Spiro[(2,3-dihydro-2-oxo-imidazo[1,2-a]pyridine)-3,3-(3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide)]-A novel product derived from piroxicam

A novel compound, spiro[(2,3-dihydro-2-oxo-imidazo[1,2-a]pyridine)-3,3-(3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide)] (3) , was isolated during an attempt to convert 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide ( 1 ) (Piroxicam) to an O-trifluoromethanesulfonyl ester. A possible mechanism is offered to explain this unusual transformation.     

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 ).     

Preparation and nitrosation of 3,4-dimethyl-3-penten-2-one (e)- and (z)-oximes. Formation of 3,3,4,5-tetramethyl-3H-pyrazole 1,2-dioxide and of 2-isoxazoline derivatives

The stereoisomeric (E)- and (Z)-oximes of 3,4-dimethyl-3-penten-2-one were prepared and nitrosated with butyl nitrite in methanol. The (E)-oxime gave 3,3,4,5-tetramethyl-3H-pyrazole 1,2-dioxide in nearly quantitative yield, while the (Z)-oxime reacted less readily, giving a lower yield of the same product, with five other products identified as isoxazoline derivatives. Three of these were 4-hydroxy-, 4-methoxy-, and 4-nitro-3,4,5,5-tetramethyl-2-isoxazoline. The fourth was the O-(3,4,5,5-tetramethyl-2-isoxazolin-4-yl) derivative of the starting (Z)-oxime, and the fifth was 4-methylene-3,5,5-trimethyl-2-isoxazoline.     

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 ).     

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.     

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.     

Synthesis and properties of a dithiirane trans-1,2-dioxide, a three-membered vic-disulfoxide

cis- and trans-3-(1-adamantyl)-3-tert-butyldithiirane 1-oxides were oxidized with dimethyldioxirane to give the trans-1,2-dioxide. Thermal decomposition of the 1,2-dioxide yielded the corresponding (E)- and (Z)-sulfines, thioketone, and cis- and trans-dithiirane 1-oxides. In the thermolysis, decomposition to the sulfines and SO was the main path and that to the thioketone and SO(2) was the minor one. The two decomposition processes and epimerization to the cis-1,2-dioxide were analyzed theoretically. SO generated in situ reacted with thioketones as additives to give the corresponding dithiirane 1-oxides.     

The transformation of saccharin into derivatives of lmidazo[1,2-b] [1,2]-benzisothiazole and benzo[g] [1,2,5]thiadiazocine

Reaction of 3-(2-hydroxyethylamino) benzo[d]isothiazole 1,1-dioxide ( 5a ) with thionyl chloride gives a mixture of the expected chloroethyl derivative ( 5h ) and the rearranged saccharin 2-(2-aminoethyl)-3-oxo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide hydrochloride ( 6a ). Separate treatment of the chloroethyl compound ( 5h ) with dilute alkali gives the expected cyclization product 2,3-dihydroimidazo[1,2-b] [1,2] benzisothiazole 5, 5-dioxide ( 7a ). Acidification of the liquors of the above reaction yields the ring expanded derivative 6-oxo-3,4,5,6-tetrahydro-[2H]benzo[g][1,2,5]thiadiazocine 1,1-dioxide ( 12f ), a representative of a new ring-system. Treatment of the imidazo derivative ( 7a ) with concentrated hydrochloric acid again yields the N-substituted saccharin ( 6a ) which upon treatment with alkali also produces the thiadiazocine ( 12f ). In contrast, treatment of the imidazo compound ( 7a ) with alkali leads to attack on the sulphonamide function to give 2-(2-imidazolin-2-yl)benzenesulphonic acid ( 8 ). It is suggested that the multitude of chemical interconversions which can be induced within this series of compounds (Scheme II) can only be accounted for if two separate cyclol intermediates are invoked. Related reactions observed with variously substituted derivatives of the starting saccharin derivative ( 5a ) are discussed as are the spectral properties and chemical reactivity of the new compounds prepared.     

