催化学报  2015, Vol. 36 Issue (5): 734-741   PDF (545 KB)    
扩展功能
加入收藏夹
复制引文信息
加入引用管理器
Email Alert
RSS
本文作者相关文章
Hossein Naeimi
Hossein Foroughi
Efficient, environmentally benign, one-pot procedure for the synthesis of 1, 5-benzodiazepine derivatives using N-methyl-2-pyrrolidonium hydrogen sulphate as an ionic liquid catalyst under solvent-free conditions
Hossein Naeimi , Hossein Foroughi    
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, 87317, Iran
Received: 2014-12-22. Accepted: 2015-01-23. Published: 2015-05-20.
* Corresponding author. Tel: +98-315-5912388; Fax: +98-315-5912397; Email: naeimi@kashanu.ac.ir
Abstract: A powerful and environmentally benign method has been developed for the one-pot synthesis of 4-substituted-1,5-benzodiazepines via the three-component reaction of a series of aldehydes with dimedone and o-phenylenediamine using [H-NMP][HSO4] as a Brönsted acidic ionic liquid catalyst under solvent-free conditions. The key benefits of this new method over existing techniques include high yields, the use of a green catalyst, short reaction times and facile catalyst separation.
© 2015, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Key words: Ionic liquid     Benzodiazepine     Solvent-free conditions     Dimedone    

1. Introduction

Fused 1,5-benzodiazepines are a highly valuable class of organic compounds that posses a wide variety of interesting biological properties [1, 2, 3, 4, 5, 6, 7]. For example, 1,5-dibenzodiazepine derivatives have been reported to exhibit inhibitory activities towards hepatitis C virus (HCV) NS5B [8] and HIV-1 protease [9, 10], as well as finding numerous applications in medicinal chemistry [11], where they have been used as anti- inflammatory [12], hypnotic [13], anticoagulant [14], antibacterial [15], antidepressant [16], antiepileptic [17, 18] and analgesic [19] agents. Several methods have been reported for the synthesis of 1,5-benzodiazepine derivatives via the condensation of o-phenylenediamine and dimedone with various aldehydes or ketones in the presence of a wide variety of Brӧnsted acid catalysts, including acyl chlorides [8, 9] oxalic acid in water [20], acetic acid in refluxing ethanol [21, 22], HCl in ethanol [23], acetic acid in toluene [24] and H2SO4 in water [25]. Several other methods have also been developed for the synthesis of 1,5-benzodiazepine derivatives, such as the cycloaddition reaction of 2,2-dihydroxy-1-phenylethanone with an o-phenylenediamine derivative and dimedone [26], the hetero-Cope rearrangement and the condensation of a 2-formyl benzoic acid substrate with an o-phenylenediamine derivative and tetronic acid in water under microwave irradiation conditions [27].

A multi-component reaction (MCR) is a chemical transformation involving the combination of three or more different starting materials in a single one-pot procedure to give a complex product. MCRs are useful tools in organic synthesis because they can be used to generate complex molecular architectures in one pot from simple starting materials [28, 29, 30, 31]. Research towards the development of MCRs has grown considerably during the last decade, and several environmentally friendly and high yielding MCRs have been reported for the production of a wide range of interesting organic compounds from readily available and commercially inexpensive starting materials [32, 33].

As part of our ongoing research towards the application of catalysts in organic synthesis [28, 29, 30, 31, 32, 33], we recently became interested in the use of catalysts in MCRs. Herein, we report the development of an efficient method for the synthesis of 4-substituted-1,5-benzodiazepines via the one-pot MCR of a series of aldehydes with o-phenylenediamine and dimedone (Scheme 1). This reaction provided facile access to the target molecules in high yields over short reaction times using [H-NMP][HSO4] as an ionic liquid catalyst. Furthermore, this method is environmentally benign and robust, and involves easy separation and work-up procedures.

2. Experimental
2.1. General

All of the reagents used in the current study were purchased from Merck, Aldrich, CDH and Fluka and used without further purification.

Fourier transform infrared (FT-IR) spectra were recorded as KBr pellets on a Perkin-Elmer 781 spectrophotometer. Ultraviolet (UV-Vis) spectra were obtained in CDCl3 on a Perkin-Elmer 550 S spectrophotometer. Nuclear magnetic resonance (1H NMR and 13C NMR) were recorded in DMSO and CDCl3 solvents on a Bruker DRX-400 spectrometer using tetramethylsilane (TMS) as an internal reference. Elemental analyses (C, H, N) were conducted on a Carlo ERBA Model EA 1108 analyzer. Electrospray ionization mass spectroscopy (ESI-MS) experiments were performed on an Agilent Technology (HP) 5973 instrument at an ionization potential of 70 eV. Melting points (M.P) determined on a Thermo Scientific 9300 melting point apparatus. The purities of the substrates and reaction monitoring were accomplished by TLC on silica-gel PolyGram SILG/UV 254 plates (Merck).

2.2. Preparation of N-methyl-2-pyrrolidonium hydrogen sulfate [H-NMP][HSO4] ionic liquid

1-Methyl-2-pyrolidone (0.2 mol) was charged into a 250-mL three-necked flask containing a magnetic stirrer. An equimolar amount of concentrated H2SO4 (98 wt%) was then added to the flask in a drop-wise manner, and the resulting mixture was heated at 80 °C for 12 h. The mixture was then cooled to ambient and washed three times with ether to remove any non-ionic residues before being dried under vacuum on a rotary evaporator at 25 °C to [H-NMP][HSO4] as a clear, viscous ionic liquid. The pH of the resulting ionic liquid (10% w/v) was determined to be 1.2.

