Carboxylic Acids, isolation from salts

Pravastatin was isolated as products of enzymatic hydroxylation by some kinds of microorganisms of [lS-[l-a(R ),7p,8P(2S, 4S )8a 3]]-2-methylbutanoic acid l,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2))-pyran-2-yl)ethyl]-l-naphthalenic lactone (campactin) or their carboxylic acid or their salts (products of animal metabolism of microorganisms from the genera Nocardia, Streptomyces et cetera). 

Due to the attractivity of this method several groups have developed onium salt supported versions of classical reactions. For example, starting from hydroxyl derived imidazolium salts, formation of supported acrylates with acryloyl chloride followed by reaction with diene in refluxing toluene afforded Diels Alder adduct in good yields (>65%). After saponification, products are isolated without further purification [127], Alternatively, starting from carboxylic acid derived imidazolium salts, acyl chloride formation with thionyl chloride in acetonitrile, followed by reaction with 4-aminophenol led to supported N-arylamide. Williamson alkylation using NaOH as a base and subsequent cleavage from the onium salt support under acidic condition (HCI/I I2()/ AcOH) allowed for isolation of various alkoxy substituted anilines with >98% purity... 

Practically all pyridazine-carboxylic and -polycarboxylic acids undergo decarboxylation when heated above 200 °C. As the corresponding products are usually isolated in high yields, decarboxylation is frequently used as the best synthetic route for many pyridazine and pyridazinone derivatives. For example, pyridazine-3-carboxylic acid eliminates carbon dioxide when heated at reduced pressure to give pyridazine in almost quantitative yield, but pyridazine is obtained in poor yield from pyridazine-4-carboxylic acid. Decarboxylation is usually carried out in acid solution, or by heating dry silver salts, while organic bases such as aniline, dimethylaniline and quinoline are used as catalysts for monodecarboxylation of pyridazine-4,5-dicarboxylic acids. 

Reactant and product structures. Because the transition state stmcture is normally different from but intermediate to those of the initial and final states, it is evident that the stmctures of the reactants and products should be known. One should, however, be aware of a possible source of misinterpretation. Suppose the products generated in the reaction of kinetic interest undergo conversion, on a time scale fast relative to the experimental manipulations, to thermodynamically more stable substances then the observed products will not be the actual products of the reaction. In this case the products are said to be under thermodynamic control rather than kinetic control. A possible example has been given in the earlier description of the reaction of hydroxide ion with ester, when it seems likely that the products are the carboxylic acid and the alkoxide ion, which, however, are transformed in accordance with the relative acidities of carboxylic acids and alcohols into the isolated products of carboxylate salt and alcohol. 

After identifying the optimal etherification conditions, our attention turned to isolation of 18 in diastereomerically pure form. Diastereomers 18 and 19 were not crystalline, but, fortunately, the corresponding carboxylic acid 71 was crystalline. Saponification of the crude etherification reaction mixture of 18 and 19 with NaOH in MeOH resulted in the quantitative formation of carboxylic acids 71 and 72 (17 1) (Scheme 7.22). Since the etherification reaction only proceeded to 75-80% conversion, there still remained starting alcohol 10. Unfortunately, all attempts to fractionally crystallize the desired diastereomer 71 from the crude mixture proved unfruitful. It was reasoned that crystallization and purification of 71 would be possible via an appropriate salt. A screen of a variety of amines was then undertaken. During the screening process it was discovered that when NEt3 was added... 

Irradiation of matrix-isolated imidazole-2-carboxylic acid gave the 2,3-dihydro-imidazol-2-ylidene-C02 complex (31) characterized by IR spectroscopy and calculated to lie 15.9 kcal mol above the starting material. A series of non-aromatic nucleophilic carbenes (32) were prepared by desulfurization of the corresponding thiones by molten potassium in boiling THF. The most hindered of the series (32 R = Bu) is stable indefinitely under exclusion of air and water and can be distilled without decomposition. The less hindered carbenes slowly dimerize to the corresponding alkenes. Stable aminoxy- and aminothiocarbenes (33 X = O, S) were prepared by deprotonation of iminium salts with lithium amide bases. The carbene carbon resonance appears at 260-297 ppm in the NMR spectrum and an X-ray structure determination of an aminooxycarbene indicated that electron donation from the nitrogen is more important than that from oxygen. These carbenes do not dimerize. 

