US20210009521A1 - Enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in presence of a chiral iridium catalyst - Google Patents

Enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in presence of a chiral iridium catalyst Download PDF

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US20210009521A1
US20210009521A1 US17/041,907 US201917041907A US2021009521A1 US 20210009521 A1 US20210009521 A1 US 20210009521A1 US 201917041907 A US201917041907 A US 201917041907A US 2021009521 A1 US2021009521 A1 US 2021009521A1
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alkyl
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Christoph SCHOTES
Dirk Eckart BROHM
Johannes SCHRANCK
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Bayer AG
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    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/189—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms containing both nitrogen and phosphorus as complexing atoms, including e.g. phosphino moieties, in one at least bidentate or bridging ligand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0202—Polynuclearity
    • B01J2531/0205—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/827—Iridium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/842—Iron

Definitions

  • 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,N)-ligand catalyst.
  • 4-aminoindane derivatives are important intermediates for preparing various N-indanyl heteroaryl carboxamides having fungicidal activity (EP 0 654 464, WO 2011/162397, WO 2012/084812, WO 2015/197530).
  • EP 3 103 789 discloses a method for optically resolving 1,1,3-trimethyl-4-aminoindane by converting the enantiomeric mixture into the diastereomeric salts of D-tartaric acid.
  • (R)- and (S)-1,1,3-trimethyl-4-aminoindane are obtained after separation and basification of the diastereomeric salts.
  • This reference also discloses a method for racemizing the undesired enantiomer, so that the whole method allows for converting the undesired enantiomer into the desired enantiomer via several process steps.
  • (R)-1,1,3-trimethyl-4-aminoindane is an important intermediate for preparing the pyrazole carboxamide fungicide inpyrfluxam.
  • 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 chiral iridium catalyst comprises a chiral ligand of the formula (IIIa), (IIIb), (IVa) or (IVb),
  • optically active 4-substituted 1,2,3,4-tetrahydroquinolines (Ia and Ib) can be prepared in high yields and excellent enantioselectivity by enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines (II) in presence of a chiral iridium (P,N)-ligand catalyst.
  • 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) C 1 -C 6 -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,
  • said group is a C 1 -C 4 -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 C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 6 -C 14 -aryl-C 1 -C 4 -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) C 2 -C 6 -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-1-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
  • 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) C 2 -C 6 -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-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-y
  • Alkylamino monoalkylamino or dialkylamino, wherein monoalkylamino represents an amino radical having one alkyl residue with 1 to 4 carbon atoms attached to the nitrogen atom.
  • monoalkylamino represents an amino radical having one alkyl residue with 1 to 4 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 4 carbon atoms each attached to the nitrogen atom.
  • Non-limiting examples include N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-iso-propyl-N-n-propylamino and N-tert-butyl-N-methylamino.
  • 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) 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-trimethylpropoxy, 1,2,
  • 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 C 3 -C 6 -cycloalkyl-C 1 -C 4 -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) C 1 -C 3 -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
  • 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) C 1 -C 3 -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-fluoroeth
  • 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.
  • enantioselective 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:
  • the major enantiomer can be controlled by the selection of the chiral ligand, for example by selecting the chiral ligand of the formula (IIIa) or the opposite enantiomer (the ligand of the formula (IIIb)), or respectively by selecting the chiral ligand of the formula (IVa) or the opposite enantiomer (the ligand of the formula (IVb)).
