A Novel Synthesis of Some 1,4‐Phenylene‐bis‐heterocyclic Derivatives and of Some Pyran,Pyrano[2,3‐c]pyrazole,and Pyrano[2,3‐d]pyrimidine Derivatives [1]

p‐Diacetyl benzene 1 undergoes bromination to afford p‐bromoacetyl phenacyl bromide 2 . Compound 2 reacts with twofold excess of malononitrile to afford 2‐{2‐[4‐(3,3‐Dicyanopropionyl)‐phenyl]‐2‐oxo‐ethyl}‐malononitrile 3 . Compound 3 could be cyclized to afford the 1,4‐phenylene‐bis‐furan derivative 4 . Compound 3 reacts also with a twofold excess of hydrazine hydrate and phenyl hydrazine under dry conditions at RT to afford the bis‐pyrazole derivatives 5a , 5b , respectively. The reaction of 5a , 5b with the same reagents in refluxing dioxane afforded the bis‐pyrazolopyridazine derivatives 7a , 7b , respectively. The azo coupling of compound 3 with arene diazonium salts afforded the bis‐pyrazole derivatives 9a , 9b , 9c . The β‐keto esters 10a , 10b react with benzaldehyde and malononitrile in a one pot synthesis to afford the pyran derivatives 11a , 11b . These latter compounds react with hydrazine hydrate and urea derivatives to afford the pyrano[2,3‐c]pyrazoles 15a , 15b and the pyrano[2,3‐d]pyrimidine derivatives 17a , 17b , respectively.     

Synthesis of Newly Substituted Pyrazoles and Substituted Pyrazolo[3,4‐b]Pyridines Based on 5‐Amino‐3‐Methyl‐1‐Phenylpyrazole

The reaction of the aminopyrazole 1 with benzenesulfonyl chloride, arenediazonium salt, chloroacetyl chloride, ethoxy methyleneamlononitrile and with ethyl 2‐cyano‐3‐ethoxyacrylate gave the substituted 3‐methyl‐1‐phenylpyrazole 2–5a,b . Compound 5b was cyclized to 6 and to 7 by treating it with AlCl₃ and with POCl₃, respectively. Compound 6 converted to 7 by boiling it in POCl₃/PCl₅. Compound 10b was produced through reaction of 9 with acetophenone. Reaction of 1 with benzylidinemalononitrile afforded 11 . New methods for preparation of 15 and 16 are described. The reaction of 8 with malononitrile, thiosemicarbazide, phenyl hydrazine and acetophenone afforded compounds 18–21 . The reaction of 21 with malononitrile gave 22 . Compounds 23–26 were produced upon reaction of 10a with malononitrile, phenyl hydrazine, thiosemicarbazide, semicarbazide and with benzaldehyde, respectively.     

One‐Pot Synthesis of Pyrido[2,3‐d]Pyrimidine‐2‐Thiones and a Study of Their Reactivity Towards Some Reagents

A series of pyrido[2,3‐d]pyrimidine‐2‐thione derivatives ( 5a‐c ) were synthesized by the one‐pot reaction of the appropriate aldehyde, malononitrile and 6‐aminothiouracil ( 1 ) in dimethyl‐formamide. The same compounds were also synthesized by the reaction of arylidine malononitrile ( 4 ) with 6‐aminothiouracil ( 1 ). Moreover, the chemical behaviour of the produced pyrimidines towards different reagents was studied.     

3‐(phenylhydrazono)‐indan‐1‐one and 2‐dimethylaminomethylene‐3‐(phenylhydrazono)‐indan‐1‐one as useful synthons for the construction of new heterocyclic systems

The hydrazone 1 reacts with DMFDMA to give 2‐dimethylaminomethylene‐3‐(phenylhydrazono)‐indan‐1‐one (2) which reacts with hydrazine hydrate and the pyrazole derivative 4 to afford the indenopyrazole derivatives 3 and the indenofluorene 5 respectively. The reaction of 2 with the active methylene compounds, mainly malononitrile, cyanoacetamide and malononitrile dimer was investigated and found to proceed successfully to yield the indenopyran 7 , indenpyridine 8b and trinitrile 9 respectively. Compound 2 reacted with lH‐benzimidazole‐2‐acetonitrile 10 to give to the diazaindenofluorene derivative 11 . Also, 2 reacted with ω‐cyano compounds 12a,b to afford the indenopyran 14 . On the other hand the hydrazone 1 was allowed to react with the enaminones 15, 18 and 21 affording the diazabenzoazulene derivatives 17, 20 and the indeno[1,2‐b]pyridin 23 , respectively.     

