Regioselective synthesis of 1-aryl-3,4-substituted/annulated-5-(methylthio)pyrazoles and 1-aryl-3-(methylthio)-4,5-substituted/annulated pyrazoles

[reaction: see text] Highly efficient and regioselective synthesis of 1-aryl-3,4-substituted/annulated-5-(methylthio)pyrazoles and 1-aryl-3-(methylthio)-4,5-substituted/annulated pyrazoles has been reported via cyclocondensation of arylhydrazines with either alpha-oxoketene dithioacetals or beta-oxodithioesters.     

Synthesis of pyrido[1,2-a]benzimidazoles from 2-acylmethyl-1H-benzimidazoles

Methods are proposed for the synthesis of previously unknown pyrido[1,2-a]benzimidazoles via the cyclocondensation of 2-acylmethyl-1H-benzimidazoles with malononitrile, triethylorthoformate ester, or ethoxymethylenemalononitrile. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1073–1079, July, 2006.     

Investigation of imidazo[1,2-a]benzimidazole derivatives

Esters of 1-alkyl- and 1-aralkyl-2-iminobenzimidazoline-3-acetic acids are converted to esters of 2,9-dimethylimidazo[1,2,-a]benzimidazole-3-carboxylic acid on heating with acetic anhydride. The brief action of acetic anhydride on the free iminobenzimidazolineacetic acids gives 2-oxo-2,3-dihydroimidazo[1,2-a]benzimidazoles, which are converted to 2,9-substituted 3-acetylimidazo[1,2-a]benzimidazoles on prolonged heating with acetic anhydride.See [1] for communication V.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 111–114, January, 1973.     

Synthesis by radical cyclization and cytotoxicity of highly potent bioreductive alicyclic ring fused [1,2-a]benzimidazolequinones

The key step in the synthesis of new five, six and seven-membered alicyclic ring [1,2-a]-fused bioreductive benzimidazolequinones was radical cyclisation. Six and seven-membered tributyltin hydride-mediated homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred in high yields (63-70 %) when quaternising the pyridine-like 3-N of imidazole with camphorsulfonic acid and using large excesses of the azo-initiator, 1,1'-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. Elaboration of benzimidazoles to the benzimidazolequinones occurred in excellent yields. The IC50 values for the cytotoxicity of benzimidazolequinones towards the human skin fibroblast cell line GM00637 were in the nanomolar range, as determined by using the MTT assay. The benzimidazolequinones were much more cytotoxic than indolequinone analogues. 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole-6,9-dione was the most potent compound prepared being more than 300 times more cytotoxic than the clinically used bioreductive drug, mitomycin C. The latter benzimidazolequinone was more potent under hypoxic conditions (associated with solid tumors), being 4.4 times more cytotoxic than under aerobic conditions, while mitomycin C was 1.8 times more selective towards hypoxia. The cyclopropane fused pyrido[1,2-a]benzimidazolequinone, 1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrido[1,2-a]benzimidazole-5,8-dione was less cytotoxic and selective than the five-membered ring analogue, 1,1a,8,8a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benzimidazole-3,6-dione. Modifying the structure of the most potent pyrido[1,2-a]benzimidazolequinone by attaching methyl substituents onto the quinone moiety increased reductive potentials and decreased cytotoxicity and selectivity towards hypoxia.     

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.     

Regioselectivity of heterocyclization of 2-substituted 3,3-bis(methylsulfanyl)acrylo-nitriles with 2-benzimidazoleacetonitrile

Functionalized pyrido[1,2-a]benzimidazoles have been synthesized by the interaction of 2-substituted 2-cyano-3,3-bis(methylsulfanyl)acrylonitriles with 2-benzimidazoleacetonitrile under S _N Vin reaction conditions.     

Efficient Pd(0)-mediated microwave-assisted arylation of 2-substituted imidazo[1,2-a]pyrimidines

A short and practical synthesis of 2,3-substituted imidazo[1,2-a]pyrimidines, based on microwave-assisted Heck-type arylation of 2-substituted imidazo[1,2-a]pyrimidines, was developed. A 45-membered library of 2,3-substituted imidazo[1,2-a]pyrimidines was obtained with good yields and purities using this optimized protocol.     

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.     

