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WO2024261094A1 - Catalyseurs chiraux à base d'hydrure d'iridium pour l'hydrogénation énantiosélective de 1,2-dihydroquinolines substituées en position 4 - Google Patents

Catalyseurs chiraux à base d'hydrure d'iridium pour l'hydrogénation énantiosélective de 1,2-dihydroquinolines substituées en position 4 Download PDF

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WO2024261094A1
WO2024261094A1 PCT/EP2024/067162 EP2024067162W WO2024261094A1 WO 2024261094 A1 WO2024261094 A1 WO 2024261094A1 EP 2024067162 W EP2024067162 W EP 2024067162W WO 2024261094 A1 WO2024261094 A1 WO 2024261094A1
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alkyl
substituted
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alkoxy
phenyl
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Christoph SCHOTES
Christoph Kubis
Dilver FUENTES
Benedict LEIDECKER
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0033—Iridium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom

Definitions

  • the invention relates to chiral iridium hydride complexes comprising a) a chiral chelating ligand comprising at least one phosphorus atom and at least one nitrogen atom that both bind to the iridium atom - in the following also referred to as “chiral (P,N)-ligand” - and b) a stabilizing enone ligand of formula (I) as defined below, as well as 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 said complex.
  • 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 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 asymmetric 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 improved conversion rates and enantioselectivity.
  • the chiral iridium (P,N)-ligand catalysts show excellent catalytic activity.
  • recovery and recycling of the spent catalyst proved to be difficult.
  • Iridium is a scarce and expensive metal and synthesis of the respective chiral iridium (P,N)-ligand catalysts is complex. Hence, recycling of the catalyst would be highly desirable, in particular in an industrial scale production process in the agrochemicals field.
  • the recovered catalyst is isolated and reused, showing essentially the same reactivity and enantioselectivity as the original catalyst.
  • BCS233012 FC -2- Unfortunately, this procedure is not suitable for recovery and recycling of the chiral iridium (P,N)-ligand catalysts disclosed in WO 2019/185541, WO 2021/058457 and WO 2021/058458, since a) reaction of the spent catalyst with cyclooctadiene proceeds too slowly to be suitable for an industrial scale process, and b) isolation and purification of the recovered catalyst as proposed by Müller et al. requires column chromatography (see Müller, Experimental Section), which again is not suitable for larger catalyst amounts necessary for an industrial scale process. Hence, there is need for catalysts that can be easily recycled.
  • chiral iridium (P,N)-ligand catalysts for the enantioselective hydrogenation of 4-substituted 1,2- dihydroquinolines that show at least the same level of reactivity and enantioselectivity in said hydrogenation as the catalysts known from WO 2019/185541, WO 2021/058457 and WO 2021/058458, but can be customized more flexibly than the known catalysts, which comprise a stabilizing diene ligand, usually 1,5- cyclooctadiene. Only few suitable diene ligands are available. Usually 1,5-cyclooctadiene is used, sometimes norbornadiene.
  • Derivatization thereof is rather complex. Catalysts that can be flexibly customized, allow for fine-tuning of important properties, like polarity, solubility in various solvents, stability, and speed of activation, which can be used to arrive at improved recoverability and recyclability.
  • the object described above is achieved by chiral iridium hydride complexes, comprising a) a chiral chelating ligand, wherein said chiral chelating ligand comprises at least one phosphorus atom and at least one nitrogen atom that both bind to the iridium atom, i.e.
  • R 1 is selected from the group consisting of hydrogen, C1-C500-alkyl, C2-C500-alkenyl, C1- C500-alkoxy, C2-C500-alkenyloxy, C1-C500-alkylamino, C2-C500-alkenylamino, di-(C1- C500-alkyl)amino, di-(C2-C500-alkenyl)amino, N-(C1-C500-alkyl)-N-(C2-C500- BCS233012 FC -3- alkenyl)amino, C3-C8-cycloalkyl, C3-C8-cycloalkoxy, C3-C8-cycloalkylamino, N-(C1- C500-alkyl)-N-(C3-C8-cycloalkyl)amin
  • Halogen fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine.
  • BCS233012 FC -5- Alkyl saturated, straight-chain or branched hydrocarbyl substituents having 1 to 500, e.g.
  • 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-d
  • 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 500, e.g.2 to 6 or 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)-
  • Alkynyl straight-chain or branched hydrocarbyl substituents having 2 to 6, 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-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, hex-1-yny
  • alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl.
  • Haloalkyl straight-chain or branched alkyl substituents having 1 to 500, e.g.1 to 6 or 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- difluor
  • 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.
  • Alkoxy saturated, straight-chain or branched alkoxy substituents having 1 to 500, e.g.1 to 6 or 1 to 4 carbon atoms, for example (but not limited to) C 1 -C 6 -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-
  • BCS233012 FC -7- Haloalkoxy straight-chain or branched alkoxy substituents having 1 to 500, e.g.1 to 6 or 1 to 4 carbon atoms 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-chloroethoxy, 1-bromoethoxy, 1- fluoroethoxy
  • alkenyloxy refers to a formula (alkenyl)-O-, in which the term “alkenyl” group has the meaning as defined herein.
  • C2-C6-alkenyloxy examples include but are not limited to ethenyloxy (or "vinyloxy"), prop-2-en-1-yloxy (or “allyloxy”), prop-1-en-1-yloxy, prop-1-en-2-yloxy (or “isopropenyloxy”), but-3-enyloxy, but-2-enyloxy, but-1-enyloxy, 2-methylprop-2-enyloxy, 1-methylprop-2- enyloxy, 2-methylprop-1-enyloxy and 1-methylprop-1-enyloxy.
  • Alkylamino monoalkylamino or dialkylamino, wherein monoalkylamino represents an amino radical having one alkyl residue with 1 to 500, e.g.1 to 6 carbon atoms attached to the nitrogen atom.
  • Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino
  • dialkylamino represents an amino radical having two independently selected alkyl residues with 1 to 500, e.g. 1 to 6 carbon atoms each attached to the nitrogen atom.
