CN113336689B - 3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性 - Google Patents

3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性 Download PDF

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CN113336689B
CN113336689B CN202110619113.XA CN202110619113A CN113336689B CN 113336689 B CN113336689 B CN 113336689B CN 202110619113 A CN202110619113 A CN 202110619113A CN 113336689 B CN113336689 B CN 113336689B
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fluorovinyl
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范学森
李娜
杨玉洁
赵杰
张新迎
姜玉钦
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Henan Normal University
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Abstract

本发明公开了3‑(α‑氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性，属于有机合成和药物发现技术领域。将N‑芳基吡唑烷酮1、偕二氟炔基化合物2、催化剂和碱性添加剂混合，在有机溶剂或含水有机溶剂中升温反应，分别得到3‑(α‑氟乙烯基)吲哚类化合物3或3‑(α‑羰基)吲哚类化合物4。本发明通过N‑芳基吡唑烷酮和偕二氟炔基化合物之间的串联反应，高效合成了3‑(α‑氟乙烯基/羰基)吲哚类化合物，该合成方法具有原料简单易得、操作简便、区域选择性好、底物适用范围广等优点。同时3‑(α‑氟乙烯基/羰基)吲哚类化合物表现出显著的抗癌活性，具有潜在的药用价值。

Description

3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性
技术领域
本发明属于有机合成和药物发现技术领域，具体涉及3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性。
背景技术
单氟烯基吲哚及其衍生物作为重要的含氮杂环，不仅在自然界中广泛存在，而且是多种抗菌、消炎、降血脂、抗病毒和抗癌药物的核心结构单元。单氟烯烃结构片段其电子性能和空间尺寸与酰胺相似，常被用作肽键模拟物而在药物化学和化学生物学等领域发挥重要作用。此外，许多单氟烯烃衍生物还表现出抗菌、降血糖和抗肿瘤等生物活性。
3-(α-氟乙烯基/羰基)吲哚同时含有吲哚和单氟烯基/羰基两种优势结构单元，具有重要的研究价值。但是，截止目前，该类化合物的合成方法尚未见报道；另外，尽管吲哚和单氟烯烃/羰基表现出多样生物性能，然而3-(α-氟乙烯基/羰基)吲哚具有何种生物活性仍然未知。因此，研究并开发3-(α-氟乙烯基/羰基)吲哚类化合物的绿色高效合成方法，然后利用该方法合成系列相应化合物并对其药物活性进行考察，具有十分重要的理论意义和实用前景。
发明内容
本发明首先提供了一类新的3-(α-氟乙烯基/羰基)吲哚类化合物，并研究了其抗癌活性。其次还提供了3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法，通过N-芳基吡唑烷酮和偕二氟炔基化合物之间的串联反应，可以高效合成3-(α-氟乙烯基/羰基)吲哚类化合物，合成方法具有原料简单易得、操作简便、区域选择性好、底物适用范围广等优点，该类化合物具有显著的抗癌活性，因此具有潜在的药用价值。
本发明第一个目的，提供了具有抗癌活性的3-(α-氟乙烯基/羰基)吲哚类化合物，包括3-(α-氟乙烯基)吲哚类化合物3和3-(α-羰基)吲哚类化合物4，其结构通式为：
Figure BDA0003099002610000011
其中，R1为氢、卤素、C1-6烷基、C1-6烷氧基或苄氧基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为叔丁基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5为C1-6烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。虚线表示也可以为萘环结构(下同)。
本发明还提供了3-(α-氟乙烯基/羰基)吲哚类化合物(结构通式3和4)及其在药学上可接受的盐在抗癌活性药物中的应用。
本发明中药学上可接受的盐(下同)包括3-(α-氟乙烯基/羰基)吲哚类化合物与有机酸或无机酸形成的盐。有机酸选自苹果酸、乳酸、樟脑磺酸、枸橼酸、富马酸或草酸中的一种或多种，有机酸选自磷酸、氢卤酸、硫酸或硝酸中一种或多种。
进一步地，在上述技术方案中，所述抗癌活性是指抗REC-1和Ramos等癌细胞活性。
本发明第二个目的还提供了用于治疗REC-1和Ramos癌症的药物，包括3-(α-氟乙烯基/羰基)吲哚类化合物(结构通式3和4)和相应药学上可接受的盐。
本发明第三个目的，还提供了上述3-(α-氟乙烯基)吲哚类化合物的合成方法，采用的技术方案为：
3-(α-氟乙烯基)吲哚类化合物的合成方法，包括如下操作：将N-芳基吡唑烷酮1、偕二氟炔基化合物2、催化剂、碱性添加剂混合，在有机溶剂或含水有机溶剂中升温反应，分别得到3-(α-氟乙烯基)吲哚类化合物3或3-(α-羰基)吲哚类化合物4。反应方程式为：
Figure BDA0003099002610000021
其中R1为氢、卤素、C1-6烷基、C1-6烷氧基或苄氧基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为叔丁基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5为C1-6烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。
进一步地，在上述技术方案中，所述反应有机溶剂为起到溶解原料的作用，优选乙腈、1,2-二氯乙烷、二氯甲烷、二氧六环或四氢呋喃。
进一步地，在上述技术方案中，所述碱性添加剂为醋酸钠、醋酸铯、二环己胺、三乙胺或N,N’-二甲基乙二胺。
进一步地，在上述技术方案中，所述催化剂为二氯双(4-甲基异丙基苯基)钌(II){简称[Ru(p-cymene)Cl2]2}、二氯(五甲基环戊二烯基)合铑(III)二聚体{简称[RhCp*Cl2]2}、二氯(五甲基环戊二烯基)合铱(III)二聚体{简称[IrCp*Cl2]2}。采用其他催化剂，例如CoCp*(CO)I2或MnBr(CO)5等时，反应未检测到产物。
进一步地，在上述技术方案中，所述N-芳基吡唑烷酮1、偕二氟炔基化合物2、碱性添加剂和催化剂的投料摩尔比为1:1-2:1-2:0.03-0.05。
进一步地，在上述技术方案中，所述反应温度为60-120℃。
发明有益效果：
本发明与现有技术相比具有以下优点：1)合成过程简单、高效，通过N-芳基吡唑烷酮和偕二氟炔基化合物的串联反应，即可高选择合成3-(α-氟乙烯基/羰基)吲哚类化合物；2)原料价廉易得，操作简便，底物的适用范围广，区域选择性高；3)3-(α-氟乙烯基/羰基)吲哚类化合物表现出显著的抗癌活性，具有潜在的药用价值。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Figure BDA0003099002610000031
向15mL反应瓶中，依次加入化合物1a、有机溶剂、催化剂、碱性添加剂和化合物2a，盖上塞子密封，置于油浴中升温搅拌反应。反应结束，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝2/1)得到白色固体产物3a或白色固体4a。
通过改变反应的有机溶剂、碱性添加剂、催化剂和反应温度等反应条件，反应结果如下：
表1不同条件下3a和4a的合成a
Figure BDA0003099002610000041
验证反应体系中水影响：
向15mL反应管中，加入3a(85.0mg,0.2mmol)、MeOH(1mL)和H2O(0.1mL)。密封反应管，空气气氛下100℃搅拌12小时。冷却至室温，减压浓缩，残余物硅胶柱色谱法纯化，石油醚/乙酸乙酯(1:1)为洗脱剂，得到白色固体4a(76.4mg,90％)。反应方程式如下：
Figure BDA0003099002610000051
实施例2
Figure BDA0003099002610000052
向15mL反应管中，加入4,4-二甲基-1-苯基吡唑烷-3-酮(1a,38.0mg,0.2mmol)、CH3CN(1mL)、[RhCp*Cl2]2(3.7mg,0.006mmol)、Cy2NH(80uL,0.4mmol)和3,3-二氟-1,5-二苯基-1-戊炔(2a,61.5mg,0.24mmol)。密封反应管，空气气氛下100℃搅拌12小时。冷却至室温，抽滤，将母液减压浓缩，残余物硅胶柱色谱法纯化，石油醚/乙酸乙酯(2:1)为洗脱剂，得到白色固体3a(61.4mg,72％)。1H NMR(600MHz,CDCl3)δ7.75(d,J＝7.8Hz,1H),7.55(d,J＝8.4Hz,1H),7.43-7.40(m,3H),7.38-7.37(m,2H),7.23-7.20(m,3H),7.17-7.14(m,2H),7.06(d,J＝7.8Hz,2H),5.60(br s,1H),5.34(br s,1H),4.83(dt,J1＝36.6Hz,J2＝7.8Hz,1H),4.42(s,2H),3.50(d,J＝7.8Hz,2H),0.86(s,6H).13CNMR(150MHz,CDCl3)δ179.3,153.6(d,1JC-F＝243.0Hz),140.7(d,4JC-F＝2.1Hz),139.9(d,3JC-F＝6.2Hz),137.2,131.8,131.3,128.7,128.6,128.4,128.3,126.2,125.9,122.7,120.9,120.0(d,4JC-F＝1.8Hz),111.7,108.7(d,2JC-F＝31.7Hz),107.6(d,2JC-F＝18.2Hz),50.9,44.3,30.3(d,3JC-F＝4.5Hz),24.3.19F NMR(565MHz,CDCl3)δ-104.8(d,J＝35.6Hz).HRMS(ESI)m/z:[M+Na]+Calcd forC28H27FN2NaO 449.2000；Found 449.1980.
实施例3
依照实施例2的方法和步骤a,b，通过改变反应物1和反应物2，合成得到3-(α-氟乙烯基)吲哚类化合物3a-3x，具体结果如下：
Figure BDA0003099002610000053
Figure BDA0003099002610000061
a反应条件:1(0.2mmol),2(0.24mmol),[RhCp*Cl2]2(0.006mmol),Cy2NH(0.4mmol),MeCN(1mL),100℃,12h.b分离收率.