  • the process according to the invention is used for preparing the compound of the formula (a) or (b), preferably (Ia).
  • the process according to the invention comprises enantioselective hydrogenation of the compound of the formula (II).
  • the substituents R 1 , R 2 , R 3 , R 4 , R 5 and the integer n in the compound of the formula (II) are each as defined for the compound of the formula (Ia) or (b).
  • 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), (IIIb), (IVa) or (IVb).
  • the ligand of the formula (IIIa) or (IIIb) is used. Depending on whether compound (Ia) or (Ib) is the desired product, the ligand of the formula (IIIa) or (IIIb) is selected.
  • the ligand of the formula (IVa) or (IVb) is used. Depending on whether compound (Ia) or (Ib) is the desired product, the ligand of the formula (IVa) or (IVb) is selected.
  • the chiral iridium catalyst is selected from the group consisting of [IrL*(COD)]Y and [IrL*(nbd)]Y, wherein
  • chiral iridium catalysts of the formulae [IrL*(COD)]Y and [IrL*(nbd)]Y, wherein Y is [Al ⁇ OC(CF 3 ) 3 ⁇ 4 ] ⁇ (VII) or [B(R 18 ) 4 ] ⁇ , wherein R 18 is phenyl, which is unsubstituted or substituted with one to five substituents selected from fluorine and trifluoromethyl.
  • chiral iridium catalysts of the general formulae (Va), (Vb), (VIa) and (VIb), wherein
  • the chiral iridium catalysts is of the general formulae (Va) and (Vb), wherein
  • the amount of iridium catalyst used is preferably within the range of from 0.001 mol % to 5 mol %, more preferably 0.005 mol % to 4 mol %, most preferably 0.01 mol % to 3 mol %, in particular 0.01 mol % to 2.0 mol %, based on the amount of the compound of the formula (II).
  • the chiral iridium catalyst may be prepared by methods known in the art from an iridium (I) catalyst precursor, such as [Ir(COD)Cl] 2 , the chiral ligand of the formula (IIIa), (IIIb), (IVa) or (IVb) and an alkali salt of the non-coordinating anion (S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197; W. J. Drury III et al., Angew. Chem. Int. Ed. 2004, 43, 70-74).
  • I iridium
  • the process according to the invention comprises enantioselective hydrogenation of the compound of the formula (II).
  • 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.
  • 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 such
  • 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.
  • the hydrogenation may optionally be conducted in presence of an acidic additive, such as acetic acid, trifluoroacetic acid, camphorsulfonic acid, p-toluenesulfonic acid, pivalic acid, benzoic acid, formic acid, butyric acid or oxalic acid. If an acidic additive is used, it is preferably used as a mixture with the solvent.
  • an acidic additive such as acetic acid, trifluoroacetic acid, camphorsulfonic acid, p-toluenesulfonic acid, pivalic acid, benzoic acid, formic acid, butyric acid or oxalic acid. If an acidic additive is used, it is preferably used as a mixture with the solvent.
  • the amount of acidic used is preferably at most 20 mol %, more preferably at most 10 mol %, and in particular within the range of from 0 to 5 mol %, based on the amount of the compound of the formula (II).
  • the ligand precursors (enantiomerically enriched secondary alcohols) were prepared according to known literature procedures like to the method disclosed in S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197 or in D. H. Woodmansee Chem. Sci 2010, 1, 72.
  • the ligands and Iridium complexes were prepared by a modified procedure based on the same literature precedents:
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (89.5 mg; 53% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (241 mg; 71% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (286 mg; 64% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the theoretical yield of the ligand was 51%.
  • the complex could be isolated as an orange solid (78.0 mg; 39% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the theoretical yield of the ligand was 90%.
  • the complex could be isolated as an orange solid (261 mg; 75% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (134 mg; 95% purity based on 31P-NMR; 39% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed (0.5 mmol scale) according to the above described procedure, but after the addition of ClP(iPr) 2 was completed, the reaction mixture was stirred at RT for 16 h.
  • the complex could be isolated as an orange solid (605 mg; 85% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (249 mg; 73% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (164 mg; 42% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (51 mg; 14% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (274 mg; 73% based on [Ir(COD) 2 ]BARF).
