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Green electrosynthesis of bis(indolyl)methane derivatives in deep eutectic solvents

BMC Chemistry volume 18, Article number: 139 (2024) Cite this article

Abstract

In this study, a new green method was developed for the synthesis of bis(indolyl)methane derivatives using electrochemical bisarylation reaction in deep eutectic solvents as a green alternative to traditional solvents and electrolytes. The effects of varying time, current, type of solvent and material of electrodes were all studied. The optimum reaction conditions involved the use of ethylene glycol/choline chloride with a ratio of 2:1 at 80 °C for 45 min. Graphite and platinum were used as cathode and anode, respectively. The newly developed method offered many advantages such as using mild reaction conditions, short reaction time and affording high product yields with a wide range of substituted aromatic aldehydes bearing electron donating or electron withdrawing substituents. In addition, the electrochemical method proved to be more effective than heating in deep eutectic solvents and afforded higher yields of products in shorter reaction time. The mechanism of the electrochemical reaction was proposed and confirmed using the cyclic voltammetry study.

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Introduction

The 3,3ʹ-bis(indolyl)methanes (BIMs) represent an important biologically active scaffold owing to its various biological activities [1, 2]. Many bisindolylmethane alkaloids were isolated from marine natural sources (Fig. 1) [3, 4]. BIM derivatives were reported to exhibit anticancer [5,6,7,8,9,10,11,12,13], antibacterial [14,15,16], antifungal, antileishmanial [17], nematocidal activity [18], antioxidant [12, 19], analgesic and anti-inflammatory activities [20, 21]. Additionally, BIMs displayed enzyme inhibitory activity against human carboxylesterase (CES1 and CES2) [22]. The application of BIMs in analytical chemistry involved their use as chemosensors for transition metal cations [23] and for Cu2+ ions [24]. The oxidized BIMs could act as selective colorimetric sensors either for fluoride ions in an aprotic solvent or for hydrogen sulfate ions in water [25].

Fig. 1
figure 1

Bis(indolyl)methane derivatives isolated from natural sources

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BIMs are prepared by alkylation of indole with aldehyde or ketone. Usually, a Lewis acid or protic acid such as HCl [5] and sulphuric acid [26] are used to catalyze the reaction. However, the use of these acids has many environmental hazards in addition to long reaction times, low yield, and difficult reaction work-up. Therefore, many catalysts were reported in the literature for the synthesis of BIMs aiming to shorten the reaction time and increase the yield with minimal hazard to the environment. Examples included the use of metal salts such as RuCl3 [27]; nickel-iodide NiI2 [28], hydrated ferric sulfate [29], lithium perchlorate [30], and aluminium triflate [16]. The reaction was catalyzed by some inorganic salts such as NaHSO3 [20, 21], KHSO4 [23], tetrabutylammonium hydrogen sulfate [31], and boric acid [32]. Other green catalysts used include oxalic acid dihydrate and N-cetyl-N,N,N-trimethylammonium bromide [5], Meldrum’s acid-induced and FeCl3-catalyzed domino reactions [33], p-toluene sulfonic acid [14, 19], squaric acid [34] and citric acid [35]. Heterogeneous catalysts like polymer supported dichlorophosphate (PEG-OPOCl2) [6], perlite-polyphosphoric acid (EP-PPA) [36], Amberlyst-15 [26, 37], silica supported-boron sulfonic acid [38], Fe-pillared interlayered clay (Fe-PILC) [17] and zeolite [39] were all used to catalyze the reaction.

Moreover, some green chemistry approaches were applied to prepare BIMs. This included the use of visible light for 3–5 h [22], and the use of microwave irradiation for 6–10 min in the presence of surfactant like sodium bis-2-ethyl hexyl sulphosuccinate [40]. The use of ultrasonication was also widely applied for the synthesis of BIMs. Examples included the use of ultrasonication either in acetic acid/water at 40 °C for 2–8 h [18] or in water and dodecylbenzenesulfonic acid catalyst at room temperature for 10–30 min [41]. BIMs were also prepared using the green natural catalyst taurine (NH2CH2CH2SO3H) in water under ultrasonic irradiation [42]. The ultrasonic irradiation using p-toluene sulfonic acid in acetonitrile was also reported [19]. Biocatalysis of the reaction involved the use of enzymes like α-chymotrypsin [43] and lipase [44].

Ionic liquids can serve as both solvents and catalysts to prepare BIMs [45,46,47,48]. Deep eutectic solvents (DESs) are considered a green alternative to ionic liquids. They are formed of H-bond donor and acceptor that interact to produce a low melting eutectic mixture. They are characterized by being nontoxic, easily prepared, recyclable, and eco-friendly [49,50,51,52,53,54,55]. The synthesis of BIM derivatives was performed in choline chloride-urea (1:2) at 70 °C for 4 h [56], choline chloride-SnCl2 (1:2) at room temperature for 60–200 min [57] and l-(+)-tartaric acid-dimethyl urea (3:7) at 70 °C for 2 h [58].

On the other hand, organic electrochemistry is considered a clean, atom-economic, and environment-friendly method of synthesis. The electrochemical synthesis relies on the use of electrons as a reactant and energy source, thereby reducing the time and energy needed for the reaction. The method was widely used in the last two decades for the synthesis of organic compounds [59,60,61,62,63,64,65,66]. To date, two publications reported the synthesis of BIMs under electrochemical conditions. The first was published in 2018 by Du and Huang [67] who reported the reaction of indole and ether under electrochemical conditions using LaCl3 as a catalyst., The authors utilized platinum as anode and cathode and lithium perchlorate as a supporting electrolyte. The reaction was conducted in THF-acetonitrile at room temperature under 5 mA constant current for 6.5 h. In 2022, Jat et al. [68] reported the BIMs synthesis using graphite as anode and cathode in acetonitrile for 90 min. Lithium perchlorate was used as a supporting electrolyte and the reaction was conducted at room temperature under a 10 mA constant current.

In continuation of our interest in developing new methods of synthesis based on electrochemical reactions [69,70,71,72], we reported herein the first synthesis of BIM derivatives under electrochemical conditions in DESs (Scheme 1). The method was characterized by being atom economic and environmentally friendly. The products were obtained in high yields in short reaction time and the reaction tolerated a wide scope of substrates.

Scheme 1
scheme 1

Synthesis of bis(indolyl)methane derivatives 3a-n

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Results and discussion

Reaction of indole and benzaldehyde in deep eutectic solvents

The reaction of two molar equivalents of indole (1) and one molar equivalent of benzaldehyde (2a) in different DESs was investigated as a preliminary study. The reaction was conducted by heating at 80 °C in a water bath. The results are presented in Table 1. The best result was obtained upon using ethylene glycol/ choline chloride (2:1) as a solvent with a 50% yield.

