Synthesis and Bioassay of Novel Substituted Pyrano[2,3‐f]cinnoline‐2‐ones

A new series of 9‐substituted‐4,10‐dimethylpyrano[2,3‐f]cinnolin‐2‐ones ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m ) were synthesized via intramolecular cyclization of the respective acyl amidrazone derivatives ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m ), catalyzed by polyphosphoric acid. Compounds ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m ) were synthesized through direct interaction of coumarin‐7‐yl hydrazonoyl chloride ( 3 ) with the corresponding cyclic sec‐amines in the presence of triethylamine. The structures of the new compounds were confirmed by elemental analyses, NMR, and MS spectral data. The antitumor activity of compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m was evaluated in vitro on breast cancer cell line (MCF‐7) by a cell viability assay utilizing the tetrazolium dye 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide. Among the compounds tested, compounds 5d , 5f , 5k , and 5h showed potential anti‐MCF‐7 activity and were able to reduce the viability after 72 h to less than 50%.     

Efficient Construction of Pyrano[3,2‐a]carbazoles: Application to a Biomimetic Total Synthesis of Cyclized Monoterpenoid Pyrano[3,2‐a]carbazole Alkaloids

We have developed a highly efficient route to 2‐hydroxy‐3‐methylcarbazole ( 1 ) via a palladium‐catalyzed construction of the carbazole skeleton. Using 1 as relay compound, different methods for annulations of pyran rings by reaction with terpenoid building blocks have been tested. The Lewis acid promoted reaction of 1 with prenal ( 21 ) opened up an efficient route to girinimbine ( 3 ) and the corresponding reaction with citral ( 25 ) afforded mahanimbine ( 5 ). Oxidation of compounds 3 and 5 provided murrayacine ( 4 ) and murrayacinine ( 6 ). Following the biogenetic proposal, mahanimbine ( 5 ) has been exploited for efficient biomimetic syntheses of the cyclized monoterpenoid pyrano[3,2‐a]carbazole alkaloids cyclomahanimbine ( 7 ), mahanimbidine ( 8 ) and bicyclomahanimbine ( 9 ). The interconversions of 5 , 7 , 8 and 9 are described and mechanistic implications are discussed. Structural assignments are unambiguously verified by X‐ray crystal structure determinations. Moreover, cyclomahanimbine ( 7 ) was transformed into murrayazolinine ( 10 ) and exozoline ( 11 ).     

Design and Synthesis of Pyrano[2,3-a]carbazoles by Multicomponent Reaction

A facile, efficient, three-component reaction of 2,3,4,9-tetrahydro-1H-carbazol-1-one, malononitrile, and aromatic/heteroaromatic aldehydes in dimethylformamide (DMF) gave pyrano[2,3-a]carbazoles in good yields, at reflux condition, using a catalytic amount of piperidine.     

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 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.     

An Efficient Synthesis of Tetracyclic Pyrano[2,3‐d]pyrimidines

A series of pyrano[2,3‐d ]pyrimidine derivatives have been synthesized by the reaction of 2‐amino‐3‐cyano‐4H‐pyrans and acetic anhydride with acid catalyst . This method is very efficient because of short reaction times and easy work‐up, and it provides an efficient and promising synthetic strategy for the construction of the tetracyclic pyrano[2,3‐d ]pyrimidine skeleton. The X‐ray crystal structures of products are confirmed, and the possible mechanism is provided in this paper.     

InCl3-Assisted Synthesis of Pyrano[2,3-a]carbazoles via Multicomponent Reaction

A facile, efficient, and environmentally friendly protocol for the synthesis of pyrano[2,3-a]carbazoles has been developed by one-pot multicomponent reaction of benzaldehyde/isatin with malononitrile and 1-hydroxycarbazoles in the presence of InCl₃ as catalyst.     

Total Synthesis of 7‐ and 8‐Oxygenated Pyrano[3,2‐a]carbazole and Pyrano[2,3‐a]carbazole Alkaloids via Boronic Acid‐Catalyzed Annulation of the Pyran Ring

The boronic acid‐catalyzed annulation of citral opens up a short route to oxygenated cyclized monoterpenoid pyranocarbazole alkaloids. Thus, murrayamine‐D is available in only three steps and 55% overall yield from the corresponding carbazole precursor.     

