σ-Bond insertion reactions of two strained diradicaloids

Abstract

The development of new synthetic methodologies are instrumental for enabling the discovery of new medicines. Those methods that provide efficient access to structural alternatives for aromatic compounds (i.e., saturated arene bioisosteres), have become highly coveted.^1,2,3,4 The incorporation of such bioisosteres typically leads to favorable drug-like properties and represents an emerging field of research. Here, we report a new synthetic method that furnishes one especially coveted motif, the bicyclo[2.1.1]hexane scaffold,^5,6 using mild reaction conditions and an operationally-simple protocol. The methodology proceeds via the uncommon coupling of two strained fragments: transiently-generated cyclic allenes and bicyclo[1.1.0]butanes, which possess considerable strain energies of ~30 kcal/mol⁷ and ~60 kcal/mol,⁶ respectively. The reaction is thought to proceed via a σ-bond insertion through a diradical pathway. However, rather than requiring an external stimulus to generate radical species, reactivity is thought to arise as a result of innate diradical character present in each reactant. This diradicaloid character,⁸ an underutilized parameter in reaction design, arises from the severe geometric distortions of each reactant. Our studies provide a means to access functionalized bicyclo[2.1.1]hexanes of value for drug discovery, underscore how geometric distortion of reactants can be used to enable uncommon modes of reactivity, and should encourage the further exploration and strategic use of diradicaloids in chemical synthesis.