Synthesis of purine-like ring systems derived from 1,2,6-thiadiazine 1,1-dioxide

7-Amino-1H,4H-imidazo[2,3-c][1,2,6]thiadiazine 5,5-dioxide was prepared by a multi-step reaction sequence form 3,5-diamino-4H-1,2,6-thiadiazine 1,1-dioxide. 7-Amino-4H-furazano-[3,4-c][1,2,6]thiadiazine 5,5-dioxide was obtained by lead tetraacetate oxidation of 3,5-diamino-4-hydroxyimino-4H-1,2,6-thiadiazine 1,1-dioxide.     

Synthesis of 4-substituted 3-hydroxy-and 3-amino-6H-1,2,6-thiadiazine 1,1-dioxides

Reaction of sulfamide with ethoxymethylene derivatives yielded 4-ethoxycarbonyl-, 4-cyano-, and 4-nitro-2H,6H-1,2,6-thiadiazine 1,1-dioxide. In some cases, the corresponding open chain sulfamidomethylene derivatives were isolated. Preparation of 4-amino- and 4-amino-5-methyl-2H,6H-1,2,6-thiadiazin-3-one 1,1-dioxide is also described. Reaction of sulfamide with ethyl 3,3-ethoxypropionate afforded 3,7-bis(etlioxycarbonylmethyl)perhydro-1,5,2,4,6,8-dithiatetra-zocine 1,1,5,5-tetroxide.     

Regioselective N-alkylation of 1,2,6-thiadiazine 1,1-dioxide derivatives

Reactivity towards alkylating agents in relation to the capacity to bind sodium ions of 1,2,6-thiadiazine 1,1-dioxide derivatives is described. The compounds studied are: 1 , 4-nitro-, 2 , 4-cyano-, 3 ,4-ethoxycarbonyl-2H,6H-1,2,6-thiadiazin-3-one 1,1-dioxide and 4 , 3-amino-4-cyano-6H-1,2,6-thiadiazine 1,1-dioxide. Methylation with dimethyl sulfate of 4-nitro- and 4-cyanothiadiazines 1 and 2 , which show the capacity to bind sodium ions, takes place regioselectively at position 2, whilst the thiadiazines which lack this feature ( 3 and 4 ) are methylated at 2 and 6, and 6 respectively. On using diazomethane, in the absence of alkaline ions, no selectivity was observed. Glycosidation reactions of 1, 3 and 4 have also been carried out. The structure of the newly synthesized compounds are discussed on the basis of their analytical and spectroscopic data.     

Synthesis of 2-S-dioxo isosteres of purine and pyrimidine nucleosides. II

The preparation of glucosyl and ribosyl derivatives of 3,4,5-triamino-2H-1,2,6-thiadiazine 1,1-dioxide ( 2 ), 7-amino-4H-furazano[3,4-c]- and 7-amino-1H, 4H-imidazo[2,3-c][1,2,6]thiadiazine 5,5-dioxide ( 3 and 4 respectively) is described. Different synthetic approaches have been used.     

Oxidation reactions of 3,4,5-triamino-1,2,6-thiadiazine 1,1-dioxide. Preparation of 3,5-diamino-4H-1,2,6-thiadiazin-4-one 1,1-dioxide

Oxidation reactions of 3,4,5-triamino-1,2,6-thiadiazine 1,1-dioxidc with hydrogen peroxide and chromium trioxide are reported. 3, 5-Diamino-4H-1,2,G-thiadiazin-4-one 1,1-dioxide is synthesized by different methods.     

Synthesis of 7-amirio-2H, 4H-vic-triazolo[4,5-c]-[1,2,6]thiadiazine 5,5-dioxides

7-Amino-2H,4H-vic-triazolo[4,5-c][1,2,6]thiadiazine 5,5-dioxide was prepared by two different ways from 3,4,5-triamirio-1,2,6-lhiadiazine 1, 1-dioxide and 3,5-diamino-4H-1,2,6-thia-diazine 1, 1-dioxide respectively. 7-A:nino-2-phenyl-4H-vic-triazolo[4,5-c] [1,2,6]thiadiazine 5,5-dioxide was obtained by lead telraacetate oxidation of 3,5-diamino-4-phenylazo-1, 2, 6-thiadiazine 1, 1-dioxide.     

