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

Article abstract of DOI:10.1016/S1872-2067(14)60304-1

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 Br?nsted 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.

Full text of DOI:10.1016/S1872-2067(14)60304-1

Chinese Journal of Catalysis 36 (2015) 734–741
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
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
A R T I C L E I N F O
A B S T R A C T
Article history:
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 Brӧnsted 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.
Received 22 December 2014
Accepted 23 January 2015
Published 20 May 2015
Keywords:
Ionic liquid
Published by Elsevier B.V. All rights reserved.
Benzodiazepine
Solvent-free conditions
Dimedone
1. Introduction
acetic acid in toluene [24] and H2SO4 in water [25]. Several
other methods have also been developed for the synthesis of
Fused 1,5-benzodiazepines are a highly valuable class of
organic compounds that posses a wide variety of interesting
biological properties [1–7]. 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-inflamma-
tory [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 cat-
alysts, including acyl chlorides [8,9] oxalic acid in water [20],
acetic acid in refluxing ethanol [21,22], HCl in ethanol [23],
1,5-benzodiazepine derivatives, such as the cycloaddition reac-
tion of 2,2-dihydroxy-1-phenylethanone with an
o-phenylenediamine derivative and dimedone [26], the het-
ero-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 condi-
tions [27].
A multi-component reaction (MCR) is a chemical transfor-
mation involving the combination of three or more different
starting materials in a single one-pot procedure to give a com-
plex product. MCRs are useful tools in organic synthesis be-
cause they can be used to generate complex molecular archi-
tectures in one pot from simple starting materials [28–31].
Research towards the development of MCRs has grown con-
siderably during the last decade, and several environmentally
* Corresponding author. Tel: +98-315-5912388; Fax: +98-315-5912397; Email: naeimi@kashanu.ac.ir
DOI: 10.1016/S1872-2067(14)60304-1 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 36, No. 5, May 2015

Hossein Naeimi et al. / Chinese Journal of Catalysis 36 (2015) 734–741
735
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].
aromatic aldehyde (1 mmol) were added to [H-NMP][HSO4]
(0.14 g) under solvent-free conditions, and the resulting mix-
ture was stirred at 100 °C for the stipulated time. Upon comple-
tion of the reaction, as determined by TLC (1:1 – ethyl ace-
tate:petroleum ether), the mixture was cooled to room tem-
perature 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 ace-
tate/n-hexane); UV-vis: λ 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 ace-
tate/n-hexane); UV-vis: λ 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 ace-
tate/n-hexane); UV-vis: λ 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,
As part of our ongoing research towards the application of
catalysts in organic synthesis [28–33], 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. Ul-
traviolet (UV-Vis) spectra were obtained in CDCl3 on a Per-
kin-Elmer 550 S spectrophotometer. Nuclear magnetic reso-
nance (1H NMR and 13C NMR) were recorded in DMSO and
CDCl3 solvents on a Bruker DRX-400 spectrometer using tet-
ramethylsilane (TMS) as an internal reference. Elemental anal-
yses (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 ambi-
ent and washed three times with ether to remove any non-ionic
residues before being dried under vacuum on a rotary evapo-
rator 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

736
Hossein Naeimi et al. / Chinese Journal of Catalysis 36 (2015) 734–741
%): 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.
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
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 ace-
tate/n-hexane); UV-vis: λ 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 ace-
tate/n-hexane); UV-vis: λ 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 ace-
tate/n-hexane); UV-vis: λ 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.
C
21H20Cl2N2O: 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: λ 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: λ
= 348 nm; IR (KBr, cm–1): υ
max
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 ace-
tate/n-hexane); UV-vis: λ 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,
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: λ max = 348 nm; IR (KBr, cm–1):

Hossein Naeimi et al. / Chinese Journal of Catalysis 36 (2015) 734–741
737
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.
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 ac-
etate/n-hexane); UV-vis: λ 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: λ 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.
3,3-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 ac-
etate/n-hexane); UV-vis: λ 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: λ 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 ace-
tate/n-hexane); UV-vis: λ 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. 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 [34–36],
and have the potential to be used in numerous other applica-
tions in organic synthesis. In a continuation of our recent work
towards the development of Lewis and Brӧnsted acid catalyzed
synthetic methodologies [37–40], 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 synthe-
sized according to literature procedures and evaluated as a
catalyst in the MCR of X and Y with Z [41–43]. 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 at-
tributed to six protons of the pyrrolidinium ring.
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 al-
dehyde with o-phenylenediamine and dimedone, followed by
the Knoevenagel cyclization of the resulting adduct (shown in
Scheme 1).
3,3-Dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-hydroxy)

