CN115093413B - 二氢吡啶螺[3,4’]吲哚和四氢吡啶并呋喃[2,3-b]吲哚-5-酮类骨架及制备 - Google Patents
二氢吡啶螺[3,4’]吲哚和四氢吡啶并呋喃[2,3-b]吲哚-5-酮类骨架及制备 Download PDFInfo
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Abstract
本发明涉及二氢吡啶螺[3,4']吲哚和四氢吡啶并呋喃[2,3‑b]吲哚‑5‑酮两类吲哚骨架及其制备方法,本发明所提供的方法通过以吲哚取代β‑氨基丙烯酸酯衍生物或Boc吲哚取代β‑氨基丙烯酸酯衍生物为底物,在高价碘试剂、路易斯酸和有机溶剂存在的条件下,室温发生反应实现,本发明提供的两类生物碱骨架的制备方法原料易得,反应条件温和,操作简单,无需对原料进行预先官能团化,底物适用范围广,收率高。有利于潜在生物活性化合物及天然产物的生产和处理。
Description
技术领域
本发明属于有机合成技术领域,具体涉及二氢吡啶螺[3,4’]吲哚和四氢吡啶并呋喃[2,3-b]吲哚-5-酮类生物碱骨架及其制备方法。
背景技术
二氢吡啶螺[3,4’]吲哚和四氢吡啶并呋喃[2,3-b]吲哚-5-酮这两类含吲哚生物碱骨架广泛存在于天然产物和具有多种药理活性的小分子化合物中。因其独特的螺吲哚片段、吲哚稠环结构以及广泛生物活性,引起了有机化学家和药物化学家的研究兴趣。对于螺吲哚骨架的合成策略,通常采用昂贵过渡金属(Au,Ag,Ir,Rh,Pd等)催化底物中的不饱和键形成预亲电中心,随后发生类似芳香亲电取代反应;在2016年,Erik V.Van der Eycken课题组报道了一种利用银纳米粒子催化丙炔酰胺底物1a实现螺吲哚骨架1b的合成。(ACSCatal.2016,6,8156-8161)2017年,Xavier Guinchard课题组以N-炔丙基色胺2a为底物,JohnPhosAu(MeCN)SbF6为催化剂经5-exo-dig环化过程实现了螺吲哚2b的合成。(Adv.Synth.Catal.2017,359,4036-4042)
近日,Jia课题组开发了一种钯催化的四取代环内烯胺3a的分子内对映选择性β-芳基化实现吲哚螺五元内酯3b的合成。(ACS Catal.2021,11,1827-1832)
Géraldine Masson课题组通过手性磷酸催化2-取代的3-吲哚甲醇4a与1,3-二烯氨基甲酸酯4a-1的环加成反应实现了具有四个连续立体中心的手性螺环己基-吲哚4b对映选择性合成。(J.Am.Chem.Soc.2021,143,11611-11619)
2017年,You课题组利用Ir催化吲哚衍生物5a的不对称烯丙基去芳构化反应实现了螺吲哚5b的合成。(Angew.Chem.Int.Ed.2017,56,15093-15097)
对于四氢吡啶并呋喃[2,3-b]吲哚骨架至今只有Ma课题组实现其合成,即在强碱LiHMDS和I2的作用下底物6a发生氧化环化串联反应实现四氢吡啶并呋喃[2,3-b]吲哚骨架6b的合成。但是该方法反应条件苛刻,底物适用性差。(Org.Lett.2012,14,1405-1407)
虽然对于1b-5b这类螺吲哚骨架的合成方法种类还有很多,(Angew.Chem.Int.Ed.2020,59,614-621;J.Org.Chem.2020,85,3010-3019;Org.Lett.2020,22,1589-1593;Org.Lett.2020,22,3291-3296;Org.Lett.2019,21,9672-9676;Org.Biomol.Chem.2018,16,2039-2042)但是均有缺点:1)昂贵过渡金属的使用不仅造成资源浪费,环境污染,而且增加了合成成本,从而限制了其应用;2)底物制备复杂繁琐,步骤冗长,不利于后期官能团修饰和转化。综上所述,开发一种简单、高效、通用的合成方法制备二氢吡啶螺[3,4’]吲哚和四氢吡啶并呋喃[2,3-b]吲哚-5-酮这两类含吲哚生物碱骨架具有重要的意义。
发明内容
本发明所要解决的技术问题在于克服现有技术中存在的缺陷,提供一系列含有螺吲哚片段的二氢吡啶螺[3,4’]吲哚以及四氢吡啶并呋喃[2,3-b]吲哚-5-酮这两类含吲哚生物碱骨架的化合物,并提供该系列含吲哚生物碱骨架化合物的制备方法,以满足条件温和、操作简单、收率可观、适用性广的需求。
为解决上述问题,本发明所采取的技术方案是:
本发明第一方面提供了一种二氢吡啶螺[3,4’]吲哚骨架化合物,其化学结构如式I所示:
其中:
R1为单取代或多取代基团,可独立的选自H,F,Cl,Br,C1-C4直链或支链烷基或C1-C4直链或支链烷氧基;
R3选自C1-C4直链或支链烷基,优选Me,Et或tBu。
作为本发明的进一步改进,其化学结构式为:
本发明第二方面提供了一种二氢吡啶螺[3,4’]吲哚骨架化合物,其化学结构如式II所示:
其中:
R4为单取代或多取代基团,可独立的选自H,Cl,Br或C1-C4直链或支链烷基。
作为本发明的进一步改进,其化学结构式为:
本发明第三方面提供了一种式I化合物的制备方法,包括如下步骤:式Ⅲ所示的吲哚取代β-氨基丙烯酸酯衍生物在高价碘试剂、路易斯酸和有机溶剂存在的条件下,发生反应即可得到目标产物,所述式Ⅲ所示化合物的结构如下:
式中R1、R2和R3的定义如前所述。
其反应机理为:吲哚取代β-氨基丙烯酸酯衍生物在高价碘和路易斯酸催化下进行分子内极性反转螺环化反应。
作为本发明的进一步改进,所述吲哚取代β-氨基丙烯酸酯衍生物与高价碘试剂和路易斯酸的摩尔比为1∶1.0~1.4∶0.05~0.5。
本发明第四方面提供了一种式II化合物的制备方法,包括如下步骤:式IV所示的N-Boc吲哚取代β-氨基丙烯酸酯衍生物与高价碘试剂和路易斯酸和有机溶剂存在的条件下,发生反应即可得到目标产物,所述式IV所示化合物的结构如下:
式中R4、R5和R6的定义如前所述。
其反应机理为以N-Boc吲哚取代β-氨基丙烯酸酯衍生物为原料,以高价碘和路易斯酸为催化剂进行分子内极性反转螺环化串联Mannich类型分子内环合反应。
作为本发明的进一步改进,所述N-Boc吲哚取代β-氨基丙烯酸酯衍生物与高价碘试剂和路易斯酸的摩尔比为1∶1.0~1.4∶0.05~0.5。
作为本发明的进一步改进,所述高价碘试剂选自如下:
其中:Ra或Rb独立的任意选自OH、OAc、OCOCF3、OTs、OMs或ONs;Rc选自F或CF3。
作为本发明的进一步改进,所述路易斯酸选自Cu(OTf)2,CuOTf,CuBr,CuCl,Zn(OTf)2,Sm(OTf)2,Sc(OTf)3,In(OTf)3,Fe(OTf)3,Bi(OTf)3,AgOTf,AgBF4,BF3·Et2O或TMSOTf。
作为本发明的进一步改进,所述有机溶剂选自苯、甲苯、二甲苯、石油醚、乙酸乙酯、二氯甲烷、氯仿、四氯化碳、乙醚、N,N-二甲基甲酰胺、四氢呋喃、环己烷、甲基环己烷、正己烷、正庚烷、1,4-二氧六环、甲醇、乙醇、异丙醇、叔丁醇和乙腈中至少一种或两种及以上的组合。
作为本发明的进一步改进,反应温度为20~35℃。
作为本发明的进一步改进,所述反应的反应时间为0.5~48h。
作为本发明的进一步改进,所述反应还包含纯化的工序,具体选自薄层层析,柱层析和减压蒸馏。
采用上述技术方案所产生的有益效果在于:
本发明提供了一种以高价碘试剂和路易斯酸共同介导,以β-氨基丙烯酸酯衍生物为原料,以发散式合成策略以对二氢吡啶螺[3,4’]吲哚和四氢吡啶并呋喃[2,3-b]吲哚-5-酮这两类吲哚骨架的合成。该合成方法催化剂廉价易得,环境污染小,催化活性高,底物适用范围广,合成螺吲哚骨架多样,反应条件温和,操作简单,有利于潜在生物活性化合物及天然产物的生产和处理。
附图说明
图1为本发明化合物II-2的晶体结构图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面结合具体实施例对发明进行清楚、完整的描述。
本实施例部分提供了一系列二氢吡啶螺[3,4’]吲哚和四氢吡啶并呋喃[2,3-b]吲哚-5-酮这两类吲哚骨架化合物的制备。其中,二氢吡啶螺[3,4’]吲哚骨架化合物制备路线和步骤如下:
在室温下,向干燥的圆底反应瓶中加入底物Ⅲ(0.2mmol,1.0equiv.),1-氟-3,3-二甲基-1,3-二氢-1-λ3-苯并[d][1,2]碘代噁唑(0.24mmol,1.2equiv.)和5mL乙酸乙酯,随后加入三氟甲磺酸铟(0.04mmol,20mol%)在室温下反应1小时,待反应结束后,减压除去溶剂,以200-300目硅胶为固定相进行柱层析分离,最终获得目标产物I(石油醚/二氯甲烷为洗脱剂)。
