Synthesis of substituted pyrimido[4,5‐b] and [5,4‐c]‐[1,8]naphthyridines

Ethyl 1‐ethyl‐7‐methyl‐4‐oxo‐1,4‐dihydro[1,8]naphthyridine‐3‐carboxylate ( 1 ), precursor of nalidixic acid, has been converted in two steps through ([1,8]naphthyridin‐3‐yl)carbonylguanidine derivatives into substituted pyrimido[4,5‐b] and [5,4‐c][1,8]naphthyridines.     

New 1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidine derivatives II

The 7‐chloro‐3‐(2‐chlorobenzyl)‐ and 7‐chloro‐3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐d]pyrimidines ( 1 and 4 ), by nucleophilic replacement with some hydrazides, gave the corresponding 7‐hydrazidoderivatives ( 2a‐e and 5a‐e ). These, by heating in Dowtherm, underwent an intramolecular cyclization to form the new tricyclic 7‐substituted‐3‐(2‐chlorobenzyl)‐ and 3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidines ( 3a‐d and 6a‐d ). The 7‐hydrazino‐3‐(2‐chlorobenzyl)‐ and 7‐hydrazino‐3‐(2‐fluorobenzyl)‐triazolo‐pyrimidines ( 9a and 9b ) were also prepared via the corresponding mercapto ( 7a and 7b ) and thiomethyl ( 8a and 8b ) derivatives.     

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 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.     

Straightforward Synthesis and Properties of Highly Fluorescent [5]‐ and [7]‐Helical Dispiroindeno[2,1‐c]fluorenes

This work presents a general approach for synthesis of substituted [5]‐helical dispiroindeno[2,1‐c]fluorenes based on Rh‐catalyzed intramolecular cyclotrimerization of triynes. This approach was further extended for the first synthesis of configurationally stable [7]‐helical dispiroindeno[2,1‐c]fluorenes. A series of variously substituted derivatives was prepared and their photophysical and electrochemical properties were evaluated. Their fluorescence emission maxima were in the region of 351–428 nm and quantum yields up to 88 % are the highest measured among the full‐carbon helical compounds.     

2,5‐Disubstituted Pyrazolo[4,3‐c]cinnolin‐3‐ones

Complementary strategies to 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones are reported herein, providing late stage substituent introduction at either the 2‐ or the 5‐position. Treating a readily prepared 4‐thiocinnoline ester with substituted hydrazines afforded late stage access to the 2‐position, while late stage substituent introduction at the 5‐position was achieved via two different strategies: alkylation of 4‐hydrazonopyrazol‐3‐ones, followed by a ring‐closing intramolecular S_NAr tactic and direct reaction of 5‐(2‐fluorophenyl)‐2,4‐dihydro‐3H‐pyrazol‐3‐ones with aryl diazonium salts, followed by cyclization. The strategies described herein provide practical and general methods to prepare 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones.     

Synthesis of benzo[b]thieno‐ and benzo[b]furano‐[2,3‐a]pyrrolo[3,4‐c]carbazole‐5‐, ‐7‐ and ‐5,7‐dione

Benzo[b]thieno[2,3‐a]pyrrolo[3,4‐c]carbazoles and benzo[b]furano[2,3‐a]pyrrolo[3,4‐c]carbazoles were prepared from 2‐(2‐benzo[b]thieno)‐ (8) and 2‐(2‐benzo[b]furano)‐3‐[3‐(2,5‐dioxo‐lH‐pyrrolidinyl)]indole (9) by a palladium(II)acetate/tetrachloro‐1,4‐benzoquinone oxidative A‐E ring closure.     

Synthesis and reactions of 11H‐benzo[b]pyrano[3,2‐f]indolizines an pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolines

2‐Methyl‐3H‐indoles 1 cyclize with two equivalents of ethyl malonate 2 to form 4‐hydroxy‐11H‐benzo[b]pyrano[3,2‐f]indolizin‐2,5‐diones 3, whereas 2‐mefhyl‐2,3‐dihydro‐1H‐indoles 9 give under similar conditions regioisomer 8‐hydroxy‐5‐methyl‐4,5‐dihydro‐pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolin‐7,10‐diones 10 . The pyrone rings of 3 and 9 can be cleaved either by alkaline hydrolysis to give 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 4 or 5‐acetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo‐[3,2,1‐ij]quinolin‐4‐ones 11 , respectively. Chlorination of 3 and 9 with sulfurylchloride gives under subsequent ring opening 7‐dichloroacetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 5 or 5‐dichloracetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 12 . The dichloroacetyl group of 5 can be reduced with zinc to 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 7. Treatment of the acetyl compounds 4, 7 and 11 with 90% sulfuric acid cleaves the acetyl group and yields 8‐hydroxy‐10H‐pyrido[1,2‐a]‐indol‐6‐ones 6 and 8 , and 6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 13 . Reaction of dichloroacetyl compounds 12 with sodium azide yields 6‐hydroxy‐2‐methyl‐5‐(1H‐tetrazol‐5‐ylcarbonyl)‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 14 via intermediate geminal diazides.     

Synthesis of Morphlinotetrahydrothieno[2,3‐c]Isoquinolines

1‐Morpholin‐4‐yl‐5,6,7,8‐tetrahydroisoquinoline‐4‐carbonitrile ( 2 ) was synthesized from 3‐amino‐1‐thioxo‐5,6,7,8‐tetrahydro‐1H‐isothiochromene‐4‐carbonitrile ( 1 ) and used as starting material to synthesize many thienotetrahydroisoquinolines ( 4 ), which in turn were used in the synthesis of many pyrimidothienotetrahydroisoquinolines.     

