Facile and efficient synthesis of benzo[b][1,5]diazepines by three-component coupling of aromatic diamines, Meldrum's acid, and isocyanides catalyzed by Fe3O4 nanoparticles

Article abstract of DOI:10.1007/s11164-014-1915-z

Highly effective one-pot synthesis of benzo[b][1,5]diazepines has been achieved by three-component (or, in situ, including catalyst and solvent, five-component) reaction of aromatic diamines, Meldrum's acid, and isocyanides catalyzed by magnetite (Fe

Full text of DOI:10.1007/s11164-014-1915-z

Res Chem Intermed
DOI 10.1007/s11164-014-1915-z
Facile and efficient synthesis of benzo[b][1,5]diazepines
by three-component coupling of aromatic diamines,
Meldrum’s acid, and isocyanides catalyzed by Fe3O4
nanoparticles
•
Mohammad Ali Ghasemzadeh Nasim Ghasemi-Seresht
Received: 21 October 2014 / Accepted: 22 December 2014
Ó Springer Science+Business Media Dordrecht 2015
Abstract Highly effective one-pot synthesis of benzo[b][1,5]diazepines has been
achieved by three-component (or, in situ, including catalyst and solvent, five-
component) reaction of aromatic diamines, Meldrum’s acid, and isocyanides cata-
lyzed by magnetite (Fe3O4) nanoparticles. Pharmaceutically and biologically active
heterocyclic compounds including benzodiazepine derivatives were efficiently
synthesized in excellent yields and short reaction times at room temperature. The
significant features of the Fe3O4 nanoparticles are: easy preparation, cost-effec-
tiveness, high stability, easy separation, low loading, and reusability of the catalyst.
The heterogeneous nanoparticles were fully characterized by XRD, EDX, BET,
SEM, TEM, and FT-IR analysis.
Keywords Fe3O4 ꢀ Nanoparticles ꢀ Benzo[b][1,5]diazepines ꢀ Multi-component
reactions ꢀ Isocyanides
Introduction
Multi-component coupling reactions (MCRs) are valuable methods for producing
compound libraries of small molecules for potential applications in medicinal and
pharmaceutical chemistry [1]. MCRs often conform to the objectives of green
chemistry in terms of economy of reaction steps and the many precise principles of
desirable organic synthesis [2]. Because of their advantages, which include facile
performance, environmentally benign nature, speed, and atom economy, MCRs
have attracted much attention in combinatorial chemistry [3]. Among the different
types of nitrogen-containing organic structures, benzodiazepine derivatives have a
wide range of pharmaceutical and biological activity, including analgesic,
M. A. Ghasemzadeh (&) ꢀ N. Ghasemi-Seresht
Department of Chemistry, Qom Branch, Islamic Azad University, Qom, Islamic Republic of Iran
e-mail: Ghasemzadeh@qom-iau.ac.ir
123

M. A. Ghasemzadeh, N. Ghasemi-Seresht
anticonvulsant, anti-depressive, anti-anxiety, sedative, anti-inflammatory, and
hypnotic [4–7]. They are also important drugs for treatment of diseases which
include cardiovascular disorders, cancer, diabetes, and viral infections (e.g. HIV)
[8–11]. Important 1,5-benzodiazepines with high medicinal activity include
olanzapine, 1, and clozapine, 2 (for treatment of schizophrenia) [12], clobazam, 3
(an anxiolytic agent) [13], and 3-carbamoyl-1,5-benzodiazepine, 4 (a selective
CCK-B antagonist as potential anxiolytic drug) [14] (Fig. 1).
Synthesis of 1,5-benzodiazepines has therefore attracted much attention and many
methods for synthesis of 1,5-benzodiazepines have been reported in the literature.
Methods for synthesis of benzodiazepines mainly entail coupling of 1,2-phenylen-
ediamines with a variety of ketones [15], chalcones [16], alkynes [17], 4,6-di-O-
benzyl-2,3-dideoxyaldehydo-D-erythro-trans-hex-2-enose [18], 3-acetyl-4-hydroxy-6-
methyl-2H-pyran-2-one [19], and alk-3-yn-1-ones [20]. Although many of these
procedures have valuable advantages, some have specific disadvantages, for example
hazardous reaction conditions, unsatisfactory yields, high cost of catalysts and
solvents, complicated work-up and processing, production of side products, and long
reaction times. Thus, development efficient, mild, simple, and environmentally benign
methods for synthesis of benzodiazepine derivatives would be highly desirable.
In recent years, metal nanocatalysts have become an important alternative to
traditional materials in the different fields of chemistry, and have attracted much
interest among chemists [21]. The utility of heterogeneous catalysts in organic
reactions can be enhanced by use of nano-sized materials, because of the very small
size, and hence high surface area, of nanoparticles in comparison with the bulk form.
Heterogeneous nanocatalysts have much potential for development of selective,
efficient, and high-yielding procedures [22]. Recently, magnetite Fe3O4 nanoparticles
(Fe3O4 NPs) have attracted much attention as nano-sized materials because of their
wide range of uses in such fields as medical applications, drug delivery, and
remediation, as catalysts, and in industry [23–26]. The salient and significant property
of magnetite nanoparticles is the simple and facile separation of these catalysts from
the reaction mixture by use of an external magnet. In the last decade Fe3O4 NPs have
been used as an effective heterogeneous nanocatalyst in such organic reactions as
synthesis of quinoxalines [27], a-aminonitriles [28], propargylic amines [29],
sulfonamides [30], 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-4(3H)ones [31],
O
N
O
O
N
O
N
Cl
N
N
NH
N
S
N
Cl
F3C
N
N
N
O
O
N
H
N
H
clozapine (2)
clobazam (3)
3-carbamoyl-1,5-benzodiazepine (4)
olanzapine (1)
Fig. 1 Some biologically important benzodiazepines
123

