CN116283765A - Chlorotrifluoromethylation method of inactive olefin - Google Patents
Chlorotrifluoromethylation method of inactive olefin Download PDFInfo
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- 150000001336 alkenes Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 22
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 96
- -1 N- (5-substituted quinoline-8-yl) pent-4-enamide Chemical class 0.000 claims abstract description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 92
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 62
- 150000001875 compounds Chemical class 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 9
- 229910052707 ruthenium Inorganic materials 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- WFSOQEZHBFMIPW-UHFFFAOYSA-L cycloocta-1,3-diene;ruthenium(2+);dichloride Chemical compound [Cl-].[Cl-].[Ru+2].C1CCC=CC=CC1 WFSOQEZHBFMIPW-UHFFFAOYSA-L 0.000 claims description 2
- WIWBLJMBLGWSIN-UHFFFAOYSA-L dichlorotris(triphenylphosphine)ruthenium(ii) Chemical compound [Cl-].[Cl-].[Ru+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 WIWBLJMBLGWSIN-UHFFFAOYSA-L 0.000 claims description 2
- 150000001993 dienes Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000007348 radical reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- BZSVVCFHMVMYCR-UHFFFAOYSA-N 2-pyridin-2-ylpyridine;ruthenium Chemical compound [Ru].N1=CC=CC=C1C1=CC=CC=N1.N1=CC=CC=C1C1=CC=CC=N1.N1=CC=CC=C1C1=CC=CC=N1 BZSVVCFHMVMYCR-UHFFFAOYSA-N 0.000 description 29
- HVAPLSNCVYXFDQ-UHFFFAOYSA-N 3,3-dimethyl-1-(trifluoromethyl)-1$l^{3},2-benziodoxole Chemical compound C1=CC=C2C(C)(C)OI(C(F)(F)F)C2=C1 HVAPLSNCVYXFDQ-UHFFFAOYSA-N 0.000 description 28
- 239000012043 crude product Substances 0.000 description 27
- 238000002955 isolation Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 27
- 238000010898 silica gel chromatography Methods 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 24
- 239000011734 sodium Substances 0.000 description 9
- 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 5
- 238000006555 catalytic reaction Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000007146 photocatalysis Methods 0.000 description 2
- 230000001699 photocatalysis Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 1
- RTTUBUXMNUJHRR-DXRVJIQQSA-N (3s)-4-[[(e)-2-[1-(4-fluorophenyl)-3-propan-2-ylindol-2-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound C12=CC=CC=C2C(C(C)C)=C(\C=C\P(O)(=O)C[C@@H](O)CC(O)=O)N1C1=CC=C(F)C=C1 RTTUBUXMNUJHRR-DXRVJIQQSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- DOIVPHUVGVJOMX-UHFFFAOYSA-N 1,10-phenanthroline;ruthenium Chemical compound [Ru].C1=CN=C2C3=NC=CC=C3C=CC2=C1.C1=CN=C2C3=NC=CC=C3C=CC2=C1.C1=CN=C2C3=NC=CC=C3C=CC2=C1 DOIVPHUVGVJOMX-UHFFFAOYSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- JWHYSEDOYMYMNM-QGZVFWFLSA-N 2-[4-[(2r)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid Chemical compound C([C@@H](OCC)CSC=1C=C(C)C(OCC(O)=O)=CC=1)OC1=CC=C(C(F)(F)F)C=C1 JWHYSEDOYMYMNM-QGZVFWFLSA-N 0.000 description 1
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- MFNYBOWJWGPXFM-UHFFFAOYSA-N cyclobutanecarboxamide Chemical compound NC(=O)C1CCC1 MFNYBOWJWGPXFM-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with 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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a chlorotrifluoromethylation method of an inactive olefin, which uses a substituted N- (5-substituted quinoline-8-yl) pent-4-enamide derivative as a starting material, utilizes a guide group to realize chlorotrifluoromethylation of the inactive olefin through a free radical reaction, and solves the problems that the prior art realizes low chlorotrifluoromethylation catalytic efficiency of the olefin, the reaction of the inactive olefin is limited, large-scale production cannot be realized, and a difunctional reagent is difficult to synthesize and operate.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a chlorotrifluoromethylation method of an inactive olefin.
Background
The introduction of trifluoromethyl with strong electron withdrawing and hydrophobic properties into organic molecules can significantly improve the bioavailability, lipophilicity, metabolic stability and binding selectivity of organic compounds; alkyl halides have important roles in medicine and are also constituent elements of useful derivatives such as amines, hydroxyl groups, and hydrogen. Therefore, it is of great importance to achieve chlorotrifluoromethylation of inactive olefins.
At present, three main methods are used for realizing chlorotrifluoromethylation of olefin:
firstly, atom transfer radical addition reaction of trifluoromethyl radicals and olefins is generated through photoinduction, which is a very good strategy for realizing radical halogenation reaction, and shows very good functional group tolerance for electron-rich olefins and partial electron-deficient olefins; secondly, forming carbon positive ions and halogen negative ions through a single electron transfer process to carry out nucleophilic attack; thirdly, the reaction can be completed without a metal catalyst by using a high-activity difunctional reagent.
Chlorotrifluoromethylation of olefins using photocatalysis and metal catalysis is disclosed in the literature of angel.chem.int.ed.2015, 54 (14), 4246-4249, ACS catalyst.2022, 12,5284-5291, j.org.chem.2020,85 (23), 15241-15255 and j.org.chem.2019,84 (21), 14209-14216, respectively. However, the adoption of photocatalysis has the problems of low catalytic efficiency and incapability of realizing large-scale production; the currently commonly used double tube functionalizing agents are partially gaseous, difficult to operate, and most are sensitive to water vapor, and highly reactive bifunctional agents are difficult to synthesize and have limited applications.
Disclosure of Invention
In order to solve the technical problems, the invention discloses a method for realizing chlorotrifluoromethylation of an inert olefin by using a guide group, which has the advantages of simple operation, mild condition, no requirement for inert gas atmosphere, good universality, insensitivity to water vapor and higher yield.
