Reactions of N-heterocyclic carbenes with nitrobenzenes: harnessing NHCs as synthetic building blocks.

INTRODUCTION

Quinazolin-4-one is a privileged scaffold in drugs with broad clinical applications. Conventionally, an o-amino group was generally needed to be pre-installed on the benzoic acid-derived starting materials for the efficient condensation reactions towards quinazolin-4-ones. The application of benzene derivatives without requisite amino and / or carbonyl groups as the quinazolin-4-one starting materials has not been disclosed. Therefore, we report herein the fabrication of NHC molecules with nitrobenzenes for facile access to quinazolin-4-one derivatives.

OBJECTIVES

To develop an unprecedented synthetic method utilizing nitrobenzenes and N-heterocyclic carbene (NHC) molecules, to elucidate the novel reaction mechanism through experimental and computational studies, to synthesize a series of quinazolin-4-one derivatives, and to evaluate their in vitro antibacterial activity.

METHODS

A synthetic method involving nitrobenzenes and NHC molecules was developed. The novel reaction mechanism was elucidated through isotopic labeling experiments and computational studies, and a series of quinazolin-4-one derivatives were synthesized. The synthesized compounds were evaluated for in vitro antifungal activity against four plant pathogens using the mycelial growth rate method.

RESULTS

We report for the first time an unprecedented synthetic method involving nitrobenzene and NHC molecules. The nitrobenzene substrate acts as a novel type of NHC acceptor, enabling a condensation reaction with the NHC molecule through a multi-step nucleophilic addition/rearrangement/dehydration cascade process. This conceptually novel reaction mechanism has been thoroughly investigated through experimental and computational studies. A variety of substituents with different electronic properties are tolerated on both the nitrobenzene and NHC reactants. A series of quinazolin-4-one products can be readily accessed using the current synthetic strategy, and they exhibit promising antifungal activity in plant protection.

CONCLUSION

We have developed a conceptually novel incorporation reaction between nitrobenzenes and NHC molecules. Synthesized compound 13 exhibited broad-spectrum antifungal activity, providing a basis for its development potential as a new framework for pesticide design.