Michael reactions malonate anion

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

Reactions on SP2 Type Unsaturated Systems Very few studies have been carried out on the stereochemistry of the Michael reaction. However, Abramovitch and Struble (36) have found that compound 101 was the main product when diethyl sodiomalonate (free of ethoxide ion and ethanol) was added to 4- t-butyl-1-cyano cyclohexene (99) in boiling toluene. This result can be rationalized by axial attack on 99 to give first 100 having a chair-like conformation which is then transformed into 101 by internal trapping (see arrow). However, when the addition of diethyl malon-ate anion was carried out in ethanol under thermodynamically controlled conditions, product 103 with an equatorial malonate group was obtained, presumably via the twist-boat intermediate 102. 

The resulting tetraethyl ester on hydrolysis and decarboxylation yields propane-1, 2,3-tricarboxylic acid.155 In this example the malonate anion is generated by using one molar proportion of sodium ethoxide this is Michael s original method. However, these conditions sometimes lead to competing side reactions and the formation of abnormal reaction products. Better yields of the required product are often obtained with small amounts of sodium ethoxide (the so-called catalytic method) or in the presence of a secondary amine (e.g. diethyl-amine, see below). 

Malonate anions react with the ri2-ethylene-Fe(CO)4 complex to afford after demetallation ethyl malonate derivatives. Reaction of nucleophiles with tetracar-bonyliron-activated c/.Jl-unsatu rated carbonyl compounds leads after protonation of the intermediate alkyl-Fe(CO)4 anions to the products of Michael addition. 

Michael reactions of this sort work best when they follow a catalytic cycle. Malonate anion 28 adds to an enone to give the enolate anion 30 that collects a proton from malonate 27 and forms another molecule of the anion 28 for the next cycle. 

Certain pyrones react with active hydrogen compounds in a quite different way they display their alkenic character by participating in Michael reactions, thus coumarin itself gives 316 with malonate anion, and coumarins 317 react with arylboronic acids catalyzed by rhodium giving 318 in greater than 99% ee <2005OL2285>. 

The mechanism is illustrated with the addition of a malonate anion across the double bond of ethyl cinnamate. The reaction is reversible in protic solvents and the thermodynamically most stable product usually predominates. When organometallic reagents are used as Michael donors (e.g., copper-catalyzed organomagnesium additions) SET-type mechanisms may be operational. 

Retro-aldol and retro-Michael reactions occur under acidic conditions. The mechanisms are the microscopic reverse of the aldol and Michael reactions, as you would expect. One of the most widely used acid-catalyzed retro-aldol reactions is the decarboxylation of jS-ketoacids, malonic acids, and the like. Protonation of a carbonyl group gives a carbocation that undergoes fragmentation to lose CO2 and give the product. Decarboxylation does not proceed under basic conditions because the carboxylate anion is much lower in energy than the enolate product. 

Nucleophilic addition of enolate anions to o , 8-unsaturated carbonyl compounds was first reported in 1887 by the American chemist Arthur Michael. Following are two examples of Michael reactions. In the first example, the nucleophile adding to the conjugated system is the enolate anion of diethyl malonate. In the second example, the nucleophile is the enolate anion of ethyl acetoacetate. 

Addition of a 1,3-diene to a solution of the acyltetracarbonylcobalt complex 4.213 results in insertion, with formation of an ti -allyl complex 4.214 (Scheme 4.77) acylation occurring at the less-hindered terminus of the diene. ° In the presence of a base, the allyl complex undergoes elimination to give an acyl diene 4.215. As the allyl complex is electrophilic, it can also be attacked by some nucleophiles, such as malonate anions and nitronates (see Chapter 9, Section 9.1). Allenes can be used in place of the 1,3-diene (Scheme 4.78). The reaction is especially useful in an intramolecular sense. The products are useful Michael acceptors. ... 

Michael reactions under PTC conditions are also possible, and are exemplified by the addition of the anion of diethyl malonate to the 3-deoxy-3-nitrohexopyrano-side (14) to produce the man/7o-derivative (15). The kinetic rather than the thermodynamic product is formed here, implying a suppression of the reversibility of the addition under these circumstances. A further example, outlined in Scheme 5,... 

Takemoto et al developed a novel bifunctional thiourea catalyst bearing amine moiety (9), which promoted the Michael reaction of malonate with nitroalkenes to give corresponding adducts with high enantioselectivity (Scheme 2.34) [85]. The bifunctional thiourea catalyst is effective for the 1,4-addition of the anion of malonitrile to a,P-unsaturated imide (Scheme 2.35) [86]. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

A variety of cyclopropyl derivatives has been prepared utilizing this methodology from malonic ester anion or related stabilized carbanions and Michael acceptors such as 56,57310 and 58311. The reactions are nonstereospecific in general as expected from the mechanism... 

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