Benzothiazines, synthesis

A number of halogenated derivatives of 155, 160, and 165 have been prepared.129 For example, the thieno-1,2-thiazine analog 166 has been converted to eneamine derivative 167 which has been acylated (phosgene/ triethylamine) to afford acid chloride 168. Treatment of 168 with 2-aminopyridine gave 169 (Eq. 36). This process is completely analogous to the 1,2-benzothiazine synthesis depicted in Eq. (6). 

One of the most commonly encountered applications of Smiles rearrangements in synthesis is to prepare fused aromatic systems via three-step cascades displaying two nucleophilic substitutions with a Smiles rearrangement in between. These sequences have been adapted into more conplex three-conponent couplings such as the benzothiazine synthesis shown in Scheme 19.9. hi this process, 19 reacts first with acyl chloride 18 leading to 20 after substitution with 17. Heating the mixture under microwave conditions tri ers the Smiles rearrangement and the final Sj Ar toward 21. 

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... 

When bromoacetyl chloride is used instead of bromoacetic acid, the anilide 33 is formed at the first stage. Its subsequent cyclization also leads to 32. This approach to benzotellurazinone is similar to that developed for the synthesis of 2//-l,4-benzothiazin-3(4//)-ones (66CJC1247). Significantly, attempts to isolate the intermediate sulfonium salts analogous to 30 were unsuccessful. 

Figure 1. General structure of 2,1-benzothiazines 1 1.2 THE SYNTHESIS OF 2,1-BENZOTHIAZINES AND RELATED COMPOUNDS...

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. 

The synthesis of 177-2,1-benzothiazine 2,2-dioxide was pioneered by Loer and coworkers <66JOC3531> and also by the Rossi group <66AC(R)728 66AC(R)741>. The general class of compounds is represented in Figure 4. 

An improved synthesis of li/-2,l-benzothiazine 4(3i/)-one 2,2-dioxide 33 that results in a relatively high overall yield was developed by Lombardino s group <710PP33 72JHC315>. This general method offered an easier entry into the 2,1-benzothiazine 2,2-dioxide heterocyclic system <67JHC403>. Treatment of methyl A-benzyl-A-methylsulfonylanthranilate 35 with sodium hydride led to 1-benzyl-4-oxo-l//-2,l-benzothiazine-4(3/7)-one 2,2-dioxide 36 in 68% yield. Reduction of 36 gave 4-oxo-17/-2,1 -... 

The Harmata group s initial report concerned a one-pot, one-operation procedure <99AG(E)2419> for the synthesis of enantiomerically pure 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm <98TL5731 OOJOC169> for sulfoximine N-arylation. For example, treatment of ortho-bromobenzaldehyde 78 with enantiomerically pure N-H sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. 

Chiacchio and co-workers <97T13855> reported a stereoselective synthesis of 133 via an intramolecular 1,3-dipolar cycloaddition. Intermediate 132 was generated in situ by the reaction of tra .v-/V-(2-formylphenyl)-i -methyl-2-phcnylcthenc- l -sulfonamide 131 with N-methylhydroxylamine and afforded a tricyclic benzothiazine 133 in 51% yield (Scheme 36). 

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