  • Non-limiting examples include N,N-di- methylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propyl- amino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino.
  • Alkenylamino is defined analogously to alkylamino except that, instead of alkyl groups, alkenyl groups are present as part of the substituent.
  • 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.
  • cycloalkyl as part of a composite substituent, for example C 3 - C 6 -cycloalkyl-C 1 -C 4 -alkyl, unless defined elsewhere.
  • BCS233012 FC -8- Cycloalkoxy refers to a formula (cycloalkyl)-O-, in which the term "cycloalkyl” group has the meaning as defined herein.
  • Examples of C3-C8-cycloalkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • Cycloalkylamino is defined analogously to alkylamino except that, instead of alkyl groups, cycloalkyl groups are present as part of the substituent.
  • 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, 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-antracenyl. Phenyl is particularly preferred.
  • the chiral hydride complexes according to the invention comprise an enone ligand of formula (I) o wherein R 1 , R 1a , R 2 and the arrow are R 1a is preferably selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, or R 1a and R 1 form together with the carbon atom to which R 1a is attached, and the carbonyl group to which R 1 is attached, a C 5 -C 7 -cycloalkanone ring, preferably a cyclohexanone ring, wherein the C 5 - C7-cycloalkanone ring is substituted by one benzylidene group in ortho position to the carbonyl group, wherein the benzylidene is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C6-alkyl, and C1-C6-alkoxy.
  • R 1a is more preferably selected from the group consisting of hydrogen, C1-C4-alkylcarbonyl, or BCS233012 FC -9- R 1a and R 1 form together with the carbon atom to which R 1a is attached and the carbonyl group to which R 1 is attached a C5-C7-cycloalkanone ring, preferably a cyclohexanone ring, wherein the C5- C7-cycloalkanone ring is substituted by one benzylidene group in ortho position to the carbonyl group, wherein the benzylidene is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C6-alkyl, and C1-C6-alkoxy.
  • R 1a is even more preferably selected from the group consisting of hydrogen and acetyl, or R 1a and R 1 form together with the carbon atom to which R 1a is attached and the carbonyl group to which R 1 is attached a cyclohexanone ring, wherein the cyclohexanone ring is substituted by one benzylidene group in ortho position to the carbonyl group, wherein the benzylidene is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1- C6-alkyl, and C1-C6-alkoxy.
  • R 1a is even more preferably selected from the group consisting of hydrogen and acetyl, or R 1a and R 1 form together with the carbon atom to which R 1a is attached and the carbonyl group to which R 1 is attached a cyclohexanone ring, wherein the cyclohexanone ring is substituted by one benzylidene group in ortho position to the carbonyl group, wherein the benzylidene is unsubstituted.
  • R 1a is acetyl, i.e.
  • the chiral iridium hydride complex comprises an enone ligand of formula (I-Ac) o wherein R 1 , R 2 and the arrow are BCS233012 FC -10-
  • R 1a is hydrogen
  • the chiral iridium hydride complex comprises an enone ligand of formula (I-H) o (I-H) wherein R 1 , R 2 and the arrow are defined as indicated above.
  • R 1a and R 1 form together with the carbon atom to which R 1a is attached, and the carbonyl group to which R 1 is attached, a cyclopentanone ring, cyclohexanone ring or cycloheptanone ring, preferably a cyclohexanone ring, wherein the cyclopentanone ring, cyclohexanone ring or cycloheptanone ring is substituted by one benzylidene group in ortho position to the carbonyl group, wherein the benzylidene is unsubstituted or substituted by one to five substituents selected independently from each other from 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), me
  • the benzylidene group is unsubstituted or substituted by one, two or three substituents selected independently from each other from methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), methoxy, ethoxy, propoxy, and 1-methylethoxy. More preferably, the benzylidene group is unsubstituted or substituted by one, two or three substituents selected independently from each other from methyl, ethyl, methoxy, and ethoxy. More preferably, the benzylidene group is unsubstituted or substituted by one, two or three substituents selected independently from each other from methyl, and methoxy.
  • the benzylidene group is unsubstituted or substituted by one substituent selected from methyl, and methoxy. More preferably, the benzylidene group is unsubstituted.
  • R 1 and R 2 as indicated below apply to enone ligands of formula (I), including enone ligands of formula (I-Ac) and enone ligands of formula (I-H).
  • R 1 is preferably selected from the group consisting of C 1 -C 500 -alkyl, C 2 -C 500 -alkenyl, C 6 -C 14 -aryl, wherein C 1 -C 500 -alkyl and C 2 -C 500 -alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C500-alkyl, C1-C500-alkoxy, C1-C500-haloalkyl, and C1-C500-haloalkoxy, and BCS233012 FC -11- wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C500-alkyl, C1-C500-haloalkyl.
  • R 1 is more preferably selected from the group consisting of C1-C400-alkyl, C2-C400-alkenyl, C6-C14-aryl, wherein C1-C400-alkyl and C2-C400-alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C400-alkyl, C1-C400-alkoxy, C1-C400-haloalkyl, and C1-C400-haloalkoxy, and wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C400-alkyl, C1-C400-haloalkyl.
  • R 1 is more preferably selected from the group consisting of C1-C300-alkyl, C2-C300-alkenyl, C6-C14-aryl, wherein C1-C300-alkyl and C2-C300-alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C300-alkyl, C1-C300-alkoxy, C1-C300-haloalkyl, and C1-C300-haloalkoxy, and wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C300-alkyl, C1-C300-haloalkyl.
  • R 1 is more preferably selected from the group consisting of C1-C200-alkyl, C2-C200-alkenyl, C6-C14-aryl, wherein C1-C200-alkyl and C2-C200-alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C200-alkyl, C1-C200-alkoxy, C1-C200-haloalkyl, and C1-C200-haloalkoxy, and wherein the C 6 -C 14 -aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 200 -alkyl, C 1 -C 200 -haloalkyl.
