CN110467558A - 一种镍催化合成3-胺基异吲哚啉酮的反应方法 - Google Patents
一种镍催化合成3-胺基异吲哚啉酮的反应方法 Download PDFInfo
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- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 23
- 229910052759 nickel Inorganic materials 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- -1 3- hydroxyl -2- phenethyl -1-isoindolinone class compound Chemical class 0.000 claims abstract description 8
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 5
- 239000012044 organic layer Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 3
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 claims description 2
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 claims description 2
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 claims description 2
- PDXOPNHXAAQJJO-UHFFFAOYSA-N nickel;trifluoromethanesulfonic acid Chemical compound [Ni].OS(=O)(=O)C(F)(F)F PDXOPNHXAAQJJO-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- ZLQBNKOPBDZKDP-UHFFFAOYSA-L nickel(2+);diperchlorate Chemical compound [Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O ZLQBNKOPBDZKDP-UHFFFAOYSA-L 0.000 claims 1
- 238000007796 conventional method Methods 0.000 abstract description 2
- 238000005406 washing Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 1
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical compound C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000004982 aromatic amines Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KXXCZYZSRRVYST-UHFFFAOYSA-N chloric acid;nickel Chemical compound [Ni].OCl(=O)=O KXXCZYZSRRVYST-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- HIUPRQPBWVEQJJ-UHFFFAOYSA-N pagoclone Chemical compound C1=CC(Cl)=NC2=NC(N3C(C4=CC=CC=C4C3=O)CC(=O)CCC(C)C)=CC=C21 HIUPRQPBWVEQJJ-UHFFFAOYSA-N 0.000 description 1
- 229950002286 pagoclone Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical group [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000820 zopiclone Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/50—Iso-indoles; Hydrogenated iso-indoles with oxygen and nitrogen atoms in positions 1 and 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及一种镍催化合成3‑胺基异吲哚啉酮的反应方法，将3‑羟基‑2‑苯乙基‑异吲哚啉‑1‑酮类化合物与胺类化合物溶于有机溶剂中，加入Ni(II)化合物催化剂，在80‑120℃搅拌反应4‑8h，将反应后的反应液进行萃取，合并有机层，洗涤，干燥，蒸除溶剂，残留物经硅胶柱层析，即得产品。本发明反应条件温和，避免了传统方法催化剂昂贵、条件苛刻的缺点；方法操作简单，反应收率较高，产物易分离纯化。
Description
技术领域
本发明涉及一种镍催化合成3-胺基异吲哚啉酮的反应方法，属于有机合成技术领域。
背景技术
3-取代异吲哚啉酮是构成具有生物活性的天然产物和药物分子的关键组分,在镇静剂、催眠药和肌肉松弛剂等领域具有重要的作用。例如epazinaclone,pagoclone,和zopiclone等等。
