CN113214224A - 多取代3-亚甲基异吲哚啉酮衍生物的制备方法 - Google Patents
多取代3-亚甲基异吲哚啉酮衍生物的制备方法 Download PDFInfo
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- WOASUPWBFMXCNJ-UHFFFAOYSA-N 3-methylideneisoindol-1-one Chemical class C1=CC=C2C(=C)NC(=O)C2=C1 WOASUPWBFMXCNJ-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 46
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 150000001879 copper Chemical class 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- -1 ketone acetate monohydrate Chemical class 0.000 claims description 67
- 150000001875 compounds Chemical class 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 10
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 6
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 229910052805 deuterium Inorganic materials 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- JIDMEYQIXXJQCC-UHFFFAOYSA-L copper;2,2,2-trifluoroacetate Chemical compound [Cu+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F JIDMEYQIXXJQCC-UHFFFAOYSA-L 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 150000007529 inorganic bases Chemical group 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical group 0.000 claims description 2
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 claims description 2
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical group [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 abstract description 34
- 239000010949 copper Substances 0.000 abstract description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052802 copper Inorganic materials 0.000 abstract description 4
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004076 pyridyl group Chemical group 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 150000003936 benzamides Chemical class 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 164
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 42
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 32
- 229940067157 phenylhydrazine Drugs 0.000 description 32
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 238000004896 high resolution mass spectrometry Methods 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 238000004293 19F NMR spectroscopy Methods 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229910014263 BrF3 Inorganic materials 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UWBIZWFBXWARES-CYVLTUHYSA-N C(/C1=CC=CC=C1)=C\1/N(C(C2=CC=CC=C/12)=O)N(C1=NC=CC=C1)C Chemical compound C(/C1=CC=CC=C1)=C\1/N(C(C2=CC=CC=C/12)=O)N(C1=NC=CC=C1)C UWBIZWFBXWARES-CYVLTUHYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- UIYKQBXRFZCXFX-UHFFFAOYSA-N 2-pyrazol-1-ylaniline Chemical compound NC1=CC=CC=C1N1N=CC=C1 UIYKQBXRFZCXFX-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KDDVVMDIQCUZDI-UHFFFAOYSA-N 4-amino-5-chloro-n-[1-[3-(oxolan-2-yl)propyl]piperidin-4-yl]-2-propoxybenzamide Chemical compound CCCOC1=CC(N)=C(Cl)C=C1C(=O)NC1CCN(CCCC2OCCC2)CC1 KDDVVMDIQCUZDI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 125000002751 aliphatic alkane group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明提供了多取代3‑亚甲基异吲哚啉酮衍生物的制备方法，包含以下内容：将苯甲酰胺衍生物与炔、铜盐、碱、溶剂混合，在有氧气存在下加热反应。该方法是一种廉价金属铜促进的、可脱除导向基团2‑(1‑甲基肼)吡啶基导向的，高效、安全、绿色地合成3‑亚甲基异吲哚啉酮衍生物的反应。
Description
技术领域
本发明涉及一种化合物的合成方法。
背景技术
多取代3-亚甲基异吲哚啉酮基本骨架广泛存在于具有重要生物活性的天然产物中，在材料科学及有机合成化学配体等领域有广泛应用。目前其传统合成途径主要涉及Sonogashira偶联等方法。
近年来，鉴于其优良的原子经济性及步数经济性，过渡金属催化或促进的C-H/N-H官能团化反应常用于各类杂环的合成。如8-氨基喹啉、2-(1氢-吡唑-1-基)苯胺、2-胺基氮氧吡啶等均可用作二啮导向基团来实现铜促进或催化地C-H/N-H官能团化反应，来完成3-亚甲基异吲哚啉酮的快速合成。然而此类导向基团在完成反应后难以脱除，极大的限制了此类反应的具体应用。2-(1-甲基肼)吡啶基(MHP)导向基团自2018年被报道以来，被广泛应用于钴催化碳氢键官能团化反应中，其在铜催化或介导的碳氢键官能团化反应中尚未见报道。应用2-(1-甲基肼)吡啶基作为导向基团的一大优点是，由于其结构中存在一个较活泼的N-N键，此类导向基团可以在较温和条件下脱除。
发明内容
为了解决上述问题，本发明拟提供一种廉价金属铜促进的、可脱除导向基团2-(1-甲基肼)吡啶基导向的，高效、安全、绿色地合成3-亚甲基异吲哚啉酮衍生物的反应。
具体地，本发明提供了如式3所示多取代3-亚甲基异吲哚啉酮衍生物的制备方法，包含以下内容：将式1化合物、式2化合物、铜盐、碱、溶剂混合，在有氧气存在下加热反应：
所述溶剂选自DMSO。
其中，所述溶剂的用量为每毫摩尔式1化合物使用溶剂1～30mL，进一步选自10～20mL。
其中，所述铜盐选自醋酸铜、醋酸铜水合物、醋酸亚铜及其水合物、硫酸铜、三氟醋酸铜及其水合物、硫酸酮中的一种或两种以上的组合物。进一步选自醋酸铜、三氟醋酸铜、硫酸酮及其水合物中的一种或两种以上的组合物；优选醋酸铜或一水醋酸酮。
其中，所述铜盐的用量为，每毫摩尔式1化合物使用酮盐0.5～5.0当量，优选1.3当量。
其中，所述碱选自无机碱和/或有机碱；进一步地，所述碱选自无机碱；所述碱选自碳酸盐、醋酸盐、磷酸盐、有机碱中的一种或几种；
进一步地，所述碱选自碳酸盐；
进一步地，所述碱选自Li2CO3、Na2CO3、K2CO3、Ru2CO3、Cs2CO3或它们的水合物中的一种或几种，优选Na2CO3、K2CO3、Cs2CO3和/或其水合物；
其中，所述式1化合物：碱的摩尔比为1：0.1～10.0，优选1：0.5～3，更优选为1：2。
其中，反应温度，大于室温，在190℃以下；进一步选自60～120℃，更优选90℃。
其中，所述反应在空气或氧气氛围下进行。
其中，R1、R2每次出现时分别独立地选自H、卤素、腈基、羟基、巯基、氨基、氰基、酰基、酯基、酰胺基、非取代或取代的烷基、非取代或取代的杂烷基、非取代或取代的环烷基、非取代或取代的杂环烷基、非取代或取代的芳基、非取代或取代的杂芳基，或两个相邻的R1共同组成非取代或取代的烷基环、非取代或取代的杂环烷基、非取代或取代的芳环、非取代或取代的杂芳环，其中，取代基选自氘、卤素、硝基、羟基、巯基、氨基、氰基、酰胺基、酰基、磺酰基、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基。
本发明还提供了一种化合物，具有式3所示结构或其立体异构体或顺反异构体、溶剂化物、水合物或药学上可接受的盐或共晶：
其中，R1，R2如权利要求1所定义；
进一步地，选自如下化合物之一：
“烷基”，是指脂肪族烷烃基团，是饱和烃基。其中，烷基可以是直链烷基或支链烷基。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等等。
“酰胺”是具有式-C(O)NHR或-NHC(O)R的化学结构，其中R选自烷基、环烷基、芳基。
“酰基”是具有式-C(O)R的化学结构，其中R选自烷基、环烷基、芳基。
“磺酰基”是指具有式-SO2R的化学结构，其中R选自烷基、非取代或取代的芳基。
“环”是指任意的共价封闭结构，其中包括如下结构：碳环(如环烷基或芳基)、杂环(如杂环烷基或杂芳基)。环可以是单环、多环或任意取代的环。典型的多环一般有二环、三环。
“杂烷基”是指含有杂原子的烷基，其中，杂原子包括但不限于N、O、S、P等；氨烷基、硫烷基、烷氧基等都属于杂烷基。
“杂原子”是指除了碳或氢以外的其它原子。杂原子可独立地选自于N、O、S、P或Si，但不限于此。
“芳香基”是指平面环具有离域的π电子系统且含有4n+2个π电子，n为整数。芳香基环可以由五、六、七、八、九或九个以上的原子构成，芳香基包括但不限于噻吩基、苯基、萘基、菲基等等。
“环烷基”是指单环或多环的烃基，其结构式中只含有原子和氢原子，可以是饱和的也可以是不饱和的。
“卤素”是指氟、氯、溴或碘。
本发明中，除非另有说明，取代基名称前未冠有“取代或未取代的”定义的均指未取代的情况，例如：“烷基”是指未取代的烷基。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
本发明上述方法，至少实现了如下技术效果：
(1)本发明方法实现了苯甲酰胺衍生物与炔C-H/N-H氧化关环，可快速制备目前一系列多取代3-亚甲基异吲哚啉酮衍生物，为药物分子的合成、修饰提供了新的方法，为药物开发奠定了基础。
(2)本发明方法底物适用范围广泛，避免了贵金属催化剂的使用，使用廉价金属铜作为催化剂及氧化剂，具有成本低、操作简便等优点，适合工业生产应用。
(3)本发明化多取代3-亚甲基异吲哚啉酮衍生物是兼容多种类型官能团，易于进行多种衍生化，在合成具有生物活性的化合物中具有重要的应用价值。
具体实施方式
以下对本发明的技术方案进行清晰、完整地描述，显然，此处所描述的实施例仅是本发明中的一部分，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明的保护范围。
本发明实施例中所使用的化合物1可通过现有技术合成，参考文献：
[1](a)Jiang,Y.-T.；Yu,Z.-Z.；Zhang,Y.-K.；Wang,B.,Org.Lett.2018,20(13),3728-3731.(b)Arcadi,A.；Cerichelli,G.；Chiarini,M.；Correa,M.；Zorzan,D.,Eur.J.Org.Chem.2003,2003(20),4080-4086.
