Hydrogenphosphonates

A. V. Nikolaev, I. A. Ivanova, V. N. Shibaev, and N. K. Kochetkov, Application of the hydrogenphosphonate approach in the synthesis of glycosyl phosphosugars linked through secondary hydroxyl groups, Carbohydr. Res., 204 (1990) 65-78. 

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. 

Hydroxyalkyt and Epoxyalky Acids. The reaction of aldehydes or ketones with dialkyl hydrogenphosphonate continues to be widely used for the synthesis of a-hydroxyalkylphosphonates ° and magnesium oxide has been reported to be an effective catalyst for the reaction. The reaction has been used in enantioselective synthesis. For example, in the preparation of chiral a, -dihydroxyphosphonic acids 171 and 172 (Scheme 14), with preferential formation of the jyn-isomer 171, and the statin analogue 2-amino-1-hydroxy-3-phenylpropylphosphonic acid (173) (Scheme 15). Catalytic asymmetric... 

A series of alkyl ester hydrogenphosphonate derivatives of AZT, d2A and d4T (18), (19) and (20) have been synthesised to investigate the metabolic pathway by which the hydrogenphosphonate (18, R = H) is transformed to AZT inside the cells2 It was found that ester residues containing primary and secondary alcohols were oxidized and hydrolysed to give AZT, whereas those containing tertiary alcohols were hydrolysed to AZT-5 -H-phosphonate. The same observations were reported for d2A and d4T. 

Ara-A)p(ara-A). (ara-A)p(xylo-A) and ara-adenosine 5 -hydrogenphosphonate showed modest cytostatic and antiviral activity in test systems, apparently due to release of ara-adenosine or ara-AMP by enzymic action. 

Reactions between diethyl hydrogenphosphonate and ArX (X = I or Br) to give diethyl arylphosphonates have been carried out in the presence of a phase transfer catalyst. Bis(trimethylsilyl) phenylphosphonite reacts with alkyl halides to give [(ar)alkylphenyl]phosphinic derivatives, and it also adds to a,P-unsaturated carboxylic esters (as well as to nitriles and amides) to give (2-functionalized-l-alkyl)phosphinic derivatives. ... 

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... 

The reactions which take place between acetophenone and PCI3 have been revisited. Reactions between diethyl hydrogenphosphonate, (Me3Si)2NM (M = Li, K, or Na), and an acyl chloride RCOCl in the ratio 2 2 1 in THF at —100 °C during periods of only seconds lead to only (155) (R = alkyl) or to mixtures of... 

The addition of hydrogenphosphonates or related compounds to imines or their trimers continues to be a widely employed procedure. Noteable is the observation that whereas the addition of hydrogenphosphonates to (193) require a period of heating at 90 °C for appreciable reaction to occur, sonication of reaction mixtures produces immediate addition to form (194). Interest has tended to be centred around the potential for stereochemical control of the addition through modification to the stereochemistry of the hydrogenphospho-nate or other phosphorus intermediate, or in the use of selected imines. Slight control was observed in the addition of (25,4i )-(195) to (196) the products, (197), exhibited diastereoisomeric ratios of 40-45 60-55. Modest diastereo-selectivity was also observed in reactions between (198) and (199) leading to... 

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. ... 

Dialkyl hydrogenphosphonates fit into this discussion, since alkoxy groups are readily displaced and secondary phosphine oxides are formed. Diethyl hydrogenphosphonate added to the propyl Grignard reagent in ether gave dipropylphosphine oxide (122). 

If the intermediate from the first stage was treated with an alkyl halide, a tertiary phosphine oxide was isolated along with the secondary phosphine oxide. The case with hexyl Grignard reagent is illustrative. When ethyl Grignard reagent was added to diethyl hydrogenphosphonate... 

Curiously, the sodium salt of diethyl hydrogenphosphonate condensed in an exothermic reaction with o-fluorobromobenzene in the presence of magnesium in tetrahydrofuran (67). Diethyl phenylphosphonate (41 %) was considered to result from attack of benzyne on the phosphorus compound since triphenylene was also isolated. 

Dialkyl hydrogenphosphonates provide diarylphosphine oxides conveniently as shown in the illustration. 

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. 

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 ... 

Reactions between dialkyl hydrogenphosphonates and haloalkanes have been performed under phase-transfer conditions some initial experiments used diethyl and diisopropyl hydrogenphosphonates with either non-functionalized (e.g. alkyl, allyl or benzyl) halides, or functionalized halides, and employed K2CO3 as base in the presence of tetra-butylammonium salts or 18-crown-6. Other workers have also reported successes in their use of the same or similar systems, but more recent work has raised doubts about the value of the potassium salt, and has illustrated the evident superiority of CS2CO3 as base ... 

Novel cyclic A-(co-haloalkyl)phosphinic amides of the general type 111 cyclize when treated with and the hydrogenphosphonic diamides 112 have also been alkylat-... 

From the experimental point of view, it is worth noting that when dimethyl hydrogen-phosphonate is treated with NaH in thf, some disproportionation to dimethyl methylphos-phonate and monomethyl phosphinate occurs this property is not important with diethyl hydrogenphosphonate, nor does it occur even with dimethy hydrogenphosphonate if the anion is generated from either NaH or BuLi in benzene or in thf at a low temperature. ... 

F. Synthesis from Hydrocarbons and Hydrogenphosphonates or Related Compounds... 

The interaction of a hydrogenphosphonate diester and an alkene occurs under free radical conditions, arising either through the use of peroxide or azo catalysts, or by exposure to appropriate radiation. Cadogan has summarized some early examples of the procedure, although at the time, there appeared to be very few examples in which non-functionalized systems were used. The commonly accepted mechanism for homolytic addition seems to be that given in Scheme 7. 

Two recent studies have examined the addition of dimethyl hydrogenphosphonate to cyclopropylalkenes in the presence of azobisisobutyronitrile or dibenzoyl peroxide and the addition of a range of dialkyl hydrogenphosphonates to cyclopentene and its methyl-substituted derivatives in the last case reactions with 1-methylcyclopentene proceeded regiospecifically and to some extent stereoselectively ". ... 

The photophosphonylation of cyclohexane has been successfully carried out using radiation from a mercury source. With dialkyl hydrogenphosphonates yields of dialkyl cyclohexylphosphonates reaching 75-80% were obtainable within one day, and the esters (EtO)RP(0)H produced similar, or at least acceptable, yields of mixed phosphinic esters CyRP(0)0Et (R = Et, Ph, or Cy) under similar conditions ... 

High reactivity is shown towards hydrogenphosphonates by highly strained hydrocarbon molecules. Thus, 1,3-dedihydroadamantane (133) reacts to give esters of 1-adamantyl-phosphonic acid under non-homolytic conditions , and tricyclo[4.1.0.0 ]heptane similarly affords the phosphonic esters 134 . 

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