Tumorhemmende wirkstoffe, XIII [1] aromatisch carbocyclisch und heterocyclisch substituierte 2-perfluoralkylpyrimido[1,2-a]benzimidazole

The interaction of 2-aminobenzimidazole with the appropriate β-diketones carrying fluoroalkyl groupings has led to the 2-perfluoroalkylpyrimido[1,2-a]benzimidazoles as follows: 4-phenyl-, 4-(2'-naphthyl)-, 4-(3'-pyridyl)-, 4-(2'-furyl)-, and 4-(2,-thienyl)-2-trifluoromethylpyrimido[1,2-a]benzimidazole, and 4-(2'-thienyl)-2-(heptafluoropropylpyrimido [1,2-a]benzimidazole.     

Pyrido[1,2-a]benzimidazoles et analogues: Synthese et etude structurale

The Cyclisation of 1-(2-propynyl)2-aminomethylbenzimidazoles leads to pyrido[1,2-a]benzimidazoles. The proposed mehcanism involves in a first step hetrocyckisation followed by a rerrangemnet. This Process is suitable for some aza analoga of benzimidazole.     

Synthese von imidazo[1,5-a]- und pyrazino[1,2-a]benzimidazolen

1,2-Dihydro-3H-imidazo[1,5-a]benzimidazoles (6), 1-oxo-1,2-dihydro-3H-imidazo[ 1,5-a] benzimidazoles (8), 3H-imidazo[1,5-a]benzimidazoles (7), 3-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a] benzimidazoles (12), and 3,4-dioxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]benzinudazoles (13) were synthesized from 2-α-aminobenzyl (benzhydryl)-benzimidazoles (2).     

A Facile Synthesis of Pyrido [1,2-a] Benzimidazoles

The synthesis and characterisation of some of the new pyrido [1,2-a] benzimidazoles from 1H-benzimidazole-2-acetonitrile and diethyl ethoxy methylene malonic ester.     

Synthesis of isoxazolo[2,3-a]quinoxalines and pyrrolo[1,2-a]quinoxalines by 1,3-dipolar cycloaddition reaction

The isoxazolo[2,3-a]quinoxalines 11a,b and pyrrolo[1,2-a]quinoxalines 12a,b were selectively synthesized from the 2-substituted 6-chloroquinoxaline 4-oxides 10a,b . The pyrrolo[1,2-a]quinoxalines 12a,b were clarified to be produced by the ring transformation of the isoxazolo[2,3-a]quinoxalines 11a,b . The pyrrolo[1,2-a]quinoxalines 14a,b were obtained from both 2,6-dichloroquinoxaline 4-oxide 9 and compounds 12a,b .     

Cyclocondensation of n-(prop-2-yn-1-yl)- and n-(penta-2,4-diyn-1-yl)- <Emphasis Type="Italic">o</Emphasis>-phenylenediamines with phenyl isothiocyanate and carbon disulfide

The cyclocondensation of N-(prop-2-yn-1-yl)-o-phenylenediamines with phenyl isothiocyanate leads to the formation of 1-(prop-2-yn-1-yl)-1,3-dihydro-2H-benzimidazole-2-thiones irrespective of the substituent nature at the triple bond. Reactions of both mono- and diacetylenic derivatives of o-phenylenediamine with carbon disulfide in the presence of KOH proceed with the formation of two heterocyclic nuclei simultaneously. From N-(prop-2-yn-1-yl)-o-phenylenediamines containing an aryl substituent at the triple bond, and N-(penta-2,4-diyn-1-yl)-o-phenylenediamines 2-methylidene-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles are formed. The latter are readily isomerized under the action of base giving thiazolo[3,2-a]benzimidazoles. The cyclocondensation of N-(alk-2-yn-1-yl)-o-phenylenediamines with CS₂ leads to [1,3]thiazino[3,2-a]benzimidazoles.     

Research on imidazo[1,2-a] benzimidazole derivatives

2-Acyl-substituted 3-methyl(phenyl)-9-methylimidazo[1,2-a]benzimidazoles were synthesized by three methods: by the reaction of -halo ketones with 3-benzoyl-2-imino-1-methylbenzimi-dazoline, by reaction of acetic anhydride or acetyl bromide with 1-methyl-2-phenacylaminobenzimidazole, and by acylation of 3-substituted imidazo[1,2-a]benzimidazoles. Some of the properties of the resulting 2-acyl-substituted compounds were studied.See [1] for communication XIV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 111–115, January, 1977.     

