α,α‐Difluoro‐H‐phosphinates: Useful Intermediates for a Variety of Phosphate Isosteres

Abstract

Addition of the radical generated from the sodium salt of hypophosphorous acid to difluoroalkenes results in the formation of α,α‐difluoro‐H‐phosphinates. These intermediates can be transformed into different phosphorus‐centered isosteres, such as difluorophosphonates, difluorophosphonothioates, and difluorophosphinates (see scheme).

Recent Developments in the Addition of Phosphinylidene‐Containing Compounds to Unactivated Unsaturated Hydrocarbons: Phosphorus–Carbon Bond Formation by Hydrophosphinylation and Related Processes

“…[xiv] Piettre similarly applied our reaction to the preparation of potentially biologically important α,α-difluoro- H -phosphinates (Scheme 6). [xv] …”

“…Piettre reported the radical functionalization of α,α-difluoro- H -phosphinic acids (Scheme 11). [xxvii] …”

Recent advances in sulfur- and phosphorous-centered radical reactions for the formation of S–C and P–C bonds

“…Markoulide and Regan applied radical addition of sodium hydrophosphonate to terminal alkene bond for the synthesis of intermediate 374 which was then converted to a phosphinate analogue of anti-tumor agent miltefosine 375 in six steps in 69% overall yield (Scheme 160) 260. Gautier, Piettre and their coworkers synthesized a series of gem-difluoroalkenes 376 for the reactions with hydrophosphonyl radicals to form novel α,α-difluoro-H-phosphinates 377 (Scheme 161) 261. These compounds can be easily converted to difluorophosphonates, difluorophosphonothioates, and difluorophosphinates.…”

Radicals in organic synthesis. Part 1

“…It appears that the sodium salt of hypophosphorus acid 507 offers a solution to this problem and is sufficiently nucleophilic to add to highly electron-poor alkenes. 323 Neither diethyl phosphite nor diethyl thiophosphite react with the electron-deficient alkene 506, yet 507 underwent clean addition to give 508 in high yield (Scheme 160). The reason for this unique reactivity is unclear at present, but the involvement of a tautomeric phosphorus(III) species has been ruled out.…”