A facile and efficient synthesis of benzo[b][1,5]diazepines
1,8-dioxodecahydroacridine [32], coupling of phenols with aryl halides [33], the
Suzuki reaction [34], the Sonogashira–Hagihara reaction [35], and the Paal–Knorr
reaction, aza-Michael addition, and pyrazole synthesis [36]. Shaabani et al. have
recently reported a novel and efficient method for synthesis of some tetrahydro-2,
4-dioxo-1H-benzo[b][1,5]diazepine-3-yl-2-methylpropanamide derivatives [37].
Although this method has valuable advantages, for example mild reaction
conditions, good yields, and no undesirable byproducts, reaction times are long and
yields are poor. So, despite its advantages, we decided to conduct research on this
method, including increasing the reactivity of the substrates. In this context, and
because of our interest in sustainable procedures for synthesis of heterocyclic
compounds by use of multi-component reactions and nanocatalysts [38–42], we report
herein a highly efficient and mild method for synthesis of tetrahydro-2,4-dioxo-1H-
benzo[b][1,5]diazepine-3-yl-2-methylpropanamides by multi-component reaction of
1,2-phenylenediamines, isocyanides, and Meldrum’s acid with Fe3O4 NPs as an
environmentally benign, readily available, and economic nanocatalyst (Scheme 1).
Experimental
Chemicals of high purity were purchased from Merck and Fluka. IR spectra were
recorded as KBr pellets on a Perkin–Elmer 781 spectrophotometer and an Impact
400 Nicolet FT-IR spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on a Bruker DRX-400 spectrometer (400 MHz) with TMS as internal
reference and DMSO-d6 as solvent. All melting points are uncorrected and were
determined in capillary tubes on a Boetius melting point microscope. TLC on silica
gel polygram SILG/UV 254 plates was used for monitoring the purity of the
reactants and the progress of reactions. Elemental analysis (C, H, N) was performed
with a Carlo Erba model EA 1108 analyzer. Powder X-ray diffraction (XRD) was
performed with a Philips X’pert diffractometer with monochromatic Cu Ka
˚
radiation (k = 1.5406 A). The microscopic morphology of products was studied by
scanning electron microscopy (SEM; LEO 1455VP). Mass spectra were acquired by
use of a Joel D-30 instrument at an electron energy of 70 eV. Transmission electron
microscopy (TEM) was performed with a Jeol JEM-2100UHR, operated at 200 kV.
N2 adsorption/desorption analysis (BET) was performed at -196 °C by use of an
automated gas adsorption analyzer (Tristar 3000, Micromeritics). Compositional
analysis was performed by energy-dispersive X-ray analysis (EDAX, Kevex, Delta
Class I).
O
H
N
R1
O
R1
NH2
O
O
Fe3O4 NPs
CH2Cl2, r.t.
+
+
R2
N
C
HN R2
N
H
O
O
NH2
O
Scheme 1 Preparation of tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-3-yl-2methylpropanamides
catalyzed by Fe3O4 NPs
123