2.3. General procedure for the synthesis of 4-substituted-1,5-benzodiazepines (3a-3o)

Dimedone (1 mmol), o-phenylenediamine (1 mmol) and an aromatic aldehyde (1 mmol) were added to [H-NMP][HSO4] (0.14 g) under solvent-free conditions, and the resulting mixture was stirred at 100 °C for the stipulated time. Upon completion of the reaction, as determined by TLC (1:1 - ethyl acetate:petroleum ether), the mixture was cooled to room temperature and washed by water before being filtered to remove the catalyst. The resulting oil was crystallized from a 6:5 (v/v) mixture of methanol and water to give a residue, which was purified by recrystallization from ethanol. The products were characterized by a comparison of their physical and spectral data with those of the authentic samples.

3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3a). Yield: 75%; pale green solid, m.p. = 246-248 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 360 nm; IR (KBr, cm-1): υ 3296, 3237, 3057, 2955, 1584, 1384, 1530, 1329, 1424, 1277; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.03 (s, 3H, CH3-), 1.08 (s, 3H, CH3), 2.11 (q, 2H, J = 16.0 Hz, CH2), 2.56 (s, 2H, CH2-C=O), 5.71 (s, 1H, N-H), 6.08 (s, 1H , C-H), 6.47-6.57 (m, 3H, Ar), 6.89 (d, 1H, J = 8.0 Hz, Ar), 6.95 (t, 1H, J = 8.0 Hz, Ar), 7.0-7.1 (m, 3H, Ar), 8.15 (d, 1H, J = 4.0 Hz, Ar), 8.69 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 27.95, 29.06, 32.21, 44.74, 50.05, 56.49, 110.68, 119.87, 120.44, 121.01, 122.98, 126.11, 127.7, 127.98, 131.49, 138.84, 145.1, 155.12, 192.52; ESI-MS (m/z, %): 318 (M+, 26), 241 (100), 149 (52), 83 (45), 77 (34), 57 (85), 55 (62); Anal. Calcd. for C21H22N2O: C 79.21, H 6.96, N 8.80; Found: C 79.24, H 6.98, N 8.84.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-nitro)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3b). Yield: 81%; yellow solid, m.p. = 280-281 °C (decomp.); Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 348 nm; IR (KBr, cm-1): υ 3355, 3279, 3181, 2955, 1591, 1381, 1511, 1339, 1425, 1275; 1H NMR (DMSO+CDCl3, 400 MHz): δ 0.99 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.14 (q, 2H, J = 16.0 Hz, CH2), 2.53 (s, 2H, CH2-C=O), 5.64 (s, 1H, N-H), 5.87 (s, 1H, C-H), 6.43 (d, 1H, J = 6.4 Hz, Ar), 6.55-6.61 (m, 2H, Ar), 6.9 (d, 1H, J = 6.4 Hz, Ar), 7.21 (d, 2H, J = 8.8 Hz, Ar), 7.84 (d, 2H, J = 8.8 Hz, Ar), 8.58 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.09, 28.80, 32.20, 44.82, 49.93, 56.63, 109.44, 120.52, 120.75, 121.09, 123.08, 123.43, 128.57, 131.39, 138.03, 146.05, 153.05, 155.05, 192.85; ESI-MS (m/z, %): 397 (M+, 29), 241 (100), 149 (66), 83 (51), 77 (32), 57 (39), 55 (47); Anal. Calcd. for C21H21N3O3: C 69.41, H 5.82, N 11.56; Found: C 69.45, H 5.85, N 11.59.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-nitro)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3c). Yield: 80%; orange solid, m.p. = 230-232 °C (decomp.); Rf = 0.281 (1:1 - ethyl acetate/n-hexane); UV-vis: l max= 346 nm; IR (KBr, cm-1): υ 3378, 3303, 3069, 2957, 1591, 1381, 1528, 1332, 1473, 1279; 1H NMR (DMSO+CDCl3, 400 MHz): δ 0.95 (s, 3H, CH3), 1.05 (s, 3H, CH3), 2.01 (q, 2H, J = 16.0 Hz, CH2), 2.58 (s, 2H, CH2-C=O), 5.04 (s, 1H, N-H), 6.01 (s, 1H, C-H), 6.32 (d, 1H, J = 8.0 Hz, Ar), 6.58 (t, 1H, J = 8.0 Hz, Ar), 6.67 (t, 1H, J = 8.0 Hz, Ar), 6.79 (d, 1H, J = 8.0 Hz, Ar), 7.04 (d, 1H, J = 8.0 Hz, Ar), 7.14-7.2 (m, 2H, Ar), 7.74 (d, 1H, J = 8.0 Hz, Ar), 8.91 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.11, 28.82, 32.22, 44.87, 49.91, 56.62, 109.46, 120.53, 120.78, 121.07, 123.1, 123.46, 126.14, 128.56, 128.59, 131.38, 138.06, 146.03, 153.08, 155.08, 192.89; ESI-MS (m/z, %): 363 (M+, 26), 241 (100), 149 (55), 83 (36), 77 (42), 57 (49), 55 (62); Anal. Calcd. for C21H21N3O3: C 69.41, H 5.82, N 11.56; Found: C 69.46, H 5.85, N 11.60.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(3-nitro)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3d). Yield: 78%; pale yellow solid, m.p. = 195-197 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max= 348 nm; IR (KBr, cm-1): υ 3375, 3328, 3049, 2959, 1589, 1383, 1529, 1345, 1431, 1277; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.05 (s, 3H, CH3), 1.09 (s, 3H, CH3), 2.14 (q, 2H, J = 16.0 Hz, CH2), 2.58 (s, 2H, CH2-C=O), 5.81 (s, 1H, N-H), 6.20 (s, 1H, C-H), 6.50 (d, 1H, J =5.2 Hz, Ar), 6.51-6.6 (m, 2H, Ar), 6.9 (d, 1H, J = 7.2 Hz, Ar), 7.29 (t, 1H, J = 8.0 Hz, Ar), 7.45 (d, 1H, J = 8.0 Hz, Ar), 7.81 (d, 1H, J = 9.2 Hz, Ar), 7.98 (s, 1H, Ar), 8.79 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.1, 28.81, 32.24, 44.86, 49.93, 56.64, 109.47, 120.56, 120.76, 121.06, 123.11, 123.47, 126.16, 128.49, 128.56, 131.39, 138.09, 146.05, 153.1, 155.09, 192.86; ESI-MS (m/z, %): 363 (M+, 30), 241 (100), 149 (38), 83 (40), 77 (41), 57 (39), 55 (58); Anal. Calcd. for C21H21N3O3: C 69.41, H 5.82, N 11.56; Found: C 69.45, H 5.86, N 11.57.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-chloro)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3e). Yield: 85%; pale green solid, m.p. = 235-237 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max= 344 nm; IR (KBr, cm-1): υ 3301, 3238, 3054, 2956, 1587, 1381, 1532, 1329, 1426, 1278; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.0 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.11 (q, 2H, J = 16.0 Hz, CH2), 2.52 (s, 2H, CH2-C=O), 5.73 (s, 1H, N-H), 5.78 (s, 1H, C-H), 6.45 (d, 1H, J = 8.2 Hz, Ar), 6.55 (m, 2H, Ar), 6.88 (d, 1H, J = 8.2 Hz, Ar), 6.98 (d, 2H, J = 8.4 Hz, Ar), 7.01 (d, 1H, J = 8.4 Hz, Ar), 8.61 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.17, 28.69, 32.24, 44.84, 49.90, 56.43, 109.38, 120.62, 120.72, 121.05, 123.11, 123.28, 128.36, 131.45, 138.06, 146.08, 150.02, 152.06, 192.81; ESI-MS (m/z, %): 362 (M+, 33), 354 (M+2+, 11), 241 (100), 149 (57), 83 (35), 77 (28), 57 (68), 55 (53); Anal. Calcd. for C21H21ClN2O: C 71.48, H 6.0, N 7.94; Found: C 71.53, H 6.5, N 7.98.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-chloro)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3f). Yield: 78%; white solid, m.p. = 239-240 °C (decomp.); Rf = 0.281 (1:1 - ethyl acetate/n-hexane); UV-vis: l max= 348 nm; IR (KBr, cm-1):υ 3292, 3235, 3062, 2959, 1589, 1382, 1515, 1314, 1422, 1278; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.02 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.09 (q, 2H, J = 16.0 Hz, CH2), 2.57 (s, 2H, CH2-C=O), 5.07 (s, 1H, N-H), 6.01 (s, 1H, C-H), 6.33 (d, 1H, J = 7.2 Hz, Ar), 6.44-6.62 (m, 2H, Ar), 6.7 (d, 1H, J = 7.6 Hz, Ar), 6.82 (d, 1H, J = 7.6 Hz, Ar), 6.85-7.0 (m, 2H, Ar), 7.20 (d, J = 7.6 Hz, 1H, Ar), 8.77 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.17, 28.72, 32.26, 44.84, 49.88, 56.42, 109.32, 120.61, 120.66, 121.12, 123.13, 123.42, 126.11, 128.53, 128.62, 131.42, 138.04, 146.06, 149.55, 151.06, 192.82; ESI-MS (m/z, %): 352 (M+, 36), 354 (M+2+, 12), 241 (100), 149 (52), 83 (49), 77 (33), 57 (42), 55 (51); Anal. Calcd. for C21H21ClN2O: C 71.48, H 6.0, N 7.94; Found: C 71.54, H 6.6, N 7.99.