Table 1 Synthesis of bisindolylmethane 3a in DESs
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Electrochemical reaction of indole and benzaldehyde in deep eutectic solvents

The reaction of two molar equivalents of indole (1) and one molar equivalent of benzaldehyde (2a) in DESs was studied as a model reaction. The temperature was adjusted to 80 °C to ensure the complete dissolution of the starting materials. Four types of DESs were examined. Choline chloride was mixed with urea, ethylene glycol, propylene glycol, or glycerol in a ratio of 1:2 to form DESs. The reaction was conducted at 10 mA and 30 mA at different times and using different electrode materials. TLC was used to monitor the progress of the reaction. The results are presented in Table 2.

Table 2 Synthesis of bisindolylmethane 3a in DESs using electrochemical conditions
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The effect of the reaction time was investigated (Entry 1–5). Conducting the reaction in choline chloride/ethylene glycol for 15 min., 30 min. and 45 min. (Entry 1–3) resulted in the production of compound 3a in yields of 31, 53 and 62%, respectively. Further increase in the reaction time to either 60 min. or 90 min. (Entry 4 and 5) did not affect the product yield. Therefore, the optimum time was chosen as 45 min. for subsequent experiments.

Next, the effect of varying the type of DES was examined. The results indicated that both ethylene glycol and glycerol gave comparable yields of bisindolyl methane 3a (Entry 3 and 6). However, the reaction was unsuccessful upon using choline chloride/urea or choline chloride/propylene glycol (Entry 7 and 8). These results were consistent with the results in Table 1 where DESs formed of urea and propylene glycol were not efficient. Additionally, the yield obtained under electrochemical conditions was higher (62%) than that obtained by the heating method only (50%) and was obtained in a shorter reaction time (45 min) than the heating method (3 h). As provided in our previous work [69, 72], the use of DESs eliminated the need for supporting electrolytes and shortened the reaction time owing to their catalytic power.

Changing the constant current used from 30 to 10 mA resulted in a lower yield and as expected the reaction needed a longer time to be completed (3 h) (Entry 9, 10).

Finally, the effect of electrode material was investigated. Platinum, copper, and graphite were used as electrodes. The material of the electrode and counter electrode may affect the yield, but the choice of the electrodes was empirical. Therefore, the reaction was performed using different electrodes to optimize the yield of the reaction. The highest yield (71%) was obtained upon using graphite as cathode and platinum as anode (Entry 12). Replacing the graphite cathode with platinum or copper resulted in a decrease in the yield with percentages of 40% and 59%, respectively (Entry 11 and 13). It was noteworthy that the reaction was initiated by anodic oxidation of the indole ring as evidenced by the cyclic voltammetry studies.

The optimum reaction conditions were conducting the reaction at 80 °C at a constant current of 30 mA for 45 min in ethylene glycol/ choline chloride (2:1) deep eutectic solvent in an undivided cell fitted with platinum as anode and graphite as cathode (Entry 12).

Electrochemical synthesis of bisindolylmethane derivatives 3a-n in deep eutectic solvents

The scope of the reaction was investigated using different types of aromatic aldehydes and the results are presented in Table 3. The reactions were conducted using the optimized conditions; Entry 12 in Table 2. All the substituted aldehydes examined afforded higher yields (82–100%) than benzaldehyde (71%). Substitution of the benzaldehyde with electron donating or electron withdrawing groups gave high yields of the products. The heterocyclic indole-3-carbaldehyde gave 82% yield. Aldehydes susceptible to electrochemical oxidation (hydroxybenzaldehydes) or reduction (nitrobenzaldydes) were also reactive and provided products in high yields.

Table 3 Electrochemical synthesis of bisindolylmethane derivatives 3a–n using the optimum reaction conditions
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Compound 3c was prepared on a gram scale. The reaction was completed in 90 min resulting in 98.5% yield.

The 1H NMR spectra revealed the appearance of the methane CH proton at δ 4.77–6.05 ppm and the two NH protons at δ 7.86–10.87 ppm. While the 13C NMR spectra revealed the appearance of the methine carbon at δ 31.38–40.58 ppm.

A comparison between the electrochemical methods reported in the literature and the present method is illustrated in Table 4. The data presented in Table 4 proved the efficiency of the present method in which no catalyst or electrolyte was needed and the reaction was completed in a shorter time. The electrochemical method developed by Jat et al. [68] used lithium perchlorate as electrolyte which is expensive, hazardous and toxic. Whilst, the present study relied on the use of the deep eutectic solvent ethylene glycol / choline chloride which is ecofriendly, more economic and served as a solvent and a supporting electrolyte.

Table 4 The different electrochemical conditions used for the synthesis of bisindolylmethanes
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Investigation of the reaction mechanism

The reaction started with anodic oxidation of the indole ring to give a radical cation I followed by a loss of a proton to afford the radical II. The latter attacked the carbonyl of the aldehyde molecule. This resulted in the formation of radical III which oxidized another molecule of indole forming another molecule of radical II; while radical III was reduced to the intermediate IV followed by the elimination of a water molecule. The intermediate IV reacted with another indole radical II forming radical VI that finally underwent a cathodic reduction to afford the final product 3 (Fig. 2).

Fig. 2
figure 2

The proposed reaction mechanism for the formation of bisindolylmethane 3a under electrochemical conditions

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The cyclic voltammetry study was consistent with this postulation. Figure 3 showed the cyclic voltammograms of both 10 mM indole, and 10 mM 3,4,5-trimethoxybenzaldehyde at pencil graphite electrode in DES between -0.1 to 1.5 V vs Ag pseudo reference electrode at scan rate 20 mV/s. The results showed a prominent oxidation peak for indole, which started around 0.8 V, while 3,4,5-trimethoxybenzaldehyde showed initiation of oxidation at 1.3 V. These results confirmed that the reaction started by oxidation of indole to produce a cation radical that reacted with the aldehyde to produce the product.

Fig. 3
figure 3

The cyclic voltammograms of 10mM indole and 3,4,5-trimethoxybenzaldehyde in DES at PGE surface vs Ag pseudoreference electrode

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Experimental and methods

Chemicals were purchased from Sigma-Aldrich, USA. The reaction progress was monitored by TLC using precoated aluminum sheet silica gel MERCK 60F 254 (Merck, Germany) and was visualized by UV lamp. The solvent system used was dichloromethane:ethanol [9:1]. Melting points were obtained using Stuart electrothermal melting point apparatus SMP10 and were uncorrected. 1H NMR spectra were conducted using a Bruker Advance 400 MHz NMR spectrometer. 13C NMR spectra were performed using a Bruker Advance 100 MHz spectrometer. Chemical shifts were recorded in ppm on a δ scale using DMSO-d6 as a solvent and coupling constants were recorded (J) in Hz. Element analyses were carried out at the Regional Center for Mycology and Biotechnology, Faculty of Pharmacy, Al Azhar University, Egypt.

