Enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in the presence of a chiral iridium (p,s)-ligand catalyst

Abstract

The invention relates to a process for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines comprising enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines in presence of a chiral iridium (P,S)-ligand catalyst.

Description

[0001] BCS233018 Foreign Countries FP / Ho 2024-01-24 - 1 - Enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in the presence of a chiral iridium (P,S)-ligand catalyst The invention relates to a process for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines by enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines in presence of a 5 chiral iridium complex having a specific chiral chelating ligand comprising at least one phosphorus atom and at least one sulphur atom that both bind to the iridium atom - in the following also referred to as “chiral (P,S)- ligand”. 4-Substituted 1,2,3,4-tetrahydroquinolines are versatile intermediates in the synthesis of N-indanyl heteroaryl carboxamide fungicides, including the recently launched pyrazole carboxamide fungicide inpyrfluxam (EP 0 10 654464, WO 2015 / 141564, WO 2019 / 185541, WO 2021 / 058457, WO 2021 / 058458). They can be obtained by hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines. WO 2015 / 141564 describes a process for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines, which process comprises the hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines in presence of a transition metal catalyst having an optically active ligand. The reported asymmetric 15 hydrogenation of 4-substituted NH-dihydroquinolines proceeded with moderate conversion rates (up to 62.6%) and enantioselectivity (up to 71.3% ee), whereas hydrogenation of N-acetyl-dihydroquinolines gave even poorer conversion (up to 14%) and enantioselectivity (up to 31% ee). WO 2019 / 185541, WO 2021 / 058457 and WO 2021 / 058458 disclose enantioselective hydrogenation of 4- substituted 1,2-dihydroquinolines in presence of a specific chiral iridium (P,N)-ligand catalyst which provides 20 improved conversion rates and enantioselectivity. The chiral iridium (P,N)-ligand catalysts show excellent catalytic activity. However, synthesis of the respective chiral iridium (P,N)-ligand catalysts is complex and recovery and recycling of the spent catalyst proved to be difficult. Hence, there is need for a process for enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines that provides advantages over the processes known from the prior art. It is an object of the present invention 25 to provide such process, in particular a process that provides the desired products with high conversion rates and enantioselectivity and allows the use of catalysts that are accessible via less complex synthesis routes and / or allow for easy recovery and recycling. The object described above is achieved by the process according to the invention, i.e. a process for preparing a compound of formula (Ia) or (Ib) BCS233018 FC -2- , wherein R1is selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C6-C14-aryl, and C6-C14-aryl-C1-C4-alkyl, wherein the C1-C6-alkyl, C3-C6-cycloalkyl and the C1-C6-alkoxy in the C1-C6-alkoxy-C1-C6-alkyl moiety, are unsubstituted or substituted by 1 to 3 substituents independently from each other selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents independently from each other selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- haloalkyl, and C1-C4-haloalkoxy, and wherein the C6-C14-aryl and the C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety in each case is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4- haloalkoxy, R2and R3are the same and are selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6- haloalkyl and C1-C6-alkoxy-C1-C6-alkyl, or R2and R3together with the carbon which they are bound to, form a C3-C6-cycloalkyl ring, R4is selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6- cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, 9-flurorenylmethyleneoxy, C6-C14-aryl, C6-C14- aryloxy, C6-C14-aryl-C1-C4-alkyloxy and C6-C14-aryl-C1-C4-alkyl, BCS233018 FC -3- wherein the C6-C14-aryl as such or as part of a composite substituent is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, n is 0, 1, 2, 3 or 4, each substituent R5, if present, is independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxyl, amino and –C(=O)-C1-C6-alkyl, comprising enantioselective hydrogenation of a compound of formula (II) , wherein the substituents R1, R2, R3, R4, R5and the integer n are each as defined for the compound of formula (Ia) or (Ib), in presence of a chiral iridium catalyst, characterized in that the chiral iridium catalyst comprises a chiral ligand of formula (IIIa) or (IIIb) wherein R6is C6-C14-aryl, which is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, R7is selected from the group consisting of phenyl, naphtyl and anthracenyl, BCS233018 FC -4- wherein the phenyl is substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, and the naphtyl and anthracenyl each are unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, each R8is C6-C14-aryl, which is substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, and R9is selected from the group consisting of C1-C6-alkyl, C3-C8-cycloalkyl and C6-C14-aryl, wherein the C1-C6-alkyl and C3-C8-cycloalkyl are unsubstituted or substituted by 1 to 3 substituents independently from each other selected from the group consisting of halogen, C1-C4- alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents independently from each other selected from halogen, C1- C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1- C4-alkoxy and C1-C4-haloalkoxy, or R9is carrier material selected from the group consisting of polyether, polystyrene, silica and alumina. Surprisingly, optically active 4-substituted 1,2,3,4-tetrahydroquinolines of formulae (Ia) and (Ib) can be prepared in high yields and enantioselectivity by enantioselective hydrogenation of the corresponding 4- substituted 1,2-dihydroquinolines of formula (II) in presence of the specific chiral iridium (P,S)-ligand catalysts mentioned above. Synthesis of said catalysts requires less steps