New Insight into Dearomatization and Decarbonylation of Antitubercular 4H‐Benzo[e][1,3]thiazinones: Stable 5H‐ and 7H‐Benzo[e][1,3]thiazines

8‐Nitro‐4H‐benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds’ antimycobacterial properties are described. Reactions of 8‐nitro‐2‐(piperidin‐1‐yl)‐6‐(trifluoromethyl)‐4H‐benzo[e][1,3]thiazin‐4‐one and the clinical drug candidate BTZ043 with the Grignard reagent CH3MgBr afford the corresponding dearomatized stable 4,5‐dimethyl‐5H‐ and 4,7‐dimethyl‐7H‐benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X‐ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non‐planar 4H‐benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH3)2S ⋅ BH3. Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays. The importance of carbonyl: Reactions of the antituberculosis drug candidate BTZ043 and its 2‐piperidinyl derivative with the Grignard reagent CH3MgBr afforded the dearomatized stable 4,5‐dimethyl‐5H‐ and 4,7‐dimethyl‐7H‐benzo[e][1,3]thiazines, which were structurally characterized by X‐ray crystallography. Reduction of the BTZ carbonyl group was achieved with the reducing agent (CH3)2S ⋅ BH3. Both chemical transformations resulted in loss of antimycobacterial activity.