吲哚作为重要的含氮杂环, 广泛存在于药物、生物活性分子及天然产物中, 是一种优势骨架结构[1]. 因此, 高效合成吲哚及其衍生物已成为有机合成化学与药物化学领域的研究热点[2]. 在众多吲哚合成方法中[3], 尽管过渡金属催化体系的持续创新推动了功能化吲哚类化合物的合成, 取得了突破性进展, 但其催化环化策略在构建含三氟甲基的吲哚环方面仍有待深入探索, 且这类含氟分子结构能显著提升药物分子的代谢稳定性和脂溶性[4].
近年来, 三氟乙酰亚胺卤化物因其可通过胺类化合物与三氟乙酸、四卤化碳及三苯基膦的一锅反应简便制备[5], 日益成为合成化学中的重要合成子, 在构建三氟甲基功能化分子骨架中得以广泛应用[6]. 例如, 周磊课题组[7]开发了可见光激发下通过C(sp2)—Cl键活化, 实现三氟乙酰亚胺氯与三键的分子内自由基环化反应, 成功合成了2-(三氟甲基)吲哚衍生物(Scheme 1a). 随后, 我们小组[8]发展了钯(0)催化的三氟乙酰亚胺氯与炔烃的分子内5-exo-dig环化反应, 同样高效地制备了2-(三氟甲基)吲哚类化合物(Scheme 1b). 尽管如此, 利用地球丰产过渡金属作为催化剂, 实现2-(三氟甲基)吲哚衍生物的制备仍将是一种极具吸引力的合成方案.
1 结果与讨论
为探究镍催化环化反应构建2-(三氟甲基)吲哚骨架的可行性, 以三氟乙酰亚胺氯1为模板底物(表1), 以水为亲核试剂, 展开反应条件优化. 初始条件为: NiBr2为催化剂、L1为配体、锰粉为还原剂、LiBr为添加剂, 在1,4-二氧六环/水混合溶剂中反应, 以62%的分离收率获得了2-(三氟甲基)吲哚产物2 (Entry 1). 在筛选多种镍(II)催化剂前体时, Ni(acac)2 (乙酰丙酮镍)表现出略高于NiBr2(dme)、NiCl2、Ni(ClO4)2•6H2O、Ni(OTf)2等二价镍的催化活性(Entries 2~6), 将产物2的分离收率提升至71% (Entry 6). 鉴于配体在过渡金属高效催化合成反应中的关键作用[11], 进一步考察了多种双齿配体对该反应的影响(Entries 7~15). 当使用1,2-双(二苯基膦)乙烷(DPPE)为配体时, 产物2的分离收率可显著提高至89% (Entry 12). 值得注意的是, 该反应对碱添加剂敏感, 加入K2CO3会显著抑制反应的进行(Entry 16). 对照实验表明, 将LiBr替换为LiCl, 会导致产率急剧下降(Entry 17); 而完全不加LiBr时, 仅能检测到极少量产物2的形成(Entry 18).
表1 反应条件优化aTable 1 Optimization of reaction conditions |
| Entry | [Ni] | Ligand | Yieldb/% |
|---|---|---|---|
| 1 | NiBr2 | L1 | 62 |
| 2 | NiBr2(dme) | L1 | 61 |
| 3 | NiCl2 | L1 | 56 |
| 4 | Ni(ClO4)2•6H2O | L1 | 58 |
| 5 | Ni(OTf)2 | L1 | 69 |
| 6 | Ni(acac)2 | L1 | 71 |
| 7 | Ni(acac)2 | L2 | 68 |
| 8 | Ni(acac)2 | L3 | 70 |
| 9 | Ni(acac)2 | L4 | 65 |
| 10 | Ni(acac)2 | Xantphos | NDc |
| 11 | Ni(acac)2 | dppBz | 81 |
| 12 | Ni(acac)2 | DPPE | 89 |
| 13 | Ni(acac)2 | DPPP | 72 |
| 14 | Ni(acac)2 | DPPF | ND |
| 15 | Ni(acac)2 | DPEphos | ND |
| 16d | Ni(acac)2 | DPPE | 72 |
| 17e | Ni(acac)2 | DPPE | 48 |
| 18f | Ni(acac)2 | DPPE | Trace |
a Reaction conditions: 15 mol% [Ni], 18 mol% ligand, 1 (0.1 mmol), Mn (0.3 mmol), and LiBr (0.2 mmol) in 1,4-dioxane/H2O (V∶V=30∶1, 1 mL) at 80 ℃ for 5 h under nitrogen. b Isolated yield. c ND=not detected. d With K2CO3 (0.15 mmol) as base. e With LiCl (0.2 mmol) as additive. f Without LiBr. |
在确定了最佳反应条件后, 首先探索了镍催化下三氟乙酰亚胺氯与多种内炔进行环化反应的适用范围. 如Scheme 2所示, 在R1位置连接的苯环上, 无论是带有吸电子基团(F, Cl, CN和CF3)还是给电子基团(Me, OMe和tBu), 该反应都能顺利进行(Scheme 2, 3~10). 总的来说, R1为富电子苯基的三氟乙酰亚胺氯底物参加反应时, 可以得到收率更高的产物. 此外, 底物中R1无论是间位还是对位氯取代的苯环, 反应后都能得到目标产物(Scheme 2, 4和5). 具有较大空间位阻的α-萘基类反应底物也能兼容该转化反应, 以82%的分离收率得到产物11. 值得注意的是, 含有芳香杂环(噻吩基和吡啶基)的反应底物在最佳反应条件下也能适用(Scheme 2, 12和13). 当将R1更换为各种联苯取代基时, 也能以67%~94%的收率得到产物14~20. 当R1处为烷基取代, 即脂肪族炔烃的底物参与反应时, 分别以66%、68%和49%的收率分离, 得到含三氟甲基的吲哚衍生物21~23. 重要的是, 官能团邻苯二甲酰亚胺基(NPhth)在该环化反应中也表现出良好的兼容性. 随后, 将底物范围拓展到不同苯胺衍生出的三氟乙酰亚胺氯, 目标环化反应均能顺利发生, 可以合成出多种带有不同官能团的2-(三氟甲基)吲哚产物24~31.
