CN101119800A - 酮的不对称氢化硅烷化方法 - Google Patents
酮的不对称氢化硅烷化方法 Download PDFInfo
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- CN101119800A CN101119800A CNA200680005345XA CN200680005345A CN101119800A CN 101119800 A CN101119800 A CN 101119800A CN A200680005345X A CNA200680005345X A CN A200680005345XA CN 200680005345 A CN200680005345 A CN 200680005345A CN 101119800 A CN101119800 A CN 101119800A
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- enantiomer
- transition metal
- enantiomers
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 150000002576 ketones Chemical class 0.000 title claims abstract description 17
- 238000006459 hydrosilylation reaction Methods 0.000 title abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 239000003054 catalyst Substances 0.000 claims abstract description 37
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 32
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 26
- 150000003624 transition metals Chemical class 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 16
- 239000000758 substrate Substances 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000010949 copper Substances 0.000 claims description 19
- 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 claims description 18
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 16
- 229910052802 copper Inorganic materials 0.000 claims description 14
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 12
- 229910016509 CuF 2 Inorganic materials 0.000 claims description 11
- 238000002444 silanisation Methods 0.000 claims description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 claims description 7
- 239000012965 benzophenone Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 5
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 5
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 5
- 239000010948 rhodium Substances 0.000 claims description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- 229910052707 ruthenium Inorganic materials 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052741 iridium Inorganic materials 0.000 claims description 4
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- 229910000077 silane Inorganic materials 0.000 claims description 4
- 150000004678 hydrides Chemical class 0.000 claims description 3
- 239000003446 ligand Substances 0.000 abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 238000003965 capillary gas chromatography Methods 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000012298 atmosphere Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- JRTHAKOHBMETRC-UHFFFAOYSA-N [3-[4-bis(3,5-dimethylphenyl)phosphanyl-2,6-dimethoxypyridin-3-yl]-2,6-dimethoxypyridin-4-yl]-bis(3,5-dimethylphenyl)phosphane