M. A. Ghasemzadeh, N. Ghasemi-Seresht
Preparation of Fe3O4 nanoparticles
Fe3O4 nanoparticles were prepared by the procedure reported by Chen et al. [43].
FeSO4ꢀ7H2O (2.5 g) was dissolved in deionized water. Poly(ethylene glycol) 20,000
solution (50 g/l, 30 ml) was added, with stirring, followed by 10 ml dilute aqueous
ammonia solution (2.5 %), again with stirring. H2O2 (0.27 ml) was then added
slowly to the solution, followed by addition of 25 ml methanol. The mixture was
stirred for 5 min to obtain a homogeneous solution. The solution was then
transferred to a sealed 100-ml autoclave and heated at 160 °C for 7 h. The autoclave
was then left to cool naturally to room temperature. The black product was
centrifuged, isolated by filtration, washed several times with deionized water and
alcohol, and finally dried at 80 °C for 8 h.
Typical procedure for synthesis of tetrahydro-2,4-dioxo-1H-
benzo[b][1,5]diazepine-3-yl-2-methylpropanamides (4a–4j)
Fe3O4 nanoparticles (0.02 g, 0.1 mmol, 10 mol %) were added to a mixture of 1,2-
phenylenediamines (1 mmol), Meldrum’s acid (1 mmol), and isocyanide (1 mmol) in
5 ml dichloromethane. The reaction mixture was stirred for 3–4 h at room temperature.
Progress of the reaction was continuously monitored by TLC. After completion of the
reaction the residue was dissolved in methanol and the nanocatalyst was separated by
use of an external magnet. The solvent was evaporated under vacuum and the solid
obtained was washed several times with acetone to afford pure benzodiazepine.
All of the products were characterized and identified by determination of m.p.
1
and by use of H NMR, 13C NMR, and FT-IR spectroscopy. Spectral data for new
products are listed below.
N-n-pentyl-2-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,5]diazepin-3-yl)-2-
methylpropanamide (4d)
White solid; mp = 286–288 °C; 1H NMR (400 MHz, DMSO-d6): 0.81–0.84 (t, 3H,
CH3 (pentyl)), 1.17–1.43 (m, 12H, 3 9 CH2 and 2 9 CH3), 2.96–2.97 (t, 2H, CH2–
NH), 3.39 (s, 1H, CH), 7.11–7.18 (m, 4H, ArH), 7.58 (bs, 1H, NH), 10.33 (bs, 2H,
2NH). 13C NMR (100 MHz, DMSO-d6): 14.4, 22.3, 28.9, 29.1, 29.8, 43.4, 48.1,
52.6, 112.4, 125.3, 130.4, 167.4, 177.1. FT-IR (KBr, cm-1): 3,347 (NH), 1,700
(C=O), 1,660 (C=O), 1,546 (C=C). Anal. calcd for C18H25N3O3: C 65.23, H 7.60, N
12.58. Found C 65.09, H 7.71, N 12.69.; MS (EI) (m/z): 331 (M?).
N-(4-methoxyphenyl)-2-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,5]diazepin-3-
yl)-2-methylpropanamide (4e)
White solid; mp = 306–308 °C; 1H NMR (400 MHz, DMSO-d6): 1.48–1.53 (s, 6H,
2 9 CH3), 3.43 (s, 1H, CH), 3.69 (s, 3H, OCH3), 6.82–6.82 (d, 2H, J = 8 Hz, ArH),
7.16–7.18 (m, 4H, ArH), 7.42–7.44 (d, 2H, J = 8 Hz, ArH), 9.53 (bs, 1H, NH), 10.47
(bs, 2H, 2NH). 13C NMR (100 MHz, DMSO-d6): 21.8, 43.1, 48.5, 56.1, 122.2, 125.5,
131.4, 133.6, 135.8, 136.2, 140.1, 167.8, 177.2. FT-IR (KBr, cm-1): 3,424 (NH),
123

