Reactions of Phosphonate Anions

The structure of lithium coordinated P-carbonyl-phosphonate and -phosphine oxide carbanions has been reviewed.6 6 

Olefinations involving phosphonate anions continue to be used and developed. The effect of the cation, temperature and THF or DME as solvent on the stereoselectivity of aliphatic aldehyde olefination with trimethyl phosphonoacetate carbanion has been investigated.71 Low ( /Z) ratios are favoured by potassium cations, low temperature and THF as solvent. The 

Unsaturated ter/-butyl esters undergo stereoselective a/iti-Michael addition of a -lithiated phosphonates to give a range of substituted 4- 

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Scheme 2.18 gives some representative olefination reactions of phosphonate anions. Entry 1 represents a typical preparative procedure. Entry 2 involves formation of a 2,4-dienoate ester using an a, 3-unsaturated aldehyde. Diethyl benzylphosphonate can be used in the Wadsworth-Emmons reaction, as illustrated by Entry 3. Entries 4 to 6 show other anion-stabilizing groups. Intramolecular reactions can be used to prepare cycloalkenes.264... 

Miscellaneous Reactions Reactions of Phosphonate Anions Selected Applications in Synthesis... 

Horner-Wadsworth-Emmons Reactions of Phosphonate Anions. - As with the Horner modification of the Wittig reaction, the principal focus of papers that mention the Horner-Wadsworth-Emmons reaction relate to synthetic applications. The use of pressure to induce the synthesis of P-amino esters, p-thioesters and P-thionitriles via tandem Horner-Wadsworth-Emmons and Michael reactions has been reported. The reagent (l-tritylimidazol-4-yl)methylphosphonate (99) has been prepared and, when treated with aldehydes and ketones, affords (E)-vinylimidazoles in high yields. ... 

The format of this chapter is similar to that used in previous volumes. The first section deals with methylene phosphoranes and their Wittig reactions, the second looks at the Horner-Wadsworth-Emmons reaction of phosphonate anions and the third the structure and reaction of lithiated phosphine oxides - an area which continues to receive particular attention. The majority of reports concerning ylides relate to their use in synthesis and in the final section some of these applications are reviewed. 

Horner-Wadsworth-Emmons Reaction of Phosphonate Anions... 

Dual pathways are available for the reaction of phosphonate anions with a,/ -enones (55). The Michael addition is frontier orbital-controlled and is favored by the presence of proton sources, which quickly neutralize the charge on the enolate anions. These products decrease with time because they are gradually channeled into the charge-controlled Horner-Emmons olefination. 

Olefination Reactions Involving Phosphonate Anions. An important complement to the Wittig reaction involves the reaction of phosphonate carbanions with carbonyl compounds 253 The alkylphosphonic acid esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are generated by treating alkylphosphonate esters with a base such as sodium hydride, n-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.254... 

Reaction of the anion from phosphonate (5-1) with ethyl meta-triflurophenoxy-methylacetate results in acylation of the phosphonate by the displacement of ethoxide and the formation of (5-3). Condensation of the yhde from this intermediate with the biphenyl ester at position 11 of Corey lactone (5-4) leads to the enone (5-5) with the usual formation of a tmns olefin expected for this reaction. The very... 

Olefination of aldehydes with the a-fluoroalkylphosphine oxide (54) provides a highly stereoselective route to the (Z)-fluoroalkenes (55) (Scheme 9).31 A similar reaction with the corresponding phosphonate gave a 1 1 mixture of ( )- and (Z)-alkenes. A new one-pot synthesis of 2-(diphenylphosphinoyl)cycloalkanes (56) by the reaction of cycloalkanone enolates with chlorodiphenylphosphine followed by oxidation has been reported (Scheme 10).32 Attempts to synthesise sarkomycin methyl ester (58) via reaction of the anion of phosphine oxide (57) with formaldehyde were unsuccessful as were similar reactions with other aldehydes, although the corresponding phosphonate anion does undergo olefination reactions. An X-ray structural analysis of (57) is reported. 

The mechanism of phosphonate anion (135) addition to carbonyl derivatives is similar to the phosphonium ylide addition however, there are several notable features to these anion additions that distinguish the reactions fix)m those of the classical Wittig. The addition of the anion gives a mixture of the erythro (136 and 137) and threo (139 and 140) isomeric p-hydroxyphosphonates (Scheme 24). In the case of phosphine oxides, the initial oxyanion intermediates may be trapped. The anion intermediates decompose by a syn elimination of phosphate or phosphinate to give the alkene. The elinunation is stereospecific, with tile erythro isomer producing the ci.r-alkene (138), and the threo addition adduct producing the... 

Methyleneaminophosphines (10), on treatment with methyl iodide, give the expected phosphonium salts (11), which on thermolysis undergo a reaction analogous to the Arbusov reaction to give imidophosphoranes. Various phosphonates and phosphine oxides have been prepared by the reaction of the anions (RO)aP—0 Na+ and R2P—0 Na+ with alkyl halides. The analogous reactions of the chlorohydrin (12) with sodium diethyl phosphonate give the cyclic phosphonate (13) as a mixture of geometrical isomers of approximately equal stability. ... 

Other uses of phosphonate anions prepared from deprotonation with LHMDS include the acylation reaction for the synthesis of (diphenylphosphono)acetic acid esters (eq 55) as well as the aza-Darzens reaction leading to aziridine 2-phosphonates (eq 56). In both cases, LHMDS proved to be equal or superior to other lithium bases. 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

The reaction was carried out analogously to the general procedure for the addition of metalated ally 1 sulfoxides given in Section 1.5.2.2.3.2. BuL.i is used, in this case, for deprotonation instead of LDA. BuLi is added to a solution of 1 - 3 mmol of the phosphine oxide or phosphonate in THF until the first permanent appearance of the red color of the anion. Thereupon, 1.1 equivalents of the BuLi is added. For the phosphonates, whose anions are less intensely colored, 1.1 equivalents of BuLi are added to the solutions after the first permanent appearance of the red color of an added indicator, 2.2 -bipyridyl. 

There are related reactions involving phosphonate esters or phosphines oxides. These reactions differ from the Wittig reaction in that they involve anions formed by deprotonation. In the case of the phosphonate esters, a second EWG substituent is usually present. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

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