Four-Step Synthesis of the β-Pyridylethylamine Core via Ring Opening of Pyrrolidines

Pyrrolidines, readily accessible saturated azaheterocycles, have emerged as valuable intermediates in the synthesis of aliphatic amines. In this work, we employed the ring cleavage of 3-aroylpyrrolidines for the four-step synthesis of 2,6-diarylpyridines and 6-aryldihydropyridin-2-ones decorated with the β-dialkylaminoethyl moiety, starting from ubiquitous enones or active methylene compounds. Namely, N-methylazomethine ylide gives rise to a wide range of pyrrolidines via 3 + 2 cycloaddition reaction with enones or one-step domino pyrrolidination of active methylene compounds. Treatment with alkyl halide and ring cleavage of the resulting quaternary ammonium salt of pyrrolidines in the presence of active methylene compounds provide α-(β-dialkylaminoethyl)-1,5-diketones or 1,5-ketoesters in good to high overall yields over three steps. Subsequent cyclization with ammonium acetate in TFEA or HFIP affords 3-pyridylethylamines and 5-pyridonylethylamines in 22-76% overall yields.