Ketones Horner-Wadsworth-Emmons reaction

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. 

Cyclopropanation, Horner-Wadsworth Emmons Reaction, and Darzens Condensation Although induction in the cyclopropanation of alkenes was reported early, this work was disputed [49]. Other reports of cyclopropanations have yielded, at best, low asymmetric inductions [llh,50]. The first example of a catalytic asymmetric Horner-Wadsworth Emmons reaction, which is promoted by a chiral quaternary ammonium salt, was reported recently by the Shioiri group (Scheme 10.10) [51]. The reaction of the prochiral ketone 74 gives optically active a,P-unsaturated ester 76 with 57% ee. 

The enantioselective desymmetrization of prochiral ketones of type 75 by means of the Horner-Wadsworth-Emmons reaction [76, 77] is an elegant means of synthe-... 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

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. 

Horner-Wadsworth-Emmons reactions are C—C-forming condensation reactions between the Li, Na, or K salt of a /J-keto- or an -(alkoxycarbonyl)phosphonic acid dialkyl ester and a carbonyl compound (cf. Figure 4.41). These reactions furnish a,f)-unsaturated ketones or a j8-unsaturated esters, respectively, as the desired products and a phosphoric acid diester anion as a water-soluble by-product. In general, starting from aldehydes, the desired compounds are produced fraus-selectively or in the case of olefins with trisubstituted C—C double bonds -selectively. 

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... 

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. ... 

In the Horner-Wadsworth-Emmons (HWE) reaction, a lithium, sodium or potassium salt of a P-keto-phosphoric acid dialkyl ester or an a-(alcoxycarbonyl) phosphoric acid dialkyl ester is reacted with an aldehyde to form an a,p-unsaturated ketone or an a,p-unsaturated ester as product and a phosphoric acid dialkyl ester as byproduct. The product of a Horner-Wadsworth-Emmons reaction possesses a new -configured C=C double bond. To obtain products with Z-confi-guration of the C=C double bond the Still-Gennari variant or the Ando variant can be employed. The Still-Gennari variant uses two partly fluorinated F3C-CH2-O groups at the phosphorus and the Ando variant uses two aryloxy residues and the transferable alcoxycarbonyl group at the phosphorus. 

Yamaguchi, M., Hirama, M. Kinetic resolution of racemic aldehydes and ketones by the asymmetric Horner-Wadsworth-Emmons reaction. Chemtracts Org. Chem. 1994, 7,401-405. 

Sano, S., Takehisa, T., Ogawa, S., Yokoyama, K., Nagao, Y. Stereoselective synthesis of tetrasubstituted (Z)-alkenes from aryl alkyl ketones utilizing the Horner-Wadsworth-Emmons reaction. Chem. Pharm. Bull. 2002, 50, 1300-1302. 

Sano, S., Takemoto, Y., Nagao, Y. (E)-Selective Horner-Wadsworth-Emmons reaction of aryl alkyl ketones with bis(2,2,2-trifluoroethyl)phosphonoacetic acid. Tetrahedron Lett. 2003,44, 8853-8855. 

Desymmetrization of Prochiral Ketones by Means of Horner-Wadsworth-Emmons Reaction... 

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). 

FIGURE 13 Et Et Horner-Wadsworth-Emmons reactions were performed with a polymer-support-bound ketone resembling the CD ring of vitamin D3. [207]... 

A modestly enantioselective pyrrole carbinol formation has been investigated <05SL2420>. Treatment of lithium pyrrolate with a ketoaldehyde in the presence of a chiral ligand preferentially led to the formation of pyrrole carbinol 49 (50% ee). A hydroxy-directed reduction of the ketone in the side chain by the addition of zinc borohydride provided 50 (88% de). Pyrrole carbinols serve as convenient precursors to aldehydes. A subsequent deprotective Horner-Wadsworth-Emmons reaction involving 50 and phosphonate ester 51 gave unsaturated ester 52. 

Introduction The extended enolate problem Kinetic and thermodynamic control Wittig and Horner-Wadsworth-Emmons Reactions Extended Aza-Enolates Extended Lithium Enolates of Aldehydes Summary a-Alkylation of Extended Enolates Reaction in the y-Position Extended Enolates from Unsaturated Ketones Diels-Alder Reactions Extended Enolates from Birch Reductions The Baylis-Hillman Reaction The Synthesis of Mniopetal F... 

