CN112500425B - A kind of 3-thiopyrrole compound and its synthetic method - Google Patents
A kind of 3-thiopyrrole compound and its synthetic method Download PDFInfo
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- CN112500425B CN112500425B CN202011195870.0A CN202011195870A CN112500425B CN 112500425 B CN112500425 B CN 112500425B CN 202011195870 A CN202011195870 A CN 202011195870A CN 112500425 B CN112500425 B CN 112500425B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- 238000010189 synthetic method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- -1 benzothiophene ketones Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 9
- YCMLQMDWSXFTIF-UHFFFAOYSA-N 2-methylbenzenesulfonimidic acid Chemical compound CC1=CC=CC=C1S(N)(=O)=O YCMLQMDWSXFTIF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 44
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical group Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 20
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 239000000654 additive Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VHEDVXOZKBKNSG-UHFFFAOYSA-N 1-phenyl-n-prop-2-ynylmethanesulfonamide Chemical compound C#CCNS(=O)(=O)CC1=CC=CC=C1 VHEDVXOZKBKNSG-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- LYGJENNIWJXYER-BJUDXGSMSA-N nitromethane Chemical group [11CH3][N+]([O-])=O LYGJENNIWJXYER-BJUDXGSMSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 abstract description 4
- 239000011593 sulfur Substances 0.000 abstract description 4
- 150000002019 disulfides Chemical class 0.000 abstract description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 238000004440 column chromatography Methods 0.000 description 21
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 12
- GIIARZBTTUBMIX-UHFFFAOYSA-N N-(1,4-diphenylbut-3-ynyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C=1C=CC=CC=1)CC#CC1=CC=CC=C1 GIIARZBTTUBMIX-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- SCAKFUJVCFIFOX-UHFFFAOYSA-N 1-phenylsulfanylpyrrolidine-2,5-dione Chemical compound O=C1CCC(=O)N1SC1=CC=CC=C1 SCAKFUJVCFIFOX-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QJIKFGXYWGGKJK-UHFFFAOYSA-N FC1=CC=C(C=C1)C=1NC=CC1SC1=CC=CC=C1 Chemical compound FC1=CC=C(C=C1)C=1NC=CC1SC1=CC=CC=C1 QJIKFGXYWGGKJK-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- WGRUUOMGUXAKMN-UHFFFAOYSA-N nitric acid;propane Chemical compound CCC.O[N+]([O-])=O WGRUUOMGUXAKMN-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000006177 thiolation reaction Methods 0.000 description 2
- 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 1
- 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
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- 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
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RBVSAVVTTMUGMJ-UHFFFAOYSA-N 1-phenylsulfanylpyrrole Chemical compound C1(=CC=CC=C1)SN1C=CC=C1 RBVSAVVTTMUGMJ-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
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 1
- ULUNQYODBKLBOE-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-1h-pyrrole Chemical compound C1=CNC(C=2NC=CC=2)=C1 ULUNQYODBKLBOE-UHFFFAOYSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- ZRSBOTGCEZGRJK-UHFFFAOYSA-N 4-methyl-N-[1-(2-phenylethynyl)cyclohexyl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1(C#CC=2C=CC=CC=2)CCCCC1 ZRSBOTGCEZGRJK-UHFFFAOYSA-N 0.000 description 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
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- 239000002841 Lewis acid Substances 0.000 description 1
- QYGYNMSKSOACIO-UHFFFAOYSA-N N-(4-chloro-1-phenylbut-3-ynyl)-4-methylbenzenesulfonamide Chemical compound CC(C=C1)=CC=C1S(NC(CC#CCl)C1=CC=CC=C1)(=O)=O QYGYNMSKSOACIO-UHFFFAOYSA-N 0.000 description 1
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- YVHPHQBRUPLYOS-UHFFFAOYSA-N dichloromethane;methane Chemical compound C.ClCCl YVHPHQBRUPLYOS-UHFFFAOYSA-N 0.000 description 1
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- 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
- MCYHPZGUONZRGO-VKHMYHEASA-N methyl L-cysteinate Chemical compound COC(=O)[C@@H](N)CS MCYHPZGUONZRGO-VKHMYHEASA-N 0.000 description 1
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003634 thiocyclization reaction Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
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Abstract
本发明公开了一种3‑硫代吡咯化合物及其合成方法，以高炔丙基甲苯磺酰胺（I）和N‑硫代丁二酰亚胺（II）为反应原料，在催化剂的作用下进行反应，在反应溶剂中合成3‑硫代吡咯（III）化合物，本发明合成方法原料易得价廉，反应操作简单，反应条件温和，产率较高，官能团耐受性良好。重要的是，以此种方法合成的3‑硫代吡咯类化合物被应用于有机光电苯并噻吩酮类和双硫醚类化合物的制备，为含硫材料分子的制备提供了新的途径。The invention discloses a 3-thiopyrrole compound and a synthesis method thereof. Homopropargyl toluenesulfonamide (I) and N-thiosuccinimide (II) are used as reaction raw materials, and under the action of a catalyst The reaction is carried out to synthesize the 3-thiopyrrole (III) compound in the reaction solvent. The synthetic method of the present invention has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and good functional group tolerance. Importantly, the 3-thiopyrrole compounds synthesized in this way were applied to the preparation of organic photoelectric benzothiophene ketones and disulfide compounds, providing a new way for the preparation of sulfur-containing material molecules.
Description
技术领域technical field
本发明涉及一种3-硫代吡咯化合物及其合成方法，属于有机化合物工艺应用技术领域。The invention relates to a 3-thiopyrrole compound and a synthesis method thereof, belonging to the technical field of organic compound technology application.
背景技术Background technique
吡咯环作为可进行多样性化学转换的N-杂环，是组成许多药物、天然产物和有机功能材料中特有的结构单元。特别是当N-杂环与含硫基团结合时，通常表现出优异的物理、化学及生物性质，比如含硫药物更易于代谢，吡咯环结构单元带来的材料发光强度的改变等。The pyrrole ring, as an N-heterocycle capable of diverse chemical transformations, is a unique structural unit in many pharmaceuticals, natural products and organic functional materials. Especially when the N-heterocycle is combined with a sulfur-containing group, it usually exhibits excellent physical, chemical and biological properties, such as the easier metabolism of sulfur-containing drugs, and the change of the luminescence intensity of the material brought by the pyrrole ring structural unit.
传统方法中对于吡咯的功能化和修饰已经得到了较好的研究，然而，吡咯的区域选择性硫代反应却鲜有研究。由于吡咯环的反应活性较高，使得区域选择性地硫代仍然是一个挑战。The functionalization and modification of pyrrole in traditional methods have been well studied, however, the regioselective thiolation of pyrrole is rarely studied. Regioselective thiolation remains a challenge due to the high reactivity of pyrrole rings.
发明内容SUMMARY OF THE INVENTION
本发明旨在提供一种3-硫代吡咯化合物及其合成方法，在路易斯酸的催化条件下，通过调整反应溶剂，利用亲电硫代环化反应由高炔丙基甲苯磺酰胺(I)和N-硫代丁二酰亚胺(II)高效高选择性地构建3-硫代吡咯化合物。本发明的合成方法简单，原料廉价易得，底物普适性广，产率较好。The present invention aims to provide a 3-thiopyrrole compound and a method for synthesizing the same. Under the catalytic condition of Lewis acid, by adjusting the reaction solvent, the electrophilic thiocyclization reaction is used to convert homopropargyl toluenesulfonamide (I) and N-thiosuccinimide (II) to construct 3-thiopyrrole compounds with high efficiency and selectivity. The synthesis method of the invention is simple, the raw materials are cheap and easy to obtain, the substrate is widely applicable, and the yield is good.
本发明提供了一种3-硫代吡咯化合物的合成方法，以高炔丙基甲苯磺酰胺(I)和N-硫代丁二酰亚胺(II)为反应原料，在催化剂和添加剂的共同作用下进行反应，在反应溶剂中合成3-硫代吡咯(III)化合物，所述反应过程如下方反应式所示：The invention provides a method for synthesizing a 3-thiopyrrole compound, which uses homopropargyl toluenesulfonamide (I) and N-thiosuccinimide (II) as reaction raw materials, and uses a catalyst and an additive together as reaction materials. The reaction is carried out under the action, and the 3-thiopyrrole (III) compound is synthesized in the reaction solvent, and the reaction process is shown in the following reaction formula:
其中，R1为芳香环、烷基或者氢原子；R2为芳香环或者取代芳香环；R3为芳香环、取代的芳香环、烷基或者取代的烷基。Wherein, R 1 is an aromatic ring, an alkyl group or a hydrogen atom; R 2 is an aromatic ring or a substituted aromatic ring; R 3 is an aromatic ring, a substituted aromatic ring, an alkyl group or a substituted alkyl group.
