Alkylthio-Fluoro-and Difluoromethylphosphonates: Synthesis and Reactivity

Abstract

The mimicry of rurtive phosphate eskrs has become a0 established in the dcsign of biologically-active compounds. Fluoromethylene and difluoromclhylene-phosphonetes have becn prepared as non hydmlysable analogues of nucleosidcs or phcsphoamino- acids. We have aaemptcd to exploit n new allemalive approach using mC radical chemistry from alkylthiofluoromuhylphosphonate 1 and alkyllhiodiflwrotylphosphonate 2. We first developped a new preparation of fluorinated alkylthiophosphonak esters using elstrophilic and nuclcophilic fluorine sources. Using N-fluorobcnzencsulfonimidc 1 could be obtained in modcrate yield (40%). On rhc other hand Seleclnuor^TM allowed to obtain the difluoromthylphosphonate 2 but in relatively low yield (10%). Using nucleophilic fluorine source′ (3HF-NEt) we showed thar phosphonate 1 and 2 could be obtained selectively from chlolo- and dichloromethylphosphonate esters. By this way, diethyl alkylsulfanyl- fluoromcthylphosphonate 1 and difluoromcthylphosphonate 2 were respectively rynthetized in 63% and 54% yields.