Mild basic ionic liquid catalyzed four component synthesis of functionalized benzo[a]pyrano[2,3-c]phenazine derivatives

Article abstract of DOI:10.1016/j.molliq.2012.11.006

An efficient, mild, and 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

Full text of DOI:10.1016/j.molliq.2012.11.006

Journal of Molecular Liquids 177 (2013) 162–166
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Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Mild basic ionic liquid catalyzed four component synthesis of functionalized
benzo[a]pyrano[2,3-c]phenazine derivatives
⁎
Hamid Reza Shaterian , 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, mild, and 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 of basic ionic liquids such as 1-butyl-3-methylimidazolium hydroxide,
3-hydroxypropanaminium acetate, pyrrolidinium formate, pyrrolidinium acetate, 1,8-diazabicyclo[5.4.0]-undec-7-
en-8-ium acetate, and piperidinium formate as the catalysts has been developed. The ionic liquid was stable during
the reaction process and could also be reused several times with consistent activity. This procedure may be a prac-
tical alternative to the existing one reported procedure to meet the need of academe as well as industries.
© 2012 Elsevier B.V. All rights reserved.
Received 19 March 2012
Accepted 12 November 2012
Available online 24 November 2012
Keywords:
Aldehydes
Malononitrile
Ionic liquid
Catalyst
o-Phenylenediamine
Base
1. Introduction
o-phenylenediamine, aldehydes, and malononitrile in the presence of
basic ionic liquids such as 1-butyl-3-methylimidazolium hydroxide
Ionic liquids (ILs) have received considerable attention as envi-
ronmentally benign reaction medium as solvent and catalysts
for chemical reactions [1–3]. The organic reaction can be carried
out in a homogeneous phase and the ionic liquid can be recycled in
a green procedure [1–5]. The importance of the ionic liquid has
been effectively utilized for the design of novel bioactive compounds
[1–6].
[Bmim]OH, 3-hydroxypropanaminium acetate [3-HPAA], pyrrolidinium
formate [Pyrr][HCOO], pyrrolidinium acetate [Pyrr][CH3COO], 1,8-
diazabicyclo[5.4.0]-undec-7-en-8-ium acetate [DBU][CH3COO], and
piperidinium formate [Pip][HCOO] as the catalysts under solvent-free
conditions (Scheme 1).
Literature survey showed us that a few research was done on the
mentioned ionic liquids. Several products were prepared using [Bmim]
OH as catalyst such as 3-benzamidocoumarins [25], quinazoline-
2,4(1H,3H)-diones [26], and 2-amino-2-chromenes [27]. [3-HPAA] was
used in synthesis of 2-amino-5-oxo-4,5-dihydropyrano[3,2-c]chromene-
3-carbonitrile derivatives [28]. The volumetric properties of [Pyrr][HCOO]
were studied [29]. [Pyrr][CH3COO] was applied in Knoevenagel conden-
sation [30]. DBU[CH3COO] was used in aza-conjugate addition of
amines to various electron deficient alkenes [31].
Phenazines are present in natural and synthetic products showing
a
variety of biological functions, including antimalarial [7,8],
trypanocidal [9], fungicidal [10,11], antitumor, and antiplatelet8
activities. In addition, chromenes moiety has been exhibited remarkable
effects as pharmaceuticals [12,13], including antifungal [14,15] and
antimicrobial activities [16]. Molecules with phenazines [17] and
chromenes [18] moieties have attracted great attention in drug discovery.
Functionalized benzo[a]pyrano[2,3-c]phenazine derivatives have these
moieties.
The designs of multi-component reactions (MCRs) for the synthesis
of diverse groups of compounds, especially the ones that are biologically
active, have commanded great attention in green organic synthesis
[19–21]. Thus, in continuation of our research on applications of ionic
liquids in multi-component reactions [22–24], herein, we wish to
describe the preparation of functionalized benzo[a]pyrano [2,3-c]
phenazine derivatives with phenazines and chromenes moieties
from four component reaction of 2-hydroxynaphthalene-1,4-dione,
2. Experimental
All reagents were purchased from Merck and Aldrich and used with-
out further purification. The weak basic ionic liquids such as 1-butyl-
3-methylimidazolium hydroxide [32], 3-hydroxypropanaminium
acetate [28], pyrrolidinium formate [33], pyrrolidinium acetate
[33], 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate [31], and
piperidinium formate [34] were prepared according to the reported
procedure. 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). IR spectra were recorded on a JASCO FT-IR 460
⁎
Corresponding author. Tel.: +98 541 2446565; fax: +98 541 2431067.
