Radical Strategy to the Boron-to-Copper Transmetalation Problem: <i>N</i>-Alkylation with Alkylboronic Esters
Ruocheng Sang, Jason E. Gestwicki
Abstract
High Resolution Image Download MS PowerPoint Slide Organoboron compounds represent highly versatile reagents in organic synthesis, but their application to forge C(sp 3 )–heteroatom bonds, particularly C(sp 3 )–N coupling, remains underdeveloped. While the integration of alkylboron reagents with copper catalysis offers a promising approach, the inherently sluggish boron-to-copper transmetalation presents a significant challenge. Here, we develop a radical strategy to circumvent the two-electron transmetalation problem via an alkyl radical-capture mechanism, wherein the alkyl radical is generated through an aminyl radical-mediated boron abstraction. Leveraging a reductively activated boron-group transfer reagent, this mechanistically distinct approach enables a general N -alkylation using a diverse array of readily available N -nucleophiles and alkylboronic esters. This transformation differs fundamentally from previous approaches to provide a greater number of N -derivatives of complex small molecules with excellent regioselectivity. This method’s operational simplicity, broad functionality compatibility, and scalability enable streamlined access to N -alkylated architectures, addressing unmet needs in medicinal and process chemistry programs.