Multigram Synthesis of Difluoromethylene Phosphonic and Phosphinic Amides and Phosphine Oxides via Formal [2,3]-Sigmatropic Allyl Phosphite–Allylphosphonate Rearrangement

Abstract

We describe a method for the preparation of CF2-P(V) building blocks and monomers for biological and material chemistry applications in multigram quantities based on a formal [2,3]-sigmatropic phospha-Wittig rearrangement of readily available fluoroallyl bis(amido)phosphites, amido(aryl)phosphonites and diarylphosphinites. The proposed intramolecular phosphorylation approach complements the currently prevailing phosphoryldifluoromethylation methods by providing a straightforward access to difluoromethylene phosphonate analogues bearing dialkylamino and/or aryl substituents at the phosphoryl group. An important advantage of the developed method is that it does not rely on ozone-depleting HCF2Cl and CF2Br2 necessary for the preparation of phosphoryldifluoromethylating reagents. 2,3,3-Trifluoroallyloxy P(III) derivatives substituted with two dialkylamino and/or aryl groups underwent a facile [2,3]-phospha-Wittig rearrangement to give difluoromethylene phosphonic, phosphinic and phosphine oxides on up to a 0.15 mol (30 g) scale. The reaction was extended to P(III) derivatives of 1-substituted 2,3,3-trifluoro- and 3,3-difluoroallylic alcohols readily available from carbonyl compounds and, respectively, 1,1,1,2-tetrafluoroethane and O-protected 2,2,2-trifluoroethanols. Products derived from O-(2-tetrahydropyranyl)-2,2,2-trifluoroethanol were synthesized and deprotected in a one-pot multistep protocol to give phosphonic, phosphinic and phosphine oxide analogues of α,α-difluoro-β-ketophosphonates on a multigram scale.

Chemistry of difluoromethylene phosphonates: history, state of the art, and prospects

“…Our group has recently reported a general method for the preparation of difluoromethylene phosphonic and phosphinic amides and phosphine oxides 33 based on the formal [2,3]-sigmatropic rearrangement of fluoroallylic P(III) derivatives 32 (Scheme 18) [172]. Although not especially well explored, the earliest precedents of such an allyl phosphiteallyl phosphonate Arbuzov rearrangement of non-fluorinated substrates can be traced back to the 1963 work by Pudovik and Aladzyeva [173] and the 1964 work by Lemper and Tieckelmann [174].…”