Acetylphosphonates

Further studies on 1,3-dipolar addition reactions of diazophosphonates have been recorded,122 and work on 2-diazo-l-hydroxyalkylphosphonates also continues.123 The ester (155 R = H) reacts with esters of acetylenedicarboxylic acid without liberation of nitrogen to give stereoisomeric C-phosphorylated pyrazolines, which can be decomposed with both phosphorus-carbon and carbon-carbon bond fission, affording mixtures containing dimethyl acetylphosphonate, dimethyl hydrogen phosphonate, and tri(alkoxycarbonyl)pyrazolines. In the reaction between the same diazophosphonate and diazomethane, the latter conceivably acts as a basic catalyst for proton transfer in a series of steps which includes phosphonate-phosphate isomerization. The importance of a labile proton is demonstrated by the fact that the ester (155 R = Me) does not react in the manner described above. 

The expected product from the reaction of diethyl acetylphosphonate with sodium bisulfite and sodium cyanide is diethyl l-cyano-l-hydroxyethylphosphonate. However, a rearrangement takes place during the preparation under alkaline conditions (pH > 8) that leads to diethyl 1-cyanoethyl phosphate (Scheme By a similar procedure, long-chain diethyl a-cyanohy-... 

The course of the reaction between acylphosphonates and 1-nitroalkane carbanions depends on the nature of the acyl group. Thus, nucleophilic addition of nitromethane to acetylphosphonates in the presence of di- or triethylamine results in the formation of dialkyl 1-hydroxy-l-methyl-2-nitro-ethylphosphonates (R = Me, = H, Scheme 7.75)." " However, the procedure is not applicable to the synthesis of dialkyl 1 -hydroxy-l-pheny 1-2-nitrocthyIphosphonate because the electron-with-drawing ability of the benzene ring destabilizes the molecule toward alkali and results in C-P or C-C bond cleavage. The fact that diisopropyl 1-hydroxy-l-phenyl-2-nitroethylphosphonate was... 

Acetylphosphonate diesters undergo an aldol-type condensation with diazoacetic ester to give (102). Another novel substituted phosphonate ester... 

The earliest detection of a Michaelis-Menten complex (MC) was on addition of a substrate analog methyl acetylphosphonate (MAP) and acetylphosphinate to several ThDP enzymes. An example is shown with acet-ylphosphinate added to YPDC (Figure 4) leading to a negative CD band at 325—3 35 nm, very reminiscent of the band observed for the AP form. In this example, the addition of ThDP alone (curve 1) did not display the AP form, the negative CD band only appeared after addition of substrate analog, hence the band must pertain to an MC-type complex. Similar results were also seen when low concentrations of pyruvate were added to Elec. ... 

Diazoalkanes are well known as reagents for carbon insertion reactions through the intermediacy of carbenes. Here, diethyl acetylphosphonate has been shown to react with diazomethane to give a mixture of 2-(diethoxyphosphinoyl)-2-methyloxirane (the major product) together with traces of diethyl (2-oxopropyl)phosphonate the reaction between dimethyl acetylphosphonate and diazoethane and that between diethyl ben-zoylphosphonate and diazomethane both afford only the (2-oxoalkyl)phosphonic... 

In the presence of piperidine in benzene, benzaldehyde reacts with diethyl (nitromethyl)-phosphonate to afford at 67% yield of diethyl (2-hydroxy-l-nitro-2-phenylethyl)phos-phonate, presumably as a mixture of diastereoisomers. However, a similar reaction with 4-nitrobenzaldehyde leads to phosphorus-carbon bond cleavage and the formation of 1-nitro-2-(4-nitrophenyl)ethane. The converse procedure, i.e. a reaction which involves a nitroalkane and an (oxoalkyl)phosphonic diester, is also subject to certain restrictions. The base-catalysed nucleophilic additions of nitromethane to dialkyl acetylphosphonates (Scheme 7 R = Me) to give dialkyl [(1-hydroxy-l-nitromethyl)alkyl]phosphonates have... 

NMR spectroscopy has shown that many compounds, previously described as (1-hydroxyalkylidene)bisphosphonic esters, are actually either totally rearranged compounds or mixtures of initial and rearranged compounds. Such was the case with the products from dialkyl hydrogenphosphonates and dialkyl acylphosphonates, for which, when R R the potential for confusion is obvious (Scheme 18). Provided that the compounds 104 are not heated above 80 °C, they may sometimes be isolated by crystallization, but others, e.g. 104 (R = Ph or aryl), rearrange very easily and cannot be isolated. (1-Hydroxyethylidene)bisphosphonic acid is stable in solution at pH 1.6 up to 125 °C, and in alkaline solutions at pH 8.5-11.5 up to 195 °C the compound then undergoes thermolysis with fission of the carbon-phosphorus bond to give, initially, acetylphosphonic and (1-hy dr oxyethy l)phosphonic acids ... 

