Synthetic approaches to 2-aryl/hetaryl- and 2-(hetaryl)ylidene derivatives of fluorinated 1,3-benzothiazin-4-ones 96 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 3. 01 Emiliya V. Nosova, Olga A. Batanova, Nataliya N. Mochulskaya, Galina N. Lipunova Chimica Techno Acta. 2020. Vol. 7, no. 3. P. 96–103. ISSN 2409–5613 Emiliya V. Nosova,ab* Olga A. Batanova,a Nataliya N. Mochulskaya,a Galina N. Lipunovab a Ural Federal University 620002, 19 Mira St., Ekaterinburg, Russia b I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of Russian Academy of Sciences, 620990, 22 Kovalevskaya St. / 20 Akademicheskaya St., Ekaterinburg, Russia *email: emilia.nosova@yandex.ru Synthetic approaches to 2‑aryl/hetaryl‑ and 2‑(hetaryl)ylidene derivatives of fluorinated 1,3‑benzothiazin‑4‑ones  A series of 2-hetaryl- and 2-(hetaryl)ylidene substituted 5-fluoro-8- nitro-1,3-benzothiazin-4-ones was synthesized by interaction of 2,6-difluoro- 3-nitrobenzoylisothiocyanate with C-nucleophiles. Cyclocondensation of poly- fluorobenzoylchlorides with aryl and hetaryl thioamides represents new approach to 1,3-benzothiazin-4-ones. Some compounds proved to be promising for further development of tuberculostatic agents. Keywords: 1,3-benzothiazin-4-ones; 2-fluorobenzoylchloride; 2-fluorobenzoyl-isothiocyanate; indole; pyrrole; cyanomethylbenzimidazole; benzoylmethylbenzimidazole; thioamide; cyclocon- densation; tuberculostatics. Received: 28.06.2020. Accepted: 25.08.2020. Published: 07.10.2020. © Emiliya V. Nosova, Olga A. Batanova, Nataliya N. Mochulskaya, Galina N. Lipunova, 2020 Introduction Many synthetic benzothia- zines are biologically actives, which play an  important role in  treatment of  vari- ous diseases. Some 2-amino substi- tuted 1,3-benzothiazin-4-ones (2-ami- no-1,3-benzothiazinones) represent a  promising new class of  antitubercular agents [1]. Other 1,3-benzothiazin-4-one derivatives, mostly 2-aryl and 2-(pyridin- 2-yl) ones, are attractive due to their abil- ity to suppress an oxidative stress-induced cardiomyocyte apoptosis [2]. Synthetic approaches to  2-amino-1,3-benzothi- azin-4-ones are sufficiently developed, whereas not many ones are available for incorporation of C–C bond into position 2 [3]. The  synthetic methods are limited to the following: • interaction of  2-mercaptobenzoic acids with aryl/hetaryl nitriles [2]; • rearrangement of N-arylthiomethy- laroylamides catalyzed by phospho- rus oxychloride, followed by oxida- tion of 4H-1,3-benzothiazines with potassium permanganate [4]; • addition of  C-nucleophiles to 2-fluorobenzoylisothiocyanates and subsequent intramolecular conden- sation [5]. The last approach opens wide oppor- tunities for modification of  position 2 of 1,3-benzothiazin-4-ones. Previously we 97 studied the interaction of polyfluorobenzo- ylisothiocyanates with CH-reactive benzi- midazoles [5], 2,6-difluorobenzoylisothio- cyanate with the same benzimidazoles and 2-cyanomethylpyridine [6], o-fluoroben- zoylisothiocyanates with N-methylpyrrole and N-methylindole [7]. We presented only