CN115010714B - 一种吖庚因并[4,5-b]吲哚生物碱骨架化合物及其制备方法 - Google Patents
一种吖庚因并[4,5-b]吲哚生物碱骨架化合物及其制备方法 Download PDFInfo
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Abstract
本发明及一种吖庚因并[4,5‑b]吲哚生物碱骨架化合物及其制备方法,本发明所提供的方法通过吲哚取代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,低温发生反应实现,该合成方法反应条件温和,操作简单,污染小,成本低,收率高,从而有利于潜在具有吖庚因并[4,5‑b]吲哚生物碱骨架的生物活性分子的生产和处理。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种吖庚因并[4,5-b]吲哚生物碱骨架化合物及其制备方法。
背景技术
吖庚因并[4,5-b]吲哚是一类重要的并环化合物,存在于多种药物和具有重要活性的天然生物碱中。吖庚因并[4,5-b]吲哚具有多种反应性,这使它们能够作为其他特殊杂环的合成前体。鉴于这种骨架的重要性,许多研究人员集中精力开发吖庚因并[4,5-b]吲哚的简便、温和的合成方法。虽然,针对吖庚因并[4,5-b]吲哚骨架合成已经开发出很多方法,但是大多数以昂贵过渡金属催化体系为基础建立合成策略,这大大增加了合成成本,造成环境污染、资源浪费,一定程度上限制了应用。
如上所述,利用过渡金属催化是合成吖庚因并[4,5-b]吲哚的常用策略,经典的方法是以强吸电子基取代色胺为底物,经氮上连有不同侧链,在金属催化下(包括Au,Ag,Cu等)实现吖庚因并[4,5-b]吲哚中氮杂七元环的构建。(Angew.Chem.Int.Ed.2006,45,4402-4404;Chem.Soc.Rev.2016,45,6270-6288;Angew.Chem.Int.Ed.2016,55,4436-4454)
除此之外,利用路易斯酸或布朗斯特酸催化合成吖庚因并[4,5-b]吲哚的反应近几年也有报道。2019年,Li课题组利用p-TsOH为催化实现吖庚因并[4,5-b]吲哚的构筑。(Org.Lett.2019,21,6225-6230)
2020年Sen课题组利用p-ABSA催化,可见光诱导重氮化合物的环化反应,构建吖庚因并[4,5-b]吲哚。(Org.Lett.2020,22,4537-4541)
综上所述,尽管近些年来科研工作者们不断发展了合成吖庚因并[4,5-b]吲哚化合物的新方法,依然有一些不足之处需要被解决,总结起来有如下几点:①底物中的氮原子须连有吸电子基作为保护基团,这就导致后期官能团转化过程中需要进行保护基的脱除,经济性较低;②合成吖庚因并[4,5-b]吲哚骨架时通常伴有其他无关环系的生成,降低了该类骨架合成的精确性;③底物的官能团耐受性不好。④合成操作繁琐,步骤冗长,使用的原料和中间体不易制得。因此,如何建立一种广谱、精确、简短、温和的吖庚因并[4,5-b]吲哚生物碱骨架化合物合成方法,是该领域亟待解决的关键科学问题。
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,提供一种合成条件温和,适用性广的吖庚因并[4,5-b]吲哚生物碱骨架化合物,并同时提供其制备方法。
为解决上述问题,本发明所采取的技术方案是:
本发明一方面提供了一种吖庚因并[4,5-b]吲哚生物碱骨架化合物,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或C1-C4直链或支链烷基;
Me或Et。
R3选自C1-C4直链或支链烷基,优选的为tBu或Me。
作为本发明的进一步改进,其化学结构式为:
本发明另一方面提供了一种式I化合物的制备方法,包括如下步骤:式II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,低温发生反应即可得到目标产物,所述式II所示化合物的结构如下:
式中R1、R2和R3的定义如权利要求1所述。
本发明的反应机理为: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串联Wagner-Meerwein重排反应。
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。
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,所述低温为-30℃~0℃。
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,柱层析或减压蒸馏。
采用上述技术方案所产生的有益效果在于:
本发明所形成的吖庚因并[4,5-b]吲哚生物碱骨架化合物适用性广泛,具有潜在的药理活性,可以作为原料、中间体进行含有这类母核的活性化合物的可行性合成。
本发明所提供的合成方法具有以下特点:1.反应条件温和,操作简单无需特殊设备,污染小环境友好。2.避免了贵重金属的使用,成本低利于后期大规模生产。3.适用于各种取代基底物的合成,具备合成的广谱性,收率可观,可达50%以上,部分可达80%以上。
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吖庚因并[4,5-b]吲哚生物碱骨架化合物的制备,制备路线和步骤如下:
实施例1
