Single-Carbon Atom Insertion into Phenols with Nitroalkanes

Abstract

The catalytic conversion of phenols into high-value structural motifs via benzene ring skeletal reconstruction remains a significant challenge in organic synthesis, particularly through single-carbon atom insertion. Traditional methods, such as the Büchner reaction, are constrained by the use of reactive carbenoid C1 synthons, poor tunability of site-selectivity, and limited scalability. Herein, we describe that simple nitroalkanes, under copper catalysis and aerobic conditions, serve as practical noncarbenoid C1 sources for direct single-carbon atom insertion into phenols. The insertion site can be diverted from the C2═C3 bond to the C1═C2 bond upon simple addition of AlCl3, thereby enabling access to two distinct classes of tropones with excellent site-selectivity. The nitro group serves three essential roles─as an electron-withdrawing group, a directing group, and a leaving group──enabling oxidative dearomative ortho-alkylation and subsequent ring reconstruction. The method tolerates a wide range of functional groups and heteroarenes, operates on a 100-g scale with low cost, and allows kinetic resolution of axially chiral 2-naphthols with up to 98% ee. This work establishes nitroalkanes as a new class of C1 building blocks and unlocks programmable skeletal editing of phenols for synthetic and materials applications.