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

Praewpan Katruna, Sakchai Hongthonga, Sornsiri Hlekhlaia, Manat Pohmakotra, Vichai Reutrakula, Darunee Soorukrama, Thaworn Jaipetchb and Chutima Kuhakarn*a
aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand. E-mail: chutima.kon@mahidol.ac.th; Fax: +66-2-3547151; Tel: +66-2-2015155
bMahidol University, Kanchanaburi Campus, Saiyok, Kanchanaburi 71150, Thailand

Received 25th March 2014 , Accepted 6th April 2014

First published on 7th April 2014


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.


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.
image file: c4ra02607a-f1.tif
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

image file: c4ra02607a-u1.tif

Entry 2a (equiv.) I2 (equiv.) PPh3 (equiv.) Solvent Time (h) Yieldb (%)
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
4c 2 1 2 Toluene 3 82
5 2 1 2 THF 3 18d
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
10c 2 1 2 DMF 3 79
11c 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
15e 1.5 1 1.5 EtOH 5 51


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 systema

image file: c4ra02607a-u2.tif

Entry R1 R2 R3 Time (h) Product, yieldb (%)
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, 32d
17 H 5-CHO pTol 5 e
18 H 3-CH3 pTol 2 image file: c4ra02607a-u3.tif


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 experimentsa

image file: c4ra02607a-u4.tif

Entry 1a or 10 (equiv.) S source (equiv.) I2 (equiv.) PPh3 (equiv.) Product, yieldb (%)
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.
1c 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
7c 10 (1.0) 1 1.5


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.


image file: c4ra02607a-s1.tif
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[double bond, length as m-dash]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.

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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

This journal is © The Royal Society of Chemistry 2014