# Patent

## Title
Process for preparing optically active cyclic amines

## Abstract

Optically active cyclic amines of the formula (I) or salts thereof




in which A, R0, R are each as defined in claim 1, and R0 and A, or R and A, or R0 and R may also form rings,

where R and the NH—R0 group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the stereochemical configuration on these carbon atoms is different from the racemic configuration, can be prepared effectively by a process, which comprises converting an imine (a racemic imine) of the formula (II)





    
    
        in which A, R0 and R are each as defined in formula (I),

in the presence of hydrogen or a hydrogen donor and a nonenzymatic catalyst which comprises a catalytically active optically active complex of one or more transition metals from the group of ruthenium, rhodium, palladium, iridium, osmium, platinum, iron, nickel and samarium with organic ligands, to the compound of the formula (I).

## Background
The invention relates to the technical field of processes for preparing optically active intermediates which can be used for syntheses of active ingredients, for example active ingredients for crop protection compositions or medicaments.
Optically active compounds are frequently required as intermediates for the preparation of optically active active ingredients. This is true of enantioselective preparation processes in which the desired spatial structure is introduced at certain chiral centers at the stage of an intermediate and is retained up to the active ingredient through one or more process steps. Suitable intermediates are optically active natural substances or compounds in which a chiral center is obtained from achiral compounds with the aid of enantioselective reactions, or racemic compounds for which, in a selective manner, only one of the enantiomers present is converted enantioselectively and used further.
Amino compounds have great significance as intermediates for active crop protection ingredients and active medicament ingredients. Numerous processes for preparing optically active amines are known; see, for example, Angew. Chem. Int. Ed. 2004 (116) 806-843 and literature cited there. In addition to classical optical resolution via diastereomeric salts with optically active acids, some relate to the use of optically active starting materials and enantioselective conversions up to the desired compound. Other processes are based on enzymatic reactions, for example transaminations using enzymes or microorganisms. Other processes again utilize the use of synthetic optically active reagents and their properties in reactions to obtain chiral centers enantioselectively.
The known processes usually have the disadvantage that they can be employed only very specifically on certain substrates. With structurally different substrates, the results with regard to parameters such as chemical yield, enantiomeric excess, selectivity, purity, reaction time and availability of starting materials and auxiliaries are often unsatisfactory. There is therefore a need, in the specific case and also generally, for the provision of alternative processes for preparing optically active amines.
It has now been found that certain optically active cyclic amines with a second, adjacent chiral center can be prepared in a particularly effective manner enantioselectively from compounds which are present in racemic form with regard to the adjacent chiral center.
The invention provides a process for preparing optically active cyclic amines of the formula (I) and salts thereof




in which

    A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring which has from 3 to 30 ring atoms, preferably from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and may be further substituted in addition to the R and NH—R0 radicals,
    R0, independently of R, is a (C1-C6)alkyl, (C2-C6)alkenyl or (C3-C6)alkynyl radical, where each of the three latter radicals may be unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkylthio, (C1-C6)alkanoyloxy, (C1-C6)haloalkanoyloxy, aryl, aryloxy, aroyl, aroyloxy and heterocyclyl, where each of the latter 5 radicals is unsubstituted or substituted, or is
    
        (C3-C9)cycloalkyl, (C4-C9)cycloalkenyl, aryl or heterocyclyl, where each of the latter 4 radicals is unsubstituted or substituted,
    
    
    R, independently of R0, is
    
        (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkylthio, aryl which is unsubstituted or substituted, and heteroaryl which is unsubstituted or substituted, or
        aryl which is unsubstituted or substituted, or is
        heteroaryl which is unsubstituted or substituted, or
    
    
    R0 and A form a ring B1 and, together with the NH group and the carbon atom which is designated with an asterisk (*) and is bonded to the NH group, are a heterocyclic ring which has from 4 to 30 ring atoms, preferably from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and is optionally additionally further substituted and which optionally contains 1 or 2 further heteroatoms from the group of N, O and S, or
    R and A form a ring B2 and, together with the carbon atom which is designated with an asterisk (*) and is bonded to R, are a carbocyclic or heterocyclic ring which has from 3 to 30 ring atoms, preferably from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and is optionally additionally further substituted, and which, in the case of a heterocyclic ring, contains 1, 2 or 3 heteroatoms from the group of N, O and S, or
    R0 and R form a ring B3 and, together with the NH group and the carbon atoms designated with an asterisk (*) in each case, are a heterocyclic ring which has from 4 to 30 ring atoms, preferably from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and is optionally additionally further substituted and which optionally contains 1 or 2 further heteroatoms from the group of N, O and S, or
    R0 and R and, if appropriate, A may simultaneously form two or more of the rings B1, B2 and B3 mentioned,

where R and the NH—R0 group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the stereochemical configuration on these carbon atoms is different from the racemic configuration,

which comprises converting an imine of the formula (II) or a salt thereof







    
    
        where A, R0 and R are each as defined in formula (I) and the compound of the formula (II), with regard to the ring carbon atom marked with an asterisk (*), is present in the form of a racemic mixture or in the form of a mixture with any other isomeric ratio of the stereoisomers in question,

in the presence of hydrogen or a hydrogen donor and a nonenzymatic catalyst which comprises a catalytically active optically active complex of one or more transition metals from the group of ruthenium, rhodium, palladium, iridium, osmium, platinum, iron, nickel and samarium, preferably one or more transition metals from the group of ruthenium, rhodium, palladium and iridium, especially ruthenium and iridium, with organic ligands, to the compound of the formula (I) or its salt.

    
    


The absolute configuration of the product depends in the individual case upon the structure of the optically active catalyst from the group of catalysts mentioned.
Compounds of the formula (I) are especially the compounds of the formulae (I-A) and (I-B)




in which A, R0 and R are each as defined above. According to the Cahn-Ingold-Prelog stereochemical nomenclature, the compound (I-A) has, according to the sequence of the substituents on the carbon atom 1, the stereochemical designation (1S-cis) or (1R-cis). The compound (I-B) correspondingly has the stereochemical designation (1R-cis) or (1S-cis).

The compounds (I) with cis configuration on the two chiral centers designated with an asterisk (*) in each case are preferably obtained with a selectivity of from 60 to 100%, preferably from 80 to 100%, in particular from 90 to 100%, very particularly from 95 to 100% in comparison to the trans configuration, the particular cis compound (I-A) or (I-B) being obtained with an enantioselectivity of in each case more than 20% ee or better more than 50% ee, preferably from 60 to 100% ee, in particular from 80 to 100% ee, very particularly from 90 to 100% ee, most preferably from 95 to 100% ee, based on the total content of cis compounds (I-A) and (I-B) in question.
The enantiomeric excess measured in % ee means the difference of the percentages of the two enantiomers based on the mixture of the enantiomers.
The particular compound of the formula (II) consists generally of a mixture of the compounds (II-A1), (II-A2), (II-B1) and (II-B2)




the compounds (II-A1) and (II-A2) being designated together for short as compounds (II-A), and the compounds (II-B1) and (II-B2) being designated together for short as compounds (II-B). The compounds (II-A) and (II-B) may be used generally in any ratio with regard to the configuration on the carbon atom 2. In general, they are present in this regard preferably in the ratio of 1:1, i.e. in a racemic mixture.

