Mykhailo Shevchuk

• For almost 40 years, difluoromethylene phosphonates – compounds of general formula RCF2P(O)(OR)2 – have attracted much interest as molecular tools to study enzymes and their behavior in biochemical processes. First, we discuss the chemistry of difluoromethylene phosphonates through the prism of its historical development and with an emphasis on general synthetic methods, highlighting the existing challenges and unsolved problems. We then explore the formal [3,3]-sigmatropic rearrangements of 2,3,3-trifluoroallyl phosphates leading to isomeric 1,1,2-trifluoroallyl phosphates under thermal and Lewis acid-promoted reaction conditions. Although the products of these rearrangements were unstable, the insights we gained while studying these reactions prompted us to explore similar formal [2,3]-sigmatropic rearrangements of 2,3,3-trifluoroallyl phosphorus (III) compounds. Finally, we describe the newly developed method for the preparation of CF2–P (V) phos- phonate analogs – difluoromethylene phosphonic and phosphinic amides, and phosphine oxides. The method is based on a formal [2,3]-sigmatropic phospha-Wittig rearrangement of readily available fluoroallyl bis(amido)phosphites, amido(aryl)phosphonites and diarylphosphinites. It allows for the preparation of title compounds in a straightforward fashion on a multigram scale, complementing the existing phosphoryldifluoromethylation methods. A powerful one-pot multistep protocol has been developed based on this method. It utilizes ubiquitous starting materials, such as THP-O-protected 2,2,2-trifluoroethanol, directly furnishing phosphonic, phosphinic and phosphine oxide analogs of α,α-difluoro-β-ketophospho- nates without the need for isolation and purification of the intermediate products. Besides providing access to unique compounds hardly accessible through other routes, the developed method benefits from the fact that, unlike most other existing general methods, it does not rely on ozone-depleting HCF2Cl and CF2Br2.