CN110526853B - 3,3-二取代-2-吲哚酮衍生物及其制备方法 - Google Patents
3,3-二取代-2-吲哚酮衍生物及其制备方法 Download PDFInfo
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- -1 3, 3-disubstituted-2-indolone Chemical class 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 20
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims abstract description 20
- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 125000003003 spiro group Chemical group 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 11
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 239000012434 nucleophilic reagent Substances 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 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
- 150000001875 compounds Chemical class 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000007259 addition reaction Methods 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000007877 drug screening Methods 0.000 abstract description 2
- 150000002475 indoles Chemical class 0.000 abstract description 2
- 239000002547 new drug Substances 0.000 abstract description 2
- 150000003233 pyrroles Chemical class 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000012038 nucleophile Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 3
- 150000005623 oxindoles Chemical class 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
Classifications
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- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开的3,3‑二取代‑2‑吲哚酮衍生物是具有如下结构式的消旋体、左旋或右旋的光学活性体;
Description
技术领域
本发明属于有机合成技术领域,具体涉及3,3-二取代-2-吲哚酮衍生物及其制备方法。
背景技术
2-吲哚酮衍生物是一类重要的含氮杂环化合物,也是一些药物活性分子的重要骨架,具有作为酶抑制剂、抗癌/抗肿瘤等药理活性((a)N.H.Greig,X.-F.Pei,T.T.Soncrant,D.K.Ingram and A.Brossi,Med.Res.Rev.,1995,15,3;(b)C.V.Galliford,K.A.Scheidt,Angew.Chem.,Int.Ed.,2007,46,8748.)。因此,研究合成2-吲哚酮衍生物,特别是不对称催化合成3,3-二取代-2-吲哚酮衍生物,受到了人们的关注((a)R.Dalpozzo,Org.Chem.Front.,2017,4,2063;(b)R.Dalpozzo,G.Bartoliand G.Bencivenni,Chem.Soc.Rev.,2012,41,7247;(c)Z.-Y.Cao and J.Zhou,Org.Chem.Front.,2015,2,849;(d)D.Cheng,Y.Ishihara,B.Tan and C.F.Barbas III,ACS Catal.,2014,4,743;(e)L.Hong and R.Wang,Adv.Synth.Catal.,2013,355,1023;(f)R.Rios,Chem.Soc.Rev.,2012,41,1060;(g)G.S.Singh and Z.Y.Desta,Chem.Rev.,2012,112,6104;(h)N.R.Ball-Jones,J.J.Badille and A.K.Franz,Org.Biomol.Chem.,2012,10,5165)。另外吡咯与吲哚及其衍生物也具有重要的药理活性(Chem.Rev.,2006,106,2875;Angew.Chem.,Int.Ed.,2009,48,9608;Chem.Rev.2004,104,2481;Tetrahedron,2006,62,7213)。醌甲基化物类化合物经常出现在天然产物,同时作为合成子用于有机合成((a)B.T.Ramanjaneyulu,S.Mahesh and R.V.Anand,Org.Lett.,2015,17,3952;(b)V.Reddy and R.V.Anand,Org.Lett.,2015,17,3390;(c)A.Lopez,A.Parra,C.Jarava-Barrera and M.Tortosa,Chem.Commun.,2015,51,17684;(d)Z.Wang and J.Sun,Synthesis,2015,47,3629.;(e)X.Zhang,Y.-H.Chen and B.Tan,Tetrahedron Lett.,2018,59,473;(f)Y.Shen,J.Qi,Z.Mao and S.Cui,Org.Lett.,2016,18,2722.(g)A.Parra and M.Tortosa,Chem-CatChem,2015,7,1524;)。那么可以预期若组装成含有2-吲哚酮衍生物,醌甲基化物和吡咯基或吲哚基等高药理活性结构的3,3-二取代-2-吲哚酮衍生物的分子将具有较高生物活性。
