Synthesis of 4-methyl-2H-1,2,3-benzothiadiazine 1,1-dioxides and their further transformation via alkylation and reduction steps

Abstract

Ortho lithiation of acetophenone ketals followed by introduction of the chlorosulphonyl group and subsequent ring closure with hydrazine monohydrate or acetohydrazide gave rise to the formation of variously substituted 4-methyl-1,2,3-benzothiadiazine 1,1-dioxides. N(2)-Alkylation and reduction of the C=N double bond were carried out successfully to give N(2)-alkyl-4-methyl-3,4-dihydro-1,2,3-benzothiadiazine 1,1-dioxides. Finally, N(3)-alkylation was accomplished by reductive alkylation with aldehydes. Certain unsaturated and also some 3,4-dihydro derivatives exhibited a significant anxiolytic effect in vivo. Detailed NMR studies and DFT calculations supported the structure elucidation of the compounds.     

A facile synthesis of 3-substituted 2-cyanoquinazolin-4(3H)-ones and 3-alkyl-2-cyanothieno[3,2-d]pyrimidin-4(3H)-ones via 1,2,3-dithiazoles

The reaction of methyl anthranilate with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel's salt) in the presence of pyridine (2 equivalents) in dichloromethane at room temperature gave methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilate ( 3a ) (50% yield), which reacted with sterically less hindered primary alkylamines to give directly 3-alkyl-2-cyanoquinazolin-4(3H)-ones 5 in moderate to good yields. With tert-butylamine, N-(2-methoxycarbonylphenyl)iminocyanomethyl N-(tert-butyl) disulfide 7 and methyl 2-(N-cyanothioformamido)anthranilate ( 8 ) were isolated in 33% and 59% yields, respectively. The cyano group of quinazoline 5a (R = CH₃) is readily displaced by various nucleophiles to give 2-substituted quinazolinones 11–19 , which indicates that compounds 5 can be utilized as starting materials for the synthesis of new 2-substituted quinazolines. Similarly 3-alkyl-2-cyanomieno[3,2,-d]pyrimidin-4(3H)-ones 22 were prepared from methyl 3-[N-(4-chloro-5H-1,2,3-dimiazol-5-ylidene)]-2-thiophencarboxylate ( 21 ) in moderate to good yields.     

Reactions of benzotriazoles with diethyl ethoxymethylenemalonate; ethylation and michael addition. Comparison with other esters and N-heterocycles

Benzotriazole and its 5-methyl-and 5-nitro derivatives react with diethyl ethoxymethylenemalonate by ethylation at each of the ring N-atoms and through Michael addition, to give the isomeric esters ethyl (E/Z) 3-[5(6)-R-benzotriazol-1-yl]propenoates. Benzotriazole and its 5-nitro derivative react similarly with ethyl acetoacetate but N-ethyl derivatives are obtained in lower yields. Other 1,2,3-triazoles derivatives and indole were ineffective in this reaction while benzimidazole produced similar results but accompanied with a small amount of a benzimidazoline addition product, whose structure has been determined by crystallo-graphic analysis.     

Synthesis and spectroscopic characterization of 1-[1,2,3-triazol-1-yl]-4-aroylazetidin-2-ones

1-(N-Phenacylidene)amino-1,2,3-triazoles 3 react with propionylchloride and phenoxyacetylchloride in the presence of triethylamine to give trans- ( 5 ) and cis- ( 6 ) 1-(1,2,3-triazol-1-yl)-4-aroylaztidin-2-ones in a 1:1 ratio, on the contrary to the 1-(N-arylidene)amino-1,2,3-triazoles, which do not give any reaction product with the same acid chlorides. The spectroscopic characteristics of these new N-triazolyl-β-lactams are also discussed.     

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 1,2,3‐Selenadiazole Derivatives

The reaction of aroyl chlorides 1 with KSeCN and ethyl diazoacetate ( 6 ) in acetone at room temperature yields ethyl 2‐aroyl‐5‐(aroylimino)‐2,5‐dihydro‐1,2,3‐selenadiazole‐4‐carboxylates 7 (Scheme 3). A reaction mechanism via the initial formation of the corresponding aroyl isoselenocyanates 2 followed by a 1,3‐dipolar cycloaddition of the diazo compound with the C=Se bond to give ethyl 5‐(aroylimino)‐4,5‐dihydro‐1,2,3‐selenadiazole‐4‐carboxylates of type D is proposed. Acylation of the latter at N(2) leads to the final products 7 . Deacetylation of 7 to give ethyl 5‐(aroylimino)‐1,2,3‐selenadiazole‐4‐carboxylates 10 is achieved by treatment of 7 with morpholine (Scheme 5). The intermediate isoselenocyanates 2 partially oligomerize to give two different oligomers. The symmetrical one reacts with morpholine to yield selenourea derivatives 12 (Scheme 6).     

