Diazomethane methyl esters

Treatment with nitrous acid. Esterification with diazomethane Methyl esters of a-hydroxycarboxylic acids 15,16... 

Although it is seldom used, esterification of pyrimidinecarboxylic acids proceeds normally. Conditions are illustrated by the conversion of pyrimidine-4-carboxylic acid (181 R = H) into its methyl ester (181 R = Me) by methanol/sulfuric acid (47%), methanol/hydrogen chloride (80%), or by diazomethane (ca. 100%) (60MI21300). The isomeric methyl pyrimidine-2-carboxylate is formed by treatment of the silver salt of the acid with methyl iodide. Higher esters, e.g. (182 R = Bu), are usually made by warming the acid (182 R = H) with the appropriate alcohol and sulfuric acid (60JOC1950). 

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). ... 

Viprostol (81) also incorporates a hydroxy group moved to C-16 and protects this from facile metabolic oxidation by vinylation. It is a potent hypotensive and vasodilatory agent both orally and transdermally. The methyl ester moiety is rapidly hydrolyzed in skin and in the liver so it is essentially a prodrug. It is synthesized from protected E-iodo olefin 78 (compare with 75) by conversion to the mixed organocuprate and this added in a 1,4-sense to olefin 79 to produce protected intermediate 80. The synthesis of viprostol concludes by deblocking with acetic acid and then reesterification with diazomethane to give 81 [19]. 

Diazomethane is a yellow gas that is toxic and explosive but that may be handled safely in solution in ether. It reacts immediately with an acid to liberate nitrogen and form the methyl ester. Its reaction with alcohols to form methyl esters requires catalysis by a Lewis acid. The procedures illustrate the use of this reagent as a methylating agent (see Chapter 17, Section III, for preparation of diazomethane). 

The acid (0.1 to 0.5 g) is dissolved or suspended in ether, and the ethereal diazomethane solution is added in small portions with swirling until the yellow color of diazomethane persists and nitrogen gas is no longer evolved. The solution is then warmed on a steam bath briefly to expel the excess reagent and the ether is evaporated to give the desired methyl ester. Examples are given in Table 7.2. 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

One frequently used method for preparing methyl esters is by reaction of carboxylic acids with diazomethane, CH2N2. 

Although the biosynthetic cascade hypothesis predicts the co-occurrence of endiandric acids D (4) and A (1) in nature, the former compound was not isolated until after its total synthesis was completed in the laboratory (see Scheme 6). Our journey to endiandric acid D (4) commences with the desilylation of key intermediate 22 to give alcohol 31 in 95% yield. The endo side chain is then converted to a methyl ester by hydrolysis of the nitrile to the corresponding acid with basic hydrogen peroxide, followed by esterification with diazomethane to afford intermediate 32 in 92% overall yield. The exo side chain is then constructed by sequential bromination, cyanide displacement, ester hydrolysis (33), reduction, and olefination (4) in a straight-... 

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). 

The cthylaluminum dichloride promoted conjugate addition of organocoppcr-tributylphos-phine to the -substituted ( )-Ar-enoyl sultam 7 produced very high diastereoselectivity (88-96% de) and moderate yield (43-86%). The adducts were converted to the corresponding methyl ester 9 upon treatment with methoxymagnesium bromide or diazomethane 34. 

The only other esterification method which rivals the present procedure in convenience, mildness of conditions, selectivity, and yield js the preparation of methyl esters wdth diazomethane [Methane, diazo-] 10 Esterification with trialkyloxonium salts, however, allows... 

Carboxylic acids can be converted to esters with diazo compounds in a reaction essentially the same as 10-15. In contrast to alcohols, carboxylic acids undergo the reaction quite well at room temperature, since the reactivity of the reagent increases with acidity. The reaction is used where high yields are important or where the acid is sensitive to higher temperatures. Because of availability, the diazo compounds most often used are diazomethane (for methyl esters) ... 

For cottonseeds, pyrithiobac-sodium is extracted with acetone-water (4 1, v/v). After filtration, the acetone is removed by evaporation under reduced pressure. The residue is adjusted to pH 1 and extracted with ethyl acetate. The extract is cleaned up by liquid-liquid partitioning and methylated with diazomethane. The methyl ester of pyrithiobac is purified by silica gel column chromatography. Pyrithiobac-methyl is determined by gas chromatography (GC) with nitrogen-phosphorus detection (NPD). 

Photolysis of the salts was followed by diazomethane worknp to yield the corresponding methyl esters. 

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. 

A series of reactions with gases have been selected for the rapid quantification of many of the major products from the oxidation of polyolefins. Infrared spectroscopy is used to measure absorptions after gas treatments. The gases used and the groups quantified include phosgene to convert alcohols and hydroperoxides to chloroformates, diazomethane to convert acids and peracids to their respective methyl esters, sulfur tetrafluoride to convert acids to acid fluorides and nitric oxide to convert alcohols and hydroperoxides to nitrites and nitrates respectively. 

The diketo acids were transformed to their methyl esters under the action of diazomethane (5), SOCl2/CH3OH (102), or methanolic hydrogen chloride (117). Like other benzils, JV-methyloxohydrasteine (109) when... 

Pyrazolopyrazolopyrazines can be prepared from a stereoselective dipolar cycloaddition between the alkene group of 284 and diazomethane (Equation 45). Ten equivalents of diazomethane are used in this reaction when only 1 equiv is used, the corresponding methyl ester of the starting material was formed <20020L773>. 

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