The formation of lead salts in situ from PbsOi and carboxylic acids is a further variant which avoids the rather tedious operations of preparation and isolation of the salts. 

Dinitrocubane (28) has been synthesized by Eaton and co-workers via two routes both starting from cubane-l,4-dicarboxylic acid (25). The first of these routes uses diphenylphos-phoryl azide in the presence of a base and tert-butyl alcohol to effect direct conversion of the carboxylic acid (25) to the tert-butylcarbamate (26). Hydrolysis of (26) with mineral acid, followed by direct oxidation of the diamine (27) with m-CPBA, yields 1,4-diiutrocubane (28). Initial attempts to convert cubane-l,4-dicarboxylic acid (25) to 1,4-diaminocubane (27) via a Curtins rearrangement of the corresponding diacylazide (29) were abandoned due to the extremely explosive nature of the latter. However, subsequent experiments showed that treatment of the acid chloride of cubane-l,4-dicarboxylic acid with trimethylsilyl azide allows the formation of the diisocyanate (30) without prior isolation of the dangerous diacylazide (29) from solution. Oxidation of the diisocyanate (30) to 1,4-dinitrocubane (28) was achieved with dimethyldioxirane in wet acetone. Dimethyldioxirane is also reported to oxidize both the diamine (27) and its hydrochloride salt to 1,4-dinitrocubane (28) in excellent yield. ... 

Completion of the synthesis of quinapril involves amide bond formation between 26 and a tetrahydroisoquinoline fragment. Two complementary protected 1,2,3,4-tetrahydro-3-isoquinoline subunits 27 and 28, each available in a single step from commercially available (6)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, were utilized (Scheme 10.7). Coupling with 26 using DCC and HOBt in dichloromethane afforded the penultimate compounds 29 and 30 as maleate salts. Cleavage of the f-butyl ester of 29 and treatment with HCl provided quinapril. Alternatively, hydrogenation of 30 under standard conditions cleanly removed the benzyl ester, and quinapril (3) was isolated after formation of the hydrochloride salt. 

A-Acyloxypyridinium salts can be isolated from the reaction of A-oxides with acid anhydride by the inclusion of a strong acid possessing a non-nucleophilic anion, e.g. HCIO4. Such acids will protonate the initially formed carboxylate ion and provide a stable anion for salt formation (Scheme 115) (65JOC1909). 

Attempts to prepare fluorothiophenes from diazonium salts (the fluoro-borate and hexafluorophosphate salts) have met only variable success. Methyl 3-fluorothiophene-2-carboxylate (32) was obtained in 89% yield by this method (Scheme 12), but the 3-diazonium salt of the corresponding 4-ester could not be isolated. Furthermore, the methyl ester of 2-diazothiophene-3-carboxylic acid coupled before decomposition could be attempted [85H(23) 1431]. 

Salts of aliphatic or aromatic carboxylic acids can be converted to the corresponding nitriles by heating with BrCN or CICN. Despite appearances, this is not a substitution reaction. When Rl4COO" was used, the label appeared in the nitrile, not in the C02,753 and optical activity in R was retained.754 The acyl isocyanate RC0N=C=0 could be isolated from the reaction mixture hence the following mechanism was proposed 753... 

Carboxylic acids often have been identified by means of paper chromatography Clarke and Bazill (10) have extracted plasticizers from polyvinyl chloride first with ether and then with methanol. Subsequently the extracts were saponified with alcoholic potassium hydroxide, and the precipitated potassium salts were isolated and converted into free acids. These, in alcoholic solution, were then applied to paper and chromatographed ascendingly with a mixture of butanol, pyridine, water, and ammonia the migration period was about six hours. A number of additional color tests facilitated identification of unknown acids. 

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