Introducing covalent warheads on spirocyclic sp²-sp³ fragments by innate C-H functionalization

Sp²-sp³ fragments play a vital role in fragment-based drug design (FBDD). Strategies to chemically modify them and efficiently access libraries of these compounds have been goals of the highest priority in the last decades. In this work, a series of sp²-sp³ fragments was synthesized and validated for that purpose, based on their measured physical-chemical properties. Selective C-H cyanation and allylation of these fragments was demonstrated by simple heating in presence of an appropriate hydrogen-atom transfer reagent and a radical acceptor. These conditions enabled a streamlined access to covalent fragments in a single step, by direct introduction of the desired covalent binder. Preliminary results on vinylation, as well as late-stage functionalization of a drug analogue were disclosed.