Synthesis and chemical reactivity of some 1,2,4-Thiadiazolo[2,3-a]-pyrimidines and related compounds

A novel synthetic approach for 1,2,4-thiadiazolo[2,3-a]pyrimidines, 1,2,4-thiadiazolo[2,3-c]-pyrimidines and 1,2,4-thiadiazolo[2,3-b] indazoles is described. Several transformations of these heterocyclic systems are presented. 1,2,4-Thiadiazolo[2,3-a] pyrimidines undergo a very facile ring cleavage to give 3-amino-5-carbethoxyamino-1,2,4-thiadiazole and similar ring opening was observed also with the isomerie [2,3-c] system. On the other hand, 1,2,4-thiadiazolo[2,3-a]-pyridines undergo under similar conditions cleavage of the thiadiazole part of the bicycle.     

On the preparation of substituted 4H- 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles

The reaction of benzoyl isothiocyanates and methoxycarbonyl isothiocyanate with 4-amino-4,5-dihydro-3-(methylthio)-1,2,4-triazin-5-ones in acetonitrile gave several substituted 4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones VIa-h instead of the expected thioureas. In addition, benzoyl isothiocyanate reacted with 4-amino-3-(methylthio)-5-(trifluoromethyl)-4H-1,2,4-triazole to give the benzoyl thiourea IX and with 4-amino-3-mercapto-5-(trifluoromethyl)-4H-1,2,4-triazole to give the bicyclic compound N-[3-(trifluoromethyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-6-yl]benzamide IX .     

Preparation and alkylation of 1,5-dihydro-3H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one 2,2-dioxides

1,5-Dihydro-3H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one 2,2-dioxides ( 3 ) are prepared by reaction of isatoic anhydrides with methyl N-(chloromethanesulfonyl)carbamimidothioate ( 6 ). The sodium salt of 3a , generated with sodium hydride in N,N-dimethylformamide, is alkylated excusively on N-10. An improved preparation of 6 is described, utilizing a two-phase sulfonylation.     

The synthesis of 3H-1,2,4-thiadiazolo[3,4-b]benzothiazoles

2-Aminobenzothiazole reacted with 1,1,1-trichloromethanesulfenyl chloride yielding 1,1,1-trichloro-N-(2-benzothiazolyl)methanesulfenamide. Subsequent cyclization using either aromatic or heteroaromatic amines readily yielded derivatives of the 3H-1,2,4-thiadiazolo[3,4-b]benzothiazole ring system. Spectral data and brominations of these benzothiazoles are described.     

On triazoles. XXXIII. The reaction of potassium triazolyldithiocarbonates with dihaloalkanes

The reaction of potassium (5-amino-3-Q-1,2,4-triazolyl)dithiocarbonates 2 with 1,ω-dihaloalkanes 7-10 to yield ω-haloalkyldithiocarbonates 11-12 , ω-alkylene-bis(dithiocarbonates) 13-15 and different by-products as the corresponding 7,8-dihydro[1,2,4]triazolo[1,5-c][1,3,5]thiadiazepine-5(9H)-thione ( 16 ), 7,8,9,10-tetrahy-dro[1,2,4]triazolo[1,5-c][1,3,5]thiadiazocine-5-thione ( 17 ) and 1,7-dihydro-5H-1,2,4-triazolo[1,5-c][1,3,5]thiadi-azine-5-thione ( 22 ) derivatives all three representing novel ring systems were obtained. Repeating the reactions with dipotassium salts 3 the corresponding iminodithietans 18 , imino-1,3-dithiolanes 19 and imino-1,3-dithianes 20 were obtained. Unexpectively, the imino-1,3-dithiolanes ( 19 ) rearranged to the corresponding thiazolidines 24-27 under rather mild conditions. A possible mechanism is proposed for this rearrangement.     

Isolation and Crystal Structure of Novel by-products Observed During the Formation of bis(thiosemicarbazones)

During the condensation of 4-methyl-4-phenyl-3-thiosemicarbazide (3) with 2,3-butanedione an unexpected by-product, 8a-methyl-6,8a-dihydro-8-methyl-2-[N-methyl-N-phenylamino]-5H-1,3,4-thiadiazolo[3,2-d][1,2,4]triazine-5-thione, (5) was obtained in addition to the desired bis(thiosemicarbazone) (4). An X-ray crystal structure was obtained and is presented together with a proposed mechanism for its formation. A brief investigation of the coordination chemistry of bicycle (5) was carried out. The formation of cyclic compounds during the synthesis of analogues with extended backbones is also described.     

