Ti-Catalyzed Multicomponent Synthesis of Pyrroles Using Allene Coupling Partners

There is significant interest indeveloping chemo- and regioselectiveintermolecular multicomponent syntheses of N-heterocycles, which arecommon motifs in pharmaceuticals and natural products. Herein we examinethe potential of allenes to serve as selective coupling partners ina Ti-catalyzed [2 + 2 + 1] pyrrole synthesis reaction, which typicallyinvolves a [2 + 2] cycloaddition with an unsaturated substrate followedby a 1,2-insertion with a second unsaturated substrate. 1,2-Cyclononadieneacts as a regioselective insertion coupling partner to afford 2,3-annulatedpyrroles through reaction with alkynes and azobenzene. Additionally,propadiene was found to undergo both [2 + 2] cycloaddition and insertionin a highly regioselective manner, yielding exclusively N-phenyl-2,5-dimethylpyrrole. In contrast, the [2 + 2 + 1] reactionof propyne, a propadiene isomer, results in an unselective regioisomericmixture. This difference highlights how allenes can provide complementary(or better) selectivity compared to alkynes in multicomponent synthesis.

Automated summary

This study examines the potential of allenes as selective coupling partners in a Ti-catalyzed [2 + 2 + 1] pyrrole synthesis reaction. The results show that 1,2-cyclononadiene acts as a regioselective insertion coupling partner, producing 2,3-annulated pyrroles through reaction with alkynes and azobenzene. Additionally, propadiene undergoes both [2 + 2] cycloaddition and insertion in a highly regioselective manner, yielding exclusively N-phenyl-2,5-dimethylpyrrole, while propyne results in an unselective regioisomeric mixture. This highlights the complementary or better selectivity provided by allenes compared to alkynes in multicomponent synthesis.