Synthesis and Antimicrobial Activity of Novel Heterocycles Utilizing 3‐(1,4‐Dioxo‐3,4‐dihydrophthalazin‐2(1H)‐yl)‐3‐oxopropanenitrile as Precursors

The reaction of 3‐(1,4‐dioxo‐3,4‐dihydrophthalazin‐2(1H)‐yl)‐3‐oxopropanenitrile 1 and salicyladehyde furnished coumarin derivatives 4 and 5 . Coupling reaction of 1 with aryl diazonium chlorides and benzene‐1,4‐bis (diazonium) chloride gave the corresponding hydrazones 6a , b and bishydrazone 9 , respectively. Hydrazones 6 underwent intramolecular cyclization upon treating with hydrazine hydrate to give 3‐aminopyrazoles 7 . Pyranyl phthalazine 13 was prepared from the reaction of 1 with ethyl 2‐cyano‐3‐ethoxyacrylate 10 . Enaminonitrile 14 was reacted with hydrazine hydrate/phenylhydrazine and hydroxylamine to afford the corresponding pyrazoles 16 and oxime 17 . The antimicrobial evaluation revealed pyrazole derivatives 7a , b and 16a , b displayed a broad spectrum activity against most strains. 3‐Aminopyrazole derivative 7b showed potent antibacterial activity against all tested microorganisms.     

Syntheses of [1,2,3]selenadiazolo[4,5‐e]benzofuran or benzothiophene, [1,2,3]thiadiazolo[4,5‐e]benzofuran or benzothiophene,and 2‐benzofuranyl‐1,3,4‐oxodiazole derivatives

Dehydrogenation of ethyl 3‐methyl‐4‐oxo‐4,5,6,7‐tetrahydrobenzofuran‐2‐carboxylate 1 with 2,2′‐azobi‐sisobutyronitrile and N‐bromosuccinimide gave ethyl 4‐hydroxy‐3‐methylbenzofuran‐2‐carboxylate 3 . Reaction of compounds 3–4 with hydrazine hydrate afforded the corresponding hydrazides 5a‐b . The reaction of 5a‐b with aldehydes yielded substituted hydrazones 6a‐l . Compounds 7a‐d were prepared from compounds 6a‐d and bromine in acetic acid. Lead tetraacetate oxidation of compounds 6e‐l afforded substituted oxadiazoles 8e‐l . Selenium dioxide oxidation of 4‐oxo‐4,5,6,7‐tetrahydrobenzofuran semicarbazones 9, 14a and 4‐oxo‐4,5,6,7‐tetrahydrobenzothiophene 14b gave the tricyclic 1,2,3‐selenadiazoles 10, 15a and 15b respectively. Reaction of semicarbazones 9, 14a and 14b with thionyl chloride afforded the corresponding 1,2,3‐thiadiazoles 12, 16a and 16b respectively.     

Synthesis of ethyl 6‐aryl‐4‐oxo‐4,6‐dihydro‐1(12)(13)h‐pyrimido‐[2′,1′:4,5][1,3,5]triazino[1,2‐a]benzimidazole‐3‐carboxylates

The synthesis of ethyl 6‐aryl‐4‐oxo‐4,6‐dihdro‐1(12)(13)H‐pyrimido[2′,1′:4,5][1,3,5]triazino[1,2‐a]‐benzimidazole‐3‐carboxylates ( 4a‐p ) was described via pyrimidine ring annulation to 4‐aryl‐3,4‐dihydro[1,3,5]triazino[1,2‐a]benzimidazole‐2‐amines ( 2a‐p ) which were obtained from 2‐guanidinobenzimidazole ( 1 ). Tautomerism in the prepared compounds was investigated using nmr spectroscopy. Compounds 2a‐p were found to be present in dimethyl sulfoxide solution predominantly as 3,4‐dihyhydro tautomeric form. Compounds 4a‐p existed in dynamic equilibrium of 1‐, 12‐ and 13H‐forms. It was found that methylation of 4a‐d led to 13‐methyl substituted derivatives 9a‐d exclusively.     

