Iodine–PPh₃-mediated C3-sulfenylation of indoles with sodium sulfinates

Abstract

3-(Alkylsulfanyl)- and 3-(arylsulfanyl)indoles were efficiently prepared by the reaction of indoles with sodium sulfinates mediated by iodine–PPh₃ in ethanol. The salient features of the present protocol are simplicity, high efficiency, non-anhydrous conditions, environmentally friendly reagents and solvent, and short reaction time.

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Sulfur-containing organic molecules are important structural motifs in organic synthesis, organic materials, and pharmaceutically important compounds.¹ The unique properties derive from the enhanced physical and chemical features of the sulfur atom. Therefore, introduction of sulfur moieties into organic molecules is an important process for organic materials and drug development and other fine chemicals synthesis. In particular, 3-sulfanylindoles are significant class of compounds due to their potential uses as drugs in several disease areas (Fig. 1), for example, HIV,² obesity,³ allergies,⁴ cancer⁵ and heart disease.⁶ Hence, the development of synthetic strategies that achieve an installation of the 3-(alkylsulfanyl)- or 3-(arylsulfanyl) functionality into an indole substrate has been the subject of intense research efforts. A number of electrophilic sulfenylating reagents are available for the preparation of 3-sulfanylindoles as well as arylsulfanyl-substituted electron-rich arenes, including reactions with disulfides,⁷ sulfonyl chlorides,⁸ sulfenyl chlorides,⁹ thiols,¹⁰ quinone mono-O,S-acetals,¹¹ N-(arylthio)phthalimide,¹² arylsulfonyl cyanide,¹³ and recently sulfonyl hydrazide.¹⁴ Although a number of synthetic approaches have been described for sulfenylation of indoles, they are often found impractical in view of expensive reagents, harsh reaction conditions, high reagent loadings, uncommon solvents, unpleasant smell of reagents, requirement of inert atmosphere as well as long reaction time. Thus, it is still desirable to develop an alternative method that is improving the efficiency, minimizing the energy, cost, and chemical waste.

Fig. 1 Some biologically active 3-(arylsulfanyl)indoles.

In continuation of our ongoing research dealing with the development of new methods for the synthesis of sulfur-containing molecules,¹⁵ we have recently described an efficient regioselective C2 sulfonylation of indoles mediated by molecular iodine.¹⁶ In our initial studies on the optimization of this reaction, the C3 sulfenylated indoles were isolated as competing products depending on the reaction conditions. Encouraged by these results and on the basis of an unprecedented use of sodium sulfinates as sulfenylating agents, we therefore decided to examine these results in details. During our investigation and preparation of the manuscript, an elegant publication by Deng and co-workers on the use of sodium sulfinates for C3 sulfenylation of indoles catalyzed by molecular iodine appeared.¹⁷ This prompts us to report our own findings. We report herein that a range of indole derivatives readily undergo C3 sulfenylation with sodium sulfinates mediated by I₂–PPh₃ in refluxing ethanol.

The reaction of indole (1a) with sodium p-toluenesulfinate (2a) was investigated to explore the optimal reaction conditions, and the results are summarized in Table 1. Without the requirement for moisture-free conditions, indole (1a) was treated with sodium p-toluenesulfinate (2a, 2 equiv.), iodine (1 equiv.) and triphenylphosphine (2 equiv.) in refluxing dichloromethane for 3 h. Much to our delight, the corresponding product 3-(p-toluenesulfanyl)indole (3a) was obtained in 67% yield (Table 1, entry 1). Among several organic solvents screened (Table 1, entries 2–11), ethanol gave the best efficiency in terms of product yield (84% yield) and as an environmentally benign solvent (Table 1, entry 8). While the reaction time can be shorten from 3 h to 2 h, reduction in the stoichiometry of sodium p-toluenesulfinate (2a) and triphenylphosphine resulted in slight decrease in yields of 3a (from 85% yield to 68% yield) (Table 1, entries 12–14). The best yield of 3a was obtained when the amounts of sodium p-toluenesulfinate (2a) and triphenylphosphine employed were as low as 1.5 equiv. each (Table 1, entry 13). Finally, when the reaction was carried out at room temperature with prolonged reaction time, the yield of 3a was significantly lower (Table 1, entry 15). Based on the experimental results shown in Table 1, the optimized reaction conditions were chosen as follows: indole substrate (1 equiv.), sodium sulfinate (1.5 equiv.), I₂ (1 equiv.), and triphenylphosphine (1.5 equiv.) in ethanol at refluxing temperature for 2 h (Table 1, entry 12).