The compounds (II-A1) and (II-A2) or (II-B1) and (II-B2) are usually present in equilibrium under the reaction conditions.
When the compounds (I) or (II) can form tautomers by shifting of hydrogen, which would structurally not be covered by the formula (I) or (II) in a formal sense, these tautomers are equally encompassed by the definition of the inventive compounds of the formula (I) or (II).
The compounds of the general formula (I) (or, correspondingly, other inventive compounds) may, depending on the type and attachment of the substituents, contain further chiral centers than the carbon atoms marked with an asterisk (*) in formula (I) and are correspondingly present in the form of stereoisomers. The possible stereoisomers defined by their specific three-dimensional form, such as enantiomers, diastereomers, Z and E isomers, are all encompassed by the formula (I). When, for example, one or more alkenyl groups are present, diastereomers (Z and E isomers) can occur. When, for example, one or more asymmetric carbon atoms are present, enantiomers and diastereomers can occur. Stereoisomers can be obtained from the mixtures obtained in the preparation by customary separation methods, for example by chromatographic separation processes. It is likewise possible to selectively prepare stereoisomers by use of stereoselective reactions using optically active starting materials and/or assistants. The invention thus also relates to all stereoisomers which are encompassed by the general formula (I) but are not specified with their specific stereochemical form, and mixtures thereof.
The possible combinations of the different substituents of the general formula (I) are to be understood such that the general principles of constructing chemical compounds are to be observed, i.e. the formula (I) does not encompass compounds which are known by the skilled worker to be chemically impossible.
The compounds of the formula (I) can form salts, for example by addition of a suitable inorganic or organic acid, for example mineral acids, for example HCl, HBr, H2SO4 or HNO3, or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid or sulfonic acids, to a basic group, for example the amino group present or other amino groups, alkylamino, dialkylamino, piperidino, morpholino or pyridino. These salts then contain the conjugate base of the acid as an ion.
Salts can be formed by the action of a base on those compounds of the formula (I) which bear an acidic hydrogen atom. Suitable bases are, for example, organic amines, and also the hydroxides, carbonates and hydrogencarbonates of ammonium, alkali metals or alkaline earth metals, especially the hydroxide, carbonate and hydrogencarbonate of sodium and potassium. These salts are compounds in which the acidic hydrogen is replaced by a cation, for example metal salts, especially alkali metal salts or alkaline earth metal salts, especially sodium and potassium salts, or else ammonium salts, salts with organic amines or quaternary ammonium salts.
Suitable substituents which are present in deprotonated form, for example sulfonic acids or carboxylic acids, may form internal salts with groups which are themselves protonatable, such as amido groups.
The compounds of the formula (I) and their salts are also referred to below for short as “compounds (I) used in accordance with the invention” or inventive “compounds (I)”.
The terms above and used below are familiar to those skilled in the art and have in particular the definitions explained below:
An inorganic radical is a radical without carbon atoms, preferably halogen, OH and its inorganic salts in which the H is replaced by a cation, for example alkali metal and alkaline earth metal salts, NH2 and its ammonium salts with (inorganic) acids, for example mineral acids, N3 (azide), N2+A− (diazonium radical where A− is an anion), NO, NHOH, NHNH2, NO2, S(O)OH (sulfinic acid radical), S(O)2OH (or else SO3H for short, sulfonic acid radical), —O—SO2H (sulfite), —O—SO3H (sulfate), —P(O)(OH)2 (phosphonic acid radical), —O—P(OH)3 (phosphate radical), and the hydrated or dehydrated forms of the latter 6 acid radicals and also their (inorganic) salts; the term “inorganic radical” also encompasses the hydrogen radical (the hydrogen atom), the latter often already being part of the unsubstituted basic structure of an organic radical in these definitions (example: “unsubstituted phenyl”); the term “inorganic radical” here preferably does not encompass pseudohalogen groups such as CN, SCN, organic metal complexes, carbonate or COOH, which can be assigned more appropriately to the organic radicals owing to the content of carbon atoms.
In contrast to an inorganic radical, an organic radical is a radical with carbon atoms, and this radical may also be bonded via heteroatoms. It is preferably an optionally substituted hydrocarbon radical or an optionally substituted heterocyclic radical. However, it preferably also encompasses acyl radicals, i.e. radicals of organic acids which are formed by removal of an OH group. Acyl radicals also include sulfonic ester groups, phosphonic ester groups, phosphinic ester groups, each with organic alcohol components (and are then derived from polybasic acids), or alkylsulfonyl or alkylsulfinyl which are derived from sulfonic acids or sulfinic acids.
A hydrocarbon radical is an aliphatic, cycloaliphatic or aromatic monocyclic radical or, in the case of an optionally substituted hydrocarbon radical, also a bicyclic or polycyclic organic radical based on the elements carbon and hydrogen, for example encompassing the radicals alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, phenyl, naphthyl, indanyl, indenyl, etc; the same applies to the hydrocarbonoxy radicals. Unless defined more specifically, the hydrocarbon and hydrocarbonoxy radicals in the above definitions have preferably from 1 to 20 carbon atoms, more preferably from 1 to 16 carbon atoms, in particular from 1 to 12 carbon atoms.
The hydrocarbon radicals and the more specific alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino and alkylthio radicals, and also the corresponding unsaturated and/or substituted radicals may each be straight-chain or branched in the carbon skeleton.
The expression “(C1-C4)alkyl” means a short notation for open-chain alkyl having from one to 4 carbon atoms in accordance with the range specification for carbon atoms, i.e. encompasses the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl or tert-butyl radicals. General alkyl radicals with a larger specified range of carbon atoms, for example “(C1-C6)alkyl”, correspondingly also encompass straight-chain or branched alkyl radicals having a larger number of carbon atoms, i.e. in the example also the alkyl radicals with 5 and 6 carbon atoms. Unless stated specifically, preference is given in the case of hydrocarbon radicals such as alkyl, alkenyl and alkynyl radicals, including in combined radicals, to the lower carbon structures, for example with from 1 to 6 carbon atoms, in particular from 1 to 4 carbon atoms, or, in the case of unsaturated groups, having from 2 to 6 carbon atoms, in particular 2-4 carbon atoms. Alkyl radicals, including in the combined definitions such as alkoxy, haloalkyl, etc., are, for example, methyl, ethyl, n- or i-propyl, n-, i-, t- or 2-butyl, pentyls, hexyls such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls such as n-heptyl, 1-methylhexyl and 1,4-dimethylpentyl; alkenyl and alkynyl radicals have the definition of the possible unsaturated radicals corresponding to the alkyl radicals; alkenyl is, for example, vinyl, allyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, pentenyl, 2-methylpentenyl or hexenyl, preferably allyl, 1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 1-methylbut-3-en-1-yl or 1-methylbut-2-en-1-yl. (C2-C6)Alkynyl is, for example, ethynyl, propargyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-butynyl, 2-pentynyl or 2-hexynyl, preferably propargyl, but-2-yn-1-yl, but-3-yn-1-yl or 1-methyl-but-3-yn-1-yl.
Alkylidene, for example including in the form of (C1-C10)alkylidene, is the radical of a straight-chain or branched alkane which is bonded via a double bond, the position of the bonding site not having been specified. In the case of a branched alkane, by its nature, only positions at which two hydrogen atoms can be replaced by the double bond are possible; radicals are, for example, ═CH2, ═CH—CH3, ═C(CH3)—CH3, ═C(CH3)—C2H5 or ═C(C2H5)—C2H5.
Cycloalkyl is a carbocyclic, saturated ring system having preferably 3-8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Substituted cycloalkyl encompasses cyclic systems with substituents, also encompassing substituents with a double bond on the cycloalkyl radical, for example an alkylidene group such as methylidene. Substituted cycloalkyl also encompasses polycyclic aliphatic systems, for example bicyclo[1.1.0]butan-1-yl, bicyclo[1.1.0]butan-2-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[2.1.0]pentan-5-yl, adamantan-1-yl and adamantan-2-yl.
Cycloalkenyl is a carbocyclic, nonaromatic, partially unsaturated ring system having preferably 4-8 carbon atoms, for example 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, or 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1,3-cyclohexadienyl or 1,4-cyclohexadienyl. In the case of substituted cycloalkenyl, the explanations for substituted cycloalkyl apply correspondingly. In particular, substituted cycloalkenyl also encompasses corresponding fused polycyclic compounds, for example benzofused compounds such as tetrahydronaphthalin-1-yl or -2-yl, fluorenyl(biphenylmethyl) or suberyl(di-[b,f]-benzocyclohepta-2,6-dien-1-yl).
The term “halogen” means, for example, fluorine, chlorine, bromine or iodine. Haloalkyl, -alkenyl and -alkynyl mean alkyl, alkenyl and alkynyl substituted partly or fully by identical or different halogen atoms, preferably form the group of fluorine, chlorine and bromine, especially from the group of fluorine and chlorine, for example monohaloalkyl such as CH2CH2Cl, CH2CH2F, CH2ClCH3, CH2FCH3, CH2Cl, CH2F; perhaloalkyl such as CCl3 or CF3 or CF3CF2; polyhaloalkyl such as CHF2, CH2F, CH2FCHCl, CHCl2, CF2CF2H, CH2CF3, CH2ClCH3, CH2FCH3; haloalkoxy is, for example, OCF3, OCHF2, OCH2F, CF3CF2O, OCH2CF3 and OCH2CH2Cl; the same applies to haloalkenyl and other radicals substituted by halogen.
Aryl is a mono-, bi- or polycyclic aromatic system having preferably from 6 to 14, in particular from 6 to 12 carbon atoms, for example phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, pentalenyl, fluorenyl, biphenylyl and the like, preferably phenyl.
A heterocyclic radical or ring (heterocyclyl) contains at least one heterocyclic ring which is saturated, unsaturated or heteroaromatic and which may be fused in the generally substituted case with other carbocyclic or heterocyclic rings; unless defined differently, the heterocyclic ring contains preferably from 3 to 9 ring atoms, in particular from 3 to 6 ring atoms, and one or more, preferably from 1 to 4, in particular 1, 2 or 3 heteroatoms in the heterocyclic ring, preferably from the group of N, O and S, although two oxygen atoms should not be directly adjacent and at least one carbon atom also has to be present in the ring, for example a radical of thiophene, furan, pyrrole, thiazole, oxazole, imidazole, isothiazole, isoxazole, pyrazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,3,4-tetrazole, benzo[b]thiophene, benzo[b]furan, indole, benzo[c]thiophene, benzo[c]furan, isoindole, benzoxazole, benzothiazole, benzimidazole, benzisoxazole, benzisothiazole, benzopyrazole, benzothiadiazole, benzotriazole, dibenzofuran, dibenzothiophene, carbazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,4,5-tetrazine, quinoline, isoquinoline, quinoxaline, quinazoline, quinoline, 1,8-naphthyridine, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, phthalazine, pyridopyrimidine, purine, pteridine, 4H-quinolizine, piperidine, morpholine, piperazine, oxetane, oxirane, pyrrolidine, oxazoline, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3- and 1,4-dioxane, isoxazolidine or thiazolidine.
Among the groups mentioned above under “heterocyclyl”, “heteroaryl” in each case means the fully unsaturated aromatic heterocyclic compounds, for example pyridine, pyrimidine, (1,2,4)-oxadiazole, (1,3,4)-oxadiazole, pyrrole, furan, thiophene, oxazole, Thiazole, imidazole, pyrazole, isoxazole, 1,2,4-triazole, tetrazole, pyrazine or pyridazine.
Preference is further given to heterocyclyl being a partially or fully hydrogenated heterocyclic radical having a heteroatom from the group of N, O and S, for example oxiranyl, oxetanyl, oxolanyl(=tetrahydrofuryl), oxanyl, pyrrolinyl, pyrrolidinyl or piperidinyl.
Preference is further given to it being a partially or fully hydrogenated heterocyclic radical having 2 heteroatoms from the group of N, O and S, for example oxazolinyl, thiazolinyl, piperazinyl, 1,3-dioxolanyl, 1,3- and 1,4-dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl and morpholinyl.
When it is a partly or fully saturated nitrogen heterocycle, it may be bonded to the radical of the molecule of the particular compound either via carbon or via the nitrogen.
Heterocyclyl is preferably an aliphatic, saturated or unsaturated, especially saturated, heterocyclyl radical having from 3 to 7, in particular from 3 to 6 ring atoms, or a heteroaromatic radical having 5 or 6 ring atoms. Heterocyclyl preferably contains heterocyclic ring atoms from the group of N, O and S.
Preferred examples of heterocyclyl are a heterocyclic radical having from 3 to 6 ring atoms from the group of pyridyl, thienyl, furyl, pyrrolyl, oxiranyl, 2-oxetanyl, 3-oxetanyl, oxolanyl (=tetrahydrofuryl), pyrrolidinyl, piperidinyl, in particular oxiranyl, 2-oxetanyl, 3-oxetanyl or oxolanyl, or a heterocyclic radical having two or three heteroatoms, for example pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, piperazinyl, dioxolanyl, dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl or morpholinyl.
When a basic structure is substituted “by one or more radicals” from a list of radicals (=group) or a generically defined group of radicals, this in each case includes the simultaneous substitution by a plurality of identical and/or structurally different radicals.
In the case of a plurality of optionally substituted basic structures, the definition “where each of the latter radicals (=basic structures) is unsubstituted or substituted” means that each of the radicals (=basic structures) is unsubstituted or substituted independently of the other radicals.
Possible substituents for a substituted heterocyclic radical include the substituents mentioned below, and additionally also oxo. The oxo group as a substituent then means, for example, a carbonyl group in the heterocyclic ring. Thus, lactones and lactams are preferably also encompassed. The oxo group may also occur on the heterocyclic ring atoms which can exist in various oxidation states, for example in the case of N and S, and in that case form, for example, the divalent groups —N(O)—, —S(O)— (also SO for short) and —S(O)2— (also SO2 for short) in the heterocyclic ring.
Substituted radicals such as a substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, phenyl, benzyl, heterocyclyl and heteroaryl radical, are, for example, a substituted radical derived from the unsubstituted basic structure, the substituents being, for example, one or more, preferably 1, 2 or 3 radicals from the group of halogen, alkoxy, alkylthio, hydroxy, amino, nitro, carboxy, cyano, azido, alkoxycarbonyl, alkanoyl, alkoxycarbonyloxy, alkanoyloxy, aryloxycarbonyl, aryloxycarbonyloxy, carbamoyl, mono- and dialkylaminocarbonyl, substituted amino such as acylamino, mono- and dialkylamino, trialkylsilyl and optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, where each of the latter cyclic groups may also be bonded via heteroatoms or divalent functional groups as in the case of the alkyl radicals mentioned, and alkylsulfinyl, alkylsulfonyl, and, in the case of cyclic radicals (=“cyclic basic structures”), also alkyl, haloalkyl, alkylthioalkyl, alkoxyalkyl, optionally substituted mono- and dialkylaminoalkyl and hydroxyalkyl; in the term “substituted radicals” such as substituted alkyl, etc., included as substituents in addition to the saturated hydrocarbon-containing radicals mentioned are corresponding unsaturated aliphatic and aromatic radicals such as optionally substituted alkenyl, alkynyl, alkenyloxy, alkynyloxy, phenyl, phenoxy, etc.
Substituted cyclic radicals with aliphatic moieties in the ring also encompass cyclic systems with such substituents which are bonded to the ring with a double bond, for example with an alkylidene group such as methylidene or ethylidene, or an oxo group, imino group or substituted imino group.
The substituents mentioned by way of example (“first substituent level”) may, when they contain hydrocarbon-containing moieties, optionally further be substituted there (“second substituent level”), for example by one of the substituents as defined for the first substituent level. Corresponding further substituent levels are possible. The term “substituted radical” preferably encompasses only one or two substituent levels.
Preferred substituents for the substituent levels are, for example, amino, hydroxy, halogen, nitro, cyano, mercapto, carboxy, carbonamide, SF5, aminosulfonyl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, monoalkylamino, dialkylamino, N-alkanoylamino, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, alkynyloxycarbonyloxy, aryloxycarbonyloxy, alkylthio, cycloalkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylsulfinyl, alkylsulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkanoylaminocarbonyl, N-alkanoyl-N-alkyl-aminocarbonyl, aryl, aryloxy, benzyl, benzyloxy, benzylthio, arylthio, arylamino, benzylamino, heterocyclyl and trialkylsilyl.
In the case of radicals with carbon atoms, preference is given to those having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms. Preference is generally given to substituents from the group of halogen, e.g. fluorine or chlorine (C1-C4)alkyl, preferably methyl or ethyl, (C1-C4)haloalkyl, preferably trifluoromethyl, (C1-C4)alkoxy, preferably methoxy or ethoxy, (C1-C4)haloalkoxy, nitro and cyano. Particular preference is given to the substituents methyl, methoxy, fluorine and chlorine.
Substituted amino such as mono- or disubstituted amino is a radical from the group of the substituted amino radicals which is n-substituted, for example, by one or two identical or different radicals from the group of alkyl, alkoxy, acyl and aryl; preferably mono- and dialkylamino, mono- and diarylamino, acylamino, N-alkyl-N-arylamino, N-alkyl-N-acylamino, and also saturated H-heterocycles; preference is given to alkyl radicals having from 1 to 4 carbon atoms; aryl is preferably phenyl or substituted phenyl; for acyl, the definition specified below applies, preferably (C1-C4)alkanoyl. The same applies to substituted hydroxylamino or hydrazino.
Optionally substituted phenyl is preferably phenyl which is unsubstituted or mono- or polysubstituted, preferably up to trisubstituted, by identical or different radicals from the group of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and nitro, for example o-, m- and p-tolyl, dimethylphenyls, 2-, 3- and 4-chlorophenyl, 2-, 3- and 4-fluorophenyl, 2-, 3- and 4-trifluoromethyl- and -trichloromethylphenyl, 2,4-, 3,5-, 2,5- and 2,3-dichlorophenyl, o-, m- and p-methoxyphenyl.
Optionally substituted cycloalkyl is preferably cycloalkyl which is unsubstituted or mono- or polysubstituted, preferably up to trisubstituted, by identical or different radicals from the group of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl and (C1-C4)haloalkoxy, especially by one or two (C1-C4)alkyl radicals.
Optionally substituted heterocyclyl is preferably heterocyclyl which is unsubstituted or mono- or polysubstituted, preferably up to trisubstituted, by identical or different radicals from the group of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, nitro and oxo, especially mono- or polysubstituted by radicals from the group of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl and oxo, very particularly by one or two (C1-C4)alkyl radicals.
Acyl is a radical of an organic acid which is formed, in a formal sense, by removing a hydroxyl group at the acid function, and the organic radical in the acid may also be bonded with the acid function via a heteroatom. Examples of acyl are the —CO—R radical of a carboxylic acid HO—CO—R and radicals of acids derived therefrom, such as of thiocarboxylic acid, optionally N-substituted iminocarboxylic acids, or the radical of carbonic monoesters, N-substituted carbamic acid, sulfonic acids, sulfinic acids, N-substituted sulfonamide acids, phosphonic acids, phosphinic acids.
Acyl is, for example, alkanoyl such as formyl or [(C1-C4)alkyl]carbonyl, phenylcarbonyl, alkyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, alkylsulfonyl, alkylsulfinyl, N-alkyl-1-iminoalkyl, N-alkyl- and N,N-dialkylcarbamoyl and other radicals of organic acids. The radicals may each be further substituted in the alkyl or phenyl moiety, for example in the alkyl moiety by one or more radicals from the group of halogen, alkoxy, phenyl and phenoxy; examples of substituents in the phenyl moiety are the substituents already mentioned above in general for substituted phenyl.
Acyl is preferably an acyl radical in the narrower sense, i.e. a radical of an organic acid in which the acid group is bonded directly to the carbon atom of an organic radical, for example alkanoyl such as formyl and acetyl, aroyl such as phenylcarbonyl, and other radicals of saturated or unsaturated organic acids.
“Aroyl” is an aryl radical as defined above which is bonded via a carbonyl group, for example the benzoyl group.
When a general radical is defined as hydrogen, this means a hydrogen atom.
“yl position” of a radical designates its binding site.
For reasons of better preparability, especially with regard to yield, space-time yield, enantioselectivity of the process and simplicity of the process, but also for reasons of usability, closer interest attaches to inventive processes for preparing amino compounds of the formula (I) in which

    A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring which has from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and, in addition to the R and NH—R0 radicals, is unsubstituted or further substituted by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C2-C4)alkenyl, (C5-C9)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl, aryl and heterocyclyl, where the latter 11 radicals are each independently unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C4-C9)cycloalkenyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl, and is optionally substituted by a fused carbocyclic or heterocyclic ring which has from 3 to 30 ring atoms and, in the case of a heterocyclic ring, contains from 1 to 3 ring atoms from the group of N, O and S, and is optionally further substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C2-C4)alkenyl, (C5-C9)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy and (C1-C4)alkylthio, where each of the latter 7 radicals is independently unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C4-C9)cycloalkenyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl,
    R0, independently of R, is a (C1-C6)alkyl, (C2-C6)alkenyl or (C3-C6)alkynyl radical, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, (C1-C4)alkanoyloxy, (C1-C4)haloalkanoyloxy, phenyl which is unsubstituted or substituted and heterocyclyl which is unsubstituted or substituted,
    
        or (C3-C9)cycloalkyl which is unsubstituted or substituted, preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and phenyl which is unsubstituted or substituted,
        or (C4-C9)cycloalkenyl which is unsubstituted or substituted, preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and phenyl which is unsubstituted or substituted, and is optionally fused, preferably benzofused, at one or more double bonds in the ring with an aromatic ring which does or does not have further substitution,
        or phenyl which is unsubstituted or substituted, preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and phenyl which is unsubstituted or substituted, and is optionally fused, preferably benzofused, at one or more double bonds in the ring with an aromatic ring which does or does not have further substitution,
        or heterocyclyl which is unsubstituted or substituted, preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and phenyl which is unsubstituted or substituted, and is optionally, in the case of an unsaturated or heteroaromatic heterocyclyl, fused, preferably benzofused, at one or more double bonds in the ring which does or does not have further substitution, or
        R0 is in particular an eliminable radical (cleavable group, leaving group) selected from the group consisting of
        i) CH2C6H5 (benzyl)
        ii) CH2CH═CH2 (allyl)
        iii) C(CH3)3 (t-butyl)
        iv) C(C6H5)3 (trityl)
        v) CH3 (methyl)
        vi) (CH2)3OCOCH3 (3-acetoxypropyl)
        vii) CH2C6H3-2,4-(OCH3)2 (2,4-dimethoxybenzyl)
        viii) C6H3-2,4-(NO2)2 (2,4-dinitrophenyl)
        ix) CH2C6H4-4-OCH3 (4-methoxybenzyl)
        x) CH2C6H4-2-OH (2-hydroxybenzyl)
        xi) CH(C6H5)2 (diphenylmethyl)
        xii) CH(C6H4-4-OCH3)2 (bis-(4-methoxyphenyl)methyl)
        xiii) C(C6H5)2(C6H44—OCH3) (4-methoxyphenyl)diphenylmethyl)
        xiv) 5-Dibenzosuberyl(dibenzo-[b,f]-cyclohepta-2,6-dien-1-yl)
        xv) 9-Phenylfluoren-9-yl (1-phenyldiphenylenemethyl),
        where each of the phenyl or heterocyclyl radicals mentioned, which is unsubstituted or substituted (i.e. is optionally substituted without specification of the substituents), is preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, nitro, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)haloalkoxy, (C1-C4)alkoxy-(C1-C4)alkyloxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkanoyl, [(C1-C4)alkoxy]carbonyl, (C1-C4)alkylamino and di[(C1-C4)alkyl]amino; in particular, each of the phenyl or heterocyclyl radicals mentioned which is unsubstituted or substituted is preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and nitro,
    
