Given the ubiquity of alkyl amines in organic molecules ranging from simple starting materials to complex natural products and drug candidates, they are ideal candidates for transition metal-catalyzed cross-coupling reactions. However, their utilization in this field remains limited, and they are predominantly employed in the preparation of nitrogen-containing products. We thus adopted a synthetic program aimed at harnessing alkyl amines with unactivated alkyl groups in Ni-catalyzed cross-coupling reactions. We have previously reported the Suzuki–Miyaura arylation of Katritzky pyridinium salts, which are easily and selectively prepared from primary alkyl amines. This reaction was the first example of a cross-coupling of an alkyl amine derivative with an unactivated alkyl group; these cross-couplings were previously restricted to alkyl amine derivatives with electronic or strain activation of the Csp3–N bond. Motivated by the potential to multiply the utility of alkyl amines in synthesis, we are presently reporting a Negishi cross-coupling for the generation of Csp3-Csp3 bonds under Ni catalysis (Figure 1). Such alkyl-alkyl cross-coupling methodologies remain underdeveloped, despite recent major advances, and we are excited about the potential the present reaction will have in the generation of new, fully unsaturated C–C bonds. The reaction enjoys broad substrate scope and functional group tolerance, with complex pharmaceutical intermediates being employed as substrates in high yields. Additionally, both primary and secondary (cyclic and acyclic) alkyl amines can be successfully employed, overcoming a significant barrier often observed in analogous transformations.

Negishi alkylation of alkyl pyridinium salts: Alkyl-alkyl cross-couplings via C–N bond activation of alkyl amine derivatives

255th National Meeting (2018)

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