Phosphonates acylphosphonates

Acylphosphonates generate acyl anion equivalents with cyanide via phosphonate-phosphate rearrangement. These anions react with aldehydes to provide cross-benzoin... 

The oxazoliumcarboxylic acid (147) is easily decarboxylated via the ylide (148) the neutral compound (149) is much more stable due to the low equilibrium concentration of the zwitterionic tautomer (150 Scheme 7). Oxazolium salts lacking substituents at the 2-position react with dialkyl acylphosphonates in the presence of triethylamine to give mixtures of l,4-oxazin-3-ones and 2-azetidinones the reaction (see Scheme 8) proceeds by electrophilic attack of the phosphonate on an oxazolium ylide, e.g. (151), followed by insertion of oxygen into the carbon-phosphorus bond, ring-opening, and formation of the enolate anion (152) which can cyclize in two alternative ways with expulsion of the phosphonate group. 

Recently, alternative methods for preparation of acylphosphonates based on oxidation of easily prepared a-hydroxy- [10,11] and a-diazo phosphonates [12] have been developed. A variety of oxidation methods Mn02, PCC (pyridinium chlorochromate), PDC (pyridinium dichromate), Pfittzner-Moffatt, Swern oxidation have been applied to a-hydroxy phosphonate substrates [13-16]. 

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]. 

Fragmentation chemistry with C-P bond cleavage has also been demonstrated in acylphosphonate oximes. a-Hydroxyiminobenzylphosphonates (a-keto-phosphonate oximes) are reported to be precursors to monomeric phosphate, and can thus serve as phosphorylating agents [2]. Monomethyl hydroxyimi-nobenzylphosphonate fragmentation is also consistent with a dissociative mechanism [87]. 

LTBA can also cleave selectively the P—C bond of acyl phosphonates 2.58, while preserving other functional groups [DSl] (Figure 2.28). Nevertheless, the reduction of similar compounds such as 2.59 by NaBH4 in EtOH buffered by boric acid does preserve the P—C bond and leads to diastereomeric a-phosphorylated alcohols [BS5, DSl] (Figure 2.28). After enolization by NaH, the P—C bond cleavage of acylphosphonates (Et0)2P(0)CH2C0R can be realized with LAH [HS7]. 

The previous reactions suggest that trialkyl phosphites are able to react with acylphosphonates. Effectively, it has been shown that the reaction of trimethyl phosphite with dimethyl aroylphos-phonates under appropriate conditions leads to the formation of anionic adducts that decompose to give phosphonyl carbenes and trimethyl phosphate. These carbene intermediates can react with further trimethyl phosphite to give ylidic phosphonates, or, when suitable < rt/z<9-substituents are present on the aromatic ring, intramolecular carbene insertion reactions can occur to give cychc systems (Scheme 7.4).38.4o,56,58-65... 

Free acylphosphonic acids are easily obtained by treatment of i z.s (trimethylsilyl) (alkoxycar-bonyl)phosphonates with EtOH or by exposure to air for several hours. Diethyl (alkoxycarbo-nyl)phosphonates are prepared by condensation of the corresponding alcohols with the diethyl (chlorocarbonyl)phosphonate in the presence of EtjN or DMAP. ... 

Certain 1,2,4-thiadiazoles undergo ring expansion on treatment with dialkyl acylphosphonates. Thus, the action of diethyl acetyl(or benzoyl)-phosphonates (383, R = Me, Ph) on 4-benzyl-3-methyl-l,2,4-thiadiazolium bromide (382) produces substituted 1,2,4-thiadiazines (384), albeit in low yield. The pyrimidyl analog (385, formally comparable with thiamin) behaves similarly, but a cyclization (to 387) competes with the ring expansion (to 386). The structure of these and other complex products, and the mechanism of their formation, were discussed in detail.286... 

Two fairly recently announced procedures allow the synthesis of fluorinated phospho-nic esters from acylphosphonic diesters. In the first of these, aroylphosphonic diesters are treated with dast reagent at room temperature and in the absence of a solvent, when the products are dialkyl (a,a-difluorobenzyl)phosphonates. ... 

The (oxoalkyl)-phosphonic and -phosphinic acids form a remarkable group of compounds whose ease or formation, stability and versatility in use depend to a high degree on the relative positions of the oxo and phosphoryl groups. From the points of view of both synthesis and reactivity, the (1-oxoalkyl) compounds, also termed acylphosphonates, stand apart from the remaining compound types, and they have been considered separately in this volume and elsewhere the discussion here is designed to offer a comparison between syntheses of acylphosphonic acids with those of other important oxoalkyl phos-phonic and phosphinic acids. 

The reaction between tris(trimethylsilyl) phosphite and a perfluoroacyl chloride proceeds without any apparent difficulty to give the predicted phosphonate diester 489 [R = Me3Si, R = CF3 or (CF3)2CH] but the use of longer chain polyfluorinated acyl halides or other heavily halogenated acyl chlorides leads to complications with such substrates, the initially formed acylphosphonate reacts with more phosphorus(III) ester to give the (Z)-enol phosphate 490 (Scheme 47). The halides, XCH2COX (X = Cl or Br) afford only the esters 491 (X = H). ... 

Rare examples of normal Michaelis-Becker reactions which involve co-chloroalkanal diethyl acetals are to be found, and although the formation of dialkyl acylphosphonates from sodium dialkyl phosphites and, for example, benzoyl chloride, is to be observed at -85 °C, the system is further complicated, even at -10 °C, by further addition steps followed by rearrangements which would seem to render the process of little value for the synthesis of oxoalkyl phosphonic esters On the other hand, in a more detailed and systematic study of reactions between sodium dialkyl phosphites, (RO)2PONa(R = Et or Bu), and the ketones R CO(CH2) Cl, Sturtz and others have observed the formation of epoxides when n = 1 and (1-hydroxy alk-2-enyl)phosphonic diesters when n = 2(R = Me or Pr ), according to the displacement in 532, and of derivatives of tetrahydrofuran or tetrahy-dropyran, according to 533 n = 3 or 4) when R = Et, the formation of the cyclic ethers was accompanied by low yields of the expected (oxoalkyl)phosphonic diester, but otherwise the latter were isolated as a single product only for R = Me, n = 5, and R = Et or Pr when n = 2. 

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 ... 

NMR spectroscopy has shown that many compounds, previously described as (1-hydroxyalkylidene)bisphosphonic esters, are actually either totally rearranged compounds or mixtures of initial and rearranged compounds. Such was the case with the products from dialkyl hydrogenphosphonates and dialkyl acylphosphonates, for which, when R R the potential for confusion is obvious (Scheme 18). Provided that the compounds 104 are not heated above 80 °C, they may sometimes be isolated by crystallization, but others, e.g. 104 (R = Ph or aryl), rearrange very easily and cannot be isolated. (1-Hydroxyethylidene)bisphosphonic acid is stable in solution at pH 1.6 up to 125 °C, and in alkaline solutions at pH 8.5-11.5 up to 195 °C the compound then undergoes thermolysis with fission of the carbon-phosphorus bond to give, initially, acetylphosphonic and (1-hy dr oxyethy l)phosphonic acids ... 

It is possible to obtain derivatives of acylphosphonic diesters when less basic nucleophiles are employed " or from preparations carried out in anhydrous media. Thus, the phenylhydrazones and 2,4-dinitrophenylhydrazones of many esters are known and hydrazones and methylhydrazones of diethyl (l-oxoalkyl)phosphonates have been satisfactorily obtained through reactions in acetic acid. Hydrazones of (l-oxoalkyl)phos-phonic diesters have been employed in the synthesis of (17/-indole-2-yl)phosphonic esters, and the derivatives from dialkyl (2-oxoalkyl)phosphonates have been used to make indole-3-yl)- and [2-(l/f-indolemethyl)]-phosphonic esters by cyclization in polyphos-phoric acid. ... 

Oximes, which are valuable intermediates for the conversion of oxoalkyl phosphonic diesters into those of aminoalkylphosphonic acids (Chapter 4, Section IV.C. 1. d), are also readily available, although it is necessary to prepare them with some care. Nevertheless, the feature of interest here is their ready degradability, particularly under aqueous conditions, and which has been intensively investigated by Breuer and coworkers. The necessity for care in the preparation of oximes of acylphosphonic diesters, is illustrated by the synthesis of dimethyl [a-(hydroxyimino)benzyl]phosphonate this compound exists in the thermodynamically more stable ( ) form which, under the influence of acid is converted into the less stable (Z) form, and both forms have been separately characterized by X-ray crystallography. The geometric isomers of the oxime differ in their behaviour under basic conditions with NaOH-MeOH, the ( ) form undergoes monodealkylation, whereas the (Z) isomer decomposes to dimethyl phosphate and benzonitrile. In aqueous solution, ( )-[a-(hydroxyimino)benzyl]phosphonic acid also decomposes into benzonitrile together with phosphoric acid, in a manner which is pH dependent, and consistent with a dissociative mechanism that involves the early formation of monomeric metaphosphate. ... 

Acylphosphonic diesters take part in condensations very often through the participation of their enol tautomers with formamidine disulphide, for example, the 1,3-thiazoles 281 can be obtained analogues of such phosphonic acid products, e.g. 282, are obtainable from (2-oxoalkyl)phosphonic diesters with the same reagents. ... 

In addition to (aminoalkyl)phosphonic diesters, several other, well characterized products have been obtained from the oximes, or derivatives of oximes, of acylphosphonic diesters. Methylation of the oximes 283 [Z = CONHR, COOR (R = Et or Pr ), R = H of undefined geometry] with MeI-K2C03, or with Me2S04, yields the O-methyl oximes 283 (Z = CONHR R = Me) methylation with diazomethane also yields the latter but together with the phosphorylated nitrones 284 (Z = CONHR or COOR), which have been characterized in E and Z forms. The interaction of283 (R = Me) and diazomethane yields the corresponding 285 . Methylene insertion also occurs in reactions between diazomethane and 0-acylated oximes ... 

Enol phosphates phosphonates were also obtained by the reaction of perfluoroalkanoyl chlorides with triethyl phosphite. In this case, it was not possible to isolate the putative intermediate perfluoroacylphosphonates. This result is in contrast with the facile formation of bis (trialkylsilyl) trifluoroacetylphosphonates (see previous section), and it indicates that acylphosphonates derived from carboxylic acids with strongly electron-withdrawing groups can be prepared using tris(trialkylsilyl) phosphites. Such silyl phosphites seem to be uniquely suitable for this purpose, by virtue of their high reactivity in the first step and their steric hindrance, which presumably retards the second step. 

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