one example of  2-indolyl-5-fluoro- 8-nitro-1,3-benzothiazin-4-one in recent paper [8]. In this article, we wish to report new data on 2-substituted 5-fluoro-8- nitro- 1,3-benzothiazinones and introduce effi- cient synthetic approach to 2-aryl/hetaryl derivatives of  1,3-benzothiazin-4-ones based on cyclocondensation of  poly- fluorobenzoyl chlorides with thioamides. Experimental 1H and 19F NMR (nuclear mag- netic resonance) spectra were recorded in  dimethylsulfoxide-d6 (DMSO-d6) on the  spectrometer “Bruker-Avance-400” (400 MHz), using tetramethylsilane as in- ternal reference for 1H NMR and CFСl3 for 19F NMR. Mass spectra were recorded on a SHIMADZU GCMS-QP2010 Ultra instrument with electron impact ionization (EI) of the sample. Microanalyses (C, H, N) were performed using the Perkin — Elmer 2400 elemental analyzer. Melting points were measured on the Stuart melting point apparatus SMP10 (AC/DC input 230 V AC, Merck supplier). 2,6-Difluorobenzoic acid 1, 2,3,4,5-te- trafluorobenzoyl chloride 10a and pen- tafluorobenzoyl chloride 10b were purchased from Merck (CAS numbers 385-00-2, 94695-48-4, 2251-50-5). 3-Ni- tro-2,6-difluorobenzoic acid 2 was syn- thesized according to  the  literature [9]. Procedure for toluene solution of 2,6-di- fluoro-3-nitrobenzoylchloride 3 was re- ported [8]. 2-Benzoylmethylbenzimidazole was prepared from 2-methylbenzimidazole [5], 2-cyanomethyl-benzimidazole was synthesized by condensation of ethyl cy- anoacetate with o-phenylenediamine [10]. Thioamides 11 were prepared by the addi- tion of hydrogen sulfide to the correspond- ing nitriles [11]. 5‑Fluoro‑8‑nitro‑2‑(1‑methylpyrrol‑ 2‑yl)  — 1,3‑benzothiazin‑4‑one (5). The  solution of  ammonium isothiocy- anate (0.4758 g, 6.26 mmol) in  acetoni- trile (10 mL) was added to toluene solution of 2,6-difluoro-3-nitrobenzoylchloride  3 (0.88 mL, 6.26 mmol). Reaction mixture was stirred at 40 °С for 5 min, the precipi- tate of NH4Cl was filtered off and 1-meth- ylpyrrole (0.761 g, 9.39 mmol) was added to a solution of 2,6-difluoro-3-nitrobenzo- ylisothiocyanate 3. The mixture was stirred at room temperature for 3 h, the precipitate of benzothiazinone 5 was filtered off and washed with hot ethanol (10 mL). Yield 1.72 g (90%), mp 194–196 °С. 1Н NMR, δ (ppm), J (Hz): 4.09 s (3Н, СН3), 6.30 dd (1Н, H4’, 3JHH 4.1, 4JHH 2.3), 7.29 dd (1Н, H 3’, 3JHH 4.2, 4JHH 1.3), 7.37 m (1Н, H 5’), 7.62 dd (1Н, Н6, 3JHH 9.2, 3JFH 9.4), 8.70 dd (1Н, H7, 3JHH 9.2, 4JFH 4.5). 19F NMR, δ (ppm), J (Hz): — 99.05 dd (1F, 3JFH 9.5, 4JFH 4.0). MS (EI), m/z (Irel (%)): 305 [M] + (14), 106 (100), 105 (15). Found, %: C 51.17; H 2.60; N 13.74. С13H8FN3O3S. Calculated, %: C 51.15; H 2.64; N 13.76. Compounds 6–9 were synthesized by the same method. 5‑Fluoro‑8‑nitro‑2‑(5‑methoxy‑ 1‑methylindol‑3‑yl) — 1,3‑benzothiazin‑ 4‑one (6). Yield 80%, mp 274–276 °С. 1Н NMR, δ (ppm), J (Hz): 3.83 s (3Н, NСН3), 3.93 s (3Н, OСН3), 7.01 d (1Н, Н 6’ , 3JHH 98 8.8), 7.54 d (1Н, Н7’, 3JHH 8.8), 7.65 dd (1Н, Н6, 3JHH 9.3, 3JFH 9.5), 7.97 s (1Н, Н 4’), 8.66 s (1Н, H2’), 8.70 dd (1Н, H7, 3JHH 9.3, 4JFH 4.3). 