Radical Strategy to the Boron-to-Copper Transmetalation Problem: N-Alkylation with Alkylboronic Esters

解决硼铜金属转移问题的激进策略:烷基硼酸酯的N-烷基化

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Abstract

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.

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