Synthesis of a novel series of 6‐chloro‐1,4,2‐benzodithiazine 1,1‐dioxide derivatives with potential biological activity

A novel series of 6‐chloro‐1,4,2‐benzodithiazine 1,1‐dioxide derivatives 2‐19 with alkyl, aryl or het‐eroaryl substituents at position 3 have been synthesized by the reaction of 4‐chloro‐2‐mercaptobenzenesul‐fonamides with aldehydes, aldehyde acetals or acid anhydrides. 6‐Chloro‐3‐(2‐hydroxyphenyl)‐7‐methyl‐2,3‐dihydro‐l,4,2‐benzodithiazine 1,1‐dioxide (7) exhibited remarkable activity on the leukemia CCRF‐CEM cell line (GI₅₀<10 nM) and moderate activity against the other 49 human tumor cell lines derived from nine different cancer type.     

Synthesis of New Chromeno[4,3‐b]pyrazolo[4,3‐e]pyridines Derivatives with Antimicrobial Evaluation

A series of 2‐oxo‐2,5‐dihydro‐1H‐chromeno[4,3‐b]pyridine derivatives were obtained by using a one‐pot three component reaction of 2,2‐disubstituted chroman‐4‐one with aromatic aldehydes and 2‐cyanoacetamide in the presence of sodium hydroxide under solvent‐free conditions. Heating chromenopyridine derivatives with phosphoryl chloride gave the corresponding chloro derivatives. The reaction of the chloro derivatives with hydrazine hydrate afforded dihydrochromeno[4,3‐b]pyrazolo[4,3‐e]pyridines derivatives. Condensation of the dimethyl derivative compound with the aromatic aldehydes gave 8‐Arylideneamino‐6,6‐dimethyl‐10H‐chromeno[4,3‐b]pyrazolo[4,3‐e]pyridine.     

A new entry to pyrazolo[4,3‐e][1,4]diazepines. Facile synthesis of pyrazolo [4,3‐e][1,4]diazepin‐5,8‐diones, 5,6,8‐triones and pyrazolo[4,3‐e]pyrrolo‐[1,2‐a][1,4]diazepin‐5,10‐diones

A facile approach to pyrazolo[4,3‐e][1,4]diazepin‐5,8‐diones and pyrazolo[4,3‐e]pyrrolo[1,2‐a][1,4]‐diazepin‐5,10‐diones is reported. Strategy involved the utility of α‐amino acid as a three‐atom segment in the construction of diazepine skeleton on the preformed pyrazole ring.     

Regioselective three‐component synthesis of novel indeno[1,2‐b]‐pyrazolo[4,3‐e]pyridines‐fused derivatives of 4‐azafluorenone alkaloid

New fused indeno[1,2‐b]pyridine derivatives have been prepared in a multicomponent reaction from benzaldehydes, indanedione and the appropriate aminoheteroaryl compound. The simple methodology permitted the syntheses of a series of indeno[1,2‐b]pyrazolo[4,3‐e]pyridines 4 from 5‐aminopyrazol 1 and modulated by the corresponding benzaldehyde 2 .     

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     

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).     

4H‐thieno[3,4‐e]‐ and 4H‐pyrazolo[4,3‐e]‐1,2,4‐thiadiazine 1,1‐dioxides synthesis,chemical properties and evaluation of their Potential Cardiovascular Activity

This paper deals with the synthesis of a number of new 4H‐thieno[3,4‐e] and 4H‐pyrazolo[4,3‐e]‐1,2,4‐thiadiazine 1,1‐dioxide derivatives 1, the study of their chemical behavior in some alkylation reactions and the evaluation of their vasorelaxant effects on spontaneous motility and on tension responses to increased extracellular KCl concentrations in isolated rat portal vein.     

