Synthesis and bioactivity evaluation of isoxazoline scaffolds using heterogeneous photocatalytic (3+2) cycloaddition

Abstract

Introduction

The (3+2) cycloaddition is a classic method for synthesizing bioactive isoxazoline and isoxazole heterocycles. However, its utility is hampered by a reliance on stoichiometric halogenating oxidants, bases, and multi-step protocols, generating significant waste and limiting synthetic efficiency.

Objectives

This study aims to develop an efficient alternative to the classical (3+2) cycloaddition. Our objective was to achieve the direct synthesis of isoxazolines and isoxazoles from oximes and alkenes under mild, additive-free conditions using a heterogeneous photocatalytic system.

Methods

We employed mesoporous graphitic carbon nitride (mpg–CN) as a recyclable, metal-free photocatalyst. Reactions were conducted under visible light irradiation using oxygen as a benign terminal oxidant. The scalability was demonstrated via a continuous-flow setup. Mechanistic pathways were elucidated through a combination of experimental studies and density functional theory (DFT) calculations.

Results

Various oximes and alkenes were successfully converted into the target heterocycles in good to excellent yields. The protocol features exceptional functional group tolerance, accommodating sensitive motifs like heterocycles and Helicid analogs. Gram-scale synthesis of pharmacologically relevant cores was achieved in a continuous-flow reactor. Mechanistic investigations indicate that an energy transfer process primarily mediates the reaction cascade. Selected synthesized compounds showed promising insecticidal activity against Plutella xylostella.

Conclusion

We have developed a heterogeneous photocatalytic (3+2) cycloaddition protocol. This one-step, additive-free method provides an efficient and scalable route to valuable isoxazoline and isoxazole scaffolds, with demonstrated potential for generating bioactive molecules.