本发明实施例中所用的铜盐、碱、溶剂等都可通过商业购买获得。
本发明系列多取代3-亚甲基异吲哚啉酮衍生物的合成通式如下：
实施例1多取代3-亚甲基异吲哚啉酮衍生物的合成
将苯甲酰胺衍生物1(0.50mmol)和炔烃2(1.5mmol)、醋酸铜(0.65mmol)、的碳酸钠(1.0mmol)混合，在空气氛围下加入二甲亚砜10.0mL。于90℃反应15小时，反应结束后反应液乙酸乙酯稀释，水洗，干燥，浓缩，硅胶柱层析(石油醚/乙酸乙酯/三乙胺＝100/10/1～50/50/1)分离纯化得到3-亚甲基异吲哚啉酮衍生物3。
通过本实施例方法，用带有不同取代基的底物制得化合物3，具体化合物结构如下：
各化合物结构表征数据如下：
(Z)-3-苯亚甲基-2-(甲基[2-吡啶基]胺基)异吲哚啉-1-酮(3aa)
遵循上述通用反应步骤，使用苯肼1a(68.2mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3aa(87.4mg,89％,Z/E＝13:1)。
M.p.:67–68℃.1H NMR(600MHz,CDCl3)δ＝8.13(ddd,J＝5.0,1.9,0.9Hz,1H),7.90(dd,J＝7.6,1.0Hz,1H),7.85–7.82(m,1H),7.70(d,J＝1.2Hz,1H),7.56(dd,J＝7.6,0.9Hz,1H),7.44(ddd,J＝8.8,7.1,1.9Hz,1H),7.17–7.05(m,5H),6.85(d,J＝0.9Hz,1H),6.67(ddd,J＝7.2,5.0,0.9Hz,1H),6.44–6.41(m,1H),3.01(s,3H).13C NMR(150MHz,CDCl3)δ＝165.7(Cq),157.6(Cq),147.7(CH),137.4(CH),136.2(Cq),133.2(Cq),132.8(CH),132.1(Cq),129.3(CH),128.7(CH),127.3(CH),127.3(CH),126.5(Cq),123.8(CH),119.8(CH),114.3(CH),107.8(CH),106.4(CH),36.7(CH3).HR-MS(ESI)m/zcalcd for C21H18N3O[M+H+]328.1444,found 328.1439.
(Z)-3-苯亚甲基-2-(甲基[2-吡啶基]胺基)-5-苯基异吲哚啉-1-酮(3ba)
遵循上述通用反应步骤，使用苯肼1b(91.0mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ba(65.3mg,54％,Z/E＝29:1)。
M.p.:135–136℃.1H NMR(600MHz,CDCl3)δ＝8.15(ddd,J＝5.0,1.9,0.9Hz,1H),8.01(dd,J＝1.6,0.7Hz,1H),7.97(dd,J＝7.9,0.7Hz,1H),7.77(dd,J＝7.9,1.5Hz,1H),7.71–7.68(m,2H),7.55–7.51(m,2H),7.48–7.44(m,2H),7.19–7.07(m,5H),6.92(s,1H),6.68(ddd,J＝7.1,5.0,0.9Hz,1H),6.46(dt,J＝8.5,0.9Hz,1H),3.03(s,3H).13C NMR(150MHz,CDCl3)δ＝165.6(Cq),157.6(Cq),147.8(CH),146.3(Cq),140.2(Cq),137.5(CH),136.9(Cq),133.2(Cq),132.2(Cq),129.0(CH),128.8(CH),128.6(CH),128.4(CH),127.4(CH),127.4(CH),127.3(CH),125.3(Cq),124.2(CH),118.5(CH),114.3(CH),107.9(CH),106.5(CH),36.7(CH3).HR-MS(ESI)m/zcalcd for C27H22N3O[M+H+]404.1757,found404.1755.
(Z)-3-苯亚甲基-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)异吲哚啉-1-酮(3ca)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ca(117.4mg,99％,Z/E＝43:1)。
M.p.:121–122℃.1H NMR(600MHz,CDCl3)δ＝8.14(ddd,J＝5.0,1.9,0.9Hz,1H),8.10(d,J＝1.5Hz,1H),8.03(d,J＝7.9Hz,1H),7.83–7.79(m,1H),7.46(ddd,J＝8.7,7.1,1.9Hz,1H),7.19–7.15(m,1H),7.13–7.06(m,4H),6.94(s,1H),6.70(ddd,J＝7.2,5.0,0.9Hz,1H),6.38(dd,J＝8.5,1.0Hz,1H),3.02(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),157.1(Cq),147.9(CH),137.6(CH),136.5(Cq),134.7(q,2JC-F＝32.6Hz,Cq),132.7(Cq),131.4(Cq),129.3(Cq),128.7(CH),127.7(CH),127.4(CH),126.0(q,3JC-F＝3.8Hz,CH),124.5(CH),123.6(q,1JC-F＝271.0Hz,Cq),117.3(q,3JC-F＝4.0Hz,CH),114.7(CH),109.7(CH),106.3(CH),36.9(CH3).19F NMR(565MHz,CDCl3)δ＝-62.49.HR-MS(ESI)m/zcalcd for C22H17F3N3O[M+H+]396.1318,found 396.1316.
