Phosphonates under acidic conditions

Figure 19.1 Synthetic scheme for example pheromone components. Abbreviations al and a2 = Wittig-Homer condensations with triethyl 2-phosphonopropionate and triethyl 2-phosphonobutyrate, respectively b = reduction of ester with lithium aluminum hydride c = partial oxidation of alcohol with manganese dioxide to aldehyde dl and d2 = Wittig condensations with ethyltriphenylphosphonium bromide and propyltriphenylphosphonium bromide, respectively e = condensation with dimethylhydrazone phosphonate reagent f = hydrolysis under acidic conditions. Compound numbers are as in Table 19.1.

Dioxolans 146 can be considered as masked carbonyl functionalities, and are cleaved under acidic conditions. In solution, the olefination of a dioxolan-protected ketone would therefore be a two-step transformation consisting of deprotection and olefination. Using polymer-supported adds, e.g., strongly addic Amberlyst resin 147 and polymer-supported phosphonates 135 (Scheme 25), the two-step transformation involving the carbonyl compound 137 as intermediate could be performed simultaneously in one pot (Scheme 27) [113]. The product 136 was isolated by filtration. This procedure would not work as a one-pot sequence in solution because the acidic catalyst would immediately quench the basic phospho-nate resin. 

Whilst arguably, the formaldehyde condensation reactions in the preceding section are, under acidic conditions, electrophilic in type, a considerably wider range of compounds result from the commercially available C4, Cg, and Cg alkylphenols with a variety of reactants in other electrophilic substitution reactions. Thus 2,6-di-tert-butylphenol condensed with formaldehyde in hydrochloric acid gives 3,5-di-tert-butyl-4-hydroxybenzyl chloride which can be utilised in an Arbuzov reaction with trialkylphosphites to afford the dialkyl phosphonate depicted (ref. 80). The diethyl ester (Irganox 1222, Ciba-Geigy Ltd.) in this series is a significant stabiliser for polyester fibres in the prevention of photo and oxidative deterioration. 

Both diethyl (chloromethyl)phosphonate and diethyl (trichloromethyl)phosphonate, when treated with chlorotrimethylsilane (Scheme 13) followed by BuLi, generate the species 129, evident from the regeneration of diethyl (chloromethyl)phosphonate under aqueous conditions, and the observed formation of 130. The alkylation of 129 leads to 131 which, in the presence of EtO", loses the silyl group, while the treatment of 129 with formic acid leads to another reactive silicon-containing species, 132 Loss of chlorine from the... 

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. 

Lee and oh d d8 employed nitriles in conjunction with lithiated phosphonate carbanions. Careful hydrolysis of the anionic ketimine adducts under acidic conditions gave the (2-oxoalkyl)phosphonic esters, but it was also possible, when the hydrolysis was performed under essentially neutral conditions, to isolate phosphorylated enamines, which themselves are hydrolysable to a corresponding ketone (Scheme 59) the procedure also allows the introduction of other groups into the C(i) position when, for example, R X = PhSCl, PhSSPh, PhSeBr, PhS02Cl or MeSS02Me. ... 

The monoaminomonophosphonic acids, either in the free state or, very often, as their diethyl esters, have been resolved by the usual techniques of repeated crystallization of appropriate salts those of L-(+)-tartaric acid (2,3-dihydroxybutanedioic acid) or its mono-or di-benzoyl derivativesor of D-(-)-mandelic acid, have been widely employed the use of di-O-benzoylated L-tartaric anhydride, which is based on the separation of diastereoisomeric amides (111), has also been employed to a limited extent. In selected cases, such as the monoaminomonophosphonocarboxylic acids or A -acylated (aminoalkyl)phosphonic acids, resolution following salt formation with organic bases has also been carried out ephedrine, quinine and both enantiomers of l-phenylethylamine have all been used. In many cases, only one enantiomer of the (aminoalkyl)phosphonic acid (or diester) has been isolated in optically pure form. Sometimes, the acidity of the substrate, and hence choice of base for resolution, can be modified by using a mono- (as opposed to di-) ester or (or even in addition to) protection of the amino group as, for example, the phthalimido, benzyloxycarbonyl (cbz) or r r -butyloxycarbonyl (boc) derivative. Resolved di- and mono-esters can be hydrolysed to the free acids under acidic conditions, and A -protection can also be removed through the customary procedures. 

The oxime from (4-chloro-l-oxobutyl)phosphonic acid has been cyclized to Pro ". An unusual rearrangement based on valence expansion of phosphorus is of interest the treatment of an (oxoalkyl)phosphonic oxime with Ph2PCl initially yields the phosphorus(III) derivative, but this rearranges spontaneously to give a phosphinic amide derivative 300, reduction of which then affords the [(V-diphenylphosphinoylamino)alkyl]phosphonic acid, readily hydrolysable under acid conditions to the free (aminoalkyl)phosphonic diester (Scheme 34)" ". 

