One-pot multicomponent synthesis of diazepine derivatives using terminal alkynes in the presence of silica-supported superparamagnetic iron oxide nanoparticles

Article abstract of DOI:10.1016/j.tetlet.2013.01.123

A new, efficient, one-pot multicomponent reaction for the synthesis of diazepine derivatives in excellent yields is described. The reactions of various 1,2-diamines, terminal alkynes, and an isocyanide take place in the presence of a catalytic amount of m

Full text of DOI:10.1016/j.tetlet.2013.01.123

Tetrahedron Letters 54 (2013) 2055–2059
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One-pot multicomponent synthesis of diazepine derivatives using terminal
alkynes in the presence of silica-supported superparamagnetic iron
oxide nanoparticles
⇑
Ali Maleki
Department of Chemistry, Iran University of Science and Technology, 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:
A new, efficient, one-pot multicomponent reaction for the synthesis of diazepine derivatives in excellent
yields is described. The reactions of various 1,2-diamines, terminal alkynes, and an isocyanide take place
in the presence of a catalytic amount of magnetically recoverable silica-supported superparamagnetic
Fe3O4 nanoparticles in ethanol (as a green reaction medium) at ambient temperature.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 9 September 2012
Revised 14 January 2013
Accepted 30 January 2013
Available online 8 February 2013
Keywords:
Superparamagnetic
Nanocatalyst
Multicomponent reaction
Fe3O4/SiO2 nanoparticles
Diazepine
Multicomponent reactions (MCRs) and sequential transforma-
tions offer significant advantages over conventional linear-step
syntheses, by reducing time, and saving money, energy, and raw-
materials, thus resulting in both economic and environmental ben-
efits. Due to the unique reactivity of the isocyanide functional
group, isocyanide-based MCRs (IMCRs) are among the most versa-
tile in terms of the number and variety of compounds which can be
generated.1–3
As a consequence of the advantages of monodispersed and size-
controllable nanoscale magnetic materials, such as core/shell nano-
particles, highly functional materials with modified properties,
techniques, and procedures for their production have advanced
considerably. They have provided many exciting opportunities
which have led to an active exploration of magnetic nanoparticles
in a wide range of nanotechnology applications, in material chemis-
try and many other fields, such as electronics, biomedical, pharma-
ceutical, optics, and catalysis.4
deal to offer on the nanoscale, including very potent catalytic
properties.9
Biological interest in diazepines has been extended to antibiot-
ics,10,11 cancer,12 viral infection (HIV),13–15 and cardiovascular dis-
orders.16,17 Figure 1 shows the structures of the commercial
diazepine-core drugs diazepam (1), clobazam (2), and triflubazam
(3). The 1,5-benzodiazepine core is found in compounds active
against a variety of target types including peptide hormones
(4),18 interleukin-converting enzymes (5),19 and potassium block-
ers (6).17 Tetrahydro-1H-1,5-benzodiazepine derivatives with
carboxamide substituents (7) are potentially important as thera-
peutic and prophylactic agents for diabetes, diabetic nephropathy,
or glomerulosclerosis.20,21
In addition, diazepines are especially useful synthons for the
rapid construction of heterocyclic systems due to the presence of
a possible electrophilic C@N site. This structural feature could
allow the diversity-oriented synthesis22 of small libraries of diaze-
pine-based compounds for pharmacological testing toward a wide
range of biological targets.23
In the literature, the syntheses of diazepine derivatives are
reported using variations of reagents and catalysts such as the con-
densation reaction of a 1,2-diamine with various ketones in the
presence of ceric ammonium nitrate (CAN),24 Yb(OTf)3,25
Sc(OTf)3,26 SiO2/ZnCl2,27 and silica sulfuric acid,28 with alkynoates
in the presence of Ga(OTf)3,29 and also with terminal alkynes in
the presence of Hg(OTf)2.30 In addition, examples of metal-free
mild syntheses of diazepines have been disclosed in the
literature.31
Nanomaterials, especially metal nanoparticles (MNPs) and sup-
ported magnetic metal nanoparticles (S-MMNPs) have emerged as
new classes of nanocatalysts. Some important features of these cat-
alysts are simple separation using an external magnet without the
need for filtration, high catalytic activity, and a high degree of
chemical stability in various organic solvents.5–8 Iron has a great
⇑
Tel.: +98 21 77240540x50; fax: +98 21 77491204.