Facile synthesis of coumarin bioisosteres—1,2-benzoxathiine 2,2-dioxides

A simple and reproducible procedure for the synthesis of bioisosteres of coumarin—1,2-benzoxathiine 2,2-dioxide is presented. The developed method is based on the intramolecular aldol cyclization of derivatives of mesylsalicyl aldehydes in the presence of strong organic bases, where best results were obtained with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It has been shown that depending on the nature of the substituent in the aromatic ring, intermediate aldol adducts (3,4-dihydro-1,2-benzoxathiin-4-ol 2,2-dioxides) in different ratios with title compound are formed. Dehydration of the intermediate aldols with POCl₃ led to full conversion into 1,2-benzoxathiine 2,2-dioxide derivatives. The scaffold of 1,2-benzoxathiine 2,2-dioxide is unequivocally proven by a single-crystal X-ray structure.     

Properties and structures of porphyrexides

The molecular and crystal structures of porphyrexides, viz., 4-amino-2-imino-(1) and (Z)-2-amino-4-bromoimino-5,5-dimethyl-4,5-dihydro-1H-imidazole 1-oxyls (7), and their diamagnetic precursors were determined. Compound 1 is kinetically unstable because it is oxidized with atmospheric oxygen to form (E)-1,2-bis[1-amino-1-(cyanoimino)-2-methyl-propan-2-yl]diazene 1,2-dioxide. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 441–447, March, 2006.     

Synthesis and configuration of 4-alkyl-2-methyl-3,4-diphenyl-1,2-thiazetidine 1,1-dioxide

4-Alkyl-2-methyl-3,4-diphenyl-1,2-thiazetidine 1,1-dioxide 5, 6 and 7 were obtained from 2-methyl-3,4-diphenyl-1,2-thiazetidine 1,1-dioxide 1 by reaction of its anion 4 with alkyl halides. cis- and trans-Configuration of the 4-alkylated products were determined by ¹H-nmr and NOE difference spectro-scopy studies.     

Fotochromic Dihetarylethenes: XIX. Synthesis of 1,2-Dihetarylethenes with 2,5-Dihydrothiophene Bridge from Thieno[3,2-b]pyrroles

Reductive cyclization by McMurry method was performed with diketosulfide obtained by treating with Na₂S of compound prepared by regioselective acylation of methyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate with chloroacetyl chloride. As a result was synthesized a photochromic 1,2-dihetarylethene where the fuzed rings are connected by a 2,5-dihydrothiophene ring. The oxidation of the latter provides 2,5-dihydrothiophene-1,1-dioxide bridge.     

3-Oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide derivatives. I. Reaction of esters with alkoxides

Reaction of 3-oxo-1,2-benzoisothiazoline-2-acetic acid alkyl esters 1,1-dioxide ( 1a-d ) with alkaline alkoxides was carried out under various conditions. Under mild conditions, o-(N-carboxymethylsulfamyl)benzoic acids dialkyl esters ( 2a-d ) were obtained with good yields. Reaction of 1a-d or 2a-d with sodium alkoxides under drastic conditions afforded 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid alkyl esters 1,1-dioxide ( 3a-d ). Transesterification was observed when esters 1b-d were treated with sodium methoxide in methanol. Esters 3a-d were hydrolyzed in concentrated aqueous sodium hydroxide affording the acid 6 . Attempts to recrystallize 6 from water resulted in its decarboxylation to give 2H-1,2-benzothiazine-4-(3H)one 1,1-dioxide (7). Compound 6 could not be obtained by acid hydrolysis of esters 3a-d or by rearrangement of 3-oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide ( 8 ). Different experimental evidence supports the suggestion that rearrangement took place by ethanolysis of the carboxamide linkage affording the open sulfonamides (fast step) followed by a Dieckmann cyclization (slow step). It was demonstrated that transesterification took place in the open sulfonamides 2 .     

1,2-Benzothiazines VIII. A novel semmler-wolff type transformation of 2-methyl-2H-1,2-benzothiazin-4-one 1,1-dioxide oxime

Refluxing the oxime ( 1 ) of 2-methyl-2H-1,2-benzothiazin-4(3H)one 1,1-dioxide with tri-fluoroacetic acid or with boron trifluoride in acetic acid gives the corresponding N-acyl derivative ( 2 or 3) of 4-amino-2-methyl-2H-1,2-benzothiazin-3(4H)one 1,1-dioxide. This transformation appears to be related to the acid catalyzed conversion of α-tetralone oxime to α-naphthylamine.     