在-30℃条件下,向干燥的圆底反应瓶中加入底物II(0.2mmol,1.0当量),醋酸碘苯试剂(0.24mmol,1.2当量)和5mL二氯甲烷溶剂,随后加入三氟甲磺酸铟(0.04mmol,20mol%),在-30℃反应4小时;随后移至室温继续反应。待反应结束后,减压除去溶剂,以硅胶为固定相进行柱层析分离,最终获得目标产物I-1。
黄色油状(59.9mg,80%yield),Rf=0.50(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.56(s,1H),7.88(d,J=1.1Hz,1H),7.43–7.38(m,2H),7.35(t,J=7.0Hz,2H),7.33–7.29(m,3H),7.07(t,J=7.5Hz,1H),7.02(t,J=7.4Hz,1H),4.55(s,2H),3.50–3.46(m,2H),3.04–3.00(m,2H),1.59(s,9H);13C-NMR(151MHz,CDCl3)δ168.9,149.1,136.2,134.3,132.0,129.1,128.3,127.9,127.8,120.4,118.7,116.3,110.7,109.3,93.3,80.2,64.8,51.4,28.7,26.2。IR(thin film):vmax(cm-1)=3374,3050,2965,2926,2847,1715,1642,1600,1549,1404,1337,1306,1110,983,952,844,760,632,580。HRMS(APCI):Calcd for C24H27N2O2[M+H]+:375.2067,found 375.2067。
实施例2
在-30℃条件下,向干燥的圆底反应瓶中加入底物II(0.2mmol,1.0当量),[双(三氟乙酰氧基)碘]苯试剂(0.24mmol,1.2当量)和5mL乙酸乙酯溶剂,随后加入三氟甲磺酸钪(0.04mmol,20mol%),在-30℃反应6小时;随后移至室温继续反应。待反应结束后,减压除去溶剂,以硅胶为固定相进行柱层析分离,最终获得目标产物I-2。
黄色油状(53.4mg,68%yield),Rf=0.47(Petroleum Ether/DCM=1:1);1H-NMR(600MHz,CDCl3)δ10.58(s,1H),7.88(s,1H),7.43–7.37(m,2H),7.35(t,J=7.2Hz,1H),7.32–7.28(m,2H),7.19(dd,J=8.7,4.4Hz,1H),6.95(dd,J=9.9,2.4Hz,1H),6.78(td,J=9.1,2.4Hz,1H),4.55(s,2H),3.54–3.40(m,2H),3.08–2.82(m,2H),1.57(s,9H);13C-NMR(151MHz,CDCl3)δ167.6,157.5,156.0,148.3,134.9,132.9,129.6,128.0,127.2,126.7,109.9,109.8,108.2,107.2,107.0,100.2,100.0,91.9,79.2,63.7,50.2,28.7,27.6。IR(thin film):vmax(cm-1)=3392,3056,2967,2853,1725,1665,1604,1559,1455,1227,1173,1004,952,795,756,699,574,562。HRMS(APCI):Calcd for C24H26FN2O2[M+H]+:393.1973,found 393.1975。
实施例3
在-30℃条件下,向干燥的圆底反应瓶中加入底物II(0.2mmol,1.0当量),羟基对甲苯磺酰氧碘苯试剂(0.24mmol,1.2当量)和5mL氯仿溶剂,随后加入三氟甲磺酸锌(0.04mmol,20mol%),在-30℃反应6小时;随后移至室温继续反应。待反应结束后,减压除去溶剂,以硅胶为固定相进行柱层析分离,最终获得目标产物I-3。
黄色油状(61.3mg,75%yield),Rf=0.54(Petroleum Ether/DCM=1:1);1H-NMR(600MHz,CDCl3)δ10.66(s,1H),7.88(s,1H),7.40(t,J=7.4Hz,2H),7.35(t,J=7.3Hz,1H),7.30(d,J=7.5Hz,2H),7.26(d,J=5.3Hz,2H),7.20(d,J=8.5Hz,1H),6.99(d,J=8.5Hz,1H),4.55(s,2H),3.53–3.39(m,2H),3.13–2.82(m,2H),1.57(s,9H);13C-NMR(151MHz,CDCl3)δ168.8,149.5,136.0,133.7,132.6,129.1,129.0,128.4,127.8,124.5,120.4,115.8,111.5,108.8,92.9,80.4,64.9,51.3,28.7,26.1。IR(thin film):vmax(cm-1)=3385,3058,2962,2854,1720,1668,1634,1602,1536,1478,1219,1112,1008,982,834,772,575,560。HRMS(APCI):Calcd for C24H26ClN2O2[M+H]+:409.1677,found 409.1678。
实施例4
在-30℃条件下,向干燥的圆底反应瓶中加入底物II(0.2mmol,1.0当量),[双(三氟乙酰氧基)碘]苯试剂(0.24mmol,1.2当量)和5mL DMSO溶剂,随后加入三氟甲磺酸银(0.04mmol,20mol%),在-30℃反应12小时;随后移至室温继续反应。待反应结束后,减压除去溶剂,以硅胶为固定相进行柱层析分离,最终获得目标产物I-4。