(Z)-3-苯基亚甲基-5-氟-2-(甲基[2-吡啶基]氨基)异吲哚啉-1-酮(3da)
遵循上述通用反应步骤，使用苯肼1d(73.6mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3da(91.2mg,88％,Z/E＝8:1)。
M.p.:119–120℃.1H NMR(600MHz,CDCl3)δ＝8.13(ddd,J＝5.0,1.9,0.9Hz,1H),7.89(dd,J＝8.4,4.9Hz,1H),7.51–7.42(m,3H),7.19–7.14(m,1H),7.11–7.07(m,4H),6.80(s,1H),6.68(ddd,J＝7.1,5.0,0.9Hz,1H),6.41(dd,J＝8.5,1.0Hz,1H),3.00(s,3H).13CNMR(150MHz,CDCl3)δ＝166.0(d,1JC-F＝252.7Hz,Cq),164.9(Cq),157.4(Cq),147.8(CH),138.7(d,3JC-F＝10.3Hz,Cq),137.5(CH),132.8(Cq),131.5(d,4JC-F＝3.5Hz,Cq),128.8(CH),127.6(CH),127.3(CH),126.2(d,3JC-F＝10.0Hz,CH),122.7(Cq),117.3(d,2JC-F＝23.8Hz,CH),114.5(CH),108.9(CH),107.0(d,2JC-F＝24.7Hz,CH),106.4(CH),36.8(CH3).19F NMR(565MHz,CDCl3)δ＝-(104.47–104.43)(m,1F).HR-MS(ESI)m/zcalcd for C21H17N3O[M+H+]346.1346,found 346.1350.
(Z)-3-苯亚甲基-5-氯-2-(甲基[2-吡啶基]胺基)异吲哚啉-1-酮(3ea)
遵循上述通用反应步骤，使用苯肼1e(78.5mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ea(97.7mg,90％,Z/E＝19:1)。
M.p.:131–132℃.1H NMR(600MHz,CDCl3)δ＝8.13(ddd,J＝5.0,1.9,0.9Hz,1H),7.85–7.80(m,2H),7.52(dd,J＝8.1,1.7Hz,1H),7.45(ddd,J＝8.7,7.2,1.9Hz,1H),7.18–7.13(m,1H),7.09(d,J＝5.8Hz,4H),6.82(s,1H),6.70–6.66(m,1H),6.39(dd,J＝8.5,1.0Hz,1H),3.00(s,3H).13C NMR(150MHz,CDCl3)δ＝164.9(Cq),157.3(Cq),147.8(CH),139.4(Cq),137.7(Cq),137.5(CH),132.8(Cq),131.3(Cq),129.7(CH),128.8(CH),128.8(CH),127.6(CH),127.3(CH),127.3(CH),125.1(CH),124.9(Cq),120.2(CH),114.5(CH),109.0(CH),106.3(CH),36.8(CH3).HR-MS(ESI)m/zcalcd for C21H17 35ClN3O[M+H+]362.1055,found362.1054.
(Z)-3-苯亚甲基-5-溴-2-(甲基[2-吡啶基]氨基)异吲哚啉-1-酮(3fa)
遵循上述通用反应步骤，使用苯肼1f(91.8mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3fa(108.5mg,89％,Z/E＝25:1)。
M.p.:140–141℃.1H NMR(600MHz,CDCl3)δ＝8.13(ddd,J＝5.0,2.1,1.0Hz,1H),7.98(d,J＝1.3Hz,1H),7.76(dd,J＝8.1,1.1Hz,1H),7.68(dd,J＝8.1,1.4Hz,1H),7.45(ddd,J＝8.4,7.2,1.5Hz,1H),7.18–7.13(m,1H),7.12–7.05(m,4H),6.82(d,J＝1.2Hz,1H),6.68(ddd,J＝7.1,5.0,1.1Hz,1H),6.39(dd,J＝8.5,1.0Hz,1H),2.99(s,3H).13C NMR(150MHz,CDCl3)δ＝165.0(Cq),157.3(Cq),147.8(CH),137.9(Cq),137.5(CH),132.8(Cq),132.5(CH),131.1(Cq),128.8(CH),128.8(CH),127.7(Cq),127.6(CH),127.4(CH),127.4(CH),125.3(Cq),125.2(CH),123.2(CH),114.5(CH),109.1(CH),106.4(CH),36.8(CH3).HR-MS(ESI)m/zcalcd for C21H17BrN3O[M+H+]406.0550,found 406.0552.
(Z)-3-苯亚甲基-5-碘-2-(甲基[2-吡啶基]胺基)异吲哚啉-1-酮(3ga)
遵循上述通用反应步骤，使用苯肼1g(105.9mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ga(81.6mg,60％,Z/E＝9:1)。M.p.:132–133℃.1HNMR(600MHz,CDCl3)δ＝8.19(d,J＝1.3Hz,1H),8.12(ddd,J＝5.0,2.0,0.9Hz,1H),7.88(dd,J＝8.0,1.3Hz,1H),7.61(d,J＝8.0Hz,1H),7.47–7.40(m,1H),7.15(p,J＝4.3Hz,1H),7.07(d,J＝4.5Hz,4H),6.80(s,1H),6.69–6.65(m,1H),6.37(d,J＝8.5Hz,1H),2.98(s,3H).13C NMR(150MHz,CDCl3)δ＝165.2(Cq),157.3(Cq),147.8(CH),138.3(CH),137.7(Cq),137.5(CH),132.9(Cq),130.9(Cq),129.1(CH),128.7(CH),127.6(CH),127.3(CH),125.8(Cq),125.1(CH),114.5(CH),109.0(CH),106.3(CH),99.8(Cq),36.8(CH3).HR-MS(ESI)m/zcalcd for C21H17IN3O[M+H+]454.0411,found 454.0408.
(Z)-3-苯亚甲基-2-(甲基(2-吡啶基)胺基)-5-(甲硫基)异吲哚啉-1-酮(3ha)
遵循上述通用反应步骤，使用苯肼1h(82.0mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ha(88.5mg,79％,Z/E＝14:1)。M.p.:71–72℃.1HNMR(600MHz,CDCl3)δ＝8.70(s,1H),8.36(s,1H),8.10(d,J＝4.5Hz,1H),7.68(d,J＝8.2Hz,1H),7.45–7.41(m,1H),7.34(dd,J＝8.3,1.2Hz,1H),7.14–7.08(m,1H),7.07–7.01(m,4H),6.79(s,1H),6.66(dd,J＝6.8,5.5Hz,1H),6.39(d,J＝8.4Hz,1H),2.95(s,3H),2.09(s,3H).13C NMR(150MHz,CDCl3)δ＝169.3(Cq),165.8(Cq),157.5(Cq),147.6(CH),143.0(Cq),137.7(CH),133.1(Cq),131.9(Cq),128.8(CH),128.8(CH),127.4(CH),127.3(CH),127.3(CH),124.3(CH),121.4(Cq),120.4(CH),114.5(CH),110.4(CH),108.6(CH),106.5(CH),36.8(CH3),24.5(CH3).HR-MS(ESI)m/zcalcd for C22H20N3OS[M+H+]374.1322,found 374.1319.
(Z)-3-苯亚甲基-2-(甲基[2-吡啶基]胺基)-1-氧异吲哚啉-5-腈(3ia)
遵循上述通用反应步骤，使用苯肼1i(75.7mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ia(100.4mg,95％,Z/E＝19:1)。M.p.:168–169℃.1H NMR(600MHz,CDCl3)δ＝8.12(dd,J＝4.7,1.5Hz,2H),8.00(dd,J＝7.8,0.8Hz,1H),7.80(dd,J＝7.8,1.3Hz,1H),7.45(ddd,J＝8.7,7.2,1.9Hz,1H),7.19–7.14(m,1H),7.11–7.09(m,4H),6.90(s,1H),6.70(ddd,J＝7.2,5.0,0.9Hz,1H),6.35(dd,J＝8.5,0.9Hz,1H),3.00(s,3H).13C NMR(150MHz,CDCl3)δ＝164.1(Cq),157.0(Cq),147.9(CH),137.6(CH),136.6(Cq),132.5(Cq),132.3(CH),130.8(Cq),129.7(Cq),128.8(CH),127.9(CH),127.4(CH),124.7(CH),124.1(CH),118.0(Cq),116.2(Cq),114.8(CH),110.4(CH),106.3(CH),37.0(CH3).HR-MS(ESI)m/zcalcd for C22H17N4O[M+H+]353.1397,found 353.1395.