A facile and efficient synthesis of benzo[b][1,5]diazepines
1,695, (C=O), 1,654 (C=O), 1,510 (C=C), 1,253 (C–O). Anal. calcd for C20H21N3O4:
C 65.38, H 5.67, N 11.44. Found C 65.51, H 5.59, N 11.35.; MS (EI) (m/z): 367 (M?).
N-n-pentyl-2-methyl-2-(7-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-
benzo[b][1,5]diazepin-3-yl)propanamide (4i)
1
White solid; mp = 246–248 °C; H NMR (400 MHz, DMSO-d6): 0.92–0.95 (t, 3H,
CH3 (pentyl)), 1.22–1.51 (m, 12H, 3 9 CH2 and 2 9 CH3), 2.22 (s, 3H, CH3), 2.93 (t,
2H, CH2–NH), 3.34 (s, 1H, CH), 7.09–7.16 (m, 3H, ArH), 8.11 (bs, 1H, NH), 10.43 (bs,
2H, 2NH). 13C NMR (100 MHz, DMSO-d6): 15.6, 19.8, 21.4, 22.8, 29.2, 29.7, 43.4,
48.2, 53.1, 112.4, 125.3, 126.7, 127.5, 128.4, 133.2, 167.2, 177.1. FT-IR (KBr, cm-1):
3,339 (NH), 1,698 (C=O), 1,659 (C=O), 1,566 (C=C). Anal. calcd for C19H27N3O3: C
66.06, H 7.88, N 12.16. Found: C 66.18, H 7.79, N 12.04.; MS (EI) (m/z): 345 (M?).
N-(4-methoxyphenyl)-2-methyl-2-(7-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-
benzo[b][1,5]diazepin-3yl)propanamide (4j)
1
White solid; mp = 283–285 °C; H NMR (400 MHz, DMSO-d6): 1.31–1.35 (s,
6H, 2 9 CH3), 2.22 (s, 3H, CH3), 3.45 (s, 1H, CH), 3.81 (s, 3H, OCH3), 6.91–6.93
(d, 2H, J = 7.9 Hz, ArH), 7.14–7.17 (m, 3H, ArH), 7.53–7.55 (d, 2H, J = 7.9 Hz,
ArH), 9.66 (bs, 1H, NH), 10.44 (bs, 2H, 2NH). 13C NMR (100 MHz, DMSO-d6):
19.9, 42.8, 43.5, 55.1, 56.7, 122.6, 123.7, 125.6, 128.4, 130.7, 131.4, 135.2, 136.5,
138.3, 142.1, 167.6, 169.9. FT-IR (KBr, cm-1): 3,448 (NH), 1,705 (C=O), 1,662
(C=O), 1,518 (C=C), 1,246 (C–O). Anal. calcd for C21H23N3O4: C 66.13, H 6.08, N
11.02. Found: C 66.24, H 5.99, N 10.93.; MS (EI) (m/z): 381 (M?).
Recycling and reuse of the catalyst
The magnetite nanoparticles recovered by use of the external magnet were washed
several times with methanol and acetone then dried at 80 °C for 8 h. To investigate
the lifetime and reusability of the Fe3O4 NPs, they were reused several times. We
observed that recovered magnetite nanoparticles could be used in six successive
runs with slight reduction in activity, as indicated in Fig. 2.
Fig. 2 Reusability of the Fe3O4
NPs
123

M. A. Ghasemzadeh, N. Ghasemi-Seresht
Results and discussion
In preliminary experiments magnetite nanoparticles were prepared and character-
ized by XRD, EDX, BET, SEM, TEM, and FT-IR analysis.
The crystalline nature of the synthesized Fe3O4 NPs was verified by XRD. The
XRD pattern of the magnetite nanoparticles is shown in Fig. 3a. All reflection peaks
in Fig. 3a can be readily indexed to those of the pure spherical phase of Fe3O4 with
the P63mc group (JCDPS no. 75-0449). The crystallite size (D) of the nanocatalysts
was calculated by use of the Debye–Scherrer equation (D = Kk/b cos h), where b
FWHM (full-width at half-maximum, or half-width) is in radians, h is the position
of the maximum of the diffraction peak, K is the so-called shape factor, which
˚
usually takes a value of approximately 0.9, and k is the X-ray wavelength (1.5406 A
for Cu Ka). The crystallite size of Fe3O4 was 28 nm.
The chemical purity of the samples and their stoichiometry were studied by EDX.
The EDX spectrum in Fig. 3b shows iron and oxygen are the only elements present.
The specific surface area was measured by nitrogen physisorption (the BET
method); the specific surface area was approximately 98 m2/g. The theoretical
particle size calculated from the surface area and density of magnetite (5.18 g/cm3)
was 11.8 nm.
ꢀ
ꢁ
6; 000
q ꢁ S
DBET
¼
Figure 4 shows FT-IR spectrum of Fe3O4 NPs. The strong peak at approximately
570 cm-1 was ascribed to the Fe–O stretching frequency. In addition, the broad
peaks at 3,452 and 1,637 cm-1 can be attributed to the m (OH) stretching and
bending vibrations, respectively. These peaks thus indicate the presence of a small
amount of water physisorbed by the nanoparticles.
The morphology and particle size of Fe3O4 NPs were studied by SEM. The SEM
image of Fe3O4 NPs in Fig. 5a shows the Fe3O4 to be a nanostructure with single-
phase primary spherical particles of average diameter between 30 and 40 nm.
The size and morphology of the magnetite nanoparticles were analyzed by TEM
(Fig. 5b). The results showed that the nanocatalyst consisted of spherical particles
Fig. 3 XRD (a) and EDX (b) patterns of magnetite nanoparticles
123

