CN116102584A - 3, 3-gem difluoro allyl compound, preparation method and application thereof - Google Patents
3, 3-gem difluoro allyl compound, preparation method and application thereof Download PDFInfo
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- CN116102584A CN116102584A CN202211091590.4A CN202211091590A CN116102584A CN 116102584 A CN116102584 A CN 116102584A CN 202211091590 A CN202211091590 A CN 202211091590A CN 116102584 A CN116102584 A CN 116102584A
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- China
- Prior art keywords
- formula
- substituted
- compound
- alkyl
- difluoroallyl
- Prior art date
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- -1 difluoro allyl compound Chemical class 0.000 title claims abstract description 86
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 238000000034 method Methods 0.000 claims abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 132
- 238000006243 chemical reaction Methods 0.000 claims description 84
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 45
- 229910052786 argon Inorganic materials 0.000 claims description 39
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 37
- 239000003054 catalyst Substances 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 101150003085 Pdcl gene Proteins 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 28
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical group 0.000 claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 17
- 239000003446 ligand Substances 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 15
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 14
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 14
- 229940045803 cuprous chloride Drugs 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 229910052802 copper Inorganic materials 0.000 claims description 11
- 239000010949 copper Substances 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 10
- 239000007789 gas Substances 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 9
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 9
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003849 aromatic solvent Substances 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 7
- 239000012298 atmosphere Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003759 ester based solvent Substances 0.000 claims description 6
- 239000004210 ether based solvent Substances 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 6
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052718 tin Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- UXRZLDREKITWRO-UHFFFAOYSA-N P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 UXRZLDREKITWRO-UHFFFAOYSA-N 0.000 claims description 5
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 5
- 229910001515 alkali metal fluoride Inorganic materials 0.000 claims description 5
- 229910052796 boron Inorganic materials 0.000 claims description 5
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- TWWJJVNUZQLCPD-UHFFFAOYSA-N diphenylphosphane;methane Chemical compound C.C=1C=CC=CC=1PC1=CC=CC=C1 TWWJJVNUZQLCPD-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 claims description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 3
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 3
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004988 dibenzothienyl group Chemical group C1(=CC=CC=2SC3=C(C21)C=CC=C3)* 0.000 claims description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 3
- IIGCYQPNZRSCLY-UHFFFAOYSA-N 1,1-dimethyl-3-prop-1-enylurea Chemical compound CC=CNC(=O)N(C)C IIGCYQPNZRSCLY-UHFFFAOYSA-N 0.000 claims description 2
- ZUENHQDDMWOOQE-UHFFFAOYSA-N benzene;diphenylphosphane Chemical compound C1=CC=CC=C1.C=1C=CC=CC=1PC1=CC=CC=C1 ZUENHQDDMWOOQE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound 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 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 125000005968 oxazolinyl group Chemical group 0.000 claims 1
- 125000005493 quinolyl group Chemical group 0.000 claims 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 abstract description 12
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 abstract description 7
- 229910000085 borane Inorganic materials 0.000 abstract description 7
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 abstract description 7
- 229910000077 silane Inorganic materials 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 229910000080 stannane Inorganic materials 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000575 pesticide Substances 0.000 abstract description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 100
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 41
- 239000003208 petroleum Substances 0.000 description 36
- 238000004440 column chromatography Methods 0.000 description 35
- 239000000047 product Substances 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 22
- 238000005303 weighing Methods 0.000 description 22
- 239000006228 supernatant Substances 0.000 description 21
- 238000011835 investigation Methods 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 239000012230 colorless oil Substances 0.000 description 17
- FDMFUZHCIRHGRG-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-ene Chemical compound FC(F)(F)C=C FDMFUZHCIRHGRG-UHFFFAOYSA-N 0.000 description 14
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 14
- 229940125782 compound 2 Drugs 0.000 description 13
- 239000011737 fluorine Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000001514 detection method Methods 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 150000002390 heteroarenes Chemical class 0.000 description 7
- GMDGXJQUWIQOLE-UHFFFAOYSA-N prop-2-enylborane Chemical compound BCC=C GMDGXJQUWIQOLE-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 6
- 150000001491 aromatic compounds Chemical class 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 238000010009 beating Methods 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical class [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 238000005937 allylation reaction Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- XRZHWZVROHBBAM-UHFFFAOYSA-N 1-bromo-3,3,3-trifluoroprop-1-ene Chemical compound FC(F)(F)C=CBr XRZHWZVROHBBAM-UHFFFAOYSA-N 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
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- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 238000012544 monitoring process Methods 0.000 description 2
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- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
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- 230000002194 synthesizing effect Effects 0.000 description 2
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- KSELABKNBIUMGG-YGBAREPYSA-N (2z,3ar,4r,5r,6as)-3,3-difluoro-4-[(e,3r,4r)-3-hydroxy-4-(3-methylphenyl)pent-1-enyl]-2-[4-(2h-tetrazol-5-yl)butylidene]-4,5,6,6a-tetrahydro-3ah-cyclopenta[b]furan-5-ol Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@H]1C1(F)F)/C=C/[C@@H](O)[C@H](C)C=2C=C(C)C=CC=2)\C1=C/CCCC=1N=NNN=1 KSELABKNBIUMGG-YGBAREPYSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- FFTOUVYEKNGDCM-OWOJBTEDSA-N (e)-1,3,3-trifluoroprop-1-ene Chemical compound F\C=C\C(F)F FFTOUVYEKNGDCM-OWOJBTEDSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- LDTMPQQAWUMPKS-UHFFFAOYSA-N 1-chloro-3,3,3-trifluoroprop-1-ene Chemical compound FC(F)(F)C=CCl LDTMPQQAWUMPKS-UHFFFAOYSA-N 0.000 description 1
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 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
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- RQXPGOCXZHCXDG-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-en-2-ylbenzene Chemical compound FC(F)(F)C(=C)C1=CC=CC=C1 RQXPGOCXZHCXDG-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- 239000004327 boric acid Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
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- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([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
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
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- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 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
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 1
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- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 description 1
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- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 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
- 230000000737 periodic effect Effects 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- 238000007086 side reaction Methods 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000002277 temperature effect Effects 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
- 150000003512 tertiary amines Chemical group 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/48—Aldehydo radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
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Abstract
The invention discloses a 3, 3-gem difluoroallyl compound, a preparation method and application thereof. The invention provides a 3, 3-gem difluoro allyl borane, silane or stannane compound shown in a formula A; the invention provides a 3, 3-gem difluoro allyl borane, silane or stannane compound which can be highThe method for effectively preparing various difluoroalkyl compounds with various structures has very wide application prospect in medicines, pesticides and materials.
Description
Technical Field
The invention relates to a 3, 3-gem difluoro allyl compound, a preparation method and application thereof; in particular to 3, 3-gem difluoro alkene compound-based borane, silane or stannane compound, a preparation method and application thereof.
Background
The alpha-aryl, heteroaryl, alkenyl, alkynyl, alkyl-alpha, alpha-difluoroallyl structural compound and the derivative building blocks thereof have wide application in the aspects of biological medicine, pesticide, material science and the like. For example: some important fluorine-containing drugs KAG-308, glecarprevir, taflupirest, etc. contain an alpha, alpha-difluoroallyl structure.
However, conventional methods of synthesizing α -aryl, heteroaryl, alkenyl, alkynyl, alkyl- α, α -difluoroalkyl blocks are generally made from carbonyl groups by DAST or Deoxofluor (e.g., markovsi, l.n.; pahinnik, v.e.; kirsanov, a.v. synthesis 1973,787. (b) Middleton, w.j.j. Org. chem.1975,40,574. (c) Lal, g.s.; pez, g.p.; pesarei, r.j.; prozonic, f.m.; cheng, h.j. Org. Chem.1999,64,7048.). However, these methods generally have disadvantages such as lengthy reaction steps, poor functional group compatibility, and the necessity of using highly toxic fluorinating agents for some reactions.
The block synthesis of transition metal catalyzed α -aryl, heteroaryl or alkenyl- α, α -difluoroalkyl structural compounds and derivatives thereof developed in the last two decades ((a) schwanebe, m.k., mcCarthy, j.r., whitten, j.p. tetrahedron lett.2000,41,791 (b) Feng, z., chen, f., zhang, x.org. lett.2012,14,1938 (c) Belhomme, m. -c., poisson, t., pannecke, x.org. lett.2013,15,3428 (d) Taguchi, t., kitagawa, o, morikawa, t., uihara, h., endo, h. koyashison, y. Let.35, tm., 35, tm, 35, 6, tm, 35, d, tm, 35, d, d., of the same kind of compounds were synthesized by the compounds. However, these methods still exist such as: the compatibility of the functional group is poor, the catalyst usage is high, the reaction condition is harsh, and the like.
In 2014, the palladium-catalyzed coupling reaction of nucleophiles with electrophilic α -bromo- α, α -difluoroallyl reagents (j.am.chem. Soc.2014,136,1230; ZL 2013 1 0658890.0) simplified the synthesis of α -aryl, heteroaryl, alkenyl- α, α -difluoroallyl structures, but the reaction still had the following limitations: 1. the structural diversity of the product is still to be further broken through under the restriction of synthesis of the alpha-bromo-alpha, alpha-difluoroallyl reagent; 2 some arylboronic acid nucleophilic reagents need to be prepared in advance, which is not beneficial to the mass preparation of the structure; 3 the compatibility of the reaction to most aryl boric acid nucleophilic reagents of heterocycles is poor, and the synthesis requirement of various alpha-heterocycles-alpha, alpha-difluoroallyls structures is difficult to meet.
For the reactions of alpha, alpha-difluoroallylation in which nucleophiles participate, other types of alpha, alpha-difluoroallylic reagents (Synlett.1996, 4,371; chem.Pharm. Bull.1985,33 (11), 5137), the preparation process is often cumbersome, and the reactions involved tend to be regioselective, difficult to control, defluorinated side reactions occur, harsh reaction conditions, limited reaction substrates and types, etc., making it difficult to achieve broad-spectrum, efficient preparation of the desired product structure, especially for heterocyclic aromatic nucleophiles.
On the other hand, 3-gem-difluoroalkenylboranes, silanes or stannanes as nucleophilic alpha, alpha-gem-difluoroallylation can likewise be coupled with widely available electrophiles of the aryl halide type in the presence of a catalyst (chem.Commun.2019, 55,3705-3708; angew.chem., int.ed.,2018,57,7196). However, the conventional preparation process of 3, 3-difluoro alkenyl borane, silane or stannane compounds has the problems of difficult acquisition of raw materials, high catalyst dosage (5% -100%), expensive ligand, difficult mass preparation or acquisition and the like, so that the large-scale preparation and wide application of the reagent are limited.
Therefore, a new method for preparing 3, 3-gem difluoro alkenyl borane, silane or stannane compounds as nucleophilic alpha, alpha-gem difluoro allylation test by using cheap fluorine-containing industrial raw materials through a high-efficiency, simple and low-cost method is developed, and the reagent is applied to the application of synthesizing alpha-heterocycle-alpha, alpha-gem difluoro allylation compounds in a broader spectrum and high efficiency, thereby having remarkable significance.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of larger structural limitation, low reaction activity controllability, limited substrate applicability and the like of the alpha, alpha-gem-difluoroallylation reagent in the prior alpha, alpha-gem-difluoroallylation reaction. The invention aims to provide 3, 3-gem difluoro alkenyl borane, silane or stannane compounds which are used as nucleophilic alpha, alpha-gem difluoro allylation tests, and various difluoro alkyl compounds with various structures can be efficiently prepared.
The invention solves the technical problems through the following technical proposal.