Table 1 Optimization of the reaction conditions for I₂–PPh₃ mediated C3 sulfenylation reaction of indole (1a)^a

Entry	2a (equiv.)	I2 (equiv.)	PPh3 (equiv.)	Solvent	Time (h)	Yield^b (%)
a Conditions: 1a (0.5 mmol) in 0.25 M of solvent.b Isolated yield after column chromatography (SiO2).c Reactions were carried out at 80 °C.d 1a was recovered in 80% yield.e Reaction was carried out at room temperature.
1	2	1	2	CH2Cl2	3	67
2	2	1	2	ClCH2CH2Cl	3	76
3	2	1	2	Hexanes	3	42
4^c	2	1	2	Toluene	3	82
5	2	1	2	THF	3	18^d
6	2	1	2	Acetone	3	49
7	2	1	2	1,4-Dioxane	3	49
8	2	1	2	EtOH	3	84
9	2	1	2	CH3CN	3	84
10^c	2	1	2	DMF	3	79
11^c	2	1	2	DMSO	3	61
12	1.5	1	1.5	EtOH	2	85
13	1.2	1	1.2	EtOH	2	79
14	1	1	1	EtOH	2	68
15^e	1.5	1	1.5	EtOH	5	51

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Having established efficient access to 3-(p-toluenesulfanyl)indole (3a), we further demonstrated that our method could be used as a general route for C3 sulfenylation of structurally different indoles and sodium sulfinates. The results are summarized in Table 2. Sodium arenesulfinates, including sodium p-toluenesulfinate, sodium benzenesulfinate, and sodium p-chlorobenzenesulfinate reacted with indole to provide the corresponding products in high yields (Table 2, entries 1–3). The reaction of 1a with sodium methanesulfinate required longer reaction time (8 h) and gave low yield of the corresponding product 3d (Table 2, entry 4). The reaction of N-methylindoles smoothly proceeded, yielding the corresponding product in good yield (Table 2, entry 5) while N-Boc-indole was untouched (Table 2, entry 6). Methyl-substituted indoles at C2, C5, C6, and C7 worked equally well, leading to the corresponding products in 81–92% yields (Table 2, entries 7–10). 5-Methoxyindole gave good results, yielding the product in 88% yield (Table 2, entry 11). Reactions of electron-deficient substituted indoles, including 5-F, 5-Cl, 5-Br, 5-CO₂CH₃ and 5-NO₂ substituted indoles were found less efficient and required longer reaction time; the corresponding products were obtained in moderate to high yields (Table 2, entries 12–16). It was found that a formyl group was incompatible under the reaction conditions; the crude reaction mixture revealed indefinite spots. (Table 2, entry 17). Finally, 3-methylindole gave 3-methyl-2-(p-toluenesulfanyl)indole (4) in 75% yield (Table 2, entry 18).¹⁸

Table 2 C3 Sulfenylation of indole derivatives with sodium sulfinates mediated by I₂–PPh₃ system^a

