methoxy methyl.
Preferred compounds of the formulae I and Il are ones in which ROi is methyl, R02 is methyl or ethyl, R03 is methyl and R04 is methoxy methyl.
The symbol * indicates predominantly one configurational isomer, which means that the enantiomeric excess (ee) is at least 50%, preferably at least 60% and particularly preferably at least 70%. The configurational isomer is preferably the S enantiomer.
R1 and R2 can each be present from one to three times in the cyclopentadienyl rings.
Hydrocarbon radicals as or in substituents Ri and R2 can in turn bear one or more, for example from one to three, preferably one or two, substituents such as halogen (F, Cl or Br, in particular F), -OH, -SH, -CH(O)1 -CN1 -NR07R08, -C(O)-O-R05, -S(O)-O-R05, -S(O)2-O-R05, -P(OR05)2j -P(O)(OR05)2, -C(O)-NR07R08, -S(O)-NR07R08, -S(O)2-NR07R08, -0-(O)C-R06, -R07N-(O)C-R06, -R07N-S(O)-R06, -R07N-S(O)2-R06, CrC4-alkyl, CrC4-alkoxy, Ci.C4-alkylthio, C5-C6-CyClOaIlQrI, phenyl, benzyl, phenoxy or benzyloxy, where R07 and R08 are each, independently of one another, hydrogen, CrC4ralkyl, cyclopentyl, cyclohexyl, phenyl, benzyl or R07 and R08 together form a tetramethylene, penta methylene or 3-oxapentane-1 ,5-diyl group, R05 is hydrogen, Ci-C8-alkyl, C5-C6-cycloalkyl, phenyl or benzyl and R06 is C1-Ci8- alkyl, preferably CrCi2-alkyl, CrC4-haloalkyl, CrC4-hydroxyalkyl, C5-C8-cycloalkyl (for example cyclopentyl, cyclohexyl), C6-Ci0-aryl (for example phenyl or naphthyl) or C7-Ci2- aralkyl (for example benzyl).
The substituted or unsubstituted substituents Ri and R2 can be, for example, Ci-Ci2-alkyl, preferably CrCa-alkyl and particularly preferably Ci-C4-alkyl. Examples are methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, pentyl, hexyl, heptyl, octyl, decyl and dodecyl. Examples of substituted alkyl are alkyl-CH(OH)-, cycloalkyl-CH(OH)-, aryl-CH(OH)-, heteroaryl-CH(OH)-, alkyl2C(OH)-, cycloalkyl2C(OH)-, aryl2-CH(OH)-, heteroaryl2CH(OH)-, alkyl-phenylC(OH)-.
The substituted or unsubstituted substituents Ri and R2 can be, for example, C5-C8- cycloalkyl, preferably C5-C6-cycloalkyl. Examples are cyclopentyl, cyclohexyl and cyclooctyl. - A -
The substituted or unsubstituted substituents Ri and R2 can be, for example, C5-C8- cycloalkyl-alkyl, preferably Cs-Ce-cycloalkyl-alkyl. Examples are cyclopentylmethyl, cyclohexyl methyl or cyclohexylethyl and cyclooctyl methyl.
The substituted or unsubstituted substituents Ri and R2 can be, for example, C6-C18-aryl, preferably C6-Ci0-aryl. Examples are phenyl or naphthyl.
The substituted or unsubstituted substituents Ri and R2 can be, for example, C7-Ci2-arylalkyl (for example benzyl or 1-phenyleth-2-yl).
The substituted or unsubstituted substituents Ri and R2 can be, for example, W(CrC4- alkyl)Si or triphenylsilyl. Examples of trial kylsilyl are trimethylsilyl, triethylsilyl, tri-n-propylsilyl, tri-n-butylsilyl and dimethyl-t-butylsilyl.
The substituents Ri and R2 can, for example, be halogen. Examples are F, Cl and Br.
The substituted or unsubstituted substituents Ri and R2 can be, for example, a thio radical or sulphoxide radical or a sulphone radical of the formulae -SR09, -S(O)R09 and -S(O)2R09, where R09 is d-C^-alkyl, preferably CrC8-alkyl and particularly preferably Ci-C4-alkyl; C5-C8- cycloalkyl, preferably C5-C6-cycloalkyl; C6-Ci8-aryl and preferably C6-Ci0-aryl; or C7-C12- aralkyl. Examples of these hydrocarbon radicals have been mentioned above for Ri.
The substituents Ri and R2 can be, for example, -CH(O), -C(O)-CrC4-alkyl Or-C(O)-C6-C10- aryl.
The substituted or unsubstituted substituents R1 and R2 can be, for example, radicals - CO2R05 or -C(O)-NR07R08, where R07, R08 and R05 have the abovementioned meanings, including the preferences.
The substituted or unsubstituted substituents Ri and R2 can be, for example, radicals - S(O)-O-R05, -S(O)2-O-R05, -S(O)-NR07R08 and -S(O)2-NR07R08, where R07, R08 and R05 have the abovementioned meanings, including the preferences. The substituted or unsubstituted substituents R1 and R2 can be, for example, radicals - P(ORoδ)2 or -P(0)(ORo5)2, where R05 has the abovementioned meanings, including the preferences.
The substituted or unsubstituted substituents R1 and R2 can be, for example, radicals - P(0)(Ro5)2 or -P(S)(ORo5)2, where R05 has the abovementioned meanings, including the preferences.
An R1 in the first cyclopentadienyl ring together with an R2 in the second cyclopentadienyl ring can form a C2-C4 chain, preferably a C2-Ce chain, for example as 1 ,2-ethylene, 1,2- and 1 ,3-propylene.
In a preferred group of the substituents R1 and R2, these are selected from among C1-C4- alkyl, substituted or unsubstituted phenyl, tri(CrC4-alkyl)Si, triphenylsilyl, halogen (in particular F, Cl and Br), -SRaj -CH2OH, -CH2O-R3, -CH(O), -CO2H, -CO2R3, where R3 is a hydrocarbon radical having from 1 to 10 carbon atoms. Ri is preferably a hydrogen atom.
