CN113372352B - 吲哚3,4位并九元中环化合物及其制备方法 - Google Patents
吲哚3,4位并九元中环化合物及其制备方法 Download PDFInfo
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Abstract
本发明公开一种吲哚3,4位并九元中环化合物及其制备方法，属于有机合成技术领域。本发明所述制备方法由吲哚衍生的邻苯二胺类化合物与苯甲醛原位反应引发[1,6]‑HT，生成的高活性亚胺正离子与负电性的吲哚C‑3位发生傅‑克反应合成吲哚类二氮杂九元稠环化合物。该反应具有原料简单易得、普适性强，反应条件温和、化学选择性好以及产物收率高等优势。
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种吲哚3,4位并九元中环化合物及其制备方法。
背景技术
吲哚骨架是大量存在于天然产物和生物活性分子中的优势骨架。在诸多吲哚类活性分子中，3,4-吲哚并氮杂中环骨架是较为常见且重要的核心骨架。因其具有潜在的生物活性，在药物化学领域应用较为广泛。例如，Indolactam V可以作为蛋白激酶C激活剂，被广泛应用于抗菌、抗疟、抗癌及干细胞分化活性研究中(Chem.Sci.2014,5,2184；Chem.Rec.2019,19,320；Angew.Chem.Int.Ed.2013,52,4902)。除此之外，Decursivine也表现出了抗疟活性(Synth.Commun.2016,46,869；Pharm.Biol.2002,40,221)。Clavinealkaloid clavicipitic acid则具有抗肿瘤活性(Tetrahedron Lett.2020,61,151696；Org.Biomol.Chem.2016,14,5894)。Communesin F在杀虫和抗增殖活性方面表现出较好的活性(Chem.Eur.J.2015,21,16318；J.Nat.Prod.2004,67,78)。上述吲哚生物碱的共同特征是都含有3,4-吲哚并氮杂中环骨架。因此，开发和发展合成该结构骨架的方法对新药研发具有重要的推动意义，所合成的新骨架分子也将为药物活性筛选提供选择空间。
近几年，氢迁移反应得到了飞速的发展，此策略是用来快速构建多环体系的高效方法，它具有高原子和步骤经济性、操作方便，绿色高效等特点。因此，通过氢迁移策略实现吲哚的衍生化构建含吲哚的多环体系将会具有较大的应用价值。截至目前，利用氢迁移策略构建复杂吲哚类多环体系的研究主要集中在吲哚-2,3-并环体系和C3螺环体系。2011年，Seidel等人发展了开创性的工作，通过微波辐射加热至150℃得到了多环吲哚稠合苯并氮杂卓类化合物(J.Am.Chem.Soc.2011,133,2100)，该反应的局限在于反应条件苛刻，底物受限。
2014年，Sun和Xu等人还利用氢迁移策略在80℃的温度下反应生成了螺环烯类化合物。以2-甲基-吲哚与邻四氢吡咯苯甲醛为底物，通过[1,5]-氢迁移成功构建了一系列螺环烯类化合物(J.Org.Chem.2015,80,1155-1162)。
此外，Wang等人通过底物设计，采用不同合成方法获得了吲哚氮杂卓类、吲哚二氮杂卓类和四氢吲哚咔唑类化合物(Chem.Commun.2018,54,7928-7931)。
氢迁移策略是构建复杂多环体系的高效策略，但从上述实例不难发现，大多数方法都是在高温条件下进行的，且基本都是2,3-吲哚并中环和螺环化合物的构建。由于不利的熵效应和跨环张力作用，关于3,4-吲哚并九元环的合成研究未见报道。
发明内容
针对现有技术中存在的不足，本发明提供一种基于吲哚骨架的3,4-位并九元中环化合物的制备方法，该方法简单实用，产率高，且反应具有原子步骤经济性和环境友好等优点。
本发明的技术方案如下：
一种吲哚3,4位并九元中环化合物，结构如式Ⅰ所示：
式Ⅰ中：
R1选自氢、苄基、对硝基苄基、对氰基苄基、对三氟甲基苄基、邻醛基苄基、丙-1-烯-1-苯基、对氯苄基、间甲基苄基、对甲氧基苄基、苄基呋喃、苄基噻吩中的一种；
R2选自氢、卤素、甲酸甲酯基、三氟甲基、甲氧基、氰基中的一种；
R3选自氢、甲基、卤素中的一种；
R4与R5成环，环选自全氢异吲哚或四氢吡咯；
R6选自氢、苯基中的一种。
上述吲哚3,4位并九元中环化合物的制备方法如下：
在室温环境下，甲醛类化合物与吲哚衍生的邻苯二胺类化合物在催化剂的作用下反应生成式Ⅰ所述吲哚3,4位并九元中环化合物，反应在溶剂中进行。
在上述方案的基础上，甲醛类化合物的结构如式Ⅱ所示：
R1-CHO
式Ⅱ
式Ⅱ中：
R1选自氢、苄基、对硝基苄基、对氰基苄基、对三氟甲基苄基、邻醛基苄基、丙-1-烯-1-苯基、对氯苄基、间甲基苄基、对甲氧基苄基、苄基呋喃、苄基噻吩中的一种。
在上述方案的基础上，吲哚衍生的邻苯二胺类化合物的结构如式Ⅲ所示：
式Ⅲ中：
R2选自氢、卤素、甲酸甲酯基、三氟甲基、甲氧基、氰基中的一种；
R3选自氢、甲基、卤素中的一种；
R4与R5成环，环选自全氢异吲哚或四氢吡咯；
R6选自氢、苯基中的一种。
在上述方案的基础上，吲哚衍生的邻苯二胺类化合物与甲醛类化合物的摩尔比为1:2。
在上述方案的基础上，催化剂选自三氟甲磺酸、醋酸、对甲苯磺酸、甲烷磺酸、樟脑磺酸、联萘酚磷酸酯、三氟甲烷磺酸钪、三氟化硼乙醚、三氯化铁中的一种。
