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 PDFInfo
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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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- United States
- Prior art keywords
- alkyl
- aryl
- group
- substituted
- phenyl
- Prior art date
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- -1 4-substituted 1,2-dihydroquinolines Chemical class 0.000 title claims abstract description 240
- 239000003054 catalyst Substances 0.000 title claims abstract description 64
- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 26
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000005984 hydrogenation reaction Methods 0.000 title claims abstract description 17
- 239000003446 ligand Substances 0.000 claims abstract description 42
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims description 128
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 122
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 101
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 97
- 229910052736 halogen Inorganic materials 0.000 claims description 92
- 150000002367 halogens Chemical group 0.000 claims description 92
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 83
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 76
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 73
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000004437 phosphorous atom Chemical group 0.000 claims description 26
- 229910052698 phosphorus Inorganic materials 0.000 claims description 26
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 17
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 239000002131 composite material Substances 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 15
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 15
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical group C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 claims description 12
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 11
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 11
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 7
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 5
- CSUFEOXMCRPQBB-UHFFFAOYSA-N 1,1,2,2-tetrafluoropropan-1-ol Chemical compound CC(F)(F)C(O)(F)F CSUFEOXMCRPQBB-UHFFFAOYSA-N 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical group C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 claims 6
- SYGWYBOJXOGMRU-UHFFFAOYSA-N chembl233051 Chemical group C1=CC=C2C3=CC(C(N(CCN(C)C)C4=O)=O)=C5C4=CC=CC5=C3SC2=C1 SYGWYBOJXOGMRU-UHFFFAOYSA-N 0.000 claims 6
- NFGODEMQGQNUKK-UHFFFAOYSA-M [6-(diethylamino)-9-(2-octadecoxycarbonylphenyl)xanthen-3-ylidene]-diethylazanium;chloride Chemical group [Cl-].CCCCCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1C1=C2C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C21 NFGODEMQGQNUKK-UHFFFAOYSA-M 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 5
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 98
- 238000006243 chemical reaction Methods 0.000 description 43
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 41
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 238000004679 31P NMR spectroscopy Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 238000004293 19F NMR spectroscopy Methods 0.000 description 21
- 238000004896 high resolution mass spectrometry Methods 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 18
- 0 CC.CC.[1*][C@@H]1CC([2*])([3*])N(C([4*])=O)C2=CC=CC=C21.[1*][C@H]1CC([2*])([3*])N(C([4*])=O)C2=CC=CC=C21 Chemical compound CC.CC.[1*][C@@H]1CC([2*])([3*])N(C([4*])=O)C2=CC=CC=C21.[1*][C@H]1CC([2*])([3*])N(C([4*])=O)C2=CC=CC=C21 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 8
- NTEBDFQFERUHKG-UHFFFAOYSA-N 1-(2,2,4-trimethylquinolin-1-yl)ethanone Chemical compound C1=CC=C2C(C)=CC(C)(C)N(C(=O)C)C2=C1 NTEBDFQFERUHKG-UHFFFAOYSA-N 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- DICCKTLYSLKYNN-UHFFFAOYSA-N 1-(2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethanone Chemical compound C1=CC=C2C(C)CC(C)(C)N(C(C)=O)C2=C1 DICCKTLYSLKYNN-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MXXBEVHDZABNOF-UHFFFAOYSA-N CC.CC.CC.CC.CC.CC.CC.CC.COC1=CC=C2C=CC=CC2=C1C1=C(OC)C=CC2=C1C=CC=C2.COC1=CC=C2C=CC=CC2=C1C1=C(OC)C=CC2=C1C=CC=C2 Chemical compound CC.CC.CC.CC.CC.CC.CC.CC.COC1=CC=C2C=CC=CC2=C1C1=C(OC)C=CC2=C1C=CC=C2.COC1=CC=C2C=CC=CC2=C1C1=C(OC)C=CC2=C1C=CC=C2 MXXBEVHDZABNOF-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RXTJLDXSGNEJIT-UHFFFAOYSA-N 2,3-dihydro-1h-inden-4-amine Chemical class NC1=CC=CC2=C1CCC2 RXTJLDXSGNEJIT-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- KYWYAWFSWFSPAY-QMMMGPOBSA-N (3S)-1,1,3-trimethyl-2,3-dihydroinden-4-amine Chemical compound C[C@H]1CC(C)(C)C2=CC=CC(N)=C12 KYWYAWFSWFSPAY-QMMMGPOBSA-N 0.000 description 1
- KYWYAWFSWFSPAY-MRVPVSSYSA-N (3r)-1,1,3-trimethyl-2,3-dihydroinden-4-amine Chemical compound C1=CC(N)=C2[C@H](C)CC(C)(C)C2=C1 KYWYAWFSWFSPAY-MRVPVSSYSA-N 0.000 description 1
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ITWFKDWNQCKASQ-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F.FC(F)(F)C(O)C(F)(F)F ITWFKDWNQCKASQ-UHFFFAOYSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- KYWYAWFSWFSPAY-UHFFFAOYSA-N 1,1,3-trimethyl-2,3-dihydroinden-4-amine Chemical compound C1=CC(N)=C2C(C)CC(C)(C)C2=C1 KYWYAWFSWFSPAY-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- MOHGKCPAQLSAOF-UHFFFAOYSA-N 1-(2,2-dimethyl-4-propyl-3,4-dihydroquinolin-1-yl)ethanone Chemical compound CCCC1CC(C)(C)N(C(C)=O)C2=CC=CC=C12 MOHGKCPAQLSAOF-UHFFFAOYSA-N 0.000 description 1
- WEBVSXHLECNHCS-UHFFFAOYSA-N 1-(2,2-dimethyl-4-propylquinolin-1-yl)ethanone Chemical compound CCCC1=CC(C)(C)N(C(C)=O)C2=C1C=CC=C2 WEBVSXHLECNHCS-UHFFFAOYSA-N 0.000 description 1
- GJYHLESHXPAPRA-UHFFFAOYSA-N 1-(3,4,4a,5-tetrahydro-2h-quinolin-1-yl)ethanone Chemical class C1C=CC=C2N(C(=O)C)CCCC21 GJYHLESHXPAPRA-UHFFFAOYSA-N 0.000 description 1
- RRWLNRQGJSQRAF-UHFFFAOYSA-N 1-(3,4-dihydro-2h-quinolin-1-yl)ethanone Chemical class C1=CC=C2N(C(=O)C)CCCC2=C1 RRWLNRQGJSQRAF-UHFFFAOYSA-N 0.000 description 1
- BHJHVXBWRQTCRB-UHFFFAOYSA-N 1-(6-fluoro-2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethanone Chemical compound CC1CC(C)(C)N(C(C)=O)c2ccc(F)cc12 BHJHVXBWRQTCRB-UHFFFAOYSA-N 0.000 description 1
- SSHJBHQGONOUQG-UHFFFAOYSA-N 1-(6-fluoro-2,2,4-trimethylquinolin-1-yl)ethanone Chemical compound CC(=O)N1c2ccc(F)cc2C(C)=CC1(C)C SSHJBHQGONOUQG-UHFFFAOYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- NBUKAOOFKZFCGD-UHFFFAOYSA-N 2,2,3,3-tetrafluoropropan-1-ol Chemical compound OCC(F)(F)C(F)F NBUKAOOFKZFCGD-UHFFFAOYSA-N 0.000 description 1
- 125000004781 2,2-dichloro-2-fluoroethyl group Chemical group [H]C([H])(*)C(F)(Cl)Cl 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000004780 2-chloro-2,2-difluoroethyl group Chemical group [H]C([H])(*)C(F)(F)Cl 0.000 description 1
- 125000004779 2-chloro-2-fluoroethyl group Chemical group [H]C([H])(*)C([H])(F)Cl 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- RAOCNZGUDXPVPT-FQEVSTJZSA-N CC(C)(C)P(O[C@H]1CCCC2=C1N=C(C1=CC=CC=C1)C=C2)C(C)(C)C Chemical compound CC(C)(C)P(O[C@H]1CCCC2=C1N=C(C1=CC=CC=C1)C=C2)C(C)(C)C RAOCNZGUDXPVPT-FQEVSTJZSA-N 0.000 description 1
- IECACGNPALJUBP-UHFFFAOYSA-N CC(C)(O[Al-](OC(C)(C(F)(F)F)C(F)(F)F)(OC(C)(C(F)(F)F)C(F)(F)F)OC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(F)(F)F.ClC1=C(Cl)C2=C(O[P-]34(O2)(OC2=C(O3)C(Cl)=C(Cl)C(Cl)=C2Cl)OC2=C(O4)C(Cl)=C(Cl)C(Cl)=C2Cl)C(Cl)=C1Cl Chemical compound CC(C)(O[Al-](OC(C)(C(F)(F)F)C(F)(F)F)(OC(C)(C(F)(F)F)C(F)(F)F)OC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(F)(F)F.ClC1=C(Cl)C2=C(O[P-]34(O2)(OC2=C(O3)C(Cl)=C(Cl)C(Cl)=C2Cl)OC2=C(O4)C(Cl)=C(Cl)C(Cl)=C2Cl)C(Cl)=C1Cl IECACGNPALJUBP-UHFFFAOYSA-N 0.000 description 1
