ZnS nanoparticles as an efficient recyclable heterogeneous catalyst for one-pot synthesis of 4-substituted-1,5-benzodiazepines

Article abstract of DOI:10.1039/c4nj01893a

An efficient and novel method was developed for the synthesis of 4-substituted-1,5-benzodiazepine derivatives via a one-pot three-component catalytic reaction. The o-phenylenediamine and dimedone were reacted with aldehyde derivatives in the presence of ZnS nanoparticles as a heterogeneous catalyst under thermal conditions. The reaction was completed with high to excellent product yields and short reaction times. Simplicity of operation, high yields, easy work-up, easily accessible catalyst and purification of products through a crystallization method (non-chromatographic) are the key advantages of this work.

Full text of DOI:10.1039/c4nj01893a

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ARTICLE TYPE
ZnS nanoparticles as efficient recyclable heterogeneous catalyst for one-
pot synthesis of 4-substituted-1,5-benzodiazepines
Hossein Naeimi*, Hossein Foroughi
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient and novel method was developed for the synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine
derivatives via oneꢀpot threeꢀcomponent catalytic reaction. The oꢀphenylenediamine and dimedone were
reacted with aldehyde derivatives in the presence of ZnS nanoparticles as heterogeneous catalyst under
thermal condition. The reaction was completed in high to excellent products yield and short reaction
10 times. Simplicity of operation, high yields, easy workꢀup, accessible catalyst and purification of products
through crystallization method (nonꢀchromatographic) are the key advantages of this work.
The Yb(OTf)3 in CH2Cl2 as solvent [7a], SiO2 under N2
atmosphere [7b], amorphous mesoporous iron alumino phosphate
(FeAlPꢀ550) catalyst under solventꢀfree condition [7c] and Fe3O4
50 nanoparticles in ethanol solvent [7d] are some of previous works.
Moreover, the synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine
derivatives have been carried out by threeꢀcomponent
condensation of oꢀphenylenediamine, dimedone and aldehyde
derivatives in various conditions such as; acetic acid in ethanol
55 using reflux [8aꢀb], oxalic acid in water [8c], acetic acid in
toluene [8d], H2SO4 in water [8e] and HCl in ethanol [8f]. In
addition, they can also be synthesized by the cycloaddition
reaction of 2,2ꢀdihydroxyꢀ1ꢀphenylethanone, oꢀphenylenediamine
and dimedone derivatives [9a], condensation of 2ꢀformyl benzoic
60 acid, oꢀphenylenediamine and tetronic acid in water under
microwave irradiation as heteroꢀCope rearrangement [9b].
In 2009 Gowan and coꢀworkers [9c] were synthesized
benzodiazepine derivatives by using acylchlorid. Also, Schimer
and coꢀworkers [9dꢀe] were reported a reaction between 4ꢀ
65 substitutedꢀ1,5ꢀbenzodiazepines and acyl chlorid derivatives by
Et3N as catalyst in THF at ꢀ43 °C. So far, the derivatives of 1,5ꢀ
benzodiazepines affected a important role in medicinal chemistry
[10a] by serving as antiꢀinflammatory [10b], antibacterial [10c],
antidepressant [10d], hypnotic [10e], anticoagulant [10f],
70 antiepileptic agents [11aꢀb], analgesic [11c], Hepatitis C Virus
(HCV) NS5B inhibitors [9c] and HIVꢀ1 protease inhibiting [9dꢀ
e] (Fig. 1).
Introduction
The multi component reactions (MCRs), which have obtained
significant attention during the past few years, do not occur through
15 a singleꢀstep procedure, but rather via several sequential steps
involving cascades or domino reactions [1aꢀf]. MCRs are processes
in which at least three different simple substrates react in oneꢀpot to
give the target materials [2aꢀb]. Although, MCRs have great
contribution in conversant synthesis of complex and important
20 organic molecules from simple and readily available starting
materials, and have emerged as powerful tools for drug discovery
[3aꢀb]. Simplicity, greater efficiency, atom economy and
generation of molecular complexity with diversity in oneꢀpot
transformations are some advantages of these reactions [4aꢀb].
25 1,5ꢀBenzodiazepines are some of the important heterocyclic
compounds from the view point of biological activities [5aꢀd].
Some examples are diazepam and chlorodiazepoxide that act as
anti anxiety drugs [5d]. Also, clozapines from the piperidinyl
dibenzodiazepine in schizophrenia drugs, as well as the platelet
30 activating factor inhibitor apafant and the muscarinic receptor
(M1) antagonist pirenzepines. Modifications in the structure of
these heterocycles have been made and the anxiolytic effect of
benzodiazepines (clobazam) has been described. Benzodiazepine
compounds shows extensively consumed psychoactive drugs
35 worldwide due to their anxiolytic and anticonvulsant activity.
Many undesirable side effects have been associated with the use
of benzodiazepines [6aꢀc].
H
N
Some types of scientist groups are studying for development of
benzodiazepine derivatives [7ꢀ9]. Some ways for the synthesis of
40 these compounds have been verified in the literature via the
condensation of one equivalent of oꢀphenylenediamine with
various aldehydes in the presence of wide variety catalysts.
O
R1
N
O
O
R2
N
O
N
H
Fig. 1 HCV NS5B inhibitors
Department of Organic Chemistry, Faculty of Chemistry, University of
45 Kashan, Kashan, 87317, I.R. Iran; Tel./Fax: 98ꢀ3155912388/ 98ꢀ
3155912397, Email: naeimi@kashanu.ac.ir
75 Nanoparticles (NPs) have drawn considerable interest in recent
years because of their special properties such as increased activity
for using as catalyst, a large surface to volume ratio, unique
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optical and electrical properties as compared to those of the bulk
materials [12aꢀb]. NPs referred to much interest in different
organic reactions provide its cost effectiveness, experimental
General procedure for preparation of ZnS nanoparticles
In a typical procedure for preparation of ZnS NPs, 1 mmol of
Zn(OAc)2 2H2O and 1 mmol of thioacetamide (TAA) were added
simplicity and ease of handling [13aꢀe]. ZnS nanoparticles (NPS) 60 into 20 ml ethylene glycol in a 50 ml roundꢀbottomed flask at
5
have been intensively investigated because of their efficient
heterogeneous catalyst, low Curie temperature and high
coercively [14aꢀc]. In recent decades, semiconductor
nanostructured materials have attracted of interest due to their
room temperature. The solution was heated to 110 oC by
microwave and kept the temperature for 5 min with stirring. After
this time, the solution was naturally cooled to room temperature.
