The synthesis of novel polycyclic heterocyclic ring system via photocyclization. 18. Benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c]quinoline and benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c] [1,2,4]triazolo[4,3-a]quinoline

The synthesis of two previously unknown polycyclic ring systems, benzo[h]naphtho[1′2′:4,5]-thieno[2,3-c]quinoline ( 1 ) and benzo[h]naphtho[1′,2′:4,5]thieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline ( 2 ), was achieved via oxidative photocyclization of 1-chloro-N-(1-naphthyl)naphtho[2,1-b]thiophene-2-carboxamide ( 5 ). The total assignment of their ¹H and ¹³C nmr spectra was determined by the concerted use of two-dimensional nmr methods.     

Synthesis of pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]pyrimidines related to zaleplon,a new drug for the treatment of insomnia

This paper describes the preparation of some pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]‐pyrimidines substituted on the pyrimidine moiety by a 4‐[(N‐acetyl‐N‐ethyl)amino]phenyl group. A new synthesis of related benzo[h]pyrazolo[1,5‐a]‐, benzo[h]pyrazolo[5,1‐b]‐ and benzo[h]1,2,4‐triazolo[1,5‐a]‐quinazolines is also reported.     

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.     

Azinoiminophosphorane mediated 4H,8H‐1,2,4‐triazolo[1,5‐C]‐[1,3]oxazepin‐4‐ones and 5,6‐dihydro‐7H, 12H‐naphtho[2,1‐f]‐[1,2,4]triazolo[1,5‐c][1,3]oxazepin‐7‐ones synthesis

The aza‐Wittig reactions of benzaldehyde‐, acetophenone‐ and benzophenone 1‐[(triphenylphosphor‐anylidene)amino]ethylidenehydrazones ( 1 ) with 2,3‐furandiones 6 provide a new route to 4H,8H‐1,2,4‐triazolo[1,5‐c][1,3]oxazepin‐4‐ones 14 or 5,6‐dihydro‐7H,12H‐naphtho[2,1‐f|[1,2,4]triazolo[1,5‐c]‐[1,3]oxazepin‐7‐ones 17 via the thermal reaction of the expected azinoimine vinylogous lactones.     

Green One‐Pot Solvent‐Free Synthesis of Pyrazolo[1,5‐a]pyrimidines,Azolo[3,4‐d]pyridiazines,and Thieno[2,3‐b]pyridines Containing Triazole Moiety

Synthesis of pyrazolo[1,5‐a]pyrimidines, [1,2,4]triazolo[1,5‐a]pyrimidine, 8,10‐dimethyl‐2‐(5‐methyl‐1‐phenyl‐4,5‐dihydro‐1H‐1,2,3‐triazol‐4‐yl)pyrido[2′,3′:3,4]‐pyrazolo[1,5‐a]pyrimidine, benzo[4,5]imidazo[1,2‐a]pyrimidine via heterocyclic amines, and sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one were carried out. Also, synthesis of isoxazoles, and pyrazoles from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one and hydroxymoyl chlorides and hydrazonoyl halides, respectively, were made. Analogously, (1,2,3‐triazol‐4‐yl)thieno[2,3‐b]pyridine derivatives were obtained from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐ triazole‐4‐yl)prop‐2‐en‐1‐one and cyanothioacetamide followed by its reacting with active methylene compounds. In addition to full characterization of all synthesized compounds, they were tested to evaluate their antimicrobial activities, and some compounds showed competitive activities to those of tetracycline, the typical antibacterial drug, and clotrimazole, the typical antifungal drug.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 8 . [1]Benzothieno[2,3-c]naphtho[1,2-h]quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline

The previously unknown polycyclic heterocyclic ring systems, namely, [1]benzothieno[2,3-c]naphtho[1,2-h]-quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline were synthesized via photocyclization of 3-chloro-N-(1′-phenanthryl)benzo[b]thiophene-2-carboxamide.     

Syntheses of New Unsymmetrical 2,5‐Disubstituted‐1,3,4‐oxadiazoles and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles Bearing Thieno[2,3‐c]pyrazolo Moiety

New series of (thieno[2,3‐c]pyrazolo‐5‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles 10a , 10b , 10c and (thieno[2,3‐c]pyrazol‐5‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)ethanones 6a , 6b , 6c has been synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by multistep reaction sequence. (5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐1H‐thieno[2,3‐c]pyrazoles 4a , 4b , 4c were also synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by cyclization with various aromatic carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3‐c]pyrazole‐5‐carboxylate 2 with hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde 1 and 2‐ethyl thioglycolate in presence of sodium alcoholate in good yield.     