A first object of the present invention is to provide a chlorotrifluoromethylation process for inactive olefins comprising the steps of:
the method comprises the steps of (1) catalyzing a compound shown in a formula with a trifluoromethyl source in the presence of a chloride ion source and a solvent to complete the reaction through a ruthenium catalyst;
R 1 -R 5 is hydrogen;
or R is 2 -R 5 Is hydrogen, R 1 One selected from the group consisting of monosubstituted methyl, disubstituted methyl, n-butyl, cyclopropylmethyl, benzyl, o-tolyl, m-tolyl, p-tolyl and cyclobutyl；
Or R is 1 、R 3 -R 5 Is hydrogen, R 2 One selected from the group consisting of monosubstituted methyl, disubstituted methyl and phenyl;
or R is 1 -R 2 、R 4 -R 5 Is hydrogen, R 3 Is methyl;
or R is 1 -R 4 Is hydrogen, R 5 One selected from methyl and ethyl;
or R is 1 -R 4 Is hydrogen, R 5 Is methyl and is a conjugated diene.
Further, in the compound represented by the formula (1), the director group X is preferably iodine.
Further, the trifluoromethyl source is selected from one of the following structures, preferably 2a:
further, the exocyclic double bond is
The double bonds in the ring with symmetrical structure are
Further, the chloride ion source is selected from one of tetramethyl ammonium chloride, tetrabutyl ammonium chloride, sodium chloride, potassium chloride, lithium chloride, sulfoxide chloride, trimethylchlorosilane, nickel chloride and ferric chloride, and is preferably lithium chloride.
Further, the ruthenium catalyst is selected from cyclooctadiene ruthenium dichloride (Ru (cod) Cl) 2 ) Tris (triphenylphosphine) ruthenium dichloride (Ru (PPh) 3 ) 3 Cl 2 ) Ruthenium trichloride (RuCl) 3 ) Tris (2, 2' -bipyridine) ruthenium dichloride (Ru (phen) 3 Cl 2 ) Preferably tris (2, 2' -bipyridine) ruthenium dichloride.
Further, the solvent is selected from one of carbon tetrachloride, dichloromethane, 1, 4-dioxane, methanol, chloroform, acetonitrile and 1, 2-dichloroethane, preferably dichloromethane.
Further, the reaction temperature is 60℃to 110℃and preferably 90 ℃.
Further, the reaction time is 3 to 8 hours.
Further, the molar ratio of the compound represented by formula (1), the trifluoromethyl source, the chloride ion source and the ruthenium catalyst is 1:1-3:1-6:0.05-0.2, preferably 1:1.25:2:0.1.
by means of the scheme, the invention has at least the following advantages:
1. the invention provides a brand new strategy, and the chlorotrifluoromethylation of the inactive olefin is realized through free radical reaction by utilizing a guide group.
2. The invention uses the substituted N- (5-substituted quinoline-8-yl) pent-4-enamide derivative as the starting material, so that the raw materials are easy to obtain and the variety is rich; the method can realize chlorotrifluoromethylation of various inactive olefins, can be directly used as a product, and can also be used for the next conversion.
3. The invention has novel reaction, simple reaction operation and post-treatment process, high yield and suitability for mass production.
The foregoing description is only an overview of the present invention and is presented in terms of preferred embodiments of the present invention so that the present invention may be more clearly understood and implemented in accordance with the teachings of the present specification.
Detailed Description
The present invention will be further described with reference to specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the present invention and practice it.
The reaction route of the invention is as follows:
taking substituted N- (5-substituted quinoline-8-yl) pent-4-enamide derivatives as an example, reacting with a trifluoromethyl source in the presence of a chloride ion source through a ruthenium catalyst to obtain a chlorotrifluoromethylated product and a chlorotrifluoromethylated derivative at the temperature of 60-110 ℃. The reaction route is as follows:
in the reaction route, trifluoromethyl free radical is generated through thermal initiation, and the chlorotrifluoromethylated derivative of the inactive olefin can be efficiently synthesized under the catalysis of metal by utilizing the guide group. The invention belongs to a free radical double-tube energy-grouping reaction of an inactive olefin under ruthenium catalysis, has mild reaction conditions and wide substrate application range, can realize high-efficiency and certain-scale synthesis, and meets the green chemical requirements.
Embodiment one: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) hexanamide
(1) N- (5-iodoquinolin-8-yl) pent-4-enamide 1a (0.07 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed into 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3a. The isolation yield was 99%.
(2) N- (5-iodoquinolin-8-yl) pent-4-enamide 1a (0.07 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed into 3mL of dichloromethane. The mixture was heated to 110 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3a. The isolation yield was 99%.
(3) N- (5-iodoquinolin-8-yl) pent-4-enamide 1a (0.07 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed into 3mL of dichloromethane. The mixture was heated to 80 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3a. The isolation yield was 75%.
(4) N- (5-iodoquinolin-8-yl) pent-4-enamide 1a (0.07 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed into 3mL of dichloromethane. The mixture was heated to 70 ℃ for reaction, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3a. The isolation yield was 47%.
(5) N- (5-iodoquinolin-8-yl) pent-4-enamide 1a (0.07 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed into 3mL of dichloromethane. The mixture was heated to 60 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3a. The isolation yield was 10%.
3a： 1 H NMR(400MHz,CDCl 3 )δ9.84(s,1H),8.75(dd,J＝4.3,1.6Hz,1H),8.49(d,J＝8.3Hz,1H),8.34(dd,J＝8.6,1.5Hz,1H),8.05(d,J＝8.3Hz,1H),7.52(dd,J＝8.5,4.2Hz,1H),4.38–4.24(m,1H),2.92–2.76(m,2H),2.76–2.56(m,2H),2.52–2.40(m,1H),2.18–2.05(m,1H).； 13 C NMR(101MHz,CDCl 3 )δ169.87,148.76,140.77,138.76,138.20,135.10,129.57,125.13(q,J＝277.7Hz),123.22,117.86,89.51,53.64,42.67(d,J＝28.7Hz),34.01,33.28.； 19 F NMR(376MHz,CDCl 3 )δ-63.59.；HRMS(ESI-TOF):m/z Calcd for C 15 H 13 ClF 3 IN 2 ONa + [M+Na + ]:374.9970,found:374.9969.
Embodiment two: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -2-methylhexanamide
N- (5-iodoquinolin-8-yl) -2-methylpent-4-enamide 1b (0.073 g,0.2 mmol) was weighed out, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3b. The isolation yield was 98%, dr=1:1.