(Z)-N-{3-苯亚甲基-2-(甲基[2-吡啶基]胺基)-1-氧异吲哚啉-5-基}乙酰胺(3ja)
遵循上述通用反应步骤，使用苯肼1j(85.3mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ja(98.0mg,85％,Z/E＝9:1)。M.p.:74–75℃.1HNMR(600MHz,CDCl3)δ＝8.12(ddd,J＝5.0,2.1,1.0Hz,1H),7.77(d,J＝7.9Hz,1H),7.62(d,J＝1.5Hz,1H),7.49–7.40(m,2H),7.38(dd,J＝8.1,1.4Hz,1H),7.17–7.12(m,1H),7.11–7.05(m,4H),6.82(s,1H),6.70–6.64(m,1H),6.42(dd,J＝8.5,1.0Hz,1H),2.99(s,3H),2.61(s,3H).13C NMR(150MHz,CDCl3)δ＝165.5(Cq),165.5(Cq),157.6(Cq),147.7(CH),145.8(Cq),137.5(CH),136.9(Cq),133.2(Cq),131.8(Cq),128.8(CH),127.4(CH),127.3(CH),126.5(CH),123.9(CH),123.0(Cq),116.1(CH),114.3(CH),107.9(CH),106.4(CH),36.7(CH3),15.3(CH3).HR-MS(ESI)m/zcalcd for C23H21N4O2[M+H+]385.1659,found385.1656.
甲基-(Z)-3-苯亚甲基-2-(甲基[2-吡吡基]胺基)-1-氧异吲哚啉-5-甲酯(3ka)
遵循上述通用反应步骤，使用苯肼1k(85.6mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ka(80.9mg,70％,Z/E＝13:1)。M.p.:155–156℃.1H NMR(600MHz,CDCl3)δ＝8.51(s,1H),8.20(dd,J＝7.9,1.3Hz,1H),8.12(ddd,J＝5.0,1.9,0.9Hz,1H),7.95(dd,J＝7.9,0.8Hz,1H),7.43(ddd,J＝8.5,7.2,1.9Hz,1H),7.18–7.12(m,1H),7.13–7.05(m,6H),6.94(s,1H),6.67(ddd,J＝7.2,5.0,0.9Hz,1H),6.38(d,J＝8.5Hz,1H),3.99(s,3H),3.00(s,3H).13C NMR(150MHz,CDCl3)δ＝166.1(Cq),164.8(Cq),157.3(Cq),147.8(CH),137.5(CH),136.2(Cq),134.1(Cq),132.9(Cq),131.6(Cq),130.1(CH),129.9(Cq),128.8(CH),127.6(CH),127.3(CH),123.8(CH),121.4(CH),114.5(CH),109.1(CH),106.3(CH),52.7(CH3),36.8(CH3).HR-MS(ESI)m/zcalcd for C23H20N3O3[M+H+]386.1499,found 386.1498.
(Z)-3-苯亚甲基-2-[甲基(2-吡啶基)胺基]-6-(三氟甲基)异吲哚啉-1-酮(3la)
遵循上述通用反应步骤，使用苯肼1l(88.6mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3la(116.2mg,98％,Z/E＝13:1)。M.p.:119–120℃.1H NMR(600MHz,CDCl3)δ＝8.17(s,1H),8.13(dd,J＝5.0,1.5Hz,1H),7.96–7.91(m,2H),7.47–7.42(m,1H),7.20–7.14(m,1H),7.12–7.05(m,4H),6.94(s,1H),6.69(dd,J＝7.3,4.9Hz,1H),6.38(d,J＝8.4Hz,1H),3.01(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),157.2(Cq),147.9(CH),139.1(Cq),137.6(CH),132.7(Cq),131.5(q,2JC-F＝35.1Hz,Cq),131.4(Cq),129.5(q,3JC-F＝3.8Hz,CH),128.8(CH),127.8(CH),127.4(CH),127.0(Cq),123.6(q,1JC-F＝272.7Hz,Cq),121.2(q,3JC-F＝4.0Hz,CH),120.5(CH),114.7(CH),110.3(CH),106.3(CH),36.9(CH3).19F NMR(565MHz,CDCl3)δ＝-62.27(s,3F).HR-MS(ESI)m/zcalcd for C22H17F3N3O[M+H+]396.1318,found396.1314.
(Z)-6-乙酰基-3-苯亚甲基-2-[甲基(2-吡啶基)胺基]异吲哚啉-1-酮(3ma)
遵循上述通用反应步骤，使用苯肼1m(80.8mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ma(70.9mg,64％,Z/E＝15:1)。M.p.:132–133℃.1H NMR(600MHz,CDCl3)δ＝8.43(s,1H),8.32(dd,J＝8.2,1.3Hz,1H),8.13(dd,J＝4.7,1.5Hz,1H),7.92(d,J＝8.1Hz,1H),7.47–7.41(m,1H),7.16(t,J＝6.9Hz,1H),7.13–7.05(m,4H),6.94(s,1H),6.69(dd,J＝6.9,5.1Hz,1H),6.40(d,J＝8.4Hz,1H),3.01(s,3H),2.69(s,3H).13C NMR(150MHz,CDCl3)δ＝196.8(Cq),165.1(Cq),157.3(Cq),147.9(CH),140.0(Cq),137.7(Cq),137.6(CH),132.8(Cq),132.2(CH),131.7(Cq),128.8(CH),128.8(CH),127.8(CH),127.4(CH),127.4(CH),126.8(Cq),124.3(CH),120.3(CH),114.6(CH),110.5(CH),106.4(CH),36.9(CH3),26.8(CH3).HR-MS(ESI)m/zcalcd for C23H20N3O2[M+H+]370.1550,found 370.1548.
(Z)-3-苯亚甲基-2-(甲基[2-吡啶基]胺基)-2,3-二氢-1氢-吡咯[3,4-c]吡啶-1-酮(3na)
遵循上述通用反应步骤，使用苯肼1n(68.5mg,0.30mmol)和末端炔烃2a(91.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3na(68.0mg,69％,Z/E＝27:1)。M.p.:143–144℃.1H NMR(600MHz,CDCl3)δ＝9.21(d,J＝1.2Hz,1H),8.83(d,J＝5.0Hz,1H),8.24–8.08(m,1H),7.76(dd,J＝5.0,1.2Hz,1H),7.44(ddd,J＝8.8,7.2,1.9Hz,1H),7.16(tt,J＝6.4,2.0Hz,1H),7.09(h,J＝6.0Hz,4H),6.97(s,1H),6.69(dd,J＝7.2,5.0Hz,1H),6.35(d,J＝8.5Hz,1H),3.00(s,3H).13C NMR(150MHz,CDCl3)δ＝164.2(Cq),157.0(Cq),149.8(CH),147.9(CH),142.7(CH),137.6(CH),133.2(Cq),132.6(Cq),130.6(Cq),130.3(Cq),128.7(CH),127.7(CH),127.4(CH),117.0(CH),114.8(CH),110.3(CH),106.3(CH),36.9(CH3).HR-MS(ESI)m/zcalcd for C20H17N4O[M+H+]329.1397,found 329.1391.
(Z)-2-[甲基(2-吡啶基)胺基]-3-(4-甲基苯亚甲基)-5-(三氟甲基)异吲哚啉-1-酮(3cb)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2b(104.5mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cb(109.3mg,89％)。M.p.:135–136℃.1H NMR(600MHz,CDCl3)δ＝8.16(ddd,J＝5.0,1.9,0.9Hz,1H),8.08(s,1H),8.01(d,J＝7.2Hz,1H),7.78(d,J＝9.3Hz,1H),7.46(ddd,J＝8.7,7.1,1.8Hz,1H),7.02(d,J＝7.9Hz,2H),6.92–6.89(m,3H),6.70(ddd,J＝7.2,5.0,0.9Hz,1H),6.42(dd,J＝8.5,0.9Hz,1H),3.03(s,3H),2.26(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),157.4(Cq),147.9(CH),137.7(Cq),137.6(CH),136.7(Cq),134.6(q,2JC-F＝32.4Hz,Cq),130.8(Cq),129.6(Cq),129.2(Cq),128.9(CH),128.2(CH),125.8(q,3JC-F＝3.6Hz,CH),124.5(CH),123.6(q,1JC-F＝273.1Hz,Cq),117.2(q,3JC-F＝4.1Hz,CH),114.7(CH),110.1(CH),106.4(CH),36.9(CH3),21.2(CH3).19F NMR(565MHz,CDCl3)δ＝-62.49(s,3F).HR-MS(ESI)m/zcalcd forC23H19F3N3O[M+H+]410.1475,found 410.1473.
