A difluorocarbene-triggered annulation/ring expansion cascade via sequential single-atom-insertions: direct assembly of 2-fluoroquinazolinones from azo compounds

Abstract

An efficient difluorocarbene-mediated tandem strategy for the synthesis of 2-fluoroquinazolin-4(3H)-ones via a sequential single-atom-insertion process has been developed. The method features a unique cascade starting from readily available azo compounds, which undergo an initial difluorocarbene-triggered annulation to form 3-halobenzopyrazole intermediates. These key intermediates are then converted into the final 2-fluoroquinazolinones through a second difluorocarbene-triggered ring expansion. This metal-free, redox-neutral protocol exhibits broad substrate scope and excellent functional group tolerance. Mechanistic investigations, including intermediate detection experiments, control experiments, isotopic labeling experiments, HRMS analysis, and Hammett studies, support the proposed reaction pathway and identify the formation of the halobenzopyrazole intermediate as a key step. The synthetic utility of the products is further demonstrated through diverse derivatizations and preliminary biological evaluation, revealing promising antitumor activity for certain fluorinated compounds compared to their defluorinated analogues, highlighting the value of the retained fluorine atom.