E-mail address: maleki@iust.ac.ir
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.123

2056
A. Maleki / Tetrahedron Letters 54 (2013) 2055–2059
O
O
O
O
N
N
N
N
O
O
N
N
Cl
O
Cl
N
Cl
F3C
NH
N
O
O
1
2
4
O
Cl
N
O
R2
N
H
N
R3
Cl
NH
R1
N
O
O
H
N
N
N
N
O
H
HO
NH
O
R4
O
R5
O
7
O
5
6
Figure 1. Some examples of medicinally and biologically important diazepine derivatives.
Due to the importance of the introduction of new, efficient, and
opens an important field involving the use of economically and
environmentally efficient nanoscale magnetic materials in organic
synthesis.
S-MMNPs were readily prepared according to the literature pro-
cedure,4–8,34–36 by the addition of water-dispersed Fe3O4 nanopar-
ticles into a basic solution of tetraethylorthosilicate (TEOS) and
stirring overnight. Next, the resulting gel was heated for 30 min
at 60 °C and the magnetic material was isolated by centrifugation,
and dried under vacuum to give the S-MMNPs, which were stable
under the employed reaction conditions.
The particle size was studied by transmission electron
microscopy (TEM) and the identification of the S-MMNPs was
based on the analysis of TEM images. The obtained TEM images
showed clearly monodispersed spherical-shaped nanoparticles
in which the Fe3O4 nanoparticles were supported on silica
(Fig. 2).
inexpensive methods for chemical transformations, and also in
continuation of our research on MCRs,32–34 herein, a new approach
for the one-pot multicomponent synthesis of diazepine derivatives
10a–h and diazepine carboxamide derivatives 12a–c, starting from
simple and readily available substrates including 1,2-diamines 8,
terminal alkynes 9, and isocyanide 11, in the presence of a catalytic
amount of silica-supported iron oxide (Fe3O4/SiO2) nanoparticles
(S-MMNPs) is reported. The reaction takes place in ethanol as a
green reaction medium at ambient temperature (Scheme 1).
This method represents a useful extension of our previous work
(Scheme 2),32–34 where a carbonyl input, such as a cyclic or acyclic
ketone, is replaced by a terminal alkyne.
To the best of our knowledge, this is the first synthesis of diaze-
pines and diazepine carboxamides using terminal alkynes cata-
lyzed by superparamagnetic MNPs via IMCRs. This new approach
R2
R2
O
H
N
Cy NC
11
R1
R1
NH2
NH2
R1
R1
+
R1
R1
N
S-MMNPs
EtOH, r.t.
2
N
H
+
N
H
10a-h
N
H
12a-c
R2
9
R2
R2
8
Product
10a
Product
12a
R1
R2
H
R1
CN
R2
H
Time (h)
4
Yield (%)
94
Time (h)
6
Yield (%)
90
CN
CH3
Br
CN
CN
12b
12c
7
7
92
83
10b
10c
10d
10e
10f
5
5
4
8
6
95
CH3
Br
CN
CN
90
H
H
92
MeO
85 (95:5)a
89
magnetic stir bar
Fe3O4
H
10g
10h
8
82 (88:12)a
70 (96:4)a
CH3
H
OH
OH
OH
OHOH
O
10
Ph
S-MMNPs
SiO2
a The regioisomeric ratio.
Scheme 1. Synthesis of diazepines 10a–h and diazepine carboxamides 12a–c in the presence of the supported Fe3O4/SiO2 nanocatalyst.

