Esterification using diazomethane

Diazomethane is often used to esterify poiar or reactive compounds for mass spectrometry analysis. For example, a urine test for cocaine might involve treating the sample with diazomethane to convert ben-zoylecgonine, the major urinary metabolite of cocaine, to its volatile methyl ester for MS analysis. 

Carboxylic acids are converted to their methyl esters very simply by adding an ether solution of diazomethane. The only byproduct is nitrogen gas, and any excess diazomethane also evaporates. Purification of the ester usually involves only evaporation of the solvent. Yields are nearly quantitative in most cases. 

Diazomethane is a toxic, explosive yellow gas that dissolves in ether and is fairly safe to use in ether solutions. The reaction of diazomethane with carboxylic acids probably involves transfer of the acid proton, giving a methyldiazonium salt This diazonium salt is an excellent methylating agent, with nitrogen gas as a leaving group. 

Step 1 Proton transfer, forming a carboxylate ion and a methyldiazonium ion. 

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The Fischer Esterification 961 Key Mechanism 20-2 Fischer Esterification 962 20-11 Esterification Using Diazomethane 965... 

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... 

Esterification Using Diazomethane 966 Conversion of an Acid Chloride to an Anhydride 1001 Conversion of an Acid Chloride to an Ester 1001 Conversion of an Acid Chloride to an Amide 1002 Conversion of an Acid Anhydride to an Ester 1002 Conversion of an Acid Anhydride to an Amide 1003 Conversion of an Ester to an Amide (Ammonolysis of an Ester) 1003 Transesterification 1008 Saponification of an Ester 1010 Basic Hydrolysis of an Amide 1012 Acidic Hydrolysis of an Amide 1012... 

The asymmetric syntheses of (-)-methyl kaur-16-en-19-oate and (-)-methyl trachyloban-19-oate was achieved by M. lhara and co-workers. One of the last transformations was the deoxygenation of the ketone carbonyl group of the tetracyclic intermediate, which was effected by the Wolff-Kishner reduction. Under the strongly basic conditions the ester functionality was hydrolyzed, so an esterification using diazomethane was necessary as the final step. The major deoxygenated product was (-)-methyl kaur-16-en-19-oate (59%). The minor product was identified as (-)-methyl trachyloban-19-oate (16%). 

Hyperflorin, an antibiotic isolated from St. John s wort Hypericum perforatum L.), has been found on the basis of chemical and spectroscopic evidence to possess structure (639). ° A review on the conformational analysis of bicyclo[3,3,l]nonanes has appeared,and the conformations of l,5-disubstituted-3,7-dimethyIenebicyclo-[3,3,l]nonane derivatives have been shown, on the basis of lanthanide-induced n.m.r. shifts, to be predominantly in the double-chair form. In a notable paper that contains a wealth of information pertinent to adamantane synthesis, it has been reported that bicyclo[3,3,l]nonane-3,7-dicarboxylic acid, its dimethyl ester, and various derivatives exist mainly in the chair-boat conformation. The synthetic entry to these systems is illustrated for the above diester (643) in which the starting point is adamantanone (640) thus, ring expansion with diazomethane followed by SeOj oxidation gave the a-diketone (641) which was cleaved with periodate to give the diacid (642). Esterification using diazomethane gave (643) which exists, as does the diacid, as... 

The way biotin participates in carbon dioxide fixation was established in the early 1960s. In 1961 Kaziro and Ochoa using propionyl CoA carboxylase provided evidence for 14C02 binding in an enzyme-biotin complex. With excess propionyl CoA the 14C label moved into a stable position in methyl malonyl CoA. In the same year Lynen found biotin itself could act as a C02 acceptor in a fixation reaction catalyzed by B-methylcrotonyl CoA carboxylase. The labile C02 adduct was stabilized by esterification with diazomethane and the dimethyl ester shown to be identical with the chemically synthesized molecule. X-ray analysis of the bis-p-bromanilide confirmed the carbon dioxide had been incorporated into the N opposite to the point of attachment of the side chain. Proteolytic digestion and the isolation of biocytin established the biotin was bound to the e-NH2 of lysine. 

Atrazine, alachlor and trifluralin were determined in the extracts of the samples by gas chromatography using a N-P detector. An EC detector was used for the determination of parathion, 2,4-D ester and the 2,4-D acid after esterification with diazomethane. Car-baryl and 1-naphthol were determined colorimetrically by the procedure of McDermott and DuVall (39). 

