General: Column chromatography was performed on silica gel 60 (Merck 230–400 mesh). Nuclear magnetic resonance spectra were recorded on a Varian Unity Plus spectrometer 1H NMR at 300 MHz; the chemical shifts (d) are expressed in parts per million (ppm) and the coupling constants (J) in Hertz (Hz). DMSO was used as the solvent and SiMe4 as the reference.
General procedure of synthesis compounds 4, 5 and 6
To a solution of (6.05 mmol) of 2-substituted)-1,4-benzothiazin-3-one 1 (2 or 3) in 15 ml of DMF, were added 11.3 mmol of potassium carbonate. The reaction mixture was stirred magnetically for 5 min then added 0.6 mmol of bromide tetra-nbutylammonium (BTBA) and 7.26 mmol of propargyl bromide, then the mixture was stirred magnetically for 24 h. After removal of salts by filtration, the solution was evaporated under reduced pressure, and the residue obtained is dissolved in dichloromethane. The remaining salts are extracted with distilled water, and the mixture obtained was chromatographed on silica gel column [eluent: ethyl acetate/hexane (1/9)].
4-(Prop-2-ynyl)-3,4-dihydro-2H-1,4-benzothiazin-3-one 4
Yield: 92%; mp = 492 K; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 7.42–7.04 (m, 4H, Harom), 4.74 (d, 2H, J = 1.9 Hz NCH2), 3.55 (s, 2H, S-CH2), 2.20 (t, 1H, J = 1.9 Hz ≡ CH,); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 165.2 (C=O), 139.0, 123.4, 79.8 (Cq), 128.6, 128.0, 124.1, 118.5 (CHarom), 75.0 (≡CH), 33.8 (NCH2), 30.6 (S-CH2).
(2Z)-2-Benzylidene-4-(prop-2-ynyl)-3,4-dihydro-2H-1,4-benzothiazin-3-one 5
Yield: 90%; mp = 403 K; 1H-NMR (DMSO-d6, 300 MHz) δ [pm]: 7.84 (s, 1H, CHvinyl), 7.66–7.09 (m, 9H, Harom), 4.90 (d, 2H, J = 1.8 Hz, NCH2), 2.21 (t, 1H, J = 1.8 Hz, ≡CH). 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 161.0 (C=O), 135.8, 134.4, 134.3, 118.4, 79.6 (Cq), 135.5 (CHvinyl), 130.6, 129.8, 129.1, 128.1, 126.8, 124.5, 117.8 (CHarom), 75.5 (≡CH), 35.0 (NCH2).
(Z)-2-(4-Chlorobenzylidene)-4-(prop-2-ynyl)-2H-1,4-benzothiazin-3-one 6
Yield: 88%; mp = 385 K; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 7.83 (s, 1H, CHvinyl), 7.69–7.11 (m, 8H, Harom), 4.86 (d, 2H, J = 1.9 Hz, NCH2), 3.31 (t, 1H, J = 1.9 Hz ≡CH). 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 161.0 (C=O), 135.77 (CHvinyl), 134.08, 134.28, 133.25, 121.04, 118.05 (Cq), 132.3, 129.12, 128.14, 126.86, 124.55, 117.85 (CHarom), 75.47 (≡CH), 35.02 (NCH2).
General procedure for the synthesis of compounds 7a–12a, 7b–12b and 13–15 via Huisgen 1,3-dipolar cycloaddition reactions
To a solution of dipolarophile 4 (5 or 6) (8 mmol) in absolute ethanol (20 ml) was added azide F (G or H) (16 mmol). The reaction mixture was stirred at reflux and the reaction monitored by thin layer chromatography (TLC). After concentration under reduced pressure, the residue was purified by column chromatography on silica gel using a mixture [ethyl acetate/hexane (1/9)] as eluent.
General procedure for the synthesis of compounds 7a–12a by click chemistry: [Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC)]
To a solution of 1 mmol of compound 4 (5 or 6) and 2 mmol of azide F (G) in 15 ml of ethanol were added 0.5 mmol of CuSO4 and 1 mmol of sodium ascorbate dissolved in 7 ml of distilled water. The reaction mixture was stirred for 24 h at room temperature. The reaction was monitored by TLC. After filtration and concentration of the solution under reduced pressure the residue obtained was chromatographed on silica gel column using as eluent ethyl acetate/hexane (1/9). The compounds have been obtained with yields ranging from 86 to 90%.