为充分展示该转化反应的优异官能团耐受性与广泛的底物适用性, 将此策略应用于带有药物分子和天然产物的底物(Scheme 3). 一方面, 对于天然醇类化合物所衍生出的反应底物, 如植物醇(phytol)、D-冰片(D-borneol)和L-薄荷醇(L-menthol), 镍催化下的该类型环化反应表现优异, 分别以37%、84%和87%的收率获得了产物32~34. 另一方面, 来源于药物分子的反应底物, 如含驱虫剂icaridin、非甾体抗炎药(S)-naproxen和降脂药gemfibrozil分子骨架的三氟乙酰亚胺氯, 在标准反应条件下, 分别以72%、80%和76%的收率得到了相应的产物35~37.
考虑到含三氟甲基吲哚类化合物潜在的生物活性, 对产物的抗肿瘤活性进行考察. 实验使用5-氟尿嘧啶(5-FU)作为阳性对照, 评估了2-(三氟甲基)吲哚衍生物对HepG2(人肝癌细胞)细胞系的抗增殖活性. 值得注意的是, 化合物25和26表现出较强的细胞毒性作用, 其IC50值分别为(7.14±0.39)和(6.86±0.24) μmol/L(图1a). 为探究化合物25和26的抑制活性是否与细胞凋亡相关, 用不同浓度(5和10 μmol/L)的化合物25和26处理HepG2细胞, 并用Annexin V/PI进行双染. 如图1b所示, 在HepG2细胞中观察到了明显的凋亡特征, 并且凋亡细胞数量的变化与浓度升高的趋势一致. 活性氧(ROS)的生成被认为是恶性细胞凋亡级联反应中的关键起始事件. 如图1c所示, 用化合物25和26处理HepG2细胞, 24 h后细胞内的ROS显著升高. 总体而言, 这些细胞实验结果表明, 化合物25和26的抗癌活性可能与其诱导细胞凋亡的作用有关, 都显示出良好的抗肿瘤药物开发前景.
图1 抗肿瘤活性Figure 1 Antitumour activity (a) Cytotoxicity of selective compounds against cancer cell lines HepG2 for 48 h using CCK-8 assay; (b) Flow cytometry analysis of apoptotic HepG2 cells that were treated with compounds 25 and 26 at increasing concentrations (5 and 10 µmol/L) for 48 h and stained with Annexin V/PI; (c) Flow cytometry analysis of reactive oxygen species (ROS) production in HepG2 cells treated with compounds 25 and 26 (5 and 10 µmol/L) for 24 h and stained with DCFH-DA. |
2 结论
综上所述, 开发了一种通过镍催化三键与三氟乙酰亚胺氯和水发生环化反应, 高效合成2-(三氟甲基) 吲哚衍生物的方法. 该催化体系在标准反应条件下展现出优异的官能团兼容性. 通过产物对HepG2细胞的抗增殖活性评估, 发现多个产物表现出较好的活性, 其中化合物25和26尤为突出, 呈现显著的抗增殖效果. 细胞实验结果表明, 化合物25和26可作为具有开发潜力的先导化合物, 值得进一步研究优化, 以用于抗癌药物开发. 此外, 我们正致力于拓展镍催化三氟乙酰亚胺氯在其他杂环化合物合成中的应用研究[12].
3 实验部分
3.1 仪器与试剂
所有化合物的核磁共振1H、13C和19F谱为Bruker Avance III 400 HD型核磁共振仪测定(1H NMR参照溶剂峰定位: CDCl3 δ 7.26/DMSO-d6 δ 2.50/CD3OD δ 3.31; 13C NMR参照溶剂峰定位: CDCl3 δ 77.0/DMSO-d6 δ 44.0/CD3OD δ 49.0). 熔点使用WRS-1B型熔点仪测定. 高分辨质谱(HRMS)使用Waters Xevo G2-XS QTof质谱仪测定. 细胞实验相关数据的采集使用Molecular Devices SpectraMax M2多功能酶标仪和BECKMAN FC 500 MCL型流式细胞仪. 采用硅胶(200~300目)进行柱层析. 除非另有说明, 所有试剂均为市售产品, 未经进一步纯化直接使用.
3.2 实验方法
在干燥的10 mL密封管中装入底物(0.1 mmol, 1.0 equiv.)、Ni(acac)2 (15 mol%)、DPPE (18 mol%)、LiBr (0.2 mmol, 2.0 equiv.)、Mn(锰粉, 0.3 mmol, 3.0 equiv.)、1,4-二氧六环/水混合溶剂(V∶V=30∶1, 1.0 mL). 随后, 将密封管用氮气置换三次, 并用聚四氟乙烯塞密封. 将混合物在80 ℃油浴下搅拌反应5 h, 冷却至室温, 并在减压条件下浓缩除去溶剂. 残余物通过硅胶柱层析, 以石油醚/乙酸乙酯混合溶液作为洗脱剂进行分离, 得到目标产物.
苯基(2-三氟甲基-1H-吲哚-3-基)甲酮(2): 25.7 mg, 淡黄色固体, 产率89%. m.p. 138~141 ℃; 1H NMR (400 MHz, CDCl3) δ: 9.66 (s, 1H), 7.91~7.88 (m, 2H), 7.65~7.60 (m, 1H), 7.51~7.46 (m, 3H), 7.38~7.32 (m, 2H), 7.19~7.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 191.6, 138.7, 134.4, 133.2, 129.8, 128.4, 127.1 (q, J=38.7 Hz), 126.3, 125.3, 122.4, 121.9, 120.6 (q, J=268.4 Hz), 116.9 (q, J=2.4 Hz), 112.2; 19F NMR (376 MHz, CDCl3) δ: －58.3; HRMS (ESI) calcd for C16H11F3NO [M＋H]＋ 290.0787, found 290.0789.