Synthesis of isomeric N-substituted 5-methyl-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides from sulfamides and diketene

The reaction of N-n-butyl and N-benzylsulfamides with diketene in acetic acid solution in the presence of mercuric cyanide as a catalyst, afforded the corresponding 5-methyl-2-substituted-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides. The reaction of the above mentioned sulfamides with diketene in an aqueous alkaline medium resulted in the isolation of the corresponding N-aceto-acetyl-N' -substituted-sulfamides, which were then converted into 5-methyl-6-substituted-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides. Catalytic hydrogenation of the 5-methyl-2- and 6-n-butyl-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides furnished the corresponding dihydro-derivatives. The structures of the isomeric 1,2,6-thiadiazine 1,1-dioxide derivatives obtained were assigned on the basis of nmr spectroscopic studies.     

Synthese von 5,6-Dimethyl-4-oxo-1,3,4,5-tetrahydro-imidazo-[4,5-c] [1,2,6]thiadiazin-2,2-dioxid und 7-Methyl-4-oxo-1H-3,4-dihydro-pyrimido[4,5-c][1,2,6]thiadiazin-2,2-dioxid

Synthesis of 5,6-Dimethyl-4-oxo-1,3,4,5-tetrahydro-imidazo[4,5-c][1,2,6]thiadiazin 2,2-dioxide and 7-Methyl-4-oxo-1H-3,4-dihydropyrimido[4,5-c][1,2,6]thiadiazin 2,2-dioxide The derivatives of the above heterocyclic ring systems were prepared by reaction of the corresponding o-amino esters with sulfamoylchloride.     

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 .     

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).     

Pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. Sulfur dioxide analogs of pteridines

Several pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide derivatives have been synthesized for the first time by condensation of suitable 4,5-diamino-1,2,6-thiadiazine 1,1-dioxides and symmetrical 1,2-dicarbonyl compounds. Structures of these compounds have been characterized by their elementary analyses, ¹H-nmr and uv spectra as well as their pK_a values. The most striking differences between this series and the corresponding pteridines are discussed.     

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.     

Sulfonylcarbamimidic azides from sulfonyl chlorides and 5-aminotetrazole

Treatment of o-nitrobenzenesulfonyl chloride ( 3 ) with 5-aminotetrazole (5-AT) gave [(2-nitrophenyl)-sulfonyl]carbamimidic azide ( 6 ), a ring-opened isomer of the expected N-(1H-tetrazol-5-yl)-2-nitrobenzenesulfonamide ( 4 ). Sulfonylcarbamimidic azide 6 was converted to 2-amino-N-(aminoiminomethyl)benzene-sulfonamide ( 7 ) with ethanolic stannous chloride, and to 3-amino-1,2,4-thiadiazine 1,1-dioxide ( 8 ) with sodium dithionite. Methanesulfonyl chloride ( 9 ) and 5-AT gave 2-(methylsulfonyl)carbamimidic azide ( 10 ), which isomerized to 5-[(methylsulfonyl)amino]-1H-tetrazole ( 11 ) in warm ethanol. Attempted cycloaddition of 2-(phenylsulfonyl)carbamimidic azide ( 13 ) and ethyl vinyl ether led only to alkylated tetrazole products. In addition, other tetrazole-alkylating reactions are described. Isomers produced from these alkylations were differentiated with ¹³C nmr spectroscopy.     

Functionalized 5,6-dihydro-2H-1,2,6-thiadiazine 1,1-dioxides. Synthesis,structure and chemistry

Treatment of sulfamide 4a and aryl-substituted sulfamides 4b-e with ethyl 3,3-diethoxypropionate ( 13 ) provided a convenient procedure for the synthesis of functionalized 5,6-dihydro-2H-1,2,6-thiadiazine 1,1-dioxides 14 . Key spectral properties of this novel class of heterocycles are reported. The generality and utility of this transformation is briefly explored.     