  • R 1 is more preferably selected from the group consisting of C 1 -C 150 -alkyl, C 2 -C 150 -alkenyl, C 6 -C 14 -aryl, wherein C 1 -C 150 -alkyl and C 2 -C 150 -alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C 1 -C 150 -alkyl, C 1 -C 150 -alkoxy, C 1 -C 150 -haloalkyl, and C 1 -C 150 -haloalkoxy, and wherein the C 6 -C 14 -aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 150 -alkyl, C 1 -C 150 -haloalkyl.
  • R 1 is more preferably selected from the group consisting of C 1 -C 100 -alkyl, C 2 -C 100 -alkenyl, C 6 -C 14 -aryl, BCS233012 FC -12- wherein C1-C100-alkyl and C2-C100-alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C100-alkyl, C1-C100-alkoxy, C1-C100-haloalkyl, and C1-C100-haloalkoxy, and wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C100-alkyl, C1-C100-haloalkyl.
  • R 1 is more preferably selected from the group consisting of C1-C100-alkyl, C2-C100-alkenyl, phenyl, wherein C1-C100-alkyl and C2-C100-alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C100-alkyl, C1-C100-alkoxy, C1-C100-haloalkyl, and C1-C100-haloalkoxy, and wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C100-alkyl, C1-C100-haloalkyl.
  • R 1 is more preferably selected from the group consisting of C1-C100-alkyl, C2-C100-alkenyl, phenyl, wherein C1-C100-alkyl and C2-C100-alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C500-alkyl, C1-C500-alkoxy, C1-C500-haloalkyl, and C1-C500-haloalkoxy and wherein in case R 1 is phenyl, this phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C100-alkyl, C1-C100-haloalkyl.
  • R 1 is more preferably selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, phenyl, wherein C 1 -C 6 -alkyl and C 2 -C 6 -alkenyl are unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C 1 -C 500 -alkyl, C 1 -C 500 -alkoxy, C 1 -C 500 -haloalkyl, and C 1 -C 500 -haloalkoxy, and wherein in case R 1 is phenyl, this phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 100 -alkyl, C 1 -C 100 -haloalkyl.
  • R 1 is more preferably selected from the group consisting of C 1 -C 3 -alkyl, vinyl, phenyl, wherein the vinyl is unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C 1 - C 500 -alkyl, C 1 -C 500 -alkoxy, C 1 -C 500 -haloalkyl, and C 1 -C 500 -haloalkoxy, and BCS233012 FC -13- wherein in case R 1 is phenyl, this phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C100-alkyl, and C1-C100-haloalkyl, preferably from the group consisting of C1-C3-alkyl.
  • R 1 is more preferably selected from the group consisting of methyl and vinyl, wherein the vinyl is unsubstituted or substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1- C500-alkyl, C1-C500-alkoxy, C1-C500-haloalkyl, and C1-C500-haloalkoxy.
  • R 1 is more preferably selected from the group consisting of methyl and vinyl, wherein the vinyl is substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C1-C100-alkyl, C1-C100- alkoxy, C1-C100-haloalkyl, and C1-C100-haloalkoxy.
  • R 1 is more preferably selected from the group consisting of methyl and vinyl, wherein the vinyl is substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one, two or three substituents selected independently from each other from methyl, ethyl, propyl (n- propyl), 1-methylethyl (iso-propyl), methoxy, ethoxy, propoxy, and 1-methylethoxy, preferably from methyl and methoxy.
  • R 1 is also more preferably selected from the group consisting of methyl, vinyl and phenyl, wherein the vinyl is substituted by phenyl, wherein the phenyl is unsubstituted or substituted by one, two or three substituents selected independently from each other from methyl, ethyl, propyl (n- propyl), 1-methylethyl (iso-propyl), methoxy, ethoxy, propoxy, and 1-methylethoxy, preferably from methyl and methoxy, more preferably from methoxy, and wherein in case R 1 is phenyl, this phenyl is unsubstituted.
  • R 2 is preferably selected from the group consisting of C 1 -C 500 -alkyl, C 6 -C 14 -aryl, wherein C 1 -C 500 -alkyl is unsubstituted or substituted by substituent(s) independently selected from the group consisting of halogen, hydroxy, C 1 -C 500 -alkoxy, C 1 -C 500 -haloalkyl, C 1 -C 500 -haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected independently from each other from halogen, C 1 -C 500 -alkyl, C 1 -C 500 -alkoxy, C 1 -C 500 -haloalkyl, and C 1 -C 500 -haloalkoxy, and BCS233012 FC -14- wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consist
  • R 2 is more preferably C6-C14-aryl, wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C500-alkyl, C1-C500-haloalkyl, C1-C500-alkoxy and C1-C500- haloalkoxy.
  • R 2 is more preferably phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C500-alkyl, C1-C500-haloalkyl, C1-C500-alkoxy and C1-C500-haloalkoxy.
  • R 2 is more preferably phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C400-alkyl, C1-C400-haloalkyl, C1-C400-alkoxy and C1-C400-haloalkoxy.
  • R 2 is more preferably phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C300-alkyl, C1-C300-haloalkyl, C1-C300-alkoxy and C1-C300-haloalkoxy.
  • R 2 is more preferably phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 200 -alkyl, C 1 -C 200 -haloalkyl, C 1 -C 200 -alkoxy and C 1 -C 200 -haloalkoxy.
  • R 2 is more preferably phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 150 -alkyl, C 1 -C 150 -haloalkyl, C 1 -C 150 -alkoxy and C 1 -C 150 -haloalkoxy.
  • R 2 is more preferably phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 100 -alkyl, C 1 -C 100 -haloalkyl, C 1 -C 100 -alkoxy and C 1 -C 100 -haloalkoxy.
  • R 2 is more preferably phenyl, BCS233012 FC -15- wherein the phenyl is unsubstituted or substituted by one, two or three substituents selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy.
  • R 2 is more preferably phenyl, wherein the phenyl is unsubstituted or substitu,ted by one, two or three substituents selected from the group consisting of methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), methoxy, ethoxy, propoxy, and 1-methylethoxy, preferably from methyl and methoxy, more preferably from methoxy.
