CN116813528A - 一种全碳季碳环酮螺环假吲哚衍生物的合成方法 - Google Patents
一种全碳季碳环酮螺环假吲哚衍生物的合成方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D209/54—Spiro-condensed
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Abstract
本发明公开了一种全碳季碳环酮螺环假吲哚衍生物的合成方法,该方法使用金属羰基化合物作为安全羰基源,涉及零价钯到二价钯的催化循环,即经过碳‑卤键对钯(0)氧化加成,CO的配位并迁移插入形成羰基钯物种,再经过吲哚C3的亲核进攻实现吲哚环的去芳构化反应,随后还原消除得到全碳季碳环酮螺环假吲哚衍生物。具体为:将化合物1和金属羰基化合物Co2(CO)8,以钯为催化剂,有机膦为配体,钠盐为碱性,加热条件下反应得到全碳季碳环酮螺环假吲哚分子。该方法是一种新型的全碳季碳环酮螺环假吲哚衍生物的合成方法,解决了现有技术中存在的需要多步反应、反应条件苛刻、底物范围窄、原料毒性大等问题。
Description
技术领域
本发明涉及一种化合物的合成方法,特别涉及一种全碳季碳环酮螺环假吲哚衍生物的合成方法。
背景技术
全碳季碳环酮螺环假吲哚衍生物广泛分布于天然产物和生物活性分子中,是许多药物分子的核心骨架。此外,全碳季碳环酮螺环假吲哚衍生物还是一些农药、染料以及功能材料的重要合成中间体。有机化学家一直在不断地探索简单直接的方法来合成此类羰基环酮螺环分子。大多数已报导的合成方法都存在了一些缺点,难以将羰基的引入和全碳季碳螺环的构建有效融合,往往需要分步完成,即分别构建螺环和引入羰基。例如:Franz,A.K.;Hanhan,N.V.;Ball-Jones,N.R.ACS Catal.2013,3,540-553;Qiu,B.;Xu,D.;Sun,Q.;Miao,C.;Lee,Y.-M.;Li,X.-X.;Nam,W.;Sun,W.ACS Catal.2018,8,2479-2487;Suzuki,Y.;Vatmurge,N.;Tanaka,S.;Kitamura,M.;Suzuki,Y.;Vatmurge,N.;Tanaka,S.;Kitamura,M.Chem.Asian J.2017,12,633–637;Ramachary,D.B.;Krishna,P.M.AsianJ.Org.Chem.2016,5,729–734;Bera,S.;Daniliuc,G.C.;Studer,A.Angew.Chem.Int.Ed.2017,56,7402–7406;Jiang,H.;Gschwend,B.;Albrecht,L.;Hansen,S.G.;Jorgensen,K.A.Chem.-Eur.J.2011,17,9032-9036。又或是反应条件苛刻,底物范围窄,并且使用剧毒的一氧化碳气体作为羰基源,不符合绿色化学和可持续发展的基本的理念。因此,对于如何寻找一种原料易得、安全高效的方法实现羰基的引入和全碳季碳螺环的同步构建碳,从而实现全碳季碳环酮螺环假吲哚衍生物的高效合成,仍然是有机化学界亟待解决的问题之一。
发明内容
发明目的:本发明旨在提供一种简便高效的全碳季碳环酮螺环假吲哚衍生物的合成方法。
技术方案:本发明所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,使用羰基金属化合物作为安全羰基源,一步完成羰基的引入和螺环的构建。其反应按照以下步骤进行:将化合物1与羰基金属化合物Co2(CO)8混合,加入钯催化剂、膦配体以及碱,在溶剂中反应后即得目标化合物2,反应式如下:
本发明是关于一种多官能团化的全碳季碳环酮螺环假吲哚的制备方法。以化合物1为反应原料,以羰基金属化合物Co2(CO)8为安全羰基源,加入钯催化剂及适量膦配体,搅拌反应,通过氧化加成、CO迁移插入、去芳构化过程,合成官能团化的全碳季碳环酮螺环假吲哚化合物。
其中,R1为氢、氟、氯,烷基或烷氧基;R2为氢、氟、氯、硝基、三氟甲基、苯基、烷基或烷氧基;R3为烷基、苯基或卤代的苯基。优选地,所述的原料吲哚衍生物取代基R1=氢、甲基、甲氧基或氯;R2=氢、氟、氯、硝基、三氟甲基、苯基、甲基或者甲氧基;R3=甲基、苯基或者4-氟取代的苯基。
