Chloro- and dichloro-3-alkyl-1,2,3-benzotriazin-4(3H)ones

Several chloro- and dichloro-3-alkyl-1,2,3-benzotriazin-4(3H)ones have been prepared by diazotization of methyl anthranilates. A brief study was made of factors affecting the formation of 3-allyl-1,2,3-benzotriazin-4(3H)one from methyl anthranilate. Good nmr evidence was obtained to substantiate the previously proposed methyl 2-(3-allyltriazeno)benzoate (VIc) intermediate.     

Palladium-catalyzed polyhetero-claisen rearrangement of 4-allylthiopyrimidin-2(1h)-ones and 5-allylthio-1,2,4-triazin-3(2h)-ones

The S → N allylic transposition of 4-allylthiopyrimidin-2(lH)-ones 4 and 5-allylthio-1,2,4-triazin-3(2H)-ones 5 has been performed successfully by catalysis of palladium(II) salts. In both cases the N-alkylated products (6 and 7) are obtained with no traces of the C-alkylated products.     

Reactions of 1,2,4-triazin-5(2H)-ones with phenols and aromatic amines

1,2,4-Triazin-5(2H)-ones 1 react as well with phenols, resorinol and its dimethyl ethers, as with dimethyland diethylaniline, yielding 6-aryl-1,6-didydro-1,2,4-triazin-5(2H)-ones 2, 4–8, 12–15. Oxidation of the 1,6-dihydroadducts 2a,b gives the corresponding 3-aryl-6-hydroxyphenyl-1,2,4-triazin-5(2H)-ones 3a,b. Rection of 1,2,4-triazinones 1 with 2-naphthylamine leads to destruction of the 1,2,4-triazine ring yielding benzo[e]indole-2,3-dione 19.     

Synthetic and spectroscopic study of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones

5-Amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 can be synthesized from 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) via a selective acylation with an acid anhydride in pyridine. The ¹H nmr spectral characteristics of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 is in particular, compared with 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) and 5-amino-2-alkyl-1,2,4-thiadiazolin-3-ones 1–2, 1–3 . The 5-amino group of 2–1 appeared as two peaks in its ¹H nmr spectrum, which merged to a single peak at a higher temperature, while those of compound 1–1, 1–2 and 1–3 appear only as a single peak. The restricted rotation of the C(5)-N(5) (at amino) bond of 5-amino-2-acetyl-1,2,4-thiadiazolin-3-one (2a-1) is about 14.5 Kcal/mol.     

Microwave synthesis and anticonvulsant activity of new 3-benzyl-1,2,3-benzotriazin-4(3H)-ones

Several 3-benzyl-1,2,3-benzotriazin-4(3H)-ones 1 were prepared by alkylation of 1,2,3-benzotriazin-4(3H)-one with benzyl halides in dimethylformamide in a microwave oven in moderate yields. Accompanying 1 were minor amounts of products believed to be the O-alkylated derivatives. Support for 3-benzylation is shown by an alternate synthesis of la from o-amino-N-benzylbenzamide by nitrous acid cyclization. The title compounds were evaluated in mice and rats in maximal electroshock (MES) and pentylenetetrazole (scMet) seizure models for anticonvulsant activity, and in the rotorod test for neurotoxi-city. They were generally non-toxic. The 3-benzyl analog was the most active (maximal electroshock) compound; it's maximal electroshock ED₅₀ value was 93 mg/kg (mouse).     

The formation of 1,2,4-triazolylimidazolidine-2,4-diones in reactions of 3-aryl-1,2,4-triazin-5(2H)-ones with alkylureas

Recyclization of the addition products of alkylureas to 3-aryl-1,2,4-triazin-5(2H)-ones affording 1,2,4-triazole derivatives was found to occur in Ac₂O.     

