2-benzazepines. 10 [1]. New d-fused 2-benzazepines

Pyrano[3,2-d][2]benzazepines were synthesized by reaction of the beta-dimethylamino unsaturated ketone 1 with malonic ester or the anion of t-butyl acetate. Conversion of the pyrano derivative to the pyrido[3,2-d]-[2]benzazepine was achieved in low yield. A pyrrolo[3,2-d][2]benzazepine was prepared via an oxazepino-[6,7-d][2]benzazepine which was obtained by reaction of 1 with the anion of ethyl isocyanoacetate.     

Utility of Pyridine‐2(1H)‐thiones in the Synthesis of Novel Bis‐Thieno[2,3‐b]pyridines and Their Fused Azines

The starting materials pyridine‐2(1H)‐thiones are prepared and reacted with halogen‐containing reagents in ethanolic sodium acetate solution to give the corresponding 2‐S‐alkylpyridines, which cyclized upon their boiling in methanolic sodium methoxide solution at reflux to give the corresponding thieno[2,3‐b]pyridines in excellent yields. Bis (thieno[2,3‐b]pyridine‐2‐carboxamides), incorporating 2,6‐dibromophenoxy moiety, are prepared by the bis‐O‐alkylation of thieno[2,3‐b]pyridine‐2‐carboxamide derivatives. Two synthetic routes are designed to prepare the target molecules pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4(3H)‐ones, pyrido[3′,2′:4,5]thieno[3,2‐d][1,2,3]triazin‐4(3H)‐ones, and their bis‐analogues using thieno[2,3‐b]pyridine‐2‐carboxamides and their bis‐analogues. The structure of the target molecules is elucidated using elemental analyses as well as spectral data.     

Selenium heterocycles XLIV. Syntheses of 8,9‐dihydro‐1,2,3‐thiadiazolo[4,5‐a]‐4,7‐dihydroxynaphthalene and 1,2,3‐selenadiazolo[4,5‐a]‐4,7‐dimethoxynaphthalene

The reaction of thionyl chloride with the semicarbazone 2 gave 4,5‐dihydro‐6,9‐dihydroxynaphtho‐[1,2‐d][1,2,3]thiadiazole ( 3 ) instead of 4,5‐dihydro‐6,9‐dimethyoxynaphtho[1,2‐d][1,2,3]thiadiazole ( 4 ). Selenium dioxide oxidation of compound 2 gave 4,5‐dihydro‐6,9‐dimethyoxynaphtho[1,2‐d][1,2,3]selenadiazole ( 5 ). Oxidation of compound 5 with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone afforded 6,9‐dimethyoxynaphtho[1,2‐d][1,2,3]selenadiazole ( 6 ).     

Synthesis of Novel Spiro Pyrano[2,3‐d]thiazolo[3,2‐a]pyrimidine via 1,3‐Dipolar Cycloaddition of Azomethine Ylide

The reaction involving 4‐phenyl‐octahydro‐pyrano[2,3‐d]pyrimidine‐2‐thione, ethyl chloroacetate and the appropriate aromatic aldehyde yielded 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones. The 1,3‐dipolar cycloaddition of 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones with azomethine ylide generated by a decarboxylative route from sarcosine and acenaphthenequinone afforded 4′‐aryl‐1′‐methyl‐5″‐phenyl‐5a″,7″,8″,9a″‐tetrahydro‐2H,5″H,6″H‐dispiro[acenaphthylene‐1,2′‐pyrrolidine‐3′,2″‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine]‐2,3″‐diones in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, elemental analysis, and X‐ray crystallographic analysis.     

Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

An Expedient Method for the Synthesis of 1,2,4‐Triazolo‐fused 1,5‐Benzodiazepine, 1,5‐Benzoxazepine,and 1,5‐Benzothiazepine Scaffolds: A Novel Seven‐membered Ring System of Biological Interest

New heterocyclic compounds 1‐(3‐methyl‐9H‐dibenzo[b,f][1,2,4]triazolo[4,3‐d][1,4]diazepin‐6‐yl)ethanone 8a , 1‐(3‐methyldibenzo[b,f][1,2,4]triazolo[4,3‐d][1,4]oxazepin‐6‐yl)ethanone 8b , and 1‐(3‐methyldibenzo[b,f][1,2,4]triazolo[4,3‐d][1,4]thiazepin‐6‐yl)ethanone 8c are synthesized from benzodiazepinone, benzoxazepinone, and benzothiazepinone derivatives. These heterocyclic scaffolds have wide medicinal importance. Best results were obtained in antibacterial screening against Escherichia coli, Enterobacter cloacae, and Staphylococcus aureus and antifungal screening against Candida albicans and Fusarium oxysporum. 1,1‐Diphenyl‐2‐picrylhydrazyl radical scavenging activities of compounds 6c , 7c , and 8c were tested in doses 10, 20, 30, 40, and 50 μg/mL and were expressed as IC₅₀ values and percent of inhibition with means ± standard deviation of three different concentrations of synthesized compounds. The assignment of the structures of synthesized compounds was made by thin‐layer chromatography, elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR, and liquid chromatography–mass spectrometry.     

Synthesis of oxazolo[3,2‐b]hetero[1,2,4]thiadiazine S,S‐dioxides

Six bromomethyl derivatives of the new 2,3‐dihydrooxazolo[3,2‐b]thieno[3,4‐e][1,2,4]thiadiazine 5,5‐dioxides, 2,3‐dihydrooxazolo[3,2‐b]thieno[2,3‐e][1,2,4]thiadiazine 5,5‐dioxides and 6,7‐dihydrooxazolo‐[3,2‐b]pyrazolo[4,3‐e][1,2,4]thiadiazine 9,9‐dioxides heterocyclic ring systems were synthesized. These compounds are good intermediates for the preparation and development of promising antiviral and psy‐chotropic drugs. The structures of the products are supported by different nmr spectroscopic methods and mass spectrometry.     

Microwave‐Assisted and Ultrasonic‐Assisted Three‐Component Heterocyclization of 4‐Amino‐5‐carboxamido‐1,2,3‐triazole,Thiopyran‐3‐one‐1,1‐dioxide,and Aromatic Aldehydes

Three‐component heterocyclization of 4‐amino‐5‐carboxamido‐1,2,3‐triazole, thiopyran‐3‐one‐1,1‐dioxide, and aromatic aldehydes under ultrasonic and microwave irradiation was studied. Regardless of the reaction parameters, 5,6,7,9‐tetrahydro‐4H‐thiopyrano[3,2‐d][1,2,3]triazolo[1,5‐a]pyrimidine‐8,8‐dioxides were isolated as sole reaction products whose structures were proven with help of NMR data and X‐ray analysis.     

Conversion of 3‐amino‐4‐arylamino‐1H‐isochromen‐1‐ones to 1‐arylisochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐ones: synthesis,spectroscopic characterization and the structures of four products and one ring‐opened derivative

An efficient synthesis of 1‐arylisochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐ones, involving the diazotization of 3‐amino‐4‐arylamino‐1H‐isochromen‐1‐ones in weakly acidic solution, has been developed and the spectroscopic characterization and crystal structures of four examples are reported. The molecules of 1‐phenylisochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, C₁₅H₉N₃O₂, (I), are linked into sheets by a combination of C—H…N and C—H…O hydrogen bonds, while the structures of 1‐(2‐methylphenyl)isochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, C₁₆H₁₁N₃O₂, (II), and 1‐(3‐chlorophenyl)isochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, C₁₅H₈ClN₃O₂, (III), each contain just one hydrogen bond which links the molecules into simple chains, which are further linked into sheets by π‐stacking interactions in (II) but not in (III). In the structure of 1‐(4‐chlorophenyl)isochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, (IV), isomeric with (III), a combination of C—H…O and C—H…π(arene) hydrogen bonds links the molecules into sheets. When compound (II) was exposed to a strong acid in methanol, quantitative conversion occurred to give the ring‐opened transesterification product methyl 2‐[4‐hydroxy‐1‐(2‐methylphenyl)‐1H‐1,2,3‐triazol‐5‐yl]benzoate, C₁₇H₁₅N₃O₃, (V), where the molecules are linked by paired O—H…O hydrogen bonds to form centrosymmetric dimers.     