优选地,所述化合物1与羰基金属化合物的摩尔配比为1:0.5~100。
优选地,所述钯催化剂为氯化钯、醋酸钯、氢氧化钯、三氟乙酸钯、四三苯基膦钯、双(乙腈)氯化钯、乙酰丙酮钯或四三苯基膦钯;溶剂为甲苯、氯苯、氟苯、二甲苯或三氟甲苯;膦配体为双三苯基膦丙烷、三苯基膦、金刚烷膦、双三苯基膦丁烷、三环己基膦、三(邻甲基苯基)膦、三叔丁基膦或1,1'-联萘-2,2'-双二苯膦;碱为氢氧化钾、叔丁醇钠、甲醇钠、叔丁醇钾、乙醇钠、氢氧化钠、正丁基锂、三乙胺或二乙胺。
优选地,该反应在室温至150℃下进行,反应时间为1-48小时,目标化合物的产率为69-85%。
优选地,所述的碱的用量为2-甲基-3-(邻溴苄基)吲哚摩尔数的1-20倍。
优选地,所述化合物1与催化剂的摩尔配比为1:0.005-0.3。
多官能团化的全碳季碳环酮螺环假吲哚化合物可以在上述反应条件下顺利构建。
所述的反应后处理简便,只需要简单的柱色谱分离方法,以石油醚与乙酸乙酯的混合溶剂为洗脱剂就可以得到纯净的全碳季碳环酮螺环假吲哚衍生物。
本发明是以金属羰基化合物为安全羰基源,利用一种零价钯催化循环体系即经过碳-卤键对钯(0)氧化加成,一氧化碳配位并迁移插入形成酰基钯物种,再经过吲哚C3的亲核进攻实现吲哚环的去芳构化过程,是一种新型全碳季碳环酮螺环假吲哚衍生物的合成方法。本发明优于文献中报道的合成方法,使用金属羰基化合物作为安全的羰基源,避免使用剧毒的一氧化碳气体。采用一锅法、操作简单,以简单易得、价格且低廉的原料合成的2-甲基-3-(邻溴苄基)吲哚为反应原料。
有益效果:与现有技术相比,本发明具有如下显著优点:(1)使用固体金属羰基化合物作为安全羰基源,替代剧毒一氧化碳气体;(2)一锅法将羰基的引入和螺环的构建同时完成,操作简单、方便;(3)官能团兼容性广;(4)不会产生有污染的副产品;(5)利用可回收的钯催化剂,在较温和的条件下促使碳-碳新键的形成,通过分子间羰基化去芳构化来构建多官能团化全碳季碳环酮螺环假吲哚衍生物,实用性强。
附图说明
图1为化合物2-8的核磁氢谱图;
图2为化合物2-8的核磁碳谱图;
图3为化合物2-9的核磁氢谱图;
图4为化合物2-9的核磁碳谱图;
图5为化合物2-10的核磁氢谱图;
图6为化合物2-10的核磁碳谱图;
图7为化合物2-11的核磁氢谱图;
图8为化合物2-11的核磁碳谱图;
图9为化合物2-12的核磁氢谱图;
图10为化合物2-12的核磁碳谱图;
图11为化合物2-13的核磁氢谱图;
图12为化合物2-13的核磁碳谱图;
图13为化合物2-14的核磁氢谱图;
图14为化合物2-14的核磁碳谱图;
图15为化合物2-15的核磁氢谱图;
图16为化合物2-15的核磁碳谱图;
图17为化合物2-16的核磁氢谱图;
图18为化合物2-16的核磁碳谱图;
图19为该发明方法的一般反应过程。
具体实施方式
下面结合具体实施例对本发明的技术方案作进一步说明。
实施例1
将2-甲基-3-(邻溴苄基)吲哚衍生物1-1(0.1mmol)、Co2(CO)8(0.1mmol)、0.5%的醋酸钯(0.0005mmol)、双三苯基膦丁烷(0.001mmol)以及氢氧化钾(0.1mmol)混合,在加热情况下反应,反应时间经历36小时,反应式参见图19。1-1的转化率为95%,2-1的产率为80%。1H NMR(500MHz,CDCl3)δ7.85(d,J=7.7Hz,1H),7.74(t,J=7.5,1H),7.66–7.59(m,2H),7.52–7.44(m,1H),7.35(td,J1=7.6Hz,J2=1.2Hz,1H),7.13(td,J1=7.5Hz,J2=1.1Hz,1H),7.00(d,J=7.5Hz,1H),3.62(d,J=17.7Hz,1H),3.49(d,J=17.7Hz,1H),2.16(s,3H).13C{1H}NMR(125MHz,CDCl3)δ200.3,179.3,156.4,152.7,140.6,136.4,135.8,128.7,128.2,126.9,125.8,125.4,121.1,120.3,72.4,35.2,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C17H14NO+248.1070,Found 248.1076.
