Facile Access to Benzothiazole‐Containing Pyrrolo[1,2‐a]quinolines and Pyrrolo[2,1‐a]isoquinolines via Nitrogen Ylides

Quinoline and isoquinoline react with 2‐(bromoacetyl)benzothiazole ( 1 ) in dry benzene to give the corresponding quinolinium and isoquinolinium salts 2 and 10 which undergo base‐mediated [3+2] 1,3‐dipolar cycloaddition with some acetylene and ethylene derivatives to give the corresponding benzothiazole‐containing pyrrolo[1,2‐a]quinoline and pyrrolo[2,1‐a]isoquinoline derivatives.     

Synthesis and Reactivity of 2‐(6,7‐Diethoxy‐3,4‐dihydroisoquinolin‐ 1‐yl)acetonitrile towards Hydrazonoyl Halides

The synthesis of 2‐(6,7‐diethoxy‐3,4‐dihydroisoquinolin‐1‐yl)acetonitrile ( 1 ) has been performed by ring closure of the corresponding amide according to the Bischler‐Napieralski method (Scheme 1). Based on spectroscopic data, the tautomeric 2‐(tetrahydroisoquinolin‐1‐ylidene)acetonitrile is the actual compound. The reactions of 1 with α‐oxohydrazonoyl halides 4 in the presence of Et₃N led to 2‐(aryldiazenyl)pyrrolo[2,1‐a]isoquinoline derivatives 8 (Scheme 2), whereas with C‐(ethoxycarbonyl)hydrazonoyl chlorides 14 , 2‐(arylhydrazono)pyrrolo[2,1‐a]isoquinoline‐1‐carbonitriles 16 were formed (Scheme 4). The structures of the products were established from their analytical and spectroscopic data and, in the case of 8b , by X‐ray crystallography.     

Synthesis and Structural Characterization of Pyrrole Heterocyclic Systems Bearing Amino Acid Units: Novel Pyrrol‐3‐ones,Pyrrolo[1,2‐a][3,1]benzoxazines,and Pyrrolo[2,1‐b][1,3]oxazoles

Furan‐3‐one derivatives 1 were converted into 2‐hydroxy‐pyrrole‐3‐ones 4 by reacting with various α‐ and β‐amino acids. In contrast, the reaction of furan‐3‐ones and 1‐aminocyclobutanecarboxylic acid afforded spiro‐pyrrolo[2,1‐b][1,3]oxazoles 5 via the pyrrole‐3‐one intermediate under the same reaction conditions. Some of 2‐hydroxy‐pyrrole‐3‐ones 3 derived from anthranilic acids were transformed to pyrrolo[1,2‐a][3,1]benzoxazines via intramolecular esterification.     

Efficient Synthesis of Pyrrolo[2,1‐a]isoquinoline and Pyrrolo[1,2‐a]quinoline Derivatives via One‐pot Two‐step Metal‐catalyzed Three‐component Reactions

A sequential one‐pot two‐step reaction for efficient synthesis of pyrrolo[2,1‐a]isoquinoline and pyrrolo[1,2‐a]quinoline derivatives in good yields has been successfully developed. The reaction included firstly Cu‐catalyzed three‐component reaction of isoquinoline (quinoline), acetylenedicarboxylate and alkynylbenzene and then Pd‐catalyzed intramolecular C(sp)‐C(sp²) coupling reaction of initially formed 1‐alkenyl‐2‐alkynyl‐1,2‐dihydroisoquinoline (1,2‐dihydroquinoline).     

Studies on the syntheses of heterocyclic compounds. Part DLXXXII . Synthesis of benzo[a] quinolizine derivatives and pyrrolo[2,1-a] isoquinoline derivatives by phenolic cyclization

Phenolic cyclization of 3-hydroxy phenethylamine with acylbutyric acid and acylpropionic acid afforded the lactam of the corresponding benzol[a] quinolizine and pyrrolo[2, 1-a]isoquinoline derivatives, which were reduced with lithium aluminum hydride to give the benzol[a]quinolizine and pyrrolo[2,1 -a] isoquinoline derivatives, respectively. The configurations of acetyl derivatives of these products were determined.     