The white products were separated, washed with absolute ethanol
unique properties which are different from the bulk materials 65 (3×10 mL) and dried at 60 oC for 3 h [12ꢀ16].
10 [15aꢀf]. The one dimensional ZnS nanostructures like
nanoparticles, nanorods and nanowires have been synthesized by
important methods such as electrochemical deposition, laser
ablation, solvothermal method, microwave irradiation, epitaxy,
sonochemical method and etc [16aꢀi].
15 In continuation of our work toward preparation of ZnS NPs [17],
herein, we report a simple, mild and facile MCR oneꢀpot
synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine in high yields with
high purity, using ZnS nanoparticles as a heterogeneous catalyst
in ethanol under thermal conditions. The developing of MCRs
20 and improving known multicomponent reactions are a wide of
considerable route interest. This green procedure has many
obvious advantages compared to those reported in the previous
literatures [1ꢀ4], including avoiding the usage of harmful
catalysts, easy workup of the reaction, excellent yields and
25 simplicity of the methodology.
The prepared ZnS NPs was confirmed and characterized by FTꢀ
IR, XRD, PL, SEM and TEM. The FTꢀIR spectra (Fig. 2) of ZnS
NPs showed very low absorption bands at 478, 1050 and 1415
cm−1 which were assigned to the fundamental stretching and
70 bending vibrations of ZnS band corresponding to sulphides. A
broad intense absorption between 3000 and 3700 cmꢀ1 is observed
due to O–H vibration of water molecules as characterized by its
bending vibration at 1627 cmꢀ1 [12ꢀ16].
Experimental
General information
75
Fig. 2 The FTꢀIR Spectum of ZnS NPs catalyst
All of the reagents were purchased from Merck, Aldrich, CDH
and Fluka and used without further purification
.
Fourier
The Xꢀray diffraction patterns of ZnS nanoparticles are shown in
Fig. 3. The position and relative intensities of all peaks confirm
well with standard XRD pattern of ZnS nanoparticles indicating
retention of the crystalline cubic spinel structure during of NPs.
30 transform infrared (FTꢀIR) spectra were obtained as KBr pellets
on a Perkin–Elmer 781 spectrophotometer. Ultraviolet (UVꢀVis)
spectra were obtained in CDCl3 solvents on a Perkin–Elmer 550 S
spectrophotometer. Nuclear magnetic resonance (1H NMR and 80 The average NPs core diameter was calculated to be 6 nm from
13C NMR) were recorded in DMSO and CDCl3 solvents on a
35 Bruker DRXꢀ400 spectrometer with tetramethylsilane (TMS) as
internal reference. Micro wave irradiation (M.W) obtained from a
the XRD results by Scherrer’s equation, D= kλ/βcosθ where k is a
constant (generally considered as 0.94), λ is the wavelength of Cu
Ka (1.54A˚), β is the corrected diffraction line fullꢀwidth at halfꢀ
maximum (FWHM), and θ is Bragg’s angle.
SAMSUNG
Model
GE4020W.
Nanostructures
were
characterized using a Holland Philips Xpert Xꢀray powder
diffraction (XRD) diffractometer (CuK, radiation, k= 0.154056
40 nm), at a scanning speed of 2°/min from 10° to 100° (2Ø).
Electron Dispersive XꢀRey (EDX) of nanoparticles was
performed on a Zeiss ∑ l GMA vp. Photoluminescence (PL)
spectra were obtained on the Avantes Avaspecꢀ2048
spectrophotometer. Scanning electron microscope (SEM) of
45 nanoparticles was performed on
a
KYKY EMꢀ3200.
Transmission electron microscope (TEM) of nanoparticles was
performed on a LEO ABꢀ912. The elemental analyses (C, H, N)
were obtained from a Carlo ERBA Model EA 1108 analyzer.
Electron Ionization Mass (EIꢀ MASS) spectra were recorded on
50 Agilent Technology (HP) 5973 instrument at an ionization
potential of 70 eV. Melting points (M.P) obtained with a Thermo
Scientific 9300. The purity determination of the substrates and
reaction monitoring were accomplished by TLC on silicaꢀgel
polygram SILG/UV 254 plates (from Merck Company).
55
85
Fig. 3 XRD spectrum of ZnS nanoparticles
The Photoluminescence (PL) properties of the synthesized ZnS
NPs were studied at room temperature with a wavelength of 307
nm as shown in Fig. 4 [12ꢀ16]. The indicated spectrum is similar
90 to that previously reported for photoluminescence (band gap) of
undoped ZnS NPs.
2
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25 nanoparticles in ethanol (5 mL). Then, the reaction mixture was
o
stirred at 80 C for the stipulated period of time. The progress of
the reaction was monitored by thin layer chromatography (TLC)
(ethyl acetate:petroleum ether 1:1). After completion of the
reaction, the mixture was cooled to room temperature and then
30 centrifuged to separate the catalyst. The reaction mixture was
concentrated on a rotary evaporator under reduced pressure. After
the solvent was evaporated, the oily mixture was crystallized
from methanol and water (6:5) to afford the product. The residue
was purified by recrystallization from ethanol. They were
35 characterized by comparison of their physical and spectral data
with those of authentic samples.
Fig. 4 PL spectrum of ZnS nanoparticles
The chemical composition of the product was further examined
with energy dispersive Xꢀray spectrometry (EDX). As can be
shown in Fig. 5, the purity of nanoparticles was confirmed by
strong peaks of Zn and S in spectrum. A relatively weak O peak
in the spectrum probably originates from unavoidable surfaceꢀ
adsorption of oxygen on to the spheres from exposure to air
during sample processing [12ꢀ16].
