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

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 alpha-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 similar to 4k in moderate to high yields. Other N-substituted enamide substrates 2b similar to 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 similar to 11(1.05 mmol) in DMA (1.0 mL) was introduced into the tube, following the addition of substrate 2a similar to 2f (0.50 mmol) in DMA (1.0 mL). The resulting mixture was stirred at 80 degrees C 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 similar to 4p. The resulting trans-2,5-diphenyl-3-pyrroline was converted to pyrrole and pyrrolidine derivative, respectively, by oxidation and reduction.