738
Hossein Naeimi et al. / Chinese Journal of Catalysis 36 (2015) 734–741
Table 2
Optimization of the reaction conditions.
Cl
O
H
N
O
NH2
O
Catalyst
H
NH2
O
N
H
Cl
3e
Entry
1
2
3
4
5
6
7
8
Catalyst
MeSO3H
CF3COOH
CuI
Fe3O4
MgO
ZnO
ZnS
None
Ionic liquid a
Ionic liquid
Ionic liquid
Ionic liquid
Time (min) Temp. (°C) Isolated yield (%)
50
40
16
16
13
16
14
40
20
20
15
15
Reflux b
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
60
65
60
55
55
25
50
55
40
55
75
85
85
Fig. 1. 1H NMR spectrum of [H-NMP][HSO4] in D2O.
9
10
11
12
80
100
120
Reaction conditions: catalyst 10 mol%, o-phenylenediamine 1 mmol,
a
dimedone 1 mmol, p-Cl-benzaldehyde 1 mmol. N-methyl-2-pyrroli-
diniume hydrogen sulfate [H-NMP][HSO4] (0.14 g). b Reflux in EtOH.
Scheme 1. Synthesis of 4-substituted-1,5-benzodiazepines under sol-
vent-free conditions.
mation.
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).
To highlight the advantages of this newly developed meth-
od, we have compared the results of the current study with
those reported in literature for the same transformation using
different conditions [20–25] (Table 1). The reaction of dim-
edone 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, reac-
tion 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.
When the reaction was carried out under solvent-free con-
ditions 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 transfor-
Table 3
The synthesis of 3e under different solvents.
R
O
H
H
N
O
N
O
HSO4
NH2
NH2
O
H
R
Solvent
N
H
O
R = 4-Cl
3e
Entry
Solvent
n-Hexane
CH2Cl2
H2O
CH3CN
MeOH
EtOH
Time (min) Temp. (°C)
Isolated yield (%)
1
2
3
4
5
6
7
16
17
18
16
14
20
15
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100
10
30
40
20
45
50
85
None
Reaction conditions: [H-NMP][HSO4] (0.14 g), o-phenylenediamine 1
mmol, dimedone 1 mmol, p-Cl-benzaldehyde 1 mmol.
Table 1
Comparison of the current method with several literature methods for the synthesis of 1,5-benzodiazepines.
Entry
1
2
3
4
5
6 *
Catalyst
Oxalic acid (40 mol %)
Acetic acid (excess)
HCl
Reaction conditions
Water, Reflux at 100 °C
Ethanol, Reflux, 2 steps reaction
Ethanol, Reflux
Time (min)
120
Yield (%)
[Ref.]
20
21
23
24
84
65
60
62
55
75
100
150
70
360
Acetic acid (excess)
p-Toluenesulfonic acid and acetic acid
[H-NMP][HSO4]
i-PrOH, Reflux at 120 °C
2 Steps reaction, Reflux
Solvent free, 100 °C
25
—
18
* Present study.

