Fe3O4/SiO2 nanoparticles: An efficient and magnetically recoverable nanocatalyst for the one-pot multicomponent synthesis of diazepines

Article abstract of DOI:10.1016/j.tet.2012.07.034

In this research, a new protocol for the one-pot multicomponent synthesis of diazepine derivatives using a 1,2-diamine, a linear or cyclic ketone, and an isocyanide in the presence of a catalytic amount of silica-supported iron oxide (Fe₃O

Full text of DOI:10.1016/j.tet.2012.07.034

Tetrahedron 68 (2012) 7827e7833
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Fe3O4/SiO2 nanoparticles: an efficient and magnetically recoverable nanocatalyst
for the one-pot multicomponent synthesis of diazepines
*
Ali Maleki
Department of Chemistry, Iran University of Science and Technology, Narmak, Tehran 16846-13114, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
In this research, a new protocol for the one-pot multicomponent synthesis of diazepine derivatives using
a 1,2-diamine, a linear or cyclic ketone, and an isocyanide in the presence of a catalytic amount of silica-
supported iron oxide (Fe3O4/SiO2) nanoparticles at ambient temperature in excellent yields is described.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 22 April 2012
Received in revised form 12 June 2012
Accepted 10 July 2012
Available online 17 July 2012
Keywords:
Fe3O4/SiO2 nanoparticles
Nanomagnetic catalyst
Multicomponent reaction
One-pot
Diazepines
1. Introduction
benzodiazepine derivatives carrying carboxamide substituents
(D) are potentially important as a therapeutic and prophylactic
Metal nanoparticles (MNPs), especially supported magnetic
metal nanoparticles (S-MMNPs), have emerged as a new class of
nanocatalyst. An important feature of these catalysts is simple
separation of them using an external magnet without filtration.
Furthermore, S-MMNPs catalysts showed not only high catalytic
activity but also a high degree of chemical stability in various or-
ganic solvents.1e5
agent for diabetes, diabetic nephropathy or glomerulosclerosis
(Fig. 1).26,27
Iron, the most ubiquitous of the transition metals and the fourth
most plentiful element in the Earth’s crust, is the structural back-
bone of our modern infrastructure. Iron however has a great deal to
offer at the nanoscale, including very potent magnetic and catalytic
properties.6
Fig. 1. The structure of some medicinally and biologically important diazepines.
Diazepines7e9 have been the object of intense investigation in
medicinal chemistry, because of their remarkable central nervous
system depressant activity, and are now one of the most widely
prescribed class of psychotropics.10 More recently, the area of bi-
ological interest of 1,5-benzodiazepines11e15 have been extended
to antibiotics,16,17 and various diseases, such as cancer,18 viral in-
fection (HIV),19e21 and cardiovascular disorders.22,23 The 1,5-
benzodiazepine core is found in compounds active against a vari-
ety of target types including peptide hormones (A),24 interleukin
converting enzymes (B),25 and potassium blockers (C).23 Two re-
cently published patents indicate that 2,3,4,5-tetrahydro-1H-1,5-
Multicomponent reactions (MCRs) offer significant advantages
over conventional linear step syntheses, by reducing time, saving
money, energy, and raw-materials, thus resulting in both eco-
nomical and environmental benefits. On the other side, because of
the unique reactivity of the isocyanide functional group,
isocyanide-based MCRs (I-MCRs) are among the most versatile, in
terms of the number and variety of compounds, which can be
generated.28e30
In continuing our interest in MCRs,31e33 in this work, we wish to
introduce a new approach for the one-pot multicomponent synthesis
of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-carboxamide de-
rivatives 4ael and 4,5,6,7-tetrahydro-1H-1,4-diazepine-5-carboxa-
mide derivatives 4meo starting from simple and readily available
* Fax: þ98 21 77491204; e-mail address: maleki@iust.ac.ir.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.034

7828
A. Maleki / Tetrahedron 68 (2012) 7827e7833
Table 1
inputs including a 1,2-diamine 1, a linear or cyclic ketone 2, and an
isocyanide 3 in the presence of a catalytic amount of silica-supported
iron oxide (Fe3O4/SiO2) nanoparticles in ethanol at ambient temper-
ature in excellent yields (Scheme 1).
Effect of solvent on the model reactiona
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
H2O
EtOH
MeOH
CH2Cl2
Toluene
Solvent-free
8
5
5
10
12
12
57
92
90
35
27
42
H
R4
N
O
R2
H
O
N
NH2
NH2
Fe3O4/SiO2
R3
R4 NC
R1
+
+
R1
R3
R2
EtOH, r.t.
3-6 h, 85-98%
a
N
H
o-Phenylenediamine (1 mmol), acetone (2 mmol), and benzyl isocyanide
2
R2
R3
3
1
4
(1 mmol) at room temperature in the presence of S-MMNPs (0.05 mmol).
b
Isolated yield.