______________________________________________________
代表性产物表征数据如下：
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-5-methyl-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3b)
White solid(59.0mg,67％).1H NMR(600MHz,CDCl3)δ7.54(s,1H),7.44(d,J＝8.4Hz,1H),7.41-7.39(m,3H),7.37-7.36(m,2H),7.23-7.20(m,2H),7.16-7.14(m,1H),7.07-7.04(m,3H),5.48(br s,1H),5.34(br s,1H),4.79(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.40(s,2H),3.49(d,J＝7.8Hz,2H),2.45(s,3H),0.87(s,6H).13CNMR(150MHz,CDCl3)δ179.3,153.8(d,1JC-F＝243.6Hz),140.7,139.9(d,3JC-F＝5.6Hz),135.5,131.9,131.3,130.3,128.59,128.56,128.34,128.32,126.4,125.9,124.3,119.6,111.4,108.3(d,2JC-F＝33.0Hz),107.4(d,2JC-F＝18.3Hz),51.0,44.3,30.3(d,3JC-F＝4.7Hz),24.2,21.6.19FNMR(565MHz,CDCl3)δ-104.6(d,J＝35.6Hz).HRMS(ESI)m/z:[M+Na]+Calcd forC29H29FN2NaO 463.2156；Found 463.2132.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-5-isopropyl-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3c)
White solid(57.2mg,61％).1H NMR(600MHz,CDCl3)δ7.59(s,1H),7.48(d,J＝9.0Hz,1H),7.42-7.39(m,3H),7.36-7.35(m,2H),7.23-7.20(m,2H),7.16-7.14(m,1H),7.12(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.06(d,J＝7.2Hz,2H),5.40(br s,1H),5.34(br s,1H),4.78(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.41(s,2H),3.51(d,J＝7.8Hz,2H),3.04-2.99(m,1H),1.31(d,J＝7.2Hz,6H),0.89(s,6H).13CNMR(150MHz,CDCl3)δ179.2,153.8(d,1JC-F＝243.0Hz),141.8,140.7,140.0(d,3JC-F＝5.0Hz),135.7,131.9,131.3,128.6,128.5,128.31,128.27,126.2,125.8,121.9,116.8(d,4JC-F＝2.1Hz),111.5,108.6(d,2JC-F＝32.9Hz),107.5(d,2JC-F＝18.6Hz),51.0,44.3,34.3,30.3(d,3JC-F＝4.8Hz),24.6,24.3.19FNMR(565MHz,CDCl3)δ-104.5(d,J＝36.2Hz).HRMS(ESI)m/z:[M+Na]+Calcd forC31H33FN2NaO 491.2469；Found 491.2471.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-5-methoxy-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3d)
White solid(60.3mg,66％).1H NMR(600MHz,CDCl3)δ7.45(d,J＝9.0Hz,1H),7.43-7.40(m,3H),7.37-7.36(m,2H),7.21(t,J＝7.8Hz,2H),7.18(d,J＝1.2Hz,1H),7.15(t,J＝7.2Hz,1H),7.06(d,J＝7.2Hz,2H),6.87(dd,J1＝9.0Hz,J2＝2.4Hz,1H),5.51(br s,1H),5.37(br s,1H),4.76(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.39(s,2H),3.84(s,3H),3.49(d,J＝7.8Hz,2H),0.86(s,6H).13C NMR(100MHz,CDCl3)δ179.3,155.0,153.7(d,1JC-F＝243.3Hz),140.7(d,4JC-F＝1.3Hz),140.4(d,3JC-F＝5.0Hz),132.2,131.8,131.2,128.62,128.58,128.33,128.26,126.7,125.9,112.8,112.6,108.4(d,2JC-F＝33.0Hz),107.5(d,2JC-F＝17.9Hz),101.4(d,4JC-F＝2.7Hz),55.8,51.1,44.3,30.3(d,3JC-F＝4.3Hz),24.2.19FNMR(376MHz,CDCl3)δ-104.9(d,J＝35.7Hz).HRMS(ESI)m/z:[M+Na]+Calcd forC29H29FN2NaO2 479.2105；Found 479.2092.
(Z)-3-(5-(Benzyloxy)-3-(1-fluoro-3-phenylprop-1-en-1-yl)-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3e)
Pale yellow oil(72.4mg,68％).1H NMR(600MHz,CDCl3)δ7.47-7.44(m,3H),7.42-7.40(m,3H),7.37-7.35(m,4H),7.31-7.29(m,1H),7.27(s,1H),7.23-7.21(m,2H),7.16(t,J＝7.2Hz,1H),7.07(d,J＝7.8Hz,2H),6.95(dd,J1＝8.4Hz,J2＝1.2Hz,1H),5.35(br s,1H),5.34(br s,1H),5.08(s,2H),4.75(dt,J1＝36.6Hz,J2＝7.8Hz,1H),4.39(s,2H),3.49(d,J＝7.8Hz,2H),0.86(s,6H).13C NMR(150MHz,CDCl3)δ179.2,154.1,153.6(d,1JC-F＝242.3Hz),140.7(d,4JC-F＝2.3Hz),140.4(d,3JC-F＝4.5Hz),137.5,132.3,131.8,131.2,128.61,128.58,128.4,128.3,127.9,127.7,126.7,125.9,113.5,112.6,108.4(d,2JC-F＝33.2Hz),107.5(d,2JC-F＝19.1Hz),102.9,70.7,51.2,44.3,30.3(d,3JC-F＝4.7Hz),24.2.19F NMR(565MHz,CDCl3)δ-104.9(d,J＝37.9Hz).HRMS(ESI)m/z:[M+Na]+Calcd forC35H33FN2NaO2 555.2418；Found 555.2394.
(Z)-3-(5-Fluoro-3-(1-fluoro-3-phenylprop-1-en-1-yl)-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3f)
White solid(51.6mg,58％).1H NMR(600MHz,CDCl3)δ7.50(dd,J1＝9.0Hz,J2＝4.2Hz,1H),7.45-7.43(m,3H),7.40-7.37(m,3H),7.23(t,J＝7.2Hz,2H),7.16(t,J＝7.2Hz,1H),7.06(d,J＝7.8Hz,2H),6.95(td,J1＝9.0Hz,J2＝2.4Hz,1H),5.46(br s,1H),5.37(br s,1H),4.77(dt,J1＝36.6Hz,J2＝7.8Hz,1H),4.41(s,2H),3.48(d,J＝7.8Hz,2H),0.87(s,6H).13CNMR(150MHz,CDCl3)δ179.2,158.5(d,1JC-F＝235.2Hz),153.2(d,1JC-F＝242.3Hz),141.3(d,3JC-F＝5.1Hz),140.5,133.5,131.5,131.1,128.8,128.7,128.4,128.3,126.5(d,3JC-F＝10.4Hz),125.9,112.6(d,3JC-F＝10.2Hz),111.0(d,2JC-F＝25.8Hz),108.8(dd,2JC-F＝32.3Hz,4JC-F＝3.9Hz),107.7(d,2JC-F＝18.2Hz),105.0(dd,2JC-F＝23.6Hz,4JC-F＝2.6Hz),51.2,44.2,30.3(d,3JC-F＝4.2Hz),24.2.19F NMR(565MHz,CDCl3)δ-105.5(d,J＝35.0Hz),-122.9(td,J1＝8.5Hz,J2＝4.0Hz).HRMS(ESI)m/z:[M+Na]+Calcdfor C28H26F2N2NaO 467.1905；Found 467.1893.
(Z)-3-(5-Chloro-3-(1-fluoro-3-phenylprop-1-en-1-yl)-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3g)
White solid(57.0mg,62％).1H NMR(600MHz,CDCl3)δ7.72(s,1H),7.49(d,J＝9.0Hz,1H),7.44-7.42(m,3H),7.38-7.36(m,2H),7.23-7.21(m,2H),7.17-7.14(m,2H),7.05(d,J＝7.2Hz,2H),5.52(br s,1H),5.37(br s,1H),4.77(dt,J1＝36.6Hz,J2＝7.8Hz,1H),4.41(s,2H),3.48(d,J＝7.8Hz,2H),0.86(s,6H).13CNMR(150MHz,CDCl3)δ179.1,153.0(d,1JC-F＝243.2Hz),141.0(d,3JC-F＝5.4Hz),140.4,135.4,131.3,131.1,128.9,128.7,128.4,128.3,127.1,126.6,125.9,122.9,119.4(d,4JC-F＝2.3Hz),112.9,108.4(d,2JC-F＝33.0Hz),108.0(d,2JC-F＝17.9Hz),51.2,44.2,30.3(d,3JC-F＝4.4Hz),24.2.19F NMR(565MHz,CDCl3)δ-105.4(d,J＝34.5Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C28H26ClFN2NaO483.1610；Found 483.1585.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-6-methyl-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3h)
White solid(60.8mg,69％).1H NMR(600MHz,CDCl3)δ7.63(d,J＝7.8Hz,1H),7.42-7.39(m,3H),7.37-7.36(m,2H),7.35(s,1H),7.23-7.21(m,2H),7.15(t,J＝7.2Hz,1H),7.07(d,J＝7.2Hz,2H),7.00(d,J＝7.8Hz,1H),5.67(br s,1H),5.34(br s,1H),4.82(dt,J1＝36.6Hz,J2＝7.8Hz,1H),4.39(s,2H),3.49(d,J＝7.8Hz,2H),2.46(s,3H),0.87(s,6H).13CNMR(150MHz,CDCl3)δ179.4,153.8(d,1JC-F＝244.2Hz),140.7,139.2(d,3JC-F＝4.8Hz),137.6,132.5,132.0,131.3,128.54,128.51,128.34,128.31,125.9,124.0,122.7,119.7,111.5,108.6(d,2JC-F＝32.3Hz),107.2(d,2JC-F＝17.3Hz),50.7,44.3,30.3(d,3JC-F＝4.4Hz),24.3,22.0.19F NMR(565MHz,CDCl3)δ-104.9(d,J＝37.9Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C29H29FN2NaO 463.2156；Found 463.2142.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-6-methoxy-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3i)
White solid(62.1mg,68％).1H NMR(400MHz,CDCl3)δ7.61(dd,J1＝8.8Hz,J2＝1.2Hz,1H),7.45-7.40(m,3H),7.38-7.36(m,2H),7.24-7.21(m,2H),7.18-7.14(m,1H),7.11(d,J＝2.0Hz,1H),7.07(d,J＝7.2Hz,2H),6.82(dd,J1＝8.8Hz,J2＝2.4Hz,1H),5.36(br s,1H),5.27(br s,1H),4.81(dt,J1＝36.4Hz,J2＝7.6Hz,1H),4.39(s,2H),3.86(s,3H),3.49(d,J＝7.2Hz,2H),0.89(s,6H).13CNMR(150MHz,CDCl3)δ179.4,156.7,153.8(d,1JC-F＝242.1Hz),140.7(d,4JC-F＝2.4Hz),138.6(d,3JC-F＝3.8Hz),137.8,132.0,131.3,128.5,128.4,128.33,128.28,125.9,120.6(d,4JC-F＝2.1Hz),120.2,111.2,108.5(d,2JC-F＝32.0Hz),107.2(d,2JC-F＝18.5Hz),94.9,55.7,50.9,44.1,30.3(d,3JC-F＝4.1Hz),24.2.19F NMR(376MHz,CDCl3)δ-105.4(d,J＝36.1Hz).HRMS(ESI)m/z:[M+Na]+Calcd forC29H29FN2NaO2 479.2105；Found 479.2096.