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.     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

Synthesis and Reactions of Pyrido[2,1‐a]isoquinolin‐4‐yl Formimidate Derivatives and Antimicrobial Activities of Isolated Products

Treatment of arylidene malononitriles 2A – C with 1‐cyanomethylisoquinoline 1 afforded 4‐amino‐2‐arylpyrido[2,1‐a ]isoquinoline‐1,3‐dicarbonitrile derivatives 5A – C , which converted to formimidates 6A – C via reaction with triethylorthoformate. Treatment of the latter compounds with hydrazine hydrate gave the corresponding amino–imino compounds 7A – C , which underwent Dimroth rearrangement to afford 13‐aryl‐1‐hydrazinylpyrimido[5′,4′:5,6]pyrido[2,1‐a ]isoquinoline‐12‐carbonitrile 8A – C . The latter reacted with aldehyde to give 9a – i . Oxidative cyclization of the latter compounds 9a – i gave [1,2,4]triazolo[4″,3″:1′,6′]‐pyrimido[5′,4′:5,6]pyrido[2,1‐a ]isoquinolines 10a , d , g . Such compounds isomerized to the thermodynamically more stable isomers [1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:5,6]‐pyrido[2,1‐a ]isoquinolines 11a , d , g . Antimicrobial activities for some compounds were studied.     

Imidazo[2,1‐b]thiazoles,imidazo[2,1‐b]imidazoles and Pyrrolo[1,2‐c]imidazoles. synthesis,structure and evaluation of benzodiazepine receptor binding

As a continuation of our studies on bicyclic heterocycles with benzodiazepine receptor affinity, derivatives with a 5:5 bicyclic skeleton, namely imidazo[2,1‐b]thiazoles, imidazo[2,1‐b]imidazoles and pyrrolo[1,2‐c]imidazoles were prepared. The compounds possessed an aromatic substituent with different spatial arrangement and distance to the bicyclic skeleton. X‐ray structure analysis was performed for Z‐2‐(4‐chlorobenzylidene)‐5,5‐diphenyl‐2,3,5,6‐tetrahydroimidazo[2,1‐b]imidazoline‐3,6‐dione ( 6a ) and 5‐amino‐6‐cyano‐7‐phenyl‐1‐oxo‐3‐thioxo‐2,3‐dihydro‐1H‐pyrrolo[1,2‐c]imidazole ( 20a ). In contrast to the previously described arylideneimidazo[2,1‐b]thiazepinones the smaller heterocyclic ring systems investigated in this study were devoid of meaningful benzodiazepine receptor affinity as well as anti‐convulsant activity.     

Reaction of cyclic imidates with α,β‐unsaturated esters: Synthesis of new pyrrolo[2,1‐b]‐1,3‐oxazine and pyrido[2,1‐b]‐1,3‐oxazine derivatives

The cycloaddition reaction of cyclic imidates, 2‐benzyl‐5,6‐dihydro‐4H‐1,3‐oxazines 1a , 1b , 1c , 1d , 1e , 1f , with dimethyl acetylenedicarboxylate 2 , trimethyl ethylenetricarboxylate 4 , or dimethyl 2‐(methoxymethylene)malonate 6 afforded new fused heterocyclic compounds, such as methyl (6‐oxo‐3,4‐dihydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐ylidene)acetates 3a , 3b , 3c , 3d , 3e , 3f (71–79%), dimethyl 2‐(6‐oxo‐3,4,6,7‐tetrahydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐yl)malonates 5b , 5c , 5d , 5e , 5f (43–71%), or methyl 6‐oxo‐3,4‐dihydro‐2H,6H‐pyrido[2,1‐b]‐1,3‐oxazine‐7‐carboxylates 7a , 7b , 7c , 7d , 7e , 7f (32–59%), respectively. In these reactions, 1a , 1b , 1c , 1d , 1e , 1f (cyclic imidates, iminoethers) functioned as their N,C‐tautomers (enaminoethers) 2 to α,β‐unsaturated esters 2 , 4, and 6 to give annulation products 3 , 5 , and 7 following to the elimination of methanol, respectively. J. Heterocyclic Chem., (2011).     

