A-alkoxycarbonyl phosphonate

The precursors for these Horner-Wadsworth-Emmons reagents are /f-ketophosphomc acid dialkyl esters or a-(alkoxycarbonyl)phosphonic acid dialkyl esters. The first type of compound, i.e., a /3-ketophosphonic acid dialkyl ester is available, for example, by acylation of a metalated phosphonic acid ester (Figure 6.48). The second type of compound, i.e., an a-(alkoxycarbonyl)phosphonic acid dialkyl ester, can be conveniently obtained via the Arbuzov reaction (Figure 11.12). 

Applicable to base-sensitive aldehydes and phosphonates for the Homer-Wadsworth-Emmons reaction. a-Keto or a-alkoxycarbonyl phosphonate required. 

Horner-Wadsworth-Emmons reactions are C—C-forming condensation reactions between the Li, Na, or K salt of a /J-keto- or an -(alkoxycarbonyl)phosphonic acid dialkyl ester and a carbonyl compound (cf. Figure 4.41). These reactions furnish a,f)-unsaturated ketones or a j8-unsaturated esters, respectively, as the desired products and a phosphoric acid diester anion as a water-soluble by-product. In general, starting from aldehydes, the desired compounds are produced fraus-selectively or in the case of olefins with trisubstituted C—C double bonds -selectively. 

Simply passing ammonia into diethyl (rncihoxycarbonyl (phosphonate at 40°C results in rapid precipitation of the amide in good yield (69%). Similarly, adding primary amines to diethyl (alkoxycarbonyl)phosphonatcs generates diethyl (A-alkylaminocarbonyl)phosphonates in moderate to good yields... 

An efficient one-pot synthesis of mikanecic acid derivatives was accomplished from allylic phosphonates, ClC02Et, and aqueous HCHO (Eq. 12.38).100 The overall process involves a cascade sequence linking together metalation-alkoxycarbonylation, Homer-Wadsworth-Emmons,... 

A rich family of 2-alkoxycarbonyl-l,3,2-oxazaphospholidine-2-oxides 179-181 was prepared from the reaction of camphor derived aminoalcohols 177 and 178 with either methoxycarbonyl phosphonic dichloride or ethyl dichlorophosphite followed by the reaction with methyl bromoacetate. The reaction with aminoalcohol 177a afforded the phosphorus epimers 179 and 180, in ratios from 1/1 to 12/1 depending on the iV-substituent which could be separated easily by column chromatography. The reaction with aminoalcohols 178a-c, however, gave a single epimer 181a-c in each case (Scheme 50) [81]. 

Further studies on 1,3-dipolar addition reactions of diazophosphonates have been recorded,122 and work on 2-diazo-l-hydroxyalkylphosphonates also continues.123 The ester (155 R = H) reacts with esters of acetylenedicarboxylic acid without liberation of nitrogen to give stereoisomeric C-phosphorylated pyrazolines, which can be decomposed with both phosphorus-carbon and carbon-carbon bond fission, affording mixtures containing dimethyl acetylphosphonate, dimethyl hydrogen phosphonate, and tri(alkoxycarbonyl)pyrazolines. In the reaction between the same diazophosphonate and diazomethane, the latter conceivably acts as a basic catalyst for proton transfer in a series of steps which includes phosphonate-phosphate isomerization. The importance of a labile proton is demonstrated by the fact that the ester (155 R = Me) does not react in the manner described above. 

A simple procedure for the preparation of trifluoromethylated vinyl- and dienyl-phosphonates with y-alkoxycarbonyl moiety of exclusively or predominantly (Z)-configuration (201) has been described. It involves acylation of ethyl-1,1-bisphosphonate (202) with trifluoroacetic anhydride, addition of selected Reformatsky reagents to the resulting 1-trifluoroacetyl-1,1-ethyl bisphos-phonates (203) and finally spontaneous Horner-Wadsworth-Emmons (HWE) olefination of the adducts (Scheme 55). " ... 

