Facile access to 3-cyano-4-azaindoles via a modified Madelung indole synthesis

An unprecedented methodology for the facile synthesis of 2-substituted 3-cyano-4-azaindoles using modified Madelung synthesis is described. The methodology relies on acid and amine coupling under very mild conditions.     

Azaindole derivatives

Electrophilic substitution reactions (cyanomethylation, bromination, nitration, Mannich reaction) are investigated in some 4-azaindoles. The effect on reactivity of the presence of an acyl group in the 1-position is examined. Conditions have been found for the synthesis in high yield of various 3-substituted 4-azaindoles.For part XXX, see [1].     

The synthesis of 5-azaindoles by substitution-rearrangement of 7-azaindoles upon treatment with certain primary amines

Certain 4-substituted 1H-pyrrolo[2,3-b]pyridines (7-azaindoles) undergo a nucleophilic substitution-rearrangement upon treatment with various primary amines at elevated temperatures to yield N-1-substituted 4-amino-1H-pyrrolo[3,2-c]pyridines (5-azaindoles). Treatment of the same 7-azaindoles with secondary amines under the same reaction conditions led to simple nucleophilic substitution products.     

Palladium-catalyzed synthesis of 2,3-disubstituted 5-azaindoles via heteroannulation reaction and of 2-substituted 5-azaindoles through domino sila-Sonogashira/5-endo cyclization

A general and efficient procedure for the synthesis of 2,3-disubstituted 5-azaindoles through the palladium-catalyzed heteroannulation of 4-acetamido-3-iodopyridines and diaryl-, dialkyl-, or arylalkylalkynes is described along with a study of the reaction regioselectivity. The preparation of 2-monosubstituted 5-azaindoles via sila-Sonogashira/5-endo cyclization is also reported. These methods allowed us to prepare 36 diversely substituted 5-azaindoles in good yields.     

Azaindole derivatives

Electrophilic substitution reactions — cyanomethylation, bromination, nitration, and the Mannich reaction- in the 5-azaindole series were studied. It is shown that, despite the literature data, 5-azaindole behaves like the isomeric 4- and 7-azaindoles in these reactions. Conditions that make it possible to synthesize various 3-substituted 5-azaindoles in high yields were found.See [1] for communication XL.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1528–1530, November, 1972.     

Synthesis of polysubstituted 5-azaindoles via palladium-catalyzed heteroannulation of diarylalkynes

A general and efficient procedure for the synthesis of functionalized 5-azaindoles through the catalyzed heteroannulation of 4-acetamido-3-iodopyridines and diarylalkynes is described. The reaction allows the preparation of a variety of substituted 2,3-diaryl-5-azaindoles in good to excellent yields.     

A novel one-step synthesis of 2-substituted 6-azaindoles from 3-amino-4-picoline and carboxylic esters

Dilithiation of 3-amino-4-picoline (1) was achieved with sec-BuLi at room temperature. Condensation of the resulting dianion (2) with carboxylic esters afforded a wide range of 2-substituted 6-azaindoles in good yields.     

Microwave-assisted flexible synthesis of 7-azaindoles

7-Azaindoles are versatile building blocks, especially in medicinal chemistry, where they serve as bioisosteres of indoles or purines. Herein, we are presenting a robust and flexible synthesis of 1,3- and 1,3,6-substituted 7-azaindoles starting from nicotinic acid derivatives or 2,6-dichloropyridine, respectively. Microwave heating dramatically accelerates the penultimate reaction step, an epoxide-opening-cyclization-dehydration sequence. The functional group compatibility of the reaction is examined as well as the application of the products in further functionalizations.     

Combination of Sonogashira coupling and 5-endo-dig cyclization for the synthesis of 2,6-disubstituted-5-azaindoles

The synthesis of a library of 2,6-disubstituted-azaindoles relying on Sonogashira cross-coupling and intramolecular cyclization is described. Eleven examples of 6-alkynyl derivatives and three examples of 3-bromo-5-azaindoles are reported. One of the 3-bromo-5-azaindoles was also further functionalized with two different aryl trifluoroborate salts via Suzuki-Miyaura coupling reaction.     

Synthesis of tetrahydro-5-azaindoles and 5-azaindoles using Pictet-Spengler reaction—appreciable difference in products using different acid catalysts

Pictet-Spengler condensation of 2-(aryl)-2-(1H-pyrrol-2-yl)ethanamines using conventional acid catalysts like TMSCl or TFA resulted in the formation of substituted 5-azaindoles involving a tandem one pot four steps reaction sequence. By contrast use of glacial acetic acid furnished the targeted tetrahydro-5-azaindoles in diastereoselective manner. These were readily dehydrogenated to 5-azaindoles.     