Hossein Naeimi et al. / Chinese Journal of Catalysis 36 (2015) 734–741
739
This method is complementary to the classical methods
Table 4
used for the synthesis of 3,3-dimethyl-2,3,4,5,10,11-hexahy-
dro-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, wa-
ter, 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 sol-
vent-free conditions (Table 3, entries 1–7).
The effect of the catalyst loading was also investigated un-
der solvent-free conditions (Table 4). The results of these ex-
periments revealed that the optimum loading of the IL catalyst
was 0.14 g, which gave the desired product 3e in 85% yield
The effect of the loading of the catalyst on the synthesis of 3e.
O
H
R
O
N
HSO4
H
N
O
O
NH2
NH2
Ionic liquid
H
Solvent-free, 100 o
C
R
N
H
O
3e
Entry
Catalyst loading (g)
Time (min)
Isolated yield (%)
1
2
3
4
5
0.06
0.10
0.14
0.18
0.22
20
20
15
15
15
45
55
85
85
82
Reaction conditions: [H-NMP][HSO4] as catalyst, o-phenylenediamine 1
mmol, dimedone 1 mmol, p-Cl-benzaldehyde 1 mmol, 100 °C.
Table 5
Synthesis of 4-substituted-1,5-benzodiazepine 3a–3o in the presence of the [H-NMP][HSO4] catalyst under solvent-free conditions.
Time Isolated
(min) yield (%)
m.p.
(°C )
Time
Isolated
m.p.
Entry
Aldehyde
Product
Entry Aldehyde
Product
(min) yield (%) (°C )
1
18
14
14
75
81
80
246–248 9
280–281* 10
230–232* 11
14
17
18
84
76
73
196–197
224–226
229–231
3a
3i
3j
2
3
3b
3c
3k
4
5
15
15
78
85
195–197 12
235–237 13
18
16
74
76
217–218*
225–227
3l
3d
Cl
O
H
N
O
N
H
Cl
3m
3n
3e
6
7
17
15
78
82
239–240* 14
256–258* 15
19
17
71
75
201–202
3f
3g
3h
287–289*
3o
8
13
83
230–232*
Reaction conditions: o-phenylenediamine (1 mmol), aldehyde (1 mmol), dimedone (1 mmol) and [H-NMP][HSO4] (0.14 g). * Decomposition point.

740
Hossein Naeimi et al. / Chinese Journal of Catalysis 36 (2015) 734–741
O
(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.
H2N
H2N
HSO4
H
I.L
N
I.L
H2N
O
O
O
Ionic Liquid (I.L)
1
-H2O
N
H
O
O
With the optimized conditions in hand, we proceeded to in-
vestigate 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-benzodi-
azepine products 3a–3o being formed in good to high yields.
Aliphatic aldehydes reacted smoothly to give the correspond-
ing 4-substituted-1,5-benzodiazepines, albeit in lower yields
(20%–25%) than the aromatic aldehydes (71%–85%).
2
O
I.L
O
I.L
R
H
NH2
HN
R
N
N
H
H
O
O
R
-H2O
3
4
H
R
I.L
R
I.L
H
N
H-transfer
H
O
H
H-transfer
N
O
5
6
N
N
H
I.L
Scheme 2. Proposed reaction mechanism for the IL-catalyzed for-
mation of 4-substituted-1,5-benzodiazepine from o-phenylenediamine,
dimedone and aldehyde.
The structures of the resulting products were confirmed by
1
FT-IR, H NMR, 13C NMR and ESI-MS analyses. The FT-IR spec-
trum 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 at-
tributed 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
100
80
60
40
20
0
75
75
75
75
71
67
1
2
3
4
5
6
Run
1
stretching. H NMR analysis of compound 3i revealed two sin-
Fig. 2. Reusability of the catalyst.
glets 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 H NMR spectrum of 3i
1
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.
also contained a signal at δ = 2.54 ppm for the CH2-C=O pro-
tons, 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. Further-
more, 13C NMR analysis of 3i revealed the presence of 21 dis-
tinct 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].
4. Conclusions
3.2. Proposed reaction mechanism
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.
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.
One molecule of dimedone (1) would undergo an initial Mi-
chael 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 intra-
molecular
cyclodehydration
reaction
to
give
the
Acknowledgments
4-substituted-1,5-benzodiazepines (4–6).
The authors are grateful to University of Kashan for sup-
porting this work by Grant No: 159148/55.
3.3. Catalyst recovery

Hossein Naeimi et al. / Chinese Journal of Catalysis 36 (2015) 734–741
741
[19] Pan X Q, Zou J P, Huang Z H; Zhang W. Tetrahedron Lett, 2008, 49:
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Graphical Abstract
Chin. J. Catal., 2015, 36: 734–741 doi: 10.1016/S1872-2067(14)60304-1
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
University of Kashan, Iran
A simple and efficient procedure has been developed for the synthesis of
1,5-benzodiazepines via the three-component coupling of a series of alde-
hydes with o-phenylenediamine and dimedone using [H-NMP][HSO4] as a
catalyst under solvent-free conditions.