Bis-enaminone Based Parallel Solution-Phase Synthesis of 1,4-Dihydropyridine Derivatives

Two variations of a parallel solution-phase synthesis of N-substituted dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates 4 and methyl 3-oxo-3,5-dihydro-2H-pyrazolol[4,3-c]pyridine-7-carboxylates 9 from dimethyl acetone-1,3-dicarboxylate (1) were developed. The first synthetic method comprises preparation of the bis-enaminone reagents 2 and 8 and their cyclization with primary amines 3 via double substitution of both dimethylamino groups to give dihydropyridines (DHPs) 4 and 9, respectively. Another variation consists of preparation of the monoenaminone reagents 5 and 10, followed by substitution of the dimethylamino group with primary amines 3, and cyclization of the so formed intermediates 6 with N,N-dimethylformamide dimethylacetal (DMFDMA). In this manner, a library of 46 analytically pure compounds, 24 intermediates 6, 11, and 13, and 22 final dihydropyridines 4 and 9 was obtained employing just a simple filtration workup.