ChemInform Abstract: The Novel Synthesis of Fluorinated Unsaturated Phosphonates.

Abstract

Phosphonic acids are very important compounds in biological system by virtue of their similarity to phosphates. The replacement of oxygen in phosphate esters by a fluoromethylene (CHF) or difluoromethylene (CF2) unit has been received much attention due to the enhancement of biological properties as compared to non-fluorinated analogs. It has been well known that α-fluorinated phosphonates mimic phosphates in their isosteric and isopolar properties. Theoretical calculations have proposed that monofluorophosphonate analogues show more similarity in isosteric and isopolar concept than difluorophosphonate ones. Although a variety of biologically interesting compounds that contain the saturated α-monofluoroalkylphosphonate or α,α-difluoroalkylphosphonate-based mimics has been discovered in recent work via various methods, the synthetic methods for the unsaturated α-monofluorophosphonates or α,α-difluorophosphonates have been quite limited. Especially, the unsaturated α-monofluorophosphonates have been prepared by more limited methods. A recent report has suggested that α-fluorovinylphosphonates are good precursors to αmonofluoroalkylphosphonates via reduction of double bond and also may have interesting biological properties. The previous methods for the preparation of α-fluorovinylphosphonates include Wadsworth-Emmons reaction of lithium fluoromethylenebisphosphonate with aldehydes and ketones, Peterson-olefination of lithium fluorotrimethylsilylphosphonate with aldehydes and ketones, and reaction of lithium fluoromethylenediphosphonate with aldehydes. However, β-phenylthio or β-phenylsulfonyl substituted α-fluorovinylphosphonates which can be transformed to another functionality via phenylthio or phenylsulfonyl group can not be prepared by previous methods. In this paper, we wish to describe a new synthetic method for the preparation of βphenylthio or β-phenylsulfonyl substituted α-fluorovinylphosphonates via addition-elimination of corresponding β-phenylthio or β-phenylsulfonyl substituted α,α-difluoroolefins with triethylphosphite or sodium diethylphosphonate. β-Phenylthio substituted α,α-difluoroolefins 2a-e as starting materials can be prepared in 75-90% yields from the reaction of trifluoromethylated dithioketals 1a-e with a mixture of TiCl4 and LiAlH4 in THF at reflux temperature for 3 h. Further oxidation of 2a-e with MCPBA in CH2Cl2 at room temperature for 3 h afforded the corresponding β-phenylsulfonyl substituted α,α-difluoroolefins 3a-e in 77-88% yields. 1,1-Difluoro-3-phenylsulfonyl-2-phenylthio-1-propene (2f) as an another starting material was prepared in 82% yield from the reaction of 3-bromo-3,3-difluoro-2-phenylthio-1-propene (4) with sodium benzenesulfinate in DMF. The further oxidation of 2f with MCPBA provided the corresponding disulfone in solution, but isolation of this disulfone compound was always failed probably due to the unstability of disulfone compound.