2.1- Benzothiazine 2,2-dioxides reactions

Benzo-l,2-thiazines.— As usual, work in this area is limited, and is mainly occasioned by the search for biologically or chemotherapeutically active compounds. In addition to several patents, which, for reasons of space, are not considered, two reports have appeared describing various alkylation and amination reactions of some benzothiazine dioxides, e.g. (2), available by base-induced rearrangement of appropriately jV- -keto-substituted saccharins (1). 

Treatment of 1-arylsulfonylpipecolinamides 46 with excess EDA gave pyrido[l,2-ft][l,2]benzothiazine 5,5-dioxides 47 in a carbanion-mediated reaction (97SL1079, 98MI2). When the reaction mixture of 46 (R = Me, R = H) was quenched with Mel an ethyl derivative 47 (R = Et, R = H) was obtained. 

An improved synthesis of 3,4-dihydro-2,l-benzothiazine 2,2-dioxide was reported by Togo and co-workers using photochemical conditions . Treatment of A-alkyl 2-(aryl)ethanesulfonamides 18 with (diacetoxyiodo)arenes under irradiation with a tungsten lamp at 20-30 °C afforded 2,1-benzothiazines 19 and 20. Chemical yields and selectivities were dependent upon the choice of solvents and the reactant s substituents 18 (Table 1). When THF and EtOH were used as solvents, the reactions failed to give the cyclized products, since their a-hydrogen was abstracted by the intermediate sulfonamidyl radical. Compound 20 was obtained as a major product when 1,2-dichloroethane was employed as a solvent. In contrast, in the case of EtOAc as solvent, compound 19 was obtained as the major product. 

In order to study heterocyclic steroid analogues, such as the 7,11-dithiaazasteroid analogues, Fravolini developed the synthesis of new heterocyclic ring systems tri- and tetracyclic 2,1-benzothiazines <82JHC1045>. Intermediate 137 was prepared from 1-methyl-4-oxo-lH-2, -bcnzothiazinc-4(3f/)-onc 2,2-dioxide 37 and thioglycolic acid and could be converted into 6-methyl-4-oxo-3,4-dihydro-2//,6//-thiopyrano[3,2-c][2,l]benzothiazine 5,5-dioxide 138 by cyclization with polyphosphoric acid. The reaction of 138 with dimethyl... 

Oxo-l,2-benzothiazine 1,1-dioxide 139 undergoes aldol condensation reactions upon deprotonation with NaOMe and treatment with an aldehyde 140 (Equation 19) <1992SC2621>. The intermediate aldol adducts are then dehydrated with acetic acid to afford condensation products 141 <2000JME2040>. 

Since the publication of CHEC-II(1996), there have been very few examples related to the reactivity of substituents attached to ring carbon atoms. One case involves the reaction of 3-benzylidene-2,3-dihydro-2-methyl-l,2-benzothiazin-4-one 1,1-dioxide 163 with the alkylidenephosphorane derived from salt 164 forming the tricyclic-fused ring compound 165 (Scheme 20) <1996J(P1)2541>. This material 165 was oxidized with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) affording the biphenyl 166. Ring-opened product 167 was produced from 165 upon exposure to />-toluene-sulfonic acid and heat. 

Intramolecular methanesulfonamide anion alkylation and aldol condensation reactions have been employed for the synthesis of 2,1-benzothiazine 2,2-dioxides. For instance, Blondet and Pascal have utilized such a process for the formation of compounds 225 and 226 from ortV o-substituted aldehyde 227 and alkyl chloride 228, respectively (Scheme 30) <1994TL2911>. 

An anionic equivalent of the Friedel-Crafts cyclization reaction has been developed for the formation of the C /C-5 bond of the 1,2-benzothiazine structure (Equation 35 Table 5) <1997SL1079>. In this reaction, directed metalation of sulfonamide-substituted aromatic systems 233 with an excess of LDA affords aryl lithium species 234 in a regiocontrolled fashion. This intermediate then reacts in situ with a proximal amide to form l,2-benzothiazine-4-one 1,1-dioxides 235. The yields of this transformation appear to be highly dependent upon the substitution pattern in 233. The authors attribute the low yield when = methyl and = H to a-deprotonation of the amide moiety. 

Reaction of o-iodobenzenesulfonamide 265 with the potassium enolate of ketones 266 in liquid ammonia under photochemical conditions affords 1,2-benzothiazine 1,1-dioxides 267 in excellent yield (Scheme 37) <2005JOC9147>. While a variety of other ketone substrates have been investigated for this reaction, those containing /3-hydrogens afford significant amounts of benzenesulfonamide by dehalogenation of the starting material 265. 

Synthesis The reaction of benzothiazolo-3(2H)-one-1,1-dioxide with methyl chloroacetate gives the methyl 2(3H) acetate derivative, which is isomerized with sodium methoxide in toluene/terf-butanol yielding methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1 -dioxide. The subsequent methylation with methyl iodide in methanol yields the 2-methyl compound. Finally this compound is treated with 2-amino-5-methylthiazole in xylene (Trummlitz et al. (Thomae GmbH), 1979 Trummlitz et al., 1989 Kleemann et al., 1999). 

A mixture of 26.9 g (0.1 mol) of the 1,1-dioxide of methyl 4-hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxylate and 12.5 g (0.11 mol) of 2-amino-5-methylthiazole was refluxed in 4 liters of xylene for 24 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed by means of a 4-A-molecular sieve mounted in a Soxhlet-extractor. The hot reaction solution was filtered. Upon cooling and standing overnight, the crude product separated out of the filtrate in the form of crystals (32.0 g, 91% of theory). After recrystallization from ethylene chloride 26.0 g (74% of theory) of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained M.P. 254°C (decomp.). 

I of 95% ethanol, 673 ml of methyl iodide (1.53 kg, 10.87 moles) and 3.14 L of 1 N aqueous sodium hydroxide. The reaction mixture was then stirred for 30 min at room temperature, under nitrogen atmosphere and then solution was stored for 23 h. The slurry was then chilled at 0°C and filtered. After washing the filter cake twice with water, ethanol and then diethyl ether there were obtained 537 g of methyl 3,4-dihydro-2-methyl-4-oxo-2H-l,2-benzothiazine-3-carboxylate 1,1-dioxide, melting point 165°-168°C after recrystallization from 1.25 L of acetonitrile. 

In 3 L round-bottomed flask there were placed methyl 3,4-dihydro-2-methyl-4-oxo-2H-l,2-benzothiazine-3-carboxylate 1,1-dioxide, 2-aminopyridin and dry xylene. Nitrogen gas was then bubbled into the suspension for 5 min, then the reaction mixture was heated to begin a period of slow distillation, with complete solution effected during the first 10 min of heating. After 5.5 h, the period of slow distillation was discontinued and reaction mixture was allowed to heat at reflux for approximately 16 h. After that the reaction mixture was cooled to room temperature and filtered. The solid material was crystallized from chloroform with methanol and againe from methanol and then there were obtained piroxicam, melting point 197°-200°C, dec. 

Iodobenzenesulfonamide (32) undergoes photostimulated SRN1 reactions in liquid ammonia, with the potassium enolates derived from acetone, pinacolone, 3-methyl-2-butanone, cyclopentanone, cyclohexanone and cyclooctanone, to give fair to good yields of 2H-l,2-benzothiazine-l, 1-dioxides (Scheme 10.59) [73],... 

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