Synthesis of novel 1,4‐dihydropyrido[3′,2′:5,6]thiopyrano[4,3‐c]‐pyrazoles and 5H‐pyrido[3′,2′:5,6]thiopyrano[4,3‐d]pyrimidines as potential antiproliferative agents

The synthesis of new planar derivatives characterized by the presence of a pyridothiopyranopyrazole or pyridothiopyranopyrimidine nucleus, carrying a substituted aryl group, is reported. The novel 1,4‐dihydropyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyrazole derivatives were obtained by condensation of 2,3‐dihydro‐3‐hydroxymethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐ones with appropriate hydrazines. The preparation of 2‐substituted pyrido[3′,2′:5,6]thiopyrano[4,3‐d]pyrimidines was accomplished from the intermediate 2,3‐dihy‐dro‐3‐dimethylaminomethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐ones by reaction with the appropriate binucleophile amidines. The antiproliferative activity of some new products was tested by an in vitro assay on human tumour cell lines (HL‐60 and HeLa), but none of them showed any significant effects in the tests performed. Accordingly, linear flow dichroism measurements indicated their inability to form a molecular complex with DNA.     

Synthesis and properties of 4,5‐dihydrobenzo[e]imidazo[2,1‐c][1,4,2]diazaphosphinine derivatives

A number of 4,5‐dihydrobenzo[e]imidazo[2,1‐c][1,4,2]diazaphosphinine derivatives were prepared by the direct phosphorylation of 1‐(4‐Chlorophenylcarboxamido)‐2‐(1H‐1‐imidazolyl)‐5‐trifluoromethylbenzene in basic medium with phosphorus(III) bromide and dibromophenylphosphine. The tricyclic compounds 6a, 6b , and 9 having a trivalent phosphorus atom undergo the diazaphosphinine ring opening upon treatment with secondary amines in the presence of sulfur. © 2002 John Wiley & Sons, Inc. Heteroatom Chem 13:84–92, 2002; DOI 10.1002/hc.10000     

An expedient synthesis of novel,fused pyrimido[4,5‐d]pyrimidine and pyrimido [5,4‐e] [1,2,4]triazolo[4,3‐c]pyrimidine analogues from 4‐amino‐2,6‐dichloro‐pyrimidine

A number of potent pyrimido[4,5‐d]pyrimidine have efficiently been synthesized by the condensation of 4‐amino‐2,6‐dichloropyrimidine with various substituted benzaldehyde followed by cyclization with ammonium thiocyanate. Also, these newly synthesized derivatives were utilized for the construction of novel pyrimido[5,4‐e][1,2,4]triazolo[4,3‐c]pyrimidine analogues via oxidative cyclization involving 1,5‐hydrogen abstraction. Structure of all the newly constructed derivatives was corroborated by the elemental and spectral data. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:245–253, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20177     

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.     

Convenient synthesis of novel 5‐substituted 3‐methylisoxazole‐4‐sulfonamides

A number of novel sulfonamide derivatives of 5‐substituted‐3‐methylisoxazole were synthesized and characterized, starting from 3,5‐dimethylisoxazole. Key steps include the generation of 3,5‐dimethylisoxazole‐4‐sulfonamides followed by their reactions with N‐(dimethoxymethyl)‐N,N‐dimethylamine or various aromatic and heteroaromatic aldehydes. As a result, a series of novel aryl/heteroaryl‐ and aminovinylsubstituted derivatives of the isoxazole heterocycle were obtained. The scope and limitations of the developed approach are discussed.     

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.     

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.     

A facile synthesis of 2‐substituted thieno[3′,2′‐5,6]‐pyrido[4,3‐d]pyrimidin‐4(3H)‐ones

The thienopyridine derivative 2 , obtained from reaction of acetoacetic ester with 1 in the presence of tin tetrachloride, was treated with triphenylphosphine in hexachloroethane and Et₃N to give iminophosphorane 3 . Iminophosphorane 3 reacted with phenyl isocyanate to give carbodiimide 4 , which was further treated with phenols or ethenol to produce 2‐substituted 5,8,9‐trimethyl‐3‐phenyl‐thieno[3′,2′‐5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 5 in presence of catalytic amount of K₂CO₃ or EtONa. The structures of compounds 5 were confirmed by ¹H NMR, IR, MS, and elemental analysis.     

Regioselective synthesis and characterization of new 3‐aryl‐7‐trifluoromethyl‐[1,2,4]triazolo[4,3–a]pyrimidines

The regioselective synthesis and characterization of a new series of 3‐aryl‐7‐trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines from the oxidative heterocyclization of 2‐(N′‐benzylidenehydrazino)‐4‐trifluoromethylpyrimidines with copper dichloride is described. J. Heterocyclic Chem., (2011).