A-hydroxyalkylphosphonates

By reaction of PC13 with aldehyde or ketone in the presence of acetic acid followed by hydrolysis, a-hydroxyalkylphosphonic acids are obtained, according to Eqs. (57)-(59). 

Neutral esters of the a-hydroxyalkylphosphonic acid are formed when PC13 is substituted by dimethoxychlorophosphine see Eqs. (60) and (61). 

By substituting n-butyldichlorophosphine for PC13 the butyl monoester of the a-hydroxyalkylphosphonic acid is formed. If there are 12 or more carbon atoms in the molecule the compound will be surface-active and still soluble in water. Alkali salts of the free phosphonic acids obtained by the reactions... 

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. 

Hydroxyalkyt and Epoxyalky Acids. The reaction of aldehydes or ketones with dialkyl hydrogenphosphonate continues to be widely used for the synthesis of a-hydroxyalkylphosphonates ° and magnesium oxide has been reported to be an effective catalyst for the reaction. The reaction has been used in enantioselective synthesis. For example, in the preparation of chiral a, -dihydroxyphosphonic acids 171 and 172 (Scheme 14), with preferential formation of the jyn-isomer 171, and the statin analogue 2-amino-1-hydroxy-3-phenylpropylphosphonic acid (173) (Scheme 15). Catalytic asymmetric... 

Okamoto, Y, and Sakurai, H., Synthesis of fatty aldehyde through the intermediate of diethyl a-hydroxyalkylphosphonate, Kogyo Kagaku Zasshi, 70, 797, 1967 Chem. Abstr, 68, 48979, 1968. 

If the starting co-hydroxyalkylphosphonate is obtained via the Abramov reaction, presenting a convenient route to a-hydroxyalkylphosphonates, the final heterocycles formed in the one-pot process may possess additional functionality such as a hydroxy (compound 70, Scheme 39) [85] or phosphoryl group (compound 71, Scheme 40) [86], In the latter case, the starting carbonyl compounds of rather complex structure gave rise to directional synthesis of biologically active compounds 72 and 73. 

It has been shown that the rearrangement of a-hydroxyalkylphosphonic acid diesters to phosphates is subject to general base catalysis and a transition state similar to (95) was proposed. Hydrolysis of the aroyl-phosphonate esters (96) in aqueous dioxan with phosphate buffer is also... 

Dialkyl alkylene diphosphonates obtained by transesterification of dialkyl H-phosphonates with diols in the excess of H-phosphonate diesters are bifunctional monomers possessing two reactive P-H groups. The addition of ketones or aldehydes to dialkyl alkylene diphosphonates resulted in the formation of the corresponding bis(a-hydroxyalkylphosphonate)s [185]. 

Chemical transformations of a-hydroxyphosphonates Phosphonate-phosphate rearrangement. Dialkyl alkylphosphonates are, in general, more reactive than the corresponding phosphate esters because the carbon has no unpaired electrons to contribute to allow a pn-dm contribution to the P-C bond. This makes the phosphorus atom of phosphonates more electrophilic than the phosphorus atom of the corresponding phosphate ester. The P-C bond is usually stable to hydrolitic procedures. However, a-hydroxyalkylphosphonates, in the presence of alkali, rearrange to give phosphate with cleavage of the P-C bond [220]. 

This assumption is supported by the fact that when a phenyl group is introduced at the P-C carbon atom, the thermal stability of the corresponding a-hydroxyalkylphosphonates decreases [221],... 

Hydrolysis. The saturated a-hydroxyalkylphosphonates are readily hydrolyzed in 18% aqueous hydrochloric add to the corresponding a-hydroxyalkylphosphonic acids (route a) [186]. In the presence of a strongy alkali, the a-hydroxyalkylphosphonates... 

General procedure for the oxidation of a-hydroxyalkylphosphonates to a-ketophospho-nates (ref Tetrahedron Lett., 2000,41, 3169). 

A solntion of the a-hydroxyalkylphosphonate (5 mmol) in dry benzene (50 mL) was prepared. Powdered potassium permanganate (0.316-0.949 g, 2-6 mmol) was added and the resulting mixture was stirred at room temperature (3-12 h). The reaction mixtnre was then filtered and the solvent was evaporated to give the crude product. The pure product was obtained (82-98% yields) by bulb-to-bnlb vacuum distillation. 

Since Kabachnik and Medved found that a-hydroxyalkylphosphonates are present in the reaction mixture of ammonia, carbonyl compound, and dialkyl H-phosphonate, they accepted that the reaction proceeds via formation of a-hydioxyalkylphosphonate followed... 

The a-hydroxyalkylphosphonates undergo facile base-catalyzed mutation to the phosphates (122, 123). The result mirrors the symbiotic stabilization of the transition state and the products. 

D-Halo-a-hydroxyalkylphosphonates (784) were kinetically resolved by use of a protease (Chirazyme P-2) and converted into the phosphonic acid analogues of amino acids (785) and (786) (Scheme 199). All amino-phosphonic adds were prepared in racemic form, but only the cyclic ones also in homochiral form. ... 

---