Ti-Catalyzed Multicomponent Synthesis of Pyrroles Using Allene Coupling Partners

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.