Synthesis of New Imidazo[4,5-b]pyridine Derivatives

New imidazo[4,5-b]pyridine derivatives with various substituents in the 2-position (,-unsaturated ketones, imines, ²-pyrazolines, pyrimidines, 1,2,3,4-tetrahydropyrimidines) and derivatives of the new pyrido[3',2':4,5]imidazo[1,2-d][1,2,4]triazine ring system were synthesized. Biological data for selected compounds are presented.     

Synthesis of derivatives of a new heterocyclic system pyrazolo[3,4-b]pyrido[1′,2′: 1,2]imidazo[4,5-d]pyridine

1-[4-Aminoarylpyrazolo[3,4-b]pyridin-5-yl]pyridinium chlorides undergo cyclization under reflux in tert-butanol in the presence of an excess of potassium tert-butoxide to form tetracyclic derivatives of pyrazolo[3,4-b]pyrido[1′,2′:1,2]imidazo[4,5-d]pyridine. The reaction scheme of the processes is proposed. The structures of the reaction products were confirmed by physicochemical methods. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 710–714, April, 2006.     

New cascade reaction of azides with malononitrile dimer to polyfunctional [1,2,3]triazolo[4,5-b]pyridine

A new cascade reaction of azides with malononitrile dimer yielding polyfunctional [1,2,3]triazolo[4,5-b]pyridine was found. It was established that during the reaction of aryl azides with malononitrile dimer, under base catalysis, the formed intermediate triazole underwent spontaneous cyclization leading to the pyridine ring annulation. The obtained products have provided a new entry to [1,2,3]triazolo[4,5-b]pyridine.     

Recent progress in the chemistry of heterocycles incorporated oxazolo[4,5-b]pyridine and oxazolo[5,4-b]pyridine skeletons

Abstract

The present study describes recent advances in the chemistry of heterocycles incorporated oxazolo[4,5-b]pyridine and oxazolo[5,4-b]pyridine skeletons. The main sections included the synthesis of the investigated compounds from readily accessible aminopyridinol derivatives or aminopyridines. The reactivity of substituents attached to ring carbon or nitrogen atoms were discussed. In addition, the synthetic and biological evaluation of the inspected oxazolopyridines were highlighted. The purpose of this review is to discuss the chemistry of the title so far. The present study will support researchers in the fields of organic and medicinal chemistry to design and develop new protocols for the construction of new biological components.     

One‐pot Sequential Reactions Featuring a Copper‐catalyzed Amination Leading to Pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines and Dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines

Tetracyclic skeletons combining an imidazo[1,2‐a]pyridine moiety with a quinoline framework such as pyrido[2′,1′:2,3]imidazo[4,5‐b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative compounds. In this paper, we report a novel methodology for the synthesis of pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines through one‐pot sequential reactions of commercially available or readily obtainable 2‐aminopyridines, 2‐bromophenacyl bromides, aqueous ammonia, and aldehydes. Moreover, dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines could also be obtained in a similar manner by using various ketones as the substrates in place of aldehydes. Notably, the whole procedure combines condensation/amination/cyclization reactions in one pot to give complex compounds in a simple and practical manner. Compared with literature methods, the synthetic strategy reported herein has the advantages of readily available starting materials, structural diversity of products, good functional group tolerance, and obviation of step‐by‐step operations.     

Reactions of 1-Substituted Benzo[4,5]imidazo[1,2-a]pyridines

Bromination of 1-oxo(imino, amino)benzo[4,5]imidazo[1,2-a]pyridines gave the corresponding 2-bromo derivatives. Acylation using the Vilsmeier complex in acetic anhydride gave the N-formyl and N-acetyl derivatives. The reaction of the amine with the Vilsmeier complex, acetyl acetone, ethyl acetoacetate, and 2,5-dimethoxytetrahydrofuran occurs at the amino group.     

Synthesis and Antioxidant,Anti-Inflammatory,and Analgesic Activity of Novel Polycyclic Pyrimido[4,5-b]quinolines

The behavior of the 2-methylthio-pyrimido[4,5-b]quinolin-4-one towards differently substituted amines is reported. Also, the reactivity of 3-aminothiazolo[3′,2′ :1,2]-pyrimido[4,5-b]quinoline-2-carbonitrile towards formic acid, urea, thiourea, formamide, and carbon disulfide is discussed. Some of the synthesized derivatives possess biological activities as anti-inflammatory and analgesic agents. Some of these selective biologically active compounds were screened for antioxidant properties.     