- QBAYEFZEHRNAMB-FWAHSXEBSA-O CC1=CC(C(F)(F)F)=CC(B(C2=CC(C)=CC(C(F)(F)F)=C2)(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)=C1.C[C@@H]1OC(C2=CC=CC=C2)=N2[C@@H]1C(CC1=CC=CC=C1)(CC1=CC=CC=C1)O[PH](C1CCCCC1)(C1CCCCC1)[Ir+]21/C2=C/CC/C=C/1CC2 Chemical compound CC1=CC(C(F)(F)F)=CC(B(C2=CC(C)=CC(C(F)(F)F)=C2)(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)=C1.C[C@@H]1OC(C2=CC=CC=C2)=N2[C@@H]1C(CC1=CC=CC=C1)(CC1=CC=CC=C1)O[PH](C1CCCCC1)(C1CCCCC1)[Ir+]21/C2=C/CC/C=C/1CC2 QBAYEFZEHRNAMB-FWAHSXEBSA-O 0.000 description 1
- PMPKVRNMUPNXBM-XMMPIXPASA-N CC1=CC(C)=CC(P(CC(C)(C)C2=N[C@@H](C(C)(C)C)CO2)C2=CC(C)=CC(C)=C2)=C1 Chemical compound CC1=CC(C)=CC(P(CC(C)(C)C2=N[C@@H](C(C)(C)C)CO2)C2=CC(C)=CC(C)=C2)=C1 PMPKVRNMUPNXBM-XMMPIXPASA-N 0.000 description 1
- TZGODYQOHHPDPC-QFIPXVFZSA-N CC1=CC=CC=C1P(CC(C)(C)C1=N[C@H](C(C)(C)C)CO1)C1=C(C)C=CC=C1 Chemical compound CC1=CC=CC=C1P(CC(C)(C)C1=N[C@H](C(C)(C)C)CO1)C1=C(C)C=CC=C1 TZGODYQOHHPDPC-QFIPXVFZSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- JAZCEXBNIYKZDI-UHFFFAOYSA-N [Ir+] Chemical compound [Ir+] JAZCEXBNIYKZDI-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- YTCIYOXHHQLDEI-SNVBAGLBSA-N inpyrfluxam Chemical compound C([C@H](C=12)C)C(C)(C)C2=CC=CC=1NC(=O)C1=CN(C)N=C1C(F)F YTCIYOXHHQLDEI-SNVBAGLBSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002503 iridium Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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.
Abstract
Description
- 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.
- It is known from EP 0 654 464 that N-acetyl-tetrahydroquinolines can be converted to the corresponding 4-aminoindane derivatives via a rearrangement reaction.
- 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.
- A method for preparing chiral intermediates of N-indanyl heteroaryl carboxamides via asymmetric synthesis is also known. 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 the 4-substituted NH-dihydroquinolines proceeded with moderate conversion rates (up to 62.6%) and enantioselectivity (up to 71.3% ee), whereas N-acetyl-dihydroquinolines gave even poorer conversion (up to 14%) and enantioselectivity (up to 31% ee).
- In the light of the prior art described above, it is an object of the present invention to provide a process for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines which process has advantages over the processes of the prior art. The process should allow the desired enantiomer to be prepared in high yield and high enantiomeric purity, with few process steps and few purification steps.
- The object described above was achieved by a process for preparing a compound of the formula (a) or (b),
- wherein
- R1 is selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C6-C14-aryl, or C6-C14-aryl-C1-C4-alkyl,
- wherein the C1-C6-alkyl, C3-C6-cycloalkyl and the C1-C6-alkoxy in the C1-C6-alkoxy-C1-C6-alkyl moiety, are 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, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and
- wherein the C6-C14-aryl and the C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy,
- R2 and R3 are the same and are selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-alkoxy-C1-C6-alkyl, or
- R2 and R3 together with the carbon to which they are bonded, form a C3-C6-cycloalkyl ring,
- R4 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, 9-flurorenylmethyleneoxy, C6-C14-aryl, C6-C14-aryloxy, C6-C14-aryl-C1-C4-alkyloxy or C6-C14-aryl-C1-C4-alkyl,
- wherein the C6-C14-aryl as such or as part of a composite substituent is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy,
- n is 0, 1, 2, 3 or 4,
- each substituent R5, if present, is independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxyl, amino and —C(═O)—C1-C6-alkyl,
- comprising enantioselective hydrogenation of a compound of the formula (II)
- wherein the substituents R1, R2, R3, R4, R5 and the integer n are each as defined for the compound of the formula (Ia) or (b),
- in presence of a chiral iridium catalyst,
- characterized in that the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa), (IIIb), (IVa) or (IVb),
- wherein
- R6, R7 and R8 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-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl and the C3-C7-cycloalkyl in the C3-C7-cycloalkyl-C1-C4-alkyl moiety are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy and C1-C4-haloalkyl and C1-C4-haloalkoxy, and
- wherein the C6-C14-aryl and the C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety are optionally 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,
- R9 and R10 are independently from one another selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, di(C1-C6-alkyl)amino, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C4-alkyl, C6-C14-aryl, C6-C14-aryloxy and C6-C14-aryl-C1-C4-alkyl,
- wherein the C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy and di(C1-C6-alkyl)amino, 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-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and
- wherein the C6-C14-aryl, C6-C14-aryloxy and C3-C12-cycloalkyl, in each case as such or as part of a composite substituent, are optionally 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 is unsubstituted or substituted by one to five C1-C6-alkyl substituents or
- R9 and R10 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C1-C6-alkyl groups, or
- R9 and R10 together form
-
- where the bonds identified by “x” and “y” are both bonded directly to the phosphorus atom,
- p and q are independently from one another selected from 0, 1 and 2,
- R11 and R12 are independently selected from C1-C6-alkyl and phenyl, which may be substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy and phenyl, which may be substituted by one or two C1-C4-alkyl substituents,
- m is 1 or 2,
- A is
-
- where the bond identified by “*” is bonded directly to the phosphorus atom and where the bond identified by “#” is bonded directly to the oxazoline moiety,
- R13 is C1-C6-alkyl, C1-C6-haloalkyl, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C4-alkyl, C1-C4-alkyl-C3-C7-cycloalkyl, C6-C14-aryl or 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 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,
- R14 and R15 are independently from one another selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C12-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C1-C4-alkyl-C3-C7-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 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, or
- R14 and R15 together with the carbon to which they are bonded, form a C5-C6-cycloalkyl ring,
- R16 and R17 are independently from one another selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, di(C1-C6-alkyl)amino, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C4-alkyl, C6-C14-aryl, C6-C14-aryloxy and C6-C14-aryl-C1-C4-alkyl,
- wherein the C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-cycloalkyl and di(C1-C6-alkyl)amino, 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-C4-alkyl, phenyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and
- wherein the C6-C14-aryl, the C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl, the C6-C14-aryloxy and C3-C12-cycloalkyl, in each case as such or as part of a composite substituent, are optionally substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, phenyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, or
- R16 and R17 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C1-C6-alkyl groups, or
- R16 and R17 together form
-
- where the bonds identified by “x” and “y” are both bonded directly to the phosphorus atom,
- p and q are independently from one another selected from 0, 1 and 2, and
- R11 and R12 are independently selected from C1-C6-alkyl and phenyl, which may be substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy and phenyl, which may be substituted by one or two C1-C4-alkyl substituents.
