Dimethyl H-phosphonate

Considerable work has been published on stoichiometric asymmetric routes to a-functionalised phosphonate esters. One of the most commonly exploited methods is the phosphonylation of a chiral aldehyde or imine by a phospho-rus(ni) ester (Scheme lb) or a by a hydrogen phosphonate (Scheme la). Thus, a team from Bristol-Myers Squibb reported the base-mediated addition of dimethyl H-phosphonate (DMHP) to a chiral aldehyde (Scheme 2) as a key step in their synthesis of renin inhibitors [6j. Subsequently, work from the Hoechst AG laboratories in Frankfurt used a related approach to the building of HIV protease inhibitor frameworks (Scheme 3) [9]. 

The synthesis of higher dialkyl H-phosphonate homologues usually includes the initial treatment of phosphoms trichloride with methyl alcohol, and then the transesterification of so-formed dimethyl H-phosphonate with higher alcohols [16,17],... 

Another approach employs treatment of H-phosphonic acid or its monoalkyl ester with a carboxylic acid anhydride and an alcohol at 20-50 C. Dimethyl H-phosphonate is obtained according to this procedure in quantitative yield based on the starting phospho-nic acid (See Appendix) [38]. 

Under normal conditions, dialkyl phosphonates are stable compounds. At elevated temperatures (above 160 °C), they begin to decompose. Dimethyl H-phosphonate is the most unstable homologue in that respect. At a temperature of 173 °C, it pyrolyzes to monomethyl H-phosphonate and dimethyl methylphosphonate [55,56]. 

Methyl phosphonic add is obtained in a high degree of purity and yield approaching 100% of theory by pyrolysis of dimethyl H-phosphonate in liquid phase [57-59], The condensation of the latter to pyromethyl phosphonic acid takes place at about 250-270 C. 

These reactions occur rapidly upon addition of dimethyl H-phosphonate to a reaction medium having a temperature of about 290-300 C. The reaction can be carried out rapidly and in good yield when a high-boiling heavy parafiBn oil (such as Nujol) is employed. 

A reactor was charged with phosphonic acid (0.5 mol) and acetic anhydride (1.5 mol) was added dropwise then methanol (1.1 mol) was added such that the temperature of the reaction mixture ranained below 50 °C. Conversion of phosphonic acid into dimethyl H-phosphonate was 100%. 

There are no published experimental geometries for the H-phosphonate diesters. Dimethyl H-phosphonate, however, was the snbject of some ab-initio computational studies [1,6]. Ab initio conformational analyses that were carried ont for dimethyl H-phosphonate with the 6-31+G basis set [7] predict that there are fonr stable conformers of this compound [6] with the different conformers being the resnlt of rotations about the C-0 bonds in the molecnle (Fignre 2.1). The relative energies of these conformers are given in Table 2.1. 

Figure 2.1 Conformers of dimethyl H-phosphonate, computed with the HF/6-31-tG basis set. A is the global minimum and D is a transition structure.

Selected optimized structural parameters for dimethyl H-phosphonate, computed with the ... 

The above data indicate that conformer A is the energy minimum structure and con-former D, because of the presence of a single imaginary frequency, corresponds to a transition structure. Selected optimized parameters for all stable conformers of dimethyl H-phosphonate are listed in Table 2.2 [6]. 

The charge distribution in the molecule of the most stable conformer of dimethyl H-phosphonate, obtained with MnUiken population analysis on HF/6-31+G //HF/6-31+G ... 

It has been established that the hydrolysis of dialkyl H-phosphonates is general-base and general-acid catalyzed [18]. The hydrolysis of phosphonic acid diesters is facilitated significantly under basic conditions. The mechanism of the base-catalyzed hydrolysis of dimethyl H-phosphonate has been proposed to take place according to the following scheme [19] ... 

The addolysis of dimethyl H-phosphonate to phosphonic acid was studied recently by H- NMR and ip H) NMR spectroscopy [27]. It was established that this is a two-stage process with the intermediate formation of monomethyl H-phosphonate. 

