Five-membered 2,3-dioxoheterocycles: XCVI. Reactions of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5h)-triones with substituted 1,3,3-trimethyl-2-azaspiro[4.5]dec-1-enes

3-Aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones react with 1,3,3,7,9-pentamethyl-2-azaspiro-[4.5] deca-1,6,9-trien-8-one and 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one providing 3-aroyl-2-hydroxy-3a-{(3,3,7,9-tetramethyl-8-oxo-2-azaspiro[4.5]deca-1,6,9-trien-1-yl)methyl}pyrrolo[1,2-a-quinoxaline-1,4(3a H,5H)-diones and 3-aroyl-2-hydroxy-3a-{(5′,5′-dimethyl-4-oxo-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-2′-yl)methyl}pyrrolo[1,2-a]-quinoxaline-1,4(3aH,5H)-diones.     

Efficient synthesis and resolution of novel 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one by lipase Pseudomonas cepacia

Lipase Pseudomonas cepacia catalyzed acylation of (±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one using vinyl acetate as the acyl donor in acetone gave (−)-(R)-2-acetoxy-2-(methyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one and (+)-(S)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one with high enantiomeric excess. Enantiomerically pure 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one are useful intermediates for the preparation of Ramelteon, an FDA approved drug for the treatment of insomnia.     

Synthesis of new Di-, Tetra-, and hexahydropyrazolo[3,4-e][1,4]diazepine derivatives

Alkaline hydrolysis of 5-(2,2-diethoxyethyl-, aroylmethyl-, or ethoxycarbonylmethyl)-1H-pyrazolo-[3,4-e]pyrimidin-4(5H)-ones gave 5-amino-N-(2,2-diethoxyethyl-, aroylmethyl-, or carboxymethyl)-1H-pyrazole-4-carboxamides which underwent cyclization to the corresponding 7-hydroxy-5,6,7,8-tetrahydropyrazolo-[3,4-e][1,4]diazepin-4(1H)-ones, 5,6-dihydropyrazolo[3,4-e][1,4]diazepin-4(1H)-ones, and 1,5,6,8-tetrahydropyrazolo[3,4-e][1,4]diazepine-4,7-diones. Reduction of the cyclization products with NaBH4 and LiAlH4 afforded 5,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepin-4(1H)-ones and 1,4,5,6,7,8-hexahydropyrazolo[3,4-e]-[1,4]diazepines.     

Synthesis of the dibenzo[f,h]phthalazine and dibenzo[f,h]cinnoline skeleton via a ‘Suzuki-Pd-catalyzed intramolecular arylation’ and a ‘Suzuki-Pschorr’ approach

Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2H)-one yielded hitherto unknown 2-benzyldibenzo[f,h]phthalazin-1(2H)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl)-4-phenylpyridazin-3(2H)-one via a Pschorr type reaction was also investigated. Similarly, the construction of 2-methyldibenzo[f,h]cinnolin-3(2H)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(2H)-one and 2-methyl-5-(2-aminophenyl)-6-phenylpyridazin-3(2H)-one is also reported. Removal of the N-benzyl protective group of 2-benzyl-dibenzo[f,h]phthalazin-1(2H)-one with AlCl₃ yielded unsubstituted dibenzo[f,h]phthalazin-1(2H)-one.     

Antimicrobial mechanism of copper (II) 1,10-phenanthroline and 2,2′-bipyridyl complex on bacterial and fungal pathogens

Copper based metallo drugs were prepared and their antibacterial, antifungal, molecular mechanism of [Cu(SAla)Phen]·H₂O and [Cu(SAla)bpy]·H₂O complexes were investigated. The [Cu(SAla)Phen]·H₂O and [Cu(SAla)bpy]·H₂O were derived from the Schiff base alanine salicylaldehyde. [Cu(SAla)Phen]·H₂O showed noteworthy antibacterial and antifungal activity than the [Cu(SAla)bpy]·H₂O and ligand alanine, salicylaldehyde. The [Cu(SAla)Phen]·H₂O complex showed significant antibacterial activity against Salmonella typhi, Staphylococcus aureus, Salmonella paratyphi and the antifungal activity against Candida albicans and Cryptococcus neoformans in well diffusion assay. The mode of action of copper (II) complex was analyzed by DNA cleavage activity and in silico molecular docking. The present findings provide important insight into the molecular mechanism of copper (II) complexes in susceptible bacterial and fungal pathogens. These results collectively support the use of [Cu(SAla)Phen]·H₂O complex as a suitable drug to treat bacterial and fungal infections.     