Synthesis of Imidazo[4,5-b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides

We have recently found that 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB) and the corresponding 2-bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,5-b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole nucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2-substituted 6,7-dichloroimidazo[4,5-b]quinoxalines involving a reaction of 2,3,6,7-tetrachloroquinoxaline with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7-dichloroimidazo[4,5-b]quinoxalin-2-one. Ribosylation of 2-substituted imidazo[4,5-b]quinoxalines was influenced by the functional group at the 2-position and the 2-one compound was found to smoothly undergo ribosylation. The 2-one group of the nucleoside was converted into specifically selected 2-substituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, that the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.     

Formylation of Furyl-substituted Imidazo[1,2-a]pyridine, Imidazo[1,2-a]pyrimidine and Imidazo[2,1-b]thiazole

Vilsmeier formylation of 2-(2-furyl)-substituted imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine, and also 6-(2-furyl)imidazo[2,1-b]thiazole with 1 mole of reagent occurs at the free position of the imidazole ring, while with an excess of the reagent it also occurs at the position 5 of the furyl group.     

Microwave-assisted three component synthesis of novel bis-fused quinazolin-8(4H)-ones linked to aliphatic or aromatic spacer via amide linkages

Abstract

A novel series of bis(tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8-ones) and bis(tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolinones) containing amide linkages were regionselectively prepared via a three-component reaction of bis(aldehydes) with dimedone and 3-amino-1,2,4-triazole (or 2-aminobenzimidazole) under conventional heating as well as under microwave irradiation.     

Synthesis of New 2-[(Substituted-pyrazolin-1-yl)carbonyl]-thieno[2,3-b]pyridine Derivatives

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate chalcones 2a-2d in the presence of acid catalyst produced the corresponding 3-amino-2-[(3,5-disubstituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d . 3-Amino-2-[(3-substituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 7a, 7b were also obtained by the cyclization reaction of carbohydrazide 1 with Mannich base derivatives 6a, 6b under basic condition.     

Synthesis and Properties of Derivatives of the new Heterocyclic System Benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine

Derivatives of a new heterocyclic system - benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine have been obtained by successive reactions in three stages - alkylation of 3-cyanopyridine-2(1H)-thiones with 2-chloromethylbenzylimidazole to give 2-benzimidazolylmethylthio-3-cyanopyridines, closing the thiophene ring in the latter to form 3-amino-2-(benzimidazolyl-2)thieno[2,3-b]pyridines, and cyclization of the pyrimidine ring by acylation with carboxylic acid anhydrides or chlorides.     

Unexpected formation of 4,5-dihydro-1H-pyrazolo[3,4-b]pyridine derivatives as a potent antitubercular agent and its evaluation by green chemistry metrics

Abstract

The present study describes L-hydroxy proline catalyzed unpredicted formation of 4,5-dihydro-1H-pyrazolo[3,4-b]pyridines instead of expected 4,7-dihydro-1H-pyrazolo[3,4-b]pyridines in aqueous ethanol at ambient temperature through one-pot three-component reaction. Furthermore, this protocol was evaluated using green chemistry metrics indicating green relevance of the present synthetic methodology. Most of the synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H37RV strain, showing excellent results based on minimum inhibitory concentrations (MIC). Among the screened derivatives 4f, 4i, and 4j exhibited antitubercular activity with promising MIC value of 1.6?μg/mL.     

Synthesis of Some New Pyrazolo[3,4-b]Pyridlne and Pyrazolo[3,4-d]Pyrimidine Derivatives1

Several pyrazolo[3,4-b]pyridine (3,4) and pyrazolo-[3,4-d]pyrimidine (5-13) derivatives were prepared using 5-amino-l-(5-ethyl-5H-1,2,4-triazino[5,6-b]-indol-3-yl)-lH-pyrazole-4-carbonitrile (2) . The pyridine derivatives 3 and 4 were obtained by reaction of 2 with malononitrile and ethyl cyanoacetate, respectively, while pyrimidine analogs 5-13 were synthesized cither by a one-step or multi-step sequence.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Green Method for the Synthesis of Benzo[f]pyrimido[4,5-b]quinoline Derivatives Catalyzed by Iodine in Aqueous Media

A convenient one-pot synthesis of benzo[f]pyrimido[4,5-b]quinoline derivatives is described via three-component reaction of benzaldehydes, naphthalen-2-amine, and barbituric acid at room temperature in aqueous media catalyzed by iodine. Compared with other methods, this three-component reaction used a green solvent, gave good yields, and was operationally simple.     