Examples of substituted or unsubstituted substituents R1 and R2 are methyl, ethyl, n- and i- propyl, n-, i- and t-butyl, pentyl, hexyl, cyclohexyl, cyclohexyl methyl, phenyl, benzyl, trimethylsilyl, F, Cl, Br, methylthio, methylsulphonyl, methylsulphoxyl, phenylthio, phenylsulphonyl, phenylsulphoxyl, -CH(O), -C(O)OH, -C(O)-OCH3, -C(O)-OC2H5, -C(O)-NH2, -C(O)-NHCH3, -C(O)-N(CHg)2, -SO3H, -S(O)-OCH3, -S(O)-OC2H5, -S(O)2-OCH3, -S(O)2-OC2H5, -S(O)-NH2, -S(O)-NHCH3, -S(O)-N(CH3)2, -S(O)-NH2, -S(O)2-NHCH3, -S(O)2-N(CH3)2, -P(OH)2, PO(OH)2, -P(OCH3)2, -P(OC2Hg)2, -PO(OCH3)2, -PO(OC2H5)2, trifluoromethyl, methylcyclohexyl, methylcyclohexylmethyl, methylphenyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, hydroxymethyl, β-hydroxyethyl, γ-hydroxypropyl, -CH2NH2, -CH2N(CHg)2, -CH2CH2NH2, -CH2CH2N(CHg)2, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, HS-CH2-, HS-CH2CH2-, CH3S-CH2-, CH3S-CH2CH2-, -CH2-C(O)OH1 -CH2CH2-C(O)OH, -CH2-C(O)OCH3, -CH2CH2-C(O)OCH3, -CH2-C(O)NH2, -CH2CH2-C(O)NH2, -CH2-C(O)-N(CH3)2, -CH2CH2-C(O)N(CH3)2, -CH2-SO3H, -CH2CH2-SO3H, -CH2-SO3CH3, -CH2CH2-SO3CH3, -CH2-SO2NH2, -CH2-SO2N(CHg)2, -CH2-PO3H2, -CH2CH2-PO3H2, -CH2-PO(OCH3), -CH2CH2-PO(OCHg)2, -C6H4-C(O)OH, -C6H4-C(O)OCH3, -C6H4-S(O)2OH, -C6H4-S(O)2OCH3, -CH2-O-C(O)CH3, -CH2CH2-O-C(O)CH3, -CH2-NH-C(O)CH3, -CH2CH2-NH-C(O)CH3, -CH2-O-S(O)2CH3, -CH2CH2-O-S(O)2CH3, -CH2-NH-S(O)2CH3, -CH2CH2-NH-S(O)2CH3, -P(O)(Ci-C8-alkyl)2, -P(S)(d-C8-alkyl)2, -P(O)(C6-C10-aryl)2, -P(S)(C6-C10-aryl)2, -C(O)-Ci -C8-alkyl and -C(O)-C6-Ci 0-aryl.
Alky I radicals R0 and R00 can be linear or branched and the alkyl preferably contains from 1 to 14, more preferably from 1 to 8 and particularly preferably from 1 to 6, carbon atoms. Cycloalkyl radicals Ro and Roo are preferably Cs-Cβ-cycloalkyl, particularly preferably Cs-Cβ- cycloalkyl. Aryl radicals R0 and R00 can be, for example, phenyl, naphthyl or anthracenyl, with phenyl being preferred. Heteroaryl radicals R0 and ROo are preferably C3-C8-heteroaryl. Substituents for R0 and ROo can be, for example, F, trifluoromethyl, methyl, ethyl, n- or i- propyl, n-, i- or t-butyl, pentyl, hexyl, methoxy, ethoxy, n- or i-propoxy, n-, i- ort-butoxy, pentoxy, hexoxy, cyclopentyl, cyclohexyl, cyclopentoxy, cyclohexoxy, phenyl, methylphenyl, dimethyl phenyl, methoxyphenyl, furyl, thienyl or pyrrolyl.
Some examples of R0 and ROo are methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cyclooctyl, phenyl, benzyl, methylphenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, methoxybenzyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, pyridyl, pyrimidyl, quinolyl, furylmethyl, thienylmethyl and pyrrolylmethyl.
In a preferred embodiment, R0 and ROo are identical radicals. In another preferred embodiment, R0 and ROo are identical radicals selected from the group consisting of CrC8- alkyl, C5-C8-cycloalkyl, phenyl and benzyl, which are unsubstituted or substituted as defined above.
The secondary phosphine groups Xi, X2 and X3 can contain two identical hydrocarbon radicals or two different hydrocarbon radicals. The secondary phosphine groups Xi, X2 and X3 preferably each contain two identical hydrocarbon radicals. Furthermore, the secondary phosphine groups Xi and X2, Xi and X3, X2 and X3 and also Xi, X2 and X3 can be identical or different.
The hydrocarbon radicals can be unsubstituted or substituted and/or contain heteroatoms selected from the group consisting of O, S and N. They can contain from 1 to 22, preferably from 1 to 12 and particularly preferably from 1 to 8, carbon atoms. A preferred secondary phosphine is one in which the phosphine group contains two identical or different radicals selected from the group consisting of linear or branched CrCi2-alkyl; unsubstituted or CrCβ- alkyl- or CrC6-alkoxy-substituted C5-Ci2-cycloalkyl or C5-Ci2-cycloalkyl-CH2-; phenyl, naphthyl, furyl or benzyl; and phenyl or benzyl substituted by halogen (for example F, Cl and Br), CrC6-alkyl, CrC6-haloalkyl (for example trifluoromethyl), CrC6-alkoxy, CrCε-haloalkoxy (for example trifluoromethoxy), (C6Hs)3Si, (C1-Ci2-BIkYl)3Si, secondary amino or -CO2-CrC6- alkyl (for example -CO2CH3).
Examples of alkyl substituents on P, which preferably contain from 1 to 6 carbon atoms, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the isomers of pentyl and hexyl. Examples of unsubstituted or alkyl-substituted cycloalkyl substituents on P are cyclopentyl, cyclohexyl, methylcyclopentyl and ethylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl and ethylcyclohexyl and dimethylcyclohexyl. Examples of alkyl-, alkoxy-, haloalkyl-, haloalkoxy- and halogen-substituted phenyl and benzyl substituents on P are o-, m- or p- fluorophenyl, o-, m- or p-chlorophenyl, difluorophenyl or dichlorophenyl, pentafluorophenyl, methylphenyl, dimethylphenyl, trimethylphenyl, ethylphenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, trifluoromethylphenyl, bistrifluoromethylphenyl, tristrifluoromethylphenyl, trifluoromethoxyphenyl, bistrifluoromethoxyphenyl, 3,5-dimethyl-4- methoxyphenyl and 3,5-di-t-butyl-4-methoxyphenyl.
Preferred secondary phosphine groups are ones in which the identical radicals are selected from the group consisting of CrC6-alkyl, unsubstituted cyclopentyl or cyclohexyl, cyclopentyl or cyclohexyl substituted by from 1 to 3 CrC4-alkyl or CrC4-alkoxy radicals, benzyl and in particular phenyl which are unsubstituted or substituted by from 1 to 3 Ci-C4-alkyl, CrC4- alkoxy, F, Cl, Ci-C4-fluoroalkyl or Ci-C4-fluoroalkoxy radicals.