在上述方案的基础上，溶剂选自1,2-二氯乙烷、乙醇、1,4-二氧六环、乙酸乙酯、六氟异丙醇、乙腈、N,N-二甲基甲酰胺中的一种。
在上述方案的基础上，催化剂的用量为20mol％。
在上述方案的基础上，溶剂的用量为每摩尔吲哚衍生的邻苯二胺类化合物添加10L溶剂。
在上述方案的基础上，室温环境为25℃，空气气氛。
本发明的有益效果为：
本发明建立了一种独特的通过醛引发的1,6-氢迁移激活胺的方法，从吲哚衍生的邻苯二胺出发，在非常温和的反应条件下以“一锅法”快速获得底物范围广的吲哚3,4位并九元中环化合物，反应组分结构多样性和良好的官能团耐受性证明了该方法具有广泛的合成应用前景。
具体实施方式
在本发明中所使用的术语，除非有另外说明，一般具有本领域普通技术人员通常理解的含义。
以
的反应为例解释甲醛类化合物与吲哚衍生的邻苯二胺类化合物的反应机理，如下：
醛胺缩合原位生成的亚胺作为负氢受体，两个苄基碳之间的1,3-氢迁移将提供异构化的亚胺V，随后两个亚胺IV和V都可以发生1,6-氢迁移实现δ-C(Sp3)-H的活化，产生亚胺中间体VI和VI’。利用吲哚3号位的亲核性实现关环，形成九元中环化合物。简要的反应过程如下：
下面结合具体实施例，并参照数据进一步详细的描述本发明。以下实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
以下实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、材料、仪器等，如无特殊说明，均可从商业途径得到。
吲哚3,4位并九元中环化合物合成条件的筛选
取0.2mmol的N-((1H-吲哚-4-基)甲基)-2-(吡咯烷-1-基)苯胺于反应瓶中，再加入0.4mmol苯甲醛，加入2mL溶剂，20mol％催化剂，持续搅拌，在室温下反应，通过薄层色谱板点样跟踪反应至原料反应完全，待反应完成后，使用硅胶柱进行分离纯化，将纯化后的产品旋蒸得目标产物。化学反应式如下所示：
根据上述反应，设置平行试验组，使用不同的催化剂和溶剂。催化剂分别为三氟甲磺酸(TfOH)、醋酸(AcOH)、对甲苯磺酸(TsOH·H2O)、甲烷磺酸(MsOH)、樟脑磺酸((-)-CSA)、联萘酚磷酸酯(PA)、三氟甲烷磺酸钪(Sc(OTf)3)、三氟化硼乙醚(BF3.OEt2)、三氯化铁。溶剂分别为1,2-二氯乙烷(DCE)、乙醇(EtOH)、1,4-二氧六环(1,4-dioxane)、乙酸乙酯(EA)、六氟异丙醇(HFIP)、乙腈(CH3CN)、N,N-二甲基甲酰胺(DMF)。试验组具体使用的催化剂、溶剂种类和浓度如表1所示：
表1
a10mol％catalyst；b5mol％catalyst。
根据上述试验结果筛选出最佳的实验方案，即反应体系中，反应原料为0.2mmol吲哚衍生的邻苯二胺类化合物与0.4mmol甲醛类化合物，在0.04mmol三氟甲烷磺酸催化下，以2mL N,N-二甲基甲酰胺作溶剂，在25℃温度下持续搅拌反应至原料反应完全。实施例1-20所述产物均以该最佳的反应条件为基础，通过替换不同的反应底物所得。
吲哚并九元中环化合物杀螨活性测试
以实施例1所述化合物为例，测试吲哚并九元中环化合物的杀螨活性，步骤如下：
(1)样品的配制过程
准确称取10mg实施例1所述化合物样品，用2mL的DMF溶解，形成母液，化合物浓度即为5000ppm，再取0.2mL母液加4.8mL吐温水，将化合物浓度配制为200ppm。阳性对照药剂乙唑螨腈按照标签说明稀释至乙唑螨腈的浓度为200ppm，取5mL备用。清水+DMF为阴性对照。
(2)喷雾接种过程
剪取健康的蚕豆叶片，叶柄剪口处用浸湿的脱脂棉包裹置于培养皿中，培养皿底垫3-4层浸湿的纱布。用喷枪将配好的药液均匀的喷在叶片的正反面。用毛笔挑取健康雌成螨接种在叶片的背面。将培养面封口，于25℃，55％RH条件下培养，48h后统计螨的死亡情况。为了避免实验误差，同时做了两组平行实验。
实验结果如表2所示。
表2吲哚并九元中环化合物杀螨活性测试
由表2可知，本发明合成的一系列吲哚并九元中环化合物具备一定的杀螨活性，可用于制备杀螨药物，也可作为先导化合物，经改造后用于杀螨，存在较好的应用价值。
实施例1-20的反应产物，其结构以及核磁共振数据如下所示：
实施例1
7-benzyl-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazo-nino[6,7,8-cd]indole(3a):According to general procedure(for 36h),1a(58.4mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3a(67.1mg,89％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 140–144℃.1H NMR(500MHz,CDCl3)δ7.95(s,1H),7.19(d,J＝4.6Hz,2H),7.08–7.04(m,3H),7.03–6.95(m,3H),6.92(dd,J＝7.8,1.6Hz,1H),6.84(d,J＝7.1Hz,1H),6.80(d,J＝7.2Hz,1H),6.77–6.70(m,1H),6.67(td,J＝7.5,1.5Hz,1H),5.33–5.24(m,2H),4.22(s,2H),3.78(d,J＝14.1Hz,1H),3.62–3.54(m,1H),3.02(dt,J＝12.1,8.3Hz,1H),2.22–2.14(m,1H),2.13–1.98(m,2H),1.98–1.89(m,1H).13C