Aldol Darzens reactions

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

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. 

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. ... 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

The development of enantioselective methods remains challenging. In principle, any of the methods that are used for stereoselective aldol additions can also be tested in the Darzens Reaction, as the first step is an aldol addition. 

The basic route to the synthesis of epoxides and, in general, vicinal bifunctional derivatives is a non-isohypsic (oxidative) transformation of alkenes (to be discussed below), Epoxides can also be formed directly as a result of certain C-C bond-forming reactions such as the Darzens reaction (modification of a classical aldol-like reaction with a-chloro esters 130 as a methylene component)... 

The Darzens reaction (tandem aldol-intramolecular cyclization sequence reaction) is a powerful complementary approach to epoxidation (see Chapter 5) that can be used for the synthesis of a,P-epoxy carbonyl and a,p-epoxysulfonyl compounds (Scheme 8.32). Currently, all catalytic asymmetric variants of the Darzens reactions are based on chiral phase-transfer catalysis using quaternary ammonium salts as catalysts. 

Chiral 2-substituted benzaldehyde chromium tricarbonyl complexes have been reacted with chloroacetophenone in the presence of KO-fert-Bu [544], After decomplexation, the E-epoxyketone is obtained with a high selectivity (Figure 6.88). This Darzens reaction with ClCF COO-tert-Bu is poorly stereoselective. Condensation of the same aldehydes with methyl aaylate or acrylonitrile in the presence of DABCO, followed by decomplexation, also leads highly selectively to P-hydroxyesters or -nitriles 6.105 (Y = COOMe or CN) [547] (Figure 6.88). An anti aldol product is also obtained with a high selectivity from a chromium complex and the titanium enolate of PhCF OCF COS-tert-Bu at -78°C [1281, 1282], Chiral aminals of a-ketoaldehydes react with lithium or sodium enolates of ethyl acetate. After treatment with acid, compounds 6.106 are obtained with a high enantiomeric excess (Figure 6.88). 

Aldol reactions. Aldol products are obtained in good yields from reaction of ketones with glyoxylic acid monohydrate with assistance of ultrasound irradiation. Substrate-control (by 1,3- + 1,5-asynmietric induction) of the aldol reaction involving y-amino-a-ketoesters under solvent-free conditions is very effective.- With lithium dicyclohexylamide and InCl, the reaction of esters with aldehydes furnishes P-hydroxy esters, and that of a-bromo esters affords a,p-epoxy esters." These are typical Reformatsky and Darzens reaction products, respectively. 

The Darzens condensation is an aldol-like reaction in which the aldolate product closes to give an epoxy ketone. The reaction has been achieved with moderate... 

Alternatively, 1-undecanal can be converted by aldol condensation with formaldehyde and subsequent hydrogenation into 2-methyl-undecanal (methyl-nonylacetaldehyde = MNA) [58]. This is a technically feasible alternative to the Darzens reaction of 2-undecananone with methyl chloroacetate. MNA is a sought-after principal ingredient in perfumery (see also Section 6.1.3.1.2). 

The aldol reaction and other venerable processes such as the Knoevenagel, Claisen-Schmidt, Perkin, Darzen, Tollens and Wittig reactions are base-catalyzed (sometimes acid-catalyzed too) reactions between an active methylene compound and an aldehyde or a ketone. In the last decade the term aldol-type reaction has been used to indicate that the initial addition step is mechanistically the same for all these reactions. 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldol condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis. ... 

Very recently, Belokon and North have extended the use of square planar metal-salen complexes as asymmetric phase-transfer catalysts to the Darzens condensation. These authors first studied the uncatalyzed addition of amides 43a-c to aldehydes under heterogeneous (solid base in organic solvent) reaction conditions, as shown in Scheme 8.19 [47]. It was found that the relative configuration of the epoxyamides 44a,b could be controlled by choice of the appropriate leaving group within substrate 43a-c, base and solvent. Thus, the use of chloro-amide 43a with sodium hydroxide in DCM gave predominantly or exclusively the trans-epoxide 44a this was consistent with the reaction proceeding via a thermodynamically controlled aldol condensation... 

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