A new approach for one-pot, green synthesis of new polycyclic indoles in aqueous solution

Article abstract of DOI:10.1016/j.cclet.2016.11.022

Electro-oxidation of phenylamine derivatives (1a and 1b) have been studied in the presence of pyrazolidine-3,5-dione (3) as a nucleophile in phosphate buffer solution mixed with ethanol, using voltammetric and spectroscopic techniques. The obtained results indicated that the oxidized form of phenylamines (2a and 2b) participate in Michael addition type reactions with pyrazolidine-3,5-dione (3) and via ECECCCCC mechanisms convert to the corresponding new polycyclic indoles (12a and 12b). In the present study, new polycyclic indole derivatives were synthesized with good yields and high purity using a facile, one-pot and environmentally friendly electrochemical method, without any chemical catalysts, toxic solvents and hard conditions.

Full text of DOI:10.1016/j.cclet.2016.11.022

Accepted Manuscript
Title: A new approach for one-pot, green synthesis of new
polycyclic indoles in aqueous solution
Author: Mohsen Ameri Alireza Asghari Ali Amoozadeh
Mohammad Bakherad
PII:
S1001-8417(16)30409-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2016.11.022
CCLET 3896
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
29-7-2016
24-10-2016
31-10-2016
Please cite this article as: Mohsen Ameri, Alireza Asghari, Ali Amoozadeh,
Mohammad Bakherad, A new approach for one-pot, green synthesis of
new polycyclic indoles in aqueous solution, Chinese Chemical Letters
http://dx.doi.org/10.1016/j.cclet.2016.11.022
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Original article
A new approach for one-pot, green synthesis of new polycyclic indoles in aqueous solution
a
a*
a
b
Mohsen Ameri , Alireza Asghari , Ali Amoozadeh , Mohammad Bakherad
a
Department of Chemistry, Semnan University, Semnan 35195-363, Iran
College of Chemistry, Shahrood University of Technology, Shahrood, Iran
b

Corresponding author.
E-mail address: aasghari@semnan.ac.ir (A. Asghari)
Graphical abstract
Electro-oxidation of phenylamine derivatives have been studied in the presence of pyrazolidine-3,5-dione as a nucleophile in
phosphate buffer solution mixed with ethanol, using voltammetric and spectroscopic techniques.
ABSTRACT
Electro-oxidation of phenylamine derivatives (1a-1b) have been studied in the presence of pyrazolidine-3,5-dione (3) as a nucleophile in
phosphate buffer solution mixed with ethanol, using voltammetric and spectroscopic techniques. The obtained results indicated that the
oxidized form of phenylamines (2a–2b) participate in Michael addition type reactions with pyrazolidine-3,5-dione (3) and via ECECCCCC
mechanisms convert to the corresponding new polycyclic indoles (12a-12b). In the present study, new polycyclic indole derivatives were
synthesized with good yields and high purity using a facile, one-pot and environmentally friendly electrochemical method, without any
chemical catalysts, toxic solvents and hard conditions.
Keywords:
Electro-oxidation
Phenylamine
Polycyclic indoles
Environmentally friendly
ECECCCCC mechanism
1