Synthesis of 2-S-dioxo isosteres of purine and pyrimidine nucleosides. I. Alkyl and glycosyl derivatives of 3,5-diamino-4H-1,2,6-thiadiazine 1,1-dioxide

Preparation of alkyl and glycosyl derivatives of 3,5-diamino-4H-1,2,6-thiadiazine 1,1-dioxide (1) is described. Reaction of 1 with dimethyl sulfate gave the 4-methyl and 2,4-dimethyl derivatives. With benzyl chloride and allyl bromide C-4 substituted compounds were obtained. Reaction of the disilyl derivative of 1 with either 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide or 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose in the presence of Friedel-Crafts catalysts afforded the α and β anomers of the N-2 nucleoside and the β-O-glucoside. When the reaction was performed with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, a β-C-glycoside and the α and β anomers of the N-2 nucleoside were obtained. The structure of the corresponding nucleosides were elucidated by ¹H nmr and uv by comparing the latter with those of the alkyl derivatives.     

N,N′-Linked 1,2-benzisothiazol-3(2H)-one 1,1-dioxides: synthesis, biological activity, and derived radicals

A number of N,N′-linked benzoannelated isothiazol-3(2H)-one 1,1-dioxides, not available via oxidation of isothiazolium salts, were obtained with good yields by reaction of N-amino heterocycles with 2-chlorosulfonylbenzoyl chloride and evaluated for their inhibitory activity toward human leukocyte elastase (HLE) and acetylcholinesterase (AChE). 2-(Phthalimid-1-yl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide and 2-(2-methyl-4-oxo-3(4H)-quinazolinyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide were found to be inhibitors of HLE and tested as potential precursors of nitrogen-centered radicals using 266 nm laser flash photolysis.     

Synthesis of 2H-1,4-thiazin-3(4H)-one 1-oxide and 2H-1,4-thiazin-3-(4H)-one 1,1-dioxide,structural analogs of uracil

The synthesis of 1,4-thiazine 1-oxide and 1,1-dioxide analogs of the antibiotic emimycin is described. Reaction of methylthioglycolate with 1-bromo-2,2-diethoxyethane gave methyl (2,2-diethoxyethylthio)acetate ( 2 ). Treatment of 2 with methanolic ammonia followed by cyclization furnished 2H-1,4-thiazin-3(4H)-one ( 5 ). Oxidation of 5 with m-chloroperoxybenzoic acid converted it to 2H-1,4-thiazin-3(4H)-one 1-oxide ( 6 ). Oxidation of 2 with potassium permanganate, followed by treatment with methanolic ammonia, and cyclization gave 2H-1,4-thiazin-3(4H)-one 1,1-dioxide.     

Alkylsulfamoyl Chlorides as Key Units in the Synthesis of Novel Biologically Active Compounds for Crop Protection

Due to their bifunctional character, alkylsulfamoyl chlorides are versatile units for the synthesis of heterocycles, polar sulfamates, and sulfonamides. In the last decade, synthetic methods of general preparative use have been developed, by means of which amine hydrochlorides, isocyanates, aziridines or tertiary alcohols can be reacted with suitable sulfuric acid derivatives to give novel, variously substituted alkylsulfamoyl chlorides. These compounds can subsequently be converted either to previously unobtainable N-alkoxyalkyl-N-alkylsulfamoyl chlorides or to novel heterocycles of the type 1H-2,1,3-benzothiadiazin-4-one-2,2-dioxide, 2H-1,2,6-thiadia-zin-3-one-1,1-dioxide and 2H-1,2,4,6-thiatriazin-5-one-1,1-dioxide; these compounds are examples of interesting models which illustrate the relation between the structure and the action of the compound, and in some cases lead to highly selective, ecologically unobjectionable herbicides. On the other hand, the alkylsulfamoyl chlorides themselves can be N-acylated to give further 3- to 5-atom bifunctional synthesis units, with which novel heterocyclic syntheses can be carried out. Further uses of the alkylsulfamoyl chlorides include the preparation of biologically active sulfamates, and cycloaddition reactions of N-sulfonylamines prepared in situ.     

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.     

Synthesis of oxidized 1,2,3-thiadiazines by hydroperoxy-induced ring enlargement of 2-benzenesulfonylaminoisothiazolium salts

Oxidation of 2-benzenesulfonylaminoisothiazolium salts 1, 2 and their imines 3, 4 with hydrogen peroxide gave 1,2,3-thiadiazine 1-oxides 5, 6, which were converted into the corresponding 1,2,3-thiadiazine 1,1-dioxides 7, 8 using m-chloroperoxybenzoic acid. Oxidation of 5, 6 with hydrogen peroxide furnished isothiazol-3(2H)-one 1,1-dioxides 9, 10 as ring contraction products.