Homolytic aromatic substitution (HAS) is a reaction class that plays an important role in organic synthesis. The reaction proceeds via addition of radicals to an arene and is recognized as a radical analogue of the conventional electrophilic aromatic substitution. The use of this strategy in (hetero)arene C–H functionalization has attracted widespread interest. In general, the positional selectivity is governed by the interplay of polar and steric effects of both the arene substrates and the incoming radicals; however, accessing a single regioisomer is still challenging when there are multiple sites in the C–H substrates to intercept radicals. The difficulty in controlling the regioselectivity significantly constrains this strategy’s broad utility in synthesis, with successful applications limited to intramolecular cyclization or reaction manifolds employing highly electronically biased arene substrates. Recent efforts in this area have enabled improved site selectivity by carefully modulating the structure of radicals and arene substrates, yet the development of a general approach that could override the regiochemical control induced by polar and steric effects and achieve high selectivity remains a challenge.
Anilines (primary aryl amines, ArNH2) are important synthetic intermediates in preparation of pharmaceuticals, agrochemicals and organic materials. Although the nitration–hydrogenation process is commonly used in industry, its utility in (late-stage) amination of functionalized arenes is hampered by the harsh conditions, resulting in poor functional-group tolerance and significant safety concerns. Although direct C–H amination is particularly attractive from the perspective of substrate accessibility and atom economy, challenges associated with site selectivity must be overcome to find broad synthetic application, with pioneering solutions using electronically biased arene substrates in electrophilic amination reactions or deploying specific directing groups in directed C–H amination. Notably, despite the substantial progress in transition metal-catalysed C–H functionalization, a general catalytic method to directly access primary aryl amines remains elusive. HAS with a nitrogen-centred radical (NCR) represents a compelling strategy for arene C–H amination due to its high reactivity and broad scope.
Recently, cooperated with Prof. Yanfeng Dang of Tianjin University, Fei Wang’s group have demonstrated an iron-catalysed HAS reaction mediated by an iron-aminyl radical that enables a general and highly ortho-selective arene C–H amination to afford structurally diverse anilines. This method exhibits broad substrate scope, ranging from simple aromatic building blocks to complex bioactive molecules, including both electron-rich and electron-deficient arenes. This approach sufficiently overrides the intrinsic regiochemical control dictated by electronic and steric effects, incorporating the NH2 group to a site that was previously inaccessible.This directed, metal-supported radical-mediated HAS strategy will find synthetic applications beyond the present amination reaction as well as widespread utility in organic synthesis and medicinal chemistry. Relevant achievements were published in Nature Catalysis, 2024, DOI: 10.1038/s41929-024-01140-5
