Highly efficient zinc oxide nanoparticles catalyzed green synthesis of 1,5-benzodiazepines under solvent-free path

Article abstract of DOI:10.14233/ajchem.2014.18319

An efficient and simple environment-friendly method for the preparation of substituted 1,5-benzodiazepines as biologically interesting compounds under heterogenous catalyst is described. The one-pot multicomponent condensation of o-phenylene-diamine and s

Full text of DOI:10.14233/ajchem.2014.18319

Asian Journal of Chemistry; Vol. 26, No. 24 (2014), 8539-8542
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.18319
Highly Efficient Zinc Oxide Nanoparticles Catalyzed Green
Synthesis of 1,5-Benzodiazepines under Solvent-Free Path
1
2
3
4,*
3,*
YUHAO ZHAO , XUEJIE YU , MANPREET SAINI , YANXU MA and RAJESH K. SINGH
1
2
3
4
School of Traditional Chinese Medicine, Capital Medical University, 100069 Beijing, P.R. China
Beijing University of Chinese Medicine, 100029 Beijing, P.R. China
Department of Pharmaceutical Chemistry, Shivalik College of Pharmacy, Nangal-140 126, India
Department of Orthopedics, Beijing Traditional Chinese Medicine Hospital, Capital Medical University, Beijing 100010, P.R. China
Corresponding authors: E-mail: rksingh244@gmail.com; yanxumabjtcm@126.com
Received: 13 June 2014; Accepted: 4 September 2014; Published online: 1 December 2014;
*
AJC-16398
An efficient and simple environment-friendly method for the preparation of substituted 1,5-benzodiazepines as biologically interesting
compounds under heterogenous catalyst is described. The one-pot multicomponent condensation of o-phenylene-diamine and substituted
ketones catalyzed by zinc oxide nanoparticles (ZnO NPs) under microwave under solvent-free condition has been developed. The present
protocol provides a green and improved pathway for the synthesis of 1,5-benzodiazepines in terms of excellent yields, short reaction
times and reusability of catalyst.
Keywords: 1,5-Benzodiazepines, Zinc oxide nanoparticles, Heterogenous catalyst.
6
reverse transcriptase) and cardiovascular diseases . Many of
INTRODUCTION
7
-9
the methods reported for the synthesis of these compounds
Multicomponent coupling reaction (MCR) is one of the
important and powerful green chemistry tools for the synthesis
are associated with the minor limitations like tedious work up
procedure, the necessity of neutralization of strong acidic
media, producing undesired washes, long reaction times, un-
satisfactory yields, require separation of the catalyst from the
product and formation of side products.
1,2
of wide varieties of biologically active medicinal compounds .
Another important aspect of green chemistry is the elimination
of solvents in chemical processes or the replacement of hazar-
dous solvents with relatively benign solvents. Some natural
active constituents extracted from herbs such as polygala,
platycladi seed and cortex albiziae have sedative effects, but
the extracting process costs great energy and fund, and so an
advanced synthesis is needed. Development of such multi-
component coupling reaction strategies under solvent-free
condition has been of considerable interest, as they provide
simple and rapid access to a large number of organic molecules
through a sustainable path.
Catalyst has played a vital role in the success of the
10
chemical industry . The use of transition-metal nanoparticles
in catalysis is decisive as they mimic metal surface activation
and catalysis at the nanoscale and thereby bring selectivity
11
and efficiency to heterogeneous catalysis . Among transition-
metal nanoparticles, zinc oxide nanoparticles (ZnO NPs) have
been of considerable interest because of the role of ZnO in
solar cells, catalysts, antibacterial materials, gas sensors,
1
2
luminescent materials, and photocatalyst . The recent literature
survey reveals that ZnO nanoparticles as a heterogeneous cata-
lyst has received considerable attention because it is inexpen-
Benzodiazepines are widely used class of bioactive com-
pounds that show interesting features, making them attractive
targets for multicomponent coupling reactions. Among
different types of the benzodiazepine class, 1,5-benzodia-
zepines are of particular interest as they belong to privileged
medicinal scaffolds serving for the generation of medicinal
compounds having pronounced central nervous system (CNS),
antiinflammatory, antifeedant, antibacterial and analgesic
1
3-17
sive, nontoxic and environment-friendly properties
In continuation of our previous studies on exploration of
.
18
various methods and catalysts in organic transformations ,
herein, we report a highly efficient, green and solvent-free
protocol for the one-pot multi-component synthesis of 1,5-
benzodiazepines using ZnO nanoparticles (Scheme-I). It is
noteworthy that this work has none of the above-mentioned
drawbacks at all. To the best of our knowledge, there is no
report available in the literature describing the use of ZnO
3-5
activities . The current interest in 1,5-benzodiazepine deriva-
tives arise from their potential application in the treatment of
cancer, viral infection (on-nucleoside inhibitors of HIV-1

