Oxoalkylphosphonates synthesis

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). 

Balczewski. P.. Novel 1-phosphonyl radicals derived from I-mono and l.l-diheterosubslilulcd 2-oxoalkylphosphonates as useful phosplioroorganic intermediates in organic synthesis, Tetrahedmn, 53, 2199, 1997. 

Good general synthetic rontes to dialkyl 1-oxoalkylphosphonates have been available for many years. Although good general methods now exist, dialkyl 2-oxoalkylphosphonates were traditionally less accessible, and many relatively specihc protocols have been developed. These ketophosphonates are important reagents for synthesis and useful intermediates for the preparation of elaborate phosphonates. This chapter describes their synthesis and applications. 

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). ° ... 

The synthesis of 2-oxoalkylphosphonates may also be accomplished in good yields under palladium catalysis conditions (Wacker process). 

Several general procedures for the synthesis of dialkyl 2-oxoalkylphosphonates have been discussed previously, but there are a number of other important methods worthy of merit. However, these methods are not always perfectly general and often require the synthesis of relatively sophisticated... 

A large-scale synthesis of dialkyl 3-oxoaIkylphosphonates proceeds by treatment of dialkyl 1-copper(l)alkylphosphonates with 2,3-dihalopropenes. Low-temperature hydrolysis of the resulting vinyl halide with H2SO4 in biphasic medium releases the y-keto functionality (Scheme 7.56). Thus, alkylation of l-copper(I)alkylphosphonates with 1,2-dichloro- or l,2-dibromo-2-propene is equivalent to the introduction of masked 3- or 4-oxoalkyl groups. In this way, 1-substituted or unsubstituted 3-oxoalkylphosphonates are prepared in high yields (90%). ... 

Similarly, the a-monochlorinated and a-monobrominated dimethyl 2-oxoalkylphosphonates are prepared in satisfactory yields (50%) by reaction of the sodium enolate of dimethyl 2-oxoalkyl-phosphonates with NCS or NBS in DME at room temperature- "- - or with bromine in Et20 (53-71%) or THE (60%) Synthesis of diethyl l-chloro-2-oxopropylphosphonate has also been reported through reduction of the 1,1-dichloro derivatives with sodium sulfite.- lodination in the Y-position of P-ketophosphonate 1,3-dianions prepared with KiCO, in MeOH has been reported. These dianions react with benzaldehyde in a Homer-Wadsworth-Emmons-Darzens reaction sequence to produce the a,P-unsaturated a, P -epoxyketones in 60-79% yields (Scheme 7.101).s ... 

Kim, D.Y, Mang, J.Y, and Oh, D.Y, Reaction of silyl enol ethers with phosphite using hypervalent iodine compound. A new synthesis of 2-aryl-2-oxoalkylphosphonates, Synth. Commun., 24, 629, 1994. Hohnquist, C.R., and Roskamp, E.J., Tin(II) chloride catalyzed addition of diazo sulfones, diazo phosphine oxides, and diazo phosphonates to aldehydes. Tetrahedron Lett., 33, 1131, 1992. 

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