Synthesis and antimicrobial activity of some 2-alkyl-2H-1,4-benzothiazin-3(4H)-ones and 2-alkylbenzo[d]imidazolo[2,1-b]-thiazolidin-3-ones

Summary Sodium 2-aminothiophenoxide (1) reacts with ethyl 2-bromoalkanoates (2) under direct cyclization to form 2-alkyl-2H-1,4-benzothiazin-3(4H)-ones (3). Reaction of the sodium salt of 2-mercaptobenzimidazole (4) with2 or 2-bromoalkanoic acids (5) affords only S-alkylated products (6 or7, respectively). The cyclization products — 2-alkylbenzo[d]imidazolo[2,1-b]thiazolidin-3-ones (8) — can be obtained only from the corresponding 2-(2-benzimidazolylthio)alkanoic acids (7) by the action of acetic anhydride. Both compounds3 and8 exhibit only moderate antimicrobial activity against some gram-positive bacteria.

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Synthese und antimikrobielle Wirkung von einigen 2-Alkyl-2H-1,4-benzothiazin-3(4H)-onen und 2-Alkylbenzo[d]imidazolo[2,1-b]thiazolidin-3-onen

Zusammenfassung Bei der Reaktion von Natrium-2-aminothiophenolat mit 2-Bromoalkansäure-ethylestern (2) entstehen als Cyclisierungsprodukte 2-Alkyl-2H-1,4-benzothiazin-3(4H)-one (3). Die Umsetzung von Natriumbenzimidazol-2-thiolat mit2 oder mit 2-Bromoalkansäuren (5) liefert nur S-Alkylierungsprodukte (6 oder7). Die Cyclisierungsprodukte — 2-Alkylbenzo[d]imidazolo[2,1-b]thiazolidin-3-one (8) — sind nur durch Umsetzung von entsprechenden 2-(2-Benzimidazolylthio)-alkansäuren (7) mit Acetanhydrid erhältlich. Die Verbindungen3 und8 weisen nur mäßige antimikrobielle Wirkung gegen einige gram-positive Bakterien aus.

     

The tert-butyl-NNO-azoxy group in the synthesis of 1,2,4-benzotriazin-3(4H)-one 1-oxides

Treatment of 2-(tert-butyl-NNO-azoxy)anilines with phosgene at 20 °C was proposed as a novel route to 1,2,4-benzotriazin-3(4H )-one 1-oxides. This method involves a new reaction, viz., an intramolecular interaction of the tert-butyl-NNO-azoxy group with a C-electrophile (leading to the formation of the N(2)—C(3) bond of the triazine ring) followed by elimination of the tert-butyl group. Complete assignment of the signals in the ¹H and ¹³C NMR spectra of the compounds obtained was performed. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1507–1509, August, 2007.     

Palladium-catalyzed cyclization reactions of 3-propargylthio 1,2,4-triazin-5(2h)-ones to thiazolo-1,2,4-triazinones

Selective transformation of 3-propargylthio-1,2,4-triazin-5(2H)-ones ($\text{1}$) to 6-methylene-6,7-dihydro-4H-thiazolo[2,3-c][1,2,4]-triazin-4-ones ($\text{2}$) and 3-methylene-2,3-dihydro-7H-thiazolo[3,2-b]-[1,2,4]triazin-7-ones ($\text{3}$) is performed under the conditions of Pd(II) salt or sodium hydroxide catalysis, respectively.     

Phase-transfer catalysis in reactions of 5-alkyl-3H-furan-2-ones with dichlorocarbene

Treatment of 5-alkyl-3H-furan-2-ones and 5-alkyl-3H-thiophen-2-ones with dichlorocarbene under conditions of phase-transfer catalysis at 20–90 °C results in insertion of the carbene at the C=C bond followed by skeletal rearrangement.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1995–1997, October, 1995.     

[1,2,4]Triazines. 4. Regiospecific ring closure reactions involving 6-amino-5-hydrazino[1,2,4]triazin-3(2H)-ones and orthoesters

6-Amino-5-hydrazino[1,2,4]triazin-3(2H)-one, 3 , was treated with a variety of orthoesters and concentrated acid forming mixtures of ring-closed and open-chain derivatives. These mixtures were converted in warm aqueous acid to the Mriazolo[5,1-d][1,2,4]triazin-3(2H)-ones, 11b, 14b , and 15b by a regiospecific ring closure at N-4 of the [1,2,4]triazine ring and subsequent Dimroth-like rearrangement of the initially formed s-triazolo[4,3-d][1,2,4]triazin-3(2H)-ones ( 11a, 14a, 15a ).     