than the catalysts known from WO 2019 / 185541, WO 2021 / 058457 and WO 2021 / 058458, and they can be bound to a solid carrier via the ether functionality to provide a heterogeneous catalyst system that can be easily separated from the product mixture and recycled. The chiral iridium (P,S)-ligand catalysts used in the process according to the invention and their synthesis have been either explicitly disclosed by J. Margalef et al. in Chem. Eur. J.2014, 20, 12201 – 12214, or are close analogues thereof. While chiral iridium (P,S)-ligand catalysts known from said reference comprising a (P,S)-ligand of formula (IIIa) or (IIIb), wherein R7is tert-butyl or unsubstituted phenyl and / or R8is unsubstituted phenyl, provide unsatisfactory conversion rates and / or enatioselectivities in the enantioselective BCS233018 FC -5- hydrogenation of 4-substituted 1,2-dihydroquinolines of formula (II), surprisingly good conversion rates and enatioselectivities are achieved by conducting the hydrogenation in the presence of the chiral iridium (P,S)- ligand catalysts comprising a (P,S)-ligand of formula (IIIa) or (IIIb), wherein R7is substituted phenyl, naphthyl or anthracenyl and R8is substituted C6-C14-aryl, i.e. both residues, R7and R8are sterically highly demanding. Nothing in J. Margalef et al. points towards this specific substitution pattern. Definitions In the definitions of the symbols given in the above formulae, collective terms were used, which are generally representative of the following substituents: Halogen: fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine. Alkyl: saturated, straight-chain or branched hydrocarbyl substituents having 1 to 6, preferably 1 to 4 carbon atoms, for example (but not limited to) C1-C6-alkyl such as methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert- butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1- dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3- dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1- methylpropyl and 1-ethyl-2-methylpropyl. Particularly, said group is a C1-C4-alkyl group, e.g. a methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or 1,1- dimethylethyl (tert-butyl) group. This definition also applies to alkyl as part of a composite substituent, for example C3-C6-cycloalkyl-C1-C4-alkyl, C6-C14-aryl-C1-C4-alkyl etc., unless defined elsewhere. Alkenyl: unsaturated, straight-chain or branched hydrocarbyl substituents having 2 to 6, preferably 2 to 4 carbon atoms and one double bond in any position, for example (but not limited to) C2-C6-alkenyl such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-l-enyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1- methylprop-1-enyl, (Z)-1-methylprop-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-l-enyl, (Z)-pent-l-enyl, 3- methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3- enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1- methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2- methylbut-1-enyl, (Z)-2- methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1- methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1- enyl, 1-propylvinyl, 1- isopropylvinyl, (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, hex-5- enyl, (E)-hex-4- enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)- BCS233018 FC -6- hex-l-enyl, (Z)-hex-l-enyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1- methylpent-4- enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3- methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)- 2-methylpent-3-enyl, (E)-1- methylpent-3-enyl, (Z)-1 -methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4- methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2- methylpent-2-enyl, (Z)-2- 5 methylpent-2-enyl, (E)-1 -methylpent-2-enyl, (Z)-1- methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4- methylpent-1-enyl, (E)-3- methylpent-1-enyl, (Z)-3-methylpent-1 -enyl, (E)-2-methylpent-1 -enyl, (Z)-2- methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut- 3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl,10 (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2- enyl, 2-isopropylprop-2- enyl, 1 -isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)- 2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2- isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1- enyl, (Z)-1- isopropylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5- dienyl or methylhexadienyl. Particularly, said group is vinyl or allyl. This definition also applies to alkenyl as 15 part of a composite substituent unless defined elsewhere. Alkynyl: straight-chain or branched hydrocarbyl substituents having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one triple bond in any position, for example (but not limited to) C2-C6- alkynyl, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methylprop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1-methylbut-2- 20 ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1- ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl 25 group is ethynyl, prop-1-ynyl, or prop-2-ynyl. This definition also applies to alkynyl as part of a composite substituent unless defined elsewhere. Alkylamino: monoalkylamino or dialkylamino, wherein monoalkylamino represents an amino radical having one alkyl residue with 1 to 6 carbon atoms attached to the nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino, and wherein 30 dialkylamino represents an amino radical having two independently selected alkyl residues with 1 to 6 carbon atoms each attached to the nitrogen atom. Non-limiting examples include N,N-dimethylamino, N,N-diethyl- amino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n- propylamino and N-tert-butyl-N-methylamino. BCS233018 FC -7- Alkoxy: saturated, straight-chain or branched alkoxy substituents having 1 to 6, more preferably 1 to 4 carbon atoms, for example (but not limited to) C1-C6-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2- dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1- ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. This definition also applies to alkoxy as part of a composite substituent unless defined elsewhere. Cycloalkyl: mono- or polycyclic, saturated hydrocarbyl