上述方法中，R1为苯基、正丁基、环己烷基、氢原子中的一种；R2为苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、4-氟苯基中的一种；R3为苯基、4-甲基苯基、4-甲氧基苯基、4-叠氮基苯基、2-溴基苯基、4-硝基苯基、2-萘基、乙基、苄基、3-(乙氧基-3-氧丙基)、L-半胱氨酸甲酯中的一种。R1，R2，R3可以相同也可以不同，R1，R2，R3可以是但不仅仅局限于如上取代基。In the above method, R 1 is one of phenyl, n-butyl, cyclohexane, and hydrogen atom; R 2 is phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-cyano One of phenyl, 4-fluorophenyl; R 3 is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-azidophenyl, 2-bromophenyl, 4 - One of nitrophenyl, 2-naphthyl, ethyl, benzyl, 3-(ethoxy-3-oxypropyl), L-cysteine methyl ester. R 1 , R 2 and R 3 can be the same or different, and R 1 , R 2 and R 3 can be but not limited to the above substituents.
上述方法中，所述反应的温度为0-100℃；优选地，反应温度为60℃；所述反应时间为1-6小时；优选地，反应时间为1h。In the above method, the reaction temperature is 0-100°C; preferably, the reaction temperature is 60°C; the reaction time is 1-6 hours; preferably, the reaction time is 1 hour.
上述方法中，所述反应溶剂选自硝基甲烷、四氢呋喃、乙腈、N,N-二甲基甲酰胺、甲苯、二甲基亚砜、1,2-二氯乙烷中的任意一种，优选地，反应溶剂为硝基甲烷；In the above method, the reaction solvent is selected from any one of nitromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, toluene, dimethyl sulfoxide, and 1,2-dichloroethane, Preferably, the reaction solvent is nitromethane;
上述方法中，所述催化剂选自氯化亚铜、醋酸铜、三氯化铝中的一种或多种；所述催化剂的摩尔用量为高炔丙基甲苯磺酰胺(I)的1-100mol％。优选地，反应催化剂为三氯化铝；优选地，所述催化剂三氯化铝(AlCl3)摩尔用量为如式(I)所示的原料高炔丙基甲苯磺酰胺的40mol％；In aforesaid method, described catalyzer is selected from one or more in cuprous chloride, cupric acetate, aluminium trichloride; The molar dosage of described catalyzer is 1-100mol of high propargyl toluenesulfonamide (I) %. Preferably, the reaction catalyst is aluminum trichloride; preferably, the molar dosage of the catalyst aluminum trichloride (AlCl 3 ) is 40 mol% of the raw material homopropargyl toluenesulfonamide shown in formula (I);
上述方法中，所述添加剂选自浓盐酸、对甲苯磺酸、三氟乙酸、三氟甲磺酸、四甲基哌啶氮氧化物、氯化铵、三甲基氯硅烷中的一种或多种；所述添加剂的摩尔用量为高炔丙基甲苯磺酰胺(I)的1-100mol％。优选地，添加剂为浓盐酸(质量浓度35.5％)；浓盐酸(质量浓度35.5％)摩尔用量为如式(I)所示的原料高炔丙基甲苯磺酰胺的100mol％。In the above method, the additive is selected from the group consisting of concentrated hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, tetramethylpiperidine nitrogen oxide, ammonium chloride, trimethylchlorosilane or The molar dosage of the additive is 1-100 mol% of the homopropargyltoluenesulfonamide (I). Preferably, the additive is concentrated hydrochloric acid (35.5% by mass); the molar dosage of concentrated hydrochloric acid (35.5% by mass) is 100 mol% of the raw material homopropargyltoluenesulfonamide shown in formula (I).
上述方法中，高炔丙基甲苯磺酰胺(I)的用量与N-硫代丁二酰亚胺(II)的用量摩尔比为1：(1-10)。In the above method, the molar ratio of the consumption of homopropargyl toluenesulfonamide (I) to the consumption of N-thiosuccinimide (II) is 1:(1-10).
上述方法中，高炔丙基甲苯磺酰胺(I)与所使用的溶剂的比例为1mmol:(1-15)mL。优选地，所述溶剂体积与原料酯的比例为15mL:1mmol。In the above method, the ratio of homopropargyl toluenesulfonamide (I) to the solvent used is 1 mmol: (1-15) mL. Preferably, the ratio of the solvent volume to the raw material ester is 15 mL: 1 mmol.
下面以硝基甲烷溶剂、三氯化铝催化剂为例来说明本发明的反应原理：本发明的反应过程主要涉及，在酸性条件下，在硝基甲烷中通过经典的Nef过程可以生成亚硝酸HNO和甲醛HCHO等氧化产物。另一方面，首先用三氯化铝活化N-硫代丁二酰亚胺(II)生成亚砜阳离子，诱导高炔丙基甲苯磺酰胺(I)分子内环化生成3-硫代吡咯啉(IV)。而在硝基甲烷溶剂中，由于亚硝酸的氧化，吡咯骨架被芳构化成3-硫代吡咯(III)。The reaction principle of the present invention is described below by taking nitromethane solvent and aluminum trichloride catalyst as examples: the reaction process of the present invention mainly involves, under acidic conditions, nitrous acid HNO can be generated by classical Nef process in nitromethane and formaldehyde HCHO and other oxidation products. On the other hand, N-thiosuccinimide (II) was first activated with aluminum trichloride to generate sulfoxide cation, which induced the intramolecular cyclization of homopropargyl tosylamide (I) to generate 3-thiopyrroline (IV). In nitromethane solvent, the pyrrole skeleton was aromatized to 3-thiopyrrole (III) due to the oxidation of nitrous acid.
本发明还提供了按照本发明上述合成方法制备得到的如式(III)所示的3-硫代吡咯化合物。The present invention also provides the 3-thiopyrrole compound represented by the formula (III) prepared according to the above-mentioned synthesis method of the present invention.
本发明提供了上述新的3-硫代吡咯化合物以及它的应用，所述化合物可应用于一系列有机光电苯并噻吩酮类和双硫醚类化合物的制备。例如，3-硫代吡咯(实施例18，化合物3r)经脱羧后与4-溴苯甲醛缩合并脱氢得到二硫代二吡咯甲烷5，再将二吡咯5置于三乙基胺和三氟化硼醚中，可获得二硫代氟硼二吡咯6(S-BODIPY)，该化合物是一种新的荧光染料。The present invention provides the above-mentioned novel 3-thiopyrrole compound and its application, and the compound can be applied to the preparation of a series of organic photoelectric benzothiophene ketones and disulfide compounds. For example, 3-thiopyrrole (Example 18, compound 3r) is decarboxylated, condensed with 4-bromobenzaldehyde and dehydrogenated to give dithiodipyrrolemethane 5, which is then placed in triethylamine and triethylamine In boron fluoride ether, dithiofluoroboron dipyrrole 6 (S-BODIPY) can be obtained, which is a new fluorescent dye.
本发明的有益效果：Beneficial effects of the present invention:
本发明合成方法原料价廉易得，反应操作简单，反应条件温和，产率较高，官能团耐受性良好；本发明合成的3-硫代吡咯类化合物可以被应用于有机光电苯并噻吩酮类和双硫醚类化合物的制备，为含硫材料分子的制备提供了新的途径。The synthesis method of the invention has cheap and easily available raw materials, simple reaction operation, mild reaction conditions, high yield and good functional group tolerance; the 3-thiopyrrole compounds synthesized in the invention can be applied to organic photoelectric benzothiophene ketones The preparation of thioether and disulfide compounds provides a new way for the preparation of sulfur-containing material molecules.
具体实施方式Detailed ways
结合以下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。The present invention will be further described in detail with reference to the following specific examples, and the protection content of the present invention is not limited to the following examples. Variations and advantages that can occur to those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the content specifically mentioned below, are all common knowledge and common knowledge in the field, and the present invention has no special limited content. The data given in the following examples include specific operating and reaction conditions and products. The purity of the product was identified by NMR.
