RuCl3·3H2O Catalyzed Reactions: Facile Synthesis of Bis(indolyl)methanes under Mild Conditions

Hong-En Qu; Chen Xiao; Ning Wang; Kai-Hui Yu; Qiao-Sheng Hu; Liang-Xian Liu

doi:10.3390/molecules16053855

. 2011 May 9;16(5):3855–3868. doi: 10.3390/molecules16053855

RuCl₃·3H₂O Catalyzed Reactions: Facile Synthesis of Bis(indolyl)methanes under Mild Conditions

Hong-En Qu ¹, Chen Xiao ¹, Ning Wang ¹, Kai-Hui Yu ¹, Qiao-Sheng Hu ^1,^*, Liang-Xian Liu ^1,^*

PMCID: PMC6263275 PMID: 21555975

Abstract

RuCl₃·3H₂O was found to be an effective catalyst for reactions of indoles, 2-methylthiophene, and 2-methylfuran with aldehydes to afford the corresponding bis(indolyl)methanes, bis(thienyl)methanes, and bis(fur-2-yl)methanes in moderate to excellent yields. Experimental results indicated that mono(indolyl)methanol is not the reaction intermediate under these reaction conditions.

Keywords: bis(indolyl)methane, RuCl₃·3H₂O, aldehyde, indole

1. Introduction

Indoles and their derivatives are known to possess various pharmacological and biological properties, including antibacterial, cytotoxic, antioxidative, and insecticidal activities [1,2]. Furthermore, bis(indolyl)alkanes and their derivatives constitute an important group of bioactive metabolites of terrestrial and marine origin [3,4,5,6,7,8]. During the past decade a large number of natural products containing bis(indolyl)methanes [9] and bis(indolyl)ethanes [10] have been isolated from marine sources. Consequently, a number of synthetic methods for the preparation of bis(indolyl)alkane derivatives by reacting indoles with various aldehydes and ketones in the presence of either a Lewis acid [11] or a protic acid [12,13,14], metal salts, such as In(OTf)₃ [15], Dy(OTf)₃ [16,17], Ln(OTf)₃ [18], and CeCl₃·7H₂O [19,20], and molecular iodine [21,22], as well as solid acidic catalysts [23,24,25], such as clays and Zeolites, have been reported in the literature. In addition, it has been reported that the reactions of indoles with various aldehydes were carried out in a protic solvent in the absence of any other catalyst to afford bis(indolyl)methanes [26]. In this study, we report a facile and efficient procedure for the synthesis of bis(indolyl)methanes, bis(thienyl)methanes, and bis(fur-2-yl)methanes under mild conditions using RuCl₃·3H₂O as catalyst.

2. Results and Discussion

In the first instance, we studied the reaction of indole with benzaldehyde as a model reaction. We found that this reaction was fast in the presence of RuCl₃·3H₂O (5 mol %) in ethylene glycol dimethyl ether (GDE) at room temperature, and the corresponding bis-indolylmethane was obtained in 87% yield after 30 min (Table 1, entry 6).

Table 1.

Effect of RuCl₃·3H₂ Oloading ^a.


Entry	RuCl₃·3H₂O [equivalents]	Solvent	Yield [%] ^b
1	0.1	Benzene	93
2	0.05	Benzene	92
3	0.03	Benzene	75
4	0.02	Benzene	60
5	0	Benzene	0
6	0.05	GDE ^c	87
7	0.05	THF	88
8	0.05	DCM	87
9	0.05	Chloroform	86
10	0.05	Acetone	83
11	0.05	Acetonitrile	89

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^a The reaction was performed with benzaldehyde (0.5 mmol), indole (1 mmol) and RuCl₃·3H₂O (0.05 mmol) in 1 mL of solvent at rt for 30 min. ^b Isolated yield. ^c Ethylene glycol dimethyl ether.

To optimize the reaction conditions, we have studied the effect of different solvents and RuCl₃·3H₂O loadings on the reaction of indole with benzaldehyde. The results are shown in Table 1. After examining different solvents, including THF, GDE, CH₂Cl₂, C₆H₆, acetone, acetonitrile, and CHCl₃, benzene, with which the highest yield of 92% was obtained when using 5 mol % RuCl₃·3H₂O for 30 min (Table 1, entry 2), was found to be most efficient. We next examined the effect of RuCl₃·3H₂O loading on the reaction; good results were obtained when using 5 mol % RuCl₃·3H₂O (Table 1, entry 2), and there was no advantage to using more than 5 mol % RuCl₃·3H₂O (Table 1, entry 1), whereas the yield significantly decreased when using only 2 mol % RuCl₃·3H₂O (Table 1, entry 4). Without the RuCl₃·3H₂O catalyst, the reaction cannot be carried out. Thus, the optimum reaction conditions for the reaction were found to be 0.05 equivalents of RuCl₃·3H₂O, with benzene as the solvent at r.t. To explore the scope of the reaction, next various indoles were reacted with different substituted aromatic aldehydes, and the results are summarized in Table 2.

Table 2.

RuCl₃·3H₂O-catalyzed reaction of indoles with aldehydes ^a.


Entry	Compounds	R₁	R₂	Time/h	Yield [%] ^b
1	2a	H	H	0.5	92
2	2b	m-CH₃	H	1	77
3	2c	p-CH₃	H	1	83
4	2d	m-OCH₃	H	1	81
5	2e	m-Cl	H	0.5	93
6	2f	o-Br	H	0.5	89
7	2g	m-NO₂	H	0.5	98
8	3a	H	N-CH₃	1	75
9	3b	m-CH₃	N-CH₃	1	70
10	3c	p-CH₃	N-CH₃	1	70
11	3d	m-OCH₃	N-CH₃	1	73
12	3e	m-Cl	N-CH₃	1	81
13	3f	o-Br	N-CH₃	1	78
14	3g	m-NO₂	N-CH₃	1	85
15	4a	m-CH₃	2-CH₃	0.5	80
16	4b	m-OCH₃	2-CH₃	0.5	78

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^a The reaction was performed with aldehyde (0.5 mmol), indole (1 mmol) and RuCl₃·3H₂O (0.05 mmol) in 1 mL of benzene at rt. ^b Isolated yield.

In general, all reactions were very clean and the bis-indolylmethanes were obtained in high yields under the optimized conditions. The results have shown that substitution plays a major role in governing the reactivity of the substrate. With electron-donating substituents in the aryl aldehyde, decreased yields of products were observed (Table 2, entries 2–4, entries 9–11). For example, the reaction of m-methylbenzaldehyde with indole gave the corresponding product in 77% yield (Table 2, entry 2). However, the effect was reversed when electron-withdrawing groups were present in the aryl aldehyde, thus such electron-withdrawing groups (e.g., NO₂) in the aryl aldehyde favored the reaction with indoles, affording the corresponding bis(indolyl)methanes in high yields (Table 2, entries 7, 14). It is noteworthy that the reaction of N-methylindole with aryl aldehydes gave the corresponding bis(indolyl)methanes in decreased yields (Table 2, entries 8–14). To expand the scope of the protocol, the reaction of various aryl aldehydes with 2-methylthiophene was also evaluated. The results are summarized in Table 3.

Table 3.

RuCl₃·3H₂O-catalyzed reaction of 2-methyl thiophene with aryl aldehydes ^a.


Entry	Compounds	R	Time/h	Yield [%] ^b
1	5a	H	6.5	96
2	5b	m-CH₃	6.0	90
3	5c	p-CH₃	13	61
4	5d	m-OCH₃	7.5	81
5	5e	m-Cl	13	84
6	5f	o-Br	5.5	75
7	5g	m-NO₂	9.0	98

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^a The reaction was performed with aldehyde (0.5 mmol), 2-methyl thiophene (1.5 mmol) and RuCl₃·3H₂O (0.05 mmol) in 1 mL of GDE at 80 °C. ^b Isolated yield.

As shown in this table, good yields were obtained in GDE at 80 °C, except in the case of p-methyl-benzaldehyde (Table 3, entry 3). Surprisingly, applying these optimised conditions to perform the reaction of aryl aldehydes with 2-methylthiophene，resulted in a zero yield of the corresponding bis(thienyl)methanes, and in this case the reaction temperature must be changed, and 80 °C was the best choice. Steric effects also had an adverse influence on the reaction. For instance, 2-bromo-benzaldehyde gave a lower yield of 61% (Table 3, entry 3).

