Carbanions from malonic ester

Nucleophilic Substitution of xi-Allyl Palladium Complexes. TT-Allyl palladium species are subject to a number of useful reactions that result in allylation of nucleophiles.114 The reaction can be applied to carbon-carbon bond formation using relatively stable carbanions, such as those derived from malonate esters and (3-sulfonyl esters.115 The TT-allyl complexes are usually generated in situ by reaction of an allylic acetate with a catalytic amount of fefrafcz s-(triphenylphosphine)palladium... 

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... 

The synthetic utility of alkylation of enolates is utilized in the syntheses of malonic ester (3.3) and acetoacetic ester (3.2). For example, carbanion generated from malonic ester undergoes an Sn2 reaction with alkyl halide to yield alkyl-substituted malonic ester. The monosubstituted malonic ester still has an active hydrogen atom. The second alkyl group (same or different) can be introduced in a similar manner. Acid-catalyzed hydrolysis or base-catalyzed hydrolysis of mono- or disubstituted derivative of malonic ester followed by acidification gives the corresponding mono- or disubstituted malonic acid, which on decarboxylation yields the corresponding monocarboxylic acid (Scheme 3.3). 

Owing to this dichotomy, a, -unsaturated aldehydes, ketones, or esters can undergo a nucleophilic attack at either the carbonyl carbon or the )S-carbon atom (Scheme 2.29). The first of these reactions is a familiar addition to the carbonyl group (1,2-addition) which leads, in this case, to the valuable allylic alcohols. Even more intriguing synthetic options, however, are offered by the alternative pathway, the 1,4-addition generally known as the Michael reaction. The classic version of this reaction employed stable carbanions such as those generated in situ from malonic ester or nitromethane under the action of bases and in the presence of Michael acceptors, e.g. methyl vinyl ketone 90 ... 

The function of the base is to abstract (step 1) a hydrogen ion from malonic ester and thus generate a carbanion which, acting as a nucleophilic reagent, then attacks (step 2) the conjugated system in the usual manner. 

For example, tertiary p-nitrocumyl halides can act as alkylating agents in high yield. The nucleophile need not be a nitroalkane anion, but can be such anions as thiolate, phenolate, or a carbanion such as those derived from malonate esters. The same... 

One of the most synthetically useful reactions involving organopalladium intermediates is that between rr-allyl complexes and relatively stable carbanions such as those derived from malonate esters and jS-ketoesters. The tt- allyl complexes can be synthesized separately and used in stoichiometric amount or they can be generated in situ by reaction of allylic acetates with a catalytic amount of tetrakis (triphenylphosphine)palladium. In the catalytic version of the reaction, the tt-allyl complex is formed by reaction of the allylic acetate and the Pd(0) species which is regenerated in the elimination step. 

Acetone cyanohydrin nitrate, a reagent prepared from the nitration of acetone cyanohydrin with acetic anhydride-nitric acid, has been used for the alkaline nitration of alkyl-substituted malonate esters. In these reactions sodium hydride is used to form the carbanions of the malonate esters, which on reaction with acetone cyanohydrin nitrate form the corresponding nitromalonates. The use of a 100 % excess of sodium hydride in these reactions causes the nitromalonates to decompose by decarboxylation to the corresponding a-nitroesters. Alkyl-substituted acetoacetic acid esters behave in a similar way and have been used to synthesize a-nitroesters. Yields of a-nitroesters from both methods average 50-55 %. 

When a catalytic amount of base is used, the reaction proceeds with thermodynamic control of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as /i-kctocstcrs or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. Scheme 1.11 provides some examples. 

C—Li bond has greater ionic character, yielding a more carbanion-Uke salt with higher reactivity.On the other hand, carbanions derived from highly acidic species such malonate esters are readily formed under mild conditions and have long been used in the generation of new carbon-carbon bonds. 

The protected malondialdehyde (320) reacts with diethyl malonate to give the substituted malonic ester, so providing access to ethyl 2-oxopyran-3-carboxylate (63JOC1443). The corresponding 6-phenyl derivative results from the reaction of 3-methoxy-l-phenylprop-2-en-l-one with malonate carbanion (64RTC31). 