8
540 Zhao et al.
Asian J. Chem.
nanoparticles as catalysts for the synthesis of 1,5-benzodia-
zepines. The effectiveness of the process was studied by
comparing the results obtained with and without catalyst under
normal conditions.
2,3-Dihydro-2-methyl-2,4-diphenyl-1H-1,5-benzodia-
-1
zepine: (entry 1) IR (KBr, νmax, cm ): 3277 (sec N-H), 3061
(aromatic C-H), 2972 (aliphatic C-H), 1559 (aromatic C=C);
1
H NMR (CDCl
.2 (d, 1H, -CH), δ 6.8-7.7 (m, 14H, ArH); Anal. Calcd. for
C H N : C, 84.58; H, 6.45; N, 8.97; found: C, 84.60; H, 6.42;
3
): δ 1.8 (s, 3H, -CH ), δ 3.1 (d, 1H, -CH), δ
3
3
R1
H
2
2
20
2
R
NH2
N
N
R
2
O
R
ZnO NPs
N, 8.94.
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine:
R3
NH2
R
1
R
2
R
4
-1
R = H, CH3, NO2
(entry 3) IR (KBr, νmax, cm ): 3292 (NH), 2955 (aromatic CH),
1
1
632 (alkene C=C), 1474 (aromatic C=C); H NMR (CDCl
δ 1.3 (s, 6H, -C(CH ), δ 2.2 (s, 2H, -CH ), δ 2.4 (s, 3H,
), δ 6.7-7.2 (m, 4H, ArH); Anal. Calcd. for C12 : C,
6.55; H, 8.57; N, 14.88; found: C, 76.51; H, 8.52; N, 14.92.
0-Spirocycloheptan-6,7,8,9,10,10a,11,12-octahydro-
benzo[b]cyclohepta[e][1,4] diazepine: (entry 6) IR (KBr, νmax
3
):
(
)
n
R
NH
NH
2
2
R
1
3
)
2
2
H
N
O
ZnO NPs
R
R2
-
CH
3
16 2
H N
R
3
7
n= 2,3
N
R
4
n
R = H, CH3, NO
2
1
Scheme-I:Chemical reaction for the synthesis of 2,3-dihydro-1H-1,5-
,
benzodiazepines using zinc oxide nanoparticles
-1
cm ): 3328 (sec. NH), 3060 (aromatic CH), 2923 (alkene CH),
2
852 (alkane CH), 1617 (imine C=N), 1493 (aromatic C=C).
1
EXPERIMENTAL
H NMR (CDCl
H, -CH ), δ 2.8 (m, 1H, -CH), δ 6.6-7.4 (m, 4H, ArH); Anal.
Calcd. for C20 : C, 81.03; H, 9.52; N, 9.45; found: C,
1.15; H, 9.56; N, 9.54.
,2,4-Trimethyl-2,3-dihydro-8-methyl-1H-1,5-benzo-
3
): δ 1.5-2.4 (m, 21H, -CH
2
, -NH), δ 2.6 (m,
2
2
The melting points were determined on Veego-program-
mable melting point apparatus (microprocessor based) and are
1
uncorrected. Proton ( H) nuclear magnetic resonance spectra
28 2
H N
8
2
were obtained using BruckerAC-400 F, 400 MHz spectrometer
and are reported in parts per million (ppm), downfield from
tetramethylsilane (TMS) as internal standard Infrared (IR)
spectra were obtained with Perkin Elmer 882 Spectrum and
-1
diazepine: (entry 7) IR (KBr, νmax, cm ): 3454 (sec. NH), 2924
(
(
(
-
aromatic CH), 2854 (alkane CH), 1437 (aromatic C=C), 1237
1
C-N), 946 (1,2,4-substituted oop); H NMR (CDCl
s, 6H, -CH ), δ 1.35 (s, 3H, -CH ), δ 2.3 (m, 5H, -CH
CH), δ 6.5 (s, 1H, ArH), δ 6.79 (d, 1H, J = 7.4,ArH), δ 7.0 (d,
3
): δ 1.2
3
3
3
, -CH,
-1
RXI, FT-IR model using potassium bromide pellets (in cm ).
Elemental analyses for C, H, and N were performed on Perkin-
Elmer 2400 CHN elemental analyzer. X-ray diffraction of
nanoparticles were obtained using X-ray diffractometer,
1
H, J = 8.7, ArH); Anal. Calcd. for C13
.97; N, 13.85; found: C, 77.22; H, 8.91; N, 13.93.
1-Spirocyclohexane-2,3,4,10,11,11a-hexahydro-8-
methyl-1H-dibenzo[b,e][1,4] diazepine: (entry 9) IR (KBr,
18 2
H N : C, 77.17; H,
8
1
α
Panlytical X' pert Pro and (CuK ) radiations were used. TEM
images were obtained from Transmission Electron Microscope,
Hitachi H-7500 with 0.204 nm resolution and 6,00,000X
magnification. Reactions were monitored and the homogeneity
of the products was checked by TLC, which were prepared
with silica gel G and activated at 110 °C for 0.5 h. The plates
were developed by exposure to iodine vapours. Anhydrous
sodium sulphate was used as a drying agent.
-1
ν
max, cm ): 3351 (sec. NH), 2931 (alkene CH), 2857 (alkane
1
CH), 1633 (imine C=N), 1484 (aromatic C=C); H NMR
CDCl ): δ 1.7-2.5 (m, 18H, -CH ), δ 3.0 (s, 3H, -CH ), δ 3 (t,
H,-CH), δ 7.3-7.9 (m, 3H, ArH); Anal. Calcd. for C19
C, 80.80; H, 9.28; N, 9.92; found: C, 80.86; H, 9.34; N, 9.98.
,2,4-Trimethyl-2,3-dihydro-8-nitro-1H-1,5-benzodia-
(
3
2
3
1
26 2
H N :
2
-1
1
zepine: (entry 11) IR (KBr, νmax, cm ): 3280, 1645, 1600. H
NMR (CDCl ), δ ppm: δ 1.90 (s, 6H), 2.95 (s, 3H), 3.20 (s,
H), 7.18 (s, 1H), 8.0-8.10 (m, 1H), 8.5-8.9 (m, 1H); Anal.
Calcd. for C12 : C, 61.78; H, 6.48; N, 18.01 %; found:
C, 61.85; H, 6.66; N, 18.12 %.
Synthesis of ZnO nanoparticles: Zinc oxide nanopar-
ticles are prepared according to the literature method with some
3
2
19
modifications . Zinc acetate (9.10 g, 0.05 mol) and oxalic
acid (5.4 g, 0.06 mol) were combined by grinding in a mortar
15 3 2
H N O
2 4 2
for 1 h at room temperature. The formed ZnC O .2H O nano-
particles were subjected to microwave irradiation at 150 W
microwave power for 20 min to produced ZnO nanoparticles
under thermal decomposition conditions (yield: 75 %).
General procedure for the preparation of 2,3-dihydro-
RESULTS AND DISCUSSION
Initially we studied the influence of ZnO nanoparticles
for the synthesis of 1,5-benzodiazepine using o-phenylened-
iammine and acetophenone as a model reaction and varying
the amount of ZnO nanoparticles by simple optimization study
1H-1,5-benzodiazepines: o-Phenylenediamine (1 mmole) and
ZnO nanoparticles (20 mol % or 0.2 mmole) were crushed in
mortar and pestle to a fine powder and transferred to a china
dish and various ketone (2.2 mmole) was added. The reaction
mixture was heated on oil bath for 40-60 min with occasional
stirring. After completion of the reaction (monitored by TLC),
the reaction mixture was cooled to room temperature and ethyl
acetate was added. The catalyst was insoluble in ethyl acetate
and it could therefore be separated by a simple filtration. The
filtrate was collected, dried and residue was recrystallized from
ethanol or subjected to column chromatography to get the pure
products.
(
Table-1). The catalyst quantity was optimized to 20 mol % of
ZnO nanoparticles and excellent results (93 % yields) were
achieved. Similarly, another 1,5-benzodiazepine derivatives
have been synthesized from o-phenylenediamines and ketones
in 85-93 % yields (Table-2). It seems that high surface area
and better dispersion of nanoparticles in the reaction mixture
are reasons for better activities of ZnO nanoparticles. The
catalytic activity of ZnO nanoparticles was evident when no
product was obtained in the absence of the catalyst.