Synthesis and Evaluation of Bioactivity of Thiazolo[3,2‐b]‐[1,2,4]‐triazoles and Isomeric Thiazolo[2,3‐c]‐[1,2,4]‐triazoles

Synthesis of 2‐(o‐nitrophenyl)‐6‐arylthiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 and its isomer 3‐(o‐nitrophenyl)‐5‐arylthiazolo[2,3‐c]‐[1,2,4]‐triazoles 6 has been achieved starting from the appropriate 1‐(o‐nitrobenzoyl)‐3‐thiosemicarbazide 1 . Compound 1 on condensation with α‐haloketones gives 2‐(o‐nitrobenzoyl)hydrazino‐4‐arylthiazole hydrobromide 5 , which, on cyclization with POCl₃, affords thiazolo[3,2‐b]‐[1,2,4]‐triazoles 6 and not the isomeric thiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 . This has been established by an unequivocal synthesis of 4 through polyphosphoric acid cyclization of 5‐aroylmethylmercapto‐3‐o‐nitrophenyl‐[1,2,4]‐triazole 3 . Compound 3 was synthesized by condensation of α‐haloketones with 5‐mercapto‐3‐(o‐nitrophenyl)‐[1,2,4]‐triazole 2 , obtained cyclization of 2‐(o‐nitrobenzoyl)hydrazinecarbothioamide 1 with NaOH. The antibacterial and antifungal activities of some of the compounds have also been evaluated.     

Formation of 6‐Methyl‐7,11‐diphenylheptaleno[1,2‐c]furanones

The dehydrogenation reaction of a mixture of heptalene‐1,2‐ and heptalene‐4,5‐dimethanols 4a and 4b with basic MnO₂ in AcOEt at room temperature led to the formation of the corresponding heptaleno[1,2‐c]furan‐1‐one 6a and heptaleno[1,2‐c]furan‐3‐one 7a (Scheme 2). Both products can be isolated by chromatography on silica gel. The methylenation of the furan‐3‐one 7a with 1 mol‐equiv. of Tebbe's reagent at ?25 to ?30° afforded the 2‐isopropenyl‐5‐methylheptalene‐1‐methanol 9a , instead of the expected 3,6‐dimethylheptaleno[1,2‐c]furan 8 (Scheme 3). Also, the treatment of 7a with Takai's reagent did not lead to the formation of 8 . On standing in solution at room temperature, or more rapidly on heating at 60°, heptalene 9a undergoes a reversible double‐bond shift (DBS) to 9b with an equilibrium ratio of 1 : 1.     

One‐pot Two‐step Reaction for Synthesis of Poly‐substituted Pyrano[3,2‐c]pyridones and Spiro[indoline‐3,4′‐pyrano[3,2‐c]pyridine]‐2,5′(6′H)‐diones in Water

An efficient four‐component approach for the synthesis poly‐substituted pyrano[3,2‐c]pyridones and spiro[indoline‐3,4′‐pyrano[3,2‐c]pyridine]‐2,5′(6′H)‐diones in water has been established. During the reaction, the products were readily achieved through one‐pot two‐step reaction using solid acid as catalyst. The advantages of atom and step economy, the recyclability of heterogeneous solid acid catalyst, easy workup procedure, and the wide scope of substrates make the reaction a powerful tool for assembling pyrano[3,2‐c]pyridone skeletons of chemical and medical interest.     

A convenient synthesis of novel 7‐phosphonylbenzyl‐2‐substituted pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]‐pyrimidine derivatives

A series of pyrazolo[4,3‐e]‐1,2,4‐triazolo‐[1,5‐c]pyrimidine derivatives, bearing phosphonylbenzyl chain in position 7, were conveniently synthesized in an attempt to obtain potent and selective antagonists for the A_2A adenosine receptor or potent pesticide lead compounds. Diethyl[(5‐amino‐4‐cyano‐3‐methylsulfanyl‐pyrazol‐1‐yl)‐benzyl]phospho‐nate ( 3 ), which was prepared by the cyclization of diethyl 1‐hydrazinobenzylphosphonate ( 1 ) with 2‐[bis(methylthio)methylene]malononitrile ( 2 ), reacted with triethyl orthoformate to afford diethyl[(4‐cyano‐5‐ethoxymethyleneamino‐3‐methylsulfanyl‐pyrazol‐1‐yl)‐benzyl]phosphonate ( 4 ), which reacted with various acyl hydrazines in refluxing 2‐methoxyethanol to give the target compounds 5a–h in good yields. Their structures were confirmed by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. The crystal structure of 5e was determined by single crystal X‐ray diffraction © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:634–638, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20478     

Spiro[pyrido[3,2,1‐ij]pyrimido[4,5‐b]quinoline‐7,5′‐pyrrolo[2,3‐d]pyrimidines] and Spiro[pyrimido[4,5‐b]quinoline‐5,1′‐pyrrolo[3,2,1‐ij]quinolines] Derived from 5,6‐Dihydro‐4H‐pyrrolo[3,2,1‐ij]quinoline‐1,2‐dione

Reaction of 5,6‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinoline‐1,2‐dione ( 1 ) with two equivalents of some 6‐aminouracils (or 6‐amino‐2‐thiouracil) generates spirocyclic tetrahydrobenzo[if]quinolizines ( 7 ). The one‐pot, three‐component reaction of amido ketone ( 1 ) with 6‐aminouracil (or 6‐amino‐2‐thiouracil) and a cyclic six‐membered 1,3‐diketone produces spirocyclic tetrahydropyrrolo[3,2,1‐ij]quinolinones ( 15 ).     

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.