7- Azaindole nitration

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. 

Good evidence for nitration at the 3-position was provided by Clayton and Kenyon. l-Benzoyl-2,5-dimethyl-4-azaindole was nitrated in 60 % yield, and followed with potassium permanganate oxidation in aqueous acetone gave 3-benzamido-6-methylpicolinic acid. Alkaline hydrolysis of the nitration product gave 3-nitro-2,5-dimethyl-4-azaindole (85% yield), which was also obtained by direct nitration of 2,5-dimethyl-4-azaindole in low yield. In addition, reduction gave the 3-amino compound, which was identical to that obtained by catalytic reduction of the product formed by coupling the azaindole with benzenediazonium chloride. 

The series of unsubstituted, 6-chloro-, and 6-methoxy-4-methyl-7-azaindoles were nitrated at —10° to give the corresponding 3-nitro compounds in 56,57, and 60 %yield, respectively. At 0°, the methoxy isomer gave what appeared to be the 1,3-dinitro compound, which decomposed explosively on heating. 

Dimethyl-4-azaindole was found to couple with benzene-diazonium chloride to give the 3-phenylazo compound in 70% yield. It was reduced to the unstable 3-amine which was isolated as l-acetyl-3-acetamido-2,5-dimethyl-4-azaindole. The same compound was obtained by reduction of the nitration product of the parent. A small amount of 3-phenylazo-7-azaindole was obtained under similar conditions. ... 

Reactions with electrophilic reagents take place with substitution at C-3 or by addition at the pyridine nitrogen. All the aza-indoles are much more stable to acid than indole (cf. 20.1.1.9), no doubt due to the diversion of protonation onto the pyridine nitrogen, but the reactivity towards other electrophiles at C-3 is only slightly lower than that of indoles. Bromination and nitration occur cleanly in all four parent systems and are more controllable than in the case of indole. Maniuch and Vilsmeier reactions can be carried out in some cases, but when the latter fails, 3-aldehydes can be prepared by reaction with hexamine, possibly via the anion of the azaindole. Alkylation under neutral conditions results in quatemisation on the pyridine nitrogen and reaction with sodium salts allows A-1-alkylation. Acylation under mild conditions also occurs at N-1. The scheme below summarises these reactions for the most widely studied system - 7-azaindole. Acylation at C-3 in all four systems can be carried out at room temperature in the presence of excess aluminium chloride. ... 

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