  • R 2 is more preferably phenyl or 4-methoxyphenyl (para-methoxyphenyl).
  • chiral iridium hydride complexes comprising an enone ligand of formula (I), wherein R 1 is methyl, phenyl, styryl or 4-methoxystyryl (para-methoxystyryl), R 1a is hydrogen or acetyl, or R 1a and R 1 form together with the carbon atom to which R 1a is attached, and the carbonyl group to which R 1 is attached, a cyclohexanone ring, wherein the cyclohexanone ring is substituted by one benzylidene group in ortho position to the carbonyl group, and R 2 is phenyl or 4-methoxyphenyl (para-methoxyphenyl).
  • R 1 is methyl, phenyl, styryl or 4-methoxystyryl (para-methoxystyryl)
  • R 1a is hydrogen or acetyl
  • R 1a and R 1 form together with the carbon atom to which R 1
  • enone ligand of formula (I-H) Particularly preferred are also chiral iridium hydride complexes comprising an enone ligand of formula (I-H), wherein R 1 is methyl or styryl, and R 2 is phenyl or 4-methoxyphenyl (para-methoxyphenyl).
  • R 1 is methyl or styryl
  • R 2 is phenyl or 4-methoxyphenyl (para-methoxyphenyl).
  • enone ligands of formula (I) is accessible via established routes. It is for example possible to incorporate long carbon chain residues, e.g.
  • Presence of at least one such group enhances solubility of the enone and the chiral iridium hydride complex comprising such ligand in non-polar solvents, BCS233012 FC -16- e.g. heptane, allowing recovery of the chiral iridium hydride complex from a reaction mixture by simple extraction with such non-polar solvent.
  • chiral iridium hydride complexes comprising an enone ligand of formula (I), wherein the enone ligand comprises at least one, preferably one, long carbon chain residue selected from the group consisting of C6-C500-alkyl, C6-C500-alkenyl, C6-C500-alkoxy, C6-C500-alkenyloxy, C6-C500- alkylamino, C6-C500-alkenylamino, di-(C6-C500-alkyl)amino, di-(C6-C500-alkenyl)amino and N-(C6-C500- alkyl)-N-(C6-C500-alkenyl)amino.
  • the long carbon chain residue is selected from the group consisting of C6-C400-alkyl, C6-C400- alkenyl, C6-C400-alkoxy, C6-C400-alkenyloxy, C6-C400-alkylamino, C6-C400-alkenylamino, di-(C6-C400- alkyl)amino, di-(C6-C400-alkenyl)amino and N-(C6-C400-alkyl)-N-(C6-C400-alkenyl)amino.
  • the long carbon chain residue is selected from the group consisting of C10-C300-alkyl, C10- C300-alkenyl, C10-C300-alkoxy, C10-C300-alkenyloxy, C10-C300-alkylamino, C10-C300-alkenylamino, di-(C10- C300-alkyl)amino, di-(C10-C300-alkenyl)amino and N-(C10-C300-alkyl)-N-(C10-C300-alkenyl)amino.
  • the long carbon chain residue is selected from the group consisting of C10-C200-alkyl, C10- C200-alkenyl, C10-C200-alkoxy, C10-C200-alkenyloxy, C10-C200-alkylamino, C10-C200-alkenylamino, di-(C10- C200-alkyl)amino, di-(C10-C200-alkenyl)amino and N-(C10-C200-alkyl)-N-(C10-C200-alkenyl)amino.
  • the long carbon chain residue is selected from the group consisting of C20-C150-alkyl, C20- C150-alkenyl, C20-C150-alkoxy, C20-C150-alkenyloxy, C20-C150-alkylamino, C20-C150-alkenylamino, di-(C20- C 150 -alkyl)amino, di-(C 20 -C 150 -alkenyl)amino, N-(C 20 -C 150 -alkyl)-N-(C 20 -C 150 -alkenyl)amino.
  • the long carbon chain residue is selected from the group consisting of C 20 -C 100 -alkyl, C 20 - C 100 -alkenyl, C 20 -C 100 -alkoxy, C 20 -C 100 -alkenyloxy, C 20 -C 100 -alkylamino, C 20 -C 100 -alkenylamino, di-(C 20 - C 100 -alkyl)amino, di-(C 20 -C 100 -alkenyl)amino, N-(C 20 -C 100 -alkyl)-N-(C 20 -C 100 -alkenyl)amino.
  • the long carbon chain residue is C 20 -C 100 -alkyl, e.g. polyisopropylene or polyisobutylene having a respective chain length.
  • Particularly preferred are, therefore, furthermore chiral iridium hydride complexes comprising an enone ligand of formula (I), wherein R 1 is methyl, phenyl or styryl, wherein the phenyl and styryl is unsubstituted or substituted by one substituent selected from C 20 -C 100 -alkyl, C 20 -C 100 -alkoxy, C 20 -C 100 -haloalkyl, and C 20 -C 100 - haloalkoxy, and BCS233012 FC -17-
  • R 2 is phenyl substituted by one substituent selected from C20-C100-alkyl, C20-C100-alkoxy, C20-C100- haloalkyl, and C20-C100-haloalk
  • chiral iridium hydride complexes comprising an enone ligand of formula (I), wherein R 1 is methyl, phenyl or styryl, wherein the phenyl or styryl is unsubstituted or substituted by C20-C100- alkyl, and R 2 is phenyl substituted by C20-C100-alkyl.
  • the chiral iridium hydride complexes according to the invention comprise furthermore a chiral chelating ligand, wherein said chiral chelating ligand comprises at least one phosphorus atom and at least one nitrogen atom that both bind to the iridium atom.
  • the chiral chelating ligand is a ligand of formula (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), BCS233012 FC -18- wherein R 3 , R 4 and R 5 are independently from one another selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7- cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C6-C14-aryl and C6-C14-aryl-C1-C4-alkyl, wherein the C1-C6-alkyl, C2-C6-
  • R 3 is preferably C1-C6-alkyl, C1-C6-haloalkyl, C3-C7-cycloalkyl or C6-C14-aryl, wherein the C6- C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and phenyl, wherein the phenyl again is unsubstituted or substituted by one to five C1-C6-alkyl substituents.
