Wittig reaction phosphonate modification

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... 

The Wittig reaction, or its phosphonate modification, can be a very useful reaction in the synthesis of anomerically functionalized precursors to C-nucleosides, particularly when the ring-closure reaction leads to five-membered, anhydro derivatives, and occurs with a high degree of stereocontrol. Zhdanov and coworkers,130 showed that the following five-membered, Wittig products (179-182) were formed from various free sugars and (p-methoxybenzoyl)- and (acetyl-methylene)-triphenylphosphoranes. 

Step 1 (3-keto phosphonates often are used for olefmation of ketones (Horner-Wadsworth-Emmons modification of the Wittig reaction). Steps 2 + 3 The cuprate-mediated 1,4-addition and subsequent Lemieux-Johnson oxidation of a vinyl group are excellent procedures for the introduction of the p-formyl group. 

Step 3 HWE-modification of the Wittig reaction tetramethylguanidine is a mild, non-nucleophilic base (much like DBU) that deprotonates the phosphonate reagent. 

The simultaneous insertion of an alkene bond and a carboxyl function into a sugar molecule is very attractive for carbohydrate chemistry in view of the further useful derivatization possible. This problem has been successfully solved by employment of the Wittig reaction, as well as its phosphonate modification (see p. 259). The compounds thus far synthesized are not numerous, although their transformations have been studied in detail and have resulted in a new method for the carbon-chain extension of carbohydrates.26... 

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. ... 

When the halogen compound employed in the first step has an activated halogen atom (RCH CHCHjX, QHjCHjX, XCH2CO2H) a simpler procedure known as the Horner phosphonate modification of the Wittig reaction is applicable. When benzyl chloride is heated with triethyl phosphite, ethyl chloride is eliminated from the initially formed phosphonium chloride with the production of diethyl benzylphosphonate. This phospho-... 

Condensation catalyst. In the synthesis of trans-stilbene by the phosphonate modification of the Wittig reaction formulated, Seus and Wilson" eifected the terminal condensation with sodium methoxide in dimethylformamide. The reaction... 

Phosphonate modification [bottom of 1, 1212]. frans-3-Stilbazole is conveniently prepared by the phosphonate modification of the Wittig reaction 43... 

Similarly, 29 can be formed by the Homer-Wadsworth-Emmons modification of the Wittig reaction via the phosphonate 28 rather than the phosphorus ylide 27. In this case, the iodo compound mixture 26 is treated with trimethyl phosphite. Cyclization requires the use of lithium chloride/Hunig s base, ° and cyclization proceeds smoothly at room temperature in similar yield to the Wittig chemistry. Details of this process with isolation and characterization of the intermediates 26, 27, and 29 can be found in a recently published world patent application." Yields for the conversion of 24 into 27 are -77% overall cyclization yield from 27 to 29 is -85%. 

The Homer-Emmons modification is a variation of a Wittig reaction in which a phosphonate-stabilized carbanion in used instead... 

The use of trialkyl phosphites in the Michaelis-Arbuzov reaction has been so widespread during the decades following its discovery that it is almost impossible to select individual examples worthy of separate comment. Some examples of the preparation of benzylic phosphonic diesters may be noted these are of some interest since they are useful reactants in the Wadsworth-Emmons modification of the Wittig reaction, and are extensively used in the synthesis of alkenes It may also be noted that when the phosphite ester possesses different alkyl groups, some selectivity of reaction is possible. ... 

In the chemistry of phosphorus-stabilized carbanions the number of publications reporting theoretical studies and those reporting mechanistic studies have increased following the reduction in these numbers last year. One of these reports includes the isolation and separate decomposition of certain oxaphosphetanes and this has allowed the first kinetic study of the second step of the Wittig reaction, albeit for a rather special system. Complex phosphonate carbanions and ylides continue to be widely used in synthesis. The number of reports of the use of the aza-Wittig and related reactions in heterocyclic synthesis remains at a high level, although many of these involve relatively minor modifications of earlier work. 

Some of the disadvantages of the Wittig reaction can be overcome by use of the Horner-Wadsworth-Emmons reaction or, in brief, the Horner-Emmons reaction [6,14-16]. The modification of the Wittig process makes use of a phosphonate-stabilized carbanion instead of a phosphorus ylide it is discussed in Section E. 

The disadvantages of the Wittig reaction described in Section A led to the development of modified olefination methods based on phosphoryl-stabilized carbanions. The most important modification of the Wittig reaction in the field of carotenoid synthesis is olefination by means of phosphonate carbanions, as introduced by Homer [55] and by Wadsworth and Emmons [56]. 

An important modification of the Wittig reaction that involves phosphonate esters has the advantage of being highly stereoselective. The use of phosphonate esters rather than phosphonium salts is illustrated in the accompanying equations ... 

The Homer-Emmons modification uses a phosphonate-stabilized carbanion in a Wittig reaction. This reagent is an anion that is more nucleophilic than the usual Wittig ylide. The byproduct (R0)2P02 is water-soluble and easily separated from the product. These phosphonate-stabilized carbanions are compatible with carbonyl groups (especially esters) in the reagent. 

Compounds based on the styryl group were prepared to lengthen the conjugated system of stilbene. l,4-Di-(stryryl)-benzenes are obtained by the Homer modification of the Wittig reaction, for example, l,4-bis-(chloromethyl)benzene is treated with 2 moles of triethyl phosphate and the resulting phosphonate reacts with 2 mol of o-cyanobenzaldehyde to yield compound 36. A strong brightening effect with a reddish cast is obtained on polyester fibers and is mainly used in the textile industry. 

The use of the phosphonate ester (Homer-Wadsworth-Emmons reaction) allows much easier separation of the product alkene, since the sodium phosphate byproduct is water soluble the byproduct of fhe Wiffig reaction, tri-phenylphosphine oxide, is not water soluble. In the Horner-Wadsworth-Emmons modification, a conjugated, or electron-withdrawing, substituent (such as a phenyl or carbonyl group) on the nucleophilic carbon is used to assist in the stabilization of the carbanion. This modification (Experiment [19B]) maybe used as an alternative to Experiment [19A] for the preparation of (E)-stilbene. The "instant-ylide" Wittig reaction yields predominantly the E isomer of... 

Because the Wittig reaction is so useful for the preparation of alkenes, chemists have explored several variations of it. One of the most useful of these, known as the Homer-Emmons-Wadsworth modification, uses a phosphonate ester derived from an a-haloester or a ketone to generate the Wittig carbanion. 

The Wadsworth-Emmons modification [56] of the Wittig reaction uses the phosphonate esters to form a,p-unsaturated esters in which the ( )-alkene is favored (Eq. 7.33) [57]. In situ alkylation is also possible (Eq. 7.34) [56]. The phosphonoesters are prepared by treating the a-bromoesters with triethyl phosphite (Arbuzov reaction) [58]. The diethyl phosphate by-product is water-soluble and easily removed. 

Also for the Wittig reaction, the product may be formed as a mixture of Z- and ii-isomers, but each of these may be improved by applying appropriate reaction conditions. Studies on modifications on the Homer-Wadsworth-Emmons reaction done by StiU and Gennari [38] and Ando [39] have resulted in improved Z-selective reactions. As of today, these reactions are limited to phosphonate esters. 

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