Entry	R^1	R^2	R^3	Time (h)	Product, yield^b (%)
a Conditions: 1 (0.5 mmol), 2 (1.5 equiv.), I2 (1 equiv.), and triphenylphosphine (1.5 equiv.) in 0.25 M of EtOH.b Isolated yield after column chromatography (SiO2).c N-Boc-indole was recovered in 68% yield.d 5-Nitroindole was recovered in 61% yield.e 5-Formylindole was totally consumed.
1	H	H	pTol	2	3a, 85
2	H	H	Ph	2	3b, 75
3	H	H	pClC6H4	2	3c, 97
4	H	H	CH3	8	3d, 44
5	CH3	H	pTol	2	3e, 88
6	Boc	H	pTol	2	—^c
7	H	2-CH3	pTol	2	3f, 89
8	H	5-CH3	pTol	2	3g, 92
9	H	6-CH3	pTol	2	3h, 81
10	H	7-CH3	pTol	2	3i, 83
11	H	5-OCH3	pTol	2	3j, 88
12	H	5-F	pTol	3	3k, 85
13	H	5-Cl	pTol	3	3l, 69
14	H	5-Br	pTol	3	3m, 72
15	H	5-CO2CH3	pTol	5	3n, 73
16	H	5-NO2	pTol	8	3o, 32^d
17	H	5-CHO	pTol	5	—^e
18	H	3-CH3	pTol	2

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To address a plausible reaction pathway, some control experiments were carried out (Table 3). Product 3a was not observed when iodine was excluded from the reaction; indole (1a) and triphenylphosphine were recovered in 88% and 95% yields, respectively (Table 3, entry 1). On the other hand, the reaction carried out in the absence of triphenylphosphine led to 2-(p-toluenesulfonyl)indole (5) as a major product in 46% yield while the desired product 3a was obtained in 21% yield (Table 3, entry 2). This means that in the absence of triphenylphosphine, sodium p-toluenesulfinate (2a) readily reacted with iodine, generating p-toluenesulfonyl iodide which can react with indole (1a) to yield 2-(p-toluenesulfonyl)indole (5) as a major pathway.¹⁶ Under the reaction conditions, p-toluenesulfonyl iodide can be reduced to generate a sulfenylating species which can react with indole (1a) to yield 3-(p-toluenesulfanyl)indole (3a) as a minor pathway.¹⁹ In the absence of indole (1a), treatment of sodium p-toluenesulfinate (2a) with I₂ (1.0 equiv.) and triphenylphosphine (1.5 equiv.) under standard reaction conditions yielded 1,2-di-p-tolyldisulfane (6, 34% yield) and S-p-tolyl 4-methylbenzenesulfonothioate (7, 38% yield) (Table 3, entry 3). It is worth to note that S-p-tolyl 4-methylbenzenesulfonothioate (7) can be converted to 1,2-di-p-tolyldisulfane (6) under the reaction conditions (Table 3, entry 4). These results imply that both sulfonothiolate 7 and disulfide 6 would probably be formed under the reaction conditions and 6 should be generated from 7. Since both of them were previously described being used as sulfenylating agents,^7a,b,14 our next attempts were to use 6 and 7 as reagents in place of sodium sulfinate (Table 3, entries 5 and 6). Both 6 and 7 exhibited poorer reactivity as sulfenylating agents under our reaction conditions; 6 led to the corresponding thiol 8 while 7 gave 2,3-disulfenylated product 9 as a major product. Finally, when 3-(p-toluenesulfonyl)indole (10) was treated with I₂ (1.0 equiv.) and triphenylphosphine (1.5 equiv.) in fluxing ethanol for 2 h, no reaction took place; 10 was recovered in 97% yield (Table 3, entry 7). This suggested that a combination of I₂–PPh₃ was unable to cause reduction of sulfone to sulfide. Thus, a reduction of sodium sulfinate mediated by a combination of I₂–PPh₃, leading to a sulfenylating species should primarily and feasibly occur prior to other processes.

Table 3 Control experiments^a

Entry	1a or 10 (equiv.)	S source (equiv.)	I2 (equiv.)	PPh3 (equiv.)	Product, yield^b (%)
					3a	5	6	7	8	9
a All reactions were carried out in refluxing EtOH (0.25 M) for 2 h.b Isolated yield after column chromatography (SiO2).c No reaction took place.
1^c	1a (1.0)	2a (1.5)	—	1.5	—	—	—	—	—	—
2	1a (1.0)	2a (1.5)	1	—	21	46	—	—	—	—
3	—	2a (1.0)	1	1.5	—	—	34	38	—	—
4	—	7 (1.0)	1	1.5	—	—	60	35	—	—
5	1a (1.0)	6 (1.0)	1	1.5	Trace	—	—	—	79	—
6	1a (1.0)	7 (1.0)	1	1.5	18	—	19	—	—	56
7^c	10 (1.0)	—	1	1.5	—	—	—	—	—	—