NMR(125MHz,CDCl3)δ145.98,142.68,139.05,138.06,134.55,128.85,127.90,127.29,126.48,121.90,121.44,121.25,120.78,120.57,120.22,120.07,116.87,110.44,61.10,59.41,55.01,46.10,28.47,24.58.HRMS(ESI-TOF)m/z calcd for C26H26N3[M+H]+:380.2121；found:380.2124.
实施例2
7-(4-nitrobenzyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3b)：According to general procedure(for36h),1a(58.4mg,0.2mmol),2b(60.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3b(69.0mg,82％)as a light yellow solid after purification on silica gel(petroleum ether/EtOAc＝15:1),mp 131–135℃.1H NMR(500MHz,CDCl3)δ8.01(s,1H),7.85(d,J＝8.7Hz,2H),7.20–7.17(m,2H),7.16(s,1H),7.05–7.00(m,1H),6.99–6.92(m,1H),6.88–6.73(m,4H),6.68(td,J＝7.6,1.4Hz,1H),5.32(d,J＝14.0Hz,1H),5.09(d,J＝7.1Hz,1H),4.34(d,J＝14.8Hz,1H),4.25(d,J＝14.8Hz,1H),3.75(d,J＝14.1Hz,1H),3.57(ddd,J＝11.5,7.6,2.9Hz,1H),3.01(dt,J＝12.2,8.2Hz,1H),2.24–2.15(m,1H),2.11–1.97(m,2H),1.97–1.89(m,1H).13C NMR(125MHz,CDCl3)δ146.97,146.71,146.03,142.19,138.10,134.04,129.55,127.12,123.16,122.44,121.56,121.49,120.82,120.42,120.26,119.41,117.31,110.77,61.67,59.89,54.43,46.14,28.54,24.64.HRMS(ESI-TOF)m/zcalcd for C26H25N4O2[M+H]+:425.1972；found:425.1976.
实施例3
4-((2,6,13,14,15,15a-hexahydro-7H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indol-7-yl)methyl)benzonitrile(3c):According to generalprocedure(for 36h),1a(58.4mg,0.2mmol),2c(52.5mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3c(64.0mg,79％)as a white solid after purification onsilica gel(petroleum ether/EtOAc＝15:1),mp 95–100℃.1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.26(d,J＝8.3Hz,2H),7.16(d,J＝9.1Hz,1H),7.10(d,J＝8.2Hz,2H),7.01–6.91(m,2H),6.86–6.72(m,4H),6.67(td,J＝7.5,1.6Hz,1H),5.29(d,J＝14.0Hz,1H),5.08(d,J＝7.1Hz,1H),4.27(d,J＝14.7Hz,1H),4.20(d,J＝14.7Hz,1H),3.73(d,J＝14.0Hz,1H),3.56(ddd,J＝11.4,7.6,2.9Hz,1H),2.99(dt,J＝12.3,8.2Hz,1H),2.23–2.12(m,1H),2.10–1.96(m,2H),1.96–1.86(m,1H).13C NMR(125MHz,CDCl3)δ146.01,144.82,142.26,138.11,134.06,131.75,129.50,127.14,122.41,121.54,121.49,120.80,120.41,120.23,119.53,119.08,117.28,110.77,110.29,61.55,59.82,54.79,46.16,28.55,24.64.HRMS(ESI-TOF)m/z calcd for C27H25N4[M+H]+:405.2074；found:405.2077.