Synthesis and Antibacterial Activity of Some New 2,5‐Disubstituted‐1,3,4‐oxadiazole Derivatives

Synthesis of some new oxadiazole derivatives starting from 1,2,3-benzo[d]triazole-1-acetic hydrazide (1) is described. The target compounds 2-(N-substituted-aminocarbonylmethylthio)-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (4a—4i) and 2-[2-(N-substituted-aminocarbonyl)ethylthio]-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (5a—5i) were obtained in good yields via cyclisation of 1 and subjected to antibacterial activity test against pathogenic bacteria. The halogen containing mono- and di-substituted derivatives showed excellent antibacterial activity compared to other analogues.     

A tandem of the Cornforth rearrangements of 4-(1,2,3-triazol-1-yl)iminomethyl-1,2,3-thiadiazole

The method for the synthesis of 5-(2,6-dimethylmorpholino)-1,2,3-thiadiazole-4-carbaldehyde was proposed. Its reaction with sodium 1-amino-4-(N-methyl)carbamoyl-1,2,3-triazol-5-olate proceeds through a tandem of the Cornforth rearrangements. The initially formed azomethine isomerizes into sodium 4"-(2,6-dimethylmorpholino)thiocarbonyl-4-(N-methyl)carbamoyl-1,1"-bis[1,2,3]triazolyl-5-olate, which then rearranges to give sodium 4-{N-[4-(2,6-dimethylmorpholinothiocarbonyl)-1,2,3-triazol-1-yl]carbamoyl}-1-methyl-1,2,3-triazol-5-olate.     

Efficient method for the synthesis of 1,2,3-triazole functionalized isoxazolidine derivatives by 1,3-dipolar cycloaddition of nitrones with terminal olefins

1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was treated with different N-alkyl hydroxylamine hydrochlorides 2 using NaHCO₃ to obtain 1,2,3-triazole substituted N-alkyl nitrones 3a–c. The nitrones 3a–c were further reacted with different substituted olefins and furnished 2-alkyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-5-(substituted)isoxazolidine derivatives 4a–p in high yields via 1,3-dipolar cycloaddition reaction.     

An Investigation on the thermolytic conversions of 5-Diazouracils into 1,2,3-Triazoles

The thermolysis of 5-diazo-6-methoxy-1-methyl-1,6-dihydrouracil ( 1 ) has afforded methyl N-(1-methyl-1,2,3-triazol-4-oyl)carbamate ( 2 ), bis-(1-methyl-1,2,3-triazol-4-oyl)amine ( 3 ) and di-methylcarbimate ( 4 ). The reaction was shown to proceed with the initial formation of 2 followed by a subsequent disproportionation of 2 to give 3 and 4 . A similar thermolysis of 5-diazo-6-ethoxy-1-methyl-1,6-dihydrouracil ( 9 ) gave ethyl N-(1-methyl-1,2,3-triazol-4-oyl)car-bamate ( 10 ) as the sole product. Double labeling experiments have indicated that a major pathway for these reactions involves an intermolecular transfer of the C-6 substituent to the C-2 position.     

An unusual cascade of <Emphasis Type="Italic">S</Emphasis><Subscript>N</Subscript> reactions of benzotetrazine 1,3-dioxide derivatives

An unusual cascade of S _NAr reactions was discovered in the series of benzo-1,2,3,4-tetrazine 1,3-dioxides containing two adjacent nucleofuges X and Y in the benzene ring. First, the 1,2,3-triazole anion displaces the anion X^s- from the more reactive site. Then the nucleo-phile X^s- displaces the adjacent group Y. For instance, 1,2,3-triazole reacts with 6-azido-5-nitrobenzotetrazine 1,3-dioxide to give 5-azido-6-(1,2,3-triazol-2-yl)benzotetrazine 1,3-dioxide, with 8-azido-7-nitrobenzotetrazine 1,3-dioxide to give 7-azido-8-(1,2,3-triazol-2-yl)benzotetrazine 1,3-dioxide and 7-azido-8-(1,2,3-triazol-1-yl)benzotetrazine 1,3-dioxide, and with 7-bromo-6-(phenylthio)benzotetrazine 1,3-dioxide to give 7-phenylthio-6-(1,2,3-triazol-2-yl)benzotetrazine 1,3-dioxide.     