利用上述通式制备条件,制备不同的实施例化合物I-1~I-5。
实施例1
黄色油状,(62.9mg,84%yield),Rf=0.35(DCM/EtOAc=20:1);1H-NMR(600MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.58(d,J=7.6Hz,1H),7.41(t,J=7.4Hz,2H),7.35(t,J=7.3Hz,1H),7.31(d,J=7.3Hz,3H),7.17(t,J=7.3Hz,1H),7.13(d,J=7.2Hz,1H),4.44(s,2H),3.28–3.23(m,1H),3.19–3.15(m,1H),2.03–1.98(m,1H),1.43–1.39(m,1H),1.10(s,9H);13C-NMR(151MHz,CDCl3)δ179.2,166.7,155.1,148.0,145.7,136.4,129.1,128.3,127.8,127.6,125.8,121.8,121.1,93.5,79.4,60.1,55.0,43.0,29.4,28.1.IR(thinfilm):vmax(cm-1)=3048,2964,2975,2853,1721,1666,1591,1449,1321,1193,1045,946,821,778,649,588,513。HRMS(APCI):Calcd for C24H27N2O2[M+H]+:375.2067,found375.2068。
实施例2
黄色油状(42.4mg,54%yield),Rf=0.18(DCM/EtOAc=40:1)。1H-NMR(600MHz,CDCl3)δ8.00(s,1H),7.86(s,1H),7.50(dd,J=8.4,4.6Hz,1H),7.42(t,J=7.4Hz,2H),7.36(t,J=7.3Hz,1H),7.30(d,J=7.4Hz,2H),6.99(t,J=8.8Hz,1H),6.84(d,J=8.0Hz,1H),4.44(s,2H),3.27–3.09(m,2H),2.00(ddd,J=13.8,9.6,4.4Hz,1H),1.41(dt,J=13.3,4.4Hz,1H),1.13(s,9H);13C-NMR(151MHz,CDCl3)δ178.9,178.9,166.3,162.4,160.8,150.9,147.9,147.7,147.7,136.0,129.0,128.3,127.7,121.6,121.5,114.0,113.9,109.6,109.5,92.9,79.4,60.0,55.4,55.4,42.6,29.1,28.0。IR(thin film):vmax(cm-1)=3354,3045,2978,2926,2854,1678,1557,1476,1452,1264,1094,1002,985,850,776,751,684,601.HRMS(APCI):Calcd for C24H26FN2O2[M+H]+:393.1973,found 393.1974。
实施例3
黄色油状(63.8mg,78%yield),Rf=0.34(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.85(s,1H),7.49(d,J=8.2Hz,1H),7.42(t,J=7.4Hz,2H),7.36(t,J=7.4Hz,1H),7.30(s,1H),7.29(s,1H),7.28(dd,J=8.2,2.1Hz,1H),7.09(d,J=2.0Hz,1H),4.45(s,2H),3.26–3.14(m,2H),2.03–1.98(m,1H),1.37(dt,J=13.3,4.3Hz,1H),1.14(s,9H);13C-NMR(151MHz,CDCl3)δ179.7,166.3,153.5,148.1,147.5,136.1,131.8,129.2,128.4,127.8,127.8,122.5,121.9,92.8,79.6,60.1,55.4,42.7,29.1,28.1。IR(thinfilm):vmax(cm-1)=3078,3050,2974,2926,2874,1903,1785,1679,1556,1548,1474,1364,1120,1032,1001,959,939,820,777,765,560。HRMS(APCI):Calcd for C24H26ClN2O2[M+H]+:409.1477,found 409.1478。
实施例4
黄色油状(66.3mg,82%yield),Rf=0.34(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ7.91(s,1H),7.85(s,1H),7.46(d,J=8.4Hz,1H),7.40(t,J=7.5Hz,2H),7.34(t,J=7.2Hz,1H),7.30(d,J=7.6Hz,2H),6.81(d,J=8.0Hz,1H),6.68(s,1H),4.43(s,1H),3.76(s,3H),3.25(t,J=9.8Hz,1H),3.19–3.06(m,1H),1.98(t,J=11.3Hz,1H),1.42(d,J=13.1Hz,1H),1.12(s,9H);13C-NMR(151MHz,CDCl3)δ177.1,166.7,158.5,148.7,147.8,147.4,136.3,129.1,128.3,127.8,121.3,112.3,108.4,93.8,79.3,60.1,55.8,55.1,42.7,29.5,28.1.IR(thin film):vmax(cm-1)=2960,2926,2854,2821,1904,1678,1558,1463,1417,1238,1262,1095,941,800,777,644,592,556。HRMS(APCI):Calcd forC25H29N2O3[M+H]+:405.2173,found 405.2175。
实施例5
黄色油状(64.5mg,83%yield),Rf=0.34(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.86(s,1H),7.58(d,J=7.6Hz,1H),7.30(t,J=7.5Hz,1H),7.24–7.15(m,5H),7.13(d,J=7.2Hz,1H),4.40(s,2H),3.24(ddd,J=13.3,9.9,3.6Hz,1H),3.16(dt,J=12.8,4.7Hz,1H),2.38(s,3H),1.98(ddd,J=13.7,9.9,4.2Hz,1H),1.42–1.36(m,1H),1.10(s,9H);13C-NMR(151MHz,CDCl3)δ179.3,166.7,155.0,148.0,145.7,138.1,133.2,129.8,127.8,127.6,125.8,121.8,121.1,93.2,79.3,59.9,55.1,42.9,29.4,28.1,21.3。IR(thin film):vmax(cm-1)=2957,2925,2869,2853,1737,1676,1608,1554,1362,1114,1095,1027,833,824,747。HRMS(APCI):Calcd for C27H33N2O2[M+H]+:417.2537,found417.2539。
本实施例部分还提供了二氢吡啶螺[3,4’]吲哚骨架化合物如下的制备方法:
在室温下,向干燥的圆底反应瓶中加入底物Ⅲ(0.2mmol,1.0equiv.),醋酸碘苯(0.24mmol,1.2equiv.)和5mL乙酸乙酯,随后加入三氟甲磺酸铟(0.04mmol,20mol%)在室温下反应1小时,待反应结束后,减压除去溶剂,以200-300目硅胶为固定相进行柱层析分离,最终获得目标产物I(石油醚/二氯甲烷为洗脱剂)。
利用上述通式制备条件,制备不同的实施例化合物I-6~I-16。
实施例6