因为3-取代异吲哚啉酮化合物应用广泛,其制备方法研究一直是有机合成专家关注的热点。现在已经有很多方法来制备这类化合物。1999年，Kundu等人报道了钯催化2-碘-N-苯基苯甲酰胺类化合物与炔丙醇类化合物进行串联反应一步构建3-取代异吲哚啉酮。该反应相继包括Sonogashira偶联,环闭合反应和氧化还原反应。同一年，Kundu继续报道了钯催化2-碘-N-苯基苯甲酰胺类化合物与三甲基硅烷基反应构建2-(2-三甲基硅基)乙炔基苯甲酰胺,然后与酰氯进行付克反应得到相应的3-亚烷基异吲哚-1-酮。最后3-亚烷基异吲哚-1-酮的双键用Pd/C加氢还原得到3-取代异吲哚啉酮。2015年Dhanasekaran等人报道了使用邻甲酰甲基苯甲酸酯、芳基胺和硅醇,通过路易斯酸催化的多Mukaiyama–Mannich反应,相继进行内酰胺化/烷基化反应得到了中等收率到高收率的不同3-取代异吲哚啉酮。
现有的3-取代异吲哚啉酮的合成方法均有明显的缺陷,如反应步骤较长、反应条件苛刻、使用价格昂贵的催化剂、操作困难等。因此开发新的简单高效构建3-胺基异吲哚啉酮的合成方法具有重要的意义。
发明内容
本发明的目的是克服上述不足，而提供一种镍催化合成3-胺基异吲哚啉酮的反应方法。该方法条件温和，操作简便，官能团的取代类型受限较小，产物易分离纯化；对3-胺基异吲哚啉酮的制备和亚胺阳离子的方法学研究具有重要意义。
本发明采取的技术方案为：
一种镍催化合成3-胺基异吲哚啉酮的反应方法，包括步骤如下：
(1)将3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物与胺类化合物溶于有机溶剂中，加入Ni(II)化合物催化剂，在80-120℃搅拌反应4-8h；所述的3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物结构式如下：
式中R1和R2相同或不同独立地选自H、C1-C5的烷基、卤素X、-NO2、-CN和-OR5；
(2)将反应后的反应液进行萃取，合并有机层，洗涤，干燥，蒸除溶剂，残留物经硅胶柱层析，即得产品。
上述反应方法中，步骤(1)所述的3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物、胺类化合物、Ni(II)化合物催化剂和有机溶剂加入量的比为1：1.5-3：0.05-0.2：2.5-10；mmol:mmol:mmol:ml。3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物、胺类化合物、Ni(II)化合物催化剂和有机溶剂加入量的比优选为1：2：0.1：5；mmol:mmol:mmol:ml。
所述的R5选自H、C1-C5的烷基中的任意一种。所述的Ni(II)化合物催化剂选自高氯酸镍、三氟甲磺酸镍、氯化镍、溴化镍、硝酸镍、硫酸镍中的一种或者几种混合。所述的胺类化合物为硫代吗啉(I)、吗啉(II)或仲胺(III)。
R3选自H、苄基和C1-C10的烷基中的任意一种；R4选自H、苄基和C1-C10的烷基中的任意一种。
所述的有机溶剂为DMF、DMSO、甲苯、乙腈、二氯甲烷、氯仿，1,2-二氯乙烷、乙酸乙酯或四氢呋喃中的一种；优选为1,2-二氯乙烷。
步骤(2)所述的硅胶柱层析的洗脱液为乙酸乙酯与石油醚、正己烷、环己烷中的一种或几种混合；优选为乙酸乙酯与石油醚。
本发明反应式如下：
式中R1和R2相同或不同独立地选自H、C1-C5的烷基、卤素X、-NO2、-CN和-OR5；R5选自H、C1-C5的烷基中的任意一种；R3选自H、苄基和C1-C10的烷基中的任意一种；R4选自H、苄基和C1-C10的烷基中的任意一种。
本发明的有益效果为：
(1)本发明方法在反应中用Ni(II)催化原位生成亚胺阳离子，使用胺类化合物与生成的亚胺阳离子发生亲核加成反应，反应条件温和，避免了传统方法催化剂昂贵、条件苛刻的缺点；
(2)本发明方法操作简单，原料和试剂简单，反应收率较高，收率达78％～95％，产物易分离纯化，在3-取代异吲哚啉酮的合成中具有重要应用价值。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
实施例1：
在100mL的圆底烧瓶中加入2.39g(10mmol)化合物I-1，2.06g(20mmol)化合物II-1，0.26g(1mmol)固体Ni(ClO4)2，最后加入20mL干燥1,2-二氯乙烷，所得混合物在85℃搅拌6小时。反应混合物冷却到室温后，倾倒到冰水中，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤一次，无水Na2SO4干燥，浓缩除去溶剂得到粗品，经柱层析分离得到化合物III-1的纯品。白色固体，2.98g，产率92％。1H NMR(400MHz,CDCl3)δ:7.88(d,J＝6.8Hz,1H),7.55–7.45(m,2H),7.43(d,J＝7.1Hz,1H),7.35–7.23(m,5H),5.21(d,J＝14.6Hz,1H),4.91(s,1H),4.31(d,J＝14.6Hz,1H),3.03–2.65(m,4H),2.59(d,J＝4.4Hz,4H)；13C NMR(CDCl3,100MHz)δ:167.46,142.07,137.45,132.72,131.52,129.15,128.69,128.44,127.52,123.82,123.36,50.07,43.62,28.54；HRMS(ESI)calcd for C19H21N2OS[M+H]+325.1369,found 325.1370.