Preparation of deep eutectic solvents DESs

Choline chloride was mixed with either ethylene glycol, propylene glycol, glycerol, or urea with a ratio of 1:2, respectively, and heated in a water bath at 80 °C till a homogenous liquid mixture was obtained [69].

Synthesis of compound 3a in DESs

A mixture of indole (1, 2 mmol) and benzaldehyde (1 mmol) in the appropriate DES was reacted at 80 °C for 3h as presented in Table 1. The reaction was traced using TLC. After the completion of the reaction, the mixture was poured into distilled water (50 mL), and the solid formed was filtered and recrystallized from an ethanol–water mixture. The results are reported in Table 1.

Electrochemical synthesis and optimization of compound 3a in DESs

A mixture of indole (1, 2 mmol) and benzaldehyde (1 mmol) in the appropriate DES was reacted in an undivided cell using two variable electrodes at 80 °C for a variable amount of time as presented in Table 2. The reaction was traced using TLC till the reactants' spots disappeared and a new spot for the product appeared. After the completion of the reaction, the mixture was poured into distilled water (50 mL), and the solid formed was filtered and recrystallized from an ethanol–water mixture. The results are reported in Table 2.

Electrochemical synthesis of bisindolyl methanes 3a-n in DESs

A mixture of indole (1, 2 mmol) and the appropriate aldehyde 2a–n (1 mmol) was dissolved in the deep eutectic solvent composed of ethylene glycol and choline chloride with a ratio of 2:1 (10 mL) at 80 °C. The mixture was exposed to an electric current of 30 mA in an undivided cell for 45 min using a platinum anode and a graphite cathode. The reaction was monitored using TLC. The mixture was poured into distilled water (50 mL), and the solid formed was filtered and recrystallized from an ethanol–water mixture to afford compounds 3a–n. The results were reported in Table 3.

Spectral data of bisindolyl methanes 3a–n

3'-(Phenylmethylene)bis(1H-indole) (3a)

Light pink solid; IR: 3414 (NH); 1H NMR (400 MHz, DMSO-d6): δ 5.83 (s, 1H, CH), 6.82–6.87 (m, 4H, ArH), 7.01–7.05 (t, 2H, ArH, J = 8 Hz), 7.15–7.19 (t, 1H, ArH, J = 8 Hz), 7.25–7.28 (t, 4H, ArH, J = 8 Hz), 7.33–7.37 (t, 4H, ArH, J = 8 Hz), 10.81 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 39.3, 111.9, 118.5, 118.6, 119.5, 121.3, 123.9, 126.2, 127.0, 128.4, 128.7, 137.0, 145.4; Anal. Calcd for C23H18N2 (322.40): C: 85.68, H: 5.63, N: 8.69. Anal Found: C: 85.51, H: 5.80, N: 8.95.

3,3′-((4-Chlorophenyl)methylene)bis(1H-indole) (3b)

Light pink solid; IR: 3410 (NH); 1H NMR (400 MHz, DMSO-d6): δ 5.86 (s, 1H, CH), 6.83–6.89 (m, 4H, ArH), 7.02–7.06 (t, 2H, ArH, J = 8 Hz), 7.26–7.28 (d, 2H, ArH, J = 8 Hz), 7.31–7.33 (m, 3H, ArH), 7.35–7.37 (m, 3H, ArH), 10.87 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 39.3, 112.0, 118.0, 118.7, 119.5, 121.4, 124.0, 126.9, 128.4, 130.5, 130.7, 137.0, 144.4; Anal. Calcd for C23H17ClN2 (356.85): C: 77.41, H: 4.80, N: 7.85. Anal Found: C: 77.63, H: 5.01, N: 8.12.

3,3′-((4-Bromophenyl)methylene)bis(1H-indole) (3c)

Buff solid; IR: 3406 (NH); 1H NMR (400 MHz, DMSO-d6): δ 5.83 (s, 1H, CH), 6.83–6.85 (m, 2H, ArH), 6.87–6.89 (t, 2H, ArH, J = 8 Hz), 7.02–7.06 (t, 2H, ArH, J = 8 Hz), 7.26–7.31 (m, 4H, ArH), 7.34–7.36 (d, 2H, ArH, J = 8 Hz), 7.44–7.46 (d, 2H, ArH, J = 8 Hz), 10.87 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 39.5, 112.0, 117.9, 118.7, 119.2, 119.4, 121.4, 124.1, 136.9, 131.0, 131.3, 137.0, 144.9; Anal. Calcd for C23H17BrN2 (401.30): C: 68.84, H: 4.27, N, 6.98. Anal Found C: 69.05, H: 4.43, N: 7.16.

3,3′-((4-Fluorophenyl)methylene)bis(1H-indole) (3d)

Buff solid; IR: 3410 (NH); 1H NMR (400 MHz, CDCl3): δ 5.79 (s, 1H, CH), 6.55—6.56 (m, 2H, ArH), 6.85–6.95 ( m, 4H, ArH), 7.07–7.11 (t, 2H, ArH, J = 8 Hz), 7.17– 7.22 (m, 2H, ArH), 7.26—7.29 (m, 4H, ArH), 7.84 ( s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, CDCl3): δ 39.4, 111.1, 114.8, 115.0, 119.3, 119.5, 119.8, 122.0, 123.6, 126.9, 130.1, 136.7, 139.7; Anal. Calcd for C23H17FN2 (340.39): C: 81.16, H: 5.03, N: 8.23. Anal Found C: 80.98, H: 5.21, N: 8.50.

3-[Di(1H-indol-3-yl)methyl]phenol (3e)

Pink solid; IR: 3500–3300 (OH), 3410 (NH); 1H NMR (400 MHz, DMSO-d6): δ, 5.86 (s, 1H, CH), 6.70 (s, 1H, OH, D2O exchangeable), 6.70–6.73 (m, 3H, ArH), 6.80–6.81 (m, 1H, ArH), 6.97–7.01 (m, 2H, ArH), 7.03–7.05 (m, 1H, ArH), 7.16–7.21 (m, 3H, ArH), 7.37–7.39 (m, 2H, ArH), 7.41–7.43 (m, 2H, ArH), 7.94 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 39.9, 111.0, 113.1, 115.6, 119.2, 119.9, 121.4, 121.9, 123.6, 127.0, 129.4, 130.9, 136.6, 146.0, 155.4; Anal. Calcd for C23H18N2O (338.14) C: 81.63, H: 5.36, N: 8.28. Anal Found C: 81.49, H: 5.53, N: 8.40.