Catalytic Divergent [3+3]‐ and [3+2]‐Cycloaddition by Discrimination Between Diazo Compounds

Highly selective divergent cycloaddition reactions of enoldiazo compounds and α‐diazocarboximides catalyzed by copper(I) or dirhodium(II) have been developed. With tetrakis(acetonitrile)copper(I) tetrafluoroborate as the catalyst epoxypyrrolo[1,2‐a]azepine derivatives were prepared in good yields and excellent diastereoselectivities through the first reported [3+3]‐cycloaddition of a carbonyl ylide. Use of Rh₂(pfb)₄ or Rh₂(esp)₂ directs the reactants to regioselective [3+2]‐cycloaddition generating cyclopenta[2,3]pyrrolo[2,1‐b]oxazoles with good yields and excellent diastereoselectivities.     

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.     

A new approach for the synthesis of some pyrazolo[5,1‐c]triazines and pyrazolo[1,5‐a]pyrimidines containing naphtofuran moiety

Naphtho[2,1‐b]furan‐2‐yl)(8‐phenylpyrazolo[5,1‐c][1,2,4]triazin‐3‐yl)methanone, ([1,2,4]triazolo[3,4‐c][1,2,4]triazin‐6‐yl)(naphtho[2,1‐b]furan‐2‐yl)methanone, benzo[4,5]imidazo[2,1‐c][1,2,4]triazin‐3‐yl‐naphtho[2,1‐b]furan‐2‐yl‐methanone, 5‐(naphtho[2,1‐b]furan‐2‐yl)pyrazolo[1,5‐a]pyrimidine, 7‐(naphtho[2,1‐b]furan‐2‐yl)‐[1,2,4]triazolo[4,3‐a]pyrimidine, 2‐naphtho[2,1‐b]furan‐2‐yl‐benzo[4,5]imidazo[1,2‐a]pyrimidine, pyridine, and pyrazole derivatives are synthesized from sodium salt of 5‐hydroxy‐1‐naphtho[2,1‐b]furan‐2‐ylpropenone and various reagents. The newly synthesized compounds were elucidated by elemental analysis, spectral data, chemical transformation, and alternative synthetic route whenever possible. J. Heterocyclic Chem., (2012).     

Synthesis of novel imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines

Several 1 1-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines have been used as starting material to prepare a number of derivatives of 9H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and 10H-pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines. The imidazole nucleus was built by reaction of amidines with ethyl bromopyruvate or aminoacetaldehyde dimethylacetal. Several derivatives of imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine have been prepared by formylation of the pyrrole ring followed by formation of thioamides. Condensation of 11-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines with diethyl ethoxymethylenemalonate afforded intermediate diesters which were transformed into the corresponding 10H-pyrimido[1,2-a]pyrrolo[2,1-c]-benzodiazepines.     

Reaction of β‐Bromo‐β,γ‐unsaturated Pyrroline Nitroxide Aldehydes and Nitriles with Aromatic N,S‐Binucleophiles

Reactions of β‐bromo‐β,γ‐unsaturated pyrroline nitroxide aldehyde ( 1 ) or nitrile ( 4 ) or their diamagnetic forms ( 5, 6 ) with 2‐aminothiophenol or 2‐mercaptobenzimidazole were evaluated. The reaction could be reproduced more easily with the application of O‐acetyl derivatives of nitroxides to generate 2‐substituted‐benzothiazole, pyrrolo[3,4‐b ]benzo[1,5]tiazepine scaffolds with 2‐aminothiophenol and benzimidazo[2,1‐b ]pyrrolo[3,4‐e ]‐[1,3]thiazine scaffold with 2‐mercaptobenzimidazole.     