发明内容
本发明的目的是提供一种3,3-二取代-2-吲哚酮衍生物及其制备方法。
一种3,3-二取代-2-吲哚酮衍生物,它是具有如下结构式的消旋体、左旋或右旋的光学活性体;
式中:R1和R6选自H、三氟甲基、二氟甲基、苄基、烯丙基、C1~C4烷基,R2~R5和R7~R11选自H、卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、苄基、C1~C4烷基或C1~C4烷氧基。
所述的3,3-二取代-2-吲哚酮衍生物的制备方法,是以靛红衍生的醌甲基化物类化合物为原料,跟如吡咯类化合物或吲哚类化合物等亲核试剂反应,以螺环磷酸为催化剂,在有机溶剂中于10~80℃,反应12~48小时,纯化得到3,3-二取代-2-吲哚酮衍生物,所述的靛红衍生的醌甲基化物类化合物和亲核试剂的摩尔比为1:1~1.2,螺环磷酸催化剂和靛红衍生的醌甲基化物类化合物的摩尔比为5~20:100。
所述的螺环磷酸催化剂为具有结构式(1)的化合物,可以是消旋体、左旋或右旋的光学活性体:
式中:R选自H、烷基、芳基或取代的芳基、9-蒽基、菲基,取代的芳基上的取代基可以是一个或多个,包括卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、苄基、苯基、C1~C4烷基或C1~C4烷氧基。
所述的靛红衍生的醌甲基化物类化合物结构如下式(2)所示:
所述的亲核试剂为吡咯类化合物或吲哚类化合物,结构如下式(3)和式(4)所示:
式中:R1~R11如权利要求1所述。
所述的有机溶剂为甲苯、二甲苯、苯、二氯甲烷、氯仿、1,2-二氯乙烷、氟苯、氯苯或乙基苯。
与现有技术相比,本发明具有以下优点:
1)无需金属催化,反应可在温和条件下进行;
2)含有取代基的吡咯或吲哚能直接作为反应底物,其来源十分广泛,这些降低了最终产品的制备成本;
3)可以获得高光学活性的含吲哚基和苯酚基的3,3-二取代-2-吲哚酮衍生物。
综上所述,本发明利用催化1,6加成反应方法合成3,3-二取代-2-吲哚酮衍生物,反应条件温和,工艺简单,操作便捷,所得产物有潜在的良好的生物活性,这将对新药筛选有重要意义。
具体实施方式
以下实施例将有助于理解本发明,但不限于本发明的内容。
靛红衍生的醌甲基化物类化合物可以按照文献H.Wang,K.Wang,Y.Man,X.Gao,L.Yang,Y.Ren,Na Li,B.Tang and G.Zhao,Adv.Synth.Catal.,2017,359,3934公开的方法制备。
实施例1
反应瓶中依次加入1a(0.05mmol)和吲哚2a(0.06mmol),和二氯甲烷(1mL),最后加入螺环磷酸催化剂(S)-4a(0.0075mmol);10度搅拌反应48小时,反应完毕,直接柱层析纯化得到手性的3,3-二取代-2-吲哚酮衍生物3a,产率85%;产物表征如下:5-Bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3,3'-biindolin-2-one(3a)85%yield;91%ee,determined by HPLC[Daicel Chiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH=80/20,0.8mL/min,254nm;tminor=5.644min,tmajor=10.951min;[α]D 20=67(c 0.2,CH2Cl2);1H NMR(400MHz,DMSO)δ11.02(d,J=2.0Hz,1H),10.76(s,1H),7.43(dd,J=8.3,2.0Hz,1H),7.37(d,J=8.2Hz,1H),7.20(d,J=1.9Hz,1H),7.13(s,2H),7.07–7.00(m,2H),6.96(d,J=8.3Hz,1H),6.88(d,J=7.9Hz,1H),6.86–6.78(m,2H),1.28(s,18H);13C NMR(101MHz,DMSO)δ178.67,152.93,140.63,138.62,137.07,136.78,130.64,130.09,127.79,125.33,24.84,123.96,121.16,119.81,118.46,115.01,113.10,111.75,57.14,34.60,30.21;IR(film):γ=3404,2983,2356,2215,2155,1677,1472,1359,1251,1026,905,826,764cm-1;HRMS(EI-TOF):calcd for C30H31BrN2O3 530.1569,found530.1572.
按照上述一样的反应过程,改变反应底物,可以得到以下3,3-二取代-2-吲哚酮衍生物:
5-Bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-4'-methyl-3,3'-biindolin-2-one(3b)86%yield;90%ee,determined by HPLC[Daicel Chiralcel OD-Hcolumn(250×4.6mm),n-hexane/i-PrOH=80/20,0.8mL/min,254nm;tminor=5.838min,tmajor=10.888min;[α]D 20=88.1(c 0.5,CH2Cl2);1H NMR(400MHz,DMSO)δ10.99(d,J=1.9Hz,1H),10.69(s,1H),7.44(dd,J=8.2,1.8Hz,1H),7.22(d,J=8.0Hz,1H),7.08(d,J=15.5Hz,2H),6.94(t,J=7.9Hz,3H),6.63(d,J=7.1Hz,1H),6.45(s,1H),1.86(s,3H),1.30(s,18H);13C NMR(101MHz,DMSO)δ152.97,140.43,138.50,137.91,130.66,127.98,124.39,121.32,121.17,112.97,111.92,109.69,57.95,34.63,30.21;IR(film):γ=3421,2924,2256,2215,1655,1472,1379,1051,1026,1005,826,764cm-1;HRMS(EI-TOF):calcd forC31H33BrN2O2 544.1725,found 544.1721.