Trichloroisocyanuric acid-mediated synthesis of 1,5-fused 1,2,4-triazoles from N-heteroaryl benzamidines via intramolecular oxidative N–N bond formation

A convenient synthesis of 1,5-fused 1,2,4-triazoles from readily available N-heteroaryl benzamidines is reported. The reaction is efficiently promoted by trichloroisocyanuric acid to afford the desired products, mostly in high yields and in relatively short time, through direct metal-free oxidative N–N bond formation. The mild nature of the synthesis and short reaction time are notable advantages of the developed protocol. This protocol is effective toward various substrates having different functionalities.     

One-pot synthesis of N-fused 1,2,4-triazoles and related heterocycles via I2/TBHP-mediated oxidative CN bond formation

A metal-free iodine/TBHP-mediated oxidative CN bond formation for the one-pot synthesis of N-fused 1,2,4-triazoles and related heterocycles via cyclization has been developed. This reaction which is amenable to scale-up affords the corresponding products with good to excellent yields and tolerates a wide range of functional groups.     

Notiz über die Reaktion von Methylhydrazin mit N-Cyano-azomethinen. Abhängigkeit des Reaktionsverlaufs von der Natur der Abgangsgruppe

The reaction of methylhydrazine with N-cyanoazomethines 1 containing a thioalkyl leaving group yields the 3-amino-1,2,4-triazole derivatives 2 , whereas the N-cyanoazomethines 1 containing an alkoxy leaving group give the isomeric 5-amino-1,2,4-triazoles 3. The yields are excellent and the position selectivity is high. The structures of the 1,2,4-triazole derivatives were determined with the aid of proton-coupled ¹³C-NMR. spectra.     

Synthesis of 2-amino-4-imino-4,5-dihydrothiazoles from N-sulfonyl-α-chloroamidines and thiourea

A number of new and interesting 2-amino-4-(N-substituted)imino-4,5-dihydrothiazoles were synthesized by reacting thiourea (or thiourea hydrochloride) with N-alkyl- or N,N-dialkyl-N′-p-toluenesulfonyl-α-chloroacetamidines, where the N,N-alkyl groups were ethyl, cyclohexyl, benzyl, β-phenethyl, (3,5-dimethyl-1-adamantyl)-methyl, as well as N,N-dimethyl- and N,N-pentamethylene. Reactions of N-alkyl-N-p-toluenesulfonyl-2-chloroacetamidines (substituents being N-ethyl, N-benzyl and N,N-dimethyl) with thiourea hydrochloride in hot 2-propanol furnished 2-amino-4-(p-toluenesulfonyl)imino-4,5-dihydrothiazole (in 51, 60 and 65% yields, respectively) and the corresponding amine hydrochloride. In hot acetone or butanone, the reactions of these N-sulfonyl-2-chloroacetamidines with excess thiourea provided 2-amino-4-N-(alkyl or N,N-dialkyl)imminium-4,5-dihydrothiazole chlorides in 25–80% yield. The by-product from these reactions was p-toluenesulfonamide. The structures of the products were established by chemical transformations and spectral methods (nmr and mass spectra).     

Reaction of 1,3,4-thiadiazolo and 1,3,4-triazolo[3,2-c]quinazoline derivatives with active methylene compounds

Fused quinazoline derivatives 1 and 4 react with active methylene compounds and depending on the annelated five-membered ring, two types of transformations have been observed. The 1,3,4-thiadiazolo[3,2-c]quinazoline 1 , underwent the five-membered ring opening reaction to afford the 3,4-dihydroquinazolines 2 in good yields, whereas the 1,3,4-triazolo[3,2-c]quinazoline 4 underwent nucleophilic attack at 2-position of the quinazoline ring to yield the corresponding 1,2,4-triazoles 5 .     

