Oxoalkylphosphonic acids

Oxoalkylarsonic acids lose arsenite by elimination, presumably after enolization, as described earlier (Section IV,B,2,c, and Fig. 9). In contrast, 3-oxoalkylphosphonic acids are stable e.g., the phosphono-methyl analogue of glycerone phosphate is a substrate for aldolase (118). The elimination of arsenite from 3-oxoalkylarsonic acids, but not of phosphite from 3-oxoalkylphosphonic acids, may reflect the fact that arsenite is relatively stable compared with arsenate, whereas phosphite is unstable compared with phosphate. 

Oxoalkylphosphonic acids can be hydrolyzed in this way (119), as in the enzyme-catalyzed hydrolysis of phosphonoacetaldehyde (73, 69-71), but with much more difficulty. The lability of 2-oxoalkylarsonic acids presumably reflects the ease with which water can more easily enter the coordination shell of arsenic than that of phosphorus, because of the larger size of the atom, i.e., the same feature expressed in the lability of esters and anhydrides of arsenate. 

Acylphosphonic acids (1-oxoalkylphosphonic acids) and their dialkyl esters undergo acid-catalyzed fission with the formation of carboxylic acids (or their alkyl esters) using a suiphonic acid as the catalyst the formation of an alkyl carboxylace is accompanied by that of an alkyl sulphonate. The reaction may be visualized as occurring through protonation on the carbonyl oxygen and migration of an alkoxy group from phosphorus... 

Natural Products.—The use of 2-oxoalkylphosphonates still appears to be the method of choice for the preparation of the C8-side-chain of prostaglandins. Examples reported this year were in the preparation of azaprostaglandins,119 aryl analogues,120 and the analogue (131),121 among others. Royal jelly acid has been... 

As seen in Scheme 1 a route similar to the biological pathway has now been explored by the independent synthesis of each precursors by chemical means. Work presented in this communication describes the production of synthetic 2-aminoethylphosphonic acids by the controlled reductive amination of 2-oxoalkylphosphonate diesters... 

Briefly we review the chemical improvements which we achieved in the oxoalkylphosphonates field which represent the key compounds. Phosphonic aldehydes are obtained in adapting the Arbuzov procedure to 6 or V haloketals (4). A modification of the phospho-nylation conditions (t°, stoichiometry) followed by removal of the protecting group in dilute acid and then continuous extraction allows synthesis of suitably branched compounds on a large scale (5). 

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... 

A relatively general procedure for the preparation of dialkyl 2-oxoalkylphosphonates by direct acylation of dialkyl 1-lithioalkylphosphonates has been introduced by Corey and Kwiatkowski in 1966. The use of phosphonate carbanions as nucleophiles in reaction with carboxylic esters avoids the problems associated with the Michaelis-Arbuzov reaction. The reaction sequence is initiated by the addition at low temperature of dimethyl 1-lithiomethylphosphonate (2 eq and frequently more) to a carboxylic ester (1 eq) to give the transient lithium phosphonoenolate. The dimethyl methylphosphonate, being readily available and easy to eliminate, is the most frequently used phosphonate, but other phosphonates such as diethyl and diisopropyl methylphosphonates can be used. When the resulting enolate is treated with acid, dimethyl 2-oxoalkylphosphonate is produced in moderate to good yields (45-95%, Scheme 7.20). The reaction has been achieved with... 

The synthesis of diethyl l,l-difluoro-2-oxoalkylphosphonates has been reported by a cerium-mediated reaction between diethyl 1-lithio-1,1-difluoromethylphosphonate and ethyl esters at low temperature in THF. After acidic quench at low temperature, diethyl I, I -difluoro-2-oxoalkyIphosphonates are isolated in good yield.- Addition of diethyl 1-lithio-1,1-difluoromethylphosphonate to di-ferf-butyl oxalate at low temperature in THF affords exclusively the addition product, an unusually stable ferf-butyl hemiketal. When a solution of this material is heated at reflux in ( ,1 f, or chromatographed on silica gel, only a few percent is converted to the hydrate. This conversion is best effected by dissolving the hemiketal in MeCN followed by reaction with aqueous Nal ICO . Subsequent azeotropic dehydration with CgHg affords diethyl l,l-difluoro-2-oxo-2-(fert-butoxycar-bonyl)ethylphosphonate. 5... 

Readily available dialkyl l-bromo-l,l-difluoromethylphosphonates can also participate in the synthesis of 2-oxoalkylphosphonates. Thus, dialkyl 1-bromo-1,1-difluoromethylphosphonates, on reaction with activated Zn metal, are converted into difluoromethylphosphonylzinc bromides, which are coupled with carboxylic acid chlorides at room temperature to give dialkyl l,l-difluoro-2-oxoalkylphosphonates in good yields.- " Dimethyl 1-lithiomethylphosphonate undergoes trans-metallation with MnCl2 in THF to give dimethyl 2-oxobutylphosphonate in 80% yield on reaction with propionyl anhydride. " ... 

The process has been extended to the synthesis of diethyl l-fluoro-2-oxoalkylphosphonates. Thus, low-temperature acylation of diethyl l-(hydroxycarbonyl)-l-fluoromethylphosphonate with carboxylic acid chlorides in the presence of -BuLi in THF followed by decarboxylation provides an expeditious route for the synthesis of diethyl l-fluoro-2-oxoalkyIphosphonates in good yields (66-78%, Scheme 7.27). ° ... 

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%). ... 

The phosphonylation, via a Michaelis-Becker-type reaction, and the phosphonomethylation, with lithiated phosphonate carbanions, " of protected ketones have been applied to the preparation of 4-oxoalkylphosphonates after acidic hydrolysis. 

The reductive amination method has been applied to the preparation of 4-aminoalkylphosphonic acids from 4-oxoalkylphosphonates (Scheme 7.65). ... 

One example of reductive amination of acylphosphonates has been reported. Thus, reaction of dimethyl 1-oxoalkylphosphonates with benzhydrylamine results in the formation of an imine reduced in situ with NalllKOAc),. The reaction is independent of the solvent, and THF, CIFCh and CHCI3 give similar results - After selective removal of the benzhydrylic group by catalytic hydrogenation and hydrolysis with concentrated HCl, the 1 -aminoalkylphosphonic acids are isolated in satisfactory yields (30-60%, Scheme 7.66) ... 

Ryglowski, A., and Kafarski, P., Preparation of 1-aminoalkylphosphonic acids and 2-aminoalkylphosphonic acids by reductive amination of oxoalkylphosphonates. Tetrahedron, 52, 10685, 1996. 

Instead of carboxylic acid chloride, 3-acylthiazolidine-2-lhiones proved to be suitable to produce 2-oxoalkylphosphonates. These acylating reagents are prepared by condensation of the methyl monoesters of (o,(o -diacids with 2-mercaptothiazoline. Addition of 3-acylthiazolidine-2-thiones to dimethyl l-lithiomethylphosphonate (2.5 eq) leads to functionalized 2-oxoalkylphosphonates in 61-70% contaminated by a slight amount of symmetric (O,(o -dioxoalkylphosphonate resulting from attack at the ester function. 

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