4-[Di(1H-indol-3-yl)methyl]phenol (3f)

Purple solid; IR: 3500–3200 (OH), 3406 (NH); 1H NMR (400 MHz, DMSO-d6): δ 5.85 ( s, 1H, CH), 6.67 (s, 1H, OH, D2O exchangeable), 6.75 (d, 2H, ArH, J = 8 Hz), 7.03 (t, 2H, ArH, J = 8 Hz), 7.17—7.24 (m, 5H, ArH), 7.37—7.42 (m, 5H, ArH), 7.93 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 39.3, 102.6, 111.0, 115.0, 119.2, 119.9, 121.9, 123.5, 127.0, 129.8, 136.3, 136.7, 153.7; Anal. Calcd for C23H18N2O (338.40) C: 81.63, H: 5.36, N: 8.28. Anal Found: C: 81.50, H: 5.42, N: 8.49.

3,3′-(p-Tolylmethylene)bis(1H-indole) (3g)

Buff solid; IR: 3410 (NH); 1H NMR (400 MHz, DMSO-d6): δ 2.31 (s, 3H, CH3), 5.83 (s, 1H, CH), 6.85—6.86 (m, 2H, ArH), 6.90 (t, 2H, ArH, J = 8 Hz), 7.06—7.13 (m, 5H, ArH), 7.27—7.33 (m, 3H, ArH), 7.39 (d, 2H, ArH, J = 8 Hz), 10.84 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 21.0, 39.3, 111.8, 118.5, 118.6, 119.5, 121.3, 123.9, 127.0, 128.6, 129.0, 135.0, 137.0, 142.4; Anal. Calcd for C24H20N2 (336.43) C: 85.68, H: 5.99, N: 8.33. Anal Found C: 85.51, H: 6.12, N: 8.54.

3,3′-((4-Methoxyphenyl)methylene)bis(1H-indole) (3h)

Buff solid; IR: 3410 (NH); 1H NMR (400 MHz, DMSO-d6): δ 3.71 (s, 3H, CH3), 5.77 (s, 1H, CH), 6.79–6.80 (m, 2H, ArH), 6.82–6.87 (m, 4H, ArH), 7.03 (t, 2H, ArH, J = 8Hz), 7.25–7.28 (q, 4H, ArH, J = 6 Hz), 7.34 (d, 2H, ArH, J = 8 Hz), 10.78 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 39.3, 55.3, 111.8, 113.8, 118.5, 118.8, 119.6, 121.2, 123.8, 127.0, 129.6, 137.0, 137.4, 157.7; Anal. Calcd for C24H20N2O (352.16) C: 81.79, H: 5.72, N: 7.95. Anal Found C: 82.05, H: 5.68, N: 8.12.

3,3′-((3,4-Dimethoxyphenyl)methylene)bis(1H-indole) (3i)

Buff solid; IR: 3406 (NH); 1H NMR (400 MHz, DMSO-d6): δ 3.70 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 5,82 (s, 1H, CH), 6.86—6.87 (d, 2H, ArH, J = 2 Hz), 6.88–6.90 (m, 2H, ArH), 6.91–6.94 (m, 2H, ArH), 7.05–7.10 (m, 3H, ArH), 7.34 (d, 2H, ArH, J = 8 Hz), 7.39 (d, 2H, ArH, J = 8 Hz), 10.82 (s, 2H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ 39.3, 55.9, 111.8, 112.0, 113.0, 118.5, 118.8, 119.6, 120.6, 121.2, 123.9, 127.1, 137.0, 137.9, 147.3, 148.8; Anal. Calcd for C25H22N2O2 (382.45) C: 78.51, H: 5.80, N: 7.32. Anal Found C: 78.69, H: 5.94, N: 7.50.

3,3′-((3,4,5-Trimethoxyphenyl)methylene)bis(1H-indole) (3j)

Buff solid, IR: 3360 (NH), 1589 (C=C), 1H NMR (400 MHz, DMSO-d6): δ 3.74 (s, 6H, two CH3), 3.86 (s, 3H, CH3), 5.85 (s, 1H, CH), 6.62 (s, 2H, ArH), 6.73 (s, 2H, ArH), 7.04 (t, 2H, ArH, J = 8 Hz), 7.02 (t, 2H, ArH, J = 8 Hz), 7.38 (d, 2H, ArH, J = 8 Hz), 7.44 (d, 2H, ArH, J = 8 Hz), 7.99 (s, 2H, NH, D2O exchangeable) ppm. 13C NMR (100 MHz, DMSO-d6): δ 40.5, 56.0, 60.8, 105.8, 111.0, 119.2, 119.5, 119.8, 121.9, 123.5, 127.0, 136.2, 136.7, 139.8, 152.9 ppm. Anal. Calcd for C26H24N2O3 (412.48) C: 75.71, H: 5.86, N: 6.79. Anal Found C: 75.54, H: 6.02, N: 6.85.

4-[Di(1H-indol-3-yl)methyl]-2-methoxyphenol (3k)

Purple solid, IR: 3610–3200 (OH), 3406 (NH), 1512 (C=C), 1H NMR (400 MHz, DMSO-d6): δ 3.69 (s, 3H, CH3), 5.74 (s, 1H, CH), 6.59 (s, 1H, ArH), 6.74 (s, 1H, ArH), 6.81 (s, 1H, ArH), 6.91–6.95 (m, 2H, ArH), 7.07–7.14 (m, 4H, ArH), 7.27(s, 1H, OH, D2O exchangeable), 7.29—7.34 (m, 4H, ArH), 7.85 (s, 2H, NH D2O exchangeable) ppm. 13C NMR (100 MHz, DMSO-d6): δ 39.9, 55.8, 111.1, 111.5, 114.0, 119.2, 119.93, 119.96, 121.3, 121.9, 123.6, 127.0, 136.1, 136.7, 143.8, 146.4 ppm. Anal. Calcd for C24H20N2O2 (368.43) C: 78.24, H: 5.47, N: 7.60. Anal Found C: 78.51 H: 5.69 N: 7.78.

3,3′-((2-Nitrophenyl)methylene)bis(1H-indole) (3l)

Buff solid, IR: 3406 (NH); 1H NMR (400 MHz, DMSO-d6): δ 4.77 (s, 1H, CH), 6.69–6.70 (m, 3H, ArH), 7.04 (t, 3H, ArH, J = 8 Hz), 7.20 (t, 3H, ArH, J = 8 Hz), 7.35–7.40 (m, 2H, ArH), 7.42–7.44 (m, 3H, ArH), 8.00 (s, 2H, NH, D2O exchangeable) ppm. 13C NMR (100 MHz, DMSO-d6): δ 34.8, 111.1, 117.6, 119.5, 119.7, 122.2, 123.8, 124.3, 126.7, 127.2, 131.0, 132.3, 136.6, 138.0, 149.8 ppm. Anal. Calcd for C23H17N3O2 (367.40) C: 75.19, H: 4.66, N: 11.44. Anal Found C: 75.43, H: 4.79, N: 11.67.

