一种N-取代含氮杂环衍生物及其制备方法与应用转让专利
申请号 : CN201910838532.5
文献号 : CN110437119B
文献日 : 2020-10-20
发明人 : 王佳毅 , 宋恭华 , 夏琦 , 吴梦莹 , 张家毓
申请人 : 华东理工大学
摘要 :
本发明涉及一种N‑取代含氮杂环衍生物及其制备方法与应用。与现有技术相比，本发明采用简便、有效的方法，合成了一系列结构新颖、具有显著抗癌活性的N‑取代吡咯或吲哚衍生物，经MTT法测试后，本发明衍生物能够显著抑制肝癌细胞系HepG2、肺癌细胞系A549等癌细胞的增殖活性；通过二醛、4‑羟基‑L‑脯氨酸或吲哚啉‑2‑甲酸的一锅法反应，即可制备出含有9,10‑二氢菲、10,11‑二氢二苯并[b,f]氧杂卓、10,11‑二氢二苯并[b,f]硫杂卓结构的N‑取代吡咯或吲哚衍生物，该制备方法便捷、快速、高效。
权利要求 :
1.一种N-取代含氮杂环衍生物，其特征在于，所述的衍生物为式I化合物、式I化合物的光学异构体、式I化合物的顺反异构体或式I化合物药学上可接受的盐：其中：
X为O、S或单键；
Y为
Ra为氢、C1～C15烷基、C1～C15卤代烷基、卤素、硝基或C1～C15烷氧基；
Rb为氢、C1～C15烷基、C1～C15卤代烷基、卤素或C1～C15烷氧基。
2.根据权利要求1所述的一种N-取代含氮杂环衍生物，其特征在于，所述的衍生物为以下化合物中的一种：
3.根据权利要求1所述的一种N-取代含氮杂环衍生物，其特征在于，所述的衍生物为以下化合物中的一种：
4.一种如权利要求1至3任一项所述的N-取代含氮杂环衍生物的制备方法，其特征在于，该方法为：在有机溶剂中，以 含氮杂环物为原料，在90-180℃下反应15-180min，反应结束后，经分离即得到所述的N-取代含氮杂环衍生物；
所述的含氮杂环物为反式-4-羟基-L-脯氨酸或吲哚啉-2-甲酸。
5.一种如权利要求1至3任一项所述的N-取代含氮杂环衍生物的应用，其特征在于，所述的衍生物用于制备抗肿瘤药物。
6.一种组合物，该组合物含有如权利要求1至3任一项所述的N-取代含氮杂环衍生物。
7.根据权利要求6所述的一种组合物，其特征在于，该组合物包括一种或更多种N-取代含氮杂环衍生物，以及药学上可接受的载体介质。
8.一种如权利要求6所述的组合物的应用，其特征在于，所述的组合物用于制备抗肿瘤药物。
说明书 :
一种N-取代含氮杂环衍生物及其制备方法与应用
技术领域
[0001] 本发明属于医药技术领域，涉及一种具有细胞毒性作用的N-取代含氮杂环衍生物及其制备方法与应用。
背景技术
[0002] 癌症是影响人类健康的最危险的疾病之一。近年来，随着癌症患者的不断增多、科学对于癌症理解的不断加深，癌症制药领域正快速发展。开发具有抗癌活性的新型化合物先导结构，进而通过结构改造和优化，快速开发高活性化合物，对于新抗癌药的开发有着重要的意义。
[0003] 多环芳烃广泛分布于自然界各种有机体内，在药物、生物模拟材料、高分子材料、染料、燃料等方面有着重要的应用。其中一些多环芳烃的衍生物已被发现具有明显的生物活性。因此，如何从种类众多的多环芳烃中筛选出具有抗癌活性的化合物，将具有很好的实用意义和价值。
发明内容
[0004] 本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种N-取代含氮杂环衍生物及其制备方法与应用。
[0005] 本发明的目的可以通过以下技术方案来实现：
[0006] 一种N-取代含氮杂环衍生物，所述的衍生物为式I化合物、式I化合物的光学异构体、式I化合物的顺反异构体或式I化合物药学上可接受的盐：
[0007]
[0008] 其中：
[0009] X为O、S或单键；
[0010] Y为
[0011] Ra、Rb分别独立地选自氢、卤素、氰基、硝基、取代的或未取代的C1～C15烷基、取代的或未取代的C1～C15烷氧基、C1～C15卤代烷基、C1～C15卤代烷氧基、-C1～C6亚烷基-O-C1～C6亚烷基-或-C1～C6亚烷基-S-C1～C6亚烷基-。
[0012] 进一步地，所述的Ra及Rb中，取代的C1～C15烷基为一个或多个取代基取代的C1～C15烷基，取代的C1～C15烷氧基为一个或多个取代基取代C1～C15烷氧基，所述的取代基为卤素、氰基、硝基、C1～C6烷基、C1～C6烷氧基、C1～C6卤代烷基或C1～C6卤代烷氧基。
[0013] 进一步地，所述的衍生物为以下化合物中的一种：
[0014]
[0015] 通过选择不同的X、Y，能够得到上述不同的式I化合物。
[0016] 进一步地，所述的衍生物为以下化合物中的一种：
[0017]
[0018] 上述衍生物为式I化合物不同的光学异构体、顺反异构体。
[0019] 一种N-取代含氮杂环衍生物的制备方法，该方法为：在有机溶剂中，以含氮杂环物为原料，在90-180℃下反应15-180min，反应结束后，经分离即得到所述的N-取代含氮杂环衍生物。
[0020] 与含氮杂环物的摩尔比1:1.0-3.0。
[0021] 进一步地，所述的含氮杂环物为反式-4-羟基-L-脯氨酸或吲哚啉-2-甲酸。
[0022] 反式-4-羟基-L-脯氨酸的结构式为：
[0023]
[0024] 吲哚啉-2-甲酸的结构式为：
[0025]
[0026] 一种N-取代含氮杂环衍生物的应用，所述的衍生物用于制备抗肿瘤药物。
[0027] 一种组合物，该组合物含有N-取代含氮杂环衍生物。
[0028] 进一步地，该组合物包括一种或更多种N-取代含氮杂环衍生物，以及药学上可接受的载体介质和/或赋形剂。该组合物可以只包含一种含氮杂环衍生物，也可以将多种含有不同X、Y、Ra、Rb的含氮杂环衍生物组合成混合物。组合物中还含有药学上可接受的载体介质和/或赋形剂。
[0029] 所述的含氮杂环衍生物在组合物中的质量百分含量为0.001-99.99％。
[0030] 一种组合物的应用，所述的组合物用于制备抗肿瘤药物。
[0031] 所述的肿瘤主要包括：鼻咽癌、食管癌、胃癌、肝癌、乳腺癌、结肠癌、前列腺癌、肺癌、宫颈癌、白血病、口腔癌、唾液腺肿瘤、鼻腔与鼻旁窦恶性肿瘤、喉癌、耳部肿瘤、眼部肿瘤、甲状腺肿瘤、纵隔肿瘤、胸壁、胸膜肿瘤、小肠肿瘤、胆道肿瘤、胰腺与壶腹周围肿瘤、肠系膜与腹膜后肿瘤、肾脏肿瘤、肾上腺肿瘤、膀胱肿瘤、前列腺癌、睾丸肿瘤、阴茎癌、子宫内膜癌、卵巢恶性肿瘤、恶性滋养细胞肿瘤、外阴癌与阴道癌、恶性淋巴瘤、多发性骨髓瘤、软组织肿瘤、骨肿瘤、皮肤及附件肿瘤、恶性黑色素瘤或神经系统肿瘤。
[0032] 药物组合物和施用方法：
[0033] 本发明所述的“组合物”指任何混合物。可以是溶液、混合液、液体、粉末、油膏、水性的、非水性的或他们的任何组合。
[0034] 本发明化合物、其光学异构体、顺反异构体或药学上可接受的盐或上述组合物可以单位剂量形式给药，给药突进可分为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
[0035] 给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括O/W、W/O型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
[0036] 本发明化合物、其光学异构体、顺反异构体或药学上可接受的盐可以制成普通制剂，也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
[0037] 为了将本发明化合物、其光学异构体、顺反异构体或药学上可接受的盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；粘合剂可以是淀粉剂、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；润湿剂可以是水、乙醇、异丙醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
[0038] 还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将给药单元制成胶囊剂，可以将有效成分(即本发明化合物、其光学异构体、顺反异构体或药学上可接受的盐)与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分先与稀释剂、粘合剂、崩解剂制成颗粒或微丸，在置于硬胶囊或软胶囊中。用于制备有效成分片剂的各稀释剂、粘合剂、润湿剂、崩解剂、助流剂品种也可用于制备有效成分的胶囊剂。
[0039] 为将本发明化合物、其光学异构体、顺反异构体或药学上可接受的盐制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等，pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等，渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
[0040] 此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
[0041] 为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
[0042] 吡咯和吲哚是含氮杂环的重要分支，很多具有生物活性的天然产物或合成化合物都含有此类结构。本发明基于结构进行设计，开发了一种有效、简便的合成路线用于合成含有9,10-二氢菲、10,11-二氢二苯并[b,f]氧杂卓、10,11-二氢二苯并[b,f]硫杂卓等多环芳烃结构的N-取代吡咯或吲哚衍生物，并发现其具有抗癌活性，这些衍生物或含有衍生物的组合物对肝癌细胞HepG2和肺癌细胞A549等癌细胞具有抗癌活性，可用于抗癌药物，具有很好的实用意义和价值。
[0043] 与现有技术相比，本发明具有以下特点：
[0044] 1)本发明采用简便、有效的方法，合成了一系列结构新颖、具有显著抗癌活性的N-取代吡咯或吲哚衍生物，经MTT法测试后，本发明衍生物能够显著抑制肝癌细胞系HepG2、肺癌细胞系A549等癌细胞的增殖活性；
[0045] 2)通过二醛、4-羟基-L-脯氨酸或吲哚啉-2-甲酸的一锅法反应，即可制备出含有9,10-二氢菲、10,11-二氢二苯并[b,f]氧杂卓、10,11-二氢二苯并[b,f]硫杂卓结构的N-取代吡咯或吲哚衍生物，该制备方法便捷、快速、高效。
具体实施方式
[0046] 下面结合具体实施例对本发明进行详细说明。本实施例以本发明技术方案为前提进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
[0047] 应理解，在本发明范围内中，本发明的上述各技术特征和在各实施例中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
[0048] 本发明中，术语“烷基”是指烷烃分子中少掉一个氢原子而成的基团；术语“亚烷基”是指烷烃分子中少掉两个氢原子而成的基团。
[0049] 术语“卤素”指氟、氯、溴或碘。术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团，例如三氟甲基、五氟乙基、七氟异丙基或类似基团。
[0050] 有机溶剂优选为惰性溶剂，即不与原料发生反应的各种溶剂，包括各种直链、支链或环状的醇、醚或酮，卤代烷，1,4-二氧六环，乙腈，四氢呋喃，N,N-二甲基甲酰胺(DMF)，二甲基亚砜(DMSO)等。
[0051] 术语“药学上可接受的盐”指本发明的式I化合物与药学上可接受的无机酸和有机酸所形成的盐，其中，优选的无机酸包括(但并不限于)：盐酸、氢溴酸、磷酸、硝酸、硫酸；优选的有机酸包括(但并不限于)：甲酸、乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸以及氨基酸。
[0052] 术语“光学异构体”指本发明式I化合物所涉及手性碳原子可以为R构型，也可以为S构型，或其组合。本发明式I化合物可以含有一个或多个不对称中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物和纯或部分纯的化合物包括在本发明的范围之内。本发明包括化合物的所有异构形式。
[0053] 除非另行定义，本发明中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。本发明中所述的较佳实施方法与材料仅做示范之用。
[0054] 实施例1：
[0055] [1,1′-联苯]-2,2′-二甲醛的合成：
[0056]
[0057] 在10mL圆底烧瓶中加入邻溴苯甲醛(0.184g，1.0mmol)、2-甲酰基苯硼酸(0.164g，1.1mmol)、双(二亚苄基丙酮)钯(0.0060g，0.01mmol)、三环己基膦(0.003g，0.012mmol)和二水合氟化钾(0.310g，3.3mmol)，2mL四氢呋喃作为溶剂，油浴中回流温度下进行反应，6h反应结束。待反应溶液温度降到室温后，减压除去溶剂，加入去离子水(10mL)洗涤，用二氯甲烷萃取(3×10mL)，合并有机相后用饱和氯化钠溶液洗涤，再用无水硫酸镁进行干燥，抽滤后旋干滤液得粗产物。经柱层析纯化分离得到黄色固体197.0mg，产率94％。1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.06(s,1H),7.68(td,J＝7.5,1.4Hz,1H),7.60(t,J＝
13
7.5Hz,1H),7.40–7.32(m,1H). C NMR(101MHz,CDCl3)δ191.07(2C),141.25(2C),134.59(2C),133.46(2C),131.73(2C),128.85(2C),128.59(2C).MS(GC-MS):m/z210.0(M+).[0058] 实施例2：
13
7.5Hz,1H),7.40–7.32(m,1H). C NMR(101MHz,CDCl3)δ191.07(2C),141.25(2C),134.59(2C),133.46(2C),131.73(2C),128.85(2C),128.59(2C).MS(GC-MS):m/z210.0(M+).[0058] 实施例2：
[0059] [4,4′-二氟-1,1′-联苯]-2,2′-二甲醛的合成：
[0060]
[0061] 在10mL圆底烧瓶中加入2-溴-5-氟苯甲醛(0.202g，1.0mmol)、四(三苯基膦)钯(0.035g，0.03mmol)、铜粉(0.320g，5.0mmol)，二甲基亚砜作为溶剂，微波回流温度下进行反应，30min反应结束。待反应溶液温度降到室温后，过滤，滤液中加入去离子水(10mL)洗涤，用乙酸乙酯萃取三次(3×10mL)，合并有机层。有机相用饱和氯化钠溶液洗涤，再用无水硫酸镁进行干燥，抽滤后旋干滤液得粗产物。经柱层析纯化分离得到橙色固体0.87g，产率71％。1H NMR(400MHz,CDCl3)δ9.77(d,J＝2.8Hz,2H),7.74(d,J＝2.6Hz,1H),7.72(d,J＝
13
2.6Hz,1H),7.43–7.35(m,4H). C NMR(101MHz,CDCl3)δ189.50(d,J＝1.7Hz),162.81(d,J＝251.5Hz),136.43(d,J＝6.3Hz),136.00(d,J＝3.5Hz),133.81(d,J＝7.3Hz),120.86(d,J＝22.1Hz),115.10(d,J＝22.5Hz).MS(GC-MS):m/z 246.0(M+).