(Z)-3-(6-Chloro-3-(1-fluoro-3-phenylprop-1-en-1-yl)-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3j)
White solid(49.8mg,54％).1H NMR(600MHz,CDCl3)δ7.65(d,J＝8.4Hz,1H),7.58(d,J＝1.2Hz,1H),7.45-7.43(m,3H),7.38-7.37(m,2H),7.23(t,J＝7.2Hz,2H),7.17-7.15(m,1H),7.12(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.06(d,J＝7.2Hz,2H),5.79(br s,1H),5.40(br s,1H),4.80(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.39(s,2H),3.49(d,J＝7.8Hz,2H),0.88(s,6H).13CNMR(150MHz,CDCl3)δ179.1,153.1(d,1JC-F＝242.0Hz),140.5,140.4(d,3JC-F＝5.9Hz),137.5,131.3,131.2,128.8,128.7,128.6,128.4,128.3,125.9,124.7,121.6,121.0(d,4JC-F＝2.9Hz),111.6,108.8(d,2JC-F＝32.6Hz),107.9(d,2JC-F＝17.7Hz),51.0,44.2,30.3(d,3JC-F＝4.5Hz),24.2.19F NMR(565MHz,CDCl3)δ-105.4(d,J＝35.0Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C28H26ClFN2NaO 483.1610；Found 483.1607.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-7-methyl-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3k)
White solid(60.8mg,69％).1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.0Hz,1H),7.45-7.44(m,2H),7.41-7.36(m,3H),7.25-7.21(m,2H),7.18-7.14(m,1H),7.10-7.06(m,3H),6.98(d,J＝7.2Hz,1H),5.42(br s,1H),5.16(br s,1H),4.79(dt,J1＝36.0Hz,J2＝8.0Hz,1H),4.67(br s,2H),3.51(d,J＝7.6Hz,2H),2.74(s,3H),0.76(s,6H).13CNMR(100MHz,CDCl3)δ178.8,153.3(d,1JC-F＝244.1Hz),141.3(d,3JC-F＝5.1Hz),140.6(d,4JC-F＝2.2Hz),137.5,131.4,131.3,128.5,128.42,128.37,127.7,126.7,125.9,122.2,121.3,118.3(d,4JC-F＝1.1Hz),110.1(d,2JC-F＝32.8Hz),108.6(d,2JC-F＝18.7Hz),51.5,45.2,30.4(d,3JC-F＝4.0Hz),23.9,21.4.19F NMR(376MHz,CDCl3)δ-103.2(d,J＝35.7Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C29H29FN2NaO 463.2156；Found 463.2137.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-7-methoxy-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3l)
White solid(52.0mg,57％).1H NMR(400MHz,CDCl3)δ7.39-7.36(m,6H),7.24-7.20(m,2H),7.17-7.13(m,1H),7.11-7.06(m,3H),6.69(d,J＝7.6Hz,1H),5.47(br s,1H),5.28(br s,1H),5.11(br s,1H),4.79(dt,J1＝36.0Hz,J2＝7.6Hz,1H),4.44(br s,1H),3.94(s,3H),3.49(d,J＝7.6Hz,2H),0.84(s,6H).13CNMR(100MHz,CDCl3)δ179.2,153.5(d,1JC-F＝244.3Hz),147.5,140.7(d,3JC-F＝5.0Hz),140.6(d,4JC-F＝1.3Hz),131.4,128.50,128.45,128.33,128.32,127.3,125.9,121.4,112.9(d,4JC-F＝1.5Hz),109.4(d,2JC-F＝32.3Hz),108.0(d,2JC-F＝19.0Hz),103.8,55.0,52.3,45.0,30.4(d,3JC-F＝4.0Hz),23.7.19F NMR(376MHz,CDCl3)δ-104.0(d,J＝36.5Hz).HRMS(ESI)m/z:[M+Na]+Calcd forC29H29FN2NaO2 479.2105；Found 479.2095.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-2-phenyl-1H-benzo[f]indol-1-yl)-2,2-dimethylpropanamide(3n)
White solid(53.4mg,56％).1H NMR(600MHz,CDCl3)δ8.24(s,1H),7.98(s,1H),7.93(dd,J1＝12.0Hz,J2＝8.4Hz,2H),7.47-7.43(m,5H),7.38-7.33(m,2H),7.25-7.23(m,2H),7.18(t,J＝7.2Hz,1H),7.11(d,J＝7.2Hz,2H),5.33(br s,1H),5.28(br s,1H),4.93(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.52(s,2H),3.56(d,J＝7.8Hz,2H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ179.3,153.5(d,1JC-F＝243.3Hz),143.7(d,3JC-F＝5.7Hz),140.6,137.6,131.6,131.0,130.4,129.3,128.9,128.6,128.4,128.3,128.2,127.8,127.4,125.9,124.2,123.3,117.6,107.84(d,2JC-F＝18.0Hz),107.79(d,2JC-F＝34.2Hz),107.4,51.1,44.3,30.4(d,3JC-F＝4.5Hz),24.3.19F NMR(565MHz,CDCl3)δ-105.2(d,J＝36.7Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C32H29FN2NaO 499.2156；Found 499.2159.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-2-(p-tolyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(3o)
White solid(55.5mg,63％).1H NMR(400MHz,CDCl3)δ7.74(d,J＝7.6Hz,1H),7.55(d,J＝8.0Hz,1H),7.25-7.22(m,5H),7.20-7.18(m,2H),7.17-7.13(m,2H),7.07(d,J＝7.2Hz,2H),5.53(br s,1H),5.36(br s,1H),4.82(dt,J1＝36.4Hz,J2＝8.0Hz,1H),4.42(s,2H),3.50(d,J＝7.6Hz,2H),2.41(s,3H),0.88(s,6H).13CNMR(100MHz,CDCl3)δ179.4,153.7(d,1JC-F＝244.4Hz),140.8(d,4JC-F＝1.7Hz),140.1(d,3JC-F＝5.1Hz),138.5,137.1,131.1,129.3,128.7,128.33,128.30,126.2,125.9,122.5,120.8,119.9(d,4JC-F＝2.1Hz),111.6,108.6(d,2JC-F＝31.9Hz),107.4(d,2JC-F＝18.4Hz),50.9,44.3,30.3(d,3JC-F＝4.4Hz),24.2,21.5.19F NMR(376MHz,CDCl3)δ-104.9(d,J＝35.7Hz).HRMS(ESI)m/z:[M+Na]+Calcdfor C29H29FN2NaO 463.2156；Found 463.2144.
(Z)-3-(2-(4-Chlorophenyl)-3-(1-fluoro-3-phenylprop-1-en-1-yl)-1H-indol-1-yl)-2,2-dimethylpropanamide(3p)
White solid(53.5mg,58％).1H NMR(600MHz,CDCl3)δ7.74(d,J＝7.8Hz,1H),7.55(d,J＝8.4Hz,1H),7.39(d,J＝7.8Hz,2H),7.31(d,J＝8.4Hz,2H),7.27-7.22(m,3H),7.19-7.16(m,2H),7.08(d,J＝7.8Hz,2H),5.53(br s,1H),5.35(br s,1H),4.84(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.41(s,2H),3.51(d,J＝7.8Hz,2H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ179.0,153.2(d,1JC-F＝243.5Hz),140.5,138.5(d,3JC-F＝4.5Hz),137.2,134.8,132.5,130.2,128.9,128.4,128.3,126.1,126.0,122.9,121.1,120.0,111.7,109.2(d,2JC-F＝33.2Hz),108.2(d,2JC-F＝17.4Hz),51.0,44.4,30.4(d,3JC-F＝4.8Hz),24.3.19F NMR(565MHz,CDCl3)δ-104.5(d,J＝36.7Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C28H26ClFN2NaO483.1610；Found 483.1596.