黄色油状(60.6mg,78%yield),Rf=0.54(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.63(s,1H),7.94(s,1H),7.40(d,J=7.8Hz,1H),7.38(d,J=8.0Hz,1H),7.32–7.25(m,4H),7.13(t,J=7.5Hz,1H),7.08(t,J=7.4Hz,1H),4.57(s,2H),3.72–3.39(m,2H),3.22–2.96(m,2H),2.44(s,3H),1.65(s,9H);13C-NMR(151MHz,CDCl3)δ168.9,149.1,138.1,134.3,133.1,132.1,129.7,127.9,127.8,120.3,118.7,116.3,110.6,109.2,93.1,80.1,64.6,51.2,28.7,26.2,21.3。IR(thin film):vmax(cm-1)=3468,3394,3053,2970,2924,2853,2730,1663,1576,1514,1453,1417,1208,1149,953,855,696,660,615。HRMS(APCI):Calcd for C25H29N2O2[M+H]+:389.2224,found 389.2225。
以下实施例5-实施例26的化合物参照实施例1的制备方法获得
实施例5
黄色油状(49.5mg,63%yield),Rf=0.54(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.54(s,1H),7.84(s,1H),7.35(d,J=7.8Hz,1H),7.33–7.30(m,1H),7.28(dd,J=8.4,5.3Hz,2H),7.12–7.05(m,3H),7.03(ddd,J=8.0,7.1,1.1Hz,1H),4.51(s,2H),3.48–3.43(m,2H),3.03–2.99(m,1H),1.59(s,9H);13C-NMR(151MHz,CDCl3)δ168.8,163.5,161.9,148.8,134.3,132.0,132.0,131.9,129.6,129.5,127.8,120.5,118.8,116.4,116.1,116.0,110.7,109.3,93.6,80.3,64.0,51.3,28.7,26.3。IR(thin film):vmax(cm-1)=3363,3047,2972,2926,2854,1678,1543,1514,1419,1208,1138,996,953,875,690,635,604,590。HRMS(APCI):Calcd for C24H26FN2O2[M+H]+:393.1973,found 393.1975。
实施例6
黄色油状(64.6mg,79%yield),Rf=0.54(Petroleum Ether/DCM=1:1);1H-NMR(600MHz,CDCl3)δ10.53(s,1H),7.82(s,1H),7.37(d,J=8.2Hz,2H),7.35(d,J=7.7Hz,1H),7.31(d,J=7.9Hz,1H),7.24(d,J=8.1Hz,2H),7.07(t,J=7.4Hz,1H),7.03(t,J=7.4Hz,1H),4.51(s,2H),3.50–3.35(m,2H),3.10–2.94(m,2H),1.59(s,9H);13C-NMR(151MHz,CDCl3)δ167.6,147.6,133.6,133.2,133.1,130.6,128.1,128.0,126.7,119.4,117.6,115.2,109.5,108.2,92.6,79.2,62.9,50.2,27.6,25.1。IR(thinfilm):vmax(cm-1)=3376,3055,2965,2925,2854,1724,1651,1601,1575,1414,1365,1306,1128,1109,978,948,833,772,655,577,506,485。HRMS(APCI):Calcd for C24H26ClN2O2[M+H]+:409.1677,found 409.1678。
实施例7
黄色油状(72.5mg,80%yield),Rf=0.51(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.55(s,1H),7.83(s,1H),7.52(d,J=8.4Hz,2H),7.36(d,J=7.8Hz,1H),7.32(d,J=7.9Hz,1H),7.17(d,J=8.4Hz,2H),7.08(t,J=7.0Hz,1H),7.04(t,J=7.0Hz,1H),4.48(s,2H),3.46–3.43(m,2H),3.02–2.99(m,2H),1.60(s,9H);13C-NMR(151MHz,CDCl3)δ168.7,148.7,135.3,134.3,132.2,131.8,129.5,127.8,122.3,120.5,118.8,116.4,110.7,109.4,93.8,80.3,64.1,51.3,28.7,26.3。IR(thin film):vmax(cm-1)=3365,3050,2964,2926,2843,1715,1645,1600,1539,1403,1368,1209,1120,1056,981,957,843,764,655,579。HRMS(APCI):Calcd for C24H25BrN2O2[M+H]+:453.1172,found453.1175。
实施例8