R1 = CN, Ar-Cl2, Ar-NO2 and Ar-COOH
R2 and R3 = acetone, cyclohexanone and acetophenone
4 = aliphatic, alicyclic and aromatic
R
of various protic solid acids (Amberlyst-21 and Montmorillonite-
K10), liquid acids (HCl, H2SO4, and HOAc), Lewis acid (AlCl3), Fe3O4,
and SiO2. The best yield was obtained with S-MMNPs. To illustrate
the need of S-MMNPs for these reactions, an experiment was
conducted in the absence of S-MMNPs (Table 2, entry 8). The yield
in this case was trace after 6 h. Obviously, S-MMNPs is an important
component of the reaction.
Scheme 1. Synthesis of diazepine-2-carboxamide derivatives 4aeo in the presence of
Fe3O4/SiO2 nanocatalyst.
To the best of our knowledge, this is the first report of the use of
MNPs in I-MCRs, and this new approach opens an important field to
the use of economically and environmentally efficient S-MMNPs in
heterocyclic synthesis.
Due to the success of the above reaction, we explored the scope
and limitations of this promising reaction by varying the structure
of the diamine, ketone, and isocyanide component (Table 3). The
reaction proceeds very cleanly under mild conditions at room
temperature, and no undesirable side reactions were observed
under these reaction conditions.
An important aspect of this reaction was the high purity of the
product. All of the products were sufficiently pure after workup, but
they were crystallized from acetone to give highly pure crystalline
products.
A possible mechanism for the formation of products 4aeo is
shown in Scheme 2. It is conceivable that the initial event is the
formation of diimine 5 from condensation between o-phenyl-
enediamine 1 and 2 mol of ketone 2 in the presence of a catalytic
amount of S-MMNPs.28e30 Then, an intramolecular imineeen-
amine cyclization of 5 affords seven-membered ring 6. On the basis
of the well-established chemistry of reaction of isocyanides with
imines,28e30 intermediate 7 was produced by nucleophilic attack of
isocyanide 3 to iminium 6 followed by nucleophilic attack of a H2O
molecule on the nitrilium moiety and production of compound 8.
Finally, tautomerization of intermediate 8 produces the diazepine-
2-carboxamide derivatives 4.
2. Results and discussion
S-MMNPs were readily prepared according to the literature
procedure,1e5,34,35 by the addition of water dispersed Fe3O4 nano-
particles into a basic solution of tetraethylorthosilicate (TEOS) and
stirring overnight. After heating the resulted gel, the magnetic
material was isolated by centrifugation and vacuum dried to obtain
the S-MMNPs, which were stable under reaction conditions.
The particle size was studied by transmission electron micro-
scope (TEM) and the identification of S-MMNPs were based on the
analysis of TEM images. The obtained TEM images of nanoparticles
clearly showed a monodispersed spherical shape in which Fe3O4
nanoparticles were supported on silica (Fig. 2).
In the case of asymmetric aromatic diamines as the 1,2-diamine
component of starting materials, this reaction was highly regiose-
lective. The 1H NMR and 13C NMR spectra obtained from 4dej were
consistent with the presence of only one isomer. It may be
explained that the selectivity is due to the electronic effect of the
electron-withdrawing groups, such as NO2 and COOH, which de-
activates the p-amino group and the reaction is initiated by the m-
Fig. 2. TEM image of the S-MMNPs.
Table 2
Monitoring of the catalyst effect on the model reactiona
In order to optimize the reaction conditions, a pilot experiment
was carried out using o-phenylenediamine and acetone stirred in
ethanol at room temperature in the presence of Fe3O4/SiO2 nano-
catalyst. The progress of the reaction was monitored by TLC. After
1 h, benzyl isocyanide was added to the reaction mixture and
stirring was continued for 4 h. After completion of the reaction,
a physical magnetic filtration of the catalyst and after that an
aqueous workup afforded compound 4a in 92% yield.
As can be seen in Table 1, the results showed that the efficiency
and the yield of the reaction in EtOH was higher than those
obtained in other solvents, such as H2O, MeOH, CH3CN, CH2Cl2, and
toluene, or under solvent-free conditions.
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
Amberlyst-21
Montmorillonite-K10
HCl
H2SO4
HOAc
AlCl3
S-MMNPs
d
8
8
6
6
7
6
5
6
6
6
40
34
73
55
48
62
92
Trace
35
Fe3O4
SiO2
28
a
o-Phenylenediamine (1 mmol), acetone (2 mmol), and benzyl isocyanide
As indicated in Table 2, the reaction of o-phenylenediamine,
acetone, and benzyl isocyanide was also carried out in the presence
(1 mmol) at room temperature in the presence of 0.05 mmol of nanocatalyst.
b
Isolated yield.

