吲哚及其衍生物作为自然界中分布最为广泛的杂环化合物体系之一, 在天然产物化学、药物研发、生物活性分子设计以及多功能材料开发等领域均具有不可替代的重要地位[1-3]. 其中, 吲哚啉作为一类重要的含氮杂环骨架, 不仅是众多高价值复杂分子的核心结构单元, 更因其在抗菌、抗肿瘤、抗炎和抗病毒等方面展现出显著的生物活性, 成为药物化学家重点关注的靶标结构(图1)[1-3]. 因此, 系统开展吲哚啉类化合物的结构多样性构建研究, 对于加速创新药物研发进程和拓展药物作用靶点具有重要的战略意义.
在吲哚啉类化合物的合成方法学领域, 其构建策略已获得显著发展. 其中, 吲哚衍生物的选择性去芳构化作为现代有机合成的重要突破, 可通过精准调控芳杂环的电子与空间结构, 高效构建具有三维立体特征的吲哚啉类化合物, 从而为复杂分子骨架的修饰与功能化提供新途径[4-11]. 目前, 已发展出多种吲哚去芳构化催化体系, 包括有机小分子催化[4]、过渡金属催化[5-9]、光催化[10]及电催化[11]等. 然而, 这些体系在应用中也各自呈现出一些特点: 有机小分子催化条件温和, 但其底物范围通常需特定设计; 金属催化能够实现高效转化, 但一般需在较为剧烈的反应条件下进行, 且可能伴随副反应发生; 电催化具有环境友好特征, 但对反应装置有特定要求, 其规模化应用仍需进一步探索. 相比之下, 光氧化还原催化体系因条件温和、适用范围宽及官能团耐受性好等优点, 近年来受到了化学家们的广泛关注, 为吲哚啉类化合物的绿色合成提供了富有潜力的新方向.
2021年, Jui团队[12]报道了一种光氧化还原催化的吲哚氢芳基化新策略(Scheme 1, a). 该体系仅需有机光催化剂、胺类还原剂与可见光照射, 即可在温和条件下实现吲哚底物的高选择性去芳构化. 值得指出的是, 该反应主要适用于卤代吡啶衍生物, 且底物范围目前仅限于2-位未取代的吲哚底物.
同年, 支志明课题组[13]在光诱导环化领域取得重要进展(Scheme 1, a). 他们以三级胺作为还原剂, 在无外源光敏剂的条件下, 成功实现了N-苯甲酰基吲哚的光诱导去芳构化反应. 该反应条件简洁、转化高效, 但其光激发依赖于紫外波段照射(<410 nm), 且所考察的底物范围集中于2-位未取代的吲哚.
随后, 通过苯硫酚盐与邻卤代芳甲酰基化合物形成电子给体-受体(EDA)复合物的策略, 宋钦华课题组[14]发展了一种可见光促进的N-(邻卤代芳甲酰基)吲哚还原去芳构化反应, 高效构建吲哚啉类衍生物(Scheme 1, a). 尽管如此, 为克服上述反应的局限并进一步丰富吲哚啉衍生物的合成方法, 发展可见光促进的吲哚自由基去芳构化新策略仍具有重要意义.
受上述研究的启发, 结合本课题组在可见光氧化还原催化[15]与杂环合成[16]方面的研究基础, 我们发展了一种可见光氧化还原催化的吲哚还原去芳构化反应. 该反应适用于2-位取代或未取代的吲哚底物, 在温和条件下以中等至良好收率及优秀的选择性, 合成了一系列含2-位季碳或叔碳中心的吲哚啉衍生物(Scheme 1, b).
1 结果与讨论
首先, 选用N-(2-溴苯甲酰基)吲哚-2-甲酸甲酯(1a)作为模板底物对该还原去芳构化反应进行了初步探索. 基于前期光催化还原反应的经验[15c], 当以Ir(ppy)2- (dtbbpy)PF6 (I, 2 mol%)为光催化剂、N,N-二异丙基乙胺(DIPEA, 1.5 equiv.)为还原剂、碳酸铯(Cs2CO3, 1.5 equiv.)为碱、三氟甲基苯(PhCF3)为溶剂, 50 ℃下用蓝光LED照射12 h, 可以顺利地以25%的收率得到去芳构化产物2a(表1, Entry 1). 为探寻更优的反应条件, 随后对溶剂、光催化剂、碱和温度等进行筛选. 首先, 对溶剂进行了筛选(表1, Entries 2~6). 1,2-二氯乙烷(DCE)、乙腈(MeCN)、四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)和N,N-二甲基乙酰胺(DMAc)均能获得目标产物, 其中乙腈作为溶剂时反应的产率最高(50%, 表1, Entry 3). 接着, 考察了光催化剂对该反应的影响(表1, Entries 7~10), 发现有机光催化剂4CzIPN (III)的催化效果最好, 可以将收率提高至87%. 随后, 对碱进行了优化(表1, Entries 11~18), 意外发现, 在不添加碱的条件下, 反应几乎定量进行, 以99%的收率获得目标产物. 最后, 探究了温度对反应的影响(表1, Entry 19), 室温条件下进行反应, 仅能取得79%的产率. 综上, 确定的最优反应条件为: III (2 mol%)为光催化剂, DIPEA (1.5 equiv.)为还原剂, 乙腈为溶剂, 50 ℃条件下蓝光LED照射12 h.
表1 2-位取代吲哚去芳构化反应的条件筛选aTable 1 Condition screening for dearomatization of 2-substi- tuted indoles |
| Entry | PC | Solvent | T/℃ | Base | Yield/% |
|---|---|---|---|---|---|
| 1 | I | PhCF3 | 50 | Cs2CO3 | 25 |
| 2 | I | DCE | 50 | Cs2CO3 | 47 |
| 3 | I | MeCN | 50 | Cs2CO3 | 50 |
| 4 | I | THF | 50 | Cs2CO3 | 20 |
| 5 | I | DMF | 50 | Cs2CO3 | 24 |
| 6 | I | DMAc | 50 | Cs2CO3 | 15 |
| 7 | II | MeCN | 50 | Cs2CO3 | 73 |
| 8 | III | MeCN | 50 | Cs2CO3 | 87 |
| 9 | IV | MeCN | 50 | Cs2CO3 | 15 |
| 10 | V | MeCN | 50 | Cs2CO3 | 32 |
| 11 | III | MeCN | 50 | K2CO3 | 93 |
| 12 | III | MeCN | 50 | KHCO3 | 82 |
| 13 | III | MeCN | 50 | K2HPO4 | 79 |
| 14 | III | MeCN | 50 | KH2PO4 | 91 |
| 15 | III | MeCN | 50 | Cs2CO3 | 88 |
| 16 | III | MeCN | 50 | CsF | 80 |
| 17 | III | MeCN | 50 | K3PO4 | 85 |
| 18 | III | MeCN | 50 | — | 99 |
| 19 | III | MeCN | r.t. | — | 76 |
a Reaction conditions: 1a (0.1 mmol), PC (0.002 mmol), DIPEA (0.15 mmol), MeCN (2 mL), stirred at 50 ℃ for 12 h, GC-Mass yields. |
确定最佳反应条件之后, 接着对该反应的底物适用范围进行了探究(表2). 首先, 研究了N-(2-溴苯甲酰基)吲哚-2-甲酸酯1吲哚环上不同位置取代基对反应的影响. 结果表明, 吲哚环4, 5, 6, 7位无论是吸电子基团还是给电子基团, 反应都可以顺利发生, 以中等至优异的收率(43%~99%)得到目标产物2b~2o. 相比之下, 吲哚环上吸电子基团取代的底物比给电子基团取代的底物可以获得更高的产率(2e~2h vs 2j~2k). 随后, 考察了N-(2-溴苯甲酰基)吲哚-2-甲酸酯中2-溴苯甲酰基上引入不同取代基时的反应活性. 苯环上不同位置带有不同取代基, 例如卤素、烷氧基或烷基等, 反应都能以中等至较高的收率(54%~84%)得到相应的去芳构化的吲哚啉产物2p~2u. 除了酯基, 进一步考察了吲哚2位引入酰基、酰胺及芳基等取代基时的反应情况. 实验结果显示, 酰基、酰胺和芳基取代的吲哚底物均可顺利参与反应, 以中等至良好的产率(41%-68%)得到相应目标产物2v~2x. 然而, 2-氰基吲哚底物在该反应条件下未能获得目标产物2y.