13
2.6Hz,1H),7.43–7.35(m,4H). C NMR(101MHz,CDCl3)δ189.50(d,J＝1.7Hz),162.81(d,J＝251.5Hz),136.43(d,J＝6.3Hz),136.00(d,J＝3.5Hz),133.81(d,J＝7.3Hz),120.86(d,J＝22.1Hz),115.10(d,J＝22.5Hz).MS(GC-MS):m/z 246.0(M+).
[0062] 实施例3：[3,3′-二氟-1,1′-联苯]-2,2′-二甲醛的合成：
[0063]
[0064] 在10mL圆底烧瓶中加入2-甲酰基-3-氟苯硼酸(0.202g，1.0mmol)、氯化亚铜(0.005g，0.05mmol)，N,N-二甲基甲酰胺(DMF)作为溶剂，室温下反应20h。待反应溶液温度降到室温后，加入去离子水(10mL)洗涤，用乙酸乙酯萃取三次(3×10mL)，合并有机层。有机相用饱和氯化钠溶液洗涤，再用无水硫酸镁进行干燥，抽滤后旋干滤液得粗产物。经柱层析纯化分离得到白色固体0.113g，产率92％。1H NMR(400MHz,CDCl3)δ10.27–10.14(m,2H),7.62–7.56(m,2H),7.26–7.21(m,2H),6.97(d,J＝7.6Hz,2H).13C NMR(101MHz,CDCl3)δ
187.49(d,J＝8.4Hz),164.74(d,J＝259.5Hz),141.89(d,J＝4.1Hz),134.99(d,J＝
10.4Hz),126.32(d,J＝3.5Hz),122.45(d,J＝7.2Hz),116.28(d,J＝21.5Hz).MS(GC-MS):
m/z 246.0(M+).
187.49(d,J＝8.4Hz),164.74(d,J＝259.5Hz),141.89(d,J＝4.1Hz),134.99(d,J＝
10.4Hz),126.32(d,J＝3.5Hz),122.45(d,J＝7.2Hz),116.28(d,J＝21.5Hz).MS(GC-MS):
m/z 246.0(M+).
[0065] 实施例4：
[0066]
[0067] 在50mL的三口烧瓶里加入邻氟苯甲醛(0.744g，6mmol)、水杨醛(0.610mg，5mmol)、碳酸钾(1.380g，10mmol)，10mL二甲基亚砜为溶剂，微波120℃条件下进行反应，40min后反应结束。待反应液冷却后，用硅藻土过滤，再加入15mL去离子水稀释，用乙酸乙酯(EA)萃取(3×15mL)，合并乙酸乙酯萃取液。用饱和氯化钠溶液洗涤萃取液，再用无水硫酸镁干燥，抽滤后旋干得粗产物。经过柱层析纯化分离得到白色固体0.971g，产率为86％。1H NMR(400MHz,CDCl3):δ10.53(s,2H),7.11(d,J＝8.3Hz,2H),7.39(t,J＝7.7Hz,2H),7.72(m,2H),7.96(dd,J＝7.7,1.5Hz,2H).MS(GC-MS)m/z:226.0(M+).
[0068] 按照上述实施例1-4所述方法，采用不同的起始原料制备如下所示的二醛类化合物。
[0069]1
H NMR(400MHz,CDCl3)δ9.85(s,1H),9.74(d,J＝3.0Hz,1H),8.06–8.03(m,1H),7.72–
7.67(m,2H),7.65–7.61(m,1H),7.39–7.36(m,3H).13C NMR(101MHz,CDCl3)δ190.93,
189.77,189.76,162.57(d,J＝250.5Hz),139.68,137.55(d,J＝3.4Hz),136.17(d,J＝
6.3Hz),134.70,133.60,133.54(d,J＝7.5Hz),132.06,129.22(d,J＝25.0Hz),120.69(d,J＝22.0Hz),114.25(d,J＝22.4Hz).MS(GC-MS):m/z 228.0(M+).
H NMR(400MHz,CDCl3)δ9.85(s,1H),9.74(d,J＝3.0Hz,1H),8.06–8.03(m,1H),7.72–
7.67(m,2H),7.65–7.61(m,1H),7.39–7.36(m,3H).13C NMR(101MHz,CDCl3)δ190.93,
189.77,189.76,162.57(d,J＝250.5Hz),139.68,137.55(d,J＝3.4Hz),136.17(d,J＝
6.3Hz),134.70,133.60,133.54(d,J＝7.5Hz),132.06,129.22(d,J＝25.0Hz),120.69(d,J＝22.0Hz),114.25(d,J＝22.4Hz).MS(GC-MS):m/z 228.0(M+).
[0070]1H NMR(400MHz,CDCl3)δ9.86(s,1H),9.76(s,1H),8.07–8.03(m,1H),7.69(td,J＝
7.4,1.5Hz,1H),7.66–7.62(m,1H),7.32(dd,J＝13.7,4.6Hz,1H).13C NMR(101MHz,CDCl3)δ
190.77,189.66,139.76,139.56,135.61,135.39,134.61,133.60,133.35,132.88,131.81,+
129.61,129.22,128.20.MS(GC-MS):m/z244.0(M).
7.4,1.5Hz,1H),7.66–7.62(m,1H),7.32(dd,J＝13.7,4.6Hz,1H).13C NMR(101MHz,CDCl3)δ
190.77,189.66,139.76,139.56,135.61,135.39,134.61,133.60,133.35,132.88,131.81,+
129.61,129.22,128.20.MS(GC-MS):m/z244.0(M).
[0071]1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.06(s,1H),7.68(td,J＝7.5,1.4Hz,1H),7.60(t,J＝7.5Hz,1H),7.40–7.32(m,1H).13C NMR(101MHz,CDCl3)δ190.75,189.65,138.96,
134.72,134.38,133.74,132.14,131.58,131.15(q,J＝33.5Hz),130.40,129.67(q,J＝
3.4Hz),129.51,125.28(q,J＝3.8Hz),123.47(q,J＝272.7Hz).MS(GC-MS):m/z 278.1(M+).
134.72,134.38,133.74,132.14,131.58,131.15(q,J＝33.5Hz),130.40,129.67(q,J＝
3.4Hz),129.51,125.28(q,J＝3.8Hz),123.47(q,J＝272.7Hz).MS(GC-MS):m/z 278.1(M+).
[0072]1H NMR(400MHz,CDCl3)δ9.86(s,1H),9.79(s,1H),8.06(dd,J＝7.7,1.0Hz,1H),7.66(td,J＝7.5,1.4Hz,1H),7.58(dd,J＝13.5,5.1Hz,1H),3.94(s,2H).13C NMR(101MHz,CDCl3)δ191.24,190.87,159.92,140.97,135.61,134.99,133.97,133.39,133.02,132.26,
128.69,128.50,120.91,110.97,55.70.MS(GC-MS):m/z 240.0(M+).
128.69,128.50,120.91,110.97,55.70.MS(GC-MS):m/z 240.0(M+).
[0073]1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.06(s,1H),7.68(td,J＝7.5,1.4Hz,1H),7.60(t,J＝7.5Hz,1H),7.40–7.32(m,1H).13C NMR(101MHz,CDCl3)δ191.14,187.72(d,J＝
6.5Hz),164.17(d,J＝261.2Hz),141.81(d,J＝1.3Hz),141.29(d,J＝2.5Hz),134.85(d,J＝10.4Hz),134.03,133.55,130.69,129.17,128.68,127.58(d,J＝3.6Hz),123.02(d,J＝
7.1Hz),116.60(d,J＝21.5Hz).MS(GC-MS):m/z 228.0(M+).
6.5Hz),164.17(d,J＝261.2Hz),141.81(d,J＝1.3Hz),141.29(d,J＝2.5Hz),134.85(d,J＝10.4Hz),134.03,133.55,130.69,129.17,128.68,127.58(d,J＝3.6Hz),123.02(d,J＝
7.1Hz),116.60(d,J＝21.5Hz).MS(GC-MS):m/z 228.0(M+).
[0074]1
H NMR(400MHz,CDCl3)δ9.82(s,1H),9.73(s,1H),8.77(d,J＝1.9Hz,1H),8.40(dd,J＝8.3,2.0Hz,1H),7.99(d,J＝6.7Hz,1H),7.72–7.62(m,1H),7.46(d,J＝8.3Hz,1H),7.27(d,J＝6.7Hz,1H).13C NMR(101MHz,CDCl3)δ190.78,188.79,148.10,148.01,137.69,
135.19,134.24,133.88,132.50,131.94,131.39,129.92,127.29,123.28.MS(GC-MS):m/+
z255.0(M).
H NMR(400MHz,CDCl3)δ9.82(s,1H),9.73(s,1H),8.77(d,J＝1.9Hz,1H),8.40(dd,J＝8.3,2.0Hz,1H),7.99(d,J＝6.7Hz,1H),7.72–7.62(m,1H),7.46(d,J＝8.3Hz,1H),7.27(d,J＝6.7Hz,1H).13C NMR(101MHz,CDCl3)δ190.78,188.79,148.10,148.01,137.69,
135.19,134.24,133.88,132.50,131.94,131.39,129.92,127.29,123.28.MS(GC-MS):m/+
z255.0(M).
[0075]1H NMR(400MHz,CDCl3)δ10.14(s,1H),9.76(s,1H),7.61(ddd,J＝8.3,7.7,5.6Hz,
1H),7.50(t,J＝1.6Hz,1H),7.26(ddd,J＝10.4,8.4,0.8Hz,1H),7.18(d,J＝1.6Hz,2H),
7.10(d,J＝7.6Hz,1H),3.91(s,3H).13CNMR(101MHz,CDCl3)δ190.72,δ187.88(d,J＝
6.0Hz),164.00(d,J＝261.7Hz),159.79,141.53(d,J＝1.3Hz),135.16,134.63(d,J＝
10.5Hz),133.86(d,J＝2.4Hz),132.10,128.20(d,J＝3.5Hz),123.41(d,J＝6.9Hz),+
120.60,116.49(d,J＝21.4Hz),111.60,55.63.MS(GC-MS):m/z258.1(M).
1H),7.50(t,J＝1.6Hz,1H),7.26(ddd,J＝10.4,8.4,0.8Hz,1H),7.18(d,J＝1.6Hz,2H),
7.10(d,J＝7.6Hz,1H),3.91(s,3H).13CNMR(101MHz,CDCl3)δ190.72,δ187.88(d,J＝
6.0Hz),164.00(d,J＝261.7Hz),159.79,141.53(d,J＝1.3Hz),135.16,134.63(d,J＝
10.5Hz),133.86(d,J＝2.4Hz),132.10,128.20(d,J＝3.5Hz),123.41(d,J＝6.9Hz),+
120.60,116.49(d,J＝21.4Hz),111.60,55.63.MS(GC-MS):m/z258.1(M).
[0076]1
H NMR(400MHz,CDCl3)δ9.86(s,2H),8.31(d,J＝0.8Hz,2H),7.96(dd,J＝8.0,1.3Hz,
2H),7.50(d,J＝7.9Hz,2H).13C NMR(101MHz,CDCl3)δ189.17(2C),142.90(2C),134.66(2C),131.96(q,J＝33.8Hz,2C),131.94(2C),130.01(q,J＝3.5Hz,2C),126.91(q,J＝
3.7Hz,2C),123.25(q,J＝272.7Hz,2C).MS(GC-MS):m/z346.0(M+).
H NMR(400MHz,CDCl3)δ9.86(s,2H),8.31(d,J＝0.8Hz,2H),7.96(dd,J＝8.0,1.3Hz,
2H),7.50(d,J＝7.9Hz,2H).13C NMR(101MHz,CDCl3)δ189.17(2C),142.90(2C),134.66(2C),131.96(q,J＝33.8Hz,2C),131.94(2C),130.01(q,J＝3.5Hz,2C),126.91(q,J＝
3.7Hz,2C),123.25(q,J＝272.7Hz,2C).MS(GC-MS):m/z346.0(M+).
[0077]1H NMR(400MHz,CDCl3)δ9.80(s,2H),7.54(d,J＝2.7Hz,2H),7.26(d,J＝8.4Hz,2H),
7.22–7.19(m,2H),3.92(s,6H).13C NMR(101MHz,CDCl3)δ191.02,159.76,135.89,133.67,
133.46,120.85,110.89,55.66.MS(GC-MS):m/z270.1(M+).
7.22–7.19(m,2H),3.92(s,6H).13C NMR(101MHz,CDCl3)δ191.02,159.76,135.89,133.67,
133.46,120.85,110.89,55.66.MS(GC-MS):m/z270.1(M+).