在实施例1～18中，反应温度为60℃。In Examples 1 to 18, the reaction temperature was 60°C.
实施例1Example 1
化合物3a的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌1小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.40)分离得黄色固体3a(58mg,yield:80％)；1H NMR(CDCl3,400MHz):δ7.55-7.52(m,2H),7.43-7.40(m,8H),7.17-7.10(m,7H),6.95-6.93(m,2H),6.23(s,1H),2.42(s,3H)；13C{1H}NMR(CDCl3,100MHz):δ144.7,141.3,140.9,136.9,134.6,132.7,131.1,131.0,129.6,129.0,128.8,128.6,128.3,127.9,127.6,127.2,127.2,125.8,121.2,119.5,21.7.HRMS(ESI)m/z calcd.forC29H23NO2S2[M+H]+:482.1243,found:482.1243.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-phenylthio-pyrrole Lin-2,5-dione (37 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitromethane (1.5 mL), Stir at 60°C for 1 hour, after completion of the reaction, dry, filter, concentrate, and separate by column chromatography (PE:EtOAc=19:1, R f =0.40) to obtain yellow solid 3a (58 mg, yield: 80%); 1 H NMR (CDCl 3 , 400MHz): δ 7.55-7.52 (m, 2H), 7.43-7.40 (m, 8H), 7.17-7.10 (m, 7H), 6.95-6.93 (m, 2H), 6.23 ( s, 1H), 2.42 (s, 3H); 13 C{ 1 H} NMR (CDCl 3 , 100MHz): δ 144.7, 141.3, 140.9, 136.9, 134.6, 132.7, 131.1, 131.0, 129.6, 129.0, 128.8, 128.6, 128.3,127.9,127.6,127.2,127.2,125.8,121.2,119.5,21.7.HRMS(ESI)m/z calcd.forC 29 H 23 NO 2 S 2 [M+H] + :482.1243,found:482.1243.
实施例2Example 2
化合物3b的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-(4-甲基)-苯硫基-吡咯啉-2,5-二酮(40mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌2小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝19:1,Rf＝0.40)分离得黄色固体3b(54.2mg,yield:73％)；1H NMR(CDCl3,400MHz):δ7.54-7.51(m,2H),7.46-7.40(m,8H),7.15-7.10(m,4H),6.98(d,J＝8.0Hz,2H),6.91(d,J＝8.0Hz,2H),6.17(s,1H),2.42(s,3H),2.29(s,3H)；13C NMR(CDCl3,100MHz):δ144.6,140.8,140.1,136.2,134.6,132.7,132.6,131.2,131.1,129.6,129.6,129.00,129.00,128.5,128.2,127.6,127.2,127.1,120.8,21.6,20.9.HRMS(ESI)m/z calcd.For C30H25NO2S2[M+H]+:496.1399,found:496.1398.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-(4-methyl) )-phenylthio-pyrroline-2,5-dione (40mg, 0.18mmol), aluminum trichloride (8.0mg, 0.06mmol), 35.5% concentrated hydrochloric acid (15.4mg, 0.15mmol), nitrate ethylmethane (1.5 mL), stirred at 60 °C for 2 hours, after completion of the reaction, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.40) to obtain a yellow solid 3b ( 54.2 mg, yield: 73%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.54-7.51 (m, 2H), 7.46-7.40 (m, 8H), 7.15-7.10 (m, 4H), 6.98 ( d, J=8.0Hz, 2H), 6.91 (d, J=8.0Hz, 2H), 6.17 (s, 1H), 2.42 (s, 3H), 2.29 (s, 3H); 13 C NMR (CDCl 3 , 100MHz): δ144.6, 140.8, 140.1, 136.2, 134.6, 132.7, 132.6, 131.2, 131.1, 129.6, 129.6, 129.00, 129.00, 128.5, 128.2, 127.6, 127.2, 127.1, 120.8, 21 mRMS(E) /z calcd.For C 30 H 25 NO 2 S 2 [M+H] + :496.1399,found:496.1398.
实施例3Example 3
化合物3c的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-(4-甲氧基)-苯硫基-吡咯啉-2,5-二酮(43mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌2小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝9:1,Rf＝0.40)分离得黄色固体3c(53.7mg,yield:70％)；1H NMR(CDCl3,400MHz):δ7.50-7.47(m,2H),7.46-7.42(m,5H),7.40-7.38(m,3H),7.10(q,J＝8.4Hz,4H),7.03(dt,J＝9.6,3.2Hz,2H),6.72(dt,J＝10.0,3.2Hz,2H),6.05(s,1H),3.75(s,3H),2.40(s,3H)；13C NMR(CDCl3,100MHz):δ158.9,144.6,140.6,138.3,134.6,132.8,132.3,131.4,131.1,129.6,129.0,128.4,128.2,127.5,127.3,127.1,125.9,122.6,120.0,114.6,55.3,21.7.HRMS(ESI)m/z calcd.forC30H25NO3S2[M+H]+:512.1349,found:512.1347.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-(4-methoxy base)-phenylthio-pyrroline-2,5-dione (43 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), Nitromethane (1.5 mL) was stirred at 60°C for 2 hours. After the reaction was completed, it was dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=9:1, Rf =0.40) to obtain a yellow solid 3c (53.7 mg, yield: 70%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.50-7.47 (m, 2H), 7.46-7.42 (m, 5H), 7.40-7.38 (m, 3H), 7.10 (q, J=8.4Hz, 4H), 7.03(dt, J=9.6, 3.2Hz, 2H), 6.72(dt, J=10.0, 3.2Hz, 2H), 6.05(s, 1H), 3.75(s, 3H), 2.40(s, 3H); 13 C NMR (CDCl 3 , 100MHz): δ 158.9, 144.6, 140.6, 138.3, 134.6, 132.8, 132.3, 131.4, 131.1, 129.6, 129.0, 128.4, 128.2, 127.5, 127.3, 127.1,125.9,122.6,120.0,114.6,55.3,21.7.HRMS(ESI)m/z calcd.forC30H25NO3S2 [ M + H] + : 512.1349 ,found:512.1347.
实施例4Example 4
化合物3d的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-(4-叠氮基)-苯硫基-吡咯啉-2,5-二酮(45mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌1小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝19:1,Rf＝0.40)分离得黄色固体3d(37.6mg,Yield:48％)；1H NMR(CDCl3,400MHz):δ7.53-7.51(m,2H),7.43-7.40(m,8H),7.12(q,J＝8.4Hz,4H),6.94(dt,J＝9.2,2.4Hz,2H),6.81(dt,J＝9.2,2.4Hz,2H),6.17(s,1H),2.42(s,3H)；13C NMR(CDCl3,100MHz):δ144.8,140.9,140.8,138.1,134.7,132.9,132.7,131.1,131.0,130.0,129.6,129.1,128.7,128.4,127.7,127.3,127.2,120.7,119.7,119.6,21.7.HRMS(ESI)m/z calcd.For C29H22N4O2S2[M+H]+:523.1257,found:523.1267.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-(4-azide) base)-phenylthio-pyrroline-2,5-dione (45mg, 0.18mmol), aluminum trichloride (8.0mg, 0.06mmol), 35.5% concentrated hydrochloric acid (15.4mg, 0.15mmol), Nitromethane (1.5 mL) was stirred at 60°C for 1 hour, after the reaction was completed, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.40) to obtain a yellow solid 3d (37.6 mg, Yield: 48%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.53-7.51 (m, 2H), 7.43-7.40 (m, 8H), 7.12 (q, J=8.4 Hz, 4H) ), 6.94(dt, J=9.2, 2.4Hz, 2H), 6.81(dt, J=9.2, 2.4Hz, 2H), 6.17(s, 1H), 2.42(s, 3H); 13 C NMR (CDCl 3 ,100MHz):δ144.8,140.9,140.8,138.1,134.7,132.9,132.7,131.1,131.0,130.0,129.6,129.1,128.7,128.4,127.7,127.3,127.2,120.7,119.7,119SI m/z calcd.For C 29 H 22 N 4 O 2 S 2 [M+H] + :523.1257,found:523.1267.