- It has been found, surprisingly, that 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.
- In the definitions of the symbols given in the above formulae, collective terms were used, which are generally representative of the following substituents:
- Halogen: fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine.
- Alkyl: saturated, straight-chain or branched hydrocarbyl substituents having 1 to 6, preferably 1 to 4 carbon atoms, for example (but not limited to) C1-C6-alkyl such as methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Particularly, said group is a C1-C4-alkyl group, e.g. a methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or 1,1-dimethylethyl (tert-butyl) group. This definition also applies to alkyl as part of a composite substituent, for example C3-C6-cycloalkyl-C1-C4-alkyl, C6-C14-aryl-C1-C4-alkyl etc., unless defined elsewhere.
- Alkenyl: unsaturated, straight-chain or branched hydrocarbyl substituents having 2 to 6, preferably 2 to 4 carbon atoms and one double bond in any position, for example (but not limited to) C2-C6-alkenyl such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-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, (E)-pent-1-enyl, (Z)-pent-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl or methylhexadienyl. Particularly, said group is vinyl or allyl. This definition also applies to alkenyl as part of a composite substituent unless defined elsewhere.
- Alkynyl: straight-chain or branched hydrocarbyl substituents having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one triple bond in any position, for example (but not limited to) C2-C6-alkynyl, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methylprop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl. This definition also applies to alkynyl as part of a composite substituent unless defined elsewhere.
- Alkylamino: monoalkylamino or dialkylamino, wherein monoalkylamino represents an amino radical having one alkyl residue with 1 to 4 carbon atoms attached to the nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino. Wherein 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) C1-C6-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. This definition also applies to alkoxy as part of a composite substituent unless defined elsewhere.
- Cycloalkyl: mono- or polycyclic, saturated hydrocarbyl substituents having 3 to 12, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl, cyclohexyl and adamantyl. This definition also applies to cycloalkyl as part of a composite substituent, for example C3-C6-cycloalkyl-C1-C4-alkyl, unless defined elsewhere.
- Haloalkyl: straight-chain or branched alkyl substituents having 1 to 6, preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) C1-C3-haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a composite substituent unless defined elsewhere.
- Haloalkenyl and haloalkynyl are defined analogously to haloalkyl except that, instead of alkyl groups, alkenyl and alkynyl groups are present as part of the substituent.
- Haloalkoxy: straight-chain or branched alkoxy substituents having 1 to 6, preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) C1-C3-haloalkoxy such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1-trifluoroprop-2-oxy. This definition also applies to haloalkoxy as part of a composite substituent, unless defined elsewhere.
- 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 term “enantioselective” as used herein means that one of the two possible enantiomers of the hydrogenation product, namely the enantiomer of the formula (Ia) or the enantiomer of the formula (Ib), is preferably formed. The “enantiomeric excess” or “ee” indicates the degree of enantioselectivity:
-
- 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).
- Preferred are compounds of the formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows:
- R1 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
- R2 and R3 are the same and are selected from C1-C4-alkyl,
- R4 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl,
- n is 0, 1 or 2,
- each substituent R5, if present, is independently selected from the group consisting of halogen, C1-C6-alkyl and C1-C6-haloalkyl.
- More preferred are compounds of the formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows:
- R1 is C1-C6-alkyl
- R2 and R3 are the same and are selected from C1-C4-alkyl,
- R4 is C1-C4-alkyl, C1-C4-haloalkyl, phenyl or benzyl,
- n is 0, 1 or 2,
- each substituent R5, if present, is independently selected from the group consisting of halogen and C1-C6-alkyl.
- Even more preferred are compounds of the formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows:
- R1 is methyl, ethyl or n-propyl,
- R2 and R3 are methyl,
- R4 is C1-C4-alkyl,
- n is 0, 1 or 2,
- each substituent R5, if present, is independently selected from the group consisting of halogen and C1-C6-alkyl.
- Most preferred are compounds of the formula (Ia) or (Ib), in particular (Ia), wherein the substituents are defined as follows:
- R1 is methyl or n-propyl,
- R2 and R3 are methyl,
- R4 is methyl,
- n is 0 or 1,
- substituent R5, if present, is fluorine.
- The process according to the invention comprises enantioselective hydrogenation of the compound of the formula (II). The substituents R1, R2, R3, R4, R5 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).
- In a preferred embodiment of the process according to the invention, the substituents of formulae (Ia), (Ib), (II), (IIIa), (IIIb), (IVa), (IVb) are defined as follows:
- R1 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
- R2 and R3 are the same and are selected from C1-C4-alkyl,
- R4 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl,
- n is 0, 1 or 2,
- each substituent R5, if present, is independently selected from the group consisting of halogen, C1-C6-alkyl and C1-C6-haloalkyl,
- R6 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,
- R7 and R8 are independently from one another hydrogen 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,
- R9 and R10 are 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,
- 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-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and
- wherein the C6-C14-aryl, C6-C14-aryloxy and C3-C12-cycloalkyl, as such or as part of a composite substituent, 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, C1-C4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five C1-C6-alkyl substituents or
- R9 and R10 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C1-C6-alkyl groups,
- m is 1 or 2,
- A is
-
- where the bond identified by “*” is bonded directly to the phosphorus atom and where the bond identified by “#” is bonded directly to the oxazoline moiety,
- R13 is C3-C6-alkyl, C3-C12-cycloalkyl, C6-C14-aryl or 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 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,
- R14 and R15 are 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
- R14 and R15 together with the carbon to which they are bonded, form a C5-C6-cycloalkyl ring,
- R16 and R17 are 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 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, or
- R16 and R17 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C1-C6-alkyl groups.