E-mail address: hrshaterian@chem.usb.ac.ir (H.R. Shaterian).
0167-7322/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molliq.2012.11.006

H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 177 (2013) 162–166
163
O
O
NH2
HO
H2N
Catalyst- free, 75oC
+
OH
N
No Separation and purification
N
NH2
O
CN
Ar
O
CN
CN
Ar
H
Basic ionic liquids (Catalyst),
N
75oC
N
Ionic liquids=1-butyl-3-methylimidazolium hydroxide, 3-hydroxypropanaminium acetate, pyrrolidinium
formate, pyrrolidinium acetate, 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate, and piperidinium formate
Scheme 1. One-pot synthesis of 3-amino-2-cyano-1-aryl-1H-benzo[a]pyrano[2,3-c]phenazines derivatives.
plus spectrophotometer. TLC was performed on silica-gel Poly Gram
SIL G/UV 254 plates.
(10 mmol), and ionic liquids including 1-butyl-3-methylimidazolium
hydroxide (15 mol%), 3-hydroxypropanaminium acetate (16 mol%),
pyrrolidinium formate (18 mol%), pyrrolidinium acetate (17 mol%),
1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate (19 mol%), and
piperidinium formate (16 mol%) as weak basic catalyst were added
and stirred under thermal solvent-free conditions at 75 °C for the
specific time. After completion of the reaction, 5 mL of water was
added to the mixture. The ionic liquid was dissolved in water, and fil-
tered for separation of the crude product. The separated product was
2.1. 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 °C until an orange solid of benzo[a]phenazine
was formed (b5 min). Then, aryl aldehydes (10 mmol), malononitrile
Table 1
Optimization conditions for the preparation of 3-amino-2-cyano-1-(4-chloro-phenyl)-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 amounts of ionic liquids A: 1-butyl-3-methylimidazolium hydroxide, B: 3-hydroxypropanaminium acetate,
C: pyrrolidinium formate, D: pyrrolidinium acetate, E: 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate, and F: piperidinium formate, as catalysts under verities temperature.
Entry
Catalyst (mol%)
Temperature (°C)
Time (min)
Yield (%)a
A
B
C
D
E
F
A
B
C
D
E
F
A
B
C
D
E
F
1
2
3
4
5
6
7
8
20
32
15
23
30
10
15
20
18
25
12
17
25
10
16
20
18
26
10
23
32
12
18
23
20
28
14
22
28
12
17
23
22
30
15
20
29
11
19
25
18
26
15
20
28
10
16
21
25
25
50
50
50
75
75
75
34
30
21
20
14
10
6
42
34
31
24
19
11
7
32
30
22
18
13
10
8
34
30
24
20
12
10
7
28
26
24
20
15
13
9
32
30
24
18
15
11
8
40
46
50
60
66
85
94
94
31
40
52
60
63
82
92
92
30
40
50
61
66
84
93
94
30
43
52
60
65
83
92
92
31
40
48
60
67
81
92
93
32
41
50
62
69
82
93
93
6
7
8
7
9
8
a
Yields refer to isolated pure product.
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 A: [Bmim]OH, B: [3-HPAA], C: [Pyrr][HCOO], D: [Pyrr][CH3COO], E: [DBU][CH3COO], and F: [Pip][HCOO] as catalysts.
