One-pot synthesis of imidazo[1,2-b]pyrazole,imidazo[1,2-b]-1,2,4-triazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,imidazo[1,2-a]benzimidazole,and 1,2,4-triazolo[4,3-a]benzimidazole derivatives

Hydrazonoyl bromides 1a-c react with 5-amino-3-phenyl-1H-pyrazole, 5-amino-1H-1,2,4-triazole, 2-aminopyridine, and 2-aminobenzimidazole to afford the corresponding imidazol[1,2-b]pyrazoles 10, imidazo[1,2-b]-1,2,4-triazoles 11, imidazo[1,2-a]pyridines 16, imidazo[1,2-a]pyrimidines 17, and imidazo[1,2-a]benzimidazoles 20, respectively. Compounds 1a-c reacted also with 2-methylthiobenzimidazole to give 1,2,4-triazolo[4,3-a]benzimidazole derivatives 21. © 1997 John Wiley & Sons, Inc.     

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.     

Studies of imidazo[1,2-a]benzimidazole derivatives. 21. Synthesis of haloketones in the imidazo[1,2-a] benzimidazole series

Methods for the synthesis of imidazo[1,2-a]benzimidazole haloketone derivatives have been investigated. It has been found that -bromoketone derivatives of this heterocycle can be prepared either by bromination of 3-acylimidazo[1,2-a]benz-imidazoles with bromine in glacial acetic acid or by acylation of 3-unsubstituted imidazo[1,2-a]benzimidazoles with haloanhydride derivatives of -bromoalkanoic acids. Treatment of imidazo[1,2-a]benzimidazoles with 3-chloropropionyl chloride results in the formation of imidazo[1,2-a]benzimidazolyl-3-propionyl chloride and bis(imidazo[1,2-a]benzimidazolyl)propan-3-one derivatives as side products. Reaction of 2-phenylimidazo[1,2-a]benzimidazoles with 3-bromopropionic acid in polyphosphoric acid gives benzocyclohepten[5,6:4,5]imidazo[1,2-a]benzimidazole derivatives.For Communication 20, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 339–345, March, 1986.     

Selective C-acylation of 2-aminoimidazo[1,2-a]pyridine: application to the synthesis of imidazopyridine-fused [1,3]diazepinones

A series of 20 optically pure 3,4-dihydro-5H-pyrido[1',2':1,2]imidazo[4,5-d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]diazepines were synthesized in four steps with 17-66% overall yields. The key step consists of a selective C-acylation reaction of easily accessible 2-aminoimidazo[1,2-a]pyridine at C-3.     

Synthesis of imidazo[4,5-b]pyridines from aminoimidazolecarbaldehydes

4-Amino-1,2-dimethylimidazole-5-carbaldehyde (1) and 5-amino-1-methylimidazole-4-carbaldehydes 3 were prepared by reduction of the corresponding aminoimidazolecarbonitriles 2 and 4. Condensation of 1 and 3 with carbonitriles, ketones and polyfunctional carbonyl compounds bearing the-CH₂CO-moiety afforded to the imidazo[4,5-b]pyridine derivatives.     

Synthesis of Hexa- and Octahydropyrido[3'2':4,5]thieno[3,2-d]pyrimidines

The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridine. Refluxing the latter with acyl chlorides in AcOH or heating in formic acid gave hexahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine.     

Studies on antiulcer drugs. III. Synthesis and antiulcer activities of imidazo[1,2-a]pyridinylethylbenzoxazoles and related compounds. A novel class of histamine H2-receptor antagonists.

A series of imidazo[1,2-a]pyridinylalkylbenzoxazole derivatives was synthesized and tested for histamine H2-receptor antagonist, gastric antisecretory and antiulcer activities. Some of 2-amino-6-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole derivatives were found to have good pharmacological activities. Among them, 2-amino-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl] benzoxazole (II-11) and 2-acetamido-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl] benzoxazole (II-38) showed potent antisecretory and cytoprotective activity. The structure-activity relationships of these compounds are discussed.     

