4.1. Chemistry
Infrared spectra were obtained using a Perkin Elmer FT-IR 1720x spectrometer. 1H NMR and 13C NMR spectra were obtained using a Bruker AC 200 NMR spectrometer at 200 and 50 MHz, respectively. All 1H NMR and 13C NMR spectral results are recorded as chemical shifts (δ) relative to the internal TMS for proton and 77.0 ppm in CDCl3 solvent and 39.4 ppm in DMSO-d6 solvent for 13C NMR. Microanalysis was performed by Chemical and Micro analytical Services (CMAS), Australia. Melting point determinations were carried out using a Stuart Scientific (SMP3) melting point apparatus and all melting points are uncorrected.
4.1.1. Starting Materials
The stating reagents benzyl amine, sodium hydrogen carbonate, methyl iodide-amino-2-hydroxybenzoic acid, and dry 1,4-dioxane were purchased from Aldrich Chemical Company and were used as received.
4.1.2. Synthesis of 4-(Acetyl amino)-2-hydroxybenzoic Acid 8a
According to the previously reported method [29, 30, 37], product 8a was prepared from the reaction of 4-amino-2-hydroxybenzoic acid 7 and acetic anhydride and recrystallised from 1,4-dioxane, 82% yield, mp 221–224°C (lit [37] and mp 235°C). The physical and spectroscopic data is consistent with the literature values [27, 35].
4.1.3. Synthesis of 4-Substituted ((Benzylidene)amino)-2-hydroxybenzoic Acid Intermediates 8b–e
According to the previously reported method [29, 30], intermediates 8b–e were prepared from the appropriate substituted benzaldehyde and 4-amino-2-hydroxy-benzoic acid 7.
Products 8b, c, and e were not identified and used immediately in the synthesis of compound 9a, b, and d.
(Z)-4-((3-Ethoxy-2-hydroxybenzylidene)amino)-2-hydroxybenzoic Acid
8d. 3-Ethoxy-2-hydroxybenzaldehyde (1.66 g, 0.01 mol) was allowed to react with 4-amino-2-hydroxybenzoic acid 7 (1.53 g, 0.01 mol) for 1 hour according to the reported procedure [29, 30] and gave solid which recrystallised from methanol to give 8d 2.95 g, 98% as red crystals, mp 185–188°C decomp. νmax (KBr)/cm−1 1655 (C=O), 1622, 1600 (C=N): 1HNMR (200 MHz, 300 K, d6-acetone) δ 8.93 (s, 1H, H-8), 8.02 (d, 1H, JH6,H5 = 8.8 Hz, H-6), 7.33 (dd, 1H, JH15,H14 = 7.8 Hz, JH15,H13 = 1.6 Hz, H-15), 7.24 (dd, 1H, JH13,H14 = 8.0 Hz, JH13,H15 = 1.6 Hz, H-13), 6.91–7.09 (m, 3H, H-3,H-5, and H-14), 4.24 (q, 2H, JH16,H17 = 7.0 Hz, H-16), 1.41 (t, 3H, JH17,H16 = 7.0 Hz, H-17). Product 8d was used immediately in the synthesis of 9d.
4.1.4. Synthesis of 4-Substituted-(benzylamino)-2-hydroxybenzoic Acids 9a–d
General Procedure A. In slight modification to a previous reported method, [28] the appropriate 4-substituted ((benzylidene) amino)-hydroxybenzoic acids 8b-c reduced using sodium borohydride (2 equiv).
4-(Benzylamino)-2-hydroxybenzoic Acid
9a. 2-Hydroxy-4-{[(E)-benzylidene] amino} benzoic acid 8b (2.41 g, 10 mmol) was allowed to react with sodium borohydride (0.76 g, 20 mmol) according to general procedure A. The resulting solid was recrystallised from methanol/water to give 9a (1.76 g, 73%), mp 122–125°C. νmax (KBr)/cm−1 3500–3200 br (OH), 3024, 2569 (NH), 1632(C=O); 1HNMR (200 MHz, 340 K d6-DMSO) δ 11.34 (bs, 1H, OH of COOH exchangeable with D2O), 7.5 (d, 1H, JH6,H5 = 8.6 Hz, H-6), 7.21–7.47 (m, 6H, 5 x CH, 8-NH exchangeable with D2O), 6.22 (dd, 1H, JH5,H6 = 8.6 Hz, JH5,H8 = 2.0 Hz, H-5), 6.03 (d, 1H, JH3,H5 = 2.0 Hz, H-3), 4.38 (s, 2H, H-9). 3.32 (2-OH under the water envelope); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 171.7 (C-7), 163.2 (C-2), 154.8 (C-4), 139.1 (C-10), 130.1 (C-6), 128.1, 126.9, 126.6 (C-12, C-11 and C-13), 105.3 (C-5), 100.4 (C-1), 96.8 (C-3), 45.8 (C-9). The resulting product 9a was not stable and was used immediately in the genral procedure B.
2-Hydroxy-4-((2-hydroxybenzyl)amino)benzoic Acid
9b. (E)-2-Hydroxy-4-((2-hydroxybenzylidene)amino)benzoic acid 8c (2.6 g, 10 mmol) was allowed to react with sodium borohydride (0.76 g, 20 mmol) according to general procedure A. The resulting solid was recrystallised from methanol/water to give 9b as white crystals (2.20 g, 85%), mp 184–186°C decomp. νmax (KBr)/cm−1 3500–3200 br (OH), 1614 (C=O); 1HNMR (200 MHz, 300 K d6-DMSO) δ 11.45 (bs, 1H, 8-NH or 11-OH exchangeable with D2O), 9.61 (bs, 1H, 11-OH or 8-NH exchangeable with D2O) 7.44 (d, 1H, JH6,H5 = 8.8 Hz, H-6), 7.1–6.7 (m, 6H, H-13, H-15, H-14, H-12 and 11-OH), 6.28 (dd, 1H, JH5,H6 = 8.8 Hz, JH5,H3 = 1.1 Hz, H-5), 5.92 (d, 1H, JH3,H5 = 1.1 Hz, H-3); 13C NMR (50 MHz, 350 K, d6-DMSO) δ 171.9 (C-7), 163.5 (C-2), 155.2/155.0 (C-11/C-4), 131.2 (C-6), 128.5 (C-13), 127.9 (C-14), 125.0 (C-10), 119.1 (C-15), 115.3 (C-12), 105.6 (C-5), 100.6 (C-1), 97.0 (C-3), 41.1 (C-8). The resulting product 9b was used immediately in the general procedure B.
4-((3-Ethoxy-2-hydroxybenzyl)amino)-2-hydroxybenzoic Acid
9c. (E)-4-((3-Ethoxy-2-hydroxybenzylidene)amino)-2-hydroxybenzoic acid 8d (10 mmol, 3.0 g) was allowed to react with sodium borohydride (20 mmol, 0.76 g) according to general procedure A. The resulting solid was collected and recrystallised from methanol/water to give 9d (2.66 g, 81%) as white crystals, mp 159–161°C decomp. νmax (KBr)/cm−1 3500–3200 br (OH, NH absorption under the OH envelope), 1625 (C=O); 1HNMR (200 MHz, 300 K d6-DMSO) δ 7.38 (d, 1H, JH6,H5 = 8.6 Hz, H-6), 6.85–6.65 (m, 3H, H-13, H-14 and H-15), 6.35 (bs, 4H, 3 x OH and NH), 6.17 (dd, 1H, JH5,H6 = 8.6 Hz, JH5,H3 = 1.8 Hz, H-5), 5.87 (d, 1H, JH3,H5 = 1.8 Hz, H-3), 4.23 (s, 2H, CH2NH, H-9), 4.05 (q, 2H, JH16,H17 = 6.8 Hz, H-16), 1.35 (t, 3H, JH17,H16 = 6.8 Hz, H-17); 13C NMR (50 MHz, 300 K, d6-DMSO) δ 172.2 (C-7), 163.6 (C-2), 155.3 (C-4), 146.6 (C-12), 144.1 (C-11), 131.4 (C-6), 125.7 (C-10), 120.3 (C-14), 119.2 (C-15), 111.8 (C-13), 105.8 (C-1), 100.2 (C-5), 96.7 (C-3), 64.4 (C-16), 40.8 (C-9), 15.0 (C-17); Anal. Calcd. For C16H17NO5: C, 63.36; H, 4.62; N, 5.65. Found: C, 63.51; H, 4.48; N, 5.66.
4.1.5. Synthesis of Substituted-dihydroxy-di-carboxylic Acids 16 and 17
According to the previously reported general procedures [23–26], the appropriate substituted phenol was used in the synthesis substituted-dihydroxy-di-carboxylic acids 16 and 17.
4.1.6. Synthesis of 7-N-Substituted-amino-1,3-oxazines 10a, b, and 11a, b, and d
General Procedure B. The substituted-2-hydroxy benzoic acid was allowed to react with the freshly prepared Ph3P(SCN)2 according to previously reported general procedure [22, 34].
N-(4-Oxo-2-thioxo-3,4-dihydro-2H-benz[e][1,3]oxazin-7-yl)acetamide
10a. Slightly modified to the previously reported general procedure B [22, 34], 4-(acetyl amino)-2-hydroxybenzoic acid 8a (1.56 g, 8 mmol) was allowed to react with freshly prepared Ph3P(SCN)2 (10 mmol) at room temperature for 2 hours then under reflux for 16 hours. At the completion of the reaction, the PbBr2 filter cake was washed by acetic acid (150 mL) to extract the desired product. The acetic acid filtrate was evaporated and minimal toluene was added to dissolve any oil with the product. The crude solid was filtered and recrystallised from ethanol to give 10a (1.22 g, 65%) as light red crystals, mp 285–287°C decomp. νmax (KBr)/cm−1 3290, 3183 (9-NH), 3072, 2923 (3-NH), 1704 (C=O), 1188 (C=S); 1HNMR (200 MHz, 390 K, d6-DMSO) δ 13.38 (bs, 1H, 9-NH), 10.56 (s, 1H, 3-NH), 7.86 (d, 1H, JH5,H6 = 8.6 Hz, H-5), 7.77 (d, 1H, JH8,H6 = 1.8 Hz, H-8), 7.44 (dd, 1H, JH6,H5= 8.6 Hz, JH6,H8 = 1.8 Hz, H-6), 2.11 (s, 3H, 11-CH3); 13C NMR (50 MHz, 330 K, d6-DMSO) δ 181.9 (C-2), 169.2 (C-10), 156.7 (C-8a), 146.0 (C-7), 127.3 (C-5), 116.3 (C-6), 109.6 (C-4a), 104.2 (C-8), 24.0 (C-11) 155.9 (C-4); Anal. Calcd. For C10H8N2O3S: C, 50.84; H, 3.41; N, 11.86 C. Found: C, 50.69; H, 3.53; N, 11.86.
Synthesis of 7-Amino-2-thioxo-2H-benz[e][1,3]oxazin-4(3H)-one
10b. A suspension of (E)-4-((3-ethoxy-2-hydroxybenzylidene)amino)-2-hydroxybenzoic acid 8d (1.2 g, 4 mmol) in dry DCM (20 mL) was added to a mixture of freshly prepared Ph3P(SCN)2 (10 mmol) according to the general procedure B. The resulting solid was isolated upon evaporation of the DCM filtrate 10b (0.74 g, 91% crude yield). The solid was recrystallised from methanol, mp 250–253°C decomp. νmax (KBr) cm−1 3443, 3328, (NH2), 3059, 2916 (NH), 1749 (C=O), 1679, 1616 (C=C), 1205 (C=S); 1HNMR (200 MHz, 370 K, d6-DMSO) δ 13.04 (s, 1H, 3-NH), 7.58 (d, 1H, JH5,H6 = 8.6 Hz, H-5), 6.65 (s, 2H, 7-NH2), 6.60 (dd, 1H, JH6,H5 = 8.6 Hz, JH6,H8 =1.8 Hz, H-6), 6.37 (d, 1H, JH8,H6 = 1.8 Hz); 13C NMR (50 MHz, 330 K, d6-DMSO) δ 182.4 (C-2), 157.3, 156.9, 156.5 (C-4, C-8a, C-7), 128.1 (C-5), 112.7 (C-6), 102.3 (C-4a), 96.8 (C-8); Anal. Calcd. For C8H6N2O2S: C, 49.47; H, 3.11; N, 14.42. Found: C, 49.51; H, 3.20; N, 14.36.