19F{1H} NMR, δ (ppm):  — 99.27 s. MS (EI), m/z (Irel (%)): 385 [M] + (31), 187 (12), 186 (100), 171 (41), 143 (28). Found, %: C 56.13; H 3.15; N 10.87. С18H12FN3O4S. Calculated, %: C 56.10; H 3.14; N 10.90. 5‑Fluoro‑8‑nitro‑2‑(2‑methylindol‑ 3‑yl) — 1,3‑benzothiazin‑4‑one (7). Yield 91%, mp 207–209 °С. 1Н NMR, δ (ppm), J (Hz): 2.87 s (3Н, СН3), 7.25 m (2Н, С6Н4), 7.45 m (1Н, С6Н4), 7.66 dd (1Н, Н 6, 3JHH 9.3, 3JFH 9.6), 8.34 m (1Н, С6Н4), 8.71 dd (1Н, H7, 3JHH 9.3, 4JFH 4.6), 12.5 br. s (1Н, NH). 19F{1H} NMR, δ (ppm): — 98.42 s. MS (EI), m/z (Irel (%)): 355 [M] + (21), 157 (12), 156 (100), 155 (50), 81 (10). Found, %: C 57.43; H 2.82; N 11.85. С17H10FN3O3S. Calculated, %: C 57.46; H 2.84; N 11.83. 1 ‑ ( 1 , 3 ‑ D i h y d r o b e n z i m i d a z o l ‑ 2‑yliden)  — 1‑(5‑fluoro‑8‑nitro‑4‑oxo‑ 4Н‑1,3‑benzothiazin‑2‑yl)  — acetoni‑ trile (8). Yield 75%, mp 319–321 °С. 1Н NMR, δ (ppm), J (Hz): 7.30 m (2Н, C6H4), 7.50 dd (1Н, Н6, 3JHH 9.2, 3JFH 9.8), 7.64 m (2Н, C6H4), 8.62 dd (1Н, H 7, 3JHH 9.2, 4JFH 4.4), 13.31 br. s (2Н, NH). 19F{1H} NMR, δ (ppm): — 97.49 s. MS (EI), m/z (Irel (%)): 381 [M]+ (39), 183 (13), 182 (100), 155 (12), 103 (23), 81 (12). Found, %: C 53.50; H 2.15; N 18.36. С17H8FN5O3S. Calculated, %: C 53.54; H 2.11; N 18.37. 2 ‑ ( 1 , 3 ‑ D i h y d r o b e n z i m i d a z o l ‑ 2‑yliden)  — 2‑(5‑fluoro‑8‑nitro‑4‑oxo‑ 4Н‑1,3‑benzothiazin‑2‑yl) — acetophe‑ none (9). Yield 89%, mp 265–267 °С. 1Н NMR, δ (ppm), J (Hz): 7.36 m (5Н, С6Н5), 7.53 m (4Н, С6Н4), 7.60 dd (1Н, Н 6, 3JHH 9.2, 3JFH 9.5), 8.56 dd (1Н, H 7, 3JHH 9.2, 4JFH 4.5), 13.36 br. s (2Н, NH). 19F {1H} NMR, δ (ppm): — 98.39 s. MS (EI), m/z (Irel (%)): 460 [M]+ (24), 432 (13), 431 (41), 355 (25), 261 (46), 260 (100), 206 (16), 156 (16), 105 (45), 77 (71), 51 (10). Found, %: C 60.03; H 2.83; N 12.20. С23H13FN4O4S. Calculat- ed, %: C 60.00; H 2.85; N 12.17. 6,7,8‑Trifluoro‑2‑phenyl‑1,3‑benzo‑ thiazin‑4‑one (12а). Tetrafluorobenzoyl- chloride 10a (0.85 g, 4 mmol) was added to thiobenzamide 11a (0.397 g, 2.9 mmol) in dry toluene (8 mL), reaction mixture was refluxed for 3 h and then cooled. The pre- cipitate of benzothiazinone 12a was filtered off and recrystallized from DMSO. Yield 0.646 g (76%), mp 160–162 0С. 1Н NMR, δ (ppm), J (Hz): 7.62 m (2Н, Ph), 7.73 m (1Н, Ph), 8.15 ddd (1Н, H5, 3J 10.3, 4J 7.4, 5J 2.2), 8.19 m (2Н, Ph). 19F NMR, δ (ppm), J (Hz): 151.84 ddd (1F, F7, 3J 22.5, 3J 21.5, 4J 7.4), 135.10 ddd (1F, F8, 3J 21.5, 4J 6.2, 5J 2.2), 132.50 ddd (1F, F6, 3J 22.5, 3J 10.3, 4J 6.2). MS (EI), m/z (Irel (%)): 293 [M] + (11), 190 (100), 162 (30). Found, %: C 57.51, H 1.88, N 4.62. C14H6F3NOS. Calculated, %: C 57.34, H 2.06, N 4.78. Compounds 12b‑h were synthesized by the same method. 6,7,8‑Trifluoro‑2‑(p‑chlorophenyl) — 1,3‑benzothiazin‑4‑one (12b). Yield 59%, mp 204–206 0С. 1Н NMR, δ (ppm), J (Hz): 7.73 d (2Н, H3’,5’, 3J 8.8), 8.23 d (2Н, H2’,6’, 3J 8.8), 8.24 ddd (1Н, H5, 3J 10.6, 4J 7.5, 5J 2.1). 