[0078]1H NMR(400MHz,CDCl3)δ10.40(s,2H),7.95(d,J＝2.6Hz,2H),7.55(d,J＝2.7Hz,1H),
7.53(d,J＝2.7Hz,1H),6.92(s,1H),6.90(s,1H).MS(GC-MS):m/z294.0(M+).
7.53(d,J＝2.7Hz,1H),6.92(s,1H),6.90(s,1H).MS(GC-MS):m/z294.0(M+).
[0079]1H NMR(400MHz,CDCl3)δ10.46(s,2H),7.77(d,J＝1.8Hz,2H),7.37(d,J＝2.0Hz,1H),
7.35(d,J＝2.0Hz,1H),6.83(s,1H),6.81(s,1H),2.39(s,6H).MS(GC-MS):m/z254.1(M+).[0080]
MS(GC-MS):m/z286.1(M+).
7.35(d,J＝2.0Hz,1H),6.83(s,1H),6.81(s,1H),2.39(s,6H).MS(GC-MS):m/z254.1(M+).[0080]
MS(GC-MS):m/z286.1(M+).
[0081]1
H NMR(400MHz,CDCl3)δ10.50(s,1H),10.43(s,1H),7.99(dd,J＝7.8,11.7Hz,1H),
7.62–7.56(m,1H),7.51(td,J＝8.4,6.1Hz,1H),7.32(t,J＝7.5Hz,1H),7.00(d,J＝9.3Hz,
1H),6.96(d,J＝7.9Hz,1H),6.72(d,J＝8.4Hz,1H).MS(GC-MS):m/z 244.0(M+).
H NMR(400MHz,CDCl3)δ10.50(s,1H),10.43(s,1H),7.99(dd,J＝7.8,11.7Hz,1H),
7.62–7.56(m,1H),7.51(td,J＝8.4,6.1Hz,1H),7.32(t,J＝7.5Hz,1H),7.00(d,J＝9.3Hz,
1H),6.96(d,J＝7.9Hz,1H),6.72(d,J＝8.4Hz,1H).MS(GC-MS):m/z 244.0(M+).
[0082]1H NMR(400MHz,CDCl3)δ10.37(s,2H),7.97(dd,J＝7.5,1.6Hz,2H),7.54–7.44(m,
4H),7.18(dd,J＝7.6,0.9Hz,2H).MS(GC-MS):m/z242.0(M+).
4H),7.18(dd,J＝7.6,0.9Hz,2H).MS(GC-MS):m/z242.0(M+).
[0083] 实施例5：
[0084] 10-(1H-吡咯-1基)-9,10-二氢菲-9-醇的制备：
[0085]
[0086] 在10mL圆底烧瓶中加入[1,1′-联苯]-2,2′-二甲醛(0.105g，0.5mmol)、反式-4-羟基-L-脯氨酸(0.098g，0.75mmol)，以1.5mL二甲基亚砜为溶剂，油浴温度140℃下进行反应，30min反应结束。待反应溶液温度降到室温后，加入去离子水(10mL)洗涤，用乙酸乙酯萃取三次，合并乙酸乙酯萃取液。用饱和氯化钠溶液洗涤萃取液，再用无水硫酸镁进行干燥，抽滤后旋干滤液得粗产物。经柱层析纯化分离得到黄色固体。trans/cis＝87:13；m.p.131-
134℃.HRMS(EI)calcd for C18H15NO[M]+261.1154,found 2261.1153.
134℃.HRMS(EI)calcd for C18H15NO[M]+261.1154,found 2261.1153.
[0087] 通过进一步分离获得反式(trans)异构体:1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,
1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–
5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ135.96,134.55,133.17,132.13,
128.79,128.57,128.56,128.50,126.60,125.62,123.77,123.67,120.53(2C),109.19(2C),71.99,65.81.
1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–
5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ135.96,134.55,133.17,132.13,
128.79,128.57,128.56,128.50,126.60,125.62,123.77,123.67,120.53(2C),109.19(2C),71.99,65.81.
[0088] 通过进一步分离获得顺式(cis)异构体:1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,
1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–
5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ135.93,133.33,133.15,132.63,
129.40,129.08,128.98,128.75,128.65,126.50,124.00,123.96,120.97(2C),108.50(2C),71.26,62.42.
1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–
5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ135.93,133.33,133.15,132.63,
129.40,129.08,128.98,128.75,128.65,126.50,124.00,123.96,120.97(2C),108.50(2C),71.26,62.42.
[0089] 按照实施例5所述方法，采用不同的起始原料制备如下N-取代吡咯或吲哚衍生物。
[0090]trans/cis＝96:4；HRMS(EI)calcd for C18H13F2NO[M]+
[0091] 297.0965,found 297.0963.
[0092] 通过进一步分离获得反式异构体:m.p.143-148℃；1H NMR(400MHz,CDCl3)δ7.71–7.64(m,2H),7.46(ddd,J＝9.4,2.7,0.8Hz,1H),7.14–7.03(m,2H),6.82(t,J＝2.1Hz,2H),
6.42–6.28(m,3H),5.14(q,J＝11.7Hz,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ162.95(d,JCF＝248.4Hz),162.86(d,JCF＝248.3Hz),138.10(d,JCF＝7.3Hz),136.86(d,JCF＝
6.8Hz),128.63(d,JCF＝3.3Hz),127.56(d,JCF＝3.3Hz),125.45(d,JCF＝8.1Hz),125.37(d,JCF＝7.9Hz),120.24,115.79(d,JCF＝21.8Hz),115.41(d,JCF＝21.9Hz),113.45(d,JCF＝
23.6Hz),112.66(d,JCF＝23.7Hz),109.98,71.51,65.70.
6.42–6.28(m,3H),5.14(q,J＝11.7Hz,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ162.95(d,JCF＝248.4Hz),162.86(d,JCF＝248.3Hz),138.10(d,JCF＝7.3Hz),136.86(d,JCF＝
6.8Hz),128.63(d,JCF＝3.3Hz),127.56(d,JCF＝3.3Hz),125.45(d,JCF＝8.1Hz),125.37(d,JCF＝7.9Hz),120.24,115.79(d,JCF＝21.8Hz),115.41(d,JCF＝21.9Hz),113.45(d,JCF＝
23.6Hz),112.66(d,JCF＝23.7Hz),109.98,71.51,65.70.
[0093]trans/cis＝60:40；1H NMR(400MHz,CDCl3)δ8.06(s,0.6H),8.00(dd,J＝15.8,8.2Hz,
0.8H),7.91(dd,J＝13.2,8.2Hz,1.2H),7.80(d,J＝3.8Hz,0.4H),7.74(d,J＝10.0Hz,
1.2H),7.71–7.66(m,0.8H),7.48(s,0.4H),6.90(s,0.6H),6.80(t,J＝2.1Hz,1.2H),6.52(t,J＝2.1Hz,0.8H),6.34(t,J＝2.0Hz,1.2H),6.11(t,J＝2.1Hz,0.8H),5.36(d,J＝
4.8Hz,0.4H),5.20(q,J＝11.6Hz,1.2H),5.11(d,J＝4.7Hz,0.4H),2.59(s,0.4H),2.04(s,
0.6H).HRMS(EI)calcd for C20H13F6NO[M]+297.0901,found 297.0900.
0.8H),7.91(dd,J＝13.2,8.2Hz,1.2H),7.80(d,J＝3.8Hz,0.4H),7.74(d,J＝10.0Hz,
1.2H),7.71–7.66(m,0.8H),7.48(s,0.4H),6.90(s,0.6H),6.80(t,J＝2.1Hz,1.2H),6.52(t,J＝2.1Hz,0.8H),6.34(t,J＝2.0Hz,1.2H),6.11(t,J＝2.1Hz,0.8H),5.36(d,J＝
4.8Hz,0.4H),5.20(q,J＝11.6Hz,1.2H),5.11(d,J＝4.7Hz,0.4H),2.59(s,0.4H),2.04(s,
0.6H).HRMS(EI)calcd for C20H13F6NO[M]+297.0901,found 297.0900.
[0094] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.91(dd,J＝13.0,8.2Hz,2H),7.75–7.64(m,2H),6.91(s,1H),6.81(t,J＝2.1Hz,2H),6.36(t,J＝2.1Hz,2H),5.21(q,J＝11.6Hz,2H),2.43(s,1H).13C NMR(101MHz,CDCl3)δ137.20,136.13,
135.18,134.14,131.50(q,JCF＝32.9Hz),131.45(q,JCF＝32.8Hz),125.86(q,JCF＝3.7Hz),
125.56(q,JCF＝3.9Hz),124.66,124.64,123.92(q,JCF＝272.3Hz),123.62(q,JCF＝
272.3Hz),123.56(q,JCF＝3.8Hz),122.90(q,JCF＝3.6Hz),120.21,110.38,71.30,65.30.[0095]
trans/cis＝82:18；1H NMR(400MHz,CDCl3)δ7.68–7.63(m,0.36H),7.59(t,J＝8.7Hz,
1.64H),7.21(d,J＝2.7Hz,0.82H),7.00(d,J＝2.5Hz,0.18H),6.93–6.84(m,2H),6.75(t,J＝2.1Hz,1.64H),6.63(d,J＝2.6Hz,0.18H),6.57(t,J＝2.1Hz,0.36H),6.24(t,J＝2.1Hz,
1.64H),6.18(d,J＝2.6Hz,0.82H),6.05(t,J＝2.1Hz,0.36H),5.05(s,1.64H),4.98(s,
0.18H),3.83(s,2.46H),3.78(s,0.54H),3.74(s,0.54H),3.67(s,2.46H),2.48(s,0.82H),
1.26(s,0.18H).HRMS(EI)calcd for C20H19NO3[M]+321.1365,found 321.1359.[0096] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.61(t,J＝8.6Hz,2H),
7.23(d,J＝2.7Hz,1H),6.90(ddd,J＝15.3,8.6,2.7Hz,2H),6.78(t,J＝2.1Hz,2H),6.27(t,J＝2.1Hz,2H),6.21(d,J＝2.6Hz,1H),5.09(s,2H),3.85(s,3H),3.69(s,3H).13C NMR(101MHz,CDCl3)δ159.37,159.30,136.74,135.32,126.01,124.93,124.51,124.36,
120.43,114.47,114.19,111.97,110.49,109.32,72.19,66.01,55.42,55.25.
135.18,134.14,131.50(q,JCF＝32.9Hz),131.45(q,JCF＝32.8Hz),125.86(q,JCF＝3.7Hz),
125.56(q,JCF＝3.9Hz),124.66,124.64,123.92(q,JCF＝272.3Hz),123.62(q,JCF＝
272.3Hz),123.56(q,JCF＝3.8Hz),122.90(q,JCF＝3.6Hz),120.21,110.38,71.30,65.30.[0095]
trans/cis＝82:18；1H NMR(400MHz,CDCl3)δ7.68–7.63(m,0.36H),7.59(t,J＝8.7Hz,
1.64H),7.21(d,J＝2.7Hz,0.82H),7.00(d,J＝2.5Hz,0.18H),6.93–6.84(m,2H),6.75(t,J＝2.1Hz,1.64H),6.63(d,J＝2.6Hz,0.18H),6.57(t,J＝2.1Hz,0.36H),6.24(t,J＝2.1Hz,
1.64H),6.18(d,J＝2.6Hz,0.82H),6.05(t,J＝2.1Hz,0.36H),5.05(s,1.64H),4.98(s,
0.18H),3.83(s,2.46H),3.78(s,0.54H),3.74(s,0.54H),3.67(s,2.46H),2.48(s,0.82H),
1.26(s,0.18H).HRMS(EI)calcd for C20H19NO3[M]+321.1365,found 321.1359.[0096] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.61(t,J＝8.6Hz,2H),
7.23(d,J＝2.7Hz,1H),6.90(ddd,J＝15.3,8.6,2.7Hz,2H),6.78(t,J＝2.1Hz,2H),6.27(t,J＝2.1Hz,2H),6.21(d,J＝2.6Hz,1H),5.09(s,2H),3.85(s,3H),3.69(s,3H).13C NMR(101MHz,CDCl3)δ159.37,159.30,136.74,135.32,126.01,124.93,124.51,124.36,
120.43,114.47,114.19,111.97,110.49,109.32,72.19,66.01,55.42,55.25.