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(2,3-dichloro) phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3g). Yield: 82%; pale green solid, m.p. = 256-358 °C (decomp.); Rf = 0.281 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 348 nm; IR (KBr, cm-1): υ 3379, 3301, 3060, 2958, 1589, 1380, 1532, 1332, 1423, 1289; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.01 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.12 (q, 2H, J = 16.0 Hz, CH2), 2.56 (s, 2H, CH2-C=O), 4.96 (s, 1H, N-H), 6.07 (s, 1H, C-H), 6.30 (d, 1H, J = 7.6 Hz, Ar), 6.53-6.60 (m, 2H, Ar), 6.62 (d, 1H, J = 7.2 Hz, Ar), 6.75 (t, 1H, J = 8.0 Hz, Ar), 6.91 (d, 1H, J = 7.6 Hz, Ar), 7.08 (d, 1H, J = 7.6 Hz, Ar), 8.64 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.14, 28.67, 32.23, 44.81, 49.92, 56.29, 109.10, 120.68, 121.08, 121.35, 123.65, 126.13, 126.84, 128.83, 131.71, 132.05, 132.57, 137.33, 143.52, 156.12, 192.90; ESI-MS (m/z, %): 386 (M+, 24), 388 (M+2+, 14), 390 (M+4+, 4), 351 (52), 241 (100), 149 (25), 83 (34), 77 (24), 69 (52), 57 (43), 55 (54); Anal. Calcd. for C21H20Cl2N2O: C 65.12, H 5.20, N 7.23; Found: C 65.15, H 5.24, N 7.26.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(2,4-dichloro) phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3h). Yield: 83%; pale green solid, m.p. = 230-232 °C (decomp.); Rf = 0.281 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 347 nm; IR (KBr, cm-1): υ 3303, 3241, 3055, 2957, 1590, 1382, 1533, 1330, 1468, 1278; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.02 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.11 (q, 2H, J = 16.0 Hz, CH2), 2.57 (s, 2H, CH2-C=O), 4.99 (s, 1H, N-H), 5.99 (s, 1H, C-H), 6.34 (d, 1H, J = 7.6 Hz, Ar), 6.56-6.63 (m, 2H, Ar), 6.65 (d, 1H, J = 8.4 Hz, Ar), 6.79 (d, 1H, J = 8.0 Hz, Ar), 6.92 (d, 1H, J = 7.2 Hz, Ar), 7.22 (s, 1H, Ar), 8.74 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.16, 28.69, 32.26, 44.78, 49.93, 56.31, 109.12, 120.72, 121.06, 121.37, 123.68, 126.15, 126.88, 128.87, 131.68, 132.04, 132.59, 137.38, 149.57, 156.18, 192.92; ESI-MS (m/z, %): 386 (M+, 26), 388 (M+2+, 16), 390 (M+4+, 6), 241 (100), 149 (66), 83 (57), 77 (30), 57 (65), 55 (45); Anal. Calcd. for C21H20Cl2N2O: C 65.12, H 5.20, N 7.23; Found: C 65.16, H 5.25, N 7.28.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-chloro-3-nitro)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3i). Yield: 77%; pale yellow solid, m.p. = 196-197 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-VIS: l max = 348 nm; IR (KBr, cm-1): υ 3305, 3240, 3039, 2958, 1600, 1381, 1532, 1339, 1426, 1276; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.02 (s, 3H, CH3), 1.07 (s, 3H, CH3-), 2.13 (q, 2H, J = 16.0 Hz, CH2), 2.54 (s, 2H, CH2-C=O), 5.77 (s, 1H, N-H), 6.08 (s, 1H, C-H), 6.50 (d, 1H, J = 8.0 Hz, Ar), 6.59 (m, 2H, Ar), 6.91 (d, 1H, J = 8.0 Hz, Ar), 7.24-7.29 (m, 2H, Ar), 7.68 (s, 1H, Ar), 8.74 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.04, 28.75, 32.19, 44.69, 49.84, 56.02, 109.07, 120.75, 120.85, 121.18, 123.36, 123.63, 124.85, 131.21, 131.44, 132.66, 138.04, 146.18, 147.33, 155.94, 192.9; ESI-MS (m/z, %): 397 (M+, 21), 399 (M+2+, 4), 241 (100), 149 (47), 83 (47), 77 (27), 69 (81), 57 (91), 55 (67); Anal. Calcd. for C21H20ClN3O3: C 63.40, H 5.07, N 10.56; Found: C 63.46, H 5.13, N 10.64.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-methyl)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3j). Yield: 76%; pale green solid, m.p. = 224-226 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 361 nm; IR (KBr, cm-1): υ 3307, 3245, 3050, 2959, 1595, 1380, 1538, 1327, 1471, 1276; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.01 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.01 (q, 2H, J = 16.0 Hz, CH2), 2.01 (s, 3H, Me), 2.52 (s, 2H, CH2-C=O), 5.69 (s, 1H, N-H), 5.69 (s, 1H, C-H), 6.45 (d, 1H, J = 7.6 Hz, Ar), 6.5-6.6 (m, 2H, Ar), 6.81 (d, 2H, J = 7.6 Hz, Ar), 6.86 (d, 1H, J = 8.4 Hz, Ar), 6.92 (d, J = 7.6 Hz, 2H, Ar), 8.53 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 27.85, 29.16, 32.23, 44.71, 50.09, 55.07, 56.51, 110.69, 119.86, 120.47, 121.07, 122.96, 126.35, 127.58, 127.94, 131.53, 138.87, 145.11, 155.14, 192.56; ESI-MS (m/z, %): 332 (M+, 43), 241 (100), 149 (55), 83 (39), 77 (41), 57 (77), 55 (46); Anal. Calcd. for C22H24N2O: C 79.48, H 7.28, N 8.43; Found: C 79.53, H 7.35, N 8.49.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-methoxy) phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3k). Yield: 73%; pale cream solid, m.p. = 229-231 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 364 nm; IR (KBr, cm-1): υ 3301, 3238, 3015, 2956, 1587, 1382, 1535, 1327, 1426, 1279; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.01 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.10 (s, 3H, Me), 2.19 (s, 1H, C-H), 2.31 (q, 2H, J = 16.0 Hz, CH2), 2.52 (s, 2H, CH2-C=O), 5.7 (s, 1H, N-H), 6.45 (d, 1H, J = 7.6 Hz, Ar), 6.5-6.58 (m, 2H, Ar), 6.81 (d, 2H, J = 8.0 Hz, Ar), 6.87 (d, 1H, J = 8.4 Hz, Ar), 6.91(d, J = 8.0 Hz, 2H, Ar), 8.55(s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 27.82, 29.19, 32.23, 44.75, 50.04, 54.11, 56.42, 110.67, 111.46, 113.56, 119.93, 120.41, 121.05, 123.06, 128.89, 131.46, 138.89, 146.66, 155.21, 192.08; ESI-MS (m/z, %): 348 (M+, 67), 241 (100), 149 (36), 83 (35), 77 (42), 57 (43), 55 (52); Anal. Calcd. for C22H24N2O2: C 75.83, H 6.94, N 8.04; Found: C 75.86, H 6.97, N 8.07.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-methoxy) phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3l). Yield: 74%; pale cream solid, m.p. = 217-218 °C (decomp.); Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 361 nm; IR (KBr, cm-1): υ 3369, 3306, 3063, 2955, 1599, 1384, 1534, 1327, 1425, 1236; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.07 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.12 (q, 2H, J = 16.0 Hz, CH2), 2.57 (s, 2H, CH2-C=O), 3.89 (s, 3H, Me), 5.0 (s, 1H, N-H), 5.95 (s, 1H, C-H), 6.28 (d, 1H, J = 7.6 Hz, Ar), 6.45-6.55 (m, 3H, Ar), 6.58 (d, 1H, J = 7.6 Hz, Ar), 6.75 (d, 1H, J = 8.4 Hz, Ar), 6.86 (d, J = 7.6 Hz, 1H, Ar), 6.94 (t, 1H, J = 8.0 Hz, Ar), 8.59 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 27.95, 29.08, 32.32, 44.77, 50.05, 54.79, 56.43, 110.75, 111.47, 113.56, 119.89, 120.06, 120.40, 121.05, 123.06, 128.85, 131.47, 138.86, 146.65, 155.26, 159.24, 192.65; EI-MASS (m/z, %): 348 (M+, 42), 241 (100), 149 (52), 83 (61), 77 (27), 57 (85), 55 (72); Anal. Calcd. for C22H24N2O2: C 75.83, H 6.94, N 8.04; Found: C 75.9, H 6.98, N 8.10.