  • R 3 is more preferably selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl or phenyl, which is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and phenyl, wherein the phenyl again is unsubstituted or substituted by one to five C 1 -C 6 - alkyl substituents.
  • R 3 is more preferably phenyl, 2,6- or 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 4-tert- butylphenyl, 4-methoxyphenyl, 3,5-bis-tert-butyl-4-methoxyphenyl, 4-tert-butyl-2,6- dimethylphenyl, 4-fluorophenyl, 4-trifluoromehtylphenyl, 1-naphtyl, 9-antracenyl 2,4,6- triisopropylphenyl, 9-phenantryl or 2,6-diethyl-4-methylphenyl.
  • BCS233012 FC -22- R 4 and R 5 are preferably independently from one another selected from the group consisting of hydrogen, C1-C6-alkyl, C6-C14-aryl, C1-C6-alkoxy or C1-C6-haloalkyl, wherein the C6-C14-aryl is unsubstituted or substituted by one to five C1-C4-alkyl substituents.
  • R 4 and R 5 are more preferred independently from one another hydrogen or C1-C6-alkyl. More preferred R 4 is hydrogen and R 5 is hydrogen or methyl.
  • R 6 and R 7 are preferably independently from one another selected from the group consisting of C1-C6- alkyl, C1-C6-alkoxy, di(C1-C6-alkyl)amino, C3-C12-cycloalkyl, C6-C14-aryl, C6-C14-aryloxy and C6-C14-aryl-C1-C4-alkyl, piperidinyl and pyridyl, wherein the C1-C6-alkyl, C1-C6-alkoxy and di(C1-C6-alkyl)amino moieties are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl may be substituted by one to five substituents selected independently from each other from halogen, C1-C
  • R 6 and R 7 are more preferred independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl.
  • R 6 and R 7 are more preferred each the same and selected from the group consisting of ethyl, iso-propyl, tert-butyl, cyclopentyl, adamantyl and cyclohexyl.
  • m is preferably 1.
  • R 8 is preferably C 3 -C 6 -alkyl, C 3 -C 12 -cycloalkyl, C 6 -C 14 -aryl or C 6 -C 14 -aryl-C 1 -C 4 -alkyl, BCS233012 FC -23- 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 selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.
  • R 8 is more preferred tert-butyl, iso-propyl or phenyl.
  • R 9 and R 10 are preferably independently from one another selected from the group consisting of C1-C6- alkyl, C3-C12-cycloalkyl, C6-C14-aryl and C6-C14-aryl-C1-C4-alkyl, wherein the C1-C6-alkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl may be substituted by one to five substituents selected independently from each other from halogen, C1-C4-alkyl, phenyl, C1-C4-alkoxy, C1-C4- haloalkyl, and C1-C4-haloalkoxy, and wherein the
  • R 9 and R 10 are more preferred each the same and 2-methylphenyl or 3,5-bismethylphenyl.
  • A is preferably A 1 .
  • R 13 and R 14 are preferably independently from one another selected from the group consisting of C1-C6- alkyl, C3-C12-cycloalkyl, C6-C14-aryl and C6-C14-aryl-C1-C4-alkyl, wherein the C6-C14-aryl and the C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, or R 13 and R 14 together with the carbon which they are bound to, form a C5-C6-cycloalkyl ring
  • R 13 and R 14 are more preferred each methyl.
  • R 15 is preferably phenyl or t-butyl, more preferred phenyl.
  • R 16 is preferably hydrogen or methyl, more preferred methyl.
  • BCS233012 FC -24- Each R 17 is preferably benzyl or methyl, more preferred benzyl.
  • Each R 18 is preferably cyclohexyl.
  • the chiral iridium hydride complexes according to the invention comprise a chiral chelating ligand of formula (IIa) or (IIb).
  • R 3 is C1-C6-alkyl, C1-C6-haloalkyl, C3-C7-cycloalkyl or C6-C14-aryl, wherein the C6-C14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4- haloalkoxy and phenyl, wherein the phenyl again is unsubstituted or substituted by one to five C1-C6-alkyl substituents, R 4 and R 5 are independently from one another selected from the group consisting of hydrogen, C1-C6- alkyl, C1-C6-alkoxy, C6-C14-aryl or C1-C
  • R 3 is selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl or phenyl, which is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-alkyl, C1-C4-haloalkyl and phenyl, wherein the phenyl again is unsubstituted or substituted by one to five C1-C6-alkyl substituents, R 4 and R 5 are independently from one another hydrogen or C1-C6-alkyl, R 6 and R 7 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl,
  • R 3 is selected from the group consisting of, phenyl, 2,6- or 3,5-dimethylphenyl, 2,4,6- trimethylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3,5-bis-tert-butyl-4-methoxyphenyl, 4-tert-butyl-2,6-dimethylphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 1-naphtyl, 9- antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl or 2,6-diethyl-4-methylphenyl, R 4 is hydrogen, R 5 is hydrogen or methyl, R 6 and R 7 are each the same and tert-butyl, cyclopentyl or cyclohexyl, and m is 1.
  • R 3 is a group of formula BCS233012 FC -26- , wherein ** denotes the bond to the 6,7-dihydro-5H-cyclopenta[b]pyridine moiety
  • R 19 is hydrogen, methyl or ethyl
  • R 20 is C 1 -C 6 -alkyl
  • R 4 is hydrogen
  • R 5 is C 1 -C 4 alkyl or phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 - C 4 -alkoxy and C 1 -C 4 -haloalkoxy
  • R 6 and R 7 are independently from one another selected from the group consisting of C 1 -C 6- alkyl, C
  • the chiral iridium hydride complexes according to the invention comprise a chiral chelating ligand of formula (IIIa) or (IIIb).