3b： 1 H NMR(400MHz,CDCl 3 )δ9.95(d,J＝17.4Hz,1H),8.77(dd,J＝4.2,1.6Hz,1H),8.52(dd,J＝8.3,6.5Hz,1H),8.34(dt,J＝8.5,1.7Hz,1H),8.05(d,J＝8.3Hz,1H),7.52(ddd,J＝8.5,4.2,1.8Hz,1H),4.31–4.13(m,1H),3.17–2.90(m,1H),2.80–2.49(m,2H),2.47–2.22(m,1H),2.14–1.71(m,1H),1.39(dd,J＝7.0,2.2Hz,3H).； 13 C NMR(101MHz,CDCl 3 )δ173.77(d,J＝33.9Hz),148.85(d,J＝5.0Hz),140.84(d,J＝6.5Hz),138.97,138.22(d,J＝6.5Hz),135.19(d,J＝5.3Hz),129.63,125.13(q,J＝279.7Hz),123.24,118.03(d,J＝5.9Hz),89.56,51.98,43.18–41.25(m),39.66(d,J＝13.3Hz),19.12,16.79.； 19 F NMR(376MHz,CDCl 3 )δ-63.28,-63.62.；HRMS(ESI-TOF):m/z Calcd for C 16 H 16 ClF 3 IN 2 O + [M+H + ]:470.9948,found:470.9942.
Embodiment III: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -2-propylhexanamide
N- (5-iodoquinolin-8-yl) -2-propyl-4-enamide 1c (0.079 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) tris (2, 2' -bipyridine) ruthenium dichloride was weighed out
(0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) were dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3c. The isolation yield was 94%, dr=1:1.
3c： 1 H NMR(400MHz,CDCl 3 )δ9.96(d,J＝24.9Hz,1H),8.78(dt,J＝4.2,1.6Hz,1H),8.55(dd,J＝8.3,6.5Hz,1H),8.35(dt,J＝8.5,1.6Hz,1H),8.06(d,J＝8.2Hz,1H),7.52(ddd,J＝8.5,4.3,1.5Hz,1H),4.43–4.03(m,1H),3.03–2.77(m,1H),2.75–2.49(m,2H),2.45–2.21(m,1H),1.90–1.52(m,3H),1.52–1.35(m,2H),0.95(td,J＝7.3,2.0Hz,3H).； 13 C NMR(101MHz,CDCl 3 )δ173.45,148.91,140.77,138.98,138.22,135.11,129.62,125.15(d,J＝277.9Hz),123.25,117.95,89.63,52.32(d,J＝3.4Hz),45.56,42.68(q,J＝28.6Hz),40.58,34.12,20.43,14.09.； 19 F NMR(376MHz,CDCl 3 )δ-63.27,-63.66.；HRMS(ESI-TOF):m/z Calcd for C 18 H 20 ClF 3 IN 2 O + [M+H + ]:499.0261,found:499.0258.
Embodiment four: synthesis of 4-chloro-2- (cyclopropylmethyl) -6, 6-trifluoro-N- (5-iodoquinolin-8-yl) hexanamide
2- (cyclopropylmethyl) -N- (5-iodoquinolin-8-yl) pent-4-enamide 1d (0.081 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) and tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) were weighed out and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3d. The isolation yield was 88%, dr=1:1.
3d： 1 H NMR(400MHz,CDCl 3 )δ10.03(d,J＝20.0Hz,1H),8.79(dd,J＝4.3,1.5Hz,1H),8.56(dd,J＝8.3,5.2Hz,1H),8.36(dt,J＝8.5,1.7Hz,1H),8.07(d,J＝8.3Hz,1H),7.53(ddd,J＝8.5,4.2,1.8Hz,1H),4.41–4.03(m,1H),3.14–2.88(m,1H),2.77–2.50(m,2H),2.48–2.25(m,1H),2.22–1.84(m,1H),1.80–1.69(m,1H),1.55–1.45(m,1H),0.85–0.71(m,1H),0.56–0.46(m,1H),0.45–0.35(m,1H),0.18–0.06(m,2H).； 13 C NMR(101MHz,CDCl 3 )δ173.26(d,J＝41.0Hz),148.90(d,J＝4.6Hz),140.72(d,J＝5.6Hz),139.01(d,J＝1.6Hz),138.22(d,J＝6.4Hz),135.18(d,J＝6.5Hz),129.62,126.75–123.52(m),123.23,117.97(d,J＝4.3Hz),89.60(d,J＝8.0Hz),52.60(dd,J＝53.0,3.3Hz),46.23(d,J＝15.9Hz),43.97–41.83(m),40.42(d,J＝49.5Hz),38.77,37.11,9.04(d,J＝15.8Hz),5.96–3.05(m).； 19 F NMR(376MHz,CDCl 3 )δ-63.26,-63.68.；HRMS(ESI-TOF):m/z Calcd for C 19 H 20 ClF 3 IN 2 O + [M+H + ]:511.0261,found:511.0260.
Fifth embodiment: synthesis of 2-benzyl-4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) hexanamide
2-benzyl-N- (5-iodoquinolin-8-yl) pent-4-enamide 1e (0.088 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) and tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) were weighed out and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3e. The isolation yield was 81%, dr=1:1.
3e： 1 H NMR(400MHz,CDCl 3 )δ10.16–9.46(m,1H),8.82–8.63(m,1H),8.61–8.45(m,1H),8.42–8.22(m,1H),8.12–7.97(m,1H),7.59–7.42(m,1H),7.30–7.08(m,5H),4.31–3.33(m,1H),3.22–2.80(m,3H),2.73–2.29(m,3H),2.28–1.79(m,1H).； 13 C NMR(101MHz,CDCl 3 )δ175.40–168.66(m),149.08–148.14(m),140.66(dd,J＝21.1,2.8Hz),139.26–138.64(m),138.47–137.90(m),137.57–135.56(m),135.24,135.00–134.60(m),129.91–129.28(m),128.92,128.68(d,J＝2.5Hz),127.33–126.50(m),123.42–123.00(m),118.12–117.74(m),89.91–89.39(m),52.51(d,J＝27.1Hz),47.74(d,J＝27.4Hz),43.53–39.33(m),38.41(d,J＝23.4Hz),34.07–31.72(m).； 19 F NMR(376MHz,CDCl 3 )δ-63.28,-63.64(d,J＝8.9Hz).；HRMS(ESI-TOF):m/z Calcd for C 22 H 19 ClF 3 IN 2 ONa + [M+Na + ]:569.0080,found:569.0073.
Example six: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -2- (o-tolyl) hexanamide
N- (5-iodoquinolin-8-yl) -2- (o-tolyl) pent-4-enamide 1f (0.088 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) and tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) were weighed out and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3f. The isolation yield was 75%, dr=1:1.
