Issue 9, 2024

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
20 Sep 2023
Accepted
06 Dec 2023
First published
13 Dec 2023
This article is Open Access
Creative Commons BY-NC license

Green Chem., 2024,26, 5253-5259

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

K. Zeng, N. K. Pandit, J. C. A. Oliveira, S. Dechert, L. Ackermann and K. Zhang, Green Chem., 2024, 26, 5253 DOI: 10.1039/D3GC03552B

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