The secondary phosphino group preferably corresponds to the formula -PR3R4, where R3 and R4 are each, independently of one another, a hydrocarbon radical having from 1 to 18 carbon atoms which is unsubstituted or substituted by halogen, Ci-C6-alkyl, Ci-C6-haloalkyl, CrCe-alkoxy, CrC6-haloalkoxy, (Ci-C4-alkyl)2amino, (C6H5)3Si, (CrCi2-alkyl)3Si or- CO2-CrC6-alkyl and/or contains heteroatoms O.
R3 and R4 are preferably identical radicals selected from the group consisting of linear or branched CrC6-alkyl, unsubstituted cyclopentyl or cyclohexyl, cyclopentyl or cyclohexyl substituted by from one to three CrC4-alkyl or Ci-C4-alkoxy radicals, furyl, unsubstitued benzyl or benzyl substituted by from one to three Ci-C4-alkyl or CrC4-alkoxy radicals, and in particular unsubstituted phenyl or phenyl substituted by from one to three CrC4-alkyl, CrC4- alkoxy, -NH2, -N(Ci-C6-alkyl)2, OH, F, Cl1 Ci-C4-fluoroalkyl or d-C4-fluoroalkoxy radicals.
R3 and R4 are particularly preferably identical radicals selected from the group consisting of CrC6-alkyl, cyclopentyl, cyclohexyl, furyl and unsubstituted phenyl or phenyl substituted by from one to three d-C4-alkyl, CrC4-alkoxy and/or CrC4-fluoroalkyl radicals.
The secondary phosphine groups Xi, X2 and X3 can be cyclic secondary phosphino, for example groups of the formulae
Figure imgf000009_0001
which are unsubstituted or substituted by one or more -OH, CrC8-alkyl, C4-C8-cycloalkyl, CrCe-alkoxy, Ci-C4-alkoxy-CrC4-alkyl, phenyl, CrC4-alkylphenyl or CrC4-alkoxyphenyl, benzyl, Ci-C4-alkyl benzyl or CrC4-alkoxybenzyl, benzyloxy, Ci-C4-aIkylbenzyloxy or CrC4- alkoxybenzyloxy, methylenedioxyl which may be unsubstituted or substituted by aryl such as phenyl, or CrC4-alkylidenedioxyl.
The substituents can be bound to the P atom in one or both α positions in order to introduce chiral C atoms. The substituents in one or both α positions are preferably d-C4-alkyl or benzyl, for example methyl, ethyl, n- or i-propyl, benzyl or-CH2-O-Ci-C4-alkyl or-
Figure imgf000009_0002
Substituents in the β,γ positions can be, for example, Ci-C4-alkyl, CrC4-alkoxy, benzyloxy or -0-CH2-O-, -O-CH(CrC4-alkyl)-O- and -O-C(CrC4-alkyl)2-O-. Some examples are methyl, ethyl, methoxy, ethoxy, -O-CH(phenyl)-O-, -O-CH(methyl)-O- and -O-C(methyl)2-O-.
In the radicals of the above formulae, an aliphatic 5- or 6-membered ring or benzene can be fused onto two adjacent carbon atoms.
Other known and suitable secondary phosphine radicals are cyclic and chiral phospholanes having seven carbon atoms in the ring, for example radicals of the formulae
Figure imgf000010_0001
in which the aromatic rings may be substituted by CrC4-alkyl, Ci-C4-alkoxy, Ci-C4-alkoxy- Ci-C2-alkyl, phenyl, benzyl, benzyloxy or Ci-C4-alkylicienedioxyl or Ci-C4-alkylenedioxyl (cf. US 2003/0073868 A1 and WO 02/048161).
Depending on the type of substitution and number of substituents, the cyclic phosphine radicals can be C-chiral, P-chiral or C- and P-chiral.
The cyclic secondary phosphino can, for example, correspond to the formulae (only one of the possible diastereomers is indicated),
Figure imgf000011_0001
where the radicals R' and R" are each Ci-C4-alkyl, for example methyl, ethyl, n- or i-propyl, benzyl, or-CH2-O-Ci-C4-alkyl or-CH2-0-C6-Cio-aryl, and R' and R" are identical or dfferent. When
R' and R" are bound to the same carbon atom, they can together form a C4-C5-alkylene group.
In a preferred embodiment of the compounds of the formula V, the radicals Xi are preferably identical and the radicals X2 and X3 are identical or different and Xi, X2 and X3 are preferably noncyclic secondary phosphine selected from the group consisting of -PCCrCe-alkyl)^ -P(C5-C8-cycloalkyl)2j -P(C7-C12-bicycloalkyl)2, -P(o-furyl)2j -P(C6Hs)2, -P[2-(CrC6- alkyl)C6H4]2, -Pβ-fd-Ce-alkyOCel-Uk -P[4-(Ci-Cβ-alM)CβHd2, -P[2-(CrC6-alkoxy)C6H4]2, -P[3-(CrC6-alkoxy)C6H4]2j -P[4-(CrC6-alkoxy)C6H4]2j -P[2-(trifluoromethyl)C6H4]2l -P[3- (trifluoromethyl)C6H4]2] -P[4-(trifluoromethyl)C6H4]2) -P[3J5-bis(trifluoromethyl)C6H3]2, -P[3,5- bis(C1-C6-alkyl)2C6H3]2J -P[3,5-bis(Ci-C6-alkoxy)2C6H3]2 and -P[3,5-bis(Ci-C6-alkyl)2-4-(CrC6- alkoxy)C6H2]2, -P[3J415-tris(Ci-C6-alkoxy)2C6H3]2, or cyclic phosphine selected from the group consisting of
Figure imgf000012_0001
which are unsubstituted or substituted by one or more
Figure imgf000012_0002
Ci-C4-alkoxy, C1-C4- alkoxy-Ci-C2-alkyl, phenyl, benzyl, benzyloxy, d-C4-alkylidenedioxyl or unsubstituted or phenyl-substituted methylenedioxyl groups.
