The Structure and Reactions of Phosphonate Anions

Olefination reactions using the N-protected phosphonate (118) have 

The phosphonates (124), prepared from diazoalkanephosphonates by rhodium catalysed O-H insertion, undergo olefination to provide a synthesis of cyclic vinyl ethers (125).64 l-(Cyclopent-l-enylcarbonyl)vinyl-phophonates (126) have been used to synthesize fused ring systems containing two or three five-membered rings. The conversion of (126) into the aldehyde (127) followed by intramolecular olefinations leads ultimately to tricyclo[6.3.0.03.7]undecenone derivatives, e.g. (128).65 

A one-pot synthesis of 4-hydroxycyclopent-2-en-l-ones (150), involving (Z)-stereoselective olefination of a-diketones to give (149) followed by intramolecular aldol condensation, has been reported. Wadsworth-Emmons reactions of bis(2,2,2-trifluoroethyl)phosphono sulfoxides (151) with aromatic aldehydes give predominantly (Z)-a,p-unsaturated sulfoxides while similar reactions with the corresponding sulfides (152) give ( )- or lower (Z)-selectivity. In olefinations using (5)-dimethyl phosphorylmethyl p-tolyl sulfoxide (153) substantial racemisation at sulfur occurs when -butyllithium is used as base.  

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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. 

A number of phosphonate and phosphinate derivatives where the phosphorus atom is directly bonded to non-aromatic cyclic systems have been reported. The synthesis and reactions of a number of compounds with the general structure 103 have been reported. Enantiomerically pure cyclopropanephosphonic acids which are constrained analogues of the GABA antagonist phaclophen, have been prepared by stereocontrolled Michael addition of a-anions derived from chiral chloromethylphosphonamides 104 to a,P-unsaturated esters followed by in situ cyclisation. Other asymmetric syntheses include those of (/ )- and (S)-piper-idin-2-ylphosphonic acid (105) via the addition to trialkyl phosphites to iminium salt equivalents and 4-thiazolidinylphosphonate 106 by catalytic asymmetric hydrophosphonylation of 3-thiazoline. In the latter case both titanium and lanthanoid (which give much better e.e. values) chiral catalysts are used. 

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. 

Spontaneous polymerization of 4-vinyl pyridine in the presence of polyacids was one of the earliest cases of template polymerization studied. Vinyl pyridine polymerizes without an additional initiator in the presence of both low molecular weight acids and polyacids such as poly(acrylic acid), poly(methacrylic acid), polyCvinyl phosphonic acid), or poly(styrene sulfonic acid). The polyacids, in comparison with low molecular weight acids, support much higher initial rates of polymerization and lead to different kinetic equations. The authors suggested that the reaction was initiated by zwitterions. The chain reaction mechanism includes anion addition to activated double bonds of quaternary salt molecules of 4-vinylpyridine, then propagation in the activated center, and termination of the growing center by protonization. The proposed structure of the product, obtained in the case of poly(acrylic acid), used as a template is ... 

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. 

Denmark and coworkers [354] have examined the alkylation of a-lithiated benzyl carbanions generated from diastereoisomeric chiral phosphonamides 1.96 and 5.10. The stereoselectivity of this process depends on the configuration at phosphorus, and it is alway higher when starting from 1.96. It is believed that planar benzylic anions are alkylated on their least sterically hindered face. Strong support for this rationale derives from the X-ray crystal structure of A. After hydrolysis and treatment of the products with diazomethane, (R)- or (S)-dimethyl phosphonates can be obtained (Figure 5.6). Hanessian and coworkers [311, 312] performed similar alkylations of phosphonamides 1.74 (Y = Me, Cl) derived from (RJR)- or ( ,.S)-trans-cyclohexanediamines bearing a C2 axis of symmetry. The reaction of the intermediate anionic species on its less hindered face, followed by... 

In the NMR spectrum of the methylammonium salt of the monomethyl ester of H-phosphonic add, the phosphorus signal appears at 4.55 ppm as a doublet of quartets with V(P,H) = 600 Hz indicating phosphonate structure. Kers et al. [23] confirm that in the reaction mixture of diethyl H-phosphonate and pyridine or pyridine with 2 equiv. of tertiary base (TEA), there were no signals that could be assigned to Iriethyl phosphite. The results obtained show that the basic activation in these reactions involves at the first step formation of the monoalkyl H-phosphonate anion [(R0)P(0)(H)0] , which further plays the key role in interactions where the phosphorus atom acts as a nucleophile. 

The structure of the final product has been verified by a combination of H, and NMR spectroscopy. The phosphorus chemical shift appears at 21.08 pp (R = CH3). The signal for the carbon atom bounded to the phosphorus appears at 50.70 ppm as a doublet with V(P,C) = 203.0 Hz (R = CH3). A two-step mechanism involving deprotonation of the dialkyl H-phosphonates by [Bu4NHC03 ], followed by nucleophihc attack of the dialkyl phosphonate anion (RO)2P(0) at the carbonyl group of the ketone, is presented. The oxirane formation during the second stage of the reaction involves displacement of the chloride ion. 

Phosphorus-based olefinations continue to be the most widely used methods for the synthesis of alkenes. An understanding of most facets of the mechanism of the Wittig reaction seems to have been achieved and this has been summarised in a substantive review. Some of the principles established in these mechanistic studies can be applied to phosphorus-based olefinations other than the Wittig reaction. However, substantive mechanistic studies of phosphine oxide-based and phosphonate-based oiefinations are urgently required. A combination of the variety of phosphorus-based methods and the improved understanding of their mechanisms now aliows a substantiai degree of controi of both reactivity and stereochemistry in olefin synthesis. However, studies are required of the applications of established structure-reactivity relationships in ylides and of the various carbon and nitrogen ylide-anions recently reported. 

In this procedure, the C-phosphorylated active methylene compound is first converted into its anion, through its reaction with KOBu BuLi, PhLi, NaH or even Et3N, and the anion is then acted upon by a sulphonyl azide the latter has been / -toluenesulphonyl azide in most recorded examples of the reaction. The first example of the adoption of this procedure to the synthesis of a phosphonic acid derivative appears to have been the conversion of triethyl phosphonoacetate into the diazo derivative (2). Since then, the procedure has been used to obtain A-substituted derivatives of the phosphonoacetamide corresponding to structure 2, but the primary amide itself undergoes further reaction to afford the C-phosphorylated 1,2,3-triazole (3)". Tetraethyl methylenebisphosphonate yields tetraethyl... 

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