The unstable silyl ether in 232 was replaced by a more stable acetoxy ketone 233 which was not isolated. A Horner-Wadsworth-Emmons reaction was used for the Wittig-style olefination (chapter 15). A nitrile 234 replaced the carbonyl group in 230 as it was found easier to reduce nitriles in conjugative fashion. 

The dknethylcyclohexane compounds are obtained in a Horner-Wadsworth-Emmons reaction from dimethylcyclohexanone with subsequent reduction. As possible starting materials, m-cresol [210], Just like acetone and methyl vinyl ketone [211], can be considered. The second methyl group may be inserted advantageously using trimethylaluminium. [212]... 

The Horner-Wadsworth-Emmons reaction (or HWE reaction) is the reaction of stabilized phosphonate carbanions with aldehydes (or ketones) to produce predominantly -alkenes. In 1958, Horner published a modified Wittig reaction using phosphonate-stabilized carbanions [32]. Wadsworth and Emmons further defined the reaction [33]. Compared to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic and more basic. Likewise, phosphonate-stabilized carbanions can be alkylated, unlike phosphonium ylides. The dialkylphosphate salt by-product is easily removed by aqueous extradion. A reliable and versatile synthesis of a stilbene derivative, 2,2-aryl-substituted cinnamic acid esters, using the Wittig reaction was reported [34—36] (Figure 1.3). 

Closely related to the Wittig reaction is the Horner-Wadsworth-Emmons reaction, where a stabilized phosphonate carbanion reacts with an aldehyde or ketone to yield an olefin. 

Reactions with Aldehydes and Ketones. The carbanion derived from the treatment of (Me0)2P(0)CH(SMe)2 with a base reacts with cyclic and acyclic, aliphatic and aromatic aldehydes and ketones in a Horner—Wadsworth—Emmons reaction to give ketene 5,5-thioacetals in high yields " (eq 2 ). The carbanion is generated using either butyllithium in THE at —78 °C > or, less commonly, sodium hydride in DME. Alternatively, with aromatic aldehydes the reaction may be performed under two-phase conditions using benzyltriethylammonium chloride (TEBA) as a phase-transfer catalyst. ... 

Related Systems. The carbanions of related 5,5-thioacetals of formylphosphonates also react with aldehydes and ketones, including Q ,/3-unsaturated aldehydes and ketones, to give the corresponding ketene 5,S-thioacetals (e.g. eq 5 ). Horner-Wadsworth-Emmons reactions of carbonyl compounds with 0,S-thioacetals of formylphosphonates [e.g. (Me0)2P(0)CH-(SMe)0Me] and mono(thio)phosphonates [e.g. (Me0)2P(0)-CH2SMe] are also known. 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

The selective conversion of serine or threonine units of di- and tripeptides (392) into substituted, unsaturated aminoacids (394) has been reported by Hernandez et al. Thus, a-aminoacids esters (392) underwent a scission-phosphorylation process to give phosphonate derivatives (393). The Horner-Wadsworth-Emmons reaction of the latter with aldehydes or ketones afforded the final products (394) with excellent Z-stereoselectivity (Z E>98 2) (Scheme 138). ... 

HORNER - WADSWORTH - EMMONS Olelination Wittig type reaction of ptwsptionale stabilized carbanions with aldehydes or ketones to form olefins... 

Shibasaki made several improvements in the asymmetric Michael addition reaction using the previously developed BINOL-based (R)-ALB, (R)-6, and (R)-LPB, (R)-7 [1]. The former is prepared from (R)-BINOL, diisobutylaluminum hydride, and butyllithium, while the latter is from (R)-BINOL, La(Oz -Pr)3, and potassium f-butoxide. Only 0.1 mol % of (R)-6 and 0.09 mol % of potassium f-butoxide were needed to catalyze the addition of dimethyl malonate to 2-cy-clohexenone on a kilogram scale in >99% ee, when 4-A molecular sieves were added [15,16]. (R)-6 in the presence of sodium f-butoxide catalyzes the asymmetric 1,4-addition of the Horner-Wadsworth-Emmons reagent [17]. (R)-7 catalyzes the addition of nitromethane to chalcone [18]. Feringa prepared another aluminum complex from BINOL and lithium aluminum hydride and used this in the addition of nitroacetate to methyl vinyl ketone [19]. Later, Shibasaki developed a linked lanthanum reagent (R,R)-8 for the same asymmetric addition, in which two BINOLs were connected at the 3-positions with a 2-oxapropylene... 

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