1,4-Benzothiazine intermediates

Ty initiates melanin synthesis by the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (Dopa) and the oxidation of dopa to dopaquinone. In the presence of L-cysteine, dopaquinone rapidly combines with the thiol group to form cysteinyldopas, which undergo nonen-zymatic conversion and polymerization to pheomelanin via benzothiazine intermediates. In the absence of thiol groups, dopaquinone very rapidly undergoes conversion to dopachrome, which is transformed to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) by dopachrome tautomerase. Alternatively, dopachrome is converted nonenzymatically to 5,6-dihydroxyindole (DHI). Oxidation of DHICA and DHI to the corresponding quinones and subsequent polymerization leads to eumelanins. It is still questionable if Ty is involved in this step. 

Tire mesoionie l,2,4-triazolo[l,5-c]quinazolines 59 were obtained upon eyelization of the 4-thioxo-l,3-benzothiazines 57 with thioearbohydra-zine through the intermediate 3-(4-thiosemiearbazido)pyrimidines 58 (86-JHC43) (Seheme 19). 

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. 

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. 

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). 

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... 

The reaction of methyl thiosalicylate with DMAD yields the Michael adduct (358), which undergoes cyclization on ammonolysis to give methyl 3-hydroxybenzo[fc]thiophene-2-carboxylate (360) through the postulated intermediate 359 (Scheme 55). On the other hand, the reaction of o-mercaptobenzamide with DMAD gives a 1 1 adduct (193) which is converted in the presence of base into the l,3-benzothiazin-4-one derivative (194) [Eq. (31)]. In the reaction of methyl... 

Oxo-l,2-benzothiazine 1,1-dioxide 139 undergoes aldol condensation reactions upon deprotonation with NaOMe and treatment with an aldehyde 140 (Equation 19) <1992SC2621>. The intermediate aldol adducts are then dehydrated with acetic acid to afford condensation products 141 <2000JME2040>. 

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>. 

An anionic equivalent of the Friedel-Crafts cyclization reaction has been developed for the formation of the C /C-5 bond of the 1,2-benzothiazine structure (Equation 35 Table 5) <1997SL1079>. In this reaction, directed metalation of sulfonamide-substituted aromatic systems 233 with an excess of LDA affords aryl lithium species 234 in a regiocontrolled fashion. This intermediate then reacts in situ with a proximal amide to form l,2-benzothiazine-4-one 1,1-dioxides 235. The yields of this transformation appear to be highly dependent upon the substitution pattern in 233. The authors attribute the low yield when = methyl and = H to a-deprotonation of the amide moiety. 

Cycloaddition of benzyne intermediates with aminothiazadienes provide access to substituted 2,4-diamino-4//-l,3-benzothiazines 196 in high yields. The benzynes are prepared by the treatment of (phenyl)[o-(trimethylsilyl)aryl]-iodonium triflates with 1.5 equiv of tetrabutylammonium fluoride (Scheme 20). Interestingly, 3-substituted-l,2-benzisothiazoles 197 are obtained when 4 equiv of tetrabutylammonium fluoride is used <2005H(65)1615>. 

A similar pathway seems operative in the 2-substituted benzo[6]thiophene case also <79JCS(Pi 13207). Here, however, the spiro intermediate rearranges to both the benzothiazine (258) and benzothiazole (259), the two products being isolated in almost equal amounts (Scheme 70). The dihydrobenzo[6]thiophene unit present in (259) does not seem to be dehydrogenated as the dihydrothiophene unit does (Scheme 69). 

The /3-chlorobenzothiazepinone 82 underwent solvolysis in dimethylformamide (DMF) solution, involving a thiir-anium intermediate 83, and affording the ring-contracted benzothiazine derivative 84 (Scheme 9) <2001CR925>. 

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>. 

Reaction of 9-(carboxymethylene)tetrahydropyridopyrimidin-4-one 546 (R = COOH) and 2-aminothiophenol gave 9-(benzothiazin-2-yl)tetrahy-dropyridopyrimidin-4-one 550 as a mixture of erythro and threo isomers (90JHC247). The addition was accompanied by spontaneous cyclization between the amino and carboxyl group of intermediate 549 to the yield 9-(benzothiazin-2-yl) moiety. 

Attempts to acylate 2-unsubstituted thiazolylium salts with dialkylacylphosphonates under basic conditions yield an intermediate (72) which rearranges with ring expansion affording a 1,4-thiazine (73 Scheme 38). Under the same reaction conditions, 2-unsubstituted benzothiazolylium salts give 1,4-benzothiazines of type (74 Scheme 39). 

Catalytic hydrogenation of 3 -phenyl-2//-1,4-benzothiazine (551) in the presence of palladium-charcoal or Raney nickel affords 2-methyl-2-phenyl-2,3-dihydrobenzothiazole (553). The reaction is probably initiated by the hydrogenolysis of the C—S bond of (551) resulting in the intermediate thiophenol (552) which cyclizes to the final benzothiazoline (553) (69JHC635). 

Sulfur blue dyes are often made using an organic solvent such as n-butanol, in what is known as the solvent reflux process. Examples are C.I. Sulfur Blue 9 and Sulfur Blue 13. In this case, intermediate structures are indophenols (e.g., 55). See Fig. 13.133. Similarly, sulfur dyes containing benzothiazine groups can be made from... 

The pyrazolo[5,l-c] 1,2,4-triazoles 56 have recently been prepared (86JHC43) from 8-thioxo-l,3-benzothiazines (52) and thiocarbohydrazide (51) through the mesoionic intermediates (53) and triazolothiadiazines (54). 

Photolysis of diazo compounds 613 yields 1,4-benzothiazines 614 (15-30%) by a [l,2]-N-shift of the carbene intermediates 615 along with methyl-enebenzothiazolines (23-42%) by [l,2]-H-shift (85BSB499). 

Very little is known about the chemistry of later steps of in vitro phaeomelanogenesis beyond the benzothiazine stage. Radiotracer studies (160) and model experiments (161) suggest that the alanyl side chain of the postulated intermediates does not take part in the polymerization process, which probably proceeds via an enamine-imine type condensation of the 1,4-thiazine ring system rather than by oxidative coupling at positions 2 and 8 and subsequent ring closure of the alanyl side chain as previously suggested by Minale et al. (162,163). 

When 4//-l,3-benzothiazine-4-thiones react with propargylamine imidazoles form in 53-72% yields by way of an amidine intermediate <87LA103>. Oxidation of the dehydration product of creatine gives creatone (205) with concurrent Dimroth rearrangement (Scheme 138) <82BCJ1912, 87BCJ4115>. 

Another synthetic route to l,2-benzothiazin-4-one 1,1-dioxides produced 13-19% of compound 11 when o-diazoacetylbenzenesulfonamide (13 (R = Me) was cyclized by formic acid in acetonitrile10 (Eq. 3). A carbene was suggested as an intermediate in this transformation.10 Much better yields (43-70%) of the corresponding Af-phenyl compound (14) were obtained when the corresponding /V-phenylsulfonamide (13 R = Ph) was cyclized.10... 

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. 

Sodium borohydride reduction of either 3-acetyl- or 3-benzoyl-4-hydroxy-2H-l,2-benzothiazine 1,1-dioxides (e.g., 21, 89, 93) produced the corresponding 3-alkylidene compounds 108.4 Evidently the intermediate alcohols are dehydrated under the conditions of the reaction. The authentic ben-zylidene derivative 108 (R1 = Ph, R2 = Me), prepared4 by another route (Eq. 20), was identical to the product isolated from the borohydride reduction of compound 107. 

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