4- Azaindole- 3-carboxylic acid

In a series of papers on the photochemical synthesis of cyclo-pentadiene and pyrrole derivatives, Siis and Moller reported the preparation of indoles which could not be made by the Fischer method. Primarily, these were indoles with electron-withdrawing substituents in the benzene ring. Included was the synthesis of 4-azaindole-3-carboxylic acid (18, Scheme 2). The reaction was extended to the synthesis of the other three azaindoles. ... 

Sodium hydride (0.36 mmol) was added to 5-hydroxy-7-azaindole (0.36 mmol) dissolved in 1.5 ml DMF at 0°C, then treated with 4-chloro-5-methylpyrrolo[2,l-f] [l,2,4]triazine-6-carboxylic acid ethyl ester (0.32mmol), and stirred 16 hours at ambient temperature. The reaction was quenched with 20 ml saturated NH4C1 solution, then extracted three times with 25 ml EtOAc, and the extract washed with 50 ml brine. The solution was dried, then concentrated, and the residue purified by preparative HPLC, RT = 7.12 minute. 

Azaindoles are nitrated readily by treatment with fuming nitric acid at 0°. In his early work, Fischer nitrated apoharmine, obtaining a high-melting crystalline compound, which reacted with methyl iodide and alkali, to give, presumedly, 3-nitro-6,7-dimethyl-6fl -6-azaindole. The stepwise decarboxylation of harminic acid gives a monocarboxylic acid, 7-methyl-6-azaindole-2-carboxylic acid, which was also nitrated. The position of nitration was not established in either case. 

Carbonation of the sodium salt of 7-azaindole (105, R = H) gives 7-azaindole-3-carboxylic acid (106, R = OH) in low yield. Robison and Robison also prepared it from 7-azaindole-3-carboxaldehyde (105, R = CHO) either by direct oxidation (28 % yield) or through the oxime, which was dehydrated with acetic anhydride to l-acetyl-3-cyano-7-azaindole. This compound was hydrolyzed in water to give 3-cyano-7-azaindole (105, R = CN) in refluxing hydrochloric acid it... 

On exposure to UV radiation in the presence of sodium nitrite, 3-amino-l,6-naphthyridine-4( 17/)-one eliminates a nitrogen molecule being thus converted into 5-azaindole-3-carboxylic acid (1958MI1, 1960JCS1794). 

Catellani [61] reported a palladium/norbomene-catalyzed synthesis of heteroatom-containing o-teraryls from aryl iodides and heteroarenes (including indoles and pyrroles) through double C-H arylation. Fagnou s group [62] applied their own protocol (Pd(II)/Ag(I)/carboxylic acid) to achieve the direct arylation of azaindoles. Itami [63] demonstrated the first iridium-catalyzed C-H arylation of heteroarenes (involving indoles and pyrroles) with aryl halides. 

Frydman et al. condensed ethyl 5-methoxy-6-azagramine-2-carboxylate (135) with diethyl sodiomalonate to give the triester (136) (80%), which was hydrolyzed with hydrochloric acid to the diacid (137) (95%). Treating this with hydrobromic acid gave the 5-hydroxy-6-azaindole, which exists in the lactam form (138). Reduction to the tetrahydrolactam (93, R = C02H), followed by decarboxylation and hydrolysis, provided a novel route to porphobilinogen (92,R = H). 

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