The invention also provides a preparation method of the 3, 3-difluoroallyl compound shown in the formula F, which comprises the following steps: in an organic solvent, in the presence of alkali and a copper catalyst, carrying out the following reaction between a compound shown in a formula A and a compound shown in a formula B to obtain a 3, 3-gem-difluoroallyl compound shown in a formula F; the organic solvent is a mixture of one or more of halogenated aromatic hydrocarbon solvents, ether solvents and ester solvents and amide solvents;
R 'and R' are H, C 1 -C 20 Is or are R a Substitution C 1 -C 20 Alkyl, 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl, C 1 -C 20 Is/are R c Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R d Substituted C 6 -C 20 Is aryl, 5-14 membered heteroaryl, substituted with one or more R e The heteroatoms in the substituted 5-14 membered heteroaryl, the 5-7 membered heterocycloalkyl, and the 5-14 membered heteroaryl are independently selected from one or more of N, O and S;
z is Si or Sn;
R 1 and R is 1’ H, C independently 1 -C 20 Is or are R a Substituted C 1 -C 20 Alkyl of (a);
alternatively, R 1 And R is 1’ Connected to and connected toTogether form: 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl; wherein the hetero atoms of the 5-7 membered heterocycloalkyl are B and O;
R 2 、R 3 and R is 4 Independently is halogen, C 1 -C 20 Is or are R c Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is/are R d Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R e Substituted C 6 -C 20 Aryl of (a);
alternatively, R 2 、R 3 And R is 4 Any 2 of which are linked together with the linked Z to form: 5-7 membered heterocycloalkyl, or by one or more R f Substituted 5-7 membered heterocycloalkyl; wherein the hetero atom of the 5-7 membered heterocycloalkyl group is Si or Sn;
R a 、R b 、R c 、R d 、R e and R is f Independently is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -, C 1 -C 20 alkyl-O-or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
In certain preferred embodiments of the present invention, certain groups in the 3, 3-difluoroallyl compounds of formula F are defined below, and the groups not mentioned are as described in any of the embodiments of the present application (hereinafter referred to as "in certain embodiments of the present invention"), the preparation process is as follows,
Wherein,,
R 1 and R is 1’ H, C independently 1 -C 20 Is or are R a Substituted C 1 -C 20 Alkyl of (a);
alternatively, R 1 And R is 1’ Connected to and connected toTogether form: 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl; wherein the hetero atoms of the 5-7 membered heterocycloalkyl are B and O;
R 2 、R 3 and R is 4 Independently is halogen, C 1 -C 20 Is or are R c Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is one or more of alkyl-O-, andr is a number of d Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R e Substituted C 6 -C 20 Aryl of (a);
alternatively, R 2 、R 3 And R is 4 Any 2 of which are linked together with the linked Z to form: 5-7 membered heterocycloalkyl, or by one or more R f Substituted 5-7 membered heterocycloalkyl; wherein the heteroatom of the 5-7 membered heterocycloalkyl is Si or Sn;
R a 、R b 、R c 、R d and R is f Independently is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
In one embodiment of the invention, R e Is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -, C 1 -C 20 alkyl-O-or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
In one embodiment of the invention, R and R' are defined as the same.
Wherein the ester solvent can be ethyl acetate; the halogenated aromatic solvent can be chlorobenzene or fluorobenzene; the ether solvent can be one or more of diethylene glycol dimethyl ether DME, dioxane and tetrahydrofuran THF; the amide solvent can be one or more of dimethylacetamide DMA, N-dimethylformamide DMF, N-methylpyrrolidone NMP and N, N-dimethylpropenyl urea DMPU; preferably tetrahydrofuran, diethylene glycol dimethyl ether, dioxane, ethyl acetate or chlorobenzene, and dimethylacetamide. The volume ratio of the total volume of one or more of the halogenated aromatic solvents, ether solvents, and ester solvents to the amide solvents in the mixture may be from 100:1 to 1:100, such as 7.2:1, 3.2:1, 2.4:1, 2:1, 1.6:1, 1:1, 1:1.25, 1:2.5.
The amount of the organic solvent is not particularly limited so as not to affect the reaction; in the present invention, the mass volume ratio of the compound represented by the formula A to the organic solvent is preferably 0.01mol/L to 2mol/L (for example, 0.15mol/L to 1 mol/L).
The molar ratio of the compound shown in the formula A to the compound shown in the formula B can be 1:1.5 to 2:1; for example 1.5:1 to 2:1.
The compounds of formula A may be added using conventional solutions, for example in dimethylacetamide DMA solutions, and for example 1.2M in DMA. Alternatively, the compound shown in the formula A can be added in a gaseous form and reacted; the gas pressure may be 1atm.
The alkali can be alcohol alkali metal alkali or alkali metal hydroxide; such as one or more of sodium hydroxide, potassium hydroxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, and lithium methoxide; preferably one or more of lithium t-butoxide, potassium methoxide and lithium methoxide.
The molar ratio of the base to the compound of formula a may be 1.5:1 to 3:1; for example 2:1 to 2.5:1.
The copper catalyst may be a copper salt catalyst, such as cuprous halide, and also such as cuprous chloride.
The molar ratio of the copper catalyst to the compound of formula a may be from 0.00001:1 to 0.1:1; for example 0.00001:1, 0.0001:1, 0.0002:1, 0.001, 0.01:1, 0.05:1; the amount can be significantly reduced as the scale of the reaction is increased.
Preferably, the reaction is carried out under an inert atmosphere, which may be argon or nitrogen.
The reaction may also be carried out in the presence of a ligand which may be selected from: 1, 3-bis (diphenylphosphine) propane dppp, 1-bis (diphenylphosphine) ethane dppe, 1-bis (diphenylphosphine) methane dppm, bis (2-diphenylphosphine phenyl) ether DPEphos, (R) - (+) -DM- (i.e., (R) - (+) -DM-SegPhos), bpy, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene XantphosOne or more of the following; preferably (R) - (+) -DM- (i.e., (R) - (+) -DM-SegPhos), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthenes Xantphos.
The molar ratio of the ligand to the compound of formula a may be 1.5:1 to 3:1; for example 2:1 to 2.5:1.
In one scheme of the preparation method, the reaction raw materials comprise the alkali, a copper catalyst, a compound shown as a formula A, a compound shown as a formula B and the organic solvent.
In one scheme of the preparation method, the reaction raw materials comprise the alkali, a copper catalyst, a compound shown as a formula A, a compound shown as a formula B, the ligand and the organic solvent.
The temperature of the reaction may be 10 to 80 ℃; for example 10 to 35 ℃.
The progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC or NMR), typically at the end of the reaction when the compound of formula a is lost or no longer reacted.
In one embodiment of the invention, R ", R'", R 1 、R 1’ 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e And R is f In (C) 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R e In R 'and R', C is as described 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R 1 、R 1’ 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R e In R 'and R', C is as described 1 -C 20 alkyl-O-, substituted C 1 -C 20 C in alkyl-O-of (C) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 1 -C 20 alkyl-O-, substituted C 1 -C 20 C in alkyl-O-of (C) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R e Wherein the halogen is F, cl or Br.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f Wherein the halogen isF、Cl、Br。
In one embodiment of the invention, R 1 And R is 1’ Connected to and connected toTogether form: 5-7 membered heterocycloalkyl, or by one or more R b In the substituted 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl is
In one embodiment of the invention, R ", R'", R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl.
In one embodiment of the invention, R e In R 'and R', C is as described 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e And R is f Independently H, cl, methyl, ethyl, n-butyl, methyl-O-, me-O-C (=o) -or phenyl.
In one embodiment of the invention, R 2 、R 3 And R is 4 Independently Cl, methyl, ethyl, phenyl, methyl-O-, n-butyl.
In one embodiment of the invention, R a Independently phenyl.
In one embodiment of the invention, R b Independently H, methyl, me-O-C (=o) -or phenyl.
In one embodiment of the invention, R d Is independently H, cl, methoxy or-COOMe.
In one embodiment of the present invention, the 3, 3-difluoroallyl compound represented by formula F has any one of the following structures:
the invention provides a 3, 3-difluoroallyl compound, which has any one of the following structures:
the invention also provides an application of the 3, 3-difluoroallyl compound shown in the formula F, wherein the 3, 3-difluoroallyl compound shown in the formula F is used as an alpha, alpha-gem difluoroallylation reagent,
Wherein R, R "and R'" are as defined above.
Wherein R and R' are as defined above.
Wherein R is defined as above.
In one aspect, the application may be: taking the 3, 3-difluoroallyl compound shown as a formula F as an alpha, alpha-gem difluoroallylation reagent, and carrying out suzuki coupling reaction (suzuki reaction) with halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound;
for example, it comprises the steps of:
in an organic solvent, in the presence of a catalyst and alkali, carrying out a suzuki coupling reaction (suzuki reaction) on a 3, 3-difluoroallyl compound shown as a formula F and a halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound.
The suzuki coupling reaction formula is as follows:
Wherein R, R "and R'" are as defined above;
X is halogen in the halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound, and the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound contains fragments shown in a formula III.
Wherein, the mol ratio of the 3, 3-difluoroallyl compound shown in the formula F to the halogenated aromatic or heteroaromatic compound can be 1.5:1 to 1:1.5.
The solvent can be one or more of ether solvents, amide solvents, nitrile solvents, halogenated aromatic solvents and ester solvents; for example, one or more of an ether solvent, a halogenated aromatic hydrocarbon solvent and an ester solvent; the ether solvent can be dioxane, tetrahydrofuran or ethylene glycol dimethyl ether DME; such as dioxane, ethylene glycol dimethyl ether; the amide solvent can be one or more of N, N-dimethylformamide and N, N-dimethylacetamide; the nitrile solvent can be acetonitrile; the halogenated aromatic solvent can be chlorobenzene; the ester solvent may be ethyl acetate.
The amount of the organic solvent is not particularly limited so as not to affect the reaction; in the present invention, the mass volume ratio of the compound represented by the formula F to the organic solvent is preferably 0.01mol/L to 2mol/L (e.g., 0.1mol/L to 0.375 mol/L).
Preferably, the compound of formula F is added as a mixture with the solvent, wherein the concentration of the compound of formula F in the mixture may be 3M.
The catalyst may be a Pd catalyst, for example selected from: pd (PPh) 3 ) 4 、PdCl 2 (dppf)、PdBr 2 、Pd(acac) 2 、PdCl 2 (PhCN) 2 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (CH 3 CN) 2 、PdCl 2 (PCy 3 ) 2 、Pd(OAc) 2 、Pd(CF 3 COO) 2 、PdCl 2 、PdI 2 、PdCl 2 (dppb)、Pd 2 (dba) 3 、PdCl 2 (dppp)、Pd(DPPF)Cl 2 、 For example Pd (PPh) 3 ) 4 、PdCl 2 (dppf)、PdBr 2 、Pd(acac) 2 、PdCl 2 (PhCN) 2 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (CH 3 CN) 2 、PdCl 2 (PCy 3 ) 2 、Pd(OAc) 2 、Pd(CF 3 COO) 2 、PdCl 2 、PdI 2 、PdCl 2 (dppb)、Pd 2 (dba) 3 And PdCl 2 (dppp); also e.g. PdBR 2 、PdCl 2 (PhCN) 2 、PdCl 2 (CH 3 CN) 2 。
The molar ratio of the catalyst to the 3, 3-difluoroallyl compound shown as the formula F can be 0.0002:1 to 0.2:1; for example 0.01, 0.0375:1, 0.05:1, 0.001:1, 0.0002:1.