    
    R, independently of R0, is
    
        (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, aryl which is optionally substituted and heteroaryl which is optionally substituted, or
        aryl which is optionally substituted, or
        heteroaryl which is optionally substituted,
        
            where the optionally substituted radicals are each independently preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C2-C4)alkenyl, (C5-C9)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, [(C1-C4)alkoxy]carbonyl, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl, (C1-C4)alkylamino, di-(C1-C4)alkylamino, aryl and heterocyclyl, where the latter 14 radicals are each independently unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C5-C9)cycloalkenyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl, or
        
        
    
    
    R0 and A form a ring B1 and, together with the NH group and the carbon atom which is designated with an asterisk (*) and is bonded to the NH group, are a heterocyclic ring having from 4 to 30 ring atoms, preferably having from 4 to 9 ring atoms, in particular having from 5 to 7 ring atoms, which is optionally additionally further substituted and which optionally contains one or more further heteroatoms from the group of N, O and S,
    
        and are preferably the heterocyclic ring mentioned which does not have further substitution or is substituted by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C9)cycloalkyl, (C2-C4)alkenyl, (C5-C9)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and (C1-C4)alkylsulfonyl, or
    
    
    R and A form a ring B2 and, together with the carbon atom which is designated with an asterisk (*) and bonded to R, form a carbocyclic or heterocyclic ring which has from 3 to 30 ring atoms, preferably from 3 to 9 ring atoms, in particular from 4 to 7 ring atoms, and may optionally additionally be further substituted and, in the case of a heterocyclic ring, contains 1 or 2 or 3 further heteroatoms selected from the group consisting of N, O and S,
    
        and are preferably the carbocyclic or heterocyclic ring mentioned which may not have further substitution or may have further substitution by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C9)cycloalkyl, (C2-C4)alkenyl, (C5-C9)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and (C1-C4)alkylsulfonyl, or
    
    
    R0 and R form a ring B3 and, together with the NH group and the carbon atoms designated with an asterisk (*) in each case, are a heterocyclic ring which has from 4 to 30 ring atoms, preferably from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and is optionally additionally further substituted and optionally contains 1 or 2 further heteroatoms from the group of N, O and S,
    
        and are preferably the heterocyclic ring mentioned which may not have further substitution or may have further substitution by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C9)cycloalkyl, (C2-C4)alkenyl, (C5-C9)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and (C1-C4)alkylsulfonyl, or
    
    
    R0 and R and, if appropriate, A simultaneously form two or more of the rings B1, B2 and B3 mentioned,

where R and the NH—R0 group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the stereochemical configuration on these carbon atoms is different from the racemic configuration.



Preferred inventive processes relate, for example, to the preparation of monocyclic compounds of the formula (Ia)




where

    A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring having from 3 to 30 ring atoms, preferably having from 4 to 9 ring atoms, in particular having from 5 to 7 ring atoms, and, in the case of a heterocyclic ring which has from 1 to 3 heterocyclic ring atoms selected from the group consisting of N, O and S and, in addition to the R1 and NH—R0 radicals is unsubstituted or further substituted by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl, aryl and heterocyclyl, where each of the latter 8 radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl,
    R0, independently of R1, is as defined above in formula (I), preferably as defined with preference for formula (I) and in particular a (C1-C6)alkyl, (C2-C6)alkenyl or (C3-C6)alkynyl radical,
    
        where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, (C1-C4)alkanoyloxy, (C1-C4)haloalkanoyloxy and phenyl which is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, nitro, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)-alkanoyl, [(C1-C4)alkoxy]carbonyl, (C1-C4)alkylamino and di[(C1-C4)alkyl]-amino, and
        heterocyclyl which is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, nitro, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)-alkanoyl, [(C1-C4)alkoxy]carbonyl, (C1-C4)alkylamino and di[(C1-C4)alkyl]-amino,
        or (C3-C6)cycloalkyl, phenyl or heterocyclyl, where each of the 3 latter radicals is optionally substituted,
        or, for example, one of the abovementioned eliminable radicals i) to xiii),
    
    
    R1, independently of R0, is
    
        (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy and (C1-C4)alkylthio,
        or aryl or heterocyclyl, where each of the 2 latter radicals is unsubstituted or substituted, preferably unsubstituted or substituted as in R in formula (I) for optionally substituted phenyl or heterocyclyl, in particular by one or more radicals selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)haloalkyl and (C1-C4)haloalkoxy,

where the substituents R1 and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound (Ia) is present in the form of a stereochemically pure compound of the formula (Ia-A) or (Ia-B)

    
    






in which the general radicals are as defined in formula (Ia), or in the form of an isomer mixture of the compounds of the formulae (Ia-A) and (Ia-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Ib)




in which

    A1 is a direct bond or a group of the formula (CR6R7)n in which n is from 1 to 6 and R6 and R7 are each independently, or, in the case that n is greater than 1, the R6 and R radicals are in each case independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, (C1-C4)alkoxy or (C1-C4)haloalkoxy, where individual CR6R7 groups may be replaced by heteroatoms from the group of O and S,
    R0 is as defined above in formula (I), preferably as defined with preference for formula (I), and is in particular, independently of R1, a (C1-C6)alkyl or (C2-C6)alkenyl radical,
    
        where each of the two latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, (C1-C4)alkanoyloxy, (C1-C4)haloalkanoyloxy and aryl which is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, nitro, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)-alkanoyl, [(C1-C4)-alkoxy]-carbonyl, (C1-C4)alkylamino and di-[(C1-C4)alkyl]-amino, and heterocyclyl which is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, nitro, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)-alkanoyl, [(C1-C4)alkoxy]carbonyl, (C1-C4)alkylamino and di[(C1-C4)alkyl]-amino,
        or is (C3-C6)cycloalkyl, phenyl or heterocyclyl, where each of the 3 latter radicals is optionally substituted,
        or, for example, is one of the eliminable radicals i) to xiii) mentioned, and
    
    
    R1, independently of R0, is
    
        (C1-C6)alkyl which is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, aryl which is optionally substituted and heterocyclyl which is optionally substituted, or
        aryl which is optionally substituted or
        heterocyclyl which is optionally substituted,
        where the optionally substituted radicals are each independently preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C2-C4)alkenyl, (C5-C9)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, [(C1-C4)alkoxy]carbonyl, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl, (C1-C4)alkylamino, di(C1-C4)alkylamino, aryl and heterocyclyl, where the latter 14 radicals are each independently unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C5-C9)cycloalkenyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl, and, preferably,
        R1, independently of R0, is
        (C1-C6)alkyl which is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy and (C1-C4)alkylthio, or phenyl or heterocyclyl and
    
    
    R2 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN,
    R3 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN,
    R4 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN and
    R5 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN,

where the substituents R1 and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound is present in the form of a stereochemically pure compound of the formula (Ib-A) or (Ib-B)







in which the general radicals are each as defined in formula (Ib), or in the form of an isomer mixture of the compounds of the formulae (Ib-A) and (Ib-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Ic)




in which

    A1 is a direct bond or a group of the formula (CR6R7)n in which n is from 1 to 6 and R6 and R7 are each independently, or, in the case that n is greater than 1, the R6 and R7 radicals are in each case independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, (C1-C4)alkoxy or (C1-C4)haloalkoxy, where individual CR6R7 groups may be replaced by heteroatoms from the group of O and S,
    A2, together with the two carbon atoms which are common with the other ring, is a carbocyclic nonaromatic ring which has from 3 to 9 carbon atoms and is unsubstituted or substituted by one or more radicals selected from the group consisting of (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy, hydroxy, amino and CN,
    R0 is as defined above in formula (I), preferably as defined with preference for formula (I) and is in particular independently as defined in formula (Ib), and
    R1 is independently as defined in formula (Ib),

where the substituents R1 and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound (Ic) is present in the form of a stereochemically pure compound of the formula (Ic-A) or (Ic-B)







in which the general radicals are each as defined in formula (Ic), or in the form of an isomer mixture of the compounds of the formulae (Ic-A) and (Ic-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Id)




in which

    A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring which has from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and, in the case of a heterocyclic ring, has from 1 to 3 heterocyclic ring atoms from the group of N, O and S, and, in addition to the A′ and NH—R0 radicals, is unsubstituted or further substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C1-C4)alkoxy and (C1-C4)alkylthio, where each of the latter 4 radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl, and
    A′ together with the NH group and the carbon atoms designated with an asterisk (*) in each case, is a heterocyclic ring which has from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and optionally contains 1 or 2 further heteroatoms from the group of N, O and S and is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and phenyl which is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, nitro, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkanoyl, [(C1-C4)alkoxy]carbonyl, (C1-C4)alkylamino and di[(C1-C4)alkyl]amino,

where the substituents A′ and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound (Id) is present in the form of a stereochemically pure compound of the formula (Id-A) or (Id-B)







in which the general radicals are each as defined in formula (Id), or in the form of an isomer mixture of the compounds of the formulae (Id-A) and (Id-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Ie)




in which

    A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring which has from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and, in the case of a heterocyclic ring, has from 1 to 3 heterocyclic ring atoms from the group of N, O and S, and, in addition to the A′′ and NH—R0 radicals, is unsubstituted or further substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C1-C4)alkoxy and (C1-C4)alkylthio, where each of the latter 4 radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl, and
    A′′, together with the A and the carbon atom designated with “2” (=the carbon atom which is bonded to A′′ and is designated with an asterisk), is a carbocyclic or heterocyclic ring which has from 4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and, in the heterocyclic case, contains 1 or 2 or 3 heteroatoms selected from the group consisting of N, O and S, and is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio and phenyl which is unsubstituted or substituted by one or more radicals from the group of halogen, cyano, nitro, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)-alkanoyl, [(C1-C4)alkoxy]-carbonyl, (C1-C4)alkylamino and di[(C1-C4)alkyl]amino,

where R0 is defined independently of A′′ as in the formulae (I), (Ia), (Ib) or (Ic), and the substituents A′′ and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound (Ie) is present in the form of a stereochemically pure compound of the formula (Ie-A) or (Ie-B)







in which the general radicals are each as defined in formula (Ie), or in the form of an isomer mixture of the compounds of the formulae (Ie-A) and (Ie-B) in an isomer ratio other than the ratio of 1:1.

The reduction of the imino group of the compound (II) may be carried out analogously to processes as are known, for example, for the reduction of carbonyl compounds, or processes developed particularly therefor, as an asymmetric catalytic hydrogenation or catalytic transfer hydrogenation in the presence of hydrogen or hydrogen donors and chiral transition metal catalysts under reaction conditions under which chemical equilibrium between imine (II-A) and imine (II-B) is enabled.
Useful chiral catalysts for the reaction are those described analogously for asymmetric reductions of ketones, for example described in the references cited below or in the references cited in each of them:

    Angew. Chem. Int. Ed. 2001 (40) p. 40-73,
    Tetrahedron Lett. 1999 (40) 5043-5046,
    J. Org. Chem. 1996, 61, 4872-4873
    Angew. Chem. Int. Ed. 2004 (116) 806-843, specifically pages 829-830 and literature cited there,
    Tetrahedron Asymmetry. 2003 (14) 1407-1446,
    Org. Lett 1999 (1) 1119-1121,
    Tetrahedron 2003 (59) 8291-8327.


Suitable catalysts for the reductions are, for example,

    1. Ruthenium diphosphine 1,2-diamine complexes of the formula (1) and (2) and analogous complexes of the formulae (1′) or (2′) with other diamine bridges






    
    
        where, in each case,
        Ar is an aryl radical, preferably phenyl radical, which is unsubstituted or substituted,
        D* is a chiral organic group,
        Ra, Rb, Rc and Rd are each hydrogen or optionally substituted aliphatic or aromatic groups which may also be joined to one another in pairs, where the 1,2-diamine bridge is chiral or achiral in the case of the compound (1) and is chiral in the case of the compound (2),
        A* is alkylene having from 1 to 4 carbon atoms, preferably 2 carbon atoms, between the binding sites, where alkylene is optionally substituted, preferably unsubstituted, or is substituted by one or more radicals selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio and (C1-C4)haloalkyl, or cycloalkylene which has from 3 to 6 carbon atoms and is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio and (C1-C4)haloalkyl, preferably correspondingly optionally substituted 1,2-cycloalkylene, or a divalent heterocyclic radical which has from 3 to 6 ring atoms and 1, 2 or 3 heterocyclic ring atoms from the group of O, S and N, where the ring is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio and (C1-C4)haloalkyl.
    
    


The compounds (1) and (2) or (1′) and (2′) may be prepared from ruthenium salts and the diphosphine bridge and diamine bridge compounds before the hydrogenation or in situ.
Examples of diphenylphosphine bridges Ar2P-D*-PAr2 for preparing catalysts (1) or (1′) are compounds of the formula (1a), (1b) and (1c):




especially the compounds:

(S)-BINAP: Ar=phenyl[1,1′-binaphthyl-2,2′-bis-(diphenylphosphine)]
(S)-TolBINAP: Ar=4-tolyl[1,1′-binaphthyl-2,2′-bis-(di-p-tolylphosphine)]
(S)-XylBINAP: Ar=3,5-xylyl[1,1′-binaphthyl-2,2′-bis-(di-m-xylylphosphine)] and correspondingly
(R)-BINAP, (R)-TolBINAP and (R)-XylBINAP




Examples of chiral diamine bridges for the preparation of catalysts (1) and (2) or (1′) and (2′) are the following compounds:
(S,S)-DPEN=(1S,2S)-1,2-diamino-1,2-diphenylethane,
(S,S)-1,2-diaminocyclohexane,
(S)-DAIPEN=(2S)-1,2-diamino-1,1-bis-(4-methoxyphenyl)-3-methylbutane,
3,4-O-isopropylidene-(3S,4S)-dihydroxy-(2S,5S)-diaminohexane and correspondingly the enantiomeric compounds
(R,R)-DPEN, (R,R)-1,2-diaminocyclohexane, (R)-DAIPEN and
3,4-O-isopropylidene-(3R,4R)-dihydroxy-(2R,5R)-diaminohexane.
An example of a useful achiral diamine for preparing compounds (1) or (1′) is 1,2-diaminoethane.

    2. Corresponding to the ruthenium complexes specified under 1, it is also possible to use similar iridium complexes, for example [Ir((R)-BINAP)(cod)]BF4+P[C6H4-2-N(CH3)2]2C6H5, where “cod” means the ligand cyclooctadiene.
    3. Corresponding to the ruthenium complexes specified under 1, it is also possible to use similar iridium complexes, for example (R,S,R,S)-Me-PennPhos-Rh oxoProNOP—Rh
    4. Metal complexes of the formula (3)






    
    
        in which
        M is a metal(II) ion from the group of Ru, Rh and Ir,
        X is O or NR*R**,
        Ar is an aryl radical, preferably phenyl, which is unsubstituted or substituted, especially alkylphenyl,
        Ra, Rb and Rc are optionally substituted aliphatic or aromatic groups which may also be joined to one another in pairs, the bridge being chiral, and
        R, R*, R** and R*** are each independently a free electron pair, H, alkyl or acyl,
        especially corresponding ruthenium(II) 1,2-diamine complexes.
    