Chemical compound COC=1N=C(OC)C=C(P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)C=1C=1C(OC)=NC(OC)=CC=1P(C=1C=C(C)C=C(C)C=1)C1=CC(C)=CC(C)=C1 JRTHAKOHBMETRC-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- JZOSBBLJKXSBBN-UHFFFAOYSA-N [3-(4-diphenylphosphanyl-2,6-dimethoxypyridin-3-yl)-2,6-dimethoxypyridin-4-yl]-diphenylphosphane Chemical compound COC=1N=C(OC)C=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C=1C(OC)=NC(OC)=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 JZOSBBLJKXSBBN-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 150000003333 secondary alcohols Chemical class 0.000 description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 4
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- MMLOBFXCWYLINK-UHFFFAOYSA-N chloro(diphenyl)methanol Chemical group C=1C=CC=CC=1C(Cl)(O)C1=CC=CC=C1 MMLOBFXCWYLINK-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000002769 thiazolinyl group Chemical group 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 3
- DZLZSFZSPIUINR-UHFFFAOYSA-N 1-(2-bromophenyl)ethanol Chemical compound CC(O)C1=CC=CC=C1Br DZLZSFZSPIUINR-UHFFFAOYSA-N 0.000 description 2
- DDUBOVLGCYUYFX-UHFFFAOYSA-N 1-(2-chlorophenyl)ethanol Chemical compound CC(O)C1=CC=CC=C1Cl DDUBOVLGCYUYFX-UHFFFAOYSA-N 0.000 description 2
- ZUBPFBWAXNCEOG-UHFFFAOYSA-N 1-(3-methoxyphenyl)ethanol Chemical compound COC1=CC=CC(C(C)O)=C1 ZUBPFBWAXNCEOG-UHFFFAOYSA-N 0.000 description 2
- KPURZDPKEGBNFL-UHFFFAOYSA-N 1-[2-(aminomethyl)phenyl]ethanol Chemical compound CC(O)C1=CC=CC=C1CN KPURZDPKEGBNFL-UHFFFAOYSA-N 0.000 description 2
- RIYYBTSTPIEMBD-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]ethanol Chemical compound CC(O)C1=CC=C(CN)C=C1 RIYYBTSTPIEMBD-UHFFFAOYSA-N 0.000 description 2
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- RMJMVSKYQLTOEM-UHFFFAOYSA-N dipyridin-2-ylphosphane Chemical compound C=1C=CC=NC=1PC1=CC=CC=N1 RMJMVSKYQLTOEM-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- WAPNOHKVXSQRPX-ZETCQYMHSA-N (S)-1-phenylethanol Chemical compound C[C@H](O)C1=CC=CC=C1 WAPNOHKVXSQRPX-ZETCQYMHSA-N 0.000 description 1
- RMAICPATZGPCIL-CYBMUJFWSA-N (r)-phenyl-[2-(trifluoromethyl)phenyl]methanol Chemical compound C1([C@@H](O)C=2C(=CC=CC=2)C(F)(F)F)=CC=CC=C1 RMAICPATZGPCIL-CYBMUJFWSA-N 0.000 description 1
- ULMJQMDYAOJNCC-UHFFFAOYSA-N 1-(3-bromophenyl)ethanol Chemical compound CC(O)C1=CC=CC(Br)=C1 ULMJQMDYAOJNCC-UHFFFAOYSA-N 0.000 description 1
- XTDTYSBVMBQIBT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanol Chemical compound CC(O)C1=CC=C(Br)C=C1 XTDTYSBVMBQIBT-UHFFFAOYSA-N 0.000 description 1
- MVOSNPUNXINWAD-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanol Chemical compound CC(O)C1=CC=C(Cl)C=C1 MVOSNPUNXINWAD-UHFFFAOYSA-N 0.000 description 1
