Chloromethylphosphonic acid

When Schwarzenbach et al. used chloromethylphosphonic acid to phosphonomethylate amines, they noted (128, p. 1185) how slowly it reacts. The slowness is presumably due to the staggered conformation of the chloromethyl and phosphono groups, so that one of the oxygen atoms must be in the Cl—C—C plane and must hinder the approach of any nucleophile that could displace the chloride. They overcame this with long reaction times and high temperatures. In view of the lability of C—As bonds, this approach is not available with 1-haloalkylarsonic acids. Indeed, arsonochloroacetic, chloromethylarsonic, and dibromo-methylarsonic acids (129) proved inert to substitution. 

Better yields of aryloxymethylphosphonic acids (65-90%) are obtained from a reaction between the disodium salt of chloromethylphosphonic acid and the corresponding sodium aryloxides. However, dilithium or disodium salts of iodomethylphosphonic acid are reported not to react with sodium phenoxide in HMPA, even at 100°C.3 5... 

We have also prepared polyimine phosphonates, analogues of the polyethers. Table V provides data for some of these compounds. The phosphonates were prepared by refluxing a mixture of chloromethylphosphonic acid with ethyleneamines in aqueous sodium hydroxide. The products were then combined with zirconyl chloride solutions, generally at temperatures from 50 to 100°, to yield layered compounds in which a portion of the amino groups is protonated. The extent of protonation can be... 

When diethyl 1-lithio-l-chloromethylphosphonate is treated with carbonyl compounds (aliphatic and aromatic aldehydes or ketones) in THF at low temperature, the intennediate chlorohydrin can eliminate upon warming to room temperature to give diethyl 1,2-epoxyphosphonates in good yields (51-90%) 2 or, in the case of aldehydes, can be treated at low temperature with LDA to give, after acidic work-up, diethyl 2-oxoalkylphosphonates in 65-92% yields (Scheme 3.63). 29. o... 

Because of the commercial importance of fosfomycin, it is not surprising that several important and attractive synthetic methods are reported in patents. They include, for example, precursors such as dimethyl hydroxymethylphosphonate, dimethyl, dibenzyl, and diallyl formylphosphonate, trimethyl phosphite and 2-cyano-1-hydroxypropene, 9 trialkyl phosphite and 2-chloro-propionaldehyde or 2-acetoxypropionaldehydc, diethyl chloromethylphosphonate, dibenzyl phosphite, and 1-chloro-1,2-propylene oxide,2 propynylphosphonic acid, propenylphos-phonic acid,2 2-chloro-(czT-l,2-epoxypropyl)phosphonic acid, and extrusion reactions on thermolysis. The resolution of racemic acids has also been reported. In search of new effective antibiotics, a large variety of substituted epoxyethylphosphonic acids have been pre-pared.249... 

An unusual application of the reaction between diethyl chloromethylphosphonate and carbonyl compounds is the formation of diethyl 2-oxoalkylphosphonates resulting from the treatment of the intermediate chlorohydrins at low temperature with an excess of LDA (2.2 eq) (Scheme 7.34). On treatment with LDA, the chlorohydrins undergo deprotonation and subsequent elimination of LiCl to provide selectively the stable lithium phosphonoenolates, which, under acidic conditions, give diethyl 2-oxoalkylphosphonates. Thus, under advantageous experimental conditions, diethyl 1-lithio-1-chloromethylphosphonate allows the direct phosphonomethylation of a large variety of aliphatic, aromatic, and heteroaromatic aldehydes in good overall yields (40-92%). ... 

Assorted anions. These are generated by deprotonation of allylic halides," chloromethylphosphonic esters, conjugated hydrazones, chiral carbamates,unsaturated a-aminonitriles, phosphonamides," and sulfonamides. The dianions derived from tu-haloalkanecarboxylic acids cyclize, and this reaction forms the basis of a synthesis of V-Boc cyclic imino acids. The conjugate bases of 2-(arylmethoxy)-methyl-2-oxazolines are unstable as [2,3]sigmatropic rearrangement takes place even at — 75°C. 

Different methods are known for the synthesis of dialkyl 1,2- epoxyalkylphosphonates. There are excellent reviews by Redmore [250], Yamamoto [251], and loga [252] describing the present methods for the synthesis of epoxyphosphonates. In this book, the following methods for the preparation of epoxyphosphonates based on diesters of H-phosphonic acid and their derivatives will be included (i) reaction of sodium dialkyl H-phosphonates with a-halo ketones, (ii) reaction of dialkyl halohydrinphosphonates with bases, (iii) the Darens reaction of dialkyl chloromethylphosphonates with carbonyl compounds, (iv) oxidation of 1,2-unsaturated phosphonates with a peroxide. 

---