5-Chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-6'-fluoro-3,3'-biindolin-2-one(3g)83%yield;97%ee,determined by HPLC[Daicel Chiralcel OD-Hcolumn(250×4.6mm),n-hexane/i-PrOH=80/20,0.8mL/min,254nm;tminor=5.363min,tmajor=7.898min;[α]D 20=107.1(c0.7,CH2Cl2);1H NMR(400MHz,DMSO)δ11.08(d,J=2.1Hz,1H),10.77(s,1H),7.30(dd,J=8.3,2.2Hz,1H),7.15(dd,J=10.0,2.3Hz,1H),7.10(d,J=2.3Hz,3H),7.01(d,J=8.3Hz,2H),6.90(dd,J=8.8,5.6Hz,1H),6.83(d,J=2.5Hz,1H),6.77–6.68(m,1H),1.27(s,18H);13C NMR(101MHz,DMSO)δ178.68,159.79,157.46,152.95,140.19,138.70,136.83(m,J F-C=121.67),136.53,130.19,127.90,125.55,125.49,124.98,123.84,122.19,115.05,111.27,97.71,97.46,57.20,34.57,30.20;19FNMR(376MHz,DMSO)δ-121.74(td,J=9.9,5.6Hz);IR(film):γ=3439,2253,2127,1910,1657,1472,1053,1026,1007,825,763,627cm-1;HRMS(EI-TOF):calcd forC30H30FClN2O2504.1980,found 504.1984.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-6'-fluoro-5-methyl-3,3'-biindolin-2-one(3m)80%yield;96%ee,determined by HPLC[Daicel Chiralcel OD-Hcolumn(250×4.6mm),n-hexane/i-PrOH=80/20,0.8mL/min,254nm;tminor=5.208min,tmajor=7.243min;[α]D 20=67(c 0.7,CH2Cl2);1H NMR(400MHz,DMSO)δ11.03(d,J=1.7Hz,1H),10.53(s,1H),7.20–7.12(m,3H),7.04(d,J=7.8Hz,1H),6.97(s,2H),6.95–6.91(m,1H),6.89(d,J=7.8Hz,1H),6.80(d,J=2.4Hz,1H),6.72(td,J=9.6,2.3Hz,1H),2.22(s,3H),1.30(s,18H);13C NMR(101MHz,DMSO)δ179.06,159.75,157.42,152.67,138.80,138.48,136.80(m,J F-C=121.67),134.60,131.06,130.29,128.14,125.77,125.38,125.35,124.00,122.46,116.04,109.42,97.54,97.29,57.00,34.57,30.27,20.73;IR(film):γ=3425,2942,2924,2834,2254,1652,1458,1190,1051,1026,1006,825,763,629cm-1;HRMS(EI-TOF):calcd for C31H33FN2O2 484.2526,found 484.2530.
实施例2
反应瓶中依次加入1a(0.05mmol)和吲哚2a(0.05mmol),和1,2-二氯乙烷(2mL),最后加入消旋体螺环磷酸催化剂4b(0.005mmol);80度搅拌反应12小时,反应完毕,直接柱层析纯化得到消旋体的3,3-二取代-2-吲哚酮衍生物3a,产率92%.