- QBSLFECDTLDUDJ-UHFFFAOYSA-N 1-[3-(aminomethyl)phenyl]ethanol Chemical compound CC(O)C1=CC=CC(CN)=C1 QBSLFECDTLDUDJ-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- YZSCPLGKKMSBMV-UHFFFAOYSA-N 5-fluoro-4-(8-fluoro-4-propan-2-yl-2,3-dihydro-1,4-benzoxazin-6-yl)-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]pyrimidin-2-amine Chemical compound FC=1C(=NC(=NC=1)NC1=NC=C(C=C1)C1CCN(CC1)C)C1=CC2=C(OCCN2C(C)C)C(=C1)F YZSCPLGKKMSBMV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 description 1
- 239000012691 Cu precursor Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- IMUHNRWTDUVXOU-UHFFFAOYSA-N [2-[2-bis(3,5-dimethylphenyl)phosphanyl-6-methoxyphenyl]-3-methoxyphenyl]-bis(3,5-dimethylphenyl)phosphane Chemical compound COC=1C=CC=C(P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)C=1C=1C(OC)=CC=CC=1P(C=1C=C(C)C=C(C)C=1)C1=CC(C)=CC(C)=C1 IMUHNRWTDUVXOU-UHFFFAOYSA-N 0.000 description 1
- ZNORAFJUESSLTM-UHFFFAOYSA-N [4-[5-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1P(C=1C(=C2OCOC2=CC=1)C=1C(=CC=C2OCOC2=1)P(C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 ZNORAFJUESSLTM-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- VHTOPLOKHYEMKS-UHFFFAOYSA-L difluorocopper phosphane Chemical class P.F[Cu]F VHTOPLOKHYEMKS-UHFFFAOYSA-L 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012041 precatalyst Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
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- 239000011265 semifinished product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- CXVGEDCSTKKODG-UHFFFAOYSA-N sulisobenzone Chemical class C1=C(S(O)(=O)=O)C(OC)=CC(O)=C1C(=O)C1=CC=CC=C1 CXVGEDCSTKKODG-UHFFFAOYSA-N 0.000 description 1
- 229960000368 sulisobenzone Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Abstract
使用催化剂将底物不对称氢化硅烷化的方法,该催化剂具有过渡金属及配体,该配体为式(I)的化合物或其对映体或其对映体混合物:其中R是任选被取代的烷基、环烷基、芳基或杂芳基;R’是氢、任选被取代的低碳烷基;且R”是氢、卤素、任选被取代的烷基、羟基、氨基(例如伯氨基、仲氨基或叔氨基)、烯基。特别合适的反应包括酮的不对称氢化硅烷化。
Description
技术领域
本发明涉及使用不对称氢化硅烷化法将酮转化为醇(例如仲醇)的方法。
背景技术
由于对映纯的仲醇这些中间体在例如药品制造中的重要性,已经对它们的有效制备方法的开发投入了相当大的努力。作为得到对映体醇的直接途径,前手性酮的催化不对称还原是被研究和开发最多的策略之一。尽管已经对不对称氢化(其对于多种简单酮表现出优异的对映选择性)进行了深入研究,但不对称氢化硅烷化也引起了很大的关注,因为它所用的反应条件温和,技术简易。
已经广泛考察了用铑(I)和钌(II)、钛、锌、锡和铜(I)的催化剂作为媒介的前手性简单酮的不对称氢化硅烷化。遗憾的是,这些反应许多通常以50至500的低的底物-配体比率(S/L)进行。催化剂的高成本和低的底物-催化剂比率使得前述氢化硅烷化操作在商业上缺乏吸引力。
近期,Lipshutz等人开发出由CuCl和非外消旋双齿膦(例如3,5-xyl-MeO-BIPHEP或DTBM-SEGPHOS)以及t-BuONa原位形成的催化剂体系。参见Lipshutz等人,Ligand-accelerated,copper-catalyzedasymmetric hydrosilylations of aryl ketones,123 J.Am.CHEM.SOC.12917-18(2001)。该体系能够在廉价化学计量还原剂聚甲基氢化硅氧烷(PMHS)存在下,甚至以高达100,000的S/L实现芳基烷基和杂芳香酮的高活性和对映选择性氢化硅烷化,这接近了在相关钌基不对称氢化中实现的水平。但是,对于最大的对映体过量(ee),这些反应必须使用标准Schlenk技术和在低温(例如-50℃至-78℃)下进行。此外,碱,例如t-BuONa的存在对于活性催化剂的生成是关键的。