表2 2-位取代吲哚底物拓展aTable 2 Substrate scope of 2-substituted indoles |
 |
a Reaction conditions: 1 (0.2 mmol), III (0.004 mmol), DIPEA (0.3 mmol), MeCN (4 mL), stirred at 50 ℃ for 12 h, isolated yields. |
表3 2-位非取代吲哚去芳构化反应的条件筛选aTable 3 Condition screening for dearomatization of 2-unsubstituted indole |
| Entry | PC | Yield/% |
|---|---|---|
| 1 | III | 40 |
| 2 | I | 95 |
| 3 | II | 2 |
| 4 | IV | 43 |
| 5 | V | 60 |
a Reaction conditions: 3a (0.1 mmol), PC (0.002 mmol), DIPEA (0.15 mmol), MeCN (2 mL), stirred at 50 ℃ for 12 h, GC-Mass yields. |
基于上述优化条件, 进行了2-位未取代的吲哚底物还原去芳构化反应的底物适用范围研究. 如表4所示, 以吲哚环和芳环上不同位置带有给电子基团或者吸电子基团的N-(2-溴苯甲酰基)吲哚3作为底物时, 都能较好地进行去芳构化反应, 以中等至优异的收率(52%~98%)得到一系列具有2-位叔碳中心的吲哚啉衍生物4a~4p.
表4 2-位非取代吲哚底物拓展aTable 4 Substrate scope of 2-unsubstituted indole |
 |
a Reaction conditions: 3 (0.2 mmol), I (0.004 mmol), DIPEA (0.3 mmol), MeCN (4 mL), stirred at 50 ℃ for 12 h, isolated yields. |
随后, 为了评估该反应的实用性, 进行了放大实验与合成转化实验(Scheme 2). 将模板反应放大到1 mmol规模时, 无论是N-(2-溴苯甲酰基)吲哚酯(1a)还是N-(2-溴苯甲酰基)吲哚(3a)都能保持较高的反应效率, 分别以良好的收率得到去芳构化产物2a和4a (Scheme 2, a).进一步对所得吲哚啉产物进行了衍生化实验(Scheme 2, b). 用NaBH4可以将2a高效地还原为相应的伯醇5. 在钯的催化下4k与4-甲氧基苯硼酸经Suzuki-Miyaura偶联反应, 以较高的收率获得芳基化产物6. 这些结果表明该反应具有一定的合成应用潜力.
接下来对反应机理进行了探究. 首先开展了一系列控制实验(Scheme 3, a). 模板反应在不加光催化剂、不加还原剂(DIPEA)或无可见光照射时, 均未能观察到还原去芳构化产物的生成, 表明光照、光催化剂以及还原剂(DIPEA)均为该反应的必要条件. 开/关灯实验进一步直观地证实了该反应依赖于可见光(图2, a). 光催化剂荧光淬灭实验显示淬灭激发态光催化剂的是还原剂DIPEA, 表明该反应为还原淬灭(图2, b). 此外, 向反应中加入自由基捕获剂四甲基哌啶氧化物(TEMPO), 反应完全被抑制. 通过高分辨质谱分析, 检测到了苄基自由基中间体被TEMPO捕获的产物7 (Scheme 3, b), 证实了自由基中间体的存在.
基于以上的实验事实并结合密度泛函理论(DFT)计算以及已有的文献报道[10,12-14], 提出了可能的反应机理(Scheme 4): 在蓝光照射下, 基态光催化剂PC吸收光子跃迁至激发态PC*, 随后与DIPEA发生还原淬灭, 生成还原态PC•－及胺自由基阳离子DIPEA•＋[15c,17]. 电位计算结果显示, 底物1a的还原电位E1/2(1a/1a•－)=－1.90 V (vs SCE)(其类似物为－1.59 V[14a])明显负于还原态4CzIPN的还原电位E1/2(PC/PC•－)=－1.21 V (vs SCE)[18b-18e] (－1.24 vs SCE[18f-18h]), 表明单一PC•－的还原能力不足以直接实现1a的单电子还原[18]. 因此, 该反应更可能遵循连续光子诱导电子转移(ConPET)机 理[19]: 生成的PC•－在再次吸收光子后形成具有更强还原能力的激发态PC•－*(双重态激发自由基阴离子), 由其向1a发生单电子转移生成关键中间体1a•－, 并完成光催化剂的再生. 随后, 1a•－发生C—Br键断裂并释放Br－, 形成碳中心自由基A, 该过程的势垒为ΔG≠=39.7 kJ/mol; A进一步经历分子内自由基环化构建新的C—C键, 经10.5 kJ/mol的低能垒过渡态生成环化自由基B. 最后, B与DIPEA•＋发生氢原子转移(HAT)过程实现自由基终止, 生成目标产物2a, 同时DIPEA•＋转化为相应的亚胺衍生物. 该步骤在热力学上高度有利, 从而完成整个自由基级联转化过程.
2 结论
综上所述, 本研究发展了一种高效的光氧化还原催化策略, 实现了吲哚2位取代与未取代底物的还原去芳构化反应, 能够以高达99%的产率合成一系列结构多样的官能化吲哚啉衍生物. 该反应以N,N-二异丙基乙胺(DIPEA)为有机还原剂, 在温和条件下进行, 具有良好的官能团耐受性与底物普适性. 此外, 放大实验与合成转化研究进一步证实了该方法在合成应用中的潜力.
3 实验部分
3.1 仪器与试剂
核磁共振(NMR)使用Bruker AVANCE NEO核磁共振波谱仪. 1H NMR谱在400 MHz或600 MHz下测定, 13C NMR谱在100 MHz或150 MHz下测定, 19F NMR谱在282 MHz下测定, 以CDCl3和DMSO-d6为溶剂, 四甲基硅烷为内标. 高分辨质谱HRMS (ESI)使用TripleTOF HRMS/MS型质谱仪测定. 商业试剂购自毕得医药、安耐吉化学、乐研试剂和TCI试剂公司, 均为市售分析纯, 直接使用. 底物N-(2-溴苯甲酰基)吲哚酯1和N-(2-溴苯甲酰基)吲哚3根据文献方法合成.
