Difluorocarbene in Cycloadditions and Annulations for the Synthesis of gem‐Difluorocarbocycles and gem‐Difluoroheterocycles

Abstract

AbstractDifluorocarbene is a simple, readily prepared, and versatile difluorinated one‐carbon synthon. It can be applied as both the difluoromethylating reagent in the carbene insertion and the difluoromethylenating reagent in various cycloadditions and annulations. This concept article provides an account of applications of difluorocarbene in cycloadditions and annulations for synthesis of gem‐difluorocarbocycles and gem‐difluoroheterocycles. The synthesized gem‐difluorocarbocycles include 2,2‐difluorobicyclo[1.1.1]pentanes, 4,4‐/5,5‐difluoro‐cyclopentenes, 2,2‐difluorocyclopentanones, and 5,5‐difluorocyclopent‐2‐enones via tandem [2+1] cycloaddition and ring‐expansion or [4+1] annulations. The prepared gem‐difluoroheterocycles involve 2,2‐/3,3‐difluoro‐2,3‐dihydrofurans, 2,2‐difluoro‐2,3‐dihydrobenzofurans, 2,2‐difluoro‐2,3‐dihydrobenzothiophenes, 2,2‐difluorobenzofuran‐3(2H)‐ones, 2,2‐difluorobenzothiophen‐3(2H)‐ones, 2,2‐difluoro‐2,3‐dihydrothieno[2,3‐b]pyridines, 2,2‐difluorothieno[2,3‐b]pyridine‐3(2H)‐ones, 5,5‐difluorooxazolines and thiazolines, and spirocyclic 2,2‐difluorobenzo[d][1,3]aza/phosphaborol‐1‐ium‐3‐yliums via [4+1] annulations, 1,1‐difluoro‐1,4,5,9b‐tetrahydro‐2H‐[1,2]diazeto[4,1‐a]isoquinolines and 1,1‐difluoro‐1,4,5,9b‐tetrahydro‐2H‐[1,2]diazeto[1,4‐a]pyrrolo[2,1‐c]pyrazines via [3+1] annulation, 1,1‐difluoro‐1,9a‐dihydropyrido[2,1‐c][1,4]thiazines and 3,3‐difluorobenzo[e][1,4,2]oxaza/phosphaborinin‐4‐ium‐2‐uides via [5+1] annulations, 9,9‐difluoro‐8‐azabicyclo[5.2.0]nona‐2,4,6‐trienes via [8+1] annulation, 4,4‐difluorooxazolidines and 3,3‐difluoropyrrolidines via [2+2+1] annulations. Difluorocarbene generated from different readily available precursors proceeds these cycloadditions and annulations well. The substrate scopes, proposed mechanisms, selected product examples and their applications are discussed.