Olivier Riant等人最近也报道了用于相同转化的无碱和空气加速的CuF2/BINAP/PhSiH3体系,其在环境条件下以100-200的较低S/L比率、以中等至良好的对映选择性生产仲醇。参见Sabine Sirol等人,Efficientenantioselective hydrosilylation of ketones catalyzed by air stable copperfluoride-phosphine complexes,3 ORG.LETT.4111-13(2001)。尽管Riant的体系是空气稳定的并在温和反应温度下进行,但活性、对映选择性和底物范围比不上Lipshutz描述的那些。
因此,需要一种用于仲醇制备方法的催化剂体系,其产生高反应性和对映选择性,并在温和条件、标准大气和不添加碱的情况下操作。本发明针对的就是这一需求。
发明概要
本发明涉及在催化剂存在下将底物(例如酮)转化为对映体醇的方法。更具体地,本发明的方法采用过渡金属催化剂,该催化剂具有与下式(I)的化合物或其对映体或其对映体混合物结合的过渡金属:
化合物(I),
其中
R是任选被取代的烷基、环烷基、芳基或杂芳基;
R’是氢、任选被取代的低碳烷基;且
R”是氢、卤素、任选被取代的烷基、羟基、氨基(例如伯氨基、仲氨基或叔氨基)、烯基。
本发明的方法可以在空气(例如标准大气)存在下并在温和温度(例如室温至-20℃)进行。此外,本发明的方法不要求在反应中使用有机或无机碱。此外,该方法使用20,000-500,000、例如30,000-250,000、例如50,000-100,000的S/L摩尔比。
在特定实施方案中,过渡金属催化剂是与配体(S)-2,2’,6,6’-四甲氧基-4,4’-双-(二苯基膦基)-3,3’-联吡啶或其对映体及其对映体混合物结合的铜。在另一实施方案中,配体是2,2’,6,6’-四甲氧基-4,4’-双-[二(3,5-二甲基苯基)膦基]-3,3’-联吡啶或其对映体及其对映体混合物。
在另一特定实施方案中,反应是将酮不对称氢化硅烷化为醇。在进一步实施方案中,反应是将二芳基酮不对称氢化硅烷化为醇。
发明详述
本发明涉及通过在催化剂存在下的不对称反应将前手性底物(例如酮)转化为对映体醇的方法。更具体地,本发明涉及使用与过渡金属催化剂结合的手性联吡啶基膦配体催化在空气气氛或标准大气、在温和温度下、在不添加有机或无机碱的情况下进行的反应。这种手性配体尤其可用于例如空气加速的铜(II)催化的不对称氢化硅烷化反应。
本文所用的联吡啶基膦配体包括式(I)的化合物或其对映体或其对映体混合物:
化合物(I)
其中
R是任选被取代的烷基、环烷基、芳基或杂芳基;
R’是氢、任选被取代的低碳烷基;且
R”是氢、卤素、任选被取代的烷基、羟基、氨基(例如伯氨基、仲氨基或叔氨基)、烯基。
本文所用的术语“任选被取代的烷基”是指含有1至20个碳原子、例如1至7个碳原子的未取代或取代的直链或支链烃基。未取代烷基的例子包括但不限于甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、新戊基、己基、异己基、庚基、辛基等。取代的烷基包括但不限于被一个或多个下列基团取代的烷基:羟基、烷基氨基、二烷基氨基、环烷基、烯基或烷氧基。
本文所用的术语“低碳烷基”是指含有1至6个碳原子的如上所述的那些任选被取代的烷基。
本文所用的术语“烯基”是指含有至少两个碳原子并进一步在连接点处含有碳-碳双键的上述任一烷基。可用的是含有2至4个碳原子的基团。
本文所用的术语“卤素”、“卤化物”或“卤代”是指氟、氯、溴和碘。
本文所用的术语“烷氧基”是指烷基-O-。
本文所用的术语“环烷基“是指3至6个碳原子的任选被取代的单环脂族烃基,其可以被一个或多个取代基(例如烷基或烷氧基)取代。
单环烃基的例子包括但不限于环丙基、环丁基、环戊基、环己基等。
本文所用的术语“芳基”是指在环部分中含有6至12个碳原子的单环或双环芳烃基团,例如苯基、联苯基、萘基和四氢萘基,它们各自可以任选被1至4个取代基(例如任选被取代的烷基、环烷基或烷氧基)取代。
本文所用的术语“单环芳基”是指如芳基部分所述的任选被取代的苯基。
本文所用的术语“杂芳基”是指芳族杂环,例如单环或双环芳基,例如吡咯基、吡唑基、咪唑基、三唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、苯并噻唑基、苯并噁唑基、苯并噻吩基、喹啉基、异喹啉基、苯并咪唑基、苯并呋喃基等;任选被例如低碳烷基或低碳烷氧基取代。
在美国专利No.5,886,182中公开了式(I)的化合物及其制备方法,其全文经此引用并入本文。
当需要时,可以引入保护基以保护存在的官能团,以免在用于进行本发明的特定化学转化的条件下与反应性组分发生不希望的反应。针对特定反应的保护基需求和选择是本领域技术人员已知的,并取决于待保护的官能团的性质(氨基、羟基等等)、该取代基是其一部分的分子的结构和稳定性、以及反应条件。
例如,在McOmie,Protective Groups in Organic Chemistry,PlenumPress,London,NY(1973);和Greene and Wuts,Protective Groups inOrganic Synthesis,John Wiley and Sons,Inc.,NY(1999)中描述了符合这些条件的公知保护基及其引入和去除。
本发明中特别有用的是R为任选被取代的芳基、R’为烷基且R”为氢的式(I)的联吡啶基膦化合物,或其对映体,或其对映体混合物。本发明中同样特别有用的是R为任选被取代的苯基、R’为甲基且R”为氢的式(I)的化合物。式(I)的化合物的示例性实施方案是:(S)-2,2’,6,6’-四甲氧基-4,4’-双-(二苯基膦基)-3,3’-联吡啶,也称作(S)-P-Phos或(S)-1a;和2,2’,6,6’-四甲氧基-4,4’-双[二(3,5-二甲基苯基)膦基]-3,3’-联吡啶,也称作(S)-Xyl-P-Phos或(S)-1b。
本发明中所用的式(I)的联吡啶基膦化合物例如具有至少85%ee、例如至少95%ee、例如98%ee的光学纯度。
