ꢂꢁꢁꢁ
N. Gautam et al.: Novel 4H-1,4-benzothiazines and their sulfone derivativesꢀ ꢀ3
compounds were checked by TLC using silica gel “G” as adsorbent in (5 mL) was added afer 15 min without heating. Then the mixture
various solvent systems with visualization by UV light or in an iodine was heated under reflux (120°C) for an additional 4–5 h, concentrat-
chamber.
ed under reduced pressure and the residue was treated with crushed
ice. The resultant solid product 5 was filtered and crystallized from
ethanol.
General method for synthesis of substituted
Ethyl-5,7‐dimethyl‐3-propyl-4H‐1,4‐benzothiazine‐2‐carboxylate
1,1‐dioxides (5a)ꢀYield 56%; mp 136–138°C (dec); IR: 3320, 1645,
1185, 1150, 1345, 1290, 1275, 580, 555, 1055 cm‐1; 1H NMR: δ 8.42 (s, 1H),
6.95–6.63 (m, 2H), 2.22 (t, 2H), 1.14 (m, 2H), 1.22 (t, 3H), 4.35 (q, 2H),
1.77 (t, 3H), 2.14 (s, 3H), 2.33 (s, 3H); MS: m/z 323 (M+), 250 (51), 208
(77), 73 (100). Anal. Calcd for C16H21NO4S: C, 59.44; H, 6.50; N, 4.33.
Found: C, 59.31; H, 6.45; N, 4.30.
4H-1,4-benzothiazines 4a–e
β-Diketone/β-ketoester 2a–d (0.01 mol) was treated with a solution of
2‐aminobenzenethiol 1a–d (0.01 mol) in 5 mL of DMSO and the result-
ing mixture was heated under reflux (190°C) for 20 min, then cooled
and concentrated on a rotary evaporator. The residue was washed
with petroleum ether and crystallized from methanol.
2-(4′-Bromobenzoyl)-7-(4′-chlorophenoxy)-3-methyl-4H-1,4-
benzothiazine 1,1-dioxides (5b)ꢀYield 45%; mp 253–255°C (dec);
IR: 3355, 1625, 1190, 1160, 1360, 1285, 1265, 565, 545, 1035 cm‐1; 1H NMR:
δ 8.82 (s, 1H), 8.02–7.28 (m, 11H), 2.13 (s, 3H). MS: m/z 504.5 (M+), 320.5
(52), 278.5 (79), 184 (100). Anal. Calcd for C22H15BrClNO4S: C, 52.48; H,
2.98; N, 2.78. Found: C, 52.66; H, 2.96; N, 2.83.
Ethyl‐5,7‐dimethyl‐3-propyl-4H‐1,4‐benzothiazine‐2‐carboxylate
(4a)ꢀYield 57%; mp 125–127°C (dec); IR: 3315, 1620, 1425, 1330,
1
1040 cm‐1; H NMR: δ 8.12 (s, 1H), 6.55–6.37 (m, 2H), 2.02 (t, 2H), 1.21
(m, 2H), 1.10 (t, 3H), 4.16 (q, 2H), 1.27 (t, 3H), 1.94 (s, 3H), 2.10 (s, 3H);
MS: m/z 291 (M+), 218 (53), 176 (76), 73 (100). Anal. Calcd for C16H21NO2S:
C, 65.97; H, 7.21; N, 4.81. Found: C, 66.22; H, 7.26; N, 4.79.
7-n-Butyl-2-(4′-bromobenzoyl)-3-methyl-4H‐1,4‐benzothiazine
1,1‐dioxides (5c)ꢀYield 47%; mp 109–111°C (dec); IR: 3350, 1640,
2-(4′-Bromobenzoyl)-7-(4′-chlorophenoxy)-3-methyl-
4H‐1,4‐benzothiazine (4b)ꢀYield 52%; mp 214–216°C (dec); IR:
1
1185, 1150, 1355, 1290, 1245, 570, 545, 1065 cm‐1; H NMR: δ 8.63 (s,
1
3310, 1605, 1270, 1070, 1465, 1350, 1015 cm‐1; H NMR: δ 8.52 (s, 1H),
1H), 7.46–6.39 (m, 7H), 2.75 (t, 2H), 1.93 (m, 2H), 1.49 (m, 2H), 1.14 (t,
3H), 1.97 (s, 3H); MS: m/z 434 (M+), 250 (41), 208 (77), 184 (100). Anal.
Calcd for C20H20BrNO3S: C, 55.42; H, 4.61; N, 3.23. Found: C, 55.58; H,
4.65; N, 3.27.