黄色油状(51.8mg,66%yield),Rf=0.33(DCM/EtOAc=20:1).1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.83(s,1H),7.58(d,J=7.6Hz,1H),7.36–7.27(m,3H),7.18(td,J=7.4,1.0Hz,1H),7.14–7.04(m,3H),4.41(s,2H),3.23(ddd,J=13.3,9.9,3.5Hz,1H),3.19–3.11(m,1H),1.99(ddd,J=13.7,9.9,4.1Hz,1H),1.46–1.36(m,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ179.1,166.6,163.5,161.9,155.0,147.7,145.6,132.1,132.1,129.6,129.5,127.7,125.8,121.7,121.1,116.1,116.0,93.9,79.5,59.4。IR(thin film):vmax(cm-1)=3045,2974,2926,2854,1678,1600,1557,1509,1476,1452,1416,1390,1365,1319,1264,1223,1161,1149,1121,1001,850,776,752。HRMS(APCI):Calcd for C24H26FN2O2[M+H]+:393.1973,found 393.1977。
实施例7
黄色油状(66.1mg,81%yield),Rf=0.34(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.82(s,1H),7.58(d,J=7.4Hz,1H),7.38(d,J=8.1Hz,2H),7.30(t,J=7.4Hz,1H),7.24(d,J=8.0Hz,2H),7.18(t,J=7.3Hz,1H),7.11(d,J=7.1Hz,1H),4.40(s,2H),3.23(t,J=9.7Hz,1H),3.19–3.08(m,1H),2.05–1.88(m,1H),1.41(d,J=13.4Hz,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ178.9,166.4,154.9,147.5,145.4,134.7,134.1,129.2,129.1,127.6,125.7,121.6,121.0,94.0,79.4,77.3,77.1,76.9,59.2,54.8,42.9,29.2,27.9。IR(thin film):vmax(cm-1)=3045,2974,2926,2853,1797,1678,1603,1578,1556,1364,1319,1236,1120,1095,1001,820,765,752,658,624。HRMS(APCI):Calcdfor C24H26ClN2O2[M+H]+:409.1677,found 409.1675。
实施例8
黄色油状(62.6mg,69%yield),Rf=0.34(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ7.96(s,1H),7.75(s,1H),7.52(s,1H),7.47(d,J=8.3Hz,2H),7.25(t,J=7.5Hz,1H),7.17–7.09(m,3H),7.05(d,J=7.3Hz,1H),4.32(s,2H),3.17(ddd,J=13.2,9.9,3.5Hz,1H),3.08(ddd,J=12.8,5.3,4.1Hz,1H),1.93(ddd,J=13.7,9.9,4.1Hz,1H),1.35(ddd,J=13.3,5.3,3.6Hz,1H),1.03(s,9H);13C-NMR(151MHz,CDCl3)δ179.0,166.6,155.0,147.7,145.5,135.4,132.3,129.5,127.7,125.9,122.3,121.7,121.1,94.1,79.5,59.4,54.9,43.0,29.3,28.0。IR(thinfilm):vmax(cm-1)=3044,2964,2926,2854,1678,1603,1556,1487,1452,1390,1318,1261,1150,1119,1011,803,765,751。HRMS(APCI):Calcd forC24H26BrN2O2[M+H]+:453.1172,found 453.1171。
实施例9
黄色油状(66.7mg,80%yield),Rf=0.31(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.05(s,1H),7.86(s,1H),7.64–7.54(m,1H),7.30(td,J=7.5,1.3Hz,1H),7.27(d,J=4.6Hz,2H),7.22(d,J=7.9Hz,2H),7.17(t,J=7.4Hz,1H),7.13(d,J=7.3Hz,1H),4.41(s,2H),3.26(ddd,J=13.3,9.9,3.6Hz,1H),3.18(dt,J=12.8,4.7Hz,1H),2.94(hept,J=6.9Hz,1H),2.00(ddd,J=13.7,9.9,4.1Hz,1H),1.40(ddd,J=13.3,5.3,3.7Hz,1H),1.27(d,J=7.0Hz,6H),1.11(s,9H);13C-NMR(151MHz,CDCl3)δ179.3,166.7,154.9,149.0,148.0,145.7,133.6,127.8,127.6,127.1,125.8,121.8,121.0,93.2,79.3,59.8,55.0,42.9,33.9,29.3,28.0,24.1。IR(thin film):vmax(cm-1)=2957,2925,2869,2853,1737,1676,1608,1554,1362,1114,1095,1027,833,824,747。HRMS(APCI):Calcd for C27H33N2O2[M+H]+:417.2537,found 417.2539。
实施例10
黄色油状(74.7mg,86%yield),Rf=0.32(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.86(s,1H),7.58(d,J=7.6Hz,1H),7.31(t,J=7.6Hz,1H),7.17(t,J=7.4Hz,1H),7.12(d,J=7.3Hz,1H),6.88(d,J=8.2Hz,1H),6.85(d,J=8.2Hz,1H),6.79(d,J=1.9Hz,1H),4.37(d,J=2.9Hz,2H),3.91(s,3H),3.90(s,3H),3.23(ddd,J=13.3,9.9,3.5Hz,1H),3.16(dq,J=12.8,4.4Hz,1H),1.99(ddd,J=13.7,9.9,4.2Hz,1H),1.42–1.37(m,1H),1.10(s,9H);13C-NMR(151MHz,CDCl3)δ179.2,166.8,155.0,149.6,149.1,147.9,145.7,128.7,127.6,125.8,121.8,121.1,120.4,111.4,110.8,93.3,79.4,60.0,56.2,56.1,55.1,42.7,29.3,28.0。IR(thin film):vmax(cm-1)=2960,2926,2854,1678,1603,1558,1516,1453,1417,1390,1262,1238,1145,1028,800,751,619。HRMS(APCI):Calcd for C26H31N2O4[M+H]+:435.2278,found 435.2274。
实施例11
黄色油状(77.3mg,84%yield),Rf=0.32(DCM/EtOAc=30:1)。1H-NMR(600MHz,CDCl3)δ8.04(s,1H),7.85(s,1H),7.57(d,J=7.6Hz,1H),7.30(t,J=7.5Hz,1H),7.20(d,J=8.4Hz,2H),7.17(t,J=7.4Hz,1H),7.12(d,J=7.3Hz,1H),6.92(d,J=8.5Hz,2H),4.36(s,2H),3.97(t,J=6.6Hz,3H),3.25–3.20(m,1H),3.17–3.13(m,1H),2.00–1.95(m,1H),1.83–1.76(m,2H),1.47–1.43(m,2H),1.41–1.36(m,3H),1.10(s,9H),0.94(t,J=7.2Hz,3H);13C-NMR(151MHz,CDCl3)δ179.4,166.8,159.2,154.9,147.9,145.7,129.2,127.9,127.6,125.8,121.8,121.0,115.0,93.1,79.3,68.2,59.6,55.1,42.7,29.3,29.1,28.3,28.1,22.6,14.2。IR(thin film):vmax(cm-1)=3319,3038,2960,2824,2868,1920,1882,1634,1581,1454,1318,1172,1100,928,809,786,744,658,579,467,420。HRMS(APCI):Calcd for C29H37N2O3[M+H]+:461.2799,found 491.2797。