Alkylation of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones

Reaction of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones with dimethyl sulfate and haloalkanes in DMF or DMSO in the presence of potassium hydroxide gives the 1-substituted 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones (N-substituted products) and 9,9a-dihydro-3H-imidazo[1,2-a]indoles (O-substituted products). The latter, on treatment with acids and bases, are converted into 1-alkoxycarbonylmethyl-2,3-dihydro-1H-indoles. 1-Ethoxycarbonyl-methyl-2,3-dihydro-1H-indoles on treatment with lithium aluminohydride undergoes cyclization to 2,3,9,9a-tetrahydrooxazolo[3,2-a]indole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 49–53, January, 1988.     

Synthesis of isoindolo[2,1-a]quinoline derivatives and their effects on N2-induced hypoxia

A variety of isoindolo[2,1-a]quinoline derivatives as well as the following related heterocycles have been prepared: 11b,12-dihydro-5H-isoindolo[2,1-b][2]benzazepine-7,13-dione (8a), 7,8,14,14a-tetrahydroisoindolo[2,1-c][3]benzazocine-5, 13-dione (8b), 6a,7-dihydroisoquinolino[2,3-a]quinoline-5,12-dione (12), 2,3,3a-4-tetrahydropyrrolo[1,2-a]quinoline-1,5-dione (14), and pyrido[2',3':3,4]pyrrolo[1,2-a]quinoline-5,11(5H)-dione (17). The key synthetic step involves an intramolecular Friedel-Crafts reaction of acid chlorides such as isoindole-1-acetyl chlorides (4), the acids (3) of which were prepared starting with 2-arylisoindole-1,3(2H)-diones (2-arylphthalimides) (1). The protective effects of isoindolo[2,1-a]quinoline derivatives (19 and 20) against N2-induced hypoxia were examined. Among them, 6-(diethylaminomethyl)isoindolo[2,1-a]quinoline-5,11(5H)-dio ne (19b) showed the most potency.     

Synthesis of 1-and 7-substituted 2,3-dihydro-1h-pyrrolo[1,2-a]benzimidazoles

Cyclization of 5-substituted 2-(-chloroalkyl)benzimidazoles in the presence of sodium ethoxide gave some benzene-and pyrroldine-ring-substituted 2,3-dihydro-1H-pyrrolo[1,2-a]-benzimidazoles.Translated from Khimiya Geterotsklicheskikh Soedinenii, No.8, pp.1137–1139, August, 1974.     

Research on imidazo[1,2-a]benzimidazole derivatives. 25. Reaction of 2,9-disubstituted imidazo[1,2-a]benzimidazoles with acrylic acids and their derivatives

The substitutive addition of acrylic acids and their esters, amides, and nitriles to 2,9-disubstituted imidazo[1,2-a]benzimidazoles, which leads to 3-(imidazo[1,2-a]benzimidazol-3-yl)propionic acids and their derivatives, was studied. The rate of addition depends on the structure of the unsaturated compound, the nature of the substituent in the 2 position, the magnitude of the charge on the carbon atom in the 3 position of the heteroring, and the reaction conditions. The addition proceeds most smoothly in polyphosphoric acid (PPA). In the case of acrylonitrile imidazo[1,2-a]benzimidazol-3-ylpropionic acid amides were isolated in PPA. In the reaction of - or -substituted acrylic acids with 2-phenylimidazo[1,2-a]benzimidazoles in PPA, in addition to the corresponding imidazo[1,2-a]benzimidazol-3-ylpropionic acids, products of their intramolecular cyclodehydration at the ortho position of the phenyl substituent are formed.See [1] for Communication 24.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1496–1502, November, 1987.     

Synthesis and transformations of 2,3-dioxo-2,3-dihydroimidazo [1,2-a]-benzimidazole derivatives

9-(H)Alkyl-2,3-dioxo-2,3-dihydroimidazo[1,2-a]benzimidazoles were synthesized by the action of oxalyl chloride on 2-amino-1(H)alkylbenzimidazoles and subsequent cyclization of the resulting 2-amino-1-(H)alkyl-3-chlorooxalylbenzimidazolium chlorides in the presence of triethylamine. The behavior of the synthesized benzimidazoles with respect to the action of alkalis, lithium aluminum hydride, and ethylmagnesium bromide was studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1391–1395, October, 1976.