Nano copper(II) oxide catalyzed four-component synthesis of functionalized benzo[a]pyrano[2,3-c]phenazine derivatives

Article abstract of DOI:10.1016/j.crci.2012.09.012

An efficient one-pot quantitative procedure for the preparation of functionalized benzo[a]pyrano[2,3-c]phenazine derivatives from four-component reaction of 2-hydroxynaphthalene-1,4-dione, o-phenylenediamine, aldehydes, and malononitrile in the presence o

Full text of DOI:10.1016/j.crci.2012.09.012

C. R. Chimie 15 (2012) 1055–1059
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Full paper/Memoire
Nano copper(II) oxide catalyzed four-component synthesis of
functionalized benzo[a]pyrano[2,3-c]phenazine derivatives
*
Hamid Reza Shaterian , Farzaneh Moradi, Majid Mohammadnia
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient one-pot quantitative procedure for the preparation of functionalized
benzo[a]pyrano[2,3-c]phenazine derivatives from four-component reaction of 2-hydro-
xynaphthalene-1,4-dione, o-phenylenediamine, aldehydes, and malononitrile in the
presence of nano CuO as the catalyst has been developed. The copper(II) oxide
nanoparticles can be recovered and reused several times without loss of its activity.
ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Received 11 May 2012
Accepted after revision 25 September 2012
Available online 8 November 2012
Keywords:
2-Hydroxynaphthalene-1,4-dione
O-phenylenediamine
Aldehydes
Malononitrile
Nano CuO
Catalyst
1. Introduction
The designs of multi-component reactions (MCRs) for
the synthesis of diverse groups of compounds, especially
Nanomaterials have attracted a great deal of attention
in organic synthesis owing to their high surface-to-volume
ratio, which are responsible for the higher catalytic activity
[1].
The catalytic activity of nano CuO and its green
chemistry exhibits good reusability, simple workup
procedure and a straightforward approach to use in
organic synthesis [2–4].
the ones that are biologically active, have commanded
great attention in green organic synthesis [17–19]. In
continuation of our research on multi-component reac-
tions [20–22], herein we wish to describe the preparation
of functionalized benzo[a]pyrano[2,3-c]phenazine deriva-
tives with phenazines and chromenes moieties from a
four-component reaction of 2-hydroxynaphthalene-1,4-
dione, o-phenylenediamine, aldehydes, and malononitrile
in the presence of nano copper(II) oxide as the catalyst
under thermal solvent-free conditions (Scheme 1).
Phenazines are present in natural and synthetic
products showing
a variety of biological functions,
including antimalarial, trypanocidal, fungicidal, antitumor,
and antiplatelet activities [5–9]. Chromenes have been
showed remarkable effects as pharmaceuticals [10,11],
including antifungal [12,13] and antimicrobial activities
[14]. Molecules with phenazines [15] and chromenes [16]
moieties have attracted great attention in drug discovery.
2. Results and discussion
First, to find optimization conditions, the one-pot four-
component reaction of 2-hydroxynaphthalene-1,4-dione,
o-phenylenediamine, 4-chlorobenzaldehyde and malono-
nitrile in the presence of the nano copper(II) oxide as
catalyst was selected as model. 2-Hydroxynaphthalene-
1,4-dione (1 mmol) and o-phenylenediamine (1 mmol)
were mixed at 75 8C until a orange solid of benzo[a]phe-
nazine was formed (< 5 min) without using any catalyst
* Corresponding author.
E-mail address: hrshaterian@chem.usb.ac.ir (H.R. Shaterian).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.09.012

