An efficient electrochemical method for the synthesis of quinoxaline-dione derivatives from oxidation of catechols in the presence of N1, N 2-dibenzylethane-1,2-diamine

Article abstract of DOI:10.1149/2.061301jes

A series of 1,4-dibenzyl-1,2,3,4-tetrahydroquinoxaline-6,7-dione derivatives (6a-6c) were electrosynthesized. In the present work, electrochemical oxidation of catechols 1a-1d in the presence of the N ¹,N²-dibenzylethane-1,2-diamine (3) as a nucleophile, has been studied in aqueous solutions using cyclic voltammetry and controlled-potential coulometry (CPC) methods. Various parameters such as the applied potential, pH of the electrolytic solution, cell configuration and also purification techniques, were carried out to optimize the yields of corresponding products. New quinoxaline-6,7-dione derivatives were synthesized in excellent yield using an electrochemical procedure coupled with a Schiff base as a facile, efficient and practical method.

Full text of DOI:10.1149/2.061301jes

G32
Journal of The Electrochemical Society, 160 (1) G32-G36 (2013)
0
013-4651/2013/160(1)/G32/5/$28.00 © The Electrochemical Society
An Efficient Electrochemical Method for the Synthesis
of Quinoxaline-dione Derivatives from Oxidation of Catechols
1
2
in the Presence of N , N -dibenzylethane-1,2-diamine
a
b,z
a
Bahram Dowlati, Davood Nematollahi, and Mohamed Rozali Othman
aSchool of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan
Malaysia, 43600 UKM Bangi Selangor, Malaysia
b
Faculty of Chemistry, Bu-Ali-Sina University, 65174 Hamedan, Iran
A series of 1,4-dibenzyl-1,2,3,4-tetrahydroquinoxaline-6,7-dione derivatives (6a-6c) were electrosynthesized. In the present work,
1
2
electrochemical oxidation of catechols 1a-1d in the presence of the N ,N -dibenzylethane-1,2-diamine (3) as a nucleophile, has
been studied in aqueous solutions using cyclic voltammetry and controlled-potential coulometry (CPC) methods. Various parameters
such as the applied potential, pH of the electrolytic solution, cell configuration and also purification techniques, were carried out to
optimize the yields of corresponding products. New quinoxaline-6,7-dione derivatives were synthesized in excellent yield using an
electrochemical procedure coupled with a Schiff base as a facile, efficient and practical method.
©
2012 The Electrochemical Society. [DOI: 10.1149/2.061301jes] All rights reserved.
Manuscript submitted July 24, 2012; revised manuscript received September 26, 2012. Published November 7, 2012.
Organic electrochemical synthesis in aqueous medium provides
an alternative strategy for the transformation of o-benzoquinones.
Because most of o-benzoquinones are unstable, they are generally
prepared in situ from their precursors, namely, catechols and 2-
methoxyphenols. Catechols can be oxidized electrochemically to the
corresponding highly active o-benzoquinones, followed by a Michael
chemical procedure coupled with a Schiff base as a facile, efficient
and practical method.
Experimental
Apparatus.— Cyclic voltammetry (CV) and controlled-potential
coulometry were performed using an Autolab model PGSTAT 302N
potentiostat/galvanostat. The working electrode used in the voltam-
metry experiments was a glassy carbon disk from France Radiometer
Analytical (1.8 mm diameter). The glassy carbon was polished with
polishing cloth before each measurement. A platinum wire was used
as a counter electrode and the reference was a saturated calomel elec-
trode (SCE). All electrodes for CV experiments were from France
Radiometer Analytical. An undivided cell was used for CPC.37 The
working electrode potentials versus the SCE were measured. The SCE
references and carbon rods were placed together, and their distance
from the counter electrode was approximately 20 mm. The applied
potential throughout CPC vs. SCE was controlled by the potentiostat.
During electrolysis, a magnetic stirrer was used.
1
addition reaction when nucleophiles are present in the system.