实施例4
7-(4-(trifluoromethyl)benzyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]Pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3d):According to generalprocedure(for 36h),1a(58.4mg,0.2mmol),2d(69.8mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3d(71.8mg,80％)as a white solid after purification onsilica gel(petroleum ether/EtOAc＝15:1),mp 192–194℃.1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.27(d,J＝7.8Hz,2H),7.19(d,J＝5.6Hz,1H),7.15(d,J＝7.8Hz,2H),7.03(s,1H),7.00–6.94(m,1H),6.91–6.85(m,1H),6.82(t,J＝7.1Hz,2H),6.77(t,J＝7.5Hz,1H),6.69(d,J＝7.5Hz,1H),5.30(t,J＝12.0Hz,1H),5.15(d,J＝5.8Hz,1H),4.26(q,J＝14.6Hz,2H),3.76(d,J＝14.0Hz,1H),3.63–3.54(m,1H),3.02(dt,J＝11.8,8.3Hz,1H),2.24–2.12(m,1H),2.12–1.98(m,2H),1.98–1.88(m,1H).13C NMR(125MHz,CDCl3)δ146.00,143.20,142.42,138.09,134.24,129.04,128.73(q,J＝32.1Hz),127.18,124.83(q,J＝3.8Hz),122.17,121.49,121.39,120.81,120.43,120.35,119.58,117.13,110.62,61.49,59.67,54.49,46.12,28.50,24.61.19F NMR(470MHz,CDCl3)δ-62.43.HRMS(ESI-TOF)m/zcalcd for C27H25F3N3[M+H]+:448.1995；found:448.1997.
实施例5
7-(4-chlorobenzyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3e):According to general procedure(for 36h),1a(58.4mg,0.2mmol),2e(56.3mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded3e(48.4mg,59％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 192–194℃.1H NMR(500MHz,CDCl3)δ7.94(s,1H),7.18(s,1H),7.06–6.89(m,6H),6.87(d,J＝7.8Hz,1H),6.84–6.76(m,2H),6.76–6.70(m,1H),6.67(t,J＝7.5Hz,1H),5.25(d,J＝14.0Hz,1H),5.16(d,J＝6.9Hz,1H),4.26–4.07(m,2H),3.75(d,J＝14.0Hz,1H),3.62–3.49(m,1H),3.00(dt,J＝12.1,8.3Hz,1H),2.22–2.11(m,1H),2.10–1.96(m,2H),1.96–1.87(m,1H).13C NMR(125MHz,CDCl3)δ153.01,146.16,142.38,141.42,138.00,134.14,127.22,122.52,121.43,121.22,120.88,120.67,120.39,120.14,116.77,110.49,110.12,108.38,60.70,57.62,47.54,46.05,28.37,24.47.HRMS(ESI-TOF)m/zcalcd for C26H25ClN3[M+H]+:414.1732；found:414.1740.
实施例6
7-(4-methoxybenzyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3f):According to general procedure(for 36h),1a(58.4mg,0.2mmol),2f(54.5mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded3f(55.8mg,68％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 95–100℃.1H NMR(500MHz,CDCl3)δ7.91(s,1H),7.15(s,1H),7.04–6.94(m,4H),6.92(dd,J＝7.8,1.6Hz,1H),6.83(d,J＝7.1Hz,1H),6.78(dd,J＝7.9,1.6Hz,1H),6.73(td,J＝7.6,1.6Hz,1H),6.67(td,J＝7.4,1.6Hz,1H),6.58(d,J＝8.6Hz,2H),5.27(d,J＝7.0Hz,1H),5.21(d,J＝14.0Hz,1H),4.14(s,2H),3.77(d,J＝14.1Hz,1H),3.61(s,3H),3.56(td,J＝8.2,7.8,3.9Hz,1H),3.00(dt,J＝12.1,8.2Hz,1H),2.21–2.12(m,1H),2.10–1.97(m,2H),1.96–1.87(m,1H).13C NMR(125MHz,CDCl3)δ158.19,146.09,142.64,138.07,134.70,131.10,130.00,127.26,121.92,121.43,121.25,120.73,120.56,120.17,120.13,116.80,113.32,110.40,61.08,59.38,55.16,54.27,46.08,28.51,24.58.HRMS(ESI-TOF)m/z calcd for C27H28N3O[M+H]+:410.2227；found:410.2230.
实施例7
7-(3-methylbenzyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3g):According to general procedure(for 36h),1a(58.4mg,0.2mmol),2g(48.1mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded3g(58.3mg,74％)as a light green solid after purification on silica gel(petroleum ether/EtOAc＝15:1),mp 192–194℃.1H NMR(500MHz,CDCl3)δ7.87(s,1H),7.13(d,J＝8.1Hz,1H),7.00–6.90(m,4H),6.90–6.84(m,2H),6.83–6.76(m,3H),6.73(dt,J＝9.0,4.6Hz,1H),6.70–6.63(m,1H),5.33(d,J＝6.5Hz,1H),5.20(d,J＝14.0Hz,1H),4.16(s,2H),3.81(d,J＝14.0Hz,1H),3.64–3.48(m,1H),3.08–2.97(m,1H),2.22–2.12(m,1H),2.12–1.97(m,5H),1.96–1.88(m,1H).13C NMR(125MHz,CDCl3)δ146.06,142.77,138.96,138.04,137.32,134.57,129.81,127.76,127.25,125.93,122.01,121.42,121.20,120.73,120.57,120.23,120.21,116.83,110.41,100.86,61.01,59.37,55.22,46.14,28.57,24.58,21.37.HRMS(ESI-TOF)m/z calcd for C27H28N3[M+H]+:394.2278；found:394.2280.