substituents having 3 to 12, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl, cyclohexyl and adamantyl. This definition also applies to cycloalkyl as part of a composite substituent, for example C3- C6-cycloalkyl-C1-C4-alkyl, unless defined elsewhere. Haloalkyl: straight-chain or branched alkyl substituents having 1 to 6, preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) C1-C3-haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2- fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a composite substituent unless defined elsewhere. Haloalkenyl and haloalkynyl are defined analogously to haloalkyl except that, instead of alkyl groups, alkenyl and alkynyl groups are present as part of the substituent. Haloalkoxy: straight-chain or branched alkoxy substituents having 1 to 6, preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) C1-C3-haloalkoxy such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1- fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro- 2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1- trifluoroprop-2-oxy. This definition also applies to haloalkoxy as part of a composite substituent, unless defined elsewhere. BCS233018 FC -8- Aryl: mono-, bi- or tricyclic aromatic or partially aromatic substituents having 6 to 14 carbon atoms, for example (but not limited to) phenyl, naphthyl, tetrahydronapthyl, anthracenyl, indenyl and indanyl. The binding to the superordinate general structure can be carried out via any possible ring member of the aryl residue. Aryl is preferably selected from phenyl, 1-naphthyl, 2-naphthyl, 9-phenantryl und 9-anthracenyl. Phenyl is particularly preferred, unless specified differently elsewhere. The term “enantioselective” as used herein means that one of the two possible enantiomers of the hydrogenation product, namely the enantiomer of the formula (Ia) or the enantiomer of the formula (Ib), is preferably formed. The “enantiomeric excess” or “ee” indicates the degree of enantioselectivity: % ee =^^^^^ ^^^^௧^^^^^ (^^^) ି ^^^^^ ^^^^௧^^^^^ (^^^)^^^^^ ^^^^௧^^^^^ (^^^) ା ^^^^^ ^^^^௧^^^^^ (^^^) ^^ 100% The major by selecting the chiral ligand of the formula (IIIa) or the opposite enantiomer (the ligand of the formula (IIIb)). The process according to the invention is used for preparing the compound of the formula (Ia) or (Ib), preferably (Ia). Preferred are compounds of formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows: R1is C1-C6-alkyl or C6-C14-aryl-C1-C4-alkyl, wherein C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety is unsubstituted or substituted by one to five substituents selected independently from each other from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy R2and R3are the same and are selected from C1-C4-alkyl, R4is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl, n is 0, 1 or 2, and each substituent R5, if present, is independently selected from the group consisting of halogen, C1-C6-alkyl and C1-C6-haloalkyl. More preferred are compounds of formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows: BCS233018 FC -9- R1is C1-C6-alkyl, R2and R3are the same and are selected from C1-C4-alkyl, or R2and R3together with the carbon which they are bound to, form a C3-C6-cycloalkyl ring, R4is C1-C4-alkyl, C1-C4-haloalkyl, phenyl or benzyl, n is 0, 1 or 2, and each substituent R5, if present, is independently selected from the group consisting of halogen and C1-C6- alkyl. Even more preferred are compounds of formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows: R1is C1-C4-alkyl, preferably methyl, ethyl or n-propyl, R2and R3are each methyl, R4is C1-C4-alkyl, n is 0, 1 or 2, and each substituent R5, if present, is independently selected from the group consisting of halogen and C1-C6- alkyl, preferably fluorine. Even more preferred are compounds of formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows: R1is methyl or n-propyl, R2and R3are each methyl, R4is methyl, n is 0 or 1, and R5, if present, is fluorine. BCS233018 FC -10- Most preferred are compounds of the formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows: R1is methyl, R2and R3are each methyl, R4is methyl, and n is 0. The process according to the invention comprises enantioselective hydrogenation of a compound of formula (II). The substituents R1, R2, R3, R4, R5and the integer n in the compound of formula (II) are each as defined for the compound of formula (Ia) or (Ib). Preferred, more preferred, even more preferred and most preferred meanings of the substituents R1, R2, R3, R4, R5and the integer n as outlined above for the compounds of formula (Ia) or (Ib) apply mutatis mutandis for compounds of formula (II). The enantioselective hydrogenation of the compound of the formula (II) is conducted in presence of a chiral iridium catalyst comprising a chiral ligand of the formula (IIIa) or (IIIb). Preferably, the substituents of formulae (IIIa) and (IIIb) are defined as follows: R6is preferably phenyl, which is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso- propyl, n-butyl, and tert-butyl. R6is more preferably selected from the group consisting of phenyl, 2-methyl-phenyl (o-tolyl), 3- methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl and 2,4,6-trimethyl-phenyl (mesityl). R6is most preferably selected from the group consisting of phenyl and 2,4,6-trimethyl-phenyl (mesityl). R7is preferably selected from the group consisting of phenyl and naphtyl, wherein the phenyl is substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl, and the naphtyl is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl. BCS233018 FC -11- R7is more preferably selected from the group consisting of phenyl and naphtyl, wherein the phenyl is substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl, and the naphtyl is unsubstituted. R7is even more preferably selected from the group consisting of 2-methyl-phenyl (o-tolyl), 3- methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2,4,6-trimethyl-phenyl (mesityl), 1-naphtyl and 2-naphtyl. R7is even more preferably selected from the group consisting of 2,6-dimethyl-phenyl, 3,5-dimethyl- phenyl and 2,4,6-trimethyl-phenyl (mesityl). R7is most preferably 2,6-dimethyl-phenyl. R8is preferably phenyl, which is substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert- butyl. R8is more preferably phenyl, which is substituted by one, two or three substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n- butyl, and tert-butyl. R8is even more preferably phenyl, which is substituted by one, two or three substituents independently from each other selected from the group consisting of methyl and ethyl. R8is even more preferably selected from the group consisting of o-tolyl, m-tolyl, p-tolyl and mesityl. R8is most preferably o-tolyl or mesityl. R9is preferably selected from the group consisting of C1-C6-alkyl, C3-C8-cycloalkyl and C6-C14-aryl, wherein the C1-C6-alkyl and C3-C8-cycloalkyl are unsubstituted or substituted by 1 to 3 substituents independently from each other selected from the group consisting of halogen, C1-C4- alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents independently from each other selected from halogen, C1- C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and BCS233018 FC -12- wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1- C4-alkoxy and C1-C4-haloalkoxy. R9is more preferably selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n- butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4- alkoxy and C1-C4-haloalkoxy. R9is even more preferably selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert-butyl. R9is even more preferably selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. R9is even more preferably selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl and phenyl. R9is most preferably methyl. Preferably, the enantioselective hydrogenation of the compound of formula (II) is conducted in presence of a chiral iridium catalyst comprising a chiral ligand of formula (IIIa) or (IIIb), wherein R6is selected from the group consisting of phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m- tolyl), 4-methyl-phenyl (p-tolyl), 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl and 2,4,6-trimethyl- phenyl (mesityl), R7is selected from the group consisting of 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2,4,6- trimethyl-phenyl (mesityl), 1-naphtyl and 2-naphtyl, R8is phenyl, which is substituted by one, two or three substituents independently from each other selected from the group consisting of methyl and ethyl, and BCS233018 FC -13- R9is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl and phenyl. More preferred, the enantioselective hydrogenation of the compound of formula (II) is conducted in presence of a chiral iridium catalyst comprising a chiral ligand of formula (IIIa) or (IIIb), wherein R6is phenyl or mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl or mesityl, and R9is methyl. Even more preferred, the enantioselective hydrogenation of the compound of formula (II) is conducted in presence of a chiral iridium catalyst of formula (IV) [Ir(L*)(L(I))]Y, (IV), wherein L* is the chiral ligand of formula (IIIa) or (IIIb) as defined above, L(I)is 1,5-cyclooctadiene or norbornadiene, and Y is a non-coordinating anion selected from the group consisting of [B(R10)4]-, PF6-, SbF6-, CF3SO3- , [Al{OC(CF3)3}4]−(VI) and ^-TRISPHAT (VII) , BCS233018 FC -14- wherein R10is selected from fluorine and phenyl, which is unsubstituted or substituted with one to five substituents independently from each other selected from C1-C4-alkyl, C1-C4-haloalkyl and halogen. Regarding L*, i.e. the chiral chelating ligand of formula (IIIa) or (IIIb), the preferred, more preferred, even more preferred and most preferred definitions given above apply mutatis mutandis. L(I)is preferably 1,5-cyclooctadiene. Y is preferably a non-coordinating anion selected from the group consisting of [B(R10)4]-, PF6- and [Al{OC(CF3)3}4]−(VI) (VI), wherein R10is phenyl, which is unsubstituted or substituted with one to five substituents selected from C1-C4-alkyl, C1-C4-haloalkyl and halogen. Y is more preferred a non-coordinating anion selected from the group consisting of [B(R10)4]- and [Al{OC(CF3)3}4]−(VI) BCS233018 FC -15- (VI), wherein R10is phenyl, which is unsubstituted or substituted with one to five substituents selected from fluorine and trifluoromethyl. Y is most preferred a non-coordinating anion selected from the group consisting of [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl. Even more preferred, the enantioselective hydrogenation of the compound of formula (II) is conducted in presence of a chiral iridium catalyst of formula (IV) [Ir(L*)(L(I))]Y, (IV), wherein L* is the chiral ligand of formula (IIIa) or (IIIb), wherein R6is phenyl or mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl or mesityl, and R9is methyl, L(I)is 1,5-cyclooctadiene, and Y is a non-coordinating anion selected from the group consisting of [B(R10)4]- and [Al{OC(CF3)3}4]−of formula (VI), wherein R10is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl. Even more preferred, the enantioselective hydrogenation of the compound of formula (II) is conducted in presence of a chiral iridium catalyst of formula (IV) [Ir(L*)(L(I))]Y, (IV), BCS233018 FC -16- wherein L* is the chiral ligand of formula (IIIa) or (IIIb), wherein R6is phenyl, R7is 2,6-dimethyl-phenyl, R8is mesityl, and R9is methyl, or R6is mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl, and R9is methyl, L(I)is 1,5-cyclooctadiene, and Y is the non-coordinating anion [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl, preferably 3,5-bis(trifluoromethyl)phenyl. Even more preferred, the enantioselective hydrogenation of the compound of formula (II) is conducted in presence of a chiral iridium catalyst of formula (Va) or (Vb) BCS233018 FC -17- wherein R6is phenyl or mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl or mesityl, R9is methyl, and Y is the non-coordinating anion [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl. Most preferred, the enantioselective hydrogenation of the compound of formula (II) is conducted in presence of a chiral iridium catalyst of formula (Va-1), (Vb-1), (Va-2) or (Vb-2) (Va-1) (Vb-1), wherein R6is phenyl, R7is 2,6-dimethyl-phenyl, R8is mesityl, R9is methyl, and Y is the non-coordinating anion [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl, BCS233018 FC -18- wherein R6is mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl, R9is methyl, and Y is the non-coordinating anion [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl. Depending on whether compound (Ia) or (Ib) is the desired product, the ligand of the formula (IIIa) or (IIIb) is selected. As mentioned above the chiral iridium (P,S)-ligand catalysts used in the process according to the invention are known from J. Margalef et al. in Chem. Eur. J.2014, 20, 12201 – 12214, or are close analogues thereof. They can be prepared by the synthesis routes disclosed in said reference or in analogy thereto. The amount of chiral iridium (P,S)-ligand catalyst used is preferably within the range of from 0.001 mol% to 5 mol%, more preferably 0.001 mol% to 4 mol%, most preferably 0.002 mol% to 3 mol%, in particular 0.005 mol% to 1.0 mol%, based on the amount of the compound of the formula (II). Preferably, the hydrogenation is conducted using hydrogen gas at a pressure of from 1 to 300 bar, preferably 3 to 200 bar, most preferably 20 to 150 bar. The hydrogenation is preferably conducted at a temperature within the range of from 20 °C to 130 °C, more preferably 30 °C to 100 °C. The process according to the invention is preferably conducted in the presence of a solvent. BCS233018 FC -19- Suitable solvents are halogenated alcohols such as 2,2,2,-trifluoroethanol, hexafluoroisopropanol (1,1,1,3,3,3- hexafluoro-2-propanol) and tetrafluoropropanol (2,2,3,3-tetrafluoro-1-propanol), halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane and trichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, 5 diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane and anisole, and esters such as ethyl acetate, isopropyl acetate, and mixtures thereof. Preferred solvents are selected from the group consisting of 2,2,2,-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, 1,4-dioxane, isopropyl acetate, toluene, and mixtures thereof. 10 More preferred solvents are selected from the group consisting of 2,2,2,-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, and mixtures thereof. Especially preferred are 2,2,2,-trifluoroethanol and hexafluoroisopropanol. Most preferred is hexafluoroisopropanol, i.e.1,1,1,3,3,3-hexafluoro-2-propanol. The amount of solvent, if present, is preferably within the range of from 0.5 to 20 mass equivalents, more 15 preferably 1 to 10 mass equivalents, most preferably 2 to 7 mass equivalents, in particular 4 to 6 mass equivalents, based on the amount of the compound of the formula (II). The process according to the invention is preferably conducted in the presence of an additive, which is selected from the group consisting of Brønsted acids and Lewis acids. The additive is preferably selected from the group consisting of hexafluorophosphoric acid, acetic acid, tri- 20 fluoromethylsulfonic acid, water, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, tetrafluoroboric acid, tetrafluoroboric acid diethylether complex, nafion, amberlyst, 1,1,1,3,3,3-hexafluoro-2-(trifluoro- methyl)propan-2-ol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluoro- phenyl)borane, borane tetrahydrofurane complex, boric acid, aluminum (III) trifluoromethanesulfonate, zinc (II) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, aluminum (III) fluoride, titanium 25 (IV) isopropoxide, trimethyl aluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof. Suitable complexes of boron trifluoride are complexes of boron trifluoride with organic solvents, such as dialkyl ethers or alcohols, and complexes of boron trifluoride with organic acids, such as carboxylic acids. Preferred boron trifluoride complexes are selected from the group consisting of boron trifluoride-diethylether 30 complex, boron trifluoride acetic acid complex and boron trifluoride n-propanol complex. BCS233018 FC -20- More preferred, the additive is selected from the group consisting of hexafluorophosphoric acid, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, tetrafluoroboric acid diethylether complex, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum (III) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, aluminum (III) fluoride, 5 titanium (IV) isopropoxide, trimethyl aluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof, wherein the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride-diethylether complex, boron trifluoride acetic acid complex and boron trifluoride n- propanol complex. Even more preferred, the additive is selected from the group consisting of hexafluorophosphoric acid,10 pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoro- methyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum (III) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, aluminum (III) fluoride, titanium (IV) isopropoxide, trimethyl aluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof, wherein the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride-diethylether complex, 15 boron trifluoride acetic acid complex and boron trifluoride n-propanol complex. Most preferred, the additive is selected from the group consisting of aluminum (III) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, tris(2,3,4,5,6-pentafluorophenyl)borane, hexafluorophosphoric acid, boron trifluoride and complexes of boron trifluoride, wherein the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride diethylether complex, boron trifluoride 20 acetic acid complex and boron trifluoride n-propanol complex. If present, the amount of additive selected from the group consisting of Brønsted acids and Lewis acids used is preferably within the range of from 0.1 mol% to 10 mol%, more preferably 0.2 mol% to 5 mol%, most preferably 0.3 mol% to 2 mol%, in particular 0.4 mol% to 1 mol%, based on the amount of the compound of the formula (II). 25 Abbreviations and Acronyms: BArF Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate cod 1,5-cyclooctadiene Et Ethyl GC Gas chromatography h Hour(s) BCS233018 FC -21- HFIP 1,1,1,3,3,3-hexafluoro-2-propanol MS HR Mass spectrometry high resolution min Minute(s) NaBArF Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate NMR Nuclear magnetic resonance spectroscopy rpm Rounds per minute TMQA 1-(2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-one