(Z)-3-(4-乙基苯亚甲基)-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)异吲哚啉-1-酮(3cd)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2d(117.2mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cd(115.6mg,91％)。M.p.:119–120℃.1H NMR(600MHz,CDCl3)δ＝8.14(ddd,J＝5.0,1.9,0.9Hz,1H),8.08(s,1H),8.01(d,J＝8.0Hz,1H),7.78(dd,J＝8.0,0.9Hz,1H),7.45(ddd,J＝8.5,7.2,1.9Hz,1H),7.05(d,J＝7.5Hz,2H),6.94–6.90(m,3H),6.69(ddd,J＝7.1,5.0,0.9Hz,1H),6.40(d,J＝8.5Hz,1H),3.04(s,3H),2.56(q,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),157.3(Cq),147.9(CH),144.0(Cq),137.6(CH),136.7(Cq),134.6(q,2JC-F＝32.5Hz,Cq),130.8(Cq),129.8(Cq),129.2(Cq),129.0(CH),126.9(CH),125.8(q,3JC-F＝3.7Hz,CH),124.5(CH),123.6(q,1JC-F＝273.0Hz,Cq),117.2(q,3JC-F＝4.0Hz,CH),114.6(CH),110.1(CH),106.4(CH),36.9(CH3),28.5(CH2),15.4(CH3).19F NMR(565MHz,CDCl3)δ＝-62.48(s,3F).HR-MS(ESI)m/zcalcd for C24H21F3N3O[M+H+]424.1631,found424.1627.
(Z)-2-(甲基[2-吡啶基]胺基)-3-(4-戊基苯亚甲基)-5-(三氟甲基)异吲哚啉-1-酮(3ce)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2e(155.1mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ce(135.5mg,97％)。M.p.:71–72℃.1H NMR(600MHz,CDCl3)δ＝8.14(ddd,J＝5.0,1.9,0.9Hz,1H),8.08(s,1H),8.01(d,J＝7.9Hz,1H),7.78(d,J＝8.1Hz,1H),7.44(ddd,J＝8.4,7.2,1.9Hz,1H),7.04(d,J＝8.4Hz,2H),6.93–6.88(m,3H),6.72–6.67(m,1H),6.38(d,J＝8.5Hz,1H),3.04(s,3H),2.51(t,J＝7.7Hz,2H),1.53(dtd,J＝9.0,7.5,6.2Hz,2H),1.37–1.20(m,4H),0.88(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),157.3(Cq),147.9(CH),142.7(Cq),137.5(CH),136.7(Cq),134.6(q,2JC-F＝32.6Hz,Cq),130.9(Cq),129.8(Cq),129.2(Cq),128.9(CH),127.5(CH),125.8(q,3JC-F＝4.1Hz,CH),124.5(CH),123.6(q,1JC-F＝273.1Hz,Cq),117.2(q,3JC-F＝4.0Hz,CH),114.6(CH),110.1(CH),106.3(CH),36.9(CH3),35.6(CH2),31.3(CH2),30.9(CH2),22.5(CH2),14.0(CH3).19F NMR(565MHz,CDCl3)δ＝-62.48(s,3F).HR-MS(ESI)m/zcalcd for C27H27F3N3O[M+H+]466.2101,found 466.2097.
(Z)-3-(4-甲氧基苯亚甲基)-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)异吲哚啉-1-酮(3cf)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2f(118.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cf(126.3mg,99％,Z/E＝10:1)。M.p.:122–123℃.1H NMR(600MHz,CDCl3)δ＝8.19–8.15(m,1H),8.07(s,1H),8.00(dd,J＝7.9,0.8Hz,1H),7.78(d,J＝1.4Hz,1H),7.47(ddd,J＝8.8,7.1,1.8Hz,1H),7.10(d,J＝9.0Hz,2H),6.88(s,1H),6.74–6.69(m,1H),6.63(d,J＝8.8Hz,2H),6.45(d,J＝8.5Hz,1H),3.74(s,3H),3.07(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),159.3(Cq),157.5(Cq),147.9(CH),137.7(CH),136.8(Cq),134.6(q,2JC-F＝32.8Hz,Cq),130.6(CH),130.3(Cq),129.0(Cq),125.7(q,3JC-F＝3.7Hz,CH),124.9(Cq),124.5(CH),123.7(q,1JC-F＝271.5Hz,Cq),117.1(q,3JC-F＝4.2Hz,CH),114.8(CH),113.0(CH),110.0(CH),106.5(CH),55.2(CH3),36.9(CH3).19F NMR(565MHz,CDCl3)δ＝-62.51(s,3F).HR-MS(ESI)m/zcalcd for C23H19F3N3O2[M+H+]426.1424,found 426.1421.
(Z)-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)-3-[4-(三氟甲基)苯亚甲基]异吲哚啉-1-酮(3cg)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2g(153.1mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cg(66.4mg,52％)。M.p.:153–154℃.1H NMR(600MHz,CDCl3)δ＝8.12–8.10(m,1H),8.09(s,1H),8.02(d,J＝7.2Hz,1H),7.84–7.81(m,1H),7.45(ddd,J＝8.8,7.2,1.9Hz,1H),7.33(d,J＝8.0Hz,2H),7.22–7.18(m,2H),6.87(s,1H),6.74–6.68(m,1H),6.34(d,J＝8.5Hz,1H),3.02(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),156.9(Cq),148.1(CH),137.7(CH),136.7(Cq),136.2(Cq),134.9(q,2JC-F＝32.9Hz,Cq),132.7(Cq),129.5(Cq),129.4(q,2JC-F＝32.7Hz,Cq),129.0(CH),126.5(q,3JC-F＝3.6Hz,CH),124.6(CH),124.2(q,3JC-F＝3.7Hz,CH),123.9(q,1JC-F＝271.7Hz,Cq),123.5(q,1JC-F＝273.1Hz,Cq),117.4(q,3JC-F＝4.1Hz,CH),115.1(CH),107.3(CH),106.2(CH),37.1(CH3).19F NMR(565MHz,CDCl3)δ＝-62.55(s,3F),-62.55(s,3F).HR-MS(ESI)m/zcalcdfor C23H16F6N3O[M+H+]464.1192,found 464.1189.
(Z)-3-(4-氟苯亚甲基)-2-(甲基[2-吡啶基]胺基)异吲哚啉-1-酮(3ah)
遵循上述通用反应步骤，使用苯肼1a(68.2mg,0.30mmol)和末端炔烃2h(108.1mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ah(89.1mg,86％,Z/E＝14:1)。M.p.:101–102℃.1H NMR(600MHz,CDCl3)δ＝8.14(ddd,J＝5.0,1.9,0.9Hz,1H),7.88(d,J＝7.6Hz,1H),7.81(d,J＝7.8Hz,1H),7.69(dd,J＝7.6,1.1Hz,1H),7.55(dd,J＝7.5,0.9Hz,1H),7.44(ddd,J＝8.5,7.1,1.9Hz,1H),7.08–7.05(m,2H),6.78–6.73(m,3H),6.69–6.66(m,1H),6.42(d,J＝8.5Hz,1H),3.02(s,3H).13C NMR(150MHz,CDCl3)δ＝165.7(Cq),162.0(d,1JC-F＝247.0Hz,Cq),157.5(Cq),147.9(CH),137.5(CH),136.2(Cq),132.9(CH),132.3(Cq),130.5(d,3JC-F＝8.0Hz,CH),129.4(CH),129.2(d,4JC-F＝3.4Hz,Cq),126.5(Cq),123.8(CH),119.8(CH),114.5(CH),114.3(d,2JC-F＝21.5Hz,CH),106.5(CH),106.4(CH),36.7(CH3).19F NMR(565MHz,CDCl3)δ＝–(113.98-114.03)(m,1F).HR-MS(ESI)m/zcalcd for C21H17FN3O[M+H+]346.1350,found 346.1347.