(4-氟苯基)(2-三氟甲基-1H-吲哚-3-基)甲酮(3): 25.0 mg, 淡黄色固体, 产率81%. m.p. 156~160 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 13.17 (s, 1H), 7.86~7.78 (m, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.40~7.34 (m, 3H), 7.21~7.13 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 189.6, 165.6 (d, J=250.5 Hz), 135.8 (d, J=2.5 Hz), 135.6, 132.7 (d, J=9.5 Hz), 126.7 (q, J=38.2 Hz), 126.1, 125.6, 122.8, 121.5, 121.4 (d, J=268.4 Hz), 116.4 (d, J=22.0 Hz), 116.0 (q, J=2.2 Hz), 113.7; 19F NMR (376 MHz, DMSO-d6) δ: －56.8, －105.7; HRMS (ESI) calcd for C16H10F4NO [M＋H]＋ 308.0693, found 308.0692.
(4-氯苯基)(2-三氟甲基-1H-吲哚-3-基)甲酮(4): 26.0 mg, 黄色粘稠液体, 产率80%. 1H NMR (400 MHz, DMSO-d6) δ: 13.20 (s, 1H), 7.79~7.75 (m, 2H), 7.64~7.60 (m, 3H), 7.40~7.35 (m, 1H), 7.21~7.16 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 189.8, 138.7, 137.9, 135.5, 131.6, 129.4, 126.9 (q, J=38.1 Hz), 126.0, 125.6, 122.9, 121.5, 121.3 (q, J=268.4 Hz), 115.7 (q, J=2.2 Hz), 113.7; 19F NMR (376 MHz, DMSO-d6) δ: －56.8; HRMS (ESI) calcd for C16H10ClF3NO [M＋H]＋ 324.0398, found 324.0399.
(3-氯苯基)(2-三氟甲基-1H-吲哚-3-基)甲酮(5): 24.5 mg, 黄色液体, 产率76%. 1H NMR (400 MHz, DMSO- d6) δ: 13.25 (s, 1H), 7.76~7.74 (m, 2H), 7.70~7.67 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.59~7.54 (m, 1H), 7.39~7.34 (m, 1H), 7.21~7.16 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 189.5, 141.2, 135.6, 134.1, 133.4, 131.3, 129.0, 128.4, 127.3 (q, J=38.4 Hz), 126.1, 125.6, 122.9, 121.5, 121.3 (q, J=268.3 Hz), 115.4 (q, J=2.1 Hz), 113.8; 19F NMR (376 MHz, DMSO-d6) δ: －56.8; HRMS (ESI) calcd for C16H10ClF3NO [M＋H]＋ 324.0398, found 324.0399.
4-(2-三氟甲基-1H-吲哚-3-甲酰基)苯甲腈(6): 19.8 mg, 黄色粘稠液体, 产率63%. 1H NMR (400 MHz, DMSO-d6) δ: 13.32 (s, 1H), 8.04~8.01 (m, 2H), 7.89 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.40~7.35 (m, 1H), 7.19~7.13 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 189.8, 142.9, 135.5, 133.3, 130.1, 127.7 (q, J=38.3 Hz), 126.0, 125.6, 123.1, 121.5, 121.2 (q, J=268.4 Hz), 118.7, 115.6, 115.1 (q, J=2.1 Hz), 113.8; 19F NMR (376 MHz, DMSO-d6) δ: －56.9; HRMS (ESI) calcd for C17H10F3N2O [M＋H]＋ 315.0740, found 315.0741.
(2-三氟甲基-1H-吲哚-3-基)(4-三氟甲基苯基)甲酮(7): 25.0 mg, 黄色粘稠液体, 产率70%. 1H NMR (400 MHz, DMSO-d6) δ: 13.29 (s, 1H), 7.96~7.90 (m, 4H), 7.63 (d, J=8.0 Hz, 1H), 7.40~7.35 (m, 1H), 7.17 (d, J=3.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 190.0, 142.7, 135.6, 133.0 (q, J=31.8 Hz), 130.3, 127.5 (q, J=38.3 Hz), 126.3 (d, J=3.6 Hz), 126.0, 125.6, 124.3 (q, J=271.0 Hz), 123.1, 121.5, 121.3 (q, J=268.3 Hz), 115.4 (q, J=2.1 Hz), 113.8; 19F NMR (376 MHz, DMSO-d6) δ: －56.9, －61.5; HRMS (ESI) calcd for C17H10F6NO [M＋ H]＋ 358.0661, found 358.0668.
对甲苯基(2-三氟甲基-1H-吲哚-3-基)甲酮(8): 28.1 mg, 灰色粘稠液体, 产率93%. 1H NMR (400 MHz, DMSO-d6) δ: 13.09 (s, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.37~7.31 (m, 3H), 7.20~7.13 (m, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 190.7, 144.5, 144.4, 136.5, 135.6, 130.0, 129.8, 126.3 (q, J=37.9 Hz), 126.1, 125.5, 122.6, 121.5, 121.5 (q, J=268.1 Hz), 116.5 (q, J=2.3 Hz), 113.6, 21.8; 19F NMR (376 MHz, DMSO-d6) δ: －56.8; HRMS (ESI) calcd for C17H13F3NO [M＋H]＋ 304.0944, found 304.0944.