实施例2
将2-甲基-3-(邻溴苄基)吲哚衍生物1-2(0.1mmol)、Co2(CO)8(2.5mmol)、1%的氢氧化钯(0.001mmol)、三环己基膦(0.002mmol)以及叔丁醇钠(0.2mmol)混合,在加热情况下反应,反应时间经历18小时。1-2的转化率为95%,2-2的产率为78%。1H NMR(500MHz,CDCl3)δ7.85(d,J=7.7Hz,1H),7.74(t,J=7.5Hz,1H),7.65(d,J=7.6Hz,1H),7.52–7.46(m,2H),7.14(d,J=7.9Hz,1H),6.80(s,1H),3.60(d,J=17.6Hz,1H),3.47(d,J=17.6Hz,1H),2.28(s,3H),2.13(s,3H).13C{1H}NMR(125MHz,CDCl3)δ200.7,178.3,154.2,152.8,140.8,136.5,135.78,135.76,129.3,128.3,126.9,125.4,121.9,119.8,72.3,35.3,21.3,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C18H16NO+262.1226,Found 262.1235.
实施例3
将2-甲基-3-(邻溴苄基)吲哚衍生物1-3(0.1mmol)、Co2(CO)8(0.35mmol)、10%的氯化钯(0.01mmol)、双三苯基膦丙烷(0.024mmol)以及叔丁醇钠(0.2mmol)混合,在加热情况下反应,反应时间经历24小时。1-3的转化率为92%,2-3的产率为82%。1H NMR(500MHz,CDCl3)δ7.82(d,J=7.8Hz,1H),7.74–7.69(m,1H),7.63(d,J=7.7Hz,1H),7.50–7.45(m,2H),6.84(dd,J1=8.5Hz,J2=2.6Hz,1H),6.54(d,J=2.4Hz,1H),3.70(s,3H),3.59(d,J=17.6Hz,1H),3.44(d,J=17.6Hz,1H),2.10(s,3H).13C{1H}NMR(125MHz,CDCl3)δ200.4,177.1,158.4,152.8,150.0,142.1,136.4,135.8,128.3,127.0,125.4,120.5,113.3,108.0,72.5,55.7,35.5,16.3.HRMS(ESI)m/z:[M+H]+Calcd.for C18H16NO2 +278.1176,Found278.1183.
实施例4
将2-甲基-3-(邻溴苄基)吲哚衍生物1-4(0.1mmol)、Co2(CO)8(0.05mmol)、1%的三氟乙酸钯(0.001mmol)、双三苯基膦丙烷(0.0016mmol)以及氢氧化钾(0.2mmol)混合,在加热情况下反应,反应时间经历30小时。1-4的转化率为95%,2-4的产率为81%。1H NMR(500MHz,CDCl3)δ7.85(d,J=7.7Hz,1H),7.75(t,J=7.5Hz,1H),7.65(d,J=7.6Hz,1H),7.51(dd,J1=8.1Hz,J2=5.5Hz,2H),7.31(dd,J1=8.3Hz,J2=2.1Hz,1H),6.97(d,J=2.1Hz,1H),3.62(d,J=17.7Hz,1H),3.48(d,J=17.6Hz,1H),2.15(s,3H).13C{1H}NMR(125MHz,CDCl3)δ199.4,179.9,155.0,152.5,142.3,136.13,136.08,131.5,128.8,128.5,127.0,125.6,121.7,121.1,72.6,35.1,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C18H16ClNO+282.0680,Found 282.0691.
