Synthesis from 1,4-Benzothiazines

Synthesis from Benzothiazines. (See Volume 1, p. 412.) A preliminary communication has briefly reported the ring-contraction of 3-phenyl-2iT-l,4-benzothiazin-2-one (34) to 2-carboxy-2-phenylbenzothiazoline (35) by the action of potassium methoxide, and to 2-phenylbenzothiazole (36) on pyrolysis.  

Numerous benzothiazoles continue to be produced by well established routes they are briefly listed in the Table. 

Physical Properties.— The solubility (6.0—6.3 x 10 moll at 20 °C) and acid dissociation constant (pJiT, 6.8—7.2) of 2-mercaptobenzothiazoIe have been determined by several methods.  

Simov and A. Antonova, Compt. rend. Acad. bulg. Sci., 1969, 22, 1027 Chem, Abs., 1970, 73, 120 552k). 

Ignatov and P. A. Pirogov, Khim. geterotsikl. Soedinenii, 1970, 89 Chem. Abs., 1970, 72, 100 584y). 

Experiments showing positive incorporation of [ C]-p-benzoquinone into live Japanese fireflies, Lucioia cruciata, indicate that the benzothiazole nucleus in firefly luciferin does arise in the manner previously suggested. 

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One failed synthesis using this method was also reported instead of the thiazine ylide its thermolysis products (see Scheme 11) were obtained, even if the reaction was performed at —78°C. The synthesis was also extended from benzothiazines to 277-1,4-thiazines, but these products were unstable <1991J(P1)2249>. 

When dihydro-1,3-benzothiazine 203 was allowed to react with KF in DMF (or NaOMe in MeOH), an open ring tautomeric isomer 204 was formed. When 2-bromoacetophenone 169 (R = H) is present in the reaction medium, a mixture of two diastereoisomers of 206 was obtained (75%) after enolate/imine addition of intermediate 205 with a slight excess of the m-isomer 206a over the trans-isomer 206b (Scheme 35). The same result was obtained by a synthesis from [6+1] fragments, reported in the next section <1995TL753>. 

Synthesis of 2-Allylanilines. The synthesis of 2-allylanilines has been reported to proceed from benzothiazines derived from the reaction of (1) with alkenes.Alkylation of the corresponding organolithium compounds using iodomethyltrimethylsilane as the electrophile followed by treatment with fluoride affords 2-allylsulfinamides which can be hydrolyzed to the corresponding anilines (eq 13). 

Benzothiazin-4-ones, dihydrosynthesis, 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... 

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... 

Harmata and Herron <91T8855>, discovered that the adducts from Lewis-acid mediated synthesis of 2,1-benzothiazines could have use in the synthesis of the other heterocyclic... 

Piroxicam Piroxicam, 1,1 -dioxid-4-hydroxy-2-methyl-iV-2-pyradyl-2//-1,2-benzothiazine-3-carboxamide (3.2.78), is synthesized from saccharin (3.2.70). Two methods for saccharin synthesis are described. It usually comes from toluene, which is sulfonated by chlorosulfonic acid, forming isomeric 4- and 2-toluenesulfonyl chlorides. The isomeric products are separated by freezing (chilling). The liquid part, 2-toluenesulfonyl chloride (3.2.68) is separated from the crystallized 4-toluenesulfochloride and reacted with ammonia, giving 2-toluenesul-fonylamide (3.2.69). Oxidation of the product with sodium permanganate or chromium (VI) oxide in sulfuric acid gives saccharin—o-sulfobenzoic acid imide (3.2.70) [123-126]. 

For the synthesis of the benzosulfonamide subclass of 1,2-thiazines, introduction of the sulfonyl chloride has been effected by treatment of electron-rich aromatic compounds with chlorosulfonic acid. Such is the case for 1,2-benzothiazine 1,1-dioxides 181 which have been accessed from phenylethylamines 182 in 67-92% yields via intermediate 183 (Scheme 23) <1998SC2137>. 

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>. 

Directed ortV o-methyl lithiation/cyclization of AT-acyl-o-toluenesulfonamides 229 provides a second approach to the synthesis of 1,2-benzothiazine 1,1-dioxides 230 via creation of the bond between C-3 and C-4 (Scheme 31) <1999CPB1730>. The best yields of cyclization products are achieved when the R group on the amide 229 is bulky. In the case of substrates with small R groups (Me, Ph, etc.), products 231 and 232 are formed from attack of the Bu"Li on the carbonyl carbon. 

Perfluoro(3-isothiocyanato-2-methyl-2-pentene) reacts with N-nucleophiles to produce a series of fluoroalkyl-substituted 6/f-l,3-thiazines <1997RJO720>. The acid-catalyzed cyclization of thioureas immobilized on Wang (X = O) or Rink resin (X = NH) provides a convenient route to a wide range of 2-amino-4/7-benzothiazine derivatives 212 (Scheme 23) <20000L3667>. The thioureas are obtained in four steps from 2-nitrocinnamic acids. A general synthesis of 2-alkylidene-4-imino-l,4-dihydrobenzo-l,3-thiazines 213-215 involves treatment of 2-isothiocyanato-benzonitrile with acidic methylene compounds under basic conditions <2003SL1503>. The ( )-isomers are the predominant isomers formed. 

Benzothiazines (542) may rearrange into benzothiazoles (543) by oxidation in the presence of a base (Scheme 291). This type of synthesis was prompted by the suggestion that the biosynthesis of firefly luciferin (544) could result from a similar rearrangement of the benzothiazine formed by the condensation of p-benzoquinone and cysteine (75CC42). The... 

Various other routes have been reported to give the 1,4-benzothiazine ring, some of which are summarized below. Synthesis of the 1,4-benzothiazine 1,1-dioxides (105) from benzaldimine and methylene sulfone ylide has been reported.147... 

A facile base-catalyzed cyclization can be induced in y-carboxamidosulfonates or y-carbo-alkoxysulfonamides, leading to the 3-oxo-l,2-thiazine 1,1-dioxide (134) (Scheme 25). These cyclization reactions leading to 1,2-thiazines are relatively general <91JOC3549>. A variation of this strategy has been successfully utilized in the synthesis of l,2-benzothiazin-3-ones (135) from... 

There are a few examples of 1,2-thiazine synthesis of this type which are of importance. The most noteworthy is the preparation of 4-hydroxy-2/f-l,2-benzothiazine 1,1-dioxides (199) from the benzisothiazolinone (200) <81AHC(28)73>. This general procedure can be extended to the preparation of 2-alkyl-4-hydroxybenzothiazines. The treatment of A-methylsaccharin (201) and an alkyl chloro-acetate with NaH in DMSO or DMF affords a 76% yield of the 1,2-benzothiazine (202) (Scheme 39) <83JOC3601, 86CCC 1113,86FES819>. 

Synthesis of 2-AlkenylaniIines. Three methods have been reported for the conversion of benzothiazines into 2-alkenylanilines. In the first, benzothiazine derived from the reaction of 1 with alkenes were treated with potassium dimsylate (KDMSO) and... 

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