Hydrogenphosphonates with phosphonic acid

Hydroxyalkyl and Epoxyalkyl Acids. - The reaction most widely adopted for the preparation of (l-hydroxyalkyl)phosphonic esters is that attributed to Abramov and involves the interaction of hydrogenphosphonates with aldehydes or ketones, sometimes in the presence of a base catalyst. The same reaction has now been shown to be catalysed by mineral phosphates e.g. fluoroapatite. The same process, catalysed by the complex (134) [(R)-form] gives the same esters in 50-95% yields and with 55-9d% e.e.s The study of the diastereoselective phosphonoylation of aldehydes using chiral 1,3,2-diazaphospholidine reagents has continued with an examination of the use of the stereoisomers of (135), which... 

Many communications have concentrated on specific amino phosphonic acids or derivative types. Thus, esters of phosphonoaminoacetic add were obtained by the reactions between trialkyl (ethyl) phosphite and (218) and which are thought to proceed via the phosphorane (219). A sequence has been presented for the preparation of the mono- and di-benzyl esters of N-chz protected (a-aminoben-zyl)phosphonic acid. A synthesis of (aminomethylene)bisphosphonic acid from dibenzylamine, dibenzyl hydrogenphosphonate and triethyl orthoformate has been noted and the asymmetric hydrogenation of (220) in the presence of chiral phosphine catalysts yields samples of (221) with e.e.s of 63-96%. The pyrrolidine-based compound (222) has been prepared from methyl S)-N-methoxycarbonyl-4-oxo-2-pyrrolidinecarboxylate and iV-coupled 4-amino-butanal diethyl acetals were the starting materials in syntheses of the pyrrolidine-2-phosphonic add derivatives (223) in which Z represents the iV-protected amino add or peptide moiety. ... 

Within this area, the most recent developments in the synthesis of esters of phosphonic acids have been the direct alkylation of hydrogenphosphonates using diazoalkanes in the presence of copper-containing catalysts in benzene as the solvent Of those catalysts examined, the most effective seem to be [Cu(acac)2] and [Cu(OTf)2], with Cu, Pd and Rh acetates and [Ni(acac)2] being less effective. The overall reaction is that represented in equation 18, in which R and R may be H, Ph or a simple alkyl group, but they may also consist of a functionalized alkyl group in reactions catalysed by trifluoromethanesul-phonic acid A similar procedure has been applied to the hydrogenphosphinate Ph(MeO)P(0)H ... 

There are other reactions which lead from prop-2-ynyl compounds to allenic phospho-nic acid derivatives. The alkylation of diethyl hydrogenphosphonate with 3-bromopropy-ne under phase transfer conditions yields a mixture of diethylpropadienyl- and (prop-l-ynyl)-phosphonates in 85 15 ratio " The action of heat on a mixture of prop-2-ynol and a phosphoramidous ester, (RO)2PNR 2, results in elimination of R 2NH followed by its re-addition to the rearranged residue to afford a dialkyl (2-amino-prop-1-enyl)-phosphonate. ... 

The interaction of a dialkyl hydrogenphosphonate with a 3-hydroxyalkanal to afford mixtures of diastereoisomers of the linear dialkyl (l,3-dihydroxyalkyl)phosphonate and derived 1,2-oxaphospholane 2-oxides has already been discussed. Lack of protection at appropriately sited hydroxy groups in carbohydrate molecules allows a similar reaction to occur. With D-erythrose, the 1 1 adduct is obtained as a mixture of epimers 324 (R, R = H, or OH) on acid-catalysed cyclization, these yield the phosphorus epimeric analogues of D-ribo and D-arabino-furanosides with phosphorus in the epimeric position 324 (R = H, R = OH) affords 325 as a mixture of the 2R, 35,4R, 5R and 25, 35,4R, 5R, forms in the ratio 2 1, and 324 (R = OH, R = H) also yields the phosphorus epimeric 321 in the same ratio ... 

The Michaelis-Arbuzov reaction is unable to provide the simplest of the acylphospho-nic acids, namely (oxomethyl)phosphonic acid, the diethyl ester of which, 493, has been obtained from triethyl phosphite and formic-acetic anhydride at -10 °C at a higher temperature, decomposition sets in with the liberation of CO and formation of diethyl hydrogenphosphonate. Ensuing reactions lead ultimately to 494 ... 