[0097]m.p.128-130℃；trans/cis＝44:56；1H NMR(400MHz,CDCl3)δ7.70(dd,J＝7.9,2.7Hz,
1.13H),7.63(d,J＝7.9Hz,0.88H),7.40(qd,J＝13.8,7.5Hz,2H),7.11–7.01(m,2H),6.49(s,0.88H),6.38(s,1.12H),6.00(d,J＝1.8Hz,0.88H),5.97(d,J＝1.8Hz,1.12H),5.75(s,
0.56H),5.58(d,J＝5.2Hz,0.44H),5.37(s,0.56H),5.33(d,J＝4.8Hz,0.44H),2.88(s,
0.44H),2.13(s,0.56H).HRMS(EI)calcd for C18H13F2NO[M]+297.0965,found 297.0966.[0098] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.72(dd,J＝7.8,
2.5Hz,2H),7.45(dd,J＝14.3,7.6Hz,2H),7.09(dd,J＝20.0,8.6Hz,2H),6.39(s,2H),5.97(s,2H),5.78(s,1H),5.41(s,1H),2.08(s,1H).13C NMR(101MHz,CDCl3)δ162.20(d,JCF＝
249.0Hz),161.41(d,JCF＝248.7Hz),134.09(t,JCF＝3.4Hz),133.89–133.77(t,JCF＝
3.4Hz),131.08(d,JCF＝8.9Hz),130.76(d,JCF＝9.0Hz),121.86(d,JCF＝16.3Hz),120.27(d,JCF＝3.3Hz),120.02(d,JCF＝3.3Hz),119.40,119.34(d,JCF＝16.3Hz),116.06(d,JCF＝
21.8Hz),116.02(d,JCF＝22.0Hz),108.34,64.25(d,JCF＝4.7Hz),53.90(d,JCF＝4.0Hz).[0099]
m.p.＝141-149℃；trans isomer:1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.91(dd,J＝
13.2,8.2Hz,2H),7.70(dd,J＝16.1,8.2Hz,2H),6.90(s,1H),6.81(t,J＝2.1Hz,2H),6.36(t,J＝2.1Hz,2H),5.23(d,J＝11.7Hz,1H),5.18(d,J＝11.6Hz,1H),2.60(s,1H)；13C NMR(100MHz,DMSO)δ148.05,147.99,141.46,139.30,136.59,136.26,126.66,126.52,123.62,
123.35,121.32,121.16,120.54(2C),108.70(2C),68.58,62.83.HRMS(EI)calcd for C18H13N3O5[M]+351.0855,found 351.0871.
1.13H),7.63(d,J＝7.9Hz,0.88H),7.40(qd,J＝13.8,7.5Hz,2H),7.11–7.01(m,2H),6.49(s,0.88H),6.38(s,1.12H),6.00(d,J＝1.8Hz,0.88H),5.97(d,J＝1.8Hz,1.12H),5.75(s,
0.56H),5.58(d,J＝5.2Hz,0.44H),5.37(s,0.56H),5.33(d,J＝4.8Hz,0.44H),2.88(s,
0.44H),2.13(s,0.56H).HRMS(EI)calcd for C18H13F2NO[M]+297.0965,found 297.0966.[0098] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.72(dd,J＝7.8,
2.5Hz,2H),7.45(dd,J＝14.3,7.6Hz,2H),7.09(dd,J＝20.0,8.6Hz,2H),6.39(s,2H),5.97(s,2H),5.78(s,1H),5.41(s,1H),2.08(s,1H).13C NMR(101MHz,CDCl3)δ162.20(d,JCF＝
249.0Hz),161.41(d,JCF＝248.7Hz),134.09(t,JCF＝3.4Hz),133.89–133.77(t,JCF＝
3.4Hz),131.08(d,JCF＝8.9Hz),130.76(d,JCF＝9.0Hz),121.86(d,JCF＝16.3Hz),120.27(d,JCF＝3.3Hz),120.02(d,JCF＝3.3Hz),119.40,119.34(d,JCF＝16.3Hz),116.06(d,JCF＝
21.8Hz),116.02(d,JCF＝22.0Hz),108.34,64.25(d,JCF＝4.7Hz),53.90(d,JCF＝4.0Hz).[0099]
m.p.＝141-149℃；trans isomer:1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.91(dd,J＝
13.2,8.2Hz,2H),7.70(dd,J＝16.1,8.2Hz,2H),6.90(s,1H),6.81(t,J＝2.1Hz,2H),6.36(t,J＝2.1Hz,2H),5.23(d,J＝11.7Hz,1H),5.18(d,J＝11.6Hz,1H),2.60(s,1H)；13C NMR(100MHz,DMSO)δ148.05,147.99,141.46,139.30,136.59,136.26,126.66,126.52,123.62,
123.35,121.32,121.16,120.54(2C),108.70(2C),68.58,62.83.HRMS(EI)calcd for C18H13N3O5[M]+351.0855,found 351.0871.
[0100]trans/cis＝58:42；1H NMR(400MHz,CDCl3)δ7.79–7.63(m,2.65H),7.44–7.32(m,2H),
7.19(ddd,J＝8.6,5.1,1.1Hz,0.39H),7.11–6.98(m,1H),6.75(t,J＝2.1Hz,0.83H),6.73(t,J＝2.1Hz,1.16H),6.60(d,J＝7.6Hz,0.39H),6.34(ddd,J＝9.3,2.6,0.8Hz,0.57H),
6.29–6.22(m,2H),5.12–5.03(m,2H),2.43(s,1H).HRMS(EI)calcd for C18H14FNO[M]+
279.1059,found 279.1033.
7.19(ddd,J＝8.6,5.1,1.1Hz,0.39H),7.11–6.98(m,1H),6.75(t,J＝2.1Hz,0.83H),6.73(t,J＝2.1Hz,1.16H),6.60(d,J＝7.6Hz,0.39H),6.34(ddd,J＝9.3,2.6,0.8Hz,0.57H),
6.29–6.22(m,2H),5.12–5.03(m,2H),2.43(s,1H).HRMS(EI)calcd for C18H14FNO[M]+
279.1059,found 279.1033.
[0101] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.71(dd,J＝8.5,5.2Hz,2H),7.43(dd,J＝9.4,2.7Hz,1H),7.36(t,J＝7.6Hz,1H),7.21(dd,J＝14.1,6.6Hz,
1H),7.08(td,J＝8.5,2.7Hz,1H),6.79(t,J＝2.1Hz,2H),6.62(d,J＝7.7Hz,1H),6.29(t,J＝2.1Hz,2H),5.20–5.04(m,2H),2.54(s,1H).13C NMR(101MHz,CDCl3)δ163.07(d,JCF＝
247.9Hz),138.63(d,JCF＝7.7Hz),134.19,132.42,128.83,128.36,128.28(d,JCF＝
3.3Hz),126.35,125.66(d,JCF＝8.2Hz),123.43,120.49,115.31(d,JCF＝21.9Hz),112.69(d,JCF＝23.5Hz),109.46,71.71,71.70,65.83.
1H),7.08(td,J＝8.5,2.7Hz,1H),6.79(t,J＝2.1Hz,2H),6.62(d,J＝7.7Hz,1H),6.29(t,J＝2.1Hz,2H),5.20–5.04(m,2H),2.54(s,1H).13C NMR(101MHz,CDCl3)δ163.07(d,JCF＝
247.9Hz),138.63(d,JCF＝7.7Hz),134.19,132.42,128.83,128.36,128.28(d,JCF＝
3.3Hz),126.35,125.66(d,JCF＝8.2Hz),123.43,120.49,115.31(d,JCF＝21.9Hz),112.69(d,JCF＝23.5Hz),109.46,71.71,71.70,65.83.
[0102]trans/cis＝69:31；1H NMR(400MHz,CDCl3)δ7.80–7.66(m,3H),7.45–7.32(m,2.42H),
7.23(ddd,J＝7.6,3.7,1.2Hz,0.77H),6.78(t,J＝2.1Hz,1.39H),6.76(t,J＝2.1Hz,
0.61H),6.70–6.61(m,1H),6.33–6.26(m,2H),5.16–5.07(m,2H),2.31(s,1H).HRMS(EI)calcd for C18H1435ClNO[M]+295.0764,found295.0762,calcd for C18H1437ClNO[M]+
297.0734,found 297.0733.
7.23(ddd,J＝7.6,3.7,1.2Hz,0.77H),6.78(t,J＝2.1Hz,1.39H),6.76(t,J＝2.1Hz,
0.61H),6.70–6.61(m,1H),6.33–6.26(m,2H),5.16–5.07(m,2H),2.31(s,1H).HRMS(EI)calcd for C18H1435ClNO[M]+295.0764,found295.0762,calcd for C18H1437ClNO[M]+
297.0734,found 297.0733.
[0103] 通过进一步分离获得反式异构体:m.p.126-131℃；1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(d,J＝4.2Hz,2H),
5.20–5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ137.71,134.46,134.43,132.21,
130.64,128.87,128.79,128.60,126.44,125.74,125.16,123.59,120.44(2C),109.53(2C),71.64,65.73.
5.20–5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ137.71,134.46,134.43,132.21,
130.64,128.87,128.79,128.60,126.44,125.74,125.16,123.59,120.44(2C),109.53(2C),71.64,65.73.
[0104]trans:cis＝33:67；1H NMR(400MHz,CDCl3)δ8.01(s,0.41H),7.90–7.77(m,2H),7.75–
7.70(m,0.6H),7.64(dd,J＝13.9,8.4Hz,1H),7.48–7.38(m,1.59H),7.28(t,J＝7.5Hz,
0.41H),6.92(s,0.58H),6.80(s,0.82H),6.76(s,1.17H),6.65(d,J＝7.7Hz,0.42H),6.36–
6.25(m,2H),5.21–5.12(m,2H),2.34(s,1H).HRMS(EI)calcd for C19H14F3NO[M]+329.1027,found 329.1021.
7.70(m,0.6H),7.64(dd,J＝13.9,8.4Hz,1H),7.48–7.38(m,1.59H),7.28(t,J＝7.5Hz,
0.41H),6.92(s,0.58H),6.80(s,0.82H),6.76(s,1.17H),6.65(d,J＝7.7Hz,0.42H),6.36–
6.25(m,2H),5.21–5.12(m,2H),2.34(s,1H).HRMS(EI)calcd for C19H14F3NO[M]+329.1027,found 329.1021.
[0105] 通过进一步分离获得反式异构体:m.p.169-173℃；1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.83(dd,J＝17.0,8.0Hz,2H),7.67(d,J＝8.1Hz,1H),7.41(t,J＝7.6Hz,1H),7.27(dd,J＝15.5,7.9Hz,1H),6.81(s,2H),6.66(d,J＝7.7Hz,1H),6.32(s,2H),5.18(q,J＝11.6Hz,2H),2.53(s,1H).13C NMR(101MHz,CDCl3)δ136.73,135.53(d,JCF＝0.9Hz),135.10,
131.81,130.28(q,JCF＝32.7Hz),129.62,128.97,126.44,125.31(q,JCF＝3.7Hz),124.16(q,JCF＝272.1Hz),124.15,124.08,122.64(q,JCF＝7.5,3.8Hz),120.46,109.65,71.58,
65.71.
131.81,130.28(q,JCF＝32.7Hz),129.62,128.97,126.44,125.31(q,JCF＝3.7Hz),124.16(q,JCF＝272.1Hz),124.15,124.08,122.64(q,JCF＝7.5,3.8Hz),120.46,109.65,71.58,
65.71.
[0106]trans/cis＝57:43；
[0107] 通过进一步分离获得反式异构体:m.p.131-134℃；1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),
5.20–5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ160.08,137.60,133.69,133.14,
128.71,127.52,126.43,125.26,124.85,122.97,120.41(2C),114.49,110.43,109.31(2C),72.13,65.94,55.44.HRMS(EI)calcd for C19H17NO2[M]+291.1259,found 291.1260.[0108] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.75–7.64(m,3H),7.39(td,J＝7.6,1.3Hz,1H),7.32(td,J＝7.5,1.2Hz,1H),6.91(dd,J＝8.6,2.7Hz,1H),6.78(t,J＝2.1Hz,2H),6.27(t,J＝2.1Hz,2H),6.24(d,J＝2.6Hz,1H),5.18–5.09(m,2H),3.70(s,3H),2.07(s,1H).13C NMR(101MHz,CDCl3)δ160.00,136.15,135.06,132.14,128.55,
127.58,125.92,125.58,125.12,123.09,120.37(2C),114.26,112.05,109.36(2C),72.13,
65.86,55.27.HRMS(EI)calcd for C19H17NO2[M]+291.1259,found 291.1254.
5.20–5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ160.08,137.60,133.69,133.14,
128.71,127.52,126.43,125.26,124.85,122.97,120.41(2C),114.49,110.43,109.31(2C),72.13,65.94,55.44.HRMS(EI)calcd for C19H17NO2[M]+291.1259,found 291.1260.[0108] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.75–7.64(m,3H),7.39(td,J＝7.6,1.3Hz,1H),7.32(td,J＝7.5,1.2Hz,1H),6.91(dd,J＝8.6,2.7Hz,1H),6.78(t,J＝2.1Hz,2H),6.27(t,J＝2.1Hz,2H),6.24(d,J＝2.6Hz,1H),5.18–5.09(m,2H),3.70(s,3H),2.07(s,1H).13C NMR(101MHz,CDCl3)δ160.00,136.15,135.06,132.14,128.55,
127.58,125.92,125.58,125.12,123.09,120.37(2C),114.26,112.05,109.36(2C),72.13,
65.86,55.27.HRMS(EI)calcd for C19H17NO2[M]+291.1259,found 291.1254.
[0109]m.p.＝142-146℃；trans isomer:1H NMR(400MHz,CDCl3)δ8.64(d,J＝1.4Hz,1H),
8.29(dd,J＝8.5,2.2Hz,1H),7.91(d,J＝8.6Hz,1H),7.85(d,J＝7.7Hz,1H),7.46(t,J＝
7.6Hz,1H),7.35(t,J＝7.6Hz,1H),6.85(t,J＝2.0Hz,2H),6.70(d,J＝7.7Hz,1H),6.37(t,J＝2.0Hz,2H),5.24(dd,J＝26.0,11.7Hz,2H),2.45(s,1H)；13C NMR(100MHz,CDCl3)δ
135.91,134.51,133.12,132.12,128.78,128.57,128.54,128.50,126.59,125.58,123.77,
123.66,120.45(2C),109.26(2C),72.02,65.80；HRMS(EI)calcd for C18H14N2O3[M]+
306.1004,found 306.1023.