19F NMR, δ (ppm), J (Hz): 151.68 ddd (1F, F7, 3J 22.5, 3J 21.2, 4J 7.5), 135.02 ddd (1F, F8, 3J 21.5, 4J 6.3, 5J 2.1), 132.29 ddd (1F, F6, 3J 22.5, 3J 10.6, 4J 6.3). MS (EI), m/z (Irel (%)): 327 [M]+ (4), 190 (100), 162 (27). Found, %: C 51.42, H 1.66, N 4.13. C14H5F3NOSCl. Calculated, %: C 51.31, H 1.54, N 4.27. 6,7,8‑Trifluoro‑2‑(p‑tolyl) — 1,3‑ben‑ zothiazin‑4‑one (12c). Yield 71%, mp 184–186 0С. 1Н NMR, δ (ppm), J (Hz): 2.46 s (3Н, СН3), 7.43 d (2Н, H 3’,5’, 3J 8.0), 8.09 d (2Н, H2’,6’, 3J 8.0), 8.14 ddd (1Н, H5, 3J 10.0, 4J 7.5, 5J 2.3). Found, %: C 58.75, H 2.70, N 4.41. C15H8F3NOS. Calculated, %: C 58.63, H 2.62, N 4.56. 99 6,7,8‑Trif luoro‑2‑(pyridyl‑2)  — 1,3‑benzothiazin‑4‑one (12d). Yield 76%, mp 166–168 0С. 1Н NMR, δ (ppm), J (Hz): 7.75 dd (1Н, H5’, 3J 8.0, 3J 4.0), 8.10 td (1H, H4’, 3J 8.0, 4J 1.8), 8.13 ddd (1Н, Н5, 3J 10.4, 4J 7.4, 5J 2.2), 8.38 d (1H, H3’, 3J 8.0), 8.79 dd (1Н, H6’, 3J 4.0, 4J 1.8). 19F NMR, δ (ppm), J (Hz): 151.95 ddd (1F, F7, 3J 22.5, 3J 21.1, 4J 7.4), 135.64 ddd (1F, F8, 3J 21.1, 4J 6.2, 5J 2.2), 132.70 ddd (1F, F6, 3J 22.5, 3J 10.4, 4J 6.2). Found, %: C 52.95, H 1.63, N 9.67. C13H5F3N2OS. Calculated, %: C 53.06, H 1.71, N 9.52. 5,6,7,8‑Tetrafluoro‑2‑phenyl‑1,3‑ben‑ zothiazin‑4‑one (12e). Yield 80%, mp 165–167 0С. 1Н NMR, δ (ppm), J (Hz): 7.63 m (2Н, Ph), 7.76 m (1Н, Ph), 8.17 m (2Н, Ph). MS (EI), m/z (Irel (%)): 311 [M] + (7), 208 (100), 180 (24), 111 (5). Found, %: C 53.83, H 1.81, N 4.67. C14H5F4NOS. Calculated, %: C 54.02, H 1.62, N 4.50. 5,6,7,8‑Tetrafluoro‑2‑(p‑chlorophe‑ nyl)  — 1,3‑benzothiazin‑4‑one (12f ). Yield 62%, mp 186–188 0С. 1Н NMR, δ (ppm), J (Hz): 7.66 d (2Н, H3’,5’, 3J 8.8), 8.20 d (2Н, H2’,6’, 3J 8.8). Found, %: C 48.83, N 3.97. C14H4F4NOSCl. Calculated, %: C 48.64, H 1.17, N 4.05. 5,6,7,8‑Tetrafluoro‑2‑(p‑tolyl)  — 1,3‑benzothiazin‑4‑one (12g). Yield 74%, mp 191–193 0С. 1Н NMR, δ (ppm), J (Hz): 2.46 s (3Н, СН3), 7.43 d (2Н, H 3’,5’, 3J 8.4), 8.08 d (2Н, H2’,6’, 3J 8.4). Found, %: C 55.46, H 2.24, N 4.19. C15H7F4NOS. Calculated, %: C 55.39, H 2.17, N 4.31. 5,6,7,8‑Tetrafluoro‑2‑(pyridyl‑2)  — 1,3‑benzothiazin‑4‑one (12h). Yield 77%, mp 182–184 0С. 1Н NMR, δ (ppm), J (Hz): 7.76 ddd (1Н, H5’, 3J 8.0, 3J 4.8, 4J 0.8), 8.10 td (1H, H4’, 3J 8.0, 4J 1.8), 8.36 dd (1H, H3’, 3J 8.0, 4J 0.8), 8.79 dd (1Н, H6’, 3J 4.8, 4J 1.8). Found, %: C 49.92, N 9.09. C13H4F4N2OS. Calculated, %: C 50.01, H 1.29, N 8.97. Results and discussion We developed an efficient synthetic ap- proach to 2-hetaryl/(hetaryl)ylidene-sub- stituted fluorinated 1,3-benzothiazinones, for this purpose we studied the interaction of  the  range of С-nucleophiles (indoles, N-methylpyrrole, 2-cyanomethyl- and 2-benzoylmethyl- benzimidazoles) with 2,6-difluoro-3-nitrobenzoylisothiocy- anate 4 in acetonitrile at room temperature (Figure 1). According to 1H and 19F NMR spectra, the reaction leads to the formation of  1,3-benzothiazin-4-ones 5–9, the  in- termediate addition products were not isolated, and fluorine atom at С5 was not subjected to substitution with nucleophilic reagent. It is worth noting that the intra- molecular cyclization proceeded at mild- er reaction conditions than in  the  case of 2,6-difluoro- and 