黄色油状(69.1mg,83%yield),Rf=0.54(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.57(s,1H),7.88(s,1H),7.36(d,J=7.8Hz,1H),7.32(d,J=7.9Hz,1H),7.27(d,J=8.5Hz,2H),7.24(d,J=8.0Hz,2H),7.07(t,J=7.4Hz,1H),7.03(t,J=7.4Hz,1H),4.53(s,2H),3.52–3.48(m,2H),3.07–3.01(m,2H),2.94(hept,J=7.0Hz,1H),1.59(s,9H),1.28(d,J=6.9Hz,6H);13C-NMR(151MHz,CDCl3)δ168.9,149.1,149.1,134.3,133.5,132.1,127.9,127.8,127.1,120.4,118.7,116.3,110.6,109.2,93.1,80.1,64.6,51.4,34.0,28.7,26.2,24.1。IR(thin film):vmax(cm-1)=3467,3389,3053,3006,2962,2926,2870,1662,1602,1575,1390,1251,1127,1109,1025,921,771。HRMS(APCI):Calcdfor C27H33N2O2[M+H]+:417.2537,found 417.2539。
实施例9
黄色油状(62.6mg,72%yield),Rf=0.54(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.54(s,1H),7.86(s,1H),7.34(d,J=7.8Hz,1H),7.30(d,J=7.9Hz,1H),7.06(t,J=7.3Hz,1H),7.01(t,J=7.3Hz,1H),6.86(q,J=9.1,8.6Hz,2H),6.78(s,1H),4.49(s,2H),3.89(s,3H),3.88(s,3H),3.49–3.45(m,2H),3.04–2.99(m,2H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ168.9,149.5,149.1,149.0,134.3,132.0,128.5,127.9,120.4,120.4,118.8,116.3,111.5,110.8,110.7,109.3,93.2,80.2,64.6,56.1,56.1,51.0,28.8,26.3。IR(thin film):vmax(cm-1)=3353,3007,2962,2926,2874,2820,1715,1665,1603,1574,1364,1248,1121,1110,983,775。HRMS(APCI):Calcd for C26H30N2O4[M+H]+:435.2278,found 435.2279。
实施例10
黄色油状(65.4mg,71%yield),Rf=0.54(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.55(s,1H),7.87(s,1H),7.33(d,J=7.8Hz,1H),7.30(d,J=7.9Hz,1H),7.21(d,J=8.2Hz,2H),7.06(t,J=7.5Hz,1H),7.01(t,J=7.4Hz,1H),6.91(d,J=8.1Hz,2H),4.48(s,2H),3.96(t,J=6.6Hz,2H),3.48–3.44(m,2H),3.01–2.95(m,2H),1.80(p,J=6.9Hz,2H),1.58(s,9H),1.45(dt,J=16.0,7.2Hz,2H),1.39(dt,J=14.5,7.2Hz,2H),0.94(t,J=7.1Hz,3H);13C-NMR(151MHz,CDCl3)δ168.9,159.3,149.0,134.3,132.1,129.2,127.9,127.8,120.3,118.7,116.3,115.0,110.6,109.2,93.0,80.1,68.2,64.3,51.1,29.1,28.8,28.3,26.3,22.6,14.2。IR(thin film):vmax(cm-1)=3393,3054,2962,2927,2869,2856,1662,1601,1583,1558,1303,1149,979,757,739,695,517。HRMS(APCI):Calcd for C29H37N2O3[M+H]+:461.2799,found 461.2802。
实施例11
黄色油状(73.0mg,81%yield),Rf=0.41(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.58(s,1H),7.91(s,1H),7.63(d,J=8.0Hz,2H),7.61(d,J=7.8Hz,2H),7.47(t,J=7.6Hz,2H),7.38(dd,J=11.1,6.2Hz,4H),7.33(d,J=7.9Hz,1H),7.08(t,J=7.3Hz,1H),7.04(t,J=7.4Hz,1H),4.59(s,2H),3.54–3.51(m,2H),3.08–3.03(m,2H),1.61(s,9H);13C-NMR(151MHz,CDCl3)δ168.9,149.0,141.3,140.6,135.2,134.3,132.0,129.0,128.3,127.9,127.8,127.7,127.2,120.4,118.7,116.3,110.7,109.3,93.4,80.2,64.5,51.4,28.7,26.3。IR(thin film):vmax(cm-1)=3361,3050,2962,2865,1710,1663,1602,1578,1553,1300,1125,1051,980,763,721。HRMS(APCI):Calcd for C30H31N2O2[M+H]+:451.2380,found 451.2384。