Tabakovic and co-workers have shown that o-benzoquinone can re-
act with nucleophiles such as 4-hydroxycoumarin and dimedone to
2
,3
form the heterocyclic compounds. Moreover, Zhang and Dryhurst
have reported that o-benzoquinone derived from oxidation of tetrahy-
dropapaveroline can be attacked by glutathione to yield the mono and
4
bis-glutathionyl compounds. In this direction, we have shown that
electrochemically generated o-quinones can be attacked by a variety of
5
6
nucleophiles such as barbituric acid derivatives, acetylacetone, 2-
7
8
9
mercaptobenzoxazole, azide ion, 3-hydroxy-1H-phenalen-1-one,
10
and Meldrum’s acid derivatives and described the efficient and one-
pot electrochemical methods for the synthesis of some new organic
compounds.
Heterocyclic quinones containing
a
nitrogen atom are
antioxidant,
Quinoxaline deriva-
11–13
14–16
17
known to possess antibacterial
antifungalous,
Reagents.— The catechols (catechol, 3-methoxycatechol, 3-
methylcatechol and 3,4-dihydroxybenzoic acid) were reagent-grade
materials from Aldrich. The KH PO , K HPO and other acids and
bases were of pro-analysis grade from E. Merck. Benzaldehyde, 99%
and ethylenediamine were purchased from Aldrich. These chemicals
were used without further purification. The reagents and solvents used
in this study were of analytical grade and were used without further
purification.
18,19
20,21
anticarcinogenic
and cytotoxic activities.
tives are nitrogen-containing heterocyclic compounds, and their im-
portance has been reported in the literature. Quinoxaline derivatives
constitute the basis of many insecticides, fungicides and herbicides
2
4
2
4
22–24
and are important in human health and as receptor antagonists.
These are useful as intermediates for many target molecules in organic
synthesis and as synthons. Many synthetic routes have been developed
for the synthesis of quinoxaline derivatives. The most common method
is the condensation of an aromatic 1,2-diamine with a 1,2-dicarbonyl
1
2
Organic synthesis of N ,N -dibenzylethane-1,2-diamine (3).— In
a typical procedure, benzaldehyde (2.12 g, 20 mmol) and ethylene-
diamine (0.60 g, 10 mmol) were mixed in an appropriate beaker in
100 mL MeOH. The obtained mixture was stirred overnight at room
temperature, and then sodium borohydride (3.02 g, 80 mmol) was
added. The mixture was refluxed for 2–3 hours, cooled and poured
25
compound in refluxing ethanol or acetic acid. However, many im-
proved methods have been reported for the synthesis of quinoxalines
2
6,27
28,29
using a microwave,
solid phase synthesis
and electrochemical
3
0,31
methods electrochemical methods.
In addition, bi-catalyzed (bis-
32
muth and copper) syntheses were also reported. Many of these meth-
ods suffer from one or more limitations such as harsh conditions, long
reaction times, critical product isolation procedures, co-occurrence of
several side products and low yields.
into 250 mL of H O. The solution was removed by filtration off
2
and evaporated to dryness. The residue was then extracted with water-
chloroform. The organic layer was separated and dried over anhydrous
Na SO . The solvent was evaporated to yield yellow oil. The product
The development of an effective method for the electrochemi-
cal synthesis of quinoxalines is still an important challenge. There
2
4
1
13
3 was characterized as a pure compound by H NMR, C NMR,
ESI-MS and IR.
3
3–36
2
38–41
have been several reports
on some quinoxalinedione derivatives
33
34
that exhibit antibacterial and antimalarial effects and antiasthmatic
3
5
and antiallergic activity. In view of the vast biological importance
of quinoxaline-6,7-dione derivatives, we decided to synthesize new
quinoxaline-6,7-dione derivatives in excellent yield using an electro-
Electro-organic synthesis of 6a-6c.— An aqueous solution of
phosphate buffer (pH 7.0, 0.20 M) was pre-electrolyzed at the cho-
sen potentials in Table I. Appropriate amounts of catechols (1a-1d)
1
2
and N ,N -dibenzylethane-1,2-diamine (3) (Table I) were added to
the undivided cell, which was equipped with a graphite anode (an
assembly of twelve rods, 6 mm diameter and 11 cm length) and a
zE-mail: nemat@basu.ac.ir
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Journal of The Electrochemical Society, 160 (1) G32-G36 (2013)
G33
Table I. Electroanalytical and preparative data.