Synthesis of Substituted Pyrrolo[3,4‐a]carbazoles

The cycloaddition between N‐protected 3‐{1‐[(trimethylsilyl)oxy]ethenyl}‐1H‐indoles and substituted maleimides (= 1H‐pyrrole‐2,5‐diones) yielded substituted pyrrolo[3,4‐a]carbazole derivatives bearing an additional succinimide (= pyrrolidine‐2,5‐dione) moiety either at C(5a) or C(10b) depending on the type of the protection group at the indole N‐atom. Derivatives substituted at C(10b) were isolated when the protection group, Me₃Si or Boc (^tBuOCO), was eliminated during the reaction (Schemes 2 and 3), whereas a substitution at C(5a) was observed when an electron‐withdrawing group, Tos (4‐MeC₆H₄SO₂) or pivaloyl (Me₃CCO), was not eliminated (Scheme 1). Complex results were found in reactions between 1‐(trimethylsilyl)‐3‐{1‐[(trimethylsilyl)oxy]ethenyl}‐1H‐indole, in contrast to formerly reported results (Scheme 3). Some derivatives of 1H,5H‐[1,2,4]triazolo[1′,2 : 1,2]pyridazino[3,4‐b]indole‐1,3(2H)‐dione were obtained from reactions with 4‐phenyl‐3H‐1,2,4‐triazole‐3,5(4H)‐dione (Scheme 2). All structures were established by spectroscopic data, by calculations, and one representative structure was confirmed by an X‐ray crystallographic analysis (Fig.). Finally, the formation of the different structure types was discussed, and compared with similar reactions reported in the literature.     

A Novel One‐pot Protocol for Silica Sodium Carbonate‐Catalyzed Synthesis of Pyrano[2,3‐h]coumarins

A novel environmentally benign condensation of 5,7‐dihydroxy‐4‐methylcoumarin, aryl aldehydes, and ethyl cyanoacetate in the presence of silica sodium carbonate (SSC) has been developed for the synthesis of new pyrano[2,3‐h]coumarins.     

Design,Synthesis, Molecular Modeling Study,and Antimicrobial Activity of Some Novel Pyrano[2,3‐b]pyridine and Pyrrolo[2,3‐b]pyrano[2.3‐d]pyridine Derivatives

Novel derivatives of pyrano[2,3‐b]pyridine and pyrrolo[2,3‐b]pyrano[2.3‐d]pyridine were prepared, and their structures were elucidated by spectral and elemental analyses. The newly prepared candidates were evaluated for their antimicrobial activity against Candida sp., Aspergillus multi, Aspergillus niger, Escherichia coli, and Staphylococcus aureus. All the tested compounds revealed potent to moderate activity toward all tested microorganisms; especially, candidate 10 showed comparable antifungal activity as that showed by the standard drug ketoconazole toward Candida sp., and ethyl 4‐methyl‐1,7,8,9‐tetrahydropyrano[2,3‐b]pyrrolo[2,3‐d]pyridine‐3‐carboxylate ( 12 ) was the most active compound against all the tested bacteria. Furthermore, the newly synthesized compounds are subjected to molecular docking study for the inhibition of the enzyme L‐glutamine: D‐fructose‐6‐phosphate amidotransferase [GlcN‐6‐P], which is a new target for antimicrobials to explain action mode of these target compounds as leads for discovering other antimicrobial agents.     

An Eco‐friendly Synthesis of Some Novel 4‐methyl‐4‐hetaryl Chromene and Pyrano[2,3‐c]pyrazole Derivatives

Some novel chromene and pyrano[2,3‐c ]pyrazole derivatives could be achieved successfully by reacting cyclic β‐diketones with 2‐acetylfuran/2‐acetylthiophene and malononitrile in a one‐pot synthesis. Active methylene pyrazolones reacted with 2‐(1‐furan‐2‐yl‐ethylidene)‐malononitrile and 2‐(1‐thiophen‐2‐yl‐ethylidene)‐malononitrile derivatives to afford the desired pyrano[2,3‐c ]pyrazole derivatives. Structures of all new compounds were established based on analytical and spectral data as well as X‐ray crystallography. A plausible mechanism for the reaction is suggested. The solvents and catalyst used are environmentally benign, and no hazardous solvents or heavy metals were involved.     