实施例5Example 5
化合物3e的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-(2-溴)-苯硫基-吡咯啉-2,5-二酮(52mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌5小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝19:1,Rf＝0.35)分离得黄色固体3e(38.6mg,yield:46％)；1H NMR(CDCl3,400MHz):δ7.56-7.53(m,2H),7.45-7.37(m,9H),7.12(q,J＝8.4Hz,4H),7.00-6.92(m,2H),6.50(dd,J＝7.6,2.0Hz,1H),6.26(s,1H),2.41(s,3H)；13C NMR(100MHz,CDCl3):δ144.9,143.0,141.2,138.8,134.7,132.8,132.6,131.1,130.6,129.6,129.1,128.8,128.4,127.7,127.6,127.5,127.3,127.2,126.5,121.4,121.3,117.7,21.7.HRMS(ESI)m/z calcd.for C29H22BrNO2S2[M+H]+:562.0328,560.0348,found:562.0338,560.0357.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-(2-bromo) - Phenylthio-pyrroline-2,5-dione (52 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitro Methane (1.5 mL) was stirred at 60°C for 5 hours. After the reaction was completed, it was dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.35) to obtain a yellow solid 3e (38.6 mg, yield: 46%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.56-7.53 (m, 2H), 7.45-7.37 (m, 9H), 7.12 (q, J=8.4 Hz, 4H), 7.00-6.92 (m, 2H), 6.50 (dd, J=7.6, 2.0 Hz, 1H), 6.26 (s, 1H), 2.41 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 144.9, 143.0 ,141.2,138.8,134.7,132.8,132.6,131.1,130.6,129.6,129.1,128.8,128.4,127.7,127.6,127.5,127.3,127.2,126.5,121.4,121.3,117.7,21.7mHRMS(ESIm/z) calcd.for C 29 H 22 BrNO 2 S 2 [M+H] + :562.0328,560.0348,found:562.0338,560.0357.
实施例6Example 6
化合物3f的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-(4-硝基)-苯硫基-吡咯啉-2,5-二酮(45mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌4小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝9:1,Rf＝0.4)分离得黄色固体3f(24.5mg,yield:41％)；1H NMR(CDCl3,400MHz):δ7.96(dt,J＝9.6,2.4Hz,2H),7.58-7.56(m,2H),7.46-7.36(m,6H),7.30(dt,J＝5.6,1.2Hz,2H),7.18(d,J＝8.4Hz,2H),7.13(d,J＝8.4Hz,2H),6.87(dt,J＝9.6,2.8Hz,2H),6.33(s,1H),2.47(s,3H)；13C NMR(CDCl3,100MHz):δ148.2,145.3,145.1,143.7,141.4,134.8,132.4,131.0,130.3,129.7,129.3,129.1,128.7,127.8,127.4,127.3,125.6,123.9,121.2,115.1,21.8.HRMS(ESI)m/zcalcd.for C29H22N2O4S2[M+H]+:527.1094,found:527.1093.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-(4-nitro )-phenylthio-pyrroline-2,5-dione (45mg, 0.18mmol), aluminum trichloride (8.0mg, 0.06mmol), 35.5% concentrated hydrochloric acid (15.4mg, 0.15mmol), nitrate ethylmethane (1.5 mL), stirred at 60 °C for 4 hours, after completion of the reaction, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=9:1, R f =0.4) to obtain a yellow solid 3f ( 24.5 mg, yield: 41%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.96 (dt, J=9.6, 2.4 Hz, 2H), 7.58-7.56 (m, 2H), 7.46-7.36 (m, 6H), 7.30(dt, J＝5.6, 1.2Hz, 2H), 7.18(d, J＝8.4Hz, 2H), 7.13(d, J＝8.4Hz, 2H), 6.87(dt, J＝9.6, 2.8 Hz, 2H), 6.33(s, 1H), 2.47(s, 3H); 13 C NMR (CDCl 3 , 100MHz): δ 148.2, 145.3, 145.1, 143.7, 141.4, 134.8, 132.4, 131.0, 130.3, 129.7, 129.3 ,129.1,128.7,127.8,127.4,127.3,125.6,123.9,121.2,115.1,21.8.HRMS(ESI)m/zcalcd.for C 29 H 22 N 2 O 4 S 2 [M+H] + :527.1094,found :527.1093.
实施例7Example 7
化合物3g的合成Synthesis of compound 3g
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-萘-(2-硫)基-吡咯啉-2,5-二酮(46mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌3小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝19:1,Rf＝0.35)分离得黄色固体3g(52.6mg,yield:66％)；1H NMR(CDCl3,400MHz):δ7.76(d,J＝7.6Hz,1H),7.64(d,J＝8.8Hz,1H),7.58(d,J＝8.0Hz,1H),7.55-7.53(m,2H),7.47-7.40(m,11H),7.18-7.13(m,4H),7.09(dd,J＝8.8,2.0Hz,1H),6.25(s,1H),2.44(s,3H)；13C NMR(CDCl3,100MHz):δ143.78,140.0,139.8,133.8,133.3,132.5,131.7,130.6,130.1,130.0,128.6,128.1,127.6,127.5,127.3,126.7,126.6,126.3,126.2,126.0,125.5,125.3,125.1,124.7,120.1,118.40,20.7.HRMS(ESI)m/z calcd.for C33H25NO2S2[M+H]+:532.1399,found:532.1398.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-naphthalene-(2- Sulfo)-pyrroline-2,5-dione (46 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitromethane (1.5 mL), stirred at 60°C for 3 hours, after completion of the reaction, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.35) to obtain 3 g (52.6 mg) of a yellow solid , yield: 66%); 1 H NMR (CDCl 3 , 400MHz): δ 7.76 (d, J=7.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.55-7.53(m, 2H), 7.47-7.40(m, 11H), 7.18-7.13(m, 4H), 7.09(dd, J=8.8, 2.0Hz, 1H), 6.25(s, 1H), 2.44(s, 3H); 13 C NMR (CDCl 3 , 100MHz): δ 143.78, 140.0, 139.8, 133.8, 133.3, 132.5, 131.7, 130.6, 130.1, 130.0, 128.6, 128.1, 127.6, 127.5, 127.3 126.7,126.6,126.3,126.2,126.0,125.5,125.3,125.1,124.7,120.1,118.40,20.7.HRMS(ESI)m/z calcd.for C 33 H 25 NO 2 S 2 [M+H] + :532.1399 ,found:532.1398.
实施例8Example 8
化合物3h的合成Synthesis of compound 3h
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-乙硫基-吡咯啉-2,5-二酮(29mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌6小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝19:1,Rf＝0.4)分离得黄色液体3h(33.8mg,yield:52％)；1H NMR(CDCl3,400MHz):δ7.54-7.51(m,2H),7.44-7.40(m,8H),7.10-7.04(m,4H),6.31(s,1H),2.62(q,J＝7.2Hz,2H),2.36(s,3H),1.06(t,J＝7.2Hz,3H)；13C NMR(CDCl3,100MHz):δ144.5,140.3,137.7,134.6,132.8,131.7,131.2,129.6,128.9,128.2,128.1,127.6,127.2,127.0,122.1,118.9,28.4,21.6,14.5.HRMS(ESI)m/zcalcd.for C25H23NO2S2[M+H]+:434.1243,found:434.1241.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-ethylthio-pyrrole Lin-2,5-dione (29 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitromethane (1.5 mL), Stirred at 60°C for 6 hours, after the reaction was completed, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, Rf =0.4) to obtain a yellow liquid for 3h (33.8 mg, yield: 52%) ); 1 H NMR (CDCl 3 , 400MHz): δ 7.54-7.51 (m, 2H), 7.44-7.40 (m, 8H), 7.10-7.04 (m, 4H), 6.31 (s, 1H), 2.62 ( q, J=7.2Hz, 2H), 2.36 (s, 3H), 1.06 (t, J=7.2Hz, 3H); 13 C NMR (CDCl 3 , 100MHz): δ 144.5, 140.3, 137.7, 134.6, 132.8, 131.7 ,131.2,129.6,128.9,128.2,128.1,127.6,127.2,127.0,122.1,118.9,28.4,21.6,14.5.HRMS(ESI)m/zcalcd.for C 25 H 23 NO 2 S 2 [M+H] + :434.1243,found:434.1241.