3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(3-methoxy) phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3m). Yield: 76%; pale green solid, m.p. = 225-227 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max= 364 nm; IR (KBr, cm-1): υ 3326, 3278, 3050, 2954, 1586, 1382, 1538, 1332, 1497, 1274; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.01 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.12 (q, 2H, J = 16.0 Hz, CH2), 2.52 (s, 2H, CH2-C=O), 3.55 (s, 3H, Me), 5.64 (s, 1H, N-H), 5.72 (s, 1H, C-H), 6.44-6.48 (m, 2H, Ar), 6.53-6.57 (m, 2H, Ar), 6.60 (s, 1H, Ar), 6.62 (d, 1H, J = 8.0 Hz, Ar), 6.86 (d, 1H, J = 7.6 Hz, Ar), 6.91 (t, 1H, J = 8.0 Hz, Ar), 8.53 (s, 1H, N-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 27.81, 29.18, 32.21, 44.72, 50.02, 54.99, 56.41, 110.64, 111.44, 113.54, 119.91, 120.08, 120.43, 121.03, 123.03, 128.87, 131.44, 138.87, 146.63, 155.24, 159.25, 192.60; ESI-MS (m/z, %): 348 (M+, 72), 241 (100), 149 (45), 83 (31), 77 (37), 69 (34), 57 (35), 55 (42); Anal. Calcd. for C22H24N2O2: C 75.83, H 6.94, N 8.04; Found: C 75.86, H 6.97, N 8.07.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-hydroxy) phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3n). Yield: 71%; pale cream solid, m.p. = 201-202 °C; Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-vis: l max = 360 nm; IR (KBr, cm-1):υ 3622, 3302, 3238, 3100, 2957, 1599, 1384, 1528, 1328,1424,1276; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.06 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.13 (q, 2H, J = 16.0 Hz, CH2), 2.56 (s, 2H, CH2-C=O), 5.18 (s, 1H, N-H), 5.93 (s, 1H, C-H), 6.35 (t, 2H, J = 7.2 Hz, Ar), 6.38 (d, 1H, J = 6.8 Hz, Ar), 6.50-6.55 (m, 3H, Ar), 6.66 (d, 1H, J = 8.0 Hz, Ar), 6.76 (t, 1H, J = 7.2 Hz, Ar), 6.86 (d, J = 7.2 Hz, 1H, Ar), 8.53 (s, 1H, N-H), 9.35 (s, 1H, O-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.04, 29.05, 32.22, 44.71, 50.11, 56.39, 110.89, 113.22, 115.08, 118.65, 119.77, 120.43, 120.96, 122.97, 128.71, 131.47, 138.95, 146.62, 155.07, 157.26, 192.55; EI-MASS (m/z, %): 348 (M+, 23), 241 (100), 149 (47), 83 (35), 77 (46), 57 (40), 55 (48); Anal. Calcd. for C21H22N2O2: C 75.42, H 6.63, N 8.38; Found: C 75.47, H 6.68, N 8.43.