(4-甲氧基苯基)(2-三氟甲基-1H-吲哚-3-基)甲酮(9): 26.2 mg, 黄色固体, 产率82%. m.p. 128~131℃; 1H NMR (400 MHz, CDCl3) δ: 9.55~9.37 (m, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.36~7.31 (m, 1H), 7.19~7.14 (m, 1H), 6.97~6.93 (m, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 190.1, 163.8, 134.5, 132.3, 131.4, 126.3, 126.3 (q, J=38.9 Hz), 125.3, 122.2, 121.9, 120.7 (q, J=268.2 Hz), 117.3 (q, J=2.7 Hz), 113.7, 112.1, 112.1, 55.5; 19F NMR (376 MHz, CDCl3) δ: －58.3; HRMS (ESI) calcd for C17H13F3NO2 [M＋H]＋ 320.0893, found 320.0899.
(4-叔丁基苯基)(2-三氟甲基-1H-吲哚-3-基)甲酮(10): 29.5 mg, 黄色粘稠液体, 产率86%. 1H NMR (400 MHz, DMSO-d6) δ: 13.07 (s, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.37~7.32 (m, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.16~7.09 (m, 1H), 1.29 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ: 190.6, 157.1, 136.3, 135.6, 129.8, 126.1 (q, J=38.0 Hz), 126.0, 125.4, 122.5, 121.4, 121.5 (q, J=268.0 Hz), 116.5 (q, J=2.3 Hz), 113.6, 35.4, 31.3; 19F NMR (376 MHz, DMSO-d6) δ: －56.8; HRMS (ESI) calcd for C20H19F3NO [M＋H]＋ 346.1413, found 346.1410.
萘-1-基(2-三氟甲基-1H-吲哚-3-基)甲酮(11): 27.8 mg, 黄色粘稠液体, 产率82%. 1H NMR (400 MHz, CDCl3) δ: 9.80 (s, 1H), 8.45~8.41 (m, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.97~7.92 (m, 1H), 7.72~7.69 (m, 1H), 7.58~7.45 (m, 3H), 7.42 (d, J=8.4 Hz, 1H), 7.30~7.25 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.07~7.02 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 192.5, 137.4, 134.3, 133.7, 132.3, 130.4, 128.9, 128.4, 128.3 (q, J=38.8 Hz), 127.7, 126.5, 126.4, 125.4, 125.3, 124.0, 122.8, 121.9, 120.5 (q, J=268.6 Hz), 118.1 (q, J=2.0 Hz), 112.3; 19F NMR (376 MHz, CDCl3) δ: －58.7; HRMS (ESI) calcd for C20H13F3- NO [M＋H]＋ 340.0944, found 340.0945.
噻吩-3-基(2-三氟甲基-1H-吲哚-3-基)甲酮(12): 25.3 mg, 白色固体, 产率86%. m.p. 142~146 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 13.04 (s, 1H), 8.16~8.14 (m, 1H), 7.70~7.67 (m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.51~7.49 (m, 1H), 7.39~7.34 (m, 2H), 7.20~7.16 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 184.5, 143.3, 136.1, 135.6, 128.3, 127.7, 125.9, 125.7 (q, J=38.0 Hz), 125.5, 122.5, 121.5 (q, J=268.1 Hz), 121.4, 117.2 (q, J=2.3 Hz), 113.5; 19F NMR (376 MHz, DMSO-d6) δ: －56.6; HRMS (ESI) calcd for C14H9F3NOS [M＋H]＋ 296.0351, found 296.0355.
3-吡啶基(2-三氟甲基-1H-吲哚-3-基)甲酮(13): 13.8 mg, 黄色粘稠液体, 产率48%. 1H NMR (400 MHz, DMSO-d6) δ: 13.29 (s, 1H), 8.88 (d, J=1.6 Hz, 1H), 8.86~8.83 (m, 1H), 8.12 (dt, J=7.6, 2.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.62~7.58 (m, 1H), 7.41~7.36 (m, 1H), 7.23~7.16 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 189.5, 153.9, 150.3, 137.0, 135.6, 135.0, 127.4 (q, J=38.0 Hz), 126.1, 125.6, 124.4, 123.1, 121.5, 121.2 (q, J=268.4 Hz), 115.4 (q, J=2.2 Hz), 113.8; 19F NMR (376 MHz, DMSO-d6) δ: －56.7; HRMS (ESI) calcd for C15H10F3N2O [M＋H]＋ 291.0740, found 291.0740.
[1'-联苯]-4-基(2-三氟甲基-1H-吲哚-3-基)甲酮(14): 34.2 mg, 黄色液体, 产率94%. 1H NMR (400 MHz, CDCl3) δ: 9.62 (s, 1H), 8.01~7.98 (m, 2H), 7.73~7.66 (m, 4H), 7.54~7.44 (m, 4H), 7.43~7.39 (m, 1H), 7.39~7.34 (m, 1H), 7.22~7.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 191.0, 145.9, 139.8, 137.3, 134.5, 130.4, 128.9, 128.2, 127.3, 127.1, 127.0 (q, J=38.7 Hz), 126.3, 125.4, 122.4, 121.9, 120.6 (q, J=268.4 Hz), 117.1 (q, J=1.7 Hz), 112.2; 19F NMR (376 MHz, CDCl3) δ: －58.2; HRMS (ESI) calcd for C22H15F3NO [M＋H]＋ 366.1100, found 366.1106.
(4'-甲氧基-[1'-联苯]-4-基)(2-三氟甲基-1H-吲哚- 3-基)甲酮(15): 29.4 mg, 黄色粘稠液体, 产率75%. 1H NMR (400 MHz, DMSO-d6) δ: 13.12 (s, 1H), 7.84~7.76 (m, 4H), 7.74~7.70 (m, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.39~7.34 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.18~7.13 (m, 1H), 7.07~7.03 (m, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 190.4, 160.2, 144.9, 137.0, 135.6, 131.5, 130.6, 128.8, 126.7, 126.3 (q, J=38.2 Hz), 126.1, 125.4, 122.6, 121.5 (q, J=268.2 Hz), 121.5, 116.4 (q, J=1.8 Hz), 115.0, 113.6, 55.7; 19F NMR (376 MHz, DMSO- d6) δ: －56.8; HRMS (ESI) calcd for C23H17F3NO2 [M＋H]＋ 396.1206, found 396.1207.