- In a more preferred embodiment of the process according to the invention, the substituents of formulae (Ia), (Ib), (II), (IIIa), (IIIb), (IVa), (IVb) are defined as follows:
- R1 is C1-C6-alkyl,
- R2 and R3 are the same and are selected from C1-C4-alkyl,
- R4 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl,
- n is 0, 1 or 2,
- each substituent R5, if present, is independently selected from the group consisting of halogen, C1-C6-alkyl and C1-C6-haloalkyl,
- R6 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,
- R7 and R8 are independently from one another hydrogen or C1-C6-alkyl,
- R9 and R10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl, and
- m is 1 or 2,
- A is
-
- where the bond identified by “*” is bonded directly to the phosphorus atom and where the bond identified by “#” is bonded directly to the oxazoline moiety,
- R13 is selected from the group consisting of C3-C6-alkyl, C3-C12-cycloalkyl, C6-C14-aryl or 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 in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen or C1-C4-alkyl,
- R14 and R15 are independently from one another selected from the group consisting of C1-C6-alkyl and C6-aryl-C1-C4-alkyl,
- wherein the C6-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 and C1-C4-alkyl,
- R14 and R15 together with the carbon to which they are bonded, form a C5-C6-cycloalkyl ring,
- R16 and R17 are 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 in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, phenyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, or
- R16 and R17 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C1-C6-alkyl groups.
- In the most preferred embodiment of the process according to the invention, the substituents of formulae (Ia), (Ib), (II), (IIIa), (IIIb), (IVa), (IVb) are defined as follows:
- R1 is C1-C4-alkyl,
- R2 and R3 are methyl,
- R4 is C1-C4-alkyl,
- n is 0 or 1
- R5 if present, is fluorine,
- R6 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,
- R7 is hydrogen,
- R8 is hydrogen or methyl,
- R9 and R10 are each the same and selected from the group consisting of ethyl, iso-propyl, tert-butyl, cyclopentyl, adamantyl and cyclohexyl,
- m is 1 or 2,
- A is
-
- where the bond identified by “*” is bonded directly to the phosphorus atom and where the bond identified by “#” is bonded directly to the oxazoline moiety,
- R13 is tert-butyl, iso-propyl or phenyl,
- R14 and R15 are methyl,
- R16 and R17 are each the same and 2-methylphenyl or 3,5-bismethylphenyl.
- In a preferred embodiment of the process according to the invention, 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.
- Preferred are ligands of the formulae (IIIa) and (IIIb), wherein the substituents are defined as follows:
- R6 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,
- R7 and R8 are independently from one another selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C6-C14-aryl or C1-C6-haloalkyl,
- wherein the C6-C14-aryl is unsubstituted or substituted by one to five C1-C4-alkyl substituents,
- R9 and R10 are 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,
- 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-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and
- wherein the C6-C14-aryloxy, C3-C12-cycloalkyl and C6-C14-aryl, as such or as part of a composite substituent, 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, C1-C4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five C1-C6-alkyl substituents or
- R9 and R10 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C1-C6-alkyl groups, and
- m is 1 or 2.
- More preferred are ligands of the formulae (IIIa) and (IIIb), wherein the substituents are defined as follows:
- R6 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,
- R7 and R8 are independently from one another hydrogen or C1-C6-alkyl,
- R9 and R10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl, and
- m is 1 or 2.
- Most preferred are ligands of the formulae (IIIa) and (IIIb), wherein the substituents are defined as follows:
- R6 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,
- R7 is hydrogen
- R8 is hydrogen or methyl,
- R9 and R10 are each the same and tert-butyl, cyclopentyl or cyclohexyl, and
- m is 1.
- In another preferred embodiment of the process according to the invention, 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.
- Preferred are ligands of the formulae (IVa) and (IVb), wherein the substituents are defined as follows:
- A is
-
- where the bond identified by “*” is bonded directly to the phosphorus atom and where the bond identified by “#” is bonded directly to the oxazoline moiety,
- R13 is C3-C6-alkyl, C3-C12-cycloalkyl, C6-C14-aryl or 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 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,
- R14 and R15 are independently from one another selected from the group consisting of C1-C6-alkyl, C6-C14-aryl, C3-C12-cycloalkyl, and C6-C14-aryl-C1-C4-alkyl,
- wherein 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
- R14 and R15 together with the carbon to which they are bonded, form a C5-C6-cycloalkyl ring,
- R16 and R17 are 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, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and
- wherein the C6-C14-aryl and the C6-C14-aryl in the C6-C14-aryl-C1-C4-alkyl moiety in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl, phenyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, or
- R16 and R17 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C1-C6-alkyl groups.
- More preferred are ligands of the formulae (IVa) and (IVb), wherein the substituents are defined as follows:
- A is
-
- where the bond identified by “*” is bonded directly to the phosphorus atom and where the bond identified by “#” is bonded directly to the oxazoline moiety,
- R13 is iso-propyl, sec-butyl, iso-butyl, tert-butyl, phenyl or benzyl,
- R14 and R15 are independently from one another selected from the group consisting of C1-C6-alkyl, and C6-aryl-C1-C4-alkyl,
- wherein the C6-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 and C1-C4-alkyl,
- R16 and R17 are independently from one another phenyl, 1-naphthyl or 2-naphthyl, which in each case is unsubstituted or substituted by one to five C1-C4-alkyl substituents
- Most preferred are ligands of the formulae (IVa) and (IVb), wherein the substituents are defined as follows:
- A is
-
- where the bond identified by “*” is bonded directly to the phosphorus atom and where the bond identified by “#” is bonded directly to the oxazoline moiety,
- R13 is tert-butyl,
- R14 and R15 are methyl, and
- R16 and R17 are independently from one another phenyl, which is substituted by one or two methyl, in particular R16 and R17 are each the same and phenyl, which is substituted by one or two methyl or R16 and R17 are each the same and 2-methylphenyl or 3,5-dimethylphenyl.
- Preferably, the chiral iridium catalyst is selected from the group consisting of [IrL*(COD)]Y and [IrL*(nbd)]Y, wherein
- L* is the chiral ligand of the formula (IIIa), (IIIb), (IVa) or (IVb),
- COD represents 1,5-cyclooctadiene,
- nbd represents norbornadiene, and
- Y is a non-coordinating anion selected from the group consisting of [B(R18)4]−, PF6 −, SbF6 −, CF3SO3 −, [Al{OC(CF3)3}4]− (VII) and Δ-TRISPHAT (VIII)
-
- wherein R18 is selected from fluorine and phenyl, which is unsubstituted or substituted with one to five substituents selected from C1-C4-alkyl, C1-C4-haloalkyl and halogen.
- More preferred are chiral iridium catalysts of the formulae [IrL*(COD)]Y and [IrL*(nbd)]Y, wherein Y is [Al{OC(CF3)3}4]− (VII) or [B(R18)4]−, wherein R18 is phenyl, which is unsubstituted or substituted with one to five substituents selected from fluorine and trifluoromethyl.
- Even more preferred are chiral iridium catalysts of the general formulae (Va), (Vb), (VIa) and (VIb)
- wherein
- R6 is selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl or phenyl,
- wherein 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl and phenyl are 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,
- R7 and R8 are independently from one another hydrogen, C1-C6-alkyl or C1-C6-alkoxy
- R9 and R10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl,
- m is 1 or 2,
- R13 is iso-propyl, sec-butyl, iso-butyl, tert-butyl, phenyl or benzyl,
- R14 and R15 are independently from one another selected from the group consisting of C1-C6-alkyl, and C6-aryl-C1-C4-alkyl,
- wherein the C6-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 and C1-C4-alkyl,
- R16 and R17 are independently from one another phenyl, 1-naphthyl or 2-naphthyl, which in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C1-C4-alkyl and C1-C4-haloalkyl, and
- R18 is phenyl, which is unsubstituted or substituted with one to five substituents selected from fluorine and C1-C4-haloalkyl.
