Studies on the syntheses of azole derivatives—V: The mass spectra of 1,2,4-triazoles and oxadiazoles (studies on the syntheses of heterocyclic compounds—CCCLXXIV)

The electron-impact induced fragmentation of twenty 3-alkyl-1-phenyl-Δ²-1,2,4-triazolin-5-ones, three 1-phenyl-1,2,4-triazolin-3,5-diones and ten 2-alkyl-4-phenyloxadiazolin-5-ones has been studied by conventional mass spectrometry. The major cleavages take place in the 1-phenyl-Δ²-1,2,4-triazolin-5-one nucleus, producing three major fragment ions. 4-Phenyloxadiazolin-5-ones exhibit a similar fragmentation pattern to 1-phenyl-Δ²-1,2,4-triazolin-5-ones. Furthermore, several additional fragmentation processes are observed in the case of specific 1,2,4-triasolines.     

Studies on the syntheses of azole derivatives. Part III. Syntheses of 1-Phenyl-Δ2-1,2,4-triazolin-5-one and 4-Phenyl-Δ2-1,3,4-oxadiazolin-5-one Derivatives by Fusion of 1-Phenyl-2-acylhydrazine with Urea

Fusion of 1-phenyl-2-acylhydrazine (III) with urea gave Δ²-1,2,4-triazolin-5-one and Δ²-1,3,4-oxadiazolin-5-one derivatives together with various by-products. Furthermore, various derivatives were synthesized for the purpose of examination in a pharmacological screening test.     

Synthesis of certain 1,2,4-triazole nucleoside derivatives

The syntheses of 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and its 2′-deoxy analog 8b as well as 5-amino-2-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-3-one ( 12 ) have been accomplished. Compounds 8a and 8b were synthesized via glycosylation of 3-bromo-5-nitro-1,2,4-triazole which was followed by replacement in three steps of the 3-bromo function to yield 3-nitro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 4a ) and its 2′-deoxy analog 4b . Compounds 4a and 4b were methylated at N², hydrogenated and deblocked to give 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and the 2′-deoxy analog 8b . Compound 12 was synthesized by glycosylation of 3-amino-1-methyl-1,2,4-triazolin-5(2H)-one ( 10 ). The structures of 8b and 12 were confirmed by single crystal X-ray diffraction analysis.     

Reaction of ethylene oxide with n-phenylated isomers of 1,2,4-triazoline-3-thione and 1-phenyltetrazoline-5-thione

It is demonstrated that ethylene oxide forms N--hydroxyethyl derivatives of the corresponding triazolin-3-ones in the reaction with 1-phenyl- and 4-phenyl-1,2,4-triazolin-3-thiones and with 3--hydroxyethylthio derivatives of 1-phenyl- and 4-phenyl-1,2,4-triazole in acetic acid. 1-Phenyltetrazolin-5-thione reacts similarly with ethylene oxide. Under the influence of ethylene oxide, 2-methyl-4-phenyl-1,2,4-triazolin-3-thione is converted to 2-methyl-4-phenyl-1,2,4-triazolin-3-one.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 700–703, May, 1971.     

5-Oxo-1H-4,5-dihydro-1,2,4-benzotriazepines. Chemical behavior towards alkylating,acidic and alkaline agents

The chemical behavior of 4-methyl and 4-phenyl-5-oxo-1H-4,5-dihydro-1,2,4-benzotriazepines towards methylating and acidic agents has been investigated. The 4-methyl derivative, when treated with methyl fluorosulfonate furnished, after crystallization from water, a quaternary salt (2,4-dimethyl-5-oxo-1H-4,5-dihydro-1,2,4-benzotriazepinium fluorosulfonate), whereas from the 4-phenyl derivative, a complex mixture was obtained, which, after boiling with water, afforded 2-methylindazolone, aniline fluorosulfonate and formic acid. In acidic medium the 4-methyl derivative underwent an isomerization reaction yielding 1-imino-3-methylquinazolin-4-one, but the 4-phenyl derivative exclusively yielded products resulting from ring opening. In alkaline medium, both compounds gave hydrolytic cleavage products.     