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On the basis of the experimental results described above and a report by Togo et. al. on the reduction of sulfonic acid by I₂–PPh₃ system,¹⁹ a plausible reaction pathway was proposed (Scheme 1). First, iodine reacts with triphenylphosphine to form iodotriphenylphosphonium iodide which then reacts with sodium sulfinate, finally leading to an electrophilic sulfenylating species, most probably, sulfenyl iodide. Depending on whether or not C3 carbon is substituted, indole substrate readily reacts with the sulfenyl iodide, yielding either 3-sulfenylation or 2-sulfenylation product.

Scheme 1 Plausible reaction pathway.

Conclusions

We have described a convenient and simple protocol to access 3-(alkylsulfanyl)- and 3-(arylsulfanyl)indoles using sodium sulfinates as the reagents mediated by I₂–PPh₃ system. The reaction readily proceeded in refluxing ethanol within a few hours. In view of simplicity, high efficiency, non-anhydrous conditions, environmentally benign solvent and short reaction time, it is believed that this protocol should offer an alternative and rapid approach to 3-sulfanylindoles.

Experimental

General information

¹H NMR spectra were recorded with a Bruker Ascend™ 400 (400 MHz) and Bruker Avance-500 (500 MHz) spectrometer in CDCl₃ by using tetramethylsilane (δ = 0 ppm) as an internal standard. ¹³C NMR spectra were recorded with a Bruker Ascend™ 400 (400 MHz) and Bruker Avance-500 (500 MHz) spectrometer. Infrared spectra were recorded with a Perkin-Elmer 683 GX FTIR System spectrometer. High-resolution mass spectra (HRMS) were recorded with a Bruker micro TOF spectrometer in the ESI mode. Melting points were recorded with a digital Electrothermal Melting 9100 apparatus and were uncorrected. All reagents and solvents were obtained from commercial sources and used without further purification. Column chromatography was performed by using Merck silica gel 60 PF₂₅₄ (Art 7734).

General procedure

Iodine (127.0 mg, 0.50 mmol) was added to a solution of indole (0.5 mmol), sodium sulfinate (0.75 mmol) and triphenylphosphine (0.75 mmol) in EtOH (2 mL; 0.25 M), and the reaction mixture was stirred at refluxing temperature for 2–8 h. The reaction mixture was quenched by the addition of sat. aq. Na₂S₂O₃ (5 mL). Further stirring was followed by extraction with EtOAc (2 × 20 mL). The combined organic extracts were washed with H₂O (20 mL) and brine (20 mL), dried (MgSO₄), filtered, and concentrated (aspirator). The residue was purified by column chromatography using acetone/hexanes as eluent to afford the corresponding product.

3-[(4-Methylphenyl)sulfanyl]-1H-indole (3a). White solid (101.7 mg, 85%); m.p. = 122–124 °C (from CH₂Cl₂/hexanes) (lit.,^10c 125–126 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.25 (br s, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.19–7.15 (m, 1H), 7.09–7.05 (m, 1H), 6.95 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 136.4 (C), 135.4 (C), 134.6 (C), 130.4 (CH), 129.4 (2 × CH), 129.0 (C), 126.2 (2 × CH), 122.9 (CH), 120.8 (CH), 119.6 (CH), 111.5 (CH), 103.4 (C), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₅H₁₃NSNa [M + Na]⁺: 262.0666, found 262.0664.