The charge distribution in the molecule of dimethyl H-phosphonate obtained with Milliken population analysis clearly indicates that the electron density at the phosphorus atom is the lowest, that is, the phosphorus atom is an electrophilic center. H-phosphonate diesters with nucleophiles undergo several characteristic reactions and the most typical one is the trans-esterification reaction, which presents an interaction between H-phosphonate diesters and hydroxyl-containing compounds. 

It has been assumed that in the noncatalyzed transesterification of dialkyl H-phos-phonates, these compounds react with their four-coordinated phosphonate form [28,29], AMI semiempirical calculations [30] of the model transesterification of dimethyl H-phosphonate with methanol indicate that in the first stage of this reaction, dimethyl H-phosphonate and the nucleophile form a pentacoordinated intermediate n via a four-centered cyclic transition structure I. The trigonal-bipyramidal intermediate n undergoes pseudorotation [17c,31] and via a new transition structure in of the same type as I, forms the monotransesterificated product. The rate of transesterification depends both on the type of substituents at phosphorus and the nucleophiUcity of the corresponding alcohol. 

It was found that the transesterification of dimethyl H-phosphonate with 1,2-propane-diol yields 4-methyl-2-hydro-2-oxo-l,3,2-dioxaphospholane [56]. Obviously, the first stage of the reaction furnished methyl-2-hydroxypropyl H-phosphonate. Subsequent intramolecular transesterification of the methyl-2-hydroxypropyl phosphonate yielded 4-methyl-2-hydro-2-oxo-l,3,2-dioxaphospholane. The specific reactivity of these esters of H-phosphonic acid is determined by the presence of a P-hydroxyl gronp. The role of the P-hydroxyl gronp may be regarded as an intramolecular catalysis. The reactivity enhancement of P-hydroxylethyl esters of H-phosphonic acid probably can be explained through hydrogen bonding, which favors the intramolecular transesterification reaction. 

In the P H NMR spectrum of the 2-hydro-2-oxo-l,3,2-dioxaphospholane obtained via transesterification of dimethyl H-phosphonate with 1,2-ethylene glycol, there is only one signal at 24.75 ppm. In this compound, mobile protons are not present in the ring ... 

Phosphorus-containing poly(propylene ether carbonate)s were obtained reacting dimethyl H-phosphonate with poly(propylene ether carbonate)diols [68] (Scheme 3.3). 

Trifluoromethanesulfonic acid catalyzes the reaction of phenyl diazomethane with dimethyl H-phosphonate. Diazoacetate and diethyl H-phosphonate react less effectively under similar conditions [76]. 

The kinetics studies indicate that the ionization of dimethyl H-phosphonate by the base occurs before the attack of diazonium salt on the phosphonate anion [77], According to this mechanism, the dimethylphosphonate anion or its 0-protonated conjugate... 

It is established that under Atherton-Todd conditions, dimethyl H-phosphonate reacts with Schiff bases containing a cyclopropyl fragment, yielding the corresponding ami-dophosphates [98]. 

Pseudoephedrine reacts via the classical Atherton-Todd reaction with dimethyl H-phosphonate to give the corresponding amidophosphate, which undergoes stereoselective heterocyclization to give 2-methoxy-3,4-dimethyl-5-phenyl-2-oxo-l,3,2-oxazaphos-pholane 1 in 82% yield based on the amidophosphate [118]. 

Dimethyl H-phosphonate adds to the C=C bond of the ethyl ester of 4,4,4-trichloro-2-cyano-2-butenoic acid [153],... 

The dimethyl H-phosphonate adds to the activated double bond of acrylamide to give dimethyIphosphonopropionamide [153]. 

Dimethyl phosphonate halohydrin is formed by the base-catalyzed reaction of dimethyl H-phosphonate and chloroacetone [176]. 

