Acyl phosphonates

Acyl phosphonates (6.290) form a special group of phosphonates because of the proximity of the carbonyl and phosphoryl groups. The electron-withdrawing nature of both these groups confers increased reactivity on each. 

Dialkyl acyl phosphonates can be synthesised by an Arbusov-type reaction (6.291), and the acids can be obtained from the esters (6.292). 

Dialkyl acyl phosphonates are rapidly hydrolysed in neutral or alkaline solution, and can be oxidised (6.293). Another synthesis is with the Bamford-Stevens reaction, [27] which can be used to obtain diazophosphonic or diazophosphinic esters via scheme (6.294). 

Products of the type (6.295) are fairly stable but often highly colored. Resonance probably occurs in these structures (6.296). 

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A general synthesis of phosphonyl thiadiazoles has been recently disclosed starting from the hydrazone 55. The hydrazones were prepared from acyl phosphonates, which in turn were made from acid chlorides 54. Thus treatment of the hydrazone 55 with thionyl chloride in the presence of DMF and sodium chloride provided the thiadiazoles in... 

The chiral BOX-copper(II) complexes are effective catalysts for enantioselective cycloaddition reactions of a,/ -unsaturated acyl phosphonates [48] and a,/ -unsaturated keto esters [38b, 49]. 

The chiral BOX-copper(ll) complexes, (S)-21a and (l )-21b (X=OTf, SbFg), were found by Evans et al. to catalyze the enantioselective cycloaddition reactions of the a,/ -unsaturated acyl phosphonates 49 with ethyl vinyl ether 46a and the cyclic enol ethers 50 giving the cycloaddition products 51 and 52, respectively, in very high yields and ee as outlined in Scheme 4.33 [38b]. It is notable that the acyclic and cyclic enol ethers react highly stereoselectively and that the same enantiomer is formed using (S)-21a and (J )-21b as the catalyst. It is, furthermore, of practical importance that the cycloaddition reaction can proceed in the presence of only 0.2 mol% (J )-21a (X=SbF6) with minimal reduction in the yield of the cycloaddition product and no loss of enantioselectivity (93% ee). 

More recently, further developments have shown that the reaction outlined in Scheme 4.33 can also proceed for other alkenes, such as silyl-enol ethers of acetophenone [48 b], which gives the endo diastereomer in up to 99% ee. It was also shown that / -ethyl-/ -methyl-substituted acyl phosphonate also can undergo a dia-stereo- and enantioselective cycloaddition reaction with ethyl vinyl ether catalyzed by the chiral Ph-BOX-copper(ll) catalyst. The preparative use of the cycloaddition reaction was demonstrated by performing reactions on the gram scale and showing that no special measures are required for the reaction and that the dihydro-pyrans can be obtained in high yield and with very high diastereo- and enantioselective excess. 

With acyl halides, the corresponding acyl phosphonates are obtained. Furthermore allylic and acetylenic halides, as well as a-halogenated carboxylic esters and dihalides, can be used as starting materials. If substituents R and R are different, a mixture of products may be obtained, because the reaction product RX 5 can further react with phosphite 1 that is still present ... 

The acyl phosphonates, acyl phosphine oxides and related compounds (e.g. 81. 82) absorb strongly in the near UV (350-400 nm) and generally decompose by rescission in a manner analogous to the benzoin derivatives.381"285 Quantum yields vary from 0.3 to 1.0 depending on structure. The phosphinyl radicals are highly reactive towards unsaturated substrates and appear to have a high specificity for addition v.v abstraction (see 3.4.3.2). 

Diazoalkanes add readily to the double bond of esters of vinylphosphonic acid, giving the pyrazoline derivatives (100), which can lose nitrogen to give esters of cyclopropylphosphonic acids. In a similar reaction, acyl-phosphonic acid esters (101) were converted to epoxy-derivatives (102). A -Phenylsydnone adds to diethyl prop-l-ynephosphonate, giving the pyra-zole (103). The addition of cyclopentadiene to dimethyl vinyl phosphate leads to an exojendo quotient of 1.2, but with hexachlorocyclopentadiene only e/ii/o-isomer is formed. ... 

The copper complex of these bis(oxazoline) compounds can also be used for hetero Diels-Alder reactions of acyl phosphonates with enol ethers.43 5 A favorable acyl phosphonate-catalyst association is achieved via complexation between the vicinal C=0 and P=0 functional groups. The acyl phosphonates are activated, leading to facile cycloaddition with electron-rich alkenes such as enol ethers. The product cyclic enol phosphonates can be used as building blocks in the asymmetric synthesis of complicated molecules. Scheme 5-36 shows the results of such reactions. 