可以通过使式(I)的化合物或其对映体或其对映体混合物与合适的过渡金属盐或其络合物反应,将本发明中所用的式(I)化合物转化为手性过渡金属催化剂,从而产生之后可用于本发明的手性过渡金属催化剂。对于本发明的催化剂的制备,合适的过渡金属盐或其络合物的选择可以选自例如在示例性例子中所述的那些。在Seyden-Penne,Chiral Auxiliaries andLigands in Asymmetric Synthesis,John Wiley&Sons,Inc.,NY(1995)中可以找到这些过渡金属盐的其它例子,该文献经此引用并入本文。催化剂可以原位生成,或可以在使用之前将其分离。
手性过渡金属催化剂包括与式(I)的化合物结合的合适的过渡金属。
对于催化剂体系,合适的过渡金属包括但不限于铜(Cu)、铱(Ir)、镍(Ni)、钯(Pd)、铂(Pt)、铑(Rh)和钌(Ru)及其盐。特别可用的是铜及其盐。
本发明中特别可用的是如下催化剂——其中过渡金属是铜,且过渡金属与式(I)的化合物或其对映体或其对映体混合物结合,其中R是任选被取代的苯基,R’是甲基且R”是氢。这类催化剂的例子包括但不限于与(S)-P-Phos结合的铜(II)和与(S)-Xyl-P-Phos结合的铜(II)。例如,铜可以以盐的形式存在于催化剂中。铜的盐形式包括但不限于CuF2、CuCl2、CuCl、CuBr2、CuBr和CuI。还发现这些催化剂在空气中和在氧存在下是稳定的。
此外,例如,本发明的催化剂在氧化剂的存在下是稳定的。
上述催化剂体系,例如,特别可用于非官能酮的氢化硅烷化。此外,该催化剂体系不需要添加有机或无机碱就可以提供用于多种芳基烷基酮的氢化硅烷化的高效体系。这类反应可以在空气气氛下和在温和温度下进行。本文所用的术语“温和温度”是指室温(RT)至-20℃的温度。此外,氢化硅烷化源(其为氢化物供体)可以是硅烷,例如苯基硅烷(PhSiH3)、PMHS、二苯基硅烷(Ph2SiH2)、(PhMeSiH2)和(Et2SiH2)。
各个氢化硅烷化反应(下述)根据下列代表性例子进行,该例子代表下表1的项目5。
在空气下称出CuF2(5.4毫克,0.054毫摩尔)和(S)-Xyl-P-Phos(1b,2.1毫克,2.72×10-3毫摩尔),并放在配有磁搅拌器的25毫升圆底烧瓶中。添加甲苯(5.4毫升)并将混合物在RT下搅拌10分钟。在剧烈搅拌下相继添加苯基硅烷(800微升,6.43毫摩尔)和苯乙酮(2a,640微升,5.43毫摩尔),并塞住烧瓶。通过薄层色谱法监测反应。在完成后,用10%HCl(3毫升)处理反应混合物,并用醚(3×20毫升)萃取有机产物。将合并的萃取物用水洗涤,用无水硫酸钠干燥,经二氧化硅塞过滤,并在真空中浓缩以产生粗制品。通过NMR和手性气相色谱分析测得产物(S)-1-苯基乙醇[(S)-3a]的转化率和ee分别为>99%和77%(柱,Chirasil-DEX CB;25米×0.25毫米,CHROMPACK,载气,N2)。通过柱色谱法分离纯产物(乙酸乙酯∶己烷= 1∶4)。
为进行分析,在室温下在Varian AS 500(分别为500,202和125MHz)上在CDCl3中记录1H NMR、13C NMR和31P NMR谱。化学位移(δ)以ppm为单位,并参照残留溶剂峰(1H NMR,13C NMR)或参照外标(85%H3PO4,31P NMR)。通过手性GC和HPLC测定不对称氢化硅烷化产物的ee。在带有FID检测器的HP 4890A上进行气相色谱分析。使用带有Waters 486 UV检测器的Waters Model 600进行HPLC分析。在10厘米池中在Perkin-Elmer Model 341旋光计上测量旋光度。如下列文章中所述合成光学纯的P-Phos(1a)和Xyl-P-Phos(1b):Cheng-Chao Pai等人,Highly effective chiral dipyridylphosphine ligands:synthesis,structuraldetermination,and applications in the Ru-catalyzed asymmetrichydrogenation reactions,122 J.Am.CHEM.SOC.11513-514(2000)和JingWu等人,A new chiral dipyridylphosphine ligand Xyl-P-Phosand itsapplication in the Ru-Catalyzed asymmetric hydrogenation of β-ketoesters,43 TETRAHEDRON LETT.1539-43(2002),它们均全文经此引用并入本文。除非另行指明,氟化铜、苯基硅烷、PMHS和酮底物购自Sigma-AldrichCo.(St.Louis,Missouri)或Fisher-Scientific(Acros Organics)(Hampton,New Hampshire),并在不经进一步提纯的情况下原样使用。
在环境温度下和在N2气氛下,使用(S)-1a配体和PhSiH3作为氢化物供体,在甲苯中的苯乙酮(2a)的氢化硅烷化中检查一系列卤化铜(I)和卤化铜(II)。如下显示在方案中。
方案1
CuF2,>99%转化,79%ee
CuCl2,CuBr2,CuCl,CuBr或Cul,<23%转化
反应速率极大依赖于铜盐中卤素的选择,且铜前体中的氟化物对于活性催化剂的生成是重要的。CuF2在24小时后以79%ee的定量收率提供所需产物,即(S)-3a。相反,其它Cu(I)和Cu(II)盐在其它方面相同的条件下表现出较低的反应性(即,小于23%的转化率)。
如表1中所示,在苯乙酮2a的氢化硅烷化中检查带有CuF2和不同配体的多种催化剂体系。反应条件使得在甲苯中的0.6-1M底物浓度下120-700毫克底物被还原。通过与Takeshi Ohkuma等人,Asymmetrichydrogenation of alkenyl,cyclopropyl and aryl ketones.RuCl2(xylbinap)(1,2-diamine)as a precatalyst exhibiting a wide scope,120J.AM.CHEM.SOC.13529-30(1998)(下文称作“Ohkuma”)的数据中发现的保留时间进行比较,确定绝对构型。
表1
项目 | CuF2,摩尔% | 配体 | S/L | T,℃ | 气氛 | 时间 | 转化率,% | ee,*% |
