3.4- Dihydro-2,1 -benzothiazin-2-ones

Piperazine NH group of 9-fluoro-10-(l-piperazinyl)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-<7e]-l,4-benzothiazine-6-carboxylate was reacted with 4-nitrophenylsulfonyl chloride, 2,6-dichloropyrazine, 2,6-dichloropyridine in DMF in the presence of pyridine, and with 4-nitrophenyl isothiocyanate in aqueous acetone in the presence of KOH (01MIP13). A side chain amino group on a 2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazin-7-one skeleton was acylated (OOMIPIO). 

Isoxicam Isoxicam, 1,1-dioxide 4-hydroxy-2-methyl-A-(5-methyl-3-isoxazolyl)-2/7-l,2-benzothiazine-3-carboxamide (3.2.80), is synthesized analogous to piroxicam, using ami-dation of 1,1-dioxide 3-methoxycarbonyl-3,4-dihydro-2-//-l,2-benzothiazine-4-one (3.2.78) in the last stage with 3-amino-5-methylisoxazole, instead of 2-aminopyridine [127-130]. 

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. 

The l,3,4-oxadiazin-6-one (240) undergoes cycloaddition followed by a remarkable rearrangement to give the triazole A(-imine 241 and an open-chain product (136). Cycloadditions have also been carried out with the following ring systems 1,2-dihydroisoquinoline (242) (137) dihydro-1,3-oxazine (243) (138,139), 2H-, 3-benzothiazine (244) (140,141), and 27/-l-pyran-2-thione (245) (142). 

Reaction of 2-cyanomethyl-4H-l,3-benzothiazin-4-one with benzoylace-tonitrile at 160°C yielded 8-cyano-7-imino-9-phenyl-7//,ll//-pyrido[2,l-6][l,3]benzothiazin-l 1-one (85MI1 86MI2). Reaction of 2-ethoxy-2,3 dihydro-4//-l,3-benzothiazin-4-one with 1,2,3,4-tetramethylbutadiene and 2,4-dimethyl-l,3-pentadiene in the presence of boron trifluoride in diethyl ether gave rise to 6,7,8,9-tetramethyl- and 7,9)9-trimethyl-5a,6,9,ll-tetrahydropyrido[2,l-6][l,3]benzothiazin-ll-one, respectively (73JHC149). 

Dihydro-l,4-benzoxazin-3-ones and -benzothiazin-3-ones are synthesized by the reductive cyclodehydration of 2-nitrophenoxyacetic acids or their thioxy equivalents and as these heterocycles have an active methylene group it is a simple matter to prepare 2-substituted derivatives by condensation reactions with aldehydes and other carbonyl compounds (Scheme 123) (79AP302). 

Benzothiazin-4-ones, dihydro-synthesis, 3, 1028 Benzothiazole, acetoacetylamino-azo pigments from, 1, 334 Benzothiazole, 2-acyl-synthesis, 6, 265 Benzothiazole, 2-alkoxy-synthesis, 6, 323 Benzothiazole, 2-alkyl-synthesis, 6, 265 Benzothiazole, 2-alkyl-6-nitro-reactions... 

The carbonyl portion of 2-iminobenzo-TA 94 can be converted into the thioxo group with the formation of derivatives 261 (67PHA611) (Scheme 102). The analogous reactions are also known for monocyclic 1,3-thiazin-4-ones (67CJC939) and for 2,3-dihydro-l,3-benzothiazin-4-ones (55BSF-1518). 

Optically active pipecolic acid and its derivatives can be prepared via 4-phenylpyrido[2,l-c][l,4]oxazin-l-one derivatives. Representatives of the third generation of quinoline-3-carboxylic acid antibacterial agents ofloxacin (19), its levorotatory enantiomer, levofloxacin (20), and rufloxacin (21) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (22) is under development. Other 10-aryl-9-fluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzox-azine-6-carboxylic acids and 7//-pyrido[l,2,3-de]-l,4-benzothiazine-6-carboxylic acids exhibit mammalian topoisomerase II inhibitory activity. 

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>. 

Shah A, Naliapara Y, Sureja D, Motohashi N, Kurihara T, Kawase M, Satoh K, Sakagami H, Molnar J (1998) Biological activity of 6,12-dihydro-l-benzopyrano[3,4-b][l,4]benzothiazin-6-ones. Anticancer Res 18 61-64... 

R = H, R = CHS) with two more equivalents of base.215 When R in compounds of type (60) contains a halogen in the ou-position (60d),217 a tricyclic system including an enol ether (e.g., 2,3-dihydro-6//-oxepino-[c][l,2]-benzothiazine-5(4//)-one-7,7-dioxide)218 is formed. 

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-l//-2,l-benzothiazine-4(3//)-one 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... 

Unexpectedly, the 3-acetyl compound was deacylated when heated in benzene with ethylene glycol in the presence of an add.6 The 4-ketal produced was then readily cleaved by dilute hydrochloric acid to give 3,4-dihydro-2H-l,2-benzothiazin-4-one 1,1-dioxide (10). As expected, Af-methylation of compound 10 produced 2-methyl-3,4-dihydro-2W-l,2-benzothiazin-4-one... 

Ring expansion of 3-bromomethyl-l,2-benzisothiazole 1,1-dioxide (15) by sodium ethoxide produced 3,4-dihydro-2H-l,2-benzothiazin-4-one (10) in 66% yield.11 The favored mechanism involves a three-membered cyclic intermediate (16) opened by ethoxide attack on the ether portion of 16 (Eq. 4).11 This synthetic route would appear to be preferred for preparing the ketone 10. 

Several synthetic approaches to the l,2-benzothiazin-3-ones have been described. Usually, an ortho-substituted sulfonamide was cyclized to form the thiazine ring. For example, Lombardino and Wiseman14,38 treated /V-methyl-o-toluenesulfonamide (45) with butyllithium the dianion with CO 2 produced o-sulfamoylphenylacetic acid 46 which was cyclodehydrated to 3,4-dihydro-2-alkyl-l,2-benzothiazin-3(2H)-one 1,1-dioxide (47) in good yield (Eq. 10). This same reaction sequence was applied to analogs of 47 such as the 7-methyl, the 7-chloro, and the 2-benzyl derivatives.38... 

Catsoulacos has synthesized 2-substituted 3,4-dihydro-6,7-dimethoxy-l,2-benzothiazin-3(2W)-one 1,1-dioxides (58) chlorosulfonation of 3,4-... 

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