Ring‐ring interconversions. Part 3. On the effect of the substituents on the thiazole moiety in the ring‐opening/ring‐closing reactions of nitrosoimidazo[2,1‐b][1,3]thiazoles with hydrochloric acid

The reaction of 6‐(4‐chlorophenyl)‐5‐nitrosoimidazo[2,1‐b][1,3]thiazole 1b , 6‐(4‐chlorophenyl)‐2‐methyl‐5‐nitrosoimidazo[2,1‐b][1,3]thiazole 1c , 6‐(4‐chlorophenyl)‐2,3‐dimethyl‐5‐nitrosoimidazo‐[2,1‐b][1,3]thiazole 1d and 2‐(4‐chlorophenyl)‐3‐nitrosobenzo[d]imidazo[2,1‐b][1,3]thiazole 1e with hydrochloric acid has been carried out in order to investigate the effect of substituents on the thiazole ring in a recently reported ring‐ring interconversion reaction. In every case the corresponding [1,4]‐thiazino[3,4‐c][1,2,4]oxadiazol‐3‐ones 2b‐e have been obtained. In particular, the benzoderivative 1e furnished the 4‐(4‐chlorophenyl)‐4‐hydroxy‐4H‐benzo[5,6][1,4]thiazino[3,4‐c][1,2,4]oxadiazol‐1‐one 2e , containing a new tricyclic system with a quasi‐planar geometry whose pharmacological potentialities appear promising.     

Green Synthesis of 6‐Aryl‐5,6‐dihydrobenzo[4,5]imidazo[1,2‐c]quinazoline Derivatives in Ionic Liquid under Catalyst‐free Conditions

Using ionic liquids as green media, a series of 6‐arylbenzo[4,5]imidazo[1,2‐c]quinazoline derivatives is synthesized via a reaction of 2‐(1H‐benzo[d]imidazol‐2‐yl)aniline and benzaldehydes in the air. While the intermediate products of 6‐aryl‐5,6‐dihydrobenzo[4,5]imidazo[1,2‐c]quinazolines were obtained in high yields at the same conditions under nitrogen protection.     

Synthesis and reactivity of some imidazo‐, triazolo‐ and tetrazolo‐isoquinoline derivatives

1‐Acetylirrüno‐3‐methyl‐1H‐isochromene‐4‐carbonitrile, 1 , reacts with glycine ethyl ester under basic conditions to give an imidazo[2,1‐a]isoquinoline derivative, while reaction with hydrazine hydrate in 1,4‐dioxane, with further chemistry, provides access to [1,2,4]triazolo[5,1‐a]isoquinoline, [1,2,4]triazolo[3,4‐a]isoquinoline and tetrazolo[5,1‐a]isoquinoline analogs. Benzene ring nitration and radical bromination of substituent methyl groups were investigated in the four tricycles, with some different positional reactivities being found. Two bromomethyl derivatives so produced were oxidised; ethyl 2‐bromomethyl‐6‐cyano‐5‐methylimidazo[2,1‐a]isoquinoline‐3‐carboxylate gave the anticipated ethyl 6‐cyano‐2‐formyl‐5‐methylimidazo[2,1‐a]isoquinoline‐3‐carboxylate (which reacted further with hydrazine to form a new system, 8,9‐dihydro‐6‐methyl‐8‐oxopyridazino[4′,5′:4,5]imidazo[2,1‐a]isoquinoline‐5‐carbonitrile), while 5‐bromomethyl‐2‐methyl[1,2,4]triazolo[5,1‐a]isoquinoline‐6‐carbonitrile unexpectedly gave directly another new system, 5,6‐dihydro‐5‐hydroxy‐2‐methyl‐7H‐pyrrolo[3,4‐c][1,2,4]triazolo[5,1‐a]isoquinolin‐7‐one.     