5
Fig. 7 TEM image of ZnS nanoparticles
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[phenyl]-1H-
40 dibenzo[b,e][1,4]diazepin-1-one(3a): pale green solid, m.p.=
246ꢀ248 oC, m.p.= 250ꢀ252 oC [18a]; Rf
= 0.125 (1:1
10
Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 360 nm; IR (KBr)/ υ
Fig. 5 The EDX spectrum of ZnS NPs catalyst
(cmꢀ1): 3296, 3237, 3057, 2955, 1584, 1384, 1530, 1329, 1424,
1
1277; H NMR (DMSO+CDCl3, 400 MHz)/ δ ppm: 1.03(s, 3H,
Also, the morphology of prepared nanoparticles was studied by
SEM (Fig. 6) and TEM (Fig. 7) analysis shows the typical images
for ZnS nanoparticles prepared under microwave irradiation with
45 CH3ꢀ), 1.08(s, 3H, CH3ꢀ), 2.11 (A.B q, 2H, J=16 Hz, CH2),
2.56(s, 2H, ꢀCH2ꢀC=O), 5.71(s, 1H, NꢀH), 6.08(s, 1H , CꢀH),
6.47ꢀ6.57(m, 3H, Arꢀ), 6.89(d, 1H, J=8 Hz, Arꢀ), 6.95(t, 1H, J=8
Hz Arꢀ), 7.0ꢀ7.1(m, 3H, Arꢀ), 8.15(d, 1H, J=4 Hz, Arꢀ), 8.69(s,
1H, NꢀH); 13C NMR (DMSO+CDCl3, 100 MHz)/ δ (ppm): 27.95,
50 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; Anal. Calcd. For C21H22N2O: C 79.21, H 6.96, N
8.80, Found C 79.24, H 6.98, N 8.84; EIꢀMASS (m/z, %):
318(M+, 26), 241(100), 149(52), 83(45), 77(34), 57(85), 55(62).
55 3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-nitro)phenyl]-1H-
dibenzo[b,e][1,4]diazepin-1-one(3b): yellow solid, m.p.= 280ꢀ
281 oC (decomp), m.p.= 274ꢀ275 oC [18b]; Rf = 0.125 (1:1
15 zinc salt and thioacetamide [12ꢀ16]. As can be determined, the
ZnS nanoparticles are assembled into about 20ꢀ30 nm spherical
structure.
Ethylacetate/ nꢀHexane); UVꢀVIS: λ max=348 nm; IR (KBr) υ
/
(cmꢀ1): 3355, 3279, 3181, 2955, 1591, 1381, 1511, 1339, 1425,
1
60 1275; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 0.99(s, 3H,
CH3ꢀ), 1.06(s, 3H, CH3ꢀ), 2.14(A.B q, 2H, J=16 Hz, CH2ꢀ),
2.53(s, 2H, ꢀCH2ꢀC=O), 5.64(s, 1H, NꢀH), 5.87(s, 1H, CꢀH),
6.43(d, 1H, J=6.4 Hz, Arꢀ), 6.55ꢀ6.61(m, 2H, Arꢀ), 6.9(d, 1H,
J=6.4Hz, Arꢀ), 7.21(d, 2H, J=8.8Hz, Arꢀ), 7.84(d, 2H, J=8.8 Hz,
65 Arꢀ), 8.58(s, 1H, NꢀH); 13C NMR (DMSO+CDCl3, 100 MHz)/ δ
(ppm): 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; Anal. Calcd. For C21H21N3O3: C 69.41, H
Fig. 6 SEM image of ZnS nanoparticles
20 General procedure for synthesis of 4-substituted-1,5-
benzodiazepine
In a 50 mL round bottom flask, dimedone (1 mmol), oꢀ
phenylenediamine (1 mmol) and selected aromatic aldehydes (1
mmol) were taken in the presence of 10 mol% (0.01g) ZnS
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5.82, N 11.56, Found C 69.45, H 5.85, N 11.59; EIꢀMASS (m/z,
υ (cmꢀ1): 3292, 3235, 3062, 2959, 1589, 1382, 1515, 1314, 1422,
1
%): 397(M+, 29), 241(100), 149(66), 83(51), 77(32), 57(39), 60 1278; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 1.02(s, 3H,
55(47).
CH3ꢀ), 1.07(s, 3H, CH3ꢀ), 2.09(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.57(s,
2H, ꢀCH2ꢀC=O), 5.07(s, 1H, NꢀH), 6.01(s, 1H, CꢀH), 6.33 (d, 1H,
J=7.2 Hz, Arꢀ), 6.44ꢀ6.62(m, 2H, Arꢀ), 6.7(d, 1H, J=7.6 Hz, Arꢀ),
6.82(d, 1H, J=7.6 Hz, Arꢀ), 6.85ꢀ7.0(m, 2H, Arꢀ), 7.20(d, J=7.6
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-nitro)phenyl]-1H-
dibenzo[b,e][1,4]diazepin-1 one(3c): orange solid, m.p.= 230ꢀ
5
o
o
232 C (decomp), m.p.= 115ꢀ117 C (decomp) [18a]; Rf = 0.281
(1:1 Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 346 nm; IR (KBr)/ 65 Hz, 1H, Arꢀ), 8.77(s, 1H, NꢀH); 13C NMR (DMSO+CDCl3, 100
υ (cmꢀ1): 3378, 3303, 3069, 2957, 1591, 1381, 1528, 1332, 1473,
1279; 1H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 0.95(s, 3H,
MHz)/ δ (ppm): 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; Anal. Calcd. For
C21H21ClN2O: C 71.48, H 6.0, N 7.94, Found C 71.54, H 6.6, N
10 CH3ꢀ), 1.05(s, 3H, CH3ꢀ), 2.01(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.58(s,
2H, ꢀCH2ꢀC=O), 5.04(s, 1H, NꢀH), 6.01(s, 1H, CꢀH), 6.32(d, 1H,
J=8 Hz, Arꢀ), 6.58(t, 1H , J=8 Hz, Arꢀ), 6.67(t, 1H, J=8 Hz, Arꢀ), 70 7.99; EIꢀMASS (m/z, %): 352(M+, 36), 354(M+2+, 12), 241(100),
6.79(d, 1H, J=8 Hz, Arꢀ), 7.04(d, 1H, J=8 Hz, Arꢀ), 7.14ꢀ7.2(m,
2H, Arꢀ), 7.74(d, 1H, J=8 Hz, Arꢀ),8.91(s, 1H, NꢀH); 13C NMR
15 (DMSO+CDCl3, 100 MHz)/ δ (ppm): 28.11, 28.82, 32.22, 44.87,
49.91, 56.62, 109.46, 120.53, 120.78, 121.07, 123.1, 123.46,
149(52), 83(49), 77(33), 57(42), 55(51).