  • the reaction was performed according to the above described procedure.
  • the complex could be isolated as an orange solid (15.6 mg; 20% based on [Ir(COD) 2 ]BARF).
  • Reactions were performed in metal autoclaves. Reaction mixtures were analyzed without workup via HPLC (Chiralpak IC column, 95/5 heptane/ethanol, 1 mL/min) or SFC (OZ-H column, 2.5% MeOH in supercritical CO 2 , 3 mL/min) chromatography.
  • a 600 mL autoclave was filled with 21 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (97.5 mmol, 1 equiv), 0.74 g of catalyst (Va-1) (0.48 mmol, 0.5 mol %) and 450 mL of 2,2,2-trifluoroethanol.
  • the autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85° C. and the reaction mixture was stirred at that temperature for 72 h.
  • a 16 mL autoclave was filled with 0.7 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3.3 mmol, 1 equiv), 4.9 mg of catalyst (Va-1) (3.3 mol, 0.1 mol %) and 4.2 mL of 1,1,1,3,3,3-hexafluor-2-propanol.
  • the autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85° C. and the reaction mixture was stirred at that temperature for 16 h.
  • a 16 mL autoclave was filled with 0.52 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (2.41 mmol, 1 equiv), 9.2 mg of catalyst (Va-1) (6 mol, 0.25 mol %) and 6 mL of 1,1,1,3,3,3-hexafluoro-2-propanol.
  • the autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85° C. and the reaction mixture was stirred at that temperature for 15 h.
  • a 100 mL autoclave was filled with 5 g of 1-(6-fluoro-2,2,4-trimethyl-1-quinolyl)ethanone (21.4 mmol, 1 equiv), 65 mg of catalyst (Va-1) (40 mol, 0.2 mol %) and 50 mL of 1,1,1,3,3,3-hexafluoro-2-propanol.
  • the autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85° C. and the reaction mixture was stirred at that temperature for 36 h.
  • a 16 mL autoclave was filled with 0.25 g of 1-(2,2-dimethyl-4-propyl-1-quinolyl)ethanone (88.7% a/a HPLC, 1.02 mmol, 1 equiv), 7.8 mg of catalyst (Va-1) (5 ⁇ mol, 0.5 mol %) and 5 mL of 1,1,1,3,3,3-hexafluoro-2-propanol.
  • the autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85° C. and the reaction mixture was stirred at that temperature for 15 h.
  • Example 6 Comparison Using Reaction Conditions from Example 6 of DE112015001290 T5
  • a 25 mL autoclave was filled with 0.5 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (2.3 mmol, 1 equiv), 43.9 mg of catalyst (Va-1) (29 mol, 1.2 mol %) and 12.2 mL of 2,2,2-trifluoroethanol.
  • the autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 70 bar of hydrogen, heated to 90° C. and the reaction mixture was stirred at that temperature for 9 h.
  • Example 7 Comparison Using Catalyst from Example 6 of DE112015001290 T5
  • a 16 mL autoclave was filled with 0.7 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3.3 mmol, 1 equiv), 5.6 mg of catalyst (Cy-UbaPHOX, CAS 880262-14-6) (3.3 mol, 0.1 mol %) and 4.2 mL of 1,1,1,3,3,3-hexafluor-2-propanol.
  • the autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85° C. and the reaction mixture was stirred at that temperature for 16 h.
  • Both the catalyst VI-a used in this invention (e.g. example 2) and the reaction conditions are superior to the benchmark catalyst and conditions from DE112015001290 T5 (example 6).
  • the reaction conditions and the catalysts (e.g. Va-1) of this invention have to be used in combination (e.g. example 2).
  • Other catalysts from this invention like Va-4, Va-6, Va-8, Va-10 and Va-22 show even superior activity to both Va-1 and Cy-UbaPHOX.
  • catalyst Va-1 of this invention is superior conversion and enantiomeric excess (ee) to Ir catalyst (I) from DE112015001290 T5 (example 6) under the conditions used in DE112015001290 T5, example 6 (1.2 mol % of catalyst in trifluoroethanol).
  • Catalyst Conv. ee Example Catalyst [mol %] Solvent [%] [%] Present invention, Ir 0.1 Hexafluoroiso- 84 81.7 example 7 catalyst (I) propanol Present invention, Va-1 0.1 Hexafluoroiso- 100 97.5 example 2 propanol
  • the Ir-complex (catalyst loading given) and 0.64 g 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3 mmol) were placed in an 8-mL autoclave vial containing a PTFE-coated stirring bar.
  • the autoclave vial was closed using a screw cap with septum and flushed with argon (10 min).
  • Hexafluoroisopropanol (HFIP, 4 mL) was added via the septum to the vial.
  • the vial was placed in an argon containing autoclave and the autoclave was flushed with argon (10 min).
  • the autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times.

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