A. Maleki / Tetrahedron Letters 54 (2013) 2055–2059
2057
H
N
R1
O
R3
H
R1
R2
O
N
NC
NC
NH2
NH2
NC
NC
p-TsOH.H2O
R3 NC
R2
R2
2
+
+
H2O, r.t., 16-24 h
N
H
R1, R2 and R3 = aliphatic, alicyclic and aromatic
R1
Scheme 2. Our earlier work.32
A pilot experiment was carried out using 2,3-diaminomaleonit-
rile and phenyl acetylene via stirring in ethanol at room tempera-
ture in the presence of the Fe3O4/SiO2 nanocatalyst. The progress of
the reaction was monitored by TLC. After completion of the reac-
tion (4 h), the S-MMNP catalyst became attached to the magnetic
stir bar when the stirring was stopped. Then, the reaction solution
was filtered and the residue was purified by washing with water,
and then crystallization from ethanol to give product 10a.
Due to the reactivity of the imine site of product 10, a further
reaction could be performed in the same reaction pot. In this step,
cyclohexyl isocyanide was added to the reaction mixture and stir-
ring was continued. After completion of the reaction, removal of
Figure 2. TEM images of silica-supported Fe3O4 (S-MMNPs) at two magnifications.
R2
R2
R2
R2
R1
R1
NH2
NH2
HN
R1
R1
R1
N
R2
+
S-MMNPs
9
R1
NH2
S-MMNPs
NH2
8
S-MMNPs
13
14
R2
R2
R2
H
N
R1
R1
R1
R1
R1
R1
N
N
R2
NH2
N
H
N
H
R2
R2
S-MMNPs
14
S-MMNPs
S-MMNPs
R2
R2
R2
R2
S-MMNPs
Cy
H
N
N
C
R1
R1
Cy
N
O
R1
N
H
N
H
R1
R1
R1
R1
N
N
Cy
H2O
+
Cy
N
11
OH
R1
N
H
N
H
N
H
H
N
H
R2
R2
R2
10
15
12
R2
16
Scheme 3. Possible mechanism for the formation of products 10a–h and 12a–c.

2058
A. Maleki / Tetrahedron Letters 54 (2013) 2055–2059
the catalyst (using a magnet) and subsequent aqueous work-up
afforded compounds 12a–c in good to excellent yields. The
S-MMNP catalyst was washed with EtOH, air-dried, and used
directly in following reactions without further purification.
In the absence of S-MMNPs, only a trace of the desired product
was obtained after 24 h.
As indicated in Scheme 1, we explored the scope and limitations
of this reaction by varying the structure of the diamine 8 and phe-
nyl acetylene 9 components. The reactions proceeded very cleanly
under mild conditions at room temperature, and no undesirable
side reactions were observed.
In the case of unsymmetrical substituted diamines, inseparable
regioisomeric mixtures of 10e, 10g, and 10h were obtained. The
approximate regioisomeric ratios in each case are indicated in
Scheme 1. At present, the structures of the major and minor iso-
mers of 10e, 10g, and 10h have not been assigned.
References and notes
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All the products were characterized from 1H, 13C NMR, and IR
spectral data and elemental analysis, and in some cases, by
comparison of the melting points with those of authentic samples.
The catalyst is very active, nontoxic, economically efficient, and
environmentally benign. One of the advantages of heterogeneous
catalysts is their recyclability. It was shown that the S-MMNP cat-
alyst could be recovered and reused in subsequent reactions, sev-
eral times, and without considerable loss of the catalytic activity
(Scheme 1, product 12a: yields of the five runs using the same
recovered catalyst were 88, 86, 89, 87, and 85%, respectively). Thus,
this process could be interesting for large-scale synthesis.