(Z)-3-(2-(4-Bromophenyl)-3-(1-fluoro-3-phenylprop-1-en-1-yl)-1H-indol-1-yl)-2,2-dimethylpropanamide(3q)
White solid(48.5mg,48％).1H NMR(600MHz,CDCl3)δ7.74(d,J＝7.8Hz,1H),7.55-7.53(m,3H),7.27-7.22(m,5H),7.20-7.16(m,2H),7.08(d,J＝7.2Hz,2H),5.57(brs,1H),5.37(br s,1H),4.83(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.41(s,2H),3.51(d,J＝7.8Hz,2H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ179.0,153.1(d,1JC-F＝244.1Hz),140.5,138.5(d,3JC-F＝4.1Hz),137.3,132.8,131.9,130.7,128.4,128.3,126.1,126.0,123.0,122.9,121.1,120.0,111.7,109.2(d,2JC-F＝31.4Hz),108.2(d,2JC-F＝17.6Hz),51.0,44.4,30.4(d,3JC-F＝4.2Hz),24.3.19F NMR(565MHz,CDCl3)δ-104.4(d,J＝36.7Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C28H26BrFN2NaO 527.1105；Found 527.1085.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(3r)
White solid(55.4mg,56％).1H NMR(600MHz,CDCl3)δ7.75(d,J＝7.8Hz,1H),7.65(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,1H),7.50(d,J＝8.4Hz,2H),7.26-7.22(m,3H),7.20-7.16(m,2H),7.06(d,J＝7.2Hz,2H),5.63(br s,1H),5.34(br s,1H),4.81(dt,J1＝36.6Hz,J2＝7.8Hz,1H),4.43(s,2H),3.50(d,J＝7.8Hz,2H),0.89(s,6H).13CNMR(150MHz,CDCl3)δ178.9,152.9(d,1JC-F＝243.9Hz),140.3,138.0(d,3JC-F＝4.7Hz),137.4,135.5,131.6,130.5(q,2JC-F＝32.1Hz),128.4,128.2,126.0,125.5(q,3JC-F＝4.8Hz),124.0(q,1JC-F＝272.0Hz),123.1,121.2,120.1,111.8,109.6(d,2JC-F＝31.7Hz),108.6(d,2JC-F＝17.7Hz),51.0,44.4,30.4(d,3JC-F＝5.3Hz),24.2.19F NMR(565MHz,CDCl3)δ-62.5(s),-104.3(d,J＝37.9Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C29H26F4N2NaO 517.1873；Found517.1862.
(Z)-3-(2-(3-Chlorophenyl)-3-(1-fluoro-3-phenylprop-1-en-1-yl)-1H-indol-1-yl)-2,2-dimethylpropanamide(3s)
White solid(47.0mg,51％).1H NMR(600MHz,CDCl3)δ7.75(d,J＝7.8Hz,1H),7.56(d,J＝8.4Hz,1H),7.43-7.39(m,2H),7.37-7.35(m,1H),7.27-7.22(m,4H),7.19-7.16(m,2H),7.11(d,J＝7.2Hz,2H),5.45(br s,1H),5.36(br s,1H),4.87(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.42(s,2H),3.52(d,J＝7.8Hz,2H),0.91(s,6H).13CNMR(150MHz,CDCl3)δ178.9,153.2(d,1JC-F＝243.6Hz),140.5,138.0(d,3JC-F＝4.5Hz),137.3,134.5,133.6,131.2,129.9,129.4,128.8,128.5,128.3,126.0,123.0,121.1,120.1,111.7,109.3(d,2JC-F＝32.3Hz),108.1(d,2JC-F＝18.6Hz),51.0,44.4,30.4(d,3JC-F＝4.1Hz),24.3.19F NMR(565MHz,CDCl3)δ-104.5(d,J＝35.0Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C28H26ClFN2NaO483.1610；Found 483.1585.
(Z)-3-(2-(tert-Butyl)-3-(1-fluoro-3-phenylprop-1-en-1-yl)-1H-indol-1-yl)-2,2-dimethylpropanamide(3t)
Pale yellow oil(24.4mg,30％).1H NMR(600MHz,CDCl3)δ7.50(d,J＝8.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.33-7.32(m,4H),7.24-7.21(m,1H),7.11(t,J＝7.2Hz,1H),7.06(t,J＝7.2Hz,1H),5.46(br s,1H),5.34(br s,1H),5.12(dt,J1＝34.2Hz,J2＝7.8Hz,1H),4.76(s,2H),3.67(d,J＝7.2Hz,2H),1.56(s,9H),1.07(s,6H).13CNMR(150MHz,CDCl3)δ181.1,152.9(d,1JC-F＝248.9Hz),147.5(d,3JC-F＝3.0Hz),140.7,137.3,129.0,128.53,128.50,126.1,121.9,120.2,118.5,111.3,110.7(d,2JC-F＝21.8Hz),107.6(d,2JC-F＝30.5Hz),51.8,43.8,34.7,31.8(d,JC(H3)-F＝3.8Hz),31.0(d,3JC-F＝2.3Hz),24.3.19F NMR(565MHz,CDCl3)δ-85.0(d,J＝32.8Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C26H31FN2NaO429.2313；Found 429.2299.
(Z)-3-(3-(1-Fluorobut-1-en-1-yl)-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(3u)
White solid(51.8mg,71％).1H NMR(600MHz,CDCl3)δ7.75(d,J＝7.8Hz,1H),7.56(d,J＝8.4Hz,1H),7.48-7.45(m,2H),7.44-7.41(m,1H),7.40-7.39(m,2H),7.23-7.20(m,1H),7.17(t,J＝7.2Hz,1H),5.36(br s,1H),5.35(br s,1H),4.61(dt,J1＝37.8Hz,J2＝7.8Hz,1H),4.44(s,2H),2.17-2.12(m,2H),0.91(t,J＝7.8Hz,3H),0.88(s,6H).13CNMR(150MHz,CDCl3)δ179.2,152.4(d,1JC-F＝242.3Hz),139.5(d,3JC-F＝4.2Hz),137.1,131.9,131.2,128.6,128.5,126.1,122.5,120.8,120.0(d,4JC-F＝2.4Hz),111.6,111.0(d,2JC-F＝18.6Hz),109.0(d,2JC-F＝32.7Hz),50.8,44.3,24.2,17.7(d,3JC-F＝4.1Hz),14.2.19F NMR(565MHz,CDCl3)δ-105.8(d,J＝40.7Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C23H25FN2NaO387.1843；Found 387.1829.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-2-phenyl-1H-indol-1-yl)-2-methylpropanamide(3v)
Pale yellow oil(45.4mg,55％).1H NMR(600MHz,CDCl3)δ7.79(d,J＝7.8Hz,1H),7.45-7.42(m,4H),7.41-7.39(m,2H),7.27-7.25(m,1H),7.23-7.18(m,3H),7.16-7.14(m,1H),7.07(d,J＝7.2Hz,2H),5.45(br s,1H),5.03(br s,1H),4.89(dt,J1＝36.6Hz,J2＝7.2Hz,1H),4.38(dd,J1＝14.4Hz,J2＝7.2Hz,1H),4.04(dd,J1＝14.4Hz,J2＝7.2Hz,1H),3.50(d,J＝7.8Hz,2H),2.55-2.49(m,1H),0.89(d,J＝7.2Hz,3H).13CNMR(150MHz,CDCl3)δ176.0,153.7(d,1JC-F＝242.6Hz),140.7,139.1(d,3JC-F＝6.0Hz),136.3,131.6,130.7,128.9,128.7,128.4,128.3,126.0,125.9,122.8,121.0,120.5(d,4JC-F＝3.2Hz),110.4,108.4(d,2JC-F＝33.0Hz),106.9(d,2JC-F＝19.1Hz),46.8,40.9,30.2(d,3JC-F＝3.9Hz),15.4.19F NMR(565MHz,CDCl3)δ:-105.9(d,J＝34.5Hz).HRMS(ESI)m/z[M+Na]+Calcd forC27H25FN2NaO 435.1843；Found 435.1829.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-2-phenyl-1H-indol-1-yl)propanamide(3w)
Pale yellow oil(50.2mg,63％).1H NMR(600MHz,CDCl3)δ7.80(d,J＝7.8Hz,1H),7.46-7.43(m,4H),7.41-7.40(m,2H),7.29-7.27(m,1H),7.23-7.19(m,3H),7.16(t,J＝7.2Hz,1H),7.07(d,J＝7.8Hz,2H),5.41(br s,1H),5.19(br s,1H),4.90(dt,J1＝37.2Hz,J2＝7.8Hz,1H),4.35(t,J＝7.8Hz,2H),3.50(d,J＝7.8Hz,2H),2.43(t,J＝7.8Hz,2H).13CNMR(150MHz,CDCl3)δ172.0,153.7(d,1JC-F＝243.3Hz),140.7(d,4JC-F＝2.3Hz),138.9(d,3JC-F＝4.5Hz),135.8,131.5,130.4,129.0,128.8,128.3,128.2,126.2,125.9,122.8,121.0,120.5(d,4JC-F＝2.7Hz),110.0,108.3(d,2JC-F＝32.6Hz),106.7(d,2JC-F＝18.0Hz),39.7,35.6,30.2(d,3JC-F＝5.0Hz).19F NMR(565MHz,CDCl3)δ-106.1(d,J＝36.7Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C26H23FN2NaO 421.1687；Found 421.1673.