Synthesis and Antimicrobial Activity of N‐Aryl‐4‐(cyano/alkoxycarbonyl)‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole Derivatives

A convenient synthesis of a new series of N‐aryl‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole‐4‐carbonitriles and alkyl N‐aryl‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole‐4‐carboxylic acid esters is reported. The newly synthesized 5‐(pyridin‐3‐yl)‐1,2,3‐triazole derivatives are evaluated for their antibacterial and antifungal activity. Some of these triazole derivatives have exhibited moderate antimicrobial activity.     

Synthesis,X‐ray crystal structure and biological activities of α‐phenoxyl‐1,2,3‐thiadiazoleacetamide

The annelation of 1,2,3‐thiadiazole rings was accomplished by the reaction of N‐acylhydrazone 2a bearing an adjacent α‐methyl with thionyl chloride to give α‐chloro‐N‐methyl‐1,2,3‐thiadiazole‐4‐acetamide 4 and was demonstrated by the X‐ray crystal structure of its derivative 5a. A novel series of α‐substituted phenoxy‐N‐methyl‐1,2,3‐thiadiazole‐4‐acetamide 5 were synthesized through the reaction of the compound 4 and phenols. The results of bioassays show that the title compounds exhibit good anti‐HBV activities. The crystal of compound 5a , N‐methyl‐α‐2‐bromophenyl‐1,2,3‐thiadiazole‐4‐acetamide, has been prepared and determined by X‐ray diffraction.     

1,2,3-thiadiazoles. I. Synthesis of sodium (or potassium) 1,2,3-thiadiazole-4-thiolates via thiocarbazonate esters and N-acylthiohydrazonate esters

A general synthesis of 1,2,3-thiadiazole-4-thiolates 1 and their derivatives 2–3 by an extension of the Hurd-Mori 1,2,3-thiadiazole synthesis is described. Treatment of methyl (or ethyl) [1-(alkylthio)alkylidene]hydrazinocarboxylates 11 (thiocarbazonate esters) or other N-acylthiohydrazonate esters [Y = ureido ( 12 ) or arenesulfonyl ( 13 )] with thionyl chloride affords 2–3 efficiently. Intermediates 11–13 are readily obtained from the N²-thioacylcarbazates 8 , N³-thioacylsemicarbazides 9 , or N²-thioacyl-N¹-(p-toluenesulfonyl)hydrazides 10 , respectively, by S-alkylation. Physicochemical properties of the 1,2,3-thiadiazoles 1–3 and N-acylthiohydrazonate esters 11–13 are also described.     

Synthesis of chiral,non-racemic ferrocene derivatives by ortho-metallation and partial reductive removal of ortho-directing amino groups

Chiral, non-racemic 1,2-disubstituted ferrocenes have been prepared from monosubstituted ferrocene derivatives by amine-mediated ortho-directed reactions and subsequent partial reductive removal of the stereogenic ortho-directing group. It was found that the ortho-directing amino group of 2-substituted derivatives of N,N-dimethylaminoethyl-ferrocene and similar compounds can, after quaternisation with methyl iodide, be reductively removed with sodium borohydride to give 2-substituted methyl- or ethylferrocenes. In most cases the substituents I, Br, COOEt, P(O)Ph₂ and CN tolerate the reaction conditions used. In addition, a few examples are reported that show how the use of LiTMP allows 2-bromo- and especially 2-cyano-substituted derivatives to be further ortho-lithiated and reacted to give 1,2,3-trisubstituted ferrocenes.     

Synthesis of 2(5H)-Furanone Derivatives with Symmetrical and Unsymmetrical Bis-1,2,3-triazole Structure

The interesting bioactivities of 2(5H)-furanone, 1,2,3-triazole, and amino acid derivatives have promoted their combination into one multifunctional molecule. The symmetrical bis-1,2,3-triazoles and mono-1,2,3-triazoles with one free azide group are synthesized respectively by controlling the molar ratio of reactants, N-[5-alkoxy-2(5H)-furanonyl] amino acid propargyl ester and 1,4-diazidobutane. The unsymmetrical bis-1,2,3-triazoles are afforded by the subsequent reaction of mono-1,2,3-triazoles with other terminal alkynes with good to excellent yields in a short time under the same mild “click” reaction conditions. The 32 new compounds obtained in the reactions are characterized by Fourier transform infrared, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Because of the diversity of four or five basic units in molecule, this methodology provides easy access to different chiral 2(5H)-furanone compounds with polyheterocyclic structure, especially with unsymmetrical bis-1,2,3-triazole moiety. Importantly, a simple approach is provided for the synthesis of unsymmetrical bis-1,2,3-triazoles using common diazides.     

