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 highpowered 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, curves 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 parentstarting molecule 1a, b by virtue of the presence of an electrondonating 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 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 NH₂ and X to C=O groups. Finally, elimination of two molecules of H₂O leads to the final products 12a, b (Scheme 1). According to the coulometric results, voltametric and spectroscopic 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 energyefficiencyand using the graphite electrode as an electron source instead of toxic catalysts, areinaccordancewith the principle of green chemistry. Cyclic voltammetry, controlledpotential coulometry and spectroscopic data indicated that the electrochemical oxidation of phenylamine derivatives (1a and 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 Metwally et al. (Scheme 2) via cyclization of ethoxycarbonylacetohydrazide using sodium methoxide [16]. The spectroscopic data (¹H and ¹³C NMR) and melting point confirmed synthesis of this compound (3), according to Ref. [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 preelectrolyzed 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 electrosynthesis (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 placed in the refrigerator (T=4±1℃) 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℃ (dec). FT-IR (KBr, cm^-1): 3417 (NH), 1660 (C=O, amide), 1570 and 1480 (C=C aromatic). ¹H NMR (400 MHz, DMSO-d₆): δ 7.63 (s, 2H, aromatic), 10.03 (s, broad, 2H, NH pyrazolidine ring), 10.52 (broad, 2H, NH, pyrazolidine ring), 11.28 (s, 2H, NH phenylamine ring). ¹³C NMR (100 MHz, DMSO-d₆): δ 110.6, 112.2, 117.7, 122.6, 129.2, 166.6. MS (EI, m/z) (relative intensity): 269 (M+, 19), 186 (70), 156 (62), 108 (45), 54 (55). Anal. Calcd. for C₁₂H₈N₆O₂: 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℃ (dec). FT-IR (KBr, cm^-1): 3390 (NH), 1664 (C=O, amide), 1570 and 1443 (C=C aromatic). ¹H NMR (400 MHz, DMSO-d₆): δ 7.58 (s, 1H, aromatic), 7.88 (s, 2H, aromatic), 10.04 (s, broad, 2H, NH pyrazolidine ring), 10.38 (broad, 2H, NH, pyrazolidine ring), 11.24 (s, 1H, NH phenylamine ring). ¹³C NMR (100 MHz, DMSO-d₆): δ 110.2, 110.3, 113.3, 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), 94 (80), 54 (60). Anal. Calcd. for C₁₂H₇N₅O₃: C, 53.54; H, 2.62; N, 26.01. Found: C, 53.57; H, 2.57; N, 25.93.

Acknowledgment

The authors thank from Semnan University Research Council for financial support of this work.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2016.11.022.