Benzo-1,3-thiazines

Benzo l,2-thiazines.—Syntheses of new 1,2-benzothiazines of pharmacological interest continue to attract most of the attention in this area. Sianesi et aL now report some convenient procedures for preparing the three isomeric dihydrobenzothiazine dioxides (9)—(11) and their N-substi-tution products. For instance, (10) is obtained in 54% yield by dehydration of o-(2-aminoethyl)benzenesulphonic acid with POCI3, and also by hydrogenation in acidic medium of the corresponding cyanosulphonamide (77% yield) or by alkaline treatment of o-(2-chloroethyl)benzenesulphonamide (83% yield). Several 3,4-dihydro-l/f-2,3-benzothiazin-4-one 2,2-dioxides and 3,4-dihydro-177-l,2-benzothiazin-4-one 2,2-dioxides, as well as 3,4- 

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Chemical Name 4-Hydroxy-3-(5-methyl-3-isoxazolocarbamyl)-2-methyl-2H-1,2-benzo-thiazine 1,1 -dioxide... 

The majority of nonsteroidal antiinflammatory agents contain an acidic carboxyl group. A series of experimental agents in this class have been prepared in which the acidic proton is supplied by a highly enolizable proton from a function such as a p-dicarbonyl incorporated into a heterocyclic system. As an example, an acylated, highly oxidized isoquinoline moiety can fulfill this function (see also the benzo-thiazines below). Toward this end, reaction of... 

As with five-membered heterocycles, phosphorus pentasulfide may replace a ring oxygen atom by sulfur, or it may effect replacement in an acyclic precursor and then bring about cyclization. Thus isochroman-l-one (99) is converted into thioisochroman-l-thione (100) under the same conditions a 3-arylisocoumarin( 101) produces a 3-ary 1-1-thioisocoumarin (102) only, with no replacement of the ring oxygen atom.122 A typical example of thiation, followed by cyclization, is the formation of 2-alkyl- or 2-aryl-3,l-benzo-thiazine-4-thiones (103) from /V-acylanthranilic acid esters (104) by treatment with phosphorus pentasulfide in boiling xylene.122... 

Heating [l,4]benzothiazines (247) in toluene in the presence of NaH afforded 10-oxopyrido[2,l-c][l,4]benzothiazine-7-carboxylates (248) (90-FES589). It was reported that methyl (E,Z)-4-(3,4-dihydro-2//-1,4-benzo-thiazin-3-ylidene)-3,4-dialkoxycarbonylbut-2-enoates gave 10-oxo-10//-pyrido[2,l-c][l,4]benzothiazine-7,8-dicarboxylates in boiling toluene in the presence of p-TSA [85H(23)1619], but the structure was later questioned [87JCS(P1)1027]. 

A convenient method for the synthesis of trioxo-benzothiazine 181 involves a ring expansion reaction of benzoisothiazole 180 <07H1843>. Directed ort/ o-mctalation of benzenesulfonamide 176 coupled with carboxylation gives rise to 2-carboxybenzene-sulfonamide 178 which is then converted to benzoisothiazole 179 under the TMSCl-Nal deprotective-cyclization conditions. Bromination of 179 followed by ring expansion mediated by 20% KOH according to the Abramovitch procedures furnishes the benzo-thiazine 181. Optical resolution of 181 using (-)-menthoxyacetyl chloride yields its (+) and (-) enantiomers. 

Similarly, nucleophilic substitution by thiourea of 2-bromo-4-hydroxy-2H-1,4-benzoxazin-3 (4//)-one, and 2-bromo-4-hydroxy-2/f-1,4-benzo-thiazin-3(4//)-one, gave rise to S-[4-hydroxy-2//-l,4-benzoxazin-3(4i )-on-2-yl]-isothiouronium bromide and S-[4-hydroxy-2fiM,4-benzothiazin-3(4/i/)-on-2-yl]-isothiouronium bromide, respectively. On alkaline cleavage the four isothiouronium bromides showed a different behaviour. 

Although an elusive compound because of its high reactivity, 1,4-benzo-thiazine has recently been prepared and shown to exist as the 2i/-tautomer... 

A versatile synthetic approach to 4-hydroxy-1,2-benzothiazines was discovered by Abe and co-workers3-. 2-phenacyl-l,2-benzisothiazolin-3-ones (8 R = Ar) with strong base produce 3-benzoyl-4-hydroxy-2//-l,2-benzo-thiazine 1,1-dioxides (9 R = Ar) (Eq. 2). Yields up to 93% could be obtained using sodium ethoxide in ethanol. 

The benzisothiazoline ester 8 (R = OR ) is isomerized to a 1,2-benzo-thiazine-3-carboxylic ester (12) by sodium ethoxide in ethanol7,8 or by sodium methoxide in dimethyl sulfoxide.9 This rearrangement appears to be more sensitive to reaction conditions and solvent than the rearrangement of 2-phenacyl-l,2-benzisothiazolin-3-ones such as 8 (R = Ar) (Eq. 2), and two laboratories8,9 report unsatisfactory attempts to rearrange compound 8 (R = OMe) to 12 (R = Me) with sodium methoxide in methanol. 