实施例12
黄色油状(69.4mg,77%yield),Rf=0.34(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.06(s,1H),7.90(s,1H),7.62(dd,J=18.0,7.9Hz,5H),7.45(d,J=7.6Hz,1H),7.38(d,J=7.9Hz,3H),7.32(d,J=7.3Hz,1H),7.18(d,J=9.4Hz,2H),4.48(s,2H),3.34–3.26(m,1H),3.26–3.15(m,1H),2.02(d,J=9.9Hz,1H),1.43(d,J=10.8Hz,1H),1.11(s,9H);13C-NMR(151MHz,CDCl3)δ179.2,166.7,155.1,147.9,145.7,141.3,140.6,135.3,129.0,128.3,127.8,127.7,127.6,127.2,125.8,121.8,121.1,93.6,79.4,59.8,55.0,43.0,29.4,28.0。IR(thin film):vmax(cm-1)=3050,3027,2975,2961,2848,2737,1952,1893,1802,1680,1514,1453,1421,1377,1098,930,786,741,643。HRMS(APCI):CalcdforC30H31N2O2[M+H]+:451.2380,found 451.2384。
实施例13
橘色油状(68.8mg,72%yield),Rf=0.25(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.28(d,J=8.4Hz,2H),8.05(s,1H),7.82(s,1H),7.60(d,J=7.7Hz,1H),7.49(d,J=8.3Hz,2H),7.33(t,J=7.5Hz,1H),7.20(t,J=7.4Hz,1H),7.14(d,J=7.3Hz,1H),4.54(s,2H),3.28(ddd,J=13.1,9.8,3.5Hz,1H),3.22–3.11(m,1H),2.04(ddd,J=13.7,9.9,4.1Hz,1H),1.46(ddd,J=13.3,5.4,3.5Hz,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ178.7,166.4,154.9,148.0,147.5,145.3,143.9,128.5,127.9,126.0,124.4,121.7,121.2,95.2,79.8,59.2,54.8,43.4,29.4,28.0。IR(thin film):vmax(cm-1)=3075,2961,2925,2854,2450,1679,1610,1523,1453,1416,1390,1364,1236,1202,1151,1015,955,799,751,737。HRMS(APCI):Calcd for C24H26N3O4[M+H]+:420.1918,found 420.1914。
实施例14
桔色油状(51.9mg,65%yield),Rf=0.13(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.04(s,1H),7.81(s,1H),7.72(d,J=8.3Hz,2H),7.59(d,J=7.6Hz,1H),7.43(d,J=8.2Hz,2H),7.32(t,J=7.6Hz,1H),7.20(t,J=7.3Hz,1H),7.13(d,J=7.2Hz,1H),4.49(s,2H),3.26(ddd,J=13.1,9.9,3.5Hz,1H),3.15(dt,J=12.6,4.3Hz,1H),2.02(ddd,J=13.7,9.9,4.1Hz,1H),1.48–1.43(m,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ178.7,166.4,155.0,147.5,145.3,141.9,133.0,128.3,127.8,126.0,121.7,121.2,118.5,112.4,95.0,79.8,59.5,54.8,43.4,29.4,28.0。IR(thin film):vmax(cm-1)=2925,2854,2229,1678,1604,1454,1414,1365,1320,1264,1236,1152,1121,1001,983,851,823,777,752。HRMS(APCI):Calcd for C25H26N3O2[M+H]+:400.2020,found 400.2023。
实施例15
黄色油状(61.9mg,70%yield),Rf=0.33(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.04(s,1H),7.83(s,1H),7.67(d,J=8.1Hz,2H),7.58(d,J=7.6Hz,1H),7.43(d,J=8.0Hz,2H),7.31(t,J=7.5Hz,1H),7.18(t,J=7.4Hz,1H),7.13(d,J=7.1Hz,1H),4.49(s,2H),3.26(ddd,J=13.1,10.0,3.5Hz,1H),3.16(dt,J=12.7,4.4Hz,1H),2.01(ddd,J=13.7,9.9,4.1Hz,1H),1.43(dt,J=13.3,4.4Hz,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ178.9,166.5,155.0,147.7,145.4,140.5,131.0,130.8,130.5,130.3,128.0,127.7,126.8,126.2,126.1,126.1,126.1,125.9,125.0,123.2,121.7,121.4,121.2,94.6,79.6,59.5,54.9,43.2,29.4,28.0。IR(thin film):vmax(cm-1)=3230,3100,3051,2974,2928,2865,1912,1654,1605,1547,1325,1258,1076,984,972,912,854。HRMS(APCI):Calcd forC25H26F3N2O2[M+H]+:443.1941,found 443.1945。
实施例16
黄色油状(38.8mg,45%yield),Rf=0.21(DCM/EtOAc=5:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.82(s,1H),7.60(s,1H),7.56(t,J=8.5Hz,3H),7.30(t,J=7.5Hz,1H),7.24(d,J=8.1Hz,2H),7.18(t,J=7.4Hz,1H),7.12(d,J=7.3Hz,1H),4.36(s,2H),3.25–3.21(m,1H),3.16–3.13(m,1H),2.19(s,3H),2.00–1.95(m,1H),1.41–1.38(m,1H),1.10(s,9H)。13C-NMR(151MHz,CDCl3)δ179.2,168.6,166.8,154.9,147.9,145.6,138.1,132.0,128.5,127.7,125.9,121.8,121.1,120.4,93.4,79.5,59.6,55.0,42.9,29.3,28.1,24.7。IR(thin film):vmax(cm-1)=3187,3122,2974,2926,2865,1898,1604,1537,1317,1270,1205,1015,976,765,742,653,541,464。HRMS(APCI):Calcd for C26H30N3O3[M+H]+:432.2282,found 432.2285。