6‐(2‐Fluorobenzylidene)‐2‐[1‐(2‐fluoro‐4‐biphenyl)ethyl]thiazolo[3,2‐b][1,2,4]triazol‐5(6H)‐one

The title compound, C₂₅H₁₇F₂N₃OS, was synthesized from 6‐(benzyl­idene)­thia­zolo­[3,2‐b][1,2,4]triazol‐5(6H)‐one. The fused thia­zolo­[3,2‐b][1,2,4]triazole system is essentially planar, and bifurcated C—H⋯O, C—H⋯N and C—H⋯F interactions are present between mol­ecules.     

Synthesis of 6‐Aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐Aryl‐thiazolo[3,2‐b][1,2,4]triazoles

The cyclization of the derivatives of 3‐aminotriazole, 2‐(5‐substituted 4H‐1,2,4‐triazol‐3‐ylamino)‐1‐arylethanones and 2‐(4H‐1,2,4‐triazol‐3‐ylthio)‐1‐arylethanones to yield 6‐aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐aryl‐thiazolo[3,2‐b][1,2,4]triazoles has been described.     

The Influence of Condensed Cycle on Regiochemistry of Electrophilic Heterocyclization of 3‐Alkenyl‐2‐Thioxopyrimidin‐4‐One by p‐Alkoxyphenyltellurium Trichloride

Electrophilic heterocyclization of 5‐alkenyl‐1‐methyl‐6‐thioxopyrazolo[3,4‐d]pyrimidin‐4‐ones and 3‐alkenyl‐2‐thioxoquinazoline‐4‐ones under the action of p‐alkoxyphenyltellurium trichloride leads to annulation of thiazoline cycle with formation of 7‐[(p‐alkoxyphenyl)telluromethyl]‐1‐methyl‐6,7‐dihydropyrazolo[3,4‐d][1,3]thiazolo[3,2‐a]pyrimidin‐4(1H)‐ones hydrochlorides and 2‐(p‐alkoxyphenyl)dichlorotelluromethyl‐2,3‐dihydro ‐ 5H‐[1,3]thiazolo[2,3‐b]quinazolin‐5‐ones hydrochlorides. Reduction of salts by the action of excess of sodium sulfite leads to formation of arylhetaryl telluride.     

Researches on thiazolobenzodiazepines: Behavior of tetrahydro‐1,5‐benzodiazepinethiones with aromatic α‐haloketones

A number of 1‐substituted 4H,5H,6H‐[1,3]thiazolo[3,2‐a][1,5]benzodiazepinium‐11‐bromides and S‐(2‐oxo‐2‐phenyl‐X‐(p)‐ethyl)‐3‐(2‐methyl‐1H‐benzimidazol‐1‐yl) propane (or butane) thioate hydrobromides were obtained by direct reaction of the 5‐acetyl(or formyl, or anilinocarbonyl)‐substituted tetrahydro‐1,5‐benzodiazepine‐2‐thiones with aromatic α‐bromoketones. 2‐[(1‐Acetyl‐2(or 3)‐methyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepin‐4‐yl) sulfanyl]‐1‐phenylethanones as intermediates of the formation of thiazolo [3,2‐a][1,5]benzodiazepine and N‐substituted 2‐methyl‐1H‐benzimidazole derivatives have been synthesized. Semiempirical AM1 calculations of a mechanism and energetic parameters for the heptatomic nucleus rearrangement to benzimidazole ring are presented. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:72–81, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20414     