(Z)-3-(4-氟苯亚甲基)-2-(甲基[2-吡啶基)胺基]-5-(三氟甲基)异吲哚啉-1-酮(3ch)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2h(108.1mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ch(33.5mg,27％)。M.p.:133–134℃.1H NMR(600MHz,CDCl3)δ＝8.17–8.13(m,1H),8.08(s,1H),8.01(d,J＝7.9Hz,1H),7.80(d,J＝7.9Hz,1H),7.46(ddd,J＝8.7,7.0,1.9Hz,1H),7.08(dd,J＝8.5,5.5Hz,2H),6.86(s,1H),6.78(d,J＝8.6Hz,2H),6.71(dd,J＝7.2,5.0Hz,1H),6.39(d,J＝8.5Hz,1H),3.03(s,3H).13C NMR(151MHz,CDCl3)δ＝164.5(Cq),162.2(d,1JC-F＝248.2Hz,Cq),157.2(Cq),148.0(CH),137.7(CH),136.4(Cq),134.7(q,2JC-F＝32.8Hz,Cq),131.6(Cq),130.6(d,3JC-F＝8.0Hz,CH),129.3(Cq),128.7(d,4JC-F＝3.5Hz,Cq),126.1(q,3JC-F＝3.6Hz,CH),124.6(CH),123.6(q,1JC-F＝273.2Hz,Cq),117.3(q,3JC-F＝4.1Hz,CH),114.9(CH),114.5(d,2JC-F＝21.6Hz,CH),108.4(CH),106.3(CH),37.0(CH3).19FNMR(565MHz,CDCl3)δ＝-62.53(s,3F),-113.34(p,J＝6.2Hz,1F).HR-MS(ESI)m/zcalcd for C22H16F4N3O[M+H+]414.1224,found414.1219.
(Z)-3-(4-溴苯亚甲基)-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)异吲哚啉-1-酮(3ci)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2i(162.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ci(44.1mg,31％)。M.p.:170–171℃.1H NMR(600MHz,CDCl3)δ＝8.16(ddd,J＝5.0,1.9,0.9Hz,1H),8.07(s,1H),8.01(dd,J＝7.9,0.8Hz,1H),7.81(dd,J＝8.0,0.9Hz,1H),7.51–7.44(m,1H),7.24–7.18(m,2H),6.98(dd,J＝8.6,0.8Hz,2H),6.80(s,1H),6.72(ddd,J＝7.2,5.0,0.9Hz,1H),6.39(dd,J＝8.5,0.9Hz,1H),3.04(s,3H).13C NMR(151MHz,CDCl3)δ＝164.5(Cq),157.1(Cq),148.1(CH),137.7(CH),136.4(Cq),134.8(q,2JC-F＝32.5Hz,Cq),131.9(Cq),131.7(Cq),130.5(CH),130.5(CH),129.4(Cq),126.3(q,3JC-F＝4.1Hz,CH),124.6(CH),123.6(q,1JC-F＝273.6Hz,Cq),121.9(Cq),117.3(q,3JC-F＝4.0Hz,CH),115.0(CH),108.0(CH),106.3(CH),37.1(CH3).19F NMR(565MHz,CDCl3)δ＝-62.53(s,3F).HR-MS(ESI)m/zcalcd for C22H16 79BrF3N3O[M+H+]474.0423,found 474.0420.
(Z)-3-(3-氟苯基亚甲基)-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)异吲哚啉-1-酮(3cj)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2j(108.1mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cj(69.4mg,56％)。M.p.:147–148℃.1H NMR(600MHz,CDCl3)δ＝8.15–8.12(m,1H),8.08(s,1H),8.02(d,J＝7.9Hz,1H),7.82(dd,J＝7.9,1.5Hz,1H),7.46(ddd,J＝8.8,7.2,1.9Hz,1H),7.06(dd,J＝8.0,5.9Hz,1H),6.90–6.83(m,3H),6.78(dd,J＝9.9,2.2Hz,1H),6.71(ddd,J＝7.2,5.0,0.9Hz,1H),6.37(d,J＝8.8Hz,1H),3.05(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),161.8(d,1JC-F＝246.3Hz,Cq),157.0(Cq),148.0(CH),137.7(CH),136.3(Cq),135.0(d,3JC-F＝8.1Hz,Cq),134.8(q,2JC-F＝33.1Hz,Cq),132.3(Cq),129.5(Cq),128.9(d,3JC-F＝8.5Hz,CH),126.4(q,3JC-F＝3.7Hz,CH),124.6(CH),124.6(d,4JC-F＝2.9Hz,CH),123.6(q,1JC-F＝273.4Hz,Cq),117.4(q,3JC-F＝4.0Hz,CH),117.3,115.7(d,2JC-F＝22.3Hz,CH),114.9(CH),114.6(d,2JC-F＝20.9Hz,CH),107.8(CH),106.2(CH),37.1(CH3).19F NMR(565MHz,CDCl3)δ＝-62.54(s,3F),-113.76(td,J＝9.3,6.2Hz,1F).HR-MS(ESI)m/zcalcd for C22H16F4N3O[M+H+]414.1224,found 414.1222.
(Z)-3-(3-氯苯亚甲基)-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)异吲哚啉-1-酮(3ck)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2k(122.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3ck(114.7mg,89％)。M.p.:131–132℃.1H NMR(600MHz,CDCl3)δ＝8.14(ddd,J＝5.0,1.8,0.9Hz,1H),8.07(s,1H),8.02(d,J＝7.9Hz,1H),7.82(d,J＝9.3Hz,1H),7.47(ddd,J＝8.7,7.1,1.8Hz,1H),7.16–7.11(m,1H),7.07–7.02(m,2H),7.01–6.98(m,1H),6.82(s,1H),6.71(dd,J＝7.2,5.0Hz,1H),6.38(dd,J＝8.5,1.0Hz,1H),3.04(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),156.9(Cq),148.1(CH),137.8(CH),136.3(Cq),134.8(q,2JC-F＝32.3Hz,Cq),134.9(Cq),132.4(Cq),131.9(CH),130.6(CH),129.4(Cq),128.9(CH),127.2(CH),126.4(q,3JC-F＝3.8Hz,CH),124.6(CH),123.6(q,1JC-F＝273.1Hz,Cq),121.3(Cq),117.4(q,3JC-F＝3.7,3.2Hz,CH),115.1(CH),107.4(CH),106.2(CH),37.0(CH3)19F NMR(565MHz,CDCl3)δ＝-62.53(s,3F).HR-MS(ESI)m/zcalcd for C22H16 35ClF3N3O[M+H+]430.0929,found430.0928.