3f： 1 H NMR(400MHz,CDCl 3 )δ9.82(d,J＝6.3Hz,1H),8.67–8.56(m,1H),8.55–8.41(m,1H),8.27(ddd,J＝8.5,4.8,1.6Hz,1H),8.02(t,J＝8.3Hz,1H),7.48–7.34(m,2H),7.33–7.16(m,3H),4.55–4.43(m,1.5H),3.88–3.77(m,0.5H),2.90(ddd,J＝14.4,10.6,2.7Hz,0.5H),2.78–2.62(m,3H),2.60(d,J＝7.6Hz,3H),1.92(ddd,J＝14.2,11.1,2.9Hz,1H).； 13 C NMR(101MHz,CDCl 3 )δ170.99(d,J＝26.9Hz),148.79(d,J＝4.7Hz),140.54(d,J＝3.6Hz),138.82(d,J＝8.5Hz),138.07(d,J＝2.7Hz),137.26(d,J＝33.1Hz),135.56,135.18,131.37(d,J＝41.7Hz),129.48(d,J＝3.5Hz),127.90(d,J＝31.9Hz),127.14(d,J＝21.1Hz),124.82(q,J＝277.6Hz),123.11(d,J＝3.5Hz),117.61(d,J＝16.6Hz),89.48(d,J＝10.4Hz),52.91(d,J＝136.7Hz),46.75(d,J＝22.7Hz),42.90(q,J＝28.4Hz),40.81(d,J＝175.6Hz),19.99(d,J＝12.8Hz).； 19 F NMR(376MHz,CDCl 3 )δ-63.40,-63.60.；HRMS(ESI-TOF):m/z Calcd for C 22 H 19 ClF 3 IN 2 ONa + [M+Na + ]:569.0080,found:569.0076.
Embodiment seven: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -2- (m-tolyl) hexanamide
1g (0.088 g,0.2 mmol) of N- (5-iodoquinolin-8-yl) -2- (m-tolyl) pent-4-enamide, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) were weighed out in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain 3g of a compound. The isolation yield was 80%, dr=1:1.
3g： 1 H NMR(400MHz,CDCl 3 )δ9.90(d,J＝26.8Hz,1H),8.67(ddd,J＝17.0,4.2,1.6Hz,1H),8.50(dd,J＝14.7,8.3Hz,1H),8.28(ddd,J＝8.5,4.3,1.6Hz,1H),8.02(dd,J＝8.3,3.8Hz,1H),7.45(dt,J＝8.8,4.5Hz,1H),7.34–7.26(m,3H),7.18–7.08(m,1H),4.47–4.35(m,0.5H),4.15(ddd,J＝21.5,
10.5,4.1Hz,1H),3.85–3.74(m,0.5H),2.91(ddd,J＝14.0,10.7,3.1Hz,0.5H),2.73–2.54(m,3H),2.37(d,J＝9.7Hz,3H),2.02(ddd,J＝14.3,10.9,3.5Hz,0.5H).； 13 C NMR(101MHz,CDCl 3 )δ170.78(d,J＝57.9Hz),148.77(d,J＝5.3Hz),140.58(d,J＝2.9Hz),139.15(d,J＝20.6Hz),138.88(d,J＝3.8Hz),138.07(d,J＝3.7Hz),136.90,135.18(d,J＝3.2Hz),125.04(q,J＝278.8Hz)129.50(d,J＝3.0Hz),129.41–128.76(m),128.51(d,J＝28.7Hz),125.13(d,J＝56.0Hz),123.13(d,J＝3.4Hz),117.69(d,J＝15.4Hz),89.54(d,J＝13.3Hz),52.57(d,J＝105.5Hz),51.07(d,J＝20.7Hz),42.84(d,J＝29.0Hz),41.36(d,J＝168.3Hz),21.48(d,J＝4.6Hz).； 19 F NMR(376MHz,CDCl 3 )δ-63.25,-63.41.；HRMS(ESI-TOF):m/z Calcd for C 22 H 19 ClF 3 IN 2 ONa +
[M+Na + ]:569.0080,found:569.0085.
Example eight: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -2- (p-tolyl) hexanamide
N- (5-iodoquinolin-8-yl) -2- (p-tolyl) pent-4-enamide 1h (0.088 g,0.2 mmol) was weighed out, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3h. The isolation yield was 85%, dr=1:1.
3h： 1 H NMR(400MHz,CDCl 3 )δ9.88(d,J＝28.0Hz,1H),8.66(ddd,J＝16.1,4.3,1.6Hz,1H),8.50(dd,J＝13.1,8.3Hz,1H),8.27(ddd,J＝8.5,3.8,1.6Hz,1H),8.02(dd,J＝8.3,3.1Hz,1H),7.44(dt,J＝8.6,4.4Hz,1H),7.40–7.31(m,2H),7.21(dd,J＝17.4,7.8Hz,2H),4.46–4.34(m,0.5H),4.23–4.07(m,1H),3.86–3.70(m,0.5H),2.91(ddd,J＝14.0,10.6,3.1Hz,0.5H),2.78–
2.49(m,3H),2.34(d,J＝12.2Hz,3H),2.02(ddd,J＝14.4,10.8,3.6Hz,0.5H).； 13 C NMR(101MHz,CDCl 3 )δ170.91(d,J＝59.0Hz),148.77(d,J＝5.1Hz),140.56(d,J＝2.7Hz),138.85(d,J＝3.6Hz),138.26–137.84(m),137.65,135.96,135.20(d,J＝3.8Hz),133.92,130.05(d,J＝22.2Hz),129.48(d,J＝3.0Hz),127.89(d,J＝53.9Hz),125.04(q,J＝279.0Hz),123.11(d,J＝3.4Hz),117.66(d,J＝14.7Hz),89.52(d,J＝13.3Hz),52.57(d,J＝100.8Hz),50.75(d,J＝20.6Hz),42.85(q,J＝28.7Hz),41.39(d,J＝168.6Hz),21.12(d,J＝7.0Hz).； 19 F NMR(376MHz,CDCl 3 )δ-63.26,-63.43.；HRMS(ESI-TOF):m/z Calcd for C 22 H 20 ClF 3 IN 2 O + [M+H + ]:547.0261,found:547.0263.
Example nine: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -2, 2-dimethylhexanamide
N- (5-iodoquinolin-8-yl) -2, 2-dimethylpent-4-enamide 1i (0.076 g,0.2 mmol) was weighed out, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3i. The isolation yield was 95%.