Nair has reported that 2-methylthiophene on reaction with benzaldehyde gave 70% of the corresponding bis(thienyl)methane using AuCl₃/AgOTf as catalyst [27]. Compared to Nair’s method, the advantages of our procedure include the simplicity of the reaction procedure, as well as higher yields. In addition, the reaction of various aryl aldehydes with 2-methylfuran was also investigated. The results are summarized in Table 4.

Table 4.

RuCl₃·3H₂O-catalyzed reaction of 2-methyl furan with aryl aldehydes ^a.


Entry	Compounds	R	Time/days	Yield [%] ^b
1	6a	m-CH₃	14	49
2	6b	p-CH₃	14	52
3	6c	m-OCH₃	14	50
4	6d	m-Cl	9	58
5	6e	o-Br	13	56
6	6f	m-NO₂	6	79

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^a The reaction was performed with aldehyde (0.5 mmol), 2-methyl furan (6 mmol) and RuCl₃·3H₂O (0.05 mmol) in 1 mL of GDE at 5 °C^oC. ^b Isolated yield.

Similarly, applying the previously optimized conditions to perform the reaction of m-methylbenzaldehyde with 2-methylfuran, resulted in a very low yield of the corresponding bis(fur-2-yl)methane. Fortunately, a mixture of m-methylbenzaldehyde and 2-methylfuran could be very slowly converted to the desired product in 49% yield after 14 days at 5 °C. Other aryl benzaldehydes also reacted well giving moderate yields under the same conditions (Table 4). Electron-withdrawing substituents on the aryl aldehyde were more beneficial for this transformation. For instance, m-nitro- benzaldehyde gave a higher reaction yield of 79% (Table 4, entry 6). To the best of our knowledge, the reports of such reactions of furans with aryl benzaldehydes are limited [27].

A Hammett analysis was performed to probe the nature of this intriguing reaction of aryl aldehydes with N-methylindole. As can be observed from the plot for C-3 substituted benzaldehydes (Figure 1), a linear correlation between the ratio of reaction rates (k_n = rate constant of the reaction of benzaldehyde with N-methyl indole; k_m = rate constant of the reaction of aryl benzaldehyde with N-methyl indole; For the determination of r, the following expression was used: k_m/k_n = log[1−xp/xr]/log[1−yp/yr], r = reaction constant; x_p = mmol product formed from substituted benzaldehyde; x_r= mmol starting N-methyl indole placed in the reaction; y_p = mmol product formed from unsubstituted benzaldehyde; y_r = mmol N-methyl indole starting placed in the reaction.) and the substituent parameter (δ_m) [28] was obtained, which provided a small, positive reaction constant (ρ = 0.26). This relatively small ρ value correlates to a slight dependence of the reaction on the polarizing influence of the aromatic substituents, which is indicative of a nucleophilic addition mechanism.

Hammett plot for C-3 substituted benzaldehydes.

According to the literature [18,21,22,24], the following mechanism was proposed to account for the reaction of benzaldehyde with indole. The aldehyde was first activated by catalyst, then underwent an electrophilic substitution reaction at C-3 of an indole molecules to give mono(indolyl)methane 7. After loss of water, intermediate 8 was generated. Compound 8 served as an electrophile to attack a second molecule of indole to form 2a. To explore the RuCl₃·3H₂O-catalyzed reaction process, the reaction of mono(indolyl)methanes 7 with indole was performed in the presence of RuCl₃·3H₂O at r.t. Unfortunately, it was found that the reaction did not work, suggesting that 7 is not the intermediate of the RuCl₃·3H₂O-catalyzed reaction. The detailed mechanism has therefore not been clarified.

Scheme 1 — Thereactionof mono(indolyl)methanes with indole.

3. Experimental

3.1. General

Infrared spectra were measured with a Nicolet Avatar 360 FT-IR spectrometer using film KBr pellet techniques. ¹H- and ¹³C-NMR spectra were recorded on a Bruker AV400 spectrometer at 400 and 100 MHz, respectively. Chemical shifts were reported in ppm relative to TMS. CDCl₃ or DMSO-d6 were used as the NMR solvents. GC-MS were recorded using a Finnigan Trace 2000 GC/MS system. Elemental analysis were carried out on a Perkin-Elmer 240B instrument. HRMS spectra were recorded on a Shimadzu LCMS-IT-TOF apparatus. Silica gel (300–400 mesh) was used for flash column chromatography, eluting (unless otherwise stated) with an ethyl acetate/petroleum ether (PE, b.p. 60–90 °C) mixture.

3.2. General Procedure for the Preparation of Bis(indolyl)Methanes 2-4

To a solution of aryl benzaldehyde (0.5 mmol) and RuCl₃·3H₂O (0.05 mmol) in benzene (1 mL) was added indole (1.0 mmol) under air atmosphere and the mixture was stirred at room temperature (monitored by TLC). Then, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent:EtOAc/PE = 1:4) to yield the corresponding product.

3,3’-Bis-indolyl phenylmethane (2a). Pink solid, mp: 126–127 °C (EtOAc/PE = 1:4) (lit [29], 125–127 °C). IR (KBr) ν_max: 3417, 3065, 1513, 1454 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.82 (s, 2H, N–H), 7.43 (d, J = 7.9 Hz, 2H, Ar–H), 7.40–7.36 (m, 3H, Ar–H), 7.35–7.29 (m, 3H, Ar–H), 7.28–7.24 (m, 1H, Ar–H), 7.21 (dt, J = 0.8, 7.9 Hz, 2H, Ar–H), 7.05 (dt, J = 0.8, 7.9 Hz, 2H, Ar–H), 6.61 (d, J = 1.5 Hz, 2H, Ar–H), 5.92 (s, 1H). ¹³C-NMR (CDCl₃): δ 144.0, 136.7, 128.8, 128.3, 127.1, 126.2, 123.7, 121.9, 120.0, 119.7, 119.2, 111.1, 40.2. MS (EI, 70 eV): m/z = 322 (M⁺, 20), 245 (75), 206 (100), 77 (10).

3,3’-Bis-indolyl-(3-methylphenyl)methane (2b). Pink solid, mp: 98–99 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3406, 3049, 1610, 1458, 1419, 745 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.88 (s, 2H, N–H), 7.42 (d, J = 7.9 Hz, 2H, Ar–H), 7.36 (d, J = 8.2 Hz, 2H, Ar–H), 7.20–7.14 (m, 5H, Ar–H), 7.05–6.99 (m, 3H, Ar–H), 6.66 (d, J = 1.6 Hz, 2H, Ar–H), 5.85 (s, 1H), 2.30 (s, 3H, CH₃). ¹³C-NMR (CDCl₃): δ 143.9, 137.6, 136.7, 129.5, 128.1, 127.1, 126.9, 125.8, 123.6, 121.9, 120.0, 119.8, 119.2, 111.0, 40.1, 21.5. MS (EI, 70 eV): m/z = 336 (M⁺, 30), 245 (100), 221 (30). Anal. calcd. for C₂₄H₂₀N₂: C, 85.68; H, 5.99; N, 8.33. Found C, 85.30; H, 5.87; N, 8.05.

3,3’-Bis-indolyl-(4-methylphenyl)methane (2c). Pink solid, mp: 93–95 °C (EtOAc/PE = 1:4) (lit [30], 94–96 °C). IR (KBr) ν_max: 3410, 3046, 1457, 743 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.89 (s, 2H, N–H), 7.42 (d, J = 7.9 Hz, 2H, Ar–H), 7.36 (d, J = 8.2 Hz, 2H, Ar–H), 7.25 (d, J = 8.0 Hz, 2H, Ar–H), 7.18 (dt, J = 1.0, 8.2 Hz, 2H, Ar–H), 7.10 (d, J = 7.9 Hz, 2H, Ar–H), 7.02 (dt, J = 1.0, 8.0 Hz, 2H, Ar–H), 6.66 (dd, J = 2.2, 0.7 Hz, 2H, Ar-H), 5.87 (s, 1H), 2.34 (s, 3H, CH₃). ¹³C-NMR (CDCl₃): δ 141.0, 136.7, 135.5, 128.9, 128.6, 127.1, 123.5, 121.9, 120.0, 119.9, 119.2, 111.0, 39.8, 21.1. MS (EI, 70 eV): m/z = 336 (M⁺, 35), 245 (100), 220 (35), 116 (10).

