Structure of the bromination product of 2-ethyl-1,4-benzothiazin-3(4H)-one

2-Ethyl-1,4-benzothiazin-3(4H)-one and bromine react smoothly to give Z-2-(1-bromoethylidine)-2(H)-1,4-benzothiazin-3(4H)-one, which results from a complex bromination-oxidation sequence. The structure of this product was determined by an X-ray study.     

Syntheses for 2-amino and 2-mercapto-2H-1,4-benzoxazin-3(4H)-one and 2H-1,4-benzothiazin-3(4H)-one as aza and thio analogues of the natural product blepharigenin

2-Amino-2H-1,4-benzoxazin-3(4H)-one 3 , 2-amino-2H-1,4-benzothiazin-3(4H)-one 4 , 2-mercapto-2H-1,4-benzoxazin-3(4H)-one 7 , and 2-mercapto-2H-1,4-benzothiazin-3(4H)-one 8 representing aza and thio analogues of the natural product's aglucone Blepharigenin (2-hydroxy-2H-1,4-benzoxazin-3(4H)-one) from Gramineae and Acantnaceae species have been synthesized for the first time from their 2-bromo precursors 1 and 2 . Attempts to similarly prepare the 4-hydroxy derivatives of 7 and 8 , which would represent new thio analogues of the naturally occurring cyclic hydroxamic acid, 2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one, have failed.     

Synthesis of 6H,8H-isoquino[2,3-c][1,3]benzothiazin-8-ones

6H,8H-Isoquino-1,3-benzothiazin-8-ones have been prepared by reaction of 6,7-dimethoxy-2H-1,3-benzo-thiazines with homophthalic anhydride and by photocyclization of 3-benzoyl-4-methylene-6,7-dimethoxy 2H-1,3-benzothiazine. The compounds are thia analogues of protoberberine alkaloids containing a sulfur atom at C-5 and a lactam function at C-8. The mass spectra of the title compounds are discussed.     

2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-one: Synthesis and investigation of serine protease inactivation

Summary 2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-one was prepared by thermal treatment of 2-(3-benzoylthioureido)-4,5-dimethoxybenzoic acid and by benzoylation of 2-amino-6,7-dimethoxy-4H-3,1-benzoxazin-4-one. The inactivation of chymotrypsin and human leukozyte elastase by the title compound and 2-benzoylamino-4H-3,1-benzoxazin-4-one is reported.

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2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-on: Synthese und Untersuchung der Inaktivierung von Serin-Proteasen

Zusammenfassung 2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-on wurde durch thermische Behandlung von 2-(3-Benzoylthioureido)-4,5-dimethoxybenzoesäure und durch Benzoylierung von 2-Amino-6,7-dimethoxy-4H-3,1-benzoxazin-4-on hergestellt. Über die Inaktivierung von Chymotrypsin und humaner Leukozyten-Elastase durch die Titelverbindung und 2-Benzoylamino-4H-3,1-benzoxazin-4-on wird berichtet.

     

Tetracarbonyl Systems: VII. Reactions of 1,3,4,6-Tetracarbonyl Compounds with o-Aminothiophenol in the Synthesis of Regioisomeric 3(2)-Aroylmethylene-1,4-benzothiazin-2(3)ones

In reaction of 1,6-diaryl-3,4-dihydroxy-2,4-hexadiene-1,6-diones with o-aminothiophenol (3Z)-3-aroylmethylene-3,4-dihydro-2H-1,4-benzothiazin-2-ones were obtained in a preparative yield. In solution of the latter compounds an enamine-imine tautomerism was observed. In reaction of ethyl esters or amides of 2-substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic acids with the o-aminothiophenol regioisomeric 2-aroylmethylene-2H-1,4-benzothiazin-3(4H)-ones were formed.     

Regiospecific synthesis of 2-methyl-4-arylcarbonyl-2H-1, 2-benzothiazin-3(4H)-one 1, 1-dioxides

Acylation of 2-methyl-2H-1, 2-benzothiazin-3(4H)-one 1, 1-dioxide 3 with aryl anhydrides in the presence of dimethylaminopyridine occurs regiospecifically to afford 2-methyl-4-arylcarbonyl-2H1, 2-benzothiazin-3(4H)-one 1, 1-dioxides 2a-f .     

Syntheses for 2-hydroxy-2H-1,4-benzothiazin-3(4H)-one derivatives as thio analogues of natural hemiacetals

Reductive cyclizations of methyl 2-(2-nitrophenylthio)acetate 2 by means of electrochemistry or by catalytic hydrogenation have been used as key steps in the syntheses of the hemiacetals 2-hydroxy-2H-1,4-benzothiazin-3(4H)-one 10 and its 4-hydroxy derivative 9 representing thio analogues of allelo chemicals found in Gramineae and Acanthaceae. In contrast to its natural counterpart 2,4-dihydroxy-2H-1,4-benzoxa-zin-3(4H)-one hydroxamic acid 9 did not undergo degradation by extrusion of formic acid.     