Δ3- and Δ4-1,2,4-oxadiazolin-5- and 3-ones

Preparations for 2,3-diphenyl- and 2-benzyI-3-phenyl-Δ³-1,2,4-oxadiazolin-5-ones (3) and (4) and for 2,5-diphenyl-Δ⁴-1,2,4-oxadiazolin-3-one ( 7 ) are reported.     

Synthesis of trifluoromethyltriazoles from trifluoroacetohydrazonoyl bromide

N-Phenyltrifluoroacetohydrazonoyl bromide ( 1 ) reacted with potassium isothiocyanate and isocyanate to give 5-imino-4-phenyl-2-trifluoromethyl-δ²-1,3,4-thiadiazoline and 1-phenyl-3-trifluoromethyl-δ²-1,2,4-triazolin-5-one, respectively. On treatment with several types of cumulative double bonds such as alkyl isothiocyanate, isocyanate, and carbodiimide, 1 afforded regioselectively the corresponding trifluoromethylthiadiazoline, -oxadiazoline, and -triazoline, respectively. These cycloadducts were assumed to form through the stepwise path involving the addition of 1 toward the cumulative double bond followed by the intramolecular cyclization. Concerning cyanamides, the corresponding triazoles were obtained and the reactions with pyridines afforded the triazolopyridinium bromides. The reactivity of the latter was found to depend on the substituents on the pyridine nucleus.     

Picryl derivatives of 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one

Treatment of 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one ( 1 ) with picryl fluoride (PkF) in 1-methyl-2-pyrrolidinone (NMP) gave a mixture of a monopicryl and a dipicryl derivative of 1 in a ratio of 2 :1 , respectively, regardless of the initial concentrations of 1 and PkF. The products were identified as 5-nitro-2-picryl-2,4-dihydro-3H-1,2,4-triazol-3-one ( 2 ) by X-ray crystallography and 5-nitro-2,4-dipicryl-2,4-dihydro-3H-1,2,4-triazol-3-one ( 4 ) by ¹⁵N labeling experiments.     

Studies on the syntheses of azole derivatives. Part IX. Formation of 2,4-disubstituted δ2 -1,3,4-oxadiazolin-5-one and 4-substituted 1,2,4-triazolidin-3,5-dione derivatives by thermal reaetion of N-aryl-N-benzylearbamoyl azides

The structure of the novel produets, 2,4-ltis-(N-benzy1-4-nitroanilino)-Δ²-1,3,4-oxadiazolin-5-one (VII), 2-benzy1-1-(N-benzy1-4-chloroanilino)-4-(4-chlorophenyl)-1,2,4-triazolidin-3,5-dione (XIVa), and 2-benzy1-1-(N-benzylanilino)-4-pheny1-1,2,4-triazolidin-3,5-dione (XIVb), obtained upon thermal reaction of N-bcnzyl-N-(4-nitrophenyl)carbamoyl azide (la), N-benzyl-N-(4-chloro-phenyl)carbamoyl azide (Ib) and N-benzyl-N-phcnylcarbamoyl azide (le), respectively, were determined.     

On the amination of 1,2,4-triazines by potassium amide in liquid ammonia and by phenyl phosphorodiamidate. A 15n-study

The amination of 5-R- and 6-R-3-X-1,2,4-triazines (R = C₆H₅, t-C₄H₉, X = SCH₃, SO₂CH₃, N⁺ (CH₃)₃, Cl) by potassium amide in liquid ammonia has been studied. In all reactions the formation of the corresponding 3-amino-1,2,4-triazines takes place; in some reactions by-products were found: from 5-phenyl- and 5-t-butyl-3-(methylthio)-1,2,4-triazine a ring contracted product i.e. 5-phenyl and 5-t-butyl-3-(methylthio)-1,2,4-triazole, from 6-phenyl-3-(methylthio)-1,2,4-triazine the dimer 3,3′-bis-(methylthio)-6,6′-bisphenyl-5,5′-bi-1,2,4-triazine and from 5-t-butyl-3-(trimethylammonio)-1,2,4-triazine chloride compound bis-(5-t-butyl-1,2,4-triazin-3-yl)- amine. Furthermore the conversion of 5-phenyl- and 5-t-butyl-1,2,4-triazin-3-one into the corresponding 3-amino compound by treatment with phenyl phosphorodiamidate (PPDA) was studied. A ¹⁵N study of these aminations showed that nearly all compounds undergo substitution according to both S_N(AE) and S_N(ANRORC) processes. The contribution of each of the competitive mechanisms to the amination is strongly influenced by the character of the leaving group.     