Oxamic acid derivaties in heterocyclic synthesis: Preparation of 1,2,4-triazolo[1,5-a]pyrazine derivatives

N-Aryl-N-(α-phenylphenacyl)oxamoyl chlorides react with N³-arylsubstituted amidrazones to give functionalized 1,2,4-triazoles which undergo ring-closure by the action of thionyl chloride to give 1,2,4-triazolo[1,5-a]-pyrazinium chlorides in excellent yields.     

Adamantylation of 3-Nitro- and 3-Ethoxycarbonyl-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4-ones

Reaction of 3-nitro- and 3-ethoxycarbonyl-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4-ones with 1-adamantanol (or 1-adamantyl nitrate) in concentrated sulfuric acid or with 1-bromoadamantane in sulfolane affords N-adamantyl derivatives. The adamantylation of 3-nitro-1,4-dihydro-7H-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4-one yields a mixture of N⁸- and N¹-isomers that undergo interconversion in concentrated sulfuric acid along intermolecular mechanism.     

Synthesis of nitrogen-containing heterocycles. 5. A new route to 5-amino-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives

Treatment of certain diaminomethylenehydrazones 1 of aromatic carbonyl compounds with ethyl N-cyanoimidate ( 2 ) in acetonitrile in the presence of a tertiary amine at room temperature gives the corresponding amino(N-cyanoiminomethyl)aminomethylenehydrazones 3 in high yields. The intermediate 3 can readily be cyclized to the corresponding 5-amino-2,3-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines 4 in moderate to good yields by brief heating in acetonitrile. When the reaction of diaminomethylenehydrazones 1 with ethyl N-cyanoimidate ( 2 ) is performed at reflux temperature in the presence of a tertiary amine, 5-amino-2,3-dihydro[1,2,4]triazolo[1,5-a]1,3,5]triazines 4 can be directly obtained in moderate yields. The yields of triazolotriazine produced by the one-step synthesis are generally comparable or even higher than the overall yields from the two-step procedure.     

1,2,4-Triazoles—XXXIV: Photodimerization of some 1,2,4-triazo[4,3--]quinoline and 1,2,4-triazolo[3,4-a]isoquinoline derivatives

Irradiation of 1,2,4-triazolo[4,3-a]quinoline and several Me derivatives at 300 nm afforded the cisoid-fused, head-to-tail cyclobutane dimers 7bα,7cα,14bα,14cα - tetrahydro - 1,2,3a,8,9,10a - hexaazadibenzo [c,i]dicyclopenta[a,g]biphenylenes. However, 1,2,4 - triazolo[3,4-a]isoquinolines gave analogous cisoid-fused, head-to-head dimers except for the 5-Me derivative where the head-to-tail dimer was obtained.Codimerization occurred when 1 - methyl - 1,2,4 - triazolo[4,3-a]quinoline and 5 - methyl - 1,2,4 -triazolo[3,4-a]isoquinoline were irradiated at 300 nm, affording a cisoid-fused head-to-tail cyclobutane co-dimer as the single photoproduct. However, irradiation of their 5-Me substituted derivatives at 300 nm afforded the cisoid-fused, head-to-head, cyclobutane codimer and also a minor amount of the dimer derived from 5 - methyl -1,2,4- triazolo[4,3-a] quinoline. Irradiation of equimolar quantities of 2(1H)-quinolinone and 5 - methyl - 1,2,4 -triazolo [4,3-a]quinoline at 300 nm gave the known 2(1H)-quinolinone dimer and a minor amount of a cisoid-fused co-dimer of undetermined configuration.     

Synthesis,Crystal Structure,and Antibacterial Activity of 1,2,4‐Triazoles and 1,2,4‐Triazol‐3‐one

A straightforward method has been developed for the synthesis of 1,2,4‐triazol‐3‐one 3 and 1,2,4‐triazoles 6a , 6b , 6c , 6d starting from N¹‐substituted‐N¹‐tosylhydrazonates 2 and hydrazine monohydrate. This methodology affords a number of 1,2,4‐triazol‐3‐one 3 and 1,2,4‐triazoles 6a , 6b , 6c , 6d in reasonable yields. The structures of all new compounds were elucidated using infrared, ¹H and ¹³C NMR, high‐resolution mass spectrometry, elemental analysis, and the X‐ray crystallography (for compounds 3 and 6a ). Some of the newly synthesized compounds were screened for their antibacterial activity.     