Reaction of 2‐Phenyl‐4‐arylidene‐1,3‐oxazolones with Different Nucleophiles for Synthesis of Some New Heterocycles

Refluxing of 1,3‐oxazolone ( 1a ) with malononitrile in dry benzene and in the presence of ammonium acetate afforded imidazolone derivative ( 2 ). However, carrying out the same reaction in absolute ethanol and in the presence of piperidine as a base gave the benzamide derivative ( 4 ). Fusion of ( 1a ) with p‐anisidine gave the open adduct benzamide ( 6 ), which cyclized in acidic medium to give imidazolone derivative ( 7 ). Heating of imidazolone ( 7 ) with malononitrile above its melting point afforded 1,3‐diazepine derivative ( 8 ). Reaction of the carbohydrazide ( 9 ) with isatin in ethanol gives the corresponding Schiff base ( 11 ), which then reacted with acetyl acetone, ethyl acetoacetate, ethyl cyanoacetate, and malononitrile in n‐butanol and piperidine to afford benzamide derivative ( 13 , 14 , 15 ) and ( 16 ), respectively. The structures of the newly synthesized compounds were established on the basis of IR, ¹H‐NMR, mass spectra, and elemental analyses.     

Synthesis of Some New Spiro,Isolated and Fused Heterocycles Based on 1H‐indole‐2‐One

The reaction of 3‐benzoylcyanomethylidine‐1(H)‐indole‐2‐one ( 1 ) with a variety of active methylene compounds, thioglycolic acid, glycine, hydrazine hydrate and phenyl hydrazine led to the formation of compounds 4a‐d‐10 . 3‐Thiosemicarbazide‐1(H)‐indole‐2‐one 2 on reaction with α‐halocarbonyl compounds gave compounds 11a‐c, 12a‐c . The latter compounds on heating with phosphoryl chloride, cyclization takes place via losing water to give the angular tetracyclic compounds 13a,b and 14a‐c . Cyanoacetic hydrazone derivative 3 readily cyclized upon heating in triethyl orthoformate to give the tricyclic system, oxopyridazino indole 15 . On the other hand, the reaction of 3 with benzylidine malononitrile and benzylidene ethylcyanoactate gave the pyranyl hydrazone derivatives 16a,b .     

Synthesis of Novel Chromene,Pyridine, Pyrazole,Pyrimidine, and Imidazole Derivatives via One‐pot Multicomponent Reaction

New series of chromenes 2 – 4 , pyridines 5 – 8 , and pyranopyrazoles 9a,b were synthesized via one‐pot multicomponent reaction of 4‐tosyloxybenzaldehyde ( 1 ) and malononitrile with phenols, amines or hydrazines, and ethyl acetoacetate, respectively. Compound 9a was reacted with acetic anhydride, formic acid, or formamide to afford N ‐acetyl derivative 10 and pyrazolopyranopyrimidines 11 – 13 , respectively. Imidazole derivatives 14 and 15a – d were obtained by multicomponent reaction between compound 1 with ammonium acetate and benzil or aromatic amines in (1:2:1) or (1:1:1:1) ratio, respectively. The structures of new compounds were elucidated by elemental and spectral analyses.     

Synthesis and Anticancer Evaluation of Some Novel Quinazolin‐4(3H)‐one Derivatives

A new series of quinazolinone derivatives bearing pyridine, pyrimidine, pyrazole, or pyran moieties were synthesized for the purpose of anticancer cell line evaluation. Synthesis of these derivatives was achieved by the reaction of the ketone 2 with the appropriate aldehydes in the presence of either ethylcyanoacetate or malononitrile and ammonium acetate in one‐pot reaction. Chalcones 6 reacted also with hydrazine hydrate to give the corresponding pyrazolines 7 and reacted with urea or thiourea to give the 2‐oxopyrimidines or the 2‐thioxopyrimidines 8 , respectively. Evaluation of some representative examples of the newly synthesized compounds against cancer cell lines showed promising activity as anticancer agents.     