Synthesis of tricyclic and tetracyclic thieno[3,2-f]-1,4-thiazepines

Treatment of 5-methylthio-2,3-dihydrothieno[3,2-f]-1,4-thiazepine ( 9 ) with acylhydrazines gave 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepines 10, 11 , and that of 9 with ethyl anthranilate gave 5,6-dihydrothieno[3′,2′:6,7][1,4]thiazepino[5,4-b]quinazolin-8-one ( 14 ). Reaction of 9 with hydrazine hydrate or 4-chlorophenylhydrazine afforded 5-hydrazino compounds 12, 15 , which were subsequently cyclized to ethyl 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepine-3-carboxylate ( 13 ), 2-(4-chlorophenyl)-5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepin-3(2H)-one ( 16 ) and 2-(4-chlorophenyl)-6,7-dihydro-2H-thieno[3,2-f][1,2,4]triazino[4,3-d][1,4]thiazepine-3,4-dione ( 17 ). New thieno-anellated heterocycles were prepared with the aim of studying their affinity for the benzodiazepine receptors.     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

CAN-promoted, diastereoselective synthesis of fused 2,3-dihydrofurans and their transformation into tetrahydroindoles

The reaction between 1,3-cyclohexanediones and chalcones (or their vinilogs) in the presence of 2.5 equiv of cerium(IV) ammonium nitrate afforded trans-2-arylcarbonyl-3-aryl (or styryl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones in good to excellent yields and in high diastereoselectivities. The method was also extended to the preparation of derivatives of the 5,6-dihydro-2H-cyclopenta[b]furan-4(3H)-one system. The fused 2,3-dihydrofuran derivatives were transformed into 1-alkyl-2-acyl-3-aryl-6,7-dihydroindole-4(5H)-ones by 2,3-dehydrogenation followed by reaction with primary amines. The direct reaction of the tetrahydrobenzofuran-4(5H)-one compounds derived from dimedone with amines gave 1-alkyl-2-alkylimino-3-aryl-6,7-dihydroindole-4(5H)-ones, while starting materials derived from 1,3-cyclohexanedione underwent an unprecedented 2-deacylation reaction and gave 1-alkyl-3-aryl-6,7-dihydroindole-4(5H)-ones.     

The synthesis of 4H-imidazo[5,1-c][1,4]benzothiazine derivatives

A facile synthesis of the 4H-imidazo[5,1-c][1,4]benzothiazine ring system is described. The synthesis utilized the annulation of an imidazole ring onto a 2H-1,4-benzothiazin-3(4H)-one via the addition of the anion of ethyl isocyanoacetate. Methods for the functionalization of the 1-, 3-, 4-, and 5-positions of the ring system are presented.     

Combined experimental and computational study on the energetics of 1,2-benzisothiazol-3(2H)-one and 1,4-benzothiazin-3(2H, 4H)-one

The present work reports an experimental and computational study of the energetics of 1,2-benzisothiazol-3(2H)-one and 1,4-benzothiazin-3(2H, 4H)-one. The standard (p° = 0.1 MPa) massic energy of combustion, at T = 298.15 K, of each compound was measured by rotating bomb combustion calorimetry, in oxygen that allowed the calculation of the respective standard molar enthalpy of formation, in the condensed phase, at T = 298.15 K. The standard molar enthalpies of sublimation, at T = 298.15 K, were measured by high-temperature Calvet microcalorimetry. From the combination of data obtained by both techniques we have calculated the standard molar enthalpies of formation, in the gaseous phase, at T = 298.15 K. In addition, computational calculations were carried using the density functional theory with the B3LYP functional and the 6-31G1 basis set and some correlations between structure and energetics were obtained for the keto and enol forms of both compounds. Using the G3(MP2)//B3LYP composite method and various appropriate reactions, the standard molar enthalpies of formation of 1,2-benzisothiazol-3(2H)-one and 1,4-benzothiazin-3(2H, 4H)-one, at T = 298.15 K, were computationally derived and compared with the experimental data. The aromaticity of 1,2-benzisothiazol-3(2H)-one, 1,4-benzothiazin-3(2H, 4H)-one and that of some related species was evaluated by analysis of nucleus independent chemical shifts (NICS).     

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.

     

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.