实施例2：
在100mL的圆底烧瓶中加入2.39g(10mmol)化合物I-1，1.76g(20mmol)化合物II-2，0.52g(2mmol)固体Ni(ClO4)2，最后加入50mL干燥DMF，所得混合物在110℃搅拌5小时至反应完全。反应混合物冷却至室温，倾倒到水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤一次，无水Na2SO4干燥，浓缩除去溶剂得到粗品，经柱层析分离得到化合物III-2的纯品。白色固体，2.71g，产率88％。1H NMR(400MHz,CDCl3)δ:7.89(d,J＝6.6Hz,1H),7.48(dt,J＝13.8Hz,6.5Hz,3H),7.36–7.18(m,5H),5.22(d,J＝14.6Hz,1H),4.96(s,1H),4.34(d,J＝14.6Hz,1H),3.65(t,J＝4.4Hz,4H),2.73–2.55(m,2H),2.52–2.27(m,2H)；13C NMR(CDCl3,100MHz)δ:167.44,141.87,137.44,132.80,131.43,129.17,128.67,128.52,127.51,123.89,123.49,77.38,67.34,47.64,43.61；HRMS(ESI)calcd forC19H21N2O2[M+H]+309.1598,found 309.1599.
实施例3：
在100mL的圆底烧瓶中加入2.39g(10mmol)化合物I-1，1.61g(15mmol)化合物II-3，0.13g(0.5mmol)固体Ni(ClO4)2，最后加入50mL干燥DMF，所得混合物在110℃时剧烈搅拌4小时。反应混合物冷却到室温后，倾倒到水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤一次，无水Na2SO4干燥，浓缩蒸去溶剂得到粗品，经柱层析纯化得到化合物III-3的纯品。油状液体，2.95g，产率90％。1H NMR(400MHz,CDCl3)δ:7.88(d,J＝7.3Hz,1H),7.59–7.41(m,3H),7.27(tt,J＝10.6Hz,7.4Hz,8H),7.15(d,J＝7.1Hz,2H),5.32(s,1H),5.17(d,J＝15.0Hz,1H),4.34(d,J＝15.0Hz,1H),3.35(d,J＝13.0Hz,1H),3.24(d,J＝13.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:156.85,143.24,140.07,128.78,128.71,128.69,128.34,128.23,127.97,127.92,127.41,127.34,119.29,116.28,62.83,51.15；HRMS(ESI)calcd for C20H20NO[M+H]+290.1539,found 290.1540.
实施例4：
在100mL的圆底烧瓶中加入2.57g(10mmol)化合物I-2，1.61g(15mmol)化合物II-3，0.18g(1mmol)固体Ni(OTf)2，最后加入50mL干燥DMSO，所得混合物在120℃时剧烈搅拌6小时。反应混合物冷却到室温后，倾倒到水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤一次，无水Na2SO4干燥，浓缩除去溶剂得到一油状残余物，经柱层析纯化得到化合物III-4的纯品。油状液体，2.77g，产率80％。1H NMR(400MHz,CDCl3)δ:7.88(d,J＝7.2Hz,1H),7.57–7.44(m,3H),7.37–7.20(m,5H),7.08(dd,J＝8.2Hz,5.7Hz,2H),6.92(t,J＝8.6Hz,2H),5.33(s,1H),5.13(d,J＝15.0Hz,1H),4.38(d,J＝15.0Hz,1H),3.31(d,J＝13.0Hz,1H),3.19(d,J＝13.0Hz,1H),2.16(s,1H)；13C NMR(CDCl3,100MHz)δ:167.76,163.20,160.76,143.18,137.40,135.41,135.38,132.79,131.91,129.66,129.58,129.22,128.86,128.26,128.22,127.66,123.57,123.18,115.26,115.05,72.38,44.80,43.37；HRMS(ESI)calcd for C22H20FN2O[M+H]+347.1554,found 347.1556.
实施例5：
在100mL的圆底烧瓶中加入2.73g(10mmol)化合物I-3，2.14g(20mmol)化合物II-3，0.13g(1mmol)固体NiCl2，最后加入30mL干燥甲苯，所得混合物在120℃时剧烈搅拌8小时。反应混合物冷却到室温后，倾倒到水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤一次，无水Na2SO4干燥，浓缩除去溶剂得到一油状残余物，经柱层析纯化得到化合物III-5的纯品。油状液体，2.97g，产率82％。1H NMR(400MHz,CDCl3)δ:7.87(d,J＝7.1Hz,1H),7.57–7.43(m,3H),7.39–7.15(m,7H),7.04(d,J＝8.3Hz,2H),5.33(s,1H),5.11(d,J＝15.0Hz,1H),4.38(d,J＝15.0Hz,1H),3.24(dd,J＝47.1Hz,13.3Hz,2H),2.17(s,1H)；13C NMR(CDCl3,100MHz)δ:167.75,143.11,138.20,137.38,132.84,132.78,131.93,129.40,129.25,128.86,128.46,128.44,128.26,127.67,123.58,123.18,72.40,44.84,43.40；HRMS(ESI)calcd for C22H20ClN2O[M+H]+363.1259,found 363.1260.
