Esters from carboxylic acids using diazomethane

The main drawback to this reaction is the toxicity of diazomethane and some of its precursors. Diazomethane is also potentially explosive. Trimethylsilyldia-zomethane is an alternative reagent,42 which is safer and frequently used in preparation of methyl esters from carboxylic acids.43 Trimethylsilyldiazomethane also O-methylates alcohols.44 The latter reactions occur in the presence of fluoroboric acid in dichloromethane. 

Diazomethane methylation is a good way of making methyl esters from carboxylic acids on a small scale because yields are excellent and the only by-product is nitrogen. However, there is a drawback diazomethane has a boiling point of-24°C, and it is a toxic and highly explosive gas. It therefore has to be used in solution, usually in ether the solution must be dilute, because concentrated solutions of diazomethane are also explosive. It is usually produced by reaction of N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulfonamide with base, and distilled out of that reaction mixture as an azeotrope with ether, straight into a solution of the carboxylic acid. 

Following are three contributing structures for diazomethane, CHjNj. This molecule is used to make methyl esters from carboxylic acids (Section 17.7C). 

Reaction with Diazomethane (Section 17.7B) Diazomethane is used to form methyl esters from carboxylic acids. The mechanism involves protonation of the diazomethane carbon atom by the carboxylic acid to make a methyldiazonium cation, followed by attack of the resulting carboxylate on the methyldiazonium cation to give the methyl ester and Nj. 

Julia substrate 41 was prepared as follows. Cyclopropylketone 42 was converted to the corresponding /3-ketoester using sodium hydride and dimethyl carbonate. The anion derived from the /3-ketoester was alkylated with allylic bromide 43 to provide 44a. Ester hydrolysis, decarboxylation of the intermediate /3-ketoacid, and esterification of the terminal carboxylic acid using diazomethane, gave ketone 44b (CJH-5). 

Diazomethane is used in the synthesis of methyl esters from carboxylic acids. However, it is exceedingly toxic and highly explosive in the gaseous state (b.p. -24°C) and in concentrated solutions. It is therefore usually generated in dilute ether solution and immediately allowed to react with the acid. This method is very mild and permits esterification of molecules possessing acid- and base-sensitive functional groups, as shown in the following example. 

Polystyrene-bound benzhydryl- or trityl halides react much more rapidly with carboxylates than chloromethyl polystyrene, and the base used to form the carboxylate no longer plays a decisive role in these reactions (see Experimental Procedure 13.7). Support-bound phenyldiazomethanes have been used to prepare esters directly from carboxylic acids under mild reaction conditions. Unfortunately, the diazomethanes required are not easy to prepare, and have not yet found widespread application. 

The method of preparing methyl esters is to treat carboxylic acids with diazomethane (Following fig.). In this method good yields are obtained because nitrogen is formed as one of the products and because it is lost from the reaction mixture, the reaction is driven to completion. However, diazomethane is a very hazardous chemical that can explode, and strict precautions are essential when using it. 

Sulphonic acids are usually esterified with diazomethane [121] by methods analogous to those used for the preparation of esters of carboxylic acids (see p. 54). If the reaction starts from the salts, it is necessary to convert them into acids either by direct acidification or with the aid of a cation-exchange resin in the H+ form. 

Esters can be prepared by acid-catalyzed esterification or by reaction of the acid chloride with the alcohol. In small-scale syntheses, it is often more convenient to prepare the ester by reaction of the carboxylic acid with the appropriate diazo compound. Diazomethane is routinely used for making methyl esters, but more highly substituted esters can be prepared if the corresponding diazo compound is available. Benzhydryl esters, for example, are readily prepared from carboxylic acids by reaction with diphenyldiazomethane ... 

In an early report on peptide hydroxamic acids as metalloprotease inhibitors, the peptide acid (Z-Gly-L-Leu-OH) was converted into the V-hydroxysuccinimide ester using DCC, which was subsequently reacted with hydroxylamineJ10 More reactive condensing reagents such as BOP can form the hydroxamic acid directly from the carboxylic acid and hydroxylamine via an intermediate HOBt ester. A number of hydroxamic acids has been synthesized by the treatment of the corresponding methyl esters with hydroxylamine in the presence of KOH 122 this reaction requires careful choice of reagent concentrations and ratios. In addition, the precursor carboxylic acid is treated with diazomethane to make the methyl ester. The use of diazomethane makes the procedure hazardous, but should be useful in special cases that require a better cost performance. 

Retinoic acid and other retinoid carboxylic acids, however, can be readily converted to derivatives that are suitable for gas chromatography. Many of these applications have used mass spectrometry for detection (see below). Diazomethane is used, at room temperature, to prepare the methyl esters without apparent isomerization. Pentafluorobenzyl esters of retinoic acid and its analogs have also been prepared for GC-MS (280) or HPLC-MS (281). Deuterated analogs of retinoic acid or other retinoid carboxylic acids have been used as internal standards, with mass spectrometric detection (88,282) (reviewed by Napoli [283] and by De Leenheer and Lambert [89]). The pentafluorobenzyl ester of a synthetic retinoid, Ro 13-7410, was analyzed by column switching the peak of interest from a SE54 colunm was cut to an OV 240 column, with subsequent detection by negative ion chemical ionization mass spectrometry (280). 

Formation of esters by reaction of diazoalkanes with carboxylic acids is a mild and often quantitative procedure. It is particularly useful for the preparation of methyl and ethyl [4], benzyl [3, 58], and benzhydryl esters [45, 59, 60], although not on a large scale. The reaction is initiated by proton transfer from the carboxyl group and 0-alkylation is a competing reaction with phenolic acids. Diazoalkanes may also add to carbonyl [61] and olefinic linkages [62]. Thus the shikimic acid derivative (16) with a limited amount of diazomethane at low temperature gives the methyl ester (17) but with an excess of the reagent forms the isomeric pyrazolines (18 and 19) [63, 64]. 

In the event, iodolactonization of the carboxylate salt derived from the ester 458 afforded 459, and subsequent warming of the iodo lactone 459 with aqueous alkali generated an intermediate epoxy acid salt, which suffered sequential nucleophilic opening of the epoxide moiety followed by relactonization on treatment with methanol and boron trifluoride to deliver the methoxy lactone 460. Saponification of the lactone function in 460 followed by esterification of the resulting carboxylate salt with p-bromophenacylbromide in DMF and subsequent mesylation with methanesulfonyl chloride in pyridine provided 461. The diazoketone 462 was prepared from 461 by careful saponification of the ester moiety using powdered potassium hydroxide in THF followed by reaction with thionyl chloride and then excess diazomethane. Completion of the D ring by cyclization of 462 to the keto lactam 463 occurred spontaneously on treatment of 462 with dry hydrogen chloride. 

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