Benzothiazines formation

The rationalization for the outcome of these cyclization reactions was based on minimizing steric interactions in the transition state leading to benzothiazine formation. For example, at least two possible transition states 101 and 102 could give rise to product 92 (or a diastereomer). Transition state 102 has gauche steric interactions that appear to be absent in the staggered transition state 101. This favors the latter and leads to the observed products 92 (Figure 8). 

Hydroxy-3,4-dihydro-2,l-benzothiazine 2,2-dioxide 15 can be synthesized in a convenient manner <94TL2911>. Blondet and co-workers used a cyclization of an ortho-(chloromethyl or carboxaldehyde) A-protected sulfonanilide 13 or 16 with sodium hydride in DMF to give the benzothiazine dioxide 14 or 17 in 35% and 47% yields, respectively (Scheme 4). Finally, removal of the methoxy group and hydrogenation led to the formation of 5-hydroxy-3,4-dihydro-2,l-benzothiazine 2,2-dioxide 15 in good yield over two steps. 

Table 1. Formation of 3,4-dihydro-2,l-benzothiazine 2,2-dioxides with A-alkyl 2...

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. 

Harmata and co-workers introduced a procedure for the reductive desulfurization of selected 2,1-benzothiazines with sodium amalgam, leading to the formation of the 2-alkylanilines in high yields <94S142>. This method is regioselective and general. As an example, alkylation of 187 followed by treatment with Na/Hg resulted in the formation of the aniline 188 in 68% overall yield (Scheme 50). 

Harmata and co-workers also discovered that 2,1-benzothiazines could be conveniently converted into 2-alkenylanilines by treatment with KDMSO in DMSO <91JOC5059 91T8855>. For example, the reaction of benzothiazine 185 with KDMSO for 20 minutes at 70 °C resulted in the formation of the 2-alkenyl sulfinamide 189 in 90% yield (Scheme 51). 

Nucleophilic Reactions.—Attack on Saturated Carbon. Selected examples of the Arbusov reaction include phosphorylation of the chloroacetophenones (1) to give phosphonates, which cyclized to (2) in the presence of acid chlorides,1 formation of the azodiphosphonate (3) from 2,2 -dichloro-2,2 -azopropane,2 3 and the reaction of 2-chloro-3,4-dihydro-3-oxo-2//-l,4-benzothiazine (4) with triethyl phosphite to give the 2-phosphonate (5), which is used as an olefin synthon.8 Bis(trimethylsilyl) trimethylsiloxymethylphosphonite (6) has been synthesized by silylation of hydroxy-methylphosphonous acid, and, as expected, undergoes a normal Arbusov reaction with alkyl halides to give the phosphonates (7).4 This series of reactions, followed by... 

In the condensations of o-aminohenzyl alcohol 376 or anthranilic acid 401 with 4,5-dichloro-l,2,3-dithiazolium chloride (Appel s salt) 402, imino-l,2,3-dithiazoles 403 were formed. Heating of the imino alcohol 403 (X = H2) in THE in the presence of NaH afforded an 11 1 mixture of 3,1-benzoxazine 404 and 3,1-benzothiazine 405 in moderate yield. Thermal cyclization of imino acid 403 (X = 0) resulted nearly quantitatively in formation of 3,1-henzoxazin-4-one 406 (Scheme 76) <1995CC1419, 1995J(P 1)2097, 1997SL704>. 

The condensation of 4-oxo-47f-3,l-benzothiazine-2-carbonitriles 572 with 1,2-dimethylhydrazine under micro-wave irradiation resulted in formation of 2-hydrazino-4/7-3,l-benzoxazine-4-thiones 573 and 5-oxo-4,5-dihydro-377-l,3,4-benzotriazepine-2-carbonitriles 574 (Equation 68). The ratio of 573 and 574 was strongly influenced by the substituents R -R methoxy substituents facilitated the formation of 574, while in their absence l,3-benzoxazine-4-thiones 573 were formed as the exclusive products <2005T8288>. 