(Z)-3-(3-(1-Fluoro-3-phenylprop-1-en-1-yl)-2-(thiophen-2-yl)-1H-indol-1-yl)-2,2-dimethylpropanamide(3x)
Pale yellow solid(53.6mg,62％).1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.49(d,J＝4.8Hz,1H),7.25-7.22(m,3H),7.19-7.11(m,6H),5.38(br s,1H),5.29(br s,1H),4.95(dt,J1＝36.0Hz,J2＝8.0Hz,1H),4.52(s,2H),3.55(d,J＝7.6Hz,2H),1.00(s,6H).13CNMR(100MHz,CDCl3)δ179.1,153.1(d,1JC-F＝243.6Hz),140.6(d,4JC-F＝1.6Hz),137.4,131.9,131.8,130.7,128.4,128.3,128.2,127.3,125.9,123.2,121.0,120.1(d,4JC-F＝2.3Hz),111.6,111.0(d,2JC-F＝32.1Hz),108.0(d,2JC-F＝17.8Hz),51.2,44.1,30.4(d,3JC-F＝4.3Hz),24.2.19F NMR(376MHz,CDCl3)δ-105.1(d,J＝36.5Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C26H25FN2NaOS 455.1564；Found 455.1553.
实施例4
向15mL反应管中，加入4,4-二甲基-1-苯基吡唑烷-3-酮(1a,38.0mg,0.2mmol)、MeOH(1mL)/H2O(0.1mL)、[RhCp*Cl2]2(3.7mg,0.006mmol)、Cy2NH(80uL,0.4mmol)和3,3-二氟-1,5-二苯基-1-戊炔(2a,61.5mg,0.24mmol)。密封反应管，空气气氛下100℃搅拌12小时。冷却至室温，抽滤，将母液减压浓缩，残余物硅胶柱色谱法纯化，石油醚/乙酸乙酯(1:1)为洗脱剂，得到白色固体4a(67.9mg,80％)。
Figure BDA0003099002610000151
1H NMR(600MHz,CDCl3)δ8.36-8.34(m,1H),7.58-7.57(m,1H),7.54-7.51(m,3H),7.40-7.38(m,2H),7.30-7.27(m,2H),7.16(t,J＝7.2Hz,2H),7.10(t,J＝7.2Hz,1H),6.90(d,J＝7.2Hz,2H),5.41(br s,1H),5.35(br s,1H),4.39(s,2H),2.83(t,J＝7.8Hz,2H),2.53(t,J＝8.4Hz,2H),0.91(s,6H).13CNMR(150MHz,CDCl3)δ197.3,179.0,145.7,141.5,137.0,132.0,131.4,129.7,128.9,128.3,128.2,126.7,125.7,123.5,122.8,122.1,116.8,111.6,51.0,43.8,43.1,30.6,24.5.HRMS(ESI)m/z:[M+Na]+Calcd for C28H28N2NaO2447.2043；Found 447.2029.
实施例5
依照实施例4的方法和步骤a,b，通过改变反应物1和反应物2，合成得到3-酰基吲哚类化合物4a-4y，具体结果如下：
Figure BDA0003099002610000152
Figure BDA0003099002610000161
a反应条件:1(0.2mmol),2(0.24mmol),[RhCp*Cl2]2(0.006mmol),Cy2NH(0.4mmol),MeOH(1mL),H2O(0.1mL),100℃,12h.b分离收率.
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代表性产物表征数据如下：
2,2-Dimethyl-3-(5-methyl-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)propanamide(4b)
White solid(67.5mg,77％).1H NMR(600MHz,CDCl3)δ8.17(s,1H),7.52-7.47(m,3H),7.44(d,J＝8.4Hz,1H),7.36(d,J＝7.2Hz,2H),7.15(t,J＝7.8Hz,2H),7.10-7.07(m,2H),6.88(d,J＝7.8Hz,2H),5.64(br s,1H),5.52(br s,1H),4.33(s,2H),2.80(t,J＝7.8Hz,2H),2.48(t,J＝7.8Hz,2H),2.46(s,3H),0.89(s,6H).13CNMR(150MHz,CDCl3)δ197.4,179.2,145.8,141.5,135.4,132.4,132.1,131.4,129.7,128.8,128.3,128.2,126.9,125.8,125.0,121.8,116.4,111.4,51.0,43.8,42.9,30.6,24.5,21.6.HRMS(ESI)m/z:[M+H]+Calcd for C29H31N2O2 439.2380；Found 439.2374.
3-(5-Methoxy-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4c)
White solid(73.6mg,81％).1H NMR(600MHz,CDCl3)δ7.92(d,J＝2.4Hz,1H),7.54-7.49(m,3H),7.46(d,J＝8.4Hz,1H),7.38(d,J＝7.2Hz,2H),7.15(t,J＝7.2Hz,2H),7.09(t,J＝7.2Hz,1H),6.90(dd,J1＝9.0Hz,J2＝2.4Hz,1H),6.87(d,J＝7.8Hz,2H),5.58(br s,1H),5.49(br s,1H),4.33(s,2H),3.88(s,3H),2.81(t,J＝7.8Hz,2H),2.45(t,J＝7.8Hz,2H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ197.4,179.1,156.5,146.0,141.4,132.1,131.9,131.4,129.8,128.9,128.21,128.19,127.6,125.7,116.6,113.9,112.6,103.2,55.8,51.2,43.8,42.7,30.6,24.4.HRMS(ESI)m/z:[M+H]+Calcd for C29H31N2O3 455.2329；Found 455.2316.
3-(5-(Benzyloxy)-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4d)
White solid(77.5mg,73％).1H NMR(600MHz,CDCl3)δ8.03(d,J＝2.4Hz,1H),7.52-7.46(m,6H),7.39-7.36(m,4H),7.31(t,J＝7.2Hz,1H),7.15(t,J＝7.8Hz,2H),7.10(t,J＝7.8Hz,1H),6.97(dd,J1＝9.0Hz,J2＝2.4Hz,1H),6.87(d,J＝7.8Hz,2H),5.49(br s,1H),5.46(br s,1H),5.14(s,2H),4.32(s,2H),2.81(t,J＝7.8Hz,2H),2.45(t,J＝7.8Hz,2H),0.89(s,6H).13CNMR(150MHz,CDCl3)δ197.3,179.1,155.7,146.1,141.4,137.5,132.1,131.4,129.8,128.9,128.6,128.24,128.21,127.9,127.7,127.5,125.8,116.6,114.5,112.6,104.6,70.5,51.2,43.8,42.8,30.6,24.4.HRMS(ESI)m/z:[M+Na]+Calcd forC35H34N2NaO3 553.2462；Found 553.2440.
3-(5-Isopropyl-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4e)
White solid(61.6mg,66％).1H NMR(600MHz,CDCl3)δ8.24(d,J＝1.8Hz,1H),7.52-7.48(m,4H),7.36(dd,J1＝7.2Hz,J2＝1.8Hz,2H),7.18-7.14(m,3H),7.11-7.08(m,1H),6.88(d,J＝7.8Hz,2H),5.48(br s,1H),5.46(br s,1H),4.35(s,2H),3.07-3.02(m,1H),2.82(t,J＝7.8Hz,2H),2.47(t,J＝7.8Hz,2H),1.32(d,J＝7.2Hz,6H),0.91(s,6H).13CNMR(150MHz,CDCl3)δ197.5,179.0,145.8,143.9,141.5,135.7,132.1,131.4,129.7,128.9,128.3,128.2,126.8,125.7,122.7,119.1,116.7,111.4,51.0,43.8,42.9,34.4,30.6,24.6,24.5.HRMS(ESI)m/z:[M+Na]+Calcd for C31H34N2NaO2 489.2512；Found489.2489.
3-(5-Fluoro-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4f)
White solid(55.8mg,63％).1H NMR(600MHz,CDCl3)δ8.05(dd,J1＝9.6Hz,J2＝2.4Hz,1H),7.55-7.50(m,4H),7.39(dd,J1＝7.8Hz,J2＝1.2Hz,2H),7.15(t,J＝7.2Hz,2H),7.11-7.09(m,1H),6.99(td,J1＝9.0Hz,J2＝3.0Hz,1H),6.88(d,J＝6.6Hz,2H),5.50(br s,2H),4.35(s,2H),2.79(t,J＝7.8Hz,2H),2.46(t,J＝7.8Hz,2H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ196.9,179.0,159.8(d,1JC-F＝236.9Hz),147.0,141.3,133.4,131.7,131.3,130.0,129.0,128.22,128.21,127.5(d,3JC-F＝10.8Hz),125.8,116.8(d,4JC-F＝4.5Hz),112.6(d,3JC-F＝8.1Hz),111.8(d,2JC-F＝26.1Hz),107.4(d,2JC-F＝26.0Hz),51.3,43.7,42.8,30.5,24.4.19F NMR(565MHz,CDCl3)δ-120.7(td,J1＝10.7Hz,J2＝4.5Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C28H27FN2NaO2 465.1949；Found 465.1942.
3-(5-Chloro-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4g)
White solid(57.8mg,63％).1H NMR(600MHz,CDCl3)δ8.38(d,J＝2.4Hz,1H),7.56-7.52(m,3H),7.50(d,J＝9.0Hz,1H),7.38(dd,J1＝7.2Hz,J2＝1.2Hz,2H),7.20(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.16(t,J＝7.8Hz,2H),7.10(t,J＝7.8Hz,1H),6.88(d,J＝7.2Hz,2H),5.48(br s,1H),5.44(br s,1H),4.35(s,2H),2.79(t,J＝7.8Hz,2H),2.45(t,J＝7.8Hz,2H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ196.9,178.9,146.6,141.3,135.3,131.5,131.3,130.0,129.0,128.7,128.23,128.22,127.8,125.8,123.8,121.7,116.4,112.8,51.3,43.7,42.8,30.5,24.4.HRMS(ESI)m/z:[M+Na]+Calcd for C28H27ClN2NaO2481.1653；Found 481.1642.