Preparation of 3-Aryl-4-(5-ARYL-Δ2-1,2,4-Oxadiazolin-3-YL)Sydnones and their Conversion into 3-ARYL-4-(5-ARYL-1,2,4-Oxadiazol-3-YL)Sydnones

3-Aryl-4-(5-aryl-Δ²-1,2,4-oxadiazolin-3-yl)sydnones (5) were synthesized in high yields by the reaction of 3-arylsydnone-4-carboxamide oximes (prepared from the corresponding 3-arylsydnone-4-carbonitriles) with aromatic aldehydes in the presence of acid catalysts. No reaction occurred when aliphatic aldehydes were used. The oxadiazolin-3-ylsydnones (5) were easily converted into the corresponding 3-aryl-4-(5-aryl-1,2,4-oxadiazol-3-yl)sydnones by N-bromosuccinimide oxidation. The 3-arylsydnone-4-carbonitrile oxides were synthesized in good yields by N-bromosuccinimide oxidation of the corresponding 3-arylsydnone-4-carboxaldehyde oximes.     

Reactions of fused dihydro-1,2,4-thiadiazoles with isocyanates and isothiocyanates to give 6aλ4-thia-1,3,4,6-tetraazapentalene derivatives

3-Methyl-6,7-dihydro-5H-1,2,4-thiadiazolo[4,5-a]pyrimidine 4a reacted with isocyanates and isothiocyanates with elimination of acetonitrile and concomitant addition of two molecules of the heterocumulene to give the 2,3-disubstituted-6,7-dihydro-5H-2aλ⁴-thia-2, 3, 4a, 7a-tetraazacyclopent[cd]indene-1 (2H), 4(3H)-diones 8a–8e and the corresponding dithiones 9a–9h , respectively. 3-Methyl-5, 10-dihydrobenzo[e]-1,2,4-thiadiazolo[4,5-a][1,3]diazepine 5a likewise reacted with isocyanates and isothiocyanates to give the 2,3-disubstituted-5,10-dihydro-2aλ⁴-thia-2,3, 4a, 10a-tetraazapentaleno[3, 3a, 4-gh]benzocyclopheptene-1, 4-diones 10a–10f and the corresponding dithiones 11a–11f . The base 4a reacted with phenyl isocyanate, methyl isothiocyanate, and phenyl isothiocyanate in toluene at room temperature to give the zwitterions 14a , 14b , and 14c , respectively, and the diazepine 5a reacted with phenyl isothiocyanate to give the zwitterion 17 .     

Synthèse de N-2 alkyl (aryl) dioxo-3,5 oxadiazolidine-1,2,4

The synthesis of new 3,5 dioxo-1,2,4 oxadiazolidines whixh are N-2 substituted bioisosters of biologically active carboxylic compounds was studies. Nitro compounds were used as starting materials, and triton B as the cyclizing base. The expected N-2 allyl and aryl substituted derivatives were obtained in satisfactory yields.     

Synthesis and thermolysis of N-heteroarylacetylazides and α-oximino-α-(N-heteroaryl)acetylazides

Treatment of N-heteroarylacethydrazides with an equimolar amount of nitrous acid afforded N-heteroaryacetylazides and subsequent thermolysis of these azides gave the analogues of 2,3-dihydroimidazo[1,5-a]pyridin-3-one. When some of these cyclized compounds were treated with nitrous acid, the ring opening reaction occurred and recyclized 3-(N-heteroaryl)-1,2,4-oxadiazolin-5-ones were obtained. Treatment of N-heteroarylacethydrazides with two equivalent moles of nitrous acid afforded α-oximino-α-(N-heteroaryl)acetylazides. Thermolysis of these azides gave mixtures of 3-(N-heteroaryl)-1,2,4-oxadiazolin-5-one and 3-hydroxy-4-(N-heteroaryl)furazan. On the basis of the effects of heterocyclic rings and solvents upon the relative yield of two types of the products, one plausible mechanistic explanation for the decomposition of such azides was proposed. α-Oximino-α-(H-heteroaryl)acetylazides were converted into cyano N-heterocycles by the action of alkali in good yields.