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): pale
green solid, m.p.= 256ꢀ258 oC (decomp); Rf = 0.281 (1:1
126.14, 128.56, 128.59, 131.38, 138.06, 146.03, 153.08, 155.08, 75 Ethylacetate/ nꢀHexane); UVꢀVIS: λ max=348 nm; IR (KBr)/ υ
192.89; Anal. Calcd. For C21H21N3O3: C 69.41, H 5.82, N 11.56,
Found C 69.46, H 5.85, N 11.60; EIꢀMASS (m/z, %): 363(M+,
20 26), 241(100), 149(55), 83(36), 77(42), 57(49), 55(62).
(cmꢀ1): 3379, 3301, 3060, 2958, 1589, 1380, 1532, 1332, 1423,
1289; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 1.01(s, 3H,
CH3ꢀ), 1.07(s, 3H, CH3ꢀ), 2.12(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.56(s,
2H, ꢀCH2ꢀC=O), 4.96(s, 1H, NꢀH), 6.07(s, 1H, CꢀH), 6.30(d, ,
1
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(3-nitro)phenyl]-1H-
dibenzo[b,e][1,4]diazepin-1-one(3d): pale yellow solid, m.p.= 80 1H, J=7.6 Hz, Arꢀ), 6.53ꢀ6.60(m, 2H, Arꢀ), 6.62(d, , 1H, J=7.2
195ꢀ197 oC, m.p.= 161ꢀ168 oC [18c]; Rf
=
0.125 (1:1
Hz, Arꢀ), 6.75(t, 1H, J=8 Hz, Arꢀ), 6.91(d, 1H, J=7.6 Hz, Arꢀ),
7.08(d, 1H, J=7.6 Hz, Arꢀ), 8.64(s, 1H, NꢀH); 13C NMR
(DMSO+CDCl3, 100 MHz)/ δ (ppm): 28.14, 28.67, 32.23, 44.81,
49.92, 56.29, 109.10, 120.68, 121.08, 121.35, 123.65, 126.13,
Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 348 nm; IR (KBr)/ υ
25 (cmꢀ1): 3375, 3328, 3049, 2959, 1589, 1383, 1529, 1345, 1431,
1
1277; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 1.05(s, 3H,
CH3ꢀ), 1.09(s, 3H, CH3ꢀ), 2.14(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.58(s, 85 126.84, 128.83, 131.71, 132.05, 132.57, 137.33, 143.52, 156.12,
2H, ꢀCH2ꢀC=O), 5.81(s, 1H, NꢀH), 6.20(s, 1H, CꢀH), 6.50 (d, 1H,
J=5.2 Hz, Arꢀ), 6.51ꢀ6.6(m, 2H, Arꢀ), 6.9(d, 1H, J=7.2 Hz, Arꢀ),
30 7.29(t, 1H, J=8.0 Hz, Arꢀ), 7.45(d, 1H, J=8.0 Hz, Arꢀ), 7.81(d,
1H, J=9.2 Hz, Arꢀ), 7.98(s, 1H, Arꢀ), 8.79(s, 1H, NꢀH); 13C NMR
192.90; Anal. Calcd. For C21H20Cl2N2O: C 65.12, H 5.20, N 7.23
Found C 65.15, H 5.24, N 7.26; EIꢀMASS (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).
(DMSO+CDCl3, 100 MHz)/ δ (ppm): 28.1, 28.81, 32.24, 44.86, 90 3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(2,4-
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,
35 192.86; Anal. Calcd. For C21H21N3O3: C 69.41, H 5.82, N 11.56,
Found C 69.45, H 5.86, N 11.57; EIꢀMASS (m/z, %): 363(M+,
30), 241(100), 149(38), 83(40), 77(41), 57(39), 55(58).
dichloro)phenyl]-1H-dibenzo[b,e][1,4]diazepin 1-one(3h): pale
o
o
green solid, m.p.= 230ꢀ232 C (decomp), m.p = 252 C [18d]; Rf
= 0.281 (1:1 Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 347 nm;
IR (KBr)/ υ (cmꢀ1): 3303, 3241, 3055, 2957, 1590, 1382, 1533,
95 1330, 1468, 1278; 1H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm):
1.02(s, 3H, CH3ꢀ), 1.07(s, 3H, CH3ꢀ), 2.11(A.Bq, 2H, J=16 Hz,
CH2ꢀ), 2.57(s, 2H, ꢀCH2ꢀC=O), 4.99(s, 1H, NꢀH), 5.99(s, 1H, Cꢀ
H), 6.34 (d, 1H, J=7.6 Hz, Arꢀ), 6.56ꢀ6.63(m, 2H, Arꢀ), 6.65(d,
1H, J=8.4 Hz, Arꢀ), 6.79(d, 1H, J=8.0 Hz, Arꢀ), 6.92(d, 1H, J=7.2
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-chloro)phenyl]-
1H-dibenzo[b,e][1,4]diazepin-1-one(3e): pale green solid, m.p.=
40 235ꢀ237 oC, m.p.= 235ꢀ237 oC [18a]; Rf
= 0.125 (1:1
Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 344 nm; IR (KBr)/ υ
(cmꢀ1): 3301, 3238, 3054, 2956, 1587, 1381, 1532, 1329, 1426, 100 Hz, Arꢀ), 7.22(s, 1H, Arꢀ), 8.74(s, 1H, NꢀH); 13C NMR
1
1278; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 1.0(s, 3H,
CH3ꢀ), 1.06(s, 3H, CH3ꢀ), 2.11(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.52(s,
45 2H, ꢀCH2ꢀC=O), 5.73(s, 1H, NꢀH), 5.78(s, 1H, CꢀH), 6.45 (d, 1H,
J=8.2 Hz, Arꢀ), 6.55(m, 2H, Arꢀ), 6.88(d, 1H, J=8.2 Hz, Arꢀ),
(DMSO+CDCl3, 100 MHz)/ δ (ppm): 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; Anal. Calcd. For C21H20Cl2N2O: C 65.12, H 5.20, N 7.23,
6.98(d, 2H, J=8.4 Hz, Arꢀ), 7.01(d, 1H, J=8.4 Hz, Arꢀ), 8.61(s, 105 Found C 65.16, H 5.25, N 7.28; EIꢀMASS (m/z, %): 386(M+, 26),
1H, NꢀH); 13C NMR (DMSO+CDCl3, 100 MHz)/ δ (ppm): 28.17,
28.69, 32.24, 44.84, 49.90, 56.43, 109.38, 120.62, 120.72,
50 121.05, 123.11, 123.28, 128.36, 131.45, 138.06, 146.08, 150.02,
152.06, 192.81; Anal. Calcd. For C21H21ClN2O: C 71.48, H 6.0,
388(M+2+, 16), 390(M+4+, 6), 241(100), 149(66), 83(57), 77(30),
57(65), 55(45).