7-(Benzylamino)-2-thioxo-2H-benz[e][1,3]oxazin-4(3H)-one
11a. In slight modification to previously reported general procedure B, 4-(benzylamino)-2-hydroxybenzoic acid 9a (0.94 g, 4 mmol) was allowed to react with the freshly prepared Ph3P(SCN)2 (10 mmol) at room temperature for 2 hours then under reflux for 16 hours. The resulting crude solids (0.94 g, 82%) were filtered, collected, and recrystallised from toluene to give 11a (0.88 g, 77%) as yellow crystals, mp 210–212°C decomp. νmax (KBr)/cm−1 3301 (9-NH) 3068, 2926 (3-NH), 1689 (C=O), 1197 (C=S); 1HNMR (200 MHz, 340 K, d6-DMSO) δ 12.90 (bs, 1H, 3-NH exchangeable with D2O), 7.61 (d, 1H, JH5,H6 = 8.8 Hz, H-5), 7.37–7.26 (m, 6H, Ar and 9-NH exchangeable with D2O), 6.73 (dd, 1H, JH6,H5 = 8.8 Hz, JH6,H8 = 2.0 Hz, H-6), 6.42 (d, 1H, JH8,H6 = 2.0 Hz, H-8), 4.41 (d, 2H, JH10,H9 = 5.9 Hz, H-10); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 182.1 (C-2), 157.2, 156.5 (C-4, C-8a), 155.2 (C-7), 138.2 (C-11), (128.2, 127.3, 127.0, 126.8), (C-13, C-12, C-14 and C-5), 111.9 (C-6), 102.5 (C-4a), 95.1 (C-8), 45.8 (C-10); Anal. Calcd. For C15H12N2O2S: C, 59.99; H, 4.03; N, 9.33. Found: C, 59.83; H, 4.14; N, 9.45.
7-((2-Hydroxybenzyl)amino)-2-thioxo-2H-benz[e][1,3]oxazin-4(3H)-one
11b. In slight modification to previously reported general procedure B, 2-hydroxy-4-((2-hydroxybenzyl)amino)benzoic acid 9b (1.07 g, 4 mmol) was allowed to react with the freshly prepared Ph3P(SCN)2 (10 mmol) at room temperature for 2 hours then under reflux for 16 hours. The resulting crude solid recrystallised from acetonitrile to give 11b (0.55 g, 46%) as yellow crystals, mp 173–175°C decomp. νmax (KBr)/cm−1 3500–3000 br (OH), 3310 (9-NH), 2926 (3-NH), 1684 (C=O), 1192 (C=S); 1HNMR (200 MHz, 340 K, d6-DMSO) δ 12.86 (bs, 1H, 3-NH), 9.50 (bs, 1H, 12-OH), 7.59 (d, 1H, JH5,H6 = 8.6 Hz, H-5), 7.41 (bs, 1H, 9-NH), 7.05–7.20 (m, 2H, H-14, H-16), 6.69–6.88 (m, 3H, H-13, H-15 and H-6), 6.42 (d, 1H, JH8,H6 = 2.0 Hz, H-8), 4.32 (s, 2H, H-10); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 182.2 (C-2), 157.3, 156.7, 155.4, 154.9 (C-4, C-8a, C-12 and C-7), 128.5, 127.9, 127.3 (C-14, C-16 and C-5) 123.9 (C-11), 118.8, 115.1 C-15, C-13), 111.9 (C-6), 102.2 (C-4a), 94.9 (C-8), 40.9 (C-10); Anal. Calcd. For C15H12N2O3: C, 59.99; H, 4.03; N, 9.33 Found: C, 59.83; H, 4.14; N, 9.45.
7-((3-Ethoxy-2-hydroxybenzyl)amino)-2-thioxo-2H-benz[e][1,3]oxazin-4(3H)-one
11c. In slight modification to previously reported general procedure [22, 34], 4-((3-ethoxy-2-hydroxybenzyl)amino)-2-hydroxybenzoic acid 9d (1.21 g, 4 mmol) was allowed to react with the freshly prepared Ph3P(SCN)2 (10 mmol) heated to room temperature for 2 hours then under reflux for 16 hours. The resulting solids (1.94 g) were recrystallised from acetic acid/water to give 11c (0.95 g, 68%) as yellow crystals, mp 227–229°C decomp. νmax (KBr)/cm−1 3500–3200 br (OH), 3496 (7-NH), 3301 (3-NH), 1686 (C=O), 1620 (C=C), 1196 (C=S); 1HNMR (200 MHz, 390 K, d6-DMSO) δ 12.86 (bs, 1H, 3-NH), 8.44 (s, 1H, 12-OH exchangeable with D2O), 7.59 (d, 1H, JH5,H6 = 8.4 Hz, H-5), 7.42 (t, 1H, 9-NH) 6.89–6.40 (m, 4H, Ar and H-6), 6.41 (d, 1H, JH8,H6 = 1.8 Hz, H-8), 4.33 (d, 2H, 10-CH2), 4.07 (q, 2H, JH17,H18 = 7.0 Hz, 17-CH2), 1.36 (t, 3H, JH18,H17 = 7.0 Hz, 18-CH3); 13C NMR (50 MHz, 390 K, d6-DMSO) δ 181.8 (C-2), 156.9, 156.1, 155.2 (C-4, C-8a, C-7), 146.2, 144.2 (C-13, C-12), 126.9, 124.4 (C-15, C-11), 120.2, 118.4 (C-5, C-16), 112.2, 111.5 (C-14, C-6), 102.1 (C-4a), 94.8 (C-8), 64.2 (C-17), 40.7 (C-10), 14.0 (C-18); Anal. Calcd. For C15H12N2O2S: C, 59.29; H, 4.68. Found: C, 59.07; H, 4.70.
4.1.7. Synthesis of Dithioxo-benz-bis-(1,3-oxazine)-diones 18a–c and 19
2,8-Dithioxo-2,3,7,8-tetrahydrobenzo[1,2-e: 5,4-e
′
]bis([1,3]oxazine)-4,6-dione 18a. In slight modification to the general procedure B, 4,6-dihydroxyisophthalic acid 16a (0.79 g, 4 mmol) was allowed to react with the freshly prepared Ph3P(SCN)2 (10 mmol) heated to room temperature for 3 hours then under reflux for 5 hours. At the completion of the reaction, the reaction mixture was filtered and the PbBr2 filter cake washed with THF (100 mL) to extract product 18a. Both THF and DCM filtrates were evaporated to dryness and minimal toluene added to remove any oil which may be present. The crude solid was recrystallised using dioxane/chloroform to give 18a (0.63 g, 56%) as yellow crystals, mp >300°C decomp. νmax (KBr)/cm−1 3104, 3031, 2939, 2856 (3 and 7-NH), 1698 (C=O), 1152 (C=S); 1HNMR (200 MHz, 350 K d6-DMSO) δ 13.65 (bs, 2H, 2 x NH), 8.27 (bs, 1H, H-5), 7.69 (bs, 1H, H-10); 13C NMR (50 MHz, d6-DMSO) δ 181.1 (C-2,8), 159.0 (C-4,6), 156.1 (C-9a,10a), 126.5 (C-5), 113.8 (C-4a,5a), 104.1 (C-10); Anal. Calcd. For C10H4N4O4S2: C, 42.85; H, 1.44; N, 9.99. Found: C, 42.71; H, 1.48; N, 10.05.
10-Hydroxy-2,8-dithioxo-2,3,7,8-tetrahydrobenzo[1,2-e:
5,4-e
′
]bis([ 1,3]oxazine)-4,6-dione 18b. In slight modification to general procedure B, 4,5,6-trihydroxyisophthalic acid 16b (0.86 g, 4 mmol) was allowed to react with the freshly prepared Ph3P(SCN)2 (10 mmol) at room temperature for 3 hours and then under reflux for 5 hours. At the completion of the reaction, the mixture was filtered and the PbBr2 cake washed with 100 mL 1,4-dioxane. Both dioxane and DCM filtrates were evaporated to dryness under reduced pressure and minimal toluene was added to remove any oil which may be present. The resulting solid was recrystallised from 1, 4 dioxane/chloroform to give 18b (0.55 g, 46%) as yellow crystals, mp 286–289°C decomp. νmax (KBr)/cm−1 3300–3000 br (OH), 3103, 3047, 2938 (NH), 1698 (C=O), 1227 (C=S); 1H NMR (200 MHz, 390 K d6-DMSO) δ 13.69 (bs, 2H, 2 x NH), 11.64 (bs, 1H, OH), 7.80 (bs, 1H, H-5); 13CNMR (50 MHz, 390 K d6-DMSO) δ 181.0 (C-2,8), 156.8 (C-4,6), 148.6 (C-9a,10a), 131.9 (C-10), 113.8 (C-5), 113.8 (C-4a,5a); Anal. Calcd. For C10H4N4O4S2: C, 42.85; H, 1.44; N, 9.99. Found: C, 42.71; H,1.48; N, 10.05.
10-Methyl-2, 8-dithioxo-2, 3, 7, 8-tetrahydrobenzo[1,2-e:
5,4-e
′
]bis([1 ,3]oxazine)-4,6-dione 18c. In slight modification to general procedure B, 4,6-dihydroxy-5-methylisophthalic acid 16c (1.7 g, 8 mmol) was allowed to react with freshly prepared Ph3P(SCN)2 [22, 34] (10 mmol) at room temperature for 3 hours then under reflux for 5 hours. At the completion of the reaction, the reaction mixture was filtered and the PbBr2 cake washed with approx 100 mL THF and filtered. Both THF and DCM filtrates were evaporated to dryness under reduced pressure and minimal toluene was added to remove any oil, which may be present. The solid which remained was then recrystallised using THF to give product 18c (1.18 g, 50%). The physical and spectroscopic data is consistent with the literature values [22].
2,9-Dithioxo-2,3,8,9-tetrahydrobenzo[1,2-e:4,3-e
′
]bis([1,3]oxazine)-4,7-dione 19. In slight modification to the general procedure B [22, 34], 2,3-dihydroxyterephthalic acid 17 (0.86 g, 4 mmol) was allowed to react with freshly prepared Ph3P(SCN)2 (10 mmol) at room temperature for 3 hours then under reflux for 5 hours. At the completion of the reaction, the reaction mixture was filtered and the PbBr2 cake was washed with THF (100 mL). Both THF and DCM filtrates were evaporated to dryness under reduced pressure and minimal toluene was added to remove any oil, which may be present. The remaining solid is recrystallised from ethyl acetate to give 19 (0.54 g, 50%) as yellow crystals, mp > 300°C decomp. νmax (KBr)/cm−1 3079, 2904, 2864 (NH), 1718 (C=O), 1252 (C=S); 1H NMR (200 MHz, 390 K d6-DMSO) δ 13.90 (bs, 2H, 2 x NH), 7.89 (s, 2H, H-5 & H-6); 13C NMR (50 MHz, 390 K (d6-DMSO) δ 181.1 (C-2,9), 157.0 (C-4,7), 142.7 (C-10a,10b), 122.5 (C-5,6), 121.3 (C-4a,6a); Anal. Calcd. For C10H4N2O4S2: C, 42.85; H, 1.44; N, 9.99. Found: C, 42.74; H, 1.50; N, 9.93.