Table 5-21 shows that the addition of even small proportions of EPD solvents affeets the reaetion rate markedly. The rate acceleration thus obtained is produced by a specific solvation of sodium ion, which tends to dissociate the high-molecular mass ion-pair aggregate of the sodio-malonic ester that exists in benzene solution (degree of aggregation n is equal to 40... 50 in benzene). This indicates that the kinetically active species is a lower aggregate of the free carbanion. Further evidence for a specific cation solvation is derived from the six-fold rate difference observed in tetrahydrofuran (fir = 7.6) and 1,2-dimethoxyethane (fir = 7.2), despite the fact that these two solvents possess nearly equal relative permittivities. The latter solvent is able to solvate sodium ions in the manner shown in Eq. (5-127). Especially noteworthy is the high reactivity exhibited on the addition of dicyclohexyl[18]crown-6. In benzene solution containing only 0.036 mol/L of this crown ether, the alkylation rate is already equal to that observed in neat 1,2-dimethoxyethane [351]. 

Of the very many alkylation methods that have been developed, we can look at only a few first, two classics of organic synthesis, the malonic ester synthesis and the acetoacetic ester synthesis and then, several newer methods. In doing this we shall be concerned not only with learning a bit more about how to make new molecules from old ones, but also with seeing the variety of ways in which carbanion chemistry is involved. 

By the malonic ester and acetoacetic ester we make a-substituted acids and a-substituted ketones. But why not do the job directly 1 Why not convert simple acids (or esters) and ketones into their carbanions, and allow these to react with alkyl halides There are a number of obstacles (a) self-condensation—aldol condensation, for example, of ketones (b) polyalkylation and (c) for unsym-metrical ketones, alkylation at both a-carbons, or at the wrong one. Consider self-condensation. A carbanion can be generated from, say, a simple ketone but competing with attack on an alkyl halide is attack at the carbonyl carbon of another ketone molecule. What is needed is a base-solvent combination that can convert the ketone rapidly and essentially completely into the carbanion before appreciable self-condensation can occur. Steps toward solving this problem have been taken, and there are available methods—so far, of limited applicability— for the direct alkylation of acids and ketones. 

In the first part of the malonic ester synthesis, the a-carbon of the diester is alkylated (Section 19.8). A proton is easily removed from the a-carbon because it is flanked by two ester groups (pK =13). The resulting a-carbanion reacts with an alkyl halide, forming an a-substituted malonic ester. Because alkylation is an Sn2 reaction, it works best with methyl halides and primary alkyl halides (Section 10.2). Heating the a-substituted malonic ester in an acidic aqueous solution hydrolyzes it to an a-substituted malonic acid, which, upon further heating, loses CO2, forming a carboxylic acid with two more carbons than the alkyl halide. 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

PhSSPh with retention/ or photochemically/ Methyl phenyl N-methyl-sulphoximide gives adducts with ketones after conversion into its carban-ion, from which either tertiary alcohols are obtained by Al-Hg reduction under neutral conditions, or alkenes by reduction in aqueous acid, thus providing an alternative to the Wittig methylenation reaction/ Oxosul-phonium ylides formed by N-dimethylation followed by carbanion formation with NaH are useful as alkylidene-transfer reagents/ Uses of sulphoximides in heterocyclic synthesis have been reported methyl phenyl sulphoximide reacts through N with ethoxymethylene malonate esters. ... 

The carbanion derived from dimethyl malonate reacts with the cyclic nitro compounds 422 of ring size 5, 6, 7, 8 and 12 to afford the corresponding esters 423. Acyclic allylic nitro compounds 424 (R = Me, CH2OAC or CC Et) are attacked by bulky nucleophiles, such as dimethyl malonate anion, mainly at the terminal primary carbon atom to give rearranged products 425, whereas smaller nucleophiles, e.g. the anion derived from methyl cyanoacetate, react at the tertiary carbon atom to yield 426409a 453 455. 

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