A useful magnesium reagent for the preparation of 1,1-difluoro-2-hydroxyphosphonates from diethyl bromodifluoromethylphosphonate via a metal—halogen exchange reaction

Abstract

When (EtO) 2 P(O)CF 2 Br (1) is treated with isopropylmagnesium chloride in THF at low temperature it gives a magnesium species (2) which undergoes reactions with strong electrophiles (HCl, TMSCl, halogens, aldehydes and ketones). The formation of products strongly depends on the reaction conditions. With 1.5 equivalents of (2) between -78°C and 0°C, a conversion of more than 90% of aldehydes and ketones into 2-hydroxyphosphonates ( 7) and ( 8) can be achieved. These compounds ( 7) and ( 8) in the presence of base (NaH, LDA) are rearranged into 2,2-difluoroethylphosphates without concomitant formation of 1,1-difluoroolefines.

Experimental and theoretical studies on the transannular cyclizations of 3,7-dimethylenebicyclo[3.3.1]nonane with polyfluoroalkyl radicals

“…Ethyl iododifluoroacetate [25] and diethyl iododifluoromethylphosphonate [38,39] were prepared by literature procedures. Copper powder was activated before use [40].…”

Analogues of nucleotides and oligonucleotides featuring difluorophosphonate, difluorophosphonothioate and difluorophosphinate functional groups

“…Lithium reagent 17 was replaced with the organomagnesium reagent 33, readily prepared by treating bromide 19 with 1.1 Eq. of freshly prepared isopropyl magnesium chloride in diethyl ether [20]. For the reason cited above, adduct 34 was obtained as a single diastereomer.…”

New Prospects toward the Synthesis of Difluoromethylated Phosphate Mimics

“…The reported access to the difluoromethylphosphonate motif focused on five main retrosynthetic disconnections. First, the venerable Arbuzov [15] or Michaelis-Becker [16] reactions were used to synthesize this key scaffold. The electrophilic fluorination of alkyl phospho- nates, initially developed by Differding, [17] represented an elegant alternative pathway to the widely used deoxyfluorination reaction of keto-phosphates by means of DAST or other fluorinating agents.…”