Easy formation of SNH products in reactions of indoles and pyrroles with 3-aryl-1,2,4-triazin-5(2H)-ones in the presence of tosyl chloride

The reactions of 3-aryl-1,2,4-triazin-5(2H)-ones with indoles and pyrroles in the presence of p-toluenesulfonyl chloride afforded 3-aryl-6-hetaryl-1,2,4-triazin-5(2H)-ones in high yields. The latter are products of the nucleophilic substitution of hydrogen.     

1,2,4-Triazines. 8. Reduction of 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride. Regioselective preparation of dihydro-1,2,4-triazin-5(4H)-ones

Reduction of 3-methylthio-1,2,4-triazin-5(4H)-one ( 1a ) with sodium borohydride afforded 3-methylthio-1,6-dihydrotriazin-5(4H)-one ( 2b ) selectively. 3-Methylthio-6-t-butyl-1,2,4-triazin-5(4H)-one ( 1d ) reacted with sodium borohydride to give mainly 6-t-butyl-2,3-dihydro-1,2,4-triazin-5(4H)-one ( 3d ). The reaction of various 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride and the influence of bulkiness and electronic effect of the substituents at the 3- and 6-positions upon the product ratio, are also discussed.     

Synthesis of new 1,2,4-oxadiazolidin-3-ones by cycloaddition of 2-alkyl-3-aryloxaziridines with chlorosulfonylisocyanate

2-Alkyl-4-chlorosulfonyl-5-aryl-1,2,4-oxadiazolidin-3-ones 5 were prepared via cycloaddition of 2-alkyl-3-aryloxaziridines 3 with chlorosulfonylisocyanate. The structure of 5 was proved by a crystal X-ray analysis. Hydrolysis of 5 in the presence of triethylamine afforded 2-alkyl-5-aryl-1,2,4-oxadiazolidin-3-ones 6.     

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.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. X. Synthesis of N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones and of 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted 1-amino-4-methyl-1-penten-3-ones and 1-amino-4,4-dimethyl-1-penten-3-ones occurred in moderate to fair yield only in the case of aromatic N-substitution to give N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution, cyclo-addition led directly to 6-alkyl-4-dialkylamino-3-chloro-2H-pyran-2-ones only for N,N-disubstituted 1-amino-4,4-dimethyl-1-penten-3-ones. The reaction between 1-dimethylamino-4-methyl-1-penten-3-one and dichloroketene gave 3-chloro-4-dimethylamino-3,6-dihydro-6-isopropylidene-2H-pyran-2-one in low yield.     

Synthesis of 8-Aryl[1,2,4]triazolo[1,5-d][1,2,4]triazin-5(6H)-ones by S HN Reactions

A new procedure has been proposed for the synthesis of 8-aryl[1,2,4]triazolo[1,5-d][1,2,4]-triazin-5(6H)-ones by reaction of 6-aryl-1,2,4-triazin-3(2H)-ones with hydrazides derived from aliphatic, aromatic, and heterocyclic carboxylic acids. The process invloves nucleophilic substitution of hydrogen (S_N ^H)in aryltriazinones, oxidative closure of azole ring, and Dimroth rearrangement.     

Aroylation of 5-amino-2H-1,2,4-thiadiazolin-3-ones

2-Aroyl-5-aroylamino-1,2,4-thiadiazolin-3-ones ( 2 ) have been synthesized through aroylation of 5-arruno-2H-1,2,4-thiadiazolin-3-one ( 1 ) as an analog of cytosine. The aroylation was carried out with a substituted aroyl chloride in pyridine at 56～58°C. It has been established that the intermediates of the reactions are 2-aroyl-5-amino-1,2,4-thiadiazolin-3-ones ( 3 ) on the basis of the spectral data, additional experimental information and ab initio molecular orbital calculations.     

NaNO2/I2 as an alternative reagent for the synthesis of 1,2,3-benzotriazin-4(3H)-ones from 2-aminobenzamides

An efficient transformation of 2-aminobenzamides to 1,2,3-benzotriazin-4(3H)-ones in the presence of sodium nitrite (NaNO₂) and Iodine (I₂) is described. The reaction is proposed to proceed via formation of nitrosyl halide that induces nitrosylation of the amino group of 2-aminobenzamide leading to diazotization followed by intramolecular cyclization.