12345 | 31131 | (S)-1a(S)-1a(S)-1a(S)-1b(S)-1b | 3320002000332000 | RTRTRTRTRT | N2空气空气N2空气 | 3h25分钟3h3h10分钟 | 2052>9963>99 | 78(S)77(S)78(S)76(S)77(S) |
6789 | 10.533 | (R)-BINAP(S)-BINAP(S)-1a(S)-1b | 200020033100 | RTRT-20-20 | 空气空气空气空气 | 25分钟6h24h6h | 149491>99 | 73(R)78(S)89(S)87(S) |
表1还表明,空气在反应体系中的存在显著地、令人惊讶地提高了反应速率。例如,当2a的氢化硅烷化用3摩尔%CuF2和(S)-Xyl-P-Phos(1b)在RT和N2下进行时,在3小时后观察到63%转化。相反,在空气下,在2,000的S/L下仅在数分钟后就观察到完全转化,且对映选择性没有减少。此外,这比母体配体P-Phos(1a)的快。P-Phos(1a)和Xyl-P-Phos(1b)与2,2’-双(二苯基膦基)-1,1’-联萘(BINAP)的催化活性的直接比较表明,含有1a和1b的体系均优于含有BINAP的体系[项目7的数据取自Sabine Sirol等人,Efficient enantioselective hydrosilylation of ketonescatalyzed by air stable copper fluoride-phosphine complexes,3ORG.LETT.4111-13(2001)]。进一步的研究表明,反应温度从室温降至-20℃提高了对映选择性。
表2显示了在空气气氛下用Cu(II)和联苯基膦1催化的芳基烷基酮2的不对称氢化硅烷化。
表2
项目 | Ar | Ra | CuF2,摩尔% | 配体 | S/L | T,℃ | 时间 | ee,*% | |
1234567891011121314151617181920 | 2b2c2d2e2f2g2h2i2j2k2l2m2n2n2o2o2o2o2o2m | C6H52′-萘基2-CH3C6H42-ClC6H42-BrC6H43-CH3C6H43-CH3OC6H43-BrC6H43-CF3C6H44-CH3C6H44-ClC6H44-BrC6H44-CF3C6H44-CF3C6H44-NO2C6H44-NO2C6H44-NO2C6H44-NO2C6H44-NO2C6H44-BrC6H4 | CH2CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3 | 33333333333333131.21.233 | (S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1a(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b(S)-1b | 1001001001001001001001001001001001003310010010020,000100,00050,00050,000 | -20-20-20-20-20-20-20-20-20-20-20-20-20-20RT-20RTRT-10-10 | 12h24h24h10h10h12h12h12h12h24h6h6h24h6h1h4h30分钟20h48h48h | 9392727770879289919194969694939791909493 |
反应条件:100毫克-42克底物,底物浓度=0.6-1M甲苯,在所有情况下均观察到>99%的转化率。
*通过与Ohkuma的数据比较旋光信号或保留时间,确定绝对构型。
+通过柱色谱法分离的产物的收率为95%。
通过使用1b,多数底物的完全氢化硅烷化在数小时(例如4-12小时)内实现。苯乙酮的芳环上取代基的位置影响反应结果。例如,邻位取代苯乙酮(2d-2f)以中等的对映选择性(70-77%ee)转化为所需醇,而间位和对位取代的苯乙酮(2g-2o)始终产生高的对映选择性(87-97%ee)。
为了进一步评测本催化剂的活性和空气稳定性,进行在空气中在RT下以S/L比率20,000还原2o的实验。仅在30分钟后就没有检测出未反应的2o。此外,该反应甚至在S/L比率升至高达100,000时也进行。因此,在仅存在2毫克(S)-1b的情况下,42克2o的氢化硅烷化在RT下在标准大气下平稳进行,并在三十小时内产生100%转化,实现了产生(S)-3o的始终较高的对映选择性。此外,通过在-10℃以50,000的S/L比率进行反应,证实(S)-1b/CuF2/PhSiH3的催化效力。对于2m和2o的氢化硅烷化,均保持了净转化率和高的对映选择性。这些结果表明,使用联吡啶基膦配体的这种空气加速的铜(II)催化剂体系的活性明显高于使用BINAP时。
已知的是,与使用金属膦催化剂有关的常见问题是它们的空气敏感性,尤其是在溶液中,反应体系中的痕量空气通常会破坏活性催化剂并产生不可再现的结果。令人惊讶地,在本发明的反应中,空气提高了反应速率。
下面列出表1和2(即3a-5h)的手性仲醇的分析条件。
1-苯基乙醇(3a)。毛细管气相色谱,Chirasil-DEX CB柱;120℃;等温;tR(2a)=5.25分钟;tR(R)=10.36分钟;tR(S)=11.09分钟。
1-苯基丙醇(3b)。毛细管气相色谱,Chirasil-DEX CB柱;122℃;等温;tR(2b)=7.35分钟;tR(R)=15.62分钟;tR(S)=16.12分钟。
1-(2’-萘基)乙醇(3c)。毛细管气相色谱,Chirasil-DEX CB柱;160℃;等温;tR(2c)=13.40分钟;tR(R)=20.71分钟;tR(S)=21.65分钟。
1-(2-甲基苯基)乙醇(3d)。毛细管气相色谱,Chirasil-DEX CB柱;140℃;等温;tR(2d)=3.79分钟;tR(R)=7.78分钟;tR(S)=8.90分钟。
1-(2-氯苯基)乙醇(3e)。毛细管气相色谱,Chirasil-DEX CB柱;145℃;等温;tR(2e)=4.91分钟;tR(R)=9.40分钟;tR(S)=11.02分钟。
1-(2-溴苯基)乙醇(3f)。毛细管气相色谱,Chirasil-DEX CB柱;150℃;等温;tR(2f)=5.21分钟;tR(R)=11.79分钟;tR(S)=14.48分钟。