3.2 实验方法
3.2.1 2-位取代吲哚底物还原去芳构化反应
手套箱氮气氛围下, 在装有磁性搅拌子的8 mL螺纹盖反应管中, 加入光敏剂4CzIPN (3.2 mg, 0.004 mmol, 2.0 mol%)、N-(2-溴苯甲酰基)吲哚酯1 (0.2 mmol, 1.0 equiv)和DIPEA (38.8 mg, 0.3 mmol, 1.5 equiv). 然后加入无水乙腈(4.0 mL). 用聚四氟乙烯螺纹盖密封反应管后移出手套箱. 将反应混合物在45 W蓝光LED照射下, 于50 ℃剧烈搅拌12 h. 薄层色谱(TLC)监测反应, 反应结束后, 将反应液转移至50 mL圆底烧瓶中, 用25 mL二氯甲烷稀释. 有机相经真空浓缩, 通过硅胶柱层析(石油醚/乙酸乙酯, V∶V=30∶1)纯化, 得到纯净产物2.
6-氧代-6H-异吲哚并[2,1-a]吲哚-10b(11H)-羧酸甲酯(2a): 产率99%, 55.6 mg, 白色固体. m.p. 156.5~157.3 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.67~7.60 (m, 2H), 7.56~7.52 (m, 1H), 7.33~7.28 (m, 1H), 7.24~7.20 (m, 1H), 7.12~7.06 (m, 1H), 3.98 (d, J=15.6 Hz, 1H), 3.67 (s, 3H), 3.32 (d, J=15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 170.9, 167.3, 143.4, 138.9, 133.1, 132.2, 132.1, 128.8, 127.2, 124.2, 124.0, 123.8, 122.0, 115.7, 76.2, 52.5, 37.0; IR (KBr) ν: 3224, 2828, 2717, 2110, 1576, 1355, 1137, 775 cm－1; HRMS (ESI-TOF) calcd for C17H14NO3 [M＋H]＋ 280.0968, found 280.0964.
1-氟-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2b): 产率77%, 45.8 mg, 白色固体. m.p. 125.2~126.1 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.91~7.85 (m, 1H), 7.69~7.61 (m, 2H), 7.58~7.48 (m, 2H), 7.32~7.26 (m, 1H), 6.85~6.77 (m, 1H), 4.08 (d, J=16.0 Hz, 1H), 3.70 (s, 3H), 3.30 (d, J=16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 171.5, 168.3, 158.7 (d, J=246 Hz), 144.3, 142.1 (d, J=8 Hz), 133.5, 132.9, 130.2 (d, J=8 Hz), 130.0, 125.2, 123.1, 120.0 (d, J=20 Hz), 112.6 (d, J=4 Hz), 112.0 (d, J=21 Hz), 77.0, 53.6, 34.6; 19F NMR (282 MHz, CDCl3) δ: －116.74; IR (KBr) ν: 3448, 2830, 2716, 1631, 1596, 1384, 1150, 775 cm－1; HRMS (ESI- TOF) calcd for C17H13FNO3 [M＋H]＋ 298.0874, found 298.0869.
1-氯-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸乙酯(2c): 产率43%, 28.2 mg, 白色固体. m.p. 115.6~116.4 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, J=7.6 Hz, 1H), 7.70~7.59 (m, 3H), 7.58~7.52 (m, 1H), 7.29~7.22 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 4.05 (d, J=16.4 Hz, 1H), 3.34 (d, J=16.4 Hz, 1H), 1.18 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.8, 168.6, 144.5, 141.3, 133.5, 132.8, 132.5, 130.6, 129.9, 129.7, 125.2, 124.9, 123.1, 114.9, 76.2, 62.8, 37.4, 13.9; IR (KBr) ν: 3454, 2830, 2716, 1593, 1383, 1355, 1145, 775 cm－1; HRMS (ESI-TOF) calcd for C18H15ClNO3 [M＋H]＋ 328.0735, found 328.0737.
1-甲基-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸乙酯(2d): 产率49%, 29.9 mg, 白色固体. m.p. 142.3~143.0 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J=7.6 Hz, 1H), 7.67~7.59 (m, 2H), 7.57~7.51 (m, 2H), 7.24~7.19 (m, 1H), 6.91 (d, J=7.6 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.93 (d, J=15.6 Hz, 1H), 3.21 (d, J=15.6 Hz, 1H), 2.25 (s, 3H), 1.15 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.5, 168.5, 144.8, 139.7, 134.8, 133.4, 133.1, 132.9, 129.7, 128.2, 125.9, 125.0, 122.9, 114.1, 76.6, 62.6, 36.7, 18.7, 13.9; IR (KBr) ν: 3454, 2830, 2716, 1593, 1383, 1355, 1145, 775 cm－1; HRMS (ESI- TOF) calcd for C19H17NNaO3 [M＋Na]＋ 330.1101, found 330.1097.
2-氟-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸乙酯(2e): 产率92%, 57.2 mg, 白色固体. m.p. 109.3~109.7 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.91~7.86 (m, 1H), 7.81~7.76 (m, 1H), 7.69~7.61 (m, 3H), 7.60~7.54 (m, 1H), 7.49 (s, 1H), 4.15 (q, J=7.2 Hz, 2H), 4.02 (d, J=16.0 Hz, 1H), 3.36 (d, J=16.4 Hz, 1H), 1.16 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.9, 167.4, 159.2 (d, J=241 Hz), 143.3, 135.1 (d, J=4 Hz), 135.2 (d, J=10 Hz), 132.2, 132.0, 128.8, 124.1, 121.9, 116.4 (d, J=9 Hz), 113.6 (d, J=24 Hz), 111.8 (d, J=24 Hz), 76.1, 61.7, 37.0, 12.9; 19F NMR (282 MHz, CDCl3) δ: －117.79; IR (KBr) ν: 3450, 2829, 2717, 1593, 1384, 1354, 1144, 775 cm－1; HRMS (ESI-TOF) calcd for C18H15FNO3 [M＋H]＋ 312.1030, found 312.1029.
2-氯-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2f): 产率96%, 60.4 mg, 白色固体. m.p. 147.9~148.2 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, J=7.6 Hz, 1H), 7.66~7.60 (m, 3H), 7.58~7.52 (m, 1H), 7.30~7.25 (m, 1H), 7.20 (s, 1H), 3.96 (d, J=16.0 Hz, 1H), 3.69 (s, 3H), 3.31 (d, J=16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 171.6, 168.3, 144.2, 138.6, 136.0, 133.5, 132.9, 130.2, 130.0, 128.3, 125.5, 125.2, 123.1, 117.5, 76.8, 53.6, 38.0; IR (KBr) ν: 3461, 2830, 2717, 1593, 1384, 1354, 1145, 775 cm－1; HRMS (ESI-TOF) calcd for C17H13ClNO3 [M＋H]＋ 314.0578, found 314.0578.
2-溴-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2g): 产率98%, 69.9 mg, 白色固体. m.p. 164.3~165.1 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, J=7.6 Hz, 1H), 7.66~7.62 (m, 2H), 7.60~7.52 (m, 2H), 7.45~7.40 (m, 1H), 7.35 (s, 1H), 3.96 (d, J=16.4 Hz, 1H), 3.69 (s, 3H), 3.32 (d, J=16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 171.6, 168.2, 144.2, 139.1, 136.3, 133.5, 132.9, 131.3, 130.0, 128.4, 125.2, 123.1, 118.0, 117.8, 77.3, 53.7, 37.9; IR (KBr) ν: 3454, 2831, 2717, 1593, 1354, 1152, 1079, 775 cm－1; HRMS (ESI-TOF) calcd for C17H13BrNO3 [M＋H]＋ 358.0073, found 358.0075.