3,3′-((4-Nitrophenyl)methylene)bis(1H-indole) (3m)

Reddish brown solid, IR: 3410 (NH); 1H NMR (400 MHz, DMSO-d6): δ 6.04 (s, 1H, CH), 6.87–6.91 (m, 3H, ArH), 7.06 (t, 3H, ArH, J = 8 Hz), 7.29 (d, 2H, ArH, J = 8 Hz), 7.37 (d, 2H, ArH, J = 8 Hz), 7.62 (d, 2H, ArH, J = 8 Hz), 8.15 (d, 2H, ArH, J = 8 Hz), 10.94 (s, 2H, NH, D2O exchangeable) ppm. 13C NMR (100 MHz, DMSO-d6): δ 39.2, 112.0, 117.1, 118.9, 119.3, 121.6, 123.8, 124.3, 126.8, 129.9, 137.0, 146.2, 153.6 ppm. Anal. Calcd for C23H17N3O2 (367.40) C: 75.19, H: 4.66, N: 11.44. Anal Found C: 75.40, H: 4.59, N: 11.63.

Tri(1H-indol-3-yl)methane (3n)

Buff solid, IR: 3406 (NH); 1H NMR (400 MHz, DMSO-d6): δ 6.05 (s, 1H, CH), 6.85 (t, 3H, ArH, J = 7 Hz), 6.93–6.94 (m, 3H, ArH), 7.01 (t, 3H, ArH, J = 8 Hz), 7.32 (d, 3H, ArH, J = 8 Hz), 7.39 (d, 3H, ArH, J = 8 Hz), 10.71 (s, 3H, NH, D2O exchangeable) ppm. 13C NMR (100 MHz, DMSO-d6): δ 31.3, 111.8, 118.4, 118.7, 119.7, 121.1, 123.6, 127.2, 137.0 ppm. Anal. Calcd for C25H19N3 (361.44) C: 83.08, H: 5.30, N: 11.63. Anal Found C: 82.87, H: 5.46, N: 11.85.

Electrochemical synthesis of compound 3c at gram-scale

A mixture of indole (1) (1.26 g, 0.01 mol) and 4-bromobenzladehyde (2c) (1 g, 0.005 mol) was suspended in ethylene glycol/choline chloride (2:1; 20 mL) in an undivided cell equipped with graphite as cathode and platinum as anode. The electrochemical reaction was conducted at constant current (30 mA), at 80 °C for 90 min. The reaction was cooled and poured into water (250 mL). The solid formed was filtered, dried, and recrystallized from ethanol. The product was obtained in 98.5% yield (1.28 g).

Cyclic voltammetry study

Experimental setup

The study used the traditional three electrode configuration, where silver and platinum wires were employed as quasi-reference electrode and counter electrode, respectively. While the working electrode was a Pencil graphite electrode (PGE). The solvent was choline chloride/ethylene glycol (1:2) which also acted as a supporting electrolyte. The DES was degassed with N2 for 15 min then the study was carried out at 80 °C. The results are presented in Fig. 3.

Conclusion

In summary, this study focused on developing a new environmental friendly method for the synthesis of 3,3′-bis(indolyl)methanes due to their various pharmaceutical applications. Accordingly, an electrochemical method was developed for the synthesis of bis(indolyl)methanes in deep eutectic solvents in good to excellent yields. The use of deep eutectic solvents proved to be easy to use, affordable, and environmentally friendly. Moreover, the use of deep eutectic solvents eliminated the need for another electrolyte or catalyst which fulfilled the atom economy principle for green sustainable chemistry. A series of aromatic aldehydes was reacted with indole successfully using the optimum reaction parameters. The newly developed method was effective across a wide array of substituted aldehydes with different substituents at different positions as well as heterocyclic aldehydes. The reaction mechanism was validated using cyclic voltammetry. Further work are currently ongoing to examine the effect of the prepared compounds as chemosensors for the detection of ions.

Data availability

All data that supports the findings of this study is available on request by the authors.

References

  1. Imran S, Taha M, Ismail N. A review of bisindolylmethane as an important scaffold for drug discovery. Curr Med Chem. 2015;22:4412–33.

    Article  CAS  PubMed  Google Scholar 

  2. Shiri M, Zolfigol MA, Kruger HG, Tanbakouchian Z. Bis- and trisindolylmethanes (BIMs and TIMs). Chem Rev. 2010;110:2250–93.

    Article  CAS  PubMed  Google Scholar 

  3. Praveen PJ, Parameswaran PS, Majik MS. Bis(indolyl)methane alkaloids: isolation, bioactivity, and syntheses. Synthesis. 2015;47:1827–37.

    Article  CAS  Google Scholar 

  4. Fang SY, Chen SY, Chen YY, Kuo TJ, Wen ZH, Chen YH, et al. Natural indoles from the bacterium Pseudovibrio denitrificans P81 isolated from a marine sponge. Aaptos Species Nat Prod Commun. 2021;16:1–6.

    Google Scholar 

  5. Marrelli M, Cachet X, Conforti F, Sirianni R, Chimento A, Pezzi V, et al. Synthesis of a new bis(indolyl)methane that inhibits growth and induces apoptosis in human prostate cancer cells. Nat Prod Res. 2013;27:2039–45.

    Article  CAS  PubMed  Google Scholar 

  6. ReddiMohanNaidu K, Khalivulla SI, Rasheed S, Fakurazi S, Arulselvan P, Lasekan O, et al. Synthesis of bisindolylmethanes and their cytotoxicity properties. Int J Mol Sci. 2013;14:1843–53.

    Article  Google Scholar 

  7. Liang Q, Linxia X, Rui L. Convenient synthesis and biological evaluation of bis(indolyl)methane alkaloid and bis(aryl)alkanes derivatives with anti-cancer properties. Beilstein Arch. 2020;202060.

  8. Tian X, Liu KD, Zu X, Ma F, Li Z, Lee MH, et al. 3,3’-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2. Cancer Lett. 2018;2019(448):20–30.

    Google Scholar 

  9. Jiang Y, Fang Y, Ye Y, Xu X, Wang B, Gu J, et al. Anti-cancer effects of 3,3′-diindolylmethane on human hepatocellular carcinoma cells is enhanced by calcium ionophore: the role of cytosolic Ca2+ and P38 mapk. Front Pharmacol. 2019;1–23.

  10. Kim SM. Cellular and molecular mechanisms of 3,3′-diindolylmethane in gastrointestinal cancer. Int J Mol Sci. 2016;17:1155.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lee J. 3,3′-Diindolylmethane inhibits TNF-α- and TGF-β-induced epithelial-mesenchymal transition in breast cancer cells. Nutr Cancer. 2019;71:992–1006.