The alkali can be one or more of alkali metal fluoride, alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate and alkali metal phosphate; for example, one or more of alkali metal fluoride, alkali metal hydroxide, alkali metal alkoxide, and alkali metal carbonate; the alkali metal fluoride may be LiF, csF or KF, such as LiF, csF; the alkali metal hydroxide can be NaOH, and the alkali metal alcoholThe compound may be Meona, meoli or t-Buona, for example Meona, and the alkali carbonate may be K 2 CO 3 、Cs 2 CO 3 For example K 2 CO 3 The alkali metal phosphate can be K 3 PO 4 The method comprises the steps of carrying out a first treatment on the surface of the The base is preferably CsF.
The molar ratio of the alkali to the 3, 3-difluoroallyl compound shown in the formula F can be 1.5:1 to 3:1; for example 2.25:1.
The reaction is preferably carried out under an inert atmosphere, which may be argon or nitrogen.
The suzuki coupling reaction may be carried out in the presence of a ligand selected from the group consisting of: triphenylphosphine PPh 3 1, 2-bis (diphenylphosphine) benzene dppbz, 1' -bis (diphenylphosphine) ferrocene dppf, 1, 3-bis (diphenylphosphine) propane dppp, 1-bis (diphenylphosphine) ethane dppe, 1-bis (diphenylphosphine) methane dppm, bis (2-diphenylphosphine phenyl) ether DPEphos, (R) - (+) -DM- (i.e., (R) - (+) -DM-SegPhos), bpy, and 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene Xantphos; for example PPh 3 。
The molar ratio of the ligand to the catalyst may be from 1:1 to 5:1, for example from 2:1 to 3.7:1.
The temperature of the reaction may be 10 to 100 ℃, for example 60 to 80 ℃.
The progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC or NMR), typically by taking the compound of formula F or the vanishing or halogenated heteroaromatics as the end point of the reaction when they are no longer reacted.
In one embodiment, the halogen in the halogenated aromatic or heteroaromatic compound and the alpha, alpha-gem difluoroallyl substituted aromatic or heteroaromatic compound thereof may be F, cl, br, I; such as Cl, br, I.
In one embodiment, the halogenated aromatic hydrocarbon compound and the alpha, alpha-gem-difluoroallyl substituted aromatic hydrocarbon compound thereof can be Ar-X and Ar-XThe alpha, alpha-gem-difluoroallyl-substituted aromatic compounds are preferablyWherein Ar is C substituted or unsubstituted by a substituent 6 -C 14 Aryl radicals, e.g. C substituted or unsubstituted by substituents 6 -C 14 An aryl group; x is the halogen; the number of X may be 1 or more, for example 1, 2; the C is 6 -C 14 The aromatic ring may be a benzene ring or a naphthalene ring; the substituents may be: halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、For example halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/> />
In one scheme, the halogenated heteroarene compound and the alpha, alpha-geminal difluoroallyl substituted heteroarene compound thereof are hetAr-X andthe alpha, alpha-gem-difluoroallyl-substituted heteroarenes are preferably +.>Wherein HetAr is a 5-14 membered heteroaryl substituted or unsubstituted with a substituent; x is the halogen; the number of X may be 1 or more, for example 1, 2; the heteroatom in HetAr may be selected from one or more of N, O and S; for example furan Radicals (e.g.)>) Thienyl (e.g.)>) Pyridyl (e.g For example->) Pyrimidinyl (e.g.)>) Pyrazinyl (e.g.)>) Pyrazolo [3,4-b]Pyridyl (e.g.)>) Indazolyl (e.g) Benzothiazolinyl (e.g.)>) Pyrrolo [2,3-b]Pyridyl (e.g) Benzo [ d ]]Thiazolyl (e.g., quinolinyl (e.g.)> For example->) Isoquinolinyl (e.g.)> For example->) Quinazolinyl (e.g.)>) Quinoxalinyl (e.g) Bipyridyl (e.g.)>) Benzothienyl (e.g.)>For example->) Pyrazolyl (e.g.)>) Dibenzothienyl (e.g) Benzofuranyl (e.g.)> ) Benzothiazolonyl (e.g.)>) The method comprises the steps of carrying out a first treatment on the surface of the For example, furyl (e.g.)>) Thienyl (e.g.)>) Pyridyl (e.g.)> ) Pyrimidinyl (e.g.)>) Pyrazinyl (e.g.)>) Pyrazolo [3,4-b]Pyridyl (e.g.)>) Indazolyl (e.g.)>) Benzo [ d ]]Thiazolyl (e.g.)>) Pyrrolo [2,3-b]Pyridyl (e.g.)>) Benzo [ d ]]Thiazolyl (e.g) Quinolinyl (e.g.)>) Different typesQuinolinyl (e.g.)>) Quinazolinyl (e.g.)>) Quinoxalinyl (e.g.)>) Benzothienyl (e.g.)>) Pyrazolyl (e.g.)>) The method comprises the steps of carrying out a first treatment on the surface of the The substituents may be: halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, ethyl-O-, phO-, boc-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/> For example halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
In one scheme, the halogenated heteroarene compound and the alpha, alpha-geminal difluoroallyl substituted heteroarene compound thereof are X-HetAr-X andfor example, -HetAr-is bipyridyl, for example
In one embodiment, the halogenated aromatic or heteroaromatic compound and the corresponding α, α -gem difluoroallyl substituted aromatic or heteroaromatic compound may be any one of the following groups:
unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
Definition of groups
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1 -C 6 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In this context, a numerical range as defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.
In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.
The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. The term "C x -C y Alkyl "refers to a straight or branched chain saturated hydrocarbon containing from x to y carbon atoms. For example, the term "C 1 ~C 6 Alkyl "or" C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group; "C 1-4 Alkyl "refers specifically to independently disclosed methyl, ethyl, C 3 Alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
When none of the recited substituents indicates through which atom it is attached to a chemical structural formula (including but not specifically mentioned compounds), such substituents may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When any variable (e.g. R a ) In the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and the meanings of the variable are independent and do not influence each other. Thus, if a group is substituted with 1, 2 or 3R a The radical is substituted, that is to say, it may be substituted by up to 3R a Substituted, at position R a Definition of (d) and the remaining position R a Are defined independently of each other. In addition, substituents And/or combinations of variables are allowed only if the combination yields a stable compound.
Where no substituent is explicitly indicated in a recited group, such a group is merely unsubstituted. For example when "C 1 -C 4 Alkyl "not previously" substituted or unsubstituted "refers only to" C 1 -C 4 Alkyl "as such or" unsubstituted C 1 -C 4 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" group, it will be understood that the "alkyl" represents a linked alkylene group.
In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo-C 1 -C 6 C in alkyl' 1 -C 6 Alkyl is understood to mean C 1 -C 6 An alkylene group.
The term "halogen" means fluorine, chlorine, bromine or iodine, in particular F or Cl.
In this application, as part of a group or other group (e.g., as used in haloalkyl, deuterated alkyl, etc.), the term "alkyl" is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, and being attached to the remainder of the molecule by a single bond. For example having from 1 to 20 (preferably from 1 to 10, more preferably from 1 to 6, more preferably from 1 to 4) carbon atoms. Wherein propyl is C 3 Alkyl (including isomers such as n-propyl or isopropyl); butyl is C 4 Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C 5 Alkyl (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, t-pentyl or neopentyl); hexyl isC 6 Alkyl (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, decyl and the like.
In the present application, the term "alkylene" as part of a group or other group means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group; i.e. one hydrogen in the alkyl group is substituted, the definition of alkyl group being as described above. Examples of alkylene groups include methylene (-CH) 2 (-), ethylene { including-CH 2 CH 2 -or-CH (CH) 3 ) - } isopropylidene { including-CH (CH) 3 )CH 2 -or-C (CH) 3 ) 2 - }, and the like.
In this application, the term "alkoxy" as part of a group or other group refers to an-O-alkyl group, the definition of alkyl being as described above.
In the present application, as part of a group or other group, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting of carbon and hydrogen atoms only, and being linked to the remainder of the molecule by a single bond. For example having from 2 to 20 (preferably from 2 to 10, more preferably from 2 to 6, most preferably from 2 to 4) carbon atoms, including for example, but not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2-dimethylpropenyl, n-hexenyl, heptenyl, 2-methylhexenyl, 3-methylhexenyl, octenyl, nonenyl, decenyl and the like.
In this application, as part of a group or other group, the term "cycloalkyl" means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring system) carbocyclic substituent, and which may be attached to the remainder of the molecule via any suitable carbon atom by a single bond. For example, a 3-20 membered cycloalkyl group having 3 to 20 carbon atoms, preferably a 3-10 membered cycloalkyl group having 3 to 10 carbon atoms, more preferably a 3-7 membered cycloalkyl group having 3 to 7 carbon atoms, most preferably a 3-6 membered cycloalkyl group having 3 to 6 carbon atoms. In one embodiment, a typical monocyclic cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
In the present application, the term "heterocycloalkyl" as part of a group or other group means a group having a heteroatom or heteroatom group consisting of carbon atoms and 1 or more heteroatoms selected from O, S, N (in the form of tertiary amine moieties), B, P, sn or Si (e.g. C (=o), S (=o) 2 、P(=O)、P(=O) 2 The method comprises the steps of carrying out a first treatment on the surface of the The a-terminal represents the attachment position). For example from 2 to 20 (preferably 2 to 6) carbon atoms and 1 to 6 are selected from C (=o), S, S (=o), S (=o) 2 、O、N、Si、P、P(=O)、P(=O) 2 And B is a stable 3 to 26 membered (preferably 3 to 20 membered, more preferably 4 to 10 membered, most preferably 3 to 7 membered) saturated heterocyclic hydrocarbon group consisting of heteroatoms or heteroatom groups; preference is given to heterocyclic hydrocarbon radicals having 1, 2 or 3 ring heteroatoms independently selected from N, O and S, which are saturated, 4-to 10-membered, mono-or polycyclic (e.g. bicyclic, tricyclic or more bridged, fused or spiro ring systems). The ring system of the heterocycloalkyl bicyclic ring may include one or more heteroatoms in one or both rings; and is saturated. In some embodiments, "heterocycloalkyl" is a 5-to 7-membered monocyclic heterocycloalkyl, a 6-to 8-membered ring-attached heterocycloalkyl, a 6-to 8-membered bridged ring-attached heterocycloalkyl, or a 7-to 10-membered spiro-attached heterocycloalkyl.
In this application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group that satisfies the 4n+2 rule. For example, a conjugated hydrocarbon ring system group having 6 to 20 carbon atoms (preferably having 6 to 10 carbon atoms) satisfying the 4n+2 rule. For the purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl groups as defined above, provided that the aryl groups are linked to the rest of the molecule via atoms on the aromatic ring by single bonds. In one embodiment, the term "aryl" refers to an aromatic group consisting of carbon atoms, each ring having aromaticity. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.
In the present application, the term "heteroaryl" as part of a group or other group means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and when they are bicyclic, tricyclic or more bicyclic (fused) rings, they may also include being fused to cycloalkyl or heterocycloalkyl groups as defined herein, provided that heteroaryl groups are linked to the rest of the molecule by a single bond via an atom on an aromatic ring. Preferably a 5-14 membered heteroaryl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, more preferably a 5-6 membered heteroaryl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, indolizinyl, phenanthridinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, or benzisoxazolyl.
The "-" at the end of a group means that the group is attached to other fragments in the molecule through that site.
As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise.
The term "one(s)" or "one(s) or two or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.
Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.
The present invention employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance detection.
In addition, unless explicitly indicated otherwise, the description of the invention as "…" independently is to be understood broadly as meaning that each individual described may be independent of the other, and may be the same or different. In more detail, the description "… is independently" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.
Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used inIs->It means that the corresponding group R is linked to other fragments, groups in the compound through this site.
Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used inRepresents a single bond or a double bond.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
The above preferred conditions can be arbitrarily combined to obtain the preferred examples of the present invention without departing from the common sense in the art
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: (1) The method provided by the invention uses cheap trifluoropropene as a raw material and a cheap catalyst (copper catalyst such as copper salt catalyst and copper chloride) to prepare nucleophilic alpha, alpha-gem difluoroallylation reagent with high efficiency under the condition of no ligand (the copper catalyst content can be as low as one thousandth to one thousandth), and the preparation process has potential industrial application value; (2)
The prepared 3, 3-difluoro alkenyl borane, silane or stannane can be used for efficiently preparing various difluoro alkyl compounds with various structures, and the prepared various difluoro alkyl compounds have very wide application prospects in medicines, pesticides and materials.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
In the invention, room temperature refers to the ambient temperature, which is 10-35 ℃. Overnight means 8-15 hours. Reflux refers to the reflux temperature of the solvent at atmospheric pressure.
Example 1
Investigation of ligand Effect
Weighing ligand (10 mol%), B 2 Pin 2 (1.5 eq) was put into a glove box to be called cuprous chloride (10 mol%), lithium t-butoxide (3.0 eq), double rows were connected, argon was exchanged three times, 1.5mL of THF was added, stirring was performed for 15 minutes, trifluoropropene (0.25mmol,1.2M in DMA) was added, and the reaction was performed at room temperature for 4 hours. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
The reaction time is shortened to 1-2h, and other operations and conditions are the same.
Example 2
Investigation of alkali effect:
weighing ligand Xantphos (10 mol%), B 2 Pin 2 (1.5 eq) was put into a glove box and weighed as cuprous chloride (10 mol%), lithium t-butoxide (x eq), double rows were connected, argon was exchanged three times, 1.5mL THF was added, stirring was performed for 15 minutes, trifluoropropene (0.25mmol,1.2M in DMA) was added, and the reaction was performed at room temperature for 4 hours.
50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Example 3
Investigation of solvent Effect
Weighing ligand (10 mol%), B 2 Pin 2 (1.5 eq) was put into a glove box and was named cuprous chloride (10 mol%), lithium t-butoxide (2 eq), the double rows were connected, argon was exchanged three times, 1.5mL of solvent was added, stirring was performed for 15 minutes, trifluoropropene (0.25mmol,1.2M in DMA) was added, and the reaction was performed at room temperature for 5 hours. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Example 4
B 2 Pin 2 Investigation of the amount:
weighing B 2 Pin 2 (y eq) into a glove box, namely cuprous chloride (10 mol%), lithium tert-butoxide (2 eq), connecting double rows, pumping argon three times, adding 1.5mL THF, stirring for 15 minutes, adding trifluoropropene (0.25mmol,1.2M in DMA), and reacting for 5 hours at room temperature. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Example 5
Investigation of alkali at optimal ratio:
weighing B 2 Pin 2 (0.25 mmol), put into a glove box and called cuprous chloride (10 mol%), alkali (2 eq), connect double rows, pump argon three times, add 1.5mL THF, stir for 15 minutes, add trifluoropropene (1.5eq,1.2M in DMA), react for 5h at room temperature. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Example 6
Optimization of catalyst dosage:
weighing B 2 Pin 2 (x mmol), put into a glove box, call cuprous chloride (z mol%), meOLi (2 eq), connect double rows, pump argon three times, add THF, stir for 15 minutes, add trifluoropropene (1.5eq,1.2M in DMA), and react overnight at room temperature. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
6-1:
6-2:
6-3:
6-4: preliminary investigation of 1% catalyst amplification reaction:
example 7
Investigation of 1atm trifluoropropene gas atmosphere:
weighing B 2 Pin 2 (25.4 g,100 mmol), was put into a glove box and weighed cuprous chloride (0.1 mmol,10 mg), meOLi (3.8 g,200 mmol), connected in double rows, argon was exchanged three times, freshly distilled anhydrous THF (40 mL) and ultra-dry DMF (40 mL) were added, stirred at room temperature for 15 minutes, then trifluoropropene gas was slowly bubbled in, and the reaction was carried out at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm the nuclear magnetic yield. The obtained reaction mixed solution is added with 500mL of normal hexane for dilution and beating for 2 hours, then is kept still, supernatant is sucked out (repeated 3-5 times for beating with 500mL of normal hexane), water is added for dilution after the last beating is finished, and 250mL of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. N-hexane is recovered by distillation and concentration under normal pressure, the mixture obtained after decompression and concentration is recrystallized by a proper amount of n-pentane at the temperature of minus 78 ℃ to obtain n-pentane solution (which can be directly used for subsequent reaction) of the expected target product, 17.4g of pure product can be obtained by further distillation and concentration under normal pressure, and the separation yield is 85 percent.
Example 8
Investigation of 1atm trifluoropropene gas atmosphere:
weighing B 2 Pin 2 (100 g, 390 mol) and put into a glove box to be chloridizedCuprous (0.390 mmol,39.4 mg) and MeOLi (29.9 g,8mol,2 eq) were connected in double rows, argon was exchanged three times, freshly distilled anhydrous THF (160 mL) and ultra-dry DMF (160 mL) were added, stirred at room temperature for 15 minutes, then trifluoropropene gas was bubbled slowly, and the reaction was carried out at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm that the nuclear magnetic yield is 99%. The obtained reaction mixed solution is added with 800mL of normal hexane for dilution and pulping for 2 hours, then is kept still, supernatant is sucked out (repeated 3-5 times for pulping with 800mL of normal hexane), water is added for dilution after the last pulping is finished, and 500mL of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. N-hexane is recovered by distillation and concentration under normal pressure, the mixture obtained after decompression and concentration is recrystallized by a proper amount of n-pentane at the temperature of minus 78 ℃ to obtain n-pentane solution (which can be directly used for subsequent reaction) of the expected target product, 64.3g of pure product can be obtained by further distillation and concentration under normal pressure, and the separation yield is 80 percent.
Example 9
Preparation of 600 hundred gram grade boron reagent:
weighing B 2 Pin 2 (1.02 kg,4 mol), into a glove box, cuprous chloride (0.8 mmol,80 mg) and Meoli (304 g,8mol,2 eq) were weighed, double rows were connected, argon was exchanged three times, freshly distilled anhydrous THF (800 mL) and ultra-dry DMF (400 mL) were added, stirred at room temperature for 15 minutes, and then trifluoropropene gas was slowly bubbled in and reacted at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm that the nuclear magnetic yield is 95%. The obtained reaction mixed solution is added with 2L of normal hexane for dilution and pulping for 2 hours, then is kept still, supernatant is sucked out (3-5 times of pulping with 2L of normal hexane is repeated), water is added for dilution after the last pulping is finished, and 1L of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. Often timesThe normal hexane is recovered by distillation and concentration under reduced pressure, the mixture obtained after the concentration under reduced pressure is recrystallized by a proper amount of normal pentane at the temperature of minus 78 ℃ to obtain a normal pentane solution (which can be directly used for subsequent reaction) of the expected target product, 694g of pure product can be obtained by further distillation and concentration under normal pressure, and the separation yield is 85 percent. 1 H NMR(400MHz,Chloroform-d)δ4.20(dtd,J=25.6Hz,8.0Hz,2.1Hz,2H),1.51(d,J=8.0Hz,2H),1.25(s,12H). 19 F NMR(376MHz,Chloroform-d)δ-90.1(dd,J=50.3Hz,1.3Hz,1F),-92.9(dd,J=50.3Hz,25.6Hz,1F).
Example 10
Investigation of 1atm trifluoropropene gas atmosphere:
weighing B 2 Pin 2 (58.1 g,100 mmol), cuprous chloride (1 mmol,100 mg) and MeOLi (3.8 g,200 mmol) were weighed into a glove box, the double rows were connected, argon was exchanged three times, freshly distilled anhydrous THF (40 mL) and ultra-dry DMF (40 mL) were added, stirring was carried out at room temperature for 15 minutes, and then trifluoropropene gas was slowly bubbled and reacted at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm the nuclear magnetic yield. The obtained reaction mixed solution is added with 500mL of normal hexane for dilution and beating for 2 hours, then is kept still, supernatant is sucked out (repeated 3-5 times for beating with 500mL of normal hexane), water is added for dilution after the last beating is finished, and 250mL of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. And distilling, concentrating and recycling normal hexane under normal pressure, decompressing and distilling the mixture obtained after decompressing and concentrating by an oil pump to obtain 25.0g of pure product, and separating and obtaining 68% of yield.
Example 11
Weighing [ Pd ], potassium carbonate and phenylboronic acid in a 500mL Schlenck bottle, connecting the two rows, pumping argon for three times, adding water, THF and bromotrifluoropropene, and stirring at 60 ℃ for 24 hours. Cool to room temperature and quench with water. PE extraction, spin drying and direct casting.
Weighing B 2 Pin 2 The cuprous chloride and the lithium methoxide are placed in a Schlenck bottle, double rows are connected, argon is pumped for three times, and the 2-phenyl trifluoropropene, THF and DMA which are the products of the previous reaction are added and stirred for one day at room temperature. Washing with water, and extracting with ethyl acetate. Spin drying and column passing. The product was obtained (94% yield, 95% purity). 1 H NMR(400MHz,CD 3 OD)δ7.40–7.28(m,4H),7.23(t,J=7.1Hz,1H),1.96(s,2H),1.16(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-90.8(dt,J=45.4Hz,3.1Hz,1F),-92.2(d,J=45.4Hz,1F).
Example 12
Weigh PdCl 2 (PPh 3 ) 2 Adding potassium carbonate and arylboronic acid into a 500mL solvent bottle, connecting the two rows, pumping argon for three times, adding water and tetrahydrofuran, stirring for 2 minutes, adding bromotrifluoropropene, heating and stirring for 24 hours at 60 ℃. And (5) recovering to room temperature, extracting by EA, washing by using brine, spin-drying, and passing through a column.
Weighing B 2 Pin 2 In a 250mL three-necked flask, cuCl and Meoli were placed in a flask, ar was exchanged, THF and DMA were added, the mixture was stirred for 2 minutes, the product of the previous reaction was added, and the mixture was stirred at room temperature overnight. The diatomite and the silica gel are filtered once, a large amount of DMA is removed by water washing, EA extraction, spin drying and column passing.
1 H NMR(400MHz,CD 3 OD)δ7.33–7.26(m,2H),6.89–6.81(m,2H),3.80(s,3H),1.92(s,2H),1.16(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-91.8(d,J=48.0Hz,1F),-93.1(d,J=48.0Hz,1F).
1 H NMR(400MHz,CD 3 OD)δ7.24(t,1H),6.99–6.87(m,2H),6.83–6.72(m,1H),3.80(s,3H),1.94(s,2H),1.16(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-90.3(dt,J=44.5Hz,2.7Hz,1F),-91.3(d,J=44.4Hz,1F).
1 H NMR(400MHz,CD 3 OD)δ8.03(s,1H),7.91(d,J=7.8Hz,1H),7.55(d,J=9.0Hz,1H),7.39(t,J=7.8Hz,1H),3.90(s,3H),1.95(s,2H),1.15(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-89.8(dt,J=43.7Hz,2.6Hz,1F),-91.3(d,J=43.2Hz,1F).
Example 13
Weighing B 2 Pin 2 In a 500mL three-necked flask, cuCl and Meoli were placed in a flask, ar was exchanged, THF and DMA were added, the mixture was stirred for 2 minutes, the product of the previous reaction was added, and the mixture was stirred at room temperature for 2 days. (the fluorine spectrum shows that most of the starting material remains one day of reaction). The diatomite and the silica gel are filtered once, a large amount of DMA is removed by water washing, EA extraction, spin drying and column passing. PE→PE:EA 100: 1- & gt PE: EA 80: 1- & gt PE: EA 60:1 pass out. A pale yellow oily liquid was obtained, 8.0g, 37% yield in two steps.