(2',4'-二甲基-[1'-联苯]-4-基)(2-三氟甲基-1H-吲 哚-3-基)甲酮(16): 26.2 mg, 黄色液体, 产率67%. 1H NMR (400 MHz, DMSO-d6) δ: 13.14 (s, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.50~7.46 (m, 2H), 7.39~7.34 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.19~7.07 (m, 4H), 2.30 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 190.6, 146.7, 137.8, 137.7, 137.3, 135.6, 135.0, 131.7, 129.9, 129.7, 127.2, 126.5 (q, J=38.0 Hz), 126.1, 125.5, 122.6, 121.5, 121.4 (q, J=268.2 Hz), 116.3 (q, J=2.2 Hz), 113.6, 21.1, 20.6; 19F NMR (376 MHz, DMSO-d6) δ: －56.8; HRMS (ESI) calcd for C24H19F3NO [M＋H]＋ 394.1413, found 394.1418.
(4'-乙烯基-[1'-联苯]-4-基)(2-三氟甲基-1H-吲 哚-3-基)甲酮(17): 27.6 mg, 黄色粘稠液体, 产率71%. 1H NMR (400 MHz, DMSO-d6) δ: 13.13 (s, 1H), 7.89~7.82 (m, 4H), 7.76 (d, J=8.4 Hz, 2H), 7.64~7.58 (m, 3H), 7.37 (t, J=7.6 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.18~7.13 (m, 1H), 6.83~6.75 (m, 1H), 5.92 (d, J=17.6 Hz, 1H), 5.32 (d, J=11.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 190.4, 144.6, 138.5, 137.8, 137.7, 136.5, 135.6, 130.5, 127.7, 127.4, 127.1, 126.4 (q, J=38.0 Hz), 126.0, 125.5, 122.6, 121.5, 121.4 (q, J=268.5 Hz), 116.3 (q, J=2.2 Hz), 115.6, 113.6; 19F NMR (376 MHz, DMSO- d6) δ: －56.8; HRMS (ESI) calcd for C24H17F3NO [M＋ H]＋ 392.1257, found 392.1257.
1-[4'-(2-三氟甲基-1H-吲哚-3-甲酰基)-[1'-联苯]-4-基]乙酮(18): 31.2 mg, 黄色粘稠液体, 产率77%. 1H NMR (400 MHz, DMSO-d6) δ: 13.17 (s, 1H), 8.09~8.04 (m, 2H), 7.95~7.86 (m, 6H), 7.63 (d, J=8.4 Hz, 1H), 7.40~7.34 (m, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.19~7.13 (m, 1H), 2.63~2.61 (m, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 198.0, 190.4, 143.8, 143.6, 138.6, 136.8, 135.6, 130.5, 129.5, 127.8, 126.6 (q, J=38.1 Hz), 126.1, 125.5, 122.7, 121.5, 121.4 (q, J=268.0 Hz), 116.1 (q, J=2.2 Hz), 113.7, 27.3; 19F NMR (376 MHz, DMSO-d6) δ: －56.8; HRMS (ESI) calcd for C24H17F3NO2 [M＋H]＋ 408.1206, found 408.1202.
(4-(萘-1-基)苯基)(2-三氟甲基-1H-吲哚-3-基)甲酮(19): 34.0 mg, 黄色粘稠液体, 产率82%. 1H NMR (400 MHz, DMSO-d6) δ: 13.16 (s, 1H), 8.04~7.99 (m, 2H), 7.92 (d, J=8.0 Hz, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.67~7.50 (m, 7H), 7.41~7.32 (m, 2H), 7.23~7.18 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 190.6, 145.4, 138.8, 138.0, 135.6, 133.9, 131.0, 130.7, 130.0, 129.0, 128.9, 127.6, 127.3, 126.6, 126.5 (q, J=38.1 Hz), 125.5, 125.5, 122.7, 121.5, 121.5 (q, J=268.0 Hz), 116.3 (q, J=2.3 Hz), 113.7; 19F NMR (376 MHz, DMSO-d6) δ: －56.7; HRMS (ESI) calcd for C26H17F3NO [M＋H]＋ 416.1257, found 416.1257.
(4-(噻吩-3-基)苯基)(2-三氟甲基-1H-吲哚-3-基)甲酮(20): 26.5 mg, 黄色粘稠液体, 产率72%. 1H NMR (400 MHz, CDCl3) δ: 9.61 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.62~7.60 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.48~7.42 (m, 3H), 7.36 (t, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 190.8, 190.7, 141.0, 140.3, 137.1, 134.4, 130.6, 126.9 (q, J=38.0 Hz), 126.8, 126.3, 126.2, 126.1, 125.4, 122.4, 122.2, 121.9, 120.6 (q, J=268.6 Hz), 117.0 (q, J=2.1 Hz), 112.2; 19F NMR (376 MHz, CDCl3) δ: －58.2; HRMS (ESI) calcd for C20H13F3NOS [M＋H]＋ 372.0664, found 372.0656.
3-苯基-1-(2-三氟甲基-1H-吲哚-3-基)丙-1-酮(21): 20.9 mg, 黄色液体, 产率66%. 1H NMR (400 MHz, CDCl3) δ: 9.33 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.42~7.27 (m, 6H), 7.24~7.19 (m, 1H), 3.42~3.37 (m, 2H), 3.17~3.12 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 195.4, 141.1, 134.0, 128.5, 128.4, 127.4 (q, J=38.4 Hz), 126.1, 125.7, 125.4, 123.5, 122.5, 120.7 (q, J=268.4 Hz), 177.1, 122.3 (q, J=2.3 Hz), 44.5, 30.0; 19F NMR (376 MHz, CDCl3) δ: －63.5; HRMS (ESI) calcd for C18H15F3NO [M＋H]＋ 318.1100, found 318.1106.