8.29(dd,J＝8.5,2.2Hz,1H),7.91(d,J＝8.6Hz,1H),7.85(d,J＝7.7Hz,1H),7.46(t,J＝
7.6Hz,1H),7.35(t,J＝7.6Hz,1H),6.85(t,J＝2.0Hz,2H),6.70(d,J＝7.7Hz,1H),6.37(t,J＝2.0Hz,2H),5.24(dd,J＝26.0,11.7Hz,2H),2.45(s,1H)；13C NMR(100MHz,CDCl3)δ
135.91,134.51,133.12,132.12,128.78,128.57,128.54,128.50,126.59,125.58,123.77,
123.66,120.45(2C),109.26(2C),72.02,65.80；HRMS(EI)calcd for C18H14N2O3[M]+
306.1004,found 306.1023.
[0110]trans/cis＝62:38；
[0111] major:1H NMR(400MHz,CDCl3)δ7.91–7.84(m,1H),7.68(dd,J＝11.8,8.0Hz,1H),7.48–7.25(m,4H),7.07–6.96(m,1H),6.36(d,J＝1.5Hz,2H),5.97(s,0.76H),5.94(s,
1.24H),5.67(s,0.62H),5.33(s,0.76H),4.86(s,0.62H),2.06(s,1H).13C NMR(101MHz,CDCl3)δ162.26(d,JCF＝248.8Hz),134.96(d,JCF＝3.7Hz),131.60,130.65(d,JCF＝9.1Hz),
130.58,130.23,129.39,124.71,121.77(d,JCF＝15.8Hz),119.82(d,JCF＝3.2Hz),119.57,
119.54,115.60(d,JCF＝21.9Hz),108.16,72.19,54.63(d,JCF＝3.8Hz).
1.24H),5.67(s,0.62H),5.33(s,0.76H),4.86(s,0.62H),2.06(s,1H).13C NMR(101MHz,CDCl3)δ162.26(d,JCF＝248.8Hz),134.96(d,JCF＝3.7Hz),131.60,130.65(d,JCF＝9.1Hz),
130.58,130.23,129.39,124.71,121.77(d,JCF＝15.8Hz),119.82(d,JCF＝3.2Hz),119.57,
119.54,115.60(d,JCF＝21.9Hz),108.16,72.19,54.63(d,JCF＝3.8Hz).
[0112] HRMS(EI)calcd for C18H14FNO[M]+279.1059,found 279.1055.
[0113]trans/cis＝83:17,major:1H NMR(400MHz,CDCl3)δ7.82(d,J＝7.7Hz,1H),7.64(d,J＝7.9Hz,1H),7.43–7.37(m,2H),7.28(t,J＝7.5Hz,1H),7.08(t,J＝8.6Hz,1H),7.02(t,J＝2.0Hz,2H),6.72(d,J＝7.7Hz,1H),6.30(t,J＝2.1Hz,2H),5.34(t,J＝2.7Hz,2H),2.00(s,1H).13C NMR(101MHz,CDCl3)δ159.99(d,JCF＝247.4Hz),134.85(d,JCF＝4.2Hz),
133.82,131.87,130.81(d,JCF＝8.9Hz),129.16,128.35,126.84,124.15,123.70(d,JCF＝
10.8Hz),122.75(d,JCF＝17.2Hz),121.80,115.17(d,JCF＝22.3Hz),108.69,64.08(d,JCF＝
2.3Hz),62.52.
133.82,131.87,130.81(d,JCF＝8.9Hz),129.16,128.35,126.84,124.15,123.70(d,JCF＝
10.8Hz),122.75(d,JCF＝17.2Hz),121.80,115.17(d,JCF＝22.3Hz),108.69,64.08(d,JCF＝
2.3Hz),62.52.
[0114] HRMS(EI)calcd for C18H14FNO[M]+279.1059,found 279.1050.
[0115]trans/cis＝38:62；1H NMR(400MHz,CDCl3)δ7.77(dd,J＝8.7,2.7Hz,1H),7.56(t,J＝
7.4Hz,1H),7.33(tt,J＝8.1,5.3Hz,1H),6.98–6.88(m,2H),6.86(d,J＝2.6Hz,0.38H),
6.77(d,J＝2.7Hz,0.62H),6.37(dd,J＝4.7,2.7Hz,2H),5.96(dt,J＝7.0,2.1Hz,2H),5.61(d,J＝2.2Hz,0.62H),5.28(d,J＝2.7Hz,0.38H),5.25(d,J＝2.8Hz,0.38H),4.75(d,J＝
2.5Hz,0.62H),3.73(d,J＝1.5Hz,3H),2.30(s,1H).HRMS(EI)calcd for C19H16FNO2[M]+
309.1165,found 309.1163.
7.4Hz,1H),7.33(tt,J＝8.1,5.3Hz,1H),6.98–6.88(m,2H),6.86(d,J＝2.6Hz,0.38H),
6.77(d,J＝2.7Hz,0.62H),6.37(dd,J＝4.7,2.7Hz,2H),5.96(dt,J＝7.0,2.1Hz,2H),5.61(d,J＝2.2Hz,0.62H),5.28(d,J＝2.7Hz,0.38H),5.25(d,J＝2.8Hz,0.38H),4.75(d,J＝
2.5Hz,0.62H),3.73(d,J＝1.5Hz,3H),2.30(s,1H).HRMS(EI)calcd for C19H16FNO2[M]+
309.1165,found 309.1163.
[0116] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–5.03(m,2H),2.34
13
(s,1H). C NMR(101MHz,CDCl3)δ160.90(d,JCF＝248.2Hz),160.83,138.36,135.78(d,JCF＝3.6Hz),130.88(d,JCF＝9.1Hz),125.71,124.52(d,JCF＝2.9Hz),120.71(2C),119.56(d,JCF＝16.4Hz),118.97(d,JCF＝3.2Hz),114.17(d,JCF＝21.8Hz),113.92,110.69,108.46(2C),70.13,55.38,54.12(d,JCF＝9.0Hz).
13
(s,1H). C NMR(101MHz,CDCl3)δ160.90(d,JCF＝248.2Hz),160.83,138.36,135.78(d,JCF＝3.6Hz),130.88(d,JCF＝9.1Hz),125.71,124.52(d,JCF＝2.9Hz),120.71(2C),119.56(d,JCF＝16.4Hz),118.97(d,JCF＝3.2Hz),114.17(d,JCF＝21.8Hz),113.92,110.69,108.46(2C),70.13,55.38,54.12(d,JCF＝9.0Hz).
[0117]trans/cis>20:1；HRMS(EI)calcd for C19H16FNO2[M]+309.1165,found
309.1160.trans:1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.6Hz,1H),7.53(d,J＝7.9Hz,1H),
7.38(td,J＝8.1,5.9Hz,1H),7.02–6.97(m,3H),6.88(dd,J＝8.6,2.5Hz,1H),6.28(t,J＝
2.1Hz,2H),6.24(d,J＝1.6Hz,1H),5.28(dd,J＝16.1,2.8Hz,2H),3.68(s,3H),2.07(s,
1H).13C NMR(101MHz,CDCl3)δ160.58,160.04(d,JCF＝247.3Hz),135.86,134.91(d,JCF＝
4.0Hz),130.75(d,JCF＝8.9Hz),125.71,124.61(d,JCF＝2.8Hz),122.04(d,JCF＝16.6Hz),
121.88(2C),119.31(d,JCF＝3.2Hz),114.16(d,JCF＝22.1Hz),113.69,112.37,108.73(2C),64.18(d,JCF＝4.2Hz),62.64,55.28.
309.1160.trans:1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.6Hz,1H),7.53(d,J＝7.9Hz,1H),
7.38(td,J＝8.1,5.9Hz,1H),7.02–6.97(m,3H),6.88(dd,J＝8.6,2.5Hz,1H),6.28(t,J＝
2.1Hz,2H),6.24(d,J＝1.6Hz,1H),5.28(dd,J＝16.1,2.8Hz,2H),3.68(s,3H),2.07(s,
1H).13C NMR(101MHz,CDCl3)δ160.58,160.04(d,JCF＝247.3Hz),135.86,134.91(d,JCF＝
4.0Hz),130.75(d,JCF＝8.9Hz),125.71,124.61(d,JCF＝2.8Hz),122.04(d,JCF＝16.6Hz),
121.88(2C),119.31(d,JCF＝3.2Hz),114.16(d,JCF＝22.1Hz),113.69,112.37,108.73(2C),64.18(d,JCF＝4.2Hz),62.64,55.28.
[0118]trans/cis＝56:44；HRMS(EI)calcd for C18H13NO2[M]+277.1103,found 277.1104.[0119] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.68–7.51(m,1H),
7.30–7.19(m,5H),7.05–6.95(m,1H),6.90(d,J＝7.7Hz,1H),6.76(t,J＝2.1Hz,2H),6.22(t,J＝2.1Hz,2H),5.61(d,J＝9.7Hz,1H),5.22(d,J＝9.7Hz,1H),2.38(s,1H)；13C NMR(100MHz,CDCl3)13C NMR(101MHz,CDCl3)δ154.71,154.66,131.40,130.93,129.53,129.39,
128.35,127.37,124.86,124.72,121.65(2C),121.23,120.74,108.17(2C),71.82,63.95.[0120] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.32–7.21(m,4H),
7.19–7.14(m,1H),7.13–7.07(m,1H),7.03(m,J＝8.4,1H),6.86(d,J＝7.9Hz,1H),6.54(t,J＝2.1Hz,2H,),6.08(t,J＝2.1Hz,2H,),5.73(d,J＝2.5Hz,1H),5.57(s,1H),2.33(s,1H)；13C NMR(101MHz,CDCl3)δ156.50,155.79,132.10,131.21,129.41,128.93,127.67,
126.88,125.39,124.75,121.36,120.62(2C),120.30,109.21(2C),71.52,66.16.[0121]
trans/cis<1:20；cis:1H NMR(400MHz,CDCl3)δ7.28–7.22(m,2H),7.21(s,1H),7.17(s,1H),7.15(d,J＝2.9Hz,1H),6.88(d,J＝2.4Hz,1H),6.50(t,J＝2.1Hz,2H),6.13(t,J＝
2.1Hz,2H),5.66(d,J＝2.6Hz,1H),5.54(s,1H),2.29(s,1H)；13C NMR(101MHz,CDCl3)δ
153.02,152.79,133.04,130.77,130.49,130.13,129.83,129.38,128.47,128.10,122.68,
122.00,121.45(2C),108.78(2C),70.96,63.59.HRMS(EI)calcd for C18H1335Cl2NO2[M]+
37 +
345.0323,found345.0324,calcd for C18H13 Cl2NO2[M] 349.0264,found 349.0265,calcd for C18H1335Cl37ClNO2[M]+347.0294,found 347.0294.
7.30–7.19(m,5H),7.05–6.95(m,1H),6.90(d,J＝7.7Hz,1H),6.76(t,J＝2.1Hz,2H),6.22(t,J＝2.1Hz,2H),5.61(d,J＝9.7Hz,1H),5.22(d,J＝9.7Hz,1H),2.38(s,1H)；13C NMR(100MHz,CDCl3)13C NMR(101MHz,CDCl3)δ154.71,154.66,131.40,130.93,129.53,129.39,
128.35,127.37,124.86,124.72,121.65(2C),121.23,120.74,108.17(2C),71.82,63.95.[0120] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.32–7.21(m,4H),
7.19–7.14(m,1H),7.13–7.07(m,1H),7.03(m,J＝8.4,1H),6.86(d,J＝7.9Hz,1H),6.54(t,J＝2.1Hz,2H,),6.08(t,J＝2.1Hz,2H,),5.73(d,J＝2.5Hz,1H),5.57(s,1H),2.33(s,1H)；13C NMR(101MHz,CDCl3)δ156.50,155.79,132.10,131.21,129.41,128.93,127.67,
126.88,125.39,124.75,121.36,120.62(2C),120.30,109.21(2C),71.52,66.16.[0121]
trans/cis<1:20；cis:1H NMR(400MHz,CDCl3)δ7.28–7.22(m,2H),7.21(s,1H),7.17(s,1H),7.15(d,J＝2.9Hz,1H),6.88(d,J＝2.4Hz,1H),6.50(t,J＝2.1Hz,2H),6.13(t,J＝
2.1Hz,2H),5.66(d,J＝2.6Hz,1H),5.54(s,1H),2.29(s,1H)；13C NMR(101MHz,CDCl3)δ
153.02,152.79,133.04,130.77,130.49,130.13,129.83,129.38,128.47,128.10,122.68,
122.00,121.45(2C),108.78(2C),70.96,63.59.HRMS(EI)calcd for C18H1335Cl2NO2[M]+
37 +
345.0323,found345.0324,calcd for C18H13 Cl2NO2[M] 349.0264,found 349.0265,calcd for C18H1335Cl37ClNO2[M]+347.0294,found 347.0294.
[0122]trans/cis＝34:66；HRMS(EI)calcd for C20H19NO2[M]+305.1416,found 305.1417.[0123] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.37(s,1H),7.14(d,J＝8.2Hz,1H),7.11–6.97(m,3H),6.76(s,2H),6.69(s,1H),6.22(s,2H),5.55(d,J＝9.4Hz,
1H),5.16(d,J＝9.5Hz,1H),2.36(s,1H),2.32(s,3H),2.15(s,3H)；13C NMR(101MHz,CDCl3)δ154.68,154.06,134.88,134.17,131.58,131.33,130.10,129.29,127.21,127.15,
121.07,120.59(2C),119.89,109.08(2C),71.71,66.24,20.95,20.64.
1H),5.16(d,J＝9.5Hz,1H),2.36(s,1H),2.32(s,3H),2.15(s,3H)；13C NMR(101MHz,CDCl3)δ154.68,154.06,134.88,134.17,131.58,131.33,130.10,129.29,127.21,127.15,
121.07,120.59(2C),119.89,109.08(2C),71.71,66.24,20.95,20.64.