The most systematically investigated acyl anion equivalents have been the IMS ethers of aromatic and heteroaromatic aldehyde cyanohydrins, TBDMS-protected cyanohydrins, benzoyl-protected cyanohydrins, alkoxycarbonyl-protected cyanohydrins, THP-protected cyanohydrins, ethoxyethyl-protected cyanohydrins, a-(dialkylamino)nitriles, cyanophosphates, diethyl l-(trimethylsiloxy)-phenylmethyl phosphonate and dithioacetals. Deprotonation of these masked acyl anions under the action of strong base, usually LDA, followed by treatment with a wide variety of electrophiles is of great synthetic value. If the electrophile is another aldehyde, a-hydroxy ketones or benzoins are formed. More recently, the acyl carbanion equivalents formed by electroreduction of oxazolium salts were found to be useful for the formation of ketones, aldehydes or a-hydroxy ketones (Scheme 4). a-Methoxyvinyl-lithium also can act as an acyl anion equivalent and can be used for the formation of a-hydroxy ketones, a-diketones, ketones, y-diketones and silyl ketones. - ... 

Other applications of the hydrophosphonylation reaction include the addition of dialkyl phosphite to 2-(alkoxycarbonyl)- or 2-cyanoacrylonitriles. The reaction is carried out in the absence of catalysT - or in the presence of NaNH2, RONa,- - or TFAA. The Michael addition can be combined with an elimination reaction. For example, because of the presence of a methylthio leaving group, dialkyl 2,2-dicyano- or 2-cyan()-2-clhoxyc irbonyl-l-methyl thio-(/ )-vinyl phosphonates are the products of the conjugate addition of dialkyl phosphite to the corresponding ketene dithioacetals in the presence of NaH (2 eq) in THF (Scheme 6.24).--°... 

Several reports show that it is possible to carry out a transesterification selectively at the carboxylic ester moiety of dialkyl l-(alkoxycarbonyl)methyIphosphonates rather than at the phosphonic ester moiety with primary and secondary alcohols in the presence of NaH or DMAPP For example, a number of chiral phosphonates have been prepared in high yields (80-96%) by DMAP-catalyzed transesterification of dialkyl l-(alkoxycarbonyl)methylphospho-nates with 8-phenytmenthol in toluene at reflux." " -" ... 

The ready alkylation of sodium phosphonate carbanions with chloro- or bromoacetates in THF provides a useful access to dialkyl 2-(alkoxycarbonyl)ethylphosphonates bearing a variety of alkyl, aryl, cyano, keto, or phosphoryl groups at the cx-carbon (Scheme 8.43). By using a chiral auxiliary, the alkylation of phosphorus-stabilized benzylic carbanions with bromoacetate proceeds with high diastereoselectivity to provide an easy access to optically active alkylphosphonic acids. ... 

Michael addition has been applied to the formation of cyclopropanic systems. Thus, the addition of phosphonate carbanions generated by LDA in THF, by NaH in THF, by thallium(I) ethoxide in refluxing THF, or by electrochemical technique to oc,P-unsaturated esters provides a preparation of substituted 2-(alkoxycarbonyl)cyclopropylphosphonates in moderate to good yields via a tandem Michael addition-cyclization sequence (Scheme 8.47). The cyclopropanation has also been achieved via oxidation with iodine in the presence of KF-AI2O3. Nitrile ylides prepared from acyl chlorides and diethyl isocyanomethylphosphonate in the presence of Et3N react with methyl acrylates by a 1,3-dipolar cycloaddition to give phosphoryl pyrrolines or pyrroles. ... 

A relatively general procedure for the preparation of aromatic phosphonates containing alkoxycarbonyl groups has been developed from trietliyl phosphite and a variety of substituted haloben-zenes " " Thus, direct phosphonylation of ethyl 2-, 3-, or 4-bromobenzoates with triethyl phosphite at 160°C, catalyzed by NiClj affords die corresponding diethyl ortho-, meta-, or para-(ethoxycarbonyl)phenylphosphonates in variable yields (Scheme 8.54). 

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