A. Maleki / Tetrahedron 68 (2012) 7827e7833
7829
Table 3
Synthesis of diazepine-2-carboxamides 4aeo in the presence of S-MMNPs
Entry
Diamine
Ketone
Isocyanide
Benzyl
Product
Time (h)
Yielda (%)
1
o-Phenylenediamine
Acetone
5
92
97
85
98
4a
2
3
4
4,5-Dichloro-1,2-phenylenediamine
4,5-Dichloro-1,2-phenylenediamine
4-Nitro-1,2-phenylenediamine
Acetone
Acetone
Acetone
Benzyl
5
4
3
4b
Cyclohexyl
Cyclohexyl
4c
4d
4e
5
6
4-Nitro-1,2-phenylenediamine
4-Nitro-1,2-phenylenediamine
Acetone
Acetone
tert-Butyl
3
4
96
95
Benzyl
4f
7
8
4-Nitro-1,2-phenylenediamine
4-Nitro-1,2-phenylenediamine
Acetone
Acetone
2,6-Dimethylphenyl
6
5
86
93
4g
1,1,3,3-Tetramethylbutyl
4h
4i
9
3,4-Diaminobenzoic acid
3,4-Diaminobenzoic acid
Cyclohexanone
Cyclohexanone
Cyclohexyl
5
6
90
86
10
Benzyl
4j
11
4,5-Dichloro-1,2-phenylenediamine
Cyclohexanone
tert-Butyl
4
94
4k
(continued on next page)

7830
A. Maleki / Tetrahedron 68 (2012) 7827e7833
Table 3 (continued )
Entry
Diamine
Ketone
Isocyanide
Benzyl
Product
Time (h)
Yielda (%)
12
4,5-Dichloro-1,2-phenylenediamine
Cyclohexanone
4
91
4l
13
14
2,3-Diaminomaleonitrile
Acetone
Cyclohexyl
3
97
4m
2,3-Diaminomaleonitrile
2,3-Diaminomaleonitrile
Cyclohexanone
Acetophenone
tert-Butyl
4
5
90
87
4n
4o
15
Cyclohexyl
a
Isolated yield.
next round of reactions without further purification. It was shown
that the S-MMNPs catalyst could be recovered and reused in sub-
sequent reactions several times without considerable loss of cata-
lytic activity (Table 4). Thus, this process could be interesting for
large-scale synthesis.
Table 4
Reusability of Fe3O4/SiO2 nanoparticles for the synthesis of compound 4a
Run
Yielda (%)
1
2
3
4
5
6
92
91
90
88
90
89
a
Isolated yields of the subsequent runs by using the same recovered catalyst.
Scheme 2. Possible mechanism for the formation of products 4aeo.
3. Conclusion
amino group to give iminium ion 6 as favored intermediate
(Fig. 3).11e15
In summary, we have introduced a new approach for the one-
pot multicomponent synthesis of diazepine derivatives starting
from simple and readily available precursors including a 1,2-
diamine, a linear or cyclic ketone, and an isocyanide using mag-
netically recoverable Fe3O4/SiO2 nanocatalyst. This new and effi-
cient protocol for the preparation of synthetically, biologically and
pharmaceutically relevant diazepine derivatives includes some
important aspects like the easy workup procedure, reusability of
catalyst, high atom economy, excellent yields, and mild reaction
conditions.
The catalyst is very active, non-toxic, economically efficient, and
environmentally benign. One of the advantages of the heteroge-
neous catalysts is their ability to perform as a recyclable reaction
medium. The S-MMNPs were adsorbed onto the magnetic stirring
bar when the magnetic stirring was stopped. The nanoparticles
were then washed with EtOH, air-dried, and used directly for the
4. Experimental
4.1. General
All solvents, chemicals, and reagents were purchased from
Merck, Fluka and SigmaeAldrich international chemical
Fig. 3. The structure of intermediates 6 and 60.

A. Maleki / Tetrahedron 68 (2012) 7827e7833
7831
companies. Melting points were measured on an Electrothermal
9200 apparatus and are uncorrected. Mass spectra were recorded
on a Finnigan-MAT 8430 mass spectrometer operating at an ioni-
zation potential of 70 eV. IR spectra were recorded on a Shimadzu
IR-470 spectrometer. The 1H NMR spectra were recorded at
300.13 MHz on Bruker DRX-300 Avance spectrometer; chemical
br s, CH2), 4.29 (2H, m, CH2 of benzyl), 4.62 (1H, br s, NH), 5.39 (1H,
br s, NH), 6.90-7.15 (7H, m, H-Ar), 7.91 (1H, br s, NH-CO). 13C NMR
(75.47 MHz, DMSO-d6) d: 30.2, 30.5, 32.1, 43.0, 48.6, 53.2, 60.5,
119.5,119.9,121.3,127.0,127.4,128.5,137.5,138.7,140.0,175.7. MS m/
z: 393 (Mþ, 37Cl, 6), 391 (Mþ, 35Cl, 8), 259 (85), 257 (100), 203 (48),
201 (72), 166 (12), 91 (30), 65 (12), 41 (22). Anal. Calcd for
C20H23Cl2N3O: C, 61.23; H, 5.91; N, 10.71. Found C, 61.35; H, 5.80; N,
10.48.
shifts (d
scale) are reported in parts per million (ppm). 1H NMR
spectra are reported in order: number of protons, multiplicity and
approximate coupling constant (J value) in hertz (Hz); signals were
characterized as s (singlet), d (doublet), t (triplet), m (multiplet), br
s (broad signal), and Ar (aryl). The 13C NMR spectra were recorded
4.3.2. 7,8-Dichloro-N-cyclohexyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-
1H-benzo[b][1,4]diazepine-2-carboxamide 4c. Pink crystals; mp
169e172 ꢁC. IR (KBr) cmꢂ1: 3378, 3286, 3130, 3018, 2961, 2929,
2852, 1651, 1587, 1513, 1491, 1448, 1366. 1H NMR (300.13 MHz,
at 75.47 MHz; chemical shifts (d scale) are reported in parts per
million (ppm). The elemental analyses were performed with an
Elementar Analysensysteme GmbH VarioEL. TEM images were
obtained on a Philips EM208.