3-(Phenylsulfanyl)-1H-indole (3b). White solid (84.5 mg, 75%); m.p. = 147–148 °C (from CH₂Cl₂/hexanes) (lit.,^10e 149–151 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.34 (br s, 1H), 7.61 (d, J = 7.9 Hz, 1H) 7.44 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.28–7.23 (m, 1H), 7.18–7.02 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 139.2 (C), 136.4 (C), 130.7 (CH), 129.0 (C), 128.7 (2 × CH), 125.8 (2 × CH), 124.8 (CH), 123.0 (CH), 120.9 (CH), 119.6 (CH), 111.6 (CH), 102.7 (C); HRMS (ESI-TOF) calcd for C₁₄H₁₁NSNa [M + Na]⁺: 248.0510, found 248.0508.

3-[(4-Chlorophenyl)sulfanyl]-1H-indole (3c). White solid (126.0 mg, 97%); m.p. = 126–128 °C (from CH₂Cl₂/hexanes) (lit.,^10c 127.5–128.3 °C); ¹H NMR (500 MHz, CDCl₃): δ 8.42 (br s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.32–7.29 (m, 1H), 7.22–7.19 (m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 137.8 (C), 136.5 (C), 130.7 (CH), 130.5 (C), 128.77 (C), 128.72 (2 × CH), 127.1 (2 × CH), 123.2 (CH), 121.0 (CH), 119.5 (CH), 111.7 (CH), 102.4 (C); HRMS (ESI-TOF) calcd for C₁₄H₁₀ClNS [M]⁺: 259.0222, found 259.0225.

3-(Methylsulfanyl)-1H-indole (3d)^7a. White oil (35.9 mg, 44%); ¹H NMR (400 MHz, CDCl₃): δ 8.08 (br s, 1H), 7.70–7.68 (m, 1H), 7.26–7.23 (m, 1H), 7.17–7.10 (m, 3H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 136.2 (C), 128.6 (C), 127.8 (CH), 122.6 (CH), 120.2 (CH), 119.1 (CH), 111.5 (CH), 107.9 (C), 20.1 (CH₃).

1-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3e)^8b. White solid (111.5 mg, 88%); m.p. = 115.5–117 °C (from CH₂Cl₂/hexanes); ¹H NMR (400 MHz, CDCl₃): δ 7.53 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.22–7.18 (m, 2H), 7.09–7.05 (m, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 3.73 (s, 3H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 137.5 (C), 135.9 (C), 134.8 (CH), 134.5 (C), 129.8 (C), 129.4 (2 × CH), 126.1 (2 × CH), 122.4 (CH), 120.4 (CH), 119.7 (CH), 109.6 (CH), 101.1 (C), 33.1 (CH₃), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₆H₁₅NSNa [M + Na]⁺: 276.0823, found 276.0837.

2-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3f). Brown solid (112.7 mg, 89%); m.p. = 96.5–98 °C (from CH₂Cl₂/hexanes) (lit.,^7a 98.2–100 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.16 (br s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.22–7.12 (m, 2H), 6.98 (s, 4H), 2.49 (s, 3H), 2.26 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 140.9 (C), 135.6 (C), 135.3 (C), 134.3 (C), 130.2 (C), 129.4 (2 × CH), 125.7 (2 × CH), 122.0 (CH), 120.6 (CH), 118.9 (CH), 110.6 (CH), 99.7 (C), 20.8 (CH₃), 12.0 (CH₃); HRMS (ESI-TOF) calcd for C₁₆H₁₅NSNa [M + Na]⁺: 276.0823, found 276.0827.

5-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3g). White solid (116.5 mg, 92%); m.p. = 135.5–137 °C (from CH₂Cl₂/hexanes) (lit.,^7g 137–138 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.18 (br s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.14–7.01 (m, 5H), 2.45 (s, 3H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 135.7 (C), 134.6 (C), 134.5 (C), 130.7 (CH), 130.2 (C), 129.4 (2 × CH), 129.3 (C), 125.9 (2 × CH), 124.5 (CH), 119.0 (CH), 111.2 (CH), 102.2 (C), 21.4 (CH₃), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₆H₁₅NSNa [M + Na]⁺: 276.0823, found 276.0825.