1056
H.R. Shaterian et al. / C. R. Chimie 15 (2012) 1055–1059
O
O
NH2
HO
NH2
Catalyst-Free, 75 oC
Solvent-Free
+
N
OH
N
NH2
CN
Ar
O
O
N
CN
CN
+
Ar
H
N
Nano CuO (Catalyst), 75 oC
Solvent -Free
Scheme 1. Synthesis of 3-amino-2-cyano-1-aryl-1H-benzo[a]pyrano[2,3-c]phenazines derivatives.
Table 1
Optimization conditions for preparation 3-amino-2-cyano-1-(4-chlorophenyl)-1H-benzo[a]pyrano[2,3-c]phenazine from 2-hydroxynaphthalene-1,
4-dione, o-phenylenediamine, 4-chlorobenzaldehyde, and malononitrile in the presence of different amount of nano copper(II) oxide as catalyst in
varieties temperature.
Entry
Catalyst (mol%)
Temperature ( 8C)
Time (min)
Yield (%)a
1
2
3
4
5
6
25
15
25
5
25
50
50
75
75
75
30
30
28
12
7
Trace
35
50
83
10
15
94
7
95
a
Yields refer to isolated pure product.
under solvent-free conditions. Then, 4-chlorobenzalde-
hyde (1 mmol), malononitrile (1 mmol), and nano cop-
per(II) oxide as catalyst was added and stirred under
thermal conditions. The reaction was carried out with
different amount of nano copper(II) oxide as catalyst (5, 10,
15, 25 mol%) at various temperatures (25, 50, 75 8C) (Table
1). As it was shown from Table 1, 10 mol% of nano
copper(II) oxide as catalyst at 75 8C afforded 3-amino-2-
cyano-1-(4-chlorophenyl)-1H-benzo[a]pyrano[2,3-
c]phenazine in 7 min with 94% of yield.
Next, four-component condensation reaction of 2-
hydroxynaphthalene-1,4-dione, o-phenylenediamine, ar-
omatic aldehydes, and malononitrile under solvent-free
conditions for preparation of 3-amino-2-cyano-1-aryl-1H-
benzo[a]pyrano[2,3-c]phenazines was investigated (Table
2). The wide ranges of substituted and structurally diverse
aldehydes afforded the corresponding products in high to
excellent yields using the nano copper(II) oxide as catalyst
(Table 2). Aliphatic aldehyde such as heptanal was intact in
this reaction (Table 2, Entry 13).
Table 2
Four-component synthesis of 3-amino-2-cyano-1-aryl-1H-benzo[a]pyrano[2,3-c]phenazine derivatives from the reaction of 2-hydroxynaphthalene-1,
4-dione, o-phenylenediamine, malononitrile and aldehydes in the presence of nano copper(II) oxide as catalyst.
Entry
Aldehydes
Time (min)
Yield (%)a
Melting Point
m.p. ( 8C)/Lit. m.p. ( 8C) [Ref]
1
Ph
8
92
90
93
91
94
89
89
90
91
90
90
91
–
301–302/(298–300) [23]
282–283/(281–283) [23]
276–277/(274–276) [23]
285–286/(283–285) [23]
290–291/(288–291) [23]
280/(278–279) [23]
248–249/(247–248) [23]
292/(290–291) [23]
253–254/(252–254) [23]
293–295/(293–294) [23]
273/(270–272) [23]
295/(292–294) [23]
–
2
4-NO2C6H4
4-FC6H4
8
3
7
4
4-BrC6H4
7
5
4-ClC6H4
7
6
3-NO2C6H4
4-OH-3-CH3OC6H3
4-OH-3-NO2C6H3
3,4,5-(CH3O)3C6H2
4-CH3C6H4
8
7
7
8
8
9
7
10
11
12
13
7
2-CH3OC6H4
2,3-(CH3O)2C6H3
n-Heptanal
7
8
24 h
a
Yields refer to the isolated pure products. The desired known pure products were characterized by comparison of their physical data (melting points, IR,
1H and 13C NMR) with those of known compounds [23]. The same products are made in the presence of acetic acid as catalyst (2.0 mL, 3500% mol) under
microwave heating (120 8C) [23].