    Article  CAS  PubMed  Google Scholar 

  12. Benabadji SH, Wen R, Bin ZJ, Dong XC, Yuan SG. Anticarcinogenic and antioxidant activity of diindolylmethane derivatives. Acta Pharmacol Sin. 2004;25:666–71.

    CAS  PubMed  Google Scholar 

  13. Noguchi-Yachide T, Tetsuhashi M, Aoyama H, Hashimoto Y. Enhancement of chemically-induced HL-60 cell differentiation by 3,3′-diindolylmethane derivatives. Chem Pharm Bull. 2009;57:536–40.

    Article  CAS  Google Scholar 

  14. Kumar A, Das R, Ahmad G, Kosti P, Kashaw S. Antibacterial activity of bis(indolyl) methane derivatives against Staphylococcus aureus. Adv J Chem A. 2020;3:722–9.

    Google Scholar 

  15. Panov AA, Lavrenov SN, Mirchink EP, Isakova EB, Korolev AM, Trenin AS. Synthesis and antibacterial activity of novel arylbis(indol-3-yl)methane derivatives. J Antibiot (Tokyo). 2021;74:219–24.

    Article  CAS  PubMed  Google Scholar 

  16. Kamal A, Khan MNA, Srinivasa Reddy K, Srikanth YVV, Kaleem Ahmed S, Pranay Kumar K, et al. An efficient synthesis of bis(indolyl)methanes and evaluation of their antimicrobial activities. J Enzyme Inhib Med Chem. 2009;24:559–65.

    Article  CAS  PubMed  Google Scholar 

  17. Bharate SB, Bharate JB, Khan SI, Tekwani BL, Jacob MR, Mudududdla R, et al. Discovery of 3,3′-diindolylmethanes as potent antileishmanial agents. Eur J Med Chem. 2013;63:435–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rani M, Utreja D, Dhillon NK, Kaur K. A convenient one-pot synthesis of bis(indolyl)methane derivatives and evaluation of their nematicidal activity against the root knot nematode meloidogyne incognita. Russ J Org Chem. 2022;58:1527–33.

    Article  CAS  Google Scholar 

  19. Bahe AK, Naikoo GA, Raghuvansi J, Kosti P, Das R, Mishra M, et al. Design, synthesis and 3D-QSAR studies of new bis(indolyl) methanes as antioxidant agents. J Adv Sci Res. 2021;12:212–21.

    CAS  Google Scholar 

  20. Kaishap PP, Dohutia C, Chetia D. Synthesis and study of analgesic, anti-inflammatory activities of bis(indolyl)methanes (BIMs). Int J Pharm Sci Res. 2012;3:4247–53.

    Google Scholar 

  21. Süküroglu M, Ergün BÇ, Ünlü S, Sahin MF, Küpeli E. Synthesis, analgesic and anti-inflammatory activities of bis(indolyl)methanes. Indian J Chem. 2009;48B:267–72.

    Google Scholar 

  22. Zhao YS, Ruan HL, Wang XY, Chen C, Song PF, Lü CW, et al. Catalyst-free visible-light-induced condensation to synthesize bis(indolyl)methanes and biological activity evaluation of them as potent human carboxylesterase 2 inhibitors. RSC Adv. 2019;9:40168–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Batista RMF, Costa SPG, Silva RMP, Lima NEM, Raposo MMM. Synthesis and evaluation of arylfuryl-bis(indolyl)methanes as selective chromogenic and fluorogenic ratiometric receptors for mercury ion in aqueous solution. Dye Pigment. 2014;102:293–300.

    Article  CAS  Google Scholar 

  24. Martínez R, Espinosa A, Tárraga A, Molina P. Bis(indolyl)methane derivatives as highly selective colourimetric and ratiometric fluorescent molecular chemosensors for Cu2+ cations. Tetrahedron. 2008;64:2184–91.

    Article  Google Scholar 

  25. He X, Hu S, Liu K, Guo Y, Xu J, Shao S. Oxidized bis(indolyl)methane: a simple and efficient chromogenic-sensing molecule based on the proton transfer signaling mode. Org Lett. 2006;8:333–6.

    Article  CAS  PubMed  Google Scholar 

  26. Almshantaf M, Keshe M, Merza J, Karam A. Synthesis of bis(indolyl) methane and some devices using hytrogenous catalysts (acidic) in ecofriendly media. Chem Mater Res. 2016;8:32–6.

    Google Scholar 

  27. Qu HE, Xiao C, Wang N, Yu KH, Hu QS, Liu LX. RuCl3·3H2O catalyzed reactions: facile synthesis of bis(indolyl)methanes under mild conditions. Molecules. 2011;16:3855–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ramesh S, Saravanan D. An efficient method for the synthesis of bis(indolyl) methane catalyzed by nickel(II) iodide. Org Chem Curr Res. 2020;9:199.

    Google Scholar 

  29. Noland WE, Kumar HV, Flick GC, Aspros CL, Yoon JH, Wilt AC, et al. Hydrated ferric sulfate-catalyzed reactions of indole with aldehydes, ketones, cyclic ketones, and chromanones: synthesis of bisindoles and trisindoles. Tetrahedron. 2017;73:3913–22.

    Article  CAS  Google Scholar 

  30. Yadav JS, Subba Reddy BV, Murthy CVSR, Kumar GM, Madan C. Lithium perchlorate catalyzed reactions of indoles: an expeditious synthesis of bis(indolyl)methanes. Synthesis (Stuttg). 2001;2001:783–7.

    Article  Google Scholar 

  31. Siadatifard SH, Abdoli-Senejani M, Bodaghifard MA. An efficient method for synthesis of bis(indolyl)methane and di-bis(indolyl)methane derivatives in environmentally benign conditions using TBAHS. Cogent Chem. 2016;2:1188435.

    Article  Google Scholar 

  32. Meshram HM, Rao NN, Thakur PB, Reddy BC, Ramesh P. Boric acid promoted convenient synthesis of bis (indolyl) methane in aqueous medium. Indian J Chem Sect B Org Med Chem. 2013;52:814–7.

    Google Scholar 

  33. Fan C, Li R, Duan J, Xu K, Liu Y, Wang D, et al. Meldrum’s acid-induced and FeCl3-catalyzed one-pot domino reactions for construction of bis(indolyl)methanes. Synth Commun. 2022;52:1155–64.

    Article  CAS  Google Scholar 

  34. Azizi N, Gholibeghlo E, Manocheri Z. Green procedure for the synthesis of bis(indolyl)methanes in water. Sci Iran. 2012;19:574–8.

    Article  CAS  Google Scholar 

  35. Seyedi N, Kalantari M. An efficient green procedure for the synthesis of bis (indolyl) methanes in water. J Sci Islam Repub Iran. 2013;24:205–8.