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): pale
N 7.94, Found C 71.53, H 6.5, N 7.98; EIꢀMASS (m/z, %): 110 yellow solid, m.p.= 196ꢀ197 oC; Rf = 0.125 (1:1 Ethylacetate/ nꢀ
362(M+, 33), 354(M+2+, 11), 241(100), 149(57), 83(35), 77(28),
57(68), 55(53).
Hexane); UVꢀVIS: λ max=348 nm; IR (KBr)/ υ (cmꢀ1): 3305,
3240, 3039, 2958, 1600, 1381, 1532, 1339, 1426, 1276; 1H NMR
(DMSO+CDCl3, 400MHz)/ δ (ppm): 1.02(s, 3H, CH3ꢀ), 1.07(s,
3H, CH3ꢀ), 2.13(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.54(s, 2H, ꢀCH2ꢀ
55 3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-chloro)phenyl]-
1H-dibenzo[b,e][1,4]diazepin-1-one(3f): white solid, m.p.= 239ꢀ
240 oC (decomp), m.p.= 233ꢀ235 oC (decomp) [18a]; Rf = 0.281 115 C=O), 5.77(s, 1H, NꢀH), 6.08(s, 1H, CꢀH), 6.50(d, 1H, J=8 Hz,
(1:1 Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 348 nm; IR (KBr)/
Arꢀ), 6.59(m, 2H, Arꢀ), 6.91(d, 1H, J=8 Hz, Arꢀ), 7.24ꢀ7.29(m,
4
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DOI: 10.1039/C4NJ01893A
2H, Arꢀ), 7.68(s, 1H, Arꢀ), 8.74(s, 1H, NꢀH); 13C NMR
(m/z, %): 348(M+, 42), 241(100), 149(52), 83(61), 77(27),
(DMSO+CDCl3, 100 MHz)/ δ (ppm): 28.04, 28.75, 32.19, 44.69, 60 57(85), 55(72).
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; Anal. Calcd. For C21H20ClN3O3: C 63.40, H 5.07, N 10.56,
Found C 63.46, H 5.13, N 10.64; EIꢀMASS (m/z, %): 397(M+,
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(3-methoxy)phenyl]-
1H-dibenzo[b,e][1,4]diazepin-1-one(3m): pale green solid, m.p.=
225ꢀ227 oC, Rf = 0.125 (1:1 Ethylacetate/ nꢀHexane); UVꢀVIS: λ
max= 364 nm; IR (KBr)/ υ (cmꢀ1): 3326, 3278, 3050, 2954, 1586,
5
21), 399(M+2+, 4), 241(100), 149(47), 83(47), 77(27), 69(81), 65 1382, 1538, 1332, 1497, 1274; 1H NMR (DMSO+CDCl3,
57(91), 55(67).
400MHz)/ δ (ppm): 1.01(s, 3H, CH3ꢀ), 1.06(s, 3H, CH3ꢀ),
2.12(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.52(s, 2H, ꢀCH2ꢀC=O), 3.55(s,
3H, Meꢀ), 5.64(s, 1H, NꢀH), 5.72(s, 1H, CꢀH), 6.44ꢀ6.48(m, 2H,
Arꢀ), 6.53ꢀ6.57(m, 2H, Arꢀ), 6.60(s, 1H, Arꢀ), 6.62(d, 1H, J=8 Hz,
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-methyl)phenyl]-
10 1H-dibenzo[b,e][1,4]diazepin-1-one(3j): pale green solid,
o
o
m.p.=224ꢀ226 C, m.p.= 157ꢀ158 C (decomp) [18e]; Rf = 0.125
(1:1 Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 361 nm; IR (KBr)/ 70 Arꢀ), 6.86(d, 1H, J= 7.6 Hz, Arꢀ), 6.91(t, 1H, J=8 Hz, Arꢀ),
υ (cmꢀ1): 3307, 3245, 3050, 2959, 1595, 1380, 1538, 1327, 1471,
1276; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 1.01(s, 3H,
15 CH3ꢀ), 1.07(s, 3H, CH3ꢀ), 2.01 (A.Bq, 2H, J=16 Hz, CH2ꢀ),2.01(s,
3H, Meꢀ), 2.52(s, 2H, ꢀCH2ꢀC=O), 5.69(s, 1H, NꢀH), 5.69(s, 1H,
8.53(s, 1H, NꢀH); 13C NMR (DMSO+CDCl3, 100 MHz)/ δ
(ppm): 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; Anal. Calcd. For
1
CꢀH), 6.45 (d, 1H, J=7.6 Hz, Arꢀ),6.5ꢀ6.6 (m, 2H, Arꢀ),6.81 (d, 75 C22H24N2O2: C 75.83, H 6.94, N 8.04, Found C 75.86, H 6.97, N
2H, J=7.6 Hz, Arꢀ), 6.86(d, 1H, J=8.04 Hz, Arꢀ), 6.92(d, J=7.6
Hz, 2H, Arꢀ), 8.53(s, 1H, NꢀH); 13C NMR (DMSO+CDCl3, 100
20 MHz)/ δ (ppm): 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,
8.07; EIꢀMASS (m/z, %): 348(M+, 72), 241(100), 149(45),
83(31), 77(37), 69(34), 57(35), 55(42).
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-hydroxy)phenyl]-
1H-dibenzo[b,e][1,4]diazepin-1-one(3n): pale cream solid,
131.53, 138.87, 145.11, 155.14, 192.56; Anal. Calcd. For 80 m.p.=201ꢀ202 oC, m.p.=164ꢀ166 oC [18b]; Rf = 0.125 (1:1
C22H24N2O: C 79.48, H 7.28, N 8.43, Found C 79.53, H 7.35, N
8.49; EIꢀMASS (m/z, %): 332(M+, 43), 241(100), 149(55),
25 83(39), 77(41), 57(77), 55(46).
Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 360 nm; IR (KBr)/ υ
(cmꢀ1): 3622, 3302, 3238, 3100, 2957, 1599, 1384, 1528,
1
1328,1424,1276; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm):
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(4-methoxy)phenyl]-
1.06(s, 3H, CH3ꢀ), 1.08(s, 3H, CH3ꢀ), 2.13(A.Bq, 2H, J=16 Hz,
1H-dibenzo[b,e][1,4]diazepin-1-one(3k): pale cream solid, 85 CH2ꢀ),2.56(s, 2H, ꢀCH2ꢀC=O), 5.18(s, 1H, NꢀH), 5.93(s, 1H, Cꢀ
m.p.=229ꢀ231 oC, m.p.=203ꢀ205 oC [18b]; Rf = 0.125 (1:1
Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 364 nm; IR (KBr)/ υ
30 (cmꢀ1): 3301, 3238, 3015, 2956, 1587, 1382, 1535, 1327, 1426,
H), 6.35 (t, 2H, J=7.2 Hz, Ar), 6.38(d, 1H, J=6.8 Hz, Arꢀ), 6.50ꢀ
6.55 (m, 3H, Arꢀ),6.66 (d, 1H, J=8Hz, Arꢀ), 6.76(t, 1H, J=7.2 Hz,
Arꢀ), 6.86(d, J=7.2 Hz, 1H, Arꢀ), 8.53(s, 1H, NꢀH), 9.35(s, 1H, Oꢀ
H); 13C NMR (DMSO+CDCl3, 100 MHz)/ δ (ppm): 28.04, 29.05,
1
1279; H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm): 1.01(s, 3H,
CH3ꢀ), 1.06(s, 3H, CH3ꢀ), 2.10(s, 3H, Meꢀ), 2.10(s, 1H, CꢀH), 90 32.22, 44.71, 50.11, 56.39, 110.89, 113.22, 115.08, 118.65,
2.11(A.Bq, 2H, J=16 Hz, CH2ꢀ),2.52(s, 2H, ꢀCH2ꢀC=O), 5.7(s,
1H, NꢀH), 6.45 (d, 1H, J=7.6 Hz, Arꢀ),6.5ꢀ6.58 (m, 2H, Arꢀ),6.81
35 (d, 2H, J=8Hz, Arꢀ), 6.87(d, 1H, J=8.4 Hz, Arꢀ), 6.91(d, J=8 Hz,
2H, Arꢀ), 8.55(s, 1H, NꢀH); 13C NMR (DMSO+CDCl3, 100
119.77, 120.43, 120.96, 122.97, 128.71, 131.47, 138.95, 146.62,
155.07, 157.26, 192.55; Anal. Calcd. For C21H22N2O2: C 75.42, H
6.63, N 8.38, Found C 75.47, H 6.68, N 8.43; EIꢀMASS (m/z, %):
348(M+, 23), 241(100), 149(47), 83(35), 77(46), 57(40), 55(48).
MHz)/ δ (ppm): 27.82, 29.19, 32.23, 44.75, 50.04, 54.11, 56.42, 95 3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(3-hydroxy)phenyl]-
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; Anal. Calcd. For
40 C22H24N2O2: C 75.83, H 6.94, N 8.04, Found C 75.86, H 6.97, N
8.07; EIꢀMASS (m/z, %): 348(M+, 67), 241(100), 149(36),
83(35), 77(42), 57(43), 55(52).
1H-dibenzo[b,e][1,4]diazepin-1-one (3o): pale green solid, m.p.=
o
287ꢀ289 C (decomp), Rf = 0.125 (1:1 Ethylacetate/ nꢀHexane);
UVꢀVIS: λ max= 348 nm; IR (KBr)/ υ (cmꢀ1): 3447, 3307, 3048,
2927, 1585, 1386, 1519, 1332, 1425, 1275;
1H NMR
100 (DMSO+CDCl3, 400MHz)/ δ (ppm): 1.03(s, 3H, CH3ꢀ), 1.08(s,
3H, CH3ꢀ), 2.11(A.Bq, 2H, J=16 Hz, CH2ꢀ), 2.54(s, 2H, ꢀCH2ꢀ
C=O), 5.60(s, 1H, NꢀH), 5.94(s, 1H, CꢀH), 6.37(d, 1H, J=7.6 Hz,
Arꢀ), 6.48ꢀ6.57(m, 5H, Arꢀ), 6.82(t, 1H, J=7.6 Hz, Arꢀ), 6.89(d,
1H, J=7.6 Hz, Arꢀ), 8.64(s, 1H, NꢀH), 8.90(s, 1H, OꢀH); 13C
3,3-dimethyl-2,3,4,5,10,11-hexahydro-11-[(2-methoxy)phenyl]-
1H-dibenzo[b,e][1,4]diazepin-1-one(3l): pale cream solid,
45 m.p.=217ꢀ218 oC (decomp), m.p.=213ꢀ215 oC (decomp) [18a]; Rf
= 0.125 (1:1 Ethylacetate/ nꢀHexane); UVꢀVIS: λ max= 361 nm;
IR (KBr)/ υ (cmꢀ1): 3369, 3306, 3063, 2955, 1599, 1384, 1534, 105 NMR (DMSO+CDCl3, 100 MHz)/ δ (ppm): 28.02, 29.09, 32.20,
1327, 1425, 1236; 1H NMR (DMSO+CDCl3, 400MHz)/ δ (ppm):
1.07(s, 3H, CH3ꢀ), 1.08(s, 3H, CH3ꢀ), 2.12(A.Bq, 2H, J=16 Hz,
50 CH2ꢀ),2.57(s, 2H, ꢀCH2ꢀC=O) 3.89(s, 3H, Meꢀ), 5.0(s, 1H, NꢀH),
5.95(s, 1H, CꢀH), 6.28 (d, 1H, J=7.6 Hz, Arꢀ),6.45ꢀ6.55 (m, 3H,
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; Anal. Calcd. For C21H22N2O2: C 75.42, H 6.63, N
8.38, Found C 75.46, H 6.66, N 8.42; EIꢀMASS (m/z, %):
Arꢀ),6.58 (d, 1H, J=7.6Hz, Arꢀ), 6.75(d, 1H, J=8.4 Hz, Arꢀ), 110 334(M+, 34), 241(100), 149(61), 83(57), 77(25), 69(84), 57(90),
6.86(d, J=7.6 Hz, 1H, Arꢀ), 6.94(t, 1H, J=8Hz, Arꢀ), 8.59(s, 1H,
NꢀH); 13C NMR (DMSO+CDCl3, 100 MHz)/ δ (ppm): 27.95,
55 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,
55(72).