实施例5
将2-甲基-3-(邻溴苄基)吲哚衍生物1-5(0.1mmol)、Co2(CO)8(0.05mmol)、10%的双(乙腈)氯化钯(0.01mmol)、三苯基膦(0.02mmol)以及甲醇钠(0.5mmol)混合,在加热情况下反应,反应时间经历24小时。1-5的转化率为90%,2-5的产率为76%。1H NMR(500MHz,CDCl3)δ7.62(s,1H),7.58(d,J=7.8Hz,1H),7.56–7.50(m,2H),7.34–7.30(m,1H),7.11(t,J=7.5Hz,1H),6.98(d,J=7.4Hz,1H),3.54(d,J=17.5Hz,1H),3.42(d,J=17.5Hz,1H),2.45(s,3H),2.14(s,3H).13C{1H}NMR(125MHz,CDCl3)δ200.4,179.5,156.4,150.2,140.8,138.4,137.1,136.6,128.6,126.6,125.8,125.3,121.1,120.2,72.8,34.9,21.1,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C18H16NO+262.1226,Found 262.1235.
实施例6
将2-甲基-3-(邻溴苄基)吲哚衍生物1-6(0.1mmol)、Co2(CO)8(0.2mmol)、2.5%的醋酸钯(0.0025mmol)、双三苯基膦丁烷(0.005mmol)以及叔丁醇钾(0.2mmol)混合,在加热情况下反应,反应时间经历24小时。1-6的转化率为95%,2-6的产率为81%。1H NMR(500MHz,CDCl3)1H NMR(500MHz,CDCl3)δ7.73(d,J=7.8Hz,1H),7.59(d,J=7.7Hz,1H),7.44(s,1H),7.36–7.28(m,2H),7.12(t,J=7.5Hz,1H),7.00(d,J=7.3Hz,1H),3.56(d,J=17.6Hz,1H),3.43(d,J=17.6Hz,1H),2.52(s,3H),2.15(s,3H).13C{1H}NMR(125MHz,CDCl3)δ199.7,179.6,156.4,153.3,147.4,140.8,134.2,129.6,128.6,127.3,125.8,125.3,121.1,120.3,72.6,35.1,22.2,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C18H16NO+262.1226,Found 262.1234.
实施例7
将2-甲基-3-(邻溴苄基)吲哚衍生物1-7(0.1mmol)、Co2(CO)8(0.3mmol)、1%的醋酸钯(0.001mmol)、Ad2PnBu(0.0024mmol)以及乙醇钠(0.8mmol)混合,在加热情况下反应,反应时间经历18小时。1-7的转化率为95%,2-7的产率为76%。1H NMR(500MHz,CDCl3)δ7.58(d,J=7.7Hz,1H),7.51(d,J=8.4Hz,1H),7.35–7.30(m,2H),7.25(d,J=2.5Hz,1H),7.12(t,J=7.5Hz,1H),7.00(d,J=7.4Hz,1H),3.85(s,3H),3.51(d,J=17.3Hz,1H),3.39(d,J=17.3Hz,1H),2.14(s,3H).13C{1H}NMR(125MHz,CDCl3)δ200.3,179.4,160.1,156.4,145.6,140.7,137.7,128.7,127.6,125.8,125.3,121.1,120.3,106.4,73.2,55.7,34.5,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C18H16NO2 +278.1176,Found 278.1184.
实施例8
将2-甲基-3-(邻溴苄基)吲哚衍生物1-8(0.1mmol)、Co2(CO)8(0.85mmol)、1%的醋酸钯(0.001mmol)、双三苯基膦丁烷(0.002mmol)以及氢氧化钾(0.3mmol)混合,在加热情况下反应,反应时间经历36小时。1-8的转化率为95%,2-8的产率为71%。核磁氢谱和碳谱图如图1-2所示。1H NMR(500MHz,CDCl3)δ7.76(d,J=8.2Hz,1H),7.64(s,1H),7.59(d,J=Hz,1H),7.48-7.46(m,1H),7.34(dt,J1=7.6Hz,J2=1.2Hz,1H),7.12(dt,J1=8.7Hz,J2=1.1Hz,1H),6.98(d,J=7.4Hz,1H),3.57(d,J=17.9Hz,1H),3.45(d,J=17.9Hz,1H),2.15(s,3H).13C{1H}NMR(125MHz,CDCl3)δ198.8,178.7,156.3,154.1,142.5,140.2,134.8,129.1,128.8,127.1,126.3,125.9,121.0,120.3,72.3,34.7,16.3.HRMS(ESI)m/z:[M+H]+Calcd.for C17H13ClNO+282.0680,Found 282.0689.
