Methyl esters, from diazomethane with carboxylic acid

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. 

Whereas all the alkylations in Figure 2.26 take place in basic or neutral solutions, carboxylic acids can be methylated as such with diazomethane (Figure 2.27). The actual nucleophile (the carboxylate ion) and the actual methylating agent (H3C—N+=N) Fig. 2.27. Preparation of are then produced from the reaction partners by proton transfer, methyl esters from carboxylic acids and di azomethane. 

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. 

The reaction of diazomethane with a carboxylic acid is an efficient way to produce a methyl ester however, the procedure is dangerous. Figure 12-25 illustrates the formation of a methyl ester from benzoic acid and diazomethane. 

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. 

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]. 

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. 

The methyl ester (100, R = CH3), derived from this A-nor acid by treatment with diazomethane, is different from the ester (102) obtained either by Favorskii rearrangement of 2a-bromo-5a-cholestan-3-one (101) or by the action of cyanogen azide on 3-methoxy-5a-cholest-2-ene (103) followed by hydrolysis on alumina. The ketene intermediate involved in photolysis of (99) is expected to be hydrated from the less hindered a-side of the molecule to give the 2j -carboxylic acid. The reactions which afford (102) would be expected to afford the 2a-epimer. These configurational assignments are confirmed by deuteriochloroform-benzene solvent shifts in the NMR spectra of esters (100) and (102). ... 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

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. 

Simply heating this white powder with a ketone leads to efficient carboxylation and the unstable keto-acid may be trapped with diazomethane to form the stable methyl ester. The mechanism is presumably very like that drawn above for the transfer of CO2 from carboxybiotin to acetyl CoA, Reactions like this prove nothing about the biochemical reaction but they at least show us that such reactions are possible and help us to have confidence that we are right about what Nature is doing. 

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