实施例8
2-((2,6,13,14,15,15a-hexahydro-7H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indol-7-yl)methyl)benzaldehyde(3h):According to generalprocedure(for 36h),1a(58.4mg,0.2mmol),2h(53.7mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3h(61.7mg,76％)as a light yellow solid after purificationon silica gel(petroleum ether/EtOAc＝15:1),mp 96–100℃.1H NMR(500MHz,CDCl3)δ10.02(s,1H),7.95(s,1H),7.62(d,J＝7.5Hz,1H),7.36–7.25(m,2H),7.22–7.19(m,1H),7.07(d,J＝8.0Hz,1H),6.99–6.93(m,1H),6.88(t,J＝7.6Hz,2H),6.73(td,J＝14.0,12.9,6.9Hz,3H),6.66–6.56(m,1H),5.52–5.33(m,1H),5.10(d,J＝14.0Hz,1H),4.71(d,J＝14.4Hz,1H),4.51(d,J＝14.4Hz,1H),4.05(d,J＝14.0Hz,1H),3.44(dd,J＝13.7,5.1Hz,1H),2.99(dt,J＝11.5,8.4Hz,1H),2.23–1.99(m,3H),1.98–1.88(m,1H).13C NMR(125MHz,CDCl3)δ153.01,146.16,142.38,141.42,138.00,134.14,127.22,122.52,121.43,121.22,120.88,120.67,120.39,120.14,116.77,110.49,110.12,108.38,60.70,57.62,47.54,46.05,28.37,24.47.HRMS(ESI-TOF)m/z calcd for C27H26N3O[M+H]+:408.2070；found:408.2073.
实施例9
7-(furan-2-ylmethyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3i):According to general procedure(for 36h),1a(58.4mg,0.2mmol),2i(38.5mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded3i(58.6mg,79％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 192–194℃.1H NMR(500MHz,CDCl3)δ7.74(s,1H),7.15(d,J＝1.8Hz,1H),7.07(d,J＝8.0Hz,1H),7.05(d,J＝7.7Hz,1H),6.95(q,J＝7.8,6.5Hz,1H),6.89–6.84(m,1H),6.81(d,J＝7.1Hz,1H),6.77(d,J＝4.3Hz,2H),6.69(dq,J＝8.4,4.2Hz,1H),6.11(dd,J＝3.2,1.8Hz,1H),5.98(d,J＝3.1Hz,1H),5.39(d,J＝6.2Hz,1H),5.09(d,J＝14.2Hz,1H),4.25–4.09(m,2H),3.87(d,J＝14.2Hz,1H),3.52(td,J＝7.9,3.7Hz,1H),2.98(dt,J＝12.1,8.2Hz,1H),2.20–2.10(m,1H),2.10–1.98(m,2H),1.95–1.87(m,1H).13CNMR(125MHz,CDCl3)δ153.01,146.16,142.38,141.42,138.00,134.14,127.22,122.52,121.43,121.22,120.88,120.67,120.39,120.14,116.77,110.49,110.12,108.38,60.70,57.62,47.54,46.05,28.37,24.47.HRMS(ESI-TOF)m/z calcd for C24H24N3O[M+H]+:370.1914；found:370.1915.
实施例10
7-(thiophen-2-ylmethyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3j):According to generalprocedure(for 36h),1a(58.4mg,0.2mmol),2j(44.9mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3j(65.0mg,84％)as a white solid after purification onsilica gel(petroleum ether/EtOAc＝15:1),mp 105–107℃.1H NMR(500MHz,CDCl3)δ7.78(s,1H),7.13–7.08(m,1H),6.99–6.89(m,4H),6.83(d,J＝7.1Hz,1H),6.80–6.73(m,3H),6.71(dd,J＝5.0,3.5Hz,1H),6.66(td,J＝7.7,1.8Hz,1H),5.48(d,J＝4.8Hz,1H),5.17(d,J＝14.0Hz,1H),4.47(d,J＝15.1Hz,1H),4.31(d,J＝15.1Hz,1H),3.83(d,J＝14.0Hz,1H),3.55(dq,J＝11.4,3.5Hz,1H),3.00(dt,J＝12.1,8.3Hz,1H),2.20–2.13(m,1H),2.12–2.00(m,2H),1.95–1.86(m,1H).13C NMR(125MHz,CDCl3)δ153.01,146.16,142.38,141.42,138.00,134.14,127.22,122.52,121.43,121.22,120.88,120.67,120.39,120.14,116.77,110.49,110.12,108.38,60.70,57.62,47.54,46.05,28.37,24.47.HRMS(ESI-TOF)m/zcalcd for C24H24N3S[M+H]+:386.1685；found:386.1688.
