Alkylation of acids

The alkylation of acids with triazenes is superior to alkylation with diazomethane and other diazoalkanes in that the triazenes are crystalline, stable materials which are easy to prepare and store. Alkylations with triazenes are unlikely to be accompanied by side reactions, such as addition to strained or conjugated double bonds, which are frequently observed in alkylations with diazoalkanes. 

Alkylation, of acids, 50,61 with benzyl chloromethyl ether, 52,... 

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

RCu/S(CHj)2. Various alkylcoppers are more thermally stable and also more reactive in dimethyl sulfide than in ether or tetrahydrofuran. This solvent can improve yields in conjugate additions and in alkylation of acid chlorides.2... 

It is not essential for the reaction that the amine be present, as such, before hydrogenation. Any functional group that gives an amine on hydrogenation can be used (Eqn. 19.57). Interestingly, the reductive alkylation of acid hydrazides took place in preference to the hydrogenolysis of the N-N bond when the reaction was run over either platinum or palladium at 75°-100°C and 40 atmospheres pressure (Eqn. 19.58). ... 

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. 

Photoreleasable esters. A method for carboxyl group protection is based on esters obtained by O-alkylation of acids with the phenacyl chloride. The photochemical decomposition that regenerates the acids does not require a photosensitizer. 

Alkylation of acid chlorides to form ketones. Hegedus and co-workers have developed a method for synthesis of ketones from acid chlorides with this complex (1). Treatment of (1) with an organolithium (or Grignard reagent)... 

TDA-1, like Aliquat 336 a cheap and perhaps less toxic substitute for crown ethers, can be used to assist in the formation of phenacyl esters (104) from phenacyl bromides when potassium carbonate is employed as the base.100 An electrochemical procedure for the alkylation of acids by alkyl halides or tosylates gives variable but often excellent yields and could be useful in special... 

Quirion has reported the first application of chiral carboxylic acids as activating agents and chiral inducers for a-lithiation of tetrahydroisoquinolines [67]. The diastereoselective lithiation and alkylation of acid-derived amides 78 provided 79 in 41-57% yields with moderate drs of up to 92 8 (Scheme 22). The chiral auxiliary can be removed under refluxing basic conditions (KOH/MeOH) in 60-70% yields. 

Diazoalkanes 2.8 Selective alkylation of acidic functions in the presence of aliphatic hydroxyls esterification The reaction should be alkyl homogeneous (see Note, procedure 2.8) de-O-acetylation... 

Alkyl aryl triazenes provide an alternative reagent for alkylation of acids via alkyl diazonium ions. The triazenes are stable crystalline materials that can be stored. Reaction with carboxylic acids occurs rapidly to afford the corresponding ester... 

Alkylation of acids may also be accomplished via ester or amide intermediates. See section 113 (Esters from Esters) and section 81 (Amides from Amides)... 

Further examples of the alkylation of esters with halides are included in section 113 (Esters from Esters). Examples of the alkylation of acids with halides are included in section 17 (Carboxylic Acids from Carboxylic Acids)... 

Dtinges, W. (1973) Alkylation of acidic organic compounds for gas chromatographic analysis. Chromatographia, 6,196-197. 

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