3,3’-Bis-indolyl-(3-methoxyphenyl)methane (2d). Pink solid, mp: 188.5–189.5 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3410, 3046, 2923, 1487, 1441, 1263, 1152, 1049, 745 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.91 (s, 2H, N–H), 7.42 (d, J = 7.8 Hz, 2H, Ar–H), 7.36 (d, J = 8.2 Hz, 2H, Ar–H), 7.22 (d, J = 7.8 Hz, 1H, Ar–H), 7.18 (dt, J = 0.9, 8.2 Hz, 2H, Ar–H), 7.02 (dt, J = 0.9, 7.8 Hz, 2H, Ar–H), 6.97 (d, J = 7.7 Hz, 1H, Ar–H), 6.93 (t, J = 2.2 Hz, 1H, Ar–H), 6.77 (dq, J = 0.6, 7.7 Hz, 1H, Ar–H), 6.68 (dd, J = 2.2, 0.6 Hz, 2H, Ar–H), 5.87 (s, 1H), 2.34 (s, 3H, CH₃), 3.75 (s, 3H, OCH₃). ¹³C-NMR (CDCl₃): δ 159.6, 145.7, 136.7, 129.1, 127.1, 123.6, 121.9, 121.3, 119.9, 119.6, 119.2, 114.7, 111.3, 111.0, 55.1, 40.2. MS (EI, 70 eV): m/z = 352 (M⁺, 35), 337 (35), 321 (8), 245 (100), 130 (40). Anal. calcd for C₂₄H₂₀N₂O: C, 81.79; H, 5.72; N, 7.95. Found C, 81.52; H, 5.33; N, 7.66.

3,3’-Bis-indolyl-(3-chlorophenyl)methane (2e). Pink solid, mp: 64–68 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3412, 3046, 1458, 1418, 1094, 744 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.88 (s, 2H, N–H), 7.42–7.34 (m, 5H, Ar–H), 7.26–7.17 (m, 5H, Ar–H), 7.04 (dt, J = 0.8, 7.8 Hz, 2H, Ar–H), 6.62 (s, 2H, Ar–H), 5.86 (s, 1H). ¹³C-NMR (CDCl₃): δ 146.2, 136.7, 134.0, 129.5, 128.8, 126.9, 126.8, 126.4, 123.6, 122.1, 119.7, 119.4, 119.0, 111.1, 40.0. MS (EI, 70 eV): m/z = 283 (25), 281 (100), 245 (80). Anal. calcd. for C₂₃H₁₇N₂Cl: C, 77.41; H, 4.80; N, 7.85. Found C, 77.51; H, 4.67; N, 7.48.

3,3’-Bis-indolyl-(2-bromophenyl)methane (2f). Pink solid, mp: 89–91 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3411, 3043, 1443, 1022, 744 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.90 (s, 2H, N–H), 7.64 (d, J = 7.9 Hz, 1H, Ar–H), 7.42 (d, J = 7.9 Hz, 2H, Ar–H), 7.37 (d, J = 8.2 Hz, 2H, Ar–H), 7.25–7.14 (m, 4H, Ar–H), 7.10 (dt, J = 1.9, 7.9 Hz, 1H, Ar–H), 7.04 (dt, J = 0.9, 8.0 Hz, 2H, Ar–H), 6.62 (dd, J = 2.3, 0.9 Hz, 2H, Ar–H), 6.33 (s, 1H). ¹³C-NMR (CDCl₃): δ 143.0, 136.7, 132.9, 130.5, 127.8, 127.3, 127.0, 124.8, 123.8, 122.0, 119.9, 119.3, 118.5, 111.1, 39.6. MS (EI, 70 eV): m/z = 351 (100), 349 (100), 245 (80). Anal. calcd. for C₂₃H₁₇N₂Br: C, 68.84; H, 4.27; N, 6.98. Found C, 68.64; H, 4.05; N, 6.81.

3,3’-Bis-indolyl-(3-nitrophenyl)methane (2g). Pink solid, mp: 262–264 °C (EtOAc/PE = 1:4) (lit [29], 265–266 °C). IR (KBr) ν_max: 3410, 3053, 2924, 1524, 1455, 1346, 1092, 741 cm⁻¹. ¹H-NMR (CDCl₃): δ 8.23 (t, J = 2.0 Hz, 1H, Ar–H), 8.10 (dq, J = 1.0, 8.2 Hz, 1H, Ar–H), 8.01 (s, 2H, N–H), 7.71 (d, J = 7.9 Hz, 1H, Ar–H), 7.46 (t, J = 7.9 Hz, 1H, Ar–H), 7.39 (d, J = 8.2 Hz, 2H, Ar–H), 7.37 (d, J = 7.9 Hz, 2H, Ar–H), 7.22 (dt, J = 0.9, 7.2 Hz, 2H, Ar–H), 7.04 (dt, J = 0.9, 7.2 Hz, 2H, Ar–H), 6.68 (dd, J = 2.0, 0.9 Hz, 2H, Ar–H), 6.01 (s, 1H). ¹³C-NMR (CDCl₃): δ 148.5, 146.4, 136.7, 134.9, 129.2, 126.6, 123.7, 123.6, 122.3, 121.5, 119.6, 119.5, 118.3, 111.3, 40.0. MS (EI, 70 eV): m/z = 367 (100), 321 (10), 245 (85), 122 (20). Anal calcd. for C₂₃H₁₇N₃O₂: C, 75.19; H, 4.66; N, 11.44. Found C, 75.07; H, 4.36; N, 11.14.

3,3’-Bis-(N-methylindolyl)phenylmethane (3a). Pink solid, mp: 185–187 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3046, 2930, 1607, 1474, 1329, 1125, 743 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.43 (d, J = 7.9 Hz, 2H, Ar–H), 7.39 (d, J = 8.6 Hz, 2H, Ar–H), 7.35–7.29 (m, 4H, Ar–H), 7.26-7.21 (m, 3H, Ar–H), 7.03 (dt, J = 0.8, 7.9 Hz, 2H, Ar–H), 6.57 (s, 2H, Ar–H), 5.93 (s, 1H), 3.71 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 144.5, 137.4, 128.7, 128.3, 128.2, 127.5, 126.0, 121.4, 120.1, 118.7, 118.3, 109.1, 40.1, 32.7. MS (EI, 70 eV): m/z = 350 (M⁺, 100), 273 (85), 220 (25), 130 (15). Anal. calcd. for C₂₅H₂₂N₂: C, 85.68; H, 6.33; N, 7.99. Found C, 85.90; H, 6.58; N, 7.64.

3,3’-Bis-(N-methylindolyl)-(3-methylphenyl)methane (3b). Pink waxy solid. IR (KBr) ν_max: 3049, 2932, 1475, 1123, 737 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.42 (d, J = 7.9 Hz, 2H, Ar–H), 7.31 (d, J = 8.2 Hz, 2H, Ar–H), 7.25–7.14 (m, 5H, Ar–H), 7.07–6.99 (m, 3H, Ar–H), 6.56 (s, 2H, Ar–H), 5.87 (s, 1H), 3.70 (s, 6H, 2 × CH₃), 2.32 (s, 3H, CH₃). ¹³C-NMR (CDCl₃): δ 144.4, 137.6, 137.4, 129.4, 128.2, 128.0, 127.5, 126.8, 125.7, 121.4, 120.1, 118.6, 118.4, 109.0, 40.0, 32.7, 21.6. MS (EI, 70 eV): m/z = 364 (M⁺, 95), 349 (85), 273 (100), 257 (25), 130 (20). Anal. calcd. for C₂₆H₂₄N₂: C, 85.68; H, 6.64; N, 7.69. Found C, 85.30; H, 6.60; N, 7.36.

3,3’-Bis-(N-methylindolyl)-(4-methylphenyl)methane (3c). Pink solid, mp: 146–148 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3050, 2928, 1470, 1125, 745 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.40 (d, J = 7.9 Hz, 2H, Ar–H), 7.30 (d, J = 8.2 Hz, 2H, Ar–H), 7.26–7.17 (m, 4H, Ar–H), 7.09 (d, J = 7.9 Hz, 2H, Ar–H), 7.00 (dt, J = 1.0, 7.9 Hz, 2H, Ar–H), 6.54 (s, 2H, Ar–H), 5.85 (s, 1H), 3.69 (s, 6H, 2 × CH₃), 2.32 (s, 3H, CH₃). ¹³C-NMR (CDCl₃): δ 141.4, 137.4, 135.4, 128.9, 128.5, 128.2, 127.5, 121.4, 120.1, 118.6, 118.5, 109.0, 39.6, 32.6, 21.1. MS (EI, 70 eV): m/z = 364 (M⁺, 15), 273 (100), 257 (60), 130 (60). Anal. calcd. for C₂₆H₂₄N₂: C, 85.68; H, 6.64; N, 7.69. Found C, 85.44; H, 6.96; N, 7.32.

