Alkylation of carboxylates

1 Mendez, F. Romero, M. d. De Proft, F. Geer-lings, P. The basicity of p-substituted pheno-lates and the elimination-substitution ratio in p-nitrophenethyl bromide a HSAB theoretical study./. Org. Chem. 1998, 63, 5774-5778. 

2 Le Noble, W. J. Conditions for the alkylation of ambident anions. Synthesis 1970, 1-6. 

3 Albanese, D. Landini, D. Penso, M. Hydrated TBAF as a powerful nucleophilic fluorinating agent./. Org Chem. 1998, 63, 9587-9589. 

Fukuhara, T. Yoneda, N. Deiodina-tive fluorination of alkyl iodides with p-iodoto- 

New method of fluorination using KF in ionic liquid significantly enhanced reactivity of fluoride and improved selectivity. J. Am. Chem. Soe. 2002, 324, 10278-10279. 

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Alkylation of Carboxylic Acids With Diazo Compounds... 

Conjugated dienes give 1,4 addition. This reaction has also been performed with salts of carboxylic acids in what amounts to a method of alkylation of carboxylic acids (see also 10-96). ... 

Alkylation of carboxylic acids with diazo compounds... 

Barium oxide and sodium hydride are more potent catalysts than silver oxide. With barium oxide catalysis, reactions occur more rapidly but O-acetyl migration is promoted. With sodiun hydride, even sterically hindered groups may be quantitatively alkylated but unwanted C-alkylation Instead of, or in addition to, 0-alkylatlon is a possibility. Sodium hydroxide is a suitable catalyst for the alkylation of carboxylic acids and alcohols [497J. 

Two methods for converting carboxylic acids to esters fall into the mechanistic group under discussion the reaction of carboxylic acids with diazo compounds, especially diazomethane and alkylation of carboxylate anions by halides or sulfonates. The esterification of carboxylic acids with diazomethane is a very fast and clean reaction.41 The alkylating agent is the extremely reactive methyldiazonium ion, which is generated by proton transfer from the carboxylic acid to diazomethane. The collapse of the resulting ion pair with loss of nitrogen is extremely rapid. 

Scheme 7.102 Polymer-supported O-alkylation of carboxylic acids.

The group of Lindau has demonstrated the effective O-alkylation of carboxylic acids using a polymer-supported O-methylisourea reagent [123], Under conventional conditions, complete esterifications were observed only after refluxing for several hours in tetrahydrofuran, and the acidic work-up required limited the scope of applicable substituents. In contrast, employing microwave heating led to complete esterifications within 15-20 min, with only 2 equivalents of the polymer-bound... 

PP Pfeffer, LS Silbert. Esterification by alkylation of carboxylate salts. Influence of steric factors and other parameters on reaction rates. J Org Chem 41, 1373, 1976. 

Scheme 24 Cathodic alkylation of carboxylic acids to esters R alkyl, aryl, R alkyl, yields 24-96%.

For each alkylated extract, there was an absorption at 1700 cm which was absent in the untreated extract. This absorption may be attributed to esters that form from alkylation of carboxylic acids. This interpretation is consistent with the NMR analysis described below. For each O-alkylated extract, there was an increase in the intensity of the C-H absorption bands at 2800-3000 cm consistent with the introduction of aliphatic carbon. 

Alkylation of Carboxylic Acid Salts Acyloxy-de-halogenation... 

Alkylation of Carboxylic Acids with Diazo Compounds Hydro,acyloxy-de-dlazo-bisubstitution... 

Alcoholysis of trihalides 0-6 Hydrolysis of ortho esters 0-20 Alcoholysis of acyl halides 0-21 Alcoholysis of anhydrides 0-22 Esterification of carboxylic acids 0-23 Transesterification 0-24 Alkylation of carboxylic acid salts 0-25 Cleavage of ethers with anhydrides 0-26 Alkylation of carboxylic acids with diazo compounds... 

Alkylation of carboxylic esters 0-97 Alkylation of aryl esters 0-98 Alkylation and alcoholysis of oxazines... 

This procedure describes the use of pseudoephedrine as a chiral auxiliary for the asymmetric alkylation of carboxylic acid amides. In addition to the low cost and availability in bulk of both enantiomeric forms of the chiral auxiliary, pseudoephedrine, a particular advantage of the method is the facility with which the pseudoephedrine amides are formed. In the case of carboxylic acid anhydrides, the acylation reaction occurs rapidly upon mixing with pseudoephedrine. Because pseudoephedrine amides are frequently crystalline materials, the acylation products are often isolated directly by crystallization, as illustrated in the procedure above. 

Simple alkylations of carboxylate anions, by such alkylating agents as alkyl halides, dialkyl sulphates, and quaternary ammonium compounds, are generally straightforward SN2 reactions, and will not be discussed here. 

Three different strategies are generally used for the attachment of carboxylic acids to resins as benzyl esters (a) acylation of resin-bound benzyl alcohols [38-40], (b) O-alkylation of carboxylates by resin-bound benzylic halides [4143], or (c) O-alkylation of carboxylic acids under Mitsunobu conditions [44,45] (Figure 3.3). These reactions are treated in detail in Section 13.4. 

Esters, which have no possible site of attachment, cannot be directly linked to supports, but may be generated upon cleavage from a support. This cleavage can be mediated by electrophiles, nucleophiles, or oxidants. Only a few examples have been reported of the preparation of esters by O-alkylation of carboxylates by resin-bound alkylating agents, such as sulfonic esters [369-372] or diazonium salts [373] (see also Section 3.13). 

Crosignani, S., White, P.D. and Linclau, B., Microwave-accelerated O-alkylation of carboxylic acids with O-alkylisoureas, Org. Lett., 2002, 4, 2961. 

Solid-liquid phase-transfer catalyzed alkylation of anions. Aliquat 336 is a particularly effective catalyst for alkylation of carboxylate anions (equation 1). The combination of Bu4NBr and Ti02 is slightly less effective (93% yield).6... 

Fig. 7. Triazenes as versatile polymer-supported diazoalkane analogues (resins 10) were obtained from polymeric diazonium salts (resins 9) and releasing carbenium ions upon acidic activation. The reaction can be employed for the alkylation of carboxylic acids with a reaction half life of ca. 5 min.

Protocol for the Alkylation of Carboxylic Acids by Use of Alkylating Resins37... 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

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