2H-1,3-Benzothiazines

H- 1,3-Benzothiazines (170) are available through a Bischler-Napieralski type cycliz-ation of amides (169) using phosphorus oxychloride as reagent (77ACH(92)317). 

H—1,3—Benzothiazines (e.g. 375) have been prepared by a modified Ritter reaction and characterised by methiodide formation (Scheme 84). 4H-1,4-Benzothiazines(377) are... 

In connection with studies on the thermolysis of oxazolin-5-ones, the 2-arylthio-substituted derivative (49) has been observed to undergo thermally induced cycloelimination of carbon dioxide to give the 2H-1,3-benzothiazine (52), presumably via the ylide intermediates (50) and (51). Like 2-ethoxybenzoxazin-4-one, the sulphur analogue (53) undergoes ethanol elimination under the influence of an acid catalyst to give the unstable cyclic acylamine (54), which can be trapped as Diels-Alder adducts... 

A mixture of 40.5 g (0.15 mol) of 3-carbethoxy-4-hydroxy-2-methyl-2H-1.2-benzothiazine 1,1 -dioxide, 20.6 g (0.21 mol) of 3-amino-5-methylisoxazole, and 2,500 ml of xylene was refluxed for 24 hours in a Soxhiet apparatus, the thimble of which contained 60 g of Linde type 4A molecular sieve. The mixture was cooled to 25°C and the resulting crystalline precipitate was collected and washed with ether to give 44 g of crude product. Recrystallization from 1,6(X) ml of 1,4-dioxan gave 34.7 g of material, MP 265°C to 271°C dec. 

Carbethoxy-4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1 -dioxide Isoxicam... 

Hydroxy-2-methyl-1,1dioxo-1,2-dihydro-U6-benzo[e][1,2]thiazine-3-carboxylic acid isoxazo-3-ylamide, 4-hydroxy-2-methyl-/V-(5-methyl-3-isoxa-zolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1 dioxide, Ci4H13N305S, Mr 335.34, mp 265-271 °C (decomp.) sodium salt,... 

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). 

An improved procedure using 2-methoxyethyl 2-chloroacetate in place of methyl 2-chloroacetate for the alkylation of sodium saccharin has been described. The resulting 2-methoxyethyl saccharin-2-acetate is treated with sodium 2-methoxyethoxide in dimethyl sulfoxide, then acidified to give 2-methoxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, which is N-alkylated with methyl iodide in acetone-aqueous sodium hydroxide. The resulting 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is heated with 2-aminopyridine in xylene to give piroxicam. 

Hydroxy-2-methyl-1,1-dioxo-1,2-di-hydro-1A.6-benzo[e][1,2] thia-zine-3-carboxylic acid pyri-din-2-ylamide, 4-hydroxy-2-methyl-/V-2-pyridinyl-2H-1,2-benzothiazine-3-carboxam-ide-1,1-dioxide, C15H13N304S, Mr 331.35, mp 198-200 °C. 

Lombardino, J. G., Wisemann, E. H., Chiaini, J. Potent anti-inflammatory N-heterocyclic 3-carboxamides of 4-hydroxy-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, J. Med. Chem. 1973, 5, 493-496. 

Zinnes, H., Sircar, J. C., Lindo, N., Schwartz, M. L, Fabian, A. C., Shavel, J. Jr, Kasulanis, C. F., Genzer, J. D., Lutomski, C., DiPasquale, G. Isoxicam and related 4-hydroxy-N-isoxazolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides. Potent nonsteroidal antiinflammatory agents, J. Med. Chem. 1982, 25, 12-18. 

Zinnes, H., Schwartz, M., Shavel, J. (Warner-Lambert) 4-Hydroxy-3-(3-isoxazolocarbamyl-2H-1,2-benzothiazin-1,1 -dioxyde und Verfahren zu ihrer Herstellung, DOS 2 208 351,1972. 

Aqueous base causes hydrolytic ring opening, although the ease with which this is achieved varies from system to system. AH- 1,3-Benzothiazines are quite stable at room temperature to aqueous alkali, but on heating the heterocyclic ring is destroyed by initial nucleophilic attack at C-2 (Scheme 9) (68ACH(58)179). 2H- 1,3-Benzoxazines are easier to hydrolyze and here both O-alkyl and imine bonds are cleaved by the action of water (Scheme 10) (3UA644). 

Phenylsulfonyl)furo[2,3- ]quinoline and its parent unsubstituted heterocycle were found to have very similar absorption maxima hence, the sulfone group does not provide an additional conjugative effect <83JOC774>. In addition, furo[2,3-/ quinoline and its isomeric furo[3,2-< ] counterpart were found to exhibit UV absorption maxima that are almost identical. An absorption maximum at 435 nm consistent with the presence of a 2H-1,4-benzothiazine chromophore was one of the key pieces of data that enabled the structure determination of compounds based upon the new 1,2-dihydro-3//,8//-pyrrolo[2,3-/z][l,4]benzothiazine skeleton <87T5357>. The UV spectrum of l,4-benzodioxano[6,7-c]furoxan was found to exhibit four characteristic band maxima in the 350-480 nm region <88JHC803>. 

Similar ring systems were prepared from 3-acety 1-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide (93) and ethylenimine (190 R = H)137,138 (Eq. 43) or ethylene dibromide (forming 95).8,139 The ethylenimine reaction gave only... 

The first synthesis of a derivative was reported by Unger,11 who claimed that reaction of phenacyl bromide with 2-aminobenzenethiol gave 3-phenyl-2H- 1,4-benzothiazine (10a). Nearly 70 years later Friedrich et al. proposed the 4H structure (10b).12... 

Trichochromes E and F are based on the 2H-1,4-benzothiazine ring, while trichochromes B and C are mixed systems, with both 1,4-benzothiazine and l,4-benzothiazin-3-one fragments. These may be extracted from red hair and feathers under alkaline conditions.31,32 Apparently33 only trichochromes B and C occur in red feathers, and trichochromes E and F, reportedly isolated from this source, arise as artifacts. The chromophore in the trichochrome... 

Prota and co-workers34 prepared 18 by oxidative coupling of 3-aryl-2H-1,4-benzothiazines, and established the structures of the cis and trans isomers of the 3-p-bromophenyl derivatives by X-ray crystallography. The cis and trans isomers are readily interconverted in solution at room temperature, with the red, cis isomer predominating over the yellow, trans isomer, both isomers being stable in the solid state. 

All of the synthetic routes reviewed so far have primarily involved the use of sulfur as a nucleophile. Sulfur can also act as an electrophile in the formation of precursors of the benzothiazine ring system. Reaction of sulfenyl chloride with ketones gives / -keto sulfides. The acetophenone adduct 90 has been cyclized with stannous chloride and hydrogen chloride in acetic acid to give 3-phenyl-6-chloro-2H-1,4-benzothiazine (91).135... 

Ring contraction has also been observed in hydrogenation reactions of benzothiazines. Catalytic hydrogenation of 3-phenyl-2H-1,4-benzothiazine (141) gave 2-methyl-2-phenylbenzothiazoline (142), and not the dihydro-1,4-benzothiazine as might have been expected.14... 

Acctyl-3-methyl-l,3-benzothiazolium-trifluormethansulfonat laBt sich mit 0,1 N Salzsaure in 2,4-Dime-thyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazin uberfiihren1073 (73%) ... 

Dihydro-1,3-thiazines, dihydro-1,3-lhiazinones, 2H-1,3-benzolhiazines, 4H-1,3-benzothiazines, and related compounds... 

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