Continuous 1,4/1,6- and 1,2-addition reactions combined with the skeletal rearrangement of 5aH,13H-chromeno[2,3-b]quinolizin-13-ones with isocyanides to enable the synthesis of pyrido[2,3-b]indolizines

Abstract

We developed a protocol for synthesizing highly functionalized pyrido[2,3-b]indolizines (PDIZs, 3) from 5aH,13H-chromeno[2,3-b]quinolizin-13-ones using ((isocyanomethyl)sulfonyl)benzene derivatives. The continuous cycloaddition of [1,4], [1,6], and [1,2] bonds, along with skeletal rearrangement, was achieved by heating a mixture of substrates 1 and 2 in DMSO, facilitated by Cs₂CO₃ and catalyzed by Ag₂CO₃. This process led to the cleavage of three bonds (C–C, C–N, and C–O) and the formation of four bonds (C–N and three C–C) in a single step, enabling the rapid conversion of tricyclic systems from 5aH,13H-chromeno[2,3-b]quinolizin-13-ones (CMQZs) to PDIZs. The rearrangement and transformation of these scaffolds are significant for drug discovery. Additionally, the reactions can be enhanced by Ag catalysis to produce functionalized PDIZs suitable for combinatorial and parallel synthesis via one-pot reactions.