实施例12
黄色油状(56.2mg,67%yield),Rf=0.45(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.51(s,1H),8.25(d,J=8.6Hz,2H),7.80(s,1H),7.47(d,J=8.5Hz,2H),7.35(d,J=7.8Hz,1H),7.32(d,J=8.0Hz,1H),7.09(t,J=7.4Hz,1H),7.03(t,J=7.4Hz,1H),4.63(s,2H),3.52–3.43(m,2H),3.16–2.93(m,2H),1.77–1.46(m,9H);13C-NMR(151MHz,CDCl3)δ168.5,148.4,148.0,143.9,134.4,131.5,128.4,127.7,124.4,120.8,118.9,116.5,110.8,109.6,94.8,80.6,63.9,51.7,28.7,26.3。IR(thin film):vmax(cm-1)=3387,3053,2960,2922,2851,1663,1599,1522,1344,1328,1251,1128,1109,1025,976,799,771,562。HRMS(APCI):Calcd for C24H26N3O4[M+H]+:420.1918,found 420.1922。
实施例13
黄色油状(48.7mg,61%yield),Rf=0.54(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.50(s,1H),7.79(s,1H),7.69(d,J=7.8Hz,2H),7.42(d,J=8.0Hz,2H),7.35(d,J=7.8Hz,1H),7.32(d,J=8.0Hz,1H),7.08(t,J=7.5Hz,1H),7.03(t,J=7.4Hz,1H),4.60(s,2H),3.48–3.45(m,2H),3.05–3.03(m,2H),1.58(s,9H)。13C-NMR(151MHz,CDCl3)δ168.6,148.5,142.0,134.4,132.9,131.5,128.3,127.7,120.8,118.9,118.5,116.5,112.3,110.8,109.6,94.6,80.6,64.2,51.7,28.7,26.3。IR(thin film):vmax(cm-1)=3387,2960,2924,2853,2228,1663,1602,1458,1366,1212,1110,977,771,695,545。HRMS(APCI):Calcd for C25H26N3O2[M+H]+:400.2020,found 400.2022。
实施例14
黄色油状(53.4mg,65%),Rf=0.42(Petroleum Ether/DCM=1:1);1H-NMR(600MHz,CDCl3)δ10.56(s,1H),7.83(s,1H),7.66(d,J=8.0Hz,2H),7.39(dd,J=31.9,7.9Hz,3H),7.09(t,J=7.0Hz,1H),7.04(t,J=7.4Hz,1H),4.58(s,2H),3.50–3.44(m,2H),3.11–2.98(m,1H),1.60(s,9H);13C-NMR(151MHz,CDCl3)δ168.7,148.7,140.5,134.3,131.7,130.9,130.7,130.5,130.3,128.0,127.8,126.8,126.1,126.1,126.1,126.0,123.2,121.4,120.6,118.8,116.4,110.7,109.5,94.2,80.4,64.1,51.6,28.7,26.3。IR(thin film):vmax(cm-1)=3365,2962,2926,2864,1679,1603,1438,1371,1206,1100,988,932,861,730,682。HRMS(APCI):Calcd for C25H26F3N2O2[M+H]+:443.1941,found 443.1945。
实施例15
黄色油状(44.1mg,51%yield),Rf=0.23(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.53(s,1H),7.85(s,1H),7.51(d,J=8.1Hz,2H),7.35–7.28(m,3H),7.24(d,J=8.2Hz,2H),7.06(t,J=7.6Hz,1H),7.01(t,J=7.5Hz,1H),4.48(s,2H),3.54–3.35(m,2H),3.03–2.89(m,2H),2.17(s,3H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ168.9,168.5,149.0,138.0,134.3,132.0,131.9,128.6,127.9,120.4,120.3,118.7,116.3,110.6,109.3,93.3,80.2,64.3,51.2,28.7,26.3,24.7。IR(thin film):vmax(cm-1)=3372,3254,3123,2967,2853,1657,1573,1536,1333,1264,1130,1042,945,937,693,620,529。HRMS(APCI):Calcd for C26H30N3O3[M+H]+:432.2282,found 432.2284。