Synthesis and Biological Activity of Novel Ethyl Esters of 4‐R‐6,8‐Dimethyl‐1‐oxo‐1,2‐dyhidropyrrolo[1,2‐d][1,2,4]triazine‐7‐carboxylic Acids

The novel heterocyclizations of ethyl 5‐(hydrazinocarbonyl)‐2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylate are developed. New derivatives of ethyl esters of 4‐R‐6,8‐dimethyl‐1‐oxo‐1,2‐dyhidropyrrolo[1,2‐d][1,2,4]triazine‐7‐carboxylic acids were obtained. The in vitro anticancer and antibacterial activities of the synthesized compounds were revealed. The most potent antibacterial compound appeared to be 1.3 inhibiting Staphylococcus aureus. Pyrrolo[1,2‐d][1,2,4]triazine 2.15 showed significant antifungal activity against Candida tenuis. The anticancer activity of the synthesized compounds was determined.     

Synthesis and Anticancer Evaluation of Some Novel 5‐Amino[1,2,4]Triazole Derivatives

Novel [1,2,4]triazole derivatives were synthesized via various synthetic pathways. Among which were different substituted [1,2,4]triazole analogues that were synthesized, in addition to various fused [1,2,4]triazolo[1,5‐a]pyrimidine derivatives, [1,2,4]triazolo[1,5‐a][1,3,5]triazines, and [1,2,4]triazolo[5,1‐c][1,2,4]triazines. Besides, benzo[h][1,2,4]triazolo[5,1‐b]quinazolines, [1,2,4]triazolo‐[5,1‐b]quinazoline, [1,2,4]triazolo[1,5‐a]quinazoline and [1,2,4]triazolo[5,1‐d][1,2,3,5]tetrazine derivatives were also synthesized. The newly synthesized compounds were evaluated for their in vitro anticancer activity against liver cancer HepG2 and breast cancer MCF7 cell lines compared with the reference drug doxorubicin. Compounds 4 , 7 , 15 , 17 , 28 , 34 , and 47 were found to exert promising anticancer activity against HepG2 cell line showing IC₅₀ values ranging from 17.69 to 25.4 μM/L, while compounds 7 , 14a , 17 , 28 , and 34 showed significant activity against MCF7 cell line with IC₅₀ values ranging from 17.69 to 27.09 μM/L.     

Eight 7‐benzyl‐3‐tert‐butyl‐1‐phenylpyrazolo[3,4‐d]oxazines,encompassing structures containing no intermolecular hydrogen bonds,and hydrogen‐bonded structures in one,two or three dimensions

7‐Benzyl‐3‐tert‐butyl‐1‐phenyl‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₂H₂₅N₃O, (I), and 3‐tert‐butyl‐7‐(4‐methylbenzyl)‐1‐phenyl‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₃H₂₇N₃O, (II), are isomorphous in the space group P2₁, and molecules are linked into chains by C—H...O hydrogen bonds. In each of 3‐tert‐butyl‐7‐(4‐methoxybenzyl)‐1‐phenyl‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₃H₂₇N₃O₂, (III), which has cell dimensions rather similar to those of (I) and (II), also in P2₁, and 3‐tert‐butyl‐1‐phenyl‐7‐[4‐(trifluoromethyl)benzyl]‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₃H₂₄F₃N₃O, (IV), there are no direction‐specific interactions between the molecules. In 3‐tert‐butyl‐7‐(4‐nitrobenzyl)‐1‐phenyl‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₂H₂₄N₄O₃, (V), a combination of C—H...O and C—H...N hydrogen bonds links the molecules into complex sheets. There are no direction‐specific interactions between the molecules of 3‐tert‐butyl‐7‐(2,3‐dimethoxybenzyl)‐1‐phenyl‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₄H₂₉N₃O₃, (VI), but a three‐dimensional framework is formed in 3‐tert‐butyl‐7‐(3,4‐methylenedioxybenzyl)‐1‐phenyl‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₃H₂₅N₃O₃, (VII), by a combination of C—H...O, C—H...N and C—H...π(arene) hydrogen bonds, while a combination of C—H...O and C—H...π(arene) hydrogen bonds links the molecules of 3‐tert‐butyl‐1‐phenyl‐7‐(3,4,5‐trimethoxybenzyl)‐6,7‐dihydro‐1H,4H‐pyrazolo[3,4‐d][1,3]oxazine, C₂₅H₃₁N₃O₄, (VIII), into complex sheets. In each compound, the oxazine ring adopts a half‐chair conformation, while the orientations of the pendent phenyl and tert‐butyl substituents relative to the pyrazolo[3,4‐d]oxazine unit are all very similar.     

