Preparation of the isomeric azaindoline family by intramolecular carbolithiation

An operationally convenient, one-pot, three-step sequence has been developed that provides access to 3-substituted 4-, 5-, 6-, and 7-azaindolines (2,3-dihydro-1H-pyrollopyridines) via intramolecular carbolithiation of the aryllithium derived from an appropriate (N,N-diallylamino)bromopyridine. Whereas cyclization proceeds as expected to give 1-allyl-3-methyl-4-azaindoline and 1-allyl-3-methyl-6-azaindoline following protonation of the 3-CH2Li group of the azaindoline, the isomeric 3-methyl-5-azaindoline and 3-methyl-7-azaindoline are generated as 3-methyl-N-allyl anions prior to quench with MeOH.     

7-azaindole derivatives

A new method for synthesizing 5- and 7-azaindoles is given, -Chlorobutyronitrile and malonyl chloride give 2, 4, 6-trichloro-3-(ß-chloroethyl) pyridine, which is cyclized with ammonia to 4, 6-dichloro-7-azaindoline and 4, 6-dichloro-5-azaindoline. 6-Chloro derivatives of 7-azaindolines are not dehydrogenated by chlorainil, but 2, 3-dichloro-S, 6-dicyanobenzoquinone converts them to 6-chloro-7-azaindoles. It is shown that sodium in liquid ammonia is an effective means of dehydrogenating the 5-azaindoline to 5-azaindole. In this case, dehydrogenation of 4, 6-dichloro-7-azaindoline is followed by dehalogenation.For Part IX see [1].     

Investigation of the protonation of 5-azaindole derivatives by pmr spectroscopy

The protonation of some 5-azaindoles and 5-azaindolines by trifluoroacetic acid in media with different dielectric constants was studied by PMR spectroscopy. Protonation occurs at the nitrogen atom of the pyridine ring. The structures of the monocations of 5-azaindole, 5-azaindoline, and their 1-phenyl derivatives correspond to a considerable contribution of the quinoid structure with transfer of positive charge to the nitrogen atom of the pyrrole fragment of the molecule. On the basis of an investigation of the chemical shifts of the protons of 1-phenyl-5-azaindole and 1-phenyl-5-azaindoline on the trifluoroacetic acid concentration in methylene chloride, acetonitrile, and deuteroacetone, a protonation mechanism in which transfer of a proton from the donor to the acceptor in slightly polar media occurs through the formation of a hydrogen-bonded complex of the base with the acid is proposed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 767–772, June, 1973.     

Azaindole derivatives

The reaction of 2,4-dichloro-5-(-chloroethyl)pyridine with ammonia and N-ethylaniline, leading to the formation of 5-azaindoline derivatives, has been studied. The processes of the formation of 6-phenylamino and 6-(N-alkyl-N-phenylamino) derivatives of 7-azaindoline, 5-azaindoline, and 5,7-diazaindoline taking place with N-dealkylation and without it have been compared.For part XXVI, see [16].     

Azaindole derivatives

In addition to normal nucleophilic substitution, redox processes to form dehalogenation products of 7-azaindoline and the corresponding oxidized compounds — 6-amino-7-azaindole derivatives — occur during the reactions of various primary and secondary amines with 6-chloro-7-azaindolines. The quantitative ratios of the products of nucleophilic substitution and the redox reaction depend mainly on the nucleophilicity of the attacking amine and, by selecting the amine component of the reaction, one can accomplish either predominantly nucleophilic substitution or direct the process primarily along the path of the redox reaction.See [1] for communication XXXVIII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 789–794, June, 1971.     

Azaindole derivatives

1-Benzyl-6-hydroxy-7-cyano-5-azaindoline, which was converted to 6-chloro-5-azaindoline through 6-hydroxy-5-azaindoline, was synthesized from O-methylbutyrolactim through 1-benzyl-2-pyrrolidone, 1-benzyl-2-cyano (carbamoylmethylene)-pyrrolidine, and the product of its condensation with dimethylformamide diethylacetal.See [1] for communication LII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 355–358, March, 1978.     

Azaindole derivatives. 59. Synthesis and chemical properties of 1-benzyl-4-dimethylamino-6-chloro-7-cyano-5-azaindoline

The condensation of 1-benzyl-2-cyanocarbamoylmethylene-pyrrolidine with tetramethylurea diethylacetal and subsequent cyclization gave 1-benzyl-4-dimethyl-amino-6-chloro-7-cyano-5-azaindoline, for which nucleophilic substitution and dehydrogenation reactions are described. The reactivity of this product is compared with that of 1-benzyl-6-chloro-7-cyano-5-azaindoline.See [1] for Communication 58.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 215–220, February, 1981.     