Synthesis of poly-α,α-diphenylglycine. II. Cationic polymerization of 4,4-diphenyl-Δ2-1,2,3-triazolin-5-one

4,4-Diphenyl-Δ²-1,2,3-triazolin-5-one (I) was found to undergo a cationic polymerization under the influence of boron trifluoride etherate in an anhydrous solvent. The poly-α,α-diphenylglycine (III) thus formed contained a larger amount of oligomers than the polymer obtained by thermal decomposition as described in the preceding paper. The molecular weight distribution was further shown to depend on the monomer and catalyst concentration and on the nature of the solvent. A mechanistic rationalization is proposed, involving propagating triazolinium ion pairs (VII) which are not interrupted by chain transfer or termination in the absence of water or alcohol. In the presence of water or alcohol, no polymerization occurred, but the normal acid-catalyzed decomposition products (IV and V) were then obtained. 1-Methyl-4,4-diphenyl-Δ²-1,2,3-triazolin-5-one (VIII) was also treated with BF₃ · OEt₂ in a dry solvent at room temperature and furnished 1-methyl-3-phenyl-indolin-2-one (XII) instead of a polyamide. This reaction constitutes a new method for the synthesis of these heterocycles.     

Reaction of 4-thioxo-1,3-benzothiazines with thiocarbohydrazine: Synthesis and reactivity of 1,3,4-triazolo[3,2-c]quinazoline derivatives

2-Aryl-4-thioxo-1,3-benzothiazines react with thiocarbohydrazide to give the new mesoionic compounds an-hydro 1-amino-5-aryl-2-mercapto-1,3,4-triazolo[3,2-c]quinazolin-4-ium hydroxides. These compounds react with methyl iodide, aldehydes and phenacyl bromides to give 1-amino-5-aryl-2-methylthio-1,3,4-triazolo-[3,2-c]quinazolin-4-ium iodides, 4-arylidenamino-3-(o-aroylamino)phenyl-1H-1,2,4-triazolin-5-thiones and 3-(o-aroylamino)phenyl-6-aryl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines, respectively. These latter compounds by sequential treatment with methyl trifluoromethanesulphonate and triethylamine lead to 3-(o-aroylamino)-phenyl-6-aryl-1-methyl-7-mercapto-1H-pyrazolo[5,1-c]-1,2,4-triazoles.     

Reactions with heterocyclic amidines 1. Cyanoethylation of cyclic amidines

2-Amino-5-phenyl-1,3,4-oxadiazole ( 1a ) and 2-amino-1,3,4-thiadiazole ( 1b ) reacted with acrylonitrile to yield β-cyanoethylamino derivatives. On the other hand, 2-amino-4-phenylthiazole ( 2 ) reacted with acrylonitrile under the same experimental conditions to yield a di-β-cyanoethylaminothiazole derivative. 3-Phenyl-Δ²-1,2,4-triazoline-5-thione reacted with acrylonitrile to yield the corresponding adduct. The structure of the adduct was established by its conversion into the acid 13 which could be synthesised via another independent route.     

