Hydrogenphosphonates derivatives

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. 

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. 

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. ... 

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. ... 

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 ". ... 

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. ... 

Addition of hydrogenphosphonates to the 1,4-quinonemethides 383 to give the 4-hydroxyphenyl polyphosphonic acids as their esters 384 is well established , and that of hydrogenphosphonates to / -benzoquinone itself is reported to give the 2,5-dihydrox-yphenyl-l,4-bisphosphonic acid derivative. ... 

In the many recorded examples of the reaction, and because of its very nature, reports have tended to concentrate on compounds derived from a range of simple carbonyl compounds and a single (or at most two) dialkydiaryP or diheteroaryP hydrogenphosphonate or, alternatively, on combinations of a selection of hydrogenphosphonates with a relatively few carbonyl compounds, including propanal, benzenoid aldehydes " furan and thiophene aldehydes 3-formylindole ° 2- and 3-formyl-chromones " , diethyl oxomalonate and others . It is worthy of comment that... 

Much attention has been devoted to the conversion of aldehydes into the trimethylsilyl ethers of (a-hydroxyalkyl)-phosphonic acids 210 or analogous -phosphinic acids, or of the corresponding (a-hydroxyalkyl)phosphonic diamides 211 by the use of dialkyl trimethylsilyl phosphite or Me3SiOP(NEt2)2 (or other phosphorodiamidite) It is a reaction which occurs very readily, even at room temperature, and the ready methanolytic or hydrolytic removal of the silyl protecting group makes the procedure an attractive alternative to the direct synthesis of the (a-hydroxyalkyl)phosphonic acids from dialkyl hydrogenphosphonates and carbonyl compounds. Silyl-protected hydroxy-phosphonic and -phosphinic acid derivatives are useful for further synthetic development. ... 

The reaction between dimethyl hydrogenphosphonate and 3-hydroxybutanal produces a mixture of diastereoisomeric dimethyl (l,3-dihydroxybutyl)phosphonates, 262a and b, in the proportions 3 7 the relative configurations at the C(i) and C ) chiral centres in individual isomers were ascertained through NMR analysis of the benzylidene derivatives. 

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 ... 

Application of the Abramov reaction has received little more attention, but it has been used in conjunction with toluenesulphonyl derivatives of hydroxyketones in the presence of dbu (Scheme 28) when acted upon by thiourea in MeOH at room temperature, the oxi-ranes 344 (R = Me or Et, R = Me or Cy) are converted into the corresponding thiiranes 345 ". The reaction between the protected oxoacetal 346 with methyl phenylphosphinate in the presence of dbu provides the epoxide 347 as a mixture of the diastereoisomeric 4RS and 4SR pairs in the ratio 7 3. Reduction of the product with H2 and Raney nickel yields the linear phosphinate ester 348 Similarly, the reactions between the ketose 349 (R = Me or CH2Ph) with either dialkyl hydrogenphosphonate or alkyl phenylphosphinate, again in the presence of dbu, gave the epoxides 350 (R = Me or CH2Ph R = R = MeO R = Ph,... 

The addition of hydrogenphosphonic diesters to ethenylphosphonic or ethenylphos-phinic derivatives follows equation 26, and that of the hydrogenphosphonates to the (1,2-butadiene)phosphonic system is represented by equation 27. 

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... 

The formation of diethyl (3-oxobutyl)phosphonate from triethyl phosphite and 3-oxobutyl acetate can be formulated also as taking place through a phosphorane intermediate. As further examples, the phosphoranes 587 have been prepared from the benzylidene derivatives 583, 584 585 and 586 Careful hydrolysis of the phosphoranes 587 with one equivalent of water in diethyl ether leads to the corresponding 588, which in turn tautomerize to the ketonic alkylphosphonic dimethyl esters 589, which can also be obtained independently by the addition of dimethyl hydrogenphosphonate to the original benzylidene compounds the latter, when heated, generate the dihydro-1,2-oxaphosph(V)oles 590. In the same way, the esters 593 have been obtained from the eth-ylidene compounds 591 via the respective oxyphosphoranes 592 (R = Me, Et, or EtO) ". ... 

A novel procedure for the preparation of acids which ultimately contain a free amino group consists in the reduction of a nitrile with diisosbutvlalane followed by the sequential addition of the hydrogenphosphonate, and hydrolysis Normally the imines have been derived from aliphatic aldehydesor ketones ", simple benzenoid aldehy-desi3i,i33,142,146,156,16, 277-287 j g Q es including fluorenone or aldehydes based on... 

For the addition of diethyl hydrogenphosphonate, the composition (estimated from the NMR signals for the anomeric carbons) of the reaction product was p S P-R (x-S a-R = 83 5.5 10.3 1.2, but this ratio can be altered by a careful choice in the adopted experimental procedure. The major isomer may be isolated by crystallization or HPLC and the cleavage of those adducts by 1 m HCL in MeOH yields the ( -aminophosphonic acid. The Schiff base from D-arabinopyranosylamine, 200, reacts to form selectively the R adduct (the ratio of R to 5 products is 5 1). By a careful choice of the carbohydrate nucleus, the major diastereoisomer adduct is formed with a purity sufficient to allow crystallization in pure form, as with the glucosylamine derivative 198 which afforded the adducts in the... 

Carbonyl hydrazones also participate in reactions with hydrogenphosphonate esters, as is illustrated by the formation of the hydrazine derivative 209. The outcome of the reaction between diethyl hydrogenphosphonate and an aromatic aldazine, typically 210, depends on the ratio of reactants. With the reactants in the ratio 1 1, the initial step is the formation of the use of a mixture of the hydrogenphosphonate and sodium... 

The alkylation of C-arylnitrones affords oximinium salts which also undergo addition reactions with hydrogenphosphonates or hydrogenphosphinates the products are O-alkylated derivatives of the hydroxy amino acids Although fairly complex... 

The course of the condensation between an acylphosphonate and a 1-nitroalkane car-banion depends on the nature of the acyl group. Base catalysts are commonly employed, but an acylphosphonate derived from an aromatic acid requires an acidic catalyst otherwise the intermediate anion fragments to hydrogenphosphonate and nitroketone (Scheme 20)207 jYiQ reaction between a nitroalkane carbanion and a dialkyl (trichloroacetyl)phos-phonate results in a rearrangement to phosphate with additional dehydrochlorination (Scheme 21) . ... 

A similar reaction occurs much more readily with tris(trimethylsilyl) phosphonofor-mate, which undergoes spontaneous fragmentation to tris(trimethylsilyl) phosphite. A cyclic mechanism was proposed for this reaction (equation 74)" This reaction was utilized in nucleoside chemistry for the preparation of nucleoside hydrogenphosphonates and related derivatives ... 

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