Hydrogenphosphonates reactions

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... 

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. ... 

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. 

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 ... 

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. ... 

Replacement of iodine ortho to NH2, OH, COOH, COOEt, CONH2 or CSOEt is possible on reaction of the 2-substituted iodobenzene with diethyl hydrogenphosphonate". The 2-position is also sufficiently activated in the quaternary salts 247 [COOEt at C(4), C(5)... 

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 . ... 

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... 

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 addition of hydrogenphosphonates to chloroketones, and also to other mono halo-genated carbonyl compounds, is aided by the presence of AI2O3, yields of 78-96% being achievable. However, reactions between dialkyl or diphenyl hydrogenphosphonates and chloroacetone " ", 5 m-dichloroacetone or a ym-dichloroacetone " do occur in the absence of a catalyst when mixtures of reactants are heated to 100-120 °C the products are the phosphonates 173 (R = H or Cl). Aryl trichloromethyl ketones are mon-odechlorinated by the action of trialkyl phosphites or dialkyl hydrogenphosphonates and both further dechlorination and the formation of phosphate esters have been... 

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... 

Experimental conditions and substituents of sp carbon govern reactions between a,j -unsaturated aldehydes or ketones and dialkyl hydrogenphosphonates. Summaries of the field have been presented , as also has an extensive compilation of reactions and products ... 

In the reactions between diethyl hydrogenphosphonate and indantrione or 2-benzyli-deneindan-1,3-dione, the former substrate yields phosphate adducts,but in the latter case, addition affords the phosphonate 203 The additions of hydrogenphosphonic diesters to propynal and ethynyl methyl ketone and to the ketones RC=CCOMe (R = Me or Ph) ", give 1,2-adducts. 

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. ... 

Biacetyl reacts with a dialkyl hydrogenphosphonate in a manner identical with that observed in the first stage for glyoxal, and gives the esteis 239 A reaction between lithium diethyl phosphite and the 1,2-dioxocyclobutene 240 affords the hydroxy phosphonate... 

Hexafluoroacetylacetone, through its enol form, (Z)-1,1,1,5,5,5-hexafluoro-4-hydrox-ypent-3-en-2-one, undergoes, as might be expected a complex reaction with a dialkyl hydrogenphosphonate with, initially, the formation of 250 (R = Me) or 251 (R = Et or RR = CMe2CMe2). For those compounds with R = Me, further steps lead to diastereoiso-meric pairs 252 and 253 of 2,5-dialkoxy-2-oxo-3,5-bis(trifluoromethyl)-l,2-oxaphospho-lan-3-ol via the phosphorane intermediates 254a and... 

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. 

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