A Green Synthesis of 7‐amino‐5‐(4‐aroyl)‐1,3‐dimethyl‐2,4‐dioxo‐1,2,3,4,5,8‐hexahydropyrido[2,3‐d]pyrimidine‐6‐carbonitrile Derivatives by a One‐pot Three‐component Reaction

The synthesis of polyfunctionalized 7‐amino‐5‐(4‐aroyl)‐1,3‐dimethyl‐2,4‐dioxo‐1,2,3,4,5,8‐hexahydropyrido[2,3‐d ]pyrimidine‐6‐carbonitrile derivatives by a green approach was achieved via one‐pot three‐component reaction of arylglyoxals, malononitrile, and 1,3‐dimethyl‐6‐aminouracil in the presence of urea as organocatalyst in EtOH:H₂O (1:1) at 60°C. This protocol provides a mild and fast procedure to structurally diverse bicyclic pyridopyrimidines in good to excellent yields.     

Hetaryl‐1,5 Benzodiazepines—Part I: Synthesis of 3‐pyrimidinyl‐ and Imidazolyl‐1,5‐benzodiazepines

Nucleophilic substitution of 3‐bromo‐4‐phenyl‐1H‐[1,5]benzodiazepin‐2‐one ( 1 ) with thiourea or guanidine in presence of potassium carbonate afforded 1,5‐benzodiazepin‐3‐ylimidothiocarbamate 2 or 1,5‐benzodiazepin‐3‐ylguanidine 3 , respectively. Pyrimidylthiobenzodiazepines 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 were obtained via the reaction of compound 2 with malononitrile dimer, diethyl malonate, methylenemalononitriles, or a mixture of an aldehyde and β‐keto esters or acetylacetone, catalyzed using ceric ammonium nitrate. Reaction of compound 2 or 3 with α‐halo esters, nitriles, and/or ketones afforded imidazoles 14 , 15 , 16 , 17 , 18 , 19 , 20 , respectively.     

Synthesis and Antimicrobial Activity of Some Novel Substituted Bis‐Pyridone,Pyrazole, and Thiazole Derivatives

A variety of novel bis‐heterocyclic derivatives were synthesized via the reaction of bis‐cyanoacetanilide derivative 3 with various aromatic aldehydes (1:2 molar ratio), to give the corresponding bis‐arylidene derivatives 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m . On the other hand, reacting compound 3 with substituted 2‐hydroxybenzaldehydes 6a , 6b , 6c afforded 2‐iminochromene‐3‐carboxamides 7a , 7b , 7c . The reaction of compound 5 with malononitrile afforded the novel bis‐pyridones 9a , 9b , 9c , 9f , 9g , 9h . The reaction of 5 with hydrazine derivatives afforded pyrazoles 11a , 11b , 11c , 11d , 11e , 11f , respectively. Compound 3 reacts with phenyl isothiocyanate in the presence of potassium hydroxide at room temperature followed by addition of some different halo‐carbonyl compounds to afford bis‐poly‐functionalized thiazole derivatives 13a , 13b , 13c . The bis‐enamine derivative 15 reacts also with hydrazine hydrate, guanidine, and hydroxylamine to give bis‐pyrazole 17 , pyrimidine 19 , and isoxazole 21 derivatives, respectively. Some of the newly synthesized compounds show moderate to high antimicrobial activity.     

An Efficient One‐Pot Three‐Component Synthesis of Some New Polyhydroquinolines via Enaminone Intermediates

For a wide spectrum of pharmacological effects of polyhydroquinolines, this study introduces a developed safe, simple, higher yields and fast method for the synthesis of some new hexahydroquinoline derivatives using one‐pot three‐component cyclocondensation reaction, via the reaction of 1,3‐cyclohexanedione with primary amine and arylidinemalononitrile or salicylaldehyde derivatives. The prepared compounds were reacted with different reagents as N ,N‐dimethylformamide dimethylacetal, acetic anhydride, sulphuric acid, and hydrazine hydrate forming several polycyclic hexahydroquinoline and acridine derivatives. All these new compounds have been characterized by spectral data and expected to be effective pharmaceutical drugs.     