- Particularly preferred are chiral iridium catalysts of the general formulae (Va), (Vb), (VIa) and (VIb), wherein
- R6 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 and 2,6-diethyl-4-methylphenyl,
- R7 is hydrogen,
- R8 is hydrogen or methyl
- R9 and R10 are each the same and tert-butyl, adamantly, cyclopentyl or cyclohexyl,
- m is 1 or 2,
- R13 is tert-butyl,
- R14 and R15 are methyl,
- R16 and R17 are independently from one another phenyl, which is substituted by one or two methyl, in particular R16 and R17 are each the same and 2-methylphenyl or 3,5-dimethylphenyl, and
- R18 is 3,5-bis(trifluoromethyl)phenyl.
- In an alternative embodiment the chiral iridium catalysts is of the general formulae (Va) and (Vb), wherein
- R6 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 and 2,6-diethyl-4-methylphenyl,
- R7 is hydrogen
- R8 is C1-C6-alkoxy
- R9 and R10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl, and
- m is 1.
- 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).
- The process according to the invention comprises enantioselective hydrogenation of the compound of the formula (II).
- Preferably, the hydrogenation is conducted using hydrogen gas at a pressure of from 1 to 300 bar, preferably 3 to 200 bar, most preferably 20 to 150 bar.
- The hydrogenation is preferably conducted at a temperature within the range of from 20° C. to 130° C., more preferably 30° C. to 100° C.
- 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 as ethyl acetate, isopropyl acetate, and mixtures thereof.
- Preferred solvents are selected from the group consisting of 2,2,2,-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, 1,4-dioxane, isopropyl acetate, toluene, and mixtures thereof.
- More preferred solvents are selected from the group consisting of 2,2,2,-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, and mixtures thereof.
- Especially preferred are 2,2,2,-trifluoroethanol and hexafluoroisopropanol.
- Most preferred is hexafluoroisopropanol.
- 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.
- 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).
- Preparation of Iridium Catalysts
- 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:
- Procedure of ligand synthesis (under Ar): A solution of alcohol precursor in THE (0.25 mmol, in 5.0 mL THF) was cooled to −78° C. and n-BuLi (0.1 mL of a 2.5 M n-BuLi solution in hexane; 0.25 mmol; 1 eq.) was added dropwise to the continuously stirred solution. After completion of the addition the solution was allowed to warm to room temperature and was stirred at this temperature for further 30 min. The solution was cooled to −78° C. again and R2PCl (0.25 mmol, 1 eq.) was added to the continuously stirred solution. The mixture was allowed to warm to room temperature and subsequently heated to 50° C. and kept at this temperature overnight. The theoretical yield of ligand was calculated using 31P-NMR and the ligand was used for the next step without further purification.
- Procedure of complexation (under Ar): To the crude ligand solution was added [Ir(COD)2]BARF (BARF=Tetrakis[3,5-bis(trifluoromethyl)phenyl]-borate) (as a solid, 1 eq. based on the theoretical yield). The resulting mixture was heated to 50° C. and kept at this temperature for 3 h.
- Work-up (under air): After cooling to room temperature the reaction solution is rotary evaporated onto silica, loaded onto a column of silica. Side components were eluted using pentane/diethylether and the desired complexes subsequently with DCM. The solvent was then evaporated under reduced pressure.
- The following specified catalysts were synthesized and characterized:
- with m=1 and R18=3,5-bis(trifluoromethyl)phenyl
-
Catalyst R6 R7 R8 R9, R10 Va-1 phenyl H H tert-butyl Va-2 phenyl H methyl tert-butyl Vb-3 phenyl H H cyclohexyl Va-4 phenyl H methyl cyclohexyl Vb-5 4-tert-butylphenyl H H cyclohexyl Va-6 4-tert-butylphenyl H methyl cyclohexyl Vb-7 9-antracenyl H H cyclohexyl Va-8 9-antracenyl H methyl cyclohexyl Va-9 2,6-dimethylphenyl H methyl cyclohexyl Va-10 2,4,6-trimethylphenyl H methyl cyclohexyl Va-11 3,5-dimethylphenyl H methyl cyclohexyl Va-12 1-naphtyl H methyl cyclohexyl Va-13 4-methoxyphenyl H methyl tert-butyl Va-14 4-fluorophenyl H methyl tert-butyl Va-15 4-(trifluoromethyl)phenyl H methyl tert-butyl Va-16 phenyl H methyl cyclopentyl Vb-17 phenyl H H ethyl Va-18 phenyl H methyl isopropyl Va-19 methyl H methyl cyclohexyl Va-20 3,5-bis-tert.-butyl,-4- H methyl cyclohexyl methoxyphenyl Va-21 2,4,6-triisopropylphenyl H methyl cyclohexyl Va-22 4-tert-butyl-2,6- H methyl cyclohexyl dimethylphenyl Va-23 phenyl H H adamantyl - Va-2
- 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).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.26 (dd, J=7.9, 1.7 Hz, 2H), 7.81-7.36 (in, 16H), 5.75 (dt, J=8.0, 5.2 Hz, 1H), 5.34-5.29 (in, 1H), 4.51 (q, J=5.3, 3.2 Hz, 1H), 4.11 (dq, J=12.5, 7.6, 5.9 Hz, 1), 3.08 (ddd, J=16.6, 10.3, 3.8 Hz, 1H), 2.99-2.70 (i, 2H), 2.61-2.00 (m, 8H), 1.92-1.79 (i, 1H), 1.69 (dd, J=14.8, 8.1 Hz, 1H), 1.51 (s, 9H), 1.29-1.24 (i, 3H), 1.06 (d, J=14.4 Hz, 9H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=142.09. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.85. HR-MS (ESI) m/z calcd for C31H44NOPIr [M]+ 670.2790 found 670.2798.
- Va-4
- 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).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.38-8.14 (m, 2H), 7.83-7.43 (m, 16H), 5.76 (dt, J=7.7, 4.9 Hz, 1H), 4.81 (t, J=7.6 Hz, 1H), 4.70-4.46 (m, 1H), 3.56-3.39 (m, 1H), 3.06 (ddd, J=16.7, 10.3, 3.6 Hz, 1H), 2.98-2.73 (m, 2H), 2.71-2.57 (m, 1H), 2.44 (s, 3H), 2.41-2.02 (m, 6H), 2.00-1.75 (m, 7H), 1.72-1.54 (m, 4H), 1.46-0.94 (m, 13H), 0.72-0.50 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=121.27. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.86. HR-MS (ESI) m/z calcd for C35H48NOPIr [M]+ 722.3103 found 722.3116.
- Vb-5
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated as an orange solid (261 mg; 74% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.25 (d, J=8.3 Hz, 2H), 7.87 (d, J=8.1 Hz, 1H), 7.81-7.64 (m, 111H), 7.56 (s, 4H), 5.74 (dt, J=8.2, 4.6 Hz, 1H), 4.95-4.74 (m, 1H), 4.74-4.51 (m, 1H), 3.60-3.45 (m, 1H), 3.23-2.91 (m, 2H), 2.90-2.70 (m, 1H), 2.67-2.50 (m, 1H), 2.52-2.23 (m, 4H), 2.28-2.04 (m, 3H), 2.04-1.77 (m, 7H), 1.69-1.58 (m, 4H), 1.45-1.26 (m, 17H), 1.17-0.95 (m, 4H), 0.68-0.42 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=121.12. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.85.
- HR-MS (ESI) m/z calcd for C38H54NOPIr [M]+ 764.3572 found 764.3586.
- Va-6
- 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).