实施例9
将2-甲基-3-(邻溴苄基)吲哚衍生物1-9(0.1mmol)、Co2(CO)8(0.5mmol)、5%的氢氧化钯(0.005mmol)、三环己基膦(0.012mmol)以及氢氧化钠(0.2mmol)混合,在加热情况下反应,反应时间经历28小时。1-9的转化率为96%,2-9的产率为73%。核磁氢谱和碳谱图如图3-4所示。1H NMR(500MHz,CDCl3)δ7.64-7.52(m,3H),7.44(d,J=7.6Hz,1H),7.34(dt,J1=7.7Hz,J2=1.3Hz,1H),7.12(t,J=7.6Hz,1H),6.98(d,J=7.4Hz,1H),3.58(d,J=17.7Hz,1H),3.42(d,J=17.7Hz,1H),2.18(s,3H).13C{1H}NMR(125MHz,CDCl3)δ196.8,178.8,156.2,154.8,140.4,135.9,133.4,132.4,129.9,128.8,125.8,125.2,121.0,120.3,72.7,34.4,16.5.HRMS(ESI)m/z:[M+H]+Calcd.for C17H13ClNO+282.0680,Found282.0683.
实施例10
将2-甲基-3-(邻溴苄基)吲哚衍生物1-10(0.1mmol)、Co2(CO)8(0.8mmol)、10%的氯化钯(0.01mmol)、双三苯基膦丙烷(0.016mmol)正丁基锂(0.5mmol)混合,在加热情况下反应,反应时间经历18小时。1-10的转化率为90%,2-10的产率为69%。核磁氢谱和碳谱图如图5-6所示。1H NMR(500MHz,CDCl3)δ7.76-7.73(m,2H),7.61(d,J=7.8Hz,1H),7.48(t,J=7.7Hz,1H),7.36(dt,J1=7.7Hz,J2=1.2Hz,1H),7.15(t,J=7.5Hz,1H),7.0(d,J=7.5Hz,1H),3.59(d,J=18.3Hz,1H),3.48(d,J=18.3Hz,1H),2.17(s,3H).13C{1H}NMR(125MHz,CDCl3)δ199.4,178.6,156.3,150.3,140.2,138.2,135.4,133.2,129.9,128.9,126.0,123.6,121.1,120.4,72.1,34.1,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C17H13ClNO+282.0680,Found 282.0686.
实施例11
将2-甲基-3-(邻溴苄基)吲哚衍生物1-11(0.1mmol)、Co2(CO)8(1.0mmol)、1%的三氟乙酸钯(0.001mmol)、双三苯基膦丙烷(0.002mmol)以及氢氧化钾(0.5mmol)混合,在加热情况下反应,反应时间经历18小时。1-11的转化率为95%,2-11的产率为72%。核磁氢谱和碳谱图如图7-8所示。1H NMR(500MHz,CDCl3)δ7.96-7.94(m,2H),7.76(d,J=8.0Hz,1H),7.61(d,J=7.8Hz,1H),7.36(dt,J1=7.8Hz,J2=1.3Hz,1H),7.14(t,J=7.5Hz,1H),6.94(d,J=7.4Hz,1H),3.68(d,J=17.9Hz,1H),3.55(d,J=17.9Hz,1H),2.16(s,3H).13C{1H}NMR(125MHz,CDCl3)δ199.4,178.3,156.3,152.8,140.0,138.9,137.0(q,JC-F=32.5Hz),129.0,126.0,125.9,125.4(q,JC-F=3.8Hz),124.1,(q,JC-F=3.8Hz),123.4(q,JC-F=271.3Hz),121.0,120.5,72.4,35.1,16.4.HRMS(ESI)m/z:[M+H]+Calcd.for C18H13F3NO+316.0944,Found 316.0952.
