1.4- Benzothiazine ring

The 1,4-benzothiazine ring is the basic unit for the phaeomelanins and trichochrome melanin pigments found in mammals, particularly in red hair... 

Trichochromes E and F are based on the 2H-1,4-benzothiazine ring, while trichochromes B and C are mixed systems, with both 1,4-benzothiazine and l,4-benzothiazin-3-one fragments. These may be extracted from red hair and feathers under alkaline conditions.31,32 Apparently33 only trichochromes B and C occur in red feathers, and trichochromes E and F, reportedly isolated from this source, arise as artifacts. The chromophore in the trichochrome... 

A thermally stable polymer (47) based on the 1,4-benzothiazine ring has been prepared, using a bis-a-halo ketone and the diphenyl derivative 46. This polymer has a molecular weight of between 10,000 and 20,000 and is stable up to 350°C in air.97... 

Reactions of 2-aminobenzenethiol with a variety of other compounds provide the 1,4-benzothiazine ring system. An early report by Langlet claimed that the reaction with ethylene dibromide gave dihydro-1,4-benzothiazine (51).102 However, more recent work by Santacroce indicates the product is 2-methylbenzothiazole (52).94 However, 1,2-dichloroalkenes have been employed successfully by Kaul in the preparation of heterocyclic dye 53 having the l,4-benzothiazin-3-one ring.33... 

It has been found possible to construct the 1,4-benzothiazine ring by direct interaction of bis-(2-aminobenzene) disulfide (96) with carbonyl compounds.139,140 The reaction is most efficient when conducted under a nitrogen atmosphere with a 1 1 ratio of reactants otherwise, the principle products are benzothiazoles. While reduction of the benzothiazine 97 with sodium borohydride gives a stable dihydro derivative, the unsaturated benzothiazines themselves were prone to autoxidation, giving rise to benzothiazoles and benzothiazine sulfoxides.141... 

The postulated mechanism for the formation of the 1,4-benzothiazine ring involves the formation of the imine 98, followed by cleavage of the disulfide bond (see Section VI,A,5). This reaction is general for keto compounds, / -keto esters,142 and acetylenic ketones and esters143 the heterocycle is produced in yields of 70-80%. 

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... 

Triethylamine 1,4-Benzothiazine ring and N-condensed benzothiazoline ring from o-aminomercaptans... 

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. 

The two preceding sections have discussed replacement of the benzene ring of a 1,2-benzothiazine with other aromatic or heteroaromatic systems. This section details reactions of 1,2-benzothiazines leading to more complex tri- and tetracyclic 1,2-benzothiazine ring systems. 

Literature reports on heterocyclic compounds containing a 1,2- or 2,1-benzothiazine ring have appeared in increasing numbers in recent years. This trend is likely to continue as a result of the anti-inflammatory activity of 4-hydroxy-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxides (the oxicams ). 

All of the synthetic routes reviewed so far have primarily involved the use of sulfur as a nucleophile. Sulfur can also act as an electrophile in the formation of precursors of the benzothiazine ring system. Reaction of sulfenyl chloride with ketones gives / -keto sulfides. The acetophenone adduct 90 has been cyclized with stannous chloride and hydrogen chloride in acetic acid to give 3-phenyl-6-chloro-2H-1,4-benzothiazine (91).135... 

Benzylsulfonamides (138) and aldehydes can be combined under strongly acidic conditions to afford 2,3-benzothiazine 2,2-dioxides (139) via a preparative scale intramolecular sulfonamido-methylation. This highly effective procedure provides a rapid entry into the 2,3-benzothiazine ring skeleton (Scheme 26). When this reaction is carried out with weak acids or short reaction times, uncyclized intermediates can be isolated <86JHC1701>. The treatment of 3-nitrobenzylamine derivatives (140) with NaOH in DMSO leads to 2,3-benzothiazines (141a) and (141b) by an intramolecular nucleophilic aromatic substitution (Scheme 26) <92S57i>. 

The parent 1,4-thiazine exists exclusively as the 2H tautomer 86, independently of the medium used, as do its pyrimidino-fused derivatives 87 (76AHCS1, p. 80 84MI2). However, the equilibrium could be affected significantly by a substitution pattern in the thiazine ring, as was shown in the example of 1,4-benzothiazine. Thus, 3-phenyl-1,4-benzothiazine 88 (R = H, R = Ph) is present in aqueous hydrochloric acid as a 4 1 mixture of 2H (88a) and AH (88b) isomers... 

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