Direct C-H Difluoromethylation of Quinoxalin-2(1H)-ones/Coumarins Based on the Oxidation of Hypervalent Iodine (III) Reagent.

INTRODUCTION

Fluorine exhibits unique atomic properties that profoundly influence the biological and chemical characteristics of compounds. Fluorinated compounds are widely applied in pharmaceuticals and agrochemicals, with the difluoromethyl (CF₂H) group being particularly valuable. The industrialization of photocatalytic reactions is complex, and non-photocatalytic difluoromethylation methods predominantly rely on transition metals. Therefore, the development of a metal-free protocol for difluoromethylation holds considerable significance.

METHODS

This study aims to develop a metal-free, direct C-H quinoxalin-2(1H)-ones/coumarins difluoromethylation method using inexpensive and readily available raw materials and to evaluate the antifungal activity of selected substrates against phytopathogenic fungi. In the difluoromethylation reaction, [Bis(trifluoroacetoxy)iodo]benzene served as the difluoromethylating source, with mCPBA as the oxidant, to carry out the difluoromethylation of quinoxalin-2(1H)-ones/coumarins in the solvent ethyl acetate. We evaluated the antifungal activity using the mycelial growth rate method.

RESULTS

This approach is applicable to diverse quinoxalin-2(1H)-ones/coumarins, demonstrates excellent functional group tolerance, and is scalable to gram-scale reactions. Additionally, antifungal assays identified compound 7 as the most effective against R. solani, F. graminearum, and C. orbiculare.

DISCUSSION: This metal-free protocol enables quinoxalin-2(1H)-ones/coumarins difluoromethylation and scales to gram quantities without significant yield loss, facilitating industrial applications. Selected compounds exhibit potent antifungal activity and merit further study.

CONCLUSION

We developed a simple, metal-free protocol for the direct oxidative C-H difluoromethylation of quinoxalin-2(1H)-ones/coumarins using inexpensive, readily available starting materials. Upon evaluation of the antifungal activity of selected substrates against phytopathogenic fungi, compound 7 exhibited the strongest inhibitory effects and demonstrated potential for the synthesis of agrochemical intermediates.