Preparation and Some Reactions of 1H-1,4-Benzothiazine Ylides (= 1H-1,4-Benzothioniaazin-4-ide)

A series of fifteen 1H-1,4-benzothiazine ylides were obtained by alkylation of the corresponding 4H-1,4-benzothiazines 1 . Ylides of type 2g–r showed slight [1,2] rearrangements upon thermolysis besides main dealkylation to 1 and olefin production. The ylides of this type underwent redox reactions when treated with hydrazine hydrate alone, giving 3,4-dihydro-2H-1,4-benzothiazines mainly, while ylides of type 2a–f failed to react.     

Synthesis of quinazolino-1,3-benzothiazine derivatives

The ring-closure reactions of N-(3,4-dimethoxyphenylthiomethyl)-2-nitrobenzamide derivatives 5a,b with phosphoryl chloride gave 4-(2-nitrophenyl)-2H1,3-benzothiazine derivatives 7a,b , which on reduction yielded 4-(2′-aminophenyl)-3,4-dihydro-2H-1,3-benzothiazines 8a,b. Reaction of these compounds with phosgene led to a new heterocyclic ring system, 6H,8H-quinazolino[3,4-c][1,3]benzothiazine derivatives 9a,b. The structures of the title compounds were proved via their ir and nmr (¹H, ¹³C) spectra.     

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.     

Preparation of potentially bioactive aza and thiaza polycyclic compounds containing a bridgehead nitrogen atom. Synthesis of pyrrolo[1,2,3-de]-1,4-benzothiazine derivatives

The synthesis of some pyrrolo[1,2,3-de]-1,4-benzothiazine derivatives by using a modified Bischler type cyclization of N-(2,2-diethoxyethyl)-2H-1,4-benzothiazines as a crucial step is described. The alternative approach based on Friedel-Crafts alkylation of the N-(2-chloroethyl)-2H-1,4-benzothiazines is shown to be impractical due to the low yield obtained.     

Cycloaddition reactions of benzothiete with azomethines

A new synthetic route to 3,4-dihydro-2H-1,3-benzothiazines 5 has been developed by the regiospecific cycloaddition of Schiff bases 4 and benzothiete 1 , which is primarily opened by heating to the corresponding o-quinoidal form 2 .     

Oxidative coupling of 2H-1,4-Thiazine derivatives

When treated with oxidizing agents, 3,5-disubstituted 2H-1,4-thiazines undergo oxidative coupling at the 2-position yielding 2,2′-bithiazines. Under similar conditions 3-substituted 2H-1,4-benzothiazines behave similarly to give the corresponding 2,2′-dehydrodimers. Evidence is presented that the oxidative coupling of all compounds examined proceeds preferentially to give the meso-isomers.     

Intermolecular 1,3-dipolar cycloaddition of benzonitrile oxide to 2H-1,3-benzothiazines and hexahydro-4H-1,3-benzothiazine

The thermal [3 + 2] intermolecular cycloaddition of benzonitrile oxide to 2H-1,3-benzothiazines 1a-g and hexahydro-4H-1,3-benzothiazine ( 5 ) gives new types of tricyclic angularly and linearly condensed 1,2,4-oxadiazolo-1,3-benzothiazine-fused nitrogen-bridgehead ring systems 2a-g, 6 .     

A study of the synthesis and some reactions of 3-phenyl-1,4-benzothiazines

Condensation of o-aminothiophenol with 2-bromoacetophenone yields 3-phenyI-1,4-benzo-thiazine hydrobromide, which upon treatment with alkali gave a mixture of 3-phenyl-2H-1,4-benzothiazine (VIIa) and 3-phenyl-4H-1,4-benzothiazine (VIIb). Catalytic hydrogenation led to rearrangement of the benzothiazine (VIIa) to 2-phenyl-2-methyl-2,3-dihydrobenzothiazole (X), while reduction with lithium aluminium hydride resulted in 3-phenyl-2,3-dihydro-4H-1,4-benzothiazine (XVI). The latter was transferred to 3-phenyl-4-aminoalkyl-2,3-dihydro-4H-1,4-benzothiazines (XVII and XVIII).     

Expected and unexpected reactions of 1,3-benzothiazine derivatives, II. Formation of isomeric 5,6-dihydro-1,5-benzothiazocines

A method for the synthesis of medium-sized 1,5-benzothiazocines by ring enlargement of 1,3-benzothiazines has been developed. When N-alkyl-1,3-benzothiazines were reacted with dimethyl acetylenedicarboxylate in acetonitrile at room temperature, regioisomeric 5,6-dihydro-2H-1,5-benzothiazocines and 5,6-dihydro-4H-1,5-benzothiazocines were obtained as novel ring systems. Dimethyl acetylenedicarboxylate could attack either the nitrogen or the sulfur atom of the thiazines. NMR spectroscopic and X-ray crystallographic investigations confirmed the structures of the products.     