2-(2-氧代-2-(2-三氟甲基-1H-吲哚-3-基)乙基)异吲哚啉-1,3-二酮(22): 25.2 mg, 黄色粘稠液体, 产率68%. 1H NMR (400 MHz, DMSO-d6) δ: 13.44 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.99~7.89 (m, 4H), 7.67 (d, J=8.0 Hz, 1H), 7.48~7.38 (m, 2H), 5.14 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 187.2, 168.0, 135.3, 128.7 (q, J=38.6 Hz), 125.7, 125.2, 124.2, 123.9, 122.3, 121.2 (q, J=268.6 Hz), 114.2, 113.3 (q, J=1.9 Hz), 47.4; 19F NMR (376 MHz, DMSO-d6) δ: －58.4; HRMS (ESI) calcd for C19H12F3N2O3 [M＋H]＋ 373.0795, found 373.0798.
2-三氟甲基-1H-吲哚-3-甲醛(23): 10.4 mg, 白色固体, 产率49%. m.p. 246~249 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 13.44 (s, 1H), 10.23 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.46~7.41 (m, 1H), 7.39~7.34 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 184.8, 135.9, 131.5 (q, J=39.0 Hz), 126.4, 124.9, 124.4, 122.5, 121.3 (q, J=269.1 Hz), 116.0 (q, J=1.6 Hz), 113.8; 19F NMR (376 MHz, DMSO-d6) δ: －55.5; HRMS (ESI) calcd for C10H7F3NO [M＋H]＋ 214.0474, found 214.0476.
(5-氟-2-三氟甲基-1H-吲哚-3-基)(苯基)甲酮(24): 22.0 mg, 黄色液体, 产率72%. 1H NMR (400 MHz, DMSO-d6) δ: 13.30 (s, 1H), 7.76~7.73 (m, 2H), 7.72~7.67 (m, 1H), 7.65~7.61 (m, 1H), 7.58~7.53 (m, 2H), 7.28~7.22 (m, 1H), 6.83 (dd, J=10.0, 2.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 190.5, 158.6 (d, J=235.1 Hz), 139.1, 133.8, 132.3, 129.5, 129.2, 128.3 (q, J=38.3 Hz), 126.5 (d, J=10.9 Hz), 121.1 (q, J=269.0 Hz), 116.1 (q, J=2.6 Hz), 115.4 (d, J=9.8 Hz), 114.5 (d, J=26.5 Hz), 106.1 (d, J=24.7 Hz); 19F NMR (376 MHz, DMSO- d6) δ: －57.1, －119.9~－120.1; HRMS (ESI) calcd for C16H10F4NO [M＋H]＋ 308.0693, found 308.0695.
(2,5-双(三氟甲基)-1H-吲哚-3-基)(苯基)甲酮(25): 18.8 mg, 黄色液体, 产率53%. 1H NMR (400 MHz, CD3OD) δ: 7.81~7.78 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.70~7.65 (m, 1H), 7.61~7.57 (m, 2H), 7.54~7.50 (m, 2H); 13C NMR (100 MHz, CD3OD) δ: 192.4, 140.2, 138.1, 134.6, 130.5, 130.2 (q, J=38.9 Hz), 129.7, 127.4, 126.8, 126.1 (q, J=271.3 Hz), 125.5 (q, J=31.8 Hz), 122.5 (q, J=3.2 Hz), 122.0 (q, J=267.9 Hz), 120.2 (q, J=4.4 Hz), 118.0 (q, J=2.2 Hz), 114.8; 19F NMR (376 MHz, CD3OD) δ: －59.8, －62.7; HRMS (ESI) calcd for C17H10F6NO [M＋H]＋ 358.0661, found 358.0661.
(5-甲基-2-三氟甲基-1H-吲哚-3-基)(苯基)甲酮(26): 20.2 mg, 淡黄色固体, 产率67%. m.p. 158~162 ℃; 1H NMR (400 MHz, CD3OD) δ: 7.80~7.77 (m, 2H), 7.66~7.61 (m, 1H), 7.49 (t, J=8.0 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.19~7.14 (m, 1H), 6.99 (s, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, CD3OD) δ: 193.5, 140.6, 135.0, 134.3, 132.9, 130.6, 129.6, 128.4 (q, J=38.4 Hz), 127.9, 127.8, 122.4 (q, J=267.4 Hz), 121.6, 116.7 (q, J=2.1 Hz), 113.4, 21.6; 19F NMR (376 MHz, CD3OD) δ: －59.5; HRMS (ESI) calcd for C17H13F3NO [M＋H]＋ 304.0944, found 304.0949.
(5-甲氧基-2-三氟甲基-1H-吲哚-3-基)(苯基)甲酮(27): 19.5 mg, 黄色粘稠液体, 产率61%. 1H NMR (400 MHz, DMSO-d6) δ: 13.03 (s, 1H), 7.77~7.74 (m, 2H), 7.68 (t, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 7.50 (d, J=9.2 Hz, 1H), 7.01 (dd, J=9.2, 2.4 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 3.56 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 191.0, 155.6, 139.4, 133.5, 130.6, 129.5, 129.1, 126.8 (q, J=38.2 Hz), 126.8, 121.3 (q, J=267.9 Hz), 116.4, 115.7 (q, J=2.1 Hz), 114.6, 102.2, 55.5; 19F NMR (376 MHz, DMSO-d6) δ: －56.7; HRMS (ESI) calcd for C17H13F3NO2 [M＋H]＋ 320.0893, found 320.0891.