A possible mechanism for the formation of products 10a–h and
12a–c is shown in Scheme 3. It is conceivable, that the initial event
is the formation of complex 13 via condensation between 1,2-dia-
mine 8 and phenyl acetylene 9 (as a keto-methyl equivalent) in the
presence of a catalytic amount of S-MMNPs.30 Next, imine–
enamine tautomerization and intramolecular cyclization of 14 via
a 1,4- or a Michael addition affords seven-membered diazepines
10a–h. On the basis of the well-established chemistry of the
reactions of isocyanides with imines,1–3,32–34 intermediate 15 was
produced by nucleophilic attack of isocyanide 11 on imine 10 fol-
lowed by nucleophilic attack of an H2O molecule on the nitrilium
moiety and production of compound 16. Finally, tautomerization
of 16 produces the diazepine carboxamide derivatives 12a–c.
In conclusion, we have introduced a new, one-pot multicom-
ponent synthesis of diazepine and diazepine carboxamide deriv-
atives starting from simple and readily available precursors
including various 1,2-diamines, terminal alkynes, and an isocya-
nide in the presence of a catalytic amount of a magnetically
recoverable Fe3O4/SiO2 nanocatalyst. This efficient protocol for
the preparation of synthetically, biologically, and pharmaceuti-
cally relevant diazepine derivatives includes some important as-
pects such as the easy work-up procedure, reusability of the
catalyst, high atom economy, excellent yields, and mild reaction
conditions.
15. Parker, K. A.; Coburn, C. A. J. Org. Chem. 1992, 57, 97.
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1998; Chem. Abstr. 1998, 129, 67837.
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19. Batchelor, M. J.; Bebbington, D.; Bemis, G. W.; Fridman, W. H.; Gillespie, R. J.;
Golec, J. M. C.; Lauffer, D. J.; Livingston, D. J.; Matharu, S. S.; Mullican, M. D.;
Murcko, M. A.; Murdoch, R.; Zelle, R. E. U.S. Patent 6423840B1, 2002; Chem.
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D. E. Patent 1820799 A1, 2007; Chem. Abstr. 2007, 147, 680386.
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22. Schreiber, S. L. Science 2000, 287, 1964.
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35. Sun, S. H.; Zeng, H. J. Am. Chem. Soc. 2002, 124, 8204.
36. Preparation of silica-supported Fe3O4 nanoparticles (S-MMNPs): Fe3O4 [<50 nm
particle size (TEM), P98%] (10 mL) as a H2O dispersion was adjusted to pH 11
with NaOH (1 M). Then, 2.10 mL of TEOS was added and the mixture was
stirred overnight. The resulting gel was heated at 60 °C over 30 min. The
magnetic material was isolated by centrifugation (8000 rpm, 15 min) and dried
under vacuum over 24 h to obtain the S-MMNPs.
General procedure for the synthesis of compounds 10a–h: To a reaction tube
containing a magnetic stir bar and Fe3O4/SiO2 nanoparticles (5 mol %) in 5 mL
of EtOH, 1,2-diamine 8 (1 mmol) and a terminal alkyne 9 (2 mmol) were added.
The reaction mixture was stirred at ambient temperature for the appropriate
time. After completion of the reaction, as indicated by TLC (EtOAc/n-hexane, 3/
1), stirring was stopped and the S-MMNP catalyst became attached to the
magnetic stir bar. The S-MMNPs were then washed with EtOH, air-dried, and
used directly for subsequent reactions without further purification. The
reaction solution was filtered and the residue purified by washing with H2O,
and then crystallized from EtOH to give products 10a–h.
Acknowledgements
The author gratefully acknowledges the financial support from
the Iran National Science Foundation (INSF), the Research Council
of the Iran University of Science and Technology (IUST), and the
reviewer for valuable comments and suggestions.