A facile and efficient synthesis of benzo[b][1,5]diazepines
Fig. 4 FT-IR spectrum of Fe3O4 NPs
Fig. 5 SEM (a) and TEM (b) images of Fe3O4 NPs
with a crystallite size approximately 30 nm, in good agreement with the XRD
crystal size.
In an initial study to find the optimum reaction conditions, preparation of N-
cyclohexyl-2-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,5]diazepin-3-yl)-2-meth-
ylpropanamide 4a was selected as model reaction (Scheme 2).
A mixture of o-phenylenediamine (1 mmol), Meldrum’s acid (1 mmol), and
cyclohexyl isocyanide (1 mmol) were reacted under different reaction conditions.
When the reaction was conducted without Fe3O4 NPs as catalyst, a moderate yield
of product was obtained after 9 h. We examined use of a variety of catalysts in this
multi-component reaction. Many homogenous and heterogeneous catalysts
123

M. A. Ghasemzadeh, N. Ghasemi-Seresht
C
N
O
H
N
NH2
NH2
O
O
O
+
+
HN
O
O
N
H
O
4 a
Scheme 2 Model reaction for synthesis of 1,5-benzodiazepin-2-one 4a
Table 1 Synthesis of
benzo[b][1,5]diazepin 4a using
Entry
Catalysta
Time (h)
Yield (%)
various catalysts
1
None
9
62
65
62
55
Trace
55
51
78
45
38
94
75
82
90
94
94
2
SiO2
6
3
CH3COOH
4
4
MgSO4
7
5
NaOH
9
6
MgO NPs
8
7
CaO NPs
8
8
CuO NPs
4
9
HCl
7
10
11
12
13
14
15
16
H2SO4
8
Fe3O4 NPs
Fe3O4 NPs (1 mol %)
Fe3O4 NPs (4 mol %)
Fe3O4 NPs (7 mol %)
Fe3O4 NPs (10 mol %)
Fe3O4 NPs (12 mol %)
3
6
Bold line refers to best result
a
20 mol % except where
indicated
4.5
3.5
3
Reactions were performed in
dichloromethane at room
temperature
3
(including SiO2, CH3COOH, MgSO4, NaOH, MgO NPs, CaO NPs, CuO NPs, HCl,
H2SO4, and Fe3O4 NPs) were used to investigate the model reaction. Dichloro-
methane was used as solvent at room temperature and, initially, 20 mol % of each
catalyst was used. The results summarized in Table 1 show that, although most of
the Brønsted and Lewis acids could be used to perform the model reaction, the best
results were obtained by use of Fe3O4 NPs.
The greater catalytic activity of magnetite Fe3O4 NPs compared with the other
catalysts is because of their high surface area-to-volume ratio, which enables highly
efficient diffusion. When the effect of using different amounts (1, 4, 7, 10, and
12 mol %) of Fe3O4 NPs was investigated, we observed that 10 mol % Fe3O4 NPs
gave the best results and was sufficient to complete the reaction (Table 1).
In another experiment, we examined the effect of different solvents and of
solvent-free conditions on synthesis of 4a. As shown in Table 2, the results were
highly dependent on the nature of the solvent. In each experiment the reactants were
123