    
    5. Rhodium(III) and iridium(III) complexes of the formulae (4) and (5) which contain chiral ligands and their enantiomeric forms






in which M is an Rh or Ir and Ra, Rb and Rc are each organic radicals. Some catalysts from this group are also commercially available (®Cathy catalysts from Avecia), for example rhodium(III) and iridium(III) complexes of the formulae (4a) or (4b) which contain chiral bicyclic ligands and their enantiomeric forms





The asymmetric hydrogenation can generally be carried out by hydrogenating the compound of the formula (II) in a suitable solvent in the presence of a suitable amount of the dissolved catalyst, optionally with addition of bases. The catalyst may optionally also be obtained in situ during the reaction from the components.
The hydrogenation may be effected, for example, as an asymmetric hydrogenation using hydrogen gas as a hydrogen donor or under conditions of asymmetric transfer hydrogenation with other hydrogen donors.
The quantitative ratio of compound (II) to catalyst may be varied within a wide range and is generally in the range from 100 000 mol to 10 mol of compound (II) per mole of the catalyst, preferably from 100 000 mol to 50 mol, in particular from 10 000 mol to 100 mol, of compound (II) per mole of the catalyst.
The suitable temperatures for the inventive reaction may be determined in preliminary experiments. They are generally within a temperature range of from −80° C. up to the boiling point of the mixture, preferably at temperatures of from 0° C. to 100° C., in particular from 15° C. to 60° C., very particularly at room temperature. The reaction is usually carried out at a hydrogen pressure of from 1 to 100 bar, preferably from 1 bar to 10 bar.
Suitable solvents for the catalytic hydrogenation are solvents inert under the reaction conditions, as are typically used in hydrogenation reactions, or mixtures thereof, for example

    
    
        alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, t-butanol,
        water,
        carboxylic esters such as ethyl acetate,
        carboxylic acids such as glacial acetic acid,
        aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and paraffins, preferably toluene, xylene or mesitylene or else mixtures such as ®Solvesso (mineral oil mixture with aromatic fractions),
        halogenated aliphatic or aromatic hydrocarbons, for example chlorinated alkanes and alkenes, chlorobenzene, o-dichlorobenzene,
        nitriles such as acetonitrile,
        ethers such as diethyl ether or cyclic ethers such as dioxane or tetrahydrofuran,
        amides such as dimethylformamide, sulfones such as sulfolane,

and mixtures of the solvents mentioned.

    
    


As a variant of the hydrogenation, an asymmetric transfer hydrogenation may be carried out with a hydrogen donor in the presence of the above-described catalysts. Suitable hydrogen donors are compounds which can themselves be oxidized under the conditions. Suitable hydrogen donors are, for example, formic acid and its salts, as are also used for the performance of the Leukart-Wallach reaction (see, for example, Houben-Weyl 11/1, 648-664 and Synthesis 1988, 92 and literature cited there). A suitable hydrogen donor is thus formic acid which can be used optionally in combination with a base, for example a tertiary amine base. Bases are, for example, ammonia or primary, secondary and tertiary amines, for example those with alkyl, aralkyl and/or aryl radicals, preferably corresponding amines with (C1-C4)alkyl radicals. Suitable salts are corresponding (substituted) ammonium formates. Further hydrogen donors are isopropanol or cyclohexadiene (cf. Adv. Synth. Catal. 2003, Vol. 345, pages 67-77, Tetrahedron: Asymmetry 10 (1999) 2045-2061, Eur. J. Inorg. Chem. 2002, 2239-2251), also in each case in combination with the catalysts mentioned specifically in the references.
Preference is given to the use of catalysts of the abovementioned formulae (3), (4) and (5) in combination with formic acid and tertiary amines such as triethylamine.
Suitable mixing ratios of formic acid:amine are from 10:1 to 1:10 based on the weight. The donor system may be used directly as a solvent or be used in a mixture with other solvents as cosolvents.
Suitable solvents for the catalytic transfer hydrogenation are solvents inert under the reaction conditions or mixtures thereof, for example

    
    
        alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, t-butanol,
        water,
        carboxylic esters such as ethyl acetate,
        carboxylic acids such as glacial acetic acid,
        aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and paraffins, preferably toluene, xylene or mesitylene or else mixtures such as ®Solvesso (mineral oil mixture with aromatic fractions),
        halogenated aliphatic or aromatic hydrocarbons, for example chlorinated alkanes and alkenes, chlorobenzene, o-dichlorobenzene,
        nitriles such as acetonitrile,
        ethers such as diethyl ether or cyclic ethers such as dioxane or tetrahydrofuran,
        amides such as dimethylformamide, sulfones such as sulfolane,

and mixtures of the solvents mentioned.

    
    


The catalytic hydrogenation and the catalytic transfer hydrogenation may be carried out analogously to the customary conditions, as described in the literature mentioned for the reduction of ketones to optically active alcohols.
The performance of the reaction with regard to amount of catalyst and reaction time should be optimized in preliminary experiments in order to achieve a high conversion rate, chemical yield and enantiomeric excess.
Surprisingly, it is possible in the hydrogenations to achieve good enantioselectivity of the amine (I) not only with regard to the chiral center at which the amino group is bonded but also with regard to the adjacent chiral center.
The starting materials of the formula (II) are known or can be prepared analogously to known processes. A simple possibility is the preparation via the corresponding ketone. Cyclic ketones are in many cases commercially available or can be prepared by a large number of reactions known to those skilled in the art from other compounds such as alcohols, halogen compounds, or from esters or carboxylic acids by ring-closure reactions. Bicyclic ketones are, for example, also described in WO 97/031904 and WO 2004/069814.
A particular means of preparing the optically active amines (I) and their salts also consists in carrying out a two-stage process with in situ preparation of the imine from a corresponding ketone and direct reduction in the presence of the catalyst. The imine is formed by reaction of the ketone with a suitable amount of a primary amine R0—NH2 where R0 is as defined in formula (I) and is reduced to the amine without intermediate isolation. The in situ process can be carried out, for example, with an amount of from 0.1 mol up to a several-fold excess of primary amine per mole of ketone, preferably from 1 to 10 mol, in particular from 1 to 5 mol, more preferably from 1 to 2 mol, of primary amine per mole of ketone. The two-stage reaction can generally be controlled by adding the optically active catalyst. The temperature conditions depend substantially upon the suitable temperature for the catalytic reaction.
The resulting compounds of the formula (I) are suitable as optically active synthons for preparing optically active active ingredients. A particularly frequent use of the compounds (I) and their salts is the preparation of the corresponding free amines (I′), the difference of the formula (I′) from the formula (I) consisting in the replacement of the R0 radical by hydrogen.
The free optically active cis-amines of the formula (I′) and their salts therefore likewise form part of the subject matter of the invention. They can be prepared from suitable compounds of the formula (I) by standard reactions, for example by elimination of protecting groups R0 for which an elimination reaction, preferably a gentle elimination reaction, is known. Examples of such eliminable groups are the groups i)-xv) mentioned above. The preparation of these groups and their common and preferred elimination methods are described, for example, in the handbook “Protective Groups in Organic Synthesis, 3rd ed., T. W. Greene and P. G. M. Wuts; 1999, John Wiley & Sons, Inc. (see in particular pages 575 to 585) and literature cited there.
The experiments are illustrated in detail by the examples which follow without any intention that the invention be restricted to these embodiments. Amounts are based on weight unless stated otherwise.
ABBREVIATIONS IN THE EXAMPLES


    Me=methyl
    Et=ethyl
    n- or i-Pr or t-butyl=n-propyl or isopropyl or t-butyl
    Ph=phenyl
    Ts=p-tosyl=p-tolylsulfonyl
    Allyl=CH2—CH═CH2 
    Bzl=benzyl ═CH2Ph
    p-MeO-Bzl=para-methoxybenzyl=(p-methoxyphenyl)methyl




EXAMPLE A1
cis-(S,S)-Benzyl-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)amine
A1a) Preparation of the catalyst Ru(p-cymene)-(S,S)-TsDPEN
Bis(p-cymeneruthenium dichloride) is initially charged in an organic solvent and reacted at room temperature with (S,S)-TsDPEN [(S,S)-N-tosyl-1,2-diamino-1,2-diphenylethane]. Concentration and removal of the solvent under high vacuum affords Ru(p-cymene)(S,S)-TsDPEN of the formula:




Correspondingly, the compound Ru(p-cymene)(R,R)-TsDPEN is obtained using (R,R)-TsDPEN.
A1b) (1S,2S)-N-Benzyl-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)amine
3 mg (4.7 μmol) of the catalyst from example Ala are dissolved in 1 ml of a mixture of formic acid and triethylamine (5:2 v/v) and stirred for 20 min. A solution of 350 mg (1.141 mmol) of racemic N-benzyl-(2-methyl-3,4-dihydro-2H-naphth-1-ylidene)amine in 1.7 ml of dichloromethane is then added and the mixture is stirred at room temperature for 5 days. After removal of the solvent, the dissolution in 5 ml of methanol, treatment with approx. 200 mg of potassium hydroxide and admixing with 10 ml of water at room temperature, extraction is effected three times with in each case 15 ml of dichloromethane and the organic phase is dried over sodium sulfate. After removal of the solvent and column chromatography (20:1 hexane/ethyl acetate), 229 mg (65% yield) of (1S,2S)-N-benzyl-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)amine are obtained as a light yellow oil.
[α]21D=−31.1° (c 0.8, CHCl3); 1H NMR (400 MHz, C6D6) δ=6.98-7.22 (m, 9H), 3.75 (d, 1H, J=14.0 Hz), 3.71 (d, 1H, J=14.0 Hz), 3.47 (d, 1H, J=3.6 Hz), 2.68 (dt, 1H, J=17.2, 5.6 Hz), 2.55 (dt, 1H, J=16.8, 8.0 Hz), 1.84 (m, 4H), 1.63 (m, 1H), 1.48 (m, 1H), 0.95 (d, 3H, J=6.5 Hz), 13C NMR (100 MHz, C6D6) δ=141.8, 140.2, 136.5, 129.5, 129.2, 128.7, 128.6, 127.2, 127.0, 125.8, 259.3, 52.6, 32.5, 28.0, 26.5, 16.5. The enantiomeric excess (ee %) was determined by chromatography (ee=98%); HPLC on Chiralpak AD (Daicel), 96:4 n-hexane:isopropanol, 30° C., flow rate: 0.5 ml/min; RT: 7.07 min.
EXAMPLE A2
(1R,2S)-N-Allyl-(2-methylcyclohexyl)amine
A solution of 22.5 mg (35 μmol) of the catalyst from example Ala in 3.2 ml of a mixture of formic acid and triethylamine (5:2 v/v) is added dropwise to a mixture of 676 mg (6 mmol) of 2-methylcyclohexanone, 2.74 g (48 mmol of allylamine and 100 mg of magnesium sulfate, and stirred. After 7 days at room temperature, the reaction mixture is diluted with 20 ml of water and extracted three times with 15 ml of dichloromethane. The organic phase is dried over sodium sulfate. After removal of the solvent and column chromatography (silica gel, 10:1 dichloromethane/methanol), 708 mg (77% yield) of (1R,2S)-N-allyl-(2-methylcyclohexyl)amine are obtained.
[α]21D=+8.2° (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ=5.88 (m, 1H), 5.14 (dd, 1H, J=1.6, 16.2 Hz), 5.03 (m, 1H), 3.19 (m, 1H), 2.58 (m, 1H), 1.90 (m, 1H), 1.7-1.2 (m, 9H), 0.86 (d, 1H, J=7.0 Hz),
13C NMR (75 MHz) δ=137.8, 115.8, 58.8, 49.9, 31.4, 28.4, 24.1, 22.2, 19.6, 13.8.
The enantiomeric excess (ee %) was determined by chromatography (ee=95.9%); HPLC on Chiralpak OJ (Daicel), 99.5:0.5 n-hexane:isopropanol, 30° C., flow rate: 0.5 ml/min; RT: 17.16 min.
EXAMPLE A3
(1R,2R)-N-Benzyl-(2-phenylcyclohexyl)amine
16.6 mg of IrCl[(S,S)-TsDPEN]Cp* and a solution of racemic 1-benzyl-N-[2-phenylcyclohexylidene]amine in 10 ml of dry dichloromethane are added to 3.2 ml of a mixture of formic acid and triethylamine (5:2 v/v). After stirring at room temperature for 24 h, the mixture is diluted with 0.5 M aq. Na2CO3 until pH 10 is attained and then extracted with dichloromethane (2×30 ml). The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified by column chromatography (silica gel, 1:12 ethyl acetate/hexane). (1R,2R)-N-Benzyl-(2-phenylcyclohexyl)amine is obtained in 60% yield. [α]22D=+33.4° (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ=6.9-7.4 (m, 10H), 3.68 (d, J=13.8 Hz, 1H), 3.0 (m, 1H), 2.85 (dt, J=13.3, 3.2 Hz), 1H), 1.1-2.2 (m, 8H);
13C NMR (75 MHz) δ=143.9, 140.3, 127.7, 127.5, 127.1, 125.9, 125.5, 56.1, 50.7, 46.5, 29.2, 25.9, 24.1, 19.1. The diastereomeric excess (de) was determined by means of 1H-NMR (de>98%). The enantiomeric excess was determined after debenzylation and subsequent acetylation of the released amino function (ee=50%).
According to examples A1, A2 and A3 and the variants mentioned in the description, the example compounds mentioned in the following tables 1 and 2 are also obtained.
Comments on Tables 1 and 2:
Methods for determining the retention time by HPLC on chiral phase. All measurements with n-hexane/isopropanol as eluent at 30° C. References reported as follows: Rt (min), eluent and flow rate (vnHex/viProH−ml/min)
(1) Chiralpak AD (Daicel)
(2) Chiralpak OJ (Daicel)
(3) Chiralpak OB (Daicel)
(4) characterized as the N-benzoyl derivative
Some data on the compounds are reported at the end of each table.







TABLE 1







Compounds of the formula (Ia-A) and (Ia-B)









(Ia-A)









 



(Ia-B)









 







The numbers in the first column of the table relate to the


compounds of the formula (Ia-A) with the substituent 


definitions in the columns under A, R0 and R1. Correspondingly,


the numbers in the second column relate to the compounds of the formula


(Ia-B) with the substituent definitions in the columns under A, R0 and R1.











