Carboxylic esterification with diazomethane

Two methods for converting carboxylic acids to esters fall into the mechanistic group under discussion the reaction of carboxylic acids with diazo compounds, especially diazomethane and alkylation of carboxylate anions by halides or sulfonates. The esterification of carboxylic acids with diazomethane is a very fast and clean reaction.41 The alkylating agent is the extremely reactive methyldiazonium ion, which is generated by proton transfer from the carboxylic acid to diazomethane. The collapse of the resulting ion pair with loss of nitrogen is extremely rapid. 

Modifications at the carboxyl group include reduction (with dibor-ane260 or borohydride, after activation with soluble carbodiimide261,262), esterification (with diazomethane,101,223,283,264 or acyl or aryl chlorides224,264), and formation of amide esters.263,265... 

Pyrrole-2-carboxylic acid esters have been prepared from ethyl chloroformate and pyrrolylmagnesium bromide1 2 or pyrrolyllithium,3 by hydrolysis and decarboxylation of dimethyl pyrrole-1,2-dicarboxylate followed by re-esterification of the 2-acid4 and by oxidation of pyrrole-2-carboxaldehyde followed by esterification with diazomethane.4... 

Again the diol is oxidized to the carboxylic acid with Ru04 generated from RuC13 and NaI04. Subsequent esterification with diazomethane (see Chapter 13) yields 12 in 64 % over two steps. 

Tolmetin, an anti-inflammatory drug, and its metabolites were chromatographed after esterification of the carboxyl group with diazomethane [564], The extraction was performed with diethyl ether and was followed by purification and analysis on 3% of OV-17. The determination of pethidine in plasma [565] involves extraction, purification of the extract by partition chromatography and derivatization, which is performed by treatment with trichloroethyl formate in the presence of anhydrous sodium carbonate. The detection limit with an ECD was reported to be 5 pg. 

O-substituted derivatives of methyl a-90 and /3-D-gl ucopy ranos ides into a carboxyl group,91 to give, after esterification with diazomethane, high yields of the corresponding methyl (methyl D-glucopyranosid)uron-ates. 

The asymmetric cyclization of 2[( )-3-pentenyl]phenol (1) performed with (f/3-pinene)palladium acetate (see Section 4.6.2.2.2.) in the presence of copper(II) acetate in methanol under an oxygen atmosphere, gives 3,4-dihydro-2-vinyl-27/-1 -benzopyran (2) in 64% yield and 25% ee87. The enantiomeric excess is determined by H-NMR analysis, in the presence of Eu(tfc)3, of methyl 3,4-dihydro-2//-1 -benzopyran-2-carboxylate, derived from 2 by oxidation with potassium permanganate, followed by esterification with diazomethane. 

The reactions illustrated in equations (62-64) are each catalyzed by rhodium acetate. Diazo compounds, especially diazoalkanes, can also react by a simple ionic mechanism. The esterification of a carboxylic acid with diazomethane is a familiar example. The ionic pathway is especially likely when the intermediate carbocation would be stabilized. Thus, diazine (158) couples smoothly with phenols, presumably by thermal rearrangement to the corresponding diazo sugar, followed by acid-catalyzed N2 loss... 

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... 

Photolysis of ammonium salts of prochiral acids 255 and 256 may lead to a mixture of two diastereoisomers. When photolyzed in acetone solution, the optically active salts of 255 or 258 with proline tert-butylester provide only racemic products. However, photolysis of the chiral crystals, followed by esterification of the carboxylic group with diazomethane after acidification, affords the chiral photoproducts 257 and 259, respectively, in over 95% ee [196]. From the absolute configuration of the new asymmetric centers and X-ray analysis of the starting salts, it became apparent that both salts reacted in such a way that interaction between the carboxy substituents was minimized in the benzo-vinyl bridging transition state. 

Esterification with diazomethane is employed for the profiling of carboxylic acids in body fluids [164, 165]. The mass spectra of organic acid methyl esters show a variety of structurally informative base peaks compared with the corresponding TMS esters. However, artefacts are produced on reaction of diazomethane with 2-keto acids and 2,3-unsaturated acids [166, 167]. The methyl esters also have the disadvantage of providing low molecular weight increments, especially for the low molecular weight volatile acids such as lactic acid. 

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. Acetone has been found to be a good solvent for reaction of carboxylate anions with alkyl iodides.Cesium fluoride in DMF is another useful combination. 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 3.4.2. Sections F and G of Scheme 3.2 give some specific examples of ester synthesis by the reaction of carboxylic acids with diazomethane and by carboxylate alkylation. 

Two other related compounds were isolated from a different colony of the same species growing in a separate district. Endiandric acid B, ( )-4-(6 -phenyl-tetracyclo-[5,4,2,0 ]trideca-4, 6 -dien-l r-yl)but-2-enoic acid (116), was purified from the small amount of co-existing endiandric acid A (115) by esterification with diazomethane, separation, and subsequent hydrolysis (4). Chemical and spectroscopic evidence proved that endiandric acid B was a vinylog of endiandric acid A. The structure of the other compound, abbreviated as acid C, was determined by H-NMR spectroscopy and also by X-ray crystallography on a Diels-Alder adduct with A-methyl-maleimide as 4-[(E, E )-5 -phenylpenta-2, 4 -dien-r-yl]tetracyclo-[5,4,0,0 , 0 ]undec-10-ene-8-carboxylic acid (117) (6). 

A suitable method for determining the anhydride group is titration with aqueous potassium hydroxide in pyridine after previous esterification of the carboxyl group with diazomethane. This esterification is carried out in diethyl ether methanol (9 + 1). After methylation, which takes about 10 minutes for 0.5 g of sample, solvents are removed by evaporation and a portion of the derivatised polymer is dissolved in pyridine and titrated. In the IR spectra of the resin before and after methylation, the absorption band of the acid group at 1710 cm (5.84 pm) disappears and a carbonyl band of the ester at 7104 cm (5.74 pm) is formed. The acid content of the sample is found from the difference in titres of an unmethylated and a methylated product. 

Nine years after Queguiner paper the Shlosser group have studied lithiation of another trifluoromethyl-substituted pyrimidines [761]. According to in situ trapping method for pyrimidine 1247 with trimethylsilyl chloride no silylated pyrimidine was detected in the reaction mixture, only dimer 1248 was isolated in low yield. But consecutive treatment of 1247 with butyllithium in toluene at -90 °C leads to bromo/Uthium permutation. Subsequent reaction with carbon dioxide followed by neutralization and esterification with diazomethane afforded methyl 4-(trifluoro-methyl)pyrimidine-2-carboxylate 1250 in 36 % yield (Scheme 276). 

It is evident that the elimination of adsorption is essential for the full utilization of zone electrophoresis. When the supporting medium has a charge opposite to that of the substances, it is probable that electrostatic forces are in part responsible for the adsorption. In this institute an attempt has been made to reduce the number of charged groups in paper by esterification of carboxyl groups with diazomethane (Porath and... 

The e.e. values were determined by gas chromatography on p-cyclodextrin phases after hydrolysis to the carboxylic acid and esterification with diazomethane [25]. 

The scope of the multi-residue method is extended permanently by testing and then including further active substances that can be determined by GC. Acidic analytes (such as phenoxyacetic acids or RCOOH metabolites) are included into the homogeneous partitioning by acidifying the raw extracts to a pH below the pKs value of the carboxylic acids. To include these analytes in the GC determination scheme they have to be derivatized with diazomethane, diazoethane, trimethylsilyldiazomethane, acidic esterification or benzylation, or by silanizing the COOH moiety. 

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