Novel Synthesis of 3‐Amino‐4‐oxo‐(2H)‐pyrazolo[3′,4′:4,5]pyrimido‐[2,1‐b]benzothiazole and its 2‐ and 3‐Substituted Derivatives

Reaction of 4H‐pyrimido[2,1‐b]benzothiazole‐2‐thiomethyl‐3‐cyano‐4‐one (1) with hydrazine hydrate/aryl hydrazine/heteryl hydrazine in the presence of anhydrous potassium carbonate and dimethyl formamide afforded 3‐amino‐4‐oxo‐(2H)/aryl/heteryl pyrazolo[3′,4′:4,5]pyrimido[2,1‐b]benzothiazoles in good yield. These pyrazole derivatives on diazotization followed by replacement with hydroxy, chloro, bromo, iodo and on reduction gave the corresponding 3‐substituted derivatives.     

Pyrazoles and pyrazolo[4,3‐e]pyrrolo[1,2‐a]pyrazines II

Synthesis of the title compounds was achieved using the anils 2a , 2b , 2c , 2d , 2e and 5a , 5b , 5c derived from the 4‐aminopyrazole 1 as starting materials. These compounds were allowed to react with mercaptoacetic acid in boiling dry benzene to afford the corresponding thiazolidinones and spiro‐thiazolidinones 3a , 3b , 3c , 3d , 3e and 6a , 6b , 6c , respectively. Pictet—Spengler reaction of the 4‐aminopyrazole hydrochloride 7 with aromatic aldehydes and cyclic ketones resulted in the formation of new pyrazolo[4,3‐e]pyrrolo[1,2‐a]pyrazines 8a , 8b , 8c , 8d , 8e and 9a , 9b , respectively. Other derivatives of pyrazolo pyrrolopyrazines 10 and 11 were obtained via the reaction of the amino derivative 1 with 1,1′‐carbonyldiimidazol and CS₂, respectively. J. Heterocyclic Chem., (2011).     

Facile Chemoselective synthesis of 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids and 3H,3’H‐Spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives

Oxidation of some derivatives of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐one have been investigated in detail using lead(IV) acetate in acetic acid under reflux conditions and periodic acid in aqueous ethanol at room temperature. We realized that during the first 5–15 minutes of the oxidation reactions in lead(IV) acetate/acetic acid system, 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives have been synthesized chemo selectively, while, if the reaction mixtures stirred for additional 3 hours, the main products would be 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids. Moreover, room temperature oxidation of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐ones by periodic acid (H₅IO₆), leads to the formation of 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives in good to excellent yields.     

A Diastereoselective Synthesis of Functionalized Tetrahydroindeno[2′,1′,3,4]pyrido[2,1‐a]isoquinolines

An effective route to alkyl 9a‐(2,3‐dihydro‐1,3‐dioxo‐1H‐inden‐2‐yl)‐9a,14,14a,14b‐tetrahydro‐14‐oxoindeno[2′,1′:3,4]pyrido[2,1‐a]isoquinoline‐9‐carboxylates via a diastereoselective one‐pot four‐component reaction of isoquinoline and alkyl prop‐2‐ynoates with two equivalents of indane‐1,3‐dione, in aqueous MeOH at room temperature, is described.     

Asymmetric Hydroformylation of Vinylfurans Catalyzed by {(11bS)‐4‐{[(1R)‐2′‐Phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f]‐ [1,3,2]dioxaphosphepin}rhodium(I) [RhI{(R,S)‐binaphos}] Derivatives

The asymmetric hydroformylation of 2‐ and 3‐vinylfurans ( 2a and 2b , resp.) was investigated by using [Rh{(R,S)‐binaphos}] complexes as catalysts ((R,S)‐binaphos = (11bS)‐4‐{[1R)‐2′‐phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin; 1 ). Hydroformylation of 2 gave isoaldehydes 3 in high regio‐ and enantioselectivities (Scheme 2 and Table). Reduction of the aldehydes 3 with NaBH₄ successfully afforded the corresponding alcohols 5 without loss of enantiomeric purity (Scheme 3).