1
. Introduction
The indole moiety is a privileged structural motif in many biologically active and medicinally valuable molecules [1, 2]. Polycyclic
frameworks lead to relatively rigid structures that might be expected to show substantial selectivity in their interactions with enzymes
or receptors [3]. Construction of polycyclic indoles usually requires multistep reactions [4]. The preparation of polyfunctional indoles
is therefore an important research field. On the other hand, indole and its derivatives are found in molasses tar and coal tar [5]. Indole
nucleus is also found in amino acids such as tryptophan, plant hormones, and certain important alkaloids [6], as well as in liver,
pancreas [7], brain [8] and bile [9]. Furthermore, indole is a powerful anti-oxidant and appears to be especially effective against breast
and cervical cancer because of its ability to increase the break-down of estrogen in the human body [10]. Electrochemistry has
recognized as a high-powered tool to develop environmentally friendly processes [11, 12]. Graphite electrode may be regarded as a
catalyst (non-toxic and safe) that is easily separated from the obtained product. Hence, it can be concluded that electro-synthesis is a
green and safe waste approach for synthesis of various organic compounds. Over the last two years, electro-oxidation of phenylamine
derivatives such as p-phenylenediamines, 4-aminophenols and 2-aminophenols have been studied in some details, in both the presence
and absence of various compound, based on different electrochemical mechanisms [9, 13-15]. According to the wide applications of
indole derivatives, complexity of chemical synthesis of polycyclic indoles and importance of green chemistry in the recent years, we
encouraged to develop a facile, non-catalyst, easy handling, clean, safe waste, one-pot and fast method for the electrochemical
synthesis of new polycyclic indoles. In this way, the electrochemical oxidation of phenylamine derivatives (1a-b) has been investigated
in the presence and absence of pyrazolidine-3,5-dione (3) as a nucleophile under mild conditions (no heat, no reflux, no pressure and
without any chemical catalyst) in a mixture of phosphate buffer solution with ethanol as a green medium.
2
. Results and discussion
A cyclic voltammogram of 2 mmol/L of 4-aminophenol (1a) in a phosphate buffer solution (0.15 mol/L, pH 7.0) mixed with EtOH
(70:30, v/v) shows one anodic (A1) and corresponding cathodic peak (C1), which are related to the transformation of 4-aminophenol
(1a) to 4-iminocyclohexa-2,5-dienone (2a) and vice versa within a quasi-reversible 2e- process (Fig. 1, curve a). A peak current ratio
(IpC1/IpA1) of nearly unity, particularly during the recycling of potential, can be considered as criteria for the stability of 4-
iminocyclohexa-2,5-dienone (2a) formed at the surface of the working electrode (GC) under the optimum experimental conditions. In
other words, any side reactions [9, 13-15] are too slow to be observed in the time scale of cyclic voltammetry. The electro-oxidation of
4
-aminophenol (1a) in the presence of 3,5-pyrazolidinedione (3) was investigated in detail. As can be seen, curve b (Fig. 1) shows the
cyclic voltammogram obtained for solution of 2 mmol/L of 1a in the presence of 4 mmol/L of 3,5-pyrazolidinedione (3) as a
nucleophile. Under experimental conditions, the cathodic counterpart of anodic peak A1 decreases and a new cathodic peak (C0)
appears at potentials more negative than cathodic peak (C1) which is related to electrochemical reduction of intermediate 6a to 5a.
Furthermore, in Fig. 1, curve c shows the cyclic voltammogram obtained for a solution of 2 mmol/L of 3,5-pyrazolidinedione (3) in the
absence of 4-aminophenol (1a) under experimental condition for comparison. The same electrochemical behavior was seen (Fig. 1,
curve d and e) for 1,4-diaminobenzene (1b) in the absence and presence of 3,5-pyrazolidinedione (3) in a phosphate buffer solution
(0.15 mol/L, pH 6.0) mixed with EtOH (70:30 v:v).
The cyclic voltammograms of 2 mmol/L of 4-aminophenol (1a) in the presence of 4 mmol/L of 3,5-pyrazolidinedione (3) are shown
in Fig. 2, at various scan rates. It can be seen that proportional to the raising of the scan rate in parallel with the decrease in the height
of C0 peak (cathodic peak of intermediate), the height of the cathodic (C1) peak of 4-aminophenol (1a) increases. A similar situation is
also seen when the pyrazolidinedione (3) to 4-aminophenol (1a) concentration ratio is decreased (data not shown). In other words,
increasing current ratio IpC1/IpA1 with the increasing scan rate is a good indication of the reactivity of 3 toward 4-iminocyclohexa-
2
,5-dienone (2a).
Controlled-potential coulometry was carried out in phosphate buffer solution (0.15 mol/L, pH 7) mixed with EtOH (70:30, v/v),
containing 0.5 mmol of 4-aminophenol (1a) and 1 mmol of 3,5-pyrazolidinedione (3), at 0.3 V vs. Ag/AgCl (3 mol/L) electrode. In the
case of 1b, coulometry was carried out in phosphate buffer solution with pH 6 mixed with ethanol containing 0.5 mmol of 1b and 1
mmol of 3 at 0.3 V. The electro-synthesis progress was monitored by using cyclic voltammetry technique (Fig. 3). It is shown that,
proportionally to the progress of coulometry, under constant potential, the anodic peak (A1) decreases and disappears when the charge
consumption becomes about 4e− per molecule of 1b, and the new anodic peak (A0) is related to the electrochemical oxidation of
intermediate 5b to 6b (Scheme 1).
Regarding the results, it seems that the 1,4-Michael addition reaction of 3a to 2a, b is faster than the other side reactions and leads
to the formation of intermediates 5a, b. The oxidation of these compounds (5a, b) is easier than the oxidation of the parent-starting
molecule 1a, b by virtue of the presence of an electron-donating group [17-20]. Hence, 5a, b can be oxidized on the surface of
electrode and produces 6a, b. This step causes the apparent numbers of transferred electrons to increase from the limit of n=2 to n=4
2