[0124] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.02(m,,8.3Hz,2H),6.94(m,,2H),6.85(s,1H),6.55(s,1H),6.47(d,J＝0.7Hz,2H),6.00(d,J＝0.8Hz,2H),
5.57(s,1H),5.38(d,J＝8.4Hz,1H),2.23(s,1H),2.15(s,3H),2.09(s,3H)；13C NMR(101MHz,CDCl3)δ152.82,152.77,134.28,134.17,130.91,130.89,130.15,129.80,
128.86,127.08,121.67(2C),120.90,120.36,108.03(2C),71.90,63.84,20.75,20.71.[0125]
trans/cis＝16:84；major:1H NMR(400MHz,CDCl3)δ7.11(dd,J＝14.0,8.8Hz,2H),
6.73(dd,J＝8.8,2.7Hz,2H),6.64(d,J＝2.8Hz,1H),6.50(s,2H,),6.33(d,J＝2.8Hz,1H),
13
6.04(s,2H),5.61(d,J＝1.6Hz,1H),5.46(s,1H),3.64(s,3H),3.58(s,3H),2.62(s,1H)；C NMR(101MHz,CDCl3)δ156.52,156.23,149.12,148.88,132.50,128.38,121.91(2C),121.67(2C),121.34,115.12,114.82,112.74,108.15(2C),71.47,63.83,55.75,55.56.HRMS(EI)calcd for C20H19NO4[M]+337.1314,found 337.1315.
5.57(s,1H),5.38(d,J＝8.4Hz,1H),2.23(s,1H),2.15(s,3H),2.09(s,3H)；13C NMR(101MHz,CDCl3)δ152.82,152.77,134.28,134.17,130.91,130.89,130.15,129.80,
128.86,127.08,121.67(2C),120.90,120.36,108.03(2C),71.90,63.84,20.75,20.71.[0125]
trans/cis＝16:84；major:1H NMR(400MHz,CDCl3)δ7.11(dd,J＝14.0,8.8Hz,2H),
6.73(dd,J＝8.8,2.7Hz,2H),6.64(d,J＝2.8Hz,1H),6.50(s,2H,),6.33(d,J＝2.8Hz,1H),
13
6.04(s,2H),5.61(d,J＝1.6Hz,1H),5.46(s,1H),3.64(s,3H),3.58(s,3H),2.62(s,1H)；C NMR(101MHz,CDCl3)δ156.52,156.23,149.12,148.88,132.50,128.38,121.91(2C),121.67(2C),121.34,115.12,114.82,112.74,108.15(2C),71.47,63.83,55.75,55.56.HRMS(EI)calcd for C20H19NO4[M]+337.1314,found 337.1315.
[0126]trans/cis＝56:44；
[0127] Trans:1H NMR(400MHz,CDCl3)δ7.53–7.47(m,2H),7.20–7.12(m,5H),6.93–6.88(m,1H),6.50(t,J＝2.0Hz,2H),6.04(t,J＝2.1Hz,2H),5.95(d,J＝1.6Hz,1H),5.88(d,J＝6.2Hz,1H),2.28(s,1H).13C NMR(101MHz,CDCl3)δ141.19,137.88,132.30,131.52,131.27,
131.00,130.83,128.78,128.26,128.14,128.09,127.98,121.79,107.81,72.73,+
65.14.HRMS(EI)calcd for C18H15NOS[M]293.0874,found293.0870.
131.00,130.83,128.78,128.26,128.14,128.09,127.98,121.79,107.81,72.73,+
65.14.HRMS(EI)calcd for C18H15NOS[M]293.0874,found293.0870.
[0128] Cis:1H NMR(400MHz,CDCl3)δ7.72(d,J＝7.7Hz,1H),7.57(dd,J＝7.6,0.9Hz,1H),7.54–7.48(m,1H),7.38(t,J＝7.6Hz,1H),7.17(td,J＝7.5,0.9Hz,1H),7.09–7.04(m,2H),
7.01(dq,J＝7.0,3.4Hz,1H),6.83(t,J＝2.1Hz,2H),6.18(dt,J＝12.4,6.1Hz,3H),5.19
13
(d,J＝10.0Hz,1H),2.51(s,1H). C NMR(101MHz,CDCl3)δ142.25,138.64,135.21,134.12,
132.64,132.59,132.04,129.21,128.25,127.76,127.51,126.67,120.40,109.14,73.03,
68.62.HRMS(EI)calcd for C18H15NOS[M]+293.0874,found 293.0876.
7.01(dq,J＝7.0,3.4Hz,1H),6.83(t,J＝2.1Hz,2H),6.18(dt,J＝12.4,6.1Hz,3H),5.19
13
(d,J＝10.0Hz,1H),2.51(s,1H). C NMR(101MHz,CDCl3)δ142.25,138.64,135.21,134.12,
132.64,132.59,132.04,129.21,128.25,127.76,127.51,126.67,120.40,109.14,73.03,
68.62.HRMS(EI)calcd for C18H15NOS[M]+293.0874,found 293.0876.
[0129]trans/cis＝73:27；1H NMR(400MHz,CDCl3)δ7.88–7.78(m,2H),7.67–7.62(m,0.73H),
7.60(d,J＝7.6Hz,1H),7.49–7.30(m,3.6H),7.27(d,J＝3.3Hz,0.73H),7.22–7.15(m,
0.73H),7.14–7.09(m,2.3H),7.01(d,J＝3.3Hz,0.73H),6.97–6.92(m,0.54H),6.64(d,J＝
7.7Hz,0.73H),6.54(d,J＝3.0Hz,0.73H),6.38(d,J＝3.2Hz,0.27H),5.77(d,J＝4.1Hz,
0.27H),5.58(d,J＝10.3Hz,0.73H),5.31(d,J＝10.3Hz,0.73H),5.03(d,J＝4.1Hz,+
0.27H),2.38(s,0.27H),1.99(s,0.73H).HRMS(EI)calcd for C22H17NO[M]311.1310,found
311.1305.
7.60(d,J＝7.6Hz,1H),7.49–7.30(m,3.6H),7.27(d,J＝3.3Hz,0.73H),7.22–7.15(m,
0.73H),7.14–7.09(m,2.3H),7.01(d,J＝3.3Hz,0.73H),6.97–6.92(m,0.54H),6.64(d,J＝
7.7Hz,0.73H),6.54(d,J＝3.0Hz,0.73H),6.38(d,J＝3.2Hz,0.27H),5.77(d,J＝4.1Hz,
0.27H),5.58(d,J＝10.3Hz,0.73H),5.31(d,J＝10.3Hz,0.73H),5.03(d,J＝4.1Hz,+
0.27H),2.38(s,0.27H),1.99(s,0.73H).HRMS(EI)calcd for C22H17NO[M]311.1310,found
311.1305.
[0130] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ136.63,136.22,133.49,133.32,132.23,129.21,128.90,
128.74,128.62,128.50,127.14,126.40,126.05,123.91,123.89,121.91,121.33,120.06,
110.55,102.93,70.94,62.48.
128.74,128.62,128.50,127.14,126.40,126.05,123.91,123.89,121.91,121.33,120.06,
110.55,102.93,70.94,62.48.
[0131]trans/cis＝87:13；
[0132] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.73–7.64(m,3H),7.33(ddd,J＝9.3,2.6,0.8Hz,1H),7.19(dt,J＝7.0,2.5Hz,1H),7.15–7.02(m,5H),6.61(d,J＝3.2Hz,1H),6.30(ddd,J＝9.2,2.6,0.9Hz,1H),5.48(d,J＝11.3Hz,1H),5.24(d,J＝
11.3Hz,1H),2.38(s,1H).13C NMR(101MHz,CDCl3)δ162.97(d,JCF＝248.1Hz),162.75(d,JCF＝248.5Hz),138.52(d,JCF＝7.6Hz),136.49,135.68(d,JCF＝7.1Hz),129.10,129.01(d,JCF＝3.2Hz),127.69(d,JCF＝2.9Hz),126.22,125.67(d,JCF＝7.7Hz),125.60(d,JCF＝7.8Hz),
122.23,121.56,120.39,115.92(d,JCF＝21.9Hz),115.56(d,JCF＝21.8Hz),113.86(d,JCF＝
23.6Hz),112.99(d,JCF＝23.5Hz),110.49,103.60,70.50,62.5.HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found311.1105.
11.3Hz,1H),2.38(s,1H).13C NMR(101MHz,CDCl3)δ162.97(d,JCF＝248.1Hz),162.75(d,JCF＝248.5Hz),138.52(d,JCF＝7.6Hz),136.49,135.68(d,JCF＝7.1Hz),129.10,129.01(d,JCF＝3.2Hz),127.69(d,JCF＝2.9Hz),126.22,125.67(d,JCF＝7.7Hz),125.60(d,JCF＝7.8Hz),
122.23,121.56,120.39,115.92(d,JCF＝21.9Hz),115.56(d,JCF＝21.8Hz),113.86(d,JCF＝
23.6Hz),112.99(d,JCF＝23.5Hz),110.49,103.60,70.50,62.5.HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found311.1105.
[0133] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.86–7.71(m,2H),7.61(d,J＝7.8Hz,1H),7.50(d,J＝8.3Hz,1H),7.27–7.22(m,1H),7.19–7.08(m,4H),6.84(d,J＝3.3Hz,1H),6.75(dd,J＝8.8,2.6Hz,1H),6.40(d,J＝3.3Hz,1H),5.75(d,J＝4.3Hz,1H),5.05(d,J＝3.7Hz,1H),1.96(s,1H).13C NMR(101MHz,CDCl3)δ162.90(d,JCF＝249.0Hz),
162.61(d,JCF＝249.6Hz),138.08(d,JCF＝6.9Hz),137.17,134.90(d,JCF＝7.4Hz),129.05(d,JCF＝3.4Hz),128.38,128.14(d,JCF＝3.4Hz),126.53,125.93(d,JCF＝8.2Hz),125.82(d,JCF＝8.3Hz),122.16,121.13,120.16,116.51(d,JCF＝21.7Hz),116.21(d,JCF＝
21.7Hz),115.83(d,JCF＝22.7Hz),114.18(d,JCF＝22.7Hz),109.38,103.09,71.28,
57.62.HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found 311.1118.
162.61(d,JCF＝249.6Hz),138.08(d,JCF＝6.9Hz),137.17,134.90(d,JCF＝7.4Hz),129.05(d,JCF＝3.4Hz),128.38,128.14(d,JCF＝3.4Hz),126.53,125.93(d,JCF＝8.2Hz),125.82(d,JCF＝8.3Hz),122.16,121.13,120.16,116.51(d,JCF＝21.7Hz),116.21(d,JCF＝
21.7Hz),115.83(d,JCF＝22.7Hz),114.18(d,JCF＝22.7Hz),109.38,103.09,71.28,
57.62.HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found 311.1118.
[0134]trans/cis＝81:19；
[0135] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.95(dd,J＝20.5,7.9Hz,3H),7.71(dd,J＝17.1,8.4Hz,3H),7.23–7.13(m,3H),7.07(d,J＝3.2Hz,1H),6.97(s,1H),6.67(d,J＝3.2Hz,1H),5.62(d,J＝11.1Hz,1H),5.34(d,J＝11.1Hz,1H),2.25(s,
1H).13C NMR(101MHz,CDCl3)δ137.50,136.56,135.69,134.87,134.26,131.46(q,JCF＝
32.9Hz),131.40(q,JCF＝32.9Hz),129.11,125.99(q,JCF＝3.8Hz),125.85(d,JCF＝2.6Hz),
125.71(q,JCF＝3.8Hz),124.99,124.79,124.01(q,JCF＝3.7Hz),123.96(q,JCF＝272.7Hz),
123.57(q,JCF＝272.5Hz),123.23(q,JCF＝3.8Hz),122.39,121.67,120.56,110.32,
104.09,70.52,62.09.HRMS(EI)calcd for C24H15F6NO[M]+447.1058,found 447.1052.[0136] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ8.09–8.01(m,2H),7.77(dd,J＝13.4,6.5Hz,3H),7.63(d,J＝7.9Hz,1H),7.57(d,J＝8.3Hz,1H),7.42(s,1H),7.29(t,J＝7.7Hz,1H),7.17(t,J＝7.5Hz,1H),6.74(d,J＝3.3Hz,1H),6.44(d,J＝3.3Hz,1H),
5.91(d,J＝4.4Hz,1H),5.19(d,J＝5.0Hz,1H),2.00(s,1H).HRMS(EI)calcd for C24H15F6NO[M]+447.1058,found 447.1050.
1H).13C NMR(101MHz,CDCl3)δ137.50,136.56,135.69,134.87,134.26,131.46(q,JCF＝
32.9Hz),131.40(q,JCF＝32.9Hz),129.11,125.99(q,JCF＝3.8Hz),125.85(d,JCF＝2.6Hz),
125.71(q,JCF＝3.8Hz),124.99,124.79,124.01(q,JCF＝3.7Hz),123.96(q,JCF＝272.7Hz),
123.57(q,JCF＝272.5Hz),123.23(q,JCF＝3.8Hz),122.39,121.67,120.56,110.32,
104.09,70.52,62.09.HRMS(EI)calcd for C24H15F6NO[M]+447.1058,found 447.1052.[0136] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ8.09–8.01(m,2H),7.77(dd,J＝13.4,6.5Hz,3H),7.63(d,J＝7.9Hz,1H),7.57(d,J＝8.3Hz,1H),7.42(s,1H),7.29(t,J＝7.7Hz,1H),7.17(t,J＝7.5Hz,1H),6.74(d,J＝3.3Hz,1H),6.44(d,J＝3.3Hz,1H),
5.91(d,J＝4.4Hz,1H),5.19(d,J＝5.0Hz,1H),2.00(s,1H).HRMS(EI)calcd for C24H15F6NO[M]+447.1058,found 447.1050.