Concentrationa
(mmol)
Applied potential
(V) (SCE)
Conversion
Product yield (%)
1
1
1
1
a→6a
b→6b
c→6c
d→6a
0.25
0.35
0.50
0.50
0.45
0.29
0.30
0.35
94.8
93.2
92.6
95.5
a
1
2
Appropriate amounts of catechols (1a-1d) and N ,N -dibenzylethane-
1
,2-diamine (3) were added to the cell.
large platinum gauze cathode37 at room temperature. The process was
interrupted during the electrolysis, and the graphite anode was washed
in acetone to reactivate it. At the end of electrolysis, the solids that
separated were filtered, washed with water and then dried by sodium
1
sulfate. After purification, products were characterized by H NMR,
C NMR, ESI-MS and IR.
Figure 1. Cyclic voltammograms of: (a) 1.0 mM catechol (1a); (b) 1.0 mM
13
2
1
2
catechol (1a) in the presence of 1.0 mM N ,N -dibenzylethane-1,2-diamine
1
2
(
3); (c) 1.0 mM N ,N -dibenzylethane-1,2-diamine (3), at a glassy carbon elec-
1
2
Characteristic of products (3, and 6a-6c)—N ,N -dibenzylethane-
trode (1.8 mm diameter) in the phosphate buffer solution KH PO /K HPO
(0.2 M, pH 7). Scan rate: 50 mVs ; T = 25 ± 1 C.
2
4
2
4
1
−1
◦
1
,2-diamine (C16
ppm (600 MHz CDCl
.77 (s, 4H methylene), 7.24–7.25 (t, 4H aromatic), 7.27–7.31 (t, 2H
H
20
N
2
) (3).— Isolated yield = 67.6%, H NMR, δ
3
): 2.01 (s, 2H amine), 2.76 (s, 4H methylene),
3
13
aromatic), 7.32–7.34 (t, 4H, aromatic). C NMR, δ ppm (150 MHz
between benzaldehyde with ethylenediamine in a methanol solution
under reflux conditions. In this experiment, a Schiff base compound
3 that potentially contains a nitrogen-containing heterocycle has been
2
CDCl
(
3
): 48.6, 53.9, 126.9, 128.2, 128.45, 140.3. ESI-MS : m/z, 263.1
+
+
M +Na), 241.1 (M +1). IR(KBr): 3304, 3084, 3061, 3027, 2924,
44–48
2
1
829, 1950, 1877, 1811, 1603, 1584, 1494, 1452, 1407, 1358, 1202,
easily prepared.
A two-step mechanism can be presented based on the Schiff base
−1
108, 1074, 1054, 1028, 982, 911, 820, 736, 698 and 591 cm
.
1
2
reaction for the preparation of N ,N -dibenzylethane-1,2-diamine
49
1
,4-dibenzyl-1,2,3,4-tetrahydroquinoxaline-6,7-dione
(3). The first step in the reaction is reversible, progressing through a
carbinolamine intermediate and requires the removal of water, often
by azeotropic distillation with benzene, to achieve high yields. The re-
action is acid catalyzed, but catalysts are not generally required when
aliphatic amines are involved. The second step of the reaction involves
the reduction of the resulting compound containing two azomethine
groups (C=N) to the product 3 using sodium borohydride. According
to our results, the analytical and spectral data are completely consistent
with the proposed formulation.
1
(
C
22
H
20
N
2
O
2
)
(6a).— Isolated yield = 94.8%,
ppm (600 MHz CDCl ): 3.56 (s, 4H), 4.53 (s, 4H), 5.57 (s, 2H),
.25 (t, 4H), 7.32 (t, 4H), 7.38 (t, 2H). C NMR, δ ppm (150 MHz
CDCl ): 47.0, 56.2, 99.8, 127.0, 128.3, 129.2, 134.0, 149.5, 179.0.
H NMR, δ
3
13
7
3
2
+
+
ESI-MS : m/z, 367.1 (M +Na), 345.1 (M +1). IR(KBr): 3060, 3024,
3
1
5
002, 2979, 2917, 1597, 1542, 1483, 1451, 1442, 1362, 1323, 1300,
245, 1156, 1130, 1091, 1077, 1027, 916, 886, 786, 748, 735, 703,
−
1
97 and 460 cm
.