In the absence of a solvent and excess of chloral, the reaction rate for this reaction may be expressed by a third-order equation-second order with respect to dimethyl H-phosphonate and first order with respect to the chloral [177]. In dioxane solution and excess dimethyl H-phosphonate, the dependence of the reaction rate on the chloral concentration is the same. In addition to the chloro-containing a-hydroxyalkyl phosphonate, which is the main product under the above conditions, a side product formed as a result of dehydrochlorination of the main product, followed by phosphonate-phosphate rearrangement, has been also isolated. The presence of a base such as triethylamine, alkali metal alkoxides and hydroxides, or sodium carbonate accelerates the dehydrochlorination process. An example of this side reaction is the transformation of dialkyl-2,2,2-trichloro-l-hydroxyethyl phosphonates into dialkyl-2,2-dichlQrovinyl phosphates in the presence of sodium hydroxide [181,182]. 

It was shown that ot-hydroxyalkylphosphonate derived from dimethyl H-phosphonate and 2-nitrobenzaldehyde undergoes such rearrangement when traces of triethylamine are present [220d]. 

Dialkyl acylphosphonates are used for acylation of alcohols. Kabachnik [236] reported that dimethyl benzoylphosphonate formed crystalline 1 1 addition products with aUphatic alcohols, which can be converted in the presence of dry hydrogen chloride into carboxylic esters and dimethyl H-phosphonate in moderate yields. Sakurai reported that dialkyl acylphosphonates underwent slow acylation with a large excess amount of alcohols to give esters [237]. It was shown that triethylamine catalyzed acylation of alcohols with dialkyl acylphosphonates [238]. It was found that use of l,5-diazabicyclo[5,4,0]undec-5-ene (DBU) increased the rate of the acylation of alcohols with diethyl benzoylphosphonate dramatically [239]. When one equivalent of DBU was used in CHjClj, the acylation was completed within 10 min and the corresponding ester 1 was obtained in 99% yield. The use of 0.1 equivalent of DBU gave 1 in 95% yield. Under this condition, the formation of 3 was suppressed remarkably and only a trace of 3 was formed. 

Dimethyl H-phosphonate adds to the double bond of alkenyl cyclopropanes in the presence of benzoil peroxide with the formation of the corresponding aUcyl dimethyl phos-phonates [278]. 

In the recent ab initio smdy [286], a comparison has been made between deprotonation and alkylation pathways for the model system dimethyl H-phosphonate-ammonia. 

Scheme 3.4 Deprotonation and alkylation pathways for the model system dimethyl H-phosphonate-ammonia.

Figure 3.4 8 2 transition structure for the alkylation of ammonia with dimethyl H-phosphonate obtained with the HF/6-31+G basis set. 

Figure 3.6 MP2/6-31+G //HF/6-31+G + ZPE gas-phase energy profile of the alkylation reaction between dimethyl H-phosphonate and ammonia.

Alkylation of amino gronps bonded to a polymer chain with H-phosphonates was studied in order to obtain physiologically active polymers. Polymeric physiologically active substances have nnmerons advantages over low-molecular ones, for example, lower toxicity, prolonged action, and higher selectivity. Poly(A-vinylpyrrolidone-co-vinylamine) was phosphorylated by dimethyl H-phosphonate [290,293]. 

Methylalkylammonium salts, obtained by alkylation of primary amines with dimethyl H-phosphonate, are thermally unstable and easily yield the corresponding alkylammonium salts [292,295,296]. 

This transformation takes place readily at room temperature and can be carried out quantitatively by stirring the reaction mixture at 50-70 °C under vacuum for several hours. Ethylene is formed as a result of recombination of the carbon that probably forms at the first step of the decomposition. On the other hand, it was found [292, 295, 296] that quaternary methylammonium salts obtained by alkylation of tertiary amines (MiV-dimethyl aniline or triethyl amine) with dimethyl H-phosphonate are quite stable with respect to the above conversion when heated up to 130 °C and 70 °C, respectively. 

It was shown for the first time that the reaction of dimethyl H-phosphonate with acetanilide represents an alkylation of the amido group [299],... 

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