TABLE 9.20. ENANTIOSELECTIVE HETERO-DIELS-ALDER REACTIONS OF a,P-UNSATURATED ACYL PHOSPHONATES... 

Evans has reported that the cationic C2-symmetric chiral Lewis acid Cu(ll)bis(oxazoline) complex promotes the hetero-Diels-Alder reaction of 0 ,/3-unsaturated acyl phosphonates with enol ethers to give the cycloadducts with excellent ee (Scheme 52). As well as simple dihydropyrans, various fused bis-dihydropyrans are also reported <1998JA4895, 2000JA1635>. 

The chiral bis(oxazoline)/Cu(II) complex with OTf or SbFg as a counter anion effectively promotes the enantioselective hetero Diels-Alder reaction of enol ethers with acyl phosphonates to give chiral enol phosphonates as synthetically useful chiral building blocks [64] (Eq. 8A.40). 

Chiral 2-(3-oxoalkyl)pyrroles and 3-(3-oxoalkyl)indoles can also be accessed by reaction in the presence of 10 mol% of chiral bis(oxazoline)/metal complexes in CH2C12 in very high yields and with ee values over 90% <2005JA4154>. Alkylation of pyrrole and of substituted indoles with, -unsaturated acyl phosphonates <2003JA10780> or 2-acyl N-methylimidazoles catalyzed by a chiral bis(oxazolinyl)pyridine (pybox)/scandium(III) triflate complex also exhibits good enantioselectivity over a broad range of substrates <2005JA8942>. 

Inverse electron demand hetero-Diels-Alder reactions of acyl phosphonates or a-keto ester heterodienes and enol ethers are also catalyzed by (5, iS )-t-Bu-box complexes. High levels of enantioselectivity are obtained with y-alkyl-, -aryl-, -alkoxy-... 

Copper Lewis acids have also found utility in hetero-Diels-Alder reactions. In these transformations the Lewis acid can activate either the diene or the dienophile and both types of reaction have been reported. Evans et al. have evaluated unsaturated acyl phosphonates [95] and acyl esters (amides) [87] as dienes in hetero-Diels-Alder reactions. The reactions proceed with excellent chemical efficiency and high stereoselectivity with as little as 0.2 mol % of the catalyst (Sch. 50). The reaction tolerates a variety of substituents on the diene and the dienophile. A square-planar model 226 wherein the phosphonate and the carbonyl groups form a chelate with copper, and addition occurring from the less hindered face, accounts for the selectivity observed. It is interesting to note that the reaction of 185 with phosphonate 228 gives 230, an inverse-electron-demand product, in preference to the normal Diels-Alder adduct 229. This unusual reaction pathway has been attributed to the electron-withdrawing capacity of the phosphonate group. 

Acyl phosphonates (444) have been converted into tertiary a-hydroxy al-kenylphosphonates (445) through an indium mediated allylation. The allylation proceeds equally well with different allylic bromides and does not appear to be sensitive to steric hindrance at the p-carbon atom (Figure 82)/ ... 

Gordon, N. J., Evans, S. A., Jr. Acyl phosphates from acyl phosphonates. A novel Baeyer-Villiger rearrangement. J. Org. Chem. 1993, 58, 4516 519. 

Particularly good results have been achieved with Cr02 in refluxing acetonitrile, a system that proved effective with a variety of structurally different a-hydroxy phosphonates [17]. Similar conversions can be carried out under surface-mediated solid-phase conditions [18], acyl phosphonates being obtained under mild reaction conditions by treatment of a-hydroxy phosphonates on alumina (neutral-supported Cr03 without solvent. An oxidative method proved successful in the synthesis of novel phosphonopeptides for evaluation as inhibitors of human calpain I [19]. 

Protein-tyrosine (PTP) inhibitors are potentially valuable pharmacological tools for studying cellular signal transduction and for therapeutic intervention. Derivatives of 1,1-difluoromethylphosphonic acid are known to be potent PTP inhibitors. An important method for synthesis of these compounds is fluorina-tion of acyl phosphonates by diethylaminosulfur trifluoride (DAST). This method allows synthesis of fcrf-butyl-protected difluoro(aryl)- or (naphthal-enyl)methylphosphonates, which under mildly acidic deprotection conditions afford desirable phosphonic acids [16, 39]. Acyl phosphonate fluorination by DAST has also been utilized for synthesis of a,a-(difluoroprop-2-ynyl)phos-phonates [14]. 