[0002] BCS233018 FC -22- Examples Preparation of chiral iridium (P,S)-ligand catalysts: Chiral ligands of formula (IIIa) and (IIIb) and respective chiral iridium (P,S)-ligand catalysts, e.g. chiral iridium (P,S)-ligand catalysts of formula (Va) and (Vb), can be prepared as disclosed in J. Margalef et al. in 5 Chem. Eur. J.2014, 20, 12201 – 12214, or in analogy thereto. General procedure for the synthesis of chiral iridium (P,S)-ligand catalysts: The corresponding ligand (IIIa) or (IIIb) (0.074 mmol) was dissolved in CH2Cl2 (5 mL) and [Ir( ^-Cl)(cod)]2 (25.0 mg, 0.037 mmol) was added. The reaction mixture was heated at reflux at 50°C for 1 hour. After 5 min at room temperature, NaBArF (77.2 mg, 0.080 mmol) and water (5 mL) were added and the reaction mixture 10 was stirred vigorously for 30 min at room temperature. The phases were separated and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried with MgSO4, filtered through a plug of Celite and the solvent was evaporated to give the product as an orange solid. Example 1, synthesis of chiral iridium (P,S)-ligand catalysts of formula (Va-1): Ligand of formula (IIIa-1) 15 wherein Mes is mesityl has been prepared as follows: Bis(2,4,6-trimethylphenyl)phosphorus chloride (0.55 mmol) was dissolved in toluene (2.5 mL), and pyridine20 (0.15 mL, 2.9 mmol) was added. The free alcohol (1R,2S)-1-((2,6-dimethylphenyl)thio)-3-methoxy-1- phenylpropan-2-ol (0.5 mmol) was azeotropically dried using toluene and then dissolved in dry toluene (2.5 mL) to which pyridine (0.15 mL, 2.9 mmol) was added. The alcohol solution was then transferred slowly to the bis(2,4,6-trimethylphenyl)phosphorus chloride / pyridine solution. The reaction mixture was stirred at 80 °C for 90 min, after which the pyridine salts were removed by filtration. Evaporation of the solvent gave a BCS233018 FC -23- white foam, which was purified by flash chromatography on alumina (toluene / NEt3=100:1) to produce the corresponding ligand (IIIa-1) as a white solid. Chiral iridium (P,S)-ligand catalysts of formula (Va-1) wherein R6is phenyl, R7is 2,6-dimethyl-phenyl, R8is mesityl, R9is methyl, and Y is the non-coordinating anion [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl, has been prepared according to the general procedure outlined above from the ligand of formula (IIIa-1). Yield: 114 mg (89%).31P NMR (162 MHz, C6D6, 25^C, H3PO4): δ= 98.3 ppm (s).1H NMR (400 MHz, C6D6, 25^C, TMS): δ= 7.1-8.0 (m, 24H; CH= aromatic), 4.82 (b, 1H; CH=, cod), 4.78 (s, 1H; CH-S), 4.62 (b, 1H; CH=, cod), 4.40 (m, 1H; CH-O), 3.64 (m, 1H; CH=, cod), 3.37 (m, 1H; CH2), 3.16 (m, 1H; CH2), 3.11 (s, 3H ; CH3-O), 2.94 (b, 1H; CH=, cod), 2.41 (m, 2H; CH2 cod), 2.82 (s, 3H; CH3), 2.1-2.4 (m, 9H; CH2 cod and CH3), 2.08 (s, 3H; CH3), 2.00 (s, 3H; CH3), 1.79 (s, 6H; CH3), 1.71 (s, 3H; CH3), 1.67 ppm (s, 3H; CH3).13C NMR (126 MHz, C6D6, 25^C, TMS): δ= 161.9 (q,1J(C,B) = 49.9 Hz; C-B, BArF), 117.6-143.0 (aromatic carbons), 101.3 (d, J(C,P) = 12.4 Hz; CH=, cod), 98.4 (d, J(C,P) = 9.2 Hz; CH=, cod), 79.8 (d,2J(C,P) = 3.6 Hz; CH-O), 75.9 (s; CH=, cod), 70.9 (s; CH=, cod), 64.9 (d,3J(C,P) = 4.0 Hz; CH2), 59.3 (s; CH3-O), 58.4 (s; CH-S), 33.0 (s; CH2, cod), 32.1 (s; CH2, cod), 30.1 (s; CH2, cod), 29.1 (b; CH2, cod), 23.2 (s; CH3), 22.5 (s; BCS233018 FC -24- CH3), 22.3 (s; CH3), 22.1 (s; CH3), 22.0 (s; CH3), 21.9 (s; CH3), 20.6 ppm (s; CH3). MS HR-ESI [found 871.3272, C44H55IrO2PS (M-BArF)+requires 871.3284]. Example 2, synthesis of chiral iridium (P,S)-ligand catalysts of formula (Va-2): Ligand of formula (IIIa-2) wherein Tol is o-tolyl has been to described above for ligand of formula (IIIa-1). Chiral iridium (P,S)-ligand catalysts of formula (Va-2) wherein R6is mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl, BCS233018 FC -25- R9is methyl, and Y is the non-coordinating anion [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl, has been prepared according to the general procedure outlined above from the ligand of formula (IIIa-2). Yield: 115 mg (92%).31P NMR (162 MHz, CDCl3, 25ºC, H3PO4): δ= 105.2 ppm (s).1H NMR (400 MHz, CDCl3, 25ºC, TMS): δ= 6.62-7.93 (m, 25 H; CH= aromatic), 4.79 (m, 1 H; CH-O), 4.61 (m, 1 H; CH= cod), 4.17 (b, 2 H; CH-S, CH=, cod), 3.91 (b, 1 H; CH=, cod), 3.12 (m, 2 H; CH2, CH= cod), 2.99 (s, 3 H; CH3-O), 2.96 (b, 1 H; CH2), 2.93 (s, 3 H; CH3), 2.67 (s, 3 H; CH3), 2.54 (b, 1 H; CH2, cod), 2.52 (s, 3 H; CH3), 2.13 (s, 6 H; CH3), 1.9-2.4 (b, 7 H; CH2, cod), 1.72 (s, 3 H; CH3), 1.12 ppm (s, 3 H; CH3).13C NMR (126 MHz, CDCl3, 25ºC, TMS): δ= 161.8 (q,1J(C,B) = 49.8 Hz; C-B, BArF), 117.6-144.5 (aromatic carbons), 101.2 (d, J(C,P) = 12.5 Hz; CH=, cod), 99.1 (d, J(C,P) = 12.1 Hz; CH=, cod), 73.4 (s; CH=, cod), 79.5 (s; CH-O), 72.4 (d,3J(C,P) = 6.9 Hz; CH2), 70.2 (s; CH=, cod), 58.9 (s; CH3-O), 50.1 (s; CH-S), 34.0 (b; CH2, cod), 30.3 (d, J(C,P) = 3.2 Hz; CH2, cod), 30.1 (s; CH2, cod), 27.0 (s; CH2, cod), 23.6 (s; CH3), 22.9 (s; CH3), 22.4 (s; CH2), 21.6 (s; CH3), 21.3 (s; CH2), 20.7 (s; CH3), 19.3 ppm (s; CH3). MS HR-ESI [found 855.3103, C43H53IrO2PS (M-BArF)+requires 855.3104]. Comparative examples 3-5, synthesis of comparative chiral iridium (P,S)-ligand catalysts of formula (Va-3), (Va-4) and (Va-5): Comparative ligands of formula (IIIa-3), (IIIa-4), and (IIIa-5)

