Synthesis in the phenothiazine series

Quaternary salts of imidazo[4,5,1-k,l]phenothiazine were reduced with potassium borohydride to 1,2-dihydro-2-methylimidazo[4,5,1-k,l]phenothiazine, which was converted to 1,2 dihydro-2-methylimidazo[4,5,1-k,l]phenothiazine-1-thione and 1-methylamino-10-formylphenothiazine. The latter was hydrolyzed to 1-methylaminophenothiazine, which was also obtained by reduction of methyl phenothiazine-1-carbamate. The PMR and IR spectra of some of the derivatives are discussed.See [1] for communication XXXV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 372–374, March, 1974.     

Synthesis in the phenothiazine series

The corresponding amines were obtained by reduction of 1-nitro-3-bromophenothiazine and 2-bromo-4-nitrophenothiazine. 1-Amino-3-bromophenothiazine reacts with formic acid to give 4-bromoimidazo[4,5,1-k, l ]phenothiazine and with carbon disulfide to give 4-bromo-1,2-dihydroimidazo [4,5,1-k, l ]phenothiazine-1-thione. 4-Aminophenothiazine reacts with sulfur and carbon disulfide to give 2, 3-dihydrothiazolo[5,4-c]phenothiazine-2-thione.See [1] for communication XXXIV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 202–203, February, 1974.     

New heterocyclic ring systems. IX. Polyazadithiasteroid analogues

The synthesis of the novel tricyclic ring 5-rnethyl-4-oxo-2,3,4,5-tetrahydrothiopyrano[3,2-c]-[1,2]benzothiazine 6,6-dioxide (III) is described. By the reaction of hydrazine and hydroxylamine with the glyoxylate (IV) and ester (V) obtained from III, several polyazadithiasteriod analogues have been synthesized.     

Heterocycles with a benzothiadiazepine moiety. 3. Synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide

The synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide ( 5 ), a novel sulfur-containing tetracyclic benzodiazepine, is reported starting from pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-diox-ide ( 6 ) by cycloaddition of tosylmethyl isocyanide to the azomethine double bond. Pyrrolobenzothiadiazepine 6 was obtained by iron powder/acetic acid reduction of 1-(2-nitrobenzenefulfonyl)pyrrole-2-carboxaldehyde ( 7 ) and subsequent ring closure of intermediate aminoaldehyde or by cyclization of 1-(2-formamidobenzene-sulfonyl)pyrrole ( 8 ) with phosphorus oxychloride via a Bischler-Napieralski reaction. Formylation of 1-(2-ami-nobenzenesulfonyl)pyrrole with acetic-formic anhydride gave 8. The structure of 5 was confirmed by oxidation with activated manganese dioxide of dihydro derivative 9 , obtained through cyclization of 11-amino-methyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide ( 10 ) with triethyl orthoformate. The last compound was prepared alternatively by catalytic reduction of nitro derivative 11 , obtained by addition of nitromethane to pyrrolobenzothiadiazepine 6 , or by lithium aluminum hydride/sulfuric acid reduction of amide 13 , synthesized starting from ethyl 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-carboxyl-ate 5,5-dioxide.     

On the synthesis of 3-amino-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine 5,5-dioxide and of 3-amino-1,2-dihydro-3H-dibenzo[c,jk]pyrido[2,1-c]-1,4-thiazepine 7,7-Dioxide

3-Amino-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine 5,5-dioxide and 3-amino-1,2-dihydro-3H-dibenzo-[c,jk]pyrido[2,1-c]-1,4-thiazepine 7,7-dioxide were synthesized from the corresponding 3-oxime acetates by reduction with the borane-tetrahydrofuran complex. Reduction was not successful in the case of 2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine-3-oxime acetate.     

Synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline and related compounds

This paper describes the synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline ( 10 ), tetrazolo[4,3-b]pyridazino[4,5-b]quinoxaline ( 11 ) and some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 . Starting with 2-ethoxycarbonyl-3-methylquinoxaline 1,4-dioxide ( 1 ), 1,2-dihydro-1-oxopyridazino[4,5-b]quinoxaline ( 5 ) was prepared by three different ways: (a) chlorination of 1 in acetic acid gave 2-ethoxycarbonyl-3-dichloromethylquinoxaline 1,4-dioxide, which reacts with an excess of hydrazine to give about 60% of 5 ; (b) oxidation of 1 with selenium dioxide gave 90% of 2-ethoxycarbonyl-3-formylquinoxaline 1,4-dioxide ( 3 ), which reacts with hydrazine to give 5 (63%); (c) compound 3 was treated with hydrazine to give 1,2-dihydro-1-oxopyridazino-[4,5-b]quinoxaline 1,4-dioxide ( 4 ) (70%), which by reduction with sodium dithionite gave 5 (80%). Compound 5 reacts with phosphorus pentasulfide or the Lawesson reagent to give 1,2-dihydro-1-thiocarbonylpyridazino[4,5-b]quinoxaline ( 9 ), which treated with hydrazine gave 5 (80%). This last compound reacts with nitrous acid to give 11 . Some hydrazones 12 from 10 are described. Heating the aldehyde hydrazones 12a,c,d with dimethylsulfoxide some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 were obtained. Compound 13a was also obtained in the reaction of 10 with benzoyl chloride. Reaction of 3 with phenylhydrazine gave 1,2-dihydro-1-oxo-2-phenylpyridazino[4,5-b]quinoxaline ( 6 ). Reactions of 5 with acetic anhydride and dimethylsulfate gave, respectively, 1-acetoxypyridazino[4,5-b]quinoxaline ( 8 ) and 1,2-dihydro-1-oxo-2-methylpyridazino-[4,5-b]quinoxaline ( 7 ). All the compounds were characterized by elemental analysis and ¹H-nmr spectra. Compounds 5 and 10 showed antihypertensive activity in rats.     

Pyrrolophenothiazines. 1. Synthesis of isomeric pyrrolophenothiazine dioxides

The synthesis of 1H-pyrrolo[3,2-b]phenothiazine 10,10-dioxide and 3H-pyrrolo-[2,3-c]phenothiazine 11,11-dioxide was realized on the basis of 3-aminophenothiazine 5,5-dioxide by means of the Fischer reaction. The structures of the synthesized compounds were proved by data from the IR, UV, PMR, and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1637–1640, December, 1981.     

Syntheses of Examples of the 5,6-dihydro-4H-[1,2,3]triazolo[4,5,1-ij]quinoline, 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5,1-jk][1,4]benzodiazepine,and 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[4,5,1-kl][1]benzazocine ring systems

Lithiation of 1-vinylbenzotriazole 9 with n-BuLi (2 equiv) generates dianion 10, which upon subsequent reaction with 1,2- and 1,4-diketones affords 14 and 13, representatives of the 5,6-dihydro-4H-[1,2,3]triazolo[4,5,1-ij]quinoline 1 and 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[4,5,1-kl][1]benzazocine 2 ring systems, respectively. Reactions of dianion 10 with isocyanates give 15a,b, which contain the 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5,1-jk][1,4]benzodiazepine 3 ring system.     