1 H NMR(400MHz,CD 3 OD)δ7.32–7.26(m,2H),7.23–7.13(m,3H),2.60(t,J=7.4Hz,2H),2.13–1.98(m,2H),1.73(p,J=7.8Hz,2H),1.54(s,2H),1.23(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-96.0(d,J=59.4Hz,1F),-97.0(d,J=59.3Hz,1F).
Example 14
Weighing [ Ni ] in a 100mL Schlenck bottle, connecting double rows, pumping argon for three times, adding chlorotrifluoropropene and dioxane, and dripping zinc reagent. Stirring for 2h at room temperature. Quenching with water, PE extraction, spin drying, and PE column chromatography to give 5.7g of crude product (impure, mixed with more by-products and agent) which is directly fed to the next step.
Weighing B 2 Pin 2 The cuprous chloride and the lithium methoxide are placed in a 50mL Schlenck bottle, double rows are connected, argon is pumped for three times, and the trifluoropropene compound, THF and DMA which are obtained in the previous step are added and stirred at room temperature overnight. Washing with water, extracting with ethyl acetate. Spin drying, passing through column, and passing out PE and EA 80:1. A viscous liquid, 5.8g, was obtained in 67% yield.
1 H NMR(400MHz,CD 3 OD)δ7.32–7.25(m,2H),7.19(t,J=6.4Hz,3H),4.15(ddd,J=25.8Hz,10.7Hz,2.7Hz,1H),2.72–2.50(m,2H),1.97–1.82(m,1H),1.78–1.53(m,3H),1.52–1.36(m,1H),1.25(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-89.4(d,J=49.9Hz,1F),-91.9(dd,J=49.8Hz,25.8Hz,1F).
Application example 1
Palladium catalyzed geminal difluoroallylation of aryl heterocycles:
general procedure for the examples:
weighing bromoquinoline and PdCl 2 (dppf), base, and then argon was replaced three times in vacuo. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Application example 2
Application examples 2-1 to 2-6 of bromoheterocycle:
weighing brominated heterocyclic raw materials and PdCl 2 (PhCN) 2 CsF, PPh 3 Argon was then replaced three times in vacuo. Under the protection of argon, 1.5mL of dioxane was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 8h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
(the product is the corresponding geminal difluoroallylated structure).
Application example 3
Weighing 3-bromopyridine and PdCl 2 (dppf), csF, and then argon was vacuum-replaced three times. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Application example 4
Investigation of catalyst types and equivalent weights
3-bromopyridine, catalyst, csF were weighed and then argon was purged three times in vacuo. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Weighing 3-bromopyridine, catalyst, csF and the mixtureBulk PPh 3 Argon was then replaced three times in vacuo. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Application example 5
Concentration Effect investigation
Weighing 3-bromopyridine and PdCl 2 (PhCN) 2 CsF, PPh 3 Argon was then replaced three times in vacuo. Under argon, 1.5mL of solvent (is dioxane) was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 3h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Application example 6
Investigation of solvent Effect
Weighing 3-bromopyridine and PdCl 2 (PhCN) 2 CsF, PPh 3 Argon was then replaced three times in vacuo. Under the protection of argon1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Application example 7
Further investigation of heterocyclic substrate adaptability:
(the product is a corresponding geminal difluoroallylated structure of bromo).
Application example 8
Investigation of other types of heterocycles:
(the product is a corresponding geminal difluoroallylated structure of bromo).
Application example 9
Application examples after further optimization of conditions:
application example 10
Add B to 1000mL three-necked flask under air conditions 2 pin 2 (200 mmol,1.0 eq.) CuCl (0.2 mmol,0.1 mol%) and MeOLi (400 mmol,2.0 eq.) were added under argon, the three-necked flask was replaced with argon 3 times, then with 3, 3-trifluoropropene, after which tetrahydrofuran (200 mL) and N, N-dimethylformamide (200 mL) were added under argon, the reaction system was reacted at 0deg.C for 2h, then warmed to room temperature for 10h. And after the reaction is finished, diluting with n-pentane, adding a certain amount of fluorobenzene as an internal standard, and carrying out fluorine spectrum quantitative detection. The reaction was then filtered through celite, the filtrate was diluted with n-pentane, the organic phase was washed with water multiple times and once again through celite. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product as a pale yellow liquid. The crude product was distilled under reduced pressure (6 mbar,60 ℃) to give 29.2g of the desired product 2 as a colorless oil in 71% yield. 1 H NMR(400MHz,Chloroform-d)δ4.20(m,1H),1.51(d,J=8.0Hz,2H),1.25(s,12H). 19 F NMR(376MHz,Chloroform-d)δ-90.1(d,J=50.3Hz,1F),-92.71–-93.06(m,1F).
To a Schlenk flask under air conditions were added (hetero) aryl bromide 1a (0.4 mmol,1.0 eq.) andP(t-Bu) 2 Ph·PdCl 2 (3 mol%). CsF (2.0 eq.) and 1, 4-dioxane (1.5 mL) were added under argon followed by difluoroallylboron 2 (0.44 mmol,1.1 eq.) and 1, 4-dioxane (0.5 mL) under argon. The reaction flask was capped and then reacted at 100℃for 2 hours. After the reaction is finished, adding 2mL of ethyl acetate into the reaction system for dilution, and adding a certain amount of fluorobenzene as an internal standard for quantitative fluorine spectrum detection. After the fluorine spectrum determines the yield, the reaction system is filtered and the filtrate is concentrated. And finally, carrying out column chromatography on the concentrated crude product to obtain the product 3a which is wanted by us.
Application example 11
Investigation of ligand Effect
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction. c Without PPh 3 .
Application example 12
Investigation of solvent Effect
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
a Reaction conditions 1a (0.4 mmol,1.0 eq.) 2 (0.44 mmol,1.1 eq.). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 13
Investigation of the alkali Effect
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 14
Temperature effect investigation
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; 2 yield refers to the post-reaction compound2, residual amount of the catalyst.
Application example 15
Investigation of the ratio of the reactants
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
a Reaction conditions 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 16
Investigation of reaction time
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR was examined and isolated yields are in brackets; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 17
To a Schlenk flask under air conditions were added (hetero) aryl bromide 1a (6.70 mmol,1.0 eq.) and P (t-Bu) 2 Ph·PdCl 2 (0.5 mol%). CsF (2.0 eq.) and 1, 4-dioxane (33 mL) were added under argon followed by difluoroallylboron 2 (7.40 mmol,1.1 eq.) under argon. The reaction flask was capped and then reacted at 100℃for 2 hours. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated. Finally, column chromatography (petroleum ether/ethyl acetate=20:1) of the concentrated crude product afforded 1.04g of the target product 3a as a yellow oil in 71% yield.
Application example 18
Examination of the adaptability of heterocyclic substrates
Preparation of 3a-3z,3aa,3ab,4a and 4b Compounds
3a-3z,3aa and 3ab are prepared by reacting the corresponding bromo compound with The reaction was carried out under the same experimental conditions as in application example 10.
Preparation of Compounds 4a and 4b, etc. byRespectively and->The reaction was carried out under the same experimental conditions as in application example 10.
When R' is H, compound 2 is used to make 3a-3z,3aa and 3ab;
After the reaction, the reaction was carried out using fluorobenzene as an internal standard 19 F NMR detection measures isolated yields. The nuclear magnetic data of the above compounds are as follows:
compound (3 a) column chromatography (petroleum ether/ethyl acetate=20:1) gave 67mg of a yellow oil in 81% yield. 1 H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.79(s,1H),7.68(d,J=8.4Hz,2H),7.47(t,J=7.8Hz,2H),7.33(t,J=7.8Hz,1H),6.32–6.15(m,1H),5.70(dt,J=17.2,2.8Hz,1H),5.54(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-85.9(dd,J=9.4,3.0Hz,1H,2F). 13 C NMR(101MHz,Chloroform-d)δ139.59,138.73(t,J=3.8Hz),133.26(t,J=29.9Hz),129.50,127.19,125.75(t,J=4.9Hz),120.75(t,J=32.7Hz),120.12(t,J=8.9Hz),119.43,116.78(t,J=233.7Hz).MS(FI):m/z(%)220(M) + HRMS theoretical value C 12 H 10 N 2 F 2 220.0807; found 220.0810.
Compound (3 b) column chromatography (petroleum ether/ethyl acetate=20:1) gave 80mg of a colorless oil in 97% yield. 1 H NMR(400MHz,Chloroform-d)δ8.99(d,J=2.0Hz,1H),8.28(s,1H),8.14(d,J=8.4Hz,1H),7.85(d,J=8.4Hz,1H),7.77(t,J=7.4Hz,1H),7.58(t,J=7.4Hz,1H),6.23(dq,J=17.6,10.1Hz,1H),5.64(dt,J=17.2,2.8Hz,1H),5.57(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.2(dd,J=9.8,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ148.44,147.40(t,J=5.0Hz),133.33(t,J=6.1Hz),132.99(t,J=5.0Hz),130.74,129.31,128.96(t,J=5.0Hz),128.31,127.41,126.66,120.93(t,J=9.2Hz),118.60(t,J=239.3Hz).MS(ESI):m/z(%)206.1(M+H) + HRMS theoretical value C 12 H 10 NF 2 206.0776; found 206.0777.
Compound (3 c) column chromatography (petroleum ether/ethyl acetate=20:1) gave 90mg of a colorless oil in 74% yield. 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J=8.4Hz,1H),8.18(d,J=8.5Hz,1H),7.86(d,J=8.0Hz,1H),7.80–7.70(m,2H),7.61(t,J=7.4Hz,1H),6.51(dq,J=17.6,10.9Hz,1H),5.81(dt,J=17.2,2.4Hz,1H),5.60(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-97.2(dd,J=10.9,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ154.53(t,J=30.6Hz),147.22,137.51,132.34(t,J=27.4Hz),130.12,129.91,128.16,127.67,127.57,120.15(t,J=9.2Hz),117.46(t,J=240.9Hz),117.16(t,J=3.4Hz).MS(EI):m/z(%)205(M) + HRMS theoretical value C 12 H 9 NF 2 205.0698; found 205.0701.
Compound (3 d). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 86mg of a yellow oil in 90% yield. 1 H NMR(400MHz,Chloroform-d)δ8.85(d,J=4.4Hz,1H),8.41(s,1H),8.19(d,J=9.2Hz,1H),7.90–7.81(m,1H),7.56(d,J=4.8Hz,1H),6.25(dq,J=17.2,10.0Hz,1H),5.66(dt,J=17.2,2.6Hz,1H),5.58(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.6(dd,J=9.4,2.6Hz,2F). 13 CNMR(126MHz,Chloroform-d)δ151.10,149.38,143.3,135.44(t,J=27.9Hz),133.22(t,J=29.9Hz),130.51,127.34(t,J=4.7Hz),125.88,121.96,121.68(t,J=6.7Hz),120.64(t,J=9.1Hz),118.94(t,J=239.8Hz).MS(EI):m/z(%)239(M) + HRMS theoretical value C 12 H 8 ClNF 2 239.0308; found 239.0307.