Synthesis and some properties of N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1??,2??:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2??,1??:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.     

Five-membered 2,3-dioxoheterocycles: LXXXVI. Spiro-heterocyclization of 1-aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones under the action of 3-arylamino-1H-inden-1-ones. Crystal and molecular structure of 4′-hydroxy-3′-(2,4-dimethylbenzoyl)-1,1′-diphenyl-1H-spiro[indeno[1,2-b]pyrrole-3,2′-pyrrole]-2,4,5′(1′H)-trione

1-Aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones react with 3-arylamino-1H-inden-1-ones affording 1,1??-diaryl-3??-aroyl-4??-hydroxy-1H-spiro[indeno[1,2-b]pyrrole-3,2??-pyrrole]-2,4,5??(1??H)-triones. The crystal and molecular structure of 4??-hydroxy-3??-(2,4-dimethylbenzoyl)-1,1??-diphenyl-1H-spiro[indeno[1,2-b] pyrrole-3,2??-pyrrole]-2,4,5??(1??H)-trione.     

Synthesis of novel spiro[indole-3,3′-pyrrolidin]-2(1H)-ones

Diastereoselective [3+2] cycloaddition of azomethine ylide to 1,3-dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-[1,2,4]triazine-2,7(1H,6H)-dione yields hitherto unknown 1,1′,3-trimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydrodispiro(imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indole)-2,2″,7(1H,1″H)-triones.     

Reaction of 3-phenyl-3-aminoquinoline-2,4-diones with isothiocyanates. Facile access to novel spiro-linked 2-thioxoimidazolidine-oxindoles and imidazoline-2-thiones

3-Phenyl-3-amino-1H,3H-quinoline-2,4-diones (1) react with alkyl or aryl isothiocyanates to give novel 9b-hydroxy-3a-phenyl-1,2,3,3a-tetrahydro-2-thioxo-5H-imidazo[4,5-c]quinolin-4(9bH)-ones in high yields. These compounds rearrange in boiling acetic acid or concentrated hydrochloric acid to give novel 5-phenyl-2-thioxospiro[4H-imidazol-4,3′-[3H]indol]-2′(1′H,3H)-ones, 5-hydroxy-5-phenyl-2-thioxospiro[imidazolidine-4,3′-[3H]indol]-2′-ones and (2-methylaminophenyl)-5-phenyl-1H-imidazole-2(3H)-thiones. All compounds were characterized by their ¹H, ¹³C, IR and MS data, and in some cases also by ¹⁵N NMR data. The structures and compositions of four compounds were confirmed by single crystal X-ray diffraction.     

Convenient Synthesis of N-Heterocycle-Fused Tetrahydro-1,4-diazepinones

A general approach towards the synthesis of tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-a]indol-1-one and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1H-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation—yielding target pyrazolo[1,5-a][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1H-indole- and ethyl 1H-benzo[d]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by ¹H, ¹³C, and ¹⁵N-NMR spectroscopy and HRMS investigation.     

Application of N,3-diaryl-3-oxo-propanethioamide in synthesis: an efficient and mild domino approach to highly substituted fused chromenones

A convenient and rapid synthesis of hitherto unknown 3-aroyl-4-aryl-2-phenylamino-4H-benzo[g]chromene-5,10-diones in high yield from β-aroyl-thioacetanilide, aromatic aldehyde, and 2-hydroxy-1,4-naphthoquinone via InCl₃ catalyzed one-pot three-component tandem Knoevenagel condensation–Michael addition–intramolecular cyclization–elimination reaction sequence is disclosed for the first time. This domino protocol has been used to obtain highly substituted pyrano[3,2-c]chromen-5(4H)-ones and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-ones from N,3-diaryl-3-oxo-propanethioamide, aromatic aldehyde, and 4-hydroxycoumarine or dimedone under mild reaction conditions. A plausible reaction mechanism is proposed. The 4H-pyrano[3,2-c]chromen-5-one and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-one derivatives possessing 3-(2-chlorobenzoyl)-2-phenylamino-substituents further cyclized under basic conditions to yield penta-cyclic 7,13-diaryl-5,14-dioxa-13-aza-benzo[a]naphthacen-6,8(7H,13H)-dione and tetra-cyclic 6,12-diaryl-3,3-dimethyl-3,4-dihydro-2H-chromeno[2,3-b]quinolin-1,11(6H,12H)-dione, respectively.     