1-(3-甲基苯基)乙醇(3g)。毛细管气相色谱,Chirasil-DEX CB柱;122℃;等温;tR(2g)=6.90分钟;tR(R)=14.02分钟;tR(S)=15.05分钟。
1-(3-甲氧基苯基)乙醇(3h)。毛细管气相色谱,Chirasil-DEX CB柱;135℃;等温;tR(2h)=8.11分钟;tR(R)=16.50分钟;tR(S)=17.63分钟。
1-(3-溴苯基)乙醇(3i)。毛细管气相色谱,Chirasil-DEX CB柱;145℃;等温;tR(2i)=6.65分钟;tR(R)=15.19分钟;tR(S)=16.32分钟。
1-(3-三氟甲基苯基)乙醇(3j)。毛细管气相色谱,Chirasil-DEX CB柱;125℃;等温;tR(2i)=3.82分钟;tR(R)=9.90分钟;tR(S)=11.06分钟。
1-(4-甲基苯基)乙醇(3k)。毛细管气相色谱,Chirasil-DEX CB柱;125℃;等温;tR(2k)=6.93分钟;tR(R)=10.78分钟;tR(S)=12.01分钟。
1-(4-氯苯基)乙醇(3l)。毛细管气相色谱,Chirasil-DEX CB柱;144℃;等温;tR(2l)=5.75分钟;tR(R)=10.89分钟;tR(S)=11.97分钟。
1-(4-溴苯基)乙醇(3m)。毛细管气相色谱,Chirasil-DEX CB柱;150℃;等温;tR(2m)=6.87分钟;tR(R)=13.02分钟;tR(S)=14.15分钟。
1-(4-三氟甲基苯基)乙醇(3n)。毛细管气相色谱,Chirasil-DEX CB柱;125℃;等温;tR(2n)=4.72分钟;tR(R)=12.38分钟;tR(S)=14.53分钟。
1-(4-硝基苯基)乙醇(3o)。毛细管气相色谱,Chirasil-DEX CB柱;172℃;等温;tR(2o)=5.86分钟;tR(R)=14.01分钟;tR(S)=15.30分钟。
邻氯二苯基甲醇(5a)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;232℃;等温;tR(4a)=8.60分钟;tR(5a)=14.88分钟。通过带有25cm×4.6mm Daicel Chiralcel OD柱的手性HPLC分析(洗脱剂,10∶90 2-丙醛-己烷;流速=10毫升/分钟;检测:254纳米光)测定ee值;tR(R)=8.33分钟;tR(S)=10.33分钟。
邻氟二苯基甲醇(5b)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;230℃;等温;tR(4b)=6.23分钟;tR(5b)=9.95分钟。通过带有25cm×4.6mm Daicel Chiralcel OD柱的手性HPLC分析(洗脱剂,4∶96 2-丙醛-己烷;流速=0.4毫升/分钟;检测:254纳米光)测定ee值;tR(R)=29.96分钟;tR(S)=34.35分钟。
邻甲基二苯基甲醇(5c)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;230℃;等温;tR(4c)=6.18分钟;tR(5c)=11.76分钟。通过带有25cm×4.6mm Daicel Chiralcel OB-H柱的手性HPLC分析(洗脱剂,10∶90 2-丙醛-己烷;流速=0.5毫升/分钟;检测:254纳米光)测定ee值;tR(R)=19.96分钟;tR(S)=21.74分钟。
邻三氟甲基二苯基甲醇(5d)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;230℃;等温;tR(4d)=5.06分钟;tR(5d)=6.96分钟。通过带有25cm×4.6mm Daicel Chiralcel OD柱的手性HPLC分析(洗脱剂,10∶90 2-丙醛-己烷;流速=0.9毫升/分钟;检测:254纳米光)测定ee值;tR(R)=6.39分钟;tR(S)=7.64分钟。
间甲基二苯基甲醇(5e)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;232℃;等温;tR(4e)=6.90分钟;tR(5e)=10.73分钟。通过带有25cm×4.6mm Daicel Chiralcel OB-H柱的手性HPLC分析(洗脱剂,10∶90 2-丙醛-己烷;流速=0.9毫升/分钟;检测:254纳米光)测定ee值;tR=14.96分钟(次要)和27.55分钟(主要)。
对氯二苯基甲醇(5f)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;232℃;等温;tR(4f)=9.20分钟;tR(5f)=19.93分钟。通过带有25cm×4.6mm Daicel Chiralcel OB-H柱的手性HPLC分析(洗脱剂,10∶90 2-丙醛-己烷;流速=0.8毫升/分钟;检测:254纳米光)测定ee值;tR(R)=19.98分钟;tR(S)=29.03分钟。
对甲基二苯基甲醇(5g)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;230℃;等温;tR(4g)=8.13分钟;tR(5g)=12.28分钟。通过带有25cm×4.6mm Daicel Chiralcel OB-H柱的手性HPLC分析(洗脱剂,10∶90 2-丙醛-己烷;流速=0.4毫升/分钟;检测:254纳米光)测定ee值;tR(R)=28.90分钟;tR(S)=33.38分钟。
对三氟甲基二苯基甲醇(5h)。通过带有30m×0.25mm J & W ScientificINNOWAX柱的毛细管气相色谱测定转化率;230℃;等温;tR(4h)=4.67分钟;tR(5h)=9.62分钟。通过带有25cm×4.6mm Daicel Chiralcel OB-H柱的手性HPLC分析(洗脱剂,10∶90 2-丙醛-己烷;流速=0.8毫升/分钟;检测:254纳米光)测定ee值;tR(R)=9.17分钟;tR(S)=11.95分钟。
表3显示了在空气气氛下用Cu(II)和联吡啶基膦1催化的取代二苯甲酮4的不对称氢化硅烷化反应。
表3
项目 | 酮 | CuF2,摩尔% | 配体[摩尔%] | T,℃ | 时间,h | 转化率,% | ee,*% |
