范 威

吲哚骨架4位的乙酯基化研究

范 威

（滁州城市職業(yè)學(xué)院科研處，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療、神經(jīng)毒素、抗菌劑。因此，吲哚骨架4位的修飾研究值得探討。從-芳基環(huán)己-2-烯酮、苊醌、乙酸酐出發(fā)，120℃微波輻射條件下，一步合成了4-乙酯基吲哚衍生物，補(bǔ)充了吲哚骨架4位的修飾。其結(jié)構(gòu)也得到了單晶的證實(shí)。反應(yīng)機(jī)理涉及分子內(nèi)環(huán)化、脫水、互變異構(gòu)、酯化等諸多步驟。

苊醌；乙酸酐；4-乙酯基吲哚衍生物

Arbidol[1]、Psilocin[2]、Clavicipitic酸[3]（圖1）等活性化合物均為4位官能化的吲哚衍生物，可用作流感的臨床抗病毒治療、神經(jīng)毒素、抗菌劑等。吲哚[4]骨架4位的修飾得到了廣泛的報(bào)道[5-9]，在這些研究中，關(guān)于吲哚骨架4位的乙酯基化研究尤其引人注目。

圖1 4位官能化的吲哚衍生物

Cho課題組[10]從4,5-二羥基吲哚酮出發(fā)，分兩步反應(yīng)，最終以81%的產(chǎn)率實(shí)現(xiàn)了吲哚骨架4位的乙酯基化。該反應(yīng)的缺點(diǎn)是使用的吡啶為致癌物質(zhì)（圖2a）。Be?langer課題組[11]先活化甲酰胺，然后經(jīng)分子內(nèi)Vilsmeier-Haack反應(yīng)，分子內(nèi)環(huán)加成等過程，最終合成了4-乙酯基化的吲哚衍生物，該反應(yīng)的主要缺點(diǎn)是原料不容易制得（圖2b）。Bj?rsvik課題組[12]從1,3-二甲氧基-2-甲基苯出發(fā)，經(jīng)多步反應(yīng)合成了4-乙酯基吲哚衍生物，該反應(yīng)的主要缺點(diǎn)是反應(yīng)步驟過多（圖2c）。

本課題組從-芳基環(huán)己-2-烯酮、苊醌、乙酸酐出發(fā)，120℃微波輻射條件下，一步合成了4-乙酯基吲哚衍生物，從而補(bǔ)充了吲哚骨架4位的修飾（圖2d）。

圖2 合成4-乙酯基吲哚衍生物

1 材料與方法

1.1 儀器與試劑

儀器：單晶衍射儀；核磁共振儀。

試劑：-芳基環(huán)己-2-烯酮；苊醌；乙酸酐。

1.2 表征數(shù)據(jù)

7-（4-氟苯基）-7-苊并[1,2-]吲哚-11-基乙酸酯4a核磁氫譜 (, 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核磁氫譜 (, 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-（鄰甲苯基）-7-苊并[1,2-]吲哚-11-基乙酸酯4c核磁氫譜 (, 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核磁氫譜 (, 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核磁氫譜 (, 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核磁氫譜 (, 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 晶體學(xué)參數(shù)

表1 4f的晶體學(xué)參數(shù)

Table 1 Crystallographic parameters of 4f

Empirical formulaC32H20BrNO2 Formula weight530.40 Temperature298(2) K Wavelength0.71073 ? Crystal systemMonoclinic Space groupP2(1)/c Unit cell dimensionsa = 12.5369(9) ? α = 90.00 deg b = 25.344(2) ? β = 106.687(2) deg c = 7.6693(6) ? γ = 90.00 deg Volume2334.2(3) ?3 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 晶胞圖

圖3 4f的晶胞圖

2 實(shí)驗(yàn)結(jié)果與分析

2.1 底物拓展

當(dāng)R為氫原子時(shí)，考查原料1中Ar的多樣性（圖4）。實(shí)驗(yàn)表明，Ar是吸電子的取代基（4-FPh，3-BrPh）和給電子的取代基（2-MePh），都能生成相應(yīng)的4-乙酯基吲哚衍生物4。

圖4 合成4-乙酯基吲哚衍生物4a-4c

當(dāng)Ar為對溴苯基時(shí)，考查原料1中R的多樣性（圖5）。實(shí)驗(yàn)表明，R無論是H，Me還是Ph，均不影響反應(yīng)的進(jìn)行，以72%-82%的產(chǎn)率生成產(chǎn)物4d-4f。

圖5 合成4-乙酯基吲哚衍生物4d-4f

2.2 機(jī)理研究

如圖6所示，-芳基環(huán)己-2-烯酮1和苊醌2通過連續(xù)的加成（1、2到A）、分子內(nèi)環(huán)化（A到B）、脫水（B到C）、互變異構(gòu)（C到D），酯化（D、3到4）等步驟，最終生成4-乙酯基吲哚衍生物4。

圖6 反應(yīng)機(jī)理

3 小結(jié)

從-芳基環(huán)己-2-烯酮、苊醌、乙酸酐出發(fā)，120℃微波輻射條件下，一步串聯(lián)合成了4-乙酯基吲哚衍生物，對吲哚骨架的4位修飾進(jìn)行了更好地補(bǔ)充。反應(yīng)機(jī)理涉及分子內(nèi)環(huán)化、脫水、互變異構(gòu)、酯化等諸多步驟。其結(jié)構(gòu)也得到單晶的證實(shí)。

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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

國家自然科學(xué)基金項(xiàng)目（21272095）；安徽省教育廳科學(xué)研究重點(diǎn)項(xiàng)目（KJ2020A1003）

范 威(1988-)，男，江蘇徐州人，講師，博士，主要從事有機(jī)化學(xué)研究(E-mail: fanweipujing@126.com).