DMSO-d6) d: 1.04 (3H, s, CH3), 1.11 (3H, s, CH3), 1.23 (3H, s, CH3),
1.00e1.63 (11H, m, 5CH2 of cyclohexyl and 1H of CH2), 2.30 (1H, d,
J¼14.1 Hz, CH2), 3.50 (1H, m, CH of cyclohexyl), 4.67 (1H, br s, NH),
5.37 (1H, br s, NH), 6.85 (1H, s, HeAr), 6.98 (1H, s, HeAr), 7.04 (1H,
All of the products were characterized by IR, 1H NMR and 13C
NMR spectra and Mass spectral data.
d, J¼7.1 Hz, NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d: 24.5, 24.6,
25.6, 29.6, 30.2, 32.2, 32.3, 32.4, 47.8, 48.8, 53.0, 60.2, 119.8, 120.3,
121.2, 138.3, 138.7, 174.6. MS m/z: 385 (Mþ, 37Cl, 5), 391 (Mþ, 35Cl, 7),
259 (80), 257 (100), 166 (10), 55 (20), 41 (34). Anal. Calcd for
C19H27Cl2N3O: C, 59.37; H, 7.08; N, 10.93. Found C, 59.50; H, 7.23; N,
10.66.
4.2. Preparation of silica-supported Fe3O4 nanoparticles
(S-MMNPs)
Fe3O4 (<50 nm particle size (TEM), ꢀ98%) (10 mL) in water
dispersion was adjusted to pH 11 with NaOH (1 M). Then, TEOS
(2.10 mL) was added and the reaction stirred overnight. After that,
the resulted gel was heated at 60 ꢁC during 30 min. The magnetic
material was isolated by centrifugation (8000 rpm, 15 min) and
vacuum dried during 24 h to obtain the S-MMNPs.
4.3.3. N-Cyclohexyl-2,4,4-trimethyl-8-nitro-2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepine-2-carboxamide
185e187 ꢁC. IR (KBr) cmꢂ1: 3412, 3365, 3320, 3018, 2931, 2847, 1641,
1592, 1531, 1492, 1450, 1318. 1H NMR (300.13 MHz, DMSO-d6)
4d. Red
crystals;
mp
d:
0.99e1.61 (20H, m, 3CH3, 5CH2 of cyclohexyl and 1H of CH2), 2.48 (1H,
d, J¼13.7 Hz, CH2), 3.50 (1H, m, CH of cyclohexyl), 5.34 (1H, br s, NH),
6.13 (1H, br s, NH), 6.64 (1H, d, J¼8.8 Hz, HeAr), 7.06 (1H, d, J¼7.6 Hz,
HeAr), 7.51 (1H, d, J¼6.9 Hz, NHeCO), 7.70 (1H, s, HeAr). 13C NMR
4.3. Typical procedure for the synthesis of compound 4a
To a reaction tube charged with a magnetic stir bar and Fe3O4/
SiO2 nanoparticles (0.05 mmol, 5 mol %) in ethanol (5 mL), o-phe-
nylenediamine (0.108 g, 1 mmol) and acetone (0.116 g, 2 mmol)
were added. The tube was then stoppered. The reaction mixture
was stirred for 1 h at ambient temperature. After completion of the
reaction, as indicated by TLC (ethyl acetate/n-hexane, 3/1), benzyl
isocyanide (0.117 g, 1 mmol) was added to the reaction mixture.
Then, the resulting mixture was stirred for 4 h at ambient tem-
perature. After completion of the reaction, as indicated by TLC
(ethyl acetate/n-hexane, 4/1), the S-MMNPs catalyst was adsorbed
on to the magnetic stirring bar when the stirring was stopped. The
S-MMNPs were then washed with EtOH, air-dried, and used di-
rectly for the next round of reactions without further purification.
After that, the reaction solution was filtered off and the residue was
purified by washing further with water, and then crystallized from
acetone to give N-benzyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepine-2-carboxamide 4a as yellow crystals
(0.297 g, 92%): mp 136e138 ꢁC. IR (KBr) cmꢂ1: 3410, 3382, 3292,
3025, 2936, 2853, 1635, 1545, 1442. 1H NMR (300.13 MHz, DMSO-
(75.47 MHz, DMSO-d6) d: 24.5, 24.7, 25.6, 29.3, 30.8, 32.3, 32.4, 32.9,
47.2, 47.9, 53.6, 60.8, 116.0, 117.2, 118.3, 134.1, 138.1, 147.3, 174.4. MS m/z:
360 (Mþ, 5), 234 (100), 218 (12), 178 (50), 132 (45), 55 (20), 41 (30).
