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.     

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.     

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].     

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.     

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

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

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

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.     

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.     

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.     

Azaindole derivatives

The polarographic oxidation of a series of 5-azaindoline, 7-azaindoline, and 5,7-diazaindoline derivatives (22 compounds) was studied, and the results are compared with the ease of dehydrogenation of these substances under the influence of quinones. It is shown that E_1/2 increases on passing from 7-azaindolines to 5-azaindolines and then to 5,7-diazaindolines. The effect of substituents is satisfactorily described by cross-correlation equations, while the deviations from the correlation are associated with the peculiarities of the lactam-lactim tautomeric equilibrium in a number of 6-hydroxy-5- and 7-azaindolines.See [1] for communication XLI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 773–776, June, 1973.     

Effect of the medium on the reaction of 4-methyl-7-azaindoline with acetic and trifluoroacetic acids

The effect of the medium on the equilibrium involved in proton transfer via a hydrogen bond and dissociation of ion pairs in systems composed of 4-methyl-7-azaindoline and acetic and trifluoroacetic acids was examined by means of PMR and IR spectroscopy. The position of the molecular H complex ? ion pair equilibrium depends on the proton-donor-acceptor properties of the solvent and is shifted to favor the ionic form in the order CH₃CN < CH₂Cl₂< CDCl₃. A change in the dielectric constant of the medium affects mainly the degree of dissociation of the ion pairs.     

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

On the basis of a comparative study of the influence of various factors (ratio of the reactants, temperature, reaction time, polarity of the medium, and the catalytic action of metals) on the reaction of 2,6-dichloro-3-(-chloroethyl)-4-methylpyridine (trichlorocollidine) with 2,6-dimethylamine, it has been shown that, in addition to 6-chloro-1,4-dimethyl-7-azaindoline, the process gives rise to various amounts, depending on the conditions of its performance, of other products: 3-(-dimethylaminoethyl)-2,6-dichloro-4-methylpyridine, 2-chloro-3-(-chloroethyl)-6-dimethylamino-4-methylpyridine, 2-chloro-6-dimethylamino-3-(-dimethylaminoethyl)-4-methylpyridine, and 6-dimethylamino-1,4-dimethyl-7-azaindoline. The best method for directing the process to the formation of azaindoline derivatives is the use of highly polar solvents.For Communication XXXIII, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 6, No. 8, pp. 1122–1126, August, 1970.     

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.     

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.     

Energy barriers to rotation in axially chiral analogues of 4-(dimethylamino)pyridine.

The barriers to enantiomerization of a series of axially chiral biaryl analogues of 4-(dimethylamino)pyridine (DMAP) 1-10 were determined experimentally by means of dynamic HPLC measurements and racemization studies. The barriers to rotation in derivatives 1-6 (based on the bicyclic 5-azaindoline core) were lower than those in the corresponding derivatives 7-10 (based on the monocyclic DMAP core). Semiempirical (PM3), ab initio Hartree-Fock (HF/STO-3G), and density functional theory (DFT/B3LYP/6-31G*) calculations reveal that these differences in barriers to rotation are the result of differing degrees of hybridization of the non-pyridyl nitrogen in the enantiomerization transition states (TSs). The importance of heteroatom hybridization as a factor in determining nonsteric contributions to barriers to rotation in azabiaryls of this type is discussed.     

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.     

Synthesis of various acylating agents directly from carboxylic acids

Abstract

A straightforward synthesis of acylating reagents such as Weinreb and MAP amides from aromatic, aliphatic carboxylic acids, and amino acids using PPh₃/NBS combination is described. A chemo-selective modification of the carboxylic acid group into Weinreb amide in the presence of more reactive aldehydes and ketones is presented. All reactions were performed at ambient temperature under air using undried commercial grade solvent. Furthermore, the present methodology could be performed at a gram scale under inert-free reaction conditions. In addition, 7-azaindoline amide auxiliary (used for catalytic asymmetric aldol- and Mannich-type reactions), which behaves like Weinreb amide is also synthesized under similar reaction conditions.     

Derivatives of azaindoles. 65. Synthesis of 1-benzyl-4-methyl-5-cyano-6-hydroxy-7-azaindoline

Treatment of the ammonium (I) or benzylammonium salt of 2,6-dihydroxy-3-(-hydroxyethyl)-4-methyl-5-cyanopyridine (II) with a mixture of benzylamine and phosphorus pentoxide yielded 2-benzylamino-3-(-hydroxyethyl)-4-methyl-5-cyano-6-hydroxypyri-dine (III), which, when heated with phosphorus oxychloride, is converted to 1-benzyl-4-methyl-5-cyano-6-hydroxy-7-azaindoline (IV). The products of thermal fragmentation of II with benzylamine were studied by the method of chromato-mass spectrometry. In addition to compound III, N,N-dibenzylurea (V) and the dibenzylamide of malonic acid (VI) were preparatively isolated from the reaction products. The cyclization of I and II to 4-methyl-6-hydroxy-2,3-dihydro-7-azabenzofuran (VII) and 4-methyl-5-cyano-6-hydroxy-2,3-dihydro-7-azabenzofuran (VIII) was carried out. Heating VIII with benzylamine at 200–210°C led to compound III.For communication 64, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1105–1109, August, 1984.