实施例16
黄色油状(53.4mg,65%yield),Rf=0.48(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.53(s,1H),7.80(d,J=1.2Hz,1H),7.36(d,J=7.8Hz,1H),7.32(d,J=8.0Hz,1H),7.19(q,J=8.4Hz,1H),7.14–7.07(m,2H),7.04(t,J=7.4Hz,2H),4.47(s,2H),3.46–3.42(m,2H),3.04–3.00(m,2H),1.60(s,9H);13C-NMR(151MHz,CDCl3)δ168.7,151.6,151.5,151.1,151.0,149.9,149.8,149.5,149.4,148.5,134.3,133.4,133.4,133.4,131.7,127.8,123.8,123.8,123.7,123.7,120.6,118.8,118.0,117.9,116.8,116.7,116.4,110.7,109.5,94.1,80.4,63.6,51.4,28.7,26.3。IR(thin film):vmax(cm-1)=3359,3042,2964,2926,2847,1683,1579,1532,1403,1218,1109,933,915,874,625,589。HRMS(APCI):Calcd for C24H24N2O2[M+H]+:411.1879,found 411.1875。
实施例17
黄色油状(49.7mg,64%yield),Rf=0.28(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.52(s,1H),7.46(s,1H),7.38(d,J=7.4Hz,1H),7.34–7.28(m,2H),7.25(t,J=7.3Hz,2H),7.20(d,J=7.1Hz,2H),7.08–7.00(m,2H),3.60(t,J=7.1Hz,2H),3.57–3.52(m,2H),3.14–3.08(m,2H),2.96(t,J=7.1Hz,2H),1.51(s,9H);13C-NMR(151MHz,CDCl3)δ168.8,148.7,138.1,134.3,132.3,129.1,128.9,127.9,127.0,120.3,118.7,116.2,110.6,108.8,92.7,79.9,63.1,52.0,36.0,28.6,26.5。IR(thin film):vmax(cm-1)=3360,3057,2962,2924,2865,1723,1633,1408,1389,1217,1201,1049,987,930,882,840。HRMS(APCI):Calcd for C25H29N2O2[M+H]+:389.2224,found 389.2227。
实施例18
黄色油状(46.5mg,70%yield),Rf=0.56(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.49(s,1H),7.98(s,1H),7.39(dd,J=8.1,6.5Hz,2H),7.37–7.31(m,3H),7.32–7.27(m,2H),7.08(t,J=7.5Hz,1H),7.03(t,J=7.8Hz,1H),4.57(s,2H),3.84(s,3H),3.56–3.43(m,2H),3.08–2.95(m,2H);13C-NMR(151MHz,CDCl3)δ169.6,149.4,136.1,134.3,131.6,129.1,128.4,127.9,127.7,120.6,118.8,116.4,110.7,109.4,91.9,64.9,51.5,51.4,29.8,26.2。IR(thin film):vmax(cm-1)=3357,3051,2965,2876,1704,1659,1603,1549,1367,1306,1121,1065,993,981,874,856,742,660。HRMS(APCI):Calcdfor C21H21N2O2[M+H]+:333.1598,found 333.1595。
实施例19
黄色油状(54.4mg,70%yield),Rf=0.47(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.62(s,1H),7.87(s,1H),7.40(t,J=7.4Hz,2H),7.35(t,J=7.3Hz,1H),7.30(d,J=7.5Hz,2H),7.16(d,J=8.1Hz,1H),6.92(t,J=7.6Hz,1H),6.77–6.62(m,1H),4.53(s,2H),3.56–3.44(m,2H),3.40–3.29(m,2H),2.63(s,3H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ169.0,149.0,136.3,134.5,132.0,129.1,128.6,128.3,127.8,126.1,120.9,120.4,110.8,109.0,93.2,80.1,64.4,52.0,28.8,28.7,21.2.IR(thinfilm):vmax(cm-1)=3423,3381,3056,2976,2853,1663,1604,1572,1450,1080,1004,952,863,669,650。HRMS(APCI):Calcd for C25H29N2O2[M+H]+:389.2224,found 389.2225。