The anion from (cyanomethyl)phosphonic bis(dimethylamide) (331 R = R = H) may be mono- or di-alkylated, and the products sequentially reduced with H2-Raney nickel and hydrolysed under acidic conditions to give (2-aminoethyl)phosphonic acid or its C(i) alkylated derivatives. In the search for simple procedures which might lead to better asymmetric induction and so provide products of reasonable optical purity, the... 

Monoalkyl esters of the same acid likewise decompose under acidic conditions to give benzonitrile and monoalkyl metaphosphates. The nature of the solvent in which degradation occurs can have a profound effect on the course of such degradation the predominantly ( )-oximes from the mono-2,2,2-trihaloethyl esters 121 and 122 of [a-(hydroxyimino)benzyl]phosphonic acid, as their anions, lose benzonitrile in boiling ethanol or propan-2-ol and yield mixed phosphodiesters 124 (R = Et or Pr ) ( )-(121) does... 

Enol ethers from (2-oxoalkyl)phosphonic diesters are themselves highly reactive in hydrolysis and addition reactions. (2-Butoxyethenyl)phosphonic dichloride in CCI4 solution readily adds bromine in the cold, but attempts to distil the resultant (1,2-dibro-mo-2-butoxyethyl)phosphonic dichloride result in dehydrobromination the product 334 is unreactive to further attempted bromination, but suffers ready hydrolysis to (1-hydroxy-2-oxoethyl)phosphonic acid, and similarly, hydrolysis of the precursor dichloride yields (2-oxoethyl)phosphonic acid. Reactions between enol ethers and amides, carbamates or phosphoramidates, under acidic conditions, yield the enamides 335 [R = CO-alkyl, CO-aryl, COO-alkyl or P(0)(0Pr%f (2-Alkoxyethenyl)phosphonic diisocyanates act as precursors to phosphapyrimidines 336 and analogous phosphapurines ... 

Acidic and basic hydrolysis of GA result in different products (Fig. 4). Under acidic conditions, ethylphosphoryl cyanidate and dimethylamine are formed under basic and neutral conditions, ethyl A,A-dimethylamido phosphoric acid and hydrogen cyanide are formed. Although the latter pathway is predominant, di-methylphosphoramidate, phosphorocyanidate, and dimethylphosphoramide cyanidate may also be formed (Sanches et al. 1993). The phosphorus-containing compounds are slowly hydrolyzed to phosphoric acid. Although theoretically possible, there is little likelihood of formation of a detectable amount of methyl phosphonic acid from GA. Hydrolysis products are listed in Table 37. 

The fluorophosphonates GB and GD hydrolyze first through the loss of fluorine and second, more slowly, through the loss of the alkoxy group (Kingery and Allen 1995 MacNaughton and Brewer 1994). Under acidic conditions, the products of GB hydrolysis are isopropyl methylphosphonic acid and fluoride the former slowly hydrolyzes to methyl phosphonic acid with the loss of isopropanol (Fig. 5). According to Clark (1989), alkaline hydrolysis results in isopro-... 

Figure 9.2 Synthesis of adenylylated amino acids, (a) On resin approach via H-phosphonation of the compieted peptide. Limited compatibiiity with amino acids in the backbone, (b) The buiiding biock approach for SPPS with ester-protected adenosine gives rise to depurination under acidic conditions, (c) Switching the protective group...

Kaur et al. presented the inhibition of class D p-lactamases by different acyl-phosphonates (01JACS10436). These compounds were synthetized starting with ethyl o-toluate 109. Benzylic bromination with N-bromosuccinimide followed by a subsequent Arbuzov reaction with triethyl phosphite and hydrolysis under acidic conditions afforded the phosphonic acid 110. The final dehydration of diacid 110 in refluxing xylene produced the cycHc phospho-nolactone 111 (Scheme 26). 

Even under acidic conditions, phosphonates are considerably more effective chelating agents than the corresponding carboxylates (S). For excample, while methylenephosphonic acid is in a monoanionic form above pH 2.3, acetic acid is in a protonated, unavailable form until a pH of 4.6 is reached... 

In the second method. Stone et al. [84] copolymerized monomer 4-2 with TFS (Fig. 2.17) by emulsion polymerization in 21% isolated yield. The optimized ratio between TFS and the dimethyl phosphonate-substimted a,, -trifluorostyrene monomer in the copolymer 4-5 was 2.4 1. The molecular weights of the resulting copolymer were 38,100 and 105,900g/mol for and respectively. Homo-polymer 4-3 (membrane A) was hydrolyzed under acidic conditions (hydrochloric acid in dioxane, 100 °C, 20 h). The yield and the equivalent weight of acid functions were 95% and 130 g/mol, respectively. Copolymer 4-4 was hydrolyzed by the authors using two processes (i) basic conditions (potassium hydroxide, 84 °C, 64 h), membrane Cl, and (ii) acidic conditions with a DMF pretreatment, membrane C3. Finally, the authors concluded that the best results were obtained with an acidic hydrolysis and that membranes based on sulfonic acid-a,, -trifluorostyrene gave better results than those obtained from the phosphonic acid homolog. 

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