On the Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents: Substrate Scope and Catalyst Evaluation

This manuscript is dedicated to Professor David A. Evans, who inspired the author as an undergraduate at UCLA.

Abstract

Nitrogen-containing heterocycles are ubiquitous in FDA-approved small molecule pharmaceuticals. Herein, we expand on a novel synthetic method for the production of saturated N-heterocyclic pharmacophore motifs with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with diethylzinc followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes affords piperidines and pyrrolidines in respectable yields. Functional group tolerance is demonstrated by the inclusion of heteroatom-bearing alkynes. Unexpectedly, the use of ethyl propiolate as the trapping electrophile led to selective N-functionalization with the formation of vinylogous urethanes. Alternative Cu(I) complexes were also evaluated as prospective catalysts. This synthetic protocol can readily be achieved on a preparative scale.

Key words

cross-coupling - copper - catalysis - heterocycles - alkynes

Publication History

Received: 19 March 2023

Accepted after revision: 07 June 2023

Article published online:
04 July 2023

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