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H-ferrierite zeolite: As an effective and reusable heterogeneous catalyst for synthesis of 1,5-benzothiazepine under solvent free condition and 1,3-dipolar cycloaddition in water
⁎Corresponding author. Tel.: +20 1111458165. huwaidahassaneen@yahoo.com (Huwaida M.E. Hassaneen)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
An efficient synthesis of new derivatives of 1,5-benzothiazepine has been developed by the reaction of various chalcones (1,3-diaryl-2-propenones) with 2-amino-thiophenol in the presence of H-ferrierite zeolite as acidic catalyst without solvent. In addition, 1,3-dipolar cycloaddition of hydrazonoyl chlorides on C⚌N bond of 1,5-benzothiazepines in water in the presence of Na2CO3/THAC as a base catalyst afforded 1,2,4-triazolo[3,4-d][1,5]benzothiazepines. The structure of all the newly synthesized compounds was established on the basis of spectral data (Mass, IR, 1H NMR, 13C NMR) and elemental analysis.
Keywords
1,5-Benzothiazepine
1,3-Dipolar cycloaddition
H-ferrierite zeolite
THAC
[1,2,4]Triazolo[3,4-d][1,5]benzothiazepine
1 Introduction
A wide spectrum of biological activities of compounds bearing the 1,5-benzothiazepine moiety (Chaffmann and Bogden, 1985; Geyer et al., 1970; Hopenwasser et al., 2004; Krizanova et al., 1993; Kawakita et al., 1991; Nagao et al., 1972; Sato et al., 1971; Slade et al., 1985; Skiles et al., 1993; Yamada et al., 1973) has stimulated interest in developing new synthetic protocols for their synthesis. There remains the necessity to develop a more effective and convenient synthetic procedure as the reported methods have one or more disadvantages such as the use of a high boiling solvent (e.g., DMF) that is difficult to recover, excess amounts of acid or base, special apparatus, corrosive (e.g., HCl gas, TFA) and hazardous (e.g., pyridine, piperidine, halogenated hydrocarbon) reagents/solvents and special efforts to prepare the catalysts and adsorb the reactants on a solid support. RE exchanged Y zeolites are reported as effective catalyst in organic chemistry, petroleum industry, agriculture, domestic water treatment and their specificity in gas phase transformations are widely used in industry (Holderich et al., 1988). Many organic reactions like cyclization, alkylation, polymerization (Sen et al., 1996) or preparation of nitroalkane (Sreekumar et al., 1998) occurred in gas phase or with reactants adsorbed within zeolite. Lately, many reports on the utilization of acidic zeolites (HY) in macro-lactonization (Ookishi and Onaka, 1998), acetylation (Ballini et al., 1998a,b) and gem-diacetalization (Ballini et al., 1998a,b), moreover the synthesis and application of the organic-functionalized zeolite beta (Jones et al., 1998). Thus as part of our program aimed at achieving simple and environmentally compatible synthetic methodologies in search for important heterocycles (Farghaly and Riyadh, 2009; Hassaneen et al., 2011; Hassaneen, 2011) and the above mentioned importance attracted our attention to synthesis a new series of 1,5-benzothiazepine derivatives by using catalytic amount of zeolite ferrierite, in its acidic form H-ferrierite (H-FER), under solvent free condition. In addition, the 1,3-dipolar cycloaddition constitutes a versatile synthetic method for the construction of five-membered ring heterocycles (Elwan et al., 1996; Grigg and Sarker, 2006; Kalita et al., 2006).
