吲哚骨架4位的乙酯基化研究

范 威

吲哚骨架4位的乙酯基化研究

范 威

（滁州城市职业学院科研处，安徽，滁州 239000）

4位官能化的吲哚衍生物，可用作流感的抗病毒治疗、神经毒素、抗菌剂。因此，吲哚骨架4位的修饰研究值得探讨。从-芳基环己-2-烯酮、苊醌、乙酸酐出发，120℃微波辐射条件下，一步合成了4-乙酯基吲哚衍生物，补充了吲哚骨架4位的修饰。其结构也得到了单晶的证实。反应机理涉及分子内环化、脱水、互变异构、酯化等诸多步骤。

苊醌；乙酸酐；4-乙酯基吲哚衍生物

Arbidol[1]、Psilocin[2]、Clavicipitic酸[3]（图1）等活性化合物均为4位官能化的吲哚衍生物，可用作流感的临床抗病毒治疗、神经毒素、抗菌剂等。吲哚[4]骨架4位的修饰得到了广泛的报道[5-9]，在这些研究中，关于吲哚骨架4位的乙酯基化研究尤其引人注目。

图1 4位官能化的吲哚衍生物

Cho课题组[10]从4,5-二羟基吲哚酮出发，分两步反应，最终以81%的产率实现了吲哚骨架4位的乙酯基化。该反应的缺点是使用的吡啶为致癌物质（图2a）。Bélanger课题组[11]先活化甲酰胺，然后经分子内Vilsmeier-Haack反应，分子内环加成等过程，最终合成了4-乙酯基化的吲哚衍生物，该反应的主要缺点是原料不容易制得（图2b）。Bjørsvik课题组[12]从1,3-二甲氧基-2-甲基苯出发，经多步反应合成了4-乙酯基吲哚衍生物，该反应的主要缺点是反应步骤过多（图2c）。

本课题组从-芳基环己-2-烯酮、苊醌、乙酸酐出发，120℃微波辐射条件下，一步合成了4-乙酯基吲哚衍生物，从而补充了吲哚骨架4位的修饰（图2d）。

图2 合成4-乙酯基吲哚衍生物

1 材料与方法

1.1 仪器与试剂

仪器：单晶衍射仪；核磁共振仪。

试剂：-芳基环己-2-烯酮；苊醌；乙酸酐。

1.2 表征数据

7-（4-氟苯基）-7-苊并[1,2-]吲哚-11-基乙酸酯4a核磁氢谱 (, ppm): 2.60 (s, 3H), 7.08 (d, 1H,= 7.6 Hz), 7.22 (t, 1H,= 8.0 Hz), 7.29 (d, 1H,= 8.0 Hz), 7.42 (d, 1H,= 7.2 Hz), 7.51 (t, 1H,= 7.2 Hz), 7.65 (t, 1H,= 8.0 Hz), 7.73 (d, 1H,= 6.8 Hz), 7.78-7.80 (m, 3H), 7.88-7.90 (m, 3H)。

7-（3-溴苯基）-7-苊并[1,2-]吲哚-11-基乙酸酯4b核磁氢谱 (, ppm): 2.64 (s, 3H), 7.06 (d, 1H,= 7.6 Hz), 7.21 (t, 1H,= 8.0 Hz), 7.30 (d, 1H,= 8.4 Hz), 7.39 (d, 1H,= 7.2 Hz), 7.53 (t, 1H,= 7.6 Hz), 7.67 (t, 2H,= 7.6 Hz), 7.76 (d, 1H,= 6.8 Hz), 7.78-7.79 (m, 2H), 7.85 (d, 2H,= 7.6 Hz), 7.90 (d, 1H,= 8.0 Hz)。

7-（邻甲苯基）-7-苊并[1,2-]吲哚-11-基乙酸酯4c核磁氢谱 (, ppm): 1.28 (s, 3H), 2.49 (s, 3H), 7.08 (s, 1H), 7.30 (d, 1H,= 7.2 Hz), 7.50 (t, 1H,= 7.2 Hz), 7.55 (d, 2H,= 8.0 Hz), 7.60-7.67 (m, 4H), 7.75 (d, 2H,= 8.0 Hz), 7.83 (d, 2H,= 8.0 Hz)。

7-（4-溴苯基）-7-苊并[1,2-]吲哚-11-基乙酸酯4d核磁氢谱 (, ppm): 2.62 (s, 3H), 7.07 (d, 1H,= 8.0 Hz), 7.23 (t, 1H,= 8.0 Hz), 7.30 (d, 1H,= 8.0 Hz), 7.41 (d, 1H,= 7.6 Hz), 7.53 (t, 1H,= 7.2 Hz), 7.66 (t, 1H,= 7.2 Hz), 7.73 (d, 1H,= 6.8 Hz), 7.79 (s, 1H), 7.80 (s, 1H), 7.83 (s, 1H), 7.88 (s, 1H), 7.90-7.92 (m, 2H)。

