Michael/Darzens reaction

Scheme 7.18 One-pot Michael/Darzens reaction for the synthesis of a,P-epoxycyclohexanones.

Chiral PTC has been used effectively for making intermediates for drugs. Dolling and coworkers have used 8-R, 9-5, N-(p-trifluoromethylbenzyl) cinchonium bromide to carry out an important asymmetric alkylation, giving 95% ee (Starks, 1987). Nucleophilic epoxidations of enones, Darzens reaction, Michael additions, etc. are some examples of reactions rendered asymmetric through chiral PTCs (Nelson, 1999). 

Besides of these main types of the chiral TAA salts, numerous other chiral TAA salts and crown ethers acting as moderately enantioselective PT catalysts were reported. Chiral PTC was mostly used for enantioselective formation of chiral carbon centers via alkylation of carbanions (enolates), Michael addition, the Darzens reaction and other reactions of carbanions. There are also numerous examples of enantioselective PTC epoxidation of electron deficient alkenes (for review, see Ref 105). 

Products of VNS are generated in the form of carbanions and are isolated upon protonation. Instead of protonation, they can be introduced directly in subsequent reactions with electrophilic partners such as alkylating agents [64a] or aldehydes [64b]. For instance, the VNS in nitrobenzene with carbanion of 2-dichloromethyloxazoline produces nitrobenzylic a-chlorocarbanion that enters the Darzens reaction with aromatic aldehydes to give oxiranes (Scheme 11.40) [64b] whereas the reaction with carbanion of r-butyl dichloroacetate followed by Michael addition gives f-butyl nitroarylcyclopropane carboxylates [64c]. 

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. 

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... 

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... 

An undergraduate experiment using sodium hydride involves the crossed condensation of ethyl acetate and dimethyl phthalate (eq 18). Sodium hydride is also effective as a base in the Stobbe condensation and the Darzens condensation. It is also effective in a stereoselective intramolecular Michael reaction (eq 19). ... 

A diastereo- and enantioselective Michael addition combined with a Darzens condensation reaction can be used to form two products of interest in the field of medicinal and natural products chemistry [60]. Additionally, depending on the workup conditions, an optically active epoxycyclohexanone, 92, can be prepared through an Sf 2 reaction, or the ElcB reaction pathway to 91 can be accessed (Scheme 7.17). In the early stages of the proposed mechanism, a planar iminium ion is suggested between the 2-[bis(3,5-bistrifluoromethylphenyl) trimethylsilany-loxymethyljpyrrolidine 61 and the aldehyde moiety of compound 88, which is subsequently attacked by the P-ketoester 89. For the synthesis of the epoxide, a... 

Since this pioneering study, a breathtaking number of naturally occurring alkaloid derivatives have emerged, finding application in a wide range of processes such as alkylations, Michael additions, aldol reactions, Darzens... 

Such important processes as alkylation of arylacetonitriles, cyclopentadiene hydrocarbons, aldehydes and ketones, esters, sulfo-nes etc., condensation of carbanions with aldehydes and ketones, the Knoevenagel, Darzens, Michael and related reactions as well as many reactions involving sulfonium and phosphonium ylides have been successfully carried out under these conditions. 

Polymer-supported podands appear to be more commonly used in solid-liquid systems. A variety of chemical transformations including nucleophilic substitutions at saturated carbon atoms [214,215], esterifications [214], sodium bo-rohydride reduction [214], fluoride-catalyzed Michael addition [214], phenacyl ester synthesis, Darzen s reaction, Wittig alkenylation, and dichlorocarbene reactions can be carried out under these conditions [214],... 

Other strong base reactions such as Michael additions, aldol condensations, Wittig reactions, Darzens condensations, carbene reactions Oxidations using hypochlorite, hydrogen peroxide, oxygen, permanganate Epoxidations... 

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