3i： 1 H NMR(400MHz,CDCl 3 )δ10.32(s,1H),8.80(dd,J＝4.2,1.6Hz,1H),8.54(d,J＝8.3Hz,1H),8.39(dd,J＝8.5,1.5Hz,1H),8.08(d,J＝8.3Hz,1H),7.55(dd,J＝8.5,4.2Hz,1H),4.31–4.22(m,1H),2.74–2.54(m,2H),2.39(dd,J＝15.0,9.5Hz,1H),2.26–2.17(m,1H),1.53(d,J＝1.6Hz,6H).； 13 C NMR(101MHz,CDCl 3 )δ175.40,148.92,140.76,139.38,138.28,135.28,129.62,125.11(q,J＝277.4Hz),123.46,117.79,89.45,50.73,48.28,44.10–42.20(m),26.71,25.26.； 19 F NMR(376MHz,CDCl 3 )δ-63.46.；
HRMS(ESI-TOF):m/z Calcd for C 17 H 17 ClF 3 IN 2 ONa + [M+Na + ]:506.9924,found:506.9924.
Example ten: synthesis of 1- (2-chloro-4, 4-trifluorobutyl) -N- (5-iodoquinolin-8-yl) cyclobutane-1-carboxamide
1-allyl-N- (5-iodoquinolin-8-yl) cyclobutane-1-carboxamide 1j (0.078 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed into 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3j. The isolation yield was 85%.
3j： 1 H NMR(400MHz,CDCl 3 )δ10.33(s,1H),8.78(dd,J＝4.2,1.6Hz,1H),8.57(d,J＝8.3Hz,1H),8.36(dd,J＝8.5,1.6Hz,1H),8.08(d,J＝8.3Hz,1H),7.53(dd,J＝8.5,4.2Hz,1H),4.27–4.14(m,1H),2.78–2.54(m,4H),2.55–2.36(m,3H),2.23–1.98(m,3H).； 13 C NMR(101MHz,CDCl 3 )δ
174.59,148.99,140.73,139.28,138.24,135.10,129.64,125.04(q,J＝277.8Hz),123.22,117.77,89.57,51.17(d,J＝3.4Hz),49.56,46.86,42.91(q,J＝28.4Hz),31.97,31.72,16.35.； 19 F NMR(376MHz,CDCl 3 )δ-63.29.；
HRMS(ESI-TOF):m/z Calcd for C 18 H 18 ClF 3 IN 2 O + [M+H + ]:497.0104,found:497.0105.
Example eleven: synthesis of 3-chloro-N- (5-iodoquinolin-8-yl) -3- (2, 2-trifluoroethyl) cyclobutane-1-carboxamide
N- (5-iodoquinolin-8-yl) -3-methylenecyclobutane-1-carboxamide 1k (0.073 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) and tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) were weighed out and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=40:1) to obtain compound 3k. The isolation yield was 90%.
3k： 1 H NMR(400MHz,CDCl 3 )δ9.81(s,1H),8.76(dd,J＝4.2,1.6Hz,1H),8.50(d,J＝8.3Hz,1H),8.35(dd,J＝8.5,1.6Hz,1H),8.05(d,J＝8.3Hz,1H),7.53(dd,J＝8.5,4.2Hz,1H),3.83–3.71(m,1H),3.02–2.91(m,2H),2.90–2.76(m,4H).； 13 C NMR(101MHz,CDCl 3 )δ171.59,148.85,140.80,138.83,138.17,134.98,129.59,125.21(q,J＝278.6Hz),123.29,117.93,89.82,62.02(d,J＝2.8Hz),46.12(q,J＝28.0Hz),41.78,36.25.； 19 F NMR(376MHz,CDCl 3 )δ-61.48.；HRMS(ESI-TOF):m/z Calcd for C 16 H 14 ClF 3 IN 2 O +
[M+H + ]:468.9791,found:468.9791.
Embodiment twelve: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -3-methylhexanamide
1l (0.073 g,0.2 mmol) of N- (5-iodoquinolin-8-yl) -3-methylpent-4-enamide, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) were weighed out and dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to give 3l of compound. The isolation yield was 94%, dr=1:1.
3l： 1 H NMR(400MHz,CDCl 3 )δ9.84(d,J＝3.9Hz,1H),8.76(dt,J＝4.1,1.9Hz,1H),8.51(dd,J＝8.3,1.4Hz,1H),8.34(ddd,J＝8.5,2.6,1.6Hz,1H),8.05(dd,J＝8.3,2.7Hz,1H),7.52(ddd,J＝8.5,4.2,2.8Hz,1H),4.59–
4.04(m,1H),2.86–2.73(m,1H),2.73–2.45(m,4H),1.16(dd,J＝45.3,6.5Hz,3H).； 13 C NMR(101MHz,CDCl 3 )δ169.52(d,J＝4.0Hz),148.80(d,J＝1.9Hz),140.76(d,J＝3.7Hz),138.78(d,J＝2.3Hz),138.18(d,J＝1.5Hz),135.05(d,J＝2.4Hz),129.57,125.40(q,J＝278.6Hz)123.24(d,J＝2.8Hz),117.89(d,J＝1.7Hz),89.63(d,J＝6.8Hz),58.62(d,J＝66.8Hz),41.11(d,J＝281.2Hz),41.51–39.95(m),36.14(d,J＝89.8Hz),15.58(d,J＝473.8Hz).； 19 F NMR(376MHz,CDCl 3 )δ-63.92(d,J＝12.5Hz).；HRMS(ESI-TOF):m/z Calcd for C 16 H 16 ClF 3 IN 2 O + [M+H + ]:470.9948,found:470.9943.
Embodiment thirteen: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -3-phenylhexanamide
N- (5-iodoquinolin-8-yl) -3-phenylpent-4-enamide 1m (0.086 g,0.2 mmol) was weighed out, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3m. The isolation yield was 71%, dr=1:1.
3m： 1 H NMR(400MHz,CDCl 3 )δ9.65(s,1H),8.66(dd,J＝4.2,1.6Hz,1H),8.35(d,J＝8.3Hz,1H),8.26(dd,J＝8.5,1.6Hz,1H),7.94(d,J＝8.3Hz,1H),7.44(dd,J＝8.5,4.2Hz,1H),7.32–7.26(m,4H),7.22–7.17(m,1H),4.36(td,J＝8.1,4.6Hz,1H),3.62(td,J＝9.0,4.4Hz,1H),3.39(dd,J＝15.3,4.4Hz,1H),2.95(dd,J＝15.4,9.3Hz,1H),2.52–2.39(m,2H).； 13 C NMR(101MHz,CDCl 3 )δ168.93,148.65,140.69,139.63,138.69,138.13,134.99,129.48,129.23,128.03(d,J＝3.5Hz),125.45(d,J＝277.7Hz),123.15,117.83,89.45,57.64,48.83,41.27,40.70(d,J＝28.7Hz).； 19 F NMR(376MHz,CDCl 3 )δ-63.78.；HRMS(ESI-TOF):m/z Calcd for C 21 H 17 ClF 3 IN 2 ONa +
[M+Na + ]:554.9924,found:554.9920.