Some specific examples are -P(CH3J2, -P(J-C3Hr)2, -P(n-C4H9)2) -P(i-C4H9)2, -P(C6Hn)2, -P(norbornyl)2l -P(o-furyl)2, -P(C6Hg)2, -P[2-(methyl)C6H4]2, -P[3-(methyl)C6H4]2) -P[4- (methyl)C6H4]2j -P[2-(methoxy)C6H4]2, -P[3-(methoxy)C6H4]2j -P[4-(methoxy)C6H4]2, -P[3- (trifluoromethyl)C6H4]2, -P[4-(trifluoromethyl)C6H4]2, -P[3)5-bis(trifluoromethyl)C6H3]2, -P[3,5- bis(methyl)2C6H3]2, -P[3,5-bis(methoxy)2C6H3]2 and -P[3,5-bis(methyI)2-4-(methoxy)C6H2]2, and groups of the formulae
Figure imgf000012_0003
where
R' is methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, methoxy methyl, ethoxymethyl or benzyloxymethyl and R" has the same meaning as R'. The compounds of the formula V are preferably present as diastereomers of the formula Va (R,S,R',S' configuration) or Vd (S,R,S',R' configuration) or mixtures thereof, or as diastereomers of the formula Vc (R,R,R',R' configuration) or Vb (S,S,S',S' configuration) or mixtures thereof,
Figure imgf000013_0001
Figure imgf000013_0002
The compounds of the formula V and diastereomers or mixtures of diastereomers can be prepared by methods known per se or analogous methods, as are described, for example, in US-A-5,463,097, by T. Hayashi et al. in J. of Organometallic Chemistry, 370 (1989), pages 229-139 or in WO 96/16971.
Ferrocenes having -CHR0-O-acyl Or-CHR0-NR2 groups or-CHR00-O-acyl or -CHR0O-NR2 groups on each cyclopentadienyl ring are known. Reaction of these compounds with two equivalents of alkylLi (butylLi, methylLi) and addition of two equivalents of a monochloro- phosphine enables the secondary phosphine groups X2 and X3 to be introduced. The diphosphines obtained have become known as ferriphos when they contain a -CHR-NR2 group. The two -O-acyl Or-NR2 groups are then substituted in a known manner using two equivalents of the secondary phosphine XrH. In this process it is possible to block an ortho position in the cyclopentadienyl ring by means of an auxiliary substituent such as trimethylsilyl which can be eliminated, thus enabling diastereomers of the formulae Vc and Vd to be prepared in a targeted manner.
In the processes for preparing the ferrocene phosphines, intermediates can be purified, for example by means of distillation, crystallization or chromatography, before they are used in subsequent steps. The intermediates are obtained in high optical purity in the known processes. The compounds of the formula I are obtained in good yields and purities.
In the iridium complexes, from 1 to 2 equivalents, for example, of iridium can be bound to a compound of the formula V. The amount of bound iridium is preferably from 1.2 to 2 equivalents, particularly preferably from 1.5 to 2 equivalents and very particularly preferably from 1.7 to 2 equivalents. The iridium complexes can be catalyst precursors or catalytically active complexes.
The iridium complexes can correspond to the formulae Vl, VII and VIII,
[ZYMeA1MeYZ] (Vl), [YMeA1MeY]2+(Er)2 (VII), [YMeA1MeY]2+(E2 2") (VIII),
where
A1 is one of the compounds of the formula V, preferably of one of the formulae Va to Vb;
Me is iridium;
Y is two olefins or one diene;
Z is Cl, Br or I; and
E1 ' or E2 2' is the anion or dianion of an oxo acid or complex acid.
With regard to the compounds of the formula I, the above-described embodiments and preferences apply.
Olefins Y can be C2-C12-, preferably C2-C6- and particularly preferably C2-C4-olefins. Examples are propene, 1-butene and in particular ethylene. The diene can contain from 5 to 12 carbon atoms, preferably from 5 to 8 carbon atoms, and can be an open-chain, cyclic or polycyclic diene. The two olefin groups of the diene are preferably connected by one or two CH2 groups. Examples are 1,4-pentadiene, cyclopentadiene, 1,5-hexadiene, 1,4- cyclohexadiene, 1,4- or 1,5-heptadiene, 1,4- or 1 ,5-cycloheptadiene, 1,4- or 1,5-octadiene, 1,4- or 1,5-cyclooctadiene and norbomadiene. Y is preferably two ethylene molecules or 1,5- hexadiene, 1 ,5-cyclooctadiene or norbomadiene.
E can be -Cr, -Bf1 -I", CIO4 ", CF3SO3 ', CH3SO3-, HSO4 ", SO4 2", oxalate, (CF3SOz)2N", (CF3SO2)3C", tetraaryl borates such as B(phenyl)4 ", B[bis(3,5-trifluoromethyl)phenyl]4 ", B[bis(3,5-dimethyl)phenyl]4 ", B(C6F5J4 " and B(4-methylphenyl)4 ", BF4 ", PF6 ", SbCI6 ", AsF6 " or SbF6 ".
In the formulae Vl, VII and VIII, Z is preferably Cl or Br. Examples of E1 are BF4 ", CIO4 ", CF3SO3 ", CH3SO3 ", HSO4 ", B(phenyl)4 ", B[bis(3,5-trifluoromethyl)phenyl]4 ", PF6 ", SbCI6 ", AsF6 " or SbF6 ".
The metal complexes are prepared by methods known from the literature (see also US-A-5,371,256, US-A-5,446,844, US-A-5,583,241 and E. Jacobsen, A. Pfalte, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I to III, Springer Verlag, Berlin, 1999, and references cited therein).
The process of the invention can be carried out at low or elevated temperatures, for example temperatures of from -20 to 1500C, preferably from -10 to 10O0C and particularly preferably from 10 to 800C. The optical yields are generally better at relatively low temperature than at higher temperatures, while a more rapid conversion can be achieved at higher temperatures.
The process of the invention can be carried out at atmospheric pressure or super- atmospheric pressure. The pressure can be, for example, from 105 to 2 x 107 Pa (pascal).
Catalysts are preferably used in amounts of from 0.00001 to 10 mol%, particularly preferably from 0.00001 to 50 mol% and very particularly preferably from 0.00001 to 1 mol%, based on the compound to be hydrogenated.
The hydrogenation can be carried out in the presence or absence of an inert solvent, with one solvent or mixtures of solvents being able to be used. Suitable solvents are, for example, aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (methylene chloride, chloroform, dichloroethane and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol monomethyl or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carboxylic esters and lactones (ethyl or methyl acetate, valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxamides (dimethylamide, dimethylformamide), acyclic ureas (dimethylimidazoline) and sulphoxides and sulphones (dimethyl sulphoxide, dimethyl sulphone, tetramethylene sulphoxide, tetramethylene sulphone) and fluorinated or unfluorinated alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, 1,1,1-trifluoroethanol) and water. Further suitable solvents are low molecular weight carboxylic acids such as acetic acid. The solvents can be used alone or as mixtures of at least two solvents.
