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.     

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.     

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.     

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.     

Site-selective C–H nitration of N-aryl-7-azaindoles under palladium(II) catalysis

The site-selective C–H nitration reaction of 7-azaindoles with t-butyl nitrite under palladium catalysis is described. This protocol provides an efficient method for the construction of ortho-nitrated N-aryl-7-azaindoles with excellent site-selectivity and functional group compatibility. The formed 7-azaindole derivatives can be readily transformed into 7-azaindoles containing an aniline functional group under palladium-catalyzed hydrogenation conditions.     

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.     

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.     

A general method for the preparation of 4- and 6-azaindoles

Nitropyridines reacted with an excess of vinyl Grignard reagent to produce 4- or 6-azaindoles. Improved yields were obtained when a halogen atom was present at the position alpha to the nitrogen atom in the pyridine ring.     

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].     

Lewis acid-mediated cross-coupling reaction of 7-azaindoles and aldehydes: Cytotoxic evaluation of C3-linked bis-7-azaindoles

The synthesis of 3,3′-bis-7-indolylmethane derivatives is important for their further development as pharmaceutical compounds and other synthetic purposes. Herein, we describe the zinc- or acid-mediated cross-coupling reaction of 7-azaindoles with aldehydes, such as paraformaldehyde, alkyl aldehydes, aryl aldehydes, enal, and α-ketoaldehyde, providing the corresponding C3-linked bis-7-azaindole derivatives, which are a crucial class towards the development of novel bioactive compounds. High levels of site selectivity and functional group tolerance were observed. Synthesized 3,3′-bis-7-azaindole derivatives were evaluated against human breast adenocarcinoma cells (MCF-7) and human ovarian carcinoma cells (SKOV-3), respectively. Notably, compounds 3s and 4e displayed promising anticancer properties competitive with anticancer doxorubicin as a positive control.     

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.     

Synthesis and Chemical Reactivity of 5-Methoxy-2-vinyl-4-azaindoles

2-Vinyl-4-azaindoles are less reactive with dienophiles than 2-vinylindoles. 5-Methoxy-2-vinyl-4-azaindole 2a and its 1-methyl derivative 2a reacts with N-phenylmaleimide to yield cycloadducts only under vigorous conditions. 2b produces a cycloadduct with dimethyl acetylenedicarboxylate, while 2a yields a Michael-type adduct. Reactions with more reactive dienophiles gave only polymeric products.     

A highly effective synthesis of 2-alkynyl-7-azaindoles: Pd/C-mediated alkynylation of heteroaryl halides in water

The reaction of 4-chloro-2-iodo-7-azaindole with terminal alkynes was investigated using 10% Pd/C-PPh₃-CuI as a catalyst system in water. This study afforded a new, mild and selective process for the preparation of 2-alkynyl-4-chloro-7-azaindole in good yields via C-C bond forming reaction. The resulting chloro derivative can be functionalized further via another Pd-mediated C-C bond forming reaction with arylboronic acid.     

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.     

Palladium-catalysed tandem alkenyl- and aryl-C-N bond formation: a cascade N-annulation route to 1-functionalised 7-azaindoles

A series of 3-(2-haloalkenyl)-2-pyridyl-halides undergo consecutive palladium-catalysed inter- and intramolecular amination reactions to deliver a series of 1-functionalised 7-azaindoles. Anilines and amines can be readily employed as the N-nucleophile and incorporation of both electron-donating and electron withdrawing substituents on the pyridine core is possible.     

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.     

Synthesis of functionalized 7-azaindoles via directed ortho-metalations

Functionalization at C-5 of 4-fluoro- and 4-chloro-1-triisopropylsilyl-7-azaindole, 1 and 2, respectively, leads to a variety of new substituted 7-azaindole derivatives. We also describe two approaches to introduce functionality at C-6.     

Syntheses of 3-Chloro-7-[(Chlorocarbonyl)Methoxy]-4-Methylcoumarin

Two efficient syntheses of 3-chloro-7-[(chlorocarbonyl)methoxy]-4-methylcoumarin are described, one utilizing traditional chemistry starting from 3-chloro-7-hydroxy-4-methylcoumarin, while the other uses a novel reagent, sulfuryl chloride/thionyl chloride, in a one-pot reaction starting from 7-(carboxymethoxy)-4-methylcoumarin.     

Application of cyclic sulfates in the synthesis of enantiomers of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one

The synthesis of enantiomers of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one derivatives is described. These enantiomers were synthesized starting from (R)- or (S)-1-chloro-2,3-dihydroxypropane using relevant cyclic sulfates as chiral intermediates. The enantiomeric purities of the final compounds were in the range of 99.3–100.0%, as determined by high performance liquid chromatography. The final compounds were found to display moderate potency as ligands for α₁-adrenoreceptors.     

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.