  • ligands of formulae (IIIa) and (IIIb) are those, wherein the substituents are defined as follows: A is , in which the bond to the phosphorus atom and in which the bond identified by "#" is bound directly to the oxazoline moiety, 8 R is tert-butyl, R 13 and R 14 are each methyl, and BCS233012 FC -29- R 9 and R 10 are independently from one another phenyl, which is substituted by one or two methyl, in particular R 9 and R 10 are each the same and phenyl, which is substituted by one or two methyl or R 9 and R 10 are each the same and 2-methylphenyl or 3,5-dimethylphenyl.
  • the chiral iridium hydride complexes according to the invention comprise a chiral chelating ligand of formula (IVa) or (IVb).
  • Preferred ligands of formulae (IVa) and (IVb) are those, wherein the substituents are defined as follows: R 15 is selected from phenyl, benzyl, t-butyl, isopropyl or cyclohexyl, R 16 is selected from hydrogen, methyl, ethyl or isopropyl, R 17 is selected from hydrogen, benzyl, methyl or ethyl, and R 18 is selected from cyclohexyl, phenyl, 2-methylphenyl, 4-methylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl or 2,4,6-trimethylphenyl.
  • More preferred ligands of formulae (IVa) and (IVb) are those, wherein the substituents are defined as follows: R 15 is phenyl or t-butyl, R 16 is hydrogen or methyl, R 17 is benzyl or methyl, and R 18 is cyclohexyl. Most preferred ligands of formulae (IVa) and (IVb) are those, wherein the substituents are defined as follows: R 15 is phenyl, R 16 is methyl, R 17 is benzyl, and R 18 is cyclohexyl.
  • the chiral iridium hydride complex is a complex of formula (V) [IrH(L*)(L (I) )]Y, (V) BCS233012 FC -30- wherein L* is the chiral chelating ligand of formula (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), L (I) is the enone ligand of formula (I), and Y is a non-coordinating anion selected from the group consisting of [B(R 21 )4]-, PF6-, SbF6-, CF3SO3-, [Al ⁇ OC(CF3)3 ⁇ 4] ⁇ (VI) and ⁇ -TRISPHAT (VII) CI (VI) (VII) wherein R 21 is selected from fluorine and phenyl, which is unsubstituted or substituted with one to five substituents selected from C1-C4-alkyl, C1-C4-halo
  • L* i.e. the chiral chelating ligand of formula (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), and L (I) , i.e. the enone ligand of formula (I), the preferred, more preferred and most preferred definitions given above apply mutatis mutandis.
  • Y is preferably a non-coordinating anion selected from the group consisting of [B(R 21 )4]-, PF6- and [Al ⁇ OC(CF3)3 ⁇ 4] ⁇ (VI) F 3C CF3 F 3C CF3 BCS233012 FC -31- (VI) wherein R 21 is 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(R 21 )4]- and [Al ⁇ OC(CF3)3 ⁇ 4] ⁇ (VI) F 3C CF3 F 3C CF3 wherein R 21 is 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(R 21 )4]-, wherein R 21 is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.
  • the chiral iridium hydride complex is a complex of formula (V) [IrH(L*)(L (I) )]Y, (V) wherein L* is the chiral chelating ligand of formula (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), BCS233012 FC -32- R 3 is C1-C6-alkyl, C1-C6-haloalkyl, C3-C7-cycloalkyl or C6-C14-aryl, wherein the C6-C14- aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and phenyl, wherein the phenyl again is unsubstituted or substituted by one to
  • the chiral iridium hydride complex is a complex of formula (V) [IrH(L*)(L (I) )]Y, (V) wherein L* is the chiral chelating ligand of formula (IIa) or (IIb), 6 R 6 R m wherein R 3 is a group of formula , wherein ** denotes the bond to the 6,7-dihydro-5H-cyclopenta[b]pyridine moiety, R 19 is hydrogen, methyl or ethyl, preferably ethyl, and R 20 is C1-C6-alkyl, preferably methyl, R 4 is hydrogen, BCS233012 FC -38- R 5 is C1-C4 alkyl or phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4- haloalkyl, C
  • R 1a is selected from the group consisting of hydrogen, C 1 -C 4 -alkylcarbonyl, or R 1a and R 1 form together with the carbon atom to which R 1a is attached and the carbonyl group to which R 1 is attached a C5-C7-cycloalkanone ring, preferably a cyclohexanone ring, wherein the C5-C7-cycloalkanone ring is substituted by one benzylidene group in ortho position to the carbonyl group, wherein the benzylidene is unsubstituted or BCS233012 FC -39- substituted by one to five substituents selected independently from each other from halogen, C1-C6-alkyl, and C1-C6-alkoxy, R 2 is phenyl, wherein the phenyl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C100-alkyl, C1-C100
  • the chiral iridium hydride complex is a complex of formula (V) [IrH(L*)(L (I) )]Y, (V) wherein L* is the chiral chelating ligand of formula (IIa) or (IIb), wherein R 3 is 2,6-diethyl-4-methylphenyl, R 4 is hydrogen, R 5 is methyl, R 6 and R 7 are each cyclohexyl, and m is 1, L (I) is the enone ligand of formula (I), wherein R 1 is methyl, phenyl, styryl or 4-methoxystyryl (para-methoxystyryl), BCS233012 FC -41- R 1a is hydrogen or acetyl, or R 1a and R 1 form together with the carbon atom to which R 1a is attached and the carbonyl group to which R 1 is attached a cyclohexanone ring, wherein the cyclohexanone
  • the chiral iridium hydride complex is a complex of formula (V) [IrH(L*)(L (I) )]Y, (V) wherein L* is the chiral chelating ligand of formula (IIa) or (IIb), wherein R 3 is 2,6-diethyl-4-methylphenyl, R 4 is hydrogen, R 5 is methyl, R 6 and R 7 are each cyclohexyl, and m is 1, L (I) is the enone ligand of formula (I-H), wherein R 1 is methyl or styryl, and BCS233012 FC -42- R 2 is phenyl, and Y is a non-coordinating anion selected from the group consisting of [Al ⁇ OC(CF3)3 ⁇ 4] ⁇ of formula (VI) and [B(R 21 )4]-, wherein R 21 is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluoroph
  • the chiral iridium hydride complex is a complex of formula (VIII), - (VIII), wherein R 1’ is methyl, phenyl or styryl, and [Y]- is the non-coordinating anion [B(R 21 )4]-, wherein R 21 is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.