3,3’-Bis-(N-methylindolyl)-(3-methoxyphenyl)methane (3d). Pink solid, mp: 149–151 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3054, 2930, 1478, 1256, 1135, 740 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.42 (d, J = 7.9 Hz, 2H, Ar–H), 7.30 (d, J = 8.2 Hz, 2H, Ar–H), 7.22 (t, J = 7.9 Hz, 3H, Ar–H), 7.02 (dt, J = 0.9, 7.9 Hz, 2H, Ar–H), 6.97 (d, J = 7.9 Hz, 1H, Ar–H), 6.94 (t, J = 2.0 Hz, 1H, Ar–H), 6.78 (dd, J = 8.2, 2.0 Hz, 1H, Ar–H), 6.57 (s, 2H, Ar–H), 5.87 (s, 1H), 3.76 (s, 3H, OCH₃), 3.70 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 159.6, 146.2, 137.4, 129.1, 128.2, 127.5, 121.4, 121.3, 120.0, 118.6, 118.1, 114.8, 111.1, 109.0, 55.1, 40.1, 32.7. MS (EI, 70 eV): m/z = 380 (M⁺, 65), 365 (85), 349 (30), 273 (100), 130 (25). Anal. calcd. for C₂₆H₂₄N₂O: C, 82.07; H, 6.36; N, 7.36. Found C, 81.72; H, 5.96; N, 6.99.

3,3’-Bis-(N-methylindolyl)-(3-chlorophenyl)methane (3e). Pink solid, mp: 195–197 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3051, 2930, 1458, 1420, 1094, 743 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.45 (t, J = 7.9 Hz, 2H, Ar–H), 7.42 (s, 1H), 7.37 (d, J = 8.2 Hz, 2H, Ar–H), 7.36-7.25 (m, 5H, Ar–H), 7.10 (dt, J = 0.7, 7.9 Hz, 2H, Ar–H), 6.61 (s, 2H, Ar–H), 5.94 (s, 1H), 3.73 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 146.8, 137.5, 134.1, 129.5, 128.8, 128.3, 127.3, 127.0, 126.4, 121.6, 119.9, 118.9, 117.5, 109.2, 39.9, 32.7. MS (EI, 70 eV): m/z = 386 (M⁺, 20), 384 (M⁺, 60), 371 (5), 369 (15), 273 (100). Anal. calcd. for C₂₅H₂₁N₂Cl: C, 78.01; H, 5.50; N, 7.28. Found C, 77.80; H, 5.50; N, 7.16.

3,3’-Bis-(N-methylindolyl)-(2-bromophenyl)methane (3f). Pink solid, mp: 247–249 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3046, 2926, 1457, 1227, 1023, 792 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.63 (dd, J = 7.9, 1.2 Hz, 1H, Ar–H), 7.42 (d, J = 7.9 Hz, 2H, Ar–H), 7.31 (d, J = 8.2 Hz, 2H, Ar–H), 7.28–7.20 (m, 3H, Ar–H), 7.17 (dt, J = 1.2, 7.6 Hz, 1H, Ar–H), 7.09 (dt, J = 1.8, 7.6 Hz, 1H, Ar–H), 7.03 (dt, J = 0.9, 7.9 Hz, 2H, Ar–H), 6.51 (s, 2H, Ar–H), 6.33 (s, 1H), 3.70 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 143.4, 137.5, 132.8, 130.5, 128.5, 127.7, 127.4, 127.2, 124.8, 121.5, 120.0, 118.7, 117.0, 109.1, 39.4, 32.7. MS (EI, 70 eV): m/z = 430 (M⁺, 20), 428 (M⁺, 20), 350 (55), 273 (100), 130 (30). Anal. calcd. for C₂₅H₂₁N₂Br: C, 69.94; H, 4.93; N, 6.52. Found C, 69.82; H, 4.55; N, 6.54.

3,3’-Bis-(N-methylindolyl)-(3-nitrophenyl)methane (3g). Yellow solid, mp: 157–159 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3063, 2926, 1525, 1474, 1349, 743 cm⁻¹. ¹H-NMR (CDCl₃): δ 8.27 (t, J = 1.9 Hz, 1H, Ar–H), 8.12 (dd, J = 8.2, 1.9 Hz, 1H, Ar–H), 7.74 (d, J = 7.9 Hz, 1H, Ar–H), 7.47 (t, J = 7.9 Hz, 1H, Ar–H), 7.41 (d, J = 7.9 Hz, 2H, Ar–H), 7.38 (d, J = 8.2 Hz, 2H, Ar–H), 7.28 (dt, J = 0.9, 7.9 Hz, 2H, Ar–H), 7.18 (dt, J = 0.9, 7.9 Hz, 2H, Ar–H), 6.61 (s, 2H, Ar–H), 6.05 (s, 1H), 3.75 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 148.5, 146.9, 137.5, 134.9, 129.1, 128.4, 127.1, 123.6, 121.9, 121.4, 119.7, 119.0, 116.8, 109.4, 40.0, 32.8. MS (EI, 70 eV): m/z = 395 (M⁺, 80), 380 (5), 349 (5), 273 (100), 122 (5). Anal. calcd. for C₂₅H₂₁N₃O₂: C, 75.93; H, 5.35; N, 10.63. Found C, 75.76; H, 4.98; N, 10.54.

3,3’-Bis-(2-methylindolyl)-(3-methylphenyl)methane (4a). Pink solid, mp: 181–184 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3383, 2915, 1677, 1607, 1459, 740 cm⁻¹. ¹H-NMR (DMSO-d6): δ 10.71 (s, 2H, N–H), 7.19 (d, J = 8.0 Hz, 2H, Ar–H), 7.11 (t, J = 8.0 Hz, 1H, Ar–H), 7.03–6.96 (m, 3H, Ar–H), 6.87 (dt, J = 0.9, 8.0 Hz, 2H, Ar–H), 6.81 (d, J = 8.0 Hz, 2H, Ar–H), 6.66 (dt, J = 0.9, 8.0 Hz, 2H, Ar–H), 5.87 (s, 1H), 2.19 (s, 3H, CH₃), 2.04 (s, 6H, 2 × CH₃). ¹³C-NMR (DMSO-d6): δ 144.65, 137.20, 135.48, 132.44, 129.81, 128.76, 128.20, 126.88, 126.24, 119.93, 118.92, 118.34, 112.69, 110.73, 39.00, 21.64, 12.38. MS (EI, 70 eV): m/z = 364 (M⁺, 15), 349 (100), 234 (40), 130 (70). Anal. calcd. for C₂₆H₂₄N₂: C, 85.68; H, 6.64; N, 7.69. Found C, 85.50; H, 6.91; N, 7.45.

3,3’-Bis-(2-methylindolyl)-(3-methoxylphenyl)methane (4b). Pink solid, mp: 147–150 °C (EtOAc/PE = 1:4). IR (KBr) ν_max: 3385, 1594, 1459, 1147, 744 cm⁻¹. ¹H-NMR (DMSO-d6): δ 10.73 (s, 2H, N–H), 7.21 (d, J = 8.0 Hz, 2H, Ar–H), 7.16 (t, J = 8.0 Hz, 1H, Ar–H), 6.88 (dt, J = 0.9, 8.0 Hz, 2H, Ar–H), 6.83 (d, J = 8.0 Hz, 2H, Ar–H), 6.79–6.72 (m, 3H, Ar–H), 6.67 (dt, J = 0.9, 8.0 Hz, 2H, Ar–H), 5.88 (s, 1H), 3.62 (s, 3H, OCH₃), 2.07 (s, 6H, 2 × CH₃). ¹³C-NMR (DMSO-d6): δ 159.55, 146.39, 135.49, 132.47, 129.31, 128.71, 121.71, 119.97, 118.93, 118.36, 115.48, 112.57, 110.98, 110.75, 55.27, 39.05, 12.36. MS (EI, 70 eV): m/z = 380 (M⁺, 95), 365 (35), 349 (45), 273 (100), 130 (35). Anal. calcd. for C₂₆H₂₄N₂O: C, 82.07; H, 6.36; N, 7.36. Found C, 81.85; H, 6.02; N, 7.17.

