Acta Chim. Sinica ›› 2015, Vol. 73 ›› Issue (10): 1018-1024.DOI: 10.6023/A15060400 Previous Articles     Next Articles



何玲a, 顾梦迪b, 王德先a, 赵亮b, 王梅祥b   

  1. a 分子识别与功能院重点实验室 中国科学院化学研究所 北京 100190;
    b 生命有机磷化学及化学生物学教育部重点实验室 清华大学化学系 北京 100084
  • 投稿日期:2015-06-08 发布日期:2015-08-18
  • 通讯作者: 王德先, 王梅祥;
  • 基金资助:


Tandem Heck Reaction of Tertiary Enamides: A Novel Access to trans-2,5-Disubstituted-3-Pyrroline Derivatives

He Linga, Gu Mengdib, Wang Dexiana, Zhao Liangb, Wang Meixiangb   

  1. a Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190;
    b MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084
  • Received:2015-06-08 Published:2015-08-18
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21320102002).

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 4a4k in moderate to high yields. Other N-substituted enamide substrates 2b2e 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 1a1l (1.05 mmol) in DMA (1.0 mL) was introduced into the tube, following the addition of substrate 2a2f (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 4a4p. 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