3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(3-hydroxy) phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3o). Yield: 75%; pale green solid, m.p. = 287-289 °C (decomp.); Rf = 0.125 (1:1 - ethyl acetate/n-hexane); UV-VIS: l max= 348 nm; IR (KBr, cm-1): υ 3447, 3307, 3048, 2927, 1585, 1386, 1519, 1332, 1425, 1275; 1H NMR (DMSO+CDCl3, 400 MHz): δ 1.03 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.11 (q, 2H, J = 16.0 Hz, CH2), 2.54 (s, 2H, CH2-C=O), 5.60 (s, 1H, N-H), 5.94 (s, 1H, C-H), 6.37 (d, 1H, J = 7.6 Hz, Ar), 6.48-6.57 (m, 5H, Ar), 6.82 (t, 1H, J = 7.6 Hz, Ar), 6.89 (d, 1H, J = 7.6 Hz, Ar), 8.64 (s, 1H, N-H), 8.90 (s, 1H, O-H); 13C NMR (DMSO+CDCl3, 100 MHz): δ 28.02, 29.09, 32.20, 44.74, 50.07, 56.36, 110.86, 113.19, 115.05, 118.60, 119.75, 120.39, 120.98, 122.94, 128.74, 131.43, 138.93, 146.59, 155.04, 157.21, 192.50; ESI-MS (m/z, %): 334 (M+, 34), 241 (100), 149 (61), 83 (57), 77 (25), 69(84), 57 (90), 55 (72); Anal. Calcd. for C21H22N2O2: C 75.42, H 6.63, N 8.38; Found: C 75.46, H 6.66, N 8.42.