Compound (3 e) column chromatography (petroleum ether/ethyl acetate=3:1) gave 59mg of a colorless oil in 72% yield. 1 H NMR(400MHz,Chloroform-d)δ9.33(s,1H),8.76(s,1H),8.15(d,J=8.4Hz,1H),8.04(d,J=8.0Hz,1H),7.77(ddd,J=10.0,6.8,1.6Hz,1H),7.67(t,J=7.6Hz,1H),6.44–6.32(m,1H),5.65–5.56(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-89.8(d,J=9.4Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ155.57,141.31(t,J=9.1Hz),133.20(t,J=29.1Hz),132.34(t,J=1.5Hz),131.20,128.53,128.36,127.53,124.58(t,J=3.3Hz),121.55(t,J=9.4Hz),119.73(t,J=239.5Hz).MS(FI):m/z(%)205(M) + HRMS theoretical value C 12 H 9 NF 2 205.0698; found 205.0701.
Compound (3 f) column chromatography (petroleum ether/ethyl acetate=2:1) gave 67mg of a yellow oil in 82% yield. 1 H NMR(400MHz,Chloroform-d)δ9.35(s,1H),8.62(s,1H),8.10–7.96(m,2H),7.80–7.65(m,2H),6.22(dq,J=17.2,10.1Hz,1H),5.64(dt,J=17.2,2.8Hz,1H),5.57(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-94.3(d,J=10.5Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ152.39,143.89,138.00(t,J=27.7Hz),135.13,133.21(t,J=29.7Hz),128.73,128.26,124.23(t,J=4.8Hz),123.80(t,J=6.6Hz),120.99,120.62(t,J=9.2Hz),118.92(t,J=239.7Hz).MS(EI):m/z(%)205(M) + HRMS theoretical value C 12 H 9 NF 2 205.0698; found 205.0701.
Compound (3 g) column chromatography (petroleum ether/ethyl acetate=20:1) gives 50mg of a colourless oil in 62% yield. 1 H NMR(400MHz,Chloroform-d)δ8.99(d,J=5.6Hz,1H),8.39(d,J=2.0Hz,1H),8.12(dd,J=5.2,2.0Hz,1H),6.33(dq,J=17.6,11.2Hz,1H),5.83(dt,J=17.6,2.6Hz,1H),5.64(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-98.2(dd,J=11.3,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ157.86(t,J=31.9Hz),154.63,151.96,131.16(t,J=26.9Hz),121.26(t,J=9.2Hz),117.36,116.43(t,J=241.6Hz),113.25(t,J=4.4Hz).MS(FI):m/z(%)200(M) + HRMS theoretical value C 8 H 6 O 2 N 2 F 2 200.0392; found 200.0393.
Compound (3 h) column chromatography (petroleum ether/ethyl acetate=15:1) gave 73mg of a colorless oil in 81% yield. 1 H NMR(400MHz,Chloroform-d)δ9.24(s,1H),8.41(dd,J=8.0,2.0Hz,1H),7.73(d,J=8.0Hz,1H),6.32(dq,J=17.6,10.9Hz,1H),5.76(dt,J=17.2,2.4Hz,1H),5.57(d,J=11.2Hz,1H),4.43(q,J=7.1Hz,2H),1.41(t,J=7.2Hz,3H). 19 F NMR(376MHz,Chloroform-d)δ-98.7(dd,J=10.9,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ164.48,157.96(t,J=31.9Hz),150.55,138.36,131.79(t,J=27.2Hz),127.16,120.59(t,J=9.2Hz),119.60(t,J=4.0Hz),116.93(t,J=240.7Hz),61.73,14.20.MS(FI):m/z(%)227(M) + HRMS theoretical value C 11 H 11 O 2 NF 2 227.0752; found 227.0755.
Compound (3 i). Column chromatography (petroleum ether/ethyl acetate=3:1) gave 63mg of a colorless oil in 85% yield. 1 H NMR(400MHz,Chloroform-d)δ8.36(d,J=12.4Hz,2H),7.31–7.27(m,1H),6.21–6.08(m,1H),5.61(dt,J=17.6,2.8Hz,1H),5.55(d,J=10.8Hz,1H),3.89(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-93.7(dd,J=9.8,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ155.32,139.37(t,J=1.8Hz),139.22(t,J=6.1Hz),132.85(t,J=29.4Hz),132.56,120.74(t,J=9.2Hz),118.18(t,J=239.7Hz),117.27(t,J=5.6Hz),55.68.MS(EI):m/z(%)185(M) + HRMS theoretical value C 9 H 9 ONF 2 185.0647; found 185.0649.
Compound (3 j). Column chromatography (petroleum ether/ethyl acetate=7:1) gave 60mg of a colorless oil in 83% yield. 1 H NMR(400MHz,Chloroform-d)δ10.17(s,1H),9.16(s,1H),8.99(s,1H),8.28(s,1H),6.17(dq,J=17.6,10.3Hz,1H),5.70–5.58(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-94.23(dd,J=10.2,2.6Hz,2F). 13 CNMR(101MHz,Chloroform-d)δ189.77,152.97,151.93(t,J=5.6Hz),133.17(t,J=5.5Hz),132.32(t,J=29.1Hz),130.87,121.49(t,J=9.3Hz),117.86(t,J=240.8Hz).MS(FI):m/z(%)183(M) + HRMS theoretical value C 9 H 7 ONF 2 183.0490; found 183.0493.
Compound (3 k). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 67mg of a colorless oil in 91% yield. 1 H NMR(400MHz,Chloroform-d)δ8.22(d,J=5.2Hz,1H),6.95(d,J=5.2Hz,1H),6.85(s,1H),6.07(dq,J=17.3,10.2Hz,1H),5.60(dt,J=17.2,2.8Hz,1H),5.51(d,J=10.8Hz,1H),3.95(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-96.7(dd,J=9.8,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ164.43,147.55,147.05(t,J=25.8Hz),132.51(t,J=29.2Hz),120.70(t,J=9.3Hz),117.85(t,J=239.9Hz),113.08(t,J=5.0Hz),107.71(t,J=6.0Hz),53.69.MS(EI):m/z(%)185(M) + HRMS theoretical value C 9 H 9 ONF 2 185.0647; found 185.0650.
Compound (3 l) column chromatography (petroleum ether/ethyl acetate=10:1) gave 67mg of a colorless oil in 85% yield. The product (67 mg,85% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate=10:1) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ8.21(d,J=5.2Hz,1H),6.63–6.55(m,2H),6.09(dq,J=17.2,10.1Hz,1H),5.61(dt,J=17.2,2.6Hz,1H),5.49(d,J=10.8Hz,1H),3.11(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-96.9(dd,J=9.8,3.0Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ159.40,148.47,145.31(t,J=28.0Hz),132.98(t,J=20.9Hz),120.29(t,J=9.3Hz),118.46(t,J=240.0Hz),107.71(t,J=25.0Hz),101.71(t,J=6.3Hz),38.10.MS(EI):m/z(%)198(M) + HRMS theoretical value C 10 H 12 N 2 F 2 198.0963; found 198.0967.
Compound (3 m) column chromatography (petroleum ether/ethyl acetate=2:1) gave 52mg of a colorless oil in 73% yield. 1 H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.92(d,J=4.8Hz,1H),7.63(d,J=5.2Hz,1H),6.16(dq,J=17.2,10.5Hz,1H),5.77(dt,J=17.2,2.6Hz,1H),5.69(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-96.3(dd,J=10.5,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ154.29,153.58,146.89(t,J=29.5Hz),130.41(t,J=28.3Hz),122.89(t,J=9.3Hz),120.05(t,J=6.5Hz),116.74(t,J=243.2Hz),114.55,107.02.MS(FI):m/z(%)180(M) + HRMS theoretical value C 9 H 6 N 2 F 2 180.0494; found 180.0497.
Compound (3 n) columnChromatography (petroleum ether/ethyl acetate=15:1) gave 84mg of a colorless oil in 91% yield. 1 H NMR(400MHz,Chloroform-d)δ8.96(s,2H),6.31(dq,J=17.6,11.0Hz,2H),5.82(dt,J=17.6,2.4Hz,2H),5.64(d,J=11.2Hz,2H). 19 FNMR(376MHz,Chloroform-d)δ-98.9(dd,J=11.3,2.3Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ151.10(t,J=31.6Hz),140.83(t,J=4.8Hz),131.06(t,J=27.0Hz),121.46(t,J=9.5Hz),116.58(t,J=241.4Hz).MS(ESI):m/z(%)233(M+H) + HRMS theoretical value C 10 H 9 N 2 F 2 233.0696; found 233.0699.
Compound (3 o). Column chromatography (petroleum ether/ethyl acetate=10:1) gave 60mg of a yellow oil in 75% yield. 1 H NMR(400MHz,Chloroform-d)δ8.61(s,2H),6.25–6.05(m,1H),5.76–5.55(m,2H),4.46(q,J=7.1Hz,2H),1.44(t,J=7.0Hz,3H). 19 FNMR(376MHz,Chloroform-d)δ-92.59(dd,J=9.4,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ165.96,157.26(t,J=5.2Hz),132.48(t,J=29.5Hz),123.59(t,J=29.5Hz),121.25(t,J=9.2Hz),117.93(t,J=238.5Hz),64.15,14.32.MS(FI):m/z(%)200([M] + ) HRMS theoretical value C 9 H 10 O 2 N 2 F 2 200.0756; found 200.0751.
Compound (3 p) column chromatography (petroleum ether/ethyl acetate=10:1) gave 81mg of yellow oil in 82% yield. 1 H NMR(400MHz,Chloroform-d)δ8.67(s,2H),7.45(t,J=8.0Hz,2H),7.29(t,J=7.4Hz,1H),7.24–7.17(m,2H),6.23–6.07(m,1H),5.71–5.59(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-92.8(dd,J=9.8,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ166.11,157.72(t,J=5.2Hz),152.50,132.23(t,J=29.4Hz),129.72,125.87,125.06(t,J=5.2Hz),121.55,121.49(t,J=8.3Hz),117.66(t,J=239.0Hz).MS(FI):m/z(%)248(M + ) HRMS theoretical value C 13 H 10 ON 2 F 2 248.0756; found 248.0753.
Compound (3 q). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 86mg of a yellow oil in 92% yield. The product (86 mg,92% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate=20:1) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ8.92(s,2H),8.56–8.44(m,2H),7.61–7.43(m,3H),6.30–6.10(m,1H),5.74–5.59(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-94.1(dd,J=9.8,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ165.87,154.84(t,J=5.4Hz),136.66,132.39(t,J=29.4Hz),131.43,128.69,128.54,127.36(t,J=29.2Hz),121.51(t,J=9.3Hz),117.88(t,J=239.7Hz).MS(EI):m/z(%)232(M + ) HRMS theoretical value C 13 H 10 N 2 F 2 232.0807; found 232.0811.
Compound (3 r) column chromatography (petroleum ether/ethyl acetate=7:1) gave 84mg of a yellow oil in 87% yield. 1 H NMR(400MHz,Chloroform-d)δ8.40(s,2H),6.20–6.05(m,1H),5.61(dt,J=17.2,2.8Hz,1H),5.54(d,J=10.8Hz,1H),3.88–3.73(m,8H). 19 F NMR(376MHz,Chloroform-d)δ-91.8(dd,J=9.4,2.6Hz,2F). 13 CNMR(126MHz,Chloroform-d)δ161.87,155.74(t,J=5.2Hz),132.92(t,J=30.3Hz),120.64(t,J=9.0Hz),118.57(t,J=237.3Hz),118.25(t,J=29.4Hz),66.72,44.17.MS(FI):m/z(%)241(M + ) HRMS theoretical value C 11 H 13 ON 3 F 2 241.1021; found 241.1019.
