Carboxylic acids heteroaromatic, oxidation

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. 

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. 

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

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. 

The standard methods of oxidation of pyridines and other heteroaromatic nitrogen compounds malfw use of peroxy (u ids or hydrogen peroxide in carboxylic acid solution. Peracetic acid, peroxymono-phdialic acid and MCraA can all convert simple pyridines to the N-oxides. For example, the pyridine... 

It was reported [39] that osmium tetroxide promoted catalytic oxidative cleavage of ds-stilbene and other olefins. The ds-stilbene catalytic oxidative cleavage gave benzoic acid in 95% yield. The process for the preparation of substituted aromatic and heteroaromatic aldehydes and carboxylic acids by the oxidation of substituted stilbenes has been patented [40]. Stilbenes of various substituents (Ri, R2 = H, Cl-4 alkyl, Cl-4 alkoxy, OH, NO2, CN, COjH, CONH2, SO3H, halogen X = C, N Z = CHO, CO2H ... 

In 2011, Ueyama et al. [68] reported the ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes. The vinylation occurred at the C3-position of the heteroaromatic substrate (Figure 4.34). 

The oxidation of aldehydes to the corresponding carboxylic acids has been widely investigated and numerous procedures are known in aqueous and organic media [33]. Aromatic aldehydes have recently been oxidized at 0-4°C in aqueous performic acid produced by the addition of H2O2 to formic acid [34]. Generally, the carboxylic acid precipitates out of the reaction mixture and can be isolated simply by filtration. When heteroaromatic aldehydes such as formylpyridines, formylquinolines and formylazaindoles are oxidized, the formation of N-oxides is avoided. The use of cosolvents (tetrahydrofuran (THE), Af,A-dimethylformamide (DMF)) gives less satisfactory results. 

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