7-（4-溴苯基）-9-甲基-7-苊并[1,2-]吲哚-11-基乙酸酯4e核磁氢谱 (, ppm): 2.41 (s, 3H), 2.60 (s, 3H), 6.92 (s, 1H), 7.11 (s, 1H), 7.38 (d, 1H,= 6.8 Hz), 7.52 (t, 1H,= 6.8 Hz), 7.60-7.64 (m, 1H, ArH), 7.71 (d, 1H,= 6.4 Hz), 7.78 (d, 1H,= 8.4 Hz), 7.80-7.82 (m, 1H), 7.83-7.84 (m, 1H), 7.86-7.88 (m, 3H)。

7-（4-溴苯基）-9-苯基-7-苊并[1,2-]吲哚-11-基乙酸酯4f核磁氢谱 (, ppm): 2.65 (s, 3H), 7.36 (t, 1H,= 7.2 Hz), 7.43-7.48 (m, 4H), 7.51-7.55 (m, 2H), 7.64-7.70 (m, 3H), 7.75 (d, 1H,= 6.8 Hz), 7.79 (d, 1H,= 8.0 Hz), 7.86-7.95 (m, 5H)。

1.3 晶体学参数

表1 4f的晶体学参数

Table 1 Crystallographic parameters of 4f

Empirical formulaC32H20BrNO2 Formula weight530.40 Temperature298(2) K Wavelength0.71073 Å Crystal systemMonoclinic Space groupP2(1)/c Unit cell dimensionsa = 12.5369(9) Å α = 90.00 deg b = 25.344(2) Å β = 106.687(2) deg c = 7.6693(6) Å γ = 90.00 deg Volume2334.2(3) Å3 Z4 Density (calculated)1.383 Mg/m3 Absorption coefficient0.196 mm-1 F(000)1008 Crystal size0.37 x 0.18 x 0.11 mm Theta range for data collection2.89 to 25.02 deg Limiting indices-14<=h<=9, -30<=k<=29, -9<=l<=9 Reflections collected/ unique11671 / 4093 [R(int) = 0.0825] Data / restraints / parameters4093 / 0 / 325 Goodness-of-fit on F21.057 Final R indices [I>2σ(I)]R1 = 0.0576, wR2 = 0.1086 R indices (all data)R1 = 0.1280, wR2 = 0.1252 Largest diff. peak and hole0.254 and -0.311 e.A^-3

1.4 晶胞图

图3 4f的晶胞图

2 实验结果与分析

2.1 底物拓展

当R为氢原子时，考查原料1中Ar的多样性（图4）。实验表明，Ar是吸电子的取代基（4-FPh，3-BrPh）和给电子的取代基（2-MePh），都能生成相应的4-乙酯基吲哚衍生物4。

图4 合成4-乙酯基吲哚衍生物4a-4c

当Ar为对溴苯基时，考查原料1中R的多样性（图5）。实验表明，R无论是H，Me还是Ph，均不影响反应的进行，以72%-82%的产率生成产物4d-4f。

图5 合成4-乙酯基吲哚衍生物4d-4f

2.2 机理研究

如图6所示，-芳基环己-2-烯酮1和苊醌2通过连续的加成（1、2到A）、分子内环化（A到B）、脱水（B到C）、互变异构（C到D），酯化（D、3到4）等步骤，最终生成4-乙酯基吲哚衍生物4。

图6 反应机理

3 小结

从-芳基环己-2-烯酮、苊醌、乙酸酐出发，120℃微波辐射条件下，一步串联合成了4-乙酯基吲哚衍生物，对吲哚骨架的4位修饰进行了更好地补充。反应机理涉及分子内环化、脱水、互变异构、酯化等诸多步骤。其结构也得到单晶的证实。

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ETHYLATION OF 4-POSITION OF INDOLE SKELETON

FAN Wei

（Office of Research Affairs, Chuzhou City Vocation College, Chuzhou, Anhui 239000, China）

The 4-position functionalized indoles can be used as antiviral therapy for influenza, neurotoxins and antibacterial agents. Therefore, the modification study on the 4-position of indole skeleton is worth discussing. Starting from N-arylcyclohex-2-enone, acenaphthoquinone, and acetic anhydride, under the condition of microwave irradiation at 120 ℃, 4-ethyl ester indoles were synthesized in one step and supplemented the modification of the 4-position of indole skeleton. The structure is confirmed by single crystal. The reaction mechanism involves steps such as intramolecular cyclization, dehydration, tautomerism and esterification.

acenaphthoquinone; acid anhydride; 4-ethyl ester indoles

1674-8085（2022）01-0038-04

O626

A

10.3969/j.issn.1674-8085.2022.01.006

2021-08-22；

2021-10-02

国家自然科学基金项目（21272095）；安徽省教育厅科学研究重点项目（KJ2020A1003）

范 威(1988-)，男，江苏徐州人，讲师，博士，主要从事有机化学研究(E-mail: fanweipujing@126.com).