按照上述一样的反应过程,改变反应底物,可以得到以下3,3-二取代-2-吲哚酮衍生物:
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1’-methyl-3,3'-biindolin-2-one(3t)89%yield;1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.29(q,J=7.9Hz,3H),7.25(d,J=1.3Hz,1H),7.22–7.16(m,1H),7.15–7.05(m,1H),7.02(t,J=7.2Hz,1H),6.94(dd,J=7.6,4.2Hz,2H),6.91–6.84(m,1H),6.80(d,J=2.5Hz,1H),5.14(s,1H),3.32(s,3H),1.32(s,18H);13C NMR(101MHz,CDCl3)δ178.27,152.96,143.07,136.92,135.26,134.24,130.16,127.92,125.93,125.64,124.93,124.37,124.15,122.52,121.96,120.88,120.71,119.78,119.45,117.50,111.15,108.17,102.59,57.13,34.45,30.28,26.64;IR(film):γ=3637,3301,2956,2920,1706,1619,1471,1321,1237,1143,1122,1055,909,803,750cm-1;HRMS(EI-TOF):calcd for C31H34N2O2 466.2620,found 466.2617.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1-methyl-3,3'-biindolin-2-one(3s)88%yield;1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.29(q,J=7.9Hz,3H),7.25(d,J=1.3Hz,1H),7.22–7.16(m,1H),7.15–7.05(m,1H),7.02(t,J=7.2Hz,1H),6.94(dd,J=7.6,4.2Hz,2H),6.91–6.84(m,1H),6.80(d,J=2.5Hz,1H),5.14(s,1H),3.32(s,3H),1.32(s,18H);13C NMR(101MHz,CDCl3)δ178.27,152.96,143.07,136.92,135.26,134.24,130.16,127.92,125.93,125.64,124.93,124.37,124.15,122.52,121.96,120.88,120.71,119.78,119.45,117.50,111.15,108.17,102.59,57.13,34.45,30.28,26.64;IR(film):γ=3637,3301,2956,2925,1706,1619,1471,1436,1321,1237,1143,1122,1055,909,803,750,668cm-1;HRMS(EI-TOF):calcd for C31H34N2O2 466.2620,found 466.2617.
实施例3
反应瓶中依次加入1a(0.05mmol)和吡咯5a(0.06mmol),和二氯甲烷(1mL),最后加入螺环磷酸催化剂(S)-4a(0.0075mmol);10度搅拌反应48小时,反应完毕,直接柱层析纯化得到手性的3,3-二取代-2-吲哚酮衍生物6,产物表征如下:
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(1H-pyrrol-2-yl)indolin-2-one(6)70%yield;84%ee,determined by HPLC[Daicel Chiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH=80/20,0.8mL/min,254nm;tminor=5.12min,tmajor=10.143min;[α]D 20=68(c 0.5,CH2Cl2);1H NMR(400MHz,DMSO)δ10.56(s,2H),7.39(d,J=7.4Hz,1H),7.21(td,J=7.7,1.1Hz,1H),7.00(td,J=7.6,0.8 Hz,1H),6.95–6.89(m,2H),6.82(s,2H),6.68(dd,J=4.3,2.6 Hz,1H),5.91(dd,J=5.6,2.6 Hz,1H),5.82(dd,J=4.5,3.0Hz,1H),1.25(s,18H);13C NMR(101 MHz,DMSO)δ177.91,152.88,141.27,138.55,133.76,132.19,129.34,127.86,125.39,123.62,121.61,118.97,109.59,107.37,106.27,57.37,34.43,30.15;IR(film):γ=3637,3201,2956,2925,1706,1645,1540,1471,1436,1247,955,803,750,608 cm-1;HRMS(EI-TOF):calcd for C26H30 N2O2 402.2707,found 402.2701.
Claims (2)
1.一种3,3-二取代-2-吲哚酮衍生物的制备方法,其特征在于,3,3-二取代-2-吲哚酮衍生物是具有如下结构式的消旋体、左旋或右旋的光学活性体;
式中:R1和R6选自H、三氟甲基、二氟甲基、苄基、烯丙基、C1~C4烷基,R2~R5和R7~R11选自H、卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、苄基、C1~C4烷基或C1~C4烷氧基;
所述制备方法为:以靛红衍生的醌甲基化物类化合物为原料,跟亲核试剂反应,以螺环磷酸为催化剂,在有机溶剂中于10~80℃,反应12~48小时,纯化得到3,3-二取代-2-吲哚酮衍生物,所述的靛红衍生的醌甲基化物类化合物和亲核试剂的摩尔比为1:1~1.2,螺环磷酸催化剂和靛红衍生的醌甲基化物类化合物的摩尔比为5~20:100;
所述的螺环磷酸催化剂为具有结构式(1)的化合物,可以是消旋体、左旋或右旋的光学活性体:
式中:R选自H、烷基、芳基或取代的芳基,取代的芳基上的取代基是一个或多个,包括卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、苄基、苯基、C1~C4烷基或C1~C4烷氧基;
所述的靛红衍生的醌甲基化物类化合物结构如下式(2)所示:
所述的亲核试剂为吡咯类化合物或吲哚类化合物,结构如下式(3)和式(4)所示:
2.根据权利要求1所述的3,3-二取代-2-吲哚酮衍生物的制备方法,其特征在于,所述的有机溶剂为甲苯、二甲苯、苯、二氯甲烷、氯仿、1,2-二氯乙烷、氟苯、四氢呋喃、氯苯或乙基苯。
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