CN114437124B - 官能团化的氟代烷基硅烷及其合成方法和应用 - Google Patents
官能团化的氟代烷基硅烷及其合成方法和应用 Download PDFInfo
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- CN114437124B CN114437124B CN202011228303.0A CN202011228303A CN114437124B CN 114437124 B CN114437124 B CN 114437124B CN 202011228303 A CN202011228303 A CN 202011228303A CN 114437124 B CN114437124 B CN 114437124B
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- fluoroalkyl
- reaction
- functionalized
- alkyl
- ester
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- -1 fluoroalkyl silane Chemical compound 0.000 title claims abstract description 35
- 229910000077 silane Inorganic materials 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 13
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 125000000524 functional group Chemical group 0.000 claims abstract description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 18
- 150000001555 benzenes Chemical group 0.000 claims description 18
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 17
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- 229930192474 thiophene Natural products 0.000 claims description 13
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004185 ester group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- CPPKAGUPTKIMNP-UHFFFAOYSA-N cyanogen fluoride Chemical compound FC#N CPPKAGUPTKIMNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 150000003233 pyrroles Chemical class 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 150000003577 thiophenes Chemical class 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 238000006276 transfer reaction Methods 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims 1
- 238000006884 silylation reaction Methods 0.000 claims 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000007259 addition reaction Methods 0.000 abstract description 3
- 150000002576 ketones Chemical class 0.000 abstract description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 2
- 150000001298 alcohols Chemical class 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 239000011737 fluorine Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- GGZSWFOKWNWRBP-UHFFFAOYSA-N chloromethyl(trifluoromethyl)silane Chemical compound ClC[SiH2]C(F)(F)F GGZSWFOKWNWRBP-UHFFFAOYSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- KIEXGUUJAYEUSM-UHFFFAOYSA-N trifluoromethylsilane Chemical compound FC(F)(F)[SiH3] KIEXGUUJAYEUSM-UHFFFAOYSA-N 0.000 description 5
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006692 trifluoromethylation reaction Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- GTDKXDWWMOMSFL-UHFFFAOYSA-M tetramethylazanium;fluoride Chemical compound [F-].C[N+](C)(C)C GTDKXDWWMOMSFL-UHFFFAOYSA-M 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- IALVDLPLCLFBCF-CHWSQXEVSA-N befloxatone Chemical compound O=C1O[C@@H](COC)CN1C1=CC=C(OCC[C@@H](O)C(F)(F)F)C=C1 IALVDLPLCLFBCF-CHWSQXEVSA-N 0.000 description 2
- 229950000017 befloxatone Drugs 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- NJDRXTDGYFKORP-LLVKDONJSA-N garenoxacin Chemical compound N([C@@H](C1=CC=2)C)CC1=CC=2C(C=1OC(F)F)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 NJDRXTDGYFKORP-LLVKDONJSA-N 0.000 description 2