Anal. Calcd for C19H28N4O3: C, 63.31; H, 7.83; N, 15.54. Found C, 63.57;
H, 7.66; N, 15.28.
4.3.4. N-tert-Butyl-2,4,4-trimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo
[b][1,4]diazepine-2-carboxamide 4e. Red crystals; mp 224e226 ꢁC. IR
(KBr) cmꢂ1: 3423, 3363, 3331, 3047, 2970, 2929, 2870, 1655, 1592,
1529, 1473, 1450, 1365, 1324. 1H NMR (300.13 MHz, DMSO-d6)
d: 1.16
(9H, s, 3CH3), 1.24 (9H, s, 3CH3), 1.54 (1H, d, J¼14.3 Hz, CH2), 2.48 (1H,
d, J¼13.8 Hz, CH2), 5.38 (1H, br s, NH), 6.18 (1H, br s, NH), 6.66 (1H, d,
J¼8.8 Hz, HeAr), 6.71 (1H, br s, NH), 7.52 (1H, d, J¼8.8 Hz, HeAr), 7.68
(1H, br s, NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d: 28.6, 29.2, 30.8,
33.0, 47.2, 47.0, 50.4, 53.6, 61.2, 116.0, 117.0, 118.5, 133.8, 137.9, 147.5,
174.7. MS m/z: 334 (Mþ, 7), 234 (100), 218 (20), 178 (85), 132 (76), 57
(24), 41 (40). Anal. Calcd for C17H26N4O3: C, 61.06; H, 7.84; N, 16.75.
Found C, 60.82; H, 7.95; N, 16.48.
d6) d 1.05 (3H, s, CH3), 1.08 (3H, s, CH3), 1.28 (3H, s, CH3), 1.56 (1H, d,
J¼14.2 Hz, CH2), 2.25 (1H, d, J¼14.1 Hz, CH2), 4.12 (1H, br s, NH),
4.26e4.31 (2H, m, CH2 of benzyl), 4.98 (1H, br s, NH), 6.55e6.75
(4H, m, HeAr), 7.15e7.25 (5H, m, HeAr), 7.95 (1H, m, NHeCO). 13C
4.3.5. N-Benzyl-2,4,4-trimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo
[b][1,4]diazepine-2-carboxamide 4f. Red crystals; mp 150e152 ꢁC.
IR (KBr) cmꢂ1: 3376, 3326, 3271, 3015, 2976, 2929, 2847, 1649,
NMR (75.47 MHz, DMSO-d6) d 30.1, 30.4, 32.2, 42.9, 48.7, 52.8, 60.2,
1590, 1536, 1497, 1474, 1327. 1H NMR (300.13 MHz, DMSO-d6)
d:
119.4, 120.1, 121.6, 127.0, 127.5, 128.6, 138.2, 139.9, 176.4. MS m/z 323
(Mþ, 12), 189 (100), 133 (60), 91 (25), 65 (18). Anal. Calcd for
C20H25N3O: C, 74.37; H, 7.49; N, 12.53. Found C, 74.42; H, 7.64; N,
12.85.
1.19 (3H, s, CH3), 1.26 (3H, s, CH3), 1.34 (3H, s, CH3), 1.68 (1H, d,
J¼14.6 Hz, CH2), 2.52 (1H, d, J¼16.5 Hz, CH2), 4.17e4.64 (2H, AB-
system, JAB¼11.3 Hz, CH2 of benzyl), 6.78 (1H, d, J¼8.4 Hz, HeAr),
7.11 (3H, m, HeAr), 7.20 (3H, m, 2HeAr and NH), 7.48 (1H, d,
J¼7.2 Hz, HeAr), 7.59 (1H, d, J¼7.6 Hz, HeAr), 7.75 (1H, br s,
NHeCO), 8.09 (1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6)
d:
4.3.1. N-Benzyl-7,8-dichloro-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepine-2-carboxamide 4b Light yellow crystals; mp
194-197 ꢁC. IR (KBr) cmꢂ1: 3411, 3377, 3338, 3183, 3018, 2971, 2928,
2870, 1647, 1590, 1522, 1426, 1365. 1H NMR (300.13 MHz, DMSO-d6)
29.1, 30.4, 32.5, 40.8, 43.0, 47.0, 54.2, 61.1, 116.5, 118.4, 118.5,
126.0, 127.1, 127.5, 128.5, 128.6, 138.3, 139.3, 139.7, 175.2. MS m/z:
368 (Mþ, 3), 234 (100), 205 (30), 178 (30), 132 (35), 106 (55), 91
(40), 77 (26), 63 (24), 55 (25), 41 (70). Anal. Calcd for
d: 1.11 (6H, s, 2CH3), 1.29 (3H, s, CH3), 1.58 (1H, br s, CH2), 2.42 (1H,

7832
A. Maleki / Tetrahedron 68 (2012) 7827e7833
C20H24N4O3: C, 65.20; H, 6.57; N, 15.21. Found C, 65.52; H, 6.74;
N, 15.02.
(22), 41 (32). Anal. Calcd for C27H33N3O3: C, 72.46; H, 7.43; N, 9.39.
Found C, 72.33; H, 7.65; N, 9.44.