In particular, the 1,3-dipolar cycloaddition of nitrile imine to C⚌N bond affords 1,2,4-triazoles, which have important pharmaceutical properties (Demirbas et al., 2002a,b; Demirbas and Ugurluoglu, 2004; El-Agrody et al., 2001; Zhang et al., 2002). Using 1,2,4-triazole derivatives as promising antimicrobial, antibacterial, antihypertensive and antifungal agents has been described and discussed in several publications (Demirbas et al., 2002a,b; Demirbas and Ugurluoglu, 2004; El-Agrody et al., 2001; Zhang et al., 2002). Also, from the literature we found that the use of environmentally benign solvents like water represents green solvent, being economical and eco-friendly for synthetic transformations (Amantini et al., 2001; Gopalakrishnan et al., 2006; Tamami and Fadavi, 2006). However, low solubility of reactant, incompatibility of certain intermediate or competition between the desired reaction and hydrolysis restrict the use of water as a common solvent, although many reactions have been studied in water using different catalysts (Brafola et al., 1996; Deb and Bhuyan, 2005; Ren et al., 2002; Wang, 2004) or addition of cationic surfactant such as tetrahexylammonium chloride (THAC) is used in water media in many organic reactions (Molteni et al., 2002) in which it increases the internal pressure of the water and accelerates the reaction rate (Salager, 2002). From the above findings and in continuation of our recent work in studying the regioselectivity of the reaction of nitrilimine with some compounds containing active center (Farghaly and Shawali, 2010; Riyadh and Farghaly, 2012; Shawali et al., 2008), we will study the regioselectivity of nitrilimine with 1,5-benzothiazepine derivatives by using basic aqueous sodium carbonate/THAC.
2 Experimental
2.1 Chemistry
All melting points were determined on an electrothermal Gallenkamp apparatus and are uncorrected. The IR spectra were recorded in KBr using a PyeUnicam SP-1000 spectrophotometer. 1H NMR spectra were obtained on a Varian EM-300 MHz spectrometer (1H NMR 300 MHz) using DMSO-d6, solvent with TMS as internal standard. 13C NMR spectra were measured on a Varian EM-300 MHz spectrometer (75 MHz). Mass spectra were recorded on an AEI MS 30 mass spectrometer operating at 70 eV. Elemental analyses were carried out by the Microanalytical Center of Cairo University, Giza, Egypt.
2.1.1 Procedure for the synthesis of 2,3-dihydro-2-(4-substituted-phenyl)-4-(4-substituted-phenyl)-1,5-benzothiazepine derivatives 4
Method A: An equimolar mixture of o-aminothiophenol1 (1 mmol) and 1,3-disubstituted phenyl-2-propen-1-ones 2 (1 mmol) was refluxed for 7–10 h in ethanol, methanol or water in the presence of drops of conc. hydrochloric acid, glacial AcOH or (PTSA) (0.2 g), respectively. The reaction was monitored by TLC. After completion, the solvent was evaporated under reduced pressure. The crude product was filtered and crystallized from ethanol solvent.
Method B: To a stirred heterogeneous mixture of o-aminothiophenol 1 (1 mmol) and α,β-unsaturated ketones 2 (1 mmol), H-ferrierite zeolite (2 g) was added at 80 °C. The resulting mixture was stirred at 100 °C for 8–15 min (Table 3). After the completion of reaction (TLC analysis), the zeolite catalyst was filtered first and the reaction mass was cooled to room temperature and the solid separated was filtered and washed with water, dried and recrystallized from the ethanol solvent. Zeolite was washed with water/acetone. When a catalyst was reused, it was dried overnight in air.
| Entry | Medium | Reaction conditions | Reaction temperature (°C) | Time (min) | Yieldb (%) |
|---|---|---|---|---|---|
| 1 | EtOH + conc. HCl | Reflux | 80 | 420 | 60 |
| 2 | MeOH + gl AcOH | Reflux | 115 | 420 | 44 |
| 3 | H2O + PTSA | Reflux | 100 | 240 | 60 |
| 4 | H-FER zeolitea | Reflux | 100 | 60 | 75 |
| 5 | H-FER zeolitea | Stirring | 100 | 10 | 90 |
| 6 | H-FER zeolitea | Stirring | 80 | 15 | 75 |
| 7 | H-FER zeolitea | Stirring | 60 | 16 | 55 |
| 8 | H-FER zeolitea | Stirring | rt | 20 | 45 |
| Entry | H-FER catalyst amount (g) | Time (min) | Yielda (%) |
|---|---|---|---|
| 1 | 0 | 20 | No reaction |
| 2 | 0.5 | 15 | Traces of product |
| 3 | 1.0 | 12 | 20 |
| 4 | 1.5 | 10 | 62 |
| 5 | 2.0 | 8 | 90 |
| 6 | 2.5 | 8 | 90 |
| 7 | 3.0 | 8 | 88 |
| Entry | Reaction time (min) | Yieldb (%) |
|---|---|---|
| 4a | 10 | 88 |
| 4b | 8 | 90 |
| 4c | 8 | 90 |
| 4d | 10 | 85 |
| 4e | 15 | 80 |
| 4f | 15 | 82 |
Method C: To a mixture of the o-nitrothiophenol 7 (2 mmol), and the chalcone derivatives 2 (2 mmol) in acetic acid (20 mL), Zn powder (2 g) was added. The reaction mixture was refluxed for 4 h. After the completion of reaction (TLC analysis), reaction mixture was filtered the solvent was evaporated under reduced pressure. The crude product was filtered and crystallized from ethanol solvent to afford pure products 4.