electrons per molecule of 1a, b. Then, 1,4-Michael addition reaction [21] of the second molecule of 3a to 6a, b is followed by two
intramolecular cyclizations originating from two nucleophilic attacks of NH and X to C=O groups. Finally, elimination of two
molecules of H O leads to the final products 12a, b (Scheme 1). According to the coulometric results, voltametric and spectroscopic
2
2
data, the ECECCCCC electrochemical mechanism is proposed for the electrochemical oxidation of phenylamine derivatives (1a, b) in
the presence of 3,5-pyrazolidinedione (3), under experimental optimum condition (Scheme 1).
3
. Conclusions
The prominent features of this work such as the one-pot, simple electrochemical synthesis of polycyclic indole derivatives in
aqueous/ethanol mixture instead of toxic solvents, at room temperature, high energy efficiency and using the graphite electrode as an
electron source instead of toxic catalysts, are in accordance with the principle of green chemistry. Cyclic voltammetry, controlled-
potential coulometry and spectroscopic data indicated that the electrochemical oxidation of phenylamine derivatives (1a-1b) in the
presence of 3,5-pyrazolidinedione (3) were adopted with ECECCCCC mechanism (Scheme 1). Four-electron process of the
electrochemical mechanism reaction was confirmed by coulometry, under constant potential data. In the present study, the obtained
results explained that the electrochemistry can be applied as a green method for facile, high yield, safe waste, catalyst-free, rapid and
one-pot synthesis of organic compounds, under mild conditions. In addition, this work introduces electrochemistry as a “powerful tool”
for the synthesis of new supra heterocyclic compounds such as polycyclic indole derivatives.
4
. Experimental
4
.1. Apparatus and reagents
The reaction equipment was used as described in the Supporting information. All chemical materials were purchased from Merck
(Darmstadt, Germany). These chemicals were used without further purification.
4
.2. Typical procedure for the chemical synthesis of pyrazolidine-3,5-dione (3)
As an important starting material in this work, 3,5-pyrazolidinedione (3) was prepared according to the mechanism proposed by
1
Metwally et al. (scheme 1) via cyclization of ethoxycarbonylacetohydrazide using sodium methoxide [16]. The spectroscopic data ( H
1
3
and C NMR) and melting point confirmed synthesis of this compound (3), according to reference 16 (data not shown).
4
.3. Typical procedure for the electrochemical synthesis of indoles (12a, 12b)
In the proposed method, 100 mL of phosphate buffer solution (0.15 mol/L) mixed with ethanol (80:20, v/v), as supporting electrolyte
(in the case of 12a pH 7 and 12b pH 6), was pre-electrolyzed at the 0.3 V vs. Ag/AgCl in an undivided cell. Then, 0.2 mmol of 4-
aminophenol (1a) or 1,4-diaminobenzene (1b) and 0.4 mmol of 3,5-pyrazolidinedione (3) were added to the electrochemical cell.
Finally, the electrochemical synthesis under constant potential was performed using the 0.3 V vs. Ag/AgCl. The electrolysis was
finished when the current decreased more than 95%. The process was interrupted several times during the electro-synthesis (for
ensuring to complete the reaction), and the working electrodes (five carbon anodes) were washed in ethanol to reactivate (to clear the
surface of working electrode from formed side products such as polymers). At the end of electrolysis, the electrochemical cell was
o
placed in the refrigerator (T= 4±1 C) for 24 h. The precipitated solid was collected by filtration and washed with warm
etanol/acetonitrile (1:1, v/v) to separate the remained 4-aminophenol (1a) or 1,4-diaminobenzene (1b). Then, it was washed several
times with cold water to more purification. After purification, the products (12a and 12b) were characterized using FT-IR, mass
spectroscopy (MS), elemental analysis (CHN), NMR.
4
.4. Characterization of products
Compound 12a: Yield: 83%. Mp> 260 °C (dec). FT-IR (KBr, cm ): 3417 (NH), 1660 (C=O, amide), 1570 and 1480 (C=C
-
1
1
aromatic). H NMR (400 MHz, DMSO-d
pyrazolidine ring), 11.28 (s, 2H, NH Phenylamine ring). 13C NMR (100 MHz, DMSO-d
6
): δ 7.63 (s, 2H, aromatic), 10.03 (s, broad, 2H, NH pyrazolidine ring), 10.52 (broad, 2H, NH,
): δ 110.6, 112.2, 117.7, 122.6, 129.2, 166.6.
6
8 6 2
MS (EI, m/z) (relative intensity): 269 (M+, 19), 186 (70), 156 (62), 108 (45), 54 (55). Anal. Calcd. for C12H N O : C, 53.73; H, 3.01;
N, 31.33. Found: C, 53.69; H, 3.07; N, 31.27.
Compound 12b: Yield: 78%. Mp> 260 °C (dec). FT-IR (KBr, cm ): 3390 (NH), 1664 (C=O, amide), 1570 and 1443 (C=C
-
1
1
aromatic). H NMR (400 MHz, DMSO-d
6
): δ 7.58 (s, 1H, aromatic), 7.88 (s, 2H, aromatic), 10.04 (s, broad, 2H, NH Pyrazolidine
): δ 110.2, 110.3,
13.3, 117.6, 123.3, 124.6, 125.3, 131.5, 141.5, 143.3, 166.2, 166.9. MS (EI, m/z) (relative intensity): 270 (M+, 28), 187 (76), 161 (55),
4 (80), 54 (60). Anal. Calcd. for C12 : C, 53.54; H, 2.62; N, 26.01. Found: C, 53.57; H, 2.57; N, 25.93.
ring), 10.38 (broad, 2H, NH, pyrazolidine ring), 11.24 (s, 1H, NH phenylamine ring). 13CNMR (100 MHz, DMSO-d
6
1
9
7 5 3
H N O
Acknowledgment
The authors thank from Semnan University Research Council for financial support of this work.
3

