Synthesis of a Library of 5,6-Unsubstituted 1,4-Dihydropyridines Based on a One-Pot 4CR/Elimination Process and Their Application to the Generation of Structurally Diverse Fused Nitrogen Heterocycles

摘要

Indium trichloride is an efficient catalyst for the sequential four-component reaction between aliphatic amines, β-ketoesters, α,β-unsaturated aldehydes, and ethanol to afford 6-ethoxy-1,4,5,6-tetrahydropyridines, which were converted in situ into 5,6-unsubstituted 1,4-dihydropyridines via ethanol elimination in the presence of neutral Al₂O₃, in a very efficient, one-pot protocol from acyclic, readily available starting materials that involves the generation of two C−N σ and one C−C π bonds. The structural variety of the dihydropyridine library thus generated was extended by base-promoted γ-alkylation of their C-2 position. The application of these 1,4-dihydropyridines to the facile generation of molecular diversity and complexity was demonstrated by employing them as dienophiles for Yb(OTf)₃-catalyzed imino Diels−Alder (Povarov) reactions leading diastereoselectively to hexahydrobenzo[h][1,6]-naphthyridine derivatives containing three adjacent stereocenters. The synthesis of fused dihydropyridines derived from the pyrido[2,1-a]azepine (homoquinolizine) frameworks was also achieved using a four-component tetrahydropyridine synthesis/ring-closing metathesis/elimination strategy.