Introduction of substituents in the pyridine proton of 7-azaindoline

Electropilic substitution (nitration, bromination, and chlorination) of 4-methyl-6-chloro-7-azaindoline (and its N-acetyl derivative) takes place in the 5 position. 4-Methyl-5-amino-7-azaindoline, 4-methyl-5-nitro-7-azaindoline, and 1-acetyl-4-methyl-5-amino-6-chloro-7-azaindoline were obtained by reduction of 1-acetyl-4-methyl-5-nitro-6-chloro-7-azaindoline under various conditions. A method was developed for the preparation of a new three-ring system — 1,2,3-oxadiazolo[5,4-b]-pyrrolo[2,3-e]pyridine.Communication L from the series Derivatives of Azaindoles. See [1] for communication XLIX.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 380–384, March, 1977.     

Azaindole derivatives

A mechanism for the polarographic oxidation of azaindolines that includes electrochemical and chemical steps is proposed. The preparative electrolysis of 1-phenyl-4-methyl-6-morpholino-7-azaindoline, which gives the corresponding 7-azaindole and (7-aza-5-indolinyl)-7-azaindoline, was accomplished.See [1] for communication XLVIII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1277–1283, September, 1975.     

Azaindole derivatives. 57. Dehydrogenation of substituted 5- and 7-az aindolines with activated manganese dioxide

A number of 5- and 7-azaindolines were oxidized to the corresponding azaindoles by means of activated manganese dioxide. The dependence of the ease of dehydrogenation of 5- and 7-azaindolines by activated manganese dioxide on their oxidation potentials is demonstrated.See [1] for communication 56.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 375–378, March, 1979.     

Azaindole derivatives. 62. Synthesis and transformations of condensed three-ring systems that include a 5-azaindoline fragment

The reaction of 7-carbamoyl- and 7-cyano-6-chloro-5-azaindolines with hydrazine leads to the formation of pyrrolo[2,3-d]pyrazolo[5,4-b]pyridine, whereas the reaction of 7-carbamoyl-5-azaindolines with dimethylformamide diethylacetal gives pyrrolo[1,2-c]pyrido]4,3-d]pyrimidines — two new heterocyclic systems. The chemical properties of the synthesized compounds, including cleavage of the pyrimidine ring under the influence of nucleophilic agents, were studied.See [1] for communication 61.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1370–1373, October, 1982.     

The tautomerism of 6-hydroxy-, 6-amino- and 6-acylamino-7-azaindolines

The lactam-lactim tautomerism of 6-hydroxy-7-azaindolines and amino-imine tautomerism of 6-amino- and 6-acylamino-7-azaindolines has been studied by IR and UV spectroscopy. It is shown that the lactam-lactim tautomeric equilibrium of 6-hydroxy-7-azaindolines in contrast to the other analogous N-heteroaromatic compounds is not completely shifted for the lactam. The commensurable amounts of both tautomeric forms can be observed in the solutions of 6-hydroxy-7-azaindolines and it is possible to elucidate the influence of the solvent polarity upon the lactam-lactim tautomeric equilibrium. The tautomeric equilibrium of 6-amino- and 6-acylamino-7-azaindolines is practically completely shifted for the amino form, and even acylation with p-toluene-sulfonic acid does not result in a noticeable shift of the tautomeric equilibrium for the amino form in contrast to the other N-heterocyclic amines.     

Azaindole derivatives

The reaction of 6-chloro-7-azaindolines with naphthyllithium and subsequent treatment with benzophenone give (7-aza-6-indolinyl)diphenylcarbinol and 6-unsubstituted 7-azaindolines, the ratios of the amounts of which are determined by the character of the substituent attached to the nitrogen atom in the 1 position of the azaindoline molecules. In the presence of acidic catalysts (1-butyl-4-methyl-7-aza-6-indolinyl)diphenylcarbinol undergoes dehydration to 1-butyl-4-methyl-6-diphenylmethyl-7-azaindole. Ideas regarding the mechanism of this reaction are expressed.See [1] for communication L.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1527–1530, November, 1977.The authors thank Yu. N. Sheinker, K. F. Turchin, L. F. Linberg, E. M. Peresleni, and T. Ya. Filipenko for conducting the spectral investigations.     

