Nickel-catalyzed ring-opening difunctionalization of methylenecyclobutanes via strain-release-enabled C-C activation.

Wang, Tingting; Liu, Haina; Luo, Meihong; Zhao, Wen-Wen; Ma, Chao; Zhang, Mingshuai; Liu, Jian-Biao; Wang, Hongyu · Nat Commun · 2026

basic_science · Level V

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Abstract

The efficient construction of molecular complexity from simple building blocks is a significant goal in catalysis, and the controlled ring-opening functionalization of strained carbocycles provides a powerful strategy to achieve it. However, selective catalytic strategies for ring-opening difunctionalization of methylenecyclobutanes (MCBs) remain elusive. Here, we report a nickel-catalyzed method that enables the 1,4-dicarbofunctionalization and 1,4-hydrocarbofunctionalization of MCBs via selective C-C bond cleavage. This protocol exploits the strain energy and dual reactivity of MCBs to deliver nonadjacent C(sp<sup>3</sup>)/C(sp<sup>2</sup>) frameworks in good to excellent yields under mild conditions. A broad substrate scope, scalability to the gram scale, and versatile downstream transformations demonstrate the synthetic utility of this approach. Mechanistic studies, including control, isotope-labeling experiments, and DFT calculations, reveal a distinct cooperative pathway involving strain-driven β-carbon elimination, offering new opportunities for catalyst-controlled activation of MCBs.