三级烯酰胺的串联Heck反应——一种反式2,5-二芳基-3-吡咯啉化合物新颖的合成方法

doi:10.6023/A15060400

摘要/Abstract

3-吡咯啉化合物不仅是重要的有机合成中间体, 而且其骨架结构广泛存在于具有生物活性的化合物中. 利用五元环三级烯酰胺的串联Heck反应, 实现了反式2,5-双取代-3-吡咯啉化合物简便、快捷的合成. 该方法首次将环状烯酰胺的α-芳基化反应和双键异构化进行了有效的结合, 为2,5-双取代-3-吡咯啉化合物的合成提供了一种全新的合成方法. 得到的3-吡咯啉产物可分别经氧化反应和还原反应方便地转化成吡咯或吡咯烷化合物.

关键词: 三级烯酰胺, Heck反应, 串联反应, 3-吡咯啉

3-Pyrroline structure is a common scaffold in natural products and synthetic bioactive molecules. 3-Pyrroline derivatives are also important intermediates in organic synthesis. The synthetic study of 3-pyrroline compounds has therefore always attracted great attention. Tertiary enamides are a class of unique and versatile synthons. They are able to participate in intramolecular and intermolecular reactions with various electrophiles, affording diverse nitrogen-containing heterocyclic compounds. Recently, we attempted the Heck reaction of the five-membered cyclic tertiary enamides and discovered the formation of α-arylated product with the double bond being shifted. We then envisioned a tandem diarylation reaction to synthesize 2,5-disubstituted-3-pyrroline derivatives. Herein, we reported the investigation of the Heck reaction of cyclic tertiary enamides, a simple and convenient approach to trans-2,5-disubstituted-3-pyrrolines. Silver salts were found to be effective additives to accelerate the reaction, while PdCl₂(PPh₃)₂ appeared as the best catalyst to improve the regioselectivity. Under the optimized conditions, a variety of differently substituted aryl iodides reacted smoothly with N-benzoyl-2,3- dihydro-1H-pyrrole 2a to afford the desired products 4a～4k in moderate to high yields. Other N-substituted enamide substrates 2b～2e underwent similar tandem reactions to give the corresponding products in moderate chemical yields. A representative procedure for this reaction is as follows: to an oven-dried Schlenk tube was successively added PdCl₂(PPh₃)₂ (18 mg, 0.025 mmol, 5 mol%), AgNO₃ (177 mg, 1.05 mmol, 2.1 equiv.), DABCO (168 mg, 1.5 mmol, 3.0 equiv.) and dry DMA (1.0 mL) under argon atmosphere. After stirring for 5 min at room temperature and the mixture turned black, aryl iodides 1a～1l (1.05 mmol) in DMA (1.0 mL) was introduced into the tube, following the addition of substrate 2a～2f (0.50 mmol) in DMA (1.0 mL). The resulting mixture was stirred at 80 ℃ until starting enamides and mono-arylated compounds were consumed, which was monitored by TLC analysis. After filtration, extraction and concentration in vacuo, the reaction residue was flash chromatographed on a silica gel column eluted with a mixture of petroleum ether and ethyl acetate (V:V=6:1) to give the pure product 4a～4p. The resulting trans-2,5-diphenyl-3-pyrroline was converted to pyrrole and pyrrolidine derivative, respectively, by oxidation and reduction.

Key words: tertiary enamide, Heck reaction, tandem reaction, 3-pyrroline

引用此文

何玲, 顾梦迪, 王德先, 赵亮, 王梅祥. 三级烯酰胺的串联Heck反应——一种反式2,5-二芳基-3-吡咯啉化合物新颖的合成方法[J]. 化学学报, 2015, 73(10): 1018-1024.

He Ling, Gu Mengdi, Wang Dexian, Zhao Liang, Wang Meixiang. Tandem Heck Reaction of Tertiary Enamides: A Novel Access to trans-2,5-Disubstituted-3-Pyrroline Derivatives[J]. Acta Chim. Sinica, 2015, 73(10): 1018-1024.

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