2,2-Dimethyl-3-(2-phenyl-3-(3-phenylpropanoyl)-5-(trifluoromethyl)-1H-indol-1-yl)propanamide(4h)
White solid(57.1mg,58％).1H NMR(600MHz,CDCl3)δ8.70(s,1H),7.68(d,J＝9.0Hz,1H),7.59-7.54(m,3H),7.49(dd,J1＝8.4Hz,J2＝1.2Hz,1H),7.40(d,J＝6.0Hz,2H),7.16(t,J＝7.2Hz,2H),7.10(t,J＝7.2Hz,1H),6.88(d,J＝7.2Hz,2H),5.43(br s,1H),5.34(br s,1H),4.41(s,2H),2.81(t,J＝7.8Hz,2H),2.47(t,J＝7.8Hz,2H),0.91(s,6H).13CNMR(150MHz,CDCl3)δ197.2,178.7,147.0,141.2,138.3,131.3,130.2,129.1,128.2,126.2,125.8,125.07(q,2JC-F＝30.6Hz),125.03(q,1JC-F＝271.7Hz),120.3(q,3JC-F＝3.5Hz),120.1(q,3JC-F＝4.8Hz),117.3,112.0,51.2,43.7,42.8,30.4,24.4.19F NMR(565MHz,CDCl3)δ-60.7(s).HRMS(ESI)m/z:[M+Na]+Calcd for C29H27F3N2NaO2 515.1917；Found 515.1909.
3-(5-Cyano-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4i)
White solid(45.0mg,50％).1H NMR(600MHz,CDCl3)δ8.72(s,1H),7.68(d,J＝8.4Hz,1H),7.61-7.55(m,3H),7.46(d,J＝8.4Hz,1H),7.41(d,J＝7.2Hz,2H),7.16(t,J＝7.2Hz,2H),7.10(t,J＝7.2Hz,1H),6.88(d,J＝7.8Hz,2H),5.56(br s,1H),5.54(br s,1H),4.40(s,2H),2.79(t,J＝7.8Hz,2H),2.45(t,J＝7.8Hz,2H),0.92(s,6H).13CNMR(150MHz,CDCl3)δ196.9,178.7,147.5,141.0,138.6,131.2,130.9,130.4,129.1,128.24,128.21,127.8,126.5,126.4,125.9,120.2,117.0,112.7,105.9,51.3,43.7,42.8,30.3,24.4.HRMS(ESI)m/z:[M+Na]+Calcd for C29H27N3NaO2 472.1995；Found 472.1984.
2,2-Dimethyl-3-(5-nitro-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)propanamide(4j)
White solid(40.4mg,43％).1H NMR(600MHz,CDCl3)δ9.17(d,J＝2.4Hz,1H),8.10(dd,J1＝9.6Hz,J2＝2.4Hz,1H),7.68(d,J＝8.4Hz,1H),7.61-7.56(m,3H),7.43(d,J＝7.2Hz,2H),7.17(t,J＝7.2Hz,2H),7.11(t,J＝7.2Hz,1H),6.89(d,J＝7.2Hz,2H),5.60(brs,1H),5.50(br s,1H),4.42(s,2H),2.81(t,J＝7.8Hz,2H),2.47(t,J＝7.8Hz,2H),0.94(s,6H).13CNMR(150MHz,CDCl3)δ196.7,178.6,148.2,143.8,141.0,139.8,131.2,130.8,130.4,129.2,128.3,128.2,126.2,125.9,119.2,118.9,118.0,111.9,51.6,43.7,42.8,30.2,24.3.HRMS(ESI)m/z:[M+Na]+Calcd for C28H27N3NaO4 492.1894；Found 492.1875.
2,2-Dimethyl-3-(6-methyl-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)propanamide(4k)
White solid(61.4mg,70％).1H NMR(600MHz,CDCl3)δ8.22(d,J＝7.8Hz,1H),7.52-7.48(m,3H),7.38-7.36(m,3H),7.16(t,J＝7.2Hz,2H),7.12-7.08(m,2H),6.89(d,J＝7.2Hz,2H),5.64(br s,1H),5.46(br s,1H),4.34(s,2H),2.81(t,J＝7.8Hz,2H),2.52(t,J＝7.8Hz,2H),2.46(s,3H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ197.2,179.1,145.2,141.5,137.5,133.4,132.1,131.1,129.6,128.8,128.3,128.2,125.7,124.50,124.47,121.8,116.7,111.5,50.8,43.9,43.0,30.6,24.5,22.0.HRMS(ESI)m/z:[M+Na]+Calcd forC29H30N2NaO2 461.2199；Found 461.2184.
3-(6-Methoxy-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4l)
White solid(65.5mg,72％).1H NMR(600MHz,CDCl3)δ8.22(d,J＝9.0Hz,1H),7.53-7.50(m,3H),7.39-7.37(m,2H),7.17-7.15(m,2H),7.12-7.09(m,2H),6.92(dd,J1＝9.0Hz,J2＝1.8Hz,1H),6.89(d,J＝7.2Hz,2H),5.46(br s,1H),5.33(br s,1H),4.33(s,2H),3.86(s,3H),2.81(t,J＝7.2Hz,2H),2.50(t,J＝7.8Hz,2H),0.91(s,6H).13CNMR(150MHz,CDCl3)δ197.2,179.2,157.2,144.7,141.5,137.8,132.1,131.5,129.6,128.8,128.25,128.18,125.7,122.8,120.6,116.7,112.6,95.0,55.7,51.0,43.6,42.9,30.6,24.4.HRMS(ESI)m/z:[M+Na]+Calcd for C29H30N2NaO3 477.2149；Found 477.2132.
3-(6-Chloro-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4m)
White solid(57.8mg,63％).1H NMR(600MHz,CDCl3)δ8.20(d,J＝8.4Hz,1H),7.51(s,1H),7.47-7.44(m,3H),7.31(d,J＝6.6Hz,2H),7.15(d,J＝8.4Hz,1H),7.08(t,J＝7.2Hz,2H),7.04-7.01(m,1H),6.81(d,J＝7.8Hz,2H),5.74(br s,1H),5.43(br s,1H),4.26(s,2H),2.73(t,J＝7.8Hz,2H),2.41(t,J＝7.8Hz,2H),0.83(s,6H).13CNMR(150MHz,CDCl3)δ197.1,178.9,146.1,141.3,137.5,131.5,131.3,130.0,129.4,128.9,128.23,128.21,125.8,125.2,123.4,123.2,116.8,111.6,51.1,43.8,42.9,30.5,24.4.HRMS(ESI)m/z:[M+H]+Calcd for C28H28ClN2O2 459.1834；Found 459.1827.
3-(6-Bromo-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4n)
White solid(58.4mg,58％).1H NMR(600MHz,CDCl3)δ8.22(d,J＝9.0Hz,1H),7.74(d,J＝1.8Hz,1H),7.56-7.50(m,3H),7.38-7.35(m,3H),7.17-7.14(m,2H),7.11-7.08(m,1H),6.88(d,J＝7.2Hz,2H),5.93(br s,1H),5.53(br s,1H),4.32(s,2H),2.80(t,J＝7.8Hz,2H),2.47(t,J＝7.8Hz,2H),0.90(s,6H).13CNMR(150MHz,CDCl3)δ197.1,178.9,146.1,141.3,137.9,131.4,131.3,130.0,129.0,128.23,128.21,126.0,125.8,125.6,123.5,117.0,116.8,114.6,51.1,43.8,42.9,30.5,24.4.HRMS(ESI)m/z:[M+Na]+Calcdfor C28H27BrN2NaO2 525.1148；Found 525.1141.
2,2-Dimethyl-3-(7-methyl-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)propanamide(4o)
White solid(62.3mg,71％).1H NMR(600MHz,CDCl3)δ8.14(d,J＝7.8Hz,1H),7.51-7.48(m,3H),7.44-7.42(m,2H),7.25-7.14(m,3H),7.13-7.09(m,1H),7.03(d,J＝7.2Hz,1H),6.87(d,J＝7.2Hz,2H),5.42(br s,1H),5.31(br s,1H),4.69(br s,2H),2.80(t,J＝7.8Hz,2H),2.73(s,3H),2.47(br s,2H),0.77(s,6H).13CNMR(150MHz,CDCl3)δ198.6,178.7,146.0,141.4,137.1,131.6,129.7,128.8,128.3,128.2,127.6,127.5,125.8,122.8,121.8,120.0,118.0,51.4,44.7,43.5,30.9,24.0,21.4.HRMS(ESI)m/z:[M+Na]+Calcd for C29H30N2NaO2 461.2199；Found 461.2185.
3-(7-Methoxy-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4p)
White solid(61.8mg,68％).1H NMR(600MHz,CDCl3)δ7.96(dd,J1＝8.4Hz,J2＝1.2Hz,1H),7.51-7.47(m,3H),7.39(br s,2H),7.19(t,J＝8.4Hz,1H),7.16-7.13(m,2H),7.10-7.07(m,1H),6.87(d,J＝7.8Hz,2H),6.74(d,J＝7.8Hz,1H),5.65(br s,1H),5.40(brs,1H),5.14(br s,1H),4.33(br s,1H),3.93(s,3H),2.79(t,J＝7.8Hz,2H),2.46(br s,2H),0.87(br s,6H).13CNMR(150MHz,CDCl3)δ197.7,179.3,147.1,146.0,141.4,131.6,129.7,128.8,128.3,128.2,127.1,125.7,123.2,117.2,114.8,104.6,55.0,52.3,44.3,43.1,30.7,24.0.HRMS(ESI)m/z:[M+Na]+Calcd for C29H30N2NaO3 477.2149；Found477.2139.
