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

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.

Automated summary

This article presents a novel synthetic method for the production of saturated N-heterocyclic pharmacophore motifs, utilizing N,N-dimethylhydrazinoalkenes and diethylzinc followed by a Cu(I)-catalyzed cross-coupling reaction with 1-bromoalkynes to afford piperidines and pyrrolidines. The synthesis tolerates heteroatom-bearing alkynes and, unexpectedly, the use of ethyl propiolate as the trapping electrophile leads to selective N-functionalization with the formation of vinylogous urethanes. Alternative Cu(I) complexes were also evaluated as potential catalysts. This synthetic protocol can be easily scaled up for preparative purposes.