Carboxylic heteroaromatic

Hydrazides of vicinal acetylene-substituted derivatives of benzoic and azole carboxylic acids are important intermediate compounds because they can be used for cyclization via both a- and /3-carbon atoms of a multiple bond involving both amine and amide nitrogen atoms (Scheme 131). Besides, the hydrazides of aromatic and heteroaromatic acids are convenient substrates for testing the proposed easy formation of a five-membered ring condensed with a benzene nucleus and the six-membered one condensed with five-membered azoles. 

It is appropriate to add here some comments on diazotization in anhydrous carboxylic acids. They may be relevant for the diazotization of heteroaromatic amines carried out in acetic acid/propionic acid mixtures (Sec. 2.2). Extensive studies by Casado et al. (1983, 1984) showed that in nitrosation of secondary amines the nitrosyl ion, nitrosyl acetate, and dinitrogen trioxide are formed, and all three may act as nitrosating agents. The results do not, however, account for the considerable improvement that is claimed in the patent literature (Weaver and Shuttleworth, 1982) to result from the addition of carboxylic acids in the diazotization of heteroaromatic amines. 

Various heterocyclic moieties have been incorporated at the glyphosate carboxylate center as potential "masked" carboxyl derivatives 62. All of those reported to date contain a fully unsaturated heteroaromatic ring. 

Lonza, for example, has commercialized processes for highly chemo- and regioselective microbial ring hydroxylation and side-chain oxidation of heteroaromatics (see Fig. 2.32 for examples) (Kiener, 1995, 1999). The pharmaceutical intermediate 5-methylpyrazine-2-carboxylic acid, for example, is manufactured by microbial oxidation of 2,5-dimethylpyrazine. Many conversions of the type shown in Fig. 2.32 would not be possible by conventional chemical means. 

Conjugation with amino acids is a major route of metabolism for carboxylic acids including aromatic, heteroaromatic, arylacetic, cinnamic, and arylox-yacetic acids. Although a wide range of amino acid conjugates has been ob-... 

The development of diversification linkers allows introduction of an additional element of diversity. Upon completion of the synthesis sequence, the linker is activated facilitating nucleophilic release of the library members from support In the ideal case, as implemented with the acylsulfonamide linker (Scheme 4a), the activated linker is sufficiently reactive that limiting amounts of nucleophile may be added to provide pure product after resin filtration.181 Diversification linkers have been developed for the preparation of carboxylic acid derivatives (Scheme 4a), amines (Scheme 4b),191 aromatic (Scheme 4c) and even heteroaromatic compounds (Scheme 4d).1101... 

Few examples of preparatively useful intermolecular C-H insertions of electrophilic carbene complexes have been reported. Because of the high reactivity of complexes capable of inserting into C-H bonds, the intermolecular reaction is limited to simple substrates (Table 4.9). From the results reported to date it seems that cycloalkanes and electron-rich heteroaromatics are suitable substrates for intermolecular alkylation by carbene complexes [1165]. The examples in Table 4.9 show that intermolecular C-H insertion enables highly convergent syntheses. Elaborate structures can be constructed in a single step from readily available starting materials. Enantioselective, intermolecular C-H insertions with simple cycloalkenes can be realized with up to 93% ee by use of enantiomerically pure rhodium(II) carboxylates [1093]. 

In this review reactions are described which start from AAs, some j8-AAs, and unsaturated AAs. Aromatic AAs having the amino and carboxylic group attached directly to the aromatic or heteroaromatic ring are not included. 

The oxidative decarboxylation of carboxylic acids is the most convenient source for the alkylation of protonated heteroaromatic bases owing to their easy availability and the high versatility of the reaction, which permits methyl, primary, secondary, and tertiary alkyl radicals to be obtained under very simple experimental conditions. The following methods have been utilized. 

The mechanism of the photochemical alkylation shows particular characteristics as regards the formation of alkyl radicals, the reaction of these radicals with the heteroaromatic substrates, and the rearomatization of the intermediate products. A variety of alkylating agents (hydrocarbons, alcohols, amines, carboxylic acids, amino acids) have been used for photochemical and y-ray-induced alkylation. " ... 

Radicals similar to carbamoyl are the alkoxycarbonyl radicals, ROCO. Also, these radicals were successfully used to carboxylate protonated heteroaromatic bases with good yields and selectivity. " ... 

The usual sources used for the homolytic aromatic arylation have been utilized also in the heterocyclic series. They are essentially azo- and diazocompounds, aroyl peroxides, and sometimes pyrolysis and photolysis of a variety of aryl derivatives. Most of these radical sources have been described in the previous review concerning this subject, and in other reviews concerning the general aspects of homolytic aromatic arylation. A new source of aryl radicals is the silver-catalyzed decarboxylation of carboxylic acids by peroxydisulfate, which allows to work in aqueous solution of protonated heteroaromatic bases, as for the alkyl radicals. 

