# Divergent photochemical ring-replacement of isoxazoles

## TL;DR

A new photochemical method converts isoxazoles into various heterocycles, enabling easier drug discovery.

## Contribution

A solvent-controlled photochemical ring-replacement platform for isoxazoles into multiple heterocycles is introduced.

## Key findings

- A photochemical method enables conversion of isoxazoles into oxazoles, pyrazoles, pyrroles, and isothiazoles.
- The transformation occurs via α-ketonitrile intermediates under mild conditions.
- The method shows selectivity, functional group tolerance, and applicability in late-stage drug discovery.

## Abstract

Isoxazoles, oxazoles, and other five-membered heteroaromatics are prevalent motifs in core structure of pharmaceuticals and agrochemicals. In early-stage drug discovery, it is common practice to prepare libraries of analogues featuring different heterocyclic cores and this generally requires a de novo synthesis for each scaffold. A valuable but currently unavailable strategy would involve the possibility for direct heterocycle “ring-replacement”. Here we report a photochemical platform for the selective conversion of isoxazoles into oxazoles, pyrazoles, pyrroles, and isothiazoles by exploiting excited-state reactivity. Starting from a successful isoxazole-to-oxazole transformation, we uncover position-sensitive reactivity that prompted computational investigation. These insights guide a systematic reactivity survey and reveal a solvent-controlled deconstruction–reconstruction pathway via α-ketonitrile intermediates. This approach enables scaffold diversification without de novo synthesis, affording access to five distinct azole classes under mild conditions. The method’s selectivity, functional group tolerance, and late-stage applicability suggest broad utility in heterocyclic library design for pharmaceutical research.

Isoxazoles, oxazoles, and other five-membered heteroaromatics are prevalent motifs in core structure of pharmaceuticals and agrochemicals. Here the authors report a photochemical platform for the selective conversion of isoxazoles into oxazoles, pyrazoles, pyrroles, and isothiazoles by exploiting excited-state reactivity.