4.1.8. Synthesis of Benzyl Thiourea 13a–q
General Procedure C. The appropriate 2-thio-1,3-benzoxazines (1.7 mmole) 6, 10a,b, 11c, and 12a–m were suspended in a mixture of sodium bicarbonate (1 gm) and water (5 mL)/methanol (5 mL) with stirring, then the reaction mixture was warm to 40°C for few minutes then benzyl amine (4.25 mmol) was added dropwise, directly from the a pipette, left stirring at room temperature for 4 hours. At the completion of the reaction, the mixture was evaporated to dryness under reduced pressure and the pH was adjusted to 5-6 by using conc. HCl. The resulting solid was collected by vacuum filtration and washed with minimal water and recrystallized from an appropriate solvent.
N-(Benzyl carbamothioyl)-2-hydroxybenzamide
13a. 2-Thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12a was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from toluene to give 13a (75% yield), mp 176-177°C (Lit. [19, 20] 179°C). νmax (KBr)/cm−1 3301 (N–H), 3200–2700 (O–H), 1661 (C=O), 1605 (C=S); 1H NMR (d6-DMSO) δ 12.42 (bs, 1H, H-2′), 11.41 (s, 1H, O–H), 11.00 (t, 1H, J = 5.4 Hz, H-4′), 7.70–7.00 (m, 9H, ArH), 4.9 (d, 2H, J = 5.2 Hz, H-5′); 13C NMR (d6-DMSO) δ 179.6 (C-3′), 168.3 (C-1′), 160.7 (C-2), 136.3 (C-6′), 135.9 (C-4), 129.0 (C-6), 128.1 (C-7′), 127.9 (C-8′), 127.5 (C-9′), 120.1 (C-5), 118.8 (C-3), 113.3 (C-1), 50.0 (C-5′).
N-(Benzyl carbamothioyl)-2-hydroxy-3-methylbenzamide
13b. 8-Methyl-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12b was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from toluene to give 13b (79% yield), mp 220–223°C. νmax (KBr)/cm−1 3062, 2883 (N–H), 1696 (C=O), 1610 (C=S); 1H NMR (d6-DMSO) δ 11.32 (bs, 1H, H-2′), 10.73 (s, 1H, O–H), 8.80 (t, 1H, J = 5.4 Hz, H-4′), 7.82 (d, 1H, J = 7.5 Hz, H-6), 7.40–7.20 (m, ArH, H-4), 6.8 (t, 1H, J = 7.5 Hz, H-5), 4.43 (d, 2H, J = 6.0 Hz, H-5′), 2.20 (s, 3H, 8-CH3); 13C NMR (d6-DMSO) δ 169.9 (C-3′), 157.7 (C-1′), 152.9 (C-2), 137.5 (C-6′), 136.0 (C-4), 128.4 (C-7′), 127.3 (C-8′), 127.0 (C-9′), 126.9 (C-3), 126.5 (C-6), 119.0 (C-5), 115.1 (C-1), 42.9 (C-5′), 15.9 (CH3); Anal. Calcd. For C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.10; H, 5.38; N, 9.25.
N-(Benzyl carbamothioyl)-2-hydroxy-[1,1
′
-biphenyl]-3-carboxamide 13c. 8-Phenyl-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12c was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from toluene to give 13c (80% yield), mp 250–253°C. νmax (KBr)/cm−1 3062, 2883 (N–H), 1686 (C=O), 1595 (C=S); 1H NMR (d6-DMSO) δ 11.30 (s, 1H, 2′-N–H), 10.70 (s, 1H, O–H), 8.80 (t, 1H, J = 5.4 Hz, 4′-N–H), 7.90 (d, 1H, J = 7.6 Hz, H-6), 7.80 (d, 1H, J = 7.6 Hz, H-4), 7.60 (dd, 1H, JH8,H10 = 1.6 Hz, JH8,H9 = 8.0 Hz, H-8), 7.50 (m, 4H, H-5/H-9/H-10), 7.30–7.20 (m, ArH, H-4), 4.90 (d, 2H, J = 6.0 Hz, H-5′); 13C NMR (d6-DMSO) δ 169.4 (C-3′), 157.7 (C-1′), 155.3 (C-2), 137.2 (C-6′), 134.2 (C-4), 129.5 (C-6), 128.4 (C-7′), 127.3 (C-8′), 127.0 (C-9′), 126.3 (C-3), 120.1 (C-1), 118.9 (C-5), 50.1 (C-5′); Anal. Calcd. For C15H14N2O2S: C, 62.92; H, 4.93; N, 9.78. Found: C, 63.03; H, 4.88; N, 9.80.
N-(Benzyl carbamothioyl)-5-bromo-2-hydroxybenzamide
13d. 6-Bromo-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12d was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from toluene to give 13d (82% yield), mp 185°C. νmax (KBr)/cm−1 3296, 3073 (N–H), 1678 (C=O), 1601 (C=S); 1H NMR (d6-DMSO) δ 12.42 (bs, 1H, H-2′), 11.41 (s, 1H, O–H), 11.00 (t, 1H, J = 5.4 Hz, H-4′), 7.90 (d, 1H, J = 2.2 Hz, H-6), 7.60 (dd, 1H, JH4,H6 = 2.2 Hz, JH4,H3 = 7.5 Hz, H-4), 7.40–7.30 (m, 5H, ArH), 7.00 (d, 1H, J = 7.5 Hz, H-3), 4.90 (d, 2H, J = 5.5 Hz, H-5′); 13C NMR (d6-DMSO) δ 179.4 (C-3′), 163.3 (C-1′), 155.9 (C-2), 137.4 (C-4), 137.3 (C-6′), 132.9 (C-6), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 119.7 (C-1), 118.8 (C-3), 111.1 (C-5), 48.3 (C-5′); Anal. Calcd. For C15H13BrN2O2S: C, 49.33; H, 3.59; N, 7.67. Found: C, 49.39; H, 3.68; N, 7.93.
N-(Benzyl carbamothioyl)-5-ethoxy-2-hydroxybenzamide
13e. 6-Ethoxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12e was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from toluene to give 13e (87% yield), mp 210°C. νmax (KBr)/cm−1 3300, 3051 (N–H), 1665 (C=O), 1630 (C=S); 1H NMR (d6-DMSO) δ 12.00 (bs, 1H, H-2′), 11.32 (s, 1H, O–H), 11.12 (t, 1H, J = 5.4 Hz, H-4′), 7.50 (s, 1H, H-6), 7.30–7.10 (m, 7H, ArH/H-3/H-4), 4.80 (d, 2H, J = 5.5 Hz, H-5′), 4.10–4.00 (q, 2H, J = 6.7 Hz, O–CH2), 1.30–1.20 (t, 3H, J = 6.7 Hz, CH3); 13C NMR (d6-DMSO) δ 179.8 (C-3′), 164.3 (C-1′), 164.0 (C-2), 158.3 (C-5), 137.4 (C-6′), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 120.2 (C-1), 107.9 (C-3), 107.7 (C-4), 101.7 (C-6), 63.6 (O–CH2), 48.2 (C-5′), 14.5 (CH3); Anal. Calcd. For C17H18N2O3S: C, 61.80; H, 5.49; N, 8.48. Found: C, 61.90; H, 5.55; N, 8.61.
N-(Benzyl carbamothioyl)-4-ethoxy-2-hydroxybenzamide
13f. 7-Ethoxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12f was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from ethyl acetate to give 13f (73% yield), mp 215–218°C. νmax (KBr)/cm−1 3307, 3071 (N–H), 1655 (C=O), 1506 (C=S); 1H NMR (d6-DMSO) δ 11.91 (bs, 1H, H-2′), 11.00 (s, 1H, O–H), 10.90 (t, 1H, J = 5.6 Hz, H-4′), 7.80 (d, 1H, J = 8.9 Hz, H-6), 7.30–7.20 (m, 5H, ArH), 6.60 (d, 1H, J = 8.9 Hz, H-5), 6.40 (sd, 1H, J = 1.5 Hz, H-3), 4.80 (d, 2H, J = 5.5 Hz, H-5′), 4.10–4.00 (q, 2H, J = 6.7 Hz, O–CH2), 1.30–1.20 (t, 3H, J = 6.7 Hz, CH3); 13C NMR (d6-DMSO) δ 179.8 (C-3′), 164.3 (C-1′), 164.0 (C-4), 158.3 (C-2), 137.4 (C-6′), 130.9 (C-6), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 109.2 (C-5), 107.9 (C-1), 101.7 (C-3), 63.6 (O–CH2), 48.2 (C-5′), 14.5 (CH3); Anal. Calcd. For C17H18N2O3S C, 61.80; H, 5.49; N, 8.48. Found: C, 62.02; H, 5.55; N, 8.51.
N-(Benzyl carbamothioyl)-3-ethoxy-2-hydroxybenzamide
13g. 8-Ethoxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12g was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from toluene to give 13g (82% yield), mp 188–190°C. νmax (KBr)/cm−1 3310, 3080 (N–H), 1656 (C=O), 1525 (C=S); 1H NMR (d6-DMSO) δ 11.80 (s, 1H, 2′-N–H), 11.60 (s, 1H, O–H), 11.00 (t, 1H, J = 5.4 Hz, 4′-N–H), 7.30–7.20 (m, 6H, ArH/H-5), 7.10 (d, 1H, J = 7.5 Hz, H-6), 6.90 (d, 1H, J = 7.5 Hz, H-4), 4.80 (d, 2H, J = 5.5 Hz, H-5′), 4.00–3.90 (q, 2H, J = 6.7 Hz, O–CH2), 1.30–1.20 (t, 3H, J = 6.7 Hz, CH3); 13C NMR (d6-DMSO) δ 179.5 (C-3′), 164.3 (C-1′), 151.8 (C-3), 150.5 (C-2), 137.3 (C-6′), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 123.0 (C-5), 118.5 (C-6), 116.5 (C-1), 114.2 (C-4), 63.5 (O–CH2), 48.3 (C-5′), 14.6 (CH3); Anal. Calcd. For C17H18N2O3S: C, 61.80; H, 5.49; N, 8.48. Found: C, 61.96; H, 5.61; N, 8.54.
N-(Benzyl carbamothioyl)-2-hydroxy-5-methoxybenzamide
13h. 6-Methoxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12h was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from ethyl acetate to give 13h (69% yield), mp 140°C. νmax (KBr)/cm−1 3313, 3081 (N–H), 1667 (C=O), 1610 (C=C), 1516 (C=S); 1H NMR (d6-DMSO) δ 12.40 (s, 1H, 2′-N–H), 11.30 (s, 1H, O–H), 11.20 (t, 1H, J = 5.4 Hz, 4′-N–H), 7.50–7.30 (m, 8H, ArH/H-3/H-4/H-6), 3.80 (s, 3H, O–CH3); 13C NMR (d6-DMSO) δ 179.9 (C-3′), 165.4 (C-1′), 151.5 (C-5), 149.0 (C-2), 137.4 (C-6′), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 121.8 (C-3), 117.9 (C-4), 116.4 (C-1), 56.2 (O–CH3), 48.1 (C-5′); Anal. Calcd. For C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85. Found: C, 60.82; H, 5.18; N, 8.93.