- 229960001430 garenoxacin Drugs 0.000 description 2
- 229960001962 mefloquine Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- NINOYJQVULROET-UHFFFAOYSA-N n,n-dimethylethenamine Chemical group CN(C)C=C NINOYJQVULROET-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 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
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- VDOSWXIDETXFET-UHFFFAOYSA-N Afloqualone Chemical compound CC1=CC=CC=C1N1C(=O)C2=CC(N)=CC=C2N=C1CF VDOSWXIDETXFET-UHFFFAOYSA-N 0.000 description 1
- 101150116295 CAT2 gene Proteins 0.000 description 1
- 101100326920 Caenorhabditis elegans ctl-1 gene Proteins 0.000 description 1
- 101100494773 Caenorhabditis elegans ctl-2 gene Proteins 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- 241000157855 Cinchona Species 0.000 description 1
- 101100112369 Fasciola hepatica Cat-1 gene Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101100005271 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cat-1 gene Proteins 0.000 description 1
- 101100126846 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) katG gene Proteins 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229950009353 afloqualone Drugs 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- RJCQBQGAPKAMLL-UHFFFAOYSA-N bromotrifluoromethane Chemical compound FC(F)(F)Br RJCQBQGAPKAMLL-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
- C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
-
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Abstract
本发明公开了一种官能团化的氟代烷基硅烷类化合物及其合成方法,所述方法为:将卤代硅烷和氟代烷基源溶于有机溶剂,在碱或叔膦类化合物作用下合成所述官能团化的氟代烷基硅烷。所述官能团化的氟代烷基硅烷可用于构建传统TMSRf所能构建的氟代烷基取代的醇、酮、胺等系列高附加值化合物外,还能在加成反应中,通过适当的转化,把硅保护基上带有的官能团转移到所得的加成产物中,用来合成一些利用传统TMSRf试剂不能合成的含氟化合物,极大提高合成效率和反应的原子经济性。本发明还公开了三氟甲基氯甲基硅烷在合成2‑三氟甲基喹啉类化合物,以及在与α,β‑不饱和酮的不对称三氟甲基化反应中,所展示出的比传统TMSCF3更优越的反应效率和对映选择性。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种官能团化的氟代烷基硅烷及其合成方法和应用。
背景技术
在有机化合物中选择性地引入氟代烷基通常会显著改变其母体化合物的物理、化学以及生物活性,具有提高生物活性分子代谢稳定性和生物利用率等作用,从而使得含氟代烷基结构的化合物广泛存在于各种药物及相关活性化合物中。例如:抗艾滋特效药依法韦伦(Efavirenz)、抗疟疾药甲氟喹((+)-erythro-Mefloquine)、抗抑郁药物贝氟沙通(Befloxatone)、治疗小儿麻痹症药物氟喹酮(Afloqualone)、抗肿瘤药物加雷沙星(Garenoxacin)以及抗高血压药物KC-515等均是含有这一类优势结构单元的药物,上述药物的结构如下所示。
在引入三氟甲基的方法中,利用对酸和水都较为稳定的氟代烷基硅烷参与的亲核三氟甲基化反应是最为直接有效的方法,已被广泛用于合成各种氟代烷基取代的醇、酮或胺等高附加值化合物。因此,如何高效地合成结构多样性的氟代烷基硅烷一直是化学家们研究的热点问题。以(三氟甲基)三甲基硅烷(TMSCF3)为例,常见的合成方法包括:
1)1984年,Ruppert报道了TMSCF3的首例合成。他们发现在六乙基亚磷酰胺[(Et2N)3P]作用下,三甲基氯硅烷(TMSCl)和三氟溴甲烷(CF3Br)可顺利生成TMSCF3。随后1999年,Prakash对该方法进行了优化,发现以苯甲腈作溶剂,在氮气保护下,反应在-78到-30℃下能以75%的收率大规模制备TMSCF3,反应过程如式(II)路线1所示。(Ruppert,I.etal,Tetrahedron Lett.1984,25,2195-2198;Prakash,G.K.S.et al,J.Org.Chem.1991,56,984-989.)
2)1989年,Pawelke等利用三氟碘甲烷(CF3I)与TMSCl在四三(二甲胺基)乙烯的作用下进行反应来制备TMSCF3。发现在-196℃下反应能以高达94%的收率获得TMSCF3,如式(II)路线2所示。需要指出的是,该方法所使用的四三(二甲胺基)乙烯价格较为昂贵,不利于三氟甲基硅烷的大规模制备生产。(Pawelke,G.J.Fluorine Chem.1989,42,429-433.)
3)2003年,Prakash以氟仿(CF3H)为三氟甲基源,首先将其制备成相应的砜基、亚砜基或硫醚类噁三氟甲基化合物,随后在金属镁的作用下与TMSCl进行反应,以高收率合成目标的TMSCF3,如式(II)路线3所示。该方法虽然使用更廉价易得的氟仿作为三氟甲基源,但步骤经济性较差,且反应过程中产生气味不友好的含硫副产物。(Prakash,G.K.S.et al,J.Org.Chem.2003,68,4457-4463.)
4)2012年,Prakash等进一步优化从CF3H出发合成TMSCF3的方法。经过不断探索,发现以甲苯为溶剂,在强碱双三甲基硅基胺基钾(KHMDS)的作用下,CF3H与TMSCl经过一步反应即以80%的产率获得TMSCF3,如式(II)路线4所示。这是目前规模合成TMSCF3的常用方法。(Prakash,G.K.S.et al,Science 2012,338,1324-1327.)