2.1.2 2,3-Dihydro-2-(4-fluorophenyl)-4-(4-methylphenyl)-1,5-benzothiazepine (4a)
Yellow solid, mp 138–140 °C. IR (KBr): 1596 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 7.11–8.03 (m, 12 H, ArH), 5.2 (dd, H2x, Jax = 12.81 Hz, Jbx = 3.39 Hz, 1H), 3.38 (dd, H3b, Jbx = 3.39 Hz, Jab = 12.4 Hz, 1H), 2.88 (dd, H3a, Jax = 12.81 Hz, Jab = 12.4 Hz, 1H), 2.40 (s, 3H, CH3), MS: m/z (%) 349 (M++2, 11), 348 (M++1, 15), 347 (M+, 25), 310 (50), 225 (100), 199 (56), 119 (17), 95 (63), 65 (38); Anal. Calcd for C22H18FNS (347.45): C, 76.05; H, 5.22; N, 4.03. Found: C, 76.24; H, 5.10; N, 4.19%.
2.1.3 2,3-Dihydro-2,4-di-(4-fluorophenyl)-1,5-benzothiazepine (4b)
Yellow solid, mp 144–146 °C. IR (KBr): 1594 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 7.11–8.21 (m, 12 H, ArH), 5.20 (dd, H2x, Jax = 12.81 Hz, Jbx = 3.39 Hz, 1H), 3.38 (dd, H3b, Jbx = 3.40 Hz, Jab = 12.4 Hz, 1H), 2.84 (dd, H3a, Jax = 12.81 Hz, Jab = 12.4 Hz, 1H), MS: m/z (%) 353 (M++2, 2), 352 (M++1, 3), 351 (M+, 5), 316 (2), 225 (100), 199 (50), 119 (17), 95 (62), 65 (32); Anal. Calcd for C21H15F2NS (351.41): C, 71.77; H, 4.30; N, 3.99. Found: C, 71.58; H, 4.25; N, 3.75%.
2.1.4 2,3-Dihydro-4-(4-bromophenyl)-2-(4-fluorophenyl)-1,5-benzothiazepine (4c)
Yellow solid, mp 140–142 °C. IR (KBr): 1595 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 7.05–7.93 (m, 12 H, ArH), 5.12 (dd, H2x, Jax = 12.81 Hz, Jbx = 3.39 Hz, 1H), 3.32 (dd, H3b, Jbx = 3.39 Hz, Jab = 12.4 Hz, 1H), 2.78 (dd, H3a, Jax = 12.81 Hz, Jab = 12.4 Hz, 1H); MS: m/z (%) 414 (M++2, 4), 413 (M++1, 3), 412 (M+, 10), 330 (8), 289 (100), 210 (30), 119 (10), 95 (10), 65 (17); Anal. Calcd for C21H15BrFNS (412.32): C, 61.17; H, 3.67; N, 3.40. Found: C, 61.03; H, 3.49; N,3.18%.
2.1.5 2,3-Dihydro-4-(4-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1,5-benzothiazepine (4d)
Yellow solid, mp 156–158 °C. IR (KBr): 1596 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 7.06–8.01 (m, 10 H, ArH), 5.15 (dd, H2x, Jax = 12.81 Hz, Jbx = 3.39 Hz, 1H), 3.29 (s, 9H, 3CH3O), 3.37 (dd, H3b, Jbx = 3.39 Hz, Jab 12.4 Hz, 1H), 2.85 (dd, H3a, Jax = 12.81 Hz, Jab = 12.4 Hz, 1H); MS: m/z (%) 425 (M++2, 2), 424 (M++1, 3), 423 (M+, 5), 330 (8), 290 (5), 194 (100), 119 (5), 95 (2), 65 (10); Anal. Calcd for C24H22FNO3S (423.50): C, 68.07; H, 5.24; N, 3.31. Found C, 67.91; H, 5.08; N, 3.54%.
