Hydrogenphosphonates alkylation

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. 

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. ... 

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... 

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... 

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 ... 

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. ... 

R = O-alkyl, n= 1) in the same way, diethyl phenylphosphonite affords 11 (R = Ph, R = Et, = 1, X = I). Bromoform and iodoform, although reactive to trialkyl phosphites, tend to yield alkyl halide, dialkyl hydrogenphosphonate and dialkyl phosphorohalidate, but (halomethyl)phosphonate esters are not obtained. With tetrahalomethanes, particularly those based on two or more different halogens, a more interesting picture is presented. Triethyl phosphite and tetrabromomethane are reported to yield EtBr quantitatively but... 

The use of trichloroacetaldehyde is also to be particularly noted. Although reactions between this aldehyde and various dialkyl hydrogenphosphonates have been report- 269,274,294,295 it is the dimethyl ester of (l-hydroxy-2,2,2-trichloroethyl)phosphonic acid which has received particular attention, and which has been studied widely from the structural point of view in the light of its commercial importance as the powerful insecticide dipterex (also known as trichlorphon and chlorophos). Polyfluoroalkyl esters of the related alkyl(l-hydroxy-2,2,2-trichloroethyl)phosphinic acids have been prepared by the unusual combination of chloral hydrate and the bis(polyfluoroalkyl) alkylphosphonite ester ... 

The mode of addition of hydrogenphosphonates to fluorinated ketones can also be complex. The addition of dialkyl, diphenyl or bis(trimethylsilyl) hydrogenphosphonates to methyl trifluoromethyl ketones occurs in the expected manner, but this contrasts with the behaviour of aryl perfluoralkyl ketones in the presence of triethylamine at room temperature, when the products, obtained even under such mild conditions, are phosphate esters (reaction 6), a situation which represents lack of stability of the hydroxyphospho-nate rather than novelty of the reaction under identical conditions, the corresponding alkyl aryl ketones fail to react. The same reaction with mixed-halogen ketones is still more involved, and the nature of the products depends on the reaction conditions if these are of a mild nature, and with catalysis by triethylamine or pyridine (depending on the particular ketone), the product is the expected (hydroxyalkyl)phosphonate 177, whereas with... 

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,... 

Through the acylation or alkylation of hydrogenphosphonates and related compounds... 

Latterly, attention has been turned to the alkylation of the hydrogenphosphonates themselves under essentially neutral conditions, thus obviating the several possible side reactions. The formation (in 38% yield) of triethyl phosphonoacetate from diethyl hydro-genphosphonate and ethyl diazoacetate has been known for some time, and the synthetically useful methyl (di-tcrt-butoxyphosphinoyl)acetate (in 40% yield) has been similarly and more recently obtained Steps have been to tiy to improve yields under photoinitiation in the presence of copper salts or complexes ", or through catalysis by trifluoromethanesulphonic acid Such procedures allow the ready synthesis of the esters 411 (R = alkyl or RO). 

The simplest of these reactions consists in the addition of hydrogenphosphonate esters to isocyanates or isothiocyanates, when the products are the amides 391b (R = RO) with R = alkyl or aryl or 391c (R = RO) with R = alkyl"" "" or Ph""". Differences in reactivity on the part of the isocyanate are to be noted the use of MeCNO requires the presence of a catalysis, unlike that of PhNCO. Hydrogenphosphonic bis(dialkylamides) also react with isocyanates " or isothiocyanates " " when the products are the triamides 412 (Z = O or S). 

The alternative addition mechanism, introduced briefly in the paragraph immediately preceding, seems to have arisen from observations on the comparative behaviour of propenoic and 3-phenylpropenoic acids towards dialkyl chlorophosphites, (RO)2PCf and involves attack on the protonated ester molecule by the acid anion, a sequence which liberates the dialkyl hydrogenphosphonate (and isolated in some experiments ) and alkyl propenoate (Scheme 42) the overall reaction sequence is then terminated by the addition of dialkyl hydrogenphosphonate to the alkyl propenoate to give the observed product. 

Reactions between propenoic anilide and phosphorus(III) esters or amides appear to follow a pathway comparable to that given in Scheme 42 and yield A-alkylated products 455 (R = R = OR, R = Et R = RO, R=Et, R = NEt2 R = R =NEt2, R = Et) and, indeed, separate additions of dialkyl hydrogenphosphonates to the appropriate propenamides yield the same products in not dissimilar yields ... 

The direct alkylation of hydrogenphosphonic diesters with a diazoketone has been recorded alongside that with diazoalkanoic esters, and explored particularly with methyl 2-diazo-3-oxobutanoate but also for several chloroacetones. Reactions involving 1-chloro-3-diazo-2-propanone are effectively catalysed by [Cu(acac)2], but more heavily chlorinated substrates suffer stepwise dechlorination. Thus l,l,l-trichloro-3-diazo-propan-2-one initially yields the expected dialkyl (3,3,3-trichloro-2-oxopropyl)phospho-nate, but under the experimental conditions, dechlorination then proceeds to give the dialkyl (3,3-dichloro-2-oxopropyl)phosphonate only the monochloroketone undergoes a reaction in which the original halogen content is retained in the final product ... 

The addition of dialkyl hydrogenphosphonate or alkyl phosphinate to compounds which possess two C=N bonds is of some mechanistic interest. Such additions to 190 yield 191 (R = OEt and Ph ), but no comments seem to have been made about the relative... 

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... 

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