Alkyl halides self-condensation

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

C-Alkylation takes place in the reaction of methyl nitroacetate with alkyl halides the products are useful intermediates for preparing amino acids (Eq. 5.1).2 The requisite nitro acetate is prepared by self condensation of nitromethane.3... 

Alkyl- and Atylhydridohalonium Ions. The self-condensation of alkyl halides in strongly acidic media represents a convenient preparative route to symmetric dialkylhalonium ions 127 [Eq. (4.97)]. This reaction involves hydridohalonium ions 126 as intermediates that subsequently undergo nucleophilic attack by excess alkyl halide. 

Disconnection 37 again uses the natural polarity of the carbonyl group but at the next bond 37 since we hope to use some enolate derivative 38 in an alkylation reaction. But—and it is a big but—do not think for a moment that you can make 37 just by mixing the ketone 39 with an alkyl halide and some base. The problem is that the ketone is itself electrophilic and the self-condensation by the aldol reaction (chapter 19) is generally preferred to alkylation. 

The enamines prepared from acetaldehyde or monosubstituted acetaldehydes undergo self-condensation in the reaction mixture very readily so that alkylation is practically impossible. Enamines prepared from disubstituted aldehydes are exclusively iV-alkylated on treatment with aliphatic alkyl halides,218 whereas allyl halides cause... 

Synthesis of aldehydes and ketones. This substance can function as a protected cyanohydrin of formaldehyde in an extension of Stork and Maldonado s synthesis of ketones from aldehydes, RCHO —> RCOR, by way of cyanohydrins (4, 300-301). Thus the anion of 1, generated with LDA, does not undergo self-condensation, but can be alkylated the product on hydrolysis gives the homologous aldehyde of the alkyl halide. Thus the reagent serves as the latent anion of formaldehyde, HC=0. An example is shown in equation (I). 

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. 

Besides the addition of such reagents as halogens, hydrogen halides, or the hypohalous acids, there are other reactions which appear to proceed through addition mechanisms, but the exact course of the process is sometimes considerably obscured. The Friedel-Crafts addition of alkyl halides to olefins (p. 145), the self-condensation of olefins, and the alkylation of isoparaffins are examples in which attack at the double bond seems to be led by a carbonium ion. 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

Quaternary salts, isolation of, 10 Quaternization, by alkyl halides, 2-7 by aryl halides, 7-9 on carbon, 53 definition of, 2 by dimethyl sulfate, 9 electronic effects in, 11 in JV-heterocycles, 16, 38 by heterocyclyl halides, 7—9 isotope effect on, 55 mechanism of, 53-56 by methyl euyl-sulfonates, 9, 10 on oxygen, 52 rates of, 55 reagents for, 2-10 by self-condensation, 8 solvent effect on, 10, 55 solvents for, 10 steric effects on, 12, 13 substituents, influence on, 11, 19, 23 on sulfur, 51 Quinaldine, 4-amino-, 4 Quinazolines, 2-alkyl-, salt formation of, 6... 

In Chapter 1 we mentioned that efficient alkylation of aldehydes and ketones requires essentially quantitative formation of their enolates. When a low concentration of an enolate ion is generated, it may react more competitively with the parent aldehyde or ketone present in the reaction mixture than it does with an alkyl halide. The aldol condensation reaction is this acid- or base-catalyzed self-condensation of... 

Depending on the respective reaction partner, acetic acid esters can react either as C-H acidic compounds or as acylating agents. Both are illustrated by the self-condensation of ethyl [ 1 acetate in the presence of 0.5 equivalent of sodium ethoxide or triphenymethyl sodium to give ethyl [1,3- C2]acetoacetate (Claisen condensation). In the first case, however, because of the relatively low radiochemical yields (40-45%) obtained by this procedure, it is of minor importance for the preparation of labeled ethyl acetoacetate. The deprotonation of alkyl acetates with LiHMDS followed by acylation with unlabeled or labeled acyl halides to labeled give /3-keto esters is discussed in Section 6.4. Claisen condensation of alkyl [ CJacetates with esters lacking a-hydrogens (i.e. ethyl formate, diethyl oxalate, aromatic/heteroaromatic carboxylic acid esters) proceed unidirectionally and are valuable pathways in the synthesis of ethyl [ C]formyl acetate (521. diethyl [ C]-oxaloacetate (53) and ethyl 3-oxo-3-pyrid-3-yl[2- C]acetate (54). The last example... 

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