Weak-coordination-auxiliary aminocatalysis enables directed [3 + 2] cyclization for 2-acylindolizines

Abstract

The synthesis of 2-acylindolizines, possessing a readily modifiable ketone group, is of significant importance as it provides versatile precursors for the preparation of various indolizines. However, due to the electronically less active and more sterically demanding nature of α,β-unsaturated ketones toward iminium formation with an aminocatalyst, the efficient one-pot transformation of α,β-unsaturated ketones for distinct 2-acylindolizines bearing sensitive groups represents a challenge for synthetic chemists. Herein, we report a weak-coordination-auxiliary amino-catalyzed approach that enables directed [3 + 2] cyclization of α,β-unsaturated ketones and N-heteroaryl ketones for the desired 2-acylindolizines via an iminium ion/enamine tandem sequence. A highly broad range of commercially available α,β-unsaturated ketones (internal, terminal, and cyclic enones) can act as coupling partners for readily accessible 2-acylindolizines relative to the existing state-of-the-art methods. Control experiments and in-depth DFT calculations highlight the importance of weakly coordinated glycine's carboxylic group in promoting the intramolecular cyclization and 1,5-proton transfer processes.