实施例12
将2-甲基-3-(邻溴苄基)吲哚衍生物1-12(0.1mmol)、Co2(CO)8(0.5mmol)、10%的双(乙腈)氯化钯(0.01mmol)、三苯基膦(0.018mmol)以及二乙胺(0.6mmol)混合,在加热情况下反应,反应时间经历48小时。1-12的转化率为93%,2-12的产率为79%。核磁氢谱和碳谱图如图9-10所示。1H NMR(500MHz,CDCl3)δ8.51(s,1H),8.36-8.33(m,1H),7.99(d,J=8.3Hz,1H),7.61(d,J=7.8Hz,1H),7.39-7.36(m,1H),7.15(t,J=7.15Hz,1H),6.97(d,J=7.4Hz,1H),3.59(d,J=18.0Hz,1H),3.72(d,J=18.0Hz,1H),2.17(s,3H).13C{1H}NMR(125MHz,CDCl3)δ198.8,177.9,156.2,153.4,152.4,140.3,139.7,129.2,126.3,126.1,123.7,122.3,120.9,120.6,72.6,35.0,16.5.HRMS(ESI)m/z:[M+H]+Calcd.for C17H13N2O3 +293.0921,Found 293.0929.
实施例13
将2-甲基-3-(邻溴苄基)吲哚衍生物1-13(0.1mmol)、Co2(CO)8(0.05mmol)、1%的醋酸钯(0.001mmol)、双三苯基膦丁烷(0.0024mmol)以及二乙胺(0.2mmol)混合,在加热情况下反应,反应时间经历30小时。1-13的转化率为95%,2-13的产率为83%。核磁氢谱和碳谱图如图11-12所示。1H NMR(500MHz,CDCl3)δ7.60(d,J=7.8Hz,1H),7.34(dt,J1=7.6Hz,J2=1.3Hz,1H),7.24(s,1H),7.14(t,J=7.5Hz,1H),7.04-7.02(m,2H),4.04(s,3H),3.94(s,3H),3.51(d,J=17.5Hz,1H),3.40(d,J=17.5Hz,1H),2.15(s,3H).13C{1H}NMR(125MHz,CDCl3)δ198.6,179.7,156.4,156.3,150.1,148.2,140.7,129.3,128.6,125.8,121.1,120.2,107.5,105.5,72.7,56.4,56.2,34.9,16.2.HRMS(ESI)m/z:[M+H]+Calcd.forC19H18NO3 +308.1281,Found 308.1286.
实施例14
将2-甲基-3-(邻溴苄基)吲哚衍生物1-14(0.1mmol)、Co2(CO)8(0.3mmol)、10%的醋酸钯(0.01mmol)、Ad2PnBu(0.02mmol)以及乙醇钠(0.5mmol)混合,在加热情况下反应,反应时间经历12小时。1-14的转化率为95%,2-14的产率为85%。核磁氢谱和碳谱图如图13-14所示。1H NMR(500MHz,CDCl3)δ9.02(d,J=8.3Hz,1H),8.20(d.J=8.4Hz,1H),7.98(d,J=8.2Hz,1H),7.71-7.41(m,4H),7.36(dt,J1=7.8Hz,J2=1.3Hz,1H),7.13(t,J=7.5Hz,1H),7.03(d,J=7.4Hz,1H),3.71(d,J=18.1Hz,1H),3.59(d,J=18.0Hz,1H),2.19(s,3H)13C{1H}NMR(125MHz,CDCl3)δ200.2,179.5,156.5,156.4,140.6,137.0,133.0,130.8,129.8,129.6,128.6,128.3,127.3,125.8,124.0,123.7,121.0,120.2,72.8,35.4,16.3.HRMS(ESI)m/z:[M+H]+Calcd.for C21H16NO+298.1226,Found298.1234.