4-[(1′-1″,2″:3″,4″-Di-O-isopropylidene-α-d-galactopyranosid-6″-yl)-1′,2′,3′-triazol-4′-yl)methyl]-2H-1,4-benzothiazin-3-one 7a
Yield: 63%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 1.40, 1.31, 1.30, 1.23 (s, 12H, 4CH3), 3.52 (s, 2H, CH2–S), 4.69, 4.53, 4.39, 4.22 (m, 4H, 4CH, H2, H3, H4, H5), 4.35 (d, 2H, CH2–N), 5.32 (d, 2H, CH2–N, H6), 5.47 (d, 1H, CH, H1), 7.55–7.03 (m, 4H, Harom), 8.31 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 164.04 (CO), 142.78, 140.17, 123.50, 109.62, 108.29 (Cq), 128.89 (CHtriazole), 127.39, 124.69, 124.23, 119.00 (CHarom), 97.01, 71.74, 70.75, 69.96, 66.97 (5CH, C1, C2, C3, C4, C5), 50.26, 41.00 (CH2–N), 31.23 (CH2–S), 26.34, 25.81, 25.27, 24.95 (4CH3);
4-[(1′-1″,2″:3″,4″-Di-O-isopropylidene-α-d-galactopyranosid-6″-yl)-1′,2′,3′-triazol-5′-yl) methyl]-2H-1,4-benzothiazin-3-one 7b
Yield: 19%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 1.38, 1.29, 1.28, 1.21 (s, 12H, 4CH3), 3.52 (s, 2H, CH2–S), 4.62, 4.50, 4.33, 4.15 (m, 4H, 4CH, H2, H3, H4, H5), 4.33 (d, 2H, CH2–N), 5.12 (d, 2H, CH2–N, H6), 5.38 (d, 1H, CH, H1), 7.50–7.00 (m, 4H, Harom), 7.93 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 165.24 (CO), 143.56, 139.84, 123.27, 109.31, 108.60 (Cq), 128.46 (CHtriazole), 127.76, 124.49, 123.91, 118.63 (CHarom), 95.96, 71.04, 70.59, 70.16, 67.26 (5CH, C1, C2, C3, C4, C5), 50.58, 40.78 (CH2–N), 30.79 (CH2–S), 26.34, 26.05, 25.27, 24.70 (4CH3);
(2Z)-2-Benzylidene-4-[(1′-1″,2″:3″,4″-di-O-isopropylidene-α-d-galactopyranosid-6″-yl)-1′,2′,3′-triazol-4′-yl)methyl]-2H-1,4-benzothiazin-3-one 8a
Yield: 65%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 1.41, 1.33, 1.31, 1.25 (s, 12H, 4CH3), 4.67, 4.39, 4.38, 4.36 (m, 4H, 4CH, H2, H3, H4, H5), 4.39 (d, 2H, CH2–N), 5.47 (d, 2H, CH2–N, H6), 5.32 (d, 1H, CH, H1), 7.67–7.06 (m, 4H, Harom), 7.85 (s, 1H, CHvinyl), 8.29 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 161.44 (CO), 136.06, 134.68, 134.51, 132.47, 130.06,109.44, 108.74 (Cq), 135.26 (CHvinyl), 132.47 (CHtriazole), 130.61, 129.72, 129.08, 127.95, 126.85, 124.49, 118.06 (CHarom), 96.12, 70.90, 70.62, 70.22, 68.37 (5CH, C1, C2, C3, C4, C5), 48.56, 39.77 (CH2–N), 26.43, 26.13, 25.27, 24.85 (4CH3).
(2Z)-2-Benzylidene-4-[(1′-1″,2″:3″,4″-di-O-isopropylidene-α-d-galactopyranosid-6″-yl)-1′,2′,3′-triazol-5′-yl)methyl]-2H-1,4-benzothiazin-3-one 8b
Yield: 20%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 1.37, 1.27, 1.26, 1.17 (s, 12H, 4CH3), 4.63, 4.60, 4.49, 4.31 (m, 4H, 4CH, H2, H3, H4, H5), 4.49 (d, 2H, CH2–N), 5.26 (d, 2H, CH2–N, H6), 5.37 (d, 1H, CH, H1), 7.49–7.06 (m, 4H, Harom), 7.81 (s, 1H, CHvinyl), 8.01 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 161.10 (CO), 143.16, 136.53, 134.47, 120.63, 118.22, 109.33, 108.59 (Cq), 134.72 (CHvinyl), 130.47 (CHtriazole), 129.69, 129.12, 127.96, 126.68, 124.75, 124.29, 117.99 (CHarom), 95.94, 71.04, 70.56, 70.15, 67.26 (5CH, C1, C2, C3, C4, C5), 50.64, 41.57 (CH2–N), 26.34, 25.98, 25.26, 24.69 (4CH3).
