Radical-promoted “unstrained” C–C and C–N bond cleavage: a blueprint for deconstructive skeletal editing

Abstract

Unstrained cyclic scaffolds are commonly regarded as inert backbones; however, recent radical and radical-ion strategies show that their connectivity can be deliberately reprogrammed when appropriate functional gateways are embedded in the ring. This Tutorial Review treats radical-promoted C–C and C–N bond cleavage as a design problem defined by three interdependent elements: the gateway that enables bond scission (alcohols, ketones, and amines), the activation mode that generates oxygen- or nitrogen-centred intermediates (single-electron transfer (SET), proton-coupled electron transfer (PCET), ligand-to-metal charge transfer (LMCT), and electron donor–acceptor (EDA) activation), and the downstream interception that determines whether deconstruction evolves into productive skeletal editing. Rather than compiling reactions, we distil practical rules for aligning activation with radical polarity and lifetime, and show how closely related intermediates can be steered toward ring opening and functionalisation or, under tighter kinetic constraints, toward ring contraction and expansion. Particular emphasis is placed on ketone-derived gateways that channel C–C scission through iminyl radicals or pre-aromatic intermediates, and on the direct use of cyclic alcohols via alkoxy radicals, organised through a two-step framework that separates radical generation from the divergent reactivity of the β-scission-derived carbon-centred radical.