Many patents cover synthetic routes to anti-inflammatory compounds such as 20, 25, or 29. The transformations shown in Scheme 1 are included in process patents.25-29 Transamidation of certain 3-carboxanilides (32) produces novel N-substituted carboxamides of 4-hydroxy-2H-l,2-benzo-thiazine 1,1-dioxides (25) (Eq. 7).30... 

A few reports have appeared of syntheses of 1,2-benzothiazines lacking a ketone group in the thiazine ring. Bicking and Sprague52 treated l-(2-chloroethyl)benzene-2,4-disulfonylchloride derivatives (68) with a variety of primary amines to afford 7-sulfamoyl-3,4-dihydro-2//-l,2-benzo-thiazine 1,1-dioxides (69) in poor to fair overall yield. The requisite starting materials (68) were readily prepared by exhaustive chlorosulfonation of phenethyl halides (67) (Eq. 15), but the scope was limited by the concomitant introduction of a sulfamoyl substituent into the benzene ring of the 1,2-benzothiazine 1,1-dioxide (69). 

Helferich and Klebert58 obtained the 5,6,7,8-tetrahydro-2//-l,2-benzo-thiazine 1,1-dioxide 84 by treating the bicyclic sultone derivative 83 with aniline (Eq. 18). The sultone 83 was readily prepared by reacting the a,/ -unsaturated ketone 82 with sulfuric acid/acetic anhydride. 

Acylation and alkylation reactions of the enolic 4-hydroxy-1,2-benzo-thiazines have been studied. Zinnes et al.A O-alkylated compound 21 with isopropyl iodide (potassium carbonate in acetone) (see Scheme 1), and formed the 4-acetoxy compound 85 from 2-methyl-2f/-1,2-benzothiazin-4-one 1,1-dioxide (11) with acetyl chloride and sodium hydride (Eq. 19).6... 

The activated 4-methylene function of 3,4-dihydro-2-alkyl-l,2-benzo-thiazin-3(2ff )-one 1,1-dioxide (47) permits the formation of an anion. Treatment of the anion in DMSO14,38 or DMF74 with isocyanates yields the corresponding 4-carboxamides (116) (Eq. 28). 

Numerous spectra recorded for 1,2-benzothiazines include the 13CNMR of piroxicam (29),78 the electron spin resonance spectrum of the paramagnetic semidione obtained from base/oxygen oxidation of 3,4-dihydro-1,2-benzo-thiazin-4(2H)-one 1,1-dioxide 10,79 and the mass spectral fragmentations of 4-hydroxy-1,2-benzothiazines described in detail by Rasmussen8 and by Heyes et al.i0 The infrared, ultraviolet, and nuclear magnetic resonance spectra of various 1,2-benzothiazines are reported.4,6 8-10 17,21 34 66 Representative spectral data of 1,2-benzothiazines are presented in Table I. 

Trummlitz and co-workers126 also prepared derivatives of 150 by treatment of 2-methyl-2H-naphtho [2,1-c] [l,2]thiazin-4-(3H)-one 1,1-dioxide (151) with sodium hydride and an aryl isocyanate. The starting material (151) for this sequence was synthesized analogously to the related benzo-thiazine 11. 

Rasmussen142 143 prepared the 2tf,5//-l,3-oxazino [5,6-c][l,2]benzo-thiazine-2,4(3H)-dione 5,5-dioxide (202) by heating 1,2-benzothiazine derivative 201 (Eq. 46). Anti-inflammatory and antiarthritic activities were claimed for 202 (R = aryl).143... 

The involvement of cysteine in the biosynthesis of phaeomelanins and trichochromes, natural pigments in mammals, has prompted work on the reaction of cysteine with a variety of reagents to produce the 1,4-benzo-thiazine ring system. 

As outlined in Section II, the reaction between benzoquinones, or their phenolic precursors, and 2-aminoethanethiols leads to a variety of benzo-thiazines, depending on reaction conditions.41-43... 

The reaction of 2-mercaptobenzimidazole with pentafluorobenzoyl chloride forms 1,2,3,4-tetrafluoro-12//-benzimidazo[2,1 -b, 3]benzo-thiazin-1,2-one (yield 50%), whose structure was confirmed by X-ray data (94JOC7688) (Scheme 165). 

Although an elusive compound because of its high reactivity, 1,4-benzo-thiazine has recently been prepared and shown to exist as the 2//-tautomer 3.13 Derivatives of 2//-l,4-benzothiazine, however, have been fully studied during the past decade because of their occurrence in trichochromes, pigments that are responsible for the color of feathers and hair thus tri-chochrome F, a violet pigment isolated from New Hampshire hens,... 

Similarly, N-arylsulfoximines and related species have been prepared by Pd-catalyzed coupling of a sulfoximine with aryl chlorides under the influence of microwave irradiation [72], Appropriately functionalized systems gave rise to benzo-thiazines directly in a one pot process. 

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