Compound (3 s) column chromatography (petroleum ether/ethyl acetate=7:1) gave 47mg of a yellow oil in 63% yield. 1 H NMR(400MHz,Chloroform-d)δ9.94(s,1H),7.74–7.66(m,1H),7.35–7.30(m,1H),6.20(dq,J=17.6,10.3Hz,1H),5.76(dt,J=16.8,2.4Hz,1H),5.62(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-85.2(d,J=9.4Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ182.98,147.48(t,J=32.9Hz),145.05(t,J=1.3Hz),135.28,132.00(t,J=32.9Hz),127.70(t,J=5.0Hz),121.27(t,J=8.8Hz),116.59(t,J=239.3Hz).MS(FI):m/z(%)188(M + ) HRMS theoretical value C 8 H 6 OSF 2 188.0102; found 188.0105.
Compound (3 t). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 76mg of a yellow oil in 82% yield. 1 H NMR(400MHz,Chloroform-d)δ7.78(s,1H),7.68(s,1H),6.24–6.07(m,1H),5.62(dt,J=17.2,2.6Hz,1H),5.52(d,J=10.8Hz,1H),4.35(q,J=7.2Hz,2H),1.37(t,J=7.0Hz,3H). 19 F NMR(376MHz,Chloroform-d)δ-89.3(dd,J=10.0,2.8Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ161.52,138.33(t,J=31.2Hz),135.50,132.75(t,J=29.5Hz),130.84(t,J=3.6Hz),130.40(t,J=5.9Hz),120.44(t,J=9.1Hz),116.72(t,J=237.1Hz),61.50,14.23.MS(FI):m/z(%)232(M + ) HRMS theoretical value C 10 H 10 O 2 SF 2 232.0364; found 232.0366.
Compound (3 u). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 80mg of yellow oil in 95% yield. 1 H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.94(d,J=8.4Hz,1H),7.53(d,J=5.6Hz,1H),7.50–7.43(m,1H),7.39(d,J=5.6Hz,1H),6.24(dq,J=17.2,10.0Hz,1H),5.62(dt,J=17.2,2.8Hz,1H),5.52(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-92.2(dd,J=9.4,2.6Hz). 13 C NMR(126MHz,Chloroform-d)δ141.10,139.20,133.90(t,J=30.4Hz),132.49(t,J=27.6Hz),127.71,124.05,122.58,121.40(t,J=5.2Hz),120.79(t,J=6.3Hz),119.86(t,J=9.2Hz),119.63(t,J=238.9Hz).MS(FI):m/z(%)210(M + ) HRMS theoretical value C 11 H 8 SF 2 210.0309; found 210.0312.
Compound (3 v). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 100mg of yellow oil in 96% yield. 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),8.23–8.17(m,1H),7.95–7.83(m,2H),7.59(d,J=8.0Hz,1H),7.54–7.46(m,2H),6.28(dq,J=17.2,9.9Hz,1H),5.66(dt,J=17.2,2.8Hz,1H),5.56(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-92.2(dd,J=9.8,2.6Hz,2F). 13 CNMR(101MHz,Chloroform-d)δ141.07(t,J=1.5Hz),139.78,135.41,135.04,133.89(t,J=30.5Hz),132.66(t,J=27.8Hz),127.19,124.62,123.86(t,J=5.4Hz),122.85,122.81,121.77,120.04(t,J=9.1Hz),119.61(t,J=239.4Hz),118.68(t,J=6.2Hz).MS(FI):m/z(%)260(M + ) HRMS: theoretical 260.0466; found 260.0467.
Compound (3 w). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 68mg of a colorless oil in 88% yield. 1 H NMR(400MHz,Chloroform-d)δ7.77(t,J=1.8Hz,1H),7.68(d,J=7.6Hz,1H),7.53(d,J=8.0Hz,1H),7.34(dt,J=25.2,7.8Hz,2H),6.37–6.20(m,1H),5.75(dt,J=17.2,2.6Hz,1H),5.59(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-90.2(dt,J=9.9,2.2Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ155.53,143.78(t,J=8.1Hz),132.48(t,J=29.3Hz),125.21,124.16(t,J=2.0Hz),123.48,120.87(t,J=8.7Hz),120.80,118.19(t,J=32.1Hz),117.41(t,J=233.6Hz),111.76.MS(FI):m/z(%)194(M + ) HRMS theoretical value C 11 H 8 OF 2 194.0538; found 194.0540.
Compound (3 x) column chromatography (petroleum ether/ethyl acetate=20:1) gave 68mg of a colorless oil in 88% yield. 1 H NMR(400MHz,Chloroform-d)δ7.78(s,1H),7.69(d,J=2.4Hz,1H),7.55(d,J=8.8Hz,1H),7.48–7.42(m,1H),6.82(d,J=2.0Hz,1H),6.30–6.13(m,1H),5.59(dt,J=17.6,2.8Hz,1H),5.50(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-91.3(dd,J=9.4,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ155.45,146.08,134.12(t,J=30.5Hz),131.09(t,J=27.6Hz),127.30,121.96(t,J=5.5Hz),119.68(t,J=239.2Hz),119.66(t,J=9.1Hz),118.84(t,J=6.2Hz),111.38,106.83.MS(FI):m/z(%)194(M + ) HRMS theoretical value C 11 H 8 OF 2 194.0538; found 194.0536.
Compound (3 y). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 95mg of a colorless oil in 98% yield. 1 H NMR(400MHz,Chloroform-d)δ8.13(s,1H),8.01–7.95(m,1H),7.66–7.57(m,3H),7.54–7.47(m,1H),7.41–7.35(m,1H),6.36–6.20(m,1H),5.64(dt,J=17.2,2.8Hz,1H),5.55(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-91.3(dd,J=9.5,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ156.75(t,J=1.6Hz),156.70,134.03(t,J=30.5Hz),131.00(t,J=27.8Hz),127.73,124.76(t,J=5.5Hz),124.27,123.70,123.07,120.81,119.92(t,J=9.1Hz),119.62(t,J=239.4Hz),118.25(t,J=6.1Hz),111.83,111.61.MS(FI):m/z(%)244(M + ) HRMS theoretical value C 15 H 10 OF 2 244.0694; found 244.0693.
Compound (3 z). Column chromatography (petroleum ether/ethyl acetate=10:1) gave 105mg of a colorless oil in 90% yield. 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=1.6Hz,1H),8.02(d,J=1.6Hz,1H),7.71(d,J=4.0Hz,1H),6.55(d,J=4.0Hz,1H),6.21(dq,J=17.6,9.5Hz,1H),5.61–5.45(m,2H),1.67(s,9H). 19 F NMR(376MHz,Chloroform-d)δ-91.7(dd,J=9.4,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ148.73,147.66,142.84(t,J=5.8Hz),133.52(t,J=30.2Hz),127.92,126.92(t,J=28.0Hz),126.61(t,J=5.7Hz),122.26,120.52(t,J=9.1Hz),119.11(t,J=239.0Hz),104.56,84.55,28.02.MS(FI):m/z(%)244(M + ) HRMS theoretical value C 15 H 16 O 2 N 2 F 2 294.1174; found 294.1181.
Compound (3 aa) column chromatography (petroleum ether/ethyl acetate=20:1) gave 76mg of a colorless oil in 87% yield. 1 H NMR(400MHz,Chloroform-d)δ7.56(d,J=8.4Hz,2H),7.45(d,J=8.4Hz,2H),7.12(s,2H),6.37(s,2H),6.25–6.10(m,1H),5.61(dt,J=17.6,2.4Hz,1H),5.52(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.0(dd,J=9.8,2.3Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ141.85,133.57(t,J=30.4Hz),133.32(t,J=28.1Hz),127.03(t,J=5.7Hz),120.03(t,J=9.2Hz),120.01,119.17,119.07(t,J=239.3Hz),111.01.MS(EI):m/z(%)219(M + ) HRMS theoretical value C 13 H 11 NF 2 219.0854; found 219.0856.
Compound (3 ab). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 76mg of a colorless oil in 87% yield. 1 H NMR(400MHz,Chloroform-d)δ7.96(d,J=2.4Hz,1H),7.80–7.72(m,3H),7.59(d,J=8.8Hz,2H),6.49(t,J=2.0Hz,1H),6.18(dq,J=17.2,9.8Hz,1H),5.59(dt,J=17.6,2.8Hz,1H),5.51(d,J=11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.0(d,J=9.4Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ141.55,141.20,134.09(t,J=28.2Hz),133.52(t,J=30.1Hz),126.90(t,J=5.7Hz),126.73,120.13(t,J=9.2Hz),119.04(t,J=239.3Hz),118.76,108.09.MS(EI):m/z(%)220(M + ) HRMS theoretical value C 12 H 10 N 2 F 2 220.0807; found 220.0812.
Compound (3 ac). Column chromatography (petroleum ether/ethyl acetate=30:1) gave 120mg of a yellow oil in 94% yield. 1 H NMR(400MHz,Chloroform-d)δ8.18(d,J=7.6Hz,2H),7.77(s,1H),7.73–7.61(m,3H),7.49–7.40(m,4H),7.37–7.30(m,2H),6.24(dq,J=17.2,10.1Hz,1H),5.70(dt,J=17.2,2.6Hz,1H),5.57(d,J=10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.7(dd,J=9.8,2.6Hz,2F). 13 CNMR(101MHz,Chloroform-d)δ140.61,138.38(t,J=28.2Hz),138.02,133.38(t,J=29.9Hz),130.12,128.49,126.09,124.39(t,J=5.7Hz),124.28(t,J=5.8Hz),123.50,120.39,120.25(t,J=9.2Hz),120.23,118.79(t,J=240.1Hz),109.53.MS(FI):m/z(%)319(M + ) HRMS theoretical value C 21 H 15 NF 2 319.1167; found 319.1170.
Compound (3 ad) column chromatography (petroleum ether/ethyl acetate=3:1) gives 76mg of a white solidThe yield was 91%. 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=8.0Hz,1H),7.72–7.62(m,2H),6.15(dq,J=17.2,10.3Hz,1H),5.62(dt,J=17.6,2.8Hz,1H),5.56(d,J=10.8Hz,1H),5.37(s,2H). 19 F NMR(376MHz,Chloroform-d)δ-94.2(dd,J=9.8,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ170.09,146.69,142.20(t,J=27.8Hz),132.88(t,J=29.5Hz),127.22,126.73(t,J=5.4Hz),126.02,120.78(t,J=9.3Hz),119.49(t,J=6.0Hz),118.58(t,J=240.5Hz),69.58.MS(FI):m/z(%)210(M + ) HRMS theoretical value C 11 H 8 O 2 F 2 210.0487; found 210.0485.
Compound (4 a) column chromatography (petroleum ether/ethyl acetate=3:1) gave 106mg of a yellow oil in 90% yield. The product (106 mg,90% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate=20:1) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.70(s,1H),7.63(d,J=8.4Hz,2H),7.50–7.40(m,4H),7.36–7.29(m,4H),5.84(t,J=1.8Hz,1H),5.66(s,1H). 19 FNMR(376MHz,Chloroform-d)δ-84.2(s,2F). 13 C NMR(126MHz,Chloroform-d)δ145.13(t,J=25.9Hz),139.52,139.03(t,J=3.8Hz),136.19,129.49,128.35,128.29,128.16,127.14,126.02(t,J=5.1Hz),121.30(t,J=32.8Hz),119.34,118.84(t,J=7.8Hz),117.79(t,J=238.0Hz).
Compound (4 b) column chromatography (petroleum ether/ethyl acetate=6:1) gave 126mg of yellow oil in 89% yield. 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),8.00(d,J=7.6Hz,1H),7.97(s,1H),7.69(s,1H),7.63(d,J=7.6Hz,3H),7.43(dt,J=16.1,7.7Hz,3H),7.32(t,J=7.4Hz,1H),5.89(s,1H),5.71(s,1H),3.91(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-84.34(s,2F). 13 C NMR(126MHz,Chloroform-d)δ166.68,144.43(t,J=26.2Hz),139.47,138.96(t,J=3.8Hz),136.46,132.49,130.33,129.50,129.45(t,J=8.9Hz),128.41,127.22,126.00(t,J=5.0Hz),120.92(t,J=8.9Hz),119.96(t,J=7.7Hz),119.39,117.73(t,J=238.2Hz),52.23.