综上所述,尽管目前已发展了多条合成路线来制备氟代烷基硅烷,但是这些方法绝大多数只报道用来合成简单的氟代烷基硅烷(RfTMS),对于官能团化的氟代烷基硅烷的合成,到目前为止尚无任何文献报道。
发明内容
为了解决现有技术存在的不足,本发明的目的是提供一种以商业可得的卤代硅烷化合物1和氟代烷基源(RfX)为原料,在廉价易得的碱或叔膦类化合物(PR2 3)的作用下,高产率合成一系列高纯度的新型官能团化的氟代烷基硅烷类化合物2。
本发明提供了一种官能团化的氟代烷基硅烷类化合物的合成方法,在溶剂中,以氟代烷基源RfX与卤代硅烷化合物为原料,在碱或叔膦类化合物(PR2 3)的作用下反应,得到官能团化的氟代烷基硅烷类化合物;
本发明合成方法的反应路线,如式(I)所示:
其中,
FG为卤素、OMs、OTs、NO2、CF3、CN、CO2R、CONR2、-CH=CR2、-C≡CR等,R为H、C1-10烷基、C1-15芳环、噻吩、呋喃、吡咯、吡啶等;
Rf为含氟原子的C1-10烷基等;
R1为C1-10烷基、芳基等;
所述芳基为给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基等;其中,所述给电子基包括C1-10烷基、C1-10烷氧基等,所述拉电子基包括三氟甲基、酯基、硝基、氰基、卤素等;
Y为卤素、OTf等;
n=1-10;
X为H、卤素等;
优选地,
FG为F、Cl、Br、I、OMs、OTs、NO2、CF3、CN、CO2R、CONR2、-CH=CR2、-C≡CR等,R为H、C1-10烷基、C1-15芳环、噻吩、呋喃、吡咯、吡啶等;
Rf为CF3、CF2H、CFH2、C2F5、CF2CF2H、CF2CF2Cl、CF2CF2Br、CF2CH3、C3F7、CF2CF2CF2H、CF2CF2CH3、CF2CH2CH3、C4F9、CF2CF2CF2CF2H、CF2CF2CF2CH3、CF2CF2CH2CH3、CF2CH2CH2CH3等;
R1为C1-10烷基、给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基等;其中,所述给电子基包括甲基、甲氧基等,所述拉电子基包括三氟甲基、酯基、硝基、氰基、氟、氯、溴、碘等;
Y为Cl、Br、I、OTf等;
n=1-10;
X为H、Br、I等。
其中,所述碱为双三甲基硅基胺基锂(LiHMDS)、双三甲基硅基胺基钾(KHMDS)、双三甲基硅基胺基钠(NaHMDS)、氨基钠(NaNH2)、氢化钠(NaH)等中的一种或几种;优选地,为双三甲基硅基胺基钾(KHMDS)。
其中,R2为C1-10烷基、C1-10烷氧基、C1-10烷胺基、芳基等,所述芳基为给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基等;其中,所述给电子基包括C1-10烷基、C1-10烷氧基等,所述拉电子基包括三氟甲基、酯基、硝基、氰基、卤素等;优选地,为C1-10烷胺基。
其中,所述反应优选在氮气氛围下进行。
其中,所述反应的温度为-78~100℃;优选地,温度为-78~-30℃。
其中,所述反应的时间为2~36小时;优选地,时间为12小时。
其中,所述卤代硅烷化合物1为商业可得的原料;RfX为提供氟代烷基源的试剂。
其中,当氟代烷基源为CF3H、CF2H2、HCF2CH3、HCF2CH2CH3、HCF2CH2CH2CH3时,反应在碱的作用下完成,其作用是攫取氟原子α位的质子;当氟代烷基源为XCF3、XCF2H、XCFH2、XC2F5、XCF2CF2H、XCF2CF2Cl、XCF2CF2Br、XCF2CH3、XC3F7、XCF2CF2CF2H、XCF2CF2CH3、XCF2CH2CH3、XC4F9、XCF2CF2CF2CF2H、XCF2CF2CF2CH3、XCF2CF2CH2CH3、XCF2CH2CH2CH3(X=Br或I)时,反应在叔膦类化合物(PR2 3)作用下进行,其作用是活化氟代烷基源。