  • the chiral iridium hydride complexes according to the invention can be prepared for example from a chiral iridium catalyst known from WO 2019/185541, WO 2021/058457 and WO 2021/058458 by hydrogenation and subsequent reaction with the desired enone compound, e.g.
  • a spent catalyst that can be converted to a chiral iridium hydride complex according to the invention by reacting the spent catalyst with the desired enone of formula (I-a).
  • the chiral (P,N)-ligand remains unchanged.
  • the chiral iridium hydride complexes according to the invention can also be prepared from a spent catalyst resulting from the hydrogenation reaction disclosed herein using an chiral iridium hydride complex according to the invention, by reacting the spent catalyst with the desired enone of formula (I-a).
  • a spent catalyst is formed, that in a further step is reacted with the desired enone of formula (I-a).
  • reaction of the spent catalyst with enone of formula (I-a) is conducted in the presence of an solvent.
  • Suitable solvents are for example 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 BCS233012 FC -44- as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dieth
  • 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. 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.
  • reaction of the spent catalyst with enone of formula (I-a) and in the hydrogenation reaction the same solvent is used.
  • reaction of the spent catalyst with enone of formula (I-a) is conducted at a temperature within the range of from 10 °C to 130 °C, more preferably 20 °C to 80 °C.
  • the invention further 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 chiral iridium hydride complex according to the invention.
  • the invention relates in particular to a process for preparing a compound of formula (IXa) or (IXb), 25 25 ( R26 OR (R26)n O R wherein R 22 is selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 - C 6 -cycloalkyl, C 6 -C 14 -aryl, or C 6 -C 14 -aryl-C 1 -C 4 -alkyl, BCS233012 FC -45- 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 selected from the group consisting of halogen, C1-
  • compounds of the formula (IXa) or (IXb), in particular (IXa), are those, wherein the substituents are defined as follows:
  • R 22 is 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 from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, R 23 and R 24 are the same and are selected from C1-C4-alkyl, R 25 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl,
  • More preferred compounds of the formula (IXa) or (IXb), in particular (IXa), are those, wherein the substituents are defined as follows: R 22 is C 1 -C 6 -alkyl, R 23 and R 24 are the same and are selected from C 1 -C 4 -alkyl, R 25 is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenyl or benzyl, n is 0, 1 or 2, and each substituent R 26 , if present, is independently selected from the group consisting of halogen, C 1 -C 6 -alkyl and C 1 -C 6 -haloalkyl.
  • Even more preferred compounds of the formula (IXa) or (IXb), in particular (IXa), are those, wherein the substituents are defined as follows: R 22 is methyl, ethyl or n-propyl, R 23 and R 24 are each methyl, R 25 is C1-C4-alkyl, n is 0 or 1, R 26 , if present, is fluorine. Even more preferred compounds of the formula (IXa) or (IXb), in particular (IXa), are those, wherein the substituents are defined as follows: R 22 is methyl or n-propyl, R 23 and R 24 are each methyl, R 25 is methyl, n is 0 or 1, and R 26 , if present, is fluorine.
  • Most preferred compounds of the formula (IXa) or (IXb), in particular (IXa), are those, wherein the substituents are defined as follows: BCS233012 FC -48- R 22 is methyl, R 23 and R 24 are each methyl, R 25 is methyl, and n is 0.
  • the process according to the invention comprises enantioselective hydrogenation of a compound of formula (X).
  • the substituents R 22 , R 23 , R 24 , R 25 , R 26 and the integer n in the compound of formula (X) are each as defined for the compound of the formula (IXa) or (IXb).
  • the amount of chiral iridium hydride complex used is preferably within the range of from 0.001 mol% to 5 mol%, more preferably 0.001 mol% to 4 mol%, even more preferably 0.002 mol% to 3 mol%, most preferably 0.005 mol% to 1.0 mol%, based on the amount of the compound of formula (X).
  • 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.
  • 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, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane and anisole, and esters
  • 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.
  • BCS233012 FC -49- More preferred solvents are selected from the group consisting of 2,2,2,-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, and mixtures thereof.
  • 2,2,2,-trifluoroethanol and hexafluoroisopropanol are especially preferred.
  • 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 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 (X).
  • the process according to the invention is preferably conducted in the presence of an additive, which is selected from the group consisting of Br ⁇ nsted acids and Lewis acids.
  • the additive is preferably selected from the group consisting of hexafluorophosphoric acid, acetic acid, tri- 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
  • 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 complex, boron trifluoride acetic acid complex and boron trifluoride n-propanol complex.
  • 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, 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-
  • the additive is selected from the group consisting of hexafluorophosphoric acid, 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, boron trifluoride acetic acid complex and boron trifluoride n-propanol
  • 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 acetic acid complex and boron trifluoride n-propanol complex.
  • the amount of additive selected from the group consisting of Br ⁇ nsted 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 (X).
  • Example 1 Chiral iridium hydride complexes of formulae (XII), (XIII), and (XIV) have been prepared analogously.
  • Example 1 255 mg catalyst (XI) (0.154 mmol) were dissolved in dry 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (30 ml) under argon by standing 30 min in ultrasound-bath. The red solution was transferred to a 50 ml Swagelok 316 stainless steel mini-reactor and hydrogenated 1 h at r.t. under 6.0 MPa H 2 . After completion of the hydrogenation reaction and pressure release, H 2 gas was replaced by argon (addition of 1.0 MPa argon followed by pressure release to 0.1 MPa).
  • HFIP 1,1,1,3,3,3-hexafluoro-2-propanol
  • Example 3 Catalyst (XI) has been used in a hydrogenation process as disclosed in WO 2021/058458 to hydrogenate 1- (2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-one. 62 mg catalyst (XI) (37.5 ⁇ mol) were dissolved in dry HFIP (7.5 ml) under argon by standing 30 min in ultrasound-bath. The red solution was transferred to a 25 ml Swagelok 316 stainless steel mini-reactor and hydrogenated 1 h at r.t. under 6.0 MPa H2. After completion of the hydrogenation reaction and pressure release, H2 gas was replaced by argon (addition of 1.0 MPa argon followed by pressure release to 0.1 MPa).