Quinolone analogues 6 [1‐5]. Synthesis of 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones

The reaction of the quinoxaline N‐oxides 7a,b with diethyl ethoxymethylenemalonate gave the 1‐methylpyridazino[3,4‐b]quinoxaline‐4,4‐dicarboxylates 8a,b , whose reaction with N‐bromosuccinimide or N‐chlorosuccinimide afforded the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxaline‐4,4‐dicarboxylates 9a‐d. The reaction of compounds 9a‐d with hydrazine hydrate resulted in hydrolysis and decarboxylation to provide the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxaline‐4‐carboxylates 10a‐d , whose reaction with nitrous acid effected oxidation to furnish the 3‐halogeno‐4‐hydroxy‐1‐methylpyridazino[3,4‐b]quinoxaline‐4‐carboxylates 11a‐d , respectively. The reaction of compounds 11a‐d with hydrazine hydrate afforded the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4‐ols 12a‐d , whose oxidation provided the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones 6a‐d , respectively. Compounds 6a‐d had antifungal activities in vitro.     

A Green Synthesis of 2‐Amino‐4‐(9H‐carbazole‐3‐yl)thiophene‐3‐carbonitriles by a Step‐wise and One‐pot Three‐component Gewald Reaction

An eco‐friendly method has been developed for the synthesis of 2‐amino‐4‐(9H‐carbazole‐3‐yl)thiophene‐3‐carbonitriles from preliminary carbazole ( 1 ) through an intermediate of 2‐(1‐(9H‐carbazole‐3‐yl)ethylidene)malononitriles using the Knoevenagel condensation followed by the Gewald reaction. On the other hand, the target compounds could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of 1‐(9H‐carbazole‐3‐yl)ethanone ( 3 ), malononitrile, and elemental sulfur. The merits of this preparation are mild reaction conditions. The Gewald reaction is executed with inorganic base NaHCO₃ (H₂O) in tetrahydrofuran, easy work‐up procedure with good yields.     

Studies on the reactions of cyclic oxalyl compounds with hydrazines or hydrazones : Synthesis and reactions of 4‐benzoyl‐1‐(3‐nitrophenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylic acid

The 1H‐pyrazole‐3‐carboxylic acid 2 , obtained from the furan‐2,3‐dione 1 and N‐Benzylidene‐N'‐(3‐nitrophenyl) hydrazine, was converted via reactions of its acid chloride 3 with various alcohols or N‐nucleo‐philes into the corresponding ester or amide derivatives 4 or 5 , respectively. Nitrile 6 and anilino‐pyrazole acid 7 derivatives of 2 were also obtained by dehydration of 5a in a mixture of SOCl₂ with DMF and reduction of 2 with sodium polysulphide, respectively. While cyclocondensation reactions of 2 or 7 with phenyl hydrazine or hydrazine hydrate and 6 with only anhydrous hydrazine lead to derivatives of pyrazolo[3,4‐d]‐pyridazinone 8 and pyrazolo[3,4‐d]pyridazine amine 9 , respectivel. The reaction of 2 with 2‐hydrazinopyri‐dine provided hydrazono‐pyrazole acid derivative 10 , which was decarboxylated to give hydrazono‐pyra‐zole derivative 11 . Pyrazolo[4,3‐d]oxazinone 12 and 2‐quinolyl pyrazolo[3,4‐d]pyridazine 13 derivatives were also prepared by cyclocondensation reactions of 2 with hydroxylamine hydrochloride and 7 with acetaldehyde, respectively.     

An efficient and facile procedure for the synthesis of 4,6‐diaryl‐2(1H)‐pyridones under solvent‐free conditions

An efficient and convenient method for the preparation of 4,6‐diaryl‐2(1H)‐pyridones by the one‐pot reaction of aromatic aldehydes, aromatic ketones and malononitrile, in the presence of sodium hydroxide under solventfree condition is reported. This method has the advantages of good yields, mild reaction conditions, easy workup, inexpensive reagents and being environmentally friendly over the existing procedures.     