Comp. (Ia-A)
Comp. (Ia-B)





No.
No.
A
R0
R1





aA1
aB1
CH2
Me
Me


aA2
aB2
CH2CH2
Me
Me


aA3
aB3
CH2CH2CH2
Me
Me


aA4
aB4
CH2CH2CH2CH2
Me
Me


aA5
aB5
CH2CH2CH2CH2CH2
Me
Me


aA6
aB6
CH2O
Me
Me


aA7
aB7
CH2OCH2
Me
Me


aA8
aB8
CH2
Me
Et


aA9
aB9
CH2
Me
n-Pr


aA10
aB10
CH2CH2
Me
Et


aA11
aB11
CH2CH2
Me
n-Pr


aA12
aB12
CH2CH2CH2
Me
Et


aA13
aB13
CH2CH2CH2
Me
n-Pr


aA14
aB14
CH2CH2CH2CH2
Me
Et


aA15
aB15
CH2CH2CH2CH2
Me
n-Pr


aA16
aB16
CH2CH2CH2CH2CH2
Me
Et


aA17
aB17
CH2CH2CH2CH2CH2
Me
n-Pr


aA18
aB18
CH2O
Me
Et


aA19
aB19
CH2O
Me
n-Pr


aA20
aB20
CH2OCH2
Me
Et


aA21
aB21
CH2OCH2
Me
n-Pr


aA22
aB22
CH2
Et
Me


aA23
aB23
CH2CH2
Et
Me


aA24
aB24
CH2CH2CH2
Et
Me


aA25
aB25
CH2CH2CH2CH2
Et
Me


aA26
aB26
CH2CH2CH2CH2CH2
Et
Me


aA27
aB27
CH2O
Et
Me


aA28
aB28
CH2OCH2
Et
Me


aA29
aB29
CH2
Et
Et


aA30
aB30
CH2
Et
n-Pr


aA31
aB31
CH2CH2
Et
Et


aA32
aB32
CH2CH2
Et
n-Pr


aA33
aB33
CH2CH2CH2
Et
Et


aA34
aB34
CH2CH2CH2
Et
n-Pr


aA35
aB35
CH2CH2CH2CH2
Et
Et


aA36
aB36
CH2CH2CH2CH2
Et
n-Pr


aA37
aB37
CH2CH2CH2CH2CH2
Et
Et


aA38
aB38
CH2CH2CH2CH2CH2
Et
n-Pr


aA39
aB39
CH2O
Et
Et


aA40
aB40
CH2O
Et
n-Pr


aA41
aB41
CH2OCH2
Et
Et


aA42
aB42
CH2OCH2
Et
n-Pr


aA43
aB43
CH2
Allyl
Me


aA44
aB44
CH2CH2
Allyl
Me


aA45
aB45
CH2CH2CH2
Allyl
Me


aA46
aB46
CH2CH2CH2CH2
Allyl
Me


aA47
aB47
CH2CH2CH2CH2CH2
Allyl
Me


aA48
aB48
CH2O
Allyl
Me


aA49
aB49
CH2OCH2
Allyl
Me


aA50
aB50
CH2
Allyl
Et


aA51
aB51
CH2
Allyl
n-Pr


aA52
aB52
CH2CH2
Allyl
Et


aA53
aB53
CH2CH2
Allyl
n-Pr


aA54
aB54
CH2CH2CH2
Allyl
Et


aA55
aB55
CH2CH2CH2
Allyl
n-Pr


aA56
aB56
CH2CH2CH2CH2
Allyl
Et


aA57
aB57
CH2CH2CH2CH2
Allyl
n-Pr


aA58
aB58
CH2CH2CH2CH2CH2
Allyl
Et


aA59
aB59
CH2CH2CH2CH2CH2
Allyl
n-Pr


aA60
aB60
CH2O
Allyl
Et


aA61
aB61
CH2O
Allyl
n-Pr


aA62
aB62
CH2OCH2
Allyl
Et


aA63
aB63
CH2OCH2
Allyl
n-Pr


aA64
aB64
CH2
Bzl
Me


aA65
aB65
CH2CH2
Bzl
Me


aA66
aB66
CH2CH2CH2
Bzl
Me


aA67
aB67
CH2CH2CH2CH2
Bzl
Me


aA68
aB68
CH2CH2CH2CH2CH2
Bzl
Me


aA69
aB69
CH2O
Bzl
Me


aA70
aB70
CH2OCH2
Bzl
Me


aA71
aB71
CH2
Bzl
Et


aA72
aB72
CH2
Bzl
n-Pr


aA73
aB73
CH2
Bzl
Ph


aA74
aB74
CH2CH2
Bzl
Et


aA75
aB75
CH2CH2
Bzl
n-Pr


aA76
aB76
CH2CH2
Bzl
Ph


aA77
aB77
CH2CH2CH2
Bzl
Et


aA78
aB78
CH2CH2CH2
Bzl
n-Pr


aA79
aB79
CH2CH2CH2
Bzl
Ph


aA80
aB80
CH2CH2CH2CH2
Bzl
Et


aA81
aB81
CH2CH2CH2CH2
Bzl
n-Pr


aA82
aB82
CH2CH2CH2CH2
Bzl
Ph


aA83
aB83
CH2CH2CH2CH2CH2
Bzl
Et


aA84
aB84
CH2CH2CH2CH2CH2
Bzl
n-Pr


aA85
aB85
CH2CH2CH2CH2CH2
Bzl
Ph


aA86
aB86
CH2O
Bzl
Et


aA87
aB87
CH2O
Bzl
n-Pr


aA88
aB88
CH2O
Bzl
Ph


aA89
aB89
CH2OCH2
Bzl
Et


aA90
aB90
CH2OCH2
Bzl
n-Pr


aA91
aB91
CH2OCH2
Bzl
Ph





Physical data on compounds from table 1:


Compound No.: aB46: Ref(2,4) Rt = 17.2, n-hexane/isopropanol = 99.5:0.5 (v/v), flow rate = 0.5 ml/mm













TABLE 2







Compounds of the formula (Ib-A) and (Ib-B)









(Ib-A)









 



(Ib-B)









 







The numbers in the first column of the table relate to the compounds of the formula


(Ib-A) with the substituent definitions in the columns under A, R0 to R5.


Correspondingly, the numbers in the second column relate to the compounds of the


formula (Ib-B) with the substituent definitions in the columns under A and R0 to R5.