N-(Benzyl carbamothioyl)-2-hydroxy-4-methoxybenzamide
13i. 7-Methoxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12i was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from ethyl acetate to give 13i (87% yield), mp 210°C. νmax (KBr)/cm−1 3313, 3081 (N–H), 1667 (C=O), 1610 (C=C), 1520 (C=S); 1H NMR (d6-DMSO) δ 12.40 (s, 1H, 2′-N–H), 11.30 (s, 1H, O–H), 11.20 (t, 1H, J = 5.4 Hz, 4′-N–H), 7.70 (d, 1H, J = 7.5 Hz, H-6), 7.50–7.30 (m, 5H, ArH), 6.70 (m, 2H, H-3/H-5), 3.80 (s, 3H, O–CH3); 13C NMR (d6-DMSO) δ 179.9 (C-3′), 165.4 (C-1′), 160.5 (C-4), 159.0 (C-2), 137.4 (C-6′), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 126.8 (C-6), 117.9 (C-5), 116.4 (C-1), 106.0 (C-3), 56.2 (O–CH3), 48.1 (C-5′); Anal. Calcd. For C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85. Found: C, 60.72; H, 5.20; N, 8.90.
N-(Benzyl carbamothioyl)-2-hydroxy-3-methoxybenzamide
13j. 8-Methoxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12j was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from toluene to give 13j (82% yield), mp 190–193°C. νmax (KBr)/cm−1 3313, 3081 (N–H), 1667 (C=O), 1610 (C=C), 1518 (C=S); 1H NMR (d6-DMSO) δ 12.40 (s, 1H, 2′N–H), 11.30 (s, 1H, O–H), 11.20 (t, 1H, J = 5.4 Hz, 4′-N–H), 7.50-7.20 (m, 8H, ArH/H-4/H-5/H-6), 3.80 (s, 3H, O–CH3); 13C NMR (d6-DMSO) δ 179.9 (C-3′), 165.4 (C-1′), 149.5 (C-3), 148.0 (C-2), 137.4 (C-6′), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 121.8 (C-6), 117.9 (C-5), 116.4 (C-1), 116.0 (C-4), 56.2 (O–CH3), 48.1 (C-5′); Anal. Calcd. For C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85. Found: C, 60.82; H, 5.18; N, 8.93.
N-(Benzyl carbamothioyl)-2-hydroxy-3,5-diiodobenzamide
13k. 6,8-diiodo-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12k was allowed to react with benzylamine according to general procedure C. The solid was collected and recrystallized from toluene to give 13k (75% yield), mp 173–175°C. νmax (KBr)/cm−1 3264, 3025 (N–H), 1633 (C=O), 1576 (C=C), 1545 (C=S); 1H NMR (d6-DMSO) δ 11.90 (s, 1H, 2′-N–H), 10.90 (t, 1H, J = 5.4 Hz, 4′-N–H), 8.20 (d, 1H, J = 2.2 Hz, H-6), 8.00 (d, 1H, J = 2.2 Hz, H-4), 7.40–7.30 (m, 5H, ArH), 4.90 (d, 2H, J = 5.5 Hz, H-5′), 13C NMR (d6-DMSO) δ 179.8 (C-3′), 165.6 (C-1′), 157.0 (C-2), 149.7 (C-4), 137.9 (C-6′), 137.3 (C-6), 128.5 (C-7′), 127.7 (C-8′), 127.3 (C-9′), 121.1 (C-1), 91.75 (C-5), 81.9 (C-3), 48.2 (C-5′); Anal. Calcd. For C15H12I2N2O2S: C, 33.48; H, 2.25; N, 5.21. Found: C, 33.43; H, 2.66; N, 5.78.
N-(Benzyl carbamothioyl)-2,4-dihydroxybenzamide
13l. 7-Hydroxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12l was allowed to react with benzylamine according to general procedure C. The solid was collected and recrystallized from toluene to give 13l (87% yield), mp190°C. νmax (KBr)/cm−1 3200–2700 (O–H), 3118, 3033 (N–H), 1665 (C=O), 1626 (C=C), 1554 (C=S); 1H NMR (d6-DMSO) δ 12.10 (bs, 1H, O–H), 11.30 (s, 1H, N–H), 11.20 (t, 1H, J = 5.4 Hz, N–H), 10.50 (O–H), 7.80 (d, 1H, J = 7.6 Hz, H-6), 7.30 (m, 5H, ArH), 6.40 (m, 2H, H-3/H-5), 4.80 (d, 2H, J = 5.7 Hz, H-5′); 13C NMR (d6-DMSO) δ 180.0 (C-3′), 164.7 (C-1′), 163.9 (C-4), 158.5 (C-2), 137.5 (C-6′), 133.3 (C-6), 128.7 (C-7′), 127.7 (C-8′), 127.5 (C-9′), 109.2 (C-5), 107.9 (C-1), 102.9 (C-3), 48.2 (C-5′); Anal. Calcd. For C15H14N2O3S: C, 59.59; H, 4,67; N, 9.27. Found: C, 59.88; H, 4.68; N, 9.59.
N-(Benzyl carbamothioyl)-2,4-dihydroxy-3-methylbenzamide
13m. 7-Hydroxy-8-methyl-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12m was allowed to react with benzylamine according to general procedure C. The solid was collected and recrystallized from ethanol to give 13m (78% yield), mp 193–195°C. νmax (KBr) 3381, 3225 (O–H), 3020–2800 (N–H), 1639 (C=O), 1613 (C=S); 1H NMR (d6-DMSO) δ 11.60 (bs, 1H, 2-OH), 11.10 (t, 1H, J = 5.6 Hz, 4′-NH), 10.40 (bs, 1H, 2′-NH), 7.70 (d, 1H, JH6,H5 = 8.8 Hz; H-6), 7.40–7.30 (m, 6H/H-7′/H-8′/H-9′/4-OH), 6.50 (d, 1H, JH5,H6 = 8.8 Hz; H-5), 4.90 (d, 2H, J = 5.6 Hz, H-5′), 2.00 (s, 3H, 3-CH3); 13C NMR (d6-DMSO) δ 179.9 (C-3′), 166.1 (C-1′), 161.5 (C-4), 157.2 (C-2), 137.3 (C-6′), 129.1 (C-7′), 128.4 (C-8′), 127.5 (C-9′), 127.2 (C-6, C-3), 111.8 (C-1), 108.3 (C-5), 48.1 (C-5′), 8.6 (3-CH3). Anal. Calcd. For C16H16N2O3S C, 60.74; H, 5.10; N, 8.85. Found: C, 60.60; H, 5.08; N, 8.80; %.
N-(Benzyl carbamothioyl)-2,3-dihydroxybenzamide
13n. 8-Hydroxy-2-thioxo-2H-benz[e]-1,3-oxazin-4(3H)-one 12n was allowed to react with benzyl amine according to general procedure C. The crude solid was collected and recrystallized from ethanol to give 13n (72% yield), mp 172°C. νmax (KBr)/cm−1 3411, 2942 br (O–H), 3118, 3033 (N–H), 1661 (C=O), 1626 (C=C), 1553 (C=S); 1H NMR (d6-DMSO) δ 11.61 (s, 1H, 2′-N–H), 11.22 (t, 1H, J = 5.6 Hz, 4′-N–H), 10.53 (O–H), 7.30 (m, 7H, ArH/H-6), 7.00 (d, 1H, J = 7.6 Hz, H-4), 6.70 (t, 1H, J = 7.9 Hz, H-5), 4.80 (d, 2H, J = 5.7 Hz, H-5′); 13C NMR (d6-DMSO) δ 179.7 (C-3′), 165.0 (C-1′), 146.6 (C-2), 146.3 (C-3), 137.3 (C-6′), 128.5 (C-7′), 127.6 (C-8′), 127.3 (C-9′), 120.5 (C-5), 119.4 (C-4), 119.2 (C-5), 116.8 (C-1), 48.2 (C-5′); Anal. Calcd. For C15H14N2O3S: C, 59.59; H, 4.67; N, 9.27. Found: C, 60.08; H, 5.06; N, 9.59.
4-Amino-N-(benzyl carbamothioyl)-2-hydroxybenzamide
13o. 7-Amino-2-thioxo-2H-benz[e][1,3]oxazin-4(3H)-one 10b was allowed to react with benzylamine following general procedure C. The resulting solid was collected and recrystallised from methanol/water to give 13o (0.35 g, 78%) as off white solid, mp 290–293°C decomp. νmax (KBr)/cm−1 3500–3200 (OH), 3442, 3332 (NH), 1750, 1677 (C=O), 1388 (C=S);. 1HNMR (200 MHz, 300 K, d6-DMSO) δ 11.54 (s, 1H, 8-NH exchangeable with D2O), 11.33–11.28 (bm, 2H, 10-NH, 2-OH exchangeable with D2O), 7.60 (d, 1H, JH6,H5 = 8.6 Hz, H-6), 7.33–7.29 (m, 7H, Ar, H-11, H-12, H-13 and 4-NH2 exchangeable with D2O), 6.21 (dd, 1H, JH5,H6&H5H3 = 8.6 Hz, JH5,H3 = 1.6 Hz, H-3), (d, 1H, JH3,H5 = 1.6 Hz, H-3), 4.84 (d, 2H, JH11,H10 = 5.7 Hz, H-11); 13C NMR (50 MHz, 300 K, d6-DMSO) δ 180.3 (C-9), 165.2 (C-7), 158.6 (C-2), 155.1 (C-4), 137.7 (C-12), 133.2 (C-6), 128.9 (C-14), 127.8, 127.7 (C-13, C-15), 108.2 (C-5), 104.3 (C-1), 99.7 (C-3), 48.4 (C-11); Anal. Calcd. For C15H15N3O2S: C, 59.78; H, 5.02; N, 13.94. Found: C, 59.55; H, 5.08; N, 13.72.
4-Acetamido-N-(benzyl carbamothioyl)-2-hydroxybenzamide
13p. N-(4-Oxo-2-thioxo-3, 4-dihydro-2H-benz[e][1,3]oxazin-7-yl) acetamide 10a was allowed to react with benzylamine following general procedure C. The resulting solid was collected and recrystallised from ethanol to give 13p (0.27 g, 47%) as off white crystals. mp 263–266°C. νmax (KBr)/cm−1 3500–3200 (OH), 3292, 3113, (NH), 1656 (C=O), 1374 (C=S); 1HNMR (200 MHz, 300 K, d6-DMSO) δ 12.09 (s, 1H, 16-NH), 11.40 (s, 1H, 8-NH), 11.18 (t, 1H, JH10,H11 = 4.6 Hz, 10-NH), 10.26 (s, 1H, 2-OH), 7.84 (d, 1H, JH6,H5 = 7.8 Hz H-6), 7.64 (s, 1H, H-3), 7.37–7.30 (m, 5H, Ar, H-13, H-14, H-15), 7.02 (d, 1H, JH5,H6 = 7.8 Hz, H-5), 4.85 (d, 2H, JH11,H10 = 4.8 Hz, H-11), 2.07 (s, 3H, CH3); 13C NMR (50 MHz, 300 K, d6-DMSO) δ 179.7 (C-9), 169.1 (C-7), 164.2 (C-17), 157.4 (C-2), 145.3 (C-4), 137.3 (C-12), 131.9 (C-6), 128.5, 127.6, 127.3 (C-13, C-14, C-15), 111.0, 110.8 (C-1, C-5), 105.9 (C-3), 48.1 (C-11), 24.2 (C-18); Anal. Calcd. For C17H17N3O3S: C, 59.46; H, 4.97; N, 12.24. Found: C, 59.20; H, 5.07; N, 12.02.
