Ketones Darzens reaction

This, the Darzens reaction, is useful in other circumstances (frames 280-1) but a nuisance here. We must use some means to make the ketone act as the nucleophile in the initial condensation. One effectiye way is to conyert it into an enamine. Draw a mechanism for this reaction. 

Darzens reaction can be used to efficiently complete the stereoselective synthesis of a"-substituted epoxy ketones. As an example, Enders and Hett reported a technique for the asymmetric synthesis of a"-silylated a,P-epoxy ketones. Thus, optically active a -silyl a-bromoketone 38 was treated with LDA followed by the addition of benzaldehyde to give a"-silyl epoxyketone 40 in 66% yield with good... 

In a separate report, the Darzens reaction was recently used by Barluenga, Concellon, and coworkers for the preparation of enantiopure a"-amino a,P-epoxy ketones. Accordingly, the Z enolate of a"-amino a-bromo ketone 41 was generated with KHMDS at -100°C. Benzaldehyde was added, and trans epoxyketone 42 was isolated in 87% yield and >95% de. ... 

The Darzens reaction involves a two-step, base-catalyzed condensation of ethyl chloroacetate with a ketone to yield an epoxy ester. The first step is a carbonyl condensation reaction, and the second step is an SK2 reaction. Write both steps, and show their mechanisms. 

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

Vinylsilanes (Chapter 3) can be readily converted into a/3-epoxysilanes, normally by treatment with mcpba (/). Alternatively, a-chloro-a-lithio-a-trimethylsilanes react efficiently with aldehydes and ketones in a manner reminiscent of the Darzens reaction (2). 

An unexpected, one-step synthesis of a-chloro-P-lactones in 40-83% yield resulted when phenyl esters of a-chlorocarboxylic acids were treated under the conditions of the Darzens reaction with strong base in the presence of ketones or aldehydes <95AG(E)2028>. Previously, phenyl esters do not appear to have been used in this reaction. 

The Darzens reaction, which is described on p T 253, is a good example of eyclisation to give a three-membered ring. The enolate of an a-halo ester, e.g. (27), adds to a ketone to give (26) v,/hieh cannot be isolated as it cyclises so readily. 

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular Sn2 reaction, forming an epoxide as its final product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone. 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

S. Arai, Y. Shirai, T. Ishida, T. Shioiri, Phase-Transfer Catalyzed Asymmetric Darzens Reactions of Cyclic a-Chloro Ketones , J. Chem. Soc., Chem. Commun. 1999, 49-50. 

The Darzens reaction between aldehydes and ketones with activated halomethyl compounds is an effective route to oxiranes under phase-transfer catalytic conditions and the catalyst has a profound stereochemical control of the substituents (see Chapter 12). The reaction has been conducted in high yield under liquidtliquid and solidrliquid two-phase conditions with a range of halomethyl compounds [e.g. 25-30], Ketones tend to be much slower in their reaction and benzylic ketones undergo alkylation with chloroacetonitrile in preference to the Darzens reaction [25]. 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

A number of glycidates are important intermediates in the synthesis of fragrance materials. A few glycidates are fragrance materials in themselves. They are prepared either by epoxidation of the corresponding acrylates or by condensation of aldehydes or ketones with a-chloro substituted fatty acid esters (Darzens reaction). 

Makosza and co-workers have reported the preparation of epoxides from a-halo carbanions and ketones, according to the Darzens reaction, under PT conditions, using TEBA72,73 or dibenzo-18-crown-6.74 The ratio of isomers depends on the reaction conditions.75,76 Asymmetric induction has been reported in the Darzens reaction using chiral catalysts.77,78 The use of several chloro carbanions as well as K2C03 and Na2C03 in the solid state has also been studied. 

The Darzens reaction is the base-promoted generation of epoxides XIII from aldehydes (or ketones) XI and alkyl halides XII, the latter carrying an electron withdrawing group, for example the carbonyl, nitrile, or sulfonyl, in the a-position (Scheme 6.83) [188, 189]. It is, formally, addition of a carbene to the C=0 double bond (Scheme 6.83, path B) and thus complements oxygen atom transfer to olefins... 

A complementary approach to similar products involved the asymmetric Darzens reaction of a-chloro ketones such as 29 with aldehydes. The cinchoninium salt 2f allowed the epoxide 30 to be prepared with reasonably high enantiomeric excess (Scheme 11) [19]. 

Enantiomerically enriched epoxides have also been generated using (1) in the Darzens reaction of a-chloro ketones with aldehydes, as well as through ring closure of racemic halohydrins. The extent of enantioselectivity for both reactions is similar (optical purity 6-8% 1), suggesting a moderate degree of kinetic resolution occurring in each case. 

Enantioselective Darzens Reaction. An enantioselective Darzens reaction between ethyl methyl ketone and chloromethyl p-tolyl sulfone in the presence of a chiral ammonium salt derived from (1) and chloromethylpolystyrene affords an optically active a,p-epoxy sulfone in 23% ee. ... 

The Darzens reaction has been performed enantioselectively, by coupling optically active a-bromo-p-hydroxy esters with aldehydes.Chiral phase-transfer agents have been used to give epoxy ketones with modest enantioselectivity. Chiral additives have proven to be effective. 

Treatment of a, ) -unsaturated ketones with a-halo esters often results in oxirane (205) formation (Darzens reaction). However, the reaction of the dienone 203 with ethyl bromoacetate (204) produces the bicyclo[4.1.0]heptenone derivative 206 (equation 55) ... 

The dissonant charge pattern for 2,5-hexanedione exhibits a positive (-1-) polarity at one of the a-carbons, as indicated in the acceptor synthon above. Thus, the a-carbon in this synthon requires an inversion of polarity Umpolung in German) from the negative (-) polarity normally associated with a ketone a-carbon. An appropriate substrate (SE) for the acceptor synthon is the electrophilic a-bromo ketone. It should be noted that an enolate ion might act as a base, resulting in deprotonation of an a-halo ketone, a reaction that could lead to the formation of an epoxy ketone Darzens condensation). To circumvent this problem, a weakly basic enamine is used instead of the enolate. 

Alternatively, epoxy esters may be prepared via the Darzens reaction, which involves base-mediated condensation of a-chloro esters with aldehydes or ketones. ... 

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