实施例20
黄色油状(51.0mg,65%yield),Rf=0.28(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.61(s,1H),7.85(s,1H),7.40(t,J=7.4Hz,2H),7.35(t,J=7.3Hz,1H),7.32–7.28(m,2H),7.20(dd,J=8.6,5.2Hz,1H),6.98(dd,J=9.8,2.3Hz,1H),6.77(ddd,J=10.7,8.6,2.3Hz,1H),4.55(s,2H),3.51–3.43(m,2H),3.01–2.93(m,2H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ168.9,160.1,158.6,148.9,136.1,134.2,134.1,132.5,132.3,132.3,131.1,129.1,129.0,128.4,127.8,124.6,116.8,116.8,109.1,107.2,107.1,97.1,96.9,93.2,80.3,64.8,51.2,28.7,26.3。IR(thinfilm):vmax(cm-1)=3390,3052,2972,2963,2826,1725,1665,1598,1545,1455,1200,992,875,731,699。HRMS(APCI):Calcd for C24H26FN2O2[M+H]+:393.1973,found 393.1973。
实施例21
黄色油状(51.0mg,65%yield),Rf=0.28(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.68(s,1H),7.89(s,1H),7.43(d,J=1.8Hz,1H),7.40(t,J=7.4Hz,2H),7.35(t,J=7.3Hz,1H),7.31–7.27(m,2H),7.16(d,J=8.4Hz,1H),7.12(dd,J=8.5,1.8Hz,1H),4.55(s,2H),3.49–3.39(m,2H),2.96–2.91(m,2H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ168.8,149.6,135.9,133.6,132.9,129.7,129.1,128.4,127.8,122.9,118.9,112.0,112.0,108.6,92.9,80.4,64.9,51.3,28.7,26.1.IR(thinfilm):vmax(cm-1)=3365,3048,2962,2926,2845,1719,1630,1597,1539,1380,1360,1201,1051,992,981,957,864,635,580。HRMS(APCI):Calcd for C24H25BrN2O2[M+H]+:453.1172,found 453.1171。
实施例22
黄色油状(44.7mg,75%yield),Rf=0.28(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.53(s,1H),7.68(s,1H),7.39(dd,J=7.7,1.2Hz,1H),7.34–7.28(m,1H),7.05(p,J=8.0,7.5Hz,2H),3.54–3.49(m,2H),3.23(s,3H),3.17–3.12(m,2H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ168.8,149.1,134.3,132.3,127.9,120.3,118.7,116.3,110.6,108.9,92.8,80.0,53.2,48.1,28.7,25.8。IR(thinfilm):vmax(cm-1)=3320,3050,2972,2826,1675,1600,1450,1083,1004,934,867.HRMS(APCI):Calcd for C18H23N2O2[M+H]+:299.1754,found299.1756。
实施例23
黄色油状(45.0mg,72%yield),Rf=0.28(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.54(s,1H),7.71(s,1H),7.38(dd,J=7.3,1.6Hz,1H),7.30(d,J=7.3Hz,1H),7.14–6.93(m,2H),3.61–3.50(m,2H),3.43(q,J=7.2Hz,2H),3.29–3.03(m,2H),1.58(s,9H),1.31(t,J=7.2Hz,3H);13C-NMR(151MHz,CDCl3)δ168.9,148.4,134.3,132.3,127.9,120.2,118.7,116.2,110.6,108.8,92.7,80.0,56.1,51.1,28.8,26.7,14.5.IR(thinfilm):vmax(cm-1)=3350,3047,2972,2926,2854,2826,1680,1643,1438,1368,1083,1004,934,867。HRMS(APCI):Calcd for C19H25N2O2[M+H]+:313.1911,found313.1912。
实施例24