3. Results and discussion
3.1. Catalytic performance

Ionic liquids (ILs) have been successfully used as solvents and catalyst in a wide variety of different reactions [34, 35, 36], and have the potential to be used in numerous other applications in organic synthesis. In a continuation of our recent work towards the development of Lewis and Brӧnsted acid catalyzed synthetic methodologies [37, 38, 39, 40], we became interested in the use of ILs as catalysts for MCRs. The 1H NMR spectrum of the IL [H-NMP][HSO4] is shown in Fig. 1. This material was synthesized according to literature procedures and evaluated as a catalyst in the MCR of X and Y with Z [41, 42, 43]. The peak in the 1H NMR spectrum of [H-NMP][HSO4] at 2.41 ppm was assigned to the three protons of the methyl group belonging to the NMP moiety, and the peaks at 1.61, 2.05, and 3.10 ppm were attributed to six protons of the pyrrolidinium ring.

Fig. 1. 1H NMR spectrum of [H-NMP][HSO4] in D2O.

A general method has been developed in this study for the synthesis of 4-substituted-1,5-benzodiazepines and related heterocycles via the condensation reaction of an aromatic aldehyde with o-phenylenediamine and dimedone, followed by the Knoevenagel cyclization of the resulting adduct (shown in Scheme 1).

Scheme 1. Synthesis of 4-substituted-1,5-benzodiazepines under solvent-free conditions.

To highlight the advantages of this newly developed method, we have compared the results of the current study with those reported in literature for the same transformation using different conditions [20, 21, 22, 23, 24, 25] (Table 1). The reaction of dimedone with o-phenylenediamine and benzaldehyde to give 3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one was selected as a model reaction to compare the different methods. The methods themselves were compared on the basis of the catalyst, reaction conditions, reaction time and percentage yield of the product. The results of this comparison revealed that our newly developed method is more efficient, faster and simpler than some of the existing methods.

Table 1
 Comparison of the current method with several literature methods for the synthesis of 1,5-benzodiazepines.

When the reaction was carried out under solvent-free conditions at 60 °C, the product was isolated in 55% yield (Table 2, entry 9). Furthermore, when the reaction was conducted in the presence of 0.14 g of the [H-NMP][HSO4] catalyst at 100 °C, the desired product 3e was isolated in a 85% yield (Table 2, entry 11). These experiments therefore demonstrate that [H-NMP][HSO4] works well as a catalyst for this transformation.

Table 2
Optimization of the reaction conditions.

The results of the optimization experiments indicated that the MCR was being catalyzed much more effectively by [H-NMP][HSO4] that any of the other catalysts tested, because the desired product was obtained in much higher yields over shorter reaction times when the reaction was conducted in the presence of this IL catalyst (Table 2, entries 1-12).

This method is complementary to the classical methods used for the synthesis of 3,3-dimethyl-2,3,4,5,10,11- hexahydro-11-[(4-chloro)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-one (3e). The performance of the reaction was also evaluated using a variety of different solvents, including n-hexane, CH2Cl2, water, CH3CN, MeOH and EtOH under refluxing conditions. The results of these experiments revealed that the use of a solvent led to a significant reduction in the yield of the desired product 3e in all cases compared with the yield obtained under solvent-free conditions (Table 3, entries 1-7).

Table 3
The synthesis of 3e under different solvents.

The effect of the catalyst loading was also investigated under solvent-free conditions (Table 4). The results of these experiments revealed that the optimum loading of the IL catalyst was 0.14 g, which gave the desired product 3e in 85% yield (Table 4, entry 3). Increasing or decreasing the loading of the catalyst did not lead to any further improvements in the yield of the reaction or a decrease in the reaction time.

Table 4
The effect of the loading of the catalyst on the synthesis of 3e.