Typical procedure for the synthesis of compound 12a: To
a reaction tube
Supplementary data
containing a magnetic stir bar and Fe3O4/SiO2 nanoparticles (5 mol %) in 5 mL
of EtOH, 2,3-diaminomaleonitrile (0.108 g, 1 mmol) and phenyl acetylene
(0.205 g, 2 mmol) were added. The mixture was stirred for 4 h at ambient
temperature. After completion of the reaction, as indicated by TLC (EtOAc/n-
hexane, 3/1), cyclohexyl isocyanide (0.109 g, 1 mmol) was added. The resulting
mixture was stirred for 6 h at ambient temperature. After completion of the
reaction, as indicated by TLC (EtOAc/n-hexane, 4/1), stirring was stopped and
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.123. These data include MOL files and InChiKeys of the most
important compounds described in this article.

A. Maleki / Tetrahedron Letters 54 (2013) 2055–2059
2059
the S-MMNP catalyst became attached to the magnetic stir bar. The S-MMNPs
were then washed with EtOH, air-dried, and used directly for subsequent
reactions without further purification. The reaction solution was filtered and
the residue purified by washing with H2O, and then crystallized from acetone
to give product 12a.
8.32. 12a: Yellow crystals; mp 221–223 °C. IR (KBr) cmÀ1: 3352, 3256, 3054,
2927, 2859, 2217, 1570, 1543, 1513, 1451. 1H NMR (300 MHz, DMSO-d6) d:
1.00–2.00 (10H, m, 5CH2 of cyclohexyl), 2.25 (3H, s, CH3), 2.90 (1H, d,
J = 14.6 Hz, CH2), 3.85 (1H, m, CH of cyclohexyl), 4.07 (1H, d, J = 14.5 Hz, CH2),
6.94–7.58 (10H, m, H-Ar), 7.34 (1H, d, J = 7.6 Hz, NH–CO), 7.96 (1H, br s, NH),
9.06 (1H, br s, NH). 13C NMR (75 MHz, DMSO-d6) d: 20.8, 21.3, 25.2, 31.8, 32.1,
46.6, 50.7, 55.4, 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. Anal. Calcd for
Spectral data for selected products:
Compound 10d: Light yellow crystals; mp 150–151 °C; IR (KBr) cmÀ1: 3332,
1637, 1598, 1426. 1H NMR (300 MHz, CDCl3), d: 1.70 (3H, s, CH3), 2.95 (1H, d,
J = 13.2 Hz, CH2), 3.15 (1H, d, J = 13.2 Hz, CH2), 3.35 (1H, br s, NH), 6.65–7.10
(2H, m, C6H4), 7.25–7.48 (10H, m, C6H5), 7.55–7.68 (2H, m, C6H4). 13C NMR
(75 MHz, CDCl3), d: 29.7, 41.4, 74.3, 121.6, 122.0, 125.4, 126.7, 127.3, 127.4,
128.3, 128.5, 128.8, 129.6, 138.1, 139.2, 140.6, 145.3, 166.3. Anal. Calcd for
C27H29N5O: C, 73.78; H, 6.65; N, 15.93; Found: C, 73.81; H, 6.72; N, 15.85.