黄色油状(56.8mg,78%yield),Rf=0.32(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.54(s,1H),7.79(s,1H),7.43(dd,J=1.8,0.9Hz,1H),7.37(d,J=7.7Hz,1H),7.33–7.28(m,1H),7.16–6.93(m,2H),6.38(dd,J=3.4,1.9Hz,1H),6.35(d,J=3.2Hz,1H),4.47(s,2H),3.55–3.52(m,2H),3.05–3.01(m,2H),1.58(s,7H);13C-NMR(151MHz,CDCl3)δ168.8,149.9,148.3,143.3,134.3,131.9,127.9,120.4,118.7,116.4,110.7,109.4,109.2,94.0,80.2,57.0,51.4,28.7,26.2.IR(thinfilm):vmax(cm-1)=3354,3160,2962,2924,2655,2438,2020,1739,1692,1265,1175,991,869。HRMS(APCI):Calcdfor C22H25N2O3[M+H]+:365.1860,found 365.1863。
实施例25
黄色油状(45.3mg,67%yield),Rf=0.28(Petroleum Ether/DCM=1:1)。1H-NMR(600MHz,CDCl3)δ10.55(s,1H),7.71(s,1H),7.39(d,J=7.6Hz,1H),7.34–7.30(m,1H),7.15–6.91(m,2H),5.03(s,1H),4.98(s,1H),3.86(s,2H),3.58–3.33(m,2H),3.22–2.91(m,2H),1.77(s,3H),1.59(s,9H);13C-NMR(151MHz,CDCl3)δ168.9,149.1,140.6,134.3,132.1,127.9,120.4,118.7,116.3,114.7,110.6,109.1,93.0,80.1,67.2,51.1,28.7,26.3,20.0。IR(thinfilm):vmax(cm-1)=3258,3035,2962,2928,2862,1689,1573,1468,1062,997,864,712。HRMS(APCI):Calcd for C21H27N2O2[M+H]+:339.2067,found 339.2067。
实施例26
黄色油状(49.7mg,70%yield),Rf=0.28(Petroleum Ether/DCM=1:1。1H-NMR(600MHz,CDCl3)δ10.52(s,1H),7.71(s,1H),7.41(dd,J=7.7,1.3Hz,1H),7.38–7.28(m,1H),7.06(dtd,J=21.0,7.1,1.2Hz,2H),4.12(d,J=2.5Hz,2H),3.71–3.43(m,2H),3.31–3.04(m,2H),2.46(s,1H),1.58(s,9H);13C-NMR(151MHz,CDCl3)δ168.6,147.4,134.4,131.6,127.8,120.6,118.8,116.5,110.7,109.8,94.9,80.4,77.7,74.6,51.4,49.5,28.7,26.2。IR(thinfilm):vmax(cm-1)=3373,3291,2962,2926,2853,1696,1573,1468,1070,943,847,649。HRMS(APCI):Calcd for C20H23N2O2[M+H]+:323.1754,found 323.1755。
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)
1.一种式I所示吖庚因并[4,5-b]吲哚生物碱骨架化合物的制备方法,其特征在于,包括如下步骤:式II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,低温发生反应即可得到目标产物,所述式I和式II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或C1-C4直链或支链烷基;
R3选自C1-C4直链或支链烷基;
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;
所述路易斯酸选自Zn(OTf)2,Sc(OTf)3,In(OTf)3或AgOTf;
所述低温为-30℃~0℃。
2.根据权利要求1所述的制备方法,其特征在于,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。
3.根据权利要求1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。
4.根据权利要求1所述的制备方法,其特征在于,所述反应的反应时间为0.5~48h。
5.根据权利要求1所述的制备方法,其特征在于,所述反应还包含纯化的工序,具体选自薄层层析、柱层析或减压蒸馏。
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CN113527177A (zh) * | 2021-08-31 | 2021-10-22 | 南京林业大学 | 一种2-氰基吲哚取代的偕二氟烯烃化合物及其制备方法和应用 |
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CN113527177A (zh) * | 2021-08-31 | 2021-10-22 | 南京林业大学 | 一种2-氰基吲哚取代的偕二氟烯烃化合物及其制备方法和应用 |
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