- 1H-NMR (300 MHz, CDCl3): δ (ppm)=8.20 (d, J=8.2 Hz, 2H), 7.77-7.69 (m, 8H), 7.66 (d, J=8.4 Hz, 2H), 7.53 (d, J=4.9 Hz, 5H), 5.77-5.67 (m, 1H), 4.78 (d, J=7.6 Hz, 1H), 4.57 (s, 1H), 3.47 (s, 1H), 3.08-2.89 (m, 1H), 2.89-2.66 (m, 2H), 2.59 (p, J=7.4 Hz, 1H), 2.47-1.74 (m, 15H), 1.42 (s, 17H), 1.18-0.78 (m, 5H), 0.72-0.48 (m, 1H). 31P-NMR (122 MHz, CDCl3) 121.31. 19F-NMR (282 MHz, CDCl3) δ=−62.42. HR-MS (ESI): m/z calculated for [C39H56NOP193Ir]+: 778.3729 found 778.3732.
- Vb-7
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated after two time purification as an orange solid (151 mg; 36% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.84 (s, 1H), 8.38-8.27 (m, 1H), 8.21 (ddt, J=8.5, 1.3, 0.7 Hz, 1H), 8.18-8.02 (m, 2H), 7.83-7.72 (m, 10H), 7.72-7.54 (m, 6H), 7.49 (ddd, J=8.8, 6.6, 1.4 Hz, 1H), 7.23-6.96 (m, 1H), 5.74-5.54 (m, 1H), 5.26-5.12 (m, 1H), 4.41-4.18 (m, 1H), 3.53-3.15 (m, 3H), 2.75-2.61 (m, 2H), 2.59-2.32 (m, 2H), 2.18-1.91 (m, 6H), 1.92-1.74 (m, 5H), 1.74-1.56 (m, 2H), 1.48-1.21 (m, 10H), 1.18-0.99 (m, 1H), 0.96-0.59 (m, 2H), 0.39-0.15 (m, 1H), 0.06-0.11 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=120.30. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.87. HR-MS (ESI) m/z calcd for C42H50NOPIr [M]+ 808.3259 found 808.3278.
- Va-8
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated using DCM (100%) to afford an orange solid (296 mg; 78% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.68 (s, 1H), 8.23-7.85 (m, 3H), 7.75-7.23 (m, 17H), 7.05 (dq, J=8.8, 1.0 Hz, 1H), 5.61-5.40 (m, 2H), 5.12-4.88 (m, 1H), 4.24-4.00 (m, 1H), 3.25-2.88 (m, 3H), 2.58-2.46 (m, 2H), 2.44-2.14 (m, 7H), 2.08-1.61 (m, 111H), 1.61-1.37 (m, 5H), 1.37-1.07 (m, 6H), 1.03-0.85 (m, 1H), 0.65-0.45 (m, 1H), 0.16 (dtd, J=15.8, 10.4, 5.6 Hz, 1H), −0.16 (dt, J=13.2, 9.1 Hz, 1H). 31P-NMR (122 MHz, CD2Cl2) δ=120.57. 19F-NMR (282 MHz, CD2Cl2) δ=−62.86. HR-MS (ESI) m/z calcd for C43H52NOPIr [M]+ 822.3416 found 822.3416.
- Va-9
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated as an orange solid (298 mg; 82% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=7.80-7.52 (m, 12H), 7.42-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 5.65 (td, J=5.6, 2.6 Hz, 1H), 5.48-5.42 (m, 1H), 4.43-4.37 (m, 1H), 3.38-3.30 (m, 1H), 3.21-2.89 (m, 3H), 2.67 (s, 3H), 2.58-2.45 (m, 2H), 2.42 (s, 3H), 2.38-2.16 (m, 2H), 2.13-2.05 (m, 3H), 2.02-1.89 (m, 4H), 1.84 (s, 3H), 1.81-1.72 (m, 2H), 1.64-1.49 (m, 3H), 1.39-1.19 (m, 8H), 1.12-0.99 (m, 4H), 0.68-0.56 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ=118.80. 19F-NMR (282 MHz, CD2Cl2) δ=−62.88. HR-MS (ESI) m/z calcd for CH52NOPIr [M]+ 750.3416 found 750.3420.
- Va-10
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated as an orange solid (148 mg; 40% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=7.91-7.46 (m, 12H), 7.21 (s, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 5.67-5.63 (m, 1H), 5.46-5.41 (m, 1H), 4.38-4.36 (m, 1H), 3.36-3.32 (m, 1H), 3.19-2.85 (m, 3H), 2.64 (s, 3H), 2.53-2.46 (m, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.31-2.18 (m, 2H), 2.19-1.83 (m, 14H), 1.68-1.54 (m, 6H), 1.38-1.20 (m, 5H), 1.14-0.97 (m, 5H), 0.68-0.56 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ=118.64. 19F-NMR (282 MHz, CD2Cl2) δ=−62.87. HR-MS (ESI) m/z calcd for C38H54NOPIr [M]+ 764.3572 found 764.3577.
- Va-11
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated using DCM (100%) to afford an orange solid (310 mg; 85% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=7.86 (s, 2H), 7.79-7.47 (m, 13H), 7.36 (s, 1H), 5.79-5.62 (m, 1H), 4.78-4.74 (m, 1H), 4.57-4.53 (m, 1H), 3.56-3.48 (m, 1H), 3.13-2.95 (m, 1H), 2.95-2.61 (m, 3H), 2.51 (s, 6H), 2.47-2.36 (m, 5H), 2.34-2.03 (m, 5H), 2.03-1.77 (m, 7H), 1.71-1.47 (m, 7H), 1.45-1.19 (m, 5H), 1.19-0.98 (m, 4H), 0.70-0.62 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ=121.65. 19F-NMR (282 MHz, CD2Cl2) δ=−62.88. HR-MS (ESI) m/z calcd for C37H52NOPIr [M]+ 750.3416 found 750.3406.
- Va-12
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated as an orange solid (286 mg; 78% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.61-8.48 (m, 1H), 8.28-8.15 (m, 1H), 8.11-7.98 (m, 1H), 7.98-7.81 (m, 1H), 7.79-7.50 (m, 16H), 5.70 (ddd, J=8.1, 4.9, 3.2 Hz, 1H), 5.37-5.25 (m, 1H), 4.79 (d, J=10.4 Hz, 1H), 3.53-3.41 (m, 1H), 3.13 (ddd, J=17.2, 9.5, 4.9 Hz, 1H), 2.96 (ddd, J=17.1, 9.4, 4.9 Hz, 1H), 2.88-2.66 (m, 1H), 2.49-2.34 (m, 7H), 2.27-2.14 (m, 1H), 2.09-1.56 (m, 15H), 1.43-1.12 (m, 9H), 1.06-0.92 (m, 1H), 0.78-0.59 (m, 1H), 0.42-0.25 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ=121.69. 19F-NMR (282 MHz, CD2Cl2) δ=−62.87. HR-MS (ESI) m/z calcd for C39H50NOPIr [M]+ 722.3259 found 722.3262.
- Va-13
- 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).
- 1H-NMR (300 MHz, CDCl3): δ (ppm)=8.22 (d, J=8.7 Hz, 2H), 7.80-7.63 (m, 8H), 7.63-7.43 (m, 5H), 7.16 (d, J=8.8 Hz, 2H), 5.82-5.66 (m, 1H), 5.37-5.22 (m, 1H), 4.56-4.41 (m, 1H), 4.18-4.00 (m, 1H), 3.93 (s, 3H), 3.12-2.97 (m, 1H), 2.96-2.74 (m, 2H), 2.70-2.56 (m, 1H), 2.43 (s, 3H), 2.41-2.03 (m, 4H), 1.96-1.84 (m, 1H), 1.72 (dd, J=14.6, 7.9 Hz, 1H), 1.51 (d, J=15.0 Hz, 9H), 1.34-1.23 (m, 3H), 1.05 (d, J=14.4 Hz, 9H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=141.86. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.85. HR-MS (ESI) m/z calcd for C32H46NO2PIr [M]+ 700.2895 found 700.2899.