2,3,4,5,10,11-hexahydro-11-[phenyl]-1H-dibenzo[b,e][1,4]
diazepin-1-one (3p): orange solid, m.p.= 213ꢀ216 oC, IR (KBr)/ υ
(cmꢀ1): 3307, 3245, 3030, 2930, 1530, 1364, 1020, 1008; 1H
146.65, 155.26, 159.24, 192.65; Anal. Calcd. For C22H24N2O2: C 115 NMR (DMSO+CDCl3, 400 MHz)/ δ ppm: 1.11 (m, 2H, CH2),
75.83, H 6.94, N 8.04, Found C 75.9, H 6.98, N 8.10; EIꢀMASS
2.24 (m, 2H, CH2), 2.48 (m, 2H, ꢀCH2ꢀC=O), 5.84 (s, 1H, NꢀH),
This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C4NJ01893A
6.10 (s, 1H , CꢀH), 6.62ꢀ6.78 (m, 3H, Arꢀ), 6.95 (d, 1H, J=8 Hz,
In generality and development of this protocol, the reaction of oꢀ
Arꢀ), 7.07 (t, 1H, J=8 Hz Arꢀ), 7.18ꢀ7.27 (m, 3H, Arꢀ), 8.20 (d, 40 phenylenediamine, dimedone with various aryl aldehydes was
1H, J=4 Hz, Arꢀ), 8.82 (s, 1H, NꢀH); 13C NMR (DMSO+CDCl3,
100 MHz)/ δ (ppm): 30.25, 45.21, 50.48, 55.18, 108.84, 117.69,
122.30, 120.40, 124.67, 127.94, 128.04, 129.41, 131.64, 139.07,
146.45, 157.40, 195.74.
carried out in according to the general experimental procedure. In
all of the cases, the corresponding benzodiazepines were obtained
in high to excellent yields and short reaction times. The obtained
similar products are summarized in Table 3. Furthermore, It was
45 also examined a wide variety of aldehydes (both aromatic and
aliphatic) with various substituents to establish the catalytic
importance of ZnS nanoparticles for this reaction. A wide range
of ortho, meta and para substituted aromatic aldehydes undergo
this oneꢀpot multicomponent reaction with dimedone and oꢀ
50 phenylenediamine toward benzodiazepines in excellent yields. In
all of entries, it was observed the almost same performance of
catalyst for this cycloꢀcondensation toward synthesis of the
desired products (Table 2). While, the aliphatic aldehydes gave
the corresponding 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine in lower
55 yield (20–30%) than aromatic aldehydes (73–94%) (Table 3).
Reaction profile is very clean and no side reaction products were
formed. All of the synthesized 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepines
have been characterized on the basis of elemental and spectral
studies.
5
Results and discussion
In this work, a simple energy, ecoꢀfriendly and convenient
method for the synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine
10 using ZnS nanoparticles as new catalyst was described. Initially,
in order to optimize the reaction conditions, it is considered to
represent the reaction of dimedone, oꢀphenylenediamine and
benzaldehyde in equal ratio to afford the benzodiazepines under
various reaction conditions for an appropriate time (Scheme 1).
O
H
N
O
NH2
NH2
O
ZnS Nanoparticles
EtOH, reflux
H
O
N
H
15
Scheme 1 Synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine under thermal
60 Table 2 Optimization of catalyst amount in the reactiona
conditions
Choice of a solvent is also very important factor for MCRs. The
reaction was occurred in both aprotic and protic solvents such as;
Entry
Catalyst (g)
None
0.005
0.008
0.01
Time (min)
Yieldb (%)
1
2
3
4
5
6
40
18
15
10
10
10
40
65
75
85
85
85
20 EtOH, MeOH, H2O, CH3CN, CHCl3 and nꢀHexane. But none of
the above solvents was found to be effective than ethanol for this
reaction (Table 1). Nevertheless, the reaction at 25 oC did not
give the desired product and the starting material was completely
0.013
0.015
o
a The reaction is using a different amount of catalyst, 1 mmol of
dimedone, 1mmol of oꢀphenylene diamine and 1 mmol of pꢀClꢀ
benzealdehyde in ethanol (5.0 mL). bIsolated yields.
recovered, whereas, at 50 C only trace of the desired product
25 was identified by TLC. It was found that the ethanol was a
selected solvent for the reaction using ZnS NPs as heterogeneous
o
catalyst at 80 C, the desired product was obtained in excellent
yield (Table 1, entry 16). The obtained results from the reaction
to determine the optimum amount of catalyst are presented in
30 Table 2. As can be seen from this Table, the best results were
obtained by using 10 mol % (0.01g) of ZnS NPs as catalyst in the
reaction of dimedone (1 mmol), oꢀphenylenediamine (1 mmol)
and pꢀClꢀbenzaldehyde (1 mmol) (Table 2, entry 4).
65 The possibility of recycling of the catalyst was examined through
the reaction of oꢀphenylenediamine, dimedone and 4ꢀ
chlorobenzaldehyde catalyzed by ZnS NPs under optimized
conditions. Upon completion of the reaction, the catalyst was
centrifuged, filtered and washed several times with ethyl acetate.
70 Also the recycled catalyst was saved for the next reaction. The
recycled catalyst could be reused five times without any decrease
in catalytic activity so that the yields were ranged from 85ꢀ75 %
(Fig. 8).
