Carboxylic acids using cesium salts

Carboxylate anions derived from somewhat stronger acids, such as p-nilrobcnzoic acid and chloroacetic acid, seem to be particularly useful in this Mitsunobu inversion reaction.53 Inversion can also be carried out on sulfonate esters using cesium carboxy-lates and DMAP as a catalyst in toluene.54 The effect of the DMAP seems to involve complexation and solubilization of the cesium salts. 

As a suitable model reaction, the coupling of various substituted carboxylic acids to polymer resins has been investigated by Stadler and Kappe (Scheme 7.8) [28]. The resulting polymer-bound esters served as useful building blocks in a variety of further solid-phase transformations. In a preliminary experiment, benzoic acid was attached to Merrifield resin under microwave conditions within 5 min (Scheme 7.8 a). This functionalization was additionally used to determine the effect of micro-wave irradiation on the cleavage of substrates from polymer supports (see Section 7.1.10). The benzoic acid was quantitatively coupled within 5 min via its cesium salt utilizing standard glassware under atmospheric reflux conditions at 200 °C. 

Especially for large-scale work, esters, may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents54 or with crown ether catalysts.55 The reactivity for the salts is Na+ < K+ < Rb+ < Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due both to high solubility and to the absence of ion pairing with the anion.56 Acetone has been found to be a good solvent for reaction of carboxylate anions with alkyl iodides.57 Cesium fluoride in DMF is another useful combination.58 Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters that can be relatively difficult to prepare by the acid-catalyzed esterification method (Fischer esterification) which will be discussed in Section... 

The benzoic acid was quantitatively coupled within 5 min via its cesium salt by using a dedicated multi-mode batch reactor, carried out in standard glassware under atmospheric reflux conditions. In a more extended study, various substituted carboxylic acids (Fig. 7.7) were coupled to chlorinated Wang resin, employing an identical reaction protocol. In a majority of cases, the microwave-mediated conversion reached at least 85% after 3-15 min. These microwave conditions represented a significant rate enhancement, in contrast to the conventional protocol, which took 24-48 h. The microwave protocol has additional benefits in comparison to the conventional method, as the amounts of acid and base equivalents can be reduced and potassium iodide as an additive can be eliminated from the reaction mixture27. 

Cesium salts of substituted pyridine-3,5-dicarboxylic acids were used first by Krui-zinga and Kellogg for the synthesis of macrocyclic lactones [51]. Kellogg obtained the bis-lactone 46 in a one-pot reaction of the cesium carboxylate 44 and the dibro-mo compound 45 in 85 % yield without application of high dilution conditions [1]. By comparison with other alkali metal carbonates he proved the yield-increasing effect of the cesium ions ... 

Sodium salts of carboxylic acids, including hindered acids, such as mesitoic, rapidly react with primary and secondary bromides and iodides at room temperature in dipolar aprotic solvents, especially HMPA, to give high yields of carboxylic esters. The mechanism is Sn2. Several bases or basic media have been used to generate the carboxylate salt. Sodium salts are often used, but potassium, silver, cesium, and substituted ammonium salts have also been used. An important... 

The heteropolyacids are very soluble in water. They can form sparingly soluble or insoluble salts with ions such as ammonium, cerium, cesium, potassium, silver, and such. The acids are often soluble in organic solvents, such as alcohols, ketones, carboxylic acids, and carboxylic esters. Long-chain tetraalkylammonium salts can also be soluble in organic solvents. In a sense, heteropolyacids are soluble versions of insoluble metal oxide catalysts. They can be used as catalysts both in solution and as solids. A catalyst that is soluble in water would be a solid if used alone or in a hydrocarbon medium. They can also be placed on insoluble supports. In the insoluble forms at least, they offer the advantages of easy separation and recovery for reuse. 

A differently anchored Mukaiyama reagent is the N-methylpyridinium iodide salt 57 [71], which has been obtained by reaction of the Merrifield resin with N-Boc-aminocaproic acid in the presence of cesium carbonate to give the supported ester 55 (Scheme 7.19). Further Boc-deprotection and reaction with 6-chloronicoti-noyl chloride in the presence of Hxinig s base furnished the anchored 2-chloro-pyridine 56, which was transformed into the final N-methylpyridinium salt 57 after N-methylation in neat methyl iodide. This supported reagent has been used in the rapid microwave-assisted esterification of carboxylic acids and alcohols in the presence of triethylamine as base, with dichloromethane as solvent at 80 °C, the products being obtained in high purity after simple resin filtration [72],... 

Saponification with alkali generally used for the removal of methyl and ethyl esters is avoided if instead of simple alkyl esters rather benzyl esters or tert.butyl esters are applied for the protection of carboxyl groups. In addition to acid catalyzed esterification benzyl esters can also be secured by the reaction of cesium salts of (blocked) amino acids with benzyl chloride ... 

Stereospecific conversion of peracetylated hexopyranosyl halides to 1-esters of complex carboxylic acids has been achieved in excellent yields by use of cesium salts cesium salts of amino acids), a method borrowed from peptide chemistry, the "cesium effect" ensuring a strictly 8 2... 

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