(Z)-3-(3-溴苯亚甲基)-2-[甲基(2-吡啶基)胺基]-5-(三氟甲基)异吲哚啉-1-酮(3cl)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2l(162.9mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cl(98.2mg,69％)。M.p.:135–136℃.1H NMR(600MHz,CDCl3)δ＝8.17–8.13(m,1H),8.07(s,1H),8.02(d,J＝7.9Hz,1H),7.82(d,J＝7.9Hz,1H),7.50–7.45(m,1H),7.28(dd,J＝7.9,1.0Hz,1H),7.24(s,1H),7.05(d,J＝6.8Hz,1H),7.02–6.97(m,1H),6.81(s,1H),6.72(ddd,J＝7.2,5.0,1.0Hz,1H),6.39(dd,J＝8.4,1.0Hz,1H),3.04(s,3H).13C NMR(150MHz,CDCl3)δ＝164.5(Cq),156.9(Cq),148.1(CH),137.8(CH),136.3(Cq),134.8(q,2JC-F＝32.3Hz,Cq),134.9(Cq),132.4(Cq),131.9(CH),130.6(CH),129.4(Cq),128.9(CH),127.2(CH),126.4(q,3JC-F＝3.8Hz,CH),124.6(CH),123.6(q,1JC-F＝273.1Hz,Cq),121.3(Cq),117.4(q,3JC-F＝3.7,3.2Hz,CH),115.1(CH),107.4(CH),106.2(CH),37.0(CH3).19F NMR(565MHz,CDCl3)δ＝-62.53(s,3F).HR-MS(ESI)m/zcalcd for C22H16 79BrF3N3O[M+H+]474.0423,found474.0424.
(Z)-N-[3-{(2-{甲基[2-吡啶基]胺基}-3-氧-6-(三氟甲基)异吲哚啉-1-亚基)甲基}苯基]乙酰胺(3cm)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2m(143.3mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cm(99.1mg,73％)。M.p.:75–76℃.1H NMR(600MHz,CDCl3)δ＝8.14(dd,J＝5.2,1.8Hz,1H),8.04(s,1H),7.99(d,J＝7.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.48(ddd,J＝8.7,7.2,1.9Hz,1H),7.38–7.33(m,1H),7.14(s,1H),7.10(s,1H),7.04(dd,J＝7.9,7.9Hz,1H),7.86(s,1H),6.85(d,J＝8.7Hz,1H),6.71(dd,J＝7.1,5.0Hz,1H),6.42(d,J＝8.5Hz,1H),2.96(s,3H),2.00(s,3H).13C NMR(150MHz,CDCl3)δ＝168.1(Cq),164.5(Cq),157.3(Cq),147.9(CH),137.8(CH),137.1(Cq),136.5(Cq),134.8(q,2JC-F＝32.7Hz,Cq),133.2(Cq),131.4(Cq),129.1(Cq),128.1(CH),126.1(q,3JC-F＝3.8Hz,CH),124.5(CH),124.4(CH),123.5(q,1JC-F＝272.9Hz,Cq),120.5(CH),119.2(CH),117.3(q,3JC-F＝4.1Hz,CH),114.5(CH),109.2(CH),106.5(CH),36.8(CH3),24.4(CH3).19FNMR(565MHz,CDCl3)δ＝-62.51(s,3F).HR-MS(ESI)m/zcalcd for C24H20F3N4O2[M+H+]453.1533,found 453.1533.
(Z)-3-(3-氨基苯基亚甲基)-2-(甲基[2-吡吡基]氨基)-5-(三氟甲基)异吲哚啉-1-酮(3cn)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2n(105.4mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cn(91.1mg,74％)。M.p.:115–116℃.1H NMR(600MHz,CDCl3)δ＝8.19(d,J＝5.0Hz,1H),8.07(s,1H),8.02(d,J＝7.9Hz,1H),7.79(d,J＝7.9Hz,1H),7.49(ddd,J＝8.8,7.1,1.8Hz,1H),6.94(dd,J＝7.8,7.8Hz,1H),6.86(s,1H),6.75–6.68(m,1H),6.56(d,J＝7.5Hz,1H),6.50(d,J＝8.2Hz,1H),6.45(d,J＝8.5Hz,1H),6.32(s,1H),3.24(sbr,2H),3.01(s,3H).13C NMR(150MHz,CDCl3)δ＝164.6(Cq),157.4(Cq),148.0(CH),145.4(Cq),137.7(CH),136.7(Cq),134.7(q,2JC-F＝32.6Hz,Cq),133.5(Cq),131.0(Cq),129.2(Cq),128.4(CH),126.0(q,3JC-F＝3.6Hz,CH),124.5(CH),123.6(q,1JC-F＝273.5Hz,Cq),119.2(CH),117.2(q,3JC-F＝4.2Hz,CH),116.0(CH),114.7(CH),114.4(CH),110.1(CH),106.3(CH),36.8(CH3).19F NMR(565MHz,CDCl3)δ＝-62.50(s,3F).HR-MS(ESI)m/zcalcd for C22H18F3N4O[M+H+]411.1427,found 411.1425.
(Z)-3-(3,5-二甲氧基苯亚甲基)-2-(甲基[2-吡啶基]胺基)-5-(三氟甲基)异吲哚啉-1-酮(3co)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2o(146.0mg,0.90mmol)。硅胶柱层析分得淡黄色固体3co(128.4mg,94％,Z/E＝7:1)。M.p.:115–116℃.1H NMR(600MHz,CDCl3)δ＝8.16(dd,J＝5.0,1.0Hz,1H),8.07(s,1H),8.00(d,J＝7.9Hz,1H),7.79(d,J＝7.5Hz,1H),7.46(ddd,J＝8.8,7.2,1.9Hz,1H),6.86(s,1H),6.70(ddd,J＝7.2,5.0,0.9Hz,1H),6.45(d,J＝8.5Hz,1H),6.30–6.29(m,3H),3.46(s,6H),3.05(s,3H).13C NMR(150MHz,CDCl3)δ＝164.4(Cq),159.9(Cq),157.4(Cq),148.1(CH),137.7(CH),136.5(Cq),134.7(Cq),134.7(q,3JC-F＝32.4Hz,Cq),131.5(Cq),129.3(Cq),126.1(q,3JC-F＝3.7Hz,CH),124.5(CH),123.6(q,1JC-F＝273.4Hz,Cq),117.3(q,3JC-F＝4.3Hz,CH),114.8(CH),109.5(CH),106.7(CH),106.5(CH),100.6(CH),55.0(CH3),37.0(CH3).19F NMR(565MHz,CDCl3)δ＝-62.51(s,3F).HR-MS(ESI)m/zcalcd for C24H21F3N3O3[M+H+]456.1530,found 456.1529.
(Z)-N-{3-({2-[甲基(2-吡啶基)氨基]-3-氧-6-(三氟甲基)异吲哚啉-1-亚基}甲基)苯基}异烟酰胺(3cp)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2p(200.0mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cp(136.1mg,88％)。M.p.:70–71℃.1H NMR(600MHz,CDCl3)δ＝8.77–8.71(m,2H),8.12–8.05(m,2H),7.99(d,J＝7.2Hz,1H),7.79(d,J＝8.0Hz,1H),7.70(s,1H),7.59–7.55(m,2H),7.52(d,J＝8.1Hz,1H),7.42(ddd,J＝8.7,7.1,1.9Hz,1H),7.27(s,1H),7.15(t,J＝7.9Hz,1H),7.01–6.95(m,1H),6.89(s,1H),6.57(ddd,J＝7.2,5.0,1.0Hz,1H),6.43(d,J＝8.5Hz,1H),2.97(s,3H).13C NMR(150MHz,CDCl3)δ＝164.4(Cq),163.4(Cq),157.3(Cq),150.6(CH),147.9(CH),141.7(Cq),137.8(CH),136.5(Cq),136.4(Cq),134.9(d,2JC-F＝32.5Hz,Cq),133.5(Cq),131.7(Cq),129.1(Cq),128.4(CH),126.3(q,3JC-F＝3.7Hz,CH),125.4(CH),124.6(CH),123.5(d,1JC-F＝273.2Hz,Cq),121.2(CH),120.8(CH),119.9(CH),117.3(q,3JC-F＝3.9Hz,CH),114.6(CH),108.8(CH),106.5(CH),36.8(CH3).19F NMR(565MHz,CDCl3)δ＝-62.53(s,3F).HR-MS(ESI)m/zcalcdfor C28H21F3N5O2[M+H+]516.1642,found 516.1641.