With the optimized conditions in hand, we proceeded to investigate the scope and limitations of our newly developed method using a variety of different aldehydes (Table 5). The results of these reactions revealed that aldehydes bearing an electron-donating (e.g., CH3 or CH3O) or electron-withdrawing (e.g., NO2 or Cl) group were well tolerated under the optimized conditions, with the corresponding 4-substituted-1,5- benzodiazepine products 3a-3o being formed in good to high yields. Aliphatic aldehydes reacted smoothly to give the corresponding 4-substituted-1,5-benzodiazepines, albeit in lower yields (20%-25%) than the aromatic aldehydes (71%-85%).

Table 5
 Synthesis of 4-substituted-1,5-benzodiazepine 3a-3o in the presence of the [H-NMP][HSO4] catalyst under solvent-free conditions.

The structures of the resulting products were confirmed by FT-IR, 1H NMR, 13C NMR and ESI-MS analyses. The FT-IR spectrum of 3i, as a representative example, contained broad peaks at 3305 and 3240 cm-1, which were attributed to the stretching vibrations of amine protons (2 NH groups). Furthermore, the bands at 3039 and 2958 cm-1 were attributed to the stretching vibrations of the CH, CH2, and CH3 groups in the molecules, whereas the strong bands at 1600 and 1381 cm-1 were attributed the stretching vibrations of carbonyl groups (C=O stretching). The FT-IR spectrum of 3i also contained strong bands at 1532 and 1339 cm-1, which indicated the presence of C-N stretching. The band at 1426 cm-1 in the FT-IR spectrum of 3i was characteristic of a C=C stretching vibration, and the strong band at 1276 cm-1 confirmed the presence of C-O bond stretching. 1H NMR analysis of compound 3i revealed two singlets for the gem-dimethyl groups at δ = 1.02 and 1.07 ppm, as well as an AB quartet for the CH2 protons at δ = 2.13 ppm with a coupling constant (J) of 16.0 Hz. The 1H NMR spectrum of 3i also contained a signal at δ = 2.54 ppm for the CH2-C=O protons, as well as a signal at δ = 5.77 ppm for the NH proton. A signal was also observed at δ = 6.08 ppm for a CH proton, as well as signals corresponding to the aromatic protons at δ = 6.50-7.68 ppm and an NH proton at δ = 8.74 ppm. Furthermore, 13C NMR analysis of 3i revealed the presence of 21 distinct carbons, which was in agreement with the proposed structure. Finally, ESI-MS analysis of 3i revealed the presence of a molecular ion peak with the expected m/z value [43].

Fig. 2. Reusability of the catalyst.
3.2. Proposed reaction mechanism

Based on the results of the current study, we have proposed a mechanism for which is shown in Scheme 2. The proposed mechanism is based on sequential Michael addition and Knoevenagel cyclization reactions.

Scheme 2. Proposed reaction mechanism for the IL-catalyzed formation of 4-substituted-1,5-benzodiazepine from o-phenylenediamine, dimedone and aldehyde.

One molecule of dimedone (1) would undergo an initial Michael addition reaction with activated o-phenylenediamine (2) to provide enamine intermediate. The enamine intermediate would then react with the activated aromatic aldehyde (3) to give the corresponding imine, which would undergo an intramolecular cyclodehydration reaction to give the 4-substituted-1,5- benzodiazepines (4-6).

3.3. Catalyst recovery

The reusability of the catalyst was studied using the reaction of o-phenylenediamine with dimedone and benzaldehyde for the synthesis of 1,5-benzodiazepine 3a. Upon completion of the reaction, the reaction mixture was washed three or four times with water, and the catalyst was separated by filtration. The [H-NMP][HSO4] catalyst was then dried at 100 °C for 5 h before being reused in the next reaction. Pleasingly, the catalyst could be reused up to seven times with only a slight decrease in its activity, as shown in Fig. 2.

4. Conclusions

In summary, we have developed an efficient, nontoxic and inexpensive method for the synthesis of 4-substituted-1,5- benzodiazepine derivatives using [H-NMP][HSO4] as a catalyst under solvent-free conditions. Most notably, the products were obtained in high yields over short reaction times. This newly developed method therefore represents a simple and efficient three-component procedure for the synthesis of 4-substituted- 1,5-benzodiazepine from aldehydes, o-phenylenediamine and dimedone using a simple reusable IL catalyst.

Acknowledgments

The authors are grateful to University of Kashan for supporting this work by Grant No: 159148/55.

