Carboxylic acid anhydrides diazomethane

Oxazoles are prepared from tryptophan loaded Wang resin 53 (Scheme 9.7) The deprotected N-terminal was condensed with carboxylic acids 54 or carboxylic acid anhydrides 55 to give Af-acetyltryptophans 56. The key step involved oxidation of 56 with 2 equiv of DDQ (dichlorodicyanoquinone) in THF H20 (9 1) at room temperature for 15 min, producing the key intermediate 57. Compound 57 underwent cyclocondensation in the presence of triethylamine, CCLj, and triphenylphosphine in acetonitrile at room temperature for 2h to afford the oxazole 58. After cleavage from the resin with 20% TFA in DCM, esterification was carried out using TMS diazomethane to give the final product 59. 

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). 

Illustrating the versatility of C-cyanoglycoside nitrile derivatives, Myers, et ai.,15 formed a diazoketone from the peracetylated C-cyanoglucoside shown. The reaction sequence, illustrated in Scheme 2.2.20, involved the initial hydrolysis of the nitrile to the corresponding primary amide. Subsequent hydrolysis afforded the carboxylic acid. On conversion of the acid to a mixed carbonic anhydride followed by treatment with diazomethane, the desired diazoketone was obtained. 

Nitrocoumarin and hydroxylamine in ethanol yield a 1 2 adduct (20) (see Section II,A,3) which with mineral acid cyclizes to 5-nitro-2,3-dihydro-indoxazene-3-acetic acid (63).21 With diazomethane, 63 yields the methyl ester and with acetic anhydride the JV-acetyl derivative. Oxidation to indoxazene-3-carboxylic acid is successful using selenium dioxide, whereas hydrogenation in the presence of palladium-charcoal brings about ring opening to j3-amino-j3-(2-hydroxy-5-nitrophenyl)propanoic acid. 

Y-carboxylic acid (74) by approaches involving either acyl chlorides (oxalyl chloride route) or mixed carbonic anhydrides (isobutyl chloroformate route) (Scheme 120). An alternative route to (73) involves selective attack at the Y-carbonyl of anhydride (71) with diazomethane however the DON precursor (72) could not be prepared using this method. 

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. 

One-carbon Homologation of Carboxylic Acids. l-[(Tri-methylsilyl)methyl]benzotriazole converts benzoyl chlorides to the corresponding (benzotriazol-l-yl)methyl aryl ketones in high yields (see eq 1). Treatment with triflic anhydride and 2,6-lutidine in CH2CI2 converts these ketones into their enolate triflates in 83-95% yields (eq 4). In the subsequent steps, the triflates are treated with sodium methoxide and then with ethanolic HCl to afford ethyl esters of the corresponding arylacetic acids in 89-98% yields (eq 5). The proposed reaction mechanism involves elimination of trifluoromethanesulfonic acid with sodium methoxide and final alcoholysis of the obtained l-(arylethynyl)benzotriazole intermediates with ethanolic HCl. A comparable classical method for one-carbon homologation of carboxylic acids, the Amdt-Eistert reaction, involves difficult to handle diazomethane and Q -diazoketones. ... 

Both of the previous examples describe the use of achiral dendralenes to synthesize racemic products. In 2007, the Sherburn group illustrated that chiral 3-substituted [3]dendralene 34 allowed for the preparation of enantiomerically pure cycloadducts (Scheme 12.6) [7]. DA addition of maleic anhydride, followed by in situ lactonization, yielded carboxylic acid 36. This was esterified with diazomethane to improve solubility, and then subjected to a high-pressure double DA sequence using 2,6-dimethyl-/ -benzoquinone, forming the C2 symmetric heptacycle 38 in 85% yield. 

In general, only slight modifications to the Amdt-Eistert homologation have been reported. As mentioned previously, classically two equivalents of diazomethane are required due to the production of HCl upon reaction of diazomethane with the acid chloride. Newmann and Beal reported a modification whereby triethylamine is added to capture the released HCl and therefore only one equivalent of diazomethane is required. Another major source of diversity in the reported Amdt-Eistert reactions is in the initial activation of the carboxylic acid. While thionyl chloride is classically used, other reagents that mediate the eonversion of a earboxylic acid to an acid chloride are equally suitable. As reported above, alternative activation methods such as the formation of mixed anhydrides and acyl mesylates are also be applicable. 

Diazomethane is a valuable reagent for one-carbon extension of acyl halides and anhydrides, as well as for ring expansion reactions of cyclic ketones " . It is also widely used in small-scale organic synthesis for the esterification of carboxylic acids and the etherification of phenols, enols and alcohols " . In these reactions, however, CH2N2 installs the label in positions that are potentially metabolically labile and usually unsuitable for use in metabolism smdies. For in vitro studies where metabolism is not an issue, tritiated diazomethane is usually preferred because of its higher specific activity. 

Trifluoroacetates of 18 steroids were analysed by Voelter et al. [353] on OV-17, OV-1 and XE-60 stationary phases and compared with the results for TMS derivatives. On the first two stationary phases TFA derivatives have shorter retention times, whereas on XE-60 the reverse applies. With the use of the FED, TFA derivatives gave 30—50% higher responses. These derivatives were also applied to the analysis of the bile acids [354]. In order to eliminate the treatment with diazomethane, the carboxyl group of bile acids was blocked by the reaction with hexafluoroisopropanol, as follows. A 100-pl volume of hexafluoroisopropanol and 200 pi of trifluoroacetic anhydride were added to the dried extract of bile acids and the mixture was heated at 37° C for 30 min. The mixture was evaporated under reduced pressure at room temperature and the residue dissolved in 100 pi of acetonitrile 5 pi were analysed on a 2 m X3 mm I.D. column packed with 1% QF-1 on Chromorosb W (80 100 mesh). As the FID was applied, a high ECD response was not used to advantage. 

In the case where liquid chromatography is not available, acidic herbicides need to be derivatized because they can dissociate in water and are not usually volatile to be analyzed by gas chromatography. The basic methods used for chlorophenoxy acid herbicides are esterification, silylation, and alkylation, as described in a recent exhaustive review.The derivatization step is performed after preconcentration and cleanup. The step consists of the formation of esters and ethers from the carboxyl and phenol groups of the acidic herbicides. A lot of reagents and chemical mechanisms can be used to perform derivatization reactions. The most employed derivatization reagents are diazomethane, methyliodide, trimethylsulfonium (or anilinium) hydroxide, bis (trimethylsilyl) trifluoroacetamide (BSTFA), pentafluorobenzyl bromide, and anhydride acetate. It should be noted that explosive and hazardous diazomethane was replaced by safer agents. Authors also underline that surface water generally contains humic substances, which can interfere with the derivatization reaction. ... 

The Wittig methodology applied to the synthesis of 7.162 can be used in a variety of situations. Aldehyde 7.165, for example, was converted to 7.166 [methyl 8-(2-N-benzenesulfonylamino-l-cyclopentyl)oct-6-enoate] via a Wittig reaction and diazomethane estetiHcation. The corresponding acid of 7.166 was converted to its sodium carboxylate, and was shown to inhibit arachidonic acid induced blood platelet aggregation in rabbits. A quite different approach converted anhydride 7.167 to 7.168. Note the similarity to cleavage of bicyclic derivatives in section 7.1.B (see 7.75 and 7.78). 

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