本实施例部分还提供了二氢吡啶螺[3,4’]吲哚骨架化合物如下的制备方法:
在零度下,向干燥的圆底反应瓶中加入底物Ⅲ(0.2mmol,1.0equiv.),双(三氟乙酰氧基)碘苯(0.24mmol,1.2equiv.)和5mL二氯甲烷,随后加入三氟甲磺酸铜(0.04mmol,20mol%)在室温下反应1小时,待反应结束后,减压除去溶剂,以200-300目硅胶为固定相进行柱层析分离,最终获得目标产物I(石油醚/二氯甲烷为洗脱剂)。
利用上述通式制备条件,制备不同的实施例化合物I-17~I-23。
实施例17
黄色油状(29.7mg,38%yield),Rf=0.34(DCM/EtOAc=10:1)。1H-NMR(600MHz,CDCl3)δ8.26(s,1H),8.07(s,1H),7.87(s,1H),7.59(d,J=7.6Hz,1H),7.31(t,J=7.5Hz,1H),7.19(t,J=7.3Hz,1H),7.13(t,J=7.9Hz,3H),6.90(d,J=8.4Hz,2H),4.33(s,2H),3.24(ddd,J=13.2,9.7,3.6Hz,1H),3.20–3.14(m,1H),1.97(ddd,J=13.6,9.7,4.2Hz,1H),1.43–1.38(m,1H),1.10(s,9H);13C-NMR(151MHz,CDCl3)δ179.5,167.1,157.0,154.2,148.2,145.6,129.3,127.8,127.2,126.2,121.9,120.9,116.2,92.5,79.7,59.7,55.0,42.7,29.2,28.1。IR(thin film):vmax(cm-1)=3298,3071,2963,2926,2855,1724,1658,1598,1516,1454,1391,1365,1304,1147,1124,1049,849,835,761,752。HRMS(APCI):Calcdfor C24H27N2O3[M+H]+:391.2016,found 391.2016。
实施例18
黄色油状(54.2mg,68%yield),Rf=0.37(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.04(s,1H),7.83(s,1H),7.58(d,J=7.6Hz,1H),7.54(d,J=8.1Hz,2H),7.31(td,J=7.6,1.3Hz,1H),7.27(d,J=8.1Hz,2H),7.18(t,J=7.4Hz,1H),7.12(d,J=7.3Hz,1H),4.43(s,2H),3.26–3.22(m,1H),3.17–3.13(m,1H),3.11(s,1H),2.02–1.98(m,1H),1.43–1.39(m,1H),1.10(s,9H);13C-NMR(151MHz,CDCl3)δ179.1,166.6,155.1,147.8,145.6,137.1,132.9,127.8,127.7,125.9,122.2,121.8,121.1,94.1,83.2,79.5,78.0,59.8,55.0,43.1,29.3,28.0。IR(thinfilm):vmax(cm-1)=3292,3031,2977,2964,2952,2925,2853,1928,1725,1666,1591,1162,1057,978,850,778。HRMS(APCI):Calcd for C26H27N2O2[M+H]+:399.2067,found 399.2068。
实施例19
黄色油状(53.4mg,65%yield),Rf=0.36(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.79(s,1H),7.58(d,J=7.6Hz,1H),7.32(t,J=7.6Hz,1H),7.20(dt,J=10.5,8.0Hz,2H),7.17–7.08(m,2H),7.04(d,J=7.2Hz,1H),4.38(s,2H),3.25(td,J=11.5,10.2,3.2Hz,1H),3.15(dt,J=12.5,4.5Hz,1H),2.01(ddd,J=13.5,10.1,3.9Hz,1H),1.44(dt,J=13.0,4.0Hz,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ178.9,166.5,155.0,151.6,151.5,151.1,151.1,150.0,149.9,149.5,149.4,147.5,145.4,133.5,133.5,133.4,127.7,125.9,123.8,123.8,123.7,123.7,121.7,121.2,118.1,117.9,116.8,116.7,94.6,79.6,59.0,54.9,43.1,29.4,28.0。IR(thin film):vmax(cm-1)=3045,2974,2926,2854,1678,1600,1557,1509,1476,1452,1416,1390,1365,1319,1264,1223,1161,1149,1121,1001,850,776,752。HRMS(APCI):Calcd for C24H25F2N2O2[M+H]+:411.1879,found 411.1882。
实施例20
黄色油状(51.9mg,78%yield),Rf=0.29(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.09(s,1H),7.93(s,1H),7.62(d,J=7.6Hz,1H),7.43(t,J=7.4Hz,2H),7.37(t,J=7.4Hz,1H),7.31(d,J=6.9Hz,3H),7.16(t,J=7.3Hz,1H),7.08(d,J=7.3Hz,1H),4.65–4.30(m,2H),3.44(s,3H),3.31(ddd,J=12.9,11.3,3.6Hz,1H),3.20(dt,J=13.0,4.2Hz,1H),2.11(ddd,J=13.1,11.3,4.4Hz,1H),1.29(dt,J=13.2,3.7Hz,1H);13C-NMR(151MHz,CDCl3)δ179.4,166.8,154.7,148.1,144.9,136.1,129.2,128.4,128.0,127.7,125.9,121.9,121.2,92.1,60.2,54.6,50.8,42.6,28.7。IR(thinfilm):vmax(cm-1)=3042,2976,2926,2857,1705,1654,1538,1485,1415,1380,1367,1310,1119,992,930,901,853,768。HRMS(APCI):Calcd for C21H21N2O2[M+H]+:333.1598,found 333.1594。
实施例21
黄色油状(51.3mg,74%yield),Rf=0.33(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.07(s,1H),7.93(s,1H),7.60(d,J=7.6Hz,1H),7.42(t,J=7.5Hz,2H),7.36(t,J=7.3Hz,1H),7.33–7.29(m,3H),7.16(t,J=7.4Hz,1H),7.10(d,J=7.3Hz,1H),4.47(d,J=7.3Hz,2H),3.86(qd,J=7.1,4.1Hz,2H),3.30(ddd,J=13.8,10.9,3.6Hz,1H),3.20(dt,J=12.9,4.4Hz,1H),2.07(ddd,J=12.9,10.7,4.3Hz,1H),1.35(dt,J=13.3,4.1Hz,1H),0.94(t,J=7.1Hz,3H);13C-NMR(151MHz,CDCl3)δ179.2,166.7,155.0,148.1,145.2,136.2,129.1,128.4,127.8,127.7,125.8,121.9,121.1,92.3,60.2,59.3,54.7,42.7,28.9,14.1。IR(thin film):vmax(cm-1)=3038,3104,3050,2974,2962,2928,2845,1684,1625,1575,1469,1300,1262,1076,980,973,889,854,742。HRMS(APCI):Calcd for C22H23N2O2[M+H]+:347.1754,found 347.1755。