12345678910111213141516 | 4a4a4a4b4b4c4c4d4d4e4f4f4g4g4h4h | 3444444444444444 | (S)-1a[3](S)-1a[4](S)-1b[4](S)-1a[4](S)-1b[4](S)-1a[4](S)-1b[4](S)-1a[4](S)-1b[4](S)-1b[4](S)-1a[4](S)-1b[4](S)-1a[4](S)-1b[4](S)-1a[4](S)-1b[4] | RT-10-10-10-10-10-10-10-10-10-10-10-10-10-10-10 | 30724848487248724848484848484848 | 969982>99>9999>998588>99>99>99>99>99>99>99 | 81(R)90(R)91(R)63(R)75(R)83(R)75(R)98(R)95(R)6(+)36(S)43(S)27(S)39(S)25(S)41(S) |
反应条件:100-150毫克底物,底物浓度=0.6-1M,在甲苯中
*通过与下列参考文献的数据比较旋光信号或保留时间,确定绝对构型:Takeshi Ohkuma 等人,Selective hydrogenation of benzophenones tobenzhydrols.Asymmetric synthesis of unsymmetrical diaryl methanols,2ORGANIC LETT.659-62(2000)。
+通过与参考文献Eric Brown等人,Determination ofthe ee’s of chiralacidsby 19F NMR studies of their esters deriving from(R)-(+)-2-(trifluoromethyl)benzhydrol,5 TETRAHEDRON:ASYMMETRY1191-94(1994)和Junpai Naito等人,Enantioresolution of fluorinateddiphenylmethanols and determination of their absolute configurations by X-Raycrystallographic and 1H NMR anisotropy methods,16 CHIRALITY 22-35(2004)的数据比较旋光信号,确定5d的绝对构型。
与芳基烷基酮类似,较低反应温度以反应速率为代价产生较高对映选择性。许多邻位取代的二苯甲酮(4a-4d)以良好至优异的对映选择性被还原成二苯基甲醇。在4d的情况下,在-100℃用(S)-1a配体获得98%ee的最高对映选择性。此外,具有较大邻位取代基的底物有利地反应,产生了具有较高对映纯度的产物。不受制于任何特定理论,但看起来,邻位取代基的位阻效应影响了在过渡态下带有C=O官能的苯环的共面程度,由此产生了不对称偏向。间位和对位取代的二苯甲酮(4e-4h)以低的至中等的对映选择性转化为相应的醇。明显地,(S)-1a或(S)-1b提供了具有(R)-构型的邻位取代的二苯基甲醇,而对于对位取代的产物,绝对构型反转。
因此,本发明提供了以优异的ee值将不对称二芳基酮,即,尤其以高达98%的ee将邻位取代的二苯甲酮,氢化硅烷化成二苯基甲醇的方法。
要理解的是,尽管已经结合其详述描述了本发明,但前述描述用于阐述而非限制本发明的保护范围,其保护范围由下列权利要求的范围确定。
其它方面、优点和变化落入权利要求的保护范围内。
Claims (27)
1.通过在催化剂存在下的不对称氢化硅烷化将前手性底物转化为手性产物的方法,该催化剂包含与下式(I)的化合物或其对映体或其对映体混合物结合的过渡金属:
化合物(1)
其中
R是任选被取代的烷基、环烷基、芳基或杂芳基;
R’是烷基或芳基;且
R”是氢、卤素、任选被取代的烷基、羟基、氨基、烯基。
2.权利要求1的方法,其中
R是苯基;
R’是甲基;且
R”是氢;
或其对映体;或其对映体混合物。
3.权利要求1的方法,其中
R是被取代的苯基;
R’是甲基;且
R”是氢;
或其对映体;或其对映体混合物。
4.权利要求3的方法,其中R是3,5-(CH3)2C6H3;或其对映体;或其对映体混合物。
5.前述权利要求任一项的方法,其中所述过渡金属选自由铜、铱、镍、钯、铂、铑和钌及其盐组成的组。
6.权利要求5的方法,其中所述过渡金属是铜。
7.权利要求5的方法,其中所述前手性底物是前手性酮。
8.前述权利要求任一项的方法,其中所述手性产物是醇。
9.前述权利要求任一项的方法,其中所述前手性酮是二苯甲酮,所述醇是二苯基甲醇。
11.权利要求10的方法,其中
R是苯基;
R’是甲基;且
R”是氢;
或其对映体;或其对映体混合物。
12.权利要求10的方法,其中
R是被取代的苯基;
R’是甲基;且
R”是氢;
或其对映体;或其对映体混合物。
13.权利要求12的方法,其中R是3,5-(CH3)2C6H3;或其对映体;或其对映体混合物。
14.权利要求10的方法,其中所述过渡金属选自由铜、铱、镍、钯、铂、铑和钌及其盐组成的组。
15.权利要求14的方法,其中所述过渡金属是铜。
16.权利要求15的方法,其中所述前手性酮是二苯甲酮,所述醇是二苯基甲醇。
17.权利要求10的方法,其中所述手性产物是醇。
18.权利要求10的方法,其中该方法在温和温度下进行。
19.权利要求10的方法,其中该方法在空气的存在下进行。
20.权利要求10的方法,其中该方法使用高S/L比率。
21.权利要求10的方法,其中S/L比率为20,000-500,000。
22.权利要求20的方法,其中所述反应包括硅烷作为氢化物供体。
24.权利要求23的催化剂,其中所述过渡金属选自由铜、铱、镍、钯、铂、铑和钌及其盐组成的组。
25.权利要求23的催化剂,其中所述过渡金属是铜或其盐。
26.权利要求23的催化剂,其中所述过渡金属是CuF2且所述配体是2,2’,6,6’-四甲氧基-4,4’-双-(二苯基膦基)-3,3’-联吡啶;其对映体;或其对映体混合物。
27.权利要求23的催化剂,其中所述过渡金属是CuF2且所述配体是2,2’,6,6’-四甲氧基-4,4’-双[二(3,5-二甲基苯基)膦基]-3,3’-联吡啶;其对映体;或其对映体混合物。
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