其中,所述氟代烷基源RfX、卤代硅烷化合物和碱(或PR2 3)的摩尔比为RfX:卤代硅烷化合物:碱(或PR2 3)=(1-20):(1-3):(1-3);优选地,为3:1:1.2。
其中,所述溶剂为苯甲腈、苯乙腈、乙腈、二氯甲烷、甲苯、四氢呋喃(THF)、乙醚、二甲基甲酰胺(DMF)、二甲基乙酰胺、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、六甲基磷酰三胺(HMPA)等中的任意一种或多种;优选地,为苯甲腈、甲苯、四氢呋喃(THF)中的任意一种或多种。
其中,所述新型官能团化的氟代烷基硅烷类化合物(硅氟代烷基化试剂2)为本发明合成方法的目标产物。
本发明还提供了官能团化的氟代烷基硅烷类化合物,其结构如式(1)所示:
其中,
FG为卤素、OMs、OTs、NO2、CF3、CN、CO2R、CONR2、-CH=CR2、-C≡CR等,R为H、C1-10烷基、C1-15芳环、噻吩、呋喃、吡咯、吡啶等;
Rf为含氟原子的C1-10烷基;
R1为C1-10烷基、芳基等;
所述芳基为给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基等;其中,所述给电子基包括C1-10烷基、C1-10烷氧基等,所述拉电子基包括三氟甲基、酯基、硝基、氰基、氟、氯、溴、碘等;
n=1-10;
优选地,
FG为F、Cl、Br、I、OMs、OTs、NO2、CF3、CN、CO2R、CONR2、-CH=CR2、-C≡CR,其中,所述R为H、C1-10烷基、C1-15芳环、噻吩、呋喃、吡咯、吡啶;
Rf为CF3、CF2H、CFH2、C2F5、CF2CF2H、CF2CF2Cl、CF2CF2Br、CF2CH3、C3F7、CF2CF2CF2H、CF2CF2CH3、CF2CH2CH3、C4F9、CF2CF2CF2CF2H、CF2CF2CF2CH3、CF2CF2CH2CH3、CF2CH2CH2CH3;
R1为C1-10烷基、给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基等;其中,所述给电子基包括甲基、甲氧基,所述拉电子基包括三氟甲基、酯基、硝基、氰基、氟、氯、溴、碘等;
n=1-10。
本发明还提供了所述官能团化的氟代烷基硅烷类化合物在硅氟烷基化反应和官能团转移反应中的应用。
本发明还提供了一种将所述官能团化的氟代烷基硅烷类化合物用于几类加成反应中,进一步通过适当的转化,把硅保护基上带有的官能团转移到所得的加成产物中,从而极大地提高了合成效率和反应的原子经济性,代表性实例请参见应用实施例1-4。
在硅氟烷基化反应中,在一个干燥的Schlenk管中,向原料中加入金鸡纳碱衍生的手性相转移催化剂、TMAF、甲苯和二氯甲烷混合溶剂,将所得的混合溶液在搅拌后低温下加入本发明方法所制备的官能团化的氟代烷基硅烷类化合物,反应过程通过薄层层析进行监测,待原料消耗完毕后,直接进行柱层析,并测得产率。后续官能团转移可通过自由基反应实现。
本发明的有益之处在于:本发明所用各种试剂均商业可得,原料来源广泛,价格低廉,且各种试剂常温常压下能够稳定存在,操作处理方便;本发明对设备要求简单,后处理也无特别要求;本发明所合成的官能团化的氟代烷基硅烷类化合物具有广泛的应用前景。所述官能团化的氟代烷基硅烷类化合物参与的硅氟代烷基化反应,除了可以构建经典TMSRf所能构建的氟代烷基醇、氟代烷基酮、α-氟代烷基胺等重要含氟代烷基中间体外,还能在加成反应中,通过适当的转化,把硅保护基上带有的官能团转移到所得的加成产物中,不仅能够合成传统TMSRf不能合成的含氟化合物,而且能很大程度提高反应的合成效率并展现出更优越的对映选择性。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
实施例
官能团化氟代烷基硅烷类化合物的合成:
1)由化合物1aa-1ad到化合物2a的转化