实施例11
7-cinnamyl-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]dia-zonino[6,7,8-cd]indole(3k):According to general procedure(for 36h),1a(58.4mg,0.2mmol),2k(52.9mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3k(64.6mg,80％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 122–124℃.1H NMR(500MHz,CDCl3)δ7.94(s,1H),7.16–7.10(m,5H),7.08–7.02(m,1H),7.00–6.93(m,2H),6.92–6.89(m,1H),6.86–6.80(m,2H),6.76(dtd,J＝16.6,7.3,1.6Hz,2H),6.42(d,J＝15.8Hz,1H),6.05(ddd,J＝15.9,7.2,5.5Hz,1H),5.25(d,J＝7.1Hz,1H),5.16(d,J＝14.1Hz,1H),3.84(t,J＝6.5Hz,2H),3.76(d,J＝14.2Hz,1H),3.57(ddd,J＝11.3,7.7,2.8Hz,1H),2.98(dt,J＝12.4,8.3Hz,1H),2.19–2.11(m,1H),2.12–2.01(m,1H),2.04–1.94(m,1H),1.96–1.85(m,1H).13C NMR(125MHz,CDCl3)δ146.03,143.40,138.18,137.34,134.78,131.86,128.41,128.19,127.33,127.16,126.32,121.87,121.53,121.27,120.79,120.57,120.40,120.07,116.85,110.51,61.48,58.38,52.88,45.91,27.96,24.56.HRMS(ESI-TOF)m/z calcd for C28H28N3[M+H]+:406.2278；found:406.2280.
实施例12
7-benzyl-9-(trifluoromethyl)-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3l):According to generalprocedure(for 36h),1l(71.88mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3l(66.0mg,74％)as a light green solid after purificationon silica gel(petroleum ether/EtOAc＝15:1),mp 134–136℃.1H NMR(500MHz,CDCl3)δ7.86(s,1H),7.17–7.11(m,2H),7.07–7.00(m,5H),6.98–6.93(m,3H),6.83(d,J＝7.1Hz,1H),6.72(d,J＝8.4Hz,1H),5.45(d,J＝4.9Hz,1H),5.03(d,J＝14.1Hz,1H),4.16(q,J＝14.1Hz,2H),3.87(d,J＝14.1Hz,1H),3.50(dt,J＝10.6,5.7Hz,1H),3.12–2.88(m,1H),2.25–2.10(m,1H),2.08–1.84(m,3H).13C NMR(125MHz,CDCl3)δ149.09,141.81,138.05,137.98,133.69,129.21,128.05,127.02,126.88,124.91(q,J＝269.5Hz),121.65,121.56,121.35(q,J＝31.7Hz),120.80,119.72(q,J＝3.9Hz),119.59,117.91(q,J＝4.0Hz),116.26,110.66,60.33,59.07,55.58,46.24,28.99,24.29.19F NMR(470MHz,CDCl3)δ-61.27.HRMS(ESI-TOF)m/z calcd for C27H25F3N3[M+H]+:448.1995；found:448.1997.
实施例13
7-benzyl-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazoni-no[6,7,8-cd]indole-9-carbonitrile(3m):According to generalprocedure(for 36h),1m(63.3mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3m(68.0mg,84％)as a white solid after purification onsilica gel(petroleum ether/EtOAc＝15:1),mp 198–202℃.1H NMR(500MHz,CDCl3)δ8.00(s,1H),7.16–7.02(m,8H),7.02–6.99(m,1H),6.97(t,J＝7.5Hz,1H),6.84(d,J＝7.1Hz,1H),6.61(d,J＝8.5Hz,1H),5.84(dd,J＝8.4,3.2Hz,1H),4.81(d,J＝14.2Hz,1H),4.16(d,J＝13.9Hz,1H),4.10(d,J＝14.2Hz,1H),4.07(d,J＝14.0Hz,1H),3.50–3.36(m,1H),3.08(dt,J＝11.2,8.3Hz,1H),2.29–2.21(m,1H),2.19–2.08(m,1H),2.07–1.99(m,2H).13C NMR(125MHz,CDCl3)δ150.46,140.78,137.70,137.50,132.82,129.23,128.14,128.11,127.07,126.65,125.87,121.77,121.62,120.69,120.52,118.88,116.60,110.62,101.08,59.02,58.60,56.98,46.46,29.82,24.04.HRMS(ESI-TOF)m/z calcd for C27H25N4[M+H]+:405.2074；found:405.2075.