    Google Scholar 

  36. Esmaielpour M, Akhlaghinia B, Jahanshahi R. Green and efficient synthesis of aryl/alkylbis(indolyl)methanes using Expanded Perlite-PPA as a heterogeneous solid acid catalyst in aqueous media. J Chem Sci. 2017;129:313–28.

    Article  CAS  Google Scholar 

  37. Ke B, Qin Y, Wang Y, Wang F. Amberlyst-catalyzed reaction of indole: synthesis of bisindolylalkane. Synth Commun. 2005;35:1209–12.

    Article  CAS  Google Scholar 

  38. Sajjadifar S, Mansouri G, Miraninezhad S. Silica supported-boron sulfonic acid : a versatile and reusable catalyst for synthesis of bis(indolyl) methane in solvent free and room temperature conditions. Asian J Nanosci Mater. 2018;1:11–8.

    Google Scholar 

  39. Karthik M, Tripathi AK, Gupta NM, Palanichamy M, Murugesan V. Zeolite catalyzed electrophilic substitution reaction of indoles with aldehydes: synthesis of bis(indolyl)methanes. Catal Commun. 2004;5:371–5.

    Article  CAS  Google Scholar 

  40. Saha M, Das N, Jamir S, Singh NG. A convenient and greener synthesis of bis(indolyl)methanes in surfactant medium under microwave irradiation. Org Chem An Indian J. 2011;8:1170.

    Google Scholar 

  41. Li JT, Sun MX, He GY, Xu XY. Efficient and green synthesis of bis(indolyl)methanes catalyzed by ABS in aqueous media under ultrasound irradiation. Ultrason Sonochem. 2011;18:412–4.

    Article  CAS  PubMed  Google Scholar 

  42. Chavan KA, Shukla M, Chauhan ANS, Maji S, Mali G, Bhattacharyya S, et al. Effective synthesis and biological evaluation of natural and designed bis(indolyl)methanes via taurine-catalyzed green approach. ACS Omega. 2022;7:10438–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xie ZB, Sun DZ, Jiang GF, Le ZG. Facile synthesis of bis(indolyl)methanes catalyzed by α-chymotrypsin. Molecules. 2014;19:19665–77.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Xiang Z, Liu Z, Chen X, Wu Q, Lin X. Biocatalysts for cascade reaction: porcine pancreas lipase (PPL)-catalyzed synthesis of bis(indolyl)alkanes. Amino Acids. 2013;45:937–45.

    Article  CAS  PubMed  Google Scholar 

  45. Gupta G, Chaudhari G, Tomar P, Gaikwad Y, Azad R, Pandya G, et al. Synthesis of bis(indolyl)methanes using molten N-butylpyridinium bromide. Eur J Chem. 2012;3:475–9.

    Article  CAS  Google Scholar 

  46. Sadaphal SA, Shelke KF, Sonar SS, Shingare MS. Ionic liquid promoted synthesis of bis(indolyl) methanes. Cent Eur J Chem. 2008;6:622–6.

    CAS  Google Scholar 

  47. Das PJ, Das J. Synthesis of aryl/alkyl(2,2′-bis-3-methylindolyl)methanes and aryl(3,3′-bis indolyl)methanes promoted by secondary amine based ionic liquids and microwave irradiation. Tetrahedron Lett. 2012;53:4718–20.

    Article  CAS  Google Scholar 

  48. Chakraborti AK, Roy SR, Kumar D, Chopra P. Catalytic application of room temperature ionic liquids: [bmim][MeSO4] as a recyclable catalyst for synthesis of bis(indolyl)methanes. Ion-fishing by MALDI-TOF-TOF MS and MS/MS studies to probe the proposed mechanistic model of catalysis. Green Chem. 2008;10:1111–8.

    Article  CAS  Google Scholar 

  49. Longo LS, Craveiro MV. Deep eutectic solvents as unconventional media for multicomponent reactions. J Braz Chem Soc. 2018;29:1999–2025.

    CAS  Google Scholar 

  50. Alonso DA, Baeza A, Chinchilla R, Guillena G, Pastor IM, Ramón DJ. Deep eutectic solvents: the organic reaction medium of the century. Eur J Org Chem. 2016;612–32.

  51. Liu P, Hao JW, Mo LP, Zhang ZH. Recent advances in the application of deep eutectic solvents as sustainable media as well as catalysts in organic reactions. RSC Adv. 2015;5:48675–704.

    Article  CAS  Google Scholar 

  52. Ünlü AE, Arlkaya A, Takaç S. Use of deep eutectic solvents as catalyst: a mini-review. Green Process Synth. 2019;8:355–72.

    Article  Google Scholar 

  53. Tang B, Row KH. Recent developments in deep eutectic solvents in chemical sciences. Monatshefte fur Chemie. 2013;144:1427–54.

    Article  CAS  Google Scholar 

  54. Hansen BB, Spittle S, Chen B, Poe D, Zhang Y, Klein JM, et al. Deep eutectic solvents: a review of fundamentals and applications. Chem Rev. 2021;121:1232–85.

    Article  CAS  PubMed  Google Scholar 

  55. Smith EL, Abbott AP, Ryder KS. Deep eutectic solvents (DESs) and their applications. Chem Rev. 2014;114:11060–82.

    Article  CAS  PubMed  Google Scholar 

  56. Handy S, Westbrook NM. A mild synthesis of bis(indolyl)methanes using a deep eutectic solvent. Tetrahedron Lett. 2014;55:4969–71.

    Article  CAS  Google Scholar 

  57. Azizi N, Manocheri Z. Eutectic salts promote green synthesis of bis(indolyl) methanes. Res Chem Intermed. 2012;38:1495–500.

    Article  CAS  Google Scholar 

  58. Jella RR, Nagarajan R. Synthesis of indole alkaloids arsindoline A, arsindoline B and their analogues in low melting mixture. Tetrahedron. 2013;69:10249–53.

    Article  CAS  Google Scholar 

  59. Schotten C, Nicholls TP, Bourne RA, Kapur N, Nguyen BN, Willans CE. Making electrochemistry easily accessible to the synthetic chemist. Green Chem. 2020;22:3358–75.

    Article  CAS  Google Scholar 

  60. Xiong P, Xu HC. Chemistry with electrochemically generated N-centered radicals. Acc Chem Res. 2019;52:3339–50.

    Article  CAS  PubMed  Google Scholar 

  61. Yamamoto K, Kuriyama M, Onomura O. Anodic oxidation for the stereoselective synthesis of heterocycles. Acc Chem Res. 2020;53:105–20.

    Article  CAS  PubMed  Google Scholar 

  62. Wang P, Gao X, Huang P, Lei A. Recent advances in electrochemical oxidative cross-coupling of alkenes with H2 evolution. ChemCatChem. 2020;12:27–40.