Fourteen examples: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -3, 3-dimethylhexanamide
N- (5-iodoquinolin-8-yl) -3, 3-dimethylpent-4-enamide 1N (0.076 g,0.2 mmol) was weighed out, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain a compound 3n. The isolation yield was 98%.
3n： 1 H NMR(400MHz,CDCl 3 )δ9.88(s,1H),8.77(dd,J＝4.2,1.6Hz,1H),8.53(d,J＝8.3Hz,1H),8.37(dd,J＝8.5,1.6Hz,1H),8.07(d,J＝8.3Hz,1H),7.54(dd,J＝8.5,4.2Hz,1H),4.45(dd,J＝10.3,1.6Hz,1H),2.85(d,J＝14.4Hz,1H),2.80–2.66(m,1H),2.60–2.44(m,2H),1.30(s,3H),1.22(s,3H).； 13 C NMR(101MHz,CDCl 3 )δ169.13,148.78,140.87,138.84,138.22,135.05,129.62,126.00(q,J＝277.5Hz),123.22,118.02,89.62,61.79,46.89,39.03,38.10(q,J＝28.7Hz),24.60,23.22.； 19 F NMR(376MHz,CDCl 3 )δ-63.99.；HRMS(ESI-TOF):m/z Calcd for C 17 H 18 ClF 3 IN 2 O + [M+H + ]:485.0104,found:485.0103.
Example fifteen: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -4-methylhexanamide
N- (5-iodoquinolin-8-yl) -4-methylpent-4-enamide 1o (0.073 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) and tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) were weighed out and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3o. The isolation yield was 97%.
3o： 1 H NMR(400MHz,CDCl 3 )δ9.82(s,1H),8.74(dd,J＝4.2,1.6Hz,1H),8.47(d,J＝8.3Hz,1H),8.31(dd,J＝8.5,1.6Hz,1H),8.02(d,J＝8.3Hz,1H),7.50(dd,J＝8.5,4.2Hz,1H),2.90–2.67(m,4H),2.46–2.30(m,2H),1.76(d,J＝1.3Hz,3H).； 13 C NMR(101MHz,CDCl 3 )δ170.08,148.72,140.73,138.70,138.20,135.14,129.51,124.94(q,J＝278.7Hz),123.19,117.80,89.45,66.86(d,J＝2.2Hz),46.87(q,J＝27.7Hz),38.76(d,J＝1.7Hz),33.22,29.88(d,J＝1.8Hz).； 19 F NMR(376MHz,CDCl 3 )δ-60.63.；
HRMS(ESI-TOF):m/z Calcd for C 16 H 16 ClF 3 IN 2 O + [M+H + ]:470.9948,found:470.9946.
Example sixteen: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -5-methylhexanamide
(E) -N- (5-iodoquinolin-8-yl) hex-4-enamide trans-1p (0.073 g,0.2 mmol) was weighed out, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate=40:1) to obtain a compound trans-3p. The isolation yield was 79%, dr=1:2.
trans-3p： 1 H NMR(400MHz,CDCl 3 )δ9.84(d,J＝7.3Hz,1H),8.78(dd,
J＝4.2,1.6Hz,1H),8.53(dd,J＝8.3,4.1Hz,1H),8.37(dd,J＝8.6,1.5Hz,1H),8.07(dd,J＝8.3,2.3Hz,1H),7.54(dd,J＝8.5,4.2Hz,1H),4.58–4.29(m,1H),2.96–2.68(m,3H),2.48–2.03(m,2H),1.62–1.55(m,2H),1.34(s,1H).； 13 C NMR(101MHz,CDCl 3 )δ170.12(t,J＝5.2Hz),148.78(d,J＝3.7Hz),140.75,138.81,138.21(d,J＝3.1Hz),135.15(d,J＝4.5Hz),129.57,126.56(q,J＝281.4Hz)123.23(d,J＝2.9Hz),117.83(t,J＝2.4Hz),89.44(d,J＝2.9Hz),56.74(d,J＝547.9Hz),50.09–43.15(m),35.54–23.21(m),21.48–
18.54(m),8.35(d,J＝2.9Hz).； 19 F NMR(376MHz,CDCl 3 )δ-66.24,-68.74.；HRMS(ESI-TOF):m/z Calcd for C 16 H 15 ClF 3 IN 2 ONa + [M+Na + ]:492.9767,found:492.9762.
Example seventeenth: synthesis of 4-chloro-6, 6-trifluoro-N- (5-iodoquinolin-8-yl) -5-methylhexanamide
(Z) -N- (5-iodoquinolin-8-yl) hex-4-enamide cis-1p (0.073 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) and tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) were weighed and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate=40:1) to obtain the compound cis-3p. The isolation yield was 85%, dr=1:1.4.
cis-3p： 1 H NMR(400MHz,CDCl 3 )δ9.82(d,J＝7.1Hz,1H),8.76(dd,
J＝4.2,1.5Hz,1H),8.51(dd,J＝8.2,4.6Hz,1H),8.35(dt,J＝8.5,1.1Hz,1H),8.05(dd,J＝8.3,2.5Hz,1H),7.52(dd,J＝8.5,4.2Hz,1H),4.77–4.08(m,1H),2.95–2.65(m,3H),2.48–2.01(m,2H),1.68–1.57(m,1H),1.32(d,J＝7.1Hz,2H).； 13 C NMR(101MHz,CDCl 3 )δ170.09(d,J＝5.4Hz),148.77(d,J＝3.6Hz),140.76,138.80,138.21(d,J＝3.1Hz),135.16(d,J＝2.2Hz),129.57,126.57(q,J＝281.5Hz)123.23(d,J＝3.0Hz),117.85(d,J＝1.8Hz),89.44(d,J＝2.8Hz),59.47,50.19–43.83(m),34.91,28.84,8.35(d,J＝2.6Hz).； 19 F NMR(376MHz,CDCl 3 )δ-66.23,-68.72.；HRMS(ESI-TOF):m/z Calcd for C 16 H 15 ClF 3 IN 2 ONa + [M+Na + ]:492.9767,found:492.9773.