Synthesis of nitro,nitroso, azo,and azido derivatives of (4-R<Superscript>1</Superscript>-5-R<Superscript>2</Superscript>-1,2,3-triazol-1-yl)-1,2,5-oxadiazoles by oxidation and diazotization of the corresponding amines

Nitro-, nitroso-, and azo-1,2,5-oxadiazoles with 4-R¹-5-R²-1,2,3-triazol-1-yl substituents were synthesized by oxidation of amino-(1,2,3-triazol-1-yl)-1,2,5-oxadiazoles (aminotriazolylfurazans). Azido-1,2,5-oxadiazole was prepared by diazotization of amino(triazolyl)furazan followed by treatment of the diazonium salt with sodium azide. Depending on the nature of the substituents and the reagent, triazolylfurazans can undergo destruction to give amino-R-furazans (R = NO₂, N₃, aminofurazanylazo), the amino group being formed from the triazole ring. __________ Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1859–1865, August, 2005.     

The reaction of 1-(N-phenacylidene)amino-1,2,3-triazoles with diphenylnitrilimine

Diphenylnitrilimine reacts with 1-(N-phenacylidene)amino-1,2,3-triazoles 1 to give mainly 1,2,4- and 2H-1,2,3-triazoles 2 and 3 . CNDO/2 calculations were made on the compounds 1 and the cycloaddition was also examined on the basis of the interacting frontier molecular orbitals.     

1‐(1,2,3‐triazol‐4‐yl)‐benzimidazolones,a new series of heterocyclic derivatives

New 1‐(1,2,3‐triazol‐4‐yl)‐benzimidazolone derivatives were obtained on pursuing research about new tricyclic derivatives of medicinal interest, bearing a 1,2,3‐triazole ring fused with another heterocyclic ring. 1‐[(5‐Carboxamido)‐1,2,3‐triazol‐4‐yl]‐benzimidazolone was prepared by four different chemical routes and it was unequivocally confirmed by spectroscopic methods. Its chemical behaviour, was evaluated by some common chemical reactions such as hydrolysis, esterification, decarboxylation, nitration and N‐methylation.     

Synthesis of 1,2-Diazol-4-sulfonamides, 1,2,4- and 1,2,5-Oxadiazol-3-sulfonamides, 1,2,3-Triazol-4-sulfonamides, and Pyrimidine-5-sulfonamides starting from Cyanomethanesulfonyl Chloride

Summary. Cyanomethanesulfonyl chloride was reacted with amines yielding cyanomethanesulfonamides which could be transformed into alkoxymethylidene and aminomethylidene derivatives. The reaction of alkoxymethylidene derivatives with phenylhydrazine resulted in the formation of 5-aminopyrazol-4-sulfonamides, whereas from cyanomethanesulfonamides via the N-hydroxyamidine derivatives and their reaction with esters 1,2,4-oxadiazol-3-methanesulfonamides became accessible. Nitrosation of cyanomethanesulfonamides yielded 2-hydroxyimino derivatives which were then transformed into 2-hydroxyimino N-hydroxyamidine derivatives, and finally cyclized into 4-amino-1,2,5-oxadiazol-3-sulfonamides. On the other hand diazotation of cyanomethanesulfonamides gave the 2-arylhydrazono derivatives, which after transformation into N-hydroxyamidine derivatives gave by reaction with POCl₃ 5-amino-1,2,3-triazol-4-sulfonamides. Finally, the reaction between cyanomethanesulfonamides and formamidinium acetate opened an easy access to 4-aminopyrimidine-5-sulfonamides, which could be transformed by trialkyl orthoformiates into substituted pyrimidino[4,5-e][1,2,4]thiadiazine derivatives. All intermediates as well as transformation products of the heterocyclic systems were isolated and well characterized. Mechanisms were discussed, and the stereochemistry, when necessary and possible, was elucidated.     

Synthesis of 1-Substituted 3-Alkyl-1,2,3-triazol-3-ium-5-olates

Alkylation of 1-substituted sodium 1,2,3-triazol-5-olates with halogen derivatives occurs at the nitrogen atom in position 3 of the heteroring to give zwitterionic 1,2,3-triazol-3-ium-5-olates.