Building libraries of skeletally diverse scaffolds from novel heterocyclic active methylene compound through multi-component reactions

Libraries of skeletally diverse potential bioactive polycyclic/spirocyclic heterocyclic compounds; 2-amino-7,9-dimethyl-5-oxo-4-aryl-4,5,6,7-tetrahydropyrano[2,3-d]pyrazolo[3,4-b]pyridine-3-carbonitrile, 2′-amino-7′,9′-dimethyl-2,5′-dioxo-6′,7′-dihydro-5′H-spiro[indoline-3,4′-pyrano[2,3-d]pyrazolo[3,4-b]pyridine]-3′-carbonitrile, and 5,5′-(arylmethylene)bis(4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) have been synthesized through a multi-component reaction using novel heterocyclic active methylene compound 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one as one of the building blocks. This protocol can be considered to be an efficient and eco-friendly strategy for diversity oriented synthesis.     

A regioselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-chromene thiadiazole derivatives

A variety of 4′-(4-R-phenyl)-4-(methylthio)-2′-phenyl-2′H-spiro[chromene-2,5′-[1,2,3]thiadiazole] 5a–d and 5′-(4-R-phenyl)-4-(methylthio)-3′-phenyl-3′H-spiro[chromene-2,2′-[1,3,4]thiadiazole] 6a–d were synthesized regioselectively through the reaction of 4-(methylthio)-2H-chromene-2-thione 2 with diarylnitrilimines under refluxing dry chloroform. Whilst the reaction of 4-(allylthio)-2H-chromene-2-thione 3 with diarylnitrilimines under similar reaction conditions afforded the corresponding 4-(allylthio)-5′-(4-R-phenyl)-3′-phenyl-3′H-spiro[chromene-2,2′-[1,3,4]thiadiazole] 7a–d and 5-(4-R-phenyl)-2′-methyl-3-phenyl-2′,3′-dihydro-3H-spiro[[1,3,4]thiadiazole-2,4′-thieno[3,2-c]chromene] 9a–d as two unisolable diastereoisomeric forms. The structures of the obtained spiro cycloadduct thiadiazoles have been assigned by means of spectroscopic measurements.     

Electrophoretic determination of phenyl and p-bromophenyl substituted 1H,2H,3H,4H-pyrido[4,3-d]pyrimidinium diiodobromides

Phenyl and p-bromophenyl substituted 1H,2H,3H,4H-pyrido[4,3-d]pyrimidinium diiodobromides have been identified and determined by capillary zone electrophoresis on an unmodified quartz capillary. It has been found that an increase in the number of bromine atoms in the structure of 1H,2H,3H,4H-pyrido[4,3-d]pyrimidinium derivatives consecutively decreases the electrophoretic mobility of the cations. The developed method makes possible the determination pyrido[4,3-d]pyrimidinium derivatives in the concentration range (0.03–0.25) mM with the c _min (3.1–10.0) μM.     

Five-membered 2,3-dioxo heterocycles: LXIII. Cascade recyclization of isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates with cyclic enamines. Crystalline and molecular structure of 1′-benzyl-6′,6′-dimethyl-3-[(Z)-phenyl(phenylamino)methylidene]-6′,7′-dihydro-3H-spiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraone

Isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates reacted with N-substituted 3-amino-5,5-dimethylcyclohex-2-en-1-ones to give the corresponding 1′-substituted (Z)-6′,6′-dimethyl-3-[phenyl(arylamino)methylidene]-6′,7′-dihydro-3H-spiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraones. The structure of 1′-benzyl-6′,6′-dimethyl-3-[(Z)-phenyl(phenylamino)methylidene]-6′,7′-dihydro-3Hspiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraone was proved by X-ray analysis.     