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]. 

Okamoto, Y, Nitta, T., and Sakurai, H., The synthesis of long-chain a-hydroxycarboxyhc acids from acyl phosphonates, Kogyo Kagaku Zasshi, 71, 187, 1968 Chem. Abstr., 69, 35342, 1968. 

Evans, D.A., and Johnson, J.S., Catalytic enantioselective hetero Diels-Alder reactions of a,P-unsat-urated acyl phosphonates with enol ethers, J. Am. Chem. Soc., 120, 4895, 1998. 

Liao, Y., Shabany, H., and Spilling, C.D., The preparation of acyl phosphonates by the heterogeneous oxidation of 1-hydroxy phosphonates. Tetrahedron Lett., 39, 8389, 1998. 

Burke, T.R., Jr., Smyth, M.S., Nomizu, M., Otaka, A., and Roller, PP, Preparation of fluoro- and hydroxy-4-(phosphonoinclhyl)-i),L-phcnylalanine suitably protected for solid-phase synthesis of peptides containing hydrolytically stable analogues of O-phosphotyrosine, J. Org. Chem., 58, 1336, 1993. Ganzhorn, A.J., Hoflack, J., Pelton, P.D., Strasser, E, Chanal, M.-C., and Piettre, S.R., Inhibition of myoinositol monophosphatase isoforms by aromatic phosphonates, Bioorg. Med. Chem., 6, 1865, 1998. Kaboudin. B., Surface-mediated sohd-phase reactions. The preparation of acyl phosphonates by oxidation of 1-hydroxyphosphonates on the solid surface, Tetrahedron Lett., 41, 3169, 2000. Kaboudin, B., and Nazari, R., A convenient and mild procedure for the preparation of a-keto phosphonates of 1-hydroxyphosphonates under solvent-free conditions using microwave, Synth. Commun., 31, 2245, 2001. 

Tang, K.-C., and Coward, J.K.. Synthesis of acyl phosphonate analogues of biologically important acyl phosphates. A-(2-Amino-10-methylpteroyl)-5-amino-2-oxopentanephosphonic acid, J. Org. Chem., 48, 5001, 1983. 

It has not proved possible to obtain C-alkylated products from diethyl 1-(ethoxycarbonyl )meth-ylphosphonate by the action of acetyl chloride on the alkali metal salts. However, when the ethoxymagnesium salt of diethyl l-(ethoxycarbonyl)methylphosphonate is employed, diethyl 1-ethoxycarbonyl-l-acetyhnethylphosphonate is isolated in a good yield (73%, Scheme 8.20). Similarly, diethyl 1-ethoxycarbonyl-l-benzoyhnethylphosphonate has been prepared in 56% yield from diethyl l-(ethoxycarbonyl)methylphosphonate and benzoyl chloride. The diethyl 1-lithio-1-fluoro-l-(ethoxycarbonyl)methylphosphonate generated with n-BuLi in THF reacts with acid chlorides, fluorine-substituted acid chlorides, and oxalylchloride to form the corresponding acylated phosphonates. By contrast, phosphorylation of the sodium diethyl l-(ethoxycarbonyl)meth-ylphosphonate leads to the O-phosphory lation product. The synthetically useful potassium enolate of diethyl 1,2-/ .v(ethoxycarbonyl)-2-oxocthylphosphonatc is prepared by reaction of the potassium salt of diethyl l-(ethoxycarbonyl)methylphosphonate with diethyl oxalate. ... 

Several reports have appeared - of reactions of phosphites with acid chlorides to give acyl phosphonates (37), and in one case this reaction has been used as a new route to a-amino-phosphonic acids through the oxime (38) and... 

Thus, with model substrates, we initially explored both the acylation of (3) and (4). Both ylides readily underwent acylation with acyl halides or acetic anhydride to give the C-acylated phosphonate or phosphonium salt... 

A structure somewhat related to the acyl phosphonate analogue (VIII.83) has been briefly described [278] in a report on FPGS inhibitors. The preparation of this compound (VIII.86) was achieved from V -(4-amino-4-deoxy-V °-methylpteroyl)-L-lysine and 4-nitrophenyl phosphonoacetate. While (VIII.86) obviously contained too many CH2 groups to be considered a close analogue of (VIII.83), the shorter-chain compound (VIII.87), a derivative of V -(4-amino-4-deoxy-V °-methylpteroyl)-L-2,3-diaminobutanoic acid, would seem to be reasonable candidate for this role. 

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