Azaindole derivatives. 67. Synthesis of N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles

N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles have been synthesized from the respective 1-benzyl-4-methyl-5-cyano-6-chloro(and 6-hydroxy)-7-azaindoles. The effect of the 5-cyano group on the oxidation-reduction processes accompanying nucleophilic replacement of chlorine in 6-chloro-7-azaindoles by primary and secondary amines has been considered. 7-Azaindoline compounds were dehydrogenated by chloranil to N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles.For communication 66, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 91–96, January, 1986.     

Synthesis of 4-(cyclic dialkylamino)-7-azaindoles by microwave heating of 4-halo-7-azaindoles and cyclic secondary amines

Nucleophilic aromatic substitution of 4-chloro- and 4-fluoro-7-azaindoles with cyclic secondary amines under microwave heating gave a straightforward and rapid synthesis of 4-(cyclic dialkylamino)-7-azaindoles. 4-Fluoro-7-azaindoles showed a greater reactivity towards S_NAr reactions under these conditions than 4-chloro-7-azaindole.     

Synthesis of meso-tetraphenyl porphyrins via condensation of dipyrromethanes with N-tosyl imines

A new synthetic route for the synthesis of 5,10,15,20-tetraphenyl porphyrins has been developed based on the reaction of 5-substituted dipyrromethanes with N-tosyl imines in the presence of a metal triflate catalyst. meso-Substituted tetraphenyl porphyrins were synthesized in a two-step process. The first step of the method is the metal triflate-catalyzed condensation of 5-substituted dipyrromethanes with N-tosyl imines to form a porphyrinogen intermediate and the second step is the oxidation of the porphyrinogen to porphyrin. The method was applied to the synthesis of trans-A₂B₂-tetraarylporphyrins and the products were obtained with only a trace amount of one scrambling product. The synthesis of two important building blocks for porphyrin synthesis, mono and di-sulfonamide alkylated 5-substituted dipyrromethanes, was achieved by the addition of 5-substituted dipyrromethane to N-tosyl imine. The application of mono and di-sulfonamide alkylated 5-substituted dipyrromethanes in ‘2+2’ porphyrin formation reactions is presented.     

Synthesis of 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones

The reactions of 1-substituted 2-nitro-3-phenylaminoprop-2-en-1-ones with cyanothioacetamide afforded the corresponding 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones, which were used for the synthesis of 6-substituted 3-cyano-2-methylthio-5-nitropyridines and 7-substituted 4-hydroxy-8-nitropyrido[2",3":4,5]thieno[2,3-b]pyridin-2(1H)-ones.     

Transition-metal-free access to 7-azaindoles

A novel method for transition-metal-free synthesis of 7-azaindoles is developed through a one-pot synthesis involving amination of pyridine N-oxides and intramolecular enamine formation. Remarkable features of the method include simple operation, mild reaction conditions, wide substrate scope, and easily accessible starting materials.     

A convenient one-pot synthesis of 4-, 6-, and 7-azaindoles from aminopyridines

A one-pot synthesis of a variety of substituted 4-, 6-, and 7-azaindoles from commercially available aminopyridines in moderate to good yields is described.     

New synthesis of condensed heterocycles from isoxazole derivatives VI. 2,5-Dimethyl-3-aeetyl-7-amino-1H-pyrrolo[3,2-b] pyridine

A new synthesis of pyrrolo[3,2-b] pyridine starting with pyrrole ring is described. The procedure allows the synthesis of 4-azaindoles bearing a sensitive group at C-7. The nitration of 4b with nitric acid and acetic anhydride at ?15° gave 5 . The hydrogenation of 5 led to simultaneous reduction of N-hydroxy and nitro groups and to hydrogenolysis of the isoxazole nucleus, affording an appropriate chain of atoms to building up the pyrrolo[3,2-b] pyridine ring.     

Synthesis of 2-substituted endo-hymenialdisine derivatives

The first synthesis of 2-substituted endo-hymenialdisine derivatives 1-4 is described started with 2-substituted pyrroles and 5-substituted pyrrolo-2-carboxylic acids.     

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].     

Azaindoles. 69. Some reactions of 5-cyano-6-chloro-7-azaindoles and lactam-lactim tautomerism in 5-cyano-6-hydroxy-7-azaindolines

Electrophilic substitution in the 3-position of 1-benzyl-4-methyl-5-cyano-6-chloro-7-azaindole requires more severe conditions than in 7-azaindoles without the 5-cyano-substituent. Increased ease of nucleophilic replacement of the chlorine atom by the methoxy group has been observed in 1-benzyl- (and 1-butyl)-4-methyl-5-cyano-6-chloro-7-azaindoles, and the cyano-group in these compounds has been found to be resistant to hydrolysis and alcoholysis. The introduction into 1-benzyl- (and 1-butyl)-4-methyl-6-hydroxy-7-azaindoles of a 5-cyano-substituent results in a shift of the lactam-lactim tautomeric equilibrium towards the lactim forms.For communication 68, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 100–106, January, 1987.