实施例22
黄色油状(46.7mg,69%yield),Rf=0.41(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.05(s,1H),7.73(s,1H),7.58(d,J=7.6Hz,1H),7.31(dq,J=7.9,3.9Hz,1H),7.19(d,J=4.2Hz,2H),3.47(ddd,J=13.2,9.9,3.6Hz,1H),3.40–3.32(m,1H),3.21–3.03(m,1H),2.04(ddd,J=13.7,9.9,4.1Hz,1H),1.46(ddd,J=13.1,5.4,3.6Hz,1H),1.08(s,10H),0.64(d,J=7.7Hz,2H),0.27(d,J=5.0Hz,2H);13C-NMR(151MHz,CDCl3)δ179.5,166.8,155.0,147.5,145.9,127.6,125.8,121.8,121.0,92.5,79.1,60.8,55.1,43.7,29.4,28.1,10.0,3.9,3.5。IR(thin film):vmax(cm-1)=3038,2962,2926,2854,2825,1921,1884,1710,1646,1581,1475,1337,1209,1100,991,935,810,792,744,595:HRMS(APCI):Calcd for C21H27N2O2[M+H]+:339.2067,found 339.2069。
实施例23
黄色油状(46.8mg,66%yield),Rf=0.43(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.05(s,1H),7.64(s,1H),7.58(d,J=7.7Hz,1H),7.36–7.28(m,1H),7.20(d,J=5.6Hz,2H),3.51(ddd,J=13.1,10.1,3.2Hz,1H),3.35(dd,J=12.7,4.8Hz,1H),3.04(s,2H),2.03(ddd,J=13.7,10.1,3.6Hz,1H),1.42(d,J=2.5Hz,1H),1.07(s,9H),1.00(s,9H);13C-NMR(151MHz,CDCl3)δ179.7,166.8,155.0,152.7,149.1,146.0,127.6,125.8,124.0,123.5,121.8,121.1,116.0,92.1,79.1,68.0,55.0,46.6,34.2,31.8,29.8,28.0,28.0,27.9。IR(thinfilm):vmax(cm-1)=3404,2957,2926,2855,1681,1601,1558,1510,1365,1117,1003,1048,855,766,765,563。HRMS(APCI):Calcd for C21H27N2O2[M+H]+:355.2380,found 355.2384。
本实施例部分还提供了二氢吡啶螺[3,4’]吲哚骨架化合物如下的制备方法:
在零度下,向干燥的圆底反应瓶中加入底物I(0.2mmol,1.0equiv.),羟基甲苯磺酰氧基碘苯(0.24mmol,1.2equiv.)和5m LDMSO溶剂,随后加入三氟甲磺酸亚铜(0.04mmol,20mol%)在室温下反应1小时,待反应结束后,减压除去溶剂,以200-300目硅胶为固定相进行柱层析分离,最终获得目标产物I(石油醚/二氯甲烷为洗脱剂)。
利用上述通式制备条件,制备不同的实施例化合物I-24~I-30。
实施例24
黄色油状(56.6mg,73%yield),Rf=0.18(DCM/EtOAc=25:1);yellowoil。1H-NMR(600MHz,CDCl3)δ7.91(s,1H),7.89(s,1H),7.43–7.37(m,3H),7.37–7.31(m,1H),7.31–7.27(m,2H),7.19(t,J=7.6Hz,1H),6.96(d,J=7.6Hz,1H),4.43(s,2H),3.24–3.13(m,2H),2.29(s,3H),2.35–2.23(m,1H),1.48(dt,J=13.7,3.3Hz,1H),0.96(s,9H);13C-NMR(151MHz,CDCl3)δ176.8,167.1,155.3,148.3,142.8,136.4,132.4,129.1,128.3,127.9,127.8,127.4,119.1,92.4,78.8,60.1,55.3,44.7,28.5,27.8,17.4。IR(thinfilm):vmax(cm-1)=3325,3050,2976,2923,2862,1698,1507,1432,1350,1264,1005,991,832。HRMS(APCI):Calcd for C25H29N2O2[M+H]+:339.2224,found 389.2225。
黄色油状(51.3mg,85%yield),Rf=0.35(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.76(s,1H),7.57(d,J=7.7Hz,1H),7.44(s,1H),7.30(t,J=7.5Hz,1H),7.17(t,J=7.4Hz,1H),7.10(d,J=7.3Hz,1H),6.41–6.35(m,1H),6.32(d,J=3.1Hz,1H),4.43–4.32(m,2H),3.32(ddd,J=13.3,9.9,3.6Hz,1H),3.25(dt,J=12.7,4.7Hz,1H),2.02(ddd,J=13.8,9.9,4.2Hz,1H),1.42(ddd,J=13.5,5.3,3.7Hz,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ179.2,166.5,155.0,150.0,147.3,145.6,143.2,127.6,125.8,121.9,121.1,110.6,109.0,94.5,79.4,55.0,52.4,43.3,29.3,28.0。IR(thinfilm):vmax(cm-1)=3151,3120,3050,2974,2962,2957,2923,2837,2560,2435,1684,1663,1360,1172,1052,869。HRMS(APCI):Calcd for C22H25N2O3[M+H]+:365.1860,found 365.1862。
黄色油状(48.7mg,72%yield),Rf=0.33(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.04(s,1H),7.69(s,1H),7.59(d,J=7.7Hz,1H),7.34–7.28(m,1H),7.19(d,J=7.4Hz,2H),5.00(s,1H),4.94(s,1H),3.78(s,2H),3.30(ddd,J=13.3,10.0,3.4Hz,1H),3.22(dd,J=11.4,6.4Hz,1H),2.02(ddd,J=13.7,10.0,4.0Hz,1H),1.77(s,3H),1.45(ddd,J=17.6,6.6,3.6Hz,1H),1.08(s,9H);13C-NMR(151MHz,CDCl3)δ179.4,166.7,155.1,148.0,145.8,140.4,127.6,125.8,121.8,121.1,114.4,92.9,79.3,62.3,55.1,42.9,29.4,28.0,20.1。IR(thinfilm):vmax(cm-1)=3245,3057,2962,2927,2860,1687,1575,1459,1163,951,864,720。HRMS(APCI):Calcd for C21H27N2O2[M+H]+:339.2067,found339.2068。