N-(Benzyl carbamothioyl)-4-((3-ethoxy-2-hydroxybenzyl)amino)-2-hydroxybenzamide
13q. 3-Ethoxy-2-hydroxy-1,3-benzoxazine 11c was allowed to react with benzylamine according to the general procedure C. The resulting solid was collected and recrystallised from acetonitrile to give 13q (0.59 g, 77%) as yellow crystals, mp 201–204°C. νmax (KBr)/cm−1 3500–3200 (OH), 3496, 3395, 3256 (NH), 1686, 1646 (C=O), 1342 (C=S); 1HNMR (200 MHz, 300 K, d6-DMSO) δ 11.26 (8-NH), 8.33 (m, 1H, 2-OH), 7.63 (d, 1H, JH6,H5 = 9.0 Hz, H-6), 7.66–7.28 (m, 5H, Ar H-13, H-14, H-15), 7.1 (t, 1H, JH16,H17 = 5.1 Hz, H-16), 6.92–6.66 (m, 5H, H-21, H-22, H-25, 10-NH and 19-OH exchangeable with D2O), 6.30 (dd, 1H, JH5,H6&H5,H3 = 9.0 Hz, JH5,H3 = 1.6 Hz, H-5), 6.14 (d, 1H, JH3,H5 = 1.6 Hz, H-3), 4.85 (d, 2H, JH11,H10 = 5.1 Hz, H-11), 4.25 (d, 2H, JH17,H16 = 5.3 Hz, H-17), 4.08–4.01 (m, 3H, JH24,H25 = 7.0 Hz, H-24 and 16-NH), 1.45 (t, 3H, JH25,H24 = 7.0 Hz, H-25); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 180.1 (C-9), 164.8 (C-7), 158.2 (C-2), 154.7 (C-4), 146.3, 144.1 (C-20, C-19), 137.2 (C-12), 132.1 (C-6), 128.2, 127.3, 127.0 (C-14, C-13, C-15), 125.1 (C-18), 119.9, 118.5 (C-21, C-23), 111.8 (C-22), 106.1, 103.6 (C-1, C-5), 97.2 (C-3), 64.1 (C-24), 47.9 (C-17), 40.8 (C-11), 14.4 (C-25); Anal. Calcd. For C24H25N3O4S·H2O: C, 61.39; H, 5.80; N, 8.95. Found: C, 61.59; H, 5.57; N, 9.38.
4.1.9. N1,N3-Bis(benzyl carbamothioyl)-4,6-dihydroxy-lisophthalamide 20a
In slight modification to the general procedure C, 2, 8-dithioxo-2, 3, 7, 8-tetrahydrobenzo[1,2-e: 5,4-e′]bis([1,3]oxazine)-4,6-dione 18a (1 mmol, 0.28 g) was allowed to react with benzylamine (3 mmol. 0.32 g) and sodium hydrogen carbonate solution (1 g in 12 mL methanol and 2.4 mL water) for 16 hour. The resulting solid was collected and recrystallised from ethanol to give 20a (0.31 g, 63%) as off white crystals.mp 276–279°C decomp. νmax (KBr)/cm−1 3313, (NH), 1672 (C=O), 1328 (C=S), 1HNMR (200 MHz, 340 K, d6-DMSO) δ 11.25 (bs, 2H, 2 x NH), 11.06 (t, 2H, JH10,H11 = 5.7 Hz, H-10,18), 8.60 (s, 1H, H-6), 7.38–7.29 (10H, 2 x Ar), 6.63 (s, 1H, H-3), 4.87 (d, 4H, JH11,H10 = 5.7 Hz, H-11,20), 3.3 (OH under the water envelope); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 179.5 (C-9,17), 163.3 (C-7,15), 161.5 (C-2,4), 137.0, 136.6 (C-11, 20 and C-6), 128.2, 127.3, 127.0 (C-13, 22, C-12, 21 and C-14, 25), 110.3 (C-1,15), 103.7 (C-3), 48.0 (C-11,19); Anal. Calcd. For C24H22N4O4S2: C, 58.28; H, 4.48; N, 11.33. Found: C, 58.37; H, 4.67; N, 11.22.
4.1.10. N1,N3-Bis(benzyl carbamothioyl)-4,6-dihydroxy-5-methylisophthalamide 20c
In slight modification to general procedure C, 10-methyl-2,8-bis(methylthio)benzo[1,2-e: 5,4-e′]bis([1,3]oxazine)-4,6-dione 18c (1 mmol, 0.32 g) was allowed to react with benzylamine (3 mmol. 0.32 g), Sodium hydrogen carbonate solution (1 g in 12 mL methanol and 2.4 mL water) for 16 h. The resulting solid was collected and recrystallised from ethanol to give 20c (0.25 g, 49%) as off white crystals. mp 227–229°C decomp. νmax (KBr)/cm−1 3500–3200 (OH), 3414, 3257 (NH), 1651 (C=O), 1321 (C=S); 1HNMR (200 MHz, 340 K, d6-DMSO) δ 11.51 (bs, 2H, 2 x NH), 10.96 (s, 2H, JH10-H11 = 5.7 Hz, H-10,19), 8.48 (s, 1H, H-6), 7.39–7.28 (m, 10H, 2 x Ar), 4.90 (d, 2H, JH9,H8 = 5.7 Hz, H-11, 20), 2.10 (s, 3H, H-3), 3.3 (OH under the water envelope); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 179.6 (C-9, 18), 166.3 (C-7,16), 161.3 (C-2, 4), 136.9 (C-12, 21), 131.2 (C-4), 128.1 (C-14, 23), 127.3, 127.0 (C-13, 22 and C-15, 24), 113.2 (C-1,5), 108.9 (C-3), 48.1 (C-11, 20), 8.4 (C-1, 5); Anal. Calcd. For C25H25N4O4S·H2O: C, 57.02; H, 4.98; N, 10.64. Found: C, 57.32; H, 4.48; N, 10.85.
4.1.11. N1,N4-Bis(benzyl carbamothioyl)-2,3-dihydroxyterephthalamide 21
In slight modification to the general procedure C, 2,9-dithioxo-2,3,8,9-tetrahydrobenzo[1,2-e:4,3-e′]bis([1,3]oxazine)-4,7-dione 19 (1 mmol, 0.28 g) was allowed to react with benzylamine (3 mmol. 0.32 g), sodium hydrogen carbonate solution (1 g in 12 mL methanol and 2.4 mL water) for 16 hour. The resulting solid was collected and recrystallised using ethanol to give 21 (0.31 g, 63%) as off white crystals mp 195–198°C. νmax (KBr)/cm−1 3500–3200 (OH), 3401, 3248 (NH), 1671, 1649 (C=O), 1338 (C=S); 1HNMR (200 MHz, 300 K, d6-DMSO) δ 11.88 (bs, 2 x NH, H-8,17), 11.07 (t, 1H, JH10,H11 = 5.9 Hz, H-10,19), 8.56 (bs, 2H, 2,3-OH), 7.39–7.28 (m, 12H, 2 x Ar and 2 x CH, H-13, H-14, H-15 and H-5,6), 4.88 (d, 4H, JH11,H10 = 5.9 Hz, H-11,20); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 179.6 (C-9,18), 164.9 (C-7,16), 147.9 (C-2,3), 136.9 (C-12, 21), 128.2 (C-14,23), 127.3 (C-13,22), 127.0 (C-15,24), 120.9 (C-1,4), 119.2 (C-5,6); Anal. Calcd. For C24H22N4O4S2·H2O: C, 56.23; H, 4.72; N, 11.33. Found: C, 55.79; H, 4.78; N, 10.93.
4.1.12. Synthesis N-(2-(Methylthio)-4-oxo-4H-benz[e][1,3]oxazin-7-yl)acetamide 14h
N-(4-Oxo-2-thioxo-3,4-dihydro-2H-benz[e][1,3]oxazin-7-yl)acetamide 10a (0.59 g, 2.5 mmol) was allowed to react with methyl iodide following the previously reported [35]. The resulting beige solid 14h (0.61 g, 97%) is collected and used without further purification but can be crystallised from ethanol, mp 268–269°C νmax (KBr)/cm−1 3278, 3142, 3110 (NH), 3062 (CH Ar), 2929 (CH Aliphatic), 1760, 1709, 1671 (C=O), 1615 (C=N), 1554 (C=C); 1HNMR (200 MHz, 300 K d6-DMSO) δ 10.60 (s, 1H, 9-NH), 7.88 (b, 1H, H-8), 7.87 (d, 1H, JH5,H6 = 8.6 Hz, H-5), 7.45 (d, 1H, JH6,H5 = 8.6 Hz, H-6), 2.58 (s, 3H, 11-CH3), 2.12 (s, 3H, 3′-CH3); 13C NMR (50 MHz, 300 k, d6-DMSO) δ 172.8 (C-2), 169.6 (C-10), 162.1 (C-4), 155.8 (C-8a), 145.2 (C-7), 128.0 (C-5), 117.5 (C-6), 112.1 (C-4a), 104.4 (C-8); Anal. Calcd. For C15H12N2O2S: C, 59.99; H, 4.03; N, 9.33. Found: C, 59.83; H, 4.14; N, 9.45.
4.1.13. Synthesis of 2-Benzyl amino-1,3-benzoxazines 15a–h
General Procedure D. The appropriate 2-methylthio-1,3-benzoxazine 14a–h (2.5 mmol) was suspended in dry 1,4-dioxane (10 mL) in a 50 mL round-bottomed flask. Benzyl amine (12.5 mmol) was then added dropwise, directly from the pipette, with stirring, and then the reaction mixture was heated to reflux for 4 hours. At the completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure and triturated with minimal diethyl ether. The resulting solid product 14 was collected by vacuum filtration and recrystallized from an appropriate solvent.
General Procedure E. N-(Benzyl carbamothioyl)-substituted-2-hydroxy-benzamides 13a, b, e, f, and g (0.5 mmol) were suspended in acetic acid (3 mL) in a 25 mL round-bottomed flask. The reaction mixture was heated to reflux for 2 hours then; the acetic acid was evaporated off under reduced pressure. The oily reaction mixture was triturated with minimal diethyl ether and the resulting solid products 15a, b, e, f, and g were collected by vacuum filtration and recrystallized from an appropriate solvent.
Products 15a, b, e, f, and g prepared in this procedure gave identical mp, IR, 1H NMR and 13C NMR to the analogues prepared from compound 14 with comparable yields (Scheme 3).
2-(Benzyl amino)-4H-benz[e]-1,3-oxazin-4-one
15a. 2-(Methylthio)-4H-benz[e]-1,3-oxazin-4-one 14a was allowed to react with benzyl amine according to general procedure D. The crude solid was collected and recrystallized from ethanol to give 15a (75% yield), mp 210°C. νmax (KBr)/cm−1 3065, 2872 (N–H), 1681 (C=O), 1635 (C=C), 1460 (C=N); 1H NMR (d6-DMSO) δ 8.70 (bs, 1H, N–H), 7.90 (d, 1H, J = 7.5 Hz, H-5), 7.70 (t, 1H, J = 7.5 Hz, H-6), 7.60–7.30 (m, 7H, ArH, H-7, H-8), 4.50 (s, 2H, H-9); 13C NMR (d6-DMSO) δ 165.4 (C-4), 154.9 (C-2), 151.6 (C-8a), 137.6 (C-1′), 135.2 (C-7), 127.7 (C-2′), 126.8 (C-4′), 126.4 (C-3′), 124.3 (C-5), 124.7 (C-6), 124.5 (C-8), 117.0 (C-4a), 43.8 (C-9); Anal. Calcd. For C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C, 71.65; H, 4.95; N, 11.25.