H.R. Shaterian et al. / C. R. Chimie 15 (2012) 1055–1059
1057
NH2
H2N
(3)
O
N
O
m
N
s
i
r
e
m
o
t
O
u
a
T
O
(4)
(2)
O
OH
O
(1)
NH2
CN
Ar
O
N
N
N
(5)
N
N
O
H
OH
N
(10)
CN
Nano CuO
(catalyst)
Ar
NC
Ar
H
N
(9)
NC
(8)
N
a
(
c
n
a
o
t
a
C
u
l
y
s
O
t
)
CN
O
+
CN
(6)
Ar
H
(7)
Scheme 2. Suggested mechanism for the formation of 3-amino-2-cyano-1-aryl-1H-benzo[a]pyrano[2,3-c]phenazines.
The mechanism for the formation of the products has
been suggested in Scheme 2 according to the literature
[23]. First, 2-hydroxynaphthalene-1,4-dione (1) tautom-
rizes to intermediate (2). The initial condensation of (2)
with o-phenylenediamine (3) afford 6H-benzo[a]phena-
zin-5-one (4), which in tautomerism equilibrium causes to
prepare benzo[a]phenazin-5-ol (5). In addition, standard
Knoevenagel condensation of malononitrile (6) and aryl
aldehydes (7) in the presence of nano CuO as the catalyst
was afforded benzylidenemalononitrile (8). The Michael
addition of 6H-benzo[a]phenazin-5-ol (5) with benzylide-
nemalononitrile (8) formed intermediate (9), which in
subsequent cyclization and tautomerism affords the
corresponding products (10).
reaction of 2-hydroxynaphthalene-1,4-dione, o-phenyle-
nediamine, 4-chlorobenzaldehyde, and malononitrile (Ta-
ble 2, Entry 5). After completion of the reaction, the
reaction mixture was cooled to room temperature and
dissolved in dichloromethane. Then, nano CuO as the
catalyst was separated by centrifugation and washed with
CH2Cl2 for subsequent experiments to check its reusability
under similar reaction conditions. The results showed us
that nano CuO is a stable catalyst in reaction media and
reused several times without significant loss of its catalytic
activity (Fig. 1).
In order to show the accessibility of the present work
in comparison with only one reported result in the
literature, we summarized some of the results for the
preparation of 3-amino-2-cyano-1-(4-chlorophenyl)-
1H-benzo[a]pyrano[2,3-c]phenazine in Table 3. The
We also investigated the recycling of the nano CuO as
the catalyst under solvent-free conditions using the model