[0003] BCS233018 FC -26- wherein Ph is phenyl, and Tol is o- analogy to the procedures described in Examples 1 and 2. Comparative chiral iridium (P,S)-ligand catalysts of formula (Va-3), (Va-4), and (Va-5), wherein R6, R7, R8, and R9have the an Y is the non-coordinating anion [B(R10)4]-, wherein R103,5-bis(trifluoromethyl)phenyl, have been prepared according to the general procedure outlined above from the respective ligands of formula (IIIa-3) to (IIIa-5). Table 1: Example Catalyst Ligand R6R7R8R92,6- 1 (Va-1) (IIIa-1) phenyl dimethyl- mesityl CH3 phenyl BCS233018 FC -27- Example Catalyst Ligand R6R7R8R92,6- 2 (Va-2) (IIIa-2) mesityl dimethyl- o-tolyl CH3 phenyl 3 (comparative)(Va-3) (IIIa-3) phenyl tert-butyl phenyl CH34 (comparative)(Va-4) (IIIa-4) phenyl tert-butyl o-tolyl CH35 2,6- (comparative)(Va-5) (IIIa-5) phenyldimethyl- phenyl CH3 phenyl Hydrogenation of a 4-substituted 1,2-dihydroquinoline: Examples 6 and 7 and comparative examples 8 to 10: A 20 ml glass vial containing a cross-shape stirring bar was charged with TMQA (300 mg, 1.4 mmol) and 2.8 µmol Ir-catalyst (Va-1), (Va-2), or one of the comparative catalysts (Va-3) to (Va-5) as indicated in Table 2. The vial was closed with a septum and purged under 1.2 bar of Ar for 10 min. Then, HFIP (2.8 mL) was added and the mixture was stirred for 1 min. Then the glass vial was pricked with a needle and quickly transferred to the autoclave, which was closed under positive Ar atmosphere (1.2 bar). The reactor was then pressed with 20 bar of hydrogen and released (3 times) and finally pressurized to 40 bar of hydrogen. The reactor was then heated to 45 °C and stirred at 690 rpm. After 2.5 h, the reactor was cooled to room temperature and the pressure was released carefully. The solution was analyzed by GC. Results and further reaction details are given in Table 2. Table 2: Ca Example CatalysttRimeeac(tmiointalyst n)loading Conversion Enantiomeric (mol%) GC (%a / a) excess (%ee) 6 (Va-1) 150 0.2 95 64 7(Va-2)150 0.2 38 90 8 (comparative)(Va-3)150 0.2 4 < 2 BCS233018 FC -28- Catalyst Example CatalysttRimeeac(tmioinConversion Enantiomeric n)loading (mol%) GC (%a / a) excess (%ee) 9 (comparative) (Va-4) 150 0.2 4 < 2 10 (comparative)(Va-5)150 0.2 12 40 Comparative example 8 shows that catalyst (Va-3) comprising a tert-butyl substituent at the sulfur atom (R7) and phenyl substituents at the phosphorous atom (R8) provides insufficient conversion (4%) and enatiomeric excess (< 2%) in the desired hydrogenation reaction. No improvement is observed, if just the substituents at the phosphorous atom (R8) are replaced by the more bulky residue o-tolyl as in catalyst (Va-4) (see comparative example 9). Some, but still insufficient improvement is observed, if just the substituent at the sulfur atom (R7) is replaced by the more bulky residue 2,6-dimethyl-phenyl as in catalyst (Va-5) (see comparative example 10; conversion = 12%, enantiomeric excess = 40%). Surprisingly, if both, R7and R8are sterically demanding residues as in catalyst (Va-1) (R7= 2,6-dimethyl-phenyl, R8= mesityl), significant improvement in both, conversion and enatiomeric excess is observed (see example 6; conversion = 95%, enantiomeric excess = 64%). Also example 7 using catalyst (Va-2) shows that improved conversion and enatiomeric excess is achieved, if the catalyst bears a bulky substituent both, at the sulfur atom (R7is 2,6-dimethyl-phenyl) and at the phosphorous atom (R8is o-tolyl). Examples 11 and 12: Hydrogenation in presence of the additive BF3·OEt2 A 20 ml glass vial containing a cross-shape stirring bar was charged with TMQA (300 mg, 1.4 mmol) and 2.8 µmol Ir-catalyst (Va-1) or (Va-2) as indicated in Table 3. The vial was closed with a septum and purged under 1.2 bar of Ar for 10 min. Then, HFIP (2.8 mL) was added and the mixture was stirred for 1 min. Then, BF3·OEt2 (1 µL) was added and the glass vial was pricked with a needle and quickly transferred to the autoclave, which was closed under positive Ar atmosphere (1.2 bar). The reactor was then pressed with 20 bar of hydrogen and released (3 times) and finally pressurized to 40 bar of hydrogen. The reactor was then heated to 45 °C and stirred at 690 rpm. After 2.5 h, the reactor was cooled to room temperature and the pressure was released carefully. The solution was analyzed by GC. Results and further reaction details are given in Table 3. BCS233018 FC -29- Table 3: Reaction Catalyst Example Catalyst time loading BF3*OEt2 Conversion Enantiomeric (min) (mol%) (mol%) GC (%a / a) excess (%ee) 11 (Va-1) 150 0.2 0.6 100 64 12(Va-2)150 0.2 0.6 85 94 Comparison of results of examples 11 and 12 with those of examples 6 and 7 show that presence of the additive BF3·OEt2further enhances conversion and / or enatiomeric excess and, hence, fosters the desired reaction. 5