1
,4-dibenzyl-5-methyl-1,2,3,4-tetrahydroquinoxaline-6,7-dione
Electrochemical oxidation of catechol (1a) in the presence of
3).— The electrochemical behavior of catechol (1a) was investigated
by cyclic voltammetry at room temperature in an aqueous solution
containing 0.2 M phosphate buffer (pH 7.0) as the supporting elec-
trolyte system. As shown in Fig. 1 (curve a), upon scanning anodi-
1
(
(
C
23
H
22
N
2
O
2
) (6b).— Isolated yield = 93.2%, H NMR, δ ppm
600 MHz CDCl ): 2.03 (s, 3H, methyl), 3.35 (d, 2H), 3.44 (d, 2H),
.55 (s, 2H), 4.61 (s, 2H), 5.51 (s, 1H), 7.18-7.19 (d, 2H), 7.31 (t,
(
3
4
2
1
1
3
2
1
13
3
H), 7.35 (t, 2H), 7.40 (t, 4H). C NMR, δ ppm (150 MHz CDCl ):
3.6, 46.2, 46.4, 56.0, 58.3, 96.1, 113.0, 126.8, 127.7, 128.1, 128.2,
29.1, 129.2, 134.1, 136.2, 149.4, 154.5, 177.9, 181.2. ESI-MS : m/z,
cally, the catechol exhibited one, well-defined oxidation wave (A
0.19 V (vs. SCE) corresponding to the transformation of catechol
1a) to o-benzoquinone (2a), which was reduced in the cathodic sweep
1
) at
2
+
+
+
81.1 (M +Na), 359.1 (M +1). IR(KBr): 3368, 3032, 2873, 2371,
(
(
345, 1597, 1536, 1496, 1450, 1364, 1352, 1318, 1260, 1234, 1155,
1–10
C
1
) at +0.13 V (vs. SCE). Previously,
it has been concluded that
−1
070, 1027, 953, 893, 820, 734, 697 and 464 cm
.
the number of electrons involved in the oxidation of catechol and
its simple derivatives is two. The oxidation of catechol (1a) in the
1
,4-dibenzyl-5-methoxy-1,2,3,4-tetrahydroquinoxaline-6,7-dione
1
2
presence of N ,N -dibenzylethane-1,2-diamine (3) as a nucleophile
1
(
(
4
7
5
1
C
23
H
22
N
2
O
3
) (6c).— Isolated yield = 92.6%, H NMR, δ ppm
600 MHz CDCl ): 3.40 (d, 2H), 3.51 (d, 2H), 3.62 (s, 3H, methyl),
.54 (s, 2H), 4.91 (s, 2H), 5.42 (s, 1H), 7.19 (d, 4H), 7.29 (m, 2H),
1
2
was studied in some detail. When an equivalent amount of N ,N -
dibenzylethane-1,2-diamine (3) was added in aqueous solution con-
3
taining 0.2 M phosphate buffer (pH 7.0), the cathodic counterpart C
of the anodic peak A disappeared (Fig. 1 curve (b)). Additionally, in
the negative scan, the voltammogram exhibited a new cathodic peak
) at −0.37 V vs. SCE. In the second cycle, a new anodic peak (A
appeared with an E
1
13
3
.36 (m, 4H). C NMR, δ ppm (150 MHz CDCl ): 46.9, 47.3,
6.6, 58.0, 60.5, 96.2, 126.8, 127.2, 127.8, 128.3, 128.9, 129.2,
1
2
33.9, 134.7, 136.7, 139.7, 152.6, 175.6, 177.3. ESI-MS : m/z, 397.1
(
C
0
0
)
+
+
(
M +Na), 357.1 (M +1). IR(KBr): 3061, 3026, 2982, 2935, 1952,
p
value of −0.28 V vs. SCE (Fig. 2 curve (b)). This
1
1
5
602, 1529, 1467, 1422, 1361, 1317, 1277, 1193, 1171, 1155, 1096,
peak is related to oxidation of intermediate 5a.
087, 1026, 969, 952, 931, 839, 819, 797, 756, 728, 693, 609, 589,
45, 509 and 460 cm
1
Furthermore, it was observed that the height of C peak in-
−
1
.
creased proportional to the augmentation of the potential sweep rate
1
2
(
Fig. 3 curve (a-g). A similar situation was observed when the N ,N -
Results and Discussion
dibenzylethane-1,2-diamine (3) to 1a concentration ratio decreased.