A similar method of hydrolysis was described for poly( vinyl alcohol) used as a template. In this case, T was -CH2-CH- and, after hydrolysis, poly(vinyl alcohol) and polyacrylic or polymethacrylic acid were obtained. The hydrolyzed product gives the color reaction with I2 in the presence of H3BO3 - specific to poly(vinyl alcohol). The second product of hydrolysis, after esterification by diazomethane, was identified as polyfmethyl methacrylate) by NMR and IR spectrometry. Hydrolysis was also applied in the case of ladder-type polymers obtained by polymerization of mutliallyl monomers. The polymerization should result in polymer consisting, at least partly, ladder-type blocks ... 

Oxidation of the iV-alkoxycarbonyl-2-azabicyclo[2.2.0]hex-5-ene 158 with ruthenium tetroxide followed by esterification with diazomethane affords the cis-2,3-diester of azetidine 159 (R = Me) in 67% overall yield. The N-protecting group can be easily removed from the diacid by acidic hydrolysis to give acidic amino acid 160 in 85% yield. Strangely, the 2,3-diester 159 (R = Me) upon acidic hydrolysis failed to give any of the amino acid. This approach to azetidines is useful because 158 is readily available from pyridine in three steps <2003CPB96>. 

Wood et al. [174] analysed long-chain fatty hydroxy acids. After esterification with diazomethane, hydroxyl groups were silylated with HMDS. DEGS and Apiezon L were used as the stationary phases and even the partial resolution of some diastereoisomers was achieved. TMS esters have similarly been applied to the analysis of resin acids, and retention data have been reported for several of them on SE-30, Apiezon L, QF-1, etc. [175]. 

Esterification with diazomethane [590—593] is another possible derivatization procedure for substituted phosphates. However, it has been used for only a limited number of substrates. Some workers [592] obtained very good quantitative yields with it in comparison with other methods. 

In total synthesis of the structurally unique natural product calcimycin (15), Grieco and others used Ireland-Claisen rearrangement of the ester 17 to synthesize the key intermediate (18)7 (Scheme 1.3g). Monosilylation of the diol 16 followed by treatment with propionyl chloride in pyridine gave rise to the ester 17 in 90% yield. Treatment of 17 with LDA in THF at —78 C, subsequent addition of ferf-butyldimethylsilyl chloride in HMPA, and brief heating of the resulting silylketene acetal provided the corresponding silyl ester. Subsequent hydrolysis of the silyl ester and esterification with diazomethane gave 18 in 90% yield from 17. 

The Diels-Alder cycloaddition reaction of 2,6-dimethyl-1,4-benzoquinone with methyl (ii)-3,5-hexadienoate, carried out in toluene as solvent, gives only traces of the cycloadduct shown in Eq. (5-160), even after seven days. However, when the solvent is changed to water and sodium ( )-3,5-hexadienoate is used as the diene, 77 cmol/mol of the desired cycloadduct is obtained after one hour and esterification with diazomethane [714] f Again, hydrophobic interactions between diene and dienophile in the aqueous medium seem to be responsible for this remarkable and synthetically useful rate acceleration. 

Further general route to 2-alkyl-2-butenolactones via the retro Diels-Alder reaction was developed. Fig, 5, [23]. Hydrolysis of a known lactone (15), subsequent esterification with diazomethane, and treatment with dihydropyran afforded a stereoisomeric mixture of pyranyl ether. Alkylation of the pyranyl ether with various alkyl halide yielded alkylated products (16). The retro Diels-Alder reaction of 16 was performed by heating at 200-280 C in a sealed tube to give 2-alkyl-2-butenolactones (17). The utility of the butenolactones was demonstrated by the synthesis of hinokinin (18) and dehydrolappaol A dimethyl ether (19). Similarly rather mild, simple synthesis of a-methylene-y-alkylbutyrolactones was deviced using dimethylfulvene as a protective group for the double bond, Fig. 6. [24], The... 

The colored acid chloride was developed by Butenandt s group for use in ah investigation of the sex attractant principle secreted by the female silkworm moth, bombykol, which indeed was isolated as the 4 -nitroazobenzene-4-carboxylic ester (2). Twelve milligrams of pure ester, m.p. 95-96°, was isolated from 500,000 pairs of scent glands. Oxidation of 1 mg. of this ester with permanganate in acetone, separation of the colored fragment, and esterification with diazomethane gave an... 

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