The thesis is devoted to the development of effective and preparatively convenient methods for the synthesis of 6-azaindoles functionalized with trifluoromethyl, difluoromethyl, and formyl groups, and to the study of their chemical properties.
The reaction of [4+1]-cyclization of a number of 3-amino-4-methylpyridines and 3-amino-4-methylquinoline with trifluoroacetic anhydride resulted in the annulation of the 6-azaindole nucleus to obtain new 2,2,2-trifluoro-1-{2-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl}ethanones and 2,2,2-trifluoro-1-{2-(trifluoromethyl)-3H-pyrrolo[2,3-c]quinolin-1-yl}ethanone.
The difference in chemical behavior of isomeric 3-amino-2-methylpyridine, 2(6)-substituted 3-aminopyridines, 3-hydroxy-4-methylpyridine, 4-methylpyrimidine-5-amine and 5-methylpyridazine-4-amine in the [4+1]-cyclization reaction with trifluoroacetic anhydride was studied.
An approach to the synthesis of 6-azaindole-3-carbaldehydes based on the reaction of 3-amino-4-methylpyridines and 3-amino-4-methylquinoline with the Vilsmeier–Haack reagent was developed. It was determined that the presence of substituents in position 2 or 6 significantly affects the course of the formylation reaction and leads to the formation of only N'-(4-methylpyridin-3-yl)-N,N-dimethylformimidates.
It was found that in the case of using such electrophilic reagents as acetic anhydride and trichloroacetic acid in the reaction of [4+1]-cyclization with 3-amino-4-methylpyridine, the formation of the pyrrole nucleus does not occur, and acylated derivatives of aminopyridines were isolated. Whereas in the case of more electrophilic difluoroacetic anhydride, difluoromethyl-substituted 6-azaindole was obtained.
Limitations of the [4+1]-cyclization reaction by only α-unsubstituted pyridines for the formation of the 6-azaindole nucleus were investigated, which is explained by the formation of the N-trifluoroacetylated pyridinium salt which is the key step of the reaction.
It was found that when 2,2,2-trifluoro-1-{2-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl}ethanone is treated with hydrochloric acid, both water molecule and hydrogen chloride are added with the formation of the corresponding hydrate. On the other hand, heating 2,2,2-trifluoro-1-{2-(trifluoromethyl)-6-azaindole in an aqueous solution of sodium carbonate is accompanied by deacylation and formation of 2-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine, further heating of which leads to the formation of 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid.
It was shown that N(1)-methyl-substituted 6-azaindoles differ from N(1)-unsubstituted derivatives by easy reactivity in basic hydrolysis, and 1-methyl-2-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid was thus obtained.
The conditions for the selective reduction of the carbonyl group and the pyridine nucleus of 2,2,2-trifluoro-1-{2-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl}ethanone and of the pyridine nucleus of 2-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine were determined.
The synthesis of 2,2,2-trifluoro-1-{6-methyl-2-(trifluoromethyl)-6H-pyrrolo[2,3-c]pyridin-3-yl}ethanone was performed, and the stability of N(6)-methyl-substituted derivatives to hydrolytic conditions was investigated on its example. It was established that hydrolysis in aqueous sodium carbonate solution stops at the stage of formation of 6-methyl-2-(trifluoromethyl)-6-azaindole-3-carboxylic acid.
Position 3 of the 6-azaindole core was successfully used in electrophilic substitution reactions for oriented structural modification with a bromine atom and a nitro group. Obtained 3-nitro-6-azaindole was selectively reduced to the corresponding amine, which was reacted with 4-methoxybenzoyl chloride to obtain an N-acylated derivative.
Using the example of 6-azaindole-3-carbaldehyde, the synthetic potential of the formyl group was studied, the reduction of which produced (1H-pyrrolo[2,3-c]pyridin-3-yl)methanol. The reactive OH-group of the latter was used in a nucleophilic substitution reaction with diphenylphosphoryl azide for the synthesis of the corresponding azide derivative. 6-Аzaindole-3-methanamine dihydrochloride was obtained by the interaction of 3-(azidomethyl)-1H-pyrrolo[2,3-c]pyridine with triphenylphosphine and subsequent acidification of the reaction mixture with a dioxane solution of HCl.
It was established that the selective oxidation of 6-azaindole-3-carbaldehyde by KMnO4 in an aqueous-acetone solution leads to the formation of 6-azaindole-3-carboxylic acid. 3-Formyl-6-azaindole-4-carboxylic acid was synthesized by alkaline hydrolysis of methyl 3-formyl-1H-pyrrolo[2,3-c]pyridine-4-carboxylate.