2-氰基-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸乙酯(2h): 产率99%, 62.7 mg, 白色固体. m.p. 104.5~105.2 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.89 (d, J=7.6 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.68~7.64 (m, 2H), 7.63~7.61 (m, 1H), 7.59~7.54 (m, 1H), 7.49 (s, 1H), 4.15 (q, J=7.2 Hz, 2H), 4.02 (d, J=16.0 Hz, 1H), 3.36 (d, J=16.4 Hz, 1H), 1.16 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.5, 168.0, 144.3, 143.7, 135.3, 133.9, 133.4, 132.5, 130.1, 128.7, 125.4, 123.2, 118.9, 116.9, 108.0, 76.5, 63.0, 37.5, 13.9; IR (KBr) ν: 3455, 2830, 2717, 1593, 1384, 1354, 1140, 775 cm－1; HRMS (ESI-TOF) calcd for C19H15N2O3 [M＋H]＋ 319.1077, found 319.1078.
2-甲基-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2i): 产率75%, 43.9 mg, 白色固体. m.p. 101.2~101.7 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J=7.4 Hz, 1H), 7.65~7.58 (m, 3H), 7.55~7.50 (m, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.04 (s, 1H), 3.92 (d, J=16.0 Hz, 1H), 3.66 (s, 3H), 3.28 (d, J=16.0 Hz, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 172.1, 168.3, 144.4, 137.6, 134.7, 134.3, 133.4, 133.1, 129.8, 128.7, 125.9, 125.0, 123.0, 116.4, 76.9, 53.5, 38.1, 21.2; IR (KBr) ν: 3455, 2830, 1593, 1384, 1353, 1152, 1079, 775 cm－1; HRMS (ESI-TOF) calcd for C18H15NNaO3 [M＋Na]＋ 316.0944, found 316.0944.
2-乙氧基-6-氧代-6H-异吲哚并-[2,1-a]吲哚- 10b(11H)-羧酸乙酯(2j): 产率88%, 59 mg, 无色油状物. 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J=7.6 Hz, 1H), 7.64~7.57 (m, 3H), 7.54~7.49 (m, 1H), 6.83~6.77 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.99 (q, J=7.2 Hz, 2H), 3.91 (d, J=16.0 Hz, 1H), 3.28 (d, J=16.0 Hz, 1H), 1.38 (t, J=6.8 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.3, 168.3, 156.7, 144.4, 135.8, 133.4, 133.4, 132.9, 129.7, 124.9, 122.9, 117.2, 113.4, 112.4, 77.2, 64.0, 62.5, 38.2, 14.9, 13.9; IR (KBr) ν: 3442, 2830, 2716, 1596, 1355, 1138, 1068, 774 cm－1; HRMS (ESI-TOF) calcd for C20H20NO4 [M＋H]＋ 338.1381, found 338.1384.
2-(苄氧基)-6-氧代-6H-异吲哚并-[2,1-a]吲哚- 10b(11H)-羧酸乙酯(2k): 产率53%, 44.6 mg, 白色固体. m.p. 174.8~175.2 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J=7.6 Hz, 1H), 7.65~7.57 (m, 3H), 7.56~7.50 (m, 1H), 7.45~7.35 (m, 4H), 7.35~7.30 (m, 1H), 6.93~6.85 (m, 2H), 5.04 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.92 (d, J=16.0 Hz, 1H), 3.28 (d, J=16.0 Hz, 1H), 1.15 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.3, 168.4, 156.5, 144.5, 136.9, 135.9, 133.8, 133.4, 133.0, 129.7, 128.6, 128.0, 127.5, 125.0, 122.9, 117.2, 113.8, 112.8, 77.2, 70.5, 62.6, 38.2, 13.9; IR (KBr) ν: 3464, 2830, 2716, 1593, 1384, 1354, 1141, 774 cm－1; HRMS (ESI-TOF) calcd for C25H22NO4 [M＋H]＋ 422.1363, found 422.1357.
3-氯-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸乙酯(2l): 产率94%, 61.5 mg, 白色固体. m.p. 181.2~181.9 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, J=7.6 Hz, 1H), 7.70 (s, 1H), 7.66~7.59 (m, 2H), 7.58~7.50 (m, 1H), 7.14~7.09 (m, 1H), 7.07~6.99 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.92 (d, J=16.0 Hz, 1H), 3.26 (d, J=16.0 Hz, 1H), 1.15 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.9, 168.2, 144.4, 141.0, 133.9, 133.5, 132.8, 132.6, 129.9, 125.9, 125.2, 124.8, 123.1, 117.2, 77.1, 62.8, 37.6, 13.9; IR (KBr) ν: 3455, 2830, 2716, 1593, 1384, 1354, 1139, 774 cm－1; HRMS (ESI-TOF) calcd for C18H15- ClNO3 [M＋H]＋ 328.0735, found 328.0736.
3-溴-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2m): 产率91%, 65.1 mg, 白色固体. m.p. 195.9~196.8 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.91~7.85 (m, 2H), 7.66~7.62 (m, 2H), 7.58~7.52 (m, 1H), 7.24~7.19 (m, 1H), 7.09~7.05 (m, 1H), 3.93 (d, J=16.0 Hz, 1H), 3.68 (s, 3H), 3.25 (d, J=16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 171.6, 168.2, 144.3, 141.1, 133.6, 133.2, 132.8, 130.0, 127.8, 126.3, 125.2, 123.1, 121.6, 120.0, 76.9, 53.6, 37.7; IR (KBr) ν: 3454, 2830, 2717, 1593, 1383, 1354, 1140, 774 cm－1; HRMS (ESI-TOF) calcd for C17H13BrNO3 [M＋H]＋ 358.0068, found 358.0059.
4-溴-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸乙酯(2n): 产率85%, 62.8 mg, 白色固体. m.p. 102.9~103.7 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J=7.6 Hz, 1H), 7.68~7.58 (m, 2H), 7.57~7.50 (m, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.00~6.92 (m, 1H), 4.13 (q, J=12.0, 7.2 Hz, 2H), 3.86 (d, J=16.0 Hz, 1H), 3.26 (d, J=16.0 Hz, 1H), 1.15 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.6, 168.0, 143.60, 140.5, 138.3, 133.3, 132.7, 132.6, 129.9, 126.9, 125.2, 123.9, 122.9, 112.1, 77.8, 62.6, 39.5, 13.9; IR (KBr) ν: 3451, 2830, 2716, 1593, 1383, 1354, 1141, 775 cm－1; HRMS (ESI-TOF) calcd for C18H15BrNO3 [M＋H]＋ 372.0230, found 372.0231.
4-甲基-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸乙酯(2o): 50%产率, 30.7 mg, 白色固体. m.p. 98.0~98.4 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, J=7.6 Hz, 1H), 7.68~7.58 (m, 2H), 7.57~7.50 (m, 1H), 7.14~7.07 (m, 1H), 7.05~6.98 (m, 2H), 4.18~4.07 (m, 2H), 3.83 (d, J=15.6 Hz, 1H), 3.24 (d, J=15.6 Hz, 1H), 2.70 (s, 3H), 1.15 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.1, 168.7, 144.1, 139.5, 135.7, 133.3, 132.9, 130.3, 129.7, 129.0, 125.6, 124.9, 122.8, 122.3, 77.9, 62.4, 39.0, 19.5, 13.9; IR (KBr) ν: 3458, 2829, 2717, 1593, 1384, 1353, 1141, 775 cm－1; HRMS (ESI-TOF) calcd for C19H18NO3 [M＋H]＋ 308.1281, found 308.1283.