A variety of methods have been developed for the preparation of substituted benzimidazoles. Of these, one of the most traditional methods involves the condensation of an o-phenylenediamine with carboxylic acid or its derivatives. Subsequently, several improved protocols have been developed for the synthesis of benzimidazoles via the condensation of o-phenylenediamines with aldehydes in the presence of acid catalysts under various reaction conditions. However, many of these methods suffer from certain drawbacks, including longer reaction times, unsatisfactory yields, harsh reaction conditions, expensive reagents, tedious work-up procedures, co-occurrence of several side reactions, and poor selectivity. Bismuth triflate provides a handy alternative to the conventional methods. It catalyzes the reaction of mono- and disubstituted aryl 1,2-diamines with aromatic aldehydes bearing either electron-rich or electron-deficient substituents on the aromatic ring in the presence of Bi(OTf)3 (10 mol%) in water, resulting in the formation of benzimidazole [119] (Fig. 29). Furthermore, the reaction also works well with heteroaromatic aldehydes. 

Kiener, A. (1992) Enzymic oxidation of methyl groups on heteroarenes. A versatile method for the preparation of heteroaromatic carboxylic acids. Angew. Chemie... 

As already indicated for acrolein and for the five-membered heteroaromatic rings (e.g. furan Fig. 2.11), resonance may also be important between nonbonded electrons on a single atom and a 7T-bond system. For example, an unshared electron pair of oxygen greatly contributes to the stabilization of the carboxylate anion ... 

With aromatic and heteroaromatic aldehydes,193 4-oxo-6,7,8,9-tetra-hydro-4T/-pyrido[l,2-a]pyrimidines yielded the 9-arylmethylene derivatives,133,266 whereas with glyoxylic acid the 9-carboxymethylene derivative was formed.266,267 The primary addition product (237) could be isolated from the reaction mixture of ethyl 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidine-3-carboxylate and benzaldehyde. On dehydration the addition product (237) gave the 9-benzylidene compound.266 The 9-carboxymethylene derivatives may be transformed by catalytic hydrogenation to the 9-acetic acids, which can be esterified.266,267... 

The reagent is generally useful for conversion of aromatic, heteroaromatic, and aliphatic aldehydes into the homologous carboxylic acid in satisfactory yield.1... 

In some cases the application of a basic catalyst can be followed by further oxidation of dihydropyrimidene-2-thiones, yielding heteroaromatized heterocycles [60, 61]. For example (Scheme 3.14), it was shown that the reaction of 4-oxo-4-arylbut-2-enoic acids 45 with thiourea 28 in the presence of sodium hydroxide led to 2-mercapto-6-arylpyrimidine-4-carboxylic acids 46 [60], while their dihydro analogues were not isolated. 

Treatment of arylidenepyruvic acids 236 with 5-amino-3-arylpyrazoles 222 (R is Ar, Ri is H) in most cases was not regioselective and yielded mixtures of several regioisomers and products of their heteroaromatization 2,7-diaryl-4,7-dihydropyrazolo[l,5-tf]pyrimidine-5-carboxylic acids 246 (main product), 3,4-diaryl-4,7-dihydropyrazolo[3,4-Z ]pyridine-6-carboxylic acids 247 and their heteroaromatized derivatives 248 (Scheme 3.68). 

Chebanov et al. [202] noted that condensation of the unsaturated acids 236 with 5-aminopyrazoles 220-222 never yielded isomers with opposite location of the aryl and carboxyl groups on the pyridine or pyrimidine rings, respectively. In the case of the multicomponent reaction of aminopyrazoles 220-222 with pyruvic acid 239 and aromatic aldehydes a different direction was observed. Refluxing of the starting materials in acetic acid led exclusively to pyrazolo[3,4-Z ]pyridine-4-carboxylic acids 249-251 instead of the anticipated carboxylic acids 243-248 (Scheme 3.69). The three-component procedures led only to the formation of heteroaromatized compounds even under a nitrogen atmosphere [202]. 

In a convenient experimental procedure, nitrogen heterocycles 3 are alkylated by a mixture of a carboxylic acid 4 and [bis(trifluoroacetoxy)iodo]benzene in boiling benzene or under irradiation in dichloromethane at room temperature (Scheme 2) [11, 12]. A similar procedure has been used for the stereoselective synthesis of C-nucleosides and their analogs via photolysis of the gulonic acid derivatives, (diacetoxy)iodobenzene, and the appropriate heteroaromatic bases [13]. 

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