Nitrogen-containing heterocycles represent the majority of FDA-approved small-molecule pharmaceuticals. Herein, we describe a synthetic method to produce saturated N-heterocyclic drug scaffolds with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with Et2Zn, followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes, results in piperidines and pyrrolidines with a good yield. Five examples are reported and a proposed mechanism for the Cu(I)-catalyzed cross-coupling is presented.
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.
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