3.3. General Procedure for the Preparation of Bis(thienyl)methanes 5a-5g

To a solution of aryl benzaldehyde (0.5 mmol) and RuCl₃·3H₂O (0.05 mmol ) in ethylene glycol dimethyl ether (1 mL) was added 2-methylthiophene (1.0 mmol) under air atmosphere and the mixture was stirred at 80 °C (monitored by TLC). Then, the reaction mitxure was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:8) to yield the corresponding product.

5,5’-Bis-(2-methylthienyl)phenylmethane (5a). Yellow waxy solid. IR (KBr) ν_max: 3059, 2919, 1525, 1448, 1225, 794 cm⁻¹. ¹H-NMR (MHz, CDCl₃): δ 7.33–7.28 (m, 4H), 7.27–7.21 (m, 1H), 6.61–6.55 (m, 4H), 5.67 (s, 1H), 2.41 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 145.3, 143.8, 139.1, 128.4, 128.3, 127.0, 125.7, 124.5, 47.8, 15.4. MS (EI, 70 eV): m/z = 284 (M⁺, 100), 269 (95), 207 (50), 187 (20), 97 (5), 77 (5). HRESIMS calcd. for [C₁₇H₁₆S₂ + H]⁺: 285.4469; found: 285.4466.

5,5’-Bis-(2-methylthienyl)-(3-methylphenyl)methane (5b). Yellow waxy solid. IR (KBr) ν_max: 3058, 2919, 2859, 1446, 800, 755 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.19 (t, J = 7.5 Hz, 1H), 7.13–7.03 (m, 3H), 6.58 (dd, J = 0.5, 3.5 Hz, 2H), 6.54 (dd, J = 1.0, 3.5 Hz, 2H), 5.66 (s, 1H), 2.44 (s, 6H, 2 × CH₃), 2.35 (s, 3H, CH₃). ¹³C-NMR (CDCl₃): δ 145.4, 143.7, 139.0, 138.0, 129.0, 128.3, 127.8, 125.6, 125.3, 124.5, 47.8, 21.5, 15.4. MS (EI, 70 eV): m/z = 298 (M⁺, 98), 283 (100), 201 (15), 91 (5), 77 (5). HRESIMS calcd. for [C₁₈H₁₈S₂ + H]⁺: 299.4735; found: 299.4733.

5,5’-Bis-(2-methylthienyl)-(4-methylphenyl)methane (5c). Yellow waxy solid. IR (KBr) ν_max: 3062, 2920, 1533, 1448, 745 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.24 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.63 (d, J = 3.4 Hz, 2H), 6.61 (d, J = 3.4 Hz, 2H), 5.68 (s, 1H), 2.45 (s, 6H, 2 × CH₃), 2.37 (s, 3H, CH₃). ¹³C-NMR (CDCl₃): δ 145.5, 140.9, 138.9, 136.5, 129.1, 128.1, 125.5, 124.4, 47.4, 21.0, 15.3. MS (EI, 70 eV): m/z = 298 (M⁺, 90), 283 (100), 201 (20), 91 (5), 77 (5). Anal. calcd. for C₁₈H₁₈S₂: C, 72.43; H, 6.08. Found C, 72.80; H, 6.43.

5,5’-Bis-(2-methylthienyl)-(3-methoxyphenyl)methane (5d). Yellow waxy solid. IR (KBr) ν_max: 2922, 1599, 1487, 1448, 1265, 1156, 1046 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.26 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.89 (t, J = 2.0 Hz, 1H), 6.82 (dd, J = 0.6, 8.1 Hz, 1H), 6.63 (dd, J = 0.5, 3.5 Hz, 2H), 6.58 (dd, J = 1.0, 3.5 Hz, 2H), 5.67 (s, 1H), 3.80 (s, 3H, OCH₃), 2.44 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 159.6, 145.4, 145.0, 139.1, 129.4, 125.7, 124.5, 120.8, 114.3, 112.1, 55.2, 47.8, 15.4. MS (EI, 70 eV): m/z = 314 (M⁺, 100), 299 (15), 283 (10), 207 (90), 122 (15). Anal. calcd. for C₁₈H₁₈S₂O: C, 68.75; H, 5.77. Found C, 68.91; H, 5.84.

5,5’-Bis-(2-methylthienyl)-(3-chlorophenyl)methane (5e). Yellow waxy solid. IR (KBr) ν_max: 3063, 2919, 1473, 1262, 1095, 1034, 802 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.33 (s, 1H), 7.28–7.21 (m, 3H), 6.64–6.59 (m, 4H), 5.68 (s, 1H), 2.46 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 145.8, 144.3, 139.4, 134.3, 129.7, 128.5, 127.2, 126.6, 125.9, 124.7, 47.4, 15.4. MS (EI, 70 eV): m/z = 320 (M⁺, 24), 318 (M⁺, 99), 305 (25), 303 (100), 283 (10), 223 (8), 221 (25), 207 (99), 113 (7), 111 (20). Anal. calcd. for C₁₇H₁₅S₂Cl: C, 64.03; H, 4.74. Found C, 64.06; H, 4.92.

5,5’-Bis-(2-methylthienyl)-(2-bromophenyl)methane (5f). Yellow waxy solid. IR (KBr) ν_max: 3063, 2923, 2856, 1442, 1229, 1028, 795 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.55 (dd, J = 7.9, 1.2 Hz, 1H), 7.32 (dd, J = 7.9, 1.8 Hz, 1H), 7.25 (dt, J = 1.2, 7.9 Hz, 1H), 7.10 (dt, J = 1.8, 7.9 Hz, 1H), 6.59–6.54 (m, 4H), 6.13 (s, 1H), 2.42 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 143.8, 143.0, 139.3, 132.9, 130.1, 128.6, 127.6, 126.2, 124.6, 124.4, 46.7, 15.4. . MS (EI, 70 eV): m/z = 364 (M⁺, 100), 362 (M⁺, 100), 349 (60), 347 (60), 283 (25), 207 (60), 97 (25). Anal. calcd. for C₁₇H₁₅S₂Br: C, 56.20; H, 4.16. Found C, 56.53; H, 4.47.

5,5’-Bis-(2-methylthienyl)-(3-nitrophenyl)methane (5g). Yellow waxy solid. IR (KBr) ν_max: 3061, 2918, 1529, 1350, 804 cm⁻¹. ¹H-NMR (CDCl₃): δ 8.18 (t, J = 1.9 Hz, 1H), 8.13 (dq, J = 0.9, 8.2 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 6.63-6.58 (m, 4H), 5.80 (s, 1H), 2.44 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 148.4, 145.9, 143.4, 139.9, 134.4, 129.4, 126.2, 124.8, 123.3, 122.1, 47.3, 15.4. MS (EI, 70 eV): m/z = 329 (M⁺, 100), 314 (96), 283 (5), 232 (5), 207 (70), 97 (5), 77 (5). Anal. calcd. for C₁₇H₁₅NO₂S₂: C, 61.98; H, 4.59; N, 4.25. Found C, 62.37; H, 4.63; N, 4.45.

3.4. General Procedure for the Preparation of Bis(fur-2-yl)methanes 6a-6f

To a cooled (0 °C) solution of aryl benzaldehyde (0.5 mmol) and RuCl₃·3H₂O (0.05 mmol) in ethylene glycol dimethyl ether (1 mL) was added 2-methylfuran (6.0 mmol) under air atmosphere and the mixture was placed into refrigerator to stay without stirring at 5 °C. The mixture was shaken for several seconds every day to ensure homodispersity (monitored by TLC). The reaction mitxure was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:8) to yield the corresponding product.