A variety of methods exist for the formation of 1,2-thiazines via the construction of an S-N bond by nucleophilic attack of nitrogen onto a sulfur-bearing leaving group. For example, the reaction of aryl bromide 189 with potassium thiocyanate in the presence of copper(l) iodide and triethylamine affords benzothiazine 190, although in low yield and as a mixture with indoline by-product 191 (Equation 28) <2000JOC8152>. 

An alternative approach to N-S bond formation involves the aza-Wittig-type reaction of sulfoxides (Scheme 26) <2004SL101>. Initial Staudinger ligation of aryl azide 195 with triphenylphosphine afforded iminophosphorane 196, which was purified by column chromatography and then heated in anhydrous toluene, producing benzothiazines 62 and 197. The N-S bond was found to be rather sensitive to hydrolysis and cleavage to 198 was observed upon treatment of benzothiazines 62 or 197 with wet THF. 

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>. 

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. 

The 2//-l,4-benzothiazine 200 reacts with dichlorocarbene to form aziridine 201 (Equation 12) <2007S225>, and benzothiazine 202 underwent a [2+4] cycloaddition with a range of vinyl ethers (Equation 13) <1992CB1507>. A [2+2] cycloaddition was the initial step in the formation of 89 (Scheme 19) <1989JPR141>. 

Deprotonation of the A -acyl substituent of benzothiazines gives a nucleophile that reacts by deacylation with a second molecule of starting material (Equation 46) < 1980TL3001 >. Such anions also react with ketones in an erythro-selective aldol condensation (Equation 47) <1983TL3883>. The selectivity is due to the formation of a Z-enolate and the reaction was also extended to A -acylphenothiazines. 

O-protonated 3-azathiopyrylium forms 38 (Scheme 8). On the basis of H NMR spectra it was assumed that 2-cyanomethyl-l,3-benzothiazin-4-one exists in one of its three protonated forms (84H1677). In several papers (53AP437 57MI1 60MI1), the formation of crystalline hydrochlorides of 1,3-benzo-TA was mentioned these compounds proved to be unstable,... 

The carbonyl portion of 2-iminobenzo-TA 94 can be converted into the thioxo group with the formation of derivatives 261 (67PHA611) (Scheme 102). The analogous reactions are also known for monocyclic 1,3-thiazin-4-ones (67CJC939) and for 2,3-dihydro-l,3-benzothiazin-4-ones (55BSF-1518). 

Equation (48) <87T5357>. A mechanism similar to that commonly accepted for the formation of 2H-1,4-benzothiazines via condensation of /1-aminothiols with simple o- and p-benzoquinones was suggested. It was noted that the products (87 R3 = H) rapidly decompose to oligomeric materials whereas the others are much more stable to this presumed oxidative lability. 

Cycloaddition of 1,3-benzothiazines (423) to hydrazonyl halides 424 led (84H537) to the formation of examples (425) of the title compounds. 

Analogously, the reaction of 2-bromophenyl-A-methylsulfoximine 432 with terminal alkynes in the presence of a palladium catalyst results in the formation of both 1,2-benzothiazine 433 and 1,2-benzisothiazoles 434. A preference for the former is seen with alkylalkynes while the latter are preferentially formed with alkynylarenes <20050L143>. 

Several examples have been reported of similar ring closures with the formation of heterocyclic Y-oxides, Y-hydroxy compounds, or hydroxamic acids [55-58]. For the ring closure of 2-(2-nitrophenylthio)-acetic acid to 4-hydroxy-2Y-l,4-benzothiazine-3(4Y)-one the reduction in an ammonical buffer is preferable [59]. 

The 2-mercapto group was introduced following a two step method [127] of formation and alkaline cleavage of the corresponding iso-thiouronium bromides. Both S-[2//-l,4-benzoxazin-3(4i7)-on-2-yl]-isothiouronium bromide and S-[2/f-l,4-benzothiazin-3(4/7)-on-2-yl]-isothiouronium bromide were obtained. 

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