Wadsworth-Emmons method

The (Horner-)Wadsworth-Emmons reaction generally is superior to the Wittig reaction, and has found application in many cases for the synthesis of a ,/3-unsaturated esters, a ,/3-unsaturated ketones and other conjugated systems. Yields are often better then with the original Wittig procedure. However the Wadsworth-Emmons method is not suitable for the preparation of alkenes with simple, non-stabilizing alkyl substituents. 

This variation of the Wittig reaction uses ylides prepared from phosphonates.12 The Horner-Wadsworth-Emmons method has several advantages over the use of phosphoranes. These ylides are more reactive than the corresponding phosphoranes, especially when substituted with an electron withdrawing group. In addition the phosphorus product is a phosphate ester and soluble in water - unlike the Ph3PO product of the Wittig reaction - which makes it easy to separate from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction from phosphanes and halides. 

The reaction of the ketone (681) with the phosphonate (646) gave a mixture of the isomeric carboxylates (682) and (683), from which the trans compound was very easily isolated in crystalline form. Alkaline hydrolysis of either the caiboxy-late (682) or the nitrile (684) gave the carboxylic acid (21). The nitriles (684) and (685) were also synthesized from the ketone (681) and ethyl p-cyanobenzylphos-phonate (657) by the Homer-Wadsworth-Emmons method (F. Frickel, unpublished). 

Horner-Wadsworth-Emmons method already described. In contrast to what is known from other carbon- 14-labeled acrylates, 256 proved to be unexpectedly stable towards radiation-induced polymerization, probably due to the bulky auxiliary. 

This method, sometimes called the Horner-Emmons, Wadsworth-Emmons, or... 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

Statine was identified as a starting material that contains predetermined stereochemistry at the C4 and C5 atoms. Nakano and co-workers155 56 degraded statine to an aldehyde, (45,5R)-4-alkyl-3-benzyloxycarbonyl-5-formyl-2,2-dimethyloxazolidine, which is an intermediate of the method described in Scheme 17. Then, the elongation of this aldehyde was carried out by the Wadsworth-Emmons reaction with diethyl phosphonate. 

The preparation of a,/ -unsaturated aldehydes and ketones is exemplified by the following four important methods (a) the oxidation of the corresponding unsaturated primary or secondary alcohol (b) the Horner-Emmons or Wadsworth-Emmons modification of the Wittig reaction248 (c) the aldol con-... 

As for the unsaturated carbonyl compounds, the most significant groups are the oc,/ -unsaturated acids or esters. Some of their methods of formation are closely analogous, for example, (a) the Horner-Emmons or Wadsworth-Emmons reaction, and (b) the aldol-type reactions. Rather more specific methods are considered below for the formation of a,/ -acetylenic acids, and for the conversion of the unsaturated dicarboxylic acid, maleic acid, into its anhydride or into fumaric acid. 

At this point it should be noted, that olefination involving reaction of PO-stabilized carbanions like those from phosphonates, phosphinates, phosphine oxides, phos-phonamides or thiophosphonates (Horner reaction 47), Horner-Wadsworth-Emmons reaction48 ) with carbonyl compounds almost exclusively yields ( )-olefins. This olefination is essentially restricted to PO-activated compounds carrying stabilizing groups on the carbanionic C-atom. However, these compounds are more reactive than the corresponding resonance-stabilized ylides. Therefore, this olefination method... 

Protocol 2 produces the protected fi-formylphosphonate 12 f)-ketophospho-nates may also be synthesized by other methods,23 however, they may not be prepared in unprotected form by the Michaelis-Arbuzov reaction because the Perkow reaction, in which an a-haloaldehyde or ketone and a trialkyl phosphite yield an enol phosphate (e.g. 13, Scheme 5,24 i.e. [P—O] bond formation), competes and frequently dominates (see Section 4). Conversely halocarboxylic acid derivatives (e.g. see Table 7.1, entry 3) and acyl halides (see Protocol 3) react well in the Michaelis-Arbuzov reaction to yield useful functionalized phosphonates. fi-Ketophosphonates are useful reagents for the synthesis of a,fi-unsaturated carbonyl compounds by the Horner-Wadsworth-Emmons reaction,3,4 25 and have other applications.23... 

Preparation of Derivatives. A -Acyl- and A-enoylsul-tam derivatives are routinely prepared in good yields using either sodium hydride-acid chloride or trimethyl-aluminum-methyl ester single-step protocols. A variant of the former method employing in situ stabilization of labile enoyl chlorides with CuCl/Cu has also been reported. A two-step procedure via the A-TMS derivative (1) is useful when a nonaqueous work-up is desirable and for synthesis of the A-acryloyl derivative. A-Enoyl derivatives may also be prepared via the phosphonate derivative (2) by means of an Homer-Wadsworth-Emmons reaction (eq... 

Norrby, P.-O., Brandt, P., Rein, T. Rationalization of Product Selectivities in Asymmetric Horner-Wadsworth-Emmons Reactions by Use of a New Method for Transition-State Modeling. J. Org. Chem. 1999, 64, 5845-5852. 

Sano, S., Yokoyama, K., Shiro, M., Nagao, Y. A facile method for the stereoselective Homer-Wadsworth-Emmons reaction of aryl alkyl ketones. Chem. Pharm. Bull. 2002, 50, 706-709. 

The Honor-Wadsworth-Emmons (HWE) reaction of a-fluoro-a-phosphonoacetate 1 with aldehydes or ketones, providing a-fluoro-a,P-unsaturated carbonyl compounds, is one of commonest methods for fluoro-olefins having suitable functionality for further elaboration to the target molecules (see equation 1, Scheme 10.1) [9]. The stereochemical outcome of this reaction with both aliphatic and aromatic aldehydes is generally excellent, giving rise... 

The enantioselective desymmetrization of prochiral ketones of the type 46 by means of the Horner-Wadsworth-Emmons reaction is an elegant approach to the synthesis of the enantioenriched enone products 47. Enones such as 47 bearing a remote stereogenic center are difficult to prepare by other methods. The first catalytic asymmetric Horner-Wadsworth-Emmons reaction was realized by using cinchona-based PTCs as organocatalysts [40]. Up to 55-57% ee values and satisfactory yields were obtained using catalytic amounts (20 mol%) of the N-benzylcinchoninium salts 48 and RbOH as a base (Scheme 11.25). 

Standard Wittig/Horner-Wadsworth-Emmons reaction conditions (Table 8, entries 25, 26) [477] The method presented here yields predominantly (E)-alkenes. 

To date long-chain phosphonylated aldehydes (n > 10) have been prepared exclusively as precursors for the synthesis of 11- to 17-membered macrocycles via intramolecular Homer-Wadsworth-Emmons reactions (Scheme 5.63). This widely used cyclization step provides the best method for preparing macrocycles. 

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