Ring contraction during the 6pi-electrocyclisation of naphthopyran valence tautomers

The thermal and photochemical ring-opening of spiro(3H-naphtho[2,1-b]pyran-3,9'-thioxanthene-10,10-dioxide) results in the facile ring-contraction to 9-(naphtho[2,1-b]furan-2-yl)-9H-thioxanthene-10,10-dioxide . Similar behaviour is displayed by the isomeric spiro(2H-naphtho[1,2-b]pyran-2,9'-thioxanthene-10,10-dioxide) affording 9-(naphtho[1,2-b]furan-2-yl)-9H-thioxanthene-10,10-dioxide , though more severe reaction conditions were required. The comparative ease of this rearrangement for the isomers and was rationalised on the basis of the relative isomer populations of the ring-opened naphthopyrans. The rearrangement of simple mono- and bis-methylsulfonylphenyl substituted photochromic naphthopyrans , was examined; the former failed to rearrange whereas the latter could be induced to rearrange only under prolonged UV irradiation. The photochromism of diastereoisomerically pure sulfoxides derived from the oxidation of spiro(3H-naphtho[2,1-b]pyran-3,9'-thioxanthene) and spiro(2H-naphtho[1,2-b]pyran-2,9'-thioxanthene) resulted in conversion to the most thermodynamically stable trans-isomer in each case.     

Formation of 1,1,4,4-tetramethoxy-2,3,5,6-tetrahydroximinocyclohexane by the interaction of trinitrosophloroglucinol with hydroxylamine hydrochloride in methanol

1,1,4,4-Tetramethoxy-2,3,5,6-tetrahydroximinocyclohexane was obtained by the treatment of trinitrosoploroglucinol with hydroxylamine hydrochloride in methanol. Oxidation of the product with an alkaline solution of potassium hexacyanoferrrate(III) gave a mixture of the isomers 4,4,8,8-tetramethoxy-4H, 8H-benzo[1,2-c:4,5-c']bis[1.2.5]oxadiazole-1,7-dioxide.and 4,4,8,8-tetramethoxy-4H, 8H-benzo[1,2-c:4,5-c']bis-[1.2.5]oxadiazole-1,7-dioxide. Removal of the N-oxide groups from these compounds with triethyl phosphite followed by hydrolysis of the diketal groups gave 4,8-dioxo-4H, 8H-benzo[1,2-c:4,5-c']bis[1.2.5]-dioxazole. Reaction with malonodinitrile gave 4,8-di(dicyanomethylene)-4H, 8H-benzo[1,2-c:4,5-c']bis[1.2.5]-oxadiazole which is an analog of known electron acceptors. Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Acaemy of Sciences, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 549–553, April, 1997.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Heterocycles With a Benzothiadiazepine Moiety. IV. Synthesis of Novel Tetracyclic Rings by Intramolecular Cyclization of 10-Bromoacetyl-10,11-dihydro-11-ethoxycarbonyl-pyrrolo[1,2-b] [1,2,5] Benzothiadiazepine 5,5-Dioxide and Its Derivatives

Two novel tetracyclic derivatives, namely 5 and 8, have been synthesized by intramolecular cyclization of the 10-bromoacetyl-10,11-dihydro-11-ethoxycarbonylpyrrolo[1,2-b] [1,2,5]benzothiadiazepine 5,5-dioxide (3) and, respectively, the bis-methylamide of 11-carboxy-10,11-dihydropyrrolo[1,2-b] [1,2,5]benzothiadiazepine-11-acetic acid 5,5-dioxide (4). The last compound formed when treating with an excess of methylamine either the lactam 5 or the diethyl ester of 11-carboxy-10,11-dihydropyrrolo[1,2-b] [1,2,5]benzothiadiazepine-11-acetic acid 5,5-dioxide (7). An unambiguous synthesis of the diester 7 was achieved to confirm the chemical structure of derivatives 4 and 5.     