The reaction can be carried out in the presence of cocatalysts, for example alkali metal halides (Li, K, Na) or ammonium halides, in particular quaternary ammonium halides, with halide preferably being Br or I and particularly preferably being I. Tetrabutylammonium iodide has been found to be particularly useful. The amount of cocatalysts can be, for example, from 0.1 to 100 equivalents, preferably from 1 to 80 equivalents, based on the iridium complex. The hydrogenation can also be carried out in the presence of cocatalysts and protic acids, for example mineral acids, carboxylic acids or sulphonic acids (for cocatalysts and acids, see, for example, US-A-5,371,256, US-A-5,446,844, US-A-5,583,241 and EP-A-O 691 949). The acid can, for example, be used as solvent or in amounts of from 0.001 to 50% by weight, preferably from 0.1 to 50% by weight, based on the amount of imine. The presence of fluorinated alcohols such as 1,1,1-trifluoroethanol can likewise promote the catalytic reaction. In the hydrogenation of the invention, the use of iridium complexes in combination with tetra-Ci-C4-alkylammonium iodides and mineral acids, preferably HI, has been found to be useful. Hydroiodic acid can be generated in situ from an ammonium iodide and an acid.
The metal complexes used as catalysts can be added as separately prepared, isolated compounds, or they can be formed in situ prior to the reaction and then mixed with the substrate to be hydrogenated. It can be advantageous in the case of a reaction using isolated metal complexes to add additional ligands or, in the in situ preparation, to use an excess of ligands. The excess can be, for example, up to 6 mol and preferably up to 2 mol, based on the iridium compound used for the preparation. The process of the invention is generally carried out by placing the catalyst in a reaction vessel and then adding the substrate, if desired reaction auxiliaries, pressurizing the vessel with hydrogen and then starting the reaction. The process can be carried out continuously or batchwise in various types of reactor.
The preparative process of the invention gives the amines of the formulae I and Il in high yields and very good optical purity. The optical purity can be up to 80% ee and more. The optical purity can be improved further by purification or separation methods known per se, for example preparative chromatography or recrystallization. The amines of the formulae I and Il are highly suitable for the preparation of enriched or optically pure chloroacetamides in the form of the desired S configuration, for example (S)-N-(I '-methyl-2'-ethoxymethyl)-N- chloroacetyl-2,6-dimethylaniline.
The invention further provides a process for preparing compounds of the formulae
Figure imgf000017_0001
where
Roiι Ro2 and R03 are each, independently of one another, CrC4-alkyl, R04 is Ci-C4-alkyl, CrC4-alkoxymethyl or C1-C4-alkoxyethyll and * indicates predominantly an S enantiomer, by hydrogenation of a ketimine of the formula III or IV,
(IV)1
Figure imgf000017_0002
in the presence of catalytic amounts of an enantioselective iridium complex with chiral ferrocene phosphines to form the amine and subsequent chloroacetylation of the amine, which is characterized in that the ferrocene phosphine is a compound of the formula V,
Figure imgf000018_0001
where
R0 and R00 are each, independently of one another, hydrogen, Ci-C2o-alkyl, C3-C8-cycloalkyI,
C6-C14-aryl or C3-C12-heteroaryl having heteroatoms selected from the group consisting of O,
S and N, which are unsubstituted or substituted by CrCβ-alkyl, CrCβ-alkoxy, Cβ-Cβ- cycloalkyl, Cs-Cβ-cycloalkoxy, phenyl, CrC6-alkylphenyl, CrC6-alkoxyphenyl, C3-C8- heteroaryl, F or trifluoromethyl;
Ri and R2 are each, independently of one another, a hydrogen atom, a halogen atom or a substituent bound to the cyclopentadienyl rings via a C atom, S atom, Si atom, a P(O) or
P(S) group; the two indices m are each, independently of one another, 1 , 2 or 3; and
X1, X2 and X3 are each, independently of one another, a secondary phosphine group.
The above-described preferences and embodiments apply to ROi, R02. R03. R<M, RO. ROO, RI. R2, X1, X2, X3 and m and to the process conditions in the hydrogenation. The chloroacetylation is carried out in a manner known per se, for example as described in EP-A-O 115470. The enantiomeric excess (ee) of the S enantiomer is preferably at least 70%, more preferably at least 75% and particularly preferably at least 80%.
The following examples illustrate the invention.
Abbreviations:
Me is methyl, Bu is butyl, Ph is phenyl, XyI is 3,5-dimethylphen-i-yl, Cy is cyclohexyl, MOD is
3,5-dimethyl-4-methoxyphenyl, TBME is t-butyl methyl ether, THF is tetrahydrofuran. A) Preparation of ligands
Example A1 :
Figure imgf000019_0001
(1 ) (AI )
0.34 ml (1.7 mmol) of dicyclohexylphosphine is added to 536 mg (0.77 mmol) of the (R,S)- diamine-diphosphine compound 1) in 5 ml of acetic acid and the red solution is stirred overnight at 1050C. After cooling, the reaction mixture is shaken with toluene and water and saturated aqueous NaCI solution. The organic phases are combined, dried over sodium sulphate and evaporated on a rotary evaporator. The red crude product is purified by chromatography (silica gel 60, eluent: heptane/TBME 50:1). The product (A1) is obtained as a solid crystalline substance. The yield is 424 mg (55% of theory).
1H-NMR (C6D6), characteristic signals: δ 1.05-2.0 (m, 50H), 3.11 (s, 2H), 3.56 (m, 2H)1 4.40- 4.55 (m, 4H), 6.85-7.55 (m, 20H). 31P-NMR (C6D6): δ +16.3 (d); -25.5 (d).
Example A2:
Figure imgf000019_0002
1.7 mmol of di-3,5-xylylphosphine (24.3% strength solution in toluene) are added to 518 mg (0.74 mmol) of the (S,R)-diamine-diphosphine compound (1) in 2.5 ml of acetic acid and the red solution is stirred overnight at 1050C. After cooling, the reaction mixture is shaken with toluene and water. The organic phases are combined, dried over sodium sulphate and evaporated on a rotary evaporator. The red crude product is purified by chromatography (siiica gel Merck 60, eluent: heptane/TBME 10:1). The substance (A2) is obtained as a solid material. The yield is 540 mg (67% of theory).
1H-NMR (C6D6): δ 1.78 (t, 6H)1 1.99 (s, 12H), 2.06 (S1 12H), 3.16 (s, 2H), 4.10 (m, 2H), 4.44
(s, 2H), 4.57 (m, 2H)5 6.60-7.55 (m, 32H).
31P-NMR (C6D6): δ +8.3 (d), -25.1 (d).