- Va-14
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated as an orange solid (245 mg; 70% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CDCl3): δ (ppm)=8.38-8.12 (m, 2H), 7.82-7.63 (m, 8H), 7.51 (s, 5H), 7.44-7.17 (m, 2H), 5.81-5.63 (m, 1H), 4.81-4.67 (m, 1H), 4.67-4.49 (m, 1H), 3.57-3.35 (m, 1H), 3.05-2.90 (m, 1H), 2.88-2.61 (m, 3H), 2.36 (s, 3H), 2.31-2.04 (m, 7H), 2.01-1.73 (m, 7H), 1.70-1.48 (m, 6H), 1.42-1.20 (m, 6H), 1.16-0.97 (m, 4H), 0.63-0.40 (m, 1H). 31P-NMR (122 MHz, CDCl3) δ (ppm)=121.31. 19F-NMR (282 MHz, CDCl3) δ (ppm)=−62.43, −106.61. HR-MS (ESI) m/z calcd for C35H47NOFPIr [M]+ 740.3009 found 740.3013.
- Va-15
- The reaction was performed according to the above described procedure using 287 mg of [Ir(COD)2]BARF (0.225 mmol). The complex could be isolated as an orange solid (180.0 mg; 48% based on [Ir(COD)2]BARF).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.46 (d, J=7.9 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H), 7.82-7.38 (m, 13H), 5.83-5.69 (m, 1H), 4.94-4.78 (m, 1H), 4.73-4.54 (m, 1H), 3.65-3.38 (m, 1H), 3.15-2.72 (m, 3H), 2.61-2.27 (m, 7H), 2.25-2.04 (m, 4H), 2.04-1.72 (m, 8H), 1.75-1.58 (m, 3H), 1.43-1.22 (m, 8H), 1.19-0.93 (m, 1H), 0.63-0.44 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=121.74. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.88, −63.40. HR-MS (ESI) m/z calcd for C36H47NOF3PIr [M]+ 790.2977 found 790.2990.
- Va-16
- 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).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=8.28-8.11 (m, 2H), 7.93-7.45 (m, 16H), 5.81 (dt, J=9.3, 5.0 Hz, 1H), 4.89 (t, J=6.9 Hz, 1H), 4.72-4.51 (m, 1H), 3.86-3.66 (m, 1H), 3.18-3.04 (m, 1H), 3.04-2.57 (m, 4H), 2.49 (s, 3H), 2.46-1.61 (m, 18H), 1.56-1.36 (m, 5H), 1.36-1.14 (m, 1H), 1.13-0.93 (m, 1H), 0.77-0.66 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=129.37. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.88. HR-MS (ESI) m/z calcd for C33H44NOPIr [M]+ 694.2790 found 694.2789.
- Vb-17
- 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).
- 1H-NMR (300 MHz, CDCl3): δ (ppm)=8.00-7.92 (m, 2H), 7.81-7.76 (m, 1H), 7.75-7.64 (m, 10H), 7.62-7.55 (m, 2H), 7.52 (d, J=1.9 Hz, 4H), 5.88 (dt, J=8.3, 4.9 Hz, 1H), 4.52 (dt, J=8.3, 4.2 Hz, 1H), 4.37 (ddt, J=7.4, 5.0, 2.5 Hz, 1H), 3.61 (td, J=8.0, 3.8 Hz, 1H), 3.17-2.64 (m, 4H), 2.34-1.79 (m, 9H), 1.68-1.55 (m, 1H), 1.36-0.90 (m, 9H). 31P-NMR (122 MHz, CDCl3) δ=116.36 (mayor product; 95%), 111.79 (minor species; 5%). 19F-NMR (282 MHz, CDCl3) δ=−62.41. HR-MS (ESI) m/z calcd for C2H34NOPIr [M]+ 600.2006 found 600.2006.
- Va-18
- 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).
- 1H-NMR (300 MHz, CDCl3): δ (ppm)=8.17 (dd, J=7.1, 1.8 Hz, 2H), 7.78-7.40 (m, 16H), 5.74 (dt, J=9.0, 4.7 Hz, 1H), 4.83 (t, J=6.9 Hz, 1H), 4.61 (dt, J=8.7, 4.1 Hz, 1H), 3.62-3.53 (m, 1H), 3.11-2.94 (m, 1H), 2.91-2.67 (m, 2H), 2.67-2.44 (m, 2H), 2.39 (s, 3H), 2.36-1.93 (m, 6H), 1.85 (dd, J=14.5, 7.3 Hz, 1H), 1.46 (dd, J=15.2, 7.1 Hz, 3H), 1.39-1.31 (m, 1H), 1.23 (dd, J=13.3, 6.9 Hz, 4H), 1.08 (dd, J=19.4, 7.1 Hz, 3H), 0.52 (dd, J=15.5, 7.1 Hz, 3H). 31P-NMR (122 MHz, CDCl3) δ (ppm)=129.53. 19F-NMR (282 MHz, CDCl3) δ (ppm)=−62.42. HR-MS (ESI) m/z calcd for C29H40NOPIr [M]+ 642.2477 found 642.2480.
- Va-19
- 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).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=7.81-7.61 (m, 9H), 7.56 (d, J=2.0 Hz, 4H), 7.34 (d, J=8.0 Hz, 1H), 5.76 (dt, J=8.7, 4.5 Hz, 1H), 5.05-4.84 (m, 2H), 3.74-3.57 (m, 1H), 3.56-3.36 (m, 1H), 3.07 (s, 3H), 3.01-1.49 (m, 23H), 1.42-1.01 (m, 9H), 0.85-0.70 (m, 1H), 0.51-0.25 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=126.20. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.88. HR-MS (ESI) m/z calcd for C29H4NOPIr [M]+ 644.2766 found 644.2762.
- Va-20
- 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).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=7.86-7.62 (m, 10H), 7.56 (s, 4H), 7.38 (s, 1H), 5.72 (dt, J=8.1, 5.2 Hz, 1H), 4.85-4.63 (m, 2H), 3.80 (s, 3H), 3.49-3.30 (m, 1H), 3.18-2.60 (m, 4H), 2.54-2.23 (m, 6H), 2.23-1.57 (m, 16H), 1.53-1.49 (m, 20H), 1.46-0.93 (m, 10H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=123.26. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.87. HR-MS (ESI) m/z calcd for C44H66NO2PIr [M]+ 864.4460 found 864.4448.
- Va-21
- 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).
- 1H-NMR (400 MHz, CD2Cl2): δ (ppm)=7.80-7.64 (m, 8H), 7.56 (s, 4H), 7.23 (s, 2H), 7.04 (s, 1H), 5.65 (dt, J=5.9, 3.7 Hz, 1H), 5.45-5.35 (m, 1H), 4.04 (ddd, J=8.2, 5.4, 3.6 Hz, 1H), 3.34 (dd, J=11.2, 6.4 Hz, 1H), 3.19-3.08 (m, 3H), 3.06-2.89 (m, 2H), 2.56-2.44 (m, 2H), 2.41 (s, 3H), 2.33-1.84 (m, 9H), 1.84-1.43 (m, 15H), 1.35-1.24 (m, 12H), 1.23-1.14 (m, 5H), 1.09 (dd, J=10.0, 6.8 Hz, 6H), 0.95 (d, J=6.6 Hz, 3H), 0.60-0.46 (m, 1H). 31P-NMR (162 MHz, CD2Cl2) δ (ppm)=119.43. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.86. HR-MS (ESI) m/z calcd for C4H66NOPIr [M]+ 848.4511 found 848.4512.