Studies in the heterocyclic series. XXI. A novel tetraaza-analog of phenothiazine

As a continuation of our search for new pharmaco-active phenothiazine compounds, the synthesis of 1,4,6,8-tetraazabenzo[b]phenothiazine ring system is described. Derivatives of this new heterocycle were prepared by converting 4,5-diamino-6-hydroxypyrimidine to 4,5-diaminopyrimidine-6-(1H)thione followed by the action of 2,3-dichloroquinoxaline in refluxing DMF or DMAC. The reaction of mixed nitric and sulfuric acids with 9-amino-12-chloro-1,4,6,8-tetraazabenzo[b]phenothiazine gave 9-amino-12-chloro-13-nitro-1,4,6,8-tetraazabenzo[b]phenothiazine 5-oxide in satisfactory yields. Diazotization of 9-amino-1,4,6,8-tetraazabenzo-[b]phenothiazine led to 1,4,6,8-tetraazatriazolo[4,5,1-kl]benzo[b]phenothiazine which is a new heterocyclic compound and the parent compound of this ring system. The mechanistic pathways to these compounds are also proposed.     

New heterocyclic ring systems. XI. Azadithiasteroid analogues

Synthesis of the title compounds has been achieved starting from 4-oxo-3,4-dihydro-2H,5H-thiopyrano[3,2-c][1]benzothiopyran 6,6-dioxide (III), which was converted to glyoxylate (IV), β-ketoester (V), difluoride complex (VII) and β-diketone (XII) gave with hydrazine, hydroxyl-amine and glycine ethyl ester several azadithiasteroid analogues.     

The preparation of 2H-1,2,3-benzothiadiazine-1,1-dioxides, 11H-11a-dihydrobenzimidazo[1,2-b] [1,2] benzisothiazole-5,5-dioxides, 6H-dibenzo[c,g] [1,2,5] thiadiazocine-5,5-dioxides and 5H-Dibenzo[c,g] [1,2,6] thiadiazocine-6,6-dioxides

o-Benzoylbenzenesulfonyl chlorides (I) were prepared conveniently from aminobenzophenones by diazotization followed by reaction with sulphur dioxide in the presence of Cu⁺, according to the general method of Meerwein. Reaction of the sulfonyl chlorides with hydrazine led to 4-phenyl-2H-1,2,3-benzothiadiazine-1,1-dioxides (II). The latter compounds could be methylated and acetylated readily in the 2-position. The 2-methyl derivative (III) could be prepared also by reaction of the sulfonyl chloride (Ia) with methylhydrazine. Catalytic hydrogenation of 6-chloro-4-phenyl-2H-1,2,3-benzothiadiazine-1,1-dioxide (IIa) gave the 3,4-dihydro derivative (V). Reaction of the sulfonyl chlorides (I) with o-phenylenediamine followed by cyclodehydration led to 11H-11,11a-dihydrobenzimidazo[1,2-b] [1,2]benzisothiazole-5,5-dioxides (VII). One of the latter compounds (VIIa) in sodium hydroxide solution in the presence of methyl iodide or benzyl chloride was transformed into 6-methyl- and 6-benzyl-5H-dibenzo[c,g] [1,2,6]thiadiazocine-5,5-dioxides (VIII), respectively. 5H-Dibenzo[c,g] [1,2,6] thiadiazocine-6,6-dioxides (XIV) were prepared also by cyclodehydration of 2-amino-2′-benzoylbenzenesulfonanilides (XIII).     

Formation and Ring Contraction of Benzo[f][1,2]Thiazepine-1,1-Dioxides from and to Benzo[e][1,2]Thiazine-1,1-Dioxides

Alkoxide-promoted ring expansion of the novel ethyl 2-(6,7-dimethoxy-3-oxo-3,4-dihydrobenzo[e][1,2]thiazine-1,1-dioxide-2-yl)acetate 3a and analogous 4,4-diethyl derivative 3b and cyclization of methyl 2-[2-(phenylaminocarbonylmethyl sulfamoyl)-4,5-dimethoxyphenyl] acetate 9 to the corresponding new 3-carboxylates and 3-carboxanilide of 7,8-dimethoxy-4-hydroxy-2,5-dihydrobenzo[f][1,2]thiazepine-1,1-dioxide (5a,b and 10 respectively) is described. Compound 5a was deacylated upon treatment with sodium hydroxide followed by hydrochloric acid to give 7,8-dimethoxy-2,3-dihydrobenzo[f][1,2]thiazepine-1,1-dioxide-4 (5H)-one 8 and its N-ethyl derivative transferred to 6,7-dimethoxy-2-ethyl-3-oxo-3,4-dihydrobenzo[e][1,2]thiazine-1,1-dioxide 7 by the reaction with ethyl methyl ketone in the presence of pyrrolidine.     

