Recent Advances in the Deuteration of Indoles

Abstract

Deuteration has evolved into a transformative strategy in medicinal chemistry, materials science, and mechanistic research, owing to its ability to modulate molecular properties without perturbing core structures. As a privileged heterocyclic scaffold in natural products, pharmaceuticals, and functional materials, indole has become a prime target for deuteration. This review summarizes recent advances in regioselective indole deuteration, highlighting two core strategies: transition-metalcatalyzed hydrogen isotope exchange (HIE) (both directed and undirected) and non-metallic catalytic/chemical reagentmediated methods. Key breakthroughs include site-selective labeling of challenging positions (such as C2, C4) and late-stage deuteration of complex drug molecules, overcoming intrinsic reactivity biases of the indole ring. Despite these strides, critical challenges remain: limited regioselectivity for benzenoid ring (C4-C7) deuteration, functional group incompatibility, and practical barriers in cost-effective deuterium sources and scalability. Future directions focus on developing directing-groupfree catalytic systems, integrating green strategies (electro/photocatalysis) with low-cost D2O, and expanding applications in pharmaceutical optimization and materials innovation. This review provides a comprehensive overview of the field, bridging synthetic innovation with translational potential.