2,3,4,5-tetrafluoroben- zoyl derivatives (refluxing in acetonitrile or dimethylformamide in the presence of tri- methylamine [7]). The signals of Н6 and Н7 in  1H NMR spectra of  benzothiazinones 5–9 ex- hibit more complicated multiplicity than in  the  case of  2,5-diaminobenzothi- azinones [8], which indicates that the fluo- rine atom remains in position 5. To prove that the alternative product of cyclization, 5-fluoro-6-nitro isomer, was not formed 19F NMR spectra without suppression of F-H spin-spin interaction were registered. In such spectra of compounds 5–9 double doublet signals with 3JFH = 9.5–10.1 Hz and 4JFH = 3.9–4.0 Hz are present, so the for- mation of  5-fluoro-8-nitroisomers was confirmed. The  peaks of  molecular ions in the mass spectra of benzothiazinones 5–9 have a relative intensity of 14–39%. 100 Thus, we demonstrated the  differ- ence in  behavior of  С-nucleophiles and N-nucleophiles under the  reaction with 2,6-difluoro-3-nitrobenzoylisothiocy- anate 4: application of  С-nucleophiles allows to  obtain derivatives of  5-fluoro- 8-nitrobenzothiazinone, whereas the re- action with cycloalkylimines fails to avoid the  nucleophilic substitution of  fluorine at position 5. The proposed strategy opens wide opportunities for varying the substit- uent at position 2 of 8-nitrobenzothiazin- 4-ones. We presented novel one-stage syn- thetic approach to 2-substituted fluorine- containing 1,3-benzothiazin-4-ones based on cyclocondensation of  polyfluoroben- zoyl chlorides with thioamides as  S,N- dinucleophiles. New 6,7,8-trifluoro- and 5,6,7,8-tetrafluoro-derivatives of 1,3-ben- zothiazin-4-ones 12a‑h were obtained by the reaction of polyfluorobenzoylchlo- rides 10a,b and thioamides 11a‑d in boil- ing toluene for 3 h in 59–80% yields (Figure 2), notably that intermediate N-aroylation products were not isolated. Signals of NH groups are absent in  1H NMR spectra of compounds 12a‑h, spectra of 6,7,8-tri- fluorobenzothiazinones 12a‑d exhibited ddd signal of fluoroarene residue Н5 pro- ton at 8.13–8.24 ppm. The number of sig- nals in  19F NMR spectra is in accordance with the structure of benzothiazinones 12. The peaks of molecular ions in the mass F O OH F O OH F NO2 F F F O Cl NO2 H2SO4 , HNO3 SOCl2 , NH4NCS, MeCN, F F NO2 O NCS 1 2 3 4 S N F NO2 O S N F NO2 O S N F NO2 O S N F NO2 O S N F NO2 O 7 6 8 5 NN N HN NH N N NH N O N O NH N H N NH O Ph Ph O HN NH MeCN, room t MeCN, room t MeCN, room t MeCN, room t MeCN, room t 9 toluene toluene Fig. 1. Synthesis of 5-fluoro-8-nitro-1,3-benzothiazin-4-ones 5–9 101 spectra of benzothiazinones 12 have low relative intensity of 4–11%. The ions m/z 190 or m/z 208 with 100% intensity were observed for benzothiazinones 12, moreo- ver, peaks m/z 162 or m/z 180 correspond to ions [М-RCN-CO]+. The most abundant peak was reported to be characteristic for elimination of  RCN fragment from mo- lecular ions of 2-R-6,7,8-trifluoro-1,3-ben- zothiazin-4-ones [5–7]. The presented approach allows to ob- tain a variety of 2-aryl/hetaryl-substituted 1,3-benzothiazinones and