7.72–6.28 (m, 11H), 1.83 (s, 3H); MS: m/z 472.5 (M+), 288.5 (54), 246.5
(82), 184 (100). Anal. Calcd for C22H15BrClNO2S: C, 56.05; H, 3.18; N,
2.97. Found: C, 56.80; H, 3.21; N, 2.83.
7-n-Butyl-2-(4′-bromobenzoyl)-3-methyl-4H‐1,4‐benzothiazine
(4c)ꢀYield 40%; mp 119–121°C (dec); IR: 3315, 1610, 1275, 1080, 1465,
1355, 1035 cm‐1; 1H NMR: δ 8.53 (s, 1H), 7.36–6.29 (m, 7H), 2.65 (t, 2H),
1.83 (m, 2H), 1.39 (m, 2H), 1.04 (t, 3H), 1.87 (s, 3H); MS: m/z 402 (M+),
218 (44), 176 (73), 184 (100). Anal. Calcd for C20H20BrNOS: C, 59.85; H,
4.98; N, 3.49; Found: C, 59.78; H, 4.92; N, 3.42.
3-Ethyl-7-fluoro-2-propionyl-4H‐1,4‐benzothiazineꢀ1,1‐dioxides
(5d)ꢀYield 60%; mp 140–142°C (dec); IR: 3360, 1680, 1190, 1145, 1385,
1
1295, 1260, 575, 560, 1045 cm‐1; H NMR: δ 9.03 (s, 1H), 7.33–6.76 (m,
3H), 2.39 (q, 2H), 1.66 (t, 3H), 3.54 (q, 2H), 2.26 (t, 3H); MS: m/z 283
(M+), 226 (41), 162 (22), 161 (76), 57 (100). Anal. Calcd for C13H14FNO3S:
C, 55.12; H, 4.94; N, 4.94. Found: C, 55.27; H, 4.89; N, 4.97.
3-Ethyl-7-fluoro-2-propionyl-4H‐1,4‐benzothiazineꢀ(4d)ꢀYield
56%; mp 133–135°C (dec); IR: 3340, 1655, 1240, 1455, 1350, 1025 cm‐1;
1H NMR: δ 8.63 (s, 1H), 7.23–6.46 (m, 3H), 1.99 (q, 2H), 1.16(t, 3H), 3.14
(q, 2H), 1.56 (t, 3H); MS: m/z 251 (M+), 194 (44), 162 (24), 161 (75), 57
(100). Anal. Calcd for C13H14FNOS: C, 62.15; H, 5.57; N, 5.57. Found: C,
63.32; H, 5.48; N, 5.54.
Isopropyl-7-fluoro-3-methyl-4H‐1,4‐benzothiazine‐2‐carboxylate
1,1‐dioxides (5e)ꢀYield 34%; mp 158–160°C (dec); IR: 3340, 1640,
1180, 1155, 1355, 1285, 1265, 585, 565, 1065 cm‐1; 1H NMR: δ 8.88 (s, 1H),
7.77–6.13 (m, 3H), 2.55 (s, 3H), 4.63 (m, 1H), 2.22 (d, 6H); MS: m/z 299
(M+), 212 (38), 170 (81), 87 (100). Anal. Calcd for C13H14FNO4S: C, 52.17;
H, 4.68; N, 4.68. Found: C, 52.37; H, 4.67; N, 4.59.
Isopropyl-7-fluoro-3-methyl-4H‐1,4‐benzothiazine‐2‐carboxylate
(4e)ꢀYield 60%; mp 154–156°C (dec); IR: 3335, 1625, 1245, 1455, 1355,
1045 cm‐1; 1H NMR: δ 8.69 (s, 1H), 7.47–6.83 (m, 3H), 2.27 (s, 3H), 4.23–
4.12 (m, 1H), 1.92 (d, 6H); MS: m/z 267 (M+), 180 (36), 138 (78), 87 (100).
Anal. Calcd for C13H14FNO2S: C, 58.42; H, 5.24; N, 5.24. Found: C, 58.65;
H, 5.30; N, 5.19.
Antimicrobial assessment
MIC The broth microdilution method was used to determine the
MICs (μg/mL) of the compounds in accordance with the NCCLS
1992 manual. The strains used for quality control were Micromono-
spora sp. MTCC 3296 (Gram-positive) and Z. mobilis MTCC 88 (Gram-
negative) bacteria. Aspergillus solani MTCC 2101 and F. culmorum
MTCC 349 were the reference strains for testing antifungal activi-
ties of the compounds. The standard antibacterial and antifungal
drugs used were ampicillin sodium salt and fluconazole, respec-
tively. DMSO was used for preparing solutions of test compounds
and standard drugs. For preparing stock solution, each synthesized
General method for synthesis of 4H-1,4-
benzothiazine 1,1-dioxides (sulfones) 5a–e
A solution of 0.01 mol of 4H‐1,4‐benzothiazine in 20 mL glacial ace-
tic acid was added to 30% hydrogen peroxide (5 mL) and then the
mixture was heated under reflux for 15 min keeping the tempera- drug was diluted to obtain concentration of 1000 μg/mL. For primary
ture between 50°C and 55°C. Another lot of 30% hydrogen peroxide screening, 500, 250 and 125 μg/mL concentrations of the synthesized
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