Example eighteenth: synthesis of 4-chloro-N- (5-iodoquinolin-8-yl) -5- (trifluoromethyl) heptanamide
N- (5-iodoquinolin-8-yl) hept-4-enamide 1q (0.076 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol) tris (2, 2' -bipyridine) ruthenium dichloride was weighed out
(0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) were dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=40:1) to obtain compound 3q. The isolation yield was 75%, dr=1:2.
3q： 1 H NMR(400MHz,CDCl 3 )δ9.82(d,J＝7.5Hz,1H),8.76(dt,J＝4.2,1.4Hz,1H),8.58–8.46(m,1H),8.35(dd,J＝8.5,1.6Hz,1H),8.05(dt,J＝8.3,1.2Hz,1H),7.53(ddd,J＝8.5,4.2,1.0Hz,1H),4.41–4.12(m,1H),2.97–2.47(m,3H),2.45–2.09(m,2H),2.02–1.70(m,2H),1.09(t,J＝7.3,3H).； 13 C NMR(101MHz,CDCl 3 )δ170.43–169.98(m),148.79(d,J＝3.3Hz),140.76,138.81,138.21(d,J＝2.9Hz),135.16(d,J＝3.3Hz),129.58,126.76(q,J＝284.17Hz),123.24(d,J＝2.5Hz),117.94–117.71(m),89.45(d,J＝4.9Hz),62.71–58.32(m),52.81–45.12(m),36.89–32.78(m),29.93(d,J＝14.7Hz),21.16–17.22(m),13.46–10.35(m).； 19 F NMR(376MHz,CDCl 3 )δ-65.19,-65.28,-66.63.；HRMS(ESI-TOF):m/z Calcd for C 17 H 18 ClF 3 IN 2 O +
[M+H + ]:485.0104,found:485.0102.
Example nineteenth: synthesis of 3-chloro-N- (5-iodoquinolin-8-yl) -4- (trifluoromethyl) cyclopentane-1-carboxamide
N- (5-iodoquinolin-8-yl) cyclopent-3-ene-1-carboxamide 1r (0.073 g,0.2 mmol) was weighed out, togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) dissolved in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=40:1) to obtain compound 3r. The isolation yield was 77%, dr=1:6.
3r： 1 H NMR(400MHz,CDCl 3 )δ9.87(s,1H),8.76(dd,J＝4.3,1.6Hz,1H),8.50(d,J＝8.3Hz,1H),8.36(dd,J＝8.5,1.6Hz,1H),8.06(d,J＝8.3Hz,1H),7.54(dd,J＝8.5,4.2Hz,1H),4.38–4.24(m,1H),3.18–3.02(m,2H),2.77(dt,J＝13.8,7.1Hz,1H),2.69–2.57(m,1H),2.42(dt,J＝13.3,9.8Hz,1H),2.30–2.16(m,1H).； 13 C NMR(101MHz,CDCl 3 )δ171.03,148.86,140.85,138.82,138.20,134.92,129.60,126.85(q,J＝278.0Hz)123.31,118.03,89.87,55.35(d,J＝2.8Hz),51.81(q,J＝27.5Hz),44.30,41.37,28.79(d,J＝2.5Hz).； 19 F NMR(376MHz,CDCl 3 )δ-70.80,-70.87.；HRMS(ESI-TOF):m/z Calcd for C 16 H 13 ClF 3 IN 2 ONa + [M+Na + ]:490.9611,found 490.9605.
Example thirty: synthesis of 5-chloro-7, 7-trifluoro-N- (5-iodoquinolin-8-yl) heptanamide
N- (5-iodoquinolin-8-yl) hex-5-enamide 1ac (0.073 g,0.2 mmol) Togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol) and lithium chloride (0.017 g,0.4 mmol) were weighed into 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3ac. The isolation yield was 82%.
3ac： 1 H NMR(400MHz,CDCl 3 )δ9.80(s,1H),8.75(dd,J＝4.3,1.6Hz,1H),8.52(d,J＝8.3Hz,1H),8.35(dd,J＝8.5,1.6Hz,1H),8.05(d,J＝8.3Hz,1H),7.52(dd,J＝8.5,4.2Hz,1H),4.24–4.11(m,1H),2.75–2.50(m,4H),2.18–2.06(m,1H),2.05–1.81(m,3H).； 13 C NMR(101MHz,CDCl 3 )δ170.73,148.71,140.81,138.79,138.26,135.19,129.57,125.23(q,J＝277.6Hz),123.20,117.87,89.37,53.75(d,J＝3.5Hz),42.40(q,J＝28.6Hz),37.37,36.87,21.81.； 19 F NMR(376MHz,CDCl 3 )δ-63.76.；HRMS(ESI-TOF):m/z Calcd for C 16 H 15 ClF 3 IN 2 O + [M+H + ]:470.9948,found:470.9948.
Example thirty-one: synthesis of 6-chloro-8, 8-trifluoro-N- (5-iodoquinolin-8-yl) octanamide
N- (5-iodoquinolin-8-yl) hept-6-enamide 1ad (0.076 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed out in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3ad. The isolation yield was 70%.
3ad： 1 H NMR(400MHz,CDCl 3 )δ9.79(s,1H),8.74(dd,J＝4.2,1.6Hz,1H),8.52(d,J＝8.3Hz,1H),8.34(dd,J＝8.5,1.6Hz,1H),8.04(d,J＝8.3Hz,1H),7.51(dd,J＝8.5,4.2Hz,1H),4.13(m,1H),2.71–2.45(m,4H),1.97–
1.78(m,4H),1.74–1.66(m,1H),1.59(m,1H).； 13 C NMR(101MHz,CDCl 3 )δ171.25,148.71,140.74,138.85,138.25,135.29,129.55,125.25(q,J＝277.5Hz),123.17,117.81,89.26,58.65–48.53(m),42.44(q,J＝28.4Hz),37.82,37.77,25.65,24.68.； 19 F NMR(376MHz,CDCl 3 )δ-63.74.；HRMS(ESI-TOF):m/z Calcd for C 17 H 18 ClF 3 IN 2 O + [M+H + ]:485.0104,found:485.0103.
Example thirty-two: synthesis of 9-chloro-11,11,11-trifluoro-N- (5-iodoquinolin-8-yl) undecanamide
N- (5-iodoquinolin-8-yl) dec-9-enamide 1ae (0.084 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed out in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3ae. The isolation yield was 73%.