successfully complements the previously described cy- clocondensation of polyfluorobenzoylchlo- rides with benzimidazol-2-thiones as cyclic S,N-dinucleophiles leading to [b]-annelat- ed fluorobenzothiazinones [12]. Unfortu- nately, we failed to  obtain 5-fluoro- and 5-fluoro-8-nitro analogs using the method shown in Figure 2. Tuberculostatic activity of polyfluori- nated benzothiazinnes 12 was studied at two laboratories, namely Ural Research Institute for Phthisiopulmonology (URIP) and University of Illinois, Chicago Institute for Tuberculosis Research (INR); the data are presented in Table 1. Table 1 Data on tuberculostatic activity of fluorinated 2‑aryl/pyridyl‑1,3‑benzothiazin‑4‑ones 12 against Mycobacterium tuberculosis H37Rv* Comp MIC values (URIP data), mg/mL % Inhibition at 128 mg/mL (ITR data) MIC values, mg/mL (ITR data) IC50, mg/mL (ITR data) MABA LORA MABA LORA 12b 12.5 28 66 - - — 12c 12.5 95 100 58.0 52.3 >128 12d 0.3 — — >128 >128 — 12f 3.12 0 100 — 3.7 53.5 12g nd 74 99 — 26.3 — 12h 12.5 0 100 — 55.8 65.9 * MIC–Minimal inhibitory concentration; IC50 — the half maximal inhibitory concentration; URIP — Ural Research Institute for Phthisiopulmonology; INR — Chicago Institute for Tuberculosis Research; MABA — microplate Alamar Blue assay; LORA — low- oxygen recovery assay. O F F F F Cl Y 10а,b 12а-h H2N R S R F F S N O F Y toluene, t 11а-d 10: Y = H (a), F (b); 11: R = Ph (a), 4-Cl-C6H4 (b), 4-Me-C6H4 (c), 2-Py (d); 12: Y = H, R = Ph (a), 4-Cl-C6H4 (b), 4-Me-C6H4 (c), 2-Py (d); Y = F, R = Ph (e), 4-Cl-C6H4 (f), 4-Me-C6H4 (g), 2-Py (h). Fig. 2. Synthesis of polyfluorinated 2-aryl/pyridyl-1,3-benzothiazin-4-ones 12a‑h 102 According to trials conducted in URIP, benzothiazinone 12d exhibited the high- est activity (MIC 0.3 mg/mL, isoniazide as  reference compound with MIC 0.15 mg/mL). Data obtained in  ITR revealed 12f as the most promising derivative to- wards the dormant multi-resistant strain of  micobacteria H37RV–CA-luxAB (MIC 3.7 mg/mL, rifampicinum as reference com- pound with MIC 8.26 mg/mL). Conclusions To sum up, we developed efficient syn- thetic approaches to fluorine-containing 1,3-benzothiazin-4-ones bearing aryl, hetaryl and (hetaryl)ylidene residues at po- sition 2 and demonstrate that some of them are promising for design of new antituber- cular agents. Acknowledgements The work was carried out with financial support from the Ministry of Science and Higher Education of Russian Federation (project № FEUZ-2020–0058 (Н687.42Б.223/20)). References 1. Chetty S, Ramesh M, Singh-Pillay A, Soliman M. Recent advancements in the de- velopment of anti-tuberculosis drugs. Bioorg Med Chem Lett. 2017;27(3):370–86. DOI: 10.1016/j.bmcl.2016.11.084 2. Kimura H, Sato Y, Tajima Y, Suzuki H, Yukitake H, Imaeda T, Kajino M, Oki H, Takizawa M, Tanida S. BTZO-1, a Cardioprotective Agent, Reveals that Macrophage Migration Inhibitory Factor Regulates ARE-Mediated Gene Expression. Chem Biol- ogy. 2010;17(12):1282–94. DOI: 10.1016/j.chembiol.2010.10.011 3. 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