Synthesis and characterization of substituted (benzo[b]thiophen‐2‐yl)‐4‐methyl‐4,5‐dihydro‐1H‐imidazol‐5‐ones

Reactions of 3‐chlorobenzo[b]thiophene‐2‐carbonyl chloride with 2‐alkyl‐2‐aminopropanamides have been used to prepare a series of carboxamides 1a‐d (yields 61‐85%). The products were submitted to base‐catalysed ring closure reactions to give the corresponding 4,5‐dihydro‐1H‐imidazol‐5‐ones 2a‐d (yields 69‐97%). By N‐methylation and N‐benzylation were prepared the corresponding 1‐alkyl derivatives 3a (91%) and 3b (85%). These two alkyl derivatives were studied from the standpoint of potential replacement of 3‐chlorine substituent by piperidine via the Buchwald‐Hartwig reaction. It was found that the reaction gives besides except required products of C‐N coupling 5a (14%) and 5b (12%) also products of reductive dechlorination 4a (max. 57%) and 4b (max. 56%). The reductive dechlorination product 4a is formed exclusively (42%) if butyl‐di‐(1‐adamantyl)phosphine (BDAP) is used.     

One‐pot Synthesis of 1,2,3,4‐Tetrahydropyrimidin‐2(1H)‐thione Derivatives and their Biological Activity

2‐Thioxo/oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate derivatives 2a , 2b , 2c , 2d were prepared by the reaction of ethyl acetoacetate and thiourea or urea with aldehydes using NH₄Cl as a catalyst. Compounds 2a and 2c reacted with mono and bihalogenated compounds such as ethyl iodide, chloroacetonitrile, epichlorohydrin, acetyl chloride, ethyl bromoacetate, chloroacetic acid, chloroacetylchloride, and/or oxalyl chloride to afford compounds 3 , 4a , 4b , 5 , 6a , 6b , 7 , 8 , 9 and 10 , respectively. Compounds 2a , 2c , and 7 were allowed to react with p‐fluorobenzaldehyde to yield the corresponding products 11a , 11b , and 12 , respectively. Oxidation of 2a and 2c gave 2b , 13a , 13b , 14 , 15 , 16 dependent on the oxidizing agent used. Vilsmeiere‐Haack formylation of 2a and 2b with POCl₃/DMF afforded 17a and 17b . Chlorination of 2b and 2d gave the chlorinated derivative 18a and 18b , which reacted with thiourea to give thioureidopyrimidine 19a and 19b . Reactions of 2a with hydrazine monohydrate, semicarbazide hydrochloride, and sodium hydroxide gave compounds 20 , 21 , 22 , respectively. The cytotoxicity and in vitro anticancer evaluation of some prepared compounds have been assessed against two different human tumor cell lines including breast adenocarcinoma MCF‐7 and human hepatocellular carcinoma HepG2. Antimicrobial and antioxidant activities of some compounds were investigated. The newly synthesized compounds were characterized by IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral data.     

Synthesis of 5‐chloro‐2‐methyl‐3‐(5‐methylthiazol‐2‐yl)‐4(3H)‐quinazolinone and related compounds with potential biological activity

Eight new 2‐methyl‐4(3H)‐quinazolinones (8a‐8d, 9c, 9d, 10c, 10d) with one or two chlorine atoms in the benzene ring and a 5‐methyl‐1,3‐thiazol‐2‐yl, 4‐methyl‐1,3‐thiazol‐2‐yl, and 5‐ethyl‐1,3,4‐thiadiazol‐2‐yl substituent in position 3 of the heterocyclic ring were synthesized and characterized. The two step procedure (Scheme 1) utilizes chlorosubstituted anthranilic acids (3a‐3d) and acetic anhydride as the starting materials, with the respective chlorosubstituted 2‐methyl‐4H‐3,1‐benzoxazin‐4‐ones (4a‐4d) as the intermediates. The quinazoline derivatives were characterized by their melting points, elemental analyses and the mass, ultraviolet, infrared, and ¹H and ¹³C nmr spectra. The new compounds are expected to be biologically active.     