实施例9Example 9
化合物3i的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，1-苄硫基-吡咯啉-2,5-二酮(40mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌1小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝19:1,Rf＝0.4)分离得黄色液体3i(40.1mg,yield:54％)；1HNMR(CDCl3,400MHz):δ7.46-7.36(m,9H),7.24(d,J＝3.6Hz,1H),7.19-7.15(m,3H),7.08(d,J＝8.4Hz,2H),7.03-6.99(m,4H),6.18(s,1H),3.75(s,2H),2.3(s,3H)；13C NMR(CDCl3,100MHz):δ144.5,139.7,139.1,137.3,134.9,132.8,131.3,131.3,129.7,129.0,128.8,128.3,128.2,128.2,127.5,127.1,127.0,120.9,119.8,39.6,21.6.HRMS(ESI)m/z calcd.for C30H25NO2S2[M+H]+:496.1399,found:496.1397.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 1-benzylthio-pyrrole Lin-2,5-dione (40 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitromethane (1.5 mL), Stirred at 60°C for 1 hour, after the reaction was completed, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.4) to obtain yellow liquid 3i (40.1 mg, yield: 54%) ); 1 HNMR (CDCl 3 , 400MHz): δ 7.46-7.36(m, 9H), 7.24(d, J=3.6Hz, 1H), 7.19-7.15(m, 3H), 7.08(d, J=8.4 Hz, 2H), 7.03-6.99(m, 4H), 6.18(s, 1H), 3.75(s, 2H), 2.3(s, 3H); 13 C NMR (CDCl 3 , 100MHz): δ 144.5, 139.7, 139.1 ,137.3,134.9,132.8,131.3,131.3,129.7,129.0,128.8,128.3,128.2,128.2,127.5,127.1,127.0,120.9,119.8,39.6,21.6.HRMS(ESI)m/z calcd.for C 30 H 25 NO 2 S 2 [M+H] + :496.1399,found:496.1397.
实施例10Example 10
化合物3j的合成Synthesis of compound 3j
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，3-(2,5-二氧代吡咯烷-1-基)硫基丙酸乙酯(42mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌2小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝6:1,Rf＝0.4)分离得黄色液体3j(53.8mg,yield:71％)；1H NMR(CDCl3,400MHz):δ7.53-7.51(m,2H),7.44-7.40(m,8H),7.26(q,J＝8.4Hz,4H),6.32(s,1H),4.04(q,J＝7.2Hz,2H),2.82(t,7.2Hz,2H),2.36-2.33(m,5H),1.19(t,J＝6.8Hz,3H)；13C NMR(CDCl3,100MHz):δ171.4,144.6,140.3,134.6,132.6,131.3,131.3,129.7,128.9,128.2,127.6,127.2,127.0,120.6,119.0,60.6,34.4,29.4,21.6,14.1.HRMS(ESI)m/z calcd.for C28H27NO4S2[M+H]+:506.1454,found:504.1452.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), 3-(2,5- Ethyl dioxopyrrolidin-1-yl)thiopropionate (42 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), Nitromethane (1.5 mL) was stirred at 60°C for 2 hours. After the reaction was completed, it was dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=6:1, R f =0.4) to obtain a yellow liquid 3j (53.8 mg, yield: 71%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.53-7.51 (m, 2H), 7.44-7.40 (m, 8H), 7.26 (q, J=8.4 Hz, 4H) ), 6.32(s, 1H), 4.04(q, J=7.2Hz, 2H), 2.82(t, 7.2Hz, 2H), 2.36-2.33(m, 5H), 1.19(t, J=6.8Hz, 3H) The _ 14.1.HRMS(ESI)m/z calcd.for C 28 H 27 NO 4 S 2 [M+H] + :506.1454,found:504.1452.
实施例11Example 11
化合物3k的合成
在10mL反应瓶中，加入N-(1,4-二苯基-丁-3-炔-1-基)-4-甲基苯磺酰胺(56mg,0.15mmol)，N-(叔丁氧羰基)-S-(2,5-二氧代吡咯烷-1-基)-L-半胱氨酸甲酯(60mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),硝基甲烷(1.5mL)，60℃条件下搅拌2小时，反应完毕后，干燥，过滤，浓缩，经经柱层析(PE:EtOAc＝6:1,Rf＝0.35)分离得黄色液体3k(21.8mg,yield:24％)；1H NMR(CDCl3,400MHz):δ7.48-7.38(m,10H),7.07(d,J＝8.4Hz,2H),7.01(d,J＝8.4Hz,2H),6.30(s,1H),4.95(d,J＝8.0Hz,1H),4.39-4.32(m,1H),3.51(s,3H),3.05(dd,J＝14.0,4.8Hz,1H),2.95(dd,J＝10.0,4.8Hz,1H),2.36(s,3H),1.39(s,9H)；13C NMR(CDCl3,100MHz):δ170.7,144.8,140.1,139.3,134.9,132.6,131.4,131.2,129.8,129.1,128.5,128.3,127.6,127.3,127.1,119.6,119.3,80.1,53.1,52.4,36.9,28.3,21.6.HRMS(ESI)m/z calcd.for C32H34N2O6S2[M+H]+:607.1931,found:607.1930.In a 10 mL reaction flask, add N-(1,4-diphenyl-but-3-yn-1-yl)-4-methylbenzenesulfonamide (56 mg, 0.15 mmol), N-(tert-butoxycarbonyl) )-S-(2,5-dioxopyrrolidin-1-yl)-L-cysteine methyl ester (60 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), nitromethane (1.5 mL), stirred at 60°C for 2 hours, after completion of the reaction, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=6:1, R f =0.35) to obtain a yellow liquid 3k (21.8 mg , yield: 24%); 1 H NMR (CDCl 3 , 400MHz): δ 7.48-7.38 (m, 10H), 7.07 (d, J=8.4Hz, 2H), 7.01 (d, J=8.4Hz, 2H) ),6.30(s,1H),4.95(d,J＝8.0Hz,1H),4.39-4.32(m,1H),3.51(s,3H),3.05(dd,J＝14.0,4.8Hz,1H) , 2.95(dd, J=10.0, 4.8Hz, 1H), 2.36(s, 3H), 1.39(s, 9H); 13 C NMR (CDCl 3 , 100MHz): δ 170.7, 144.8, 140.1, 139.3, 134.9, 132.6 ,131.4,131.2,129.8,129.1,128.5,128.3,127.6,127.3,127.1,119.6,119.3,80.1,53.1,52.4,36.9,28.3,21.6.HRMS(ESI)m/z calcd.for C 32 H 34 N 2 O 6 S 2 [M+H] + :607.1931,found:607.1930.
实施例12Example 12
化合物3l的合成Synthesis of compound 3l
在10mL反应瓶中，加入N-[(4-苯甲氧基)-1-苯基-丁-3-炔-1-基]-4-甲基苯磺酰胺(61mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌3小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.20)分离得黄色固体3l(56.7mg,yield:74％)；1H NMR(CDCl3,400MHz):δ7.54(dd,J＝8.0,2.0Hz,2H),7.44-7.39(m,3H),7.32(dt,J＝9.6,2.8Hz,2H),7.16-7.11(m,7H),6.94-6.89(m,4H),6.24(s,1H),3.87(s,3H),2.42(s,3H)；13C NMR(CDCl3,100MHz):δ159.9,144.7,141.7,140.6,137.2,134.7,133.0,129.5,129.1,128.8,128.2,127.7,127.6,127.2,125.7,123.3,121.6,118.4,112.9,55.3,21.7.HRMS(ESI)m/z calcd.for C30H25NO3S2[M+H]+:512.1349,found:512.1344.In a 10 mL reaction flask, add N-[(4-benzyloxy)-1-phenyl-but-3-yn-1-yl]-4-methylbenzenesulfonamide (61 mg, 0.15 mmol), 1 - Phenylthio-pyrroline-2,5-dione (37 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitro Methane (1.5 mL), stirred at 60°C for 3 hours, after the reaction was completed, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.20) to obtain a yellow solid 3l (56.7 mg) , yield: 74%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.54 (dd, J=8.0, 2.0 Hz, 2H), 7.44-7.39 (m, 3H), 7.32 (dt, J=9.6, 2.8Hz, 2H), 7.16-7.11(m, 7H), 6.94-6.89(m, 4H), 6.24(s, 1H), 3.87(s, 3H), 2.42(s, 3H); 13 C NMR (CDCl 3,100MHz ):δ159.9,144.7,141.7,140.6,137.2,134.7,133.0,129.5,129.1,128.8,128.2,127.7,127.6,127.2,125.7,123.3,121.6,118.4,112.9,5 )m/z calcd.for C 30 H 25 NO 3 S 2 [M+H] + :512.1349,found:512.1344.