Ib-A
Ib-B
A1
R0
R1
R2
R3
R4
R5





bA1
bB1
—
Me
Me
H
H
H
H


bA2
bB2
—
Me
Me
Me
H
H
H


bA3
bB3
—
Me
Me
H
Me
H
H


bA4
bB4
—
Me
Me
H
H
Me
H


bA5
bB5
—
Me
Me
H
H
H
Me


bA6
bB6
—
Me
Me
Cl
H
H
H


bA7
bB7
—
Me
Me
H
Cl
H
H


bA8
bB8
—
Me
Me
H
H
Cl
H


bA9
bB9
—
Me
Me
H
H
H
Cl


bA10
bB10
—
Me
Me
Et
H
H
H


bA11
bB11
—
Me
Me
H
Et
H
H


bA12
bB12
—
Me
Me
H
H
Et
H


bA13
bB13
—
Me
Me
H
H
H
Et


bA14
bB14
—
Me
Me
OMe
H
H
H


bA15
bB15
—
Me
Me
H
OMe
H
H


bA16
bB16
—
Me
Me
H
H
OMe
H


bA17
bB17
—
Me
Me
H
H
H
OMe


bA18
bB18
—
Me
Me
F
H
H
H


bA19
bB19
—
Me
Me
H
F
H
H


bA20
bB20
—
Me
Me
H
H
F
H


bA21
bB21
—
Me
Me
H
H
H
F


bA22
bB22
—
Et
Me
H
H
H
H


bA23
bB23
—
Et
Me
Me
H
H
H


bA24
bB24
—
Et
Me
H
Me
H
H


bA25
bB25
—
Et
Me
H
H
Me
H


bA26
bB26
—
Et
Me
H
H
H
Me


bA27
bB27
—
Et
Me
Cl
H
H
H


bA28
bB28
—
Et
Me
H
Cl
H
H


bA29
bB29
—
Et
Me
H
H
Cl
H


bA30
bB30
—
Et
Me
H
H
H
Cl


bA31
bB31
—
Et
Me
Et
H
H
H


bA32
bB32
—
Et
Me
H
Et
H
H


bA33
bB33
—
Et
Me
H
H
Et
H


bA34
bB34
—
Et
Me
H
H
H
Et


bA35
bB35
—
Et
Me
OMe
H
H
H


bA36
bB36
—
Et
Me
H
OMe
H
H


bA37
bB37
—
Et
Me
H
H
OMe
H


bA38
bB38
—
Et
Me
H
H
H
OMe


bA39
bB39
—
Et
Me
F
H
H
H


bA40
bB40
—
Et
Me
H
F
H
H


bA41
bB41
—
Et
Me
H
H
F
H


bA42
bB42
—
Et
Me
H
H
H
F


bA43
bB43
—
Allyl
Me
H
H
H
H


bA44
bB44
—
Allyl
Me
Me
H
H
H


bA45
bB45
—
Allyl
Me
H
Me
H
H


bA46
bB46
—
Allyl
Me
H
H
Me
H


bA47
bB47
—
Allyl
Me
H
H
H
Me


bA48
bB48
—
Allyl
Me
Cl
H
H
H


bA49
bB49
—
Allyl
Me
H
Cl
H
H


bA50
bB50
—
Allyl
Me
H
H
Cl
H


bA51
bB51
—
Allyl
Me
H
H
H
Cl


bA52
bB52
—
Allyl
Me
Et
H
H
H


bA53
bB53
—
Allyl
Me
H
Et
H
H


bA54
bB54
—
Allyl
Me
H
H
Et
H


bA55
bB55
—
Allyl
Me
H
H
H
Et


bA56
bB56
—
Allyl
Me
OMe
H
H
H


bA57
bB57
—
Allyl
Me
H
OMe
H
H


bA58
bB58
—
Allyl
Me
H
H
OMe
H


bA59
bB59
—
Allyl
Me
H
H
H
OMe


bA60
bB60
—
Allyl
Me
F
H
H
H


bA61
bB61
—
Allyl
Me
H
F
H
H


bA62
bB62
—
Allyl
Me
H
H
F
H


bA63
bB63
—
Allyl
Me
H
H
H
F


bA64
bB64
—
Bzl
Me
H
H
H
H


bA65
bB65
—
Bzl
Me
Me
H
H
H


bA66
bB66
—
Bzl
Me
H
Me
H
H


bA67
bB67
—
Bzl
Me
H
H
Me
H


bA68
bB68
—
Bzl
Me
H
H
H
Me


bA69
bB69
—
Bzl
Me
Cl
H
H
H


bA70
bB70
—
Bzl
Me
H
Cl
H
H


bA71
bB71
—
Bzl
Me
H
H
Cl
H


bA72
bB72
—
Bzl
Me
H
H
H
Cl


bA73
bB73
—
Bzl
Me
Et
H
H
H


bA74
bB74
—
Bzl
Me
H
Et
H
H


bA75
bB75
—
Bzl
Me
H
H
Et
H


bA76
bB76
—
Bzl
Me
H
H
H
Et


bA77
bB77
—
Bzl
Me
OMe
H
H
H


bA78
bB78
—
Bzl
Me
H
OMe
H
H


bA79
bB79
—
Bzl
Me
H
H
OMe
H


bA80
bB80
—
Bzl
Me
H
H
H
OMe


bA81
bB81
—
Bzl
Me
F
H
H
H


bA82
bB82
—
Bzl
Me
H
F
H
H


bA83
bB83
—
Bzl
Me
H
H
F
H


bA84
bB84
—
Bzl
Me
H
H
H
F


bA85
bB85
—
p-MeO-Bzl
Me
H
H
H
H


bA86
bB86
—
p-MeO-Bzl
Me
Me
H
H
H


bA87
bB87
—
p-MeO-Bzl
Me
H
Me
H
H


bA88
bB88
—
p-MeO-Bzl
Me
H
H
Me
H


bA89
bB89
—
p-MeO-Bzl
Me
H
H
H
Me


bA90
bB90
—
p-MeO-Bzl
Me
Cl
H
H
H


bA91
bB91
—
p-MeO-Bzl
Me
H
Cl
H
H


bA92
bB92
—
p-MeO-Bzl
Me
H
H
Cl
H


bA93
bB93
—
p-MeO-Bzl
Me
H
H
H
Cl


bA94
bB94
—
p-MeO-Bzl
Me
Et
H
H
H


bA95
bB95
—
p-MeO-Bzl
Me
H
Et
H
H


bA96
bB96
—
p-MeO-Bzl
Me
H
H
Et
H


bA97
bB97
—
p-MeO-Bzl
Me
H
H
H
Et


bA98
bB98
—
p-MeO-Bzl
Me
OMe
H
H
H


bA99
bB99
—
p-MeO-Bzl
Me
H
OMe
H
H


bA100
bB100
—
p-MeO-Bzl
Me
H
H
OMe
H


bA101
bB101
—
p-MeO-Bzl
Me
H
H
H
OMe


bA102
bB102
—
p-MeO-Bzl
Me
F
H
H
H


bA103
bB103
—
p-MeO-Bzl
Me
H
F
H
H


bA104
bB104
—
p-MeO-Bzl
Me
H
H
F
H


bA105
bB105
—
p-MeO-Bzl
Me
H
H
H
F


bA106
bB106
—
i-Pr
Me
Me
H
H
F


bA107
bB107
—
i-Pr
Me
H
Me
H
H


bA108
bB108
—
i-Pr
Me
H
H
Me
H


bA109
bB109
—
i-Pr
Me
H
H
H
Me


bA110
bB110
—
i-Pr
Me
Cl
H
H
H


bA111
bB111
—
i-Pr
Me
H
Cl
H
H


bA112
bB112
—
i-Pr
Me
H
H
Cl
H


bA113
bB113
—
i-Pr
Me
H
H
H
Cl


bA114
bB114
—
i-Pr
Me
Et
H
H
H


bA115
bB115
—
i-Pr
Me
H
Et
H
H


bA116
bB116
—
i-Pr
Me
H
H
Et
H


bA117
bB117
—
i-Pr
Me
H
H
H
Et


bA118
bB118
—
i-Pr
Me
OMe
H
H
H


bA119
bB119
—
i-Pr
Me
H
OMe
H
H


bA120
bB120
—
i-Pr
Me
H
H
OMe
H


bA121
bB121
—
i-Pr
Me
H
H
H
OMe


bA122
bB122
—
i-Pr
Me
F
H
H
H


bA123
bB123
—
i-Pr
Me
H
F
H
H


bA124
bB124
—
i-Pr
Me
H
H
F
H


bA125
bB125
—
i-Pr
Me
H
H
H
F


bA126
bB126
—
t-Bu
Me
H
H
H
H


bA127
bB127
—
t-Bu
Me
Me
H
H
H


bA128
bB128
—
t-Bu
Me
Me
Me
H
H


bA129
bB129
—
t-Bu
Me
H
H
Me
H


bA130
bB130
—
t-Bu
Me
H
H
H
Me


bA131
bB131
—
t-Bu
Me
Cl
H
H
H


bA132
bB132
—
t-Bu
Me
H
Cl
H
H


bA133
bB133
—
t-Bu
Me
H
H
Cl
H


bA134
bB134
—
t-Bu
Me
H
H
H
Cl


bA135
bB135
—
t-Bu
Me
H
H
H
H


bA136
bB136
—
t-Bu
Me
Et
H
H
H


bA137
bB137
—
t-Bu
Me
H
Et
H
H


bA138
bB138
—
t-Bu
Me
H
H
Et
H


bA139
bB139
—
t-Bu
Me
H
H
H
Et


bA140
bB140
—
t-Bu
Me
OMe
H
H
H


bA141
bB141
—
t-Bu
Me
H
OMe
H
H


bA142
bB142
—
t-Bu
Me
H
H
OMe
H


bA143
bB143
—
t-Bu
Me
H
H
H
OMe


bA144
bB144
—
t-Bu
Me
F
H
H
H


bA145
bB145
—
t-Bu
Me
H
F
H
H


bA146
bB146
—
t-Bu
Me
H
H
F
H


bA147
bB147
—
t-Bu
Me
H
H
H
F


bA148
bB148
—
Ph
Me
H
H
H
H


bA149
bB149
—
Ph
Me
Me
H
H
H


bA150
bB150
—
Ph
Me
Me
Me
H
H


bA151
bB151
—
Ph
Me
H
H
Me
H


bA152
bB152
—
Ph
Me
H
H
H
Me


bA153
bB153
—
Ph
Me
Cl
H
H
H


bA154
bB154
—
Ph
Me
H
Cl
H
H


bA155
bB155
—
Ph
Me
H
H
Cl
H


bA156
bB156
—
Ph
Me
H
H
H
Cl


bA157
bB157
—
Ph
Me
H
H
H
H


bA158
bB158
—
Ph
Me
Et
H
H
H


bA159
bB159
—
Ph
Me
H
Et
H
H


bA160
bB160
—
Ph
Me
H
H
Et
H


bA161
bB161
—
Ph
Me
H
H
H
Et


bA162
bB162
—
Ph
Me
OMe
H
H
H


bA163
bB163
—
Ph
Me
H
OMe
H
H


bA164
bB164
—
Ph
Me
H
H
OMe
H


bA165
bB165
—
Ph
Me
H
H
H
OMe


bA166
bB166
—
Ph
Me
F
H
H
H


bA167
bB167
—
Ph
Me
H
F
H
H


bA168
bB168
—
Ph
Me
H
H
F
H


bA169
bB169
—
Ph
Me
H
H
H
F


bA170
bB170
CH2
Me
Me
H
H
H
H


bA171
bB171
CH2
Me
Me
Me
H
H
H


bA172
bB172
CH2
Me
Me
H
Me
H
H


bA173
bB173
CH2
Me
Me
H
H
Me
H


bA174
bB174
CH2
Me
Me
H
H
H
Me


bA175
bB175
CH2
Me
Me
Cl
H
H
H


bA176
bB176
CH2
Me
Me
H
Cl
H
H


bA177
bB177
CH2
Me
Me
H
H
Cl
H


bA178
bB178
CH2
Me
Me
H
H
H
Cl


bA179
bB179
CH2
Me
Me
Et
H
H
H


bA180
bB180
CH2
Me
Me
H
Et
H
H


bA181
bB181
CH2
Me
Me
H
H
Et
H


bA182
bB182
CH2
Me
Me
H
H
H
Et


bA183
bB183
CH2
Me
Me
OMe
H
H
H


bA184
bB184
CH2
Me
Me
H
OMe
H
H


bA185
bB185
CH2
Me
Me
H
H
OMe
H


bA186
bB186
CH2
Me
Me
H
H
H
OMe


bA187
bB187
CH2
Me
Me
F
H
H
H


bA188
bB188
CH2
Me
Me
H
F
H
H


bA189
bB189
CH2
Me
Me
H
H
F
H


bA190
bB190
CH2
Me
Me
H
H
H
F


bA191
bB191
CH2
Et
Me
H
H
H
H


bA192
bB192
CH2
Et
Me
Me
H
H
H


bA193
bB193
CH2
Et
Me
H
Me
H
H


bA194
bB194
CH2
Et
Me
H
H
Me
H


bA195
bB195
CH2
Et
Me
H
H
H
Me


bA196
bB196
CH2
Et
Me
Cl
H
H
H


bA197
bB197
CH2
Et
Me
H
Cl
H
H


bA198
bB198
CH2
Et
Me
H
H
Cl
H


bA199
bB199
CH2
Et
Me
H
H
H
Cl


bA200
bB200
CH2
Et
Me
Et
H
H
H


bA201
bB201
CH2
Et
Me
H
Et
H
H


bA202
bB202
CH2
Et
Me
H
H
Et
H


bA203
bB203
CH2
Et
Me
H
H
H
Et


bA204
bB204
CH2
Et
Me
OMe
H
H
H


bA205
bB205
CH2
Et
Me
H
OMe
H
H


bA206
bB206
CH2
Et
Me
H
H
OMe
H


bA207
bB207
CH2
Et
Me
H
H
H
OMe


bA208
bB208
CH2
Et
Me
F
H
H
H


bA209
bB209
CH2
Et
Me
H
F
H
H


bA210
bB210
CH2
Et
Me
H
H
F
H


bA211
bB211
CH2
Et
Me
H
H
H
F


bA212
bB212
CH2
Allyl
Me
H
H
H
H


bA213
bB213
CH2
Allyl
Me
Me
H
H
H


bA214
bB214
CH2
Allyl
Me
H
Me
H
H


bA215
bB215
CH2
Allyl
Me
H
H
Me
H


bA216
bB216
CH2
Allyl
Me
H
H
H
Me


bA217
bB217
CH2
Allyl
Allyl
Me
H
H
H


bA218
bB218
CH2
Allyl
Allyl
H
Me
H
H


bA219
bB219
CH2
Allyl
Allyl
H
H
Me
H


bA220
bB220
CH2
Allyl
Allyl
H
H
H
Me


bA221
bB221
CH2
Allyl
Me
Cl
H
H
H


bA222
bB222
CH2
Allyl
Me
H
Cl
H
H


bA223
bB223
CH2
Allyl
Me
H
H
Cl
H


bA224
bB224
CH2
Allyl
Me
H
H
H
Cl


bA225
bB225
CH2
Allyl
Me
Et
H
H
H


bA226
bB226
CH2
Allyl
Me
H
Et
H
H


bA227
bB227
CH2
Allyl
Me
H
H
Et
H


bA228
bB228
CH2
Allyl
Me
H
H
H
Et


bA229
bB229
CH2
Allyl
Me
OMe
H
H
H


bA230
bB230
CH2
Allyl
Me
H
OMe
H
H


bA231
bB231
CH2
Allyl
Me
H
H
OMe
H


bA232
bB232
CH2
Allyl
Me
H
H
H
OMe


bA233
bB233
CH2
Allyl
Me
F
H
H
H


bA234
bB234
CH2
Allyl
Me
H
F
H
H


bA235
bB235
CH2
Allyl
Me
H
H
F
H


bA236
bB236
CH2
Allyl
Me
H
H
H
F


bA237
bB237
CH2
Bzl
Me
H
H
H
H


bA238
bB238
CH2
Bzl
Me
Me
H
H
H


bA239
bB239
CH2
Bzl
Me
H
Me
H
H


bA240
bB240
CH2
Bzl
Me
H
H
Me
H


bA241
bB241
CH2
Bzl
Me
H
H
H
Me


bA242
bB242
CH2
Bzl
Me
Cl
H
H
H


bA243
bB243
CH2
Bzl
Me
H
Cl
H
H


bA244
bB244
CH2
Bzl
Me
H
H
Cl
H


bA245
bB245
CH2
Bzl
Me
H
H
H
Cl


bA246
bB246
CH2
Bzl
Me
Et
H
H
H


bA247
bB247
CH2
Bzl
Me
H
Et
H
H


bA248
bB248
CH2
Bzl
Me
H
H
Et
H


bA249
bB249
CH2
Bzl
Me
H
H
H
Et


bA250
bB250
CH2
Bzl
Me
OMe
H
H
H


bA251
bB251
CH2
Bzl
Me
H
OMe
H
H


bA252
bB252
CH2
Bzl
Me
H
H
OMe
H


bA253
bB253
CH2
Bzl
Me
H
H
H
OMe


bA254
bB254
CH2
Bzl
Me
F
H
H
H


bA255
bB255
CH2
Bzl
Me
H
F
H
H


bA256
bB256
CH2
Bzl
Me
H
H
F
H


bA257
bB257
CH2
Bzl
Me
H
H
H
F


bA258
bB258
CH2
p-MeO-Bzl
Me
H
H
H
H


bA259
bB259
CH2
p-MeO-Bzl
Me
Me
H
H
H


bA260
bB260
CH2
p-MeO-Bzl
Me
H
Me
H
H


bA261
bB261
CH2
p-MeO-Bzl
Me
H
H
Me
H


bA262
bB262
CH2
p-MeO-Bzl
Me
H
H
H
Me


bA263
bB263
CH2
p-MeO-Bzl
Me
Cl
H
H
H


bA264
bB264
CH2
p-MeO-Bzl
Me
H
Cl
H
H


bA265
bB265
CH2
p-MeO-Bzl
Me
H
H
Cl
H


bA266
bB266
CH2
p-MeO-Bzl
Me
H
H
H
Cl


bA267
bB267
CH2
p-MeO-Bzl
Me
Et
H
H
H


bA268
bB268
CH2
p-MeO-Bzl
Me
H
Et
H
H


bA269
bB269
CH2
p-MeO-Bzl
Me
H
H
Et
H


bA270
bB270
CH2
p-MeO-Bzl
Me
H
H
H
Et


bA271
bB271
CH2
p-MeO-Bzl
Me
OMe
H
H
H


bA272
bB272
CH2
p-MeO-Bzl
Me
H
OMe
H
H


bA273
bB273
CH2
p-MeO-Bzl
Me
H
H
OMe
H


bA274
bB274
CH2
p-MeO-Bzl
Me
H
H
H
OMe


bA275
bB275
CH2
p-MeO-Bzl
Me
F
H
H
H


bA276
bB276
CH2
p-MeO-Bzl
Me
H
F
H
H


bA277
bB277
CH2
p-MeO-Bzl
Me
H
H
F
H


bA278
bB278
CH2
p-MeO-Bzl
Me
H
H
H
F


bA279
bB279
CH2
i-Pr
Me
Me
H
H
F


bA280
bB280
CH2
i-Pr
Me
H
Me
H
H


bA281
bB281
CH2
i-Pr
Me
H
H
Me
H


bA282
bB282
CH2
i-Pr
Me
H
H
H
Me


bA283
bB283
CH2
i-Pr
Me
Cl
H
H
H


bA284
bB284
CH2
i-Pr
Me
H
Cl
H
H


bA285
bB285
CH2
i-Pr
Me
H
H
Cl
H


bA286
bB286
CH2
i-Pr
Me
H
H
H
Cl


bA287
bB287
CH2
i-Pr
Me
Et
H
H
H


bA288
bB288
CH2
i-Pr
Me
H
Et
H
H


bA289
bB289
CH2
i-Pr
Me
H
H
Et
H


bA290
bB290
CH2
i-Pr
Me
H
H
H
Et


bA291
bB291
CH2
i-Pr
Me
OMe
H
H
H


bA292
bB292
CH2
i-Pr
Me
H
OMe
H
H


bA293
bB293
CH2
i-Pr
Me
H
H
OMe
H


bA294
bB294
CH2
i-Pr
Me
H
H
H
OMe


bA295
bB295
CH2
i-Pr
Me
F
H
H
H


bA296
bB296
CH2
i-Pr
Me
H
F
H
H


bA297
bB297
CH2
i-Pr
Me
H
H
F
H


bA298
bB298
CH2
i-Pr
Me
H
H
H
F


bA299
bB299
CH2
t-Bu
Me
H
H
H
H


bA300
bB300
CH2
t-Bu
Me
Me
H
H
H


bA301
bB301
CH2
t-Bu
Me
M
Me
H
H


bA302
bB302
CH2
t-Bu
Me
H
H
Me
H


bA303
bB303
CH2
t-Bu
Me
H
H
H
Me


bA304
bB304
CH2
t-Bu
Me
Cl
H
H
H


bA305
bB305
CH2
t-Bu
Me
H
Cl
H
H


bA306
bB306
CH2
t-Bu
Me
H
H
Cl
H


bA307
bB307
CH2
t-Bu
Me
H
H
H
Cl


bA308
bB308
CH2
t-Bu
Me
H
H
H
H


bA309
bB309
CH2
t-Bu
Me
Et
H
H
H


bA310
bB310
CH2
t-Bu
Me
H
Et
H
H


bA311
bB311
CH2
t-Bu
Me
H
H
Et
H


bA312
bB312
CH2
t-Bu
Me
H
H
H
Et


bA313
bB313
CH2
t-Bu
Me
OMe
H
H
H


bA314
bB314
CH2
t-Bu
Me
H
OMe
H
H


bA315
bB315
CH2
t-Bu
Me
H
H
OMe
H


bA316
bB316
CH2
t-Bu
Me
H
H
H
OMe


bA317
bB317
CH2
t-Bu
Me
F
H
H
H


bA318
bB318
CH2
t-Bu
Me
H
F
H
H


bA319
bB319
CH2
t-Bu
Me
H
H
F
H


bA320
bB320
CH2
t-Bu
Me
H
H
H
F


bA321
bB321
CH2
Ph
Me
H
H
H
H


bA322
bB322
CH2
Ph
Me
Me
H
H
H


bA323
bB323
CH2
Ph
Me
Me
Me
H
H


bA324
bB324
CH2
Ph
Me
H
H
Me
H


bA325
bB325
CH2
Ph
Me
H
H
H
Me


bA326
bB326
CH2
Ph
Me
Cl
H
H
H


bA327
bB327
CH2
Ph
Me
H
Cl
H
H


bA328
bB328
CH2
Ph
Me
H
H
Cl
H


bA329
bB329
CH2
Ph
Me