实施例14
Methyl7-benzyl-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole-9-carboxylate(3n):According to generalprocedure(for 36h),1n(69.9mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3n(65.0mg,74％)as a white solid after purification onsilica gel(petroleum ether/EtOAc＝15:1),mp 108–112℃.1H NMR(500MHz,CDCl3)δ8.02(s,1H),7.65(d,J＝1.9Hz,1H),7.42(dd,J＝8.5,2.0Hz,1H),7.13–7.00(m,6H),6.97(d,J＝2.0Hz,1H),6.93(t,J＝7.6Hz,1H),6.83(d,J＝7.1Hz,1H),6.61(d,J＝8.5Hz,1H),5.95–5.76(m,1H),4.85(d,J＝14.1Hz,1H),4.14(s,2H),4.03(d,J＝14.1Hz,1H),3.73(s,3H),3.50–3.43(m,1H),3.05(dt,J＝11.3,8.1Hz,1H),2.25–2.14(m,1H),2.12–1.93(m,3H).13CNMR(125MHz,CDCl3)δ167.52,150.76,140.55,138.23,137.78,133.56,129.46,127.97,126.82,125.62,123.47,121.60,121.51,120.58,120.45,119.29,115.74,110.47,59.29,59.08,57.05,51.63,46.42,29.57,24.10.HRMS(ESI-TOF)m/z calcd for C28H28N3O2[M+H]+:438.2176；found:438.2177.
实施例15
7-benzyl-9-chloro-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3o):According to general procedure(for36h),1o(65.2mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3o(56.0mg,68％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 133–137℃.1H NMR(500MHz,CDCl3)δ7.85(s,1H),7.12(d,J＝7.9Hz,1H),7.09–6.97(m,5H),7.08–6.98(m,1H),6.97–6.90(m,1H),6.85(s,1H),6.81(d,J＝7.1Hz,1H),6.68–6.62(m,2H),5.28–5.07(m,2H),4.23–4.08(m,2H),3.77(d,J＝14.1Hz,1H),3.56–3.32(m,1H),3.01–2.93(m,1H),2.18–2.08(m,1H),2.05–1.82(m,3H).13C NMR(125MHz,CDCl3)δ144.75,143.72,138.35,138.08,133.87,128.93,128.08,127.13,126.78,125.07,121.65,121.55,121.46,120.95,120.49,120.07,117.74,110.70,61.16,59.19,55.04,46.32,28.57,24.52.HRMS(ESI-TOF)m/z calcd for C26H25ClN3[M+H]+:414.1732；found:414.1735.
实施例16
7-benzyl-10-bromo-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3p):According to general procedure(for36h),1p(74.1mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3p(69.0mg,75％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 123–125℃.1H NMR(500MHz,CDCl3)δ7.82(s,1H),7.11–7.07(m,1H),7.07–6.98(m,5H),6.96–6.90(m,2H),6.82–6.78(m,2H),6.70(s,2H),5.39(d,J＝4.7Hz,1H),5.04(d,J＝14.1Hz,1H),4.24–4.03(m,2H),3.84(d,J＝14.1Hz,1H),3.44–3.37(m,1H),3.05–2.87(m,1H),2.21–2.08(m,1H),2.06–1.96(m,2H),1.95–1.85(m,1H).13C NMR(125MHz,CDCl3)δ147.59,141.27,138.49,137.97,133.84,128.99,128.08,127.11,126.81,122.66,122.22,121.55,120.77,120.00,119.74,115.44,110.67,60.43,59.08,55.69,46.37,28.97,24.34.HRMS(ESI-TOF)m/z calcd for C26H25BrN3[M+H]+:458.1226；found:458.1228.
实施例17
7-benzyl-10-methyl-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3q):According to general procedure(for 36h),1q(61.1mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded3q(64.0mg,81％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 112–116℃.1H NMR(500MHz,CDCl3)δ7.88(s,1H),7.13(d,J＝8.1Hz,1H),7.10–7.01(m,4H),7.01–6.90(m,3H),6.81(dd,J＝7.6,2.5Hz,2H),6.58(s,1H),6.46(d,J＝7.7Hz,1H),5.38(d,J＝6.0Hz,1H),5.16(d,J＝14.0Hz,1H),4.17(s,2H),3.78(d,J＝14.0Hz,1H),3.59–3.52(m,1H),3.08–2.91(m,1H),2.20–2.13(m,1H),2.11(s,3H),2.09–1.97(m,2H),1.96–1.88(m,1H).13C NMR(125MHz,CDCl3)δ145.80,140.03,139.18,138.03,134.68,131.38,128.93,127.92,127.30,126.50,121.41,121.29,120.65,120.56,120.52,120.07,117.75,110.41,60.85,59.63,55.47,46.10,28.63,24.54,21.22.HRMS(ESI-TOF)m/z calcd for C27H28N3[M+H]+:394.2278；found:394.2281.
实施例18
7-benzyl-9-methoxy-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3r):According to general procedure(for 36h),1r(64.3mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded3r(53.0mg,65％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 95–100℃.1H NMR(500MHz,CDCl3)δ7.99(s,1H),7.65(d,J＝2.0Hz,1H),7.43(dd,J＝8.5,2.0Hz,1H),7.15–7.06(m,5H),7.06–7.00(m,1H),7.00(d,J＝1.9Hz,1H),6.95(t,J＝7.5Hz,1H),6.84(d,J＝7.1Hz,1H),6.62(d,J＝8.5Hz,1H),5.90–5.76(m,1H),4.86(d,J＝14.1Hz,1H),4.19–4.11(m,2H),4.03(d,J＝14.1Hz,1H),3.74(s,3H),3.52–3.44(m,1H),3.06(dt,J＝11.3,8.1Hz,1H),2.28–2.12(m,1H),2.13–1.93(m,3H).13C NMR(125MHz,CDCl3)δ167.49,150.74,140.54,138.22,137.77,133.57,129.45,127.96,126.81,125.60,123.45,121.60,121.48,120.58,120.45,119.32,115.72,110.44,59.29,59.07,57.04,51.61,46.41,29.56,24.09.HRMS(ESI-TOF)m/z calcd for C27H28N3O[M+H]+:410.2227；found:410.2228.