Entry
Aldehydes
Time (min)
Yield (%)a
Melting point
m.p (°C)/Lit. m.p (°C)[Ref]
A
B
C
D
E
F
A
B
C
D
E
F
1
2
3
4
5
6
7
8
Ph
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-F C6H4
7
6
7
6
6
6
7
7
7
6
7
7
7
7
8
7
7
7
7
6
7
7
6
7
–
9
8
8
8
8
8
9
7
8
7
9
9
–
8
7
8
7
8
8
9
7
8
8
9
9
–
10
9
9
9
9
9
10
9
8
8
9
8
8
8
9
8
8
9
9
9
–
92
94
92
90
91
91
92
89
89
89
90
89
–
91
92
91
90
90
91
91
89
88
89
89
88
–
91
93
92
90
91
91
92
89
89
90
89
88
–
90
92
91
89
91
91
91
89
89
90
89
88
–
91
92
92
88
89
89
90
88
87
89
88
87
–
91
93
92
91
91
91
89
89
88
89
88
87
–
299–302/(298–300) [35]
291/(288–291) [35]
284–285/(281–283) [35]
295/(293–294) [35]
275/(274–276) [35]
284–286/(283–285) [35]
279–281/(278–279) [35]
273/(270–272) [35]
249/(247–248) [35]
291–292/(290–291) [35]
295/(292–294) [35]
253–255/(252–254) [35]
–
4-BrC6H4
3-NO2C6H4
2-CH3OC6H4
4-OH-3-CH3OC6H3
4-OH-3-NO2C6H3
2,3-di CH3OC6H3
3,4,5-tri CH3OC6H2
n-Heptanal
9
9
10
11
12
13
10
10
10
–
24 h
a
Yields refer to the isolated pure products. The desired known pure products were characterized by the comparison of their physical data (melting points, IR, 1H and 13C NMR)
with those of known compounds.

164
H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 177 (2013) 162–166
washed twice with water (2×5 mL). The solid crude product
recrystallized with acetone to give the pure yellow solid. All of
the desired product(s) were characterized by the comparison of
their physical data with those of known compounds. For recycling
the catalysts, after washing mixture of the reaction with water
completely, the water containing ionic liquid (IL is soluble in water)
was evaporated under reduced pressure and ionic liquid was recovered
and reused.
130.7, 130.4, 130.2, 130.0, 129.0, 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]pyrano[2,3-c]
phenazine (Table 2, entry 2): Yellow solid, m.p.: 291 °C.; IR (KBr):
νmax =3452, 3309, 3174, 2189, 1660, 1624, 1593, 1488, 1473,
1402, 1385, 1350, 1329, 1291, 1268, 1163, 1105, 1088, 1053,
1015, 848, 759, 749 cm−1.; 1H NMR (300 MHz, DMSO-d6):
δ=9.18–9.16 (m, 1H, Ar–H), 8.43–8.41 (m, 1H, Ar–H), 8.24–8.22
(m, 1H, Ar–H), 8.11–8.08 (m, 1H, Ar–H), 8.01–7.89 (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): δ=159.8, 152.2, 144.3,
140.6, 139.9, 131.0, 130.8, 130.6, 130.3, 130.1, 129.6, 129.2, 128.7,
128.3, 125.6, 124.9, 122.2, 120.0, 113.3, 57.6 ppm.
Selected spectra for three known products are given below:
3-Amino-2-cyano-1-phenyl-1H-benzo[a]pyrano[2,3-c]phenazine
(Table 2, entry 1): Yellow solid, m.p.: 299–302 °C.; IR (KBr):
ν
max =3442, 3311, 3174, 2188, 1658, 1623, 1593, 1541, 1495,
1473, 1401, 1385, 1350, 1327, 1269, 1162, 1126, 1052, 1026,
761, 733, 702 cm−1.; 1H NMR (300 MHz, DMSO-d6): δ=9.17
(d, 1H, J=7.6 Hz, Ar–H), 8.42 (d, 1H, J=8.0 Hz, Ar–H), 8.24–8.21
(m, 1H, Ar–H), 8.12–8.09 (m, 1H, Ar–H), 8.00–7.89 (m, 4H, Ar–H),
7.41–7.37 (m, 4H, Ar–H), 7.23 (t, 2H, J=7.6 Hz, NH2), 7.12–7.08
(m, 1H, Ar–H), 5.46 (s, 1H, CH) ppm.; 13C NMR (75 MHz,
DMSO-d6): δ=159.9, 146.2, 145.3, 141.5, 140.6, 140.0, 139.7,
3-Amino-2-cyano-1-p-tolyl-1H-benzo[a]pyrano[2,3-c]phenazine
(Table 2, entry 4): Yellow solid, m.p: 295 °C.; IR (KBr): νmax
=
3441, 3311, 3178, 2189, 1660, 1624, 1595, 1496, 1474, 1399, 1385,
1351, 1329, 1290, 1267, 1223, 1161, 1106, 1053, 1022, 830, 759,
744 cm−1.; 1H NMR (300 MHz, DMSO-d6): δ=9.23 (d, 1H, J=
8.0 Hz, Ar–H), 8.45–8.44 (m, 1H, Ar–H), 8.29–8.26 (m, 1H, Ar–H),
NH2
H2N
(3)
O
O
N
N
Tautomerism
O
O
(4)
(2)
O
OH
O
(1)
NH2
CN
Ar
O
N
N
N
(5)
N
N
O
H
OH
N
(10)
CN
Basic ionic liquids
(catalyst)
Ar
NC
Ar
H
N
(9)
NC
(8)
Basic ionic liquids
(catalyst)
CN
O
+
CN
(6)
ArH
(7)
Ionic liquids= 1-butyl-3-methylimidazolium hydroxide, 3-hydroxypropanaminium acetate, pyrrolidinium
formate, pyrrolidinium acetate, 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate, and piperidinium formate
Scheme 2. Suggested mechanism for the formation of 3-amino-2-cyano-1-aryl-1H-benzo[a]pyrano[2,3-c]phenazines.