The facility with which the phosphorus-carbon bond in acylphosphonic derivatives is cleaved by the action of the more basic nucleophiles has already been commented upon. Those nucleophiles include alkoxides and amines, but it may be noted that thiols undergo normal addition to the carbonyl group. With regard to the latter, diethyl acetylphosphonate yields the monothioacetals 256 the derivatives may not be stable thermally but their decomposition occurs with cleavage of the phosphorus-carbon bond Reactions between the same substrate and simple carboxamides in the presence of an acid catalyst under dry conditions furnish the acylated enamides 257 ". ... 

The only acylphosphonate for which the crystal structure has been determined by X-ray study is acetylphosphonic acid monosodium salt (1) acetic acid solvate. ... 

The pAa values of methyl hydrogenacetylphosphonate (9) and that of the monoanion of acetylphosphonic acid (10) were determined by spectrophotometric titration and found to be 0.5 and 5.6, respectively. In another paper, a value of 5.2, determined by titration of dilithium acetylphosphonate, was reported. 

It was proposed that this is a general characteristic of all 2-hydroxyalkane-l,l-bisphos-phonic acids. Indeed, a similar result was produced by the product of the reaction of hydroxyacetonitrile with phosphorous acid, l-amino-2-hydroxy-l,l-bisphosphonic acid, which decomposed on acidification to give acetylphosphonic acid, presumably via the corresponding enamine (equation 39f. ... 

The reaction of ketene with diethyl hydrogen phosphonate leads to diethyl ace-toxyvinylphosphonate (equation 46) This reaction was assumed to involve the initial formation of acetylphosphonate, which underwent enolization and reaction with a second molecule of ketene to the final product. Infrared spectral examination of the product mixture revealed the formation of an additonal product, presumably a jS-lactone (v = 1830 cm ) which could be formed through 2 + 2 cycloaddition of a ketene molecule to the C=0 group of the acetylphosphonate. 

Dialkyl acylphosphonates are sensitive to water in neutral and alkaline conditions and hydrolyse rapidly to the corresponding carboxylic acids and to dialkyl hydrogen-phosphonate (equation 47) This occurs following the rapid addition of water to the carbonyl group with the formation of stable hydrates. The involvement of stable carbonyl hydrates in the hydrolysis of dimethyl acetylphosphonate and aroylphosphonates was established by H NMR and UV spectroscopy, respectively. In the latter case, the rates of formation and decomposition of the tetrahedral carbonyl hydrates were also determined. 

The synthesis of l-bis(trimethylsilyl)phosphinyl-l-trimethylsilyloxyvinylphosphonate (30) was studied thoroughly, because this compound is a starting material to a diphosphorus analog of phosphoenol pyruvate (equation 88)". It was found that bis(trimethylsi-lyl) acetylphosphonate can be silylated by using either chlorotrimethylsilane with triethylamine or A, iV-diethyl-iV-(trimethylsilyl)amine. 

In another study chlorotrimethylsilane alone was reported to convert dimethyl acetylphosphonate into the trimethylsilyl enol ether. This is a general type of reaction. 

The enamine tautomer was obtained exclusively when a hydroxyiminophosphonate derived from acetylphosphonate was treated with chlorodiphenylphosphite (equation 99) The enamine was identified by X-ray crystallography and NMR spectroscopy, (5 P = 12.4 and 18.7 ppm (/pp = 29.3 Hz). Analogous compounds derived from non-enolizable acylphosphonates gave imines which showed Jpp = 60-90 Hz. 

Another more general approach to enamides derived from an acetylphosphonate is based on 1,2-dichloroethyl isocyanate. This compound underwent Arbuzov reaction with methyl phosphorodichloridite to yield the 2-chloroethyl compound which, when treated... 

Among a number of structural analogues of acetyladenylate (adenosine-5 -acetylphos-phate), adenosine-5 -acetylphosphonate was synthesized and examined. It was found that, along with the other analogues, it inhibited the enzyme . 

Phosphoenol acetylphosphonate (48) and its dimethyl ester (49) were examined as potential inhibitors of three phosphoenopyruvate (PEP) enzymes ". Both compounds inhibited enolase and PEP carboxylase but they did not bind to pyruvate kinase. Neither compounds was a substrate for any of the enzymes. 

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