Research on imidazo[1,2-a]benzimidazole derivatives XII. 3-Acyl-substituted imidazo[1,2-a]benzimidazoles

Stable 3-acetyl derivatives of imidazo[1,2-a]benzimidazole were synthesized by the action of acetic anhydride on 2,9-disubstituted imidazo[1,2-a]benzimidazole. The former were also obtained by cyclization of 1-alkyl (aralkyl) -3-acylmethyl-2-iminobenzimidazoline hydrobromides in acetic anhydride in the presence of anhydrous sodium acetate. 3-Benzoyl-substituted imidazo[1,2-a]benzimidazoles, which are unstable in acidic media, were synthesized by the action of benzoyl chloride in the presence of pyridine or excess starting imidazo [1,2-a] benzimidazole.See [1] for communication XI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 121– 125, January, 1976.     

Synthesis and in vitro cytotoxic evaluation of new derivatives of pyrido[1,2-a]benzimidazolic ring system: the pyrido[1',2':1,2]imidazo[4,5-h]quinazolines

Access to the original series of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline was developed from a 1,3-dicarbonyl unit with some "N-C-N" bisnucleophilic reagents and the derivatives obtained were evaluated for in vitro cytotoxic activities against HL60 and A2780 cells. All compounds exhibited cytotoxic activities on resistant cell lines (MDR+; HL60R and A2780R) with no resistance phenomena.     

Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-alpha-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.     

Heterocyclizations with tosylmethyl isocyanide derivatives. A new approach to substituted azolopyrimidines

An efficient synthesis of substituted azolopyrimidines such as pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidines, pyrimido[1,6-a]indoles, benzo[4,5]imidazo-[1,2-c]pyrimidines, an imidazo[1,2-c]pyrimidine, and pyrazolo[1,5-c]pyrimidines is described. The method involves the reaction of N-protected bromomethylazoles and tosylmethyl isocyanide (TosMIC) derivatives in nonanhydrous media. The study of the reaction conditions shows that the method is only successful under phase-transfer conditions (CH2Cl2/30% aq NaOH) using benzyltriethylammonium chloride as a catalyst.     

Imidazo[1,2-a]quinoxaline and its transformations. I

The transformations that occur during the reduction of 1-(o-nitrophenyl)-2-formylimidazole with sodium hydrosulfite in the presence of ammonia were studied. The 4-amino derivatives of imidazo[1,2-a]quinoxaline and the bisulfite derivatives of 1-(o-aminophenyl)-2-formylimidazole are formed along with the previously described imidazo[1,2-a]quinoxaline. 4-Aminoimidazo[1,2-a]quinoxaline was also obtained by alternative synthesis by amination of imidazo-[1,2-a]quinoxaline with sodium amide in dimethylaniline. The major product of the transformation is 4,4-bisimidazo[1,2-a]quinoxalyl when the reaction is carried out in xylene.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 416–418, March, 1972.     

Condensed Thienopyrimidines. 14. Synthesis of 10H-Thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines

Reaction of a substituted 2-aminothienothiopyran with methyl(phenyl) isothiocyanate, intramolecular cyclization of the obtained N'-methyl(phenyl) thioureido derivatives, and work up of the cyclization products with hydrazine hydrate gave 2-hydrazinodihydrothiopyranothienopyrimidines. Treatment of the latter with pyruvic acid gave the novel 10H-thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines.     

1,2,3,9a-Tetrahydro-9H-imidazo[1,2-a]indoles

When derivatives of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one or 1-carbamoylmethyl-2-methylene-2,3-dihydroindole are reacted with lithium aluminum hydride, derivatives of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole are formed. Under the same conditions 1-(N-phenylcarbamoylmethyl)-2-methylene-2,3-dihydroindole is not cyclized to an imidazo[1,2-a]indole. WHen treated with proton acids imidazo[1,2-a]indoles are converted to 3H-indolium salts. Opening of the imidazolidine ring is also found when imidazo[1,2-a]indole is acylated with benzoyl chloride.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 227–230, February, 1987.     

Triazino-1,2,4-[4,5-a] indoles IV. Etude des triazinoindolethiones

The 1,2-dihy dro-1,2,4-triazino[4,5-a] indole-1-thiones 2 and 3 obtained by sulphurization of the 1,2-dihydro-1,2,4-triazino-[4,5-a] indol-1-ones 1 and 4 with phosphorus pentasulphide are intermediate products in the synthesis of 1,2,4-triazino[4,5-a]-indolc 10 and 4-methyl-1,2,4 omdp;e 19. The thiolactam-thiolactim tautomerism was studied using the ir and nmr spectra and allowed N. and S.substitutions. The methylation with dimethyl sulphate afforded mixtures of N. and S. methyl derivatives which were separated by chromatographic analysis and identified by |21|0H nmr and unequivocal synthesis.     