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4

3
2
1
5
5
5
5
5
A1
A1
2
1
5
5
5
e
b
e
d
a
c
c
-
C0
-5
-
15
25
C0
C1
C1
-15
-
-0.2
0
0.2
0.4
-0.4
-0.1
0.2
0.5
E/ V vs. Ag/AgCl
E/ V vs. Ag/AgCl
Fig. 1. Typical cyclic voltammograms of 2 mmol/L 4-aminophenol (1a) in the absence (a), in the presence of 4 mmol/L 3,5-pyrazolidinedione (b), that
of a 2 mmol/L 3,5-pyrazolidinedione (3) in the absence of 1a (c), cyclic voltammograms of 1,4-diaminobenzene (1b) in the absence (d) and in the
-1
presence of 4 mmol/L 3,5-pyrazolidinedione (e) at the glassy carbon electrode under experimental conditions at a scan rate of 50 mVs .
5

4
3
2
1
5
5
5
5
5
5
A1
f
a
-
C0
-
15
25
C1
-
-0.35 -0.15
0.05
0.25
0.45
E/ V vs. Ag/AgCl
Fig. 2 Typical voltammograms of 2 mmol/L 4-aminophenol (1a) in the presence of 3,5-pyrazolidinedione (3) at the glassy carbon electrode, in 0.15
-1
mol/L phosphate buffer solution (pH 7) mixed with ethanol (80:20 v:v) at different scan rates a) 10, b) 25, c) 50, d)80, e) 100 and f) 150 mVs .
6

2
2
1
1
8
3
8
3
8
3
2
7
30
A1
a
a
g
2
2
1
1
5
0
5
0
5
0
b
c
d
end of
electrolysis
e
f
f
A0
-
-
C0 C1
0
25 50 75 100
Charge/ C
-0.2
0.3
0.8
E/V vs. Ag/AgCl
Fig. 3 Cyclic voltammogram of 0.2 mmol 1,4-diaminobenzene (1b) in the presenceof 0.4 mmol of 3,5-pyrazolidinedione (3), at glassy carbon
electrode in 0.15 mol/L phosphate buffer solution (pH 6) mixed with ethanol (80:20, v:v) during controlled-potential coulometry at 0.3 V vs. Ag/AgCl
(
scan rate: 50 mV/s). After the consumption of a) 0, b) 6, c) 15, d) 23, e) 38 and f) 47 C. Progress of coulometry is associated with decreased anodic
peak (A1) current. Curve g shows variation of anodic peak current (A1) versus charge consumed.
7

Scheme 1. Proposed mechanis.
8

Scheme 2. Synthesis of 3,5-pyrazolidinedione.
9