Utilization of cleavage of the [1]benzofuro[2,3‐e][1,2,4]triazine ring for the synthesis of oxygen,nitrogen and sulfur derivatives of [1,2,4]triazine

A series of 6‐azacytosines 4a‐4k and 5a‐5c were prepared by nucleophilic cleavage of furan ring of [1]benzofuro[2,3‐e][1,2,4]triazine derivative 1 . Some of them were used for the preparation of derivatives of [1,2,4]triazolo[4,3‐d][1,2,4]triazine ( 6a‐6d ) and tetrazolo[1,5‐d][1,2,4]triazine (7). The reaction of 1 with hydrogen sulfide afforded the corresponding 6‐(2‐hydroxyphenyl)‐2‐phenyl‐5‐thioxo‐4,5‐dihydro‐1,2,4‐tri‐azin‐3(2H)‐one ( 8 ), while with hydrogen selenide 6‐(2‐hydroxyphenyl)‐2‐phenyl‐4,5‐dihydro‐1,2,4‐triazin‐3(2H)‐one ( 9 ) was formed. The prepared compounds were tested for biological activity.     

Synthesis of a New Imidazo[4′,5′:3,4]pyrazolo[5,1‐c][1,2,4]triazine‐4,8‐dione Heterocyclic System

A novel imidazo[4′,5′:3,4]pyrazolo[5,1‐c][1,2,4]triazine‐4,8‐dione heterocyclic system was synthesized starting from available 4‐amino‐6‐tert‐butyl‐3‐methylthio‐1,2,4‐triazin‐5(4H)‐one in four steps with 28% overall yield.     

Synthesis of some novel pyrazolo[1,5‐a]pyrimidine, 1,2,4‐triazolo[1,5‐a]pyrimidine,pyrido[2,3‐d]pyrimidine,pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives incorporating a thiazolo[3,2‐a]benzimidazole moiety

E‐3‐(N,N‐Dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one ( 2 ) was synthesized by the reaction of 1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)ethanone ( 1 ) with dimethylformamide‐dimethylacetal. The reaction of 2 with 5‐amino‐3‐phenyl‐1H‐pyrazole ( 4a ) or 3‐amino‐1,2,4‐(1H)‐triazole ( 4b ) furnished pyrazolo[1,5‐a]pyrimidine and 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives 6a and 6b , while the reaction of enaminone 2 with 6‐aminopyrimidine derivatives 7a,b afforded pyrido[2,3‐d]pyrimidine derivatives 9a,b , respectively. The diazonium salts 11a or 11b coupled with compound 2 to yield the pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives 13a and 13b . Some of the newly synthesized compounds exhibited a moderate effect against some bacterial and fungal species.     

Design,Synthesis, and Characterization of (2‐Alkyl/aryl‐3H‐imidazo[2,1‐c][1,2,4]triazol‐3‐yl)(aryl)methanone

The important therapeutic properties of imidazole‐related drugs have encouraged the medicinal chemists to synthesize and test a large number of novel molecules. In this investigation, it was of interest to synthesize (2‐alkyl/aryl‐3H‐imidazo[2,1‐c][1,2,4]triazol‐3‐yl)(aryl)methanone by short reaction times of N‐triazol‐3‐yl imidate with phenacyl bromides under basic conditions. All compounds were elucidated by spectroscopic methods including IR, ¹H‐NMR, ¹³C‐NMR, elemental analyses, and mass spectral analysis.     

Synthesis of imidazobenzothiazine and primidobenazothiazine derivatives via the classic Ullmann cross-coupling reaction of 1,8-diiodonaphthalene with 1H-benzo[d]imidazole-2-thiols or 2-thiouracils

A feasible protocol for the synthesis of imidazobenzothiazine and primidobenazothiazine derivatives via the classic copper(I)-catalyzed Ullmann cross-coupling process has been developed. 1,8-Diiodonaphthalene could couple with 2-mercaptobenzimidazoles or 2-thiouracils to give the corresponding benzo[4,5]imidazo[2,1-b]naphtho[1,8-de][1,3]thiazines and 11H-naphtho[1,8-de]pyrimido[2,1-b][1,3]thiazin-11-ones in moderate yields.     