Five-membered 2,3-dioxo heterocycles: LXII. Reaction of 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with N,N′-dihydroxycyclohexane-1,2-diamine. Unusual rearrangement in the spiro[quinoxaline-2,2′-pyrrole] system

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with N,N′-dihydroxycyclohexane-1,2-diamine to give 3-aroyl-1′,4,4′-trihydroxy-1-(2-hydroxyphenyl)-4a′,5′,6′,7′,8′,8a′-hexahydro-1′H-spiro[pyrrole-2,2′-quinoxaline]-3′,5(1H,4′H)-diones which underwent rearrangement into 1′-aroyloxy-4,4′-dihydroxy-1-(2-hydroxyphenyl)-4a′,5′,6′,7′,8′,8a′-hexahydro-1′H-spiro[pyrrolidine-2,2′-quinoxaline]3′,4,5(4′H)-triones via [1,4]-migration of the aroyl group. The product structure was proved by X-ray analysis.     

Five-membered 2,3-dioxo heterocycles: CI. Reaction of 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with arylhydrazines. Crystal and molecular structure of substituted 2-hydrazonopyrrolo[2,1-c][1,4]benzoxazine

A new direction of nucleophilic attack was revealed in the reactions of 3-aroylpyrrolo[2,1-c][1,4]-benzoxazine-1,2,4-triones with o-tolylhydrazine and 2-hydrazinylbenzoic acid hydrochloride, which afforded the corresponding hydrazones at the C²=O carbonyl group, substituted 2-(2-o-tolylhydrazono)pyrrolo[2,1-c]-[1,4]benzoxazine-1,4(2H)-diones and pyrrolo[2,1-c][1,4]benzoxazin-2(4H)-ylidenehydrazinylbenzoic acids. The structure of (Z)-2-{2-[3-benzoyl-1,4-dioxo-1H-pyrrolo[2,1-c][1,4]benzoxazin-2(4H)-ylidene]hydrazinyl}-benzoic acid was determined by X-ray analysis.     

Intramolecular amidation: synthesis of novel imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole fused diazepinones

Novel heterocyclic systems 2-alkyl/aryl-9-(2-hydroxybenzylidene)-7,9-dihydro-8H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-d][1,2]diazepin-8-one and 9-(2-hydroxy-benzylidene)-3,3-dimethyl-3,4,7,9-tetrahydro-2H-11-thia-4b,6,7,10-tetraazaindeno[1,2-a]azulene-1,8-dione are synthesized via an intramolecular amidation reaction. An interesting ring opening and cyclization of 2-alkyl/aryl-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde and 6,6-dimethyl-8-oxo-2-(2-oxo-2H-chromen-3-yl)-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-3-carbaldehyde are discussed.     

Five-membered 2,3-dioxo heterocycles: XCVII. Reaction of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with Fischer’s base

3-Aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones reacted with 1,3,3-trimethyl-2-methylidene-2,3-dihydro-1H-indole (Fischer’s base) to give (2Z)-1-aryl-2-[3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene]-5-(1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene)pentane-1,3,4-triones.     

Isomerization of 5-(2H-Azirin-2-yl)oxazoles: An Atom-Economic Approach to 4H-Pyrrolo[2,3-d]oxazoles

An atom economical method for the preparation of variously substituted 4H-pyrrolo[2,3-d]oxazoles was developed on the basis of thermal isomerization of 5-(2H-azirin-2-yl)oxazoles. The latter were prepared by Rh₂(oct)₄ catalyzed reaction of 2-(3-aryl/heteroaryl)-2-diazoacetyl-2H-azirines with a set of substituted acetonitriles, benzonitriles, acrylonitrile and fumaronitrile. According to DFT calculations the transformation of 5-(2H-azirin-2-yl)oxazole to 4H-pyrrolo[2,3-d]oxazole occurs through the nitrenoid-like transition state to give a 3aH-pyrrolo[2,3-d]oxazole intermediate, followed by 1,5-H-shift.