A facile and efficient synthesis of benzo[b][1,5]diazepines
Table 2 Model study catalyzed
Entry
Solvent
Time (h)
Yield (%)
by Fe3O4 NPs in different
solvents
1
2
3
4
5
6
No solvent
EtOH
9
–
9
Trace
55
DMF
5.5
5
PhCH3
H2O
65
9
Trace
94
CH2Cl2
3
Bold line refers to best result
Table 3 One-pot synthesis of
benzo[b][1,5]diazepines
catalyzed by Fe3O4 NPs
Entry R1
R2
Product Time (h) Yield (%)
1
2
H
H
H
H
H
Cyclohexyl
tert-Butyl
Benzyl
4a
4b
4c
4d
3
94
95
93
91
92
95
97
95
94
93
2.5
3.2
3.5
3.5
2.5
2.2
3
3
4
n-Pentyl
5
4-Methoxyphenyl 4e
6
CH3 Cyclohexyl
CH3 tert-Butyl
CH3 Benzyl
4f
7
4g
4h
4i
Reaction conditions: aromatic
diamine (1 mmol), Meldrum’s
acid (1 mmol), isocyanide
(1 mmol), Fe3O4 NPs
8
9
CH3 n-Pentyl
3.2
3.5
10
CH3 4-Methoxyphenyl 4j
(10 mol %), 5 ml CH2Cl2
mixed with 10 mol % Fe3O4 NPs in the presence of 5 ml solvent. Among the
different solvents, it is apparent the best yield of 4a, with a very short reaction time,
was achieved by use of dichloromethane.
In the table dichloromethane is highlighted as the solvent of choice, because of
facile and efficient synthesis of the product in a short reaction time and with
satisfactory yield. In general, polar protic solvents, for example water and ethanol,
give the lowest yields because the isocyanide nucleophiles are solvated in these
solvents and, as a result, their nucleophilicity is reduced.
As shown in Table 3, we investigated the scope and limitations of multi-
component synthesis of benzo[b][1,5]diazepine derivatives by using o-phenylen-
ediamines and isocyanides with different structures under the optimized conditions.
Three-component reactions of aromatic diamines, Meldrum’s acid, and isocyanides
were conducted very efficiently and cleanly in the presence of Fe3O4 NPs at room
temperature, and no side products were observed.
In accordance with Table 3, we found that reaction of both mono and
disubstituted aromatic diamines with isocyanides proceeded very smoothly,
affording the corresponding 1,5-benzodiazepin-2-ones in excellent yields
(91–97 %, entries 1–10, Table 3) and with short reaction times. To prove the
generality of the method, we next used both aliphatic and aromatic isocyanides and,
as a result, successfully synthesized a series of benzo[b][1,5]diazepines in high
123

M. A. Ghasemzadeh, N. Ghasemi-Seresht
R1
NH2
NH2
O
O
O
Product
O
O
H2O
R2
O
O
O
H
H
N
N
R1
R1
O
N
NH2
N
H
OH
O
O
R2
N
C
H
N
R1
O
O
H
N
H2O
R1
N
H
N
H
O
O
O
H
N
R1
HN
O
R2
Fe3O
4
NPs
=
Product =
N
H
Scheme 3 Proposed reaction pathway for synthesis of 1,5-benzodiazepin-2-ones with Fe3O4 NPs as
catalyst
yields. The best results were obtained when tert-butyl isocyanide was used as
substrate (95, 97 %, entries 2 and 7, Table 3).
The proposed reaction mechanism for synthesis of tetrahydro-2,4-dioxo-1H-
benzo[b][1,5]diazepine-3-yl-2methylpropanamides is represented in Scheme 3. We
suggest that Fe3O4 NPs behave as a Lewis acid and coordinate the oxygen atoms of
Meldrum’s acid and other intermediates and activate them for nucleophilic attack of
1,2-phenylenediamine and other nucleophiles. The high surface area-to-volume
ratio of magnetite nanoparticles is mainly responsible for their catalytic properties.
Finally the prepared benzo[b][1,5]diazepines could be isolated and the Fe3O4 NPs
reused in further reactions.
123

A facile and efficient synthesis of benzo[b][1,5]diazepines
Conclusions
In summary, we have described, for the first time, use of Fe3O4 NPs as an alternative
to noble-metal-based catalysts for preparation of tetrahydro-2,4-dioxo-1H-ben-
zo[b][1,5]diazepine-3-yl-2-methylpropanamides, which are pharmaceutically and
biologically active heterocyclic compounds. This is a simple, efficient, and eco-
friendly method for three-component (or, in situ, including catalyst and solvent,
five-component) reaction of aromatic diamines, Meldrum’s acid, and isocyanides
using easily recoverable, environmentally benign, inexpensive, and nontoxic
monodispersed magnetite nanoparticles (approx. 30 nm) as catalyst. The method
is facile, avoids the use of high temperatures and expensive solvents and catalysts,
and enables synthesis of the products in excellent yields and with short reaction
times.
Acknowledgments The authors gratefully acknowledge financial support of this work by the Research
Affairs Office of the Islamic Azad University, Qom Branch, Qom, I.R. Iran.
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