3-(7-Chloro-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4q)
White solid(46.8mg,51％).1H NMR(600MHz,CDCl3)δ8.27(dd,J1＝8.4Hz,J2＝1.2Hz,1H),7.54-7.49(m,3H),7.42(d,J＝7.2Hz,2H),7.28(dd,J1＝7.8Hz,J2＝1.2Hz,1H),7.19(t,J＝7.8Hz,1H),7.16-7.13(m,2H),7.10-7.08(m,1H),6.86(d,J＝7.2Hz,2H),5.41(br s,3H),4.53(br s,1H),2.78(t,J＝7.8Hz,2H),2.43(br s,2H),0.98-0.82(m,6H).13CNMR(150MHz,CDCl3)δ198.1,178.6,146.9,141.2,133.1,130.9,130.1,129.9,128.9,128.25,128.19,126.2,125.8,123.2,121.1,117.7,117.2,50.7,44.3,43.3,30.7,23.7.HRMS(ESI)m/z:[M+H]+Calcd for C28H28ClN2O2 459.1834；Found 459.1820.
3-(7-Fluoro-2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4r)
White solid(49.6mg,56％).1H NMR(600MHz,CDCl3)δ8.13(d,J＝8.4Hz,1H),7.54-7.48(m,3H),7.40(d,J＝6.6Hz,2H),7.20-7.14(m,3H),7.11-7.08(m,1H),6.99(dd,J1＝13.2Hz,J2＝7.8Hz,1H),6.88(d,J＝7.2Hz,2H),5.62(br s,1H),5.43(br s,1H),4.58(s,2H),2.80(t,J＝7.8Hz,2H),2.47(t,J＝7.2Hz,2H),0.94(s,6H).13CNMR(150MHz,CDCl3)δ197.6,178.3,149.6(d,1JC-F＝243.0Hz),146.5,141.3,130.8,130.2(d,3JC-F＝4.5Hz),130.0,128.8,128.3,128.2,125.8,125.6(d,2JC-F＝7.5Hz),122.9(d,3JC-F＝6.0Hz),118.1(d,4JC-F＝3.2Hz),117.7,109.6(d,2JC-F＝19.4Hz),52.3(d,4JC-F＝6.6Hz),44.5,43.1,30.6,23.8.19F NMR(565MHz,CDCl3)δ-129.4(dd,J1＝13.6Hz,J2＝5.1Hz).HRMS(ESI)m/z:[M+H]+Calcd for C28H28FN2O2 443.2129；Found 443.2117.
2,2-Dimethyl-3-(3-(3-phenylpropanoyl)-2-(p-tolyl)-1H-indol-1-yl)propanamide(4s)
White solid(68.4mg,78％).1H NMR(600MHz,CDCl3)δ8.35-8.34(m,1H),7.57-7.56(m,1H),7.32(d,J＝7.8Hz,2H),7.27-7.25(m,4H),7.16(t,J＝7.2Hz,2H),7.10(t,J＝7.2Hz,1H),6.90-6.89(m,2H),5.44(br s,2H),4.38(s,2H),2.82(t,J＝7.2Hz,2H),2.53-2.50(m,2H),2.46(s,3H),0.92(s,6H).13CNMR(150MHz,CDCl3)δ197.4,179.1,146.0,141.5,139.9,137.0,131.2,129.6,128.9,128.3,128.2,126.7,125.7,123.4,122.8,122.1,116.8,111.6,50.9,43.8,42.9,30.6,24.5,21.5.HRMS(ESI)m/z:[M+Na]+Calcd forC29H30N2NaO2 461.2199；Found 461.2186.
3-(2-(4-Chlorophenyl)-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4t)
White solid(57.8mg,63％).1H NMR(600MHz,CDCl3)δ8.27-8.26(m,1H),7.57-7.56(m,1H),7.47(d,J＝8.4Hz,2H),7.30-7.27(m,4H),7.20(t,J＝7.8Hz,2H),7.13(t,J＝7.2Hz,1H),6.96(d,J＝7.2Hz,2H),5.63(br s,1H),5.47(br s,1H),4.36(s,2H),2.86(t,J＝7.8Hz,2H),2.61(t,J＝7.8Hz,2H),0.93(s,6H).13CNMR(150MHz,CDCl3)δ196.8,178.8,144.1,141.4,137.1,136.0,132.7,130.3,129.1,128.34,128.30,126.4,125.9,123.6,122.9,120.0,117.1,111.8,51.0,44.0,43.5,30.4,24.5.HRMS(ESI)m/z:[M+Na]+Calcdfor C28H27ClN2NaO2 481.1653；Found 481.1638.
3-(2-(4-Bromophenyl)-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4u)
White solid(55.3mg,55％).1H NMR(600MHz,CDCl3)δ8.27-8.25(m,1H),7.62(d,J＝7.8Hz,2H),7.57-7.56(m,1H),7.28-7.27(m,2H),7.23-7.20(m,4H),7.14(t,J＝7.2Hz,1H),6.95(d,J＝7.8Hz,2H),5.63(br s,1H),5.46(br s,1H),4.36(s,2H),2.85(t,J＝7.8Hz,2H),2.61(t,J＝7.8Hz,2H),0.93(s,6H).13CNMR(150MHz,CDCl3)δ196.8,178.8,144.1,141.3,137.2,132.9,132.1,130.8,128.4,128.3,126.4,125.9,124.2,123.6,122.9,122.0,117.1,111.8,51.0,44.0,43.5,30.4,24.5.HRMS(ESI)m/z:[M+Na]+Calcdfor C28H27BrN2NaO2 525.1148；Found 525.1121.
2,2-Dimethyl-3-(3-(3-phenylpropanoyl)-2-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propanamide(4v)
White solid(55.2mg,56％).1H NMR(600MHz,CDCl3)δ8.26-8.23(m,1H),7.74(d,J＝7.8Hz,2H),7.60-7.57(m,1H),7.49(d,J＝7.8Hz,2H),7.30-7.28(m,2H),7.18(t,J＝7.2Hz,2H),7.13(t,J＝7.2Hz,1H),6.92(d,J＝7.2Hz,2H),5.69(br s,1H),5.45(br s,1H),4.37(s,2H),2.85(t,J＝7.8Hz,2H),2.61(t,J＝7.8Hz,2H),0.92(s,6H).13CNMR(150MHz,CDCl3)δ196.6,178.7,143.6,141.2,137.3,135.8,131.9,131.6(q,2JC-F＝33.0Hz),128.4,128.2,126.3,126.0,125.7(q,3JC-F＝3.8Hz),123.8(q,1JC-F＝270.0Hz),123.7,123.0,122.0,117.2,111.9,51.0,44.0,43.7,30.3,24.5.19F NMR(565MHz,CDCl3)δ-62.7(s).HRMS(ESI)m/z:[M+Na]+Calcd for C29H27F3N2NaO2 515.1917；Found 515.1899.
3-(2-(3-Chlorophenyl)-3-(3-phenylpropanoyl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4w)
White solid(56.0mg,61％).1H NMR(600MHz,CDCl3)δ8.29-8.27(m,1H),7.57-7.56(m,1H),7.50(dd,J1＝8.4Hz,J2＝1.2Hz,1H),7.43(t,J＝7.8Hz,1H),7.40(s,1H),7.29-7.25(m,3H),7.19(t,J＝7.8Hz,2H),7.12(t,J＝7.8Hz,1H),6.97(d,J＝7.2Hz,2H),5.56(br s,1H),5.50(br s,1H),4.36(s,2H),2.86(t,J＝6.6Hz,2H),2.61(t,J＝6.6Hz,2H),0.94(s,6H).13CNMR(150MHz,CDCl3)δ196.7,178.8,143.7,141.3,137.2,134.7,133.8,131.3,130.1,129.8,129.5,128.33,128.28,126.4,125.9,123.7,122.9,122.1,117.0,111.7,51.1,43.9,43.5,30.5,24.6.HRMS(ESI)m/z:[M+Na]+Calcd for C28H27ClN2NaO2481.1653；Found 481.1635.
3-(3-Butyryl-2-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(4x)
White solid(52.2mg,72％).1H NMR(600MHz,CDCl3)δ8.36-8.34(m,1H),7.58-7.54(m,4H),7.42-7.41(m,2H),7.29-7.25(m,2H),5.47(br s,1H),5.44(br s,1H),4.39(s,2H),2.14(t,J＝7.2Hz,2H),1.51-1.45(m,2H),0.92(s,6H),0.67(t,J＝7.2Hz,3H),13CNMR(150MHz,CDCl3)δ198.7,179.1,145.5,137.0,132.0,131.4,129.7,128.7,126.7,123.4,122.7,122.1,116.9,111.6,50.9,43.82,43.79,24.5,18.3,13.8.HRMS(ESI)m/z:[M+Na]+Calcd for C23H26N2NaO2 385.1886；Found 385.1869.
2,2-Dimethyl-3-(3-(3-phenylpropanoyl)-2-(thiophen-2-yl)-1H-indol-1-yl)propanamide(4y)
White solid(60.3mg,70％).1H NMR(600MHz,CDCl3)δ8.33-8.32(m,1H),7.61(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.57-7.55(m,1H),7.29-7.27(m,2H),7.20-7.18(m,3H),7.17-7.16(m,1H),7.12(t,J＝7.2Hz,1H),7.00(d,J＝6.6Hz,2H),5.46(br s,1H),5.42(br s,1H),4.46(s,2H),2.89(t,J＝7.2Hz,2H),2.63(t,J＝7.8Hz,2H),1.01(s,6H).13CNMR(150MHz,CDCl3)δ197.4,179.1,141.5,137.3,137.1,132.2,131.5,129.5,128.33,128.25,127.7,126.5,125.8,124.0,122.9,122.2,118.9,111.6,51.3,43.7,42.6,30.7,24.5.HRMS(ESI)m/z:[M+Na]+Calcd for C26H26N2NaO2S 453.1607；Found 453.1591.