实施例15
将2-苯基-3-(邻溴苄基)吲哚1-15(0.1mmol)、Co2(CO)8(0.05mmol)、5%的乙酰丙酮钯(0.005mmol)、三环己基膦(0.008mmol)以及三乙胺(0.5mmol)混合,在加热情况下反应,反应时间经历42小时。1-15的转化率为92%,2-15的产率为71%。核磁氢谱和碳谱图如图15-16所示。1H NMR(500MHz,CDCl3)δ7.96(d,J=7.7Hz,1H),7.81-7.76(m,2H),7.69-7.66(m,3H),7.57(t,J=7.8Hz,1H),7.43-7.33(m,4H),7.13(dt,J1=7.5Hz,J2=1.1Hz,1H),6.91(d,J=7.4Hz,1H),3.84(d,J=17.7Hz,1H),3.51(d,J=17.7Hz,1H)13C{1H}NMR(125MHz,CDCl3)δ200.2,177.2,155.8,152.5,142.0,136.4,135.8,131.7,131.1,128.9,128.8,128.4,127.9,127.3,126.3,125.9,121.3,120.1,70.5,37.6.HRMS(ESI)m/z:[M+H]+Calcd.for C22H16NO+310.1226,Found 310.1232.
实施例16
将2-(4-氟苯基)-3-(邻溴苄基)吲哚1-16(0.1mmol)、Co2(CO)8(0.2mmol)、10%的四三苯基膦钯(0.01mmol)、(0.024mmol)以乙醇钠(0.9mmol)混合,在加热情况下反应,反应时间经历46小时。1-16的转化率为93%,2-16的产率为72%。核磁氢谱和碳谱图如图17-18所示。1H NMR(500MHz,CDCl3)δ7.95(d,J=7.7Hz,1H),7.81-7.56(m,5H),7.57(t,J=7.3Hz,1H),7.39(dt,J1=7.8Hz,J2=1.2Hz,1H),7.13(dt,J1=7.5Hz,J2=1.1Hz,1H),7.05-7.02(m,2H),6.91(d,J=7.3Hz,1H),3.79(d,J=17.7Hz,1H),3.52(d,J=17.7Hz,1H).13C{1H}NMR(125MHz,CDCl3)δ200.0,175.9,164.5(d,JC-F=251.3Hz),155.7,152.4,141.9,136.2,136.0,130.0(d,JC-F=8.8Hz),128.9,128.5,128.1(d,JC-F=2.5Hz),127.3,126.3,125.9,121.2,120.1,116.1(d,JC-F=21.3Hz),70.4,37.6.HRMS(ESI)m/z:[M+H]+Calcd.forC22H15FNO+328.1132,Found 328.1143。
Claims (10)
1.一种全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,使用羰基金属化合物作为安全的羰基源,采用一步反应同时完成羰基的引入和螺环的构建,其反应按照以下步骤进行:将化合物1与羰基金属化合物Co2(CO)8混合,加入钯催化剂、膦配体以及碱,在溶剂中反应后即得目标化合物2,反应式如下:
其中,R1为氢、氟、氯、烷基或烷氧基;R2为氢、氟、氯、硝基、三氟甲基、苯基、烷基或烷氧基;R3为烷基、苯基或卤代的苯基。
2.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,所述化合物1与羰基金属化合物的摩尔配比为1:0.5~100。
3.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,所述钯催化剂为氢氧化钯、醋酸钯、四三苯基膦钯、氯化钯、双(乙腈)氯化钯、乙酰丙酮钯、三氟乙酸钯或四三苯基膦钯。
4.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,所述溶剂为甲苯、氯苯、二甲苯、氟苯或三氟甲苯。
5.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,所述化合物1与催化剂的摩尔配比为1:0.005~1:0.3。
6.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,所述膦配体为金刚烷膦、三苯基膦、双三苯基膦丙烷、三环己基膦、双三苯基膦丁烷、三叔丁基膦、三(邻甲基苯基)膦或1,1'-联萘-2,2'-双二苯膦。
7.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,所述碱为叔丁醇钾、乙醇钠、叔丁醇钠、氢氧化钾、氢氧化钠、三乙胺、甲醇钠、正丁基锂或二乙胺。
8.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,该反应在室温至150℃下进行。
9.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,该反应的反应时间为1-48小时。
10.根据权利要求1所述的全碳季碳环酮螺环假吲哚衍生物的合成方法,其特征在于,所述目标化合物的产率为69-85%。
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