Transformations of phenylhydrazones of dialkyl 2‐oxo‐propane‐1,3‐dicarboxylate and of ethyl acetoacetate in concentrated sulfuric acid

The hydrazones 3a,b , prepared from phenylhydrazine ( 1 ) and dialkyl 2‐oxopropane‐1,3‐dicarboxylate ( 2a,b ) were converted in concentrated sulfuric acid at ?5 °C into a mixture of alkyl (3‐carboxyindol‐2‐yl)acetates ( 5a,b ), and ethyl (5‐ethoxy‐1‐phenyl‐1H‐pyrazol‐3‐yl)acetate 6 . The hydrazone 8 , prepared from 1 and ethyl acetoacetate ( 7 ) was transformed under the same conditions into a mixture of five compounds: ethyl 2‐methylindol‐3‐carboxylate ( 9 ), 2‐methylindol‐3‐carboxylic acid ( 10 ), 2‐methylindol ( 11 ), 5‐ethoxy‐3‐methyl‐1‐phenyl‐1H‐pyrazole ( 12 ), and 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐one ( 13 ).     

Synthesis and biological evaluation of several 3‐(coumarin‐4‐yl)tetrahydroisoxazole and 3‐(coumarin‐4‐yl)dihydropyrazole derivatives

A series of novel 3‐(coumarin‐4‐yl)tetrahydroisoxazoles 5a,b, 7, 9 and 3‐(coumarin‐4‐yl)dihydropyra‐zoles 13a‐d, 14,15a,b were synthesized from coumarin‐4‐carboxaldehyde 1 via the intermediate N‐methyl nitrone 3 and N‐phenyl or N‐methyl hydrazones 11a,b . These coumarin derivatives were isolated, characterized and evaluated in vitro for their ability to inhibit trypsin, β‐glucuronidase, soybean lipoxygenase and to interact with the stable radical 1,1‐diphenyl‐2‐picrylhydrazyl. The compounds were tested in vivo as anti‐inflammatory agents in the rat carrageenin paw edema assay. Compound 15a seems to be a lead molecule to be modified in order to improve the lipoxygenase inhibition. The results are discussed in terms of structural characteristics.     

Synthesis,Structure of Zwitterionic 2‐Amino‐N′‐(imidazolidin‐2‐ylidene)benzohydrazides,and Their Transformation into 3‐(Imidazolidin‐2‐ylideneamino)quinazolin‐4(1H)‐one Derivatives

The reaction of 2‐chloro‐4,5‐dihydroimidazole ( 5 ) with 2‐aminobenzohydrazides 6a–e led to the formation of 2‐amino‐N′‐(imidazolidin‐2‐ylidene)benzohydrazides as zwitterions 7a–e , which on treatment with carbon disulfide in the presence of triethylamine afforded 3‐(imidazolidin‐2‐ylideneamino)‐2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐ones 8a–e . Compounds 8a–d were further converted into the corresponding 3‐(imidazolidin‐2‐ylideneamino)quinazoline‐2,4(1H,3H)‐diones 9a–d using hydrogen peroxide–sodium hydroxide solution. The structures of the compounds prepared were established by elemental analyses, IR and NMR spectra as well as X‐ray crystallographic analyses of 7e and 9a .     