Although esters of (oxomethyl)phosphonic acid have proved to be so elusive, derived acetals (495 R = H, X = O) have been prepared with relatively little difficulty from the acid-catalysed interaction of dialkyl hydrogenphosphonates and orthoformic esters ", and from mixtures of phosphorus(III) chlorides and orthoformic esters when heated in sealed tubes the reaction is included here since the ultimate stage is presumably of the Michaelis-Arbuzov type. The current view (Scheme 48) appears to be that the phos-phorus(III) chloride reacts with triethyl orthoformate in a stepwise fashion where appropriate, and with the formation, in the penultimate step, of a phosphorus(III) triester and ClCH(OEt)2. Such reactions were observed in a highly detailed study, by P NMR spectroscopy, of the very slow reaction, even at 150 °C, between triethyl orthoformate and the chloride 496, from which the phosphinic ester 497 was isolated the reaction between the chloride 498 and triethyl orthoformate was much faster, but even so, took place over an... 

In addition to aldimines, reactions between dialkyl hydrogenphosphonates and ketoximes are reported to give low yields of (aminoalkyl)phosphonic acids when treated with hypophosphorous acid. ... 

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 ... 

Phosphonic derivatives bearing chlorofluorinated chains e.. diethyl-1,1,2-trifluoro-2-chloroethylphosphonate have been prepared by radical telomeriz-ation of chlorotrifluoroethylene with dialkyl hydrogenphosphonates in the presence of peroxide inhibitors. The 0,0-diethylaryldifluoromethylphos-phonothioates (230) undergo the sodium iodide-assisted thiono-thiolo rearrangement and subsequent Pd-catalysed dealkylation of (231) provides several 1,1-difluoromethylenephosphonothioic acids (232) (Scheme 61). These compounds can act as small molecule inhibitors for the protein tyrosine phosphatase enzymes. 

The interaction of an ethenyl ether and a trialkyl phosphite (trimethyl phosphite was actually used) under dry acid conditions (HCl gas in MeOH) leads to a phosphonic diester according to Scheme 2. Little dealkylation of the phosphite triester appears to occur, and the reaction appears therefore not to involve addition of dialkyl hydrogenphosphonate (the product of phosphite dealkylation), all the more so since triphenylphosphine also reacts under the same conditions to give related triphenylphosphonium salts. Ethenyl ethyl ether, 2,3-dihydrofuran and 2,3-dihydropyran were used as substratesThe ease of reaction under mild conditions, coupled with high yields, testifies to the importance of a cationic intermediate species. 

Other addition reactions include those of dialkyl hydrogenphosphonates to alkynyl-phosphonic esters under basic catalysis, observed by Saunders and Simpson" and by others (reaction 51) but also of some interest are those additions of hydrogenphosphonates to acetylenic alcohols such as 376 (Scheme 15). The addition of hypophosphorous acid to the alcohols 380 affords the alka-l,2-dienephosphinic acids 381 which, when treated with acid, cyclize to the acids 382 . ... 

The addition of dialkyl hydrogenphosphonates to tetrafluoroethene occurs in the presence of di- r butyl peroxide to give the series of polyfluoroalkyl phosphonic diesters, H(CF2CF2) P(0)(0R)2 (n = 1-3) the free acids with n = 1-5 and the corresponding phosphonic dichlorides with n = 1-9 have also been recorded ... 

Several slightly more unusual examples are worth presenting. The very vigorous reaction between a dialkyl hydrogenphosphonate and penta-2,4-dienoic acid proceeds to the phosphonic diester 419 initially but which, with more reagent, affords the diphosphonic... 

X = Se ". These and other synthesis procedures will be considered in more detail later. Unfortunately, the acetals of (oxomethyl)phosphonic diesters do not liberate the free (oxomethyl)phosphonic esters under acidic conditions, but instead, tend to decompose with the formation of dialkyl hydrogenphosphonate. 

In Section VILA, the 1,2-addition of a hydrogenphosphonic diester or related compound to an a,j5-unsaturated aldehyde or analogous ketone " " was discussed in relation to the synthesis of (l-hydroxyalkyl)phosphonic diesters. The latter are formed under condition of kinetic control whereas 1,4-addition (the so-called Pudovik reaction), which leads to the (2-oxoalkyl)phosphonic diester occur under thermodynamic controP" ". In general, reactions which involve ethylenic aldehydes, or acetylenic aldehydes or ketones, tend to result in adduct formation across the carbonyl group, whilst ethylenic ketones tend to take part in 1,4-additions and afford 3-oxoalkyl phosphonic (or phosphinic) acid systems 550 34,946-949 consistent with Markovnikov predictions. Such statements are a broad oversimplification, however, at least with regard to the formation of the oxoalkyl phosphonates. In practice, the manner of addition depends on experimental circumstances, the nature and even amount of catalyst and other factors For instance, for the additions of dimethyl hydrogenphosphonate to the ketones 561 ( = 1 or 2) and 559 (R" = H, R = 2-furyl, R = Me), carried out by the addition of a trace of saturated MeONa-MeOH solution to a mixture of reactants in diethyl ether, yielded (within 5 min) the respective 1,2-adducts (1-hydroxyalkylphosphonates) in yields of64,69 and 52% ... 

---