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Abstract

L'invention concerne des complexes chiraux d'hydrure d'iridium comprenant a) un ligand (P,N) chiral et b) un ligand d'énone stabilisant de formule (I) dans laquelle R1 est choisi dans le groupe constitué par l'hydrogène, alkyle en C1-C500, alcényle en C2-C500, alcoxy en C1-C500, alcényloxy en C2-C500, alkylamino en C1-C500, alcénylamino en C2-C500, di-(C1-C500- alkyl)amino, di-(C2-C500-alcényl)amino, N-(C1-C500-alkyl)-N-(C2-C500-alcényl)amino, cycloalkyle en C3-C8, cycloalcoxy en C3-C8, cycloalkylamino en C3-C8, N-(C1-C500-alkyl)-N-(C3-C8-cycloalkyl)amino, aryle en C6-C14, qui peut être substitué comme défini en outre dans la description, R1a est choisi dans le groupe constitué par l'hydrogène, alkyle en C1-C6, alkylcarbonyle en C1-C6, ou R1a et R1 forment conjointement avec l'atome de carbone auquel R1a est attaché et le groupe carbonyle auquel R1 est attaché un cycle cycloalcanone en C5-C7, le cycle cycloalcanone en C5-C7 étant non substitué ou substitué par un à quatre substituants choisis indépendamment les uns des autres parmi alkyle en C1-C6, et benzylidène, le benzylidène étant non substitué ou substitué par un à cinq substituants choisis indépendamment les uns des autres parmi halogène, alkyle en C1-C500, alcoxy en C1-C500, haloalkyle en C1-C500, et haloalcoxy en C1-C500, R2 est choisi dans le groupe constitué par l'hydrogène, alkyle en C1-C500, C1-C500; alkylamino en C1-C500, di-(C1-C500-alkyl)amino, cycloalkyle en C3-C8, cycloalcoxy en C3-C8, cycloalkylamino en C3-C8, N-(C1-C500-alkyl)-N-(C3-C8-cycloalkyl)amino, aryle en C6-C14, qui peut être substitué comme défini en outre dans la description, et la flèche indique une liaison à l'atome d'iridium, ainsi qu'un procédé de préparation de 1,2,3,4-tétrahydroquinolines substituées en position 4 optiquement actives par hydrogénation énantiosélective des 1,2-dihydroquinolines substituées en position 4 correspondantes en présence d'un tel complexe chiral d'hydrure d'iridium.
PCT/EP2024/067162 2023-06-23 2024-06-19 Catalyseurs chiraux à base d'hydrure d'iridium pour l'hydrogénation énantiosélective de 1,2-dihydroquinolines substituées en position 4 Pending WO2024261094A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0654464A1 (fr) 1993-10-22 1995-05-24 Shell Internationale Researchmaatschappij B.V. Procédé pour la préparation des pesticides et composés intérmediaires
WO2015141564A1 (fr) 2014-03-18 2015-09-24 住友化学株式会社 Procédé de fabrication de composé optiquement actif
WO2019185541A1 (fr) 2018-03-26 2019-10-03 Bayer Aktiengesellschaft Hydrogénation énantiosélective de 1,2-dihydroquinoléines substituées en position 4 en présence d'un catalyseur d'iridium chiral
WO2021058458A1 (fr) 2019-09-25 2021-04-01 Bayer Aktiengesellschaft Procédé comprenant l'utilisation de nouveaux catalyseurs à base d'iridium pour l'hydrogénation énantiosélective de 1,2-dihydroquinoléines substituées en position 4
WO2021058457A1 (fr) 2019-09-25 2021-04-01 Bayer Aktiengesellschaft Hydrogénation énantiosélective améliorée de 1,2-dihydroquinoléines substituées en position 4 en présence d'un catalyseur d'iridium chiral et d'un additif

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0654464A1 (fr) 1993-10-22 1995-05-24 Shell Internationale Researchmaatschappij B.V. Procédé pour la préparation des pesticides et composés intérmediaires
WO2015141564A1 (fr) 2014-03-18 2015-09-24 住友化学株式会社 Procédé de fabrication de composé optiquement actif
WO2019185541A1 (fr) 2018-03-26 2019-10-03 Bayer Aktiengesellschaft Hydrogénation énantiosélective de 1,2-dihydroquinoléines substituées en position 4 en présence d'un catalyseur d'iridium chiral
WO2021058458A1 (fr) 2019-09-25 2021-04-01 Bayer Aktiengesellschaft Procédé comprenant l'utilisation de nouveaux catalyseurs à base d'iridium pour l'hydrogénation énantiosélective de 1,2-dihydroquinoléines substituées en position 4
WO2021058457A1 (fr) 2019-09-25 2021-04-01 Bayer Aktiengesellschaft Hydrogénation énantiosélective améliorée de 1,2-dihydroquinoléines substituées en position 4 en présence d'un catalyseur d'iridium chiral et d'un additif

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DAHLENBURG LUTZ ET AL: "Rhodium and iridium complexes with 2-(diphenylphosphanyl)anilido ligands: reactions with phenylacetylene and dimethyl acetylenedicarboxylate?+", JOURNAL OF THE CHEMICAL SOCIETY. DALTON TRANSACTIONS, no. 22, 1 January 1999 (1999-01-01), GB, pages 3935 - 3939, XP093100520, ISSN: 0300-9246, DOI: 10.1039/a906430c *
MILLER, M.-A.GRUBER, S.PFALTZ, A.: "Recovery and Recycling of Chiral Iridium (N,P Ligand) Catalysts from Hydrogenation Reactions", ADV. SYNTH. CATAL., vol. 360, no. 7, 2018, pages 1340 - 1345, XP072362241, DOI: 10.1002/adsc.201701591

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