H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 177 (2013) 162–166
165
Fig. 1. The recycling of [Bmim]OH, [3-HPAA], [Pyrr][HCOO], [Pyrr][CH3COO], [DBU][CH3COO], and [Pip][HCOO] as catalysts under solvent-free conditions using a model reaction of
2-hydroxynaphthalene-1,4-dione, o-phenylenediamine, 4-chlorobenzaldehyde, and malononitrile.
8.18–8.15 (m, 1H, Ar–H), 8.03–7.92 (m, 4H, Ar–H), 7.34–7.28
(m, 4H, Ar–H), 7.02 (d, 2H, J=8.0 Hz, NH2), 5.47 (s, 1H, CH),
2.15 (s, 3H, CH3) ppm.; 13C NMR (75 MHz, DMSO-d6): δ=
168.1, 164.4, 159.8, 150.3, 146.5, 141.6, 140.1, 135.6, 130.8,
130.0, 129.5, 129.1, 128.9, 127.5, 125.7, 123.6, 122.1, 118.0,
58.2, 37.0, 20.50 ppm.
chlorophenyl)-1H-benzo[a]pyrano[2,3-c]phenazine in 6 min with 94%
of yield.
In continuation of our study, application of ionic liquids such as
[3-HPAA], [Pyrr][HCOO], [Pyrr][CH3COO], [DBU][CH3COO], and [Pip]
[HCOO], as catalysts in the preparation 3-amino-2-cyano-1-(4-
chlorophenyl)-1H-benzo[a]pyrano[2,3-c]phenazine was investigated.
According to Table 1 and its general optimization procedure,
16 mol% of [3-HPAA], 18 mol% of [Pyrr][HCOO], 17 mol% of [Pyrr]
[CH3COO], 19 mol% of [DBU][CH3COO], and 16 mol% of [Pip][HCOO]
as catalysts under solvent-free conditions at 70 °C were chosen
(Table 1).
Next, four-component condensation reaction of 2-hydroxynaphthalene-
1,4-dione, o-phenylenediamine, aromatic aldehydes, malononitrile
under optimized 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 synthe-
size the corresponding products in high to excellent yields using the six
weak basic ionic liquids as catalysts (Table 2). Aliphatic aldehyde such
as heptanal was intact in this reaction (Table 2, Entry 13).