(5,6-二甲基-2-三氟甲基-1H-吲哚-3-基)(苯基)甲酮(28): 26.0 mg, 红棕色液体, 产率82%. 1H NMR (400 MHz, DMSO-d6) δ: 12.85 (s, 1H), 7.74 (d, J=7.2 Hz, 2H), 7.71~7.65 (m, 1H), 7.55~7.51 (m, 2H), 7.36 (s, 1H), 6.93 (s, 1H), 2.31 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 191.1, 139.2, 134.8, 134.6, 133.7, 131.4, 129.6, 129.1, 125.5 (q, J=38.0 Hz), 124.6, 121.5 (q, J=267.9 Hz), 121.0, 115.7 (q, J=2.1 Hz), 113.3, 20.6, 20.4; 19F NMR (376 MHz, DMSO-d6) δ: －51.7; HRMS (ESI) calcd for C18H15F3NO [M＋H]＋ 318.1100, found 318.1101.
(6-甲基-2-三氟甲基-1H-吲哚-3-基)(苯基)甲酮(29): 25.2 mg, 黄色粘稠液体, 产率83%. 1H NMR (400 MHz, DMSO-d6) δ: 12.95 (s, 1H), 7.74 (d, J=7.2 Hz, 2H), 7.67 (t, J=7.2 Hz, 1H), 7.53 (t, J=7.6 Hz, 2H), 7.38 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 191.0, 139.2, 136.0, 135.1, 133.7, 129.6, 129.2, 126.0 (q, J=38.0 Hz), 124.6, 124.1, 121.5 (q, J=268.0 Hz), 121.1, 116.1 (q, J=2.4 Hz), 112.9, 21.8; 19F NMR (376 MHz, DMSO-d6) δ: －56.7; HRMS (ESI) calcd for C17H13F3NO [M＋H]＋ 304.0944, found 304.0944.
(6-氯-2-三氟甲基-1H-吲哚-3-基)(苯基)甲酮(30): 22.0 mg, 淡黄色固体, 产率68%. m.p.154~158 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 13.30 (s, 1H), 7.75 (d, J=7.6 Hz, 2H), 7.72~7.67 (m, 1H), 7.63 (s, 1H), 7.56~7.52 (m, 2H), 7.20~7.15 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 190.6, 138.9, 135.9, 134.0, 130.1, 129.7, 129.3, 127.4 (q, J=38.2 Hz), 124.8, 123.2, 123.1, 121.1 (q, J=268.3 Hz), 116.3 (q, J=2.2 Hz), 113.1; 19F NMR (376 MHz, DMSO-d6) δ: －57.0; HRMS (ESI) calcd for C16H10ClF3NO [M＋H]＋ 324.0398, found 324.0397.
3-苯甲酰基-2-三氟甲基-1H-吲哚-6-甲酸甲酯(31): 19.5 mg, 黄色粘稠液体, 产率56%. 1H NMR (400 MHz, DMSO-d6) δ: 13.51 (s, 1H), 8.20 (s, 1H), 7.76 (d, J=7.6 Hz, 2H), 7.73~7.67 (m, 2H), 7.57~7.51 (m, 2H), 7.29~7.22 (m, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 190.5, 166.8, 138.8, 134.9, 134.0, 129.7, 129.3, 129.4 (q, J=38.2 Hz), 126.5, 122.7, 121.7, 121.0 (q, J=268.8 Hz), 116.3 (q, J=2.1 Hz), 115.5, 52.8; 19F NMR (376 MHz, DMSO-d6) δ: －57.3; HRMS (ESI) calcd for C18H13F3NO3 [M＋H]＋ 348.0842, found 348.0843.
(7R,11R,E)-3,7,11,15-四甲基十六碳-2-烯-1-基-4-(2-三氟甲基-1H-吲哚-3-甲酰基)苯甲酸酯(32): 22.4 mg, 黄色液体, 产率37%. 1H NMR (400 MHz, CDCl3) δ: 9.57 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.37~7.32 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 5.49 (t, J=7.2 Hz, 1H), 4.90 (d, J=7.2 Hz, 2H), 2.13~1.99 (m, 2H), 1.79 (s, 3H), 1.55~1.21 (m, 13H), 1.16~1.00 (m, 6H), 0.87~0.82 (m, 12H); 13C NMR (100 MHz, CDCl3) δ: 190.6, 166.0, 143.5, 142.3, 134.4, 134.2, 129.7, 129.4 127.5 (q, J=38.7 Hz), 126.1, 125.6, 122.8, 121.9, 120.4 (q, J=268.4 Hz), 117.7, 116.5 (q, J=7.6 Hz), 112.2, 62.5, 39.9, 39.3, 37.4, 37.3, 37.2, 36.6, 32.8, 32.6, 27.9, 25.0, 24.8, 24.4, 22.7, 22.6, 19.7, 16.5; 19F NMR (376 MHz, CDCl3) δ: －58.3; HRMS (ESI) calcd for C37H49F3NO3 [M＋H]＋ 612.3659, found 612.3663.
(1R,2R,4R)-1,7,7-三甲基二环[2.2.1]庚烷-2-基-4-(2-三氟甲基-1H-吲哚-3-甲酰基)苯甲酸酯(33): 39.3 mg, 棕色液体, 产率84%. 1H NMR (400 MHz, DMSO-d6) δ: 13.25 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.39~7.34 (m, 1H), 7.18~7.10 (m, 2H), 5.05 (d, J=9.2 Hz, 1H), 2.43~2.33 (m, 1H), 2.09~2.00 (m, 1H), 1.75~1.65 (m, 2H), 1.40~1.25 (m, 2H), 1.12~1.07 (m, 1H), 0.90 (s, 3H), 0.86 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ: 190.3, 165.7, 143.0, 135.5, 134.1, 129.9, 129.8, 127.3 (q, J=38.2 Hz), 126.0, 125.5, 122.9, 121.5, 121.3 (q, J=268.3 Hz), 115.6 (q, J=2.1 Hz), 113.7, 80.9, 49.2, 48.0, 44.8, 36.8, 28.1, 27.4, 20.0, 19.1, 14.0; 19F NMR (376 MHz, DMSO-d6) δ: －56.9; HRMS (ESI) calcd for C27H27F3NO3 [M＋H]＋ 470.1938, found 470.1937.