6-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3h). White solid (102.6 mg, 81%); m.p. = 124.5–126 °C (from CH₂Cl₂/hexanes); ¹H NMR (400 MHz, CDCl₃): δ 8.15 (br s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.13 (s, 1H), 6.95–6.88 (m, 5H), 2.39 (s, 3H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 136.9 (C), 135.6 (C), 134.5 (C), 132.9 (C), 129.8 (CH), 129.4 (2 × CH), 126.9 (C), 126.1 (2 × CH), 122.6 (CH), 119.3 (CH), 111.4 (CH), 103.1 (C), 21.7 (CH₃), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₆H₁₅NS [M]⁺: 253.0925, found 253.0927.

7-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3i). White solid (105.1 mg, 83%); m.p. = 115–117 °C (from CH₂Cl₂/hexanes); ¹H NMR (500 MHz, CDCl₃): δ 8.31 (br s, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.12–7.05 (m, 4H), 6.99 (d, J = 8.3 Hz, 2H), 2.53 (s, 3H), 2.26 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 136.0 (C), 135.6 (C), 134.6 (C), 130.1 (CH), 129.4 (2 × CH), 128.7 (C), 126.3 (2 × CH), 123.5 (CH), 121.0 (CH), 120.6 (C), 117.4 (CH), 104.0 (C), 20.8 (CH₃), 16.3 (CH₃); HRMS (ESI-TOF) calcd for C₁₆H₁₅NSNa [M + Na]⁺: 276.0823, found 276.0828.

5-Methoxy-3-[(4-methylphenyl)sulfanyl]-1H-indole (3j)^7k. Pale yellow liquid (118.5 mg, 88%); ¹H NMR (400 MHz, CDCl₃): δ 8.24 (br s, 1H), 7.23 (d, J = 2.7 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.79 (dd, J = 8.8, 2.3 Hz, 1H), 3.65 (s, 3H), 2.13 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 154.9 (C), 135.5 (C), 134.5 (C), 131.3 (C), 131.2 (CH), 129.8 (C), 129.4 (2 × CH), 125.9 (2 × CH), 113.3 (CH), 112.4 (CH), 102.3 (C), 100.7 (CH), 55.7 (CH₃), 20.7 (CH₃); HRMS (ESI-TOF) calcd for C₁₆H₁₅NOSNa [M + Na]⁺: 292.0772, found 292.0767.

5-Fluoro-3-[(4-methylphenyl)sulfanyl]-1H-indole (3k). White solid (109.4 mg, 85%); m.p. = 137.5–139.5 °C (from CH₂Cl₂/hexanes); ¹H NMR (400 MHz, CDCl₃): δ 8.30 (br s, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 8.8, 4.2 Hz, 1H), 7.17 (dd, J = 8.6, 2.4 Hz, 1H), 6.95–6.88 (m, 5H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 158.5 (d, J = 235.3 Hz, C), 134.93 (C), 134.89 (C), 132.8 (C), 132.0 (CH), 129.9 (d, J = 10.1 Hz, C), 129.5 (2 × CH), 126.3 (2 × CH), 112.3 (d, J = 9.4 Hz, CH), 111.5 (d, J = 26.4 Hz, CH), 104.7 (d, J = 24.0 Hz, CH), 103.7 (d, J = 4.5 Hz, C), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₅H₁₂FNSNa [M + Na]⁺: 280.0572, found 280.0578.

5-Chloro-3-[(4-methylphenyl)sulfanyl]-1H-indole (3l). White solid (94.5 mg, 69%); m.p. = 124.5–125.5 °C (from CH₂Cl₂/hexanes); ¹H NMR (400 MHz, CDCl₃): δ 8.44 (br s, 1H), 7.63 (s, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.23 (dd, J = 8.6, 2.0 Hz, 1H), 7.07–7.02 (m, 4H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 134.94 (C), 134.88 (C), 134.7 (C), 131.7 (CH), 130.3 (C), 129.6 (2 × CH), 126.8 (C), 126.3 (2 × CH), 123.4 (CH), 119.1 (CH), 112.6 (CH), 103.4 (C), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₅H₁₂ClNS [M]⁺: 273.0379, found 273.0380.