7-氟-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2p): 产率84%, 53.6 mg, 白色固体. m.p. 157.1~158.0 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, J=8.0 Hz, 1H), 7.63~7.56 (m, 1H), 7.45~7.41 (m, 1H), 7.33~7.27 (m, 1H), 7.24~7.20 (m, 1H), 7.20~7.14 (m, 1H), 7.12~7.06 (m, 1H), 3.98 (d, J=16.0 Hz, 1H), 3.68 (s, 3H), 3.34 (d, J=15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 171.5, 165.1, 159.2 (d, J=261 Hz), 146.8, 139.8, 135.4 (d, J=8 Hz), 133.8, 128.4, 125.1 (d, J=12 Hz), 120.4 (d, J=14 Hz), 119.1 (d, J=5 Hz), 117.3 (d, J=19 Hz), 116.9, 76.4, 53.7, 38.1; 19F NMR (282 MHz, CDCl3) δ: －115.21; IR (KBr) ν: 3450, 2830, 2716, 1593, 1384, 1354, 1139, 774 cm－1; HRMS (ESI-TOF) calcd for C17H13FNO3 [M＋H]＋ 320.0693, found 320.0687.
8-溴-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2q): 产率69%, 49.5 mg, 白色固体. m.p. 169.9~170.8 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.76~7.68 (m, 2H), 7.55~7.51 (m, 1H), 7.34~7.29 (m, 1H), 7.24~7.20 (m, 1H), 7.13~7.08 (m, 1H), 3.95 (d, J=16.0 Hz, 1H), 3.68 (s, 3H), 3.31 (d, J=15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 171.4, 166.6, 143.0, 139.6, 136.1, 135.3, 134.0, 128.4, 128.1, 125.3, 125.2, 124.7, 124.1, 116.8, 76.5, 53.7, 38.0; IR (KBr) ν: 3451, 2829, 2717, 1593, 1384, 1353, 1140, 774 cm－1; HRMS (ESI- TOF) calcd for C17H13BrNO3 [M＋H]＋ 358.0073, found 358.0069.
8-甲氧基-6-氧代-6H-异吲哚并-[2,1-a]吲哚- 10b(11H)-羧酸甲酯(2r): 产率54%, 33.4 mg, 白色固体. m.p. 115.7~116.0 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, J=7.6 Hz, 1H), 7.54~7.49 (m, 1H), 7.36~7.33 (m, 1H), 7.32~7.27 (m, 1H), 7.23~7.19 (m, 1H), 7.17~7.13 (m, 1H), 7.11~7.05 (m, 1H), 3.93 (d, J=16.0 Hz, 1H), 3.87 (s, 3H), 3.66 (s, 3H), 3.28 (d, J=16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 172.1, 168.3, 161.2, 139.9, 136.7, 134.8, 134.3, 128.2, 125.2, 124.9, 124.0, 121.3, 116.7, 107.8, 76.4, 55.8, 53.4, 38.1; IR (KBr) ν: 3447, 2831, 2716, 1593, 1354, 1142, 948, 775 cm－1; HRMS (ESI-TOF) calcd for C18H16NO4 [M＋H]＋ 310.1074, found 310.1073.
9-甲氧基-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b (11H)-羧酸甲酯(2s): 产率78%, 48.2 mg, 白色固体. m.p. 125.5~126.3 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.77 (d, J=8.4 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.31~7.25 (m, 1H), 7.22~7.18 (m, 1H), 7.11~7.09 (m, 1H), 7.08~7.04 (m, 1H), 7.04~7.00 (m, 1H), 3.94 (d, J=15.6 Hz, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 3.31 (d, J=16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 172.1, 168.6, 164.1, 147.0, 140.3, 133.8, 128.2, 126.5, 125.3, 125.1, 124.6, 116.7, 116.3, 107.8, 76.3, 55.9, 53.5, 38.1; IR (KBr) ν: 3461, 2830, 2716, 1593, 1354, 1140, 948, 775 cm－1; HRMS (ESI-TOF) calcd for C18H16NO4 [M＋H]＋ 310.1074, found 310.1070.
10-氟-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b(11H)-羧酸甲酯(2t): 产率72%, 42.7 mg, 白色固体. m.p. 185.9~186.8 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.73~7.66 (m, 2H), 7.57~7.51 (m, 1H), 7.34~7.26 (m, 3H), 7.14~7.09 (m, 1H), 4.13 (d, J=16.0 Hz, 1H), 3.69 (s, 3H), 3.36 (d, J=16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 170.0, 167.3, 157.4 (d, J=252 Hz), 139.3, 136.5, 136.4, 134.3, 132.0 (d, J=7 Hz), 130.9 (d, J=17 Hz), 128.2, 125.3 (d, J=16 Hz), 121.1 (d, J=4 Hz), 120.2 (d, J=20 Hz), 116.5, 74.6, 53.7, 36.3; 19F NMR (282 MHz, CDCl3) δ: －118.22; IR (KBr) ν: 3451, 2830, 2716, 1594, 1354, 1142, 990, 774 cm－1; HRMS (ESI-TOF) calcd for C17H13FNO3 [M＋H]＋ 298.0868, found 298.0869.
10-甲基-6-氧代-6H-异吲哚并-[2,1-a]吲哚-10b (11H)-羧酸甲酯(2u): 产率83%, 48.6 mg, 白色固体. m.p. 164.8~165.6 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.74 (d, J=7.2 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.46~7.41 (m, 1H), 7.40~7.37 (m, 1H), 7.32~7.27 (m, 1H), 7.26~7.23 (m, 1H), 7.12~7.06 (m, 1H), 4.21 (d, J=15.6 Hz, 1H), 3.63 (s, 3H), 3.27 (d, J=15.6 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.2, 168.6, 143.3, 139.4, 134.7, 134.3, 133.9, 133.4, 129.8, 128.2, 125.3, 124.8, 122.7, 116.4, 76.5, 53.5, 35.6, 17.9; IR (KBr) ν: 3447, 2829, 1593, 1384, 1353, 1140, 948, 775 cm－1; HRMS (ESI-TOF) calcd for C18H16NO3 [M＋H]＋ 294.1125, found 294.1120.
10b-乙酰基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚- 6-酮(2v): 68%产率, 35.8 mg, 白色固体. m.p. 197.5~197.9 ℃; 1H NMR (600 MHz, CDCl3) δ: 7.89 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.62~7.59 (m, 1H), 7.53~7.49 (m, 1H), 7.48~7.46 (m, 1H), 7.39~7.35 (m, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.15~7.11 (m, 1H), 5.92 (d, J=9.6 Hz, 1H), 4.29 (d, J=9.6 Hz, 1H), 2.58 (s, 3H); 13C NMR (150 MHz, CDCl3) δ: 205.0, 168.6, 145.1, 140.8, 134.0, 133.3, 133.1, 129.4, 129.3, 125.1, 124.9, 124.6, 123.26, 117.3, 77.2, 66.6, 59.7, 30.4; IR (KBr) ν: 3521, 2830, 2710, 1593, 1384, 1354, 1105, 775 cm－1; HRMS (ESI-TOF) calcd for C17H14NO2 [M＋H]＋ 264.1019, found 264.1022.