Studies on quinones

Anthra[1,2-c][1,2,5]oxadiazole-6,11-dione (I) was added to benzenesulfinic acid and thiophenol with the formation of 4-phenyl-sulfonyl- and 4-phenylmercapto-substituted hydroquinones, which on oxidation were converted into the corresponding quinones III and VII. 4-Phenylsulfonylanthra[1,2-c][1,2,5]oxadiazole-6,11-dione (III), in turn, reacted readily with benzenesulfinic acid, adding a molecule of the latter to the carbonyl oxygen atom and was converted into the O-benzenesulfonic monoester [6] (IV). Using compounds IV and hydroxynaphtho[1,2-c][1,2,5]oxadiazole (XId) the capability of the nitrogen atom of the furazan ring of participating in the formation of intramolecular hydrogen bonds was shown.     

Selective construction of indeno[1,2-b]phenothiazine and indeno[2,1-c]phenothiazine via tandem annulation reaction

AcOH promoted annulation reaction of 2-arylideneindane-1,3-diones with methyl 2-(benzo[b][1,4]thiazin-3-ylidene)acetate in refluxing ethanol afforded pentacyclic tetrahydroindeno [1,2-b]phenothiazine in satisfactory yields and with high diastereoselectivity according to the unexpected tandem annulation process. When the above reaction was carried out in refluxing acetic acid, isomeric dihydroindeno [1,2-b]phenothiazines and dihydroindeno [2,1-c]phenothiazines were obtained in comparable yields according to alternate tandem annulation process.     

Novel pyrrole-annulated heterocyclic systems. Synthesis of 10H-pyrrolo[1,2-b][1,2,6]benzothiadiazocin-11(12H)-one 5,5-dioxide

Intramolecular cyclization of 1-(2-aminophenylsulfonyl)-1H-pyrrole-2-acetic acid 5 gave 10H-pyirolo[1,2-b][1,2,6]benzothiadiazocin-11(12H)-one 5,5-dioxide 4 , a novel heterocyclic system of pyrrolobenzothiadiazocine family. Compound 5 was obtained starting from 2-nitrobenzenesulfonyl chloride with ethyl 1H-pyrrole-2-(α-oxo)acetate, which were condensed to afford 1-(2-nitrophenylsulfonyl)-1H-pyrrole-2-(α-oxo)acetate 13 . Reduction of 13 gave the amino ester 7, which was hydrolyzed to the required aminoacid 5. The synthesis of 7-chloro-10H-pyrrolo[1,2-b][1,2,6]benzothiadiazocin-11(12H)-one 5,5-dioxide 16 is also described.     

Benzo-1,2,3,4-tetrazine 1,3-dioxides annulated with tetraazapentalene systems

Thermolysis of 7-azido-6-(2H-1,2,3-triazol-2-yl)-1,2,3,4-benzotetrazine 1,3-dioxide and 7-azido-6-(1H-1,2,3-triazol-1-yl)-1,2,3,4-benzotetrazine 1,3-dioxide gives rise to the new heterocyclic systems: 6,10-dehydro-6H,10H-[1,2,3]triazolo[1′,2′:2,3][1,2,3]triazolo[4,5-g]-[1,2,3,4]benzotetrazine 2,4-dioxide and 6,8-dehydro-6H,8H-[1,2,3]triazolo[1′,2′:1,2][1,2,3]-triazolo[4,5-g][1,2,3,4]benzotetrazine 2,4-dioxide, respectively, their thermal stability and spectral properties have been studied.