DDQ介导的新型3-吲哚烷酮及吡喃酮并[2,3-b]吲哚类化合物的合成

以1-(1H-吲哚-3-基)戊烷-3-醇及其衍生物为底物,以三氟甲磺酸铜为催化剂,甲醇为溶剂,DDQ（2,3-二氯-5,6-二氰基对苯醌）为氧化剂,共合成9个新型的3-吲哚烷酮衍生物及5个结构新颖的吡喃酮并[2,3-b]吲哚衍生物,其结构经¹H NMR,¹³C NMR和HR-MS(ESI)表征。对反应机理进行了推测并通过同位素实验进行了验证,反应为碳正离子参与并经分子间和分子内的亲核加成形成碳-氧键的过程。      

Synthesis of New Pyrrolo Heterocycles (I): Novel Synthesis of Pyrano[2,3‐c]pyrrole,Isoindoline, Pyrrolo[3,4‐b]pyridine,and Pyrrolo[3,4‐d]pyrimidine Derivatives

Michael addition of 1,5‐diaryl‐2,3‐dioxopyrrolidine derivatives with α‐cyanocinnamonitriles and ethyl α‐cyanocinnamates afforded 4H‐pyrano[2,3‐c]pyrrole derivatives in the presence of sodium ethoxide. Under the same reaction condition, the ylidenes of 1,5‐diaryl‐2,3‐dioxopyrrolidine were reacted with malononitrile or ethyl cyanoacetate to give isoindole derivatives; however, pyrrolo[3,4‐b]pyridine derivatives were formed when cyanoacetamide was used. Moreover, pyrrolo[3,4‐d]pyrimidine derivatives were synthesized by treating 4‐benzylidene‐1,5‐diphenyl‐2,3‐dioxopyrrolidine with urea and/or thiourea under basic conditions. The structures of all the new synthesized compounds were confirmed by elemental analysis, IR and NMR spectra.     

Synthesis of [1,4]benzodioxino[2,3‐c and 2,3‐d]pyridazinones

Reaction of chloropyridazin‐3‐one 1, 5 and 10 with catechol in the presence of potassium carbonate gave the corresponding [1,4]benzodioxino[2,3‐e and/or 2,3‐d]pyridazinones 2, 7, 8 and 11 .     

Synthesis of Novel Polyfunctionally Substituted Thieno[2,3‐c]pyridazines

4‐Cyano‐5,6‐dimethylpyridazin‐3‐(2H)‐thione 3b was used as a key intermediate for the synthesis of novel polysubstituted thieno[2,3‐c]pyridazines.     

Synthesis of Novel Pyrano[2,3‐b]pyridines from α,α′‐Bis(substituted‐benzylidene)cycloalkanones

In this paper, we describe a two‐step synthesis of a series of tacrine analogues. In the first step, α,α'‐bis(substituted‐benzylidene)cycloalkanones are reacted with malononitrile to afford 2‐amino‐3‐cyano‐4H‐pyrans. The second step involves the conversion of pyrans to pyrano[2,3‐b]pyridines with the use of AlCl₃ as catalyst.     

Synthesis of Some Novel Heteroannulated Pyrano[3,2‐c]quinoline‐2,5(6H)‐diones

6‐Butyl‐3‐((dimethylamino)methylene)pyrano[3,2‐c]quinolinone and 6‐butyl pyrano[3,2‐c]quinolone‐3‐carbonitrile were efficiently synthesized in good yield. These two new precursors were used to obtain some novel heteroannulated pyrano[3,2‐c]quinolone derivatives from heterocyclization reactions with various binucleophiles. These heteroannulation reactions afforded novel heterocyclic systems fused to the pyranoquinolinone at face c, such as pyrazole, pyrimidine, pyridine, and pyrazolopyranone.     

Convenient and Efficient Synthesis of 11‐Amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone Derivatives

The Gewald reactions of 5‐substituted‐1,3‐cyclohexanedione, malononitrile, and powdered sulfur were carried out to give the corresponding products 2‐amino‐5‐substituted‐7‐oxo‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile derivatives 1 . The intermediate enamines 2 were prepared by reaction of compounds 1 and 5‐substituted‐1,3‐cyclohexanedione with hydrochloric acid as catalyst. The title compounds 11‐amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone 3 were synthesized by cyclization of compounds 2 in the presence of K₂CO₃ and Cu₂Cl₂. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H‐NMR spectra.