2-Ethanethioamide in Heterocyclic Synthesis: Synthesis and Characterization of Several New Pyridine and Fused Azolo- and Azinopyridine Derivatives

Pyridine-2(1H)-thione derivatives 3a,b were synthesized from the reaction of 1-(phenyl-sulfanyl)acetone (1) and cinnnamonitrile derivatives 2a,b. Compounds 3a,b reacted with different halogenated reagents 7a–f to give 2-S-alkylpyridine derivatives 8a–l, which could be, in turn, cyclized into the corresponding thieno[2,3-b]pyridine derivatives 9a–l. Compounds 9d,j reacted with acetic anhydride, formic acid, carbon disulfide, phenyl isothiocyanate, and nitrous acid to yield the corresponding pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidine 12a,b, 15a,b, 17a,b, 20a,b, and pyrido[3′,2′:4,5]thieno[2,3-d][1,2,3]triazinone derivatives 22a,b, respectively.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

SYNTHESIS OF 15H-ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-B]QUINAZOLINE-7,13,15-TRIONES AND 14H-ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-B]BENZO[G]QUINAZOLINE-8,14,16-TRIONE AS NEW POLYCYCLIC FUSED-RING SYSTEMS

3-Thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione (3) and 2-sub-stituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones (4a–l) were prepared from the reaction of 2-thiohydantoin (2) and 3-substituted 2-thiohydantoin (5a–l) with 2-formyl benzoic acid (1). Alkylation of 3 under an anhydrous basic conditions afforded 4a–i. The alkylation of 3 in aqueous basic solution afforded 3-(alkylmercapto)imidazo[1,5-b]isoquinoline-1,5-diones (7a,b). Reactions of the aromatic amino acids 9a,b and 12 with 7a afforded 2-(2H-1,5 dioxoimidazo[1,5-b]isoquinazolin-3-ylideneamino)benzoic acids (10a, b) and 3-(2H-1,5-dioxoimidazo[1,5-b]isoquinazolin-3-ylideneamino)2-naphthalenecarboxylic acid (13), which were then cyclyzed by heating in acetic anhydride to afford 15H-isoquino[2′,3′ :3,4] imidazo[2,1-b]quinazoline-7,13,15-triones (11a,b) and 14H-isoquino[2′,3′:3,4]imidazo[2,1-b]benzo[g]quinazoline-8,14,16-trione (14). Some of the new compounds were tested for their antitumor activities.     

Reduction of Imidazo[4,5-c]pyridine and [1,2,3]Triazolo[4,5-c]pyridine Derivatives to Spinaceamines and 2-Azaspinaceamines

Reduction of 1-substituted [1,2,3]triazolo[4,5-c]pyridines with nickel-aluminum alloy in aqueous alkali gave 2-azaspinaceamines. Reduction of imidazo[4,5-c]pyridine and [1,2,3]triazolo[4,5-c]pyridine derivatives with formic acid in the presence of triethylamine resulted in formation of 5-formylspinaceamines and 2-azaspinaceamines. The 5-formyl group in the latter can be removed by acid hydrolysis. Unsubstituted 2-azaspinaceamine, an aza analog of natural spinaceamine, was synthesized for the first time.     

Synthesis and Reactions of 4-Oxiranylmethylfuro[3,2-b]pyrroles and Their Benzo Derivatives

Methyl 4-oxiranylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylates 2a-c and methyl 1-oxiranylmethyl-1H-benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate (2d) were prepared by reaction of the appropriate starting compounds 1a-d with excess chloromethyloxirane. The compounds 2a-d undergo oxirane ring opening by heterocyclic amines (morpholine, pyrrolidine, piperidine or 4-methylpiperazine) giving N-2-hydroxy-3-heteroaminopropyl-substituted compounds 3a-f or substituted 4,5-dihydrofuro[2',3':4,5]pyrrolo[2,1-c][1,4]oxazin-8-ones 4a-e.