Synthesis of 4- and 5-membered fluorine-stabilised semi-saturated heterocycles via alkylidene carbenes

Abstract Heterocycles are ubiquitous in biologically active molecules and central to pharmaceutical design. Their diverse reactivity and three-dimensional architectures make them essential scaffolds for tuning non-covalent interactions with biological targets. Saturated and unsaturated heterocycles are well established and widely exploited, but semi-saturated variants are rare, limited by synthetic inaccessibility and oxidative instability. Here we present a general strategy for synthesising fluorinated semi-saturated four- and five-membered nitrogen and oxygen heterocycles via alkylidene carbene intermediates, and show through kinetic, voltammetry and metabolism studies that fluorine is key to stabilising these underexplored motifs. The method affords oxidatively stable products with diastereoselectivity across diverse substitution patterns and functional groups. These scaffolds can be selectively derivatised to yield saturated, unsaturated, and semi-saturated fluorinated analogues to provide broader access to pharmaceutically-relevant chemical space.