    Article  Google Scholar 

  63. Yuan Y, Lei A. Is electrosynthesis always green and advantageous compared to traditional methods? Nat Commun. 2020;11:2018–20.

    Google Scholar 

  64. Navarro M. Recent advances in experimental procedures for electroorganic synthesis. Curr Opin Electrochem. 2017;2:43–52.

    Article  CAS  Google Scholar 

  65. Blanco DE, Modestino MA. Organic electrosynthesis for sustainable chemical manufacturing. Trends Chem. 2019;1:8–10.

    Article  CAS  Google Scholar 

  66. Frontana-Uribe BA, Little RD, Ibanez JG, Palma A, Vasquez-Medrano R. Organic electrosynthesis: a promising green methodology in organic chemistry. Green Chem. 2010;12:2099–119.

    Article  CAS  Google Scholar 

  67. Du KS, Huang JM. Electrochemical synthesis of bisindolylmethanes from indoles and ethers. Org Lett. 2018;20:2911–5.

    Article  CAS  PubMed  Google Scholar 

  68. Jat PK, Dabaria KK, Bai R, Yadav L, Badsara SS. Electrochemical bisarylation of carbonyls: a direct synthetic strategy for bis(indolyl)methane. J Org Chem. 2022;87:12975–85.

    Article  CAS  PubMed  Google Scholar 

  69. Osman EO, Mahmoud AM, El-mosallamy SS, El-nassan HB. Electrochemical synthesis of tetrahydrobenzo [b] pyran derivatives in deep eutectic solvents. J Electroanal Chem. 2022;920:116629.

    Article  CAS  Google Scholar 

  70. El-Dash YS, Mahmoud AM, El-Mosallamy SS, El-Nassan HB. Electrochemical synthesis of 5-benzylidenebarbiturate derivatives and their application as colorimetric cyanide probe. ChemElectroChem. 2023;10: e202200954.

    Article  CAS  Google Scholar 

  71. Mousa MO, Adly ME, Mahmoud AM, El-Nassan HB. Synthesis of tetrahydro-β-carboline derivatives under electrochemical conditions in deep eutectic solvents. ACS Omega. 2023;9:14198–209.

    Article  Google Scholar 

  72. El-Nassan HB, El-Mosallamy SS, Mahmoud AM. Unexpected formation of hexahydroxanthenediones by electrochemical synthesis in deep eutectic solvents. Sustain Chem Pharm. 2023;35:101207.

    Article  CAS  Google Scholar 

  73. Amiri-Zirtol L, Amrollahi MA, Mirjalili B-F. GO-Fe3O4-Ti (IV) as an efficient magnetic catalyst for the synthesis of bis (indolyl)methanes and benzo [a] xanthen-11-one derivatives. Inorg Nano-Metal Chem. 2021;1–11.

  74. Qiao J, Gao S, Wang L, Wei J, Li N, Xu X. Air-stable μ-oxo-bridged binuclear titanium(IV) salophen perfluorooctanesulfonate as a highly efficient and recyclable catalyst for the synthesis of bis(indolyl) methane derivatives. J Organomet Chem. 2020;906: 121039.

    Article  CAS  Google Scholar 

  75. Zaharani L, Khaligh NG. Study the crystal structure of 4,4′-(propane-1,3-diyl)dipiperidinium sulfate monohydrate and its hydrogen bond catalytic activity in the mechanochemical synthesis of BIMs. J Mol Struct. 2023;1278: 134917.

    Article  CAS  Google Scholar 

  76. Rinkam S, Warapong S, Watchasit S, Saeeng R, Sirion U. Brønsted acidic ionic liquid catalyzed three-component friedel-crafts reaction for the synthesis of unsymmetrical triarylmethanes. Synlett. 2022;33:1383–90.

    Article  CAS  Google Scholar 

  77. Kangari S, Yavari I. Preparation of immobilized hexamine on Fe3O4/SiO2 core/shell nanoparticles: a novel catalyst for solvent-free synthesis of bis(indolyl)methanes. Res Chem Intermed. 2016;42:8217–26.

    Article  CAS  Google Scholar 

  78. Shirini F, Fallah-Shojaei A, Samavi L, Abedini M. A clean synthesis of bis(indolyl)methane and biscoumarin derivatives using P4VPy–CuO nanoparticles as a new, efficient and heterogeneous polymeric catalyst. RSC Adv. 2016;6:48469–78.

    Article  CAS  Google Scholar 

  79. Cheng Y, Ou X, Ma J, Sun L, Ma Z-H. A new amphiphilic brønsted acid as catalyst for the Friedel-crafts reactions of indoles in water. European J Org Chem. 2019;2019:66–72.

    Article  CAS  Google Scholar 

  80. Mardani Y, Karimi-Jaberi Z, Soltanian Fard MJ. Application of magnetically recoverable core-shell nanocomposite in the synthesis of bis(indolyl)methanes at room temperature. Russ J Org Chem. 2021;57:1740–7.

    Article  CAS  Google Scholar 

  81. Mathavan S, Kannan K, Yamajala RBRD. Thiamine hydrochloride as a recyclable organocatalyst for the synthesis of bis(indolyl)methanes, tris(indolyl)methanes, 3,3-di(indol-3-yl)indolin-2-ones and biscoumarins. Org Biomol Chem. 2019;17:9620–6.

    Article  CAS  PubMed  Google Scholar 

  82. Grace G, Ghanashyam AB. Thermally activated aryl thioureas as brønsted acid catalysts for C–C bond forming reactions: synthesis of symmetrical trisubstituted methanes. Synthesis (Stuttg). 2022;55:786–98.

    Google Scholar 

  83. Galathri EM, Di Terlizzi L, Fagnoni M, Protti S, Kokotos CG. Friedel-Crafts arylation of aldehydes with indoles utilizing arylazo sulfones as the photoacid generator. Org Biomol Chem. 2023;21:365–9.

    Article  CAS  PubMed  Google Scholar 

  84. Stremski Y, Statkova-Abeghe S, Angelov P, Ivanov I. Synthesis of camalexin and related analogues. J Heterocycl Chem. 2018;55:1589–95.

    Article  CAS  Google Scholar 

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Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). This manuscript is based upon work supported by the Science, Technology and Innovation Funding Authority (STDF) under grant number 45569.

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  1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo, 11562, Egypt

    Mina E. Adly & Hala B. El-Nassan

  2. Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt

    Amr M. Mahmoud

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Hala B. El-Nassan: conceptualization; experimental work; writing—review and editing. Mina E. Adly: experimental work; writing—review and editing; Amr M. Mahmoud: experimental work; writing—review and editing.

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Adly, M.E., Mahmoud, A.M. & El-Nassan, H.B. Green electrosynthesis of bis(indolyl)methane derivatives in deep eutectic solvents. BMC Chemistry 18, 139 (2024). https://doi.org/10.1186/s13065-024-01245-9

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