Table 1 Optimization of reaction conditiona
Entry
1
2
3
4
5
6
7
8
Catalyst
MeSO3H
CF3COOH
CuI
Fe3O4
MgO
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
None
nꢀHexane
CHCl3
H2O
CH3CN
MeOH
EtOH
Time (min) Yieldb (%)
50
45
16
16
13
16
14
15
40
14
15
13
18
11
9
65
70
55
55
25
50
55
35
40
30
20
40
65
75
80
85
ZnO
ZnS
Zn (CH3COO) 2. 2H2O
None
9
10
11
12
13
14
15
16
ZnS NPsc
ZnS NPs
ZnS NPs
ZnS NPs
ZnS NPs
ZnS NPs
ZnS NPs
10
35 aAll the reactions were carried out using 10% mol of catalyst, 1mmol of
oꢀphenylenediamine, 1 mmol of dimedone and 1 mmol of pꢀClꢀ
75
benzealdehyde in solvent (5.0 mL). bIsolated yields; cZnS NPs (10 % mol)
Fig. 8 Reusability of ZnS NPs
6
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Table 3 Synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine (3a-o) catalyzed
by ZnS nanoparticles in ethanol under thermal conditiona
217ꢀ218c
Mp.(oC)
12
13
14
13
14
14
76
82
73
(213ꢀ215c)
Time Yield
Entry Aldehyde
Product
(min) (%)b Found (Lit.b)
3l
246ꢀ248
(250ꢀ252)
1
12
78
94
91
92
225ꢀ227
3a
3m
3n
280ꢀ281c
(274ꢀ275)
2
3
4
8
201ꢀ202
(164ꢀ166)
3b
230ꢀ232c
10
9
(115ꢀ117c)
3c
3d
15
13
12
81
88
287ꢀ289c
213ꢀ216
195ꢀ197
(161ꢀ168)
3o
16d
235ꢀ237
(235ꢀ237)
3p
Reaction condition: oꢀphenylenediamine (1mmol), aldehyde (1mmol),
5
6
7
10
11
10
85
82
83
a
b
dimedone (1mmol), ZnS nanoparticles 10% mol (0.01 g); Yields of
3e
c
d
5
isolated pure product; Decomposition point; Reaction condition: oꢀ
phenylenediamine (1mmol), benzaldehyde (1mmol), 1,3ꢀcyclohexadione
(1mmol), ZnS nanoparticles 10% mol (0.01 g)
239ꢀ240c
(233ꢀ235c)
In order to ascertain the effect of reaction cycles on the catalyst,
TEM analysis on the used catalyst after five subsequent runs was
10 provided and shown in Fig. 9. Compared to the TEM of catalyst
after and before (Fig 7) used in the reaction, was indicated that
the reaction cycles not affected on the morphology and dimension
of nanaparticles.
3f
256ꢀ258c
3g
3h
230ꢀ232c
(252)
8
9
9
88
73
10
196ꢀ197
3i
224ꢀ226
10
11
13
15
83
76
(157ꢀ158c)
3j
15
Fig. 9 TEM image of ZnS nanoparticles after five subsequent runs
229ꢀ231
(203ꢀ205)
The structure of the obtained products was confirmed by FTꢀIR,
1H NMR, 13C NMR and EIꢀMASS spectroscopic data. The FTꢀIR
spectrum of the 3i exhibit a broad band at 3305 and 3240 cmꢀ1
20 related to amine protons (2 NH groups). The bands at 3039 and
3k
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DOI: 10.1039/C4NJ01893A
2958 cmꢀ1 confirm the presence of CH, CH2, CH3 groups, strong
Conclusion
bands at 1600 and 1381 cmꢀ1 related to the general carbonyl
groups (C=O stretching). Moreover, strong bands at 1532 and
1339 cmꢀ1 confirm the presence of CꢀN stretching, a band at 1426
cmꢀ1 is related to the C=C stretching and a strong band at 1276
cmꢀ1 confirms the presence of CꢀO bond stretching. In addition,
the 1H NMR spectrum of compound 3i exhibited two singlet
bands for two methyl groups at δ = 1.02 ppm and δ = 1.07 ppm.
Also, a AB quartet signal at δ = 2.13 ppm with J=16 Hz for CH2
In the present work, we were described using ZnS nanoparticles
as a reusable, readily available, inexpensive and efficient catalyst
40 for the oneꢀpot synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepines.
These compounds were prepared through treatment of oꢀ
phenylenediamine and dimedone with various aromatic aldehydes
under thermal conditions at 80 °C. Simplicity of operation, high
yields, easy workꢀup, available catalyst, short reaction time, and
45 purification of compounds by crystallization method (nonꢀ
chromatographic) are the key advantages of this work. We hope
this method expand to others synthetic methods for medicinal
chemistry.
5
10 protons, a signal at δ = 2.54 ppm for CH2ꢀC=O protons, a signal
at δ = 5.77 ppm for NH proton, a signal at δ = 6.08 ppm for CH
proton, aromatic protons at δ = 6.50ꢀ7.68 ppm and a signal at δ =
8.74 ppm for NH proton are presented in this spectrum. Also, the
13C NMR spectrum of compound 3i was shown distinct 21 carbon
15 atoms in agreement with proposed structure. Finally, the mass
spectrum of product 3i was displayed molecular ion peak at the
appropriate m/z value [18a].
Acknowledgement
50 The authors are grateful to University of Kashan for supporting
this work by Grant No. 159148/45.
The formation of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine from oꢀ
phenylenediamine, dimedone and aldehyde in the presence of
20 ZnS nanoparticles as efficient catalyst can be explained. It was
proposed a mechanism for the ZnS nanoparticles catalyzed one
pot synthesis of 4ꢀsubstitutedꢀ1,5ꢀbenzodiazepine. As can be
shown in Scheme 2, the desired product was formed in this
reaction catalyzed by ZnS nanoparticles as following various
25 steps (Scheme 2). The role of ZnS nanoparticles comes in steps 2
and 3 where it catalyze the Michael type coupling of dimedone
with oꢀphenylenediamine and intermediate A with aldehyde.
Also, it catalyze the Knoevenagel type in step 5 for sevenꢀ
membered ring cyclization, finally, give 4ꢀsubstitutedꢀ1,5ꢀ
30 benzodiazepine as final product (Scheme 2).
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DOI: 10.1039/C4NJ01893A
Graphical abstract
ZnS nanoparticles as efficient recyclable heterogeneous catalyst for one-pot
synthesis of 4-substituted-1,5-benzodiazepines
Hossein Naeimi* and Hossein Foroughi
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, 87317,
I.R. Iran; Tel. No.: +98-361-5912388; Fax No.: +98-361-5912397;
E-mail: naeimi@kashanu.ac.ir