Synthesis of enantiomerically pure 2,1-benzothiazines

The Harmata group has also developed a route to enantiomerically pure 2,1-benzothiazines. The process involves the /V-arylation of sulfoximines using the Buchwald-Hartwig reaction conditions, 02MI3 99JOM(576)125 a reaction first reported by Bolm 

7 Heterocyclic Ring-fused Thiazines and Ring-fused 2,1-Benzothiazine Derivatives 

The first synthesis of pyrazolo[5,l-c]-l,2,4-thiadiazines 116 and pyrazolo[3,4-c]-l,2-thiazines 118 was reported by Aiello and co-workers 76JHC615 . Compound 115 was heated five degrees above its melting point to afford the novel ring system 116. However, compound 117 gave compound 118 when treated with triethylamine. 

134a Ar = pTol 135a Ar = pTol, 91% 136a Ar = pTol, 50% 

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 

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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. 

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