Example A3:
Figure imgf000020_0001
(0) (2) (A3)
a) Preparation of compound (2)
30.45 ml (39.6 mmol) of S-BuLi (1.3 molar in cyclohexane) are added dropwise at from 00C to 5°C to a solution of 5.144 g (16.5 mmol) of the compound (0) in 25 ml of diethyl ether over a period of about 30 minutes while stirring and the reaction mixture is stirred for another 3.5 hours at this temperature. 14.44 g (42.9 mmol) of bis-MOD-chlorophosphine are then added, the cooling is removed and the reaction mixture is stirred further overnight. The mixture is slowly admixed with water and extracted with water/TBME, the organic phases are collected, dried over sodium sulphate and the solvent is distilled off under reduced pressure on a rotary evaporator. The crude product is prepurified by chromatography on a column (silica gel 60; eluent: ethanol). Recrystallization from ethanol gives 7.03 g of pure product as a yellow, crystalline material (yield: 46%).
1H-NMR (C6D6), characteristics signals: δ 7.52 (s, 2H), 7.50 (s, 2H)1 7.14 (s, 2H), 7.11 (s, 2H)1 4.37-4.28 (m, 6H)1 3.86 (m. 2H)1 3.30 (two S1 12H)1 2.1 (s, 12H)1 2.09 (S1 12H)1 1.90 (S1 12H)1 1.40 (d, 6H). 31P-NMR (C6D6): δ -23.7 (s). b) Preparation of the compound A3
18.9 g of a 10% solution of di-t-butylphosphine (12.02 mmol) in acetic acid are added to 4.0 g (4.31 mmol) of the (S,R)-diamine-diphosphine compound (2) in 20 ml of acetic acid and the reaction mixture is stirred overnight at 1050C. After cooling, the mixture is extracted with methylene chloride/water, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure on a rotary evaporator. The crude product is purified by chromatography (silica gel 60; eluent = 10 heptane/1 TBME/0.1 triethylamine). The product is obtained as an orange, crystalline compound (yield: 50%).
1H-NMR (C6D6), characteristic signals: δ 7.73 (s, 2H), 7.70 (s, 2H)1 7.23 (s, 2H), 7.21 (s, 2H), 4.18 (m, 2H), 3.93 (m, 2H), 3.70 (q, 2H), 3.65 (m, 2H)1 3.36 (s, 6H), 3.26 (s, 6H)1 2.33 (m, 6H), 2.24 (S1 12H), 2.12 (s, 12H)1 1.42 (d, 18H)1 1.15 (d, 18H). 31P-NMR (C6D6): δ +52.2 (d), -26.5 (d).
Example A4:
Figure imgf000021_0001
a) Preparation of compound (3)
2.6 ml (14.4 mmol) of a solution of t-butyl hydroperoxide in nonane (5.5 molar) are added dropwise at 00C to a solution of 5 g (7.2 mmol) of the S1R compound (1) in 40 ml of THF while stirring. The cooling is subsequently removed and the mixture is stirred further overnight, with a yellow precipitate being formed. After addition of 40 ml of heptane, the solid is filtered off, washed with a little cold diethyl ether and dried under reduced pressure (yield: 88%). The crude product is very pure and can be used further without further purification.
1H-NMR (CDCI3), characteristic signals: δ 7.6-7.4 (m, 20H), 5.01 (m, 2H)1 4.40 (m, 2H), 4.27
(m, 2H), 3.32 (m, 2H), 1.56 (s, 12H)1 1.19 (d, 6H). 31P-NMR (CDCI3): δ +26.3 (s).
b) Preparation of the compound (4)
10.4 ml (16.8 mmol) of n-butyllithium (1.6 molar in hexane) are added dropwise at-78°C to a solution of 4 g (5.6 mmol) of the compound (3) in 200 ml of THF while stirring. The reaction mixture is stirred for another 2 hours at this temperature. 1.05 ml (16.8 mmol) of methyl iodide are then added dropwise at -78°C and the reaction mixture is stirred further for 0.5 hours at -78°C, then for 1 hour at -400C and finally for 30 minutes at -100C before being admixed with 5 ml of water at -100C while stirring vigorously. The organic solvent and any unreacted methyl iodide is immediately distilled off under reduced pressure at a maximum of 500C and the residue is extracted with methylene chloride/aqueous NaCI solution. The organic phases are collected, dried over sodium sulphate and the solvent is distilled off under reduced pressure on a rotary evaporator. The crude product is obtained as an orange solid which is used further without further purification (yield: > 98%).
1H-NMR (C6D6), characteristic signals: δ 7.89-7.7 (m, 8H), 7.1-6.9 (m, 12H), 5.40 (s, 2H), 4.30 (m, 2H), 4.09 (m, 2H), 1.68 (s, 12H), 1.46 (s, 6H), 1.38 (d, 6H). 31P-NMR (C6D6): δ +27.2
(S).
c) Preparation of the compound (5)
A suspension of 390 mg (0.53 mmol) of the phosphine oxide (4) and 1.9 ml (10.5 mmol) of HSi(OEt)3 in 10 ml of toluene is heated to reflux while stirring. 0.19 ml (0.64 mmol) of titanium(IV) isopropoxide is then slowly added dropwise over a period of 20 minutes and the reaction mixture is refluxed further overnight. After cooling, the toluene is distilled off on a rotary evaporator, the residue is suspended in 2 ml of ethyl acetate and applied to a column. Chromatography (silica gel 60; eluent = ethyl acetate with 1% of triethylamine) gives the desired product as an orange foam in a yield of 73%.
1H-NMR (C6D6), characteristic signals: δ 7.8-7.7 (m, 4H), 7.4-7.3 (m, 4H), 7.33-7.0 (m, 12H), 4.70 (s, 2H), 4.28 (m, 2H), 3.62 (m, 2H), 1.79 (s, 12H), 1.40 (s, 6H), 1.32 (d, 6H). 31P-NMR (C6D6): δ -15.3 (S). d) Preparation of the compound A4
A solution of 200 mg (0.28 mmol) of the diphosphine (5) and 860 mg (0.69 mmol) of di(3,5- xylyl)phosphine in 1 ml of acetic acid is stirred overnight at 105°C. After cooling, the acetic acid is distilled off under reduced pressure on a rotary evaporator. Chromatographic purification (silica gel 60; eluent = 1 ethyl acetate/20 heptane) gives the desired product as an orange foam (yield: 67%).
