Ti-Catalyzed Multicomponent Synthesis of Pyrroles Using Allene Coupling Partners

Abstract

There is significant interest in developing chemo- and regioselective intermolecular multicomponent syntheses of N-heterocycles, which are common motifs in pharmaceuticals and natural products. Herein we examine the potential of allenes to serve as selective coupling partners in a Ti-catalyzed [2 + 2 + 1] pyrrole synthesis reaction, which typically involves a [2 + 2] cycloaddition with an unsaturated substrate followed by a 1,2-insertion with a second unsaturated substrate. 1,2-Cyclononadiene acts as a regioselective insertion coupling partner to afford 2,3-annulated pyrroles through reaction with alkynes and azobenzene. Additionally, propadiene was found to undergo both [2 + 2] cycloaddition and insertion in a highly regioselective manner, yielding exclusively N-phenyl-2,5-dimethylpyrrole. In contrast, the [2 + 2 + 1] reaction of propyne, a propadiene isomer, results in an unselective regioisomeric mixture. This difference highlights how allenes can provide complementary (or better) selectivity compared to alkynes in multicomponent synthesis.