2.1.6 2,3-Dihydro-4,2-diphenyl-1,5-benzothiazepine (4e)
Pale yellow solid, mp 126–128 °C. IR (KBr): 1593 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.89–7.93 (m, 14 H, ArH), 4.96 (dd, H2x, Jax = 12.81 Hz, Jbx = 3.39 Hz, 1H), 3.29 (dd, H3b, Jbx = 3.39 Hz, Jab = 12.4 Hz, 1H), 2.75 (dd, H3a, Jax = 12.81 Hz, Jab = 12.4 Hz, 1H), MS: m/z (%) 316 (M++1, 7), 315 (M+, 10), 259 (100), 210 (35), 119 (15), 95 (11), 65 (13); Anal. Calcd for C21H17NS (315.43): C, 79.96; H, 5.43; N, 4.44. Found C, 79.75; H, 5.27; N, 4.19%.
2.1.7 2,3-Dihydro-4-(4-fluorophenyl)-2-phenyl-1,5-benzothiazepine (4f)
Yellow solid, mp 131–133 °C. IR (KBr): 1592 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.92–7.96 (m, 13 H, ArH), 4.96 (dd, H2x, Jax = 12.81 Hz, Jbx = 3.39 Hz, 1H), 3.28 (dd, H3b, Jbx = 3.39 Hz, Jab = 12.4 Hz, 1H), 2.78 (dd, H3a, Jax = 12.81 Hz, Jab = 12.4 Hz, 1H), MS: m/z (%) 335 (M++2, 3), 334 (M++1, 5), 333 (M+, 9), 290 (35), 194 (100), 119 (15), 95 (5), 65 (15); Anal. Calcd for C21H16FNS (333.42): C, 75.65; H, 4.84; N, 4.20. Found C, C, 75.39; H, 4.67; N, 4.05%.
2.2 Procedure for synthesis of 3,3a,4,5-tetrahyro-[1,2,4]triazolo[3,4-d][1,5]-benzo-thiazepine (11a–h)
Method A: To a mixture of the appropriate hydrazonoyl halides 9 (1.5 mmol), and the appropriate benzothiazepines 4 (1 mmol) in dioxane (20 mL), triethylamine (4 mL) was added. The reaction mixture was refluxed for 4 h. Then the solvent was evaporated under reduced pressure. The crude product was filtered and crystallized from ethanol/dioxane to afford pure products 11a–h.
Method B: A mixture of the appropriate hydrazonoyl halides 9 (2.5 mmol), and the appropriate benzothiazepines 4 (2.0 mmol), tetrahexylammonium chloride (THAC) (0.075 g, 0.2 mmol) and aqueous 0.1 M sodium carbonate (25 mL), was stirred at room temperature and left overnight. The solid formed was washed with water and dried, then crystallized from the ethanol/dioxane to give products identical in all respects (mp, mixed mp, Ms, IR and 1H NMR) with product 11a–h.
2.2.1 1,3-Diphenyl-3a,5-di-(4-fluorophenyl)-3,3a,4,5-tetrahyro-[1,2,4]triazolo[3,4-d][1,5]-benzothiazepine (11a)
Yellow solid, mp 234–236 °C. IR (KBr): 1597 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.67–7.75 (m, 22 H, ArH), 4.51 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 3.55 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.07 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 52.58, 58.97, 88.18, 116.81, 115.68, 119.27, 122.94, 123.64, 125.18, 125.98, 127.46, 128.58, 129.0, 129.37, 129.99, 131.93, 131.56, 132.82, 133.24, 133.87, 137.18, 142.12, 143.05, 146.48, 151.20, 155.04. MS: m/z (%) 547 (M++2, 1), 546 (M++1, 2), 545 (M+, 5), 194 (58), 91 (100), 64 (11); Anal. Calcd for C34H25F2N3S (545.65): C, 74.84; H, 4.62; N, 7.70. Found: C, 74.68; H, 4.51; N, 7.54%.