Vol. 26, No. 24 (2014)
Zinc Oxide Nanoparticles Catalyzed Green Synthesis of 1,5-Benzodiazepines 8541
of the attached methyl group then occurs to form an isomeric
TABLE-1
OPTIMIZATION OF CONCENTRATION OF ZINC OXIDE
enamine B, which cyclize to afford seven membered ring with
the generation of catalyst.
NANOPARTICLES FOR THE SYNTHESIS OF 2,3-DIHYDRO-1H-
1
a
,5-BENZODIAZEPINES UNDER SOLVENT-FREE CONDITION .
The XRD pattern of ZnO nanoparticles is shown in Fig. 1.
The particle size was calculated from X-ray diffraction images
of ZnO nanoparticles using Scherrer formula as follows:
b
Yield (%)
Entry Amount of catalyst mol (%) Time (min)
1
2
3
5.0
60
60
60
60
60
78
10.0
15.0
20.0
25.0
83
88
93, 90, 85, 85
93
Kλ
d =
c
4
βCos θ
5
a
Reaction conditions: o-phenylenediammine, acetophenone and
where d is the average particle size perpendicular to the
reflecting planes, K is a grain shape dependent constant (0.9),
λ is the X-ray wavelength, β is the full width at half maximum
b
catalyst; Isolated yields; Catalyst was recycled three times
c
To examine the reusability, the catalyst was recovered by
filtration from the reaction mixture after dilution with ethyl
acetate, washed with methanol, dried at 100 °C for 5 h and
reused as such for the model reaction using ZnO nanoparticles
(
FWHM), and θ is the diffraction angle. The average size of
ZnO nanoparticles obtained from the XRD is about 40 nm,
using the Scherrer formula.
(
20 %) under optimized conditions (up to three cycles). It was
1
0
8
6
4
2
0
observed that the yields of the product remained comparable
in these experiments (Table 1, entry 4) which established the
recyclability and reusability of the catalyst without any signi-
ficant loss of activity.
In order to determine the catalytic behavior of ZnO
nanoparticles, the possible mechanism of the reaction is shown
in Scheme-II. To the best of our knowledge, ZnO nanoparticles
catalyzed the reaction by the activations of both reactants
10
20
30
(°)
40
50
2+
2-
through both Lewis acids (Zn ) and basic sites (O ). At one
place, ZnO nanoparticles initiated electrophilic activation of
the carbonyl groups of ketones by coordinated to oxygen
2θ
Fig. 1. XRD Pattern of ZnO nanoparticles
2+
through Lewis acid sites (Zn ) making them susceptible to
nucleophilic attack by amines (activated by Lewis basic sites
The TEM image of ZnO nanoparticles is shown in Fig. 2.
As can be seen, the sample has a nanocrystalline structure
with a spherical shape that were gained from zinc acetate and
2
-
(
O ) giving the intermediate diimine A. A 1,3-hydrogen shift
Activate the electrophilicity
ZnO NPs
O
R
R
1,3- hydr ogen
shif t
NH2
N
N
N
CH 3
R
CH3
CH3
R
CH2
NH2
Zinc oxide NPs
N
H
CH2
R
H
A, Diimine
B, Enamine
ZnO NPs
Activate the nucleophilicity
Intr amolecular imine
enamine cyclization
R
H
N
R
CH3
N
CH 3
Regener ation
N
R
N
H
R
Substitut ed
,5-benzodiazepines
ZnO NPs
1
Scheme-II: Proposed mechanism and possible intermediates