Synthesis and Antimicrobial Evaluation of Novel Polyfused Heterocycles‐Based Quinolone

Syntheses of some new heterocyclic compounds incorporating quinolone moieties were achieved via reaction of 4‐hydroxy‐7‐methoxyquinolin‐2(1H)‐one ( 1 ) or 3‐bromo‐4‐hydroxy‐7‐methoxyquinolin‐2(1H)‐one ( 2 ) with binucleophilic reagents. The newly synthesized compounds were characterized by elemental analyses and spectral data (IR, ¹H‐NMR and mass spectra). The newly synthesized compounds were screened for their antibacterial activity against Gram‐positive bacteria (Bacillus thuringiensis) and Gram‐negative bacteria (Escherichia coli). The results showed clearly that compounds 1 and 3 are the more potent antibacterial agents against E. coli, compounds 4 , 5 , 6 and 8 , 9 , 10 , 11 , 12 , 13 exhibited moderate activities against E. coli strain, and compounds 7 and 11 exhibited weak activities compared with Gentamicin as a well known standard drug.     

Efficient and Expeditious Synthesis of Pyrano‐pyrimidines,Multi‐substituted γ‐Pyrans,and Their Antioxidant Activity

An efficient, expeditious catalytic route for the synthesis of ethyl 6‐amino‐5‐cyano‐2‐methyl‐4‐aryl‐4H‐pyran‐3‐carboxylates 2 was achieved via a three‐component, one‐pot reaction of malononitrile, ethyl acetoacetate, and various aromatic aldehydes in water as a solvent at room temperature. The key advantages are excellent yield, reaction time, and inexpensive catalyst. Also, cyclization of 4H‐pyrans 2 to the corresponding 4H‐pyrano[2,3‐d]pyrimidines 3 using silica sulfuric acid in the presence of acetic anhydride was described. Some synthesized compounds exhibited promising antioxidant activities.     

Synthesis of Some Novel 2‐Anilinothiophene, 2,3′‐Bithienyl and Thienylthiopyridine Derivatives Resistance to Penicillium Digitatum Effect the Fruit

Reaction of benzotriazol‐1‐yl acetone 1 with phenyl isothiocyanate followed with α‐chloroacetone or ethyl‐α‐chloroacetate afforded 2‐anilinothiophenes 3 or 4 , respectively. Treatment of 3 with malononitrile at different reaction conditions afforded 6 or 7 . Reaction of 1 with CS₂ in DMF and phenacylbromide afforded S‐alkylated thiophene 10 . Reactions of the latter compound with different active methylene nitriles afforded thienylthiopyridine derivatives 14 and 15 . Condensation of 10 with hydrazine hydrate afforded hydrazon derivative 16 . Reaction of thiophene 17 with formamide in DMF afforded 19 which converted to N‐thienylpyrimidine 20 when treated with malononitrile. The structure of the newly synthesized compounds has been established on the basis of their analytical and spectral data. The compounds were also investigated for antibacterial and antifungal activities.     

An Efficient One‐pot Three‐component Method for the Synthesis of 5‐Amino‐3‐(2‐oxo‐2H‐chromen‐3‐yl)‐7‐aryl‐7H‐thiazolo[3,2‐a]pyridine‐6,8‐dicarbonitriles

A facile, convenient, and adequate method has been developed for the synthesis of novel 5‐amino‐3‐(2‐oxo‐2H‐chromen‐3‐yl)‐7‐aryl‐7H‐thiazolo[3,2‐a]pyridine‐6,8‐dicarbonitriles ( 6 ) by employing 2‐(4‐(2‐oxo‐2H‐chromen‐3‐yl)thiazol‐2‐yl)acetonitrile ( 3 ) as an important precursor. Initially, we have synthesized the target compounds in a stepwise manner and then approached a tandem method to examine the feasibility of one‐pot method. Subsequently, one‐pot three‐component protocol has been established for the synthesis of title compounds by the reaction of 3 with benzaldehyde and malononitrile in refluxing ethanol engender a new six‐membered thiazolo[3,2‐a] pyridine as a hybrid scaffold. Reaction conditions were optimized for this reaction and a broad substrate scope with various aryl and heteroaryl aldehydes make this protocol very practical, attractive, and worthy. Mechanistic aspects for the formation of these compounds were outlined comprehensively. Characterization of these newly synthesized compounds was achieved by means of IR, ¹H NMR, ¹³C NMR, and HRMS.