Heterocyclic acetic acids, general

In the case of the parent acetylaminosalicylaldehyde, it was stated85 that, under similar conditions, no 3-phenyl-7-aminocoumarin was obtained. Furthermore, this reaction has also been carried out with a number of heterocyclic acetic acids of general formula 205, resulting in the formation of the various 3-heterocyclic-7-amino-substituted coumarins (206). 

The submitters have found the iV-bromosuccinimide procedure to be a very general reaction. Alkyl, alicyolio, aryl and heterocyclic acetic acids have been brominated in 50-80% yield. The reaction may be applied in the presence of labile benzylic hydrogens for example, 3-phenyl-propanoic acid gives exclusively the 2-bromo-3-phenylpropanoyl chloride. The procedure has several significant advantages it is considerably faster than the known methods (overall reaction times of 2 hours are common), the use of bromine is circumvented, and work-up is considerably simplified. 

FIGURE 13.6 General structure for heterocyclic acetic acids. 

A different kind of triazine, 3,5,6-trisubstituted 1,2,4-triazines 166, were prepared by reaction of 1,2-diketones 164 with acyl hydrazide in the presence of ammonium acetate and acetic acid at 180 °C for 5 min under microwave irradiation in a sealed tube [107]. Different substituents can be introduced in the final triazines providing a general approach for this kind of heterocycles (Scheme 59). 

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

Vinamidinium salts are important intermediates in the synthesis of heterocycles. The 2-chloro-l,3-bis(dimethylamino)trimethinium hexafluorophosphate salt has been used in the preparation of the highly selective Cox-2 inhibitor etoricoxib (Scheme 1). This method describes a straight-forward preparation of the hexafluorophosphate salt which is a crystalline, thermally and shock-stable, non-hygroscopic solid. The submitters have extensively studied the preparation of vinamidinium salts and demonstrated that the method is applicable to substituted acetic acids that contain an electron-withdrawing group (Table 1)." The annulation reaction is also general and useful for the preparation of pyridines, pyridones and pyridine N-oxides. ... 

Peroxycarboxylic Acids (1), R(C03H)n (R=alkyl, cycloalkyl, aryl, or heterocyclic n=l or 2) Acid or base hydrolysis with rate decreasing with mw increase dil NaOH decomposes acids yielding O2 dimeric as solids H-bonded in soln pure liq and vap state most powerful oxidizing agents of all peroxides, decompd by irradiation Generally not shock sens deton on heating peroxy formic and acetic acids can explode at —20° stability increases as mw increases... 

Compounds of the type 171 can generally be easily dehydrated and many reactions of isatins lead directly to isatylidene derivatives. Use of active methylene compounds such as malononitrile and cyano-acetate gave compounds of the type 184. Various 4-thiazolidones have been condensed with isatin, generally under acidic conditions, to give 185. " Similar type compounds (186) have been obtained from thianaphthenes and isatin using acetic acid. " These compounds (186) have been used as dyes. Other heterocyclic ketones... 

Thiazolidones are another class of heterocycles that attract much attention because of their wide ranging biological activity [106], They are usually synthesized by three-component condensation of a primary amine, an aldehyde, and mercapto-acetic acid with removal, by azeotropic distillation, of the water formed [107]. The reaction is believed to proceed via imine formation then attack of sulfur on the imine carbon. Finally, an intramolecular cyclization with concomitant elimination of water occurs, generating the desired product. The general applicability of the reaction is limited, however, because it requires prolonged heating with continuous removal of water. To circumvent these difficulties and to speed up the synthesis, Miller et al. developed a microwave-accelerated three-component reaction for the synthesis of 4-thiazolidinones 63 [108]. In this one-pot procedure, a primary amine, an aldehyde, and mercaptoacetic acid were condensed in ethanol under MW conditions for 30 min at 120 °C (Scheme 17.44). The desired 4-thiazolidinones 63 were obtained in 55-91% yield. 

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