(2Z)-2-(4-Chlorobenzylidene)-4-[(1′-1″,2″:3″,4″-di-O-isopropylidene-α-d-galactopyranosid-6″-yl)-1′,2′,3′-triazol-4′-yl)methyl]-2H-1,4-benzothiazin-3-one 9a
Yield: 61%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 1.40, 1.31, 1.30, 1.23 (s, 12H, 4CH3), 4.69, 4.40, 4.34, 4.24 (m, 4H, 4CH, H2, H3, H4, H5), 4.42 (d, 2H, CH2–N), 5.55 (d, 2H, CH2–N, H6), 5.45 (d, 1H, CH, H1), 7.65–7.03 (m, 4H, Harom), 7.85 (s, 1H, CHvinyl), 8.27 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 161.61 (CO), 135.80, 134.83, 134.54, 130.06, 129.51, 119.93, 109.29, 108.61 (Cq), 135.04 (CHvinyl), 132.19 (CHtriazole), 130.31, 129.53, 128.81, 127.85, 126.45, 124.48, 117.83 (CHarom), 95.85, 70.91, 70.57, 69.73, 68.12 (5CH, C1, C2, C3, C4, C5), 48.49, 39.23 (CH2–N), 26.29, 25.95, 25.27, 24.72 (4CH3).
(2Z)-2-(4-Chlorobenzylidene)-4-[(1′-1″,2″:3″,4″-di-O-isopropylidene-α-d-galactopyranosid-6″-yl)-1′,2′,3′-triazol-5′-yl)methyl]-2H-1,4-benzothiazin-3-one 9b
Yield: 17%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 1.39, 1.30, 1.26, 1.18 (s, 12H, 4CH3), 4.62, 4.39, 4.28, 4.15 (m, 4H, 4CH, H2, H3, H4, H5), 4.55 (d, 2H, CH2–N), 5.37 (d, 2H, CH2–N, H6), 5.30 (d, 1H, CH, H1), 7.63–7.04 (m, 4H, Harom), 7.82 (s, 1H, CHvinyl), 7.99 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 160.82 (CO), 143.06, 136.80, 134.58, 125.30, 120.81, 117.99, 109.90, 108.09 (Cq), 135.03 (CHvinyl), 130.06 (CHtriazole), 129.91, 129.38, 128.50, 126.68, 124.43, 118.22 (CHarom), 96.50, 71.42, 70.90, 70.15, 67.62 (5CH, C1, C2, C3, C4, C5), 50.93, 41.42 (CH2–N), 26.05, 26.71, 25.45, 24.98 (4CH3).
4-[(1′-2″,3″,4″,6″-Tétra-O-acétyl-(d)-glucopyranos-1″-yl)-1′,2′,3′-triazol-4′-yl)methyl]-2H-1,4-benzothiazin-3-one 10a
Yield: 64%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 2.01, 1.95, 1.92, 1.72 (s, 12H, 4CH3), 3.42 (s, 2H, CH2–S); 5.68, 5.55, 5.21, 4.08 (m, 5H, 4CH, H2, H3, H4, H5), 4.37 (d, 2H, CH2–N), 5.32 (d, 2H, CH2–O, H6), 6.31 (d, 1H, CH, H1), 7.61–7.02 (m, 4H, Harom), 8.35 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 170.52, 170.24, 169.88, 168.88, 161.52 (5C=O), 144.03, 136.89, 134.50, 120.16 (Cq), 130.50 (CHtriazole), 127.75, 124.10, 123.41, 118.13 (CHarom), 84.64, 73.81, 72.26, 70.70, 68.21 (5CH, C1, C2, C3, C4, C5), 62.45 (CH2–O), 41.84 (CH2–N), 30.50 (CH2–S), 21.07, 20.82, 20.46, 20.15 (4CH3).