1H-NMR (C6D6), characteristic signals: δ 7.75-7.65 (m, 4H), 7.65-7.55 (m, 4H), 7.20-6.90 (m, 20H), 6.77 (S, 2H)1 6.67 (s, 2H), 4.28 (m, 2H), 4.23 (m, 2H), 3.63 (m, 2H), 2.08 (s, 12H)1 2.02 (s, 12H), 1.69 (s, 6H), 1.61 (m, 6H). 31P-NMR (C6D6): δ +8.7 (d); -15.8 (d).
B) Hvdrogenations
Examples B1 - B5: Preparation of N-(2'-methyl-6'-ethylphen-1'-yl)-1- methoxymethylethylamine
Figure imgf000023_0001
(1) .. (2)
1.7 mg of [lr(cyclooctadiene)CI]2, 2.9 mg of ligand, 70 mg of tetrabutylammonium iodide and 10 ml of acetic acid are added to 105 g of imine (1) in an autoclave. These conditions correspond to a ratio of substrate to iridium of 95 000. The autoclave is closed and flushed with argon. The argon is then replaced by flushing with hydrogen and the autoclave is pressurized with hydrogen (80 bar). The hydrogenation is started by switching on the stirrer. After the hydrogenation, the conversion and the optical yield (ee) is determined by means of HPLC [Chiracel OD; eluent: hexane/i-propanol (99.6:0.4), flow: 1 ml/minute]. The following table shows the results, including the configuration corresponding to the optical yield (R or S configuration).
Figure imgf000024_0001
*) The inverse configuration of the product is formed, when the ligands are used in their other enantiomeric form.
C) Preparation of chloroacetic acid amides
Example C1: Preparation of (R)-2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1- methylethyl)-acetamide
105 g (0.51 mol) of (R)-2-ethyl-N-(2-methoxy-1-methylethyl)-6-methylaniline (ee 76.5%) in 200 ml of toluene are cooled to 100C and 48.1 g (0.61 mol) pyridine are added. With ice cooling, 60 g (0.53 mol) of chloroacetylchloride are then added dropwise in the course of 2 hours. The resulting suspension is then stirred at room temperature overnight. For working up, the reaction mixture is poured onto 200 ml of water and the resulting emulsion is vigo¬ rously stirred for 10 minutes. After removal of the organic phase, the aqueous phase is ex¬ tracted two times with 100 ml of hexane. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate and concentrated in a rotary evaporator. The crude product is purified by fractional distillation. B.p.0 1 135-1400C, ee 76.5.

Claims

Claims
1. Process for preparing secondary amines of the formula I or I
Figure imgf000025_0001
where
Roi, R02 and R03 are each, independently of one another, CrC4-alkyl, R04 is Ci-C4-alkyl,
CrC4-alkoxymethyl or Ci-C4-alkoxyethyl, and * indicates predominantly one configurational isomer, by hydrogenation of a ketimine of the formula III or IV,
Figure imgf000025_0002
in the presence of catalytic amounts of an enantioselective iridium complex with chiral ferrocene phosphines, characterized in that the ferrocene phosphine is a compound of the formula V1
Figure imgf000025_0003
where R0 and R00 are each, independently of one another, hydrogen, CrC2o-alkyl, C3-C8-cycloalkyl,
C6-Ci4-aryl or C3-Ci2-heteroaryl having heteroatoms selected from the group consisting of O,
S and N, which are unsubstituted or substituted by CrC6-alkyl, CrC6-alkoxy, C5-C8- cycloalkyl, Cs-Cβ-cycloalkoxy, phenyl, CrC6-alkylphenyl, CrC6-alkoxyphenyl, C3-C8- heteroaryl, F or trifluoromethyl;
Ri and R2 are each, independently of one another, a hydrogen atom, a halogen atom or a substituent bound to the cyclopentadienyl rings via a C atom, S atom, Si atom, a P(O) or
P(S) group; the two indices m are each, independently of one another, 1, 2 or 3; and
Xi, X2 and X3 are each, independently of one another, a secondary phosphine group.
2. Process according to Claim 1, characterized in that Roi, Ro2 and Ro3 are each methyl or ethyl.
3. Process according to Claim 1, characterized in that R04 is methoxyethyl or methoxymethyl.
4. Process according to Claim 1, characterized in that, in the formulae I and II, Roi is methyl, R02 is methyl or ethyl, R03 is methyl and R04 is methoxymethyl.
5. Process according to Claim 1, characterized in that the symbol * denotes an enantiomeric excess (ee) of at least 50%.
6. Process according to Claim 1 , characterized in that Ri and R2 are each hydrogen.
7. Process according to Claim 1, characterized in that R0 and Roo are identical radicals selected from the group consisting of CrC8-alkyl, C5-C8-cycloalkyl, phenyl and benzyl which are unsubstituted or substituted.
8. Process according to Claim 1, characterized in the secondary phosphino groups X1, X2 and X3 correspond to the formula -PR3R4, where R3 and R4 are each, independently of one another, a hydrocarbon radical having from 1 to 18 carbon atoms which is unsubstituted or substituted by halogen, Ci-C6-alkyl, CrC6-haloalkyl, CrC6-alkoxy, CrC6-haloalkoxy, (C1-C4-alkyl)2amino, (C6H5)3Si, (CrC12-alkyl)3Si or -CCfe-CrCe-alkyl and/or contains heteroatoms O; or X1, X2 and X3 are cyclic secondary phosphino.
9. Process according to Claim 1, characterized in that the radicals Xi are identical and the radicals X2 and X3 are identical or different and Xi, X2 and X3 are noncyclic secondary phosphine selected from the group consisting of -P(CrC6-alkyl)2) -P(C5-C8-cycloalkyl)2) -P(C7-C8-bicycloalkyl)2l -P(o-furyl)2, -P(C6Hg)2, -P[2-(CrC6-alkyl)C6H4]2, -P[3-(CrC6- alkyl)C6H4]2j -P[4-(CrC6-alkyl)C6H4]2, -P[2-(CrC6-alkoxy)C6H4]2j -P[3-(CrC6-alkoxy)C6H4]2j -P[4-(CrC6-alkoxy)C6H4]2> -P[2-(trifluoromethyl)C6H4]2j -P[3-(trifluoromethyl)C6H4]2j -P[4- (trifluoromethyl)C6H4]2J -P[3J5-bis(trifluoromethyl)C6H3]2j -P[3I5-bis(C1-C6-alkyl)2C6H3]2J -P[3,5-bis(CrC6-alkoxy)2C6H3]2j -P[3J4,5-tris(Ci-C6-alkoxy)2C6H3]2 and -P[3,5-bis(CrC6- alkyl^-^rCe-alkoxyJCeH^, or cyclic phosphine selected from the group consisting of
Figure imgf000027_0001
which are unsubstituted or substituted by one or more Ci-C4-alkyl, CrC4-alkoxy, CrC4- alkoxy-CrC2-alkyl, phenyl, benzyl, benzyloxy or Ci-C4-alkylidenedioxyl.
