Difluoromethyl phosphonate

Most of these reactions have been extended to ethyl bromodifluoromethyl phos-phonate (Figure 2.15). ° However, conversely to the anions of difluoroacetate, lithiated anions of diethyl difluoromethylphosphonate are easily generated through the deprotonation of ethyl difluoromethyl phosphonate. They are frequently used for the synthesis of difluorophosphonates (cf. Chapter 7)." ° ... 

Indeed, metallation of diethyl difluoromethyl phosphonate affords an anion. This species can displace a primary triflate in position or add onto an aldehyde (in... 

Synthesis of N-Protected Phenylalanine (Difluoromethyl)phosphonic Acids... 

Synthesis of Peptides Using Fmoc-Protected Phenylalanine (Difluoromethyl)phosphonate Dialkyl Ester Derivatives... 

Synthesis of (Difluoromethyl)phosphonate Mimetics of Phosphoserine and Phosphothreonine Peptides... 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

Stereoselective syntheses of polyhydroxycyclohexyl (a,a-difluoromethyl)-phosphonic acid (DFMPA)- esters - (229 a-b), which are stable analogues of inositol phosphates, involved Diels-Alder and conjugated addition reactions to prepare precursors. ... 

It has been demonstrated that methylsulfanyl difluoromethyl phosphonate (438) has an excellent potential as a freon-free source of phosphonodifluoro-methyl carbanion. A simple preparative procedure involving sequential treatment of the former with butyl lithium and different electrophiles allowed the preparation of a wide range of new fluorinated building blocks (439) (Figure 80). 

Methods involving electrophilic fluorination have been used to prepare a number of fluorophosphonates. Examples include benzylic a,a-difluoromethyl-phosphonates, e.g. 157, by the reaction of the carbanion of 156 with N-fluorobenzenesulfonimide (NFBS) (Scheme 10), which is claimed to be superior to DAST, and (a,a-difluoroprop-2-ynyl)phosphonates 159 by the direct di-fluorination of the a-ketophosphonate 158 (Scheme ll). Compound 158 is prepared by Pfitzner-Moffatt oxidation of the corresponding alcohol and it is worth noting that few such oxidations of a-hydroxyalkylphosphonates have been reported. 

Blades, K.. Cockerill. G.S.. Easterfield, H.J., Lequeux, T.P, and Percy, J.M., A DAST-free route to aryl(difluoromethyl)phosphonic esters, J. Chem. Soc., Chem. Commun., 1615, 1996. 

Behr, J.-B., Evina. C.M.. Phung, N., and Guillerm, G., Synthesis of (difluoromethyl)phosphonate azasugars designed as inhibitors for glycosyl transferases, J. Chem. Soc., Perkin Trans. 1, 1597. 1997. 

Two other examples are of interest in that they lead to phosphonoylated oxoalkanoic esters. In the first, the acyl halide BrCOCOOEt was used as an acylating agent for the synthesis of (Et0)2P(0)CH2C0C00Et as the first stage in a preparation of phospho-nopyruvic acid The second case concerns the acylation of diethyl (difluoromethyl)-phosphonate carbanion with di- er butyl oxalate here when worked up with aqueous NaHC03-MeCN, the initial product is the hydrated form 615 of the keto ester, from which water is removed by azeotropic distillation with benzene. 

In the presence of BuLi in thf, the active methylene compounds (Et0)2P(0)CH2Z (Z = P03Et2, COOMe, S02Me or CN) add to PhCH—CMe(N02) to give the products 78 as intermediates in a synthesis of C-phosphorylated 2-isoxazoline derivatives Other reactions have been performed between 2-aryl-1-nitroethenes and the anions from dimethyl methylphosphonate " or dimethyl (difluoromethyl)phosphonate in the initial steps towards syntheses of phaclofen 80 X = H) and its difluoro analogue (80 X = F) by the reduction (H2-Raney nickel) of the initial adduct 79 (Scheme 6). 

The preparation of 5-methylphosphonate and 5-(difluoromethyl)phosphonate analoguesof myoinositol 1,4,5-triphosphate and 1,3,4,5-tetraphosphate has been disclosed. Other phosphonate derivatives to have been synthesized include D,L-myo-inositol 1,4,5-trimethylphosphonate, 43-bis and 5-mono methyl phosphonates. ... 

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