Synthesis of 1‐methyl‐, 4‐nitro‐, 4‐amino‐and 4‐iodo‐1,2‐dihydro‐3H‐pyrazol‐3‐ones

4‐Aminopyrazole‐3‐ones 4b, e, f were prepared from pyrazole‐3‐ones 1b‐d in a four‐step reaction sequence. Reaction of the latter with methyl p‐toluenesulfonate gave 1‐methylpyrazol‐3‐ones 2b‐d . Compounds 2b‐d were treated with aqueous nitric acid to give 4‐nitropyrazol‐3‐ones 3b‐d. Reduction of compounds 3b‐d by catalytic hydrogenation with Pd‐C afforded the 4‐amino compounds 4b, e, f. Using similar reaction conditions, nitropyrazole‐3‐ones derivatives 2c, d were reduced into aminopyrazole‐3‐ones 5e, f. 4‐Iodopyrazole‐3‐ones 7a, 7c and 8 were prepared from the corresponding pyrazol‐3‐ones 2a, 2c and 6 and iodine monochloride or sodium azide and iodine monochloride.     

Fused quinoline heterocycles VI: Synthesis of 5H‐1‐thia‐3,5,6‐triazaaceanthrylenes and 5H‐1‐thia‐3,4,5,6‐tetraazaaceanthrylenes

Ethyl 3‐amino‐4‐chlorothieno[3,2‐c]quinoline‐2‐carboxylate ( 4 ) is a versatile synthon, prepared by reacting an equimolar amount of 2,4‐dichloroquinoline‐3‐carbonitrile ( 1 ) with ethyl mercaptoacetate ( 2 ). Ethyl 5‐alkyl‐5H‐1‐thia‐3,5,6‐triazaaceanfhrylene‐2‐carboxylates 9a‐c , novel perianellated tetracyclic heteroaro‐matics, were prepared by refluxing 4 with excess of primary amines 7a‐c to yield the corresponding amino‐thieno[3,2‐c]quinolines 8a‐c . Subsequent reaction with an excess of triethyl orthoformate (TEO) furnished 9a‐c . Reaction of 4 with TEO in Ac₂O at reflux, gave the simple acetylated compounds, thieno[3,2‐c]‐quinolines 12 and 13 . Refluxing 4 with benzylamine ( 7d ) gave 10 , and subsequent treatment with TEO gave the tetracyclic compound 11 . Refluxing 13 with an excess of alkylamines 7a‐d gave the fhieno[3,2‐c]quino‐lines 15 . Refluxing the aminothienoquinolines 8b with an excess of triethyl orthoacetate gave thieno[3,2‐c]quinoline 17 , while heating with Ac₂O gave 18 and 19 , with small amounts of 16 . Reaction of 8a,b with ethyl chloroformate and phenylisothiocyanate generated the new 1‐thia‐3,5,6‐triazaaceanthrylenes 20a,b and 21a,b , respectively. Diazotization of 8a‐c afforded the novel tetracyclic ethyl 5‐alkyl‐5H‐1‐fhia‐3,4,5,6‐tetraazaaceanthrylene‐2‐carboxylates 22a‐c in good yields.     

Synthesis of novel 2‐(2‐methylsulfonyl‐1‐methyl‐1H‐imidazol‐5‐yl)‐5‐(alkylsulfonyl)‐1,3,4‐thiadiazoles

Starting from 5‐hydroxymethyl‐2‐mercapto‐1‐methyl‐1H‐imidazole (1), a series of 2‐(1‐methyl‐2‐methylsulfonyl‐1H‐imidazol‐5‐yl)‐5‐alkylthio and 5‐alkylsulfonyl‐1,3,4‐thiadiazole derivatives ( 9a , 9b , 9c , 9d and 10a , 10b , 10c , 10d ) were prepared as potential antimicrobial agents. The structure of the obtained compounds was confirmed by NMR, IR, Mass spectroscopy, and elemental analysis. J. Heterocyclic Chem., (2010)     

Studies on the reaction of N‐(3‐carbethoxy‐4,5,6,7‐tetrahydrobenzo[b]thien‐2‐yl)‐N′‐phenylthiourea with hydrazine hydrate (Part 1)