4-[(1′-2″,3″,4″,6″-Tétra-O-acétyl-(d)-glucopyranos-1″-yl)-1′,2′,3′-triazol-5′-yl)methyl]-2H-1,4-benzothiazin-3-one 10b
Yield: 21%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 2.01, 1.97, 1.95, 1.72 (s, 12H, 4CH3), 3.42 (s, 2H, CH2–S); 5.68, 5.55, 5.21, 4.09 (m, 5H, 4CH, H2, H3, H4, H5), 4.37 (d, 2H, CH2–N), 5.32 (d, 2H, CH2–O, H6), 6.37 (d, 1H, CH, H1), 7.51–7.03 (m, 4H, Harom), 7.63 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 170.24, 170.03, 169.75, 168.55, 161.13 (5C=O), 144.23, 136.66, 133.48, 120.78 (Cq), 130.61 (CHtriazole), 129.29, 128.07, 124.43, 118.13 (CHarom), 84.64, 73.81, 72.59, 70.70, 68.21 (5CH, C1, C2, C3, C4, C5), 62.45 (CH2–O), 41.84 (CH2–N), 30.51 (CH2–S); 20.96, 20.82, 20.68, 20.29 (4CH3).
(2Z)-2-Benzylidene-4-[(1′-2″,3″,4″,6″-tétra-O-acétyl-(d)-glucopyranos-1″-yl)-1′,2′,3′-triazol-4′-yl)methyl]-2H-1,4-benzothiazin-3-one 11a
Yield: 66%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 2.00, 1.97, 1.93, 1.71 (s, 12H, 4CH3), 5.65, 5.51, 5.17, 4.07 (m, 5H, 4CH, H2, H3, H4, H5), 4.34 (d, 2H, CH2–N), 5.30 (d, 2H, CH2–O, H6), 6.31 (d, 1H, CH, H1), 7.84 (s, 1H, CHvinyl), 7.62–7.06 (m, 4H, Harom), 8.37 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 170.52, 170.04, 169.85, 168.83, 161.13 (5C=O), 144.13, 136.46, 134.53, 120.63, 118.31 (Cq), 130.51 (CHtriazole), 134.77 (CHvinyl), 129.51, 129.09, 127.90, 126.66, 124.27, 123.54, 117.97 (CHarom), 84.33, 73.80, 72.58, 70.58, 67.99 (5CH, C1, C2, C3, C4, C5), 62.28 (CH2–O), 41.51 (CH2–N), 20.96, 20.82, 20.68, 20.26 (4CH3).
(2Z)-2-Benzylidene-4-[(1′-2″,3″,4″,6″-tétra-O-acetyl-(d)-glucopyranos-1″-yl)-1′,2′,3′-triazol-5′-yl)methyl]-2H-1,4-benzothiazin-3-one 11b
Yield: 20%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 2.01, 1.97, 1.92, 1.72 (s, 12H, 4CH3), 5.64, 5.54, 5.21, 4.09 (m, 5H, 4CH, H2, H3, H4, H5), 4.34 (d, 2H, CH2–N), 5.30 (d, 2H, CH2–O, H6), 6.34 (d, 1H, CH, H1), 7.84 (s, 1H, CHvinyl), 7.65–7.03 (m, 4H, Harom), 7.62 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 170.52, 170.24, 169.88, 168.88, 161.39 (5C=O), 144.03, 136.66, 134.56, 120.78, 118.44 (Cq), 130.17 (CHtriazole), 134.73 (CHvinyl), 129.65, 129.29, 127.80, 126.66, 124.43, 123.67, 118.12 (CHarom), 84.40, 73.89, 72.59, 70.70, 68.21 (5CH, C1, C2, C3, C4, C5), 62.45 (CH2–O), 41.84 (CH2–N), 21.07, 20.82, 20.68, 20.40 (4CH3).
(2Z)-2-(4-Chlorobenzylidene)-4-[(1′-2″,3″,4″,6″-tetra-O-acetyl-(d)-glucopyranos-1″-yl)-1′,2′,3′-triazol-4′-yl)methyl]-2H-1,4-benzothiazin-3-one 12a
Yield: 63%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 2.01, 1.97, 1.95, 1.72 (s, 12H, 4CH3), 5.68, 5.55, 5.14, 4.13 (m, 5H, 4CH, H2, H3, H4, H5), 4.37 (d, 2H, CH2–N), 5.35 (d, 2H, CH2–O, H6), 6.34 (d, 1H, CH, H1), 7.84 (s, 1H, CHvinyl), 7.68–7.06 (m, 4H, Harom), 8.39 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 170.52, 170.24, 169.85, 169.22, 161.39 (5C=O), 144.03, 136.66, 134.76, 130.45, 120.78, 118.44 (Cq), 130.51 (CHtriazole), 134.53 (CHvinyl), 129.99, 129.09, 127.80, 126.66, 124.10, 118.12 (CHarom), 84.40, 73.1, 72.59, 70.70, 68.21 (5CH, C1, C2, C3, C4, C5), 62.12 (CH2–O), 40.99 (CH2–N), 21.07, 20.82, 20.46, 20.06 (4CH3).