实施例13Example 13
化合物3m的合成Synthesis of compound 3m
在10mL反应瓶中，加入N-[(4-氯)-1-苯基-丁-3-炔-1-基]-4-甲基苯磺酰胺(61mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌4小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.30)分离得黄色固体3m(51.8mg,yield:67％)；1H NMR(CDCl3,400MHz):δ7.53-7.50(m,2H),7.44-7.39(m,4H),7.37-7.33(m,4H),7.16-7.09(m,7H),6.93-6.91(m,2H),6.22(s,1H),2.42(s,3H)；13CNMR(CDCl3,100MHz):δ145.0,141.3,139.9,136.6,136.5,134.7,134.5,132.5,132.3,129.6,129.2,128.9,128.5,128.0,127.7,127.6,127.1,126.1,121.3,120.1,21.7.HRMS(ESI)m/z calcd.for C29H22ClNO2S2[M+H]+:516.0853,found:516.0862.In a 10 mL reaction flask, add N-[(4-chloro)-1-phenyl-but-3-yn-1-yl]-4-methylbenzenesulfonamide (61 mg, 0.15 mmol), 1-phenylthio yl-pyrroline-2,5-dione (37 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitromethane (1.5 mL), stirred at 60 °C for 4 hours, after completion of the reaction, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.30) to obtain a yellow solid 3m (51.8 mg, yield: 67%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.53-7.50 (m, 2H), 7.44-7.39 (m, 4H), 7.37-7.33 (m, 4H), 7.16-7.09 (m, 7H) ), 6.93-6.91 (m, 2H), 6.22 (s, 1H), 2.42 (s, 3H); 13 CNMR (CDCl 3 , 100MHz): δ145.0, 141.3, 139.9, 136.6, 136.5, 134.7, 134.5, 132.5, 132.3,129.6,129.2,128.9,128.5,128.0,127.7,127.6,127.1,126.1,121.3,120.1,21.7.HRMS(ESI)m/z calcd.for C 29 H 22 ClNO 2 S 2 [M+H] + :516.0853,found:516.0862.
实施例14Example 14
化合物3n的合成Synthesis of Compound 3n
在10mL反应瓶中，加入N-[(4-氰基)-1-苯基-丁-3-炔-1-基]-4-甲基苯磺酰胺(60mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌6小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝4:1,Rf＝0.40)分离得白色固体3n(57.7mg,yield:76％)；1H NMR(CDCl3,400MHz):δ7.71(dt,J＝8.0,1.6Hz,2H),7.57(dt,J＝8.4,2.0Hz,2H),7.49-7.47(m,2H),7.43-7.39(m,3H),7.19-7.14(m,5H),7.06(dt,J＝8.4,2.0Hz,2H),6.97-6.94(m,2H),6.19(s,1H),2.43(s,3H)；13C NMR(CDCl3,100MHz):δ145.3,142.3,138.3,135.9,135.6,134.2,131.9,131.4,131.1,129.8,129.3,129.1,128.8,128.6,127.8,127.1,126.6,122.3,121.1,118.9,111.7,21.7.HRMS(ESI)m/zcalcd.for C30H22N2O2S2[M+H]+:507.1195,found:507.1195.In a 10 mL reaction flask, add N-[(4-cyano)-1-phenyl-but-3-yn-1-yl]-4-methylbenzenesulfonamide (60 mg, 0.15 mmol), 1-benzene Thio-pyrroline-2,5-dione (37 mg, 0.18 mmol), aluminum trichloride (8.0 mg, 0.06 mmol), 35.5% concentrated hydrochloric acid (15.4 mg, 0.15 mmol), nitromethane ( 1.5 mL), stirred at 60 °C for 6 hours, after completion of the reaction, dried, filtered, concentrated, separated by column chromatography (PE:EtOAc=4:1, R f =0.40) to obtain a white solid 3n (57.7 mg, yield : 76%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.71 (dt, J=8.0, 1.6 Hz, 2H), 7.57 (dt, J=8.4, 2.0 Hz, 2H), 7.49-7.47 (m ,2H),7.43-7.39(m,3H),7.19-7.14(m,5H),7.06(dt,J=8.4,2.0Hz,2H),6.97-6.94(m,2H),6.19(s,1H The _ ,126.6,122.3,121.1,118.9,111.7,21.7.HRMS(ESI)m/ zcalcd.for C30H22N2O2S2 [M + H] + : 507.1195 ,found: 507.1195 .
实施例15Example 15
化合物3o的合成Synthesis of Compound 3o
在10mL反应瓶中，加入4-甲基-N-(1-苯辛-1-炔-4-基)苯磺酰胺(53mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌1小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.40)分离得黄色液体3o(29.1mg,yield:42％)；1H NMR(CDCl3,400MHz):δ7.35-7.27(m,5H),7.19-7.14(m,6H),7.09(tt,J＝7.2,1.2Hz,1H),6.97-6.95(m,2H),2.96(t,J＝7.2Hz,2H),2.41(s,3H),1.73-1.65(m,2H),1.48-1.38(m,2H),0.96(t,J＝7.2Hz,3H)；13C NMR(CDCl3,100MHz):δ144.7,139.9,139.5,137.8,136.3,131.6,130.9,129.5,128.7,128.4,127.2,127.1,126.7,125.4,116.7,116.6,31.4,29.2,22.5,21.7,14.0.HRMS(ESI)m/z calcd.for C27H27NO2S2[M+H]+:462.1556,found:462.1561.In a 10 mL reaction flask, add 4-methyl-N-(1-phenoct-1-yn-4-yl)benzenesulfonamide (53 mg, 0.15 mmol), 1-phenylthio-pyrroline-2,5 -diketone (37mg, 0.18mmol), aluminum trichloride (8.0mg, 0.06mmol), 35.5% concentrated hydrochloric acid (15.4mg, 0.15mmol), nitromethane (1.5mL), stirring at 60°C After 1 hour, the reaction was completed, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.40) to obtain a yellow liquid 3o (29.1 mg, yield: 42%); 1 H NMR ( CDCl 3 , 400MHz): δ7.35-7.27(m, 5H), 7.19-7.14(m, 6H), 7.09(tt, J=7.2, 1.2Hz, 1H), 6.97-6.95(m, 2H), 2.96 (t,J=7.2Hz,2H),2.41(s,3H),1.73-1.65(m,2H), 1.48-1.38 (m,2H),0.96(t,J=7.2Hz,3H); NMR (CDCl 3 , 100MHz): δ144.7, 139.9, 139.5, 137.8, 136.3, 131.6, 130.9, 129.5, 128.7, 128.4, 127.2, 127.1, 126.7, 125.4, 116.7, 116.6, 31.4, 2, 14.7, 22.5 HRMS(ESI)m/z calcd.for C 27 H 27 NO 2 S 2 [M+H] + :462.1556,found:462.1561.
实施例16Example 16
化合物3p的合成Synthesis of compound 3p
在10mL反应瓶中，加入4-甲基-N-[(2-苯基乙炔基)环己基]苯磺酰胺(53mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌6小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.35)分离得黄色液体3p(36.5mg,yield:53％)；1H NMR(CDCl3,400MHz):δ7.35-7.26(m,5H),7.21-7.11(m,6H),7.05(tt,J＝7.2,1.2Hz,1H),6.86-6.84(m,2H),3.01(t,J＝6.0Hz,2H),2.42(s,3H),2.20(t,J＝6.0Hz,2H),1.84-1.78(m,2H),1.68-1.62(m,2H)；13C NMR(CDCl3,100MHz):δ144.6,139.7,137.9,136.2,132.9,131.7,130.7,129.5,128.7,128.5,127.0,126.8,126.5,126.0,124.9,116.2,25.4,23.5,22.3,22.0,21.7.HRMS(ESI)m/z calcd.for C27H25NO2S2[M+H]+:460.1399,found:460.1398.In a 10 mL reaction flask, add 4-methyl-N-[(2-phenylethynyl)cyclohexyl]benzenesulfonamide (53 mg, 0.15 mmol), 1-phenylthio-pyrroline-2,5-di Ketone (37mg, 0.18mmol), aluminum trichloride (8.0mg, 0.06mmol), 35.5% concentrated hydrochloric acid (15.4mg, 0.15mmol), nitromethane (1.5mL), stirred at 60°C for 6 hours , after the reaction was completed, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.35) to obtain a yellow liquid 3p (36.5 mg, yield: 53%); 1 H NMR (CDCl 3 ,400MHz):δ7.35-7.26(m,5H),7.21-7.11(m,6H),7.05(tt,J=7.2,1.2Hz,1H),6.86-6.84(m,2H),3.01(t , J=6.0Hz, 2H), 2.42(s, 3H), 2.20(t, J=6.0Hz, 2H), 1.84-1.78(m, 2H), 1.68-1.62(m, 2H); 13 C NMR( CDCl 3 , 100MHz): δ144.6,139.7,137.9,136.2,132.9,131.7,130.7,129.5,128.7,128.5,127.0,126.8,126.5,126.0,124.9,116.2,25.4,23.5.7.0HRMS( ESI)m/z calcd.for C 27 H 25 NO 2 S 2 [M+H] + :460.1399,found:460.1398.