The reaction of N‐(3‐carbethoxy‐4,5,6,7‐tetrahydrobenzo[b]thien‐2‐yl)‐N′‐phenylthiourea ( 1 ) with hydrazine hydrate in 1‐butanol afforded a mixture of compounds 2, 3 and 4 . Treatment of 3 and 4 with nitrous acid gave 6 and 8 respectively, while reactions of 3 with acetylacetone gave 7 . Synthesis of tetracyclic compounds 9a‐f and 11 from the reactions of 3 with ethyl orthoformate or appropriate acids, acid chloride, carbon disulphide and/or ethyl chloroformate. Also its reaction with isothiocyanate derivatives gave the corresponding thiosemicarbzides 12a,b which on, refluxing in alcoholic KOH gave the unexpected tetracyclic products 14a,b . Similarly the tetracyclic compounds 16a‐e and 19 were obtained by cyclization of 4 and 18 respectively.     

Synthesis of new spiro‐[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones

A series of seven new 2′,3′,4′‐substituted spiro[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones ( 7‐13 ) has been prepared in the reaction of benzylidene(phenyl)azane oxide ( 5 ) or benzylidene(methyl)azane oxide ( 6 ) with (3Z)‐3‐(4‐substituted‐benzylidene)‐1H‐isothio‐ chromen‐4(3H)‐one ( 1‐4 ). The reaction occurs by a 1,3‐dipolar cycloaddition mechanism that leads to the regiospecific formation of various spiroisoxazolidines ( 7‐13 ).     

The synthesis of 3,3‐dimethyl‐2‐(1‐aryl‐1h‐pyrazol‐4‐yl)‐3h‐indoles

2,3,3‐Trimethylindolenine and 5‐chloro‐2,3,3‐trimethylindolenine were converted into β‐diformyl compounds by the action of the Vilsmeier reagent at 50°C. The dialdehydes reacted with various arylhydrazines and 2‐pyridylhydrazine to produce mono‐hydrazones as mixtures of cis and trans isomers. Heating the hydrazones in refluxing ethanol produced 3,3‐dimethyl‐2‐(1‐aryl‐1H‐pyrazol‐4‐yl)‐3H‐indoles in excellent yields. Reaction of the β‐diformyl compounds with hydrazine itself led directly to 3,3‐dimethyl‐2‐(pyrazol‐4‐yl)‐3H‐indoles.     

Synthesis of Novel Ethyl (substituted)phenyl‐4‐oxothiazolidin‐3‐yl)‐1‐ethyl‐4‐oxo‐1,4‐dihydroquinoline‐3‐Carboxylates as Potential Anticancer Agents

A series of ethyl (substituted)phenyl‐4‐oxothiazolidin‐3‐yl)‐1‐ethyl‐4‐oxo‐1,4‐dihydroquinoline‐3‐carboxylates ( 7a , 7b , 7c , 7d , 7e , 7f , 7g ) has been prepared from reactions between aminoquinolones 6 with arenealdehydes and mercaptoacetic acid. The critical intermediates, 6 a and 6b , were obtained from appropriate amines by a sequence of steps involving (i) reaction with diethylethoxymethylenemalonate, (ii) thermal cyclization in diphenyl ether, (iii) ethylation and (iv) Pd/C catalyzed reduction. New compounds 7a , 7b , 7c , 7d , 7e , 7f , 7g were fully identified and characterized by NMR (¹H and ¹³C) and specifically for 7d by X‐ray crystallography. Compounds 7b , 7c , 7d , 7e , 7f were found not to exhibit activity at 10 uM concentrations against gastric ascitis (AGP‐01), gastric adenocarcinoma kind intestinal (ACP‐02), colon (HCT‐116) and murine melanome (B16F10) cancer cells. However, none exhibited cytotoxicity against normal cells human fibroblast (MRC‐5), murine fibroblast (NIH3T3) and normal human melanocyte (Melan‐A).     