Claims

BCS233018 FC -30- Claims:

1. A process for preparing a compound of formula (Ia) or (Ib) whereinR1is selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy- C1-C6-alkyl, C3-C6-cycloalkyl, C6-C14-aryl, and C6-C14-aryl-C1-C4-alkyl, wherein the C1-C6-alkyl, C3-C6-cycloalkyl and the C1-C6-alkoxy in the C1-C6-alkoxy- C1-C6-alkyl moiety, are unsubstituted or substituted by 1 to 3 substituents independently from each other selected from the group consisting of halogen, C1-C4- alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents independently from each other selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4- haloalkoxy, and wherein the C6-C14-aryl and the C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety in each case is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, R2and R3are the same and are selected from the group consisting of hydrogen, C1-C6-alkyl, C1- C6-haloalkyl and C1-C6-alkoxy-C1-C6-alkyl, or R2and R3together with the carbon which they are bound to, form a C3-C6-cycloalkyl ring, R4is selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6- alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-BCS233018 FC -31- cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, 9- flurorenylmethyleneoxy, C6-C14-aryl, C6-C14-aryloxy, C6-C14-aryl-C1-C4-alkyloxy and C6-C14-aryl-C1-C4-alkyl, wherein the C6-C14-aryl as such or as part of a composite substituent is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1- C4-haloalkoxy, n is 0, 1, 2, 3 or 4, each substituent R5, if present, is independently selected from the group consisting of halogen, C1- C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxyl, amino and –C(=O)-C1-C6-alkyl, comprising enantioselective hydrogenation of a compound of formula (II) wherein the substituentsinteger n are each as defined for the compound of formula (Ia) or (Ib), in presence of a chiral iridium catalyst, characterized in that the chiral iridium catalyst comprises a chiral ligand of formula (IIIa) or (IIIb)BCS233018 FC -32- wherein R6is C6-C14-aryl, which is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, R7is selected from the group consisting of phenyl, naphtyl and anthracenyl, wherein the phenyl is substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, and the naphtyl and anthracenyl each are unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, each R8is C6-C14-aryl, which is substituted by one to five substituents independently from each other selected from the group consisting of C1-C4-alkyl, and R9is selected from the group consisting of C1-C6-alkyl, C3-C8-cycloalkyl and C6-C14-aryl, wherein the C1-C6-alkyl and C3-C8-cycloalkyl are unsubstituted or substituted by 1 to 3 substituents independently from each other selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents independently from each other selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1- C4-haloalkoxy, and wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of halogen, C1-C4- alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, or R9is carrier material selected from the group consisting of polyether, polystyrene, silica and alumina.

2. The process according to claim 1, wherein R1is C1-C6-alkyl or C6-C14-aryl-C1-C4-alkyl, wherein C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety is unsubstituted or substituted by one to five substituents independently from each other selected from theBCS233018 FC -33- group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4- haloalkoxy, R2and R3are the same and are selected from C1-C4-alkyl, R4is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl, n is 0, 1 or 2, and each substituent R5, if present, is independently selected from the group consisting of halogen, C1- C6-alkyl and C1-C6-haloalkyl.

3. The process according to claim 1, wherein R1is C1-C4-alkyl, R2and R3are methyl, R4is C1-C4-alkyl, n is 0 or 1, and R5if present, is fluorine.

4. The process according to any one of claims 1 to 3, wherein R6is phenyl, which is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n- propyl, iso-propyl, n-butyl, and tert-butyl.

5. The process according to any one of claims 1 to 3, wherein R6is phenyl or mesityl.

6. The process according to any one of claims 1 to 3, wherein R7is selected from the group consisting of phenyl and naphtyl, wherein the phenyl is substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl, and the naphtyl is unsubstituted or substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n- propyl, iso-propyl, n-butyl, and tert-butyl.BCS233018 FC -34- 7. The process according to any one of claims 1 to 3, wherein R7is 2,6-dimethyl-phenyl.

8. The process according to any one of claims 1 to 3, wherein R8is phenyl, which is substituted by one to five substituents independently from each other selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl.

9. The process according to any one of claims 1 to 3, wherein R8is o-tolyl or mesityl.

10. The process according to any one of claims 1 to 3, wherein R9is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl and phenyl.

11. The process according to any one of claims 1 to 3, wherein R9is methyl.

12. The process according to any one of claims 1 to 3, wherein the chiral iridium catalyst is a catalyst of formula (IV) [Ir(L*)(L(I))]Y, (IV) wherein L* is the chiral ligand of formula (IIIa) or (IIIb) as defined in any of claims 1 and 4 to 11, L(I)is 1,5-cyclooctadiene or norbornadiene, and Y is a non-coordinating anion selected from the group consisting of [B(R10)4]-, PF6-, SbF6- , CF3SO3-, [Al{OC(CF3)3}4]−(VI) and ^-TRISPHAT (VII)BCS233018 FC -35-,wherein R10is selected from fluorine and wh i or substituted with one to five substituents independently from each other selected C1-C4-alkyl, C1-C4-haloalkyl and halogen.

13. The process according to claim 12, wherein L* is the chiral ligand of formula (IIIa) or (IIIb), wherein R6is phenyl or mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl or mesityl, and R9is methyl, L(I)is 1,5-cyclooctadiene, and Y is a non-coordinating anion selected from the group consisting of [B(R10)4]- and [Al{OC(CF3)3}4]−of formula (VI), wherein R10is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.

14. The process according to any one of claims 1 to 3, wherein the chiral iridium catalyst is a catalyst of formula (Va) or (Vb)BCS233018 FC -36-wherein R6is phenyl or mesityl, R7is 2,6-dimethyl-phenyl, R8is o-tolyl or mesityl, R9is methyl, and Y is the non-coordinating anion [B(R10)4]-, wherein R10is 3,5-bis(trifluoromethyl)phenyl.

15. The process according to any one of claims 1 to 14, wherein the process is performed in presence of an additive selected from the group consisting of hexafluorophosphoric acid, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum (III) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, aluminum (III) fluoride, titanium (IV) isopropoxide, trimethyl aluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof.

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