Synthesis of Heterocyclic Analogs of α‐aminoadipic Acid and its Esters Based on Imidazo[2,1‐b][1,3]Thiazole

A method for the preparation of heterocyclic analogs of α‐aminoadipic acid and its esters based on the imidazo[2,1‐b][1,3]thiazole ring system was developed. In this method, free‐radical bromination of ethyl 6‐methylimidazo[2,1‐b][1,3]thiazole‐5‐carboxylate with NBS afforded a versatile building block, ethyl 6‐bromomethylimidazo[2,1‐b][1,3]thiazole‐5‐carboxylate. Coupling of ethyl 6‐bromomethylimidazo[2,1‐b][1,3]thiazole‐5‐carboxylate with Schöllkopf's chiral auxiliary followed by acidic hydrolysis generated ethyl 6‐[(2S)‐2‐amino‐3‐methoxy‐3‐oxopropyl]imidazo[2,1‐b][1,3]thiazole‐5‐carboxylate. A similar procedure using diethyl (Boc‐amino)malonate yielded racemic 2‐amino‐3‐[(5‐ethoxycarbonyl)imidazo[2,1‐b][1,3]thiazol‐6‐yl]propanoic acid.     

Reaction of 2‐acyl‐6‐methylbenzo[b]furan‐3‐acetic acids derivatives with hydrazine

Reaction of 2‐acyl‐6‐methylbenzo[b]furan‐3‐acetic acids and their derivatives such as amides and esters with hydrazine does not give expected 1‐alkyl‐5H‐benzofuro[2,3‐e]diazepin‐4‐ones ones but results in 2‐amino‐7‐methyl‐2H‐benzo[4,5]furo[2,3‐c]pyridin‐3‐ones or (3‐R‐6‐methylbenzo[b]furan‐2‐yl)alkyl ketone azines.     

An Efficient Synthesis of Pyrrolo[1,2‐a] or Pyrido[1,2‐a]benzo[4,5]imidazo[1,2‐c]quinazoline Derivatives in Ionic Liquids Catalyzed by Iodine

2‐(1H ‐benzo[d ]imidazol‐2‐yl)anilines reacted with haloketones including 5‐chloropentan‐2‐one and 6‐chlorohexan‐2‐one catalyzed by iodine, giving benzo[4,5]imidazo[1,2‐c ]pyrrolo[1,2‐a ]quinazoline and 6H ‐benzo[4,5]imidazo[1,2‐c ]pyrido[1,2‐a ]quinazoline derivatives, respectively. This domino‐type reaction formed two new heterocycles and three new covalent bonds in one‐pot procedure and provided a green method for the synthesis of fused pentacyclic heterocycles bearing both quinazoline and benzimidazole moieties in ionic liquids.     

Facile Route to Novel Pyrazolo[3,4‐d]pyrimidine,Imidazo[1,2‐b] pyrazole,Pyrazolo[3,4‐d][1,2,3]triazine,Pyrazolo[1,5‐c][1,3,5]triazine and Pyrazolo[1,5‐c][1,3,5]thiadiazine Derivatives

A regioselective synthesis of novel pyrazolo[3,4‐d]pyrimidines, imidazo[1,2‐b]pyrazoles, pyrazolo[3,4‐d][1,2,3]triazine, pyrazolo[1,5‐c][1,3,5]triazine and pyrazolo[1,5‐c][1,3,5]thiadiazine incorporating a thiazole moiety was described via the reactions of the versatile, readily accessible 5‐amino‐3‐(phenylamino)‐N‐(4‐phenylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carboxamide ( 1 ) with each of DMF‐DMA, phenylisothiocyanate, chloroacetyl chloride, phenacyl bromide, benzoylisothiocyanate and formalin, respectively. All structures of the newly synthesized compounds were elucidated by elemental analysis and spectral data.     

A Facile Synthesis of Aryl‐Substituted Hydrazono‐Pyrazolyl[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin Derivatives

Some inimitable and therapeutic coumarin‐substituted fused[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadizole derivatives were synthesized by the cyclocondensation reaction of 2‐oxo‐2H‐chromene‐3‐carboxylic acid ( 1 ) and 4‐amino‐5‐hydrazinyl‐4H‐[1,2,4]‐triazole‐3‐thiol ( 2 ) by using phosphorous oxychloride as a cyclizing agent. This cyclized intermediate 3‐(3‐hydrazino‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐chromen‐2‐one ( 3 ) later condensation with various ethyl 2‐(2‐arylhydrazono)‐3‐oxobutanoates ( 4 ) in NaOAc/MeOH under reflux conditions afforded the corresponding new series of aryl‐substituted hydrazono‐pyrazolyl‐[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin derivatives ( 5 ) in good to excellent yields. The structures of newly synthesized compounds were established on the basis of elemental analysis, IR, ¹H NMR and mass spectroscopic studies.