Azaindole derivatives. 61. Electrophilic substitution reactions in 1-benzyl-6-methoxy-7-cyano-5-azaindole and 6-oxo-5-azaindoline

The electrophilic substitution reactions (nitration, bromination, acylation, and the Mannich and Vilsmeier reactions) of 1-benzyl-6-methoxy-7-cyano-5-azaindole and the nitration and Vilsmeier reaction of 6-hydroxy-5-azaindoline were studied.See [1] for Communication 60.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 356–360, March, 1982.     

Azaindole derivatives. 66. 1,6-disubstituted 4-methyl-5-cyano-7-azaindolines

A general method was developed for the synthesis of 1,6-disubstituted 4-methyl-5-cyano-7-azalndolines from the readily available ammonium salt of 2,6-dihydroxy-3-(-hydroxyethyl)-4-methyl-5-cyanopyridine through the corresponding N-substituted ammonium salts and N-substituted 2-amino-3-(-hydroxyethyl)-4-methyl-5-cyano-6-hydroxypyridines with treatment of the latter by POCl₃. This method gives a 40% yield of 4-methyl-5-cyano-7-azaindoline compounds containing various aralkyl or alkyl substituents at N-1 and a hydroxy group or halogen atom at C-6 in three steps.For Communication 65, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 84–88, January, 1985.     

Azaindole derivatives. 60. Nucleophilic substitution reactions in 6-chloro-5-azaindolines

Reactions involving nucleophilic substitution of the halogen atoms in 1-benzyl-6-chloro-7-cyano-5-azaindoline by alkoxy groups and residues of various amines were investigated. The effect of electron-acceptor substituents on the saponification of the alkoxy groups to give hydroxy groups is demonstrated. The effect of the character of the fusion of the pyridine and pyrrole rings on the ease of nucleophilic substitution is examined.See [1] for Communication 59.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1648–1653, December, 1981.     

Reactions of 4-chloro-6-oxo-2,3-dihydro-5-azabenzofurans with amines

The reaction of 7-nitro- and 7-unsubstituted 4-chloro-6-oxo-2,3-dihydro-5-azabenzofurans with primary and secondary amines proceeds with substitution of the chlorine atoms by amine residues and with recyclization of the compounds to 5- and 7-azaindoline derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No, 10, pp. 1311–1313, October, 1973.We thank Yu. N. Sheinker, E. M. Peresleni, L. M. Alekseeva, N. A. Zosimova, and Yu. I. Pomerantsev for their assistance in conducting the spectral investigations.     

Regioselective 6-iodination of 5,7-dioxygenated flavones by benzyltrimethylammonium dichloroiodate

The iodination of 5,7-dioxygenated flavones with 1 equiv of benzyltrimethylammonium dichloroiodate (BTMA·ICl₂) in the system CH₂Cl₂-MeOH-CaCO₃ at room temperature is presented in this note. Flavones with a free phenol group at C5 and an alkoxy or a peracylglycosyloxy at C7 lead to the 6-iodoflavones with a good regioselectivity (ratio 6-iodination/8-iodination about 9).     

Azaindole derivatives

As in the case of N-substituted anilines, trichlorocollidine forms 6-chloro-7-azaindoline derivatives rather than 6-amino-7-azaindoline derivatives with sterically hindered primary amines of the β-phenylisopropylamine type. On passing to tert-butylamine, nucleophilic attack at the α and α′ positions of the pyridine ring proves to be sterically impossible, and dehydrohalogenation of trichlorocollidine to 2,6-dichloro-3-vinyl-4-methylpyridine becomes the principal reaction.     

A facile approach to the synthesis of 5,7-disubstituted indoles via a highly selective lithium-bromine exchange of 5,7-dibromoindoles

A general approach to the synthesis of 5,7-disubstituted indoles has been developed based upon a highly selective lithium-bromine exchange reaction at the 7-position when 1-alkyl-5,7-dibromoindoles were treated with t-BuLi in ether. The resulting 5-bromo-7-lithiated indoles could react with various electrophiles to afford 5-bromo-7-substituted indoles (6) upon work-up. Without isolation of 6, the intermediates thus obtained could be exposed to a second lithium-bromine exchange reaction in a one-pot procedure and further reacted with various electrophiles to afford 5,7-disubstituted indoles (1).