黄色油状(43.8mg,68%yield),Rf=0.27(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.04(s,1H),7.65(s,1H),7.59(dt,J=7.7,0.9Hz,1H),7.32(ddd,J=7.7,5.2,3.5Hz,1H),7.25–7.14(m,2H),4.10–3.95(m,2H),3.43(ddd,J=12.4,10.1,3.5Hz,1H),3.31(ddd,J=12.4,5.3,4.1Hz,1H),2.44(t,J=2.5Hz,1H),2.22–1.93(m,1H),1.49(ddd,J=13.4,5.4,3.6Hz,1H),1.09(s,9H);13C-NMR(151MHz,CDCl3)δ179.3,178.9,166.2,155.1,147.6,146.8,145.4,133.0,127.7,127.6,125.9,125.8,121.9,121.8,121.1,121.1,119.0,96.4,79.6,77.6,74.3,58.5,54.9,45.1,43.2,43.2,29.3,28.0,28.0。IR(thinfilm):vmax(cm-1)=3287,3053,2974,2957,2925,2834,2260,2140,1685,1630,1085,993,851。HRMS(APCI):Calcd for C20H23N2O2[M+H]+:323.1754,found 323.1756。
黄色油状(51.9mg,71%yield),Rf=0.21(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.03(s,1H),7.62(s,1H),7.58(d,J=7.6Hz,1H),7.31(ddd,J=7.8,6.4,2.4Hz,1H),7.22–7.13(m,2H),3.33(ddd,J=13.1,9.8,3.6Hz,1H),3.22(ddd,J=12.7,5.4,4.2Hz,1H),3.08(s,3H),2.03(ddd,J=13.7,9.8,4.2Hz,1H),1.46(ddd,J=13.3,5.4,3.6Hz,1H),1.08(s,9H);13C-NMR(151MHz,CDCl3)δ179.3,166.6,155.0,148.3,145.8,127.6,125.8,121.8,121.1,93.0,79.2,54.7,45.4,43.0,29.3,28.0。IR(thinfilm):vmax(cm-1)=2972,2957,2926,2867,2834,1730,1659,1600,1531,1362,1100,1059,947,834。HRMS(APCI):Calcd for C18H23N2O2[M+H]+:299.1754,found299.1755。
黄色油状,(54.5mg,74%yield),Rf=0.24(DCM/EtOAc=20:1);yellowoil。1HNMR(600MHz,CDCl3)δ8.04(s,1H),7.70(s,1H),7.61–7.54(m,1H),7.31(ddd,J=7.7,6.9,1.8Hz,1H),7.22–7.15(m,2H),3.38(ddd,J=13.2,9.9,3.6Hz,1H),3.36–3.30(m,2H),3.26(ddd,J=12.7,5.3,4.1Hz,1H),2.02(ddd,J=13.2,9.9,4.1Hz,1H),1.46(ddd,J=13.2,5.3,3.5Hz,1H),1.28(t,J=7.2Hz,3H),1.08(s,9H);13C-NMR(151MHz,CDCl3)δ179.5,166.8,155.0,147.3,145.9,127.6,125.8,121.8,121.1,92.6,79.1,55.1,50.7,42.9,29.4,28.1,13.9。IR(thinfilm):vmax(cm-1)=3320,3038,2982,2960,2862,2824,1914,1865,1573,1434,1308,1109,928,866,789,734。HRMS(APCI):Calcd for C19H25N2O2[M+H]+:313.1911,found 313.1910。
黄色油状,(61.6mg,68%yield),Rf=0.32(DCM/EtOAc=20:1)。1H-NMR(600MHz,CDCl3)δ8.02(s,1H),7.85(d,J=1.1Hz,1H),7.45–7.39(m,4H),7.36(t,J=7.3Hz,1H),7.30(d,J=7.4Hz,2H),7.24(s,1H),4.53–4.37(m,2H),3.32–3.11(m,2H),2.01(ddd,J=13.0,9.9,4.5Hz,1H),1.52–1.33(m,1H),1.14(s,9H);13C-NMR(151MHz,CDCl3)δ179.7,166.3,154.0,148.1,147.9,136.1,131.0,130.7,129.2,129.0,128.4,127.8,125.3,122.4,119.7,92.7,79.6,65.7,60.1,55.4,42.8,28.1.IR(thinfilm):vmax(cm-1)=3040,2958,2923,2848,1693,1628,1435,1385,1300,1260,1121,1008,963,864。HRMS(APCI):Calcd for C24H26BrN2O2[M+H]+:453.1172,found 453.1174。
本实施例部分还提供了一系列四氢吡啶并呋喃[2,3-b]吲哚-5-酮骨架化合物的制备,具体路线和步骤如下:
向干燥的圆底反应瓶中加入底物IV(0.2mmol,1.0equiv.),1-氟-3,3-二甲基-1,3-二氢-1-λ3-苯并[d][1,2]碘代噁唑(0.2mmol,1.0equiv.)和5mL二氯甲烷,随后加入三氟甲磺酸钪(19.7mg,0.04mmol,20mol%)。在室温条件下反应。待反应结束后,减压除去溶剂,以200-300目硅胶为固定相进行柱层析分离,最终获得目标产物II(石油醚/乙酸乙酯为洗脱剂)。
利用上述通式制备条件,制备不同的实施例化合物II-1~II-2。
实施例24
无色油状(39.3mg,47%yield),Rf=0.54(Petroleum Ether/EtOAc=1:1)。1H-NMR(600MHz,CDCl3)δ7.89(s,1H),7.58(s,1H),7.43(dd,J=8.1,6.6Hz,2H),7.40–7.36(m,1H),7.32–7.27(m,2H),7.24(t,J=7.9Hz,1H),6.94(td,J=7.5,1.1Hz,1H),6.79(d,J=7.5Hz,1H),6.00(s,1H),4.62–4.29(m,2H),3.48(td,J=13.5,4.4Hz,1H),3.28(ddd,J=14.1,5.3,1.6Hz,1H),1.91(ddd,J=12.5,4.5,1.6Hz,1H),1.84(td,J=12.8,5.3Hz,1H),1.59(s,9H);13C-NMR(151MHz,CDCl3)δ142.4,135.7,129.3,129.1,128.6,127.8,123.7,115.7,95.3,93.5,60.1,42.3,28.4。IR(thin film):vmax(cm-1)=2998,2976,2965,2926,2846,1715,1628,1607,1543,1333,1164,1114,1095,1024,936,847,833,74。HRMS(APCI:Calcd for C25H27N2O4[M+H]+:419.1965,found 419.1968。
实施例25
白色固体(50.7mg,55%yield),Rf=0.52(Petroleum Ether/EtOAc=1:1);m.p.=129.7–130.4℃。1H-NMR(600MHz,CDCl3)δ7.89(s,1H),7.57(s,1H),7.28(d,J=8.1Hz,2H),7.23(t,J=8.0Hz,1H),7.20(d,J=8.1Hz,2H),6.93(t,J=7.5Hz,1H),6.77(d,J=7.5Hz,1H),4.53–4.37(m,2H),3.48(td,J=13.3,4.4Hz,1H),3.29(ddd,J=14.1,5.3,1.7Hz,1H),2.95(hept,J=6.9Hz,1H),1.91(ddd,J=12.6,4.5,1.7Hz,1H),1.84(td,J=12.8,5.3Hz,1H),1.58(s,9H),1.28(d,J=6.9Hz,6H);13C-NMR(151MHz,CDCl3)δ169.9,151.5,149.5,142.5,140.9,136.2,133.0,129.0,127.9,127.3,124.2,123.6,115.6,95.3,93.3,82.4,59.9,48.4,42.3,34.0,28.4,24.1.IR(thin film):vmax(cm-1)=2967,2926,2874,2820,1719,1658,1583,1449,1323,1249,1019,999,977,821,741,681,593。HRMS(APCI):Calcd for C28H33N2O4[M+H]+:461.2435,found 461.2439。