2-(Benzyl amino)-8-methyl-4H-benz[e]-1,3-oxazin-4-one
15b. 8-Methyl-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14b was allowed to react with benzyl amine according to general procedure D. The crude solid was collected and recrystallized from ethyl acetate to give 15b (72% yield), mp 257–258°C. νmax (KBr)/cm−1 3062, 2883 (N–H), 1678 (C=O), 1639 (C=C), 1482 (C=N); 1H NMR (d6-DMSO) δ 8.80 (bs, 1H, N–H), 7.70 (d, 1H, J = 7.5 Hz, H-5), 7.50 (d, 1H, J = 7.5 Hz, H-7), 7.40–7.20 (m, ArH/H-6), 4.50 (s, 2H, H-9) 2.30 (s, 3H, 8-CH3); 13C NMR (d6-DMSO) δ 165.4 (C-4), 157.9 (C-2), 151.6 (C-8a), 137.6 (C-1′), 134.2 (C-7), 127.7 (C-2′), 126.8 (C-4′), 126.4 (C-3′), 124.3 (C-5), 124.7 (C-6), 124.5 (C-8), 117.0 (C-4a), 43.8 (C-9), 13.5 (CH3); Anal. Calcd. For C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 72.10; H, 5.38; N, 10.25.
2-(Benzyl amino)-8-phenyl-4H-benz[e]-1,3-oxazin-4-one
15c. 8-Phenyl-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14c was allowed to react with benzyl amine according to general procedure D. The crude solid was collected and recrystallized from ethanol to give 15c (65% yield), mp 215°C. νmax (KBr)/cm−1 3040, 2860 (N–H), 1679 (C=O), 1635 (C=C), 1489 (C=N); 1H NMR (d6-DMSO) δ 9.20 (bs, 1H, N–H), 7.90 (d, 1H, J = 7.5 Hz, H-5), 7.70–7.20 (m, 11H, ArH/ArH/H-7), 7.90 (d, 1H, J = 3.0 Hz, H-6), 4.50 (s, 2H, H-9); 13C NMR (d6-DMSO) δ 165.1 (C-4), 157.9 (C-2), 151.2 (C-8a), 137.6 (C-1′), 134.7 (C-7), 134.1 (C-5), 129.2–125.8 (C-2′, C-4′ C-3′, C-8 C-9, C-10 C-11, C-12), 124.8 (C-6), 117.7 (C-4a), 43.9 (C-9); Anal. Calcd. For C21H16N2O2 0.5H2O: C, 76.81; H, 4.91; N, 8.53. Found: C, 74.31; H, 4.99; N, 8.46.
2-(Benzyl amino)-7-methoxy-4H-1,3-benzoxazin-4-one
15d. 7-Methoxy-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14d was allowed to react with benzylamine according to general procedure D. The crude solid was collected and recrystallised from toluene to give 15d (83% yield), mp 234–236°C. νmax (KBr)/cm−1 3069–2891 (N–H), 1678 (C=O), 1619 (C=C), 1499 (C=N); 1H NMR (d6-DMSO) δ 9.00 (bs, 1H, N–H), 7.80 (d, 1H, J = 8.6 Hz, H-5), 7.30 (m, 5H, ArH), 6.90 (dd, 1H, JH6,H8 = 2.4 Hz, JH6,H5 = 8.6 Hz, H-6), 6.70 (d, 1H, J = 2.2 Hz, H-8), 4.50 (s, 2H, H-9), 3.90 (s, 3H, 7-OCH3); 13C NMR (d6-DMSO) δ 164.7 (C-4), 163.3 (C-7), 157.9 (C-2), 154.5 (C-8a), 137.6 (C-1′), 127.7 (C-5), 127.6 (C-2′), 126.7 (C-4′), 126.4 (C-3′), 112.2 (C-6), 110.6 (C-4a), 99.3 (C-8), 55.4 (OCH3), 43.7 (C-9); Anal. Calcd. For C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 67.86; H, 4.89; N, 10.01.
2-(Benzyl amino)-7-ethoxy-4H-1,3-benzoxazin-4-one
15e. 7-Ethoxy-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14e was allowed to react with benzylamine according to general procedure D. The crude solid was collected and recrystallized from toluene to give 15e (80% yield), mp 214–216°C. νmax (KBr)/cm−1 3069–2827 (N–H), 1673 (C=O), 1600 (C=C), 1466 (C=N); 1H NMR (d6-DMSO) δ 9.00 (bs, 1H, N–H), 7.80 (d, 1H, J = 8.6 Hz, H-5), 7.30 (m, 5H, ArH), 6.90 (dd, 1H, JH6,H8 = 2.4 Hz, JH6,H5 = 8.6 Hz, H-6), 6.70 (d, 1H, J = 2.2 Hz, H-8), 4.50 (s, 2H, H-9), 4.20 (q, 2H, J = 5.6, CH2–O), 3.90 (s, 3H, 7-OCH3), 1.30 (t, 3H, J = 5.6, CH3); 13C NMR (d6-DMSO) δ 164.4 (C-4), 163.1 (C-7), 157.9 (C-2), 154.9 (C-8a), 137.8 (C-1′), 127.6 (C-5), 127.5 (C-2′), 126.7 (C-4′), 126.4 (C-3′), 112.6 (C-6), 110.3 (C-4a), 99.8 (C-8), 63.6 (CH2–O), 43.7 (C-9), 13.5 (CH3); Anal. Calcd. For C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 69.11; H, 5.76; N, 9.28.
2-(Benzyl amino)-7-hydroxy-4H-1,3-benzoxazin-4-one
15f. 7-Hydroxy-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14f was allowed to react with benzyl amine according to general procedure D. The crude solid was collected and recrystallized from ethanol to give 15f (77% yield), mp decomp 262°C. νmax (KBr)/cm−1 3300–3058 (O–H), 3058–2851 (N–H), 1667s (C=O), 1607 m (C=C), 1543s (C=N); 1H NMR (d6-DMSO) δ 8.70 (bs, 1H, N–H), 7.50 (d, 1H, J = 8.6 Hz, H-5), 7.30–7.20 (m, 6H, ArH/7-OH), 6.50 (d, 1H, J = 8.6 Hz, H-6), 6.30 (s, 1H, H-8), 4.50 (s, 2H, H-9); 13C NMR (d6-DMSO) δ 169.6 (C-4), 166.1 (C-7), 158.1 (C-2), 155.8 (C-8a), 138.5 (C-1′), 128.3 (C-2′), 127.7 (C-4′), 127.2 (C-3′), 127.0 (C-5), 116.1 (C-6), 104.9 (C-4a), 100.6 (C-8), 43.7 (C-9); Anal. Calcd. For C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.14; H, 4.34; N, 10.49.
2-(Benzyl amino)-7-hydroxy-8-methyl-4H-1,3-benzoxazin-4-one
15g. 7-Hydroxy-8-methyl-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14g was allowed to react with benzylamine according to general procedure D. The crude solid was collected and recrystallised from ethanol to give 15g (74% yield), mp 245–247°C. νmax (KBr)/cm−1 3300–2860 (O–H), 3058–2851 (N–H), 1678 (C=O), 1608 m (C=C), 1549s (C=N); 1H NMR (d6-DMSO) δ 8.70 (bs, 1H, N–H), 7.60 (d, 1H, J = 8.6 Hz, H-5), 7.30–7.20 (m, 6H, H-2′/H-3′/H-4′/7-OH), 6.80 (d, 1H, J = 8.6 Hz, H-6), 4.50 (s, 2H, H-9); 13C NMR (d6-DMSO) δ 165.2 (C-4), 159.6 (C-7), 157.8 (C-2), 152.5 (C-8a), 137.8 (C-1′), 127.6 (C-2′), 126.7 (C-4′), 126.4 (C-3′), 124.2 (C-5), 112.0 (C-6), 109.4 (C-8), 108.1 (C-4a), 43.7 (C-9), 6.8 (8-CH3); Anal. Calcd. For C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 67.86; H, 5.28; N, 9.68.
N-(2-(Benzylamino)-4-oxo-4H-benz[e][1,3]oxazin-7-yl)acetamide
15h. In modification to the general procedure D, N-(2-(methylthio)-4-oxo-4H-benz[e][1,3]oxazin-7-yl)acetamide 14i (0.26 g 1 mmol) was allowed to react with benzylamine (0.2 mL, 1 mmol) for 4 hours. The resulting solid was collected and recrystallised from acetonitrile to give 15 h (0.1, 47%) as white crystals, mp 250–253°C. decomp. νmax (KBr)/cm−1 3284, 3234, 3215 (NH), 1669 (C=O); 1HNMR (200 MHz, 390 K, d6-DMSO) δ 10.28 (s, 1H, H-15), 8.86 (t, 1H, JH9,H10 = 4.7 Hz, H-9), 7.81–7.78 (m, 2H, H-8 and H-5), 7.37–7.26 (m, 6H, Ar, H-12–14 and H-6), 4.52 (d, 2H, JH10,H9 = 4.7 Hz, H-10), 2.10 (s, 3H, 17-CH3); 13C NMR (50 MHz, 390 K, d6-DMSO) δ 169.3 (C-16), 165.4 (C-4), 158.4 (C-8a), 154.2 (C-2), 144.3 (C-7), 138.2 (C-11), 128.4 (C-5), 127.5/127.3/127.2 (C-12/C-13/C-14), 115.7 (C-6), 112.1 (C-4a), 104.2 (C-8), 44.0 (C-10), 24.3 (C-17); Anal. Calcd. For C17H15N3O3: C, 66.01; H, 4.89; N, 13.58. Found: C, 65.93; H, 5.02; N, 13.52.
4.1.14. 10-methyl-2,8-bis(methylthio)benzo[1,2-e:5,4-e′]bis([1,3]oxazine)-4,6-dione 24
Following the previously reported [35], 10-methyl-2, 8-dithioxo-2, 3, 7, 8-tetrahydrobenzo[1,2-e:5,4-e′]bis([1,3]oxazine)-4,6-dione 18c (0.74 g, 2.5 mmol) was allowed to react with methyl iodide (5.4 mL, 86.8 mmol) and NaHCO3 (3.0 g, 32 mmol) for 2 hrs. The resulting yellow solid 24 (0.78 g, 98%) is collected and used without further purification. mp > 300°C decomp. νmax (KBr)/cm−1 1623 (C=O), 1548 (C=N); 1H NMR (200 MHz, 390 K, d6-DMSO) δ 8.27 (s, 1H, H-5), 2.64 (s, 6H, H-3′and H-9′), 2.33 (s, 3H, H-10′). 13C NMR (50 MHz, 390 K, d6-DMSO) δ 173.0 (C-2,8), 160.6 (C-4,6), 155.3 (C-6a, 9a), 124.0 (C-5) 123.6 (C-10), 115.2 (C-4a, 5a), 13.4 (C-3′, 9′), 6.7 (C-10′).
4.1.15. 2,8-Bis(benzylamino)-10-methylbenzo[1,2-e:5,4-e′]bis([1,3]oxazine)-4,6-dione 26
In slight modification to the general procedure D,10-methyl-2,8-bis(methylthio) benzo[1,2-e:5,4-e′]bis([1,3]oxazine)-4,6-dione 24 (0.29 g, 1 mmol) was allowed to react with benzyl amine 0.4 mL, (2 mmol) for 16 hours. The resulting solid was collected and recrystallised from DMSO/water to give 26 (0.25 g, 56%) as an off white solid, mp 285–288°C decomp. νmax (KBr)/cm−1 3394, 3202, 3029 (NH), 1681, 1635 (C=O); 1HNMR (200 MHz, 340 K, d6-DMSO) δ 8.90 (bs, 2H, H-11,17), 8.27 (s, 1H, H-5), 7.43–7.24 (m, 10H 2 x Ar, H-14–16 and H-20–22), 4.58 (s, 4H, H-12,18), 2.31 (s, 3H, H-10′); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 164.0 (C-4), 164.0 (C-9a,10a), 157.6 (C-2), 137.2 (C-13,19), 127.7, 126.9, 126.6, 122.5 (C-15,21, C-14,20 and C-16,22), 113.9 (C-10), 115.5 (C-4a,5a), 44.0 (C-12,17), 6.6 (C-10′); Anal. Calcd. For C25H20N4O4·2H2O: C, 63.02; H, 5.08; N, 11.76. Found: C, 63.22; H, 4.99; N, 11.96.
