Metal- and base-free syntheses of aryl/alkylthioindoles by the iodine-induced reductive coupling of aryl/alkyl sulfonyl chlorides with indoles

Abstract

An Iodine-catalysed process for an efficient and scalable sulfenylation protocol for indoles employing aryl-/alkyl sulfonyl chlorides has been developed. A series of sterically and electronically divergent aryl-/alkyl sulfonyl chlorides participated in the sulfenylation of C(sp²)–H bonds, resulting in a high to excellent yield of indole 3-sulfenylether molecules. It is noteworthy that indole-3-thiomethyl ether is efficiently generated with methanesulfonyl chloride as an electrophile, indicating the potential of this methodology.

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Introduction

Indole sulfenylether molecules are the basic motif of numerous pharmaceutically active molecules due to their inherent potential biological activity.¹ They are also important precursors of functional materials that enable the realisation of novel properties.² The critical importance of these scaffolds has resulted in the development of various synthetic methods. Thus far sulfenylating agents for the thiolation of C(sp²)–H bonds have included disulfides,³ sodium sulfinates,⁴ sulfenyl halides,⁵ N-thioarylphthalimides,⁶ and sulfonyl hydrazides,⁷ catalyzed by metal-free salts such as iodine or metal salts (Scheme 1). In spite of the availability of various thiolating agents⁸ for the sulfenylation of indole C(sp²)–H bonds, a limitation remains with regard to accessing these precursors due to the multistep synthesis process required. The thiolation can be achieved in principle, by means of aryl-/alkyl-/heteroarylsulfonyl chlorides as a sulphur source. Aryl-/alkyl-/heteroarylsulfonyl chlorides are remarkably stable, inexpensive and mostly commercially available. Fairly recently, aryl-/alkyl-/heteroarylsulfonyl chlorides^9a as a sulphur source were assessed by means of reductive coupling with indolizines, indoles, electron-rich benzenes^9b and H–phosphonates.^9c On the other hand, visible light-induced sulfenylation of indoles and N-methylindoles with arylsulfonyl chlorides was also discovred.¹⁰

Scheme 1 Prior art in the sulfenylation of indole C(sp²)–H bonds.

Interestingly, in all cases an excess of one of the reactant is essential for transformation to be observed, resulting in the concomitant quantitative production of corresponding oxidizing substrate as a by-product.¹¹ Furthermore, sulