Oxoalkylphosphonates reactions

Phosphonopyruvate systems were the first candidates submitted to reductive amination. Because of the presence of the ester group, the a-ketoester carbonyl is less reactive than traditional oxoalkylphosphonates, and yields of isolated amino-esters never exceeded 55 %. The reaction is run at pH 7 in ethanol and it is general for ammonia and primary amines. Steric hindrance represents the second limiting factor since a-substituted or thiono-phosphonopyruvates react sluggishly thus secondary amines cannot be introduced. When the reductive amination process is effected the exclusive by-product is the a-hydroxyester which arises by reduction of the carbonyl group (7j-8). 

Oxoacids. It has been shown that Cobalt(O) or magnesium-mediated reactions of a-halomethylphosphonates (294) with esters constitute a novel approach to 2-oxoalkylphosphonates (295) (Scheme 74). ... 

Reactions of Dialkyl 1-Oxoalkylphosphonates with Conservation of the P-C Bond... 

The effectiveness of dialkyl 1-aIkynylphosphonates as acelonyl equivalents for the preparation of dialkyl 2-oxoalkylphosphonates has long been established. Because 2-oxoaIkylphosphonates themselves are versatile synthetic intermediates, especially as the reagents of choice for promoting a number of Homer-Wadsworth-Emmons cyclization reactions, procedures that effect the direct conversion of dialkyl 1-alkynylphosphonates into dialkyl 2-oxoalkylphosphonates are of special importance. The procedure for the hydration of dialkyl 1-alkynylphosphonates has remained unchanged since the first report in 1966 (Scheme 1.21). Thus, treatment of diethyl 1-alkynylphosphonates with aqueous H2SO4 in MeOH in the presence of HgSO4 gives, after reflux for 15 h - ... 

Diethyl 2,3-epoxy-4-oxoalkylphosphonates can be converted on reaction with thioureas and thioamides into diethyl 2-hydroxy-2-(5-thiazolyl)ethylphosphonates or into 2-(5-thiaz-olyl)vinylphosphonates (Scheme 4.49)."" Cleavage of both systems into phosphorus-free thiazoles can be readily achieved with CsF in DMF. Reaction of diethyl 2,3-epoxy-4-oxoalkylphosphonates with 2-mercaptobenzimidazole yields oc-substituted enones arising from regioselective oxirane opening and subsequent dehydration (Scheme 4.49). °° These derivatives exist, mainly or exclusively, as cyclic tautomers. The cyclization step depends on the reaction conditions. °°... 

These contradictory results were elucidated later when, in 1952, Perkow showed for a-halogenoaldehydes and Pudovik and Allen and Johnson for oc-halogenoketones that both the Michaelis-Arbuzov reaction, with formation of 2-oxoalkylphosphonates, and the Perkow reaction, with formation of vinyl phosphates, can take place independently or simultaneously. It is important to mention that the formation of vinyl phosphates by an anomalous Michaelis-Arbuzov reaction ... 

With the presence of more than one halogen atom in the a-position of the halo ketone, the formation of 2-oxoalkylphosphonates becomes more difficult, and the reactions proceed exclusively according to the Perkow reaction. Thus, dichloromethyl, dibromomethyl, and tribromomethyl methyl ketones, in reaction with trialkyl phosphites, lead to the corresponding vinyl phosphates... 

A relatively general procedure for the preparation of dialkyl 2-oxoalkylphosphonates by direct acylation of dialkyl 1-lithioalkylphosphonates has been introduced by Corey and Kwiatkowski in 1966. The use of phosphonate carbanions as nucleophiles in reaction with carboxylic esters avoids the problems associated with the Michaelis-Arbuzov reaction. The reaction sequence is initiated by the addition at low temperature of dimethyl 1-lithiomethylphosphonate (2 eq and frequently more) to a carboxylic ester (1 eq) to give the transient lithium phosphonoenolate. The dimethyl methylphosphonate, being readily available and easy to eliminate, is the most frequently used phosphonate, but other phosphonates such as diethyl and diisopropyl methylphosphonates can be used. When the resulting enolate is treated with acid, dimethyl 2-oxoalkylphosphonate is produced in moderate to good yields (45-95%, Scheme 7.20). The reaction has been achieved with... 

The synthesis of diethyl l,l-difluoro-2-oxoalkylphosphonates has been reported by a cerium-mediated reaction between diethyl 1-lithio-1,1-difluoromethylphosphonate and ethyl esters at low temperature in THF. After acidic quench at low temperature, diethyl I, I -difluoro-2-oxoalkyIphosphonates are isolated in good yield.- Addition of diethyl 1-lithio-1,1-difluoromethylphosphonate to di-ferf-butyl oxalate at low temperature in THF affords exclusively the addition product, an unusually stable ferf-butyl hemiketal. When a solution of this material is heated at reflux in ( ,1 f, or chromatographed on silica gel, only a few percent is converted to the hydrate. This conversion is best effected by dissolving the hemiketal in MeCN followed by reaction with aqueous Nal ICO . Subsequent azeotropic dehydration with CgHg affords diethyl l,l-difluoro-2-oxo-2-(fert-butoxycar-bonyl)ethylphosphonate. 5... 

Readily available dialkyl l-bromo-l,l-difluoromethylphosphonates can also participate in the synthesis of 2-oxoalkylphosphonates. Thus, dialkyl 1-bromo-1,1-difluoromethylphosphonates, on reaction with activated Zn metal, are converted into difluoromethylphosphonylzinc bromides, which are coupled with carboxylic acid chlorides at room temperature to give dialkyl l,l-difluoro-2-oxoalkylphosphonates in good yields.- " Dimethyl 1-lithiomethylphosphonate undergoes trans-metallation with MnCl2 in THF to give dimethyl 2-oxobutylphosphonate in 80% yield on reaction with propionyl anhydride. " ... 

An unusual application of the reaction between diethyl chloromethylphosphonate and carbonyl compounds is the formation of diethyl 2-oxoalkylphosphonates resulting from the treatment of the intermediate chlorohydrins at low temperature with an excess of LDA (2.2 eq) (Scheme 7.34). On treatment with LDA, the chlorohydrins undergo deprotonation and subsequent elimination of LiCl to provide selectively the stable lithium phosphonoenolates, which, under acidic conditions, give diethyl 2-oxoalkylphosphonates. Thus, under advantageous experimental conditions, diethyl 1-lithio-1-chloromethylphosphonate allows the direct phosphonomethylation of a large variety of aliphatic, aromatic, and heteroaromatic aldehydes in good overall yields (40-92%). ... 

Dialkyl phosphites react with a variety of diazo compounds in refluxing CgHg in the presence of a homogeneous catalyst, Cu(acac)2, to give the corresponding dialkyl 2-oxoalkylphosphonates (Scheme 7.43). The optimum molecular ratio dialkyl phosphite/diazo compound is 5/1. The reaction proceeds via the carbenoid insertion into the P-H bond of the phosphite. The procedure may be useful for the preparation of symmetric dialkyl 2,2 -diketophosphonates. 

A related route to 3-oxoalkylphosphonates involves the conjugate addition of trialkyl phosphites to a,P-unsaturated ketones and hydrolysis of the intermediate oxaphospholenes. The utility of this method is enhanced by the nucleophilic character of the intermediate oxaphosphorane, which facilitates the stereoselective aldol reaction resulting in the formation of p-substituted y-ketophos-phonates. - The pentacovalent oxaphospholene reacts with dialkyl azidocarboxylates to give P-hydrazido-y-ketophosphonates in excellent yields. ... 

The more recently reported route to diethyl 3-oxoalkylhosphonates uses a zinc carbenoid-mediated approach, which is believed to proceed through the intermediacy of a cyclopropylzinc alkoxide. Thus, treatment of simple diethyl 2-oxoaIkylphosphonates with the Furukawa-modifled Simmons-Smith reagent provides a rapid and efficient preparation of 3-oxoalkyIphosphonates. The chain extension of simple, unfunctionalized P-ketophosphonates requires an excess (6 eq) of both Et2Zn and CH2I2 at room temperature. The presence of a-substitution on the 2-oxoalkylphosphonate does not diminish the efficiency of the reaction (see Section 7.2.3.7). 

The phosphonylation, via a Michaelis-Becker-type reaction, and the phosphonomethylation, with lithiated phosphonate carbanions, " of protected ketones have been applied to the preparation of 4-oxoalkylphosphonates after acidic hydrolysis. 

The addition of diethyl 1-iodo-1,1-difluoromethylphosphonate to 5-hexen-2-one catalyzed by Pd(PPh3)4 or copper metal constitutes an approach to 6-oxoalkylphosphonates. The reaction proceeds readily at room temperature in the absence of solvent and requires only few minutes to be complete. Treatment of the adduct with Zn in the presence of NiCl2 in moist THF at room temperature provides diethyl 6-oxo-3-iodo-l,l-difluoroheptylphosphonate in 55% yield (Scheme 7.62)." 2 " ... 

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) ... 

Conversion of 1-oxoalkylphosphonates into 1,1 -di 11 uoroalkylphosphonates by reaction with (dieth-ylamino)sulfur trifluoride (DAST) has been explored using a variety of solvents and temperatures. The most satisfactory results are obtained by running the reaction neat at room tempera-ture, - but the reagent is also used in large excess in CH2CI2 solution (Scheme 7.79). 

Similarly, the a-monochlorinated and a-monobrominated dimethyl 2-oxoalkylphosphonates are prepared in satisfactory yields (50%) by reaction of the sodium enolate of dimethyl 2-oxoalkyl-phosphonates with NCS or NBS in DME at room temperature- "- - or with bromine in Et20 (53-71%) or THE (60%) Synthesis of diethyl l-chloro-2-oxopropylphosphonate has also been reported through reduction of the 1,1-dichloro derivatives with sodium sulfite.- lodination in the Y-position of P-ketophosphonate 1,3-dianions prepared with KiCO, in MeOH has been reported. These dianions react with benzaldehyde in a Homer-Wadsworth-Emmons-Darzens reaction sequence to produce the a,P-unsaturated a, P -epoxyketones in 60-79% yields (Scheme 7.101).s ... 

Sodium enolates of diethyl 2-oxoalkylphosphonates react with diethyl chlorophosphate to produce enol phosphates. Low-temperature treatment of enol phosphates with tert-BuOK induces the ()-elimination of potassium diethyl phosphate and formation of diethyl 1-alkynylphosphonates in good yields (43-95%, Scheme 7.113). However, the reaction is prone to prototropic isomerization and diethyl 2-oxobutyIphosphonate leads to a mixture of diethyl 1-butynyIphosphonate (43%) and diethyl 2-butynylphosphonate (51%). ... 

Kim, D.Y, Mang, J.Y, and Oh, D.Y, Reaction of silyl enol ethers with phosphite using hypervalent iodine compound. A new synthesis of 2-aryl-2-oxoalkylphosphonates, Synth. Commun., 24, 629, 1994. Hohnquist, C.R., and Roskamp, E.J., Tin(II) chloride catalyzed addition of diazo sulfones, diazo phosphine oxides, and diazo phosphonates to aldehydes. Tetrahedron Lett., 33, 1131, 1992. 

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