3. Results and discussions
First, to find optimization conditions, the one-pot and solvent-
free four component reaction of 2-hydroxynaphthalene-1,4-dione,
o-phenylenediamine, 4-chlorobenzaldehyde and malononitrile in
the presence of the ionic liquid, 1-butyl-3-methylimidazolium hydroxide
[Bmim]OH, as catalyst was selected as model. So, 2-hydroxynaphthalene-
1,4-dione (1 mmol) and o-phenylenediamine (1 mmol) were mixed at
75 °C until an orange solid of benzo[a]phenazine was formed (b5 min)
without using any catalyst under solvent-free conditions. Then, 4-
chlorobenzaldehyde (1 mmol), malononitrile (1 mmol), and ionic
liquid,1-butyl-3-methylimidazolium hydroxide were added and
stirred under thermal solvent-free conditions. The reaction was carried
out with different amounts of 1-butyl-3-methylimidazolium hydroxide
as catalyst (10, 15, 20, 23, 30, 32 mol%) and varieties of temperature
(25, 50, 75 °C) (Table 1). As it was shown from Table 1, 15 mol% of
[Bmim]OH as catalyst at 75 °C afforded 3-amino-2-cyano-1-(4-
According to the literature [35], the suggested mechanism for
the formation of the products is shown in Scheme 2. First, 2-
hydroxynaphthalene-1,4-dione (1) tautomerizes to intermediate
(2). The initial condensation of (2) with o-phenylenediamine (3)
affords 6H-benzo[a]phenazin-5-one (4), which in tautomerism
equilibrium causes to prepare benzo[a]phenazin-5-ol (5). In addition,
Table 3
Comparison of the results of [Bmim]OH, [3-HPAA], [Pyrr][HCOO], [Pyrr][CH3COO], [DBU][CH3COO], and [Pip][HCOO] with HOAC in the synthesis 3-Amino-2-cyano-1-(4-chloro-
phenyl)-1H-benzo[a]pyrano[2,3-c]phenazine.
Entry
Catalyst (mol%)
Conditions
Time
Yield (%)a [Ref]
1
2
HOAC (2.0 mL 3500 mol%)b
[Bmim]OH (15 mol%)c
Microwave heating (120 °C)
Solvent-free,75 °C
10 min
6 min
89 [35]
94
(Present work)
92
(Present work)
93
(Present work)
92
(Present work)
92
(Present work)
93
3
4
5
6
7
[3-HPAA] (16 mol%)c
Solvent-free,75 °C
Solvent-free,75 °C
Solvent-free,75 °C
Solvent-free,75 °C
Solvent-free,75 °C
7 min
8 min
7 min
9 min
8 min
[Pyrr][HCOO] (18 mol%)c
[Pyrr][CH3COO] (17 mol%)c
[DBU][CH3COO] (19 mol%)c
[Pip][HCOO] (16 mol%)c
(Present work)
a
Yields refer to isolated pure products and based on the reaction of 2-hydroxynaphthalene-1,4-dione, o-phenylenediamine, 4-chlorobenzaldehyde, and malononitrile.
Acetic acid as catalyst isn't reusable.
The weak basic ionic liquids are recyclable catalysts.
b
c

166
H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 177 (2013) 162–166
standard Knoevenagel condensation of malononitrile (6) and aryl alde-
hydes (7) in the presence of basic ionic liquids as the catalysts afforded
benzylidenemalononitrile (8). The Michael addition of 6H-benzo[a]
phenazin-5-ol (5) with benzylidenemalononitrile (8) formed intermedi-
ate (9), which in subsequent cyclization and tautomerism affords the cor-
responding products (10).
References
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[Pyrr] HCOO] (18 mol%), [Pyrr][CH3COO] (17 mol%), [DBU][CH3COO]
(19 mol%), and [Pip][HCOO] (16 mol%) (Table 2, Entry 2). After comple-
tion of the reaction, water was added and the precipitated mixture was
filtered off for separation of crude products. After washing the solid
products with water completely, the water containing ionic liquid
(IL is soluble in water) was evaporated under reduced pressure and
ionic liquid was recovered and reused (Fig. 1). The recovered catalysts
were reused four runs without any loss of its activities.
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[DBU][CH3COO] (19 mol%), and [Pip][HCOO] (16 mol%) under solvent-
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4. Conclusion
In this research, six mild basic ionic liquids [Bmim]OH, [3-HPAA],
[Pyrr][HCOO], [Pyrr][CH3COO], [DBU][CH3COO], and [Pip][HCOO]
were used for preparation of 3-amino-2-cyano-1-aryl-1H-benzo[a]
pyrano[2,3-c]phenazine under solvent-free conditions for the first
time. The attractive features of this protocol are simple procedure,
cleaner reaction, use of inexpensive and reusable ionic liquids as
catalysts. Satisfactory yields of products, as well as a simple experimental,
isolation and purification of the products make it a useful protocol for the
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Acknowledgments
We are thankful to the University of Sistan and Baluchestan Research
Council for the partial support of this research.