3ae： 1 H NMR(400MHz,CDCl 3 )δ9.80(s,1H),8.76(dd,J＝4.2,1.6Hz,1H),8.55(d,J＝8.3Hz,1H),8.36(dd,J＝8.6,1.6Hz,1H),8.06(d,J＝8.3Hz,1H),7.52(dd,J＝8.5,4.2Hz,1H),4.15–4.04(m,1H),2.66–2.46(m,4H),1.87–1.70(m,4H),1.62–1.50(m,1H),1.50–1.32(m,7H).； 13 C NMR(101MHz,CDCl 3 )δ171.82,148.67,140.70,138.88,138.27,135.42,129.53,125.31(d,J＝277.6Hz),123.13,117.76,89.08,54.30–54.07(m),42.42(q,J＝28.4Hz),38.16,38.02,29.16,29.10,28.69,25.86,25.45.； 19 F NMR(376MHz,CDCl 3 )δ-63.78.；HRMS(ESI-TOF):m/z Calcd for C 20 H 24 ClF 3 IN 2 O + [M+H + ]:527.0574,found:527.0577.
Example thirty-three: synthesis of 10-chloro-12,12,12-trifluoro-N- (5-iodoquinolin-8-yl) dodecanamide
N- (5-iodoquinolin-8-yl) undec-10-enamide 1af (0.087 g,0.2 mmol), togni reagent 2a (0.079 g,0.25 mmol), tris (2, 2' -bipyridine) ruthenium dichloride (0.013 g,0.02 mmol), lithium chloride (0.017 g,0.4 mmol) were weighed out in 3mL of dichloromethane. The mixture was heated to 90 ℃ and reacted, TLC followed the reaction until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain compound 3af. The isolation yield was 71%.
3af： 1 H NMR(400MHz,CDCl 3 )δ9.78(s,1H),8.74(dd,J＝4.2,1.6Hz,1H),8.54(d,J＝8.3Hz,1H),8.33(dd,J＝8.5,1.6Hz,1H),8.04(d,J＝8.3Hz,1H),7.50(dd,J＝8.5,4.2Hz,1H),4.13–4.04(m,1H),2.81–2.35(m,4H),1.86–1.66(m,4H),1.60–1.48(m,1H),1.46–1.28(m,9H).； 13 C NMR(101MHz,CDCl 3 )δ171.88,148.66,140.71,138.89,138.27,135.44,129.53,125.32(q,J＝277.6Hz),123.12,117.76,89.06,54.19(d,J＝3.3Hz),42.42(q,J＝28.3Hz),29.32–29.14(m),28.80,25.88,25.51.； 19 F NMR(376MHz,CDCl 3 )δ-63.77.；HRMS(ESI-TOF):m/z Calcd for C 21 H 26 ClF 3 IN 2 O + [M+H + ]:541.0730,found:541.0728.
In summary, the invention discloses a synthesis method of a chlorotrifluoro methylation derivative of an inactive olefin, which takes a substituted N- (5-substituted quinoline-8-yl) pent-4-enamide derivative as a substrate, a Togni reagent as a trifluoromethyl source, and lithium chloride as a chloride ion source, and the compounds react in methylene dichloride at 60-110 ℃ under the catalysis of a ruthenium catalyst to obtain a plurality of chlorotrifluoro methylation derivatives with high yield.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (10)
1. A chlorotrifluoromethylation process for an inactive olefin comprising the steps of:
the method comprises the steps of (1) catalyzing a compound shown in a formula with a trifluoromethyl source in the presence of a chloride ion source and a solvent to complete the reaction through a ruthenium catalyst;
R 1 -R 5 is hydrogen;
or R is 2 -R 5 Is hydrogen, R 1 One selected from the group consisting of monosubstituted methyl, disubstituted methyl, n-butyl, cyclopropylmethyl, benzyl, o-tolyl, m-tolyl, p-tolyl and cyclobutyl;
or R is 1 、R 3 -R 5 Is hydrogen, R 2 One selected from the group consisting of monosubstituted methyl, disubstituted methyl and phenyl;
or R is 1 -R 2 、R 4 -R 5 Is hydrogen, R 3 Is methyl;
or R is 1 -R 4 Is hydrogen, R 5 One selected from methyl and ethyl;
or R is 1 -R 4 Is hydrogen, R 5 Is methyl and is a conjugated diene.
2. The method according to claim 1, characterized in that: in the compound shown in the formula (1), X is iodine.
3. The method of claim 1, wherein the trifluoromethyl source is selected from one of the following structures:
4. the method according to claim 1, characterized in that: the exocyclic double bond is
The double bond in the ring with symmetrical structure is +.>
5. The method according to claim 1, characterized in that: the chloride ion source is selected from one of tetramethyl ammonium chloride, tetrabutyl ammonium chloride, sodium chloride, potassium chloride, lithium chloride, sulfoxide chloride, trimethylchlorosilane, nickel chloride and ferric chloride.
6. The method according to claim 1, characterized in that: the ruthenium catalyst is selected from one of cyclooctadiene ruthenium dichloride, tri (triphenylphosphine) ruthenium dichloride, ruthenium trichloride and tri (2, 2' -bipyridine) ruthenium dichloride.
7. The method according to claim 1, characterized in that: the solvent is selected from one of carbon tetrachloride, dichloromethane, 1, 4-dioxane, methanol, chloroform, acetonitrile and 1, 2-dichloroethane.
8. The method according to claim 1, characterized in that: the reaction temperature is 60-110 ℃.
9. The method according to claim 1, characterized in that: the reaction time is 3-8 hours.
10. The method according to claim 1, characterized in that: the molar ratio of the compound shown in the formula (1), the trifluoromethyl source, the chloride ion source and the ruthenium catalyst is 1:1-3:1-6:0.05-0.2.
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| HENG ZHANG, ET AL.: ""β-Lactam Synthesis via Copper-Catalyzed Directed Aminoalkylation of Unactivated Alkenes with Cyclobutanone O-Benzoyloximes"", 《ORG. LETT.》, vol. 23, no. 9, 14 April 2021 (2021-04-14), pages 3620 * |
| ZIBO BAI, ET AL.: ""Enantioselective Alkylamination of Unactivated Alkenes under Copper Catalysis"", 《J. AM. CHEM. SOC.》, vol. 143, no. 2, 30 December 2020 (2020-12-30), pages 1195 * |
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