- Va-22
- 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).
- 1H-NMR (300 MHz, CD2Cl2): δ (ppm)=7.79-7.66 (m, 8H), 7.56 (s, 4H), 7.29 (s, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 5.65 (td, J=5.9, 2.2 Hz, 1H), 5.46-5.40 (m, 1H), 4.42-4.36 (m, 1H), 3.38-3.30 (m, 1H), 3.19-2.86 (m, 3H), 2.65 (s, 3H), 2.59-2.44 (m, 2H), 2.42 (s, 3H), 2.38-1.54 (m, 20H), 1.46-0.98 (m, 21H), 0.70-0.58 (m, 1H). 31P-NMR (122 MHz, CD2Cl2) δ (ppm)=118.67. 19F-NMR (282 MHz, CD2Cl2) δ (ppm)=−62.86. HR-MS (ESI) m/z calcd for C41H60NOPIr [M]+ 806.4042 found 806.4053.
- Va-23
- 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).
- 1H-NMR (300 MHz, CD2Cl2) δ=8.43-8.36 (m, 2H), 7.92-7.85 (m, 1H), 7.81-7.69 (m, 12H), 7.68-7.53 (m, 4H), 5.73-5.65 (m, 1H), 5.50-5.43 (m, 1H), 4.58-4.43 (m, 2H), 3.25-3.12 (m, 1H), 3.08-2.94 (m, 1H), 2.92-2.77 (m, 1H), 2.72-1.45 (m, 40H). 19F-NMR (282 MHz, CDCl3) δ=−62.42. 31P-NMR (122 MHz, CD2Cl2) δ=134.32. HR-MS (TOF) m/z calcd for C42H54NOPIr [M]+ 812.3572 found 812.3578.
- 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 CO2, 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. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed complete conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone (97% a/a purity according to SFC analysis) with an enantioselectivity of >98% ee.
- 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. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 99.3% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 97.5% ee.
- 1H-NMR (400 MHz, CDCl3) δ (ppm)=7.12-7.21 (m, 3H), 6.90-6.97 (m, 1H), 2.7-2.83 (m, 1H), 2.09 (s, 3H), 1.83 (d, 1H), 1.72 (s, 3H), 1.49 (s, 3H), 1.35 (d, 2H), 1.22 (t, 1H). UPLC-MS: Re: 1.26 min, UV (210 nm): 100%, m/z (ES+) 218.3. GC-MS: Rt: 4.78 min, m/z (RInt, %): 217 (15), 202 (10), 175 (5), 160 (100).
- 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. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 99.8% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 96.5% ee.
- 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. From the cooled and de-pressurized reaction mixture the solvent was evaporated to dryness under reduced pressure giving 5.6 g of the hydrogenated product 1-(6-fluoro-2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethanone (88.9% w/w purity, 98.7% yield) with an enantioselectivity of 98% ee.
- 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 μmol, 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. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 92.4% a/a HPLC conversion of starting material to the hydrogenated product 1-(2,2-dimethyl-4-propyl-3,4-dihydroquinolin-1-yl)ethanone with an enantioselectivity of 81.2% ee.
- 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. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 70% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 95.5% ee.
- In the comparative example 7 the following commercially available Cy-UbaPHOX (CAS 583844-38-6) catalyst was used:
- 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. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 84% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 81.7% ee.
- 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). For optimal results, 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.
- Detailed Comparison of Experiments with DE112015001290 T5:
-
Catalyst Conv. ee Example Catalyst [mol %] Solvent [%] [%] DE112015001290 T5, Ir 1.2 Trifluoro- 14.3 31.3 example 6 catalyst (I) ethanol Present invention, Va-1 1.2 Trifluoro- 70 95.5 example 6 ethanol - The comparison shows that 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).
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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 comparison shows that catalyst Va-1 of this invention is superior in conversion and enantiomeric excess (ee) to Ir catalyst (I) from DE112015001290 T5, example 6 under the conditions used in the present patent application (0.1 mol % of catalyst in hexafluoroisopropanol).
- Additionally, the conditions used in the present patent application (0.1 mol % of catalyst in hexafluoroisopropanol) are superior in conversion, enantiomeric excess (ee) and catalyst amount to the conditions used in DE112015001290 T5, example 6 (1.2 mol % of catalyst in trifluoroethanol).
- Under an inert gas atmosphere, one well of a 96 well-plate autoclave was filled with 9.8 mg of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (45.5 mol, 1 equiv) and 1.82 mol of catalyst (4 mol %, see table 1) in 0.49 mL of 2,2,2-trifluoroethanol. The autoclave was pressurized with 30 bar of hydrogen, heated to 40° C. and the reaction mixture was shaken at that temperature for 16 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed the % a/a HPLC conversion rates of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone. The % a/a HPLC conversion rates and enantioselectivities are depicted in table 1 below.
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Conversion Ex. Catalyst1) Ligand L* Anion Y (% a/a HPLC) % ee 8 [IrL*(COD)]Y BARF2) 47 89 9 [IrL*(COD)]Y BARF2) 47 93 10 [IrL*(COD)]Y BARF2) 55 91 11 [IrL*(COD)]Y BARF2) 44 51 1)The catalyst used in example 8 was prepared according to the method disclosed in S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197; the catalysts used in examples 9 and 10 were prepared according to the method disclosed in W. J. Drury III et al., Angew. Chem. Int. Ed. 2004, 43, 70-74; the catalyst used in example 11 was formed in situ from [Ir(COD)2]BARF and the depicted ligand. 2)BARF = Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate - 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. After this the autoclave was pressurized to 60 bar hydrogen pressure and was placed in a suitable alumina block. After heating to 85° C. the reaction was kept at this temperature for the given time. After cooling to room temperature and depressurizing, the vial was taken out of the autoclave and the reactions outcome was determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess by HPLC analysis.
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Reaction catalyst Conversion Enantiomeric time loading GC excess Example Catalyst (h) (mol %) (% a/a) (% ee) 12 Va-1 16 0.1 99.2 98.0 13 Va-1 6 0.1 81.5 97.5 14 Va-2 6 0.1 94.5 97.5 15 Vb-3 6 0.05 88.2 97.6 16 Va-4 16.5 0.05 94.4 97.3 17 Va-4 16 0.1 99.4 96.0 18 Va-4 16.5 0.1 92.0 97.0 19 Vb-5 16 0.05 98.4 96.8 20 Vb-5 6 0.025 67.2 97.3 21 Va-6 6 0.025 91.6 97.3 22 Vb-7 16.5 0.05 98.9 95.8 23 Vb-7 16.5 0.025 79.5 97.5 24 Va-8 16 0.025 94.1 97.5 25 Va-9 16.5 0.025 81.7 97.9 26 Va-10 16.5 0.025 98.0 98.1 27 Va-11 16.5 0.025 42.2 94.5 28 Va-12 16 0.05 92.4 96.9 29 Va-13 16.5 0.1 91.2 97.0 30 Va-14 16 0.05 64.7 92.4 31 Va-15 16 0.05 34.6 83.2 32 Va-16 16 0.05 87.9 95.8 33 Vb-17 16 0.1 30 90.0 34 Va-18 16 0.1 76.0 96.0 35 Va-19 16 0.025 7.2 70.8 36 Va-20 16 0.025 60 92.1 37 Va-21 16 0.025 74 98.0 38 Va-22 1 0.025 97.5 97.3 39 Va-23 16 0.1 30 94
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