5,5’-Bis-(2-methylfuryl)-(3-methylphenyl)methane (6a). Waxy solid. IR (KBr) ν_max: 2922, 1608, 1449, 1137, 1021, 779 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.24 (t, J = 7.5 Hz, 1H), 7.11 (s, 2H), 7.09 (s, 1H), 5.93 (d, J = 3.3 Hz, 2H), 5.91 (d, J = 3.3 Hz, 2H), 5.35 (s, 1H), 2.37 (s, 3H, CH₃), 2.29 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 153.0, 151.4, 139.9, 138.0, 129.1, 128.3, 127.8, 125.5, 108.1, 106.1, 45.1, 21.5, 13.6. MS (EI, 70 eV): m/z = 266 (M⁺, 60), 251 (100), 175 (60). HRESIMS calcd. for [C₁₈H₁₈O₂ + H]⁺: 267.3423; found: 267.3417.

5,5’-Bis-(2-methylfuryl)-(4-methylphenyl)methane (6b). Waxy solid. IR (KBr) ν_max: 2922, 1607, 1510, 1448, 1130, 1014, 775 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.20 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 5.92 (d, J = 3.5 Hz, 2H), 5.90 (d, J = 3.5 Hz, 2H), 5.35 (s, 1H), 2.37 (s, 3H, CH₃), 2.28 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 153.1, 151.4, 137.1, 136.5, 129.2, 128.3, 108.1, 106.1, 44.8, 21.1, 13.6. MS (EI, 70 eV): m/z = 266 (M⁺, 100), 251 (20), 185 (15), 175 (55). HRESIMS calcd. for [C₁₈H₁₈O₂ + H]⁺: 267.3423; found: 267.3422.

5,5’-Bis-(2-methylfuryl)-(3-methoxyphenyl)methane (6c). Waxy solid. IR (KBr) ν_max: 2922, 1600, 1262, 1151, 771 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.26 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.84–6.80 (m, 2H), 5.91 (d, J = 3.8 Hz, 2H), 5.89 (d, J = 3.8 Hz, 2H), 5.33 (s, 1H), 3.79 (s, 3H, OCH₃), 2.27 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 159.7, 152.7, 151.4, 141.6, 129.3, 120.8, 114.3, 112.2, 108.2, 106.1, 55.1, 45.1, 13.6. MS (EI, 70 eV): m/z = 282 (M⁺, 100), 251 (80), 175 (60). HRESIMS calcd. for [C₁₈H₁₉O₃ + H]⁺: 283.3417; found: 283.3411.

5,5’-Bis-(2-methylfuryl)-(3-chlorophenyl)methane (6d). Waxy solid. IR (KBr) ν_max: 2923, 1624, 1437, 1131 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.26–7.23 (m, 3H), 7.16–7.14 (m, 1H), 5.91 (d, J = 3.2 Hz, 2H), 5.89 (d, J = 3.2 Hz, 2H), 5.32 (s, 1H), 2.26 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 152.0, 151.7, 142.0, 134.2, 129.7, 128.5, 127.2, 126.6, 108.5, 106.2, 44.7, 13.6. MS (EI, 70 eV): m/z = 288 (M⁺, 20), 286 (M⁺, 60), 273 (M⁺, 5), 271 (M⁺, 15), 175 (100). HRESIMS calcd. for [C₁₇H₁₆O₂Cl + H]⁺: 287.7607; found: 287.7601.

5,5’-Bis-(2-methylfuryl)-(2-bromophenyl)methane (6e). Waxy solid. IR (KBr) ν_max: 2926, 1462, 1131, 1021, 747 cm⁻¹. ¹H-NMR (CDCl₃): δ 7.58 (dd, J = 7.9, 1.0 Hz, 1H), 7.27 (dt, J = 1.0, 7.9 Hz, 1H), 7.21 (dd, J = 7.9, 1.8 Hz, 1H), 7.14 (dt, J = 1.8, 7.9 Hz, 1H), 5.91 (d, J = 3.0 Hz, 2H), 5.86 (d, J = 3.0 Hz, 2H), 5.83 (s, 1H), 2.27 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 151.7, 151.6, 139.1, 132.9, 130.1, 128.5, 127.5, 124.5, 108.8, 106.1, 44.4, 13.6. MS (EI, 70 eV): m/z = 332 (M⁺, 100), 330 (M⁺, 100), 317 (20), 315 (20), 175 (65). HRESIMS calcd. for [C₁₇H₁₆O₂Br + H]⁺: 332.2117; found: 332.2109.

5,5’-Bis-(2-methylfuryl)-(3-nitrophenyl)methane (6f). Waxy solid. IR (KBr) ν_max: 2922, 1528, 1348, 1132, 781 cm⁻¹. ¹H-NMR (CDCl₃): δ 8.13–8.11 (m, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.48 (dt, J = 2.3, 7.9 Hz, 1H), 5.94 (d, J = 3.0 Hz, 2H), 5.92 (d, J = 3.0 Hz, 2H), 5.44 (s, 1H), 2.25 (s, 6H, 2 × CH₃). ¹³C-NMR (CDCl₃): δ 152.1, 151.1, 148.4, 142.2, 134.6, 129.3, 123.4, 122.2, 108.8, 106.3, 44.7, 13.6. MS (EI, 70 eV): m/z = 297 (M⁺, 90), 282 (15), 175 (100). HRESIMS calcd. for [C₁₇H₁₆NO₄ + H]⁺: 298.3132; found: 298.3129.

4. Conclusions

In summary, RuCl₃·3H₂O has been demonstrated to be a mild and effective catalyst for the reactions of aryl aldehydes with indoles, 2-methylthiophenes, and 2-methylfurans, respectively. The catalyzed reactions produced the corresponding bis(indolyl)methanes, bis(thienyl)methanes, and bis(fur-2-yl)methanes in moderate to excellent yields. The procedure offers several advantages, including mild reaction conditions and simple experimental and isolation procedures, which makes it is a useful and attractive process for the synthesis of bis(indolyl)methanes, bis(thienyl)methanes and bis(fur-2-yl)methanes.

Acknowledgments

The authors are grateful to the NSF of China (Number: 20772099), NSF of Jiangxi Province (Number: 2009GZH0013), and Jiangxi Province Key Support Program for financial support (Number: 2009BNB06200).

Footnotes

Sample Availability: Samples of compounds 2-6 are available from the authors.