(Z)-2-(甲基[2-吡啶基]氨基)-3-(3-吡啶基亚甲基)-5-三氟甲基异吲哚啉-1-酮(3cq)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2q(92.8mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cq(105.8mg,89％)。M.p.:141–142℃.1H NMR(600MHz,CDCl3)δ＝8.42(dd,J＝2.2,1.0Hz,1H),8.37(ddd,J＝4.9,1.7,0.7Hz,1H),8.12(ddd,J＝4.9,1.9,0.9Hz,1H),8.10(s,1H),8.01(d,J＝7.9Hz,1H),7.82(d,J＝7.9Hz,1H),7.45(ddd,J＝8.4,7.2,1.9Hz,1H),7.38(ddd,J＝7.8,2.4,1.7,1H),6.99(dd,J＝7.8,4.9Hz,1H),6.80(s,1H),6.73–6.68(m,1H),6.36(d,J＝8.5Hz,1H),3.07(s,3H).13C NMR(150MHz,CDCl3)δ＝164.4(Cq),156.9(Cq),149.2(CH),148.6(CH),148.1(CH),137.8(CH),136.0(Cq),135.9(CH),134.9(q,2JC-F＝32.8Hz,Cq),133.2(Cq),129.5(Cq),129.1(Cq),126.5(q,3JC-F＝3.8Hz,CH),124.6(CH),123.5(d,1JC-F＝273.1Hz,Cq)122.1(CH),117.5(q,3JC-F＝4.1Hz,CH),115.3(CH),106.3(CH),104.9(CH),37.2(CH3).19F NMR(565MHz,CDCl3)δ＝-62.55(s,3F).HR-MS(ESI)m/zcalcd for C21H16F3N4O[M+H+]397.1271,found 397.1269.
(Z)-2-(甲基[2-吡啶基]氨基)-3-(2-噻吩基亚甲基)-5-三氟甲基异吲哚啉-1-酮(3cr)
遵循上述通用反应步骤，使用苯肼1c(88.6mg,0.30mmol)和末端炔烃2r(105mg,0.90mmol)。硅胶柱层析分得淡黄色固体3cr(97.3mg,88％)。M.p.:115–116℃.1HNMR(600MHz,CDCl3)δ＝8.23(ddd,J＝5.0,1.9,0.9Hz,1H),8.07(s,1H),8.00(d,J＝7.9Hz,1H),7.78(d,J＝7.9Hz,1H),7.51–7.43(m,1H),7.18–7.17(m,1H),7.15(ddd,J＝4.1,3.0,1.1Hz,1H),6.98(dd,J＝5.0,1.3Hz,1H),6.80(s,1H),6.75(ddd,J＝7.2,5.0,0.9Hz,1H),6.49(d,J＝8.5Hz,1H),3.24(s,3H).13C NMR(150MHz,CDCl3)δ＝164.3(Cq),157.9(Cq),148.1(CH),137.9(CH),136.8(Cq),134.6(q,2JC-F＝32.7Hz,Cq),132.8(Cq),130.4(Cq),129.3(CH),128.9(Cq),125.8(q,3JC-F＝3.6Hz,CH),125.6(CH),125.0(CH),124.5(CH),123.6(d,1JC-F＝271.3Hz,Cq),117.0(q,3JC-F＝3.9Hz,CH),115.2(CH),106.7(CH),104.2(CH),37.3(CH3).19F NMR(565MHz,CDCl3)δ＝-62.49(s,3F).HR-MS(ESI)m/zcalcd forC20H15F3N3OS[M+H+]402.0882,found 402.0880.
本发明还发现，不同的条件对反应结果有显著影响:
表1.铜促进的C-H/N-H与末端炔烃的关环反应条件优化a
a Reaction conditions:25mL Schlenk tube,1a(0.30mmol),2a(0.90mmol),Cu(OAc)2(1.1equiv),base(2.0equiv),solvent(3.0mL),15h,under air.b Cu(OAc)2(0.8equiv).c Cu(OAc)2(1.3equiv).dDMSO(6.0mL).eWithoutCu(OAc)2.fUnderN2.
Z/E为顺反异构。
本发明以苯肼1a与末端炔烃2a作为标准底物进行条件优化(表1)。经初步溶剂筛选，发现在以DMSO作为溶剂时，预想的关环反应可以实现(entries 1-3)。反应温度优化显示最佳反应温度约为90℃(entries3-6)。经比较不同的碱，发现最适合的碱为碳酸钠(entries7-11)。
最终最佳反应条件确定如下：Cu(OAc)2(1.3equiv)，DMSO(6.0mL)(entries12-14)。阴性对照实验显示当反应条件相对应于最佳反应条件去掉Cu(OAc)2和\或Na2CO3时，仅有微量产物生成(entries15-16)。反应于氮气或其它惰性气体氛围下，收率也显著降低(entry17)。
Claims (10)
1.如式3所示多取代3-亚甲基异吲哚啉酮衍生物的制备方法，其特征在于，包含以下内容：将式1化合物、式2化合物、铜盐、碱、溶剂混合，在有空气存在下加热反应：
所述溶剂选自DMSO。
2.根据权利要求1所述的制备方法，其特征在于：所述溶剂的用量为每毫摩尔式1化合物使用溶剂1～30mL，进一步选自10～20mL。
3.根据权利要求1所述的制备方法，其特征在于，所述铜盐选自醋酸铜、醋酸铜水合物、醋酸亚铜及其水合物、硫酸铜、三氟醋酸铜及其水合物、硫酸酮中的一种或两种以上的组合物，进一步选自醋酸铜、三氟醋酸铜、硫酸酮及其水合物中的一种或两种以上的组合物；优选醋酸铜或一水醋酸酮。
4.根据权利要求1或3所述的制备方法，其特征在于，所述铜盐的用量为，每毫摩尔式1化合物使用酮盐0.5～5.0当量，优选1.3当量。
5.根据权利要求1所述的制备方法，其特征在于，所述碱选自无机碱和/或有机碱；进一步地，所述碱选自无机碱；所述碱选自碳酸盐、醋酸盐、磷酸盐、有机碱中的一种或几种；
进一步地，所述碱选自碳酸盐；
进一步地，所述碱选自Li2CO3、Na2CO3、K2CO3、Ru2CO3、Cs2CO3或它们的水合物中的一种或几种，优选Na2CO3、K2CO3、Cs2CO3和/或其水合物。
6.根据权利要求1或5所述的制备方法，其特征在于，所述式1化合物：碱的摩尔比为1：0.1～10.0，优选1：0.5～3，更优选为1：2。
7.根据权利要求1所述的制备方法，其特征在于，反应温度，大于室温，在190℃以下；进一步选自60～120℃，更优选90℃。
8.根据权利要求1所述的制备方法，其特征在于，所述反应在空气或氧气氛围下进行。
9.根据权利要求1所述的制备方法，其特征在于，R1、R2每次出现时分别独立地选自H、卤素、腈基、羟基、巯基、氨基、氰基、酰基、酯基、酰胺基、非取代或取代的烷基、非取代或取代的杂烷基、非取代或取代的环烷基、非取代或取代的杂环烷基、非取代或取代的芳基、非取代或取代的杂芳基，或两个相邻的R1共同组成非取代或取代的烷基环、非取代或取代的杂环烷基、非取代或取代的芳环、非取代或取代的杂芳环，其中，取代基选自氘、卤素、硝基、羟基、巯基、氨基、氰基、酰胺基、酰基、磺酰基、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基。
10.一种化合物，其特征在于，具有式3所示结构或其立体异构体或顺反异构体、溶剂化物、水合物或药学上可接受的盐或共晶：
其中，R1，R2如权利要求1所定义；
进一步地，选自如下化合物之一：
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