Alkylation of carboxylic acids

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. 

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... 

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... 

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. 

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. 

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

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). 

Scheme 6.35. O-Alkylation of carboxylic acids with S-propargyl xanthates [134],...

The same strategy can be extended to the alkylation of carboxylic acids at the a-carbon. as illustrated in the following example ... 

Mechanism 20-3 Esterification Using Diazomethane 966 20-12 Condensation ofAcids with Amines Direct Synthesis of Amides 966 20-13 Reduction of Carboxylic Acids 967 20-14 Alkylation of Carboxylic Acids to Form Ketones 968 20-15 Synthesis and Use of Acid Chlorides 969... 

Also, reaction of the aminomethyl polystyrene with cyclohexylisocyanate affords a polymer bound urea, which is converted into the carbodiimide using Ph3PBr2. Reaction of the polycarbodiimide with methanol affords an 0-alkylisourea which is used in the 0-alkylation of carboxylic acids. ... 

C. Attack by OCOR at an Alkyl Carbon 10-17 Alkylation of Carboxylic Acid Salts Acyloxy-de-halogenation... 

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