实施例19
7-benzyl-4-phenyl-6,7,13,14,15,15a-hexahydro-2H-benzo[2,3]pyrrolo[1',2':4,5][1,4]diazonino[6,7,8-cd]indole(3s):According to general procedure(for36h),1s(73.5mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3s(67.0mg,73％)as a white solid after purification on silica gel(petroleumether/EtOAc＝15:1),mp 123–125℃.1H NMR(500MHz,CDCl3)δ7.91(s,1H),7.53(d,J＝7.3Hz,2H),7.36–7.31(m,3H),7.24–7.20(m,1H),7.07(d,J＝7.0Hz,3H),7.03(t,J＝7.0Hz,3H),7.00–6.95(m,2H),6.95–6.90(m,1H),6.81(d,J＝7.7Hz,1H),6.77–6.70(m,1H),6.70–6.63(m,1H),5.38–5.22(m,2H),4.24(s,2H),3.83(d,J＝14.1Hz,1H),3.67–3.49(m,1H),3.10–2.96(m,1H),2.21–2.12(m,1H),2.12–1.97(m,2H),1.97–1.88(m,1H).13C NMR(125MHz,CDCl3)δ146.01,142.77,142.00,138.97,138.71,134.87,134.83,128.92,128.68,127.92,127.33,126.65,126.61,126.58,122.04,121.95,120.54,120.30,120.11,116.94,108.79,61.18,59.75,55.21,46.21,28.54,24.64.HRMS(ESI-TOF)m/z calcd forC32H30N3[M+H]+:456.2434；found:456.2435.
实施例20
5-benzyl-4,11,11a,12,13,14,15,15a,15b,17-decahydro-5H-benzo[2,3]isoindolo[2',1':4,5][1,4]diazonino[6,7,8-cd]indole(3t):According to generalprocedure(for 36h),1t(69.1mg,0.2mmol),2a(42.4mg,0.4mmol),TfOH(6.0mg,0.04mmol),afforded 3t(69.0mg,81％)as a white solid after purification onsilica gel(petroleum ether/EtOAc＝15:1),mp 122–126℃.1H NMR(500MHz,DMSO)δ10.96(s,1H),7.34(s,1H),7.27–7.21(m,2H),7.19(d,J＝6.9Hz,1H),7.16(d,J＝7.3Hz,5H),6.89(t,J＝7.6Hz,1H),6.79(d,J＝7.0Hz,1H),6.76–6.67(m,3H),6.45(t,J＝7.1Hz,1H),5.43(d,J＝5.6Hz,1H),4.70(d,J＝14.0Hz,1H),4.29(d,J＝14.1Hz,1H),4.15(q,J＝14.6Hz,2H),3.35(s,1H),3.21(dd,J＝9.6,4.3Hz,1H),2.90–2.73(m,1H),2.50–2.40(m,1H),1.76–1.57(m,4H),1.52–1.32(m,4H).13C NMR(125MHz,DMSO)δ146.37,139.60,138.94,138.07,132.95,129.36,128.39,127.44,127.16,123.86,123.55,120.60,119.18,118.40,116.85,116.07,111.01,62.07,58.06,57.18,52.14,42.91,36.63,26.84,26.58,23.68,23.04.HRMS(ESI-TOF)m/z calcd for C30H32N3[M+H]+:434.2591；found:434.2594.
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其它形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。
Claims (3)
1.一种吲哚3,4位并九元中环化合物，其特征在于，结构如下所示：
其中，
R1选自苄基、对硝基苄基、对氰基苄基、对三氟甲基苄基、对氯苄基、对甲氧基苄基、间甲基苄基以及邻醛基苄基中的一种。
2.权利要求1所述吲哚3,4位并九元中环化合物的制备方法，其特征在于，步骤如下：
将N-（（1H-吲哚-4-基）甲基）-2-（吡咯烷-1-基）苯胺与甲醛类化合物以摩尔比1:2混合，加入溶剂N,N-二甲基甲酰胺和20 mol%催化剂，在室温下反应，生成权利要求1所述吲哚3,4位并九元中环化合物；
所述催化剂选自三氟甲磺酸、对甲苯磺酸、甲烷磺酸、樟脑磺酸、联萘酚磷酸酯、三氟甲烷磺酸钪以及三氟化硼乙醚中的一种。
3.根据权利要求2所述的制备方法，其特征在于，所述溶剂的用量为每摩尔N-（（1H-吲哚-4-基）甲基）-2-（吡咯烷-1-基）苯胺添加10L溶剂。
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