Reaction of 2, 2′-dithiodianiline with 2-alkyl-1, 3-diketones. Synthesis and chemical behaviour of some 2-acyl-2h-1, 4-benzothiazines

The reactions of 2, 2′-dithiodianiline 1 with 2-alkyl-1, 3-diketones 2a-d have been employed in order to synthesize 2-acyl-2H-1, 4-benzothiazines. In the cases of 2a, b the expected 2-acyl-2H-1, 4-benzothiazines, i.e. 3a, b were obtained, whereas the reactions of 1 with the 1, 3-diketones 2c, d afforded the α-ketosulfide 12 and the 1, 4-benzothiazine 17 , respectively. The products 3a, b underwent the hydrolytic C₂-C₃ bond cleavage of the thiazine nucleus to give the α-ketosulfides 6 and 11 , respectively. Such an hydrolytic process explains the formation of the compound 12 in the reaction of 1 with 2c . The formation of 17 in the case of 2d is considered to be formed through a rearrangement involving the 1, 3-sulfur shift of the preformed 1, 4-benzothiazine 3d .     

An Efficient Synthesis and Antimicrobial Studies of Bioactive 4H-1,4-Benzothiazine and Their Sulfone Derivatives

Abstract

4H-1,4-benzothiazines were prepared by condensation followed by oxidative cyclization of substituted 2-aminobenzenethiols with β-diketones in dimethylsulfoxide. On refluxing with 30% hydrogen peroxide in glacial acetic acid, 4H-1,4-benzothiazines yielded 4H-1,4-benzothiazine-1,1-dioxides. Structural evaluation has been done by spectral and elemental analysis. All the synthesized compounds were evaluated for their antibacterial and antifungal activity and all these have shown moderate to high activity against the test microbes.

Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures and tables.     

Synthesis of 6-halogenated 4H-1,4-benzothiazines

The synthesis of 6-halogenated 4H-1,4-benzothiazines is reported by the condensation and oxidative cyclization of 4-substituted 2-aminobenzenethiols (I, R = Cl, Br) with β-diketones in presence of DMSO. The ir, nmr and mass spectral studies are included. 4-Substituted 2-aminobenzenethiols were also prepared by an improved and direct method.     

1,4-benzothiazine derivatives from 2-aminobenzenethiol and hydrazonoyl halides

2-Aminobenzenethiol was condensed with alkyl α-chlorophenylhydrazonoglyoxylates yielding alkyl 2-(2-aminophenylthio)-2-arylhydrazonoglyoxylates which were cyclized to the corresponding 2-arylhydrazono-2,3-dihydro-4H-1,4-benzothiazin-3-ones. Starting from α-chloro-α-arylhydrazonoacetones the corresponding 2-arylhydrazono-3-methylbenzo-1,4-benzothiazines were formed.     

Basicity,quaternization and hydrolysis of 2H- and 4H-1,3-benzothiazine isomers

Summary The basicities of 2H- and 4H-1,3-benzothiazines (1,2) were measured spectrophotometrically in buffer solutions. The rates of quaternization with methyl iodide were monitored in sealed ampoules by an oscillometric method. The stabilities were determined by measurement of the rate of acidic hydrolysis via changes in the uv/vis spectra. As a cyclic Schiff base, 4-aryl-2H-1,3-benzothiazine (2) is the stronger base, and reacts about ten times faster with methyl iodide; its stability is greater than that of 2-aryl-4H-1,3-benzothiazine (1). On the basis of these results and by means of the different water-solubilities of the hydrochlorides the isomers formed during the synthesis can be separated and purified.

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Basizität, Quaternisierung und Hydrolyse von isomeren 2H- und 4H-Benzothiazinen

Zusammenfassung Die Basizität und die Geschwindigkeit der Hydrolyse von 2H- und 4-H-Benzothiazinen (1,2) in saurer Lösung wurde UV/VIS spektroskopisch gemessen. Die Reaktionsgeschwindigkeit der Quarternisierung mit Methyljodid wurde oszillometrisch in geschlossenen Ampullen bestimmt. 4-Aryl-2H-1,3-benzothiazin (2) ist als zyklische Schiffsche Base die stärkere Base, deren Reaktionsgeschwindigkeit mit Methyljodid ungefähr zehnmal größer ist als die des 2-Aryl-4H-1,3-benzothiazin (1);2 ist auch stabiler. Aufgrund dieser Ergebnisse und der unterschiedlichen Wasserlöslichkeit ihrer Hydrochloride konnten die während der Synthese nebeneinander entstehenden Isomeren getrennt werden.

     

A novel reaction between benzothiazoles and diaroylacetylenes in the presence of Meldrum’s acid: ring expansion of benzothiazoles to functionalized 1,4-benzothiazines

A novel and efficient ring expansion of benzothiazoles to functionalized 1,4-benzothiazines is described. The reactive 1:1 zwitterionic intermediates formed by addition of benzothiazoles to diaroylacetylenes were trapped with Meldrum’s acid under mild reaction conditions to produce 2-[2-hydroxy-2-aryl-2H-1,4-benzothiazin-3(4H)-yliden]-1-aryl-1-ethanones in excellent yields.     