H
H
H
Cl


bA330
bB330
CH2
Ph
Me
H
H
H
H


bA331
bB331
CH2
Ph
Me
Et
H
H
H


bA332
bB332
CH2
Ph
Me
H
Et
H
H


bA333
bB333
CH2
Ph
Me
H
H
Et
H


bA334
bB334
CH2
Ph
Me
H
H
H
Et


bA335
bB335
CH2
Ph
Me
OMe
H
H
H


bA336
bB336
CH2
Ph
Me
H
OMe
H
H


bA337
bB337
CH2
Ph
Me
H
H
OMe
H


bA338
bB338
CH2
Ph
Me
H
H
H
OMe


bA339
bB339
CH2
Ph
Me
F
H
H
H


bA340
bB340
CH2
Ph
Me
H
F
H
H


bA341
bB341
CH2
Ph
Me
H
H
F
H


bA342
bB342
CH2
Ph
Me
H
H
H
F


bA343
bB343
CH2CH2
Me
Me
H
H
H
H


bA344
bB344
CH2CH2
Me
Me
Me
H
H
H


bA345
bB345
CH2CH2
Me
Me
H
Me
H
H


bA346
bB346
CH2CH2
Me
Me
H
H
Me
H


bA347
bB347
CH2CH2
Me
Me
H
H
H
Me


bA348
bB348
CH2CH2
Me
Me
Cl
H
H
H


bA349
bB349
CH2CH2
Me
Me
H
Cl
H
H


bA350
bB350
CH2CH2
Me
Me
H
H
Cl
H


bA351
bB351
CH2CH2
Me
Me
H
H
H
Cl


bA352
bB352
CH2CH2
Me
Me
Et
H
H
H


bA353
bB353
CH2CH2
Me
Me
H
Et
H
H


bA354
bB354
CH2CH2
Me
Me
H
H
Et
H


bA355
bB355
CH2CH2
Me
Me
H
H
H
Et


bA356
bB356
CH2CH2
Me
Me
OMe
H
H
H


bA357
bB357
CH2CH2
Me
Me
H
OMe
H
H


bA358
bB358
CH2CH2
Me
Me
H
H
OMe
H


bA359
bB359
CH2CH2
Me
Me
H
H
H
OMe


bA360
bB360
CH2CH2
Me
Me
F
H
H
H


bA361
bB361
CH2CH2
Me
Me
H
F
H
H


bA362
bB362
CH2CH2
Me
Me
H
H
F
H


bA363
bB363
CH2CH2
Me
Me
H
H
H
F


bA364
bB364
CH2CH2
Et
Me
H
H
H
H


bA365
bB365
CH2CH2
Et
Me
Me
H
H
H


bA366
bB366
CH2CH2
Et
Me
H
Me
H
H


bA367
bB367
CH2CH2
Et
Me
H
H
Me
H


bA368
bB368
CH2CH2
Et
Me
H
H
H
Me


bA369
bB369
CH2CH2
Et
Me
Cl
H
H
H


bA370
bB370
CH2CH2
Et
Me
H
Cl
H
H


bA371
bB371
CH2CH2
Et
Me
H
H
Cl
H


bA372
bB372
CH2CH2
Et
Me
H
H
H
Cl


bA373
bB373
CH2CH2
Et
Me
Et
H
H
H


bA374
bB374
CH2CH2
Et
Me
H
Et
H
H


bA375
bB375
CH2CH2
Et
Me
H
H
Et
H


bA376
bB376
CH2CH2
Et
Me
H
H
H
Et


bA377
bB377
CH2CH2
Et
Me
OMe
H
H
H


bA378
bB378
CH2CH2
Et
Me
H
OMe
H
H


bA379
bB379
CH2CH2
Et
Me
H
H
OMe
H


bA380
bB380
CH2CH2
Et
Me
H
H
H
OMe


bA381
bB381
CH2CH2
Et
Me
F
H
H
H


bA382
bB382
CH2CH2
Et
Me
H
F
H
H


bA383
bB383
CH2CH2
Et
Me
H
H
F
H


bA384
bB384
CH2CH2
Et
Me
H
H
H
F


bA385
bB385
CH2CH2
Allyl
Me
H
H
H
H


bA386
bB386
CH2CH2
Allyl
Me
Me
H
H
H


bA387
bB387
CH2CH2
Allyl
Me
H
Me
H
H


bA388
bB388
CH2CH2
Allyl
Me
H
H
Me
H


bA389
bB389
CH2CH2
Allyl
Me
H
H
H
Me


bA390
bB390
CH2CH2
Allyl
Me
Cl
H
H
H


bA391
bB391
CH2CH2
Allyl
Me
H
Cl
H
H


bA392
bB392
CH2CH2
Allyl
Me
H
H
Cl
H


bA393
bB393
CH2CH2
Allyl
Me
H
H
H
Cl


bA394
bB394
CH2CH2
Allyl
Me
Et
H
H
H


bA395
bB395
CH2CH2
Allyl
Me
H
Et
H
H


bA396
bB396
CH2CH2
Allyl
Me
H
H
Et
H


bA397
bB397
CH2CH2
Allyl
Me
H
H
H
Et


bA398
bB398
CH2CH2
Allyl
Me
OMe
H
H
H


bA399
bB399
CH2CH2
Allyl
Me
H
OMe
H
H


bA400
bB400
CH2CH2
Allyl
Me
H
H
OMe
H


bA401
bB401
CH2CH2
Allyl
Me
H
H
H
OMe


bA402
bB402
CH2CH2
Allyl
Me
F
H
H
H


bA403
bB403
CH2CH2
Allyl
Me
H
F
H
H


bA404
bB404
CH2CH2
Allyl
Me
H
H
F
H


bA405
bB405
CH2CH2
Allyl
Me
H
H
H
F


bA406
bB406
CH2CH2
Bzl
Me
H
H
H
H


bA407
bB407
CH2CH2
Bzl
Me
Me
H
H
H


bA408
bB408
CH2CH2
Bzl
Me
H
Me
H
H


bA409
bB409
CH2CH2
Bzl
Me
H
H
Me
H


bA410
bB410
CH2CH2
Bzl
Me
H
H
H
Me


bA411
bB411
CH2CH2
Bzl
Me
Cl
H
H
H


bA412
bB412
CH2CH2
Bzl
Me
H
Cl
H
H


bA413
bB413
CH2CH2
Bzl
Me
H
H
Cl
H


bA414
bB414
CH2CH2
Bzl
Me
H
H
H
Cl


bA415
bB415
CH2CH2
Bzl
Me
Et
H
H
H


bA416
bB416
CH2CH2
Bzl
Me
H
Et
H
H


bA417
bB417
CH2CH2
Bzl
Me
H
H
Et
H


bA418
bB418
CH2CH2
Bzl
Me
H
H
H
Et


bA419
bB419
CH2CH2
Bzl
Me
OMe
H
H
H


bA420
bB420
CH2CH2
Bzl
Me
H
OMe
H
H


bA421
bB421
CH2CH2
Bzl
Me
H
H
OMe
H


bA422
bB422
CH2CH2
Bzl
Me
H
H
H
OMe


bA423
bB423
CH2CH2
Bzl
Me
F
H
H
H


bA424
bB424
CH2CH2
Bzl
Me
H
F
H
H


bA425
bB425
CH2CH2
Bzl
Me
H
H
F
H


bA426
bB426
CH2CH2
Bzl
Me
H
H
H
F


bA427
bB427
CH2CH2
p-MeO-Bzl
Me
H
H
H
H


bA428
bB428
CH2CH2
p-MeO-Bzl
Me
Me
H
H
H


bA429
bB429
CH2CH2
p-MeO-Bzl
Me
H
Me
H
H


bA430
bB430
CH2CH2
p-MeO-Bzl
Me
H
H
Me
H


bA431
bB431
CH2CH2
p-MeO-Bzl
Me
H
H
H
Me


bA432
bB432
CH2CH2
p-MeO-Bzl
Me
Cl
H
H
H


bA433
bB433
CH2CH2
p-MeO-Bzl
Me
H
Cl
H
H


bA434
bB434
CH2CH2
p-MeO-Bzl
Me
H
H
Cl
H


bA435
bB435
CH2CH2
p-MeO-Bzl
Me
H
H
H
Cl


bA436
bB436
CH2CH2
p-MeO-Bzl
Me
Et
H
H
H


bA437
bB437
CH2CH2
p-MeO-Bzl
Me
H
Et
H
H


bA438
bB438
CH2CH2
p-MeO-Bzl
Me
H
H
Et
H


bA439
bB439
CH2CH2
p-MeO-Bzl
Me
H
H
H
Et


bA440
bB440
CH2CH2
p-MeO-Bzl
Me
OMe
H
H
H


bA441
bB441
CH2CH2
p-MeO-Bzl
Me
H
OMe
H
H


bA442
bB442
CH2CH2
p-MeO-Bzl
Me
H
H
OMe
H


bA443
bB443
CH2CH2
p-MeO-Bzl
Me
H
H
H
OMe


bA444
bB444
CH2CH2
p-MeO-Bzl
Me
F
H
H
H


bA445
bB445
CH2CH2
p-MeO-Bzl
Me
H
F
H
H


bA446
bB446
CH2CH2
p-MeO-Bzl
Me
H
H
F
H


bA447
bB447
CH2CH2
p-MeO-Bzl
Me
H
H
H
F


bA448
bB448
CH2CH2
i-Pr
Me
Me
H
H
F


bA449
bB449
CH2CH2
i-Pr
Me
H
Me
H
H


bA450
bB450
CH2CH2
i-Pr
Me
H
H
Me
H


bA451
bB451
CH2CH2
i-Pr
Me
H
H
H
Me


bA452
bB452
CH2CH2
i-Pr
Me
Cl
H
H
H


bA453
bB453
CH2CH2
i-Pr
Me
H
Cl
H
H


bA454
bB454
CH2CH2
i-Pr
Me
H
H
Cl
H


bA455
bB455
CH2CH2
i-Pr
Me
H
H
H
Cl


bA456
bB456
CH2CH2
i-Pr
Me
Et
H
H
H


bA457
bB457
CH2CH2
i-Pr
Me
H
Et
H
H


bA458
bB458
CH2CH2
i-Pr
Me
H
H
Et
H


bA459
bB459
CH2CH2
i-Pr
Me
H
H
H
Et


bA460
bB460
CH2CH2
i-Pr
Me
OMe
H
H
H


bA461
bB461
CH2CH2
i-Pr
Me
H
OMe
H
H


bA462
bB462
CH2CH2
i-Pr
Me
H
H
OMe
H


bA463
bB463
CH2CH2
i-Pr
Me
H
H
H
OMe


bA464
bB464
CH2CH2
i-Pr
Me
F
H
H
H


bA465
bB465
CH2CH2
i-Pr
Me
H
F
H
H


bA466
bB466
CH2CH2
i-Pr
Me
H
H
F
H


bA467
bB467
CH2CH2
i-Pr
Me
H
H
H
F


bA468
bB468
CH2CH2
t-Bu
Me
H
H
H
H


bA469
bB469
CH2CH2
t-Bu
Me
Me
H
H
H


bA470
bB470
CH2CH2
t-Bu
Me
Me
Me
H
H


bA471
bB471
CH2CH2
t-Bu
Me
H
H
Me
H


bA472
bB472
CH2CH2
t-Bu
Me
H
H
H
Me


bA473
bB473
CH2CH2
t-Bu
Me
Cl
H
H
H


bA474
bB474
CH2CH2
t-Bu
Me
H
Cl
H
H


bA475
bB475
CH2CH2
t-Bu
Me
H
H
Cl
H


bA476
bB476
CH2CH2
t-Bu
Me
H
H
H
Cl


bA477
bB477
CH2CH2
t-Bu
Me
H
H
H
H


bA478
bB478
CH2CH2
t-Bu
Me
Et
H
H
H


bA479
bB479
CH2CH2
t-Bu
Me
H
Et
H
H


bA480
bB480
CH2CH2
t-Bu
Me
H
H
Et
H


bA481
bB481
CH2CH2
t-Bu
Me
H
H
H
Et


bA482
bB482
CH2CH2
t-Bu
Me
OMe
H
H
H


bA483
bB483
CH2CH2
t-Bu
Me
H
OMe
H
H


bA484
bB484
CH2CH2
t-Bu
Me
H
H
OMe
H


bA485
bB485
CH2CH2
t-Bu
Me
H
H
H
OMe


bA486
bB486
CH2CH2
t-Bu
Me
F
H
H
H


bA487
bB487
CH2CH2
t-Bu
Me
H
F
H
H


bA488
bB488
CH2CH2
t-Bu
Me
H
H
F
H


bA489
bB489
CH2CH2
t-Bu
Me
H
H
H
F


bA490
bB490
CH2CH2
Ph
Me
H
H
H
H


bA491
bB491
CH2CH2
Ph
Me
Me
H
H
H


bA492
bB492
CH2CH2
Ph
Me
Me
Me
H
H


bA493
bB493
CH2CH2
Ph
Me
H
H
Me
H


bA494
bB494
CH2CH2
Ph
Me
H
H
H
Me


bA495
bB495
CH2CH2
Ph
Me
Cl
H
H
H


bA496
bB496
CH2CH2
Ph
Me
H
Cl
H
H


bA497
bB497
CH2CH2
Ph
Me
H
H
Cl
H


bA498
bB498
CH2CH2
Ph
Me
H
H
H
Cl


bA499
bB499
CH2CH2
Ph
Me
H
H
H
H


bA500
bB500
CH2CH2
Ph
Me
Et
H
H
H


bA501
bB501
CH2CH2
Ph
Me
H
Et
H
H


bA502
bB502
CH2CH2
Ph
Me
H
H
Et
H


bA503
bB503
CH2CH2
Ph
Me
H
H
H
Et


bA504
bB504
CH2CH2
Ph
Me
OMe
H
H
H


bA505
bB505
CH2CH2
Ph
Me
H
OMe
H
H


bA506
bB506
CH2CH2
Ph
Me
H
H
OMe
H


bA507
bB507
CH2CH2
Ph
Me
H
H
H
OMe


bA508
bB508
CH2CH2
Ph
Me
F
H
H
H


bA509
bB509
CH2CH2
Ph
Me
H
F
H
H


bA510
bB510
CH2CH2
Ph
Me
H
H
F
H


bA511
bB511
CH2CH2
Ph
Me
H
H
H
F


bA512
bB512
OCH2
Me
Me
H
H
H
H


bA513
bB513
OCH2
Me
Me
Me
H
H
H


bA514
bB514
OCH2
Me
Me
H
Me
H
H


bA515
bB515
OCH2
Me
Me
H
H
Me
H


bA516
bB516
OCH2
Me
Me
H
H
H
Me


bA517
bB517
OCH2
Me
Me
Cl
H
H
H


bA518
bB518
OCH2
Me
Me
H
Cl
H
H


bA519
bB519
OCH2
Me
Me
H
H
Cl
H


bA520
bB520
OCH2
Me
Me
H
H
H
Cl


bA521
bB521
OCH2
Me
Me
Et
H
H
H


bA522
bB522
OCH2
Me
Me
H
Et
H
H


bA523
bB523
OCH2
Me
Me
H
H
Et
H


bA524
bB524
OCH2
Me
Me
H
H
H
Et


bA525
bB525
OCH2
Me
Me
OMe
H
H
H


bA526
bB526
OCH2
Me
Me
H
OMe
H
H


bA527
bB527
OCH2
Me
Me
H
H
OMe
H


bA528
bB528
OCH2
Me
Me
H
H
H
OMe


bA529
bB529
OCH2
Me
Me
F
H
H
H


bA530
bB530
OCH2
Me
Me
H
F
H
H


bA531
bB531
OCH2
Me
Me
H
H
F
H


bA532
bB532
OCH2
Me
Me
H
H
H
F


bA533
bB533
OCH2
Et
Me
H
H
H
H


bA534
bB534
OCH2
Et
Me
Me
H
H
H


bA535
bB535
OCH2
Et
Me
H
Me
H
H


bA536
bB536
OCH2
Et
Me
H
H
Me
H


bA537
bB537
OCH2
Et
Me
H
H
H
Me


bA538
bB538
OCH2
Et
Me
Cl
H
H
H


bA539
bB539
OCH2
Et
Me
H
Cl
H
H


bA540
bB540
OCH2
Et
Me
H
H
Cl
H


bA541
bB541
OCH2
Et
Me
H
H
H
Cl


bA542
bB542
OCH2
Et
Me
Et
H
H
H


bA543
bB543
OCH2
Et
Me
H
Et
H
H


bA544
bB544
OCH2
Et
Me
H
H
Et
H


bA545
bB545
OCH2
Et
Me
H
H
H
Et


bA546
bB546
OCH2
Et
Me
OMe
H
H
H


bA547
bB547
OCH2
Et
Me
H
OMe
H
H


bA548
bB548
OCH2
Et
Me
H
H
OMe
H


bA549
bB549
OCH2
Et
Me
H
H
H
OMe


bA550
bB550
OCH2
Et
Me
F
H
H
H


bA551
bB551
OCH2
Et
Me
H
F
H
H


bA552
bB552
OCH2
Et
Me
H
H
F
H


bA553
bB553
OCH2
Et
Me
H
H
H
F


bA554
bB554
OCH2
Allyl
Me
H
H
H
H


bA555
bB555
OCH2
Allyl
Me
Me
H
H
H


bA556
bB556
OCH2
Allyl
Me
H
Me
H
H


bA557
bB557
OCH2
Allyl
Me
H
H
Me
H


bA558
bB558
OCH2
Allyl
Me
H
H
H
Me


bA559
bB559
OCH2
Allyl
Me
Cl
H
H
H


bA560
bB560
OCH2
Allyl
Me
H
Cl
H
H


bA561
bB561
OCH2
Allyl
Me
H
H
Cl
H


bA562
bB562
OCH2
Allyl
Me
H
H
H
Cl


bA563
bB563
OCH2
Allyl
Me
Et
H
H
H


bA564
bB564
OCH2
Allyl
Me
H
Et
H
H


bA565
bB565
OCH2
Allyl
Me
H
H
Et
H


bA566
bB566
OCH2
Allyl
Me
H
H
H
Et


bA567
bB567
OCH2
Allyl
Me
OMe
H
H
H


bA568
bB568
OCH2
Allyl
Me
H
OMe
H
H


bA569
bB569
OCH2
Allyl
Me
H
H
OMe
H


bA570
bB570
OCH2
Allyl
Me
H
H
H
OMe


bA571
bB571
OCH2
Allyl
Me
F
H
H
H


bA572
bB572
OCH2
Allyl
Me
H
F
H
H


bA573
bB573
OCH2
Allyl
Me
H
H
F
H


bA574
bB574
OCH2
Allyl
Me
H
H
H
F


bA575
bB575
OCH2
Bzl
Me
H
H
H
H


bA576
bB576
OCH2
Bzl
Me
Me
H
H
H


bA577
bB577
OCH2
Bzl
Me
H
Me
H
H


bA578
bB578
OCH2
Bzl
Me
H
H
Me
H


bA579
bB579
OCH2
Bzl
Me
H
H
H
Me


bA580
bB580
OCH2
Bzl
Me
Cl
H
H
H


bA581
bB581
OCH2
Bzl
Me
H
Cl
H
H


bA582
bB582
OCH2
Bzl
Me
H
H
Ci
H


bA583
bB583
OCH2
Bzl
Me
H
H
H
Cl


bA584
bB584
OCH2
Bzl
Me
Et
H
H
H


bA585
bB585
OCH2
Bzl
Me
H
Et
H
H


bA586
bB586
OCH2
Bzl
Me
H
H
Et
H


bA587
bB587
OCH2
Bzl
Me
H
H
H
Et


bA588
bB588
OCH2
Bzl
Me
OMe
H
H
H


bA589
bB589
OCH2
Bzl
Me
H
OMe
H
H


bA590
bB590
OCH2
Bzl
Me
H
H
OMe
H


bA591
bB591
OCH2
Bzl
Me
H
H
H
OMe


bA592
bB592
OCH2
Bzl
Me
F
H
H
H


bA593
bB593
OCH2
Bzl
Me
H
F
H
H


bA594
bB594
OCH2
Bzl
Me
H
H
F
H


bA595
bB595
OCH2
Bzl
Me
H
H
H
F


bA596
bB596
OCH2
p-MeO-Bzl
Me
H
H
H
H


bA597
bB597
OCH2
p-MeO-Bzl
Me
Me
H
H
H


bA598
bB598
OCH2
p-MeO-Bzl
Me
H
Me
H
H


bA599
bB599
OCH2
p-MeO-Bzl
Me
H
H
Me
H


bA600
bB600
OCH2
p-MeO-Bzl
Me
H
H
H
Me


bA601
bB601
OCH2
p-MeO-Bzl
Me
Cl
H
H
H


bA602
bB602
OCH2
p-MeO-Bzl
Me
H
Cl
H
H


bA603
bB603
OCH2
p-MeO-Bzl
Me
H
H
Cl
H


bA604
bB604
OCH2
p-MeO-Bzl
Me
H
H
H
Cl


bA605
bB605
OCH2
p-MeO-Bzl
Me
Et
H
H
H


bA606
bB606
OCH2
p-MeO-Bzl
Me
H
Et
H
H


bA607
bB607
OCH2
p-MeO-Bzl
Me
H
H
Et
H


bA608
bB608
OCH2
p-MeO-Bzl
Me
H
H
H
Et


bA609
bB609
OCH2
p-MeO-Bzl
Me
OMe
H
H
H


bA610
bB610
OCH2
p-MeO-Bzl
Me
H
OMe
H
H


bA611
bB611
OCH2
p-MeO-Bzl
Me
H
H
OMe
H


bA612
bB612
OCH2
p-MeO-Bzl
Me
H
H
H
OMe


bA613
bB613
OCH2
p-MeO-Bzl
Me
F
H
H
H


bA614
bB614
OCH2
p-MeO-Bzl
Me
H
F
H
H


bA615
bB615
OCH2
p-MeO-Bzl
Me
H
H
F
H


bA616
bB616
OCH2
p-MeO-Bzl
Me
H
H
H
F


bA617
bB617
OCH2
i-Pr
Me
Me
H
H
F


bA618
bB618
OCH2
i-Pr
Me
H
Me
H
H


bA619
bB619
OCH2
i-Pr
Me
H
H
Me
H


bA620
bB620
OCH2
i-Pr
Me
H
H
H
Me


bA621
bB621
OCH2
i-Pr
Me
Cl
H
H
H


bA622
bB622
OCH2
i-Pr
Me
H
Cl
H
H


bA623
bB623
OCH2
i-Pr
Me
H
H
Cl
H


bA624
bB624
OCH2
i-Pr
Me
H
H
H
Cl


bA625
bB625
OCH2
i-Pr
Me
Et
H
H
H


bA626
bB626