4.3.10. N-tert-Butyl-70,80-dichloro-10,20,30,40,4a0,50,100,11a00-octahy-
drospiro[cyclohexane-1,110-dibenzo[b,e][1,4]diazepine]-4a -carbox-
amide 4k. Colorless crystals; mp 168e170 ꢁC. IR (KBr) cmꢂ1: 3435,
3310, 3294, 3059, 2936, 2871, 1638, 1603, 1505, 1456, 1410, 1363. 1H
4.3.6. N-(2,6-Dimethylphenyl)-2,4,4-trimethyl-8-nitro-2,3,4,5-
tetrahydro-1H-benzo[b][1,4]diazepine-2-carboxamide 4g. Light red
crystals; mp 183e185 ꢁC. IR (KBr) cmꢂ1: 3408, 3318, 3095, 2967,
2924, 2847, 1663, 1619, 1593, 1578, 1525, 1504, 1426, 1370. 1H NMR
NMR (300.13 MHz, DMSO-d6) d: 1.10 (9H, s, 3CH3), 1.18e1.70 (18H,
(300.13 MHz, DMSO-d6) d: 1.25 (3H, s, CH3), 1.30 (3H, s, CH3), 1.46
m, 9CH2 of cyclohexyls), 2.28 (1H, t, J¼7.7 Hz, CH), 4.24 (1H, br s,
(3H, s, CH3), 1.73 (1H, d, J¼14.1 Hz, CH2), 1.96 (3H, s, CH3), 2.04 (3H,
s, CH3), 2.65 (1H, d, J¼14.7 Hz, CH2), 4.46 (1H, br s, NH), 5.19 (1H, br
s, NH), 6.74 (1H, d, J¼8.5 Hz, HeAr), 7.00 (3H, m, HeAr), 7.52 (1H, d,
J¼7.1 Hz, HeAr), 7.67 (1H, d, J¼8.4 Hz, HeAr), 8.73 (1H, br s,
NH), 5.30 (1H, br s, NH), 6.03 (1H, s, HeAr), 6.90 (1H, s, HeAr), 6.99
(1H, s, NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d: 21.1, 21.5, 23.9,
25.6, 26.3, 28.6, 32.9, 37.2, 48.0, 49.9, 57.6, 63.7, 116.7, 118.5, 121.0,
121.4, 136.3, 176.2. MS m/z: 418 (Mþꢂ19, 37Cl, 1), 416 (Mþꢂ19, 35Cl,
2), 338 (20), 336 (24), 295 (30), 293 (52), 240 (45), 213 (100), 200
(82), 172 (40), 107 (32), 77 (32), 65 (46), 55 (26), 41 (77). Anal. Calcd
for C23H33Cl2N3O: C, 63.01; H, 7.59; N, 9.58. Found C, 62.87; H, 7.85;
N, 9.45.
NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d: 18.3, 18.4, 29.9, 31.8,
32.5, 49.0, 53.6, 61.6, 116.1, 116.6, 118.3, 118.6, 126.6, 128.1, 135.2,
135.7, 135.9, 136.3, 137.9, 146.9, 173.4. MS m/z: 382 (Mþ, 1), 365 (5),
349 (5), 309 (45), 293 (100), 247 (70), 234 (60), 178 (42), 132 (30),
103 (14), 77 (32), 57 (15), 41 (22), 39 (24). Anal. Calcd for
C21H26N4O3: C, 65.95; H, 6.85; N, 14.65. Found C, 66.22; H, 6.69; N,
14.52.
4.3.11. N-Benzyl-70,80-dichloro-10,20,30,40,4a0,50,100,11a0-octahydrospiro
[cyclohexane-1,110-dibenzo[b,e][1,4]diazepine]-4a0-carboxamide
4l. Colorless crystals; mp 193e195 ꢁC. IR (KBr) cmꢂ1: 3392, 3339,
3094, 3029, 2929, 2853, 1623, 1589, 1518, 1492, 1452, 1351. 1H NMR
4.3.7. 2,4,4-Trimethyl-8-nitro-N-(2,4,4-trimethylpentan-2-yl)-2,3,4,5-
tetrahydro-1H-benzo[b][1,4]diazepine-2-carboxamide 4h. Yellow crys-
tals; mp 175e178 ꢁC. IR (KBr) cmꢂ1: 3431, 3346, 3311, 3018, 2964,
2871, 1645, 1592, 1517, 1499, 1479, 1453, 1366. 1H NMR (300.13 MHz,
(300.13 MHz, DMSO-d6) d: 1.00e2.00 (18H, m, 9CH2 of cyclohexyls),
2.37 (1H, m, CH), 4.06e4.28 (2H, m, CH2 of benzyl), 4.32 (1H, br s,
NH), 5.26 (1H, br s, NH), 6.80 (1H, s, HeAr), 6.90 (1H, s, HeAr),
7.18e7.26 (5H, m, HeAr), 7.95 (1H, br s, NHeCO). 13C NMR
DMSO-d6) d: 0.89 (9H, s, 3CH3), 1.17 (6H, s, 2CH3), 1.24 (9H, s, 3CH3),
1.29 (1H, d, J¼15.3 Hz, CH2), 1.51 (1H, d, J¼14.3 Hz, CH2), 1.80 (1H, d,
J¼14.6 Hz, CH2), 2.53 (1H, d, J¼14.4 Hz, CH2), 5.44 (1H, br s, NH), 6.10
(1H, br s, NH), 6.58 (1H, br s, NHeCO), 6.66 (1H, d, J¼8.8 Hz, HeAr),
7.51 (1H, dd, J¼8.7 and 1.3 Hz, HeAr), 7.69 (1H, d, J¼1.9 Hz, HeAr). 13C
(75.47 MHz, DMSO-d6) d: 21.1, 21.5, 24.5, 25.5, 26.4, 32.1, 38.0, 43.0,
48.2, 58.1, 63.6, 116.8, 117.8, 121.5, 121.9, 126.9, 127.4, 128.4, 135.2,
140.2, 177.1. MS m/z: 473 (Mþ, 37Cl, 3), 471 (Mþ, 35Cl, 5), 364 (3), 337
(100), 213 (30), 91 (38), 55 (20), 41 (25). Anal. Calcd for C26H31Cl2N3O:
C, 66.10; H, 6.61; N, 8.89. Found C, 66.28; H, 6.54; N, 8.54.