4.1.16. Synthesis of Substituted-1,3-benzoxazine-diones 22a–h and 25
General Procedure F. The appropriate substituted methylthio-1,3-benzoxazine 2.5 mmol was hydrolysed with 10 mL hydrochloric acid (10%) at 80°C for 4 hours. At the completion of the reaction, the reaction mixture was washed with R.O water, filtered, and recrystallised from an appropriate solvent.
Products 22a–h were used in the synthesis of products 23a–h with no further purification.
2H-Benz[e]-1,3-oxazin-2,4(3H)-dione
22a. 2-(Methylthio)-4H-benz[e]-1,3-oxazin-4-one 14a was allowed to react with hydrochloric acid (10%) according to general procedure F. The crude solid was collected and recrystallised from ethanol to give 22a (75% yield), mp 228°C. (lit. [19, 20] 229-230°C). νmax (KBr)/cm−1 3179, 2877 (N–H), 1771 (C=O), 1690 (C=O), 1610 (C=C); 1H NMR (200 MHz, d6-DMSO) δ 7.90 (d, 1H, J = 7.5 Hz, H-5), 7.80 (t, 1H, J = 7.5 Hz, H-6), 7.40 (m, 2H, H-7/H-8); 13C NMR (50 MHz, d6-DMSO) δ 161.6 (C-4), 153.7 (C-2), 147.6 (C-8a), 136.2 (C-7), 126.9 (C-5), 125.2 (C-6), 116.5 (C-8), 114.6 (C-4a).
8-Methyl-2H-benz[e]-1,3-oxazin-2,4(3H)-dione
22b. 8-Methyl-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14b was allowed to react with hydrochloric acid (10%) according to general procedure F. The crude solid was collected and recrystallised from ethanol to give 22b (85% yield), mp 210°C (lit. [19, 20] 210–212°C). νmax (KBr)/cm−1 3221, 2845 (N–H), 1746 (C=O), 1717 (C=O), 1614 (C=C); 1H NMR (200 MHz, d6-DMSO) δ 8.80 (bs, 1H, N–H), 7.70 (d, 1H, J = 7.5 Hz, H-5), 7.60 (d, 1H, J = 7.5 Hz, H-7), 7.30–7.20 (t, 1H, J = 7.1 Hz, H-6), 2.30 (s, 3H, 8-CH3); 13C NMR (50 MHz, d6-DMSO) δ 161.6 (C-4), 151.9 (C-2), 147.3 (C-8a), 136.9 (C-7), 125.5 (C-8), 124.6 (C-5), 124.4 (C-6), 114.4 (C-4a), 13.8 (CH3).
7-Methoxy-2H-benz[e]-1,3-oxazin-2,4(3H)-dione
22c. 7-Methoxy-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14d was allowed to react with hydrochloric acid (10%) according to general procedure F. The crude solid was collected and recrystallised from ethyl acetate to give 22c (78% yield), mp 213°C. νmax (KBr)/cm−1 3203, 2930 (N–H), 1771 (C=O), 1723 (C=O), 1620 (C=C); 1H NMR (200 MHz, d6-DMSO) δ 12.10 (s, 1H, N–H), 7.90 (d, 1H, J = 8.3 Hz, 5-H), 7.10 (s, 1H, 8-H), 7.00 (d, 1H, J = 8.3 Hz, 6-H), 3.0 (s, 3H, 7-OCH3); 13C NMR (50 MHz, d6-DMSO) δ 160.6 (C-4), 157.9 (C-2), 155.4 (C-7), 151.6 (C-8a), 128.2 (C-5), 113.2 (C-6), 107.1 (C-4a), 100.8 (C-8), 56.5 (7-OCH3); Anal. Calcd. For C9H7NO4: C, 55.96; H, 3.65; N, 7.25. Found: C, 55.75; H, 3.45; N, 7.55.
7-Ethoxy-2H-benz[e]-1,3-oxazin-2,4(3H)-dione
22d. 7-Ethoxy-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14e was allowed to react with hydrochloric acid (10%) according to general procedure F. The crude solid was collected and recrystallised from ethyl acetate to give 22e (75% yield), mp 225–227°C. νmax (KBr)/cm−1 3157–2862 (N–H), 1771 (C=O), 1698 (C=O), 1620 (C=C); 1H NMR (200 MHz, d6-DMSO) δ 11.90 (bs, 1H, N–H), 7.80 (d, 1H, J = 8.6 Hz, H-5), 6.90 (m, 2H, H-6/H-8), 4.10 (q, 2H, J = 6.8 Hz, O–CH2), 1.30 (t, 3H, J = 6.8 Hz, CH3); 13C NMR (50 MHz, d6-DMSO) δ 164.6 (C-4), 160.9 (C-2), 155.4 (C-7), 147.6 (C-8a), 128.2 (C-5), 113.2 (C-6), 107.1 (C-4a), 100.8 (C-8), 64.4 (CH2–O), 14.3 (CH3); Anal. Calcd. For C10H9NO4: C, 57.97; H, 4.38; N, 6.76. Found: C, 57.86; H, 4.45; N, 6.55.
7-Hydroxy-2H-benz[e]-1,3-oxazin-2,4(3H)-dione
22e. 7-Hydroxy-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14f was allowed to react with hydrochloric acid (10%) according to general procedure F. The crude solid was collected and recrystallised from ethanol to give 22e (65% yield), mp 245°C (Lit [39] 310). νmax (KBr)/cm−1 3200–2700 (O–H), 3078, 2929 (N–H), 1780 (C=O), 1688 (C=O), 1616 (C=C); 1H NMR (200 MHz, d6-DMSO) δ 11.80 (s, 1H, N–H), 11.00 (s, 1H, 7-O–H), 7.70 (d, 1H, J = 8.6 Hz, H-5), 6.80 (d, 1H, J = 8.6 Hz, H-6), 6.60 (s, 1H, H-8); 13C NMR (50 MHz, d6-DMSO) δ 164.6 (C-4), 160.9 (C-2), 155.4 (C-7), 147.6 (C-8a), 128.6 (C-5), 113.8 (C-6), 105.9 (C-4a), 101.8 (C-8); Anal. Calcd. For C8H5NO4: C, 53.64; H, 2.81; N, 7.82. Found: C, 53.75; H, 2.45; N, 7.55.
7-Hydroxy-8-methyl-2H-benz[e]-1,3-oxazin-2,4(3H)-dione
22f. 7-Hydroxy-8-methyl-2-(methylthio)-4H-benz[e]-1,3-oxazin-4-one 14g was allowed to react with hydrochloric acid (10%) according to general procedure F. The crude solid was collected and recrystallised from ethanol to give 22f (70% yield), mp 250°C decomp. νmax (KBr)/cm−1 3250, 2900 (O–H), 3188, 2956 (N–H), 1771 (C=O), 1713 (C=O), 1619 (C=C); 1H NMR (200 MHz, d6-DMSO) δ 11.70 (s, 1H, N–H), 10.10 (s, 1H, 7-O–H), 7.60 (d, 1H, J = 8.4 Hz, H-5), 6.80 (d, 1H, J = 8.4 Hz, H-6), 2.10 (s, 3H, 8-CH3); 13C NMR (50 MHz, d6-DMSO) δ 162.4 (C-4), 161.5 (C-2), 153.4 (C-7), 147.9 (C-8a), 125.4 (C-5), 112.6 (C-6), 110.8 (C-4a), 106.0 (C-8), 8.1 (8-CH3); Anal. Calcd. For C9H7NO4: C, 55.96; H, 3.65; N, 7.25. Found: C, 55.75; H, 3.45; N, 7.55.
N-(2,4-Dioxo-3,4-dihydro-2H-benz[e][1,3]oxazin-7-yl)acetamide
22g. In slight modification to the general procedure F, N-(2-(methylthio)-4-oxo-4H-benz[e][1,3]oxazin-7-yl) acetamide 14i (0.63 g, 2.5 mmol) was allowed to reflux with water (10 mL) for 2 hours. The resulting crude solid was filtered, and recrystallised from methanol to give 22 g (0.52 g, 95%) as light grey solid, mp 284–287°C (Lit [39]. 310–14° decomp.). νmax (KBr)/cm−1 3350, 3050 (NH), 1758, 1704 (C=O); 1HNMR (200 MHz, 340 K, d6-DMSO) δ 11.80 (bs, 1H, 3-NH), 10.57 (s, 1H, 9-NH), 7.83 (d, 1H, JH5,H6 = 8.6 Hz, H-5), 7.72 (d, 1H, JH8,H6 = 1.6 Hz, H-8), 7.45 (dd, 1H, JH6,H5 = 8.6 Hz, JH6,H8 = 1.6 Hz, H-6), 2.11 (s, 3H, 11-CH3); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 169.0 (C-10), 160.3 (C-4), 154.2 (C-2), 147.1, 145.7 (C-8a, C-7), 127.3 (C-5), 115.3 (C-6), 108.6 (C-4a), 104.6 (C-8), 23.5 (C-11). Anal. Calcd. For C10H8N2O4: C, 54.55; H, 3.66; N, 12.72. Found: C, 54.49; H, 3.77; N, 12.69.
7-Amino-2H-benz[e][1,3]oxazine-2,4(3H)-dione
22h. In modification to the general procedure F, N-(2-(methylthio)-4-oxo-4H-benzo[e][1,3]oxazin-7-yl) acetamide 14h (0.63 g, 2.5 mmol) was allowed to react in the presence of hydrochloric acid (15 mL, 40%) for 4 hours. At the completion of the reaction, the reaction mixture was neutralized by NaHCO3, filtered and recrystallised from ethanol to give 22h (0.34 g, 79%), mp 284–287°C decomp. νmax (KBr)/cm−1 3479, 3372 (NH), 2843 (NH), 1752, 1708 (C=O); 1HNMR (200 MHz, 340 K, d6-DMSO) δ 11.49 (s, 1H, 3-NH), 7.54 (d, 1H, JH5,H6 = 8.4 Hz, H-5), 6.52 (m, 3H, H-6 and 7-NH2), 6.31 (s, 1H, H-8).13C NMR (50 MHz, 340 K, d6-DMSO) δ 160.8 (C-4), 156.0, 155.6 (C-2, C-7), 147.9 (C-8a), 127.8 (C-5), 111.4 (C-6), 101.5 (C-4a), 97.3 (C-8). Compound 22h was used for the synthesis of compound 23g with no further purification.
10-Methyl-2H,6H-[1,3]oxazino[5,6-g][1,3]benzoxazine-2,4,6,8(3H,7H)-tetrone
25. 10-Methyl-2,8-bis(methylthio)benzo[1,2-e:5,4-e′]bis([1,3]oxazine)-4,6-dione 24 (0.74 g, 2.5 mmol) was allowed to react with hydrochloric acid (10%) for 4 hours according to the general procedure F. The resulting solid was recrystallised from DMF to give 25 (0.55 g, 85%) as off white crystals. mp > 300°C decomp. νmax (KBr)/cm−1 3183, 3119, 3049 (NH), 1784, 1714 (C=O), 1616 (C=C); 1HNMR (200 MHz, 340 K, d6-DMSO) δ 12.18 (bs, 2H, 3,7-NH), 8.26 (s, 1H, H-5), 2.31 (s, 3H, H-10′); 13C NMR (50 MHz, 340 K, d6-DMSO) δ 159.7 (C-4,6), 155.4 (C-2,8), 145.9 (C-9a,10a), 123.3 (C-5), 113.0 (C-10), 111.3 (C-4a,5a), 7.3 (C-10′); Anal. Calcd. For C11H6N2O6: C, 50.39; H, 2.31; N, 10.68. Found: C, 50.54; H, 2.42; N, 10.74.