5-Bromo-3-[(4-methylphenyl)thio]-1H-indole (3m). White solid (114.6 mg, 72%); m.p. = 120–122 °C (from CH₂Cl₂/hexanes) (lit.,^7k 123–125 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.29 (br s, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 2.6 Hz, 1H), 7.20 (dd, J = 8.6, 1.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.92–6.87 (m, 4H), 2.15 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 135.0 (C), 134.93 (C), 134.85 (C), 131.6 (CH), 130.9 (C), 129.6 (2 × CH), 126.2 (2 × CH), 125.9 (CH), 122.1 (CH), 114.3 (C), 113.0 (CH), 103.1 (C), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₅H₁₂BrNS [M]⁺: 316.9874, found 316.9877.

Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole-5-carboxylate (3n). Pale yellow solid (108.5 mg, 73%); m.p. = 181–183.5 °C (from CH₂Cl₂/hexanes); ¹H NMR (400 MHz, acetone-d₆): δ 11.13 (br s, 1H), 8.28 (s, 1H), 7.90 (dd, J = 8.6, 1.6 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.01 (s, 4H), 3.84 (s, 3H), 2.21 (s, 3H); ¹³C NMR (100 MHz, acetone-d₆): δ 168.0 (C=O), 140.7 (C), 136.4 (C), 135.6 (C), 134.6 (CH), 130.4 (2 × CH), 129.7 (C), 126.9 (2 × CH), 124.5 (CH), 123.4 (C), 122.3 (CH), 113.0 (CH), 104.2 (C), 52.1 (CH₃), 20.8 (CH₃); HRMS (ESI-TOF) calcd for C₁₇H₁₅NO₂SNa [M + Na]⁺: 320.0721, found 320.0727.

5-Nitro-3-[(4-methylphenyl)sulfanyl]-1H-indole (3o). Yellow solid (45.5 mg, 32%); m.p. = 193–195 °C (from CH₂Cl₂/hexanes) (lit.,^8a 189–193 °C); ¹H NMR (400 MHz, acetone-d₆): δ 11.42 (br s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.11 (dd, J = 9.0, 2.2 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.07–7.02 (m, 4H), 2.21 (s, 3H); ¹³C NMR (100 MHz, acetone-d₆): δ 143.3 (C), 141.1 (C), 136.4 (CH), 136.2 (C), 135.6 (C), 130.6 (2 × CH), 129.6 (C), 127.6 (2 × CH), 118.7 (CH), 116.4 (CH), 113.7 (CH), 106.0 (C), 20.9 (CH₃); HRMS (ESI-TOF) calcd for C₁₅H₁₂N₂O₂SNa [M + Na]⁺: 307.0517, found 307.0512.

3-Methyl-2-[(4-methylphenyl)sulfanyl]-1H-indole (4). White solid (95.0 mg, 75%); m.p. = 96.5–97.5 °C (from CH₂Cl₂/hexanes); ¹H NMR (500 MHz, CDCl₃): δ 7.88 (br s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.23–7.17 (m, 2H), 7.11–7.08 (m, 1H), 6.98–6.93 (m, 4H), 2.35 (s, 3H), 2.22 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 136.8 (C), 135.8 (C), 133.2 (C), 129.8 (2 × CH), 128.5 (C), 127.2 (2 × CH), 123.3 (CH), 122.3 (C), 119.5 (CH), 119.32 (CH), 119.26 (C), 110.8 (CH), 20.9 (CH₃), 9.4 (CH₃); HRMS (ESI-TOF) calcd for C₁₆H₁₅NS [M]⁺: 253.0925, found 253.0924.

Acknowledgements

We thank the Thailand Research Fund (TRF-DBG5480017), the Center of Excellence for Innovation in Chemistry (PERCH-CIC), the Office of the Higher Education Commission, Mahidol University under the National Research Universities Initiative and the Development and Promotion of Science and Technology Talent Project (DPST), the Institute for the Promotion of Teaching Science and Technology for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Spectroscopic data of all compounds (copies of ¹H and ¹³C NMR). See DOI: 10.1039/c4ra02607a

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