10. Process according to Claim 1, characterized in that the compounds of the formula V are preferably present as diastereomers of the formula Va (R,S,R',S' configuration) or Vd (S1R1S', R' configuration) or mixtures thereof, or as diastereomers of the formula Vc (R.R.R'.R' configuration) or Vb (S.S.S'.S' configuration) or mixtures thereof,
Figure imgf000028_0001
Figure imgf000028_0002
11. Process according to Claim 1 , characterized in that, in the iridium complexes, from 1 to 2 equivalents of iridium are bound to a compound of the formula V.
12. Process according to Claim 1, characterized in that the iridium complexes correspond to the formulae Vl, VII and VIII,
[ZYMeA1MeYZ] (Vl)1 [YMeA1MeY]2+(E1-J2 (VII), [YMeA1MeY]2+(E2 2-) (VIII),
where
A1 is one of the compounds of the formula V, preferably of one of the formulae Va to Vb;
Me is iridium;
Y is two olefins or one diene;
Z is Cl, Br or I; and
E1 " or E2 2- is the anion or dianion of an oxo acid or complex acid.
13. Process according to Claim 12, characterized in that Y is two ethylene molecules or 1 ,5-hexadiene, 1,5-cyclooctadiene or norbornadiene.
14. Process according to Claim 12, characterized in that E is CIO4 ", CF3SO3 ", CH3SO3 ", HSO4-, SO4 2", oxalate, (CF3SOz)2N-, (CF3SO2)SC", B(phenyl)4 ", B[bis(3,5- trifluoromethyl)phenyl]4-, B[bis(3,5-dimethyl)phenyl]4-, B(C6Fs)4 " and B(4-methylphenyl)4-, BF4 ", PF6 ", SbCI6-, AsF6- or SbF6 ".
15. Process according to Claim 12, characterized in that Z in the formulae Vl1 VII and VIII is Cl or Br.
16. Process according to Claim 1, characterized in that it is carried out at temperatures of from -20 to 1500C.
17. Process according to Claim 1, characterized in that it is carried out at atmospheric pressure or superatmospheric pressure.
18. Process according to Claim 1, characterized in that the iridium complex is used in amounts of from 0.00001 to 10 mol%, based on the compound to be hydrogenated.
19. Process according to Claim 1, characterized in that the hydrogenation is carried out in the presence of cocatalysts, preferably alkali metal halides or ammonium halides.
20. Process according to Claim 19, characterized in that a protic acid is additionally present in the reaction mixture.
21. Process for preparing compounds of the formulae
Figure imgf000029_0001
where Roi. Ro2 and R03 are each, independently of one another, d-C4-alkyl, R04 is CrC4-alkyI, CrC4-alkoxymethyl or CrC4-alkoxyethyl, and * indicates predominantly an S enantiomer, by hydrogenation of a ketimine of the formula III or IV,
Figure imgf000030_0001
in the presence of catalytic amounts of an enantioselective iridium complex with chiral ferrocene phosphines to form the amine and subsequent chloroacetylation of the amine, which is characterized in that the ferrocene phosphine is a compound of the formula V,
Figure imgf000030_0002
where
R0 and R0O are each, independently of one another, hydrogen, CrC2o-alkyl, C3-C8-cycloalkyl, C6-Ci4-aryl or C3-Ci2-heteroaryl having heteroatoms selected from the group consisting of O, S and N, which are unsubstituted or substituted by CrC6-alkyl, CrC6-alkoxy, C5-C8- cycloalkyl, C5-C8-cycloalkoxy, phenyl, CrCe-alkylphenyl, Ci-C6-alkoxyphenyl, C3-C8- heteroaryl, F or trifluoromethyl;
Ri and R2 are each, independently of one another, a hydrogen atom, a halogen atom or a substituent bound to the cyclopentadienyl rings via a C atom, S atom, Si atom, a P(O) or P(S) group; the two indices m are each, independently of one another, 1, 2 or 3; and Xi, X2 and X3 are each, independently of one another, a secondary phosphine group.
22. Process according to Claim 21 , characterized in that ROi, R02 and R03 are each methyl or ethyl.
23. Process according to Claim 21 , characterized in that R04 is methoxyethyl or methoxy methyl.
24. Process according to Claim 21, characterized in that, in the formulae Ia and Ha1 ROi is methyl, R02 is methyl or ethyl, R03 is methyl and R04 is methoxymethyl.
25. Process according to Claim 21 , characterized in that the symbol * denotes an enantiomeric excess (ee) of at least 70%.
PCT/EP2005/053168 2004-07-05 2005-07-04 Process for preparing amines and a carboxamide thereof WO2006003194A1 (en)

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WO2009083899A2 (en) * 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Process for the preparation of an enantiomeric trisubstituted 3,4-dihydro-isoquinoline derivative
US8247560B2 (en) 2007-12-28 2012-08-21 Actelion Pharmaceuticals Ltd. Trisubstituted 3,4-dihydro-1H-isoquinolin compound, process for its preparation, and its use
WO2014037962A1 (en) 2012-09-06 2014-03-13 Council Of Scientific And Industrial Research Process for the preparation of (s)-2-ethyl-n-(1-methoxypropan -2-yl)-6-methyl aniline

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009083899A2 (en) * 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Process for the preparation of an enantiomeric trisubstituted 3,4-dihydro-isoquinoline derivative
WO2009083899A3 (en) * 2007-12-28 2009-08-20 Actelion Pharmaceuticals Ltd Process for the preparation of an enantiomeric trisubstituted 3,4-dihydro-isoquinoline derivative
US8247560B2 (en) 2007-12-28 2012-08-21 Actelion Pharmaceuticals Ltd. Trisubstituted 3,4-dihydro-1H-isoquinolin compound, process for its preparation, and its use
US8314238B2 (en) 2007-12-28 2012-11-20 Actelion Pharmaceuticals Ltd. Process for the preparation of an enantiomeric trisubstituted 3,4-dihydro-isoquinoline derivative
WO2014037962A1 (en) 2012-09-06 2014-03-13 Council Of Scientific And Industrial Research Process for the preparation of (s)-2-ethyl-n-(1-methoxypropan -2-yl)-6-methyl aniline
US9199930B2 (en) 2012-09-06 2015-12-01 Council Of Scientific And Industrial Research Process for the preparation of (S)-2-ethyl-N-(1-methoxypropan-2-yl)-6-methyl aniline

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