Hydrogenolysis of the C?O bond of the 1,2,4-oxadiazine ring. Adams platinum hydrogenation of 3-aryl-5,6-dihydro-5-(substituted)-methylene-4H-1,2,4-oxadiazine derivatives

Adams platinum hydrogenation of Z-3-aryl-5,6-dihydro-5-(substituted)methylene-4H-1,2,4- oxadiazine ( 1a-f ) proceeds very slowly through C? O bond fission to give N-(1-substitutedcarbonyl-2-propylidene)benzamide ox-ime derivative 2 as the main product. In the reaction of 5-(arylcarbamoyl)methylene analogues 1d-f , 5-(aryl-carbamoyl)methyl-5,6-dihydro-3-phenyl-4H-1,2,4-oxadiazine ( 4 ) and N-aryl-3-hydroxybutanamide derivative 5 are also obtained as well as compound 2 .     

Heterocyclization reactions of azinoisocyanates. Synthesis of 2H-1,2,4-triazol-3(4H)-one derivatives

The reaction of 1-aminoethylidenehydrazones 9 with di-tert-butyl dicarbonate and 4 -dimethylaminopyridine led to the corresponding azinoisocyanates 10 , which underwent thermal rearrangement under the reaction conditions to give 4-(tert-butoxycarbonyl)-5-methyl-2H-1,2,4-triazol-3(4H)-ones 14 . However, amidrazone 17 gave 2-(2-tert-butoxycarbonyloxy-2-phenyl)ethyl-4-(tert-butoxycarbonyl)-5-methyl-2H-1,2,4-triazol-3(4H)-one 22 and N-aziridinyliminocarbamate 18 under the similar conditions.     

Direct introduction of heterocyclic units into porphyrin derivatives

In the reaction with quinazoline and 5-phenyl-1,2,4-triazin-5(2H)-one, 5,10,15,20-tetra(4-methoxyphenyl)porphyrin exhibits nucleophilic properties. In quinazoline excess, C—C coupling occurs at the C=N bond of azines and position 3 of the aryl ring to form 5,10,15,20-tetrakis(3-heteryl-4-methoxyphenyl)porphyrins. Monoheteryl-substituted porphyrin was obtained by the reaction of equimolar amounts of 5,10,15,20-tetra(4-methoxyphenyl)porphyrin and 5-phenyl-1,2,4-triazin-5(2H)-one.     

Unexpected Direction of Iodocyclization of 3-Allylthio-5-phenyl-4H-1,2,4-triazole

The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, and 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine has been studied. The structure of the products obtained was established using ¹H NMR spectroscopy of their dehydriodination products.     

Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides and of N,N-disubstituted 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 4-amino-3-phenyl-3-buten-2-ones (III) occurred in good yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides, whereas N,N-disubstituted 4-amino-1-phenyl-3-buten-2-ones (IV) did not react at all. Polar 1,4-cycloaddition of dichloroketene to III and IV occurred partly in the case of aromatic N-substitution, with the exception of the morpholino derivative IVd, giving in low yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones (VII) in good yield. In some cases of aliphatic N,N-disubstitution of III and IV, cycloaddition led directly to N,N-dialkyl derivatives VII in low yield.     

Synthesis of Some New Thiazoles and Pyrazolo[1,5-a]pyrimidines Containing an Antipyrine Moiety

Ethyl 2-{2-[4-(2,3-dimethyl-5-oxo-1-phenyl-3-(pyrazolin-4-yl)]-2-cyano-1-(phenylamino)vinylthio}-acetate, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl-(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]2-(4-oxo-3-phenyl-(1,3-thiazoilidin-2-ylidene))ethanenitrile, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]-2-(4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))ethanenitrile, 2-(5-acetyl-4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))-2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]ethanenitrile, and ethyl 2-(cyano(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)methylene)-2,3-dihydro-4-methyl-3-phenylthiazole-5-carboxylate were synthesized by treatment of 2-(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)-3-mercapto-3-(phenylamino)-acrylonitrile with appropriate halo ketones or halo esters. Also, 4-{2-[5,7-dimethyl-2-(phenylamino)(7a-hydropyrazolo[1,5-a]pyrimidin-3-yl](1,-thiazol-4-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one derivatives were synthesized via reaction of 4-{2-[5-amino-3-(phenylamino)pyrazolin-4-yl](1,3-thiazol-2-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with β-diketone or β-keto ester. All synthesized compound were established by elemental analysis, spectral data, and alternative synthesis whenever possible.