通用操作流程1:在-78℃下,将CF3X(150-300mmol)冷凝进一个干燥的250mL三颈瓶中,并在此温度下向反应瓶中缓慢加入有机溶剂(80mL)、新蒸的卤代硅烷1aa-1ad(50-300mmol)和叔膦(PR2 3)(50-300mmol);将所得的混合溶液缓慢升至表1所示的温度下搅拌进行反应。反应过程通过1H NMR进行监测,待原料1aa-1ad消耗完毕后,经减压蒸馏得到如式(Ⅲ)所示的2a。
实施例1-15的具体实验操作见通用操作流程1,各实施例的具体反应条件和产率见表1。
表1具体实施例1-15的具体反应条件和产率
化合物2a的NMR表征数据如下:
1H NMR(400MHz,CDCl3):δ2.97(s,2H),0.42(s,6H);13C NMR(100MHz,CDCl3):δ130.4(q,J=319Hz),25.3,-7.8;19F NMR(376MHz,CDCl3):δ-64.31(s,3F)。
2)由化合物1b-1e到化合物2b-2e的转化
通用操作流程2:在-78℃下,将CF3Br(300mmol)冷凝进一个干燥的250mL三颈瓶中,并在此温度下向反应瓶中缓慢加入有机溶剂(80mL)、新蒸的卤代硅烷1b-1e(150mmol)和PR2 3(150mmol);将所得的混合溶液缓慢升至表2所示的温度下搅拌进行反应。反应过程通过1H NMR进行监测,待原料1b-1e消耗完毕后,经减压蒸馏得到如式(IV)所示的2b-2e。实施例16-34的具体实验操作见通用操作流程2,各实施例的具体反应条件和产率的见表2。
表2具体实施例16-34的具体反应条件和产率
2b-2e的NMR表征数据如下:
1H NMR(400MHz,CDCl3):δ2.75(s,2H),0.39(s,6H);13C NMR(100MHz,CDCl3):δ130.8(q,J=315Hz),27.0,-6.4;19F NMR(376MHz,CDCl3):δ-64.73(s,3F)。
1H NMR(400MHz,CDCl3):5.72(m,1H),5.03-5.10(m,2H),1.67(d,J=8.0Hz,2H),0.28(s,6H);13C NMR(100MHz,CDCl3):δ135.2,132.1(q,J=311Hz),119.4,11.2,-5.6;19FNMR(376MHz,CDCl3):δ-65.56(s,3F)。
1HNMR(400MHz,CDCl3):δ3.85(t,J=8.0Hz,2H),1.49-1.63(m,2H),1.17(t,J=8.0Hz,2H),0.43(s,6H);13C NMR(100MHz,CDCl3):δ132.0(q,J=322Hz),47.2,27.6,1.4,-5.4;19F NMR(376MHz,CDCl3):δ-66.78(s,3F)。
1H NMR(400MHz,CDCl3):δ5.28(s,1H),0.59(s,6H);13C NMR(100MHz,CDCl3):δ141.3(q,J=325Hz),31.2,-3.5;19F NMR(376MHz,CDCl3):δ-62.54(s,3F)。
3)由化合物1aa到化合物2f-2i的转化
通用操作流程3:在-78℃下,将RfBr(300mmol)冷凝进一个干燥的250mL三颈瓶中,并在此温度下向反应瓶中缓慢加入有机溶剂(80mL)、新蒸的卤代硅烷1aa(150mmol)和PR2 3(150mmol);将所得的混合溶液在如表3所示的温度下搅拌进行反应。反应过程通过1H NMR进行监测,待原料1aa消耗完毕后,经减压蒸馏得到如式(V)所示的2f-2i。
实施例35-45的具体实验操作见通用操作流程3,各实施例的具体反应条件和产率的见表3。
表3具体实施例35-45的具体反应条件和产率
2f-2i的NMR表征数据如下:
1H NMR(400MHz,CDCl3):δ5.27(t,J=58.5Hz,1H),2.89(s,2H),0.35(s,6H);13CNMR(100MHz,CDCl3):δ110.4(t,J=285Hz),20.4,-5.3;19F NMR(376MHz,CDCl3):δ-140.33(s,2F)。