NMR (75.47 MHz, DMSO-d6) d: 28.6, 29.0, 29.1, 31.4, 31.6, 32.8, 47.0,
51.5, 53.6, 54.4, 61.3, 115.5, 117.3, 118.1, 134.2, 138.2, 147.0, 174.1. MS m/
z: 391 (Mþþ1, 10), 234 (100), 218 (12), 178 (48), 132 (46), 57 (38), 41
(40). Anal. Calcd for C21H34N4O3: C, 64.59; H, 8.78; N, 14.35. Found C,
64.82; H, 8.39; N, 14.46.
4.3.12. 2,3-Dicyano-N-cyclohexyl-5,7,7-trimethyl-4,5,6,7-tetrahydro-
1H-1,4-diazepine-5-carboxamide
169e172 ꢁC. IR (KBr) cmꢂ1: 3414, 3329, 3223, 2934, 2850, 2216, 1650,
1626, 1574, 1512, 1449. 1H NMR (300.13 MHz, DMSO-d6)
: 1.06 (3H, s,
4m. Colorless
crystals;
mp
d
4.3.8. 4a0-(Cyclohexylcarbamoyl)-10,20,30,40,4a0,50,100,11a0-octahy-
drospiro[cyclohexane-1,110-dibenzo[b,e][1,4]diazepine]-70-carboxylic
acid 4i. Colorless crystals; mp 213e214 ꢁC. IR (KBr) cmꢂ1: 3415,
3355, 3287, 3082, 2930, 2855, 1682, 1644, 1608, 1514, 1450, 1425,
CH3), 1.17 (3H, s, CH3), 1.22 (3H, s, CH3), 1.00e1.70 (10H, m, 5CH2 of
cyclohexyl), 1.56 (1H, d, J¼14.3 Hz, CH2), 2.37 (1H, d, J¼14.5 Hz, CH2),
3.51 (1H, m, CH of cyclohexyl), 5.56 (1H, br s, NH), 5.83 (1H, br s, NH),
7.27 (1H, d, J¼7.6 Hz, NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d: 24.3,
1357. 1H NMR (300.13 MHz, DMSO-d6)
d: 1.00e1.70 (28H, m, 14CH2
25.1, 25.2, 25.7, 29.5, 32.1, 32.2, 32.8, 48.6, 54.6, 61.9, 110.1, 110.4, 117.5,
117.6, 173.5. MS m/z: 315 (Mþ, 5), 258 (2), 242 (4), 189 (100), 160 (20),
133 (64), 56 (30), 43 (70). Anal. Calcd for C17H25N5O: C, 64.73; H, 7.99;
N, 22.20; found C, 64.85; H, 8.10; N, 22.09.
of cyclohexyls), 2.49 (1H, br s, 1H of CH2), 3.47 (1H, m, CH of
cyclohexyl), 4.45 (1H, br s, NH), 5.19 (1H, br s, NH), 6.21 (1H, d,
J¼8.0 Hz, HeAr), 6.72 (1H, d, J¼8.0 Hz, HeAr), 7.07 (1H, d, J¼8.0 Hz,
HeAr), 7.70 (1H, br s, NHeCO), 12.10 (1H, br s, COOH). 13C NMR
(75.47 MHz, DMSO-d6) d: 21.1, 21.5, 24.1, 24.3, 25.6, 26.4, 31.9, 32.6,
4.3.13. N-tert-Butyl-2,3-dicyano-1,4,5a,6,7,8,9,9a-octahydrospiro
[benzo[e][1,4]diazepine-5,10-cyclohexane]-9a-carboxamide
4n. White crystals; mp 170e173 ꢁC. IR (KBr) cmꢂ1: 3380, 3292,
2934, 2855, 2220, 2203, 1635, 1617, 1544, 1448. 1H NMR
32.8, 37.4, 47.0, 47.8, 57.9, 63.2,117.6,120.5,120.6,122.2,138.3,140.2,
168.2, 176.4. MS m/z: 439 (Mþ, 8), 313 (100), 189 (35), 55 (32), 41
(33). Anal. Calcd for C26H37N3O3: C, 71.04; H, 8.48; N, 9.56. Found C,
70.85; H, 8.63; N, 9.44.