A saccharinate–iron(II) complex with a free saccharin molecule present, [Fe(phen)3]sac2·sacH·6H2O

The crystal structure of the title compound, tris(1,10-phenanthroline-N,N′)­iron(II) bis­[1,2-benziso­thia­zol-3(2H)-onate 1,1-dioxide] 1,2-benziso­thia­zol-3(2H)-one 1,1-dioxide hexahydrate, [Fe(C₁₂H₈N₂)₃](C₇H₄NO₃S)₂·C₇H₅NO₃S·6H₂O, at 120 K consists of slightly distorted octahedral [Fe(phen)₃]²⁺ cations (phen is 1,10-phenanthroline), two saccharinate anions and a free saccharin mol­ecule, as well as six waters of crystallization. The compound has been confirmed as diamagnetic low-spin iron(II) by magnetic measurements. There is extensive hydrogen bonding leading to a three-dimensional network.     

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.     

Novel heterocyclic systems. Synthesis of 10H-Pyrrolo[1,2-b][1,2,5]-benzothiadiazocine 5,5-dioxide and related derivatives

The synthesis of 10H-pyrrolo[1,2-b][1,2,5]benzothiadiazocine 5,5-dioxide has been carried out by intramolecular cyclization of 1-(2-formamidomethylphenylsulfonyl)-1H-pyrrole, prepared from the reaction of 1-(2-aminomethylphenylsulfonyl)-1H-pyrrole with ethyl formate. Treatment of the last pyrrole derivative with triphosgene afforded 10H-pyrrolo[1,2-b][1,2,5]benzothiadiazocin-12(11H)-one 5,5-dioxide, which was also prepared by cyclization of 1-(2-methoxycarbamidomethylphenylsulfonyl)-1H-pyrrole. Methylation of the 12-one derivative furnished the corresponding -methyl benzothiadiazepine dioxide. 1-(2-Aminomethylphenylsulfonyl)-1H-pyrrole has been prepared by cleavage of the phthalimido moiety of 1-(2-phthalimidomethylphenylsulfonyl)-1H-pyrrole, obtained by reacting with potassium phmalimide 1-(2-bromomethylphenylsulfonyl)-1H-pyrrole. This compound has been obtained starting from 2-bromomethyl-benzensulfonamide by Clauson-Kaas procedure.     

Heterocycles with a Benzothiadiazeypine Moiety. I. Synthesis of Pyrrolo[1,2-b]-s-triazolo[3,4-d] [1,2,5]benzothiadiazepine 5,5-Dioxide

Condensation of 2-nitrobenzenesulfonyl chloride with 2-ethoxycarbonyl-1H-pyrrole in the presence of potassium tert-butoxide and 18-crown-6 furnished 2-ethoxycarbonyl-1-(2-nitrobenzenesulfonyl)-1H-pyrrole. Reduction of nitro group to amino and subsequent cyclization by heating the aminoester in the presence of 2-hydroxypyridine as a bifuctional catalyst led to 11-oxo(10H)-pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 5,5-dioxide. Treatment of the latter compound with di-4-morpholinylphosphinic chloride gave the corresponding phosphinyloxyimine, which on reacting with formylhydrazine underwent intramolecular cyclization to afford the title tetracyclic ring.     

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.     

Reaction of sulfene with heterocyclic N,N-disubstituted α-aminomethyleneketones. IX. Synthesis of 1,2-oxathiino[6,5-e]indole derivatives

The polar 1,4-cycloaddition of sulfene to N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-1-methylindol-4-ones occurred only in the case of aliphatic N-substitution to give, generally in good yield, 4-dialkylamino-3,4,5,6-tetrahydro-7-methyl-7H-1,2-oxathiino[6,5-e]indole 2,2-dioxides IV. Full aromatization of IVa (4-NR₂ = dimethylamino) with DDQ in refluxing benzene gave in low yield 7-methyl-7H-1,2-oxathiino-[6,5-e]indole 2,2-dioxide, whereas the same reaction of IVe (4-NR₂ = morpholinyl) with excess DDQ afforded in low yield 7-methyl-4-morpholinyl-7H-1,2-oxathiino[6,5-e]indole 2,2-dioxide.