2.2.2 3a-(4-Bromophenyl)-1,3-diphenyl-5-(4-fluorophenyl)-3,3a,4,5-tetrahyro-[1,2,4]triazolo[3,4-d][1,5]benzothiazepine (11b)
Yellow solid, mp 244–246 °C. IR (KBr): 1602 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.93–7.81 (m, 22 H, ArH), 4.54 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 3.54 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.13 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H), MS: m/z (%) 608 (M++2, 2), 607 (M++1, 3), 606 (M+, 5), 358 (20), 286 (11), 1800 (70), 129 (20), 77 (100); Anal. Calcd for C34H25BrFN3S (606.55): C, 67.33; H, 4.15; N, 6.93. Found: C, 67.26; H, 4.03; N, 6.77%.
2.2.3 Ethyl 3-(4-chlorophenyl)-5-(4-fluorophenyl)-3a-(4-methylphenyl)-3,3a,4,5-tetrahyro-[1,2,4]triazolo[3,4-d][1,5]benzothiazepine-1-carboxylate (11c)
Yellow solid, mp 218–220 °C. IR (KBr): 1727 (C⚌O), 1599 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.87–7.69 (m, 16 H, ArH), 4.89 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 4.13 (q, 2H, J = 7 Hz, CH2) 3.53 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.27 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H), 1.91 (s, 3H, CH3), 1.02 (t, 3H, J = 7 Hz, CH3), MS: m/z (%) 574 (M++2, 2), 573 (M++1, 3), 572 (M+, 7), 448 (30), 376 (100), 225 (19), 111 (25), 74 (17); Anal. Calcd for C32H27ClFN3O2S (572.09): C, 67.18; H, 4.76; N, 7.34. Found: C, 67.0; H, 4.48; N, 7.15%.
2.2.4 Ethyl 3-(4-chlorophenyl)-3a,5-di-(4-fluorophenyl)-3,3a,4,5-tetrahyro-[1,2,4]triazolo-[3,4-d][1,5]benzothiazepine-1-carboxylate (11d)
Yellow solid, mp 206–208 °C. IR (KBr): 1725 (C⚌O), 1599 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.81–7.77 (m, 16 H, ArH), 4.49 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 4.11 (q, 2H, J = 7 Hz, CH2), 3.59 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.13 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H), 1.05 (t, 3H, J = 7 Hz, CH3); MS: m/z (%) 578 (M++2, 1), 577 (M++1, 2), 576 (M+, 5), 453 (27), 380 (100), 232 (14), 229 (10), 125 (36), 122 (20), 111 (28), 75 (23), Anal. Calcd for C31H24ClF2N3O2S (576.06): C, 64.63; H, 4.20; N, 7.29. Found C, 64.43; H, 4.04; N, 7.44%.
2.2.5 Ethyl 3a-(4-bromophenyl)-5-(4-fluorophenyl)-3-phenyl-3,3a,4,5-tetrahyro-[1,2,4]triazolo[3,4-d][1,5]benzothiazepine-1-carboxylate (11e)
Yellow solid, mp 160–162 °C. IR (KBr): 1726 (C⚌O), 1601 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.90–8.12 (m, 17 H, ArH), 4.49 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 4.21 (q, 2H, J = 7 Hz, CH2), 3.55 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.13 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H), 1.17 (t, 3H, J = 7 Hz, CH3), MS: m/z (%) 604 (M++2, 1), 603 (M++1, 2), 602 (M+, 3), 407 (27), 382 (75), 290 (20), 288 (23), 210 (14), 122 (37), 108 (22), 91 (76) 75 (100), Anal. Calcd for C31H25BrFN3O2S (602.52): C, 61.80; H, 4.18; N, 6.97. Found C, 61.74; H, 4.02; N, 6.69%.