(2Z)-2-(4-Chlorobenzylidene)-4-[(1′-2″,3″,4″,6″-tetra-O-acetyl-(d)-glucopyranos-1″-yl)-1′,2′,3′-triazol-5′-yl)methyl]-2H-1,4-benzothiazin-3-one 12b
Yield: 19%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 2.00, 1,95, 1.92, 1.73 (s, 12H, 4CH3), 5.62, 5.48, 5.14, 4.08 (m, 5H, 4CH, H2, H3, H4, H5), 4.34 (d, 2H, CH2–N), 5.27 (d, 2H, CH2–O, H6), 6.34 (d, 1H, CH, H1), 7.84 (s, 1H, CHvinyl), 7.65–7.05 (m, 4H, Harom), 7.61 (s, 1H, CHtriazole); 13C-NMR (DMSO-d6, 62.5 MHz) δ [ppm]: 170.24, 170.03, 169.46, 168.55, 161.13 (5C=O), 144.55, 136.46, 134.56, 130.57, 120.16, 118.57 (Cq), 130.50 (CHtriazole), 134.17 (CHvinyl), 129.47, 129.09, 127.80, 126.66, 124.10, 118.12 (CHarom), 84.06, 73.23, 72.54, 70.24, 68.00 (5CH, C1, C2, C3, C4, C5), 62.12 (CH2–O), 41.74 (CH2–N), 20.96, 20.82, 20.74, 20.29 (4CH3).
4-[1,2,3-Triazolylmethyl]-2H-1,4-benzothiazin-3-one 13
Yield: 79%; mp = 352 K; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 7.40 (s, 1H, CHtriazole), 7.37–7.00 (m, 4H, Harom), 5.16 (d, 2H, CH2–N), 3.56 (s, 2H, CH2–S); 13C-NMR (DMSO-d6, 62.5 MHz); 165.49 (CO), 143.56, 139.75, 123.44 (Cq), 128.50 (CHtriazole), 129.11, 127.72, 123.93, 118.65 (CHarom), 40.32 (C–N), 30.76 (C–S).
(2Z)-2-Benzylidene-4-[1,2,3-triazolylmethyl]-2H-1,4-benzothiazin-3-one 14
Yield: 81%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 7.84 (s, 1H, CHvinyl), 7.70–7.10 (m, 9H, Harom), 7.54 (s, 1H, CHtriazole), 4.86 (d, 2H, CH2–N); 13C-NMR (DMSO-d6, 62.5 MHz); 160.79 (CO), 136.01, 134.48, 133.51, 121.18, 118.42 (Cq), 134.28 (CHvinyl), 128.40 (CHtriazole), 134.28, 132.55, 129.12, 128.40, 126.95, 124.73, 118.05 (CHarom), 35.47 (C–N).
(2Z)-2-(4-Chlorobenzylidene)-4-[1,2,3-triazolyl-methyl]-2H-1,4-benzothiazin-3-one 15
Yield: 77%; brown oil; 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 7.83 (s, 1H, CHvinyl), 7.67–7.10 (m, 8H, Harom), 7.53 (s, 1H, CHtriazole), 4.85 (d, 2H, CH2–N); 13C-NMR (DMSO-d6, 62.5 MHz); 160.68 (CO), 135.77, 134.28, 133.31, 132.29, 121.05, 118.05 (Cq), 134.15 (CHvinyl), 128.14 (CHtriazole) 132.30, 129.12, 128.17, 126.86, 124.73, 117.85 (CHarom), 35.01 (C-N).
Ethyl-n-(benzoyl)-2-ethoxylglycinate 16
Yield: 78%; mp = 369. 1H-NMR (DMSO-d6, 300 MHz) δ [ppm]: 9.42 (d, 1H, N–H, J = 9,41), 7.92–7.44 (m, 5H, H arom), 5.62 (d, 1H, CH, J = 5,61), 4.13 (q, 2H, CH2–O), 3.57 (q, 2H, CH 2–O), 1.19, 1.13 (t, 6H, 2CH3); 13 C-NMR (DMSO-d6, 62.5 MHz); 168.47, 167.12 (2 CO), 133.54, 132.48, 128.87, 128.27 (CHarom), 77.94 (CH), 63.70, 61.62 (2CH2), 15.38, 14.46 (2CH3).