Synthesis of new hetero[1,2,4]thiadiazin‐3‐one S,S‐dioxides and oxazolo[3,2‐b]hetero[1,2,4]thiadiazine S,S‐dioxides as potential psychotropic drugs

A series of 2‐substituted 2H‐thieno[3,4‐e][1,2,4]thiadiazin‐3(4H)‐one 1,1‐dioxides ( 2 ), 2‐substituted 2H‐thieno[2,3‐e][1,2,4]thiadiazin‐3(4H)‐one 1,1‐dioxides ( 3 ), 2‐substituted 4,6‐dihydropyrazolo[4,3‐e]‐[1,2,4]thiadiazin‐3(2H)‐one 1,1‐dioxides ( 4 ), 2‐substituted 2,3‐dihydrooxazolo[3,2‐b]thieno[3,4‐e]‐[1,2,4]thiadiazine 5,5‐dioxides, ( 5 ), 6‐substituted 6,7‐dihydro‐2H‐oxazolo[3,2‐b]pyrazolo[4,3‐e][1,2,4]thia‐diazine 9,9‐dioxides ( 6 ) and 7‐substituted 6,7‐dihydro‐2H‐oxazolo[3,2‐b]pyrazolo[4,3‐e][1,2,4]thiadiazine 9,9‐dioxides ( 7 ) were synthesized as potential psychotropic agents.     

Synthesis of β‐Lactam‐containing Pyrido[3′,2′:4,5]thieno[3,2‐e][1,4]diazepines

Novel tricyclic 1,4‐diazepine derivatives – pyrido[3′,2′:4,5]thieno[3,2‐e ][1,4]diazepin‐2‐ones – have been synthesized. Azetidin‐2‐one moiety has been incorporated into the 1,4‐diazepine scaffold by [2 + 2]cycloaddition of functionalized ketenes to imine C═N bond, and several tetracyclic azetodiazepines which can be considered as potential compounds of biological interest have been prepared. Stereoselectivity of the cycloaddition was proved by NMR and X‐ray analysis data.     

A new dimerization reaction producing 2‐amino‐9‐oxopyrrolo‐[2,1‐b]quinazoline‐1‐carbonitriles and analogous pyrrolo‐[1,2‐a]thieno[3,2‐d] pyrimidinecar bonitriles

A series of 2‐alkylthio‐4‐oxo‐3‐quinazolineacetonitriles 4 and 2‐alkylthio‐4‐oxothieno[3,2‐d]pyrimidine‐3‐acetonitriles 8 was prepared. Upon treatment with sodium hydride, compounds 4 and 8 react to give 2‐amino‐4,9‐dihydro‐9‐oxopyrrolo[2,1‐b]quinazoline‐1‐carbonitriles 9 and 6‐amino‐4,9‐dihydro‐9‐oxopyrrolo[1,2‐a]thieno[3,2‐d]pyrimidine‐7‐carbonitriles 10 , respectively. The transformation of compounds 4 and 8 to the tricyclic aminonitriles 9 and 10 involves a dimerization step followed by a pyrrole cyclization. The tert‐butyl ester derivatives 4d and 8d upon treatment with sodium hydride underwent a Thorpe‐Ziegler cyclization to provide enaminoesters of fused 1,3‐thiazines ( 16 and 17 , respectively) as major products.