OCH2
i-Pr
Me
H
Et
H
H


bA627
bB627
OCH2
i-Pr
Me
H
H
Et
H


bA628
bB628
OCH2
i-Pr
Me
H
H
H
Et


bA629
bB629
OCH2
i-Pr
Me
OMe
H
H
H


bA630
bB630
OCH2
i-Pr
Me
H
OMe
H
H


bA631
bB631
OCH2
i-Pr
Me
H
H
OMe
H


bA632
bB632
OCH2
i-Pr
Me
H
H
H
OMe


bA633
bB633
OCH2
i-Pr
Me
F
H
H
H


bA634
bB634
OCH2
i-Pr
Me
H
F
H
H


bA635
bB635
OCH2
i-Pr
Me
H
H
F
H


bA636
bB636
OCH2
i-Pr
Me
H
H
H
F


bA637
bB637
OCH2
t-Bu
Me
H
H
H
H


bA638
bB638
OCH2
t-Bu
Me
Me
H
H
H


bA639
bB639
OCH2
t-Bu
Me
Me
Me
H
H


bA640
bB640
OCH2
t-Bu
Me
H
H
Me
H


bA641
bB641
OCH2
t-Bu
Me
H
H
H
Me


bA642
bB642
OCH2
t-Bu
Me
Cl
H
H
H


bA643
bB643
OCH2
t-Bu
Me
H
Cl
H
H


bA644
bB644
OCH2
t-Bu
Me
H
H
Cl
H


bA645
bB645
OCH2
t-Bu
Me
H
H
H
Cl


bA646
bB646
OCH2
t-Bu
Me
H
H
H
H


bA647
bB647
OCH2
t-Bu
Me
Et
H
H
H


bA648
bB648
OCH2
t-Bu
Me
H
Et
H
H


bA649
bB649
OCH2
t-Bu
Me
H
H
Et
H


bA650
bB650
OCH2
t-Bu
Me
H
H
H
Et


bA651
bB651
OCH2
t-Bu
Me
OMe
H
H
H


bA652
bB652
OCH2
t-Bu
Me
H
OMe
H
H


bA653
bB653
OCH2
t-Bu
Me
H
H
OMe
H


bA654
bB654
OCH2
t-Bu
Me
H
H
H
OMe


bA655
bB655
OCH2
t-Bu
Me
F
H
H
H


bA656
bB656
OCH2
t-Bu
Me
H
F
H
H


bA657
bB657
OCH2
t-Bu
Me
H
H
F
H


bA658
bB658
OCH2
t-Bu
Me
H
H
H
F


bA659
bB659
OCH2
Ph
Me
H
H
H
H


bA660
bB660
OCH2
Ph
Me
Me
H
H
H


bA661
bB661
OCH2
Ph
Me
Me
Me
H
H


bA662
bB662
OCH2
Ph
Me
H
H
Me
H


bA663
bB663
OCH2
Ph
Me
H
H
H
Me


bA664
bB664
OCH2
Ph
Me
Cl
H
H
H


bA665
bB665
OCH2
Ph
Me
H
Cl
H
H


bA666
bB666
OCH2
Ph
Me
H
H
Cl
H


bA667
bB667
OCH2
Ph
Me
H
H
H
Cl


bA668
bB668
OCH2
Ph
Me
H
H
H
H


bA669
bB669
OCH2
Ph
Me
Et
H
H
H


bA670
bB670
OCH2
Ph
Me
H
Et
H
H


bA671
bB671
OCH2
Ph
Me
H
H
Et
H


bA672
bB672
OCH2
Ph
Me
H
H
H
Et


bA673
bB673
OCH2
Ph
Me
OMe
H
H
H


bA674
bB674
OCH2
Ph
Me
H
OMe
H
H


bA675
bB675
OCH2
Ph
Me
H
H
OMe
H


bA676
bB676
OCH2
Ph
Me
H
H
H
OMe


bA677
bB677
OCH2
Ph
Me
F
H
H
H


bA678
bB678
OCH2
Ph
Me
H
F
H
H


bA679
bB679
OCH2
Ph
Me
H
H
F
H


bA680
bB680
OCH2
Ph
Me
H
H
H
F





Physical data on compounds from table 2:


Compound No.: bA214: Ref (1), Rt = 6.7, n-hexane/isopropanol = 92:8 (v/v), flow rate = 0.5 ml/min,


Compound No.: bA218: Ref (1,4), Rt = 13.9, n-hexane/isopropanol = 90:10 (v/v), Flow rate = 1.0 ml/min,


Compound No.: bA237: Ref (3), Rt = 17.4, n-hexane/isopropanol = 99:1 (v/v), flow rate = 0.3 ml/min,


Compound No.: bB237: Ref (3), Rt = 19.9, n-hexane/isopropanol = 99:1 (v/v), flow rate = 0.3 ml/min,


Compound No.: bA239: Ref (3,4), Rt = 12.3, n-hexane/isopropanol = 90:10 (v/v), flow rate = 1.0 ml/min,


Compound No.: bA406: Ref (1), Rt = 7.1, n-hexane/isopropanol = 96:4 (v/v), flow rate = 0.5 ml/min.

## Claims

1. A process for preparing optically active cyclic amines of the formula (I) or salts thereof




in which
A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring which has from 3 to 30 ring atoms, and may be further substituted in addition to the R1 and NH—R0 radicals,
R0, independently of R, is a (C1-C6)alkyl, (C3-C6)alkenyl or (C3-C1)alkynyl radical, where each of the three latter radicals may be unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, (C1-C4)oyloxy, (C1-C4)haloalkanoyloxy, aryl, aryloxy, amyl, aroyloxy and heterocyclyl, where each of the latter 5 radicals is unsubstituted or substituted, or
(C3-C9)cycloalkyl, (C4-C9)cycloalkenyl, aryl or heterocyclyl, where each of the latter 4 radicals is unsubstituted or substituted,

R, independently of R0, is
(C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkylthio, aryl which is unsubstituted or substituted, and heteroaryl which is unsubstituted or substituted, or
aryl which is unsubstituted or substituted, or
heteroaryl which is unsubstituted or substituted,
or

R0 and A form a ring B1 and, together with the NH group and the carbon atom which is designated with an asterisk (*) and is bonded to the NH group, are a heterocyclic ring which has from 4 to 30 ring atoms, and is optionally additionally further substituted and which optionally contains 1 or 2 further heteroatoms from the group of N, O and S,
or

R and A form a ring B2 and, together with the carbon atom which is designated with an asterisk (*) and is bonded to R, are a carbocyclic or heterocyclic ring which has from 3 to 30 ring atoms, and is optionally additionally further substituted, and which, in the case of a heterocyclic ring, contains 1, 2 or 3 further heteroatoms from the group of N, O and S,
or

R0 and R form a ring B3 and, together with the NH group and the carbon atoms designated with an asterisk (*) in each case, are a heterocyclic ring which has from 4 to 30 ring atoms, and is optionally additionally further substituted and which optionally contains 1 or 2 further heteroatoms from the group of N, O and S,
or

R0 and R and, if appropriate, A may simultaneously form two or more of the rings B1, B2 and B3 mentioned,

where R and the NH—R0 group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the stereochemical configuration on these carbon atoms is different from the racemic configuration, which comprises converting an imine of the formula (II) or a salt thereof



where A, R0 and R are each as defined in formula (I) and the compound of the formula (II), with regard to the ring carbon atom marked with an asterisk (*), is present in the form of a racemic mixture or in the form of a mixture with any other isomeric ratio of the stereoisomers in question,

in the presence of hydrogen or a hydrogen donor and a nonenzymatic catalyst which comprises a catalytically active optically active complex of one or more transition metals from the group of ruthenium, rhodium, palladium, iridium, osmium, platinum, iron, nickel and samarium, with organic ligands, to the compound of the formula (I).

2. The process as claimed in claim 1, wherein the compounds (I) or salts thereof with cis configuration on the two chiral centers designated with an asterisk (*) in each case are obtained with a selectivity of from 60 to 100% in comparison to the trans configuration, one enantiomer of the cis compound being obtained with an enantioselectivity of in each case more than 20% ee based on the total content of enantiomers of the cis compound.

3. The process as claimed in claim 1, wherein compounds of the formula (Ia) or salts thereof are prepared




in which
A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring having from 3 to 30 ring atoms and, in the case of a heterocyclic ring which has from 1 to 3 heterocyclic ring atoms from the group of N, O and S and, in addition to the R1 and NH—R0 radicals is unsubstituted or further substituted by one or more radicals selected from the group consisting of halogen, hydroxy,
amino, cyano, nitro, (C1-C4)alkyl, (C3-C9)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl, aryl and heterocyclyl, where each of the latter 8 radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C3-C9)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkylthio and, in the case of cyclic radicals, also (C1-C4)alkyl and (C1-C4)haloalkyl,

R0 independently of R1, is a (C1-C6)alkyl, (C2-C6)alkenyl or (C3-C6)alkynyl radical, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, (C1-C4)alkanoyloxy, (C1-C4)haloalkanoyloxy, aryl, aryloxy, aroyl, aroyloxy and heterocyclyl, where each of the latter 5 radicals is unsubstituted or substituted,
or (C3-C9)cycloalkyl, (C4-C9)cycloalkenyl, aryl or heterocyclyl, where each of the latter 4 radicals is unsubstituted or substituted,

R1, independently of R0, is
(C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy and (C1-C4)alkylthio,
or aryl or heterocyclyl, where each of the 2 latter radicals is unsubstituted or substituted,


where the substituents R1 and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound (Ia) is present in the form of a stereochemically pure compound of the formula (Ia-A) or (Ia-B)




in which the general radicals are each as defined in formula (Ia), or in the form of an isomer mixture of the compounds of the formulae (Ia-A) and (Ia-B) in an isomer ratio other than the ratio of 1:1.

4. The process as claimed in claim 1, wherein compounds of the formula (Ib) or salts thereof are prepared




in which
A1 is a direct bond or a group of the formula (CR6R7)n in which n is from 1 to 6 and R6 and R7 are each independently, or, in the case that n is greater than 1, the R6 and R7 radicals are in each case independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, (C1-C4)alkoxy or (C1-C4)haloalkoxy, where individual CR6R7 groups may be replaced by heteroatoms from the group of O and S,
R0, independently of R1, is a (C1-C6)alkyl or (C2-C6)alkenyl radical,
where each of the two latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkylthio, (C1-C4)alkanoyloxy, (C1-C4)haloalkanoyloxy, aryl, aryloxy, aroyl, aroyloxy and heterocyclyl, where each of the latter 5 radicals is unsubstituted or substituted,
or (C3-C9)cycloalkyl, (C4-C9)cycloalkenyl, aryl or heterocyclyl, where each of the latter 4 radicals is unsubstituted or substituted,

R1, independently of R0, is
(C1-C6)alkyl which is unsubstitutcd or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)allylthio and aryl which is optionally substituted, and
heterocyclyl which is optionally substituted, or
aryl which is optionally substituted, or
heterocyclyl which is optionally substituted,
and

R2 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN,
R3 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN,
R4 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN and
R5 is H, (C1-C4)alkyl, (C1-C3)haloalkyl, halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy or CN,

where the substituents R1 and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound is present in the form of a stereochemically pure compound of the formula (Ib-A) or (Ib-B)




in which the general radicals are each as defined in formula (Ib), or in the form of an isomer mixture of the compounds of the formulae (Ib-A) and (Ib-B) in an isomer ratio other than the ratio of 1:1.

5. The process as claimed in claim 1, wherein the reaction is carried out in the presence of an inert organic solvent or in substance.

6. The process as claimed in claim 1, wherein the reaction is carried out as a catalytic hydrogenation.

7. The process as claimed in claim 1, wherein the reaction is carried out as a catalytic transfer hydrogenation.

8. The process as claimed in claim 7, wherein the reaction is carried out with formic acid as a hydrogen donor in the presence of a tertiary amine.

9. The process as claimed in claim 1, wherein the imine of the formula (II) is prepared in situ from the corresponding ketone and an amine of the formula and reduced.

10. The process as claimed in claim 2, wherein the compounds (I) or salts thereof with cis configuration on the two chiral centers designated with an asterisk (*) in each case are obtained with one enantiomer of the cis compound being obtained with an enantioselectivity of in each case more than 50% ee based on the total content of enantiomers of the cis compound.