Late-Stage Heteroarene Alkylation via Minisci Reaction with Gaseous Alkanes Enabled by Hydrogen Atom Transfer in Flow.

Abstract

The late-stage functionalization of complex molecules is a pivotal strategy in drug discovery, enabling the rapid optimization of lead compounds. However, the use of gaseous alkanes as alkylating agents in these processes remains underexplored due to their inertness and handling challenges. Here we present a photocatalytic platform that facilitates the alkylation of heteroarenes using abundant gaseous C1-C4 hydrocarbons under continuous-flow conditions. Through hydrogen atom transfer (HAT) catalysis, we achieve the efficient alkylation of pharmaceutically relevant compounds without the need for prefunctionalized reagents. Our method is not only scalable and sustainable but also extends to the functionalization of marketed drugs and natural products.