Cyclocondensation of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-R-1,2-dihydropyrid-2-ones with heterocyclic N,N-and N,C-1,3-dinucleophiles

[3+3] Cyclocondensation of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-R-1,2-dihydropyrid-2-ones with heterocyclic N,N-and N,C-1,3-dinucleophiles proceeds regioselectively to give a series of new tri-and tetracyclic heterosystems, viz. derivatives of 5,6-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-6-one, 1,2-dihydropyrido[2,3-d]pyrido[2′,3′: 3,4]pyrazolo[1,5-a]pyrimidin-2-one, 8,9-dihydro-5H-pyrido-[2,3-d]thiazolo[3,2-a]pyrimidin-8-one, 1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrido[2,3-d]pyrimidin-2-one, and 1,2-dihydrobenzo[4,5]imidazo[1,2-g][1,6]naphthyridin-2-one.     

Regiospecific synthesis of 3-substituted imidazo[1,2-a]pyridines,imidazo[1,2-a]pyrimidines,and imidazo[1,2-c]pyrimidine

3-Substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and imidazo[1,2-c]pyrimidine were obtained regiospecifically in yields of 35-92% in one pot by reaction of 2-aminopyridines or 2-(or 4-)aminopyrimidines, respectively, with 1,2-bis(benzotriazolyl)-1,2-(dialkylamino)ethanes.     

Thermolysis of benzannulated enyne-carbodiimides. Application in the synthesis of pyrido[1',2':1,2]pyrimido[4,5-b]indoles and related heteroaromatic compounds

Several derivatives of the pyrido[1',2':1,2]pyrimido[4,5-b]indoles 4 and the pyrazino[1',2':1,2]pyrimido[4,5-b]indoles 14 were synthesized by treatment of the benzannulated enyne-isocyanates 8 with the iminophosphoranes 9 and 13, respectively, for the aza-Wittig reaction followed by thermolysis. The reaction presumably proceeds through an initial formation of the corresponding benzannulated enyne-carbodiimides, such as 10, followed by a formal intramolecular hetero Diels-Alder reaction. Surprisingly, when the iminophosphorane 17 was used for condensation with 8, the expected pyrimido[1',6':1,2]pyrimido[4,5-b]indoles 16 were not obtained. Instead, the isomeric pyrimido[6',1':2,3]pyrimido[4,5-b]indoles 21 were isolated. Presumably, an alternative reaction pathway involving an initial [2 + 2] cycloaddition reaction to form 19 followed by ring opening could lead to 20 and, after an intramolecular radical-radical coupling, 21. Treatment of the urea derivatives 24 with dibromotriphenylphosphorane also produced in situ the benzannulated enyne-carbodiimides 25, which on thermolysis gave the isoquinolino[2',1':1,2]pyrimido[4,5-b]indoles 26. Methylation of 4a, 14a, and 26a with methyl iodide occurred exclusively at the site of the indolo nitrogen. The planar geometry of those novel heteroaromatic compounds, resembling many DNA-binding agents, makes them potential candidates as DNA intercalators.     

Synthesis of naphtho[2',3':4,5]imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>][1,3]-thiazole-5,10-dione and naphtho[2',3':4,5]imidazo-[2,1-<Emphasis Type="Italic">b</Emphasis>][1,3]benzothiazole-7,12-dione

The reaction of 2,3-dibromo-1,4-naphthoquinone with 2-aminothiazole in MeONa/MeOH at 60oC for 3 h gave naphtho[2',3':4,5]imidazo[2,1-b][1,3]thiazole-5,10-dione in 64% yield. The reaction of 2,3-dibromo-1,4-naphthoquinone with 2-aminobenzothiazole under the above-mentioned conditions gave 2-(benzo[d]thiazol-2-ylamino)-3-bromonaphthalene-1,4-dione in 64% yield, which on treatment with Na/THF or NaN₃/acetone under reflux conditions gave naphtho[2',3':4,5]imidazo[2,1-b][1,3]- benzothiazole-7,12-dione in 69 and 56% yields, respectively.     

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.