1058
H.R. Shaterian et al. / C. R. Chimie 15 (2012) 1055–1059
determined in open capillaries with a BUCHI 510 melting
point apparatus. TLC was performed on silica-gel Poly
Gram SIL G/UV 254 plates.
95
100
93
92
90
90
80
70
60
50
40
30
20
10
0
4.2. General procedure for the synthesis of functionalized
benzo[a]pyrano[2,3-c]phenazine derivatives under solvent-
free conditions
2-Hydroxynaphthalene-1,4-dione (10 mmol) and o-
phenylenediamine (10 mmol) were mixed at 75 8C until a
orange solid of benzo[a]phenazine was formed (< 5 min).
Then, aryl aldehydes (10 mmol), malononitrile (10 mmol),
and nano copper(II) oxide (10 mol%) was added and stirred
under thermal conditions at 75 8C for the specific time.
After completion of the reaction, monitored by TLC, the
reaction mixture was cooled to room temperature. Then,
the mixture was diluted with dichloromethane and the
catalyst was separated by centrifugation and washed with
CH2Cl2 (2 Â 5 mL) for checking the reusability. The
decanted solution containing the product was evaporated
to give the yellow solid. The solid was recrystallized with
acetone to give the pure yellow solid. All of the desired
product(s) were characterized by comparison of their
physical data with those of known compounds.
1
2
3
4
Reaction cycles
Fig. 1. The recycling of the nano CuO as catalyst.
Table 3
Comparison the results of nano CuO with HOAc in the synthesis 3-amino-
2-cyano-1-(4-chlorophenyl)-1H-benzo[a]pyrano[2,3-c]phenazine.
Entry
1
Catalyst
(mol%)
Conditions
Time
Yield
(%)a [Ref]
(min)
HOAC
Microwave
10
7
89 [23]
(2.0 mL
heating (120 8C)
3500% mol)b
Nano CuO
(10 mol%)c
2
Solvent-free,
94 (Present
work)
Selected spectra for three known products are given
below:
75 8C
a
Yields refer to isolated pure products and based on the reaction of 2-
hydroxynaphthalene-1,4-dione, o-phenylenediamine, 4-chlorobenzalde-
hyde, and malononitrile.
ꢀ
ꢀ
ꢀ
3-Amino-2-cyano-1-phenyl-1H-benzo[a]pyrano[2,3-
c]phenazine (Table 2, entry 1): yellow solid, m.p.: 301–
b
Acetic acid as catalyst is not reusable.
c
The Nano CuO is recyclable catalyst.
302 8C; IR (KBr):
1592, 1543, 1495, 1477, 1409, 1386, 1355, 1329, 1261,
1162, 1126, 1051, 1021, 765, 733, 703 cmÀ1 1H NMR
(300 MHz, DMSO-d6): = 9.16 (d, 1H, J = 7.6 Hz, Ar-H), 8.43
nmax = 3445, 3312, 3175, 2187, 1659, 1621,
;
results show that the nano CuO (10 mol%) under solvent-
free conditions relative to acetic acid as catalyst (2.0 mL,
3500 % mol) under microwave heating (120 8C) [23], are
the most efficient catalysts with respect to the reaction
time and exhibits broad applicability in terms of yields.
d
(d, 1H, J = 8.0 Hz, Ar-H), 8.25–8.21 (m, 1H, Ar-H), 8.12–8.07
(m, 1H, Ar-H), 8.02–7.89 (m, 4H, Ar-H), 7.42–7.33 (m, 4H,
Ar-H), 7.24 (t, 2H, J = 7.6 Hz, NH2), 7.12–7.07 (m, 1H, Ar-H),
5.46 (s, 1H, CH) ppm; 13C NMR (75 MHz, DMSO-d6):
d
= 159.9, 146.3, 145.1, 141.2, 140.6, 140.2, 139.6, 130.6,
3. Conclusion
130.2, 130.3, 130.0, 129.2, 129.0, 128.7, 128.3, 127.6, 126.5,
125.6, 124.8, 122.1, 120.2, 113.9, 58.1, 37.4 ppm;
3-Amino-2-cyano-1-(4-chlorophenyl)-1H-benzo[a]pyr-
ano[2,3-c]phenazine (Table 2, entry 5): yellow solid,
In this research, nano CuO was used for preparation of
3-amino-2-cyano-1-aryl-1H-benzo[a]pyrano[2,3-c]phen-
azine derivatives under solvent-free conditions for the first
time. The attractive features of this protocol are simple
procedure, cleaner reaction, use of reusable nano catalyst.
Satisfactory yields of products, as well as
experimental, isolation and purification of the products
make it a useful protocol for the green synthesis.
m.p.: 290–291 8C; IR (KBr):
nmax = 3455, 3310, 3172,
2190, 1665, 1622, 1591, 1487, 1474, 1401, 1386, 1351,
1330, 1292, 1267, 1162, 1101, 1082, 1051, 1017, 848,
; d = 9.18–
754, 744 cmÀ1 1H NMR (300 MHz, DMSO-d6):
9.15 (m, 1H, Ar-H), 8.43–8.45 (m, 1H, Ar-H), 8.23–8.22
(m, 1H, Ar-H), 8.11–8.01 (m, 1H, Ar-H), 8.02–7.89 (m, 4H,
Ar-H), 7.43–7.41 (m, 4H, Ar-H), 7.29–7.27 (m, 2H, NH2),
5.44 (s, 1H, CH) ppm; 13C NMR (75 MHz, DMSO-d6):
a simple
4. Experimental
d
= 159.9, 152.2, 144.8, 140.8, 139.6, 131.1, 130.4, 130.2,
130.2, 130.1, 129.6, 129.2, 128.7, 128.3, 125.6, 124.9,
122.2, 120.0, 113.3, 57.6 ppm;
4.1. General
3-Amino-2-cyano-1-p-tolyl
c]phenazine (Table 2, entry 10): yellow solid, m.p.:
293–295 8C; IR (KBr): max = 3445, 3315, 3177, 2188,
-1H-benzo[a]pyrano[2,3-
All reagents were purchased from Merck and Aldrich
and used without further purification. Copper(II) oxide
nanopowder, less than 50 nm particle size was purchased
from Sigma-Aldrich chemical company, CAS NO: 1317-38-
0. All yields refer to isolated products after purification. The
NMR spectra were recorded on a Bruker Avance DPX
300 MHz instrument. The spectra were measured in
DMSO-d6 relative to TMS (0.00 ppm). Melting points were
n
1664, 1623, 1592, 1491, 1472, 1392, 1382, 1352, 1328,
1291, 1267, 1222, 1161, 1102, 1053, 1022, 830, 759,
744 cmÀ1; 1H NMR (300 MHz, DMSO-d6):
d = 9.22 (d, 1H,
J = 8.0 Hz, Ar-H), 8.46–8.44 (m, 1H, Ar-H), 8.28–8.26
(m, 1H, Ar-H), 8.19–8.15 (m, 1H, Ar-H), 8.03–7.91 (m, 4H,

H.R. Shaterian et al. / C. R. Chimie 15 (2012) 1055–1059
1059
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We are thankful to the University of Sistan and
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