本实施例部分还提供了四氢吡啶并呋喃[2,3-b]吲哚-5-酮这类吲哚骨架化合物的另一种制备方法,具体如下:
向干燥的圆底反应瓶中加入底物IV(0.2mmol,1.0equiv.),醋酸碘苯(0.2mmol,1.0equiv.)和5mL氯仿,随后加入三氟甲磺酸钐(0.04mmol,20mol%)。在室温条件下反应。待反应结束后,减压除去溶剂,以200-300目硅胶为固定相进行柱层析分离,最终获得目标产物II(石油醚/乙酸乙酯为洗脱剂)。
利用上述通式制备条件,制备不同的实施例化合物II-3~II-4。
实施例26
白色固体(36.2mg,40%yield),Rf=0.52(Petroleum Ether/EtOAc=1:1),m.p.=208.1–209.2℃。1H-NMR(600MHz,CDCl3)δ7.90(s,1H),7.55(s,1H),7.40(d,J=8.4Hz,2H),7.23(t,J=8.1Hz,3H),6.96(t,J=7.5Hz,1H),6.79(d,J=7.5Hz,1H),6.19–5.86(m,1H),4.54–4.27(m,2H),3.46(td,J=13.4,12.4,6.5Hz,1H),3.25(dd,J=14.1,5.1Hz,1H),1.92(dd,J=12.8,4.2Hz,1H),1.82(td,J=12.8,5.2Hz,1H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ169.8,151.4,142.2,134.6,134.3,129.5,129.2,124.1,123.7,123.7,115.7,95.3,94.0,82.5,59.4,48.4,42.3,29.8,28.4。IR(thin film):vmax(cm-1)=3440,3083,2998,2976,2964,2916,1902,1716,1625,1578,1461,1294,1091,978,950,921,861,788,601,491,463。HRMS(APCI):Calcd for C25H26ClN2O4[M+H]+:453.1576,found 453.1578。
实施例27
黄色油状(34.3mg,37%yield),Rf=0.47(Petroleum Ether/EtOAc=1:1)。1H-NMR(600MHz,CDCl3)δ8.30(d,J=8.7Hz,2H),7.91(s,1H),7.57(s,1H),7.48(d,J=8.4Hz,2H),7.26(d,J=3.5Hz,1H),6.98(td,J=7.5,1.0Hz,1H),6.89–6.69(m,1H),6.02(s,1H),4.59(q,J=15.6Hz,2H),3.52(t,J=12.5Hz,1H),3.26(ddd,J=13.9,5.2,1.7Hz,1H),2.14–1.92(m,1H),1.86(td,J=12.8,5.1Hz,1H),1.59(s,9H);13C-NMR(151MHz,CDCl3)δ168.5,147.0,142.1,140.9,128.2,127.3,123.4,122.6,114.7,94.2,94.2,58.0,41.5,28.7,27.3.IR(thin film):vmax(cm-1)=2965,2873,2854,2801,1718,1653,1525,1378,1364,1208,1105,1018,950,921,681,684。HRMS(APCI):Calcd for C25H26N3O6[M+H]+:464.1816,found 464.1813。
实施例28
1.单晶培养:将实施例27中柱层析分离得到的主要组分化合物II-2(36mg)溶于二氯甲烷(0.3mL)中,缓慢加入石油醚(0.1mL),再沿壁加入甲醇(0.1mL),4℃静置15-20天,有单晶析出,收集单晶进行单晶衍射测试。
2.测试参数如下:
化合物关键的键长数据和键角数据如表1-5。
Ueq等效为1/3正交化的Uij。
各向异性位移因子指数采用以下形式:-2π2[h2a*2U11+2hka*b*U12+…]。
表3:化合物II-2单晶结构模型中的键长表
表4:化合物II-2单晶结构模型中的键角表
Atom | x | y | z | U(eq) |
H6 | 2729.93 | 1731.77 | 2927.77 | 39 |
H5 | 3245.93 | 2402.27 | 4021.57 | 38 |
H16 | 3768.97 | 2040.77 | 5023.72 | 38 |
H2 | 3509.29 | 2387.26 | 86.73 | 45 |
H14A | 4753.89 | 3255.7 | 3899.5 | 40 |
H14B | 4370.42 | 2709.24 | 4174.81 | 40 |
H19 | 4241.03 | 1556.07 | 8351.12 | 39 |
H8 | 3656.45 | 3218.66 | 5478.85 | 38 |
H18 | 3801.59 | 1002.07 | 6899.87 | 41 |
H17 | 3563.99 | 1238.04 | 5275.3 | 42 |
H13A | 4928.01 | 3431.05 | 5826.31 | 40 |
H13B | 4954.72 | 2956.64 | 5575.13 | 40 |
H3 | 4013.75 | 3058.53 | 1196.02 | 43 |
H11 | 4834.52 | 3241.53 | 7851.02 | 41 |
H7A | 4250.01 | 3480.14 | 2943.27 | 42 |
H7B | 3773.53 | 3409.27 | 3546.49 | 42 |
H24A | 4827.63 | 2829.41 | 11732.64 | 120 |
H24B | 5322.55 | 2919.68 | 12269.01 | 120 |
H24C | 5017.01 | 2466.55 | 11458.95 | 120 |
H25A | 5656.11 | 2680.98 | 10038.14 | 149 |
H25B | 6018.35 | 3123.58 | 10816.64 | 149 |
H25C | 5931.26 | 3209.24 | 9508.91 | 149 |
H23A | 5716.52 | 3805.25 | 10073.1 | 192 |
H23B | 5769.03 | 3738.29 | 11414.38 | 192 |
H23C | 5274.78 | 3665.63 | 10916.75 | 192 |
尽管参照前述实施例对本发明进行了详细的说明,本领域技术人员依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明实施例技术方案的精神和范围。
Claims (6)
1.一种如式I所示二氢吡啶螺[3,4']吲哚骨架化合物的制备方法,其特征在于,包括如下步骤:式Ⅲ所示的吲哚取代β-氨基丙烯酸酯衍生物在高价碘试剂、路易斯酸和有机溶剂存在的条件下,室温发生反应即可得到目标产物,所述式I和式Ⅲ所示化合物的结构如下:
其中:
R1为单取代或多取代基团,可独立的选自H,F,Cl,Br,C1-C4直链或支链烷基或C1-C4直链或支链烷氧基;
R3选自C1-C4直链或支链烷基;
所述高价碘试剂选自如下:
所述路易斯酸选自Cu(OTf)2,CuOTf或In(OTf)3。
5.据权利要求1或3所述的制备方法,其特征在于,所述式Ⅲ或式IV所示化合物与高价碘试剂和路易斯酸的摩尔比为1∶1.0~1.4∶0.05~0.5。
6.根据权利要求1或3所述的制备方法,其特征在于,所述有机溶剂选自苯、甲苯、二甲苯、石油醚、乙酸乙酯、二氯甲烷、氯仿、四氯化碳、乙醚、N,N-二甲基甲酰胺、四氢呋喃、环己烷、甲基环己烷、正己烷、正庚烷、1,4-二氧六环、甲醇、乙醇、异丙醇、叔丁醇和乙腈中至少一种或两种及以上的组合。
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