References
[1] Shorter E. Benzodiazepines. A Historical Dictionary of Psychiatry. New York: Oxford University Press, 2005. 41
[2] Bremner J B, Samosorn S. In: Newkome G R ed. Comprehensive Heterocyclic Chemistry III. Amsterdam: Elsevier, 2008
[3] Riemann D, Perlis M L. Sleep Med Rev, 2009, 13: 205
[4] Cortes E C, Cornejo A L, Garcia-Mellado de Cortes O. J Heterocycl Chem, 2007, 44: 183
[5] Makaron L, Moran C A, Namjoshi O, Rallapalli S, Cook J M, Rowlett J K. Pharmacol Biochem Behav, 2013, 104: 62
[6] Allison C, Pratt J A. Pharmacol Therapeut, 2003, 98: 171
[7] Hawkins E J, Malte C A, Imel Z E, Saxon A J, Kivlahan D R. Drug Alcohol Depend, 2012, 124: 154
[8] McGowan D, Nyanguile O, Cummings M D, Vendeville S, Vandyck K, Van-den Broeck W, Boutton C W, De Bondt H, Quirynen L, Amssoms K, Bonfanti J F, Last S, Rombauts K, Tahri A, Hu L L, Delouvroy F, Vermeiren K, Vandercruyssen G, Van der Helm L, Cleiren E, Mostmans W, Lory P, Pille G, Van Emelen K, Fanning G, Pauwels F, Lin T I, Simmen K, Raboisson P. Bioorg Med Chem Lett, 2009, 19: 2492
[9] Schimer J, Cigler P, Vesely J, Grantz-Saskova K, Lepsik M, Brynda J, Rezacova P, Kozisek M, Cisarova I, Oberwinkler H, Kraeusslich H G, Konvalinka J. J Med Chem, 2012, 55: 10130
[10] Fader L D, Bethell R, Bonneau P, Boes M, Bousquet Y, Cordingley M G, Coulombe R, Deroy P, Faucher A M, Gagnon A, Goudreau N, Grand-Maitre C, Guse I, Hucke O, Kawai S H, Lacoste J E, Landry S, Lemke C T, Malenfant E, Mason S, Morin S, O'Meara J, Simoneau B, Titolo S, Yoakim C. Bioorg Med Chem Lett, 2011, 21: 398
[11] Leggio L, Kenna G A, Swift R M. Prog Neuro-Psychopharm Biol Psych, 2008, 32: 1106
[12] Kodomari M, Noguchi T, Aoyama T. Synth Commun, 2004, 34: 1783
[13] Maiti G, Kayal U, Karmakar R, Bhattacharya R N. Tetrahedron Lett, 2012, 53: 1460
[14] Yi W B, Cai C. J Fluorine Chem, 2009, 130: 1054
[15] Xu J X, Zuo G, Chan W L. Heteroatom Chem, 2001, 12: 636
[16] Uchida H, Suzuki T, Mamo D C, Mulsant B H, Kikuchi T, Takeuchi H, Tomita M, Watanabe K, Yagi G, Kashima H. J Anxiety Disord, 2009, 23: 477
[17] Leonard B E. Human Psychopharmacol, 1999, 14: 125
[18] Holbrook A M, Crowther R, Lotter A, Cheng C, King D. Can Med Assoc J, 2000, 162: 225
[19] Pan X Q, Zou J P, Huang Z H; Zhang W. Tetrahedron Lett, 2008, 49: 5302
[20] Sangshetti J N, Chouthe R S, Jadhav M R, Sakle N S, Chabukswar A, Gonjari I, Darandale S, Shinde D B. Arab J Chem, 2013, doi:10.1016/j.arabjc.2013.04.004
[21] Cortes E C, Banos M A, Garcia-Mellado De Cortes O. J Heterocycl Chem, 2004, 41: 277
[22] Gurkovskii A L, Tonkikh N N, Petrova M V, Strakov A Y. Chem Heterocycl Compd, 1999, 35: 625
[23] Strakov A Y, Petrova M V, Tonkikh N N, Gurkovskii A I, Popelis Y, Kreishman G P, Belyakov S V. Chem Heterocycl Compd, 1997, 33: 321
[24] Tolpygin I E, Mikhailenko N V, Bumber A A, Shepelenko E N, Revinsky U V, Dubonosov A D, Bren V A, Minkin V I. Russ J Gen Chem, 2012, 82: 1243
[25] Tonkikh N N, Strakovs A Y, Rizhanova K V, Petrova M V. Chem Heterocycl Compd, 2004, 40: 949
[26] Jiang B, Li Q Y, Zhang H, Tu S J, Pindi S, Li G G. Org Lett, 2012, 14: 700
[27] Wang S L, Cheng C, Wu F Y, Jiang B, Shi F, Tu S J, Rajale T, Li G G. Tetrahedron, 2011, 67: 4485
[28] Zhu J P, Bienayme H. Multicomponent Reactions. Weinheim: Wiley-VCH, 2005
[29] Kumaravel K, Vasuki G. Curr Org Chem, 2009, 13: 1820
[30] Tietze L F, Bell H P, Brasche G. Domino Reactions in Organic Synthesis. Weinheim: Wiley-VCH, 2006
[31] Terrett N K. Combinatorial Chemistry. New York: Oxford University Press, 1998
[32] Chanda A, Fokin V V. Chem Rev, 2009, 109: 725
[33] Pirrung M C, Das Sarma K. J Am Chem Soc, 2004, 126: 444
[34] Dupont J, de Souza R F, Suarez P A Z. Chem Rev, 2002, 102: 3667
[35] Itoh H, Naka K, Chujo Y. J Am Chem Soc, 2004: 126: 3026
[36] Yue C B, Fang D, Liu L, Yi T F. J Mol Liq, 2011, 163: 99
[37] Naeimi H, Nazifi Z S. C R Chim, 2014, 17: 41
[38] Naeimi H, Nazifi Z S. J Ind Eng Chem, 2014, 20: 1043
[39] Shaterian H R, Ranjbar M. J Mol Liq, 2011, 160: 40
[40] Liu W W, Cheng L Y, Zhang Y M, Wang H P, Yu M F. J Mol Liq, 2008, 140: 68
[41] Tong X L, Li Y D. ChemSusChem, 2010, 3: 350
[42] Xie C X, Li H L, Li L, Yu S, Liu F S. J Hazard Mater, 2008, 151: 847
[43] Arellano M del R, Martinez R, Cortes E. J Heterocycl Chem, 1982, 19: 321