1
2
Chemical synthesis of N ,N -dibenzylethane-1,2-diamine (3).—
The synthesis of a Schiff base is a classical reaction. It is often
carried out with catalysis and generally by refluxing a mixture of
an aldehyde (or ketone) and an amine.
of compound 3 was achieved using a Schiff base chemical reaction
The variation of the peak current ratio (IpC1/IpA1) versus the scan
1
2
rate for a mixture of catechol (1a) and N ,N -dibenzylethane-1,2-
1
2
diamine confirms the reactivity of 2a toward N ,N -dibenzylethane-
1,2-diamine (3), appearing as an increase in the (IpC1/IpA1) ratio at
higher scan rates.
42,43
The chemical synthesis
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G34
Journal of The Electrochemical Society, 160 (1) G32-G36 (2013)
Figure 4. Cyclic voltammograms of 1.0 mM catechol in the presence of
1.0 mM N ,N -dibenzylethane-1,2-diamine in buffered solutions with various
Figure 2. Cyclic voltammograms of: (a) first cycle and (b) second cycle of
1
2
1
2
1
.0 mM catechol (1a) in the presence of 1.0 mM N ,N -dibenzylethane-1,2-
pHs. pH from (a) to (d) are 3, 5, 6 and 7, respectively. Ionic strength; 0.2 M.
diamine (3), at a glassy carbon electrode (1.8 mm diameter) in the 0.2 M
−
1
◦
−
1
Scan rate: 100 mVs ; T = 25 ± 1 C.
phosphate buffer solution (KH2PO4/K2HPO4) pH = 7. Scan rate: 25 mVs
;
◦
T = 25 ± 1 C.
0
.25 mmol of 3 at controlled potential (0.45 V vs. SCE). Based on
−
our controlled-potential coulometric analysis (consumption of 6e per
molecule of catechol) we assumed that the anodic oxidation of cat-
echols in the presence of N ,N -dibenzylethane-1,2-diamine follows
Cyclic voltammograms of 1.0 mM catechol (1a) in the presence
of 1.0 mM of 3 at various pHs are shown in Fig. 4. As is shown,
1
2
with increasing pH, the height of the anodic peak (A
the height of cathodic peak (C ) decreases and a new cathodic peak
) appears at more negative potentials. This behavior is related to
1
) increases,
31
the ECECE mechanism. These observations allow us to propose
1
the pathway illustrated in Scheme 1 for the electrooxidation of 1a
(C
0
in the presence of 3. According to the obtained results, it seems that
deprotonation of 3 and its activation toward a Michael addition reac-
tion with 3 that leads to formation of the product with more negative
oxidation potential. The rate of this intermolecular Michael addition
increases with increasing pH. As shown in Fig. 4, at neutral pHs de-
sired reaction is adequately fast. The height of the cathodic peaks
also shows that reaction is in the transition region between the dif-
fusion and kinetic situations and suitable for voltammetric study. In
basic solutions, the coupling of anionic or dianionic forms of cate-
chols with o-benzoquinone 2a (dimerization reaction) competes with
1
2
the Michael addition reaction of N ,N -dibenzylethane-1,2-diamine
3) to o-quinone (2a) (Scheme 1, Eq. (2)) is faster than other secondary
(
R
R
OH
OH
-
+
O
O
-
2e , -2H
(1)
1a-1c
2a-2c
O
HO
N
OH
R
50
Michael addition of 3 o-benzoquinone 2a. Because of the decrease
in the rate of the dimerization reaction and the increase in the rate of
the Michael addition reaction between 3 and o-benzoquinone 2a the
solution containing phosphate buffer (pH 7.0, c = 0.2 M) was selected
as the medium for a detailed electrochemical study.