References and Notes

1.Lounasmaa M., Tolvanen A. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 2000;17:175–191. doi: 10.1039/a809402k. [DOI] [PubMed] [Google Scholar]
2.Hibino S., Chozi T. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 2001;18:66–87. doi: 10.1039/b004055j. [DOI] [PubMed] [Google Scholar]
3.Porter J.K., Bacon C.W., Robins J.D., Himmelsbach D.S., Higman H.C. Indole alkaloids from Balansia epichloë. J. Agric. Food Chem. 1977;25:88–93. doi: 10.1021/jf60209a043. [DOI] [PubMed] [Google Scholar]
4.Osawa T., Namiki M. Structure elucidation of streptindole, a novel genotoxic metabolite isolated from intestinal bacteria. Tetrahedron Lett. 1983;24:4719–4722. doi: 10.1016/S0040-4039(00)86237-1. [DOI] [Google Scholar]
5.Fahy E., Potts B.C.M., Faulkner D.J., Smith K. 6-Bromotryptamine derivatives from the gulf of california tunicate didemnum candidum. J. Nat. Prod. 1991;54:564–569. doi: 10.1021/np50074a032. [DOI] [Google Scholar]
6.Bell R., Carmeli S., Sar N., Vibrindole A. A metabolite of the marine bacterium, vibrio parahaemolyticus, isolated from the toxic mucus of the boxfish ostracion cubicus. J. Nat. Prod. 1994;57:1587–1590. doi: 10.1021/np50113a022. [DOI] [PubMed] [Google Scholar]
7.Garbe T.R., Kobayashi M., Shimizu N., Takesue N., Ozawa M., Yukawa H. Indolyl carboxylic acids by condensation of indoles with α-keto acids. J. Nat. Prod. 2000;63:596–598. doi: 10.1021/np990517s. [DOI] [PubMed] [Google Scholar]
8.Faulkner D.J. Marine natural products. Nat. Prod. Rep. 2001;18:1–49. doi: 10.1039/b006897g. [DOI] [PubMed] [Google Scholar]
9.Morris S.A., Anderson R.J. Brominated bis(indole) alkaloids from the marine sponge hexadella SP. Tetrahedron. 1990;46:715–720. doi: 10.1016/S0040-4020(01)81355-7. [DOI] [Google Scholar]
10.Bifulco G., Bruno I., Riccio R., Lavayre J., Bourdy G. Further brominated bis- and tris-indole alkaloids from the deep-water new caledonian marine sponge orina sp. J. Nat. Prod. 1995;58:1254–1260. doi: 10.1021/np50122a017. [DOI] [PubMed] [Google Scholar]
11.Ji S.-J., Zhou M.-F., Gu D.-J., Jiang Z.-Q., Loh T.-P. Efficient FeIII-catalyzed synthesis of bis(indolyl)methanes in ionic liquids. Eur. J. Org. Chem. 2004:1584–1587. [Google Scholar]
12.Reddy A.V., Ravinder K., Reddy V.L.N., Goud T.V., Ravikanth V., Venkateswarlu Y. Zeolite catalyzed synthesis of bis(indolyl) methanes. Synth. Commun. 2003;33:3687–3694. [Google Scholar]
13.Mahadevan A., Sard H., Gonzalez M., McKew J.C. A general method for C3 reductive alkylation of indoles. Tetrahedron Lett. 2003;44:4589–4591. doi: 10.1016/S0040-4039(03)01010-4. [DOI] [Google Scholar]
14.Ramesh C., Banerjee J., Pal R., Das B. Silica supported sodium hydrogen sulfate and amberlyst-15: Two efficient heterogeneous catalyst for facile synthesis of bis- and tris(1H-indol-3-yl)methanes from indoles and carbonyl compounds. Adv. Synth. Catal. 2003;345:557–559. doi: 10.1002/adsc.200303022. [DOI] [Google Scholar]
15.Nagarajan R., Perumal P.T. Incl3 and In(OTf)3 catalyzed reactions: Synthesis of 3-acetyl indoles, bis-indolylmethane and indolylquinoline derivatives. Tetrahedron. 2002;58:1229–1232. doi: 10.1016/S0040-4020(01)01227-3. [DOI] [Google Scholar]
16.Giannini G., Marzi M., Marzo M.D., Battistuzzi G., Pezzi R., Brunetti T., Cabri W., Vesci L., Pisano C. Exploring bis-(indolyl)methane moiety as an alternative and innovative CAP group in the design of histone deacetylase (HDAC) inhibitors. Bioorg. Med. Chem. Lett. 2009;19:2840–2843. doi: 10.1016/j.bmcl.2009.03.101. [DOI] [PubMed] [Google Scholar]
17.Giannini G., Marzi M., Moretti G.P., Penco S., Tinti M.O., Pesci S., Lazzaro F., Angelis F.D. Synthesis of cycloalkanoindoles by an unusual DAST-triggeredrearrangement reaction. Eur. J. Org. Chem. 2004;2004:2411–2420. [Google Scholar]
18.Chen D.-P., Yu L.-B., Wang P.-G. Lewis acid-catalyzed reactions in protic media. Lanthanide-catalyzed reactions of indoles with aldehydes or ketones. Tetrahedron Lett. 1996;37:4467–4470. doi: 10.1016/0040-4039(96)00958-6. [DOI] [Google Scholar]
19.Silveira C., Mendes S.R., Líbero F.M., Lenardão E.J., Perin G. Glycerin and CeCl3·7H2O: A new and efficient recyclable medium for the synthesis of bis(indolyl)-methanes. Tetrahedron Lett. 2009;50:6060–6063. [Google Scholar]
20.Bartoli G., Bosco M., Foglia G., Giuliani A., Marcantoni E., Sambri L. Solvent-free indoles addition to carbonyl compounds promoted by CeCl 7 HO-NaI-SiO: An efficient method for the synthesis of streptindole. Synthesis. 2004;6:895–900. [Google Scholar]
21.Ji S.-J., Wang S.-Y., Zhang Y., Loh T.-P. Facile synthesis of bis(indolyl)methanes using catalytic amount of iodine at room temperature under solvent-free conditions. Tetrahedron. 2004;60:2051–2055. [Google Scholar]
22.Bandgar B.P., Shaikh K.A. Molecular iodine-catalyzed efficient and highly rapid synthesis of bis(indolyl)methanes under mild conditions. Tetrahedron Lett. 2003;44:1959–1961. doi: 10.1016/S0040-4039(03)00032-7. [DOI] [Google Scholar]
23.Chakrabarty M., Ghosh N., Basak R., Harigaya Y. Dry reaction of indoles with carbonyl compounds on montmorillonite K10 clay: A mild, expedient synthesis of diindolylalkanes and vibrindole A. Tetrahedron Lett. 2002;43:4075–4078. doi: 10.1016/S0040-4039(02)00682-2. [DOI] [Google Scholar]
24.Li J., Zhou M., Li B.-G., Zhang G.-L. Synthesis of triindolylmethanes catalyzed by zeolites. Synth. Commun. 2004;34:275–280. doi: 10.1081/SCC-120027263. [DOI] [Google Scholar]
25.Chakrabarty M., Sarkar S. Novel clay-mediated, tandem addition-elimination-(Michael) addition reactions of indoles with 3-formylindole: An eco-friendly route to symmetrical and unsymmetrical triindolylmethanes. Tetrahedron Lett. 2002;43:1351–1353. doi: 10.1016/S0040-4039(01)02380-2. [DOI] [Google Scholar]
26.Deb M.L., Bhuyan P.J. An efficient and clean synthesis of bis(indolyl)methanes in a protic solvent at room temperature. Tetrahedron Lett. 2006;47:1441–1443. doi: 10.1016/j.tetlet.2005.12.093. [DOI] [Google Scholar]
27.Nair V., Abhilash K.G., Vidya N. Practical synthesis of triaryl- and triheteroarylmethanes by reaction of aldehydes and activated arenes promoted by gold(III) chloride. Org. Lett. 2005;7:5857–5859. doi: 10.1021/ol052423h. [DOI] [PubMed] [Google Scholar]
28.Swain C.G., Lupton E.C., Jr. Field and resonance components of substituent effects. J. Am. Chem. Soc. 1968;90:4328–4337. doi: 10.1021/ja01018a024. [DOI] [Google Scholar]
29.Penieres-Carrillo G., Garcia-Estrada J.G., Gutierrez-Ramirez J.L., Alvarez-Tolendano C. Infrared-assisted eco-friendly selective synthesis of diindolylmethanes. Green Chem. 2003;5:337–339. doi: 10.1039/b211011c. [DOI] [Google Scholar]
30.Yadav J.S., Reddy B.V.S., Murthy C.V.S.R., Kumar G.M., Madan C. Lithium perchlorate catalyzed reactions of indoles: An expeditious synthesis of bis(indolyl) methanes. Synthesis. 2001;5:783–787. [Google Scholar]

[B1-molecules-16-03855] 1.Lounasmaa M., Tolvanen A. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 2000;17:175–191. doi: 10.1039/a809402k. [DOI] [PubMed] [Google Scholar]

[B2-molecules-16-03855] 2.Hibino S., Chozi T. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 2001;18:66–87. doi: 10.1039/b004055j. [DOI] [PubMed] [Google Scholar]

[B3-molecules-16-03855] 3.Porter J.K., Bacon C.W., Robins J.D., Himmelsbach D.S., Higman H.C. Indole alkaloids from Balansia epichloë. J. Agric. Food Chem. 1977;25:88–93. doi: 10.1021/jf60209a043. [DOI] [PubMed] [Google Scholar]

[B4-molecules-16-03855] 4.Osawa T., Namiki M. Structure elucidation of streptindole, a novel genotoxic metabolite isolated from intestinal bacteria. Tetrahedron Lett. 1983;24:4719–4722. doi: 10.1016/S0040-4039(00)86237-1. [DOI] [Google Scholar]

[B5-molecules-16-03855] 5.Fahy E., Potts B.C.M., Faulkner D.J., Smith K. 6-Bromotryptamine derivatives from the gulf of california tunicate didemnum candidum. J. Nat. Prod. 1991;54:564–569. doi: 10.1021/np50074a032. [DOI] [Google Scholar]

[B6-molecules-16-03855] 6.Bell R., Carmeli S., Sar N., Vibrindole A. A metabolite of the marine bacterium, vibrio parahaemolyticus, isolated from the toxic mucus of the boxfish ostracion cubicus. J. Nat. Prod. 1994;57:1587–1590. doi: 10.1021/np50113a022. [DOI] [PubMed] [Google Scholar]

[B7-molecules-16-03855] 7.Garbe T.R., Kobayashi M., Shimizu N., Takesue N., Ozawa M., Yukawa H. Indolyl carboxylic acids by condensation of indoles with α-keto acids. J. Nat. Prod. 2000;63:596–598. doi: 10.1021/np990517s. [DOI] [PubMed] [Google Scholar]