8
542 Zhao et al.
Asian J. Chem.
TABLE-2
CONDENSATION OF o-PHENYLENEDIAMINE WITH VARIOUS KETONES CATALYZED BY ZINC OXIDE NANOPARTICLES
lit
m.p. (°C)
Entry
R
H
R1
R2
R3
H
H
H
H
R4
Yield (%)
Time (min)
m.p. (°C)
149-150
97-99
10
1
2
3
4
5
6
7
8
9
C H5
6
CH3
CH3
CH3
C H
6
93
89
90
85
88
87
90
88
92
88
92
60
50
40
45
40
45
50
60
60
55
45
151-152
6
98-99
5
H
CH C H
3
CH C H
5
6
5
3
6
1
1
1
1
1
0
0
1
1
1
H
CH3
CH3
CH3
CH3
138-139
137-139
137-138
133-134
126-128
91-92
137-139
137-138
138-139
136-139
127-128
H
C H5
2
H
-(CH ) -
2
-(CH ) -
2 4
5
H
-(CH ) -
2
-(CH ) -
2 5
6
CH3
CH3
CH3
CH3
NO2
CH3
CH3
CH3
H
H
CH3
C H
1
2
C H5
6
92-93
6
5
1
2
2
-(CH ) -
2
-(CH ) -
2 4
140-142
121-122
115-117
142-143
124-125
5
1
1
1
0
1
-(CH ) -
2
-(CH ) -
2 5
6
CH3
CH3
H
CH3
114-116
Municipalit (No. Z111107058811056); Planned Project on
Beijing Traditional Chinese Medicine "inheritance of 3+3
programme" of Beijing Chinese MedicineAdministration Bureau
(
2011-SZ-C-34).
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ACKNOWLEDGEMENTS
The authors are thankful to Principal and Managing
Committee, Shivalik College of Pharmacy, Nangal, India for
providing the laboratory facilities. The authors are also thankful
to Panjab University, Chandigarh, India for cooperation for
spectral data. The Y.Z. and Y.M. thankful for research grant
supported by Capital Application Project on Clinical Chara-
cteristics of Science and Technology Commission of Beijing
1
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j.arabjc.2013.06.030.