Organic syntheses based on 2-oxoglutaric acid. V. Syntheses of novel 2H-1,4-benzothiazines and a 2,5-dihydro-1,5-benzothiazepine

Syntheses aimed on the incorporation in heterocycles of segments originating in the precursor 2-oxoglutaric acid are described. Cylocondensation of dimethyl 2-oxoglutarate 1 , dimethyl 3-bromo-2-oxoglutarate 2 , and dimethyl (E)-2-oxoglutaconate 3 with 2-aminobenzenethiol gave rise to the novel 2H-1,4-benzothiazines 4 and 5 , and the 2,5-dihydro-1,5-benzothiazepine 6 , respectively, by incorporation of either the segments C-1/C-2 or C-2/C-3 or C-3/C-4/C-5 of the precursor.     

Synthesis and antimicrobial activity of structurally flexible heterocycles with the 1,4-thiazine heterosystem

In this work, 4H-1,4-benzothiazines were synthesized by an efficient synthetic method in a single step involving heterocyclization of substituted 2-aminobenzenethiols with β-ketoester. The structures of the synthesized compounds were confirmed by their analytical and spectral data. The synthesized compounds were evaluated for their antimicrobial activity against bacterial species; E. coli and Bacillus cereus. The synthesized compounds showed significant activity against microorganisms, which can be correlated with the privileged heterocyclic structural scaffolds.     

Synthesis of 4-thia analogues of isoquinoline alkaloids

Summary (±)-4-Thiacarnegin (3) was synthesized by reaction of 6,7-dimethoxy-3-methyl-2H-1,3-benzothiazinium iodide (2) with methyl magnesium iodide, thereby opening a new synthetic route to 4-substituted dihydro-2H-1,3-benzothiazines. Compound3 was also obtained by reduction of 6,7-dimethoxy-3,4-dimethyl-2H-1,3-benzothiazinium iodide (5). In a similar way, reduction of the quaternary salts9 a–c afforded the (±)-4-thia analogues of cryptostilin-I, -II and -III (10 a–c). The isomers of the former compounds (12 a–c) were also synthesized by reduction of the 4H-1,3-benzothiazinium salts11 a–c.

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Synthese von 4-Thiaanalogen von Alkaloiden mit Isochinolingerüst

Zusammenfassung Aus 6,7-Dimethoxy-3-methyl-2H-1,3-benzothiaziniumjodid (2) wurde mit Methylmagnesiumjodid (±)-Thiacarnegin (3) dargestellt. Diese Reaktion bietet ein neues Verfahren für die Synthese von 4-substituierten Dihydro-2H-1,3-benzothiazinen.3 wurde auch durch Reduktion von 6,7-Dimethoxy-3,4-dimethyl-2H-1,3-benzothiaziniumjodid (5) erhalten. Die Reduktion der quartären Ammoniumsalze9 a–c ergab ebenfalls die Cryptostillin I-, II-, III-(±)-4-thiaanalogen Verbindungen (10 a–c). Reduktion der 4H-1,3-Benzothiazinium-Salze11 a–c lieferte die entsprechenden Isomeren12 a–c der obengenannten Verbindungen.

     

Synthesis of 1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives by the reaction of 2-chloro-1,4-benzothiazin-3-ones with ‘push-pull’ enamines

The reaction of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazines with ‘push-pull’ enamines was investigated. The reaction with the enamines occurs at the β-carbon atom in the presence of a small excess of triethylamine. As a result, a set of 3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives was prepared. On acidic hydrolysis of ethyl 2-ethyl-3-(methylimino)-2-(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)butanoate, a new rearrangement affording ethyl 11-ethyl-2,3-dimethyl-4-oxo-2,3,4,5-tetrahydro-1H-2,5-methano-6,1,3-benzothiadiazocine-11-carboxylate was discovered. A plausible mechanism and factors influencing the course of the reaction are discussed.     

Isomerization in the Oxidative Cyclocondensation of 2-Aroylmethyl-1H-benzimidazoles with o-Aminothiophenol

Oxidative cyclocondensation of 2-aroylmethyl-1H-benzimidazoles with o-aminothiophenol gave the previously unknown 3-aryl-2-(2-benzimidazolyl)-4H-1,4-benzothiazines and (or) the isomeric 2H-1,4-benzothiazines. 2-(4-Nitrophenacyl)-1H-benzimidazole and 2-phenacylbenzothiazole gave 4H-1,4-benzothiazines which are not liable to isomerize but the reaction of the first compound is complicated by a hydrolytic fission which yields 2-[2-(4-nitrobenzoylamino)phenylthiomethyl]benzimidazole. A mixture of dimethylsulfoxide, acetic acid, and water was used as oxidant and solvent. The effect of the substituent and of the solvent on the tendency of the products to undergo prototropic isomerization in the benzothiazine ring have been studied.