[B8-molecules-16-03855] 8.Faulkner D.J. Marine natural products. Nat. Prod. Rep. 2001;18:1–49. doi: 10.1039/b006897g. [DOI] [PubMed] [Google Scholar]

[B9-molecules-16-03855] 9.Morris S.A., Anderson R.J. Brominated bis(indole) alkaloids from the marine sponge hexadella SP. Tetrahedron. 1990;46:715–720. doi: 10.1016/S0040-4020(01)81355-7. [DOI] [Google Scholar]

[B10-molecules-16-03855] 10.Bifulco G., Bruno I., Riccio R., Lavayre J., Bourdy G. Further brominated bis- and tris-indole alkaloids from the deep-water new caledonian marine sponge orina sp. J. Nat. Prod. 1995;58:1254–1260. doi: 10.1021/np50122a017. [DOI] [PubMed] [Google Scholar]

[B11-molecules-16-03855] 11.Ji S.-J., Zhou M.-F., Gu D.-J., Jiang Z.-Q., Loh T.-P. Efficient FeIII-catalyzed synthesis of bis(indolyl)methanes in ionic liquids. Eur. J. Org. Chem. 2004:1584–1587. [Google Scholar]

[B12-molecules-16-03855] 12.Reddy A.V., Ravinder K., Reddy V.L.N., Goud T.V., Ravikanth V., Venkateswarlu Y. Zeolite catalyzed synthesis of bis(indolyl) methanes. Synth. Commun. 2003;33:3687–3694. [Google Scholar]

[B13-molecules-16-03855] 13.Mahadevan A., Sard H., Gonzalez M., McKew J.C. A general method for C3 reductive alkylation of indoles. Tetrahedron Lett. 2003;44:4589–4591. doi: 10.1016/S0040-4039(03)01010-4. [DOI] [Google Scholar]

[B14-molecules-16-03855] 14.Ramesh C., Banerjee J., Pal R., Das B. Silica supported sodium hydrogen sulfate and amberlyst-15: Two efficient heterogeneous catalyst for facile synthesis of bis- and tris(1H-indol-3-yl)methanes from indoles and carbonyl compounds. Adv. Synth. Catal. 2003;345:557–559. doi: 10.1002/adsc.200303022. [DOI] [Google Scholar]

[B15-molecules-16-03855] 15.Nagarajan R., Perumal P.T. Incl3 and In(OTf)3 catalyzed reactions: Synthesis of 3-acetyl indoles, bis-indolylmethane and indolylquinoline derivatives. Tetrahedron. 2002;58:1229–1232. doi: 10.1016/S0040-4020(01)01227-3. [DOI] [Google Scholar]

[B16-molecules-16-03855] 16.Giannini G., Marzi M., Marzo M.D., Battistuzzi G., Pezzi R., Brunetti T., Cabri W., Vesci L., Pisano C. Exploring bis-(indolyl)methane moiety as an alternative and innovative CAP group in the design of histone deacetylase (HDAC) inhibitors. Bioorg. Med. Chem. Lett. 2009;19:2840–2843. doi: 10.1016/j.bmcl.2009.03.101. [DOI] [PubMed] [Google Scholar]

[B17-molecules-16-03855] 17.Giannini G., Marzi M., Moretti G.P., Penco S., Tinti M.O., Pesci S., Lazzaro F., Angelis F.D. Synthesis of cycloalkanoindoles by an unusual DAST-triggeredrearrangement reaction. Eur. J. Org. Chem. 2004;2004:2411–2420. [Google Scholar]

[B18-molecules-16-03855] 18.Chen D.-P., Yu L.-B., Wang P.-G. Lewis acid-catalyzed reactions in protic media. Lanthanide-catalyzed reactions of indoles with aldehydes or ketones. Tetrahedron Lett. 1996;37:4467–4470. doi: 10.1016/0040-4039(96)00958-6. [DOI] [Google Scholar]

[B19-molecules-16-03855] 19.Silveira C., Mendes S.R., Líbero F.M., Lenardão E.J., Perin G. Glycerin and CeCl3·7H2O: A new and efficient recyclable medium for the synthesis of bis(indolyl)-methanes. Tetrahedron Lett. 2009;50:6060–6063. [Google Scholar]

[B20-molecules-16-03855] 20.Bartoli G., Bosco M., Foglia G., Giuliani A., Marcantoni E., Sambri L. Solvent-free indoles addition to carbonyl compounds promoted by CeCl 7 HO-NaI-SiO: An efficient method for the synthesis of streptindole. Synthesis. 2004;6:895–900. [Google Scholar]

[B21-molecules-16-03855] 21.Ji S.-J., Wang S.-Y., Zhang Y., Loh T.-P. Facile synthesis of bis(indolyl)methanes using catalytic amount of iodine at room temperature under solvent-free conditions. Tetrahedron. 2004;60:2051–2055. [Google Scholar]

[B22-molecules-16-03855] 22.Bandgar B.P., Shaikh K.A. Molecular iodine-catalyzed efficient and highly rapid synthesis of bis(indolyl)methanes under mild conditions. Tetrahedron Lett. 2003;44:1959–1961. doi: 10.1016/S0040-4039(03)00032-7. [DOI] [Google Scholar]

[B23-molecules-16-03855] 23.Chakrabarty M., Ghosh N., Basak R., Harigaya Y. Dry reaction of indoles with carbonyl compounds on montmorillonite K10 clay: A mild, expedient synthesis of diindolylalkanes and vibrindole A. Tetrahedron Lett. 2002;43:4075–4078. doi: 10.1016/S0040-4039(02)00682-2. [DOI] [Google Scholar]

[B24-molecules-16-03855] 24.Li J., Zhou M., Li B.-G., Zhang G.-L. Synthesis of triindolylmethanes catalyzed by zeolites. Synth. Commun. 2004;34:275–280. doi: 10.1081/SCC-120027263. [DOI] [Google Scholar]

[B25-molecules-16-03855] 25.Chakrabarty M., Sarkar S. Novel clay-mediated, tandem addition-elimination-(Michael) addition reactions of indoles with 3-formylindole: An eco-friendly route to symmetrical and unsymmetrical triindolylmethanes. Tetrahedron Lett. 2002;43:1351–1353. doi: 10.1016/S0040-4039(01)02380-2. [DOI] [Google Scholar]

[B26-molecules-16-03855] 26.Deb M.L., Bhuyan P.J. An efficient and clean synthesis of bis(indolyl)methanes in a protic solvent at room temperature. Tetrahedron Lett. 2006;47:1441–1443. doi: 10.1016/j.tetlet.2005.12.093. [DOI] [Google Scholar]

[B27-molecules-16-03855] 27.Nair V., Abhilash K.G., Vidya N. Practical synthesis of triaryl- and triheteroarylmethanes by reaction of aldehydes and activated arenes promoted by gold(III) chloride. Org. Lett. 2005;7:5857–5859. doi: 10.1021/ol052423h. [DOI] [PubMed] [Google Scholar]

[B28-molecules-16-03855] 28.Swain C.G., Lupton E.C., Jr. Field and resonance components of substituent effects. J. Am. Chem. Soc. 1968;90:4328–4337. doi: 10.1021/ja01018a024. [DOI] [Google Scholar]

[B29-molecules-16-03855] 29.Penieres-Carrillo G., Garcia-Estrada J.G., Gutierrez-Ramirez J.L., Alvarez-Tolendano C. Infrared-assisted eco-friendly selective synthesis of diindolylmethanes. Green Chem. 2003;5:337–339. doi: 10.1039/b211011c. [DOI] [Google Scholar]

[B30-molecules-16-03855] 30.Yadav J.S., Reddy B.V.S., Murthy C.V.S.R., Kumar G.M., Madan C. Lithium perchlorate catalyzed reactions of indoles: An expeditious synthesis of bis(indolyl) methanes. Synthesis. 2001;5:783–787. [Google Scholar]

PERMALINK

RuCl₃·3H₂O Catalyzed Reactions: Facile Synthesis of Bis(indolyl)methanes under Mild Conditions

Hong-En Qu

Chen Xiao

Ning Wang

Kai-Hui Yu

Qiao-Sheng Hu

Liang-Xian Liu

Abstract

1. Introduction