(1S,2S,5R)-2-异丙基-5-甲基环己基-4-(2-三氟甲基- 1H-吲哚-3-甲酰基)苯甲酸酯(34): 41.0 mg, 黄色液体, 产率87%. 1H NMR (400 MHz, DMSO-d6) δ: 13.26 (s, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.38~7.33 (m, 1H), 7.21~7.10 (m, 2H), 4.96~4.78 (m, 1H), 2.06~1.93 (m, 1H), 1.89~1.84 (m, 1H), 1.65~1.48 (m, 4H), 1.14~1.03 (m, 2H), 0.86~0.83 (m, 7H), 0.74~0.71 (m, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 190.3, 165.1, 143.0, 135.6, 134.0, 129.9, 129.8, 127.3 (q, J=38.0 Hz), 126.0, 125.5, 122.9, 121.5, 121.3 (q, J=268.3 Hz), 115.6 (q, J=2.0 Hz), 113.7, 75.2, 47.0, 34.2, 31.4, 26.6, 23.6, 22.3, 21.0, 16.9; 19F NMR (376 MHz, DMSO-d6) δ: －56.9; HRMS (ESI) calcd for C27H29F3NO3 [M＋H]＋472.2094, found 472.2098.
仲丁基2-(2-((4-(2-三氟甲基-1H-吲哚-3-甲酰基)苯甲酰)氧基)乙基)哌啶-1-甲酸酯(35): 39.0 mg, 黄色液体, 产率72%. 1H NMR (400 MHz, CDCl3) δ: 10.50 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.87 (d, J=5.6 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.34~7.28 (m, 2H), 7.12 (t, J=7.2 Hz, 1H), 4.82~4.70 (m, 1H), 4.58 (s, 1H), 4.40~4.35 (m, 2H), 4.16~4.10 (m, 1H), 2.89 (t, J=12.8 Hz, 1H), 2.33~2.21 (s, 1H), 1.98~1.88 (m, 1H), 1.73~1.42 (m, 8H), 1.19~1.15 (m, 3H), 0.88~0.83 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 190.6, 165.9, 155.7, 142.5, 134.7, 133.7, 129.5, 129.4 127.7 (q, J=38.5 Hz), 126.1, 125.3, 122.6, 121.7, 120.5 (q, J=268.5 Hz), 116.1 (q, J=1.5 Hz), 112.4, 73.3, 63.0, 63.0, 48.0, 39.0, 29.0, 28.8, 28.6, 25.4, 19.7, 19.0, 9.7, 9.6; 19F NMR (376 MHz, CDCl3) δ: －58.2; HRMS (ESI) calcd for C29H32F3N2O5 [M＋H]＋ 545.2258, found 545.2264.
(S)-2-(6-甲氧基萘-2-基)丙基 4-(2-三氟甲基-1H-吲哚-3-甲酰基)苯甲酸酯(36): 42.4 mg, 黄色液体, 产率80%. 1H NMR (400 MHz, CDCl3) δ: 9.75 (s, 1H), 8.09 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 7.75~7.67 (m, 3H), 7.50 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.37~7.30 (m, 2H), 7.19~7.13 (m, 3H), 7.60~7.49 (m, 2H), 3.92 (s, 3H), 3.47~3.36 (m, 1H), 1.35 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 190.6, 165.9, 157.4, 142.4, 138.0, 134.4, 133.9, 133.5, 129.6, 129.5, 129.1, 129.0, 127.2 (q, J=39.5 Hz), 127.0, 126.2, 126.1, 125.6, 125.5, 122.7, 121.8, 121.8 (q, J=270.5 Hz), 118.9, 112.3 (q, J=1.9 Hz), 105.6, 70.4, 55.3, 38.9, 18.1; 19F NMR (376 MHz, DMSO-d6) δ: －58.3; HRMS (ESI) calcd for C31H25F3NO4 [M＋H]＋ 532.1730, found 532.1738.
5-(2,5-二甲基苯氧基)-2,2-二甲基戊基-4-(2-三氟甲基-1H-吲哚-3-甲酰基)苯甲酸酯(37): 42.0 mg, 黄色液体, 产率76%. 1H NMR (400 MHz, DMSO-d6) δ: 13.26 (s, 1H), 8.13~8.08 (m, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.39~7.34 (m, 1H), 7.17~7.11 (m, 2H), 6.89 (d, J=7.2 Hz, 1H), 6.67 (s, 1H), 6.56 (d, J=7.6 Hz, 1H), 4.08 (s, 2H), 3.92~3.84 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.79~1.66 (m, 2H), 1.53~1.48 (m, 2H), 1.00 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ: 190.4, 165.6, 157.0, 143.0, 136.5, 135.5, 133.8, 130.4, 129.9, 129.8, 127.3 (q, J=38.3 Hz), 126.0, 125.5, 122.9, 122.9, 121.5, 121.3 (q, J=268.4 Hz), 120.9, 115.6 (q, J=2.2 Hz), 113.7, 112.4, 72.9, 68.2, 35.3, 34.1, 24.6, 24.1, 21.5, 16.0; 19F NMR (376 MHz, DMSO-d6) δ: －56.9; HRMS (ESI) calcd for C32H33F3NO4 [M＋H]＋ 552.2356, found 552.2361.
辅助材料(Supporting Information) 产物2~37的1H NMR、13C NMR和19F NMR谱图. 这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.
(Cheng, F.)