(300.13 MHz, DMSO-d6) d: 1.00e2.00 (27H, m, 9CH2 of cyclohexyls
and 9H of C(CH3)3), 2.20e2.30 (1H, m, CH of cyclohexyl), 4.66 (1H,
m, NH), 5.89 (1H, m, NH), 6.98 (1H, br s, NHeCO). 13C NMR
4.3.9. 4a0-(Benzylcarbamoyl)-10,20,30,40,4a0,50,100,11a0-octahydrospiro
[cyclohexane-1,110-dibenzo[b,e][1,4]diazepine]-70-carboxylic
acid
(75.47 MHz, DMSO-d6) d: 21.1, 21.5, 23.9, 25.2, 26.0, 28.5, 32.3, 38.3,
4j. Colorless crystals; mp 213e215 ꢁC. IR (KBr) cmꢂ1: 3410, 3363,
47.9, 48.5, 59.6, 65.2, 106.1, 113.6, 117.3, 118.1, 173.2. MS m/z: 369
(Mþ, 35), 298 (25), 268 (100), 208 (20), 98 (22), 81 (14), 67 (40), 55
(60), 41 (50). Anal. Calcd for C21H31N5O: C, 68.26; H, 8.46; N, 18.95;
found C, 68.22; H, 8.40; N, 19.01.
3310, 3015, 2931, 2847, 1640, 1590, 1531, 1492, 1455, 1340. 1H NMR
(300.13 MHz, DMSO-d6) d: 1.00e2.00 (18H, m, 9CH2 of cyclohexyls),
2.41 (1H, br s, CH), 4.09 (1H, d, J¼14.3 Hz, 1H of CH2 of benzyl), 4.28
(1H, d, J¼9.2 Hz, 1H of CH2 of benzyl), 4.42 (1H, br s, NH), 5.08 (1H,
br s, NH), 6.75 (1H, d, J¼6.9 Hz, HeAr), 6.90 (2H, m, HeAr), 7.13 (5H,
m, HeAr), 7.30 (1H, br s, NHeCO), 12.03 (1H, br s, COOH). 13C NMR
4.3.14. 2,3-Dicyano-N-cyclohexyl-7-methyl-5,7-diphenyl-4,5,6,7-
tetrahydro-1H-1,4-diazepine-5-carboxamide 4o. Light yellow crys-
tals; mp 221e222 ꢁC. IR (KBr) cmꢂ1: 3350, 3258, 3054, 2929, 2859,
(75.47 MHz, DMSO-d6) d: 21.1, 21.5, 24.3, 25.6, 26.3, 32.5, 37.7, 43.0,
2217, 1570, 1543, 1513, 1451. 1H NMR (300.13 MHz, DMSO-d6)
d:
47.8, 58.1, 63.5, 118.0, 120.3, 120.7, 122.5, 126.9, 127.3, 128.4, 138.5,
139.7, 139.9, 168.2, 177.6. MS m/z: 447 (Mþ, 2), 340 (14), 313 (100),
257 (12), 204 (30), 106 (55), 91 (30), 84 (58), 66 (68), 55 (18), 48
1.10e2.00 (10H, m, 5CH2 of cyclohexyl), 2.25 (3H, s, CH3), 2.90 (1H,
d, J¼14.6 Hz, CH2), 3.85 (1H, m, CH of cyclohexyl), 4.07 (1H, d,

A. Maleki / Tetrahedron 68 (2012) 7827e7833
7833
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13. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Tetrahedron Lett. 2001, 42,
J¼14.5 Hz, CH2), 6.94e7.58 (10H, m, HeAr), 7.34 (1H, d, J¼7.6 Hz,
NHeCO), 7.96 (1H, br s, NH), 9.06 (1H, br s, NH). 13C NMR
(75.47 MHz, DMSO-d6) d: 20.8, 21.3, 25.2, 31.8, 32.1, 46.6, 50.7, 55.4,
3193.
14. Chen, W.-Y.; Lu, J. Synlett 2005, 1337.
66.2, 104.2, 110.3, 118.0, 120.5, 121.1, 125.0, 125.1, 127.5, 129.1, 129.2,
129.5, 136.5, 137.5, 139.9, 140.6, 142.7, 166.5. MS m/z: 341 (Mþꢂ98,
2), 333 (32), 318 (54), 313 (26), 272 (10), 236 (100), 209 (30), 132
(84), 105 (82), 98 (5), 91 (75), 77 (24), 65 (40), 55 (65), 43 (80). Anal.
Calcd for C27H29N5O: C, 73.78; H, 6.65; N, 15.93; found C, 73.80; H,
6.75; N, 15.82.
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The author gratefully acknowledges financial support from the
Iran National Science Foundation (INSF), the Research Council of
the Iran University of Science and Technology (IUST), and the re-
viewers for their valuable comments and suggestions.
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