N-甲基-6-氧代-N-苯基-6H-异吲哚并[2,1-a]吲哚- 10b(11H)-甲酰胺(2w): 产率41%, 29 mg, 白色固体. m.p. 234.6~235.0 ℃; 1H NMR (600 MHz, CDCl3) δ: 7.91 (d, J=7.2 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.68~7.64 (m, 1H), 7.55~7.52 (m, 1H), 7.43~7.38 (m, 4H), 7.31~7.27 (m, 2H), 7.17~7.13 (m, 1H), 7.03~7.00 (m, 1H), 6.52~6.46 (m, 1H), 4.89 (s, 1H), 2.60 (d, J=4.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ: 170.2, 167.8, 147.0, 141.1, 138.5, 136.9, 134.0, 131.3, 129.6, 129.5, 128.9, 128.7, 128.5, 126.2, 125.7, 125.6, 124.8, 117.1, 81.4, 77.2, 58.5, 26.4; IR (KBr) ν: 3561, 2830, 2617, 1593, 1381, 1354, 1145, 775 cm－1; HRMS (ESI-TOF) calcd for C23H19N2O2 [M＋H]＋ 355.1441, found 355.1444.
10b-苯基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(2x): 产率45%, 26.7 mg, 白色固体. m.p. 189.9~190.2 ℃; 1H NMR (600 MHz, CDCl3) δ: 8.69 (d, J=7.8 Hz, 1H), 8.42~8.39 (m, 1H), 7.64~7.60 (m, 1H), 7.56~7.52 (m, 1H), 7.49~7.45 (m, 2H), 7.39~7.35 (m, 1H), 7.33~7.29 (m, 1H), 6.54 (s, 1H), 6.04~5.98 (m, 2H), 5.77~5.68 (m, 2H), 2.96~2.90 (m, 2H); 13C NMR (150 MHz, CDCl3) δ: 160.9, 144.5, 142.9, 135.3, 133.8, 130.4, 130.1, 129.2, 128.8, 127.7, 125.8, 124.5, 124.3, 123.1, 120.3, 116.9, 108.4, 77.2, 41.9, 25.4; IR (KBr) ν: 3458, 2830, 2717, 1613, 1384, 1324, 1145, 775 cm－1; HRMS (ESI-TOF) calcd for C21H16NO [M＋H]＋ 298.1226, found 298.1223.
3.2.2 2-位非取代吲哚底物还原去芳构化反应
手套箱氮气氛围下, 在装有磁性搅拌子的8 mL螺纹盖反应管中, 加入光敏剂[Ir(ppy)2(dtbbpy)]PF6 (4.0 mg, 0.004 mmol, 2.0 mol%)、N-(2-溴苯甲酰基)吲哚3 (0.2 mmol, 1.0 equiv)和DIPEA (38.8 mg, 0.3 mmol, 1.5 equiv.), 然后加入无水乙腈(4.0 mL). 用聚四氟乙烯螺纹盖密封反应管后移出手套箱. 将反应混合物在45W蓝光LED照射下, 于50 ℃剧烈搅拌12 h. TLC监测反应, 反应结束后, 将反应液转移至50 mL圆底烧瓶中, 用25 mL二氯甲烷稀释. 有机相经真空浓缩后, 通过硅胶柱层析(石油醚/乙酸乙酯, V∶V=30∶1)纯化, 得到纯净产物4.
10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4a): 产率95%, 42.1 mg, 白色固体. m.p. 130.6~130.8 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.89 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.63~7.57 (m, 1H), 7.53~7.46 (m, 2H), 7.31~7.26 (m, 1H), 7.25~7.21 (m, 1H), 7.10~7.03 (m, 1H), 5.60 (t, J=9.6 Hz, 1H), 3.45 (dd, J=15.2, 8.4 Hz, 1H), 3.04 (dd, J=15.2, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.4, 146.1, 140.7, 136.0, 134.2, 132.6, 128.7, 128.0, 125.4, 124.8, 124.5, 122.9, 116.5, 65.5, 33.8; IR (KBr) ν: 3451, 2831, 2717, 1593, 1383, 1354, 1141, 775 cm－1; HRMS (ESI-TOF) calcd for C15H12NO [M＋ H]＋ 222.0908, found 222.0911.
1-氟-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4b)[11b]: 产率98%, 47 mg, 白色固体. m.p. 139.8~140.6 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, J=7.6 Hz, 1H), 7.65~7.59 (m, 1H), 7.54~7.48 (m, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.29~7.23 (m, 1H), 6.84~6.75 (m, 1H), 5.65 (t, J=9.6 Hz, 1H), 3.57 (dd, J=15.6, 8.8 Hz, 1H), 3.01 (dd, J=15.6, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.5, 159.0 (d, J=245 Hz), 145.8, 142.8 (d, J=8 Hz), 133.8, 132.9, 129.9 (d, J=8 Hz), 128.9, 125.0, 122.9, 121.7 (d, J=20 Hz), 112.3 (d, J=3 Hz), 111.6 (d, J=21 Hz), 65.6, 30.2; 19F NMR (282 MHz, CDCl3) δ: －117.10; IR (KBr) ν: 3454, 2831, 2717, 1593, 1353, 1140, 990, 775 cm－1; HRMS (ESI-TOF) calcd for C15H11- FNO [M＋H]＋ 240.0819, found 240.0815.
1-甲氧基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4c): 产率90%, 45.3 mg, 无色油状. 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J=7.6 Hz, 1H), 7.62~7.57 (m, 1H), 7.52~7.46 (m, 2H), 7.35~7.30 (m, 1H), 7.28~7.23 (m, 1H), 6.64 (d, J=8.0 Hz, 1H), 5.60 (t, J=9.6 Hz, 1H), 3.83 (s, 3H), 3.47 (dd, J=15.6, 9.2 Hz, 1H), 2.90 (dd, J=15.2, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.6, 156.1, 146.2, 141.9, 134.2, 132.6, 129.4, 128.7, 124.8, 122.9, 122.8, 122.7, 109.4, 107.0, 65.8, 55.4, 30.7; IR (KBr) ν: 3454, 2831, 2717, 1593, 1383, 1353, 1139, 775 cm－1; HRMS (ESI-TOF) calcd for C16H14NO2 [M＋H]＋ 252.1019, found 252.1015.
2-氯-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4d): 产率98%, 50.5 mg, 白色固体. m.p. 121.9~122.6 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.90~7.85 (m, 1H), 7.64~7.55 (m, 2H), 7.53~7.46 (m, 2H), 7.26~7.18 (m, 2H), 5.61 (t, J=9.6, 1H), 3.44 (dd, J=15.6, 8.8 Hz, 1H), 3.03 (dd, J=15.6, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.4, 145.8, 139.3, 137.8, 133.8, 132.8, 129.6, 128.9, 128.0, 125.7, 125.0, 122.9, 117.2, 65.5, 33.8; IR (KBr) ν: 3448, 2831, 2717, 1593, 1355, 1080, 947, 775 cm－1; HRMS (ESI-TOF) calcd for C15H10ClNO [M＋H]＋ 256.0524, found 256.0521.