1H NMR(400MHz,CDCl3):δ3.39(s,2H),0.68(s,6H);13C NMR(100MHz,CDCl3):δ145.1(q,J=327.2Hz),113.5(t,J=265.8Hz),28.4,-4.1;19F NMR(376MHz,CDCl3):δ-129.35(s,2F):-80.45(s,3F)。
1H NMR(400MHz,CDCl3):δ3.41(s,2H),0.75(s,6H);13C NMR(100MHz,CDCl3):δ145.8(q,J=322.5Hz),117.6(t,J=262.8Hz),113.5(t,J=255.8Hz),28.4,-4.1;19F NMR(376MHz,CDCl3):δ-129.06(s,2F),-125.33(s,2F),-79.45(s,3F)。
1H NMR(400MHz,CDCl3):δ5.47(t,J=56.5Hz,1H),2.91(s,2H),0.35(s,6H);13CNMR(100MHz,CDCl3):δ111.4(t,J=280Hz),109.3(t,J=256Hz),20.4,-5.3;19F NMR(376MHz,CDCl3):δ-130.12(s,2F),-138.42(s,2F)。
3)由化合物1a-1c到化合物2a-2c、2f的转化
通用操作流程4:在一个干燥的250mL的三颈瓶中加入碱(100-300mmol),在-78℃下加入新蒸的卤代硅烷1a-1c(100-300mmol),接着将RfH(100-300mmol)气体通入该低温反应体系(鼓泡2h),将所得的混合溶液在表4所示的温度下搅拌进行反应。反应过程通过1HNMR进行监测,待原料1a-1c消耗完毕后,经减压蒸馏得到如式(VI)所示的2a-2c或2f。
实施例46-61的具体实验操作见通用操作流程4,各实施例的具体反应条件和产率的见表4。
表4具体实施例46-61的具体反应条件和产率
官能团化氟代烷基硅烷的应用:
应用例1:本发明实施例2合成的官能团化的三氟甲基硅烷2a参与的不对称三氟甲基化反应,反应路径如式(VII):
在一个干燥的25mL Schlenk管中,氮气保护下加入原料3a(29mg,0.2mmol)、Cat 1(12mg,0.02mmol)、TMAF(2mg,0.02mmol),然后加入无水甲苯和无水二氯甲烷体积比为2:1的混合溶剂(2.0mL),将所得的混合溶液在-78℃下搅拌10min后加入2a(70μL,0.4mmol)反应,反应过程通过薄层层析进行监测,待原料3a消耗完毕后,经过直接柱层析可得如式(VII)所示4a,产率为94%。
化合物4a的相关表征数据如下:
HPLC分析:Chiralcel OJ-H,异丙醇/正己烷=0.5/99.5,1.0mL/min,230nm;tr(major)=6.62min,tr(minor)=8.03min,得96%ee;
比旋光度:[α]D 25=+38.6(c=1.0,CHCl3);
1HNMR(300MHz,CDCl3):7.44-7.31(m,5H),6.90(d,J=8.0Hz,1H),6.35(d,J=8.0Hz,1H),3.96(s,3H),2.96(s,2H),0.40(d,J=2.0Hz,6H);13C NMR(100MHz,CDCl3):δ137.3,134.5,130.8,129.5,128.8,127.7(q,J=287Hz),126.28,75.8(q,J=29Hz),29.8,22.34,3.3;19F NMR(376MHz,CDCl3):δ-78.34(s,3F)。
应用例2:本发明实施例2合成的官能团化的三氟甲基硅烷2a参与的不对称三氟甲基化反应,反应路径如式(VIII):
在一个干燥的25mL Schlenk管中,氮气保护下加入原料5a(34mg,0.2mmol)、Cat 2(17mg,0.02mmol)、TMAF(4mg,0.04mmol),然后加入无水甲苯和无水二氯甲烷体积比为2:1的混合溶剂(2.0mL),将所得的混合溶液在-78℃下搅拌10min后加入2a(70μL,0.4mmol)反应,反应过程通过薄层层析进行监测,待原料5a消耗完毕后,经过直接柱层析可得如式(VIII)所示6a,产率为93%。
