Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents

Abstract

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.

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

“…We have previously shown that the addition of TMEDA as an auxiliary ligand for Cu(I) [14][15][16] conferred faster reaction times albeit with lower overall product yields due to the production of homocoupled diynes. 8 This was also noted with the formation of 4e (Table 1) and with 1-bromoalkynes 5c and 5d. The use of TMEDA was therefore determined to be deleterious and was discontinued.…”

“…The scalability of alkynylation was demonstrated by preparing 4b on a 1.5 mmol scale, using slightly altered reaction conditions (Table 1 ). 8…”

“…[4][5][6][7] We have briefly described a synthetic method in this category, which involves the copper(I)-catalyzed cross-coupling of 1-bromoalkynes with N-heterocyclic organozinc reagents derived from N,Ndimethylhydrazines bearing pendant alkenes. 8 Here, we provide a detailed account of this transformation, which encompasses the reaction scope and functional group toler-ance, and show that this method can be readily adapted to a preparative scale (Scheme 1).…”