     

Direct heterocyclization of tetrahydroisoquinolin-1-ylideneacetic acids by the action of 5-arylfuran-2,3-diones

Aroylketenes generated in situ by thermolysis of 6-aryl-2,2-dimethyl-4H-1,3-dioxin-4-ones reacted with 3,3-dialkyl-1-methyl-3,4-dihydroisoquinolines to give (1Z,3Z)-4-aryl-4-hydroxy-1-[3,3-dialkyl-3,4-dihydroisoquinolin-1(2H)-ylidene]but-3-en-4-ones. The crystalline and molecular structure of (1Z,3Z)-4-hydroxy-1-[6,7-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]-4-phenylbut-3-en-2-one was studied by X-ray diffraction.     

Synthesis and structure of 2-(nitromethylene)-2H-1,4-benzothiazin-3(4H)-one

A new representative of benzothiazines, (2Z)-2-(nitromethylene)-2H-1,4-benzothiazin-3(4H)-one, was synthesized, and its structure was studied. According to ¹H NMR, IR, and UV spectral and X-ray diffraction data, the molecules are planar highly conjugated structures that exist in crystal as centrosymmetric dimers; the latter form layers overlapping with each other and held together by strong π-π interaction between the carbonyl groups of neighboring layers.     

Synthesis of a regioisomeric analogue of the 3C-protease inhibitor thysanone via a Hauser annulation strategy

Hauser annulation of 3-cyano-5,7-dimethoxy-(3H)-isobenzofuran-1-one 4 with ethyl acrylate as a method to access activated naphthoquinone 3, a key intermediate for the synthesis of thysanone 1, proved unreliable. In contrast to this, Hauser annulation of regioisomeric 3-cyano-4,6-dimethoxy-(3H)-isobenzofuran-1-one 13 with ethyl acrylate proceeded readily affording ethyl 5,7-dimethoxy-1,4-naphthoquinone 12, after oxidation of the initial dihydroxynaphthalene 16. Allylation of naphthoquinone 12 followed by reductive methylation and Wacker oxidation afforded ketone 11 that underwent CBS reduction to (2′S)-alcohol 19 followed by cyclisation to lactone 20. Reduction of the lactone followed by oxidative demethylation afforded (1S,3S)-6,8-dimethoxy-1-hydroxy-3-methylpyrano[2,3-c]-1,4-naphthoquinone 22, a regioisomeric analogue of the 3C-protease inhibitor thysanone 1.     

Chemical Transformations of 2-(3-Aryl-4-nitrobutanoyl)-5,5-dimethylcyclohexane-1,3-diones: II. Synthesis of New 6,7-Dihydro-1,2-benzoxazol-4(5<Emphasis Type="Italic">H</Emphasis>)-ones with Functionalized Side Chain

Transformation of the nitromethyl group in 3-(2-aryl-3-nitropropyl)-6,6-dimethyl-6,7-dihydro-1,2-benzoxazol-4(5H)-ones by the Nef reaction gave the corresponding aldehydes. Jones oxidation of the latter afforded carboxylic acids together with oxidative decarboxylation products. The possibility for the construction of heterocyclic fragment on the basis of the formyl or carboxylmethyl group of the resulting 6,7-dihydro-1,2-benzoxazol-4(5H)-one derivatives was studied.     

Synthesis of heterocyclic compounds from o-aminobenzenethiol and ammonium thiocarbamate

The reaction of o-aminobenzenethiol with carbonyl sulfide in the presence of triethylamine afforded an alternate route for the synthesis of 2-benzothiazolinone ( 1 ) in 97–98% yield. The reaction of ammonium thiocarbamate ( 2 ) with 2-chlorocyclohexanone furnished the novel 4,5,6,7-tetrahydro-2-benzothiazolinone ( 3 ). 3-Ethoxy-2H-1,4-benzothiazin-2-one ( 7 ) was prepared by the reaction of o-aminobenzenethiol with diethyl oxalate. Possible pathways and supporting nmr, ir and mass spectra are discussed.     

Synthesis and Transformation of 4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoline: Spectral Characterization and Anti-cancer Properties of some Novel Quinazoline Derivatives

An efficient and simple method has been reported for the synthesis of 4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoline ( 2 ) as a key compound for further transformation to other novel 6,7-dimethoxy-2-methyl-4-substituted quinazolines. The structure of the synthesized compounds was characterized by spectroscopic methods. The pathway of some unprecedented reactions was proposed. (E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-3-(4-nitrophenyl)prop-2-en-1-one (11) exhibits high in vitro cytotoxicity on three cell lines, Hepatocellular carcinoma (Hep-G2), Human lung carcinoma (LU-1), and Human breast carcinoma (MCF-7) with IC₅₀ of 2.1, 11.6 and 2.2 μM, respectively.