2.2.6 Ethyl 3a-(4-bromophenyl)-3-(4-chlorophenyl)-5-(4-fluorophenyl)-3,3a,4,5-tetrahyro-[1,2,4]triazolo[3,4-d][1,5]benzothiazepine-1-carboxylate (11f)
Yellow solid, mp 232–234 °C. IR (KBr): 1726 (C⚌O), 1601 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.87–7.63 (m, 16 H, ArH), 4.33 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 4.12 (q, 2H, J = 7 Hz, CH2), 3.65 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.12 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H), 1.07 (t, 3H, J = 7 Hz, CH3); 13C NMR (75 MHz, DMSO-d6): δ 21.05, 36.35, 52.06, 60.64, 86.74, 115.18, 115.61, 119.23, 123.54, 127.62, 127.83, 128.69, 129.22, 129.36, 129.49, 130.65, 131.86 132.15, 134.42 137.30, 140.17, 143.10, 147.05, 152.31, 159.22. MS: m/z (%) 639 (M++2, 2), 638 (M++1, 3), 637 (M+, 3), 442 (100), 292 (17), 224 (14), 183 (11), 124 (23), 111 (54), 90 (23) 75 (43), Anal. Calcd for C31H24BrClFN3O2S (636.96): C, 58.45; H, 3.80; N, 6.60. Found: C, 58.31; H, 3.69; N, 6.52%.
2.2.7 Ethyl 3a-(4-bromophenyl)-5-(4-fluorophenyl)-3-(4-nitrophenyl)-3,3a,4,5-tetra-hyro-[1,2,4]triazolo[3,4-d][1,5]benzothiazepine-1-carboxylate (11g)
Yellow solid, mp 149–151 °C. IR (KBr): 1724 (C⚌O), 1601 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.87–7.63 (m, 16 H, ArH), 4.33 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 4.12 (q, 2H, J = 7 Hz, CH2), 3.65 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.12 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H), 1.07 (t, 3H, J = 7 Hz, CH3); 13C NMR (75 MHz, DMSO-d6): δ 20.25, 36.14, 52.11, 59.28, 87.45, 116.01, 115.24, 119.08, 122.65, 126.32, 127.66, 128.07, 129.20, 129.41, 129.49, 131.17, 131.82 132.79, 134.28 137.20, 141.27, 143.54, 147.35, 151.14, 158.36. MS: m/z (%) 649 (M++2, 1), 648 (M++1, 3), 647 (M+, 5), 451 (100), 291 (17), 259 (14), 210 (14), 149 (11), 122 (38), 108 (21), 75 (43), Anal. Calcd for C31H24BrFN4O4S (647.52): C, 57.50; H, 3.74; N, 8.65. Found: C, 57.36; H, 3.58; N, 8.42%.
2.2.8 Ethyl 3a-(4-fluorophenyl)-3-(4-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-3,3a,4,5-tetrahyro-[1,2,4]triazolo[3,4-d][1,5]benzothiazepine-1-carboxylate (11h)
Yellow solid, mp 157 °C. IR (KBr): 1726 (C⚌O), 1958 (C⚌N); 1H NMR (300 MHz, DMSO-d6): δ 6.87–7.63 (m, 14 H, ArH), 4.33 (dd, H5x, Jax = 10.85 Hz, Jbx = 2.0 Hz, 1H), 4.12 (q, 2H, J = 7 Hz, CH2), 3.32 (s, 9H, 3CH3O),3.65 (dd, H4b, Jbx = 2.0 Hz, Jab = 14.0 Hz, 1H), 3.12 (dd, H4a, Jax = 10.85 Hz, Jab = 14.0 Hz, 1H), 1.07 (t, 3H, J = 7 Hz, CH3), MS: m/z (%) 660 (M++2, 2), 659 (M++1, 3), 658 (M+, 6), 464 (11), 390 (100), 344 (23), 229 (16), 196 (10), 90 (15) 75 (19), Anal. Calcd for C34H31FN4O7S (658.70): C, 62.00; H, 4.74; N, 8.51. Found: C, 61.90; H, 4.60; N, 8.32%.
3 Results and discussion
The reaction of o-aminothiophenol 1 with α,β-unsaturated ketones 2 was carried out under several reaction conditions to afford 2,3-dihydro-1,5-benzothiazepine derivatives 4 in excellent yield with good purity (Scheme 1 and Table 1). As an initial attempt, a variety of experimental reaction conditions were examined by changing catalyst, reaction medium (conventional, and stirring), and temperature (Table 1). It was found that H-FER zeolite (Chauhan et al., 2011) was the best choice of catalyst for the preparation of 2,3-dihydro-1,5-benzothiazepine derivatives 4 compared with conc. HCl, glacial AcOH and p-toluene sulfonic acid(PTSA) (Table 1).