The above examples show that when R' is a substituent such as an aryl group, steric hindrance, charge properties of the substituent, etc. do not have a significant influence on the reaction, and similar effects can be achieved. The reaction has better substrate applicability, and further widens the subsequent application and industrialization.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. The preparation method of the 3, 3-difluoroallyl compound shown in the formula F is characterized by comprising the following steps:
in an organic solvent, in the presence of alkali and a copper catalyst, carrying out the following reaction between a compound shown in a formula A and a compound shown in a formula B to obtain a 3, 3-gem-difluoroallyl compound shown in a formula F; the organic solvent is a mixture of one or more of halogenated aromatic hydrocarbon solvents, ether solvents and ester solvents and amide solvents;
R 'and R' are H, C 1 -C 20 Is or are R a Substitution ofC 1 -C 20 Alkyl, 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl, C 1 -C 20 Is/are R c Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R d Substituted C 6 -C 20 Is aryl, 5-14 membered heteroaryl, substituted with one or more R e The heteroatoms in the substituted 5-14 membered heteroaryl, the 5-7 membered heterocycloalkyl, and the 5-14 membered heteroaryl are independently selected from one or more of N, O and S;
z is Si or Sn;
R 1 and R is 1’ H, C independently 1 -C 20 Is or are R a Substituted C 1 -C 20 Alkyl of (a);
alternatively, R 1 And R is 1’ Connected to and connected toTogether form: 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl; wherein the heteroatom of the 5-7 membered heterocycloalkyl which is substituted or unsubstituted by a substituent is B and O;
R 2 、R 3 and R is 4 Independently is halogen, C 1 -C 20 Is or are R c Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is/are R d Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R e Substituted C 6 -C 20 Aryl of (a);
alternatively, R 2 、R 3 And R is 4 Any 2 of which are linked together with the linked Z to form: 5-7 membered heterocycloalkyl, or by one or more R f Substituted 5-7 membered heterocycloalkyl; wherein the heteroatom of the 5-7 membered heterocycloalkyl group which is substituted or unsubstituted by a substituent is Si or Sn as shown;
R a 、R b 、R c 、R d 、R e and R is f Independently is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -, C 1 -C 20 alkyl-O-or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
2. The method of preparation of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) The ester solvent is ethyl acetate; the halogenated aromatic solvent is chlorobenzene or fluorobenzene; the ether solvent is one or more of diethylene glycol dimethyl ether, dioxane and tetrahydrofuran; the amide solvent is one or more of dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylpropenyl urea; preferably a mixed solvent of tetrahydrofuran and dimethylacetamide;
(2) The volume ratio of the total volume of one or more of the halogenated aromatic solvents, ether solvents, and ester solvents to the amide solvents in the mixture is 100:1 to 1:100, e.g., 7.2:1, 3.2:1, 2.4:1, 2:1, 1.6:1, 1:1, 1:1.25, 1:2.5;
(3) The mass volume ratio of the compound shown in the formula A to the organic solvent is 0.01 mol/L-2 mol/L, for example 0.15 mol/L-1 mol/L;
(4) The mol ratio of the compound shown in the formula A to the compound shown in the formula B is 1:1.5 to 2:1; for example 1.5:1 to 2:1;
(5) The compound shown in the formula A is added in a solution form, for example, in a dimethylacetamide DMA solution, for example, 1.2M in DMA; alternatively, the compound shown in the formula A is added in a gas form; the gas pressure may be 1atm;
(6) The alkali is alcohol alkali metal alkali or alkali metal hydroxide; such as one or more of sodium hydroxide, potassium hydroxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, and lithium methoxide; and for example one or more of lithium t-butoxide, potassium methoxide and lithium methoxide;
(7) The molar ratio of the alkali to the compound shown as the formula A is 1.5:1 to 3:1; for example 2:1 to 2.5:1;
(8) The copper catalyst is a copper salt catalyst, such as halogenated cuprous, and also such as cuprous chloride;
(9) The molar ratio of the copper catalyst to the compound shown as the formula A is 0.00001:1 to 0.1:1; for example 0.00001:1, 0.0001:1, 0.0002:1, 0.001, 0.01:1, 0.05:1;
(10) The reaction is carried out under an inert atmosphere, which can be argon or nitrogen;
(11) The reaction is carried out in the presence of a ligand which may be selected from: 1, 3-bis (diphenylphosphine) propane, 1-bis (diphenylphosphine) ethane, 1-bis (diphenylphosphine) methane, bis (2-diphenylphosphine phenyl) ether, (R) - (+) -DM-SegPhos, bpy, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene andone or more of the following; preferably (R) - (+) -DM-SegPhos, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene; the molar ratio of the ligand to the compound of formula a may be 1.5:1 to 3:1; for example 2:1 to 2.5:1;
(12) The temperature of the reaction is 10 to 80 ℃; for example 10 to 35 ℃;
(13) The raw materials in the reaction are the alkali, copper catalyst, compound shown in formula A, compound shown in formula B and the organic solvent;
wherein R and R' are as defined in claim 1.
3. The preparation method according to claim 1 or 2, wherein the preparation method satisfies one or more of the following conditions:
(1)R”、R”’、R 1 、R 1’ 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d and R is f In (C) 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl groups of (2), e.g. C 1 -C 6 Also for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
(2)R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e and R is f In (C) 1 -C 20 alkyl-O-, substituted C 1 -C 20 C in alkyl-O-of (C) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl groups of (2), e.g. C 1 -C 6 Also for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
(3)R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e and R is f Wherein the halogen is F, cl and Br;
(4)R”、R”’、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e and R is f In (C) 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl;
4. A method of preparation as claimed in claim 3, wherein the method of preparation satisfies one or more of the following conditions:
(1)R b independently H, methyl, me-O-C (=o) -or phenyl;
(2)R 2 、R 3 and R is 4 Independently Cl, methyl, ethyl, phenyl, methyl-O-, n-butyl;
(5)R a Independently phenyl;
(6)R d h, cl, methoxy or-COOMe;
8. The use according to claim 7, wherein,
Wherein R is as defined in any one of claims 1 to 6;
and/or, the application is as follows: taking the 3, 3-difluoroallyl compound shown as a formula F as an alpha, alpha-gem difluoroallylation reagent, and carrying out suzuki coupling reaction on the reagent and halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound;
for example, the application includes the steps of:
in an organic solvent, in the presence of a catalyst and alkali, carrying out a suzuki coupling reaction on a 3, 3-difluoroallyl compound shown as a formula F and halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound.
9. The application of claim 8, wherein the application satisfies one or more of the following conditions:
(1) The molar ratio of the 3, 3-difluoroallyl compound shown in the formula F to the halogenated aromatic hydrocarbon or heteroaromatic hydrocarbon compound is 1.5:1 to 1:1.5;
(2) The solvent is one or more of ether solvents, amide solvents, nitrile solvents, halogenated aromatic solvents and ester solvents; the ether solvent can be dioxane, tetrahydrofuran or ethylene glycol dimethyl ether; the amide solvent can be one or more of N, N-dimethylformamide and N, N-dimethylacetamide; the nitrile solvent can be acetonitrile; the halogenated aromatic solvent can be chlorobenzene; the ester solvent can be ethyl acetate;
(3) The mass volume ratio of the compound shown in the formula F to the organic solvent is 0.01 mol/L-2 mol/L; for example, 0.1mol/L to 0.375mol/L;
(4) The compound shown in the formula F is added in the form of a mixture with the solvent, and the concentration of the compound shown in the formula F in the mixture can be 3M;
(5) The catalyst is a Pd catalyst, for example selected from the group consisting of: pd (PPh) 3 ) 4 、PdCl 2 (dppf)、PdBr 2 、Pd(acac) 2 、PdCl 2 (PhCN) 2 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (CH 3 CN) 2 、PdCl 2 (PCy 3 ) 2 、Pd(OAc) 2 、Pd(CF 3 COO) 2 、PdCl 2 、PdI 2 、PdCl 2 (dppb)、Pd 2 (dba) 3 、PdCl 2 (dppp)Pd(DPPF)Cl 2 、 Also e.g. PdBR 2 、PdCl 2 (PhCN) 2 、PdCl 2 (CH 3 CN) 2 ;
(6) The molar ratio of the catalyst to the 3, 3-difluoroallyl compound shown as the formula F is 0.0002:1 to 0.2:1; for example 0.01, 0.0375:1, 0.05:1, 0.001:1, 0.0002:1;
(7) The alkali is one or more of alkali metal fluoride, alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate and alkali metal phosphate; the alkali metal fluoride can be LiF, csF or KF; the alkali metal hydroxide can be NaOH, the alkali metal alkoxide can be Meona, meoli or t-Buona, and the alkali metal carbonate can be K 2 CO 3 、Cs 2 CO 3 The alkali metal phosphate can be K 3 PO 4 The method comprises the steps of carrying out a first treatment on the surface of the Preferably CsF;
(8) The molar ratio of the alkali to the 3, 3-difluoroallyl compound shown in the formula F is 1.5:1 to 3:1; for example 2.25:1;
(9) The reaction is carried out under an inert atmosphere, which can be argon or nitrogen;
(10) The suzuki coupling reaction is carried out in the presence of a ligand selected from the group consisting of: triphenylphosphine PPh 3 1, 2-bis (diphenylphosphine) benzene dppbz, 1' -bis (diphenylphosphine) ferrocene dppf, 1, 3-bis (diphenylphosphine) propane dppp, 1-bis (diphenylphosphine) ethane dppe, 1-bis (diphenylphosphine) methane dppm, bis (2-diphenylphosphine phenyl) ether DPEphos, (R) - (+) -DM-SegPhos, bpy and 4,5- Bis (diphenylphosphine) -9, 9-dimethylxanthenes Xantphos; for example PPh 3 ;
(11) The molar ratio of the ligand to the catalyst is from 1:1 to 5:1, for example from 2:1 to 3.7:1;
(12) The temperature of the reaction is from 10 to 100 ℃, for example from 60 to 80 ℃;
(13) The halogenated aromatic hydrocarbon compound and the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon compound thereof are Ar-X andwherein Ar is C substituted or unsubstituted by a substituent 6 -C 14 An aryl group; x is the halogen; the number of X may be 1 or more, for example 1, 2; the C is 6 -C 14 The aromatic ring may be a benzene ring or a naphthalene ring; the substituents may be: halogen, -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
(14) The halogenated heteroarene compound and the alpha, alpha-gem difluoroallyl substituted heteroarene compound are hetAr-XOr X-HetAr-X +.>Wherein HetAr is a 5-14 membered heteroaryl substituted or unsubstituted with a substituent, X is said halogen; the number of X may be 1 or more, for example 1, 2; the hetero atom in HetAr is selected from one or more of N, O and S; such as furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, indazolyl, benzothiazolyl, dibenzothienyl, benzofuryl, pyrrolopyridinyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinolyl An oxazolinyl group, a bipyridyl group, a benzothienyl group, a pyrazolyl group, a dibenzothienyl group, a benzofuranyl group, a benzothiazolinyl group, and a benzothiazolonyl group; the substituents may be: halogen, -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, ethyl-O-, phO-, boc-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
10. The use according to claim 8 or 9, wherein,
the halogenated aromatic hydrocarbon or heteroaromatic hydrocarbon compound and the corresponding alpha, alpha-geminal difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound are any one group of the following:
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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