2-Methyl-3-(2-phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)propanamide(4z)
Pale yellow oil(52.5mg,64％).1H NMR(600MHz,CDCl3)δ8.43-8.41(m,1H),7.54-7.48(m,3H),7.44-7.42(m,1H),7.37-7.36(m,2H),7.30-7.27(m,2H),7.16-7.13(m,2H),7.10-7.08(m,1H),6.87(d,J＝7.8Hz,2H),5.56(br s,1H),5.39(br s,1H),4.30(dd,J1＝15.0Hz,J2＝7.2Hz,1H),3.92(dd,J1＝15.0Hz,J2＝7.2Hz,1H),2.80(t,J＝7.2Hz,2H),2.64-2.60(m,1H),2.51(t,J＝7.2Hz,2H),0.90(d,J＝7.2Hz,3H).13CNMR(150MHz,CDCl3)δ196.8,175.9,145.7,141.4,136.2,131.9,130.6,129.9,129.0,128.24,128.21,126.8,125.8,123.6,123.0,122.7,116.3,110.4,46.9,42.8,40.7,30.5,15.7.HRMS(ESI)m/z:[M+Na]+Calcd for C27H26N2NaO2 433.1886；Found 433.1877.
3-(2-Phenyl-3-(3-phenylpropanoyl)-1H-indol-1-yl)propanamide(4aa)
White solid(51.5mg,65％).1H NMR(600MHz,CDCl3)δ8.43-8.42(m,1H),7.52(t,J＝7.2Hz,1H),7.46(t,J＝7.8Hz,2H),7.39-7.37(m,1H),7.32-7.30(m,2H),7.20(d,J＝7.2Hz,2H),7.15(t,J＝7.2Hz,2H),7.10(t,J＝6.6Hz,1H),6.86(d,J＝7.2Hz,2H),5.81(brs,1H),5.64(br s,1H),4.19(t,J＝7.2Hz,2H),2.78(t,J＝7.2Hz,2H),2.48(t,J＝7.8Hz,2H),2.38(t,J＝7.8Hz,2H).13CNMR(150MHz,CDCl3)δ196.8,172.0,145.7,141.3,135.5,131.8,130.0,129.9,129.1,128.2,126.9,125.8,123.7,123.1,122.8,1116.0,109.9,42.7,39.8,35.0,30.5.HRMS(ESI)m/z:[M+Na]+Calcd for C26H24N2NaO2 419.1730；Found419.1715.
实施例6
本发明所得化合物的抗癌活性是利用CCK8分析，通过细胞抗增殖活性研究进行评估。首先，将细胞以每孔5000个细胞的密度接种到每孔装有100μL培养基的96孔板中，并在37℃和5％CO2环境下孵育过夜。次日，在每孔中加入100μL用培养基稀释的待测化合物(浓度为0.03nM-30μM)，接着细胞在37℃和5％CO2环境下孵育72小时。然后向每个孔中加入10μL的CCK8，并将96孔板置于37℃孵育2小时。使用EnVision multilatelbel Reader(Perkinermer)在450nm处测量吸光度(用630nm作为参考波长)，并用GraphPad Prism 6.0软件计算出IC50值。所有的实验均布施三个平行样品，并重复三次。选择REC-1和Ramos两种癌细胞作为研究对象，5-氟尿嘧啶(5-FU)被用作药物的阳性对照品。
代表性化合物3抗癌活性结果如下：
Figure BDA0003099002610000241
Figure BDA0003099002610000251
代表性化合物4抗癌活性结果如下：
Figure BDA0003099002610000252
实施例7
本发明所合成的产物3-(α-氟乙烯基)吲哚类化合物3进行衍生反应，从而合成进一步的衍生物。例如：
Figure BDA0003099002610000253
氮气保护下，采用冰浴控温0℃，向3a(42.7mg，0.1mmol)/THF(1mL)溶液中加入LiAlH4(19mg，0.5mmol)，然后将混合物室温搅拌2h。加入H2O(5mL)淬灭反应，EtOAc(10mL×3)萃取。合并有机相，盐水洗，无水Na2SO4干燥，过滤并减压浓缩。残余物硅胶柱色谱法纯化，乙酸乙酯/甲醇(8:1)为洗脱剂，得到白色固体3Ba(28.9mg,70％)。1H NMR(600MHz,CDCl3)δ7.77(d,J＝7.8Hz,1H),7.48(d,J＝7.8Hz,1H),7.43-7.38(m,5H),7.24-7.21(m,3H),7.18-7.15(m,2H),7.08(d,J＝6.6Hz,2H),4.83(dt,J1＝36.0Hz,J2＝7.8Hz,1H),4.59(br s,2H),4.15(s,2H),3.51(d,J＝7.8Hz,2H),2.35(s,2H),0.68(s,6H).13CNMR(150MHz,CDCl3)δ153.6(d,1JC-F＝243.9Hz),140.7(d,4JC-F＝2.1Hz),139.7(d,3JC-F＝4.1Hz),137.6,132.0,131.2,128.59,128.55,128.34,128.31,126.2,125.9,122.4,120.7,120.1(d,4JC-F＝2.0Hz),111.4,108.7(d,2JC-F＝31.8Hz),107.6(d,2JC-F＝18.5Hz),50.4,50.1,38.4,30.3(d,3JC-F＝4.2Hz),24.1.19F NMR(565MHz,CDCl3)δ-104.4(d,J＝37.9Hz).HRMS(ESI)m/z:[M+H]+Calcd for C28H30FN2 413.2388；Found 413.2381.
采用冰浴控温0℃，向3a(85.3mg，0.2mmol)/二氯甲烷(2mL)溶液中依次加入吡啶(40uL，0.5mmol)和三氟乙酸酐(40uL，0.28mmol)，然后升温至室温并搅拌过夜。向所得混合物中加入二氯甲烷(10mL)，依次采用1％HCl水溶液和水洗。分离得到的有机层MgSO4干燥，过滤并减压浓缩。残余物硅胶柱色谱法纯化，石油醚/乙酸乙酯(10:1)为洗脱剂，得到淡黄色固体3Aa(74.4mg,91％)。1H NMR(600MHz,CDCl3)δ7.79(d,J＝7.8Hz,1H),7.56(d,J＝8.4Hz,1H),7.42-7.40(m,3H),7.36-7.35(m,2H),7.30-7.27(m,1H),7.22-7.19(m,3H),7.15-7.13(m,1H),7.06(d,J＝7.2Hz,2H),4.88(dt,J1＝36.6Hz,J2＝7.8Hz,1H),4.32(s,2H),3.50(d,J＝7.8Hz,2H),1.05(s,6H).13CNMR(150MHz,CDCl3)δ153.4(d,1JC-F＝243.9Hz),140.6(d,4JC-F＝2.1Hz),139.3(d,3JC-F＝5.1Hz),137.0,131.4,131.3,129.0,128.8,128.5,128.4,126.5,126.0,124.0,123.0,121.5,120.5,111.4,109.6(d,2JC-F＝33.6Hz),108.0(d,2JC-F＝19.5Hz),50.4,34.6,30.4(d,3JC-F＝4.5Hz),25.7.19F NMR(565MHz,CDCl3)δ-105.1(d,J＝37.9Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C28H25FN2Na431.1894；Found 431.1881.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (7)

1.3-(α-氟乙烯基/羰基)吲哚类化合物，包括3-(α-氟乙烯基)吲哚类化合物3和3-(α-羰基)吲哚类化合物4，其结构通式为：
Figure FDA0003635252560000011
其中，R1为氢、卤素、C1-6烷基、C1-6烷氧基或苄氧基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为叔丁基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5为C1-6烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。
2.如权利要求1所述3-(α-氟乙烯基/羰基)吲哚类化合物及其在药学上可接受的盐在制备抗癌活性药物中的应用，其特征在于：所述抗癌活性是指抗REC-1和/或抗Ramos癌细胞活性。
3.根据权利要求2所述的应用，其特征在于：药学上可接受的盐包括3-(α-氟乙烯基/羰基)吲哚类化合物与有机酸或无机酸形成的盐；有机酸选自苹果酸、乳酸、樟脑磺酸、枸橼酸、富马酸或草酸中的一种或多种，无机酸选自磷酸、氢卤酸、硫酸或硝酸中一种或多种。
4.如权利要求1所述3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法，其特征在于，包括如下操作：将N-芳基吡唑烷酮1、偕二氟炔基化合物2、催化剂和碱性添加剂混合，在有机溶剂或含水有机溶剂中升温反应，分别得到3-(α-氟乙烯基)吲哚类化合物3或3-(α-羰基)吲哚类化合物4；所述催化剂为[Ru(p-cymene)Cl2]2、[RhCp*Cl2]2或[IrCp*Cl2]2；所述碱性添加剂为醋酸钠、醋酸铯、二环己胺、三乙胺或N,N’-二甲基乙二胺；反应方程式为：
Figure FDA0003635252560000021
其中：R1为氢、卤素、C1-6烷基、C1-6烷氧基或苄氧基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为叔丁基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5为C1-6烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。
5.根据权利要求4所述3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法，其特征在于：所述反应有机溶剂选自乙腈、1,2-二氯乙烷、二氯甲烷、二氧六环或四氢呋喃。
6.根据权利要求4所述3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法，其特征在于：所述N-芳基吡唑烷酮1、偕二氟炔基化合物2、碱性添加剂和催化剂的投料摩尔比为1:1-2:1-2:0.03-0.05。
7.根据权利要求4所述3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法，其特征在于：所述反应温度为60-120℃。
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