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

doi:10.6023/A15060400

Abstract

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

Cite this article

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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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