Compound 12b: Yellow crystals; mp 210–212 °C. IR (KBr) cmÀ1: 3352, 3255,
3053, 2927, 2857, 2218, 1578, 1542, 1513, 1454. 1H NMR (300 MHz, DMSO-d6)
d: 1.10–2.00 (10H, m, 5CH2 of cyclohexyl), 1.66 (3H, s, CH3), 2.12 (3H, s, CH3),
2.26 (3H, s, CH3), 2.89 (1H, d, J = 14.4 Hz, CH2), 3.86 (1H, m, CH of cyclohexyl),
4.07 (1H, d, J = 14.3 Hz, CH2), 6.90–7.60 (8H, m, H-Ar), 7.56 (1H, d, J = 7.2 Hz,
NH–CO), 7.96 (1H, br s, NH), 9.07 (1H, br s, NH). 13C NMR (75 MHz, DMSO-d6) d:
20.8, 21.0, 21.3, 25.3, 25.4, 31.6, 31.8, 32.1, 46.6, 50.7, 55.4, 66.2, 104.2, 110.3,
115.5, 120.5, 121.1, 125.1, 127.5, 128.9, 129.1, 129.2, 129.5, 129.7, 136.5, 137.5,
140.6, 142.7, 153.5, 166.5. Anal. Calcd for C29H33N5O: C, 74.49; H, 7.11; N,
14.98; Found: C, 74.55; H, 7.28; N, 14.80. Compound 12c: Yellow crystals; mp
202–205 °C. IR (KBr) cmÀ1: 3350, 3250, 3063, 2929, 2859, 2223, 1550, 1544,
1485, 1453. 1H NMR (300 MHz, DMSO-d6) d: 0.83–2.07 (10H, m, 5CH2 of
cyclohexyl), 1.70 (3H, s, CH3), 2.90 (1H, d, J = 14.3 Hz, CH2), 3.84 (1H, m, CH of
cyclohexyl), 4.12 (1H, d, J = 14.0 Hz, CH2), 7.07–8.04 (10H, m, 8H-Ar, NH–CO
and NH), 9.23 (1H, br s, NH). 13C NMR (75 MHz, DMSO-d6) d: 25.2, 25.6, 25.7,
31.2, 31.8, 32.1, 46.3, 50.8, 55.4, 66.9, 104.2, 111.9, 115.3, 120.1, 120.7, 121.5,
124.7, 127.5, 127.6, 129.4, 131.4, 131.6, 132.0, 138.0, 142.4, 144.7, 165.6. Anal.
Calcd for C27H27Br2N5O: C, 54.29; H, 4.56; N, 11.72; Found: C, 54.35; H, 4.40; N,
11.84.
C
22H20N2: C, 84.58; H, 6.45; N, 8.97; Found; C, 84.62; H, 6.40; N, 8.86. 10e:
Light yellow crystals; mp 123–124 °C; IR (KBr) cmÀ1: 3340, 1620, 1585, 1436.
1H NMR (300 MHz, CDCl3), d (major regioisomer): 1.76 (3H, s, CH3), 2.96 (1H, d,
J = 13.2 Hz, CH2), 3.18 (1H, d, J = 13.2 Hz, CH2), 3.45 (1H, br s, NH), 3.77 (3H, s,
OCH3), 6.35 (1H, d, J = 1.9 Hz, C6H3), 6.62 (1H, dd, J = 8.0, 1.9 Hz, C6H3), 7.10–
7.63 (11H, m, C6H3 and 2C6H5). 13C NMR (75 MHz, CDCl3),
d (major
regioisomer): 29.5, 42.3, 54.4, 74.2, 104.8, 109.4, 123.6, 126.5, 127.2, 127.6,
128.1, 128.5, 128.8, 129.6, 137.3, 145.3, 146.3, 161.2, 165.3. Anal. Calcd for
C
23H22N2O: C, 80.67; H, 6.48; N, 8.18; Found: C, 80.54; H, 6.42; N, 8.21.
Compound 10f: Light yellow crystals; mp 115–116 °C; IR (KBr) cmÀ1: 3290,
1615, 1548, 1442, 1360. 1H NMR (300 MHz, CDCl3), d: 1.70 (3H, s, CH3), 2.24
(6H, s, 2CH3), 2.95 (1H, d, J = 13.2 Hz, CH2), 3.12 (1H, d, J = 13.2 Hz, CH2), 3.38
(1H, br s, NH), 6.60 (1H, s, C6H2), 7.10 (1H, s, C6H2), 7.15–7.61 (10H, m, C6H5).
13C NMR (75 MHz, CDCl3), d: 18.6, 19.3, 29.6, 43.1, 75.1, 122.3, 125.4, 126.8,
126.9, 127.8, 128.2, 129.5, 129.6, 129.7, 134.8, 135.8, 137.7, 139.8, 147.7, 166.8.
Anal. Calcd for C24H24N2: C, 84.67; H, 7.11; N, 8.23; Found: C, 84.63; H, 7.06; N,