2-甲氧基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4e): 69%产率, 34.6 mg, 白色固体. m.p. 156.2~156.7 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.89~7.85 (m, 1H), 7.61~7.56 (m, 2H), 7.51~7.46 (m, 2H), 6.82~6.78 (m, 2H), 5.58 (t, J=9.6 1H), 3.79 (s, 3H), 3.41 (dd, J=15.6, 8.8 Hz, 1H), 3.02 (dd, J=15.6, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.4, 157.1, 145.9, 137.6, 134.3, 134.2, 132.4, 128.7, 124.8, 122.8, 116.9, 112.3, 112.1, 65.8, 55.8, 34.1; IR (KBr) ν: 3451, 2831, 2717, 1593, 1353, 1142, 990, 775 cm－1; HRMS (ESI-TOF) calcd for C16H14NO2 [M＋H]＋ 252.1019, found 252.1017.
3-氯-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4f): 产率92%, 47 mg, 白色固体. m.p. 177.6~178.4 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J=8.0 Hz, 1H), 7.66~7.57 (m, 2H), 7.53~7.45 (m, 2H), 7.14~7.08 (m, 1H), 7.04~6.97 (m, 1H), 5.60 (t, J=9.6 Hz, 1H), 3.42 (dd, J=15.2, 8.8 Hz, 1H), 2.97 (dd, J=15.2, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.4, 145.9, 141.7, 134.4, 133.7, 133.6, 132.9, 128.9, 126.0, 125.0, 124.4, 122.9, 116.9, 65.7, 33.4; IR (KBr) ν: 3458, 2831, 2717, 1593, 1354, 1140, 948, 774 cm－1; HRMS (ESI-TOF) calcd for C15H11ClNO [M＋H]＋ 256.0524, found 256.0522.
3-甲氧基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4g): 产率52%, 26 mg, 白色固体. m.p. 147.9~148.7 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.91~7.87 (m, 1H), 7.63~7.58 (m, 1H), 7.53~7.47 (m, 2H), 7.30~7.28 (m, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.63~6.59 (m, 1H), 5.63 (t, J=9.6 Hz, 1H), 3.86 (s, 3H), 3.39 (dd, J=14.4, 8.8 Hz, 1H), 2.98 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.3, 159.9, 146.1, 141.7, 134.2, 132.6, 128.7, 127.4, 125.6, 124.8, 122.8, 110.5, 102.6, 66.2, 55.7, 33.1; IR (KBr) ν: 3450, 2831, 2717, 1593, 1354, 1139, 948, 775 cm－1; HRMS (ESI-TOF) calcd for C16H14NO2 [M＋H]＋ 252.1019, found 252.1014.
4-氟-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4h): 产率88%, 42.1 mg, 白色固体. m.p. 127.6~127.9 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.92~7.86 (m, 1H), 7.64~7.59 (m, 1H), 7.53~7.48 (m, 2H), 7.08~7.03 (m, 2H), 7.02~6.99 (m, 1H), 5.64~5.57 (m, 1H), 3.43 (dd, J=15.2, 8.4 Hz, 1H), 3.03 (dd, J=15.2, 10.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.8, 154.1, 151.6, 145.7, 140.3, 140.2, 133.5, 132.8, 128.9, 128.0, 127.8, 126.2, 126.1, 125.1, 122.9, 120.9, 120.8, 116.3, 116.1, 66.6, 34.7; 19F NMR (282 MHz, CDCl3) δ: －122.11; IR (KBr) ν: 3451, 2831, 2717, 1596, 1354, 1139, 947, 774 cm－1; HRMS (ESI-TOF) calcd for C15H11FNO [M＋H]＋ 240.0819, found 240.0817.
4-甲氧基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4i): 产率62%, 31.2 mg, 白色固体. m.p. 148.3~149.1 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.89~7.85 (m, 1H), 7.61~7.56 (m, 1H), 7.51~7.46 (m, 2H), 7.09~7.04 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.85 (d, J=7.2 Hz, 1H), 5.60~5.54 (m, 1H), 4.02 (s, 3H), 3.35 (dd, J=14.8, 8.0 Hz, 1H), 2.98 (dd, J=14.8, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.9, 150.7, 145.6, 139.4, 134.1, 132.4, 129.8, 128.7, 126.4, 124.8, 122.7, 117.7, 112.9, 67.1, 56.7, 34.9; IR (KBr) ν: 3443, 2830, 2717, 1593, 1383, 1353, 1138, 774 cm－1; HRMS (ESI-TOF) calcd for C16H14NO2 [M＋H]＋ 252.1019, found 252.1017.
7-氟-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4j): 产率66%, 31.5 mg, 白色固体. m.p. 164.9~165.6 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.61 (d, J=8.0 Hz, 1H), 7.57~7.50 (m, 1H), 7.27~7.21 (m, 2H), 7.21~7.16 (m, 1H), 7.11~7.00 (m, 2H), 5.54 (t, J=9.6 Hz, 1H), 3.42 (dd, J=15.2, 8.8 Hz, 1H), 3.02 (dd, J=15.2, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 165.2, 159.4 (d, J=260 Hz), 148.7, 140.4, 135.6, 134.8 (d, J=8 Hz), 128.1, 125.4, 124.8, 121.3 (d, J=13 Hz), 118.9 (d, J=4 Hz), 116.6, 116.1 (d, J=19 Hz), 65.1, 33.8; 19F NMR (282 MHz, CDCl3) δ: －116.11; IR (KBr) ν: 3443, 2830, 2717, 1593, 1383, 1353, 1138, 774 cm－1; HRMS (ESI-TOF) calcd for C15H11FNO [M＋H]＋ 240.0819, found 240.0818.
8-溴-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4k): 产率53%, 31.9 mg, 白色固体. m.p. 161.3~162.2 ℃; 1H NMR (600 MHz, CDCl3) δ: 8.02~7.99 (m, 1H), 7.73~7.70 (m, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.31~7.27 (m, 1H), 7.24 (d, J=7.2 Hz, 1H), 7.10~7.06 (m, 1H), 5.56 (t, J=9.6 Hz 1H), 3.45 (dd, J=15.0, 8.4 Hz, 1H), 3.03 (dd, J=15.0, 10.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ: 166.7, 144.5, 140.3, 136.3, 135.8, 135.5, 128.2, 128.0, 125.5, 124.8, 124.4, 122.9, 116.5, 65.2, 33.7; IR (KBr) ν: 3451, 2830, 2717, 1593, 1353, 1138, 947, 774 cm－1; HRMS (ESI-TOF) calcd for C15H11BrNO [M＋H]＋ 300.0019, found 300.0011.
8-甲氧基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4l): 产率80%, 40.2 mg, 白色固体. m.p. 152.4~152.8 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.67 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.37~7.34 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.17~7.13 (m, 1H), 7.09~7.04 (m, 1H), 5.59~5.52 (m, 1H), 3.87 (s, 3H), 3.42 (dd, J=15.2, 8.8 Hz, 1H), 3.01 (dd, J=15.2, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.4, 160.4, 140.6, 138.4, 136.2, 135.6, 128.0, 125.4, 124.5, 123.7, 120.9, 116.5, 107.4, 65.1, 55.8, 34.0; IR (KBr) ν: 3374, 2829, 2717, 1587, 1384, 1354, 1142, 775 cm－1; HRMS (ESI-TOF) calcd for C16H14NO2 [M＋H]＋ 252.1019, found 252.1015.