4.1.17. Synthesis of N-(Benzyl carbamoyl)-2-hydroxy-substituted-benzamide 23a–g
General Procedure G. The appropriate 2-dione-1,3-benzoxazines 22a–b and 22d–i (2.5 mmol) were suspended in dry 1,4-dioxane (10 mL) in a 50 mL round-bottomed flask. Benzyl amine (12.5 mmol) was then added dropwise, directly from the pipette, with stirring, and then the reaction mixture was heated to reflux for 4 hours. At the completion of the reaction, it evaporated to dryness under reduced pressure and triturated with minimal diethyl ether. The resulting solid was collected by vacuum filtration and recrystallised from an appropriate solvent.
N-(Benzyl carbamoyl)-2-hydroxybenzamide
23a. 2H-Benz[e]-1,3-oxazin-2,4(3H)-dione 22a was allowed to react with benzyl amine according to general procedure F to give 23a which was recrystallised from ethanol (70% yield), mp211–213°C. νmax (KBr)/cm−1 3340–2940 (O–H), 3230–3161 (N–H), 1687 (C=O), 1648 (C=O); 1H NMR (200 MHz, d6-DMSO) δ 11.75 (bs, 1H, H-2′), 10.40 (bs, 1H, 1-OH), 9.05 (t, 1H, J = 5.6 Hz, 4′-NH), 7.90 (d, 1H, J = 7.7 Hz, H-3), 7.50 (m, 1H, H-5), 7.30–7.20 (m, 5H, ArH), 7.05–6.95 (m, 2H, H-4/H-6), 4.40 (d, 2H, J = 5.2 Hz, H-5′); 13C NMR (50 MHz, d6-DMSO) δ 166.3 (C-1′), 158.7 (C-2), 153.1 (C-3′), 137.2 (C-6′), 133.7 (C-4), 130.8 (C-6), 128.4 (C-8′), 127.3 (C-7′), 127.0 (C-9′), 119.9 (C-1), 117.2 (C-5/C-3), 42.8 (C-5′); Anal. Calcd. For C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C, 66.74; H, 5.36; N, 10.29.
N-(Benzyl carbamoyl)-2-hydroxy-3-methylbenzamide
23b. 8-Methyl-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 22b was allowed to react with benzyl amine according to general procedure G to give 23b which was recrystallised from ethanol (65% yield), mp 220–223°C. νmax (KBr)/cm−1 3337–2946 (O–H), 3249 (N–H), 1696 (C=O), 1642 (C=O); 1H NMR (200 MHz, d6-DMSO) δ 11.30 (bs, 1H, H-2′), 10.70 (bs, 1H, 1-OH), 8.90 (t, 1H, J = 5.6 Hz, 4′-NH), 7.80 (d, 1H, J = 7.5 Hz, H-6), 7.40–7.20 (m, 6H, ArH and H-4), 6.80 (t, 1H, J = 7.5 Hz, H-5), 7.00–6.90 (m, 2H, H-4 and H-6), 4.60 (d, 2H, J = 5.2 Hz, H-5′), 2.20 (s, 3H, CH3); 13C NMR (50 MHz, d6-DMSO) δ 167.9 (C-1′), 159.7 (C-2), 154.9 (C-3′), 137.2 (C-6′), 135.0 (C-4), 128.4 (C-8′), 127.3 (C-7′), 127.0 (C-9′), 126.3 (C-3), 125.5 (C-6), 119.0 (C-5), 115.1 (C-1), 42.9 (C-5′), 15.9 (CH3); Anal. Calcd. For C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.64; H, 5.54; N, 9.87.
N-(Benzyl carbamoyl)-4-ethoxy-2-hydroxybenzamide
23c. 7-Ethoxy-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 22d was allowed to react with benzyl amine according to general procedure F to give 23c which was recrystallised from ethanol (70% yield), mp 204–206°C. νmax (KBr)/cm−1 3333–2876 (O–H), 3225–3156 (N–H), 1692 (C=O), 1650 (C=O); 1H NMR (200 MHz, d6-DMSO) δ 11.90 (bs, 1H, H-2′), 10.20 (bs, 1H, 2-OH), 8.00 (t, 1H, J = 5.4 Hz, 4′-NH), 7.90 (d, 1H, J = 8.9 Hz, H-6), 7.30 (m, 5H, ArH), 6.60 (dd, 1H, J
H-5,H-3 = 2.6 Hz, J
H-5,H-6 = 8.9 Hz, H-5), 6.50 (d, 1H, J = 2.2 Hz, H-3), 4.40 (d, 2H, J = 6.0 Hz, H-5′), 4.10 (q, 2H, J =6.8 Hz, CH2–O), 1.30 (t, 3H, J = 6.8 Hz, CH3); 13C NMR (50 MHz, d6-DMSO) δ 166.1 (C-1′), 160.7 (C-4), 158.9 (C-2), 153.2 (C-3′), 137.2 (C-6′), 132.4 (C-6), 128.4 (C-8′), 127.3 (C-7′), 127.0 (C-9′), 110.5 (C-5), 109.4 (C-1), 101.7 (C-3), 64.6 (CH2–O), 42.8 (C-5′), 14.5 (CH3); Anal. Calcd. For C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C, 65.03; H, 5.82; N, 8.84.
N-(Benzyl carbamoyl)-2,4-dihydroxybenzamide
23d. 7-Hydroxy-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 22e was allowed to react with benzyl amine according to general procedure G and gave 23d which was recrystallised from ethanol (75% yield), mp 220°C. νmax (KBr)/cm−1 3200–2700 (O–H), 3118, 3033 (N–H), 1692 (C=O), 1665 (C=O); 1H NMR (200 MHz, d6-DMSO) δ 9.00 (t, 1H, J = 5.6 Hz, 4′-N–H), 7.70 (d, 1H, J = 7.6 Hz, H-6), 7.30 (bm, 6H, ArH, 2′-OH), 6.30 (s, 1H, H-3), 6.2 (d, 1H, J = 7.6 Hz, H-5), 5.60 (m, 2H, 4-OH and 2′-NH) 4.40 (d, 2H, J = 6.0 Hz, H-5′); 13C NMR (50 MHz, d6-DMSO) δ 163.5 (C-1′), 161.9 (C-4), 158.5 (C-2), 153.2 (C-3′), 138.5 (C-6′), 135.3 (C-6), 128.7 (C-8′), 127.7 (C-7′), 127.5 (C-9′), 109.2 (C-1), 102.9 (C-5), 107.9 (C-3), 48.2 (C-5′); Anal. Calcd. For C15H14N2O4: C, 59.59; H, 4,67; N, 9.27. Found: C, 59.88; H, 4.68; N, 9.59.
N-(Benzyl carbamoyl)-2,4-dihydroxy-3-methylbenzamide
23e. 7-Hydroxy-8-methyl-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 22f was allowed to react with benzylamine according to general procedure G to give 23g which was recrystallised from ethyl acetate (65% yield), mp 230°C. νmax (KBr)/cm−1 3381, 3225 (O–H), 3020–2800 (N–H), 1687 (C=O), 1639 (C=O); 1H NMR (200 MHz, d6-DMSO) δ 11.00 (bs, 1H, 2′-NH), 9.80 (bs, 1H, 2-OH), 8.5 (t, 1H, J = 5.6 Hz, 4′-NH), 7.5 (d, 1H, J = 8.8 Hz; H-5), 7.4 (bm, 5H, ArH), 6.9 (d, 1H, J = 8.8 Hz; H-6), 4.50 (d, 2H, J = 6.0 Hz, H-5′), 2.00 (s, 3H, CH3); 13C NMR (50 MHz, d6-DMSO) δ 165.2 (C-1′), 162.9 (C-4), 159.3 (C-2), 157.2 (C-3′), 137.5 (C-6′), 128.7 (C-8′), 127.7 (C-7′), 127.5 (C-9′), 127.3 (C-6), 112.2 (C-1), 110.9 (C-3), 107.9 (C-5), 44.2 (C-5′), 8.6 (3-CH3); Anal. Calcd. For C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C, 63.88; H, 5.68; N, 9.59.
4-Acetamido-2-hydroxy-N-(phenylcarbamoyl)benzamide
23f. N-(2,4-Dioxo-3,4-dihydro-2H-benz[e][1,3]oxazin-7-yl) acetamide 22 g was allowed to react with benzyl amine according to general procedure G. The resulting solid was filtered and recrystallised from ethanol to give 23f (0.25 g, 76%) mp 257–260°C. νmax (KBr)/cm−1 3500–3200 (OH), 3281, 3122 (NH), 1694, 1664 (C=O), 1613, 1559 (C=C); 1H NMR (200 MHz, 340 K, d6-DMSO) δ 11.63 (bs, 1H, 10-NH), 10.24, 10.06 (15-NH, 2-OH), (s, 1H, JH10,H11 = 5.4 Hz, 10-NH), 7.84 (d, 1H, JH6,H5 = 8.8 Hz, H-6), 7.58 (d, 1H, JH3,H5 = 1.8 Hz, H-3), 7.38–7.24 (m, 5H, ArH, H-13, H-14, H-15), 7.03 (dd, JH5,H6 = 8.8 Hz, JH5,H3 = 1.8 Hz, H-3), 4.45 (d, 2H, JH11,H10 = 5.9 Hz, H-11), 2.07 (s, 3H, H-17); 13C NMR (50 MHz, 300 K, d6-DMSO) δ 168.7 (C-16), 165.7 (C-7), 157.5 (C-2), 152.9 (C-9), 144.6 (C-4), 138.8 (C-12), 131.1 (C-6), 128.1, 126.9, 126.7 (C-14, C-13, C-15), 111.2 (C-1), 110.5 (C-5), 106.1 (C-3), 42.6 (C-11), 23.9 (C-17); Anal. Calcd. For C17H17N3O4: C, 62.38; H, 5.23; N, 12.84. Found: C, 62.44; H, 5.28; N, 12.90.
4-Amino-N-(benzyl carbamoyl)-2-hydroxybenzamide
23g. 7-Amino-2H-benz[e][1,3]oxazine-2,4(3H)-dione 22h was allowed to react with benzylamine for 16 h in slight modification to general procedure G. The resulting solid was filtered and recrystallised from toluene to give 23g (0.15 g, 54%) as light brown solid, mp 208–211°C decomp. νmax (KBr) cm−1 3500–3200 (OH), 3489, 3390, 3330 (NH), 1686 1645 (C=O); 1H NMR (200 MHz, 340 K, d6-DMSO) δ 10.18 (bs, 1H, 2-OH), 9.00 (t, 1H, JH10,H11 = 5.1 Hz 10-NH), 7.65 (d, 1H, JH6,H5 = 8.6 Hz, H-6), 7.34–7.27 (m, 6H, Ar, H-13, H-14, H-15 and 8-NH exchangeable with D2O), 6.19–6.11 (m, 2H, H-5 and H-3), 5.88 (bs, 2H, 4-NH2), 4.42 (d, 2H, JH11,H10 = 5.1 Hz, H-11); 13C NMR (50 MHz, 300 K, d6-DMSO) δ 166.6 (C-7), 159.4 (C-2), 154.8, 153.3 (C-4,C-9), 139.0 (C-12), 131.7 (C-6), 128.0 (C-14), 126.9, 126.6 (C-15, C-12), 106.6 (C-5), 105.5 (C-1), 99.2 (C-3), 42.5 (C-11); Anal. Calcd. For C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C, 62.78; H, 4.90; N, 14.30.