NH HN
+
(2)
O
HN
R
a-2c
3
2
3
a-3c
Controlled-potential coulometry was performed in aqueous solu-
tion containing 0.2 M phosphate buffer (pH 7), 0.25 mmol of 1a and
HO
N
OH
O
N
O
R
R
-
+
-
2e , -2H
HN
HN
(3)
3
a-3c
4a-4c
HO OH
O
N
O
R
R
HN
N
N
(4)
4a-4c
5a-5c
HO
N
OH
O
O
N
R
R
-
+
-
2e , -2H
(5)
N
N
5a-5c
6a-6c
Figure 3. Typical cyclic voltammograms of 1.0 mM catechol (1a) in the pres-
ence of 1.0 mM N ,N -dibenzylethane-1,2-diamine (3) in water containing of
1a-6a: R= -H
1b-6b: R= -CH3
1
2
1
c-6c: R= -OCH3
0
.2 M phosphates (KH2PO4/K2HPO4) as the buffer and supporting electrolyte
(
(
±
pH = 7); at a glassy carbon electrode and at various scan rates. Scan rate from
−1
a) to (g) are 10, 25, 50, 100, 250, 500 and 1000 mVs , respectively. T = 25
Scheme 1. Proposed mechanism for the electrooxidation of catechols (1a-1c)
in the presence of N ,N -dibenzylethane-1,2-diamine (3).
◦
1
2
1 C.
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Journal of The Electrochemical Society, 160 (1) G32-G36 (2013)
G35
HO
N
OH
O
N
O
HOOC
OH
OH
-
+
HOOC
O
O
-
2e , -2H
R
R
R
R
O
O
OH
OH
(
1)
HN
+
HN
+
1d
2d
3a-3c
2a-2c
4a-4c
1a-1c
HO
N
OH
O
N
O
HOOC
O
O
NH
NH
NH
COOH
R
R
+
N
+
(2a-2c or 4a-4c)
N
+
(1a-1c or 3a-3c) (2)
N
2
d
OH
5a-5c
6a-6c
OH
3
d
Scheme 2. The possible oxidation of 3a-3c and 5a-5c through a solution
3
electron transfer (SET) reaction.
-
+
-
2e , -2H
reactions, leading to the adduct 3a. The adduct 3a then undergoes the
abstraction of a second pair of electrons, leading to o-benzoquinone
4
a. The intramolecular addition of 3 to 4a leads to the formation of the
NH
N
N
N
OH
-CO2
COOH
quinoxalinediol derivative 5a, and further oxidation of this compound
produces the final product 6a. Moreover, the oxidation of 3a and 5a
may take place through a solution electron transfer (SET) reaction
OH
5
a
O
(Scheme 2, Eqs. (1) and (2)).
O
4
d
Electrochemical oxidation of other catechol derivatives (1b,1c) in
-
+
-
2e , -2H
the presence of 3.— The electrooxidation of 1b and 1c in the presence
1
2
of N ,N -dibenzylethane-1,2-diamine (3) proceeds in a way similar
to that of 1a. The o-benzoquinone formed via oxidation can act as a
Michael acceptor toward nucleophiles yielding substituted catechols.
In the cases of 1b and 1c, the presence of a methyl or methoxy group
as an electron-donating substituent on the molecular ring causes a
diminution in activity of o-quinones 2b and 2c as Michael acceptors
toward the 1,4-addition of 3. These reactions can be followed by cyclic
voltammetry.
N
N
O
O
6
a
Electrochemical oxidation of 3,4-dihydroxybenzoic acid (1d) in
the presence of 3.— For the study of the effect of the presence of a
carboxylic group in a reactive site of catechol ring, the electrochem-
ical oxidation of 3,4-dihydroxybenzoic acid (1d) has been studied
in the presence of 3. Cyclic voltammogram of 3,4-dihydroxybenzoic
acid 1d in phosphate buffer solution (pH 7.0, 0.20 M,) in the pres-
ence of 3 shows the same condition as reported for catechol. Also,
other voltammetry and coulometry data are as same as previous case.
According to obtained electrochemical data in accompany with spec-
troscopic data of final product, we propose an ECECE mechanism
with an electro-decarboxylation reaction for the electrooxidation of
Scheme 3. Proposed mechanism for the electrooxidation of 3,4-
dihydroxybenzoic acid (1d) in the presence of N ,N -dibenzylethane-1,2-
diamine (3).
1
2
ported by the Research University Grants, UKM-DIP-2012-22 (Sin-
tesis dan Katalisis), and UKM-DLP-2012-024.
1d in the presence of 3 (Scheme 3).
References
1
2
3
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Conclusions
The importance of quinoxalinedione derivatives as valuable
33–36
drugs
prompted us to synthesis a number of these compounds. The
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