Reactions of (1E)‐Buta‐1,3‐dien‐1‐yl Acetate with Diazocarbonyl Compounds

Carbene transfer to appropriate substrates is a highly versatile tool for the construction of carbon frameworks with increased functional and structural complexity. In this study, some novel cyclopropane derivatives were synthesized via carbenoid reactions and their further reactivities were investigated. (1E)‐Buta‐1,3‐dien‐1‐yl acetate was reacted with four different diazocarbonyl compounds, ethyl diazoacetate, dimethyl diazomalonate, 1‐diazo‐1‐phenylpropan‐2‐one, and methyl (3E)‐2‐diazo‐4‐phenylbut‐3‐enoate, in the presence of two catalysts. All synthesized substituted cyclopropanes were obtained chemoselectively with respect to less‐hindered C?C bonds. Under the applied conditions, while cyclopropanes 7a and 7d underwent further reactions, cyclopropanes 7b and 7c were stable enough. Cyclopropanes 7a and an additional equivalent of ethyl diazoacetate yielded polyfunctionalized cyclohexenes. Cyclopropanes from methyl (3E)‐2‐diazo‐4‐phenylbut‐3‐enoate yielded polyfunctionalyzed cycloheptadiene isomers by Cope rearrangement.     

Synthesis of 4‐hydroxyquinolin‐2(1H)‐one analogues and 2‐substituted quinolone derivatives

A versatile synthetic method for preparing 4‐hydroxyquinolone and 2‐substituted quinolone compounds from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester synthesis and reductive cyclization. The key intermediates were keto esters 4a‐e , which could be transformed to 4‐hydroxyquinolones 5a,b or 2‐substituted quinolone ethyl esters 6a‐c depending on the reaction conditions. 4‐Hydroxyquinolone analogues were prepared and investigated for N‐methyl‐D‐aspartate (NMDA) activity in vitro. Among these derivatives, 6,7‐difluoro‐3‐nitro‐4‐hydroxyquinolin‐2(1H)‐one ( 9 ) exhibited moderate activity.     

Regioselective synthesis of N(3)‐ and O‐acylmethyl derivatives of 2‐methylthio‐4(3H)‐quinazolinone

Reaction of 2‐methylthio‐4(3H)‐quinazolinone with chloroacetone, ω‐bromoacetophenone or ethyl bromoacetate in different solvents (methanol, acetonitrile, dimethylformamide and toluene) using sodium methoxide or potassium carbonate as a base were studied. Regioselective N₍₃₎‐alkylation took place in toluene using potassium carbonate, whereas in dimethylformamide O‐acylmethyl derivatives were obtained. However chloroacetone reacted with 2‐methylthio‐4(3H)‐quinazolinone under various conditions to give a mixture of N₍₃₎/O‐isomers.     

Synthesis of 1,3,4‐Oxadiazole Acyclo C‐Nucleosides Bearing 5‐Methylthio{7‐substituted‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}moieties

Oxidative cyclization of the sugar hydrazones ( 3_a‐f ) derived from {7H‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐ylsulfanyl}acetic acid hydrazide ( 1 ) and aldopentoses 2_a‐c or aldohexoses 2_d‐f with bromine in acetic acid in the presence of anhydrous sodium acetate, followed by acetylation with acetic anhydride gave the corresponding 2‐(per‐O‐acetyl‐alditol‐l‐yl)‐5‐methylthio{7H‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}‐1,3,4‐oxadiazoles ( 5_a‐f ). Condensative cyclization of the sugar hydrazones ( 3_a‐f ) by heating with acetic anhydride gave the corresponding 3‐acetyl‐2‐(per‐O‐acetyl‐alditol‐1‐yl)‐2,3‐dihydro‐5‐methylthio{7‐acetyl‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}‐1,3,4‐oxadiazoles ( 11_a‐f ). De‐O‐acetylation of the acyclo C‐nucleoside peracetates ( 5 and 11 ) with methanolic ammonia afforded the hydrazono lactones ( 7 ) and the acyclo C‐nucleosides ( 12 ), respectively. The structures of new oxadiazole derivatives were confirmed by analytical and spectral data.