化合物6a的相关表征数据如下:
HPLC分析:Chiralcel OJ-H,异丙醇/正己烷=0.5/99.5,1.0mL/min,205nm;tr(major)=5.12min,tr(minor)=5.95min,得90%ee;
比旋光度:[α]D 25=+8.3(c=1.0,CHCl3);
1H NMR(400MHz,CDCl3):7.99(s,1H),7.87-7.82(m,3H),7.65(d,J=8.0Hz,1H),7.52-7.48(m,2H),2.80(s,2H),1.94(s,3H),0.28(d,J=3.6Hz,6H);13C NMR(100MHz,CDCl3):δ128.6,128.0,127.6,126.8,126.5,126.4,125.3(q,J=284Hz),124.4,77.8(q,J=29Hz);19F NMR(376MHz,CDCl3):δ-80.98(s,3F)。
应用例3:本发明实施例2合成的官能团化的三氟甲基硅烷2a参与的喹啉的三氟甲基化反应,反应路径如式(IX):
在一个可用旋塞密封的塑料反应管中,加入原料3b(82mg,0.5mmol),KHF2(117mg,1.5mmol),DMPU(189mg,1.5mmol),1,4-二氧六环(5mL),再加入三氟乙酸(170mg,1.5mmol),将所得的混合溶液在25℃下搅拌24h后加入2a(528μL,3.0mmol)反应,25℃下搅拌24h,接着加入PhI(OAc)2(240mg,0.75mmol)搅拌2h,加入饱和碳酸钠溶液淬灭反应,乙酸乙酯萃取(10ml×6次),合并有机相,无水硫酸钠干燥,减压除去溶剂。经过柱层析纯化可得如式(IX)所示的7a,产率为80%。
化合物7a的相关表征数据如下:
1H NMR(400MHz,CDCl3):δ7.75(d,J=8.5Hz,2H),7.90(s,1H),8.16(d,J=9.0Hz,1H),8.28(d,J=8.5Hz,1H);13C NMR(100MHz,CDCl3):δ117.9(q,J=2.2Hz),121.5(q,J=275Hz),126.4,129.5,131.9,132.1,134.9,137.4,145.7,148.4(q,J=35.1Hz);19FNMR(376MHz,CDCl3):δ-69.5(s,3F)。
应用例4:本发明应用例1合成的官能团化的三氟甲基硅烷4a参与的官能团转移反应,反应路径如式(X):
在一个干燥的25mL圆底烧瓶中,加入4a(322mg,1.0mmol),NaI(900mg,6.0mmol)无水丙酮(10mL),所得的溶液加热回流搅拌6h后有大量白色固体(NaCl)产生,硅胶滤除白色固体,滤液减压除去溶剂得到8a。在一个干燥的25mL Schlenk管中加入粗品8a和乙腈(10mL)再加入二异丙基乙基胺(1.30g,10mmol)和甲酸(460mg,10mmol)的混合溶液,通过氮气鼓泡除氧,接着加入[Ir(dtbbpy)[dF(CF3)ppy]2]PF6(28mg,0.025mmol),然后将反应体系置于蓝光照射下室温搅拌10h,经过柱层析可得如式(X)所示9a,产率为68%,dr值为20:1。
化合物9a的相关表征数据如下:
HPLC分析:Chiralcel OD-H,异丙醇/正己烷=0.2/99.8,1.0mL/min,205nm;tr(major)=7.86min,tr(minor)=8.58min,得96%ee;
比旋光度:[α]D 25=+32.5(c=1.0,CHCl3);
1H NMR(400MHz,CDCl3):7.32-7.24(m,2H),7.24-7.16(m,2H),3.12-3.08(m,1H),2.50-2.44(m,1H),2.28(t,J=12.0Hz,1H),1.33(s,3H),0.94-0.88(m,1H),0.60-0.54(m,1H),0.28(s,3H),0.13(s,3H);13C NMR(100MHz,CDCl3):δ140.6,129.1,128.5,126.9(q,J=283Hz),126.3,82.36(q,J=28Hz),43.6,39.8,17.6,16.8,0.6,0.4;19F NMR(376MHz,CDCl3):δ-81.12(s,3F)。