9-氯-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4m): 产率89%, 45.3 mg, 白色固体. m.p. 152.8~153.7 ℃; 1H NMR (600 MHz, CDCl3) δ: 7.81 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.51 (s, 1H), 7.49~7.46 (m, 1H), 7.31~7.27 (m, 1H), 7.24 (d, J=7.2 Hz, 1H), 7.10~7.06 (m, 1H), 5.58 (t, J=9.6 Hz, 1H), 3.45 (dd, J=15.0, 8.4 Hz, 1H), 3.06 (dd, J=15.0, 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ: 167.3, 147.5, 140.4, 139.0, 135.6, 132.7, 129.4, 128.1, 126.0, 125.5, 124.7, 123.4, 116.5, 65.0, 33.6; IR (KBr) ν: 3441, 1689, 2829, 2717, 1596, 1353, 1139, 774 cm－1; HRMS (ESI-TOF) calcd for C15H11ClNO [M＋H]＋ 256.0524, found 256.0520.
9-甲氧基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4n): 产率86%, 43.2 mg, 白色固体. m.p. 134.2~135.0 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.78 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.29~7.24 (m, 1H), 7.23~7.19 (m, 1H), 7.06~7.02 (m, 1H), 7.01~6.96 (m, 2H), 5.53 (t, J=9.6 Hz, 1H), 3.89 (s, 3H), 3.42 (dd, J=15.2, 8.8 Hz, 1H), 3.03 (dd, J=15.2, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.7, 163.7, 148.6, 141.0, 135.6, 128.0, 126.4, 126.3, 125.3, 124.2, 116.4, 115.2, 107.8, 65.0, 55.8, 33.8; IR (KBr) ν: 3436, 2830, 2717, 1596, 1353, 1138, 947, 774 cm－1; HRMS (ESI-TOF) calcd for C16H14NO2 [M＋H]＋ 252.1014, found 252.1017.
10-氟-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4o): 产率56%, 27 mg, 白色固体. m.p. 145.1~145.8 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.73~7.64 (m, 2H), 7.54~7.46 (m, 1H), 7.33~7.27 (m, 2H), 7.26~7.23 (m, 1H), 7.13~7.06 (m, 1H), 5.66 (dd, J=10.4, 8.8 Hz, 1H), 3.53 (dd, J=15.4, 8.4 Hz, 1H), 3.11 (dd, J=15.4, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 167.1, 157.8 (d, J=249 Hz), 140.2, 137.3, 135.8, 131.8 (d, J=19 Hz), 131.0 (d, J=6 Hz), 128.1, 125.5, 124.8, 120.8 (d, J=4 Hz), 119.3 (d, J=19 Hz), 116.5, 62.9, 33.5; 19F NMR (282 MHz, CDCl3) δ: －120.01; IR (KBr) ν: 3457, 2831, 2716, 1593, 1353, 1138, 1068, 775 cm－1; HRMS (ESI-TOF) calcd for C15H11FNO [M＋H]＋ 240.0819, found 240.0815.
10-甲基-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(4p): 产率69%, 32.2 mg, 白色固体. m.p. 140.4~141.0 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.74~7.70 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.43~7.36 (m, 2H), 7.31~7.27 (m, 1H), 7.25~7.21 (m, 1H), 7.10~7.04 (m, 1H), 5.55 (dd, J=10.4, 8.6 Hz, 1H), 3.50 (dd, J=15.2, 8.8 Hz, 1H), 3.04 (dd, J=15.2, 10.4 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.7, 144.8, 140.6, 136.0, 134.0, 133.5, 133.0, 129.0, 128.0, 125.3, 124.4, 122.3, 116.5, 65.1, 33.5, 18.1; IR (KBr) ν: 3283, 2830, 2717, 1605, 1384, 1353, 1140, 774 cm－1; HRMS (ESI-TOF) calcd for C16H14NO [M＋H]＋ 236.1070, found 236.1064.
3.2.3 化合物5的合成
在氮气氛围下, 向干燥的50 mL圆底烧瓶中加入2a (55.8 mg, 0.2 mmol, 1.0 equiv.)、NaBH4 (45.6 mg, 1.2 mmol, 6.0 equiv.)、甲醇(2 mL)和THF (8 mL). 在氮气保护下搅拌反应12 h后, 用饱和NH4Cl水溶液(2 mL)淬灭反应. 用乙酸乙酯稀释反应液, 分液. 水相用乙酸乙酯萃取. 合并有机相, 水洗涤后用无水Na2SO4干燥. 过滤并真空浓缩后, 通过快速柱层析(石油醚/乙酸乙酯, V∶V=5∶2)纯化, 得到白色固体10b-羟甲基-10b,11-二氢- 6H-异吲哚并[2,1-a]吲哚-6-酮(5), 产率88%, 44.2 mg, 白色固体. 1H NMR (400 MHz, CDCl3) δ: 7.79 (d, J=7.5 Hz, 1H), 7.63~7.56 (m, 2H), 7.55~7.50 (m, 1H), 7.49~7.42 (m, 1H), 7.26~7.18 (m, 2H), 7.10~7.02 (m, 1H), 3.95~3.78 (m, 2H), 3.28~3.14 (m, 2H), 2.79 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 169.5, 148.3, 139.9, 135.5, 133.6, 133.1, 129.0, 128.0, 125.6, 125.0 124.7, 122.5, 117.0, 75.3, 67.2, 35.6; IR (KBr) ν: 3450, 2830, 2717, 1593, 1383, 1353, 1138, 775 cm－1; HRMS (ESI-TOF) calcd for C16H14NO2 [M＋H]＋ 252.1019, found 252.1015.
3.2.4 化合物6的合成
在氮气氛围下, 向干燥的25 mL圆底烧瓶中加入4k (59.8 mg, 0.2 mmol, 1.0 equiv.)、Na2CO3 (103 mg, 1.0 mmol, 5.0 equiv.)、Pd(PPh3)4 (5.8 mg, 0.005 mmol, 2.5 mol%)、对甲氧基苯硼酸(36.4 mg, 0.24 mmol, 1.2 equiv.)、水(1 mL)和甲苯(2 mL). 反应在95 ℃下搅拌12 h. 反应液用乙酸乙酯稀释, 分液. 水相用乙酸乙酯萃取. 有机相用水洗涤, 然后经无水Na2SO4干燥. 过滤并真空浓缩后, 残留物通过快速柱层析纯化(石油醚/丙酮体积比, V∶V=9∶1), 得到8-(4-甲氧基苯基)-10b,11-二氢-6H-异吲哚并[2,1-a]吲哚-6-酮(6), 产率84%, 55.0 mg, 白色固体. 1H NMR (400 MHz, DMSO-d6) δ: 8.00~7.89 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.38~7.32 (m, 1H), 7.31~7.25 (m, 1H), 7.14~7.08 (m, 1H), 7.07~6.99 (m, 2H), 5.77 (t, J=9.5 Hz, 1H), 3.81 (s, 3H), 3.56 (dd, J=15.6, 8.7 Hz, 1H), 3.01 (dd, J=15.5, 10.4 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 168.1, 159.8, 145.3, 141.1, 140.7, 137.2, 134.5, 131.9, 131.6, 128.6, 128.0, 126.2, 124.9, 124.7, 121.5, 116.2, 115.0, 65.4, 55.7, 33.9; IR (KBr) ν: 3447, 2831, 2717, 1593, 1354, 1140, 990, 775 cm－1; HRMS (ESI-TOF) calcd for C22H18NO2 [M＋H]＋ 328.1332, found 328.1327.
辅助材料(Supporting Information) 化合物2a~2x、4a~4p、5和6的1H NMR, 13C NMR图谱. 这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.
(Zhao, C.)