Phosphonate carbanion

The reaction has been extended to include carbanions generated from phosphonates. This is often referred to as the Horner-Wittig or Homer-Emmons reaction. The Horner-Emmons reaction has a number of advantages over the conventional Wittig reaction. It occurs with a wider variety of aldehydes and ketones under relatively mild conditions as a result of the higher nucleophilicity of the phosphonate carbanions. The separation of the olefinic product is easier due to the aqueous solubility of the phosphate by-product, and the phosphonates are readily available from the Arbusov reaction. Furthermore, although the reaction itself is not stereospecific, the majority favor the formation of the trans olefin and many produce the trans isomer as the sole product. 

The addition of phosphonate carbanions to 6-amino-5-nitrosopyrimidines may be regarded as an extension of the Timmis principle and it proceeds under mild conditions and in... 

Tlie interest in the preparation and use of dithiolium salts in connection with the synthesis of TTF derivatives led to the development of a new uses of heteroaromatic cations in organic synthesis. Based on that, a new carbonyl olefination for the synthesis of numerous heterofulvalenes was developed (77S861). For example, 2-dimethoxyphosphinyl-l,3-benzodithiole was deprotonated with butyllithium in THF at -78°C and the resulting phosphonate carbanion reacted with 9-alkyl-acridones to give the dithia-azafulvalenes of type 45 (78BCJ2674) (Scheme 15). 

Wittig reaction, using dichloromethyl-enetriphenylphosphorane, 45,33 using phosphonate carbanions, 46, 46... 

A new pteridine synthesis is based on the reaction of 4-amino-5-nitroso-pyrimidines with the phosphonate carbanions (173 = C02Et, >... 

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... 

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution have been utilized in macrocycle syntheses. Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction. Entries 9 to 11 illustrate the construction of new double bonds in the course of a multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10. 

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. 

An important modification to the Wittig reaction is the use of stabilized phosphonate carbanions in olefin synthesis. This reaction, originally discovered by Homer but developed by Wadsworth and Emmons, is used extensively for transformation of a carbonyl... 

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution has been utilized in macrocycle synthesis (entries 8 and 9 in Scheme 2.17)... 

Scheme 2.17. Carbonyl Oleflnation Using Phosphonate Carbanions...

The reaction of aldehydes or ketones with stabilized phosphorus ylides (phosphonate carbanions) leads to olefins with excellent E-selectivity. 

The 2-(6-formyl-2-pyridyl)-2-(4-tolyl)-l,3-dioxolan (2.5 g) was dissolved in 1,2-dimethoxyethane (10 ml) and added to a solution of the phosphonate carbanion produced from triethyl phosphonoacetate (2.0 g) and sodium hydride (0.22 g) in the same solvent. The mixture was stirred for 2 h, diluted with ether (25 ml) and treated with hydrochloric acid (5 ml, 2 mol). The organic phase was separated, washed with water, dried, and evaporated. The resulting oil was dissolved in ethanol (20 ml) containing concentrated hydrochloric acid (3 ml) and water (3 ml). After heating on the steam bath for 10 min, the solution was diluted with ice water, rendered alkaline with sodium bicarbonate solution, and extracted with ether. Evaporation gave 1.0 g ((E)-3-(6-(4-toluoyl)-2-pyridyl)acrylate as colourless platelets, melting point 108°-111°C (crystallized from cyclohexane). 

The phosphonates stabilized by an adjacent electron-withdrawing substituent, such as the carboxylate group or nitrile group, are particularly suitable. The phosphonate carbanions are very readily formed, even with aqueous alkali, and, in contrast to the triphenylalkylenephosphoranes stabilized by carbonyl groups, react not only with aldehydes but also with ketones. 

The nature of the substituents on a stabilized phosphonate carbanion is known to influence the stereochemical outcome of their reactions with aldehydes. For example, a bis(2,2,2-trifluoroethyl) substituent reverses the normal preference for (E) alkenes in a sequence referred to as the Still modification of the HWE reaction (see Protocol ll).24 This substituent is thought to favour formation of the (Z)-isomeric alkene by greatly enhancing the rate of the elimination of the phosphine oxide to give the alkene, which then suppresses equilibration to the thermodynamic product. 

The 7t-extended 1,3-dithiole 237 containing a cycloproparene moiety was synthesized in the Horner-Wittig reaction involving the phosphonate carbanion derived from 235 and the benzoyl-substituted cycloproparene 236 (Equation 16) <2004EJ0138>. 

Other examples of functionalization at C-2 via phosphorus ylides and phosphonate carbanions are described in Section 4.12.11. Utilization of 2-non-phosphorus-containing carbanions was also exemplified. Thus, 2-silicon-substituted 1,3-benzodithioles were synthesized via deprotonation of benzo-l,3-dithiole 245 with -BuLi and subsequent treatment of the resulting anion with trimethylsilyl chloride (TMSCl) to give 2-(trimethylsilyl)-benzo-l,3-dithiole 246 (Scheme 29). The second silyl group was introduced by further deprotonation of 246 ( -BuLi) followed by the reaction with an additional equivalent of TMSCl. Tin-substituted benzo-l,3-dithioles were synthesized in a similar way but the deprotonation of the monostannyl derivative was carried out with LDA (Scheme 29) <1996CL171>. 

Olefination of aldehydes with a-silyl- and a-stannyl-stabilized phosphonate carbanions derived from cyclo-[L-AP4-D-Val] allow a (Z)-selective access to a,p-substituted vinyl phosphonates (343) that have been transformed into enantiomerically pure 4-alkylidene 4PA derivatives (344) (Figure 54). " Electrophilic fluorination of lithiated bis-lactim ethers derived from cyclo-[L-AP4-D Val] (345) with commercial NFSi allow direct access to a-monofluor-inated phosphonate mimetics of naturally occurring phosphoserine (346) and phosphothreonine (347), in enantiomerically pure form and suitably protected for solid-phase peptide synthesis (Figure 55). ... 

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