实施例6：
在100mL的圆底烧瓶中加入3.17g(10mmol)化合物I-4，2.14g(20mmol)化合物II-3，0.22g(1mmol)固体NiBr2，最后加入30mL干燥甲苯，所得混合物在120℃搅拌8小时。反应混合物冷却到室温后，倾倒到水中，搅拌，用50mL×3的二氯甲烷萃取，合并萃取有机相，用饱和食盐水洗涤一次，无水Na2SO4干燥，浓缩除去溶剂得到粗品，经柱层析纯化得到化合物III-5的纯品。油状液体，3.45g，产率85％。1H NMR(400MHz,CDCl3)δ:7.88(d,J＝7.1Hz,1H),7.63–7.45(m,3H),7.42–7.21(m,7H),6.99(d,J＝8.2Hz,2H),5.33(s,1H),5.12(d,J＝15.0Hz,1H),4.38(d,J＝15.0Hz,1H),3.23(dd,J＝48.1Hz,13.3Hz,2H),2.12(s,1H)；13CNMR(CDCl3,100MHz)δ:167.75,143.06,138.6,137.34,132.77,131.94,131.43,129.75,129.26,128.87,128.25,127.68,123.60,123.16,120.94,72.37,44.88,43.42；HRMS(ESI)calcd for C22H20BrN2O[M+H]+407.0754,found 40700754.
以上是结合具体实施例对本发明的详细介绍，本发明的保护范围不限于此。
Claims (10)
1.一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，包括步骤如下：
(1)将3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物与胺类化合物溶于有机溶剂中，加入Ni(II)化合物催化剂，在80-120℃搅拌反应4-8h；所述的3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物结构式如下：
式中R1和R2相同或不同独立地选自H、C1-C5的烷基、卤素X、-NO2、-CN和-OR5；
(2)将反应后的反应液进行萃取，合并有机层，洗涤，干燥，蒸除溶剂，残留物经硅胶柱层析，即得产品。
2.根据权利要求1所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(1)所述的3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物、胺类化合物、Ni(II)化合物催化剂和有机溶剂加入量的比为1：1.5-3：0.05-0.2：2.5-10；mmol:mmol:mmol:ml。
3.根据权利要求2所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(1)所述的3-羟基-2-苯乙基-异吲哚啉-1-酮类化合物、胺类化合物、Ni(II)化合物催化剂和有机溶剂加入量的比为1：2：0.1：5；mmol:mmol:mmol:ml。
4.根据权利要求1所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(1)所述的R5选自H、C1-C5的烷基中的任意一种。
5.根据权利要求1所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(1)所述的Ni(II)化合物催化剂选自高氯酸镍、三氟甲磺酸镍、氯化镍、溴化镍、硝酸镍、硫酸镍中的一种或者几种混合。
6.根据权利要求1所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(1)所述的胺类化合物为硫代吗啉(I)、吗啉(II)或仲胺(III):
其中R3选自H、苄基和C1-C10的烷基中的任意一种；R4选自H、苄基和C1-C10的烷基中的任意一种。
7.根据权利要求1所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(1)所述的有机溶剂为DMF、DMSO、甲苯、乙腈、二氯甲烷、氯仿，1,2-二氯乙烷、乙酸乙酯或四氢呋喃中的一种。
8.根据权利要求7所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(1)所述的有机溶剂为1,2-二氯乙烷。
9.根据权利要求1所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(2)所述的硅胶柱层析的洗脱液为乙酸乙酯与石油醚、正己烷、环己烷中的一种或几种混合。
10.根据权利要求9所述的一种镍催化合成3-胺基异吲哚啉酮的反应方法，其特征是，步骤(2)所述的硅胶柱层析的洗脱液为乙酸乙酯与石油醚。
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