实施例17Example 17
化合物3q的合成Synthesis of compound 3q
在10mL反应瓶中，加入4-甲基-N-(4-苯丁-3-炔-1-基)苯磺酰胺(45mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌1小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.35)分离得灰色液体3q(46.8mg,yield:77％)；1H NMR(CDCl3,400MHz):δ7.54(d,J＝7.2Hz,1H),7.37(tt,J＝7.2,1.2Hz,1H),7.28(d,J＝7.8Hz，2H),7.23(d,J＝8.8Hz,2H),7.18-7.06(m,7H),7.00-6.98(m,2H),6.36(d,J＝3.2Hz,1H),2.39(s,3H)；13C NMR(CDCl3,100MHz):δ145.1,137.7,137.7,135.2,131.9,129.5,129.1,128.9,128.8,127.4,127.3,127.3,125.5,123.5,117.1,116.4,21.7.HRMS(ESI)m/z calcd.for C23H19NO2S2[M+H]+:406.0930,found:406.0931.In a 10 mL reaction flask, add 4-methyl-N-(4-phenbut-3-yn-1-yl)benzenesulfonamide (45 mg, 0.15 mmol), 1-phenylthio-pyrroline-2,5 -diketone (37mg, 0.18mmol), aluminum trichloride (8.0mg, 0.06mmol), 35.5% concentrated hydrochloric acid (15.4mg, 0.15mmol), nitromethane (1.5mL), stirring at 60°C After 1 hour, the reaction was completed, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.35) to obtain gray liquid 3q (46.8 mg, yield: 77%); 1 H NMR ( CDCl 3 , 400MHz): δ7.54(d, J=7.2Hz, 1H), 7.37(tt, J=7.2, 1.2Hz, 1H), 7.28(d, J=7.8Hz, 2H), 7.23(d, J=8.8Hz, 2H), 7.18-7.06 (m, 7H), 7.00-6.98 (m, 2H), 6.36 (d, J=3.2Hz, 1H), 2.39 (s, 3H); 13 C NMR (CDCl 3,100MHz ):δ145.1,137.7,137.7,135.2,131.9,129.5,129.1,128.9,128.8,127.4,127.3,127.3,125.5,123.5,117.1,116.4,21.7.HRMS(ESI)m/z calcd.for CRMS(ESI)m/z 23 H 19 NO 2 S 2 [M+H] + : 406.0930, found: 406.0931.
实施例18Example 18
化合物3r的合成Synthesis of compound 3r
在10mL反应瓶中，加入N-[4-(4-氟苯基)-丁-3-炔-1-基]-4-甲基苯磺酰胺(48mg,0.15mmol)，1-苯硫基-吡咯啉-2,5-二酮(37mg,0.18mmol)，三氯化铝(8.0mg,0.06mmol),浓度为35.5％的浓盐酸(15.4mg,0.15mmol)，硝基甲烷(1.5mL)，60℃条件下搅拌2小时，反应完毕后，干燥，过滤，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.35)分离得灰色液体3r(45.7mg,yield:72％)；1H NMR(CDCl3,400MHz):δ7.54(d,3.2Hz,1H),7.25-2.23(m,2H),7.18-7.14(m,4H),7.09(tt,J＝7.6,1.2Hz,1H),7.06(m,2H),6.98-6.94(m,4H),6.37(d,J＝3.6Hz,1H),2.40(s,3H)；13C NMR(CDCl3,100MHz):δ163.1(J＝248.0Hz),145.3,137.4,136.5,135.2,133.8(J＝8.0Hz),129.6,128.8,127.3(J＝8.0Hz),125.6,125.0(J＝4Hz),123.,117.5,116.4,114.4(J＝22.0Hz),21.7；19F NMR(CDCl3,376.3MHz):δ-112.00.HRMS(ESI)m/z calcd.for C23H18FNO2S2[M+H]+:424.0836,found:424.0842。In a 10 mL reaction flask, add N-[4-(4-fluorophenyl)-but-3-yn-1-yl]-4-methylbenzenesulfonamide (48 mg, 0.15 mmol), 1-phenylthio -pyrroline-2,5-dione (37mg, 0.18mmol), aluminum trichloride (8.0mg, 0.06mmol), 35.5% concentrated hydrochloric acid (15.4mg, 0.15mmol), nitromethane (1.5mL ), stirred at 60°C for 2 hours, after completion of the reaction, dried, filtered, concentrated, and separated by column chromatography (PE:EtOAc=19:1, R f =0.35) to obtain a gray liquid 3r (45.7 mg, yield: 72 %); 1 H NMR (CDCl 3 , 400 MHz): δ 7.54 (d, 3.2 Hz, 1H), 7.25-2.23 (m, 2H), 7.18-7.14 (m, 4H), 7.09 (tt, J=7.6 , 1.2Hz, 1H), 7.06 (m, 2H), 6.98-6.94 (m, 4H), 6.37 (d, J=3.6Hz, 1H), 2.40 (s, 3H); 13 C NMR (CDCl 3 , 100MHz ): δ163.1(J=248.0Hz), 145.3, 137.4, 136.5, 135.2, 133.8(J=8.0Hz), 129.6, 128.8, 127.3(J=8.0Hz), 125.6, 125.0(J=4Hz), 123 ., 117.5, 116.4, 114.4 (J=22.0 Hz), 21.7; 19 F NMR (CDCl 3 , 376.3 MHz): δ-112.00. HRMS (ESI) m/z calcd. for C 23 H 18 FNO 2 S 2 [ M+H] + :424.0836,found:424.0842.
实施例19Example 19
化合物6的合成Synthesis of compound 6
在10mL反应瓶中，加入2-(4-氟苯基)-3-(苯硫基)-1-甲苯磺酰基-1H-吡咯(3r,64mg,0.15mmol)，10％的NaOH水溶液(0.6mL)，四氢呋喃(1.5ml)，甲醇(0.5ml)，65℃条件下搅拌6小时，反应完毕后，用二氯甲烷(每次30mL，共90mL)萃取，15mL饱和氯化铵水溶液洗涤，分离有机层，干燥，浓缩，经柱层析(PE:EtOAc＝19:1,Rf＝0.3)分离得黄色液体2-(4-氟苯基)-3-(苯硫基)-1H-吡咯4(37.9mg,yield:94％)；1H NMR(CDCl3,400MHz):δ8.52(s,1H),7.55-7.52(m,2H),7.23-7.19(m,2H),7.13-7.03(m,5H),6.92(t,J＝2.8Hz,1H),6.41(t,J＝2.8Hz,1H)；13C NMR(CDCl3,100MHz):δ162.2(J＝245.0Hz),140.2,134.8,128.8(J＝7.0Hz),127.9(J＝3.0Hz),125.6,124.6,118.6,117.2,115.7(J＝21.0Hz),105.9；19F NMR(CDCl3,376.3MHz):δ-114.19.HRMS(ESI)m/z calcd.for C16H12FNS[M]+:269.0669,found:269.0676.In a 10 mL reaction flask, add 2-(4-fluorophenyl)-3-(phenylthio)-1-toluenesulfonyl-1H-pyrrole (3r, 64 mg, 0.15 mmol), 10% NaOH aqueous solution (0.6 mL), tetrahydrofuran (1.5 mL), methanol (0.5 mL), stirred at 65°C for 6 hours, after the reaction was completed, extracted with dichloromethane (30 mL each, 90 mL in total), washed with 15 mL of saturated aqueous ammonium chloride solution, separated The organic layer was dried, concentrated, and separated by column chromatography (PE:EtOAc=19:1, Rf =0.3) to give 2-(4-fluorophenyl)-3-(phenylthio)-1H-pyrrole as a yellow liquid 4 (37.9 mg, yield: 94%); 1 H NMR (CDCl 3 , 400 MHz): δ 8.52 (s, 1H), 7.55-7.52 (m, 2H), 7.23-7.19 (m, 2H), 7.13- 7.03 (m, 5H), 6.92 (t, J=2.8Hz, 1H), 6.41 (t, J=2.8Hz, 1H); 13 C NMR (CDCl 3 , 100MHz): δ 162.2 (J=245.0Hz) , 140.2, 134.8, 128.8 (J=7.0 Hz), 127.9 (J=3.0 Hz), 125.6, 124.6, 118.6, 117.2, 115.7 (J=21.0 Hz), 105.9; 19 F NMR (CDCl 3 , 376.3 MHz): δ-114.19.HRMS(ESI)m/z calcd.for C 16 H 12 FNS[M] + :269.0669,found:269.0676.