This can suggest that the acid sites on zeolite work as active sites for this reaction. For checking the catalyst amount effect on reaction conditions, the reaction was investigated using different amounts of catalyst and found that 2 g of catalyst amount was enough for activation reaction, but higher amount of the catalyst did not affect the product yield (Table 2). It was also, observed that classical heating gave lower yield with higher reaction time compared to reactions realized under stirring conditions and interphase catalysis. In view of all these results, we have synthesized all compounds 4a–f using H-FER zeolite under stirring at 100 °C (Table 3). The catalyst, zeolite can be reused several times without any loss of activity by filtering the catalyst, washing with acetone, drying and reusing immediately.
To account for the formation of 1,5-benzothiazepine derivatives 4, it is suggested, as depicted in Scheme 1, that the reaction starts with the formation of Michael-adduct type intermediates 3, which simultaneously undergoes dehydrative cyclization to give the desired products 4 (Scheme 1). The isolated products were completely characterized by IR, 1H NMR, and Mass spectroscopic analyses. The formation of compounds 4a–f was evident from the appearance of [M+] peak in mass spectrum. The 1H NMR spectra of compounds 4a–f showed, in addition to the aromatic proton signals, three characteristic signals at δ 2.88–2.75, 3.39–328 and 5.2–4.96 assignable to the CH2 and CH protons. On the basis of the above results the other regioisomer 6 was discarded.
Moreover, refluxing with stirring of o-nitrothiophenol 7 with α,β-unsaturated ketones 2 in the presence Zn powder as catalyst in acetic acid gave the corresponding non-isolated adducts 8 via selective thia-Michael addition to the α,β-unsaturated carbonyl moiety. The latter adducts when heated, the nitro group was reduced by Zn powder to its amine intermediate 3 followed by ring closure to yield 4 (Scheme 2).
Finally, reaction of compounds 4 with nitrilimine 10 (generated in situ by the effect of the basic catalyst on the hydrazonoyl chloride 9), was carried out in dioxane or water under both homogeneous and heterogeneous reaction conditions with triethylamine or sodium carbonate as the base and in the presence of tetrahexylammonium chloride (THAC) as catalyst (Scheme 3). Reaction with triethylamine was carried out under reflux, but only poor yields were obtained (Table 4). On the other hand, the THAC proved more effective and the reaction mixture was carried out at room temperature. When compounds 4 reacted with the nitrilimine 10, they afforded in each case, only one product, as examined by TLC, which were identified as the respective (Scheme 3) Triazolobenzothiazepine derivatives 11 or 12. The structure of our choice is 11 rather than 12, this choice is based on the results of 13C NMR of the products i.e. the 13C NMR spectra of compounds 11 display the characteristic signals of the suggested structures. The signal for C-4 resonates at about 86.74–88.18 ppm (Ferwanah et al., 2001, 2002). This is similar to the reported values of carbons flanked by two nitrogens in 5-membered heterocycles (Awadallah et al., 2002; Ferwanah et al., 2002). This provides strong evidence in support of structures 11a–h rather than the other regioisomer 12, which is expected to have a C-4 signal at about 60–70 ppm (Awadallah et al., 2002). This assignment is in good agreement with literature data for 1,3-cycloaddition on C⚌N bond (Elwan et al., 1996; Ferwanah et al., 2001; Hussein et al., 1989; Dong et al., 2001).![Synthesis of triazolo[3,4-d][1,5]benzothiazepine 11.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.12.024-fig3.png)
| Compd. no. | TEA | THAC |
|---|---|---|
| Yield (%) | Yield (%) | |
| 11a | 67 | 89 |
| 11b | 65 | 84 |
| 11c | 64 | 89 |
| 11d | 59 | 90 |
| 11e | 68 | 84 |
| 11f | 65 | 87 |
| 11g | 66 | 82 |
| 11h | 69 | 79 |
4 Conclusion
In conclusion, we have developed an efficient and facile method for the synthesis of 1,5-benzothiazepines and 1,2,4-triazolo[3,4-d][1,5]benzothiazepines by using H-FER zeolite catalysts under solvent-free and Na2CO3/THAC in water, respectively. The mild reaction conditions are reduced pollution, reusability, high selectivity, low cost, and simplicity in process and in handling. These factors are very useful both from economic and environmental points of view and especially important in industry.
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