Benzothiazines compounds

Wadsworth-Emmons reaction of the phosphonate anion of a benzothiazine (compound 239, synthesis shown in Equation (23) has been reported <2004BML1477>. Compound 35 was formylated in a Vilsmeier reaction (Equation 20) <1972CPB1325>. 

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. 

Compound 34 can be synthesized by a Bamford-Stevens procedure from compound 33. Loer explored the cyclization of 32 with polyphosphoric acid (PPA), followed by decomposition of the tosylhydrazone to form the desired 177-2,1-benzothiazine 2,2-dioxide 34 in good overall yield (Scheme 8) <66JOC3531>. 

A new chiral benzothiazine ligand 205 was synthesized by Harmata and co-workers <06JOC3650>. It could be converted into a chiral molecular receptor 207 in a simple way. This chiral species 207 could be used as a new class of chiral molecular tweezers. The synthesis of 205 commenced with the protection of the commercially available compound 202, which was then coupled with f7tj-sulfoximinc 77b using the one-pot, one-operation procedure <99AG(E)2419> affording enantiomerically pure benzothiazine 204. This was followed by deprotection to produce benzothiazine 205 in good yield. 

Compounds containing a benzodioxole moiety are oxidized by CYPs to generate a carbene that forms a tightly bound complex with the heme iron, easily measurable by UV-Vis spectroscopy. There are numerous examples in the literature paroxetine, MDP alkylamines, MDP benzothiazines, MDP benzothiazolines and MDP piperazines (see Scheme 11.2) [54—60],... 

From Lys hydrochloride pyrolyzed in vacuo at 600°C for 8-10 min, a tricyclic compound 134 is formed in low yield (80TL2679). Cystine reacts with dopachrome to give an unstable product, but the methyl ester of dopachrome gave a stable pyrrolo[2,3-/i][l,4]benzothiazine 135 (87T5357). 

The extensive examinations of aromatic heterocvcles, such as benzoxa-zines, benzothiazines, and quinazolines, and the corresponding oxo derivatives may also have been due to the fact that the starting materials of the syntheses of these hetero compounds, such as salicylic acid or anthranilic acid and their derivatives, have been industrial products since the end of the nineteenth century. In contrast, the starting materials for the stereospecific syntheses of the related cycloalkane-fused heterocycles can generally be prepared only with some difficulty and did not become available commercially until more recently [90MI1, 91MI1 92ACH(129)107]. 

The synthesis and transformations of compounds 14-16, the 5,8-methano derivatives of benzoxazines, benzothiazines, and quinazolines, are also discussed in several cases ... 

Both naphthoquinones and anthraquinones bearing annulated benzothiazine rings, as illustrated by compounds (4.16), (4.17) and (4.18), absorb in the near-lR. Unfortunately, the naphthoquinones tend to have low stability and products from both ring systems are strongly coloured, limiting their areas of application. 

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. 

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>. 

There have been no recent reviews of the area and research in this field has increased. As in the earlier editions, the reactions of 1,3-thiazines will be considered before the synthetic approaches to them, and in each of the sections and subsections the compounds will be discussed in the order of decreasing number of double bonds in the ring. Thus, 1,3-thiazines and benzothiazines will take precedence over their reduced forms and thiazinones, thiazinediones, and their derivatives will normally be dealt with last. 

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