在10mL反应瓶中，加入4-溴苯甲醛(28mg,0.15mmol)，2-(4-氟苯基)-3-(苯硫基)-1H-吡咯4(81mg,0.3mmol)，二氯甲烷(1.6mL)，室温条件下加入三氟乙酸(6.8mg,0.06mmol)，搅拌3小时，反应完毕后，干燥，浓缩得到粗产品；将粗产品溶解在二氯甲烷(3mL),接着向反应体系中滴加2,3-二氯-5,6-二氰对苯醌(37.4mg,0.165mmol)，在室温条件下搅拌1小时，干燥，浓缩，经柱层析(PE:CH2Cl2＝4:1,Rf＝0.4)分离得红色固体5(70.6mg,yield:67％)；1H NMR(CDCl3,400MHz):δ13.77(s,1H),8.02-7.98(m,4H),7.58(dt,J＝8.4,2.4Hz,2H),7.39(dt,J＝8.4,2.4Hz,2H),7.23-7.19(m,4H),7.17-7.08(m,10H),6.08(s,2H)；13C NMR(CDCl3,100MHz):163.4(J＝250.0Hz),154.0,139.9,137.4,135.6,132.3,131.3,129.80(J＝8.0Hz),129.1,128.7(J＝3.0Hz),127.2,125.9,124.0,119.7,115.8(J＝22.0Hz)；19F NMR(CDCl3,376.3MHz):δ-110.66.HRMS(ESI)m/z calcd.forC16H12FNS[M+H]+:705.0665,703.0683,found:705.0690,703.0675.In a 10 mL reaction flask, add 4-bromobenzaldehyde (28 mg, 0.15 mmol), 2-(4-fluorophenyl)-3-(phenylthio)-1H-pyrrole 4 (81 mg, 0.3 mmol), dichloromethane Methane (1.6 mL), trifluoroacetic acid (6.8 mg, 0.06 mmol) was added at room temperature, stirred for 3 hours, after the reaction was completed, dried and concentrated to obtain a crude product; the crude product was dissolved in dichloromethane (3 mL), and then added to 2,3-Dichloro-5,6-dicyano-p-benzoquinone (37.4 mg, 0.165 mmol) was added dropwise to the reaction system, stirred at room temperature for 1 hour, dried, concentrated, and subjected to column chromatography (PE:CH 2 ) . Cl 2 =4:1, R f =0.4) was isolated as a red solid 5 (70.6 mg, yield: 67%); 1 H NMR (CDCl 3 , 400 MHz): δ 13.77 (s, 1H), 8.02-7.98 ( m, 4H), 7.58 (dt, J=8.4, 2.4Hz, 2H), 7.39 (dt, J=8.4, 2.4Hz, 2H), 7.23-7.19 (m, 4H), 7.17-7.08 (m, 10H) , 6.08 (s, 2H); 13 C NMR (CDCl 3 , 100 MHz): 163.4 (J=250.0 Hz), 154.0, 139.9, 137.4, 135.6, 132.3, 131.3, 129.80 (J=8.0 Hz), 129.1, 128.7 ( J=3.0 Hz), 127.2, 125.9, 124.0, 119.7, 115.8 (J=22.0 Hz); 19 F NMR (CDCl 3 , 376.3 MHz): δ-110.66. HRMS (ESI) m/z calcd. for C 16 H 12 FNS[M+H] + :705.0665,703.0683,found:705.0690,703.0675.
在10mL反应瓶中，加入化合物5(106mg,0.15mmol)，甲苯(3mL)，在氮气条件下，加入三氟化硼乙醚(639mg,4.5mmol)，滴加三乙胺(228mg,2.25mmol)，滴加完毕后，整个反应体系在氮气条件下搅拌1小时，接着加热至85℃条件下再搅拌3小时，反应结束后，冷却，用二氯甲烷(每次30mL，共90mL)萃取，分别用15mL饱和碳酸氢钠水溶液、10mL水溶液、10mL饱和氯化钠水溶液洗涤，分离有机层，浓缩，经柱层析(PE:CH2Cl2＝2:1,Rf＝0.3)分离得深蓝色固体6(68.6mg,yield:61％)；1H NMR(CDCl3,400MHz):δ7.67(dt,J＝8.4,1.6Hz,2H),7.52-7.19(m,4H),7.45(dt,J＝8.4,1.6Hz,2H),7.21-7.17(m,4H),7.13(tt,J＝6.8,1.2Hz,2H),7.7(dt,J＝6.8,1.2Hz,4H),7.04-6.99(m,6H)；13C NMR(CDCl3,100MHz):δ163.5(J＝249.0Hz),159.8,142.4,136.3,135.2,134.2,132.3,132.1,132.0(J＝8.0Hz),129.1,128.4,126.5,126.1(J＝3.0Hz),125.7,115.0(J＝21.0Hz)；19F NMR(CDCl3,376.3MHz):δ-110.35,-130.02(q,J＝30.0Hz)；11B NMR(CDCl3,128MHz):δ0.69(t,J＝35.8Hz).HRMS(ESI)m/z calcd.for C39H24BBrF4N2S2[M+H]+:752.057,750.059,found:752.061,750.059。In a 10 mL reaction flask, compound 5 (106 mg, 0.15 mmol) and toluene (3 mL) were added, under nitrogen, boron trifluoride ether (639 mg, 4.5 mmol) was added, and triethylamine (228 mg, 2.25 mmol) was added dropwise. , after the dropwise addition, the entire reaction system was stirred for 1 hour under nitrogen, then heated to 85°C and stirred for 3 hours. After the reaction was completed, it was cooled and extracted with dichloromethane (30 mL each, 90 mL in total), respectively. Washed with 15 mL of saturated aqueous sodium bicarbonate solution, 10 mL of aqueous solution, and 10 mL of saturated aqueous sodium chloride solution, separated the organic layer, concentrated, and separated by column chromatography (PE:CH 2 Cl 2 =2:1, R f =0.3) to obtain dark blue Solid 6 (68.6 mg, yield: 61%); 1 H NMR (CDCl 3 , 400 MHz): δ 7.67 (dt, J=8.4, 1.6 Hz, 2H), 7.52-7.19 (m, 4H), 7.45 (dt ,J=8.4,1.6Hz,2H),7.21-7.17(m,4H),7.13(tt,J=6.8,1.2Hz,2H),7.7(dt,J=6.8,1.2Hz,4H),7.04- 6.99 (m, 6H); 13 C NMR (CDCl 3 , 100 MHz): δ 163.5 (J=249.0 Hz), 159.8, 142.4, 136.3, 135.2, 134.2, 132.3, 132.1, 132.0 (J=8.0 Hz), 129.1 , 128.4, 126.5, 126.1 (J=3.0 Hz), 125.7, 115.0 (J=21.0 Hz); 19 F NMR (CDCl 3 , 376.3 MHz): δ-110.35, -130.02 (q, J=30.0 Hz); 11 B NMR (CDCl 3 , 128 MHz): δ 0.69 (t, J=35.8 Hz). HRMS (ESI) m/z calcd. for C 39 H 24 BBrF 4 N 2 S 2 [M+H] + : 752.057, 750.059, found: 752.061, 750.059.
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