本发明的保护内容不局限于以上实施例。在不背离本发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (9)
1.官能团化的氟代烷基硅烷类化合物,其特征在于,所述化合物的结构如式(1)所示:
其中,
FG为Cl、Br;
Rf为CF3、CF2H、CFH2、C2F5、CF2CF2H、CF2CF2Cl、CF2CF2Br、CF2CH3、C3F7、CF2CF2CF2H、CF2CF2CH3、CF2CH2CH3、C4F9、CF2CF2CF2CF2H、CF2CF2CF2CH3、CF2CF2CH2CH3、CF2CH2CH2CH3;
R1为C1-10烷基、芳基,所述芳基为给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基;其中,所述给电子基包括甲基、甲氧基,所述拉电子基包括三氟甲基、酯基、硝基、氰基、氟、氯、溴、碘。
2.一种官能团化的氟代烷基硅烷类化合物的合成方法,其特征在于,氟代烷基源RfX与卤代硅烷化合物在溶剂中,在碱或叔膦类化合物PR2 3的作用下反应,得到官能团化的氟代烷基硅烷类化合物;
所述反应路线如式(I)所示:
其中,
FG为Cl、Br;
Rf为含氟原子的C1-10烷基;
R1为C1-10烷基、芳基,所述芳基为给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基;其中,所述给电子基包括C1-10烷基、C1-10烷氧基,所述拉电子基包括三氟甲基、酯基、硝基、氰基、卤素;
Y为卤素、OTf;
X为H、卤素。
3.如权利要求2所述的方法,其特征在于,FG为Cl、Br;R1为C1-10烷基、给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基,所述给电子基包括甲基、甲氧基,所述拉电子基包括三氟甲基、酯基、硝基、氰基、氟、氯、溴、碘;Y为Cl、Br、I、OTf;X为H、Br、I。
4.如权利要求2所述的方法,其特征在于,所述碱为双三甲基硅基胺基锂LiHMDS、双三甲基硅基胺基钾KHMDS、双三甲基硅基胺基钠NaHMDS、氨基钠NaNH2、氢化钠NaH中的一种或几种;和/或,R2为C1-10烷基、C1-10烷氧基、C1-10烷胺基、芳基,所述芳基为给电子基取代苯环、拉电子基取代苯环、萘基、噻吩、呋喃、吡咯、吡啶、酯基;其中,所述给电子基包括C1-10烷基、C1-10烷氧基,所述拉电子基包括三氟甲基、酯基、硝基、氰基、卤素。
5.如权利要求2所述的方法,其特征在于,所述反应的温度为-78~100℃;和/或,所述反应的时间为2~36小时。
6.如权利要求2所述的方法,其特征在于,所述氟代烷基源RfX、卤代硅烷化合物、碱或叔膦类化合物PR2 3的摩尔比为RfX:卤代硅烷化合物:碱或叔膦类化合物PR2 3=(1-20):(1-3):(1-3)。
7.如权利要求2所述的方法,其特征在于,所述溶剂为苯甲腈、苯乙腈、乙腈、二氯甲烷、甲苯、四氢呋喃THF、乙醚、二甲基甲酰胺DMF、二甲基乙酰胺、二甲基亚砜DMSO、N-甲基吡咯烷酮NMP、六甲基磷酰三胺HMPA中的任意一种或多种。
8.如权利要求2-7之任一项所述方法合成得到的官能团化的氟代烷基硅烷类化合物。
9.如权利要求1或8所述的官能团化的氟代烷基硅烷类化合物在硅氟烷基化反应和官能团转移反应中的应用。
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CN107473995A (zh) * | 2017-07-30 | 2017-12-15 | 复旦大学 | β‑三氟甲基烯基砜类化合物及其制备方法和应用 |
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