The [3,3]-Rearrangement Reactions Of Difluoroenol Silyl Ethers

Difluoroalkyl group is widely used in the structural modification of bioactive compounds and drugs,because this group can act as a more lipophilic isostere of the carbinol,thiol,hydroxamic acid or amide groups.The development of new strategies for difluoroalkylation of organic molecules remains highly desirable for drug discovery process.Unlike conventional aromatic difluoroalkylation reactions,the difluoroalkylation reactions of aryl iodanes and aryl sulfoxides through[3,3]-rearrangement are described in the thesis.1.[3,3]-sigmatropic rearrangement of aryliodanes with difluoroenol silyl ethers?DFSE?:In the study of the umpolung reactivity of DFESE with aryl iodanes,we serendipitously discovered the cross coupling of aryl iodanes with DFESE,allowing ortho-C-H difluoroalkylation of aryl idoanes.The reaction can proceed at remarkably low reaction temperature?-78°C?and complete in short reaction time?<5 min?,showing a powerful rearrangement driving force.This highly efficient rearrangement process endows this reaction with an excellent functional group compatibility,therefore providing a new method for difluoroalkylation of arenes.More importantly,an unconventional[3,3]-sigmatropic rearrangement was revealed by mechanistic studies.A unique fluorine effect was identified that could switch the nucleophilic center of DFESE from conventional“C”to“O”,and thus allow it to interact with activated aryl iodanes,giving the“I-O”-type rearrangement precursor.The subsequent rearrangement affords ortho-difluoroalkylated aryl iodides.As such,this study showcases the feasibility of using the unique fluorine effect to develop a new rearrangement reaction.2.The dearomatization of aryl sulfoxides with difluoroenol silyl ether?DFESE?:Following our recent study,we took advantage of the powerful rearrangement driving force of DFESE to ulteriorly develop the dearomative rearrangement reaction of aryl sulfoxides and DFESE,thus realizing the first examples of the dearomatization of ary sulfoxides.Two steps are involved in this reaction.The first is the[3,3]-rearrangement of aryl sulfoxides with DFESE that constructs ortho-difluoroalkylated dearomatized intermediate.The dearomatized intermediate shows different reactivity when different activators are applied.TFAA activator could afford the relatively stable mono-difluoroalkylated dearomatized intermediate at-40°C,which can be further trapped by external nucleophiles,giving mono-difluoroalkylated dearomative products.In contrast,using Tf₂O as activator enhances the electrophilicity of dearomatized intermediates,thus allowing the intermediate to adopt the second DFESE and thus producing dual-difluoroalkylated alicycles.It is worth mentioning that this reaction not only shows good functional group compatibility,but also has excellent regio-and stereoselectivies.As such,the developed method provides a new approach for the synthesis of difluoroalkylated alicycles.