[0137]trans/cis＝85:15；1H NMR(400MHz,CDCl3)δ7.68(ddd,J＝13.3,10.8,5.4Hz,3H),
7.39(d,J＝8.3Hz,0.15H),7.34(d,J＝8.0Hz,0.85H),7.20–7.10(m,3H),7.04(d,J＝
3.2Hz,0.85H),6.97(s,0.15H),6.91(ddd,J＝16.3,8.4,2.5Hz,1.7H),6.86–6.73(m,
0.3H),6.57(d,J＝3.2Hz,0.85H),6.55(d,J＝2.7Hz,0.15H),6.37(d,J＝3.3Hz,0.15H),
6.24(d,J＝2.0Hz,0,85H),5.73(d,J＝4.3Hz,0.15H),5.57(d,J＝10.0Hz,0.85H),5.24(d,J＝10.0Hz,0.85H),5.05(d,J＝4.3Hz,0.15H),3.81(s,2.55H),3.79(s,0.45H),3.67(s,
0.45H),3.59(s,2.55H),1.98(s,0.85H),1.26(s,0.15H).HRMS(EI)calcd for C24H21NO3[M]+
371.1521,found371.1528.
7.39(d,J＝8.3Hz,0.15H),7.34(d,J＝8.0Hz,0.85H),7.20–7.10(m,3H),7.04(d,J＝
3.2Hz,0.85H),6.97(s,0.15H),6.91(ddd,J＝16.3,8.4,2.5Hz,1.7H),6.86–6.73(m,
0.3H),6.57(d,J＝3.2Hz,0.85H),6.55(d,J＝2.7Hz,0.15H),6.37(d,J＝3.3Hz,0.15H),
6.24(d,J＝2.0Hz,0,85H),5.73(d,J＝4.3Hz,0.15H),5.57(d,J＝10.0Hz,0.85H),5.24(d,J＝10.0Hz,0.85H),5.05(d,J＝4.3Hz,0.15H),3.81(s,2.55H),3.79(s,0.45H),3.67(s,
0.45H),3.59(s,2.55H),1.98(s,0.85H),1.26(s,0.15H).HRMS(EI)calcd for C24H21NO3[M]+
371.1521,found371.1528.
[0138] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.70–7.64(m,3H),7.35(d,J＝8.0Hz,1H),7.17–7.12(m,3H),7.04(d,J＝3.2Hz,1H),6.92(ddd,J＝16.3,8.5,2.6Hz,2H),6.57(d,J＝3.2Hz,1H),6.24(dd,J＝2.6,0.7Hz,1H),5.57(d,J＝10.0Hz,1H),
5.25(d,J＝10.0Hz,1H),3.82(s,3H),3.59(s,3H),1.95(s,1H).13C NMR(101MHz,CDCl3)δ
159.39,159.24,136.83,136.67,133.97,128.99,126.36,126.19,124.97,124.67,124.63,
121.94,121.30,120.05,114.71,114.38,112.64,111.01,110.38,103.06,71.34,62.49,
55.43,55.27.
5.25(d,J＝10.0Hz,1H),3.82(s,3H),3.59(s,3H),1.95(s,1H).13C NMR(101MHz,CDCl3)δ
159.39,159.24,136.83,136.67,133.97,128.99,126.36,126.19,124.97,124.67,124.63,
121.94,121.30,120.05,114.71,114.38,112.64,111.01,110.38,103.06,71.34,62.49,
55.43,55.27.
[0139]trans/cis＝50:50；
[0140] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.68(dd,J＝8.1,4.0Hz,3H),7.57(d,J＝7.9Hz,1H),7.43(td,J＝8.1,5.6Hz,2H),7.30–7.23(m,1H),7.07(ddd,J＝24.6,16.1,7.9Hz,3H),6.65(d,J＝3.3Hz,1H),6.33(d,J＝3.3Hz,1H),6.10(d,J＝5.0Hz,1H),5.48(d,J＝4.9Hz,1H),2.59(s,1H).13C NMR(101MHz,CDCl3)δ161.67(d,JCF＝
247.2Hz),160.83(d,JCF＝250.2Hz),137.58,135.21(t,JCF＝3.3Hz),135.07–134.93(t,JCF＝3.3Hz),130.70(d,JCF＝9.0Hz),130.20(d,JCF＝9.5Hz),128.22,126.16,122.15(d,JCF＝
10.2Hz),122.01,120.81,120.73(d,JCF＝3.2Hz),120.38(d,JCF＝3.4Hz),120.16(d,JCF＝
15.5Hz),119.82,117.07(d,JCF＝23.8Hz),116.28(d,JCF＝22.2Hz),110.14,102.53,
69.24,50.95(d,JCF＝2.4Hz).HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found
311.1120.
247.2Hz),160.83(d,JCF＝250.2Hz),137.58,135.21(t,JCF＝3.3Hz),135.07–134.93(t,JCF＝3.3Hz),130.70(d,JCF＝9.0Hz),130.20(d,JCF＝9.5Hz),128.22,126.16,122.15(d,JCF＝
10.2Hz),122.01,120.81,120.73(d,JCF＝3.2Hz),120.38(d,JCF＝3.4Hz),120.16(d,JCF＝
15.5Hz),119.82,117.07(d,JCF＝23.8Hz),116.28(d,JCF＝22.2Hz),110.14,102.53,
69.24,50.95(d,JCF＝2.4Hz).HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found
311.1120.
[0141] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.77–7.71(m,3H),7.55(d,J＝7.9Hz,1H),7.44(dtd,J＝14.0,8.1,5.8Hz,2H),7.32(dd,J＝8.1,7.3Hz,1H),7.14(t,J＝7.5Hz,1H),7.11–7.05(m,1H),7.03–6.98(m,1H),6.28–6.23(m,1H),6.19(d,J＝3.1Hz,2H),5.40(d,J＝2.1Hz,1H),2.15(s,1H).13C NMR(101MHz,CDCl3)δ162.20(d,JCF＝
249.7Hz),161.55(d,JCF＝248.9Hz),135.63,134.66(t,JCF＝3.4Hz),133.78(t,JCF＝
3.5Hz),131.17(d,JCF＝8.9Hz),130.96(d,JCF＝8.9Hz),128.71,124.67,122.10,121.90(d,JCF＝16.5Hz),121.08,120.35(d,JCF＝3.2Hz),120.06,120.02,118.92(d,JCF＝
16.7Hz),116.17(d,JCF＝21.7Hz),116.12(d,JCF＝22.0Hz),109.40,101.98,62.78(d,JCF＝
4.6Hz),50.45(d,JCF＝4.1Hz).HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found
347.1118.
249.7Hz),161.55(d,JCF＝248.9Hz),135.63,134.66(t,JCF＝3.4Hz),133.78(t,JCF＝
3.5Hz),131.17(d,JCF＝8.9Hz),130.96(d,JCF＝8.9Hz),128.71,124.67,122.10,121.90(d,JCF＝16.5Hz),121.08,120.35(d,JCF＝3.2Hz),120.06,120.02,118.92(d,JCF＝
16.7Hz),116.17(d,JCF＝21.7Hz),116.12(d,JCF＝22.0Hz),109.40,101.98,62.78(d,JCF＝
4.6Hz),50.45(d,JCF＝4.1Hz).HRMS(EI)calcd for C22H15F2NO[M]+347.1122,found
347.1118.
[0142]trans/cis＝20:80,major:1H NMR(400MHz,CDCl3)δ7.92(d,J＝7.8Hz,1H),7.75(d,J＝7.9Hz,1H),7.70(d,J＝8.2Hz,1H),7.54(d,J＝7.7Hz,1H),7.45(dd,J＝12.7,6.4Hz,
2H),7.34–7.26(m,2H),7.16–7.11(m,2H),7.03(t,J＝8.6Hz,1H),6.26(d,J＝3.3Hz,1H),
6.14(dd,J＝9.5,2.2Hz,2H),4.91(d,J＝2.1Hz,1H),2.10(s,1H).13C NMR(101MHz,CDCl3)δ
162.27(d,JCF＝249.3Hz),135.63,134.47,131.56(d,JCF＝3.0Hz),131.09(d,JCF＝6.1Hz),
130.92,130.83,130.29,129.44,128.74,125.08,124.78,121.94,121.06,119.90,119.60(d,JCF＝3.2Hz),118.97(d,JCF＝16.4Hz),115.68(d,JCF＝21.8Hz),109.48,101.75,70.63,
51.08(d,JCF＝3.9Hz).HRMS(EI)calcd for C22H16FNO[M]+329.1216,found 329.1215.[0143]
trans/cis＝95:5,major:1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.8Hz,1H),7.71(d,J＝
8.3Hz,1H),7.69–7.64(m,2H),7.44(dd,J＝14.0,7.9Hz,1H),7.37(t,J＝7.6Hz,1H),7.30–
7.26(m,1H),7.22–7.14(m,3H),7.08(t,J＝8.6Hz,1H),6.66(t,J＝6.2Hz,2H),5.78(d,J＝
2.0Hz,1H),5.33(d,J＝2.9Hz,1H),2.05(s,1H).13C NMR(101MHz,CDCl3)δ160.00(d,JCF＝
247.8Hz),137.16,134.90(d,JCF＝3.9Hz),133.07,132.35(d,JCF＝2.8Hz),130.95(d,JCF＝
8.8Hz),129.14,128.51,128.40,128.14,126.95,124.45,122.97(d,JCF＝16.6Hz),121.71,
121.18,120.15(d,JCF＝3.2Hz),119.96,115.26(d,JCF＝22.1Hz),109.29,102.58,63.73(d,JCF＝4.2Hz),57.96.HRMS(EI)calcd for C22H16FNO[M]+329.1216,found 329.1214.[0144]
trans/cis＝73:27；major:1H NMR(400MHz,CDCl3)δ7.63(d,J＝7.7Hz,1H),7.39(d,J＝8.1Hz,1H),7.32–7.28(m,3H),7.28–7.22(m,2H),7.18(m,2H),7.13(d,J＝7.6Hz,2H),
6.95(t,J＝7.1Hz,1H),6.89(d,J＝3.4Hz,1H),6.68(d,J＝7.6Hz,1H),6.43(d,J＝3.3Hz,
1H),6.24(d,J＝2.1Hz,1H),5.65(d,J＝1.9Hz,1H),2.18(s,1H)；13C NMR(101MHz,CDCl3)δ
155.03,154.89,137.44,131.37,130.55,129.65,129.55(2C),129.06,128.26,127.57(2C),124.97,124.90,121.83,121.33,121.03,121.00,119.97,109.54,102.19,72.64,
59.51.HRMS(EI)calcd for C22H17NO2[M]+327.3830,found 327.3831.
2H),7.34–7.26(m,2H),7.16–7.11(m,2H),7.03(t,J＝8.6Hz,1H),6.26(d,J＝3.3Hz,1H),
6.14(dd,J＝9.5,2.2Hz,2H),4.91(d,J＝2.1Hz,1H),2.10(s,1H).13C NMR(101MHz,CDCl3)δ
162.27(d,JCF＝249.3Hz),135.63,134.47,131.56(d,JCF＝3.0Hz),131.09(d,JCF＝6.1Hz),
130.92,130.83,130.29,129.44,128.74,125.08,124.78,121.94,121.06,119.90,119.60(d,JCF＝3.2Hz),118.97(d,JCF＝16.4Hz),115.68(d,JCF＝21.8Hz),109.48,101.75,70.63,
51.08(d,JCF＝3.9Hz).HRMS(EI)calcd for C22H16FNO[M]+329.1216,found 329.1215.[0143]
trans/cis＝95:5,major:1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.8Hz,1H),7.71(d,J＝
8.3Hz,1H),7.69–7.64(m,2H),7.44(dd,J＝14.0,7.9Hz,1H),7.37(t,J＝7.6Hz,1H),7.30–
7.26(m,1H),7.22–7.14(m,3H),7.08(t,J＝8.6Hz,1H),6.66(t,J＝6.2Hz,2H),5.78(d,J＝
2.0Hz,1H),5.33(d,J＝2.9Hz,1H),2.05(s,1H).13C NMR(101MHz,CDCl3)δ160.00(d,JCF＝
247.8Hz),137.16,134.90(d,JCF＝3.9Hz),133.07,132.35(d,JCF＝2.8Hz),130.95(d,JCF＝
8.8Hz),129.14,128.51,128.40,128.14,126.95,124.45,122.97(d,JCF＝16.6Hz),121.71,
121.18,120.15(d,JCF＝3.2Hz),119.96,115.26(d,JCF＝22.1Hz),109.29,102.58,63.73(d,JCF＝4.2Hz),57.96.HRMS(EI)calcd for C22H16FNO[M]+329.1216,found 329.1214.[0144]
trans/cis＝73:27；major:1H NMR(400MHz,CDCl3)δ7.63(d,J＝7.7Hz,1H),7.39(d,J＝8.1Hz,1H),7.32–7.28(m,3H),7.28–7.22(m,2H),7.18(m,2H),7.13(d,J＝7.6Hz,2H),
6.95(t,J＝7.1Hz,1H),6.89(d,J＝3.4Hz,1H),6.68(d,J＝7.6Hz,1H),6.43(d,J＝3.3Hz,
1H),6.24(d,J＝2.1Hz,1H),5.65(d,J＝1.9Hz,1H),2.18(s,1H)；13C NMR(101MHz,CDCl3)δ
155.03,154.89,137.44,131.37,130.55,129.65,129.55(2C),129.06,128.26,127.57(2C),124.97,124.90,121.83,121.33,121.03,121.00,119.97,109.54,102.19,72.64,
59.51.HRMS(EI)calcd for C22H17NO2[M]+327.3830,found 327.3831.
