Acylphosphonates hydrolysis

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

Acyclic cationic systems, chalcogen-halogen compounds, 35 299-301 Acylarsonic acids, 44 217 Acyldiazenido complexes, mechanisms of formation, 27 223-225 Acylium cation, 9 231, 241-243 Acylphosphonic acids, 44 217 Acylsilane, hydrolysis, 42 173 Adamantane... 

An obvious synthetic application of amine addition to the a-keto group in acylphosphonates would be reductive amination. This has been demonstrated [42], and shown to be a useful route to 1-aminoalkylphosphonic acids. Thus, selected acylphosphonates were reacted with benzhydrylamine, giving after reduction of the resulting imine intermediate with triacetoxyborohydride and acid hydrolysis, satisfactory yields of the corresponding aminoalkylphosphonic acids. However, a limitation of this approach is unwanted cleavage of the phos-phonate P-C bond, which was observed with other amines such as benzylamine and a-benzylmethylamine [42]. 

A number of acylphosphonic acids are of interest for their biological activity, or as intermediates in syntheses of potentially bioactive phosphonic acids [7, 34, 48 - 50]. In many cases, they are most conveniently prepared by hydrolysis of the corresponding esters. Due to the presence of the keto function, acid hydrolysis (heating in aqueous HCl) is generally not a practical method to achieve this. Silyldealkylation of methyl-, ethyl- or isopropyl phosphonates with BTMS, followed by very mild hydrolysis is normally compatible with acyl and other sensitive functionalities [7,34,48]. 

Acylphosphonic acids have also been obtained by hydrolysis of di(ferf-butyl) acylphosphonates with 85% TFA [49] or by hydrogenolysis of corresponding... 

One example of reductive amination of acylphosphonates has been reported. Thus, reaction of dimethyl 1-oxoalkylphosphonates with benzhydrylamine results in the formation of an imine reduced in situ with NalllKOAc),. The reaction is independent of the solvent, and THF, CIFCh and CHCI3 give similar results - After selective removal of the benzhydrylic group by catalytic hydrogenation and hydrolysis with concentrated HCl, the 1 -aminoalkylphosphonic acids are isolated in satisfactory yields (30-60%, Scheme 7.66) ... 

NaBH3CN,5" BH3 MciS,-" calecholhorane," Al(O/ -Pr)3, ° or activated Zn in AcOH.5°5 Reduction of acylphosphonates using NaBH4 needs careful control of the reaction conditions (H2O or MeOH, KH2PO4, 0-5°C, pH = 6-7) to avoid hydrolysis of both starting acylphosphonates and reaction... 

The treatment of an acylphosphonic diester with borane in the presence of a chiral 1,3,2-oxazaborolidine has produced the (a-hydroxy-alkyl)phosphonic diester, very often in considerable enantiomeric excess . Moderate enantiomeric excesses have also been observed as the result of the hydrolysis of the acetates of racemic (l-hydroxyalkyl)phosphonic diesters by the lipase from Aspergillus niger ... 

Indeed, one of the main uses of j -phosphorylated ketones is the synthesis of C-phos-phorylated heterocyclic systems, and in this respect the reactions very often complement those of isomeric acylphosphonates. In the first of the examples chosen, the ketone 304 cannot be converted into 305 in a direct reaction with the appropriate amine instead, the carbonyl group must be protected as in 307, when a reaction with the amine then gives 308 hydrolysis of 308 with 3 M HCl yields 305. When treated with ZnCl2 under toluene, 305 yields the indolylphosphonic diester 310" In the same way, a direct reaction between 304 and ArONa fails to give 306, which must therefore be prepared via 307 and 309 with acid hydrolysis to 306 when the latter is treated with hot polyphosphoric acid, cyclization occurs to give the benzofuranylphosphonic diester In order to obtain the isomeric... 

Dialkyl acylphosphonates are sensitive to water in neutral and alkaline conditions and hydrolyse rapidly to the corresponding carboxylic acids and to dialkyl hydrogen-phosphonate (equation 47) This occurs following the rapid addition of water to the carbonyl group with the formation of stable hydrates. The involvement of stable carbonyl hydrates in the hydrolysis of dimethyl acetylphosphonate and aroylphosphonates was established by H NMR and UV spectroscopy, respectively. In the latter case, the rates of formation and decomposition of the tetrahedral carbonyl hydrates were also determined. 

Results concerning the behaviour of two unique acylphosphonate derivatives under hydrolytic conditions should also be mentioned. The aroylphosphonic group was used as a protecting group in the synthesis of nucleotides. In the course of this work, the stability of this group was determined examining a series of 5 -(dimethoxytrityl) thymidine-3 -aroylphosphonates (23) in 1 M sodium hydroxide-pyridine (1 1, v/v) . These aroylphosphonate monoesters were resistant to hydrolysis. In comparison, methyl sodium benzoylphosphonate under these conditions underwent complete hydrolysis to benzoic acid in 18 hat 25 °C ... 

Acylphosphonic acids react with pyridoxamine, which is a coenzyme of transaminases, with the formation of a-aminophosphonic acids (see also reductive amination. Section II. C. 4. c) The first step of the reaction is addition of the pyridoxamine to the carbonyl of the acylphosphonate, followed by prototropic rearrangement and hydrolysis to pyridoxal and an aminophosphonic acid (equation 59). This reaction is in contrast with the reverse... 

Takamizawa et al. (1972) narrated that benzothiazine derivatives (97) could be obtained by treating the benzothiazolium salts (95) with diethyl acylphosphonates followed by basic hydrolysis (Scheme-27) (Takamizawa et al. 1972). 

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