[0145]trans/cis＝75:25；major:1H NMR(400MHz,CDCl3)δ7.54(d,J＝7.4Hz,1H),7.20(d,J＝8.0Hz,1H),7.07–7.03(m,3H),6.91(d,J＝8.1Hz,2H),6.83(s,1H),6.78(d,J＝2.9Hz,
1H),6.40(d,J＝9.3Hz,2H),6.33(d,J＝3.2Hz,1H),6.05(s,1H),5.42(s,1H),2.13(s,3H),
13
1.96(s,3H),1.17(s,1H)；CNMR(101MHz,CDCl3)δ151.99,136.36,133.33,129.87,129.52,
129.08,128.92,128.22,127.17,126.59,125.98,123.08,120.81,119.90,119.83,119.59,
119.49,118.65,109.96,101.38,71.49,58.38,19.61,19.51.HRMS(EI)calcd for C24H21NO2[M]+355.1572,found 355.1573.
1H),6.40(d,J＝9.3Hz,2H),6.33(d,J＝3.2Hz,1H),6.05(s,1H),5.42(s,1H),2.13(s,3H),
13
1.96(s,3H),1.17(s,1H)；CNMR(101MHz,CDCl3)δ151.99,136.36,133.33,129.87,129.52,
129.08,128.92,128.22,127.17,126.59,125.98,123.08,120.81,119.90,119.83,119.59,
119.49,118.65,109.96,101.38,71.49,58.38,19.61,19.51.HRMS(EI)calcd for C24H21NO2[M]+355.1572,found 355.1573.
[0146]trans/cis＝76:24；major:1H NMR(400MHz,CDCl3)δ7.28–7.22(m,2H),7.21(s,1H),
7.17(s,1H),7.15(d,J＝2.9Hz,1H),6.88(t,J＝2.4Hz,1H),6.50(t,J＝2.1Hz,2H),6.13(t,J＝2.1Hz,2H),5.66(m,1H),5.54(s,1H),2.29(s,1H)；13CNMR(101MHz,CDCl3)δ162.56(d,JCF＝251.0Hz),155.92(d,JCF＝4.9Hz),153.16,132.69,130.24(d,JCF＝11.1Hz),
129.14,129.01,125.58,121.28(2C),120.17,117.04(d,JCF＝3.2Hz),114.55(d,JCF＝
15.8Hz),110.93(d,JCF＝22.5H),107.52(2C),69.73,60.35(d,JCF＝4.1Hz).HRMS(EI)calcd for C18H14FNO2[M]+295.1009,found295.1010.
7.17(s,1H),7.15(d,J＝2.9Hz,1H),6.88(t,J＝2.4Hz,1H),6.50(t,J＝2.1Hz,2H),6.13(t,J＝2.1Hz,2H),5.66(m,1H),5.54(s,1H),2.29(s,1H)；13CNMR(101MHz,CDCl3)δ162.56(d,JCF＝251.0Hz),155.92(d,JCF＝4.9Hz),153.16,132.69,130.24(d,JCF＝11.1Hz),
129.14,129.01,125.58,121.28(2C),120.17,117.04(d,JCF＝3.2Hz),114.55(d,JCF＝
15.8Hz),110.93(d,JCF＝22.5H),107.52(2C),69.73,60.35(d,JCF＝4.1Hz).HRMS(EI)calcd for C18H14FNO2[M]+295.1009,found295.1010.
[0147]trans/cis＝74:26；major:1H NMR(400MHz,CDCl3)δ7.38–7.25(m,3H),7.15(d,J＝
8.1Hz,2H),7.12(t,J＝2.0Hz,2H),6.96–6.89(m,1H),6.76(d,J＝7.6Hz,1H),6.31(t,J＝
2.1Hz,2H,5.92(s,1H),5.76(s,1H),2.26(s,1H)；13C NMR(101MHz,CDCl3)δ161.78(d,JCF＝
248.7Hz),155.78(d,JCF＝5.3Hz)153.42,130.16(d,JCF＝5.4Hz),130.08,129.31,128.53,
125.64,121.56(2C),120.66,118.49(d,JCF＝16.2Hz),117.05(d,JCF＝3.2Hz),111.07(d,+
JCF＝22.9Hz),108.61,67.82(d,JCF＝5.5Hz),61.36.HRMS(EI)calcd for C18H14FNO2[M]
295.1009,found295.1010.
8.1Hz,2H),7.12(t,J＝2.0Hz,2H),6.96–6.89(m,1H),6.76(d,J＝7.6Hz,1H),6.31(t,J＝
2.1Hz,2H,5.92(s,1H),5.76(s,1H),2.26(s,1H)；13C NMR(101MHz,CDCl3)δ161.78(d,JCF＝
248.7Hz),155.78(d,JCF＝5.3Hz)153.42,130.16(d,JCF＝5.4Hz),130.08,129.31,128.53,
125.64,121.56(2C),120.66,118.49(d,JCF＝16.2Hz),117.05(d,JCF＝3.2Hz),111.07(d,+
JCF＝22.9Hz),108.61,67.82(d,JCF＝5.5Hz),61.36.HRMS(EI)calcd for C18H14FNO2[M]
295.1009,found295.1010.
[0148]trans/cis＝7:93,cis isomer:1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.3Hz,1H),7.48(d,J＝7.8Hz,1H),7.30–7.22(m,4H),7.12(dd,J＝16.0,6.2Hz,2H),6.99(dd,J＝9.5,
4.1Hz,1H),6.91(d,J＝7.6Hz,1H),6.73–6.65(m,1H),6.23(d,J＝14.1Hz,1H),6.11(d,J＝
3.1Hz,1H),5.75–5.68(m,2H),2.54(d,J＝51.7Hz,1H)；13C NMR(101MHz,CDCl3)δ162.54(d,JCF＝251.5Hz),156.02(d,JCF＝5.0Hz),153.51,138.05,133.02,130.16(d,JCF＝11.0Hz),
129.17,127.90,126.68,126.06,125.67,121.83,120.89,120.37,119.87,117.06(d,JCF＝
3.1Hz),,115.14(d,JCF＝16.1Hz),111.00(d,JCF＝22.4Hz),109.79,101.71,70.71,56.31(d,JCF＝3.7Hz)；HRMS(EI)calcd for C22H16NO2[M]+345.1165,found 345.1166.[0149]
trans/cis＝58:42；
4.1Hz,1H),6.91(d,J＝7.6Hz,1H),6.73–6.65(m,1H),6.23(d,J＝14.1Hz,1H),6.11(d,J＝
3.1Hz,1H),5.75–5.68(m,2H),2.54(d,J＝51.7Hz,1H)；13C NMR(101MHz,CDCl3)δ162.54(d,JCF＝251.5Hz),156.02(d,JCF＝5.0Hz),153.51,138.05,133.02,130.16(d,JCF＝11.0Hz),
129.17,127.90,126.68,126.06,125.67,121.83,120.89,120.37,119.87,117.06(d,JCF＝
3.1Hz),,115.14(d,JCF＝16.1Hz),111.00(d,JCF＝22.4Hz),109.79,101.71,70.71,56.31(d,JCF＝3.7Hz)；HRMS(EI)calcd for C22H16NO2[M]+345.1165,found 345.1166.[0149]
trans/cis＝58:42；
[0150] 通过进一步分离获得反式异构体:1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.7Hz,1H),7.63(d,J＝7.7Hz,2H),7.59(d,J＝8.2Hz,1H),7.54(dd,J＝7.8,1.2Hz,1H),7.43(td,J＝
7.6,1.2Hz,1H),7.25–7.19(m,3H),7.15–7.10(m,1H),7.06(td,J＝7.5,1.8Hz,1H),6.96(dtd,J＝9.6,7.9,1.5Hz,2H),6.57(d,J＝3.1Hz,1H),6.45(d,J＝10.2Hz,1H),5.62(d,J＝
10.2Hz,1H),1.98(s,1H).13C NMR(101MHz,CDCl3)δ142.55,138.36,136.05,134.90,
134.14,132.40,132.13,129.33,128.95,128.21,127.84,127.58,127.35,127.32,126.58,
122.17,121.20,120.02,110.51,102.93,71.90,65.85.HRMS(EI)calcd for C18H15NOS[M]+
293.0874,found 293.0870.
7.6,1.2Hz,1H),7.25–7.19(m,3H),7.15–7.10(m,1H),7.06(td,J＝7.5,1.8Hz,1H),6.96(dtd,J＝9.6,7.9,1.5Hz,2H),6.57(d,J＝3.1Hz,1H),6.45(d,J＝10.2Hz,1H),5.62(d,J＝
10.2Hz,1H),1.98(s,1H).13C NMR(101MHz,CDCl3)δ142.55,138.36,136.05,134.90,
134.14,132.40,132.13,129.33,128.95,128.21,127.84,127.58,127.35,127.32,126.58,
122.17,121.20,120.02,110.51,102.93,71.90,65.85.HRMS(EI)calcd for C18H15NOS[M]+
293.0874,found 293.0870.
[0151] 通过进一步分离获得顺式异构体:1H NMR(400MHz,CDCl3)δ7.62–7.55(m,3H),7.33(d,J＝8.1Hz,1H),7.25–7.05(m,7H),6.93(s,1H),6.73(d,J＝7.6Hz,1H),6.55(d,J＝1.2Hz,1H),6.42(d,J＝3.2Hz,1H),6.01(s,1H),2.14(s,1H).13C NMR(101MHz,CDCl3)δ
140.93,138.31,137.35,132.33,131.73,131.34,131.14,130.61,130.06,128.33,128.30,
128.22,128.18,127.69,121.73,120.80,119.83,109.83,101.89,73.47,60.86.HRMS(EI)calcd for C18H15NOS[M]+293.0874,found 293.0876.
140.93,138.31,137.35,132.33,131.73,131.34,131.14,130.61,130.06,128.33,128.30,
128.22,128.18,127.69,121.73,120.80,119.83,109.83,101.89,73.47,60.86.HRMS(EI)calcd for C18H15NOS[M]+293.0874,found 293.0876.
[0152] 实施例6：
[0153] 本发明化合物的抗肿瘤活性测试
[0154] 1.实验原理
[0155] 活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为不溶于水的蓝紫色结晶甲瓒(Formazan)并沉积在细胞中，而死细胞无此功能。二甲基亚砜(DMSO)，其作用是能够溶解细胞中甲瓒，用酶标仪测定其光吸收值就可反映活细胞数量。
[0156] 2.抗肿瘤活性实验
[0157] 试样：实施例化合物
[0158] 细胞系：肝癌细胞系HepG2和肺癌细胞系A549
[0159] 试剂：0.5％MTT溶液，RPMI 1640培养液、新生牛血清；胰酶；96孔培养板；二甲基亚砜；
[0160] 仪器：超净台、培养箱、Perkin Elmer全自动多功能酶标仪
[0161] 实验步骤：
[0162] 1)将指数生长期的HepG2和A549细胞(2×105个/mL)接种到96孔板上培养过夜，然后用设定浓度的药物处理细胞。
[0163] 2)药物处理24小时后，向每个孔中加入20μL MTT试剂(5mg/mL)。5％CO2，37℃孵育孵育4小时后，吸出培养基的上清液，向每个孔中加入150μL DMSO溶解甲瓒晶体。
[0164] 3)采用双波长法测定，通过酶标仪测定在492和630nm的吸光度。
[0165] 3.抗肿瘤活性评价
[0166] 1)细胞活力抑制率计算
[0167] 细胞活力抑制率＝[1-加药(OD 492-OD630)/对照(OD 492-OD630)]×100(％)[0168] 2)IC50值计算
[0169] 试样浓度与细胞抑制率线性回归，利用软件计算试样对细胞的半数抑制浓度IC50值。
[0170] 下表1、表2为细胞活力抑制率初筛结果。
[0171] 表1细胞活力抑制率初筛结果(HepG2)
[0172]
[0173]
[0174] 表2细胞活力抑制率初筛结果(A549)
[0175]
[0176]
[0177] 由表1、表2可以看出，在24小时内，100μM浓度下，多数化合物对肿瘤细胞表现出了明显的细胞毒性。在24小时内，50μM浓度下，五个化合物对HepG2细胞表现出了明显的细胞毒性。随后对这五个化合物进行IC50值测定，测试至少5个浓度，通过试样浓度与细胞抑制率线性回归，利用软件计算试样对细胞的半数抑制浓度IC50值。在24小时内，50μM浓度下，四个化合物对A549细胞表现出了明显的细胞毒性，随后对其中最好活性化合物进行IC50值测定，测试至少5个浓度，通过试样浓度与细胞抑制率线性回归，利用软件计算试样对细胞的半数抑制浓度IC50值。
[0178] 下表3为细胞活力抑制IC50值。
[0179] 表3细胞活力抑制IC50值
[0180]
[0181]
[0182] 由表3可以看出，此类结构中，N-取代吲哚类衍生物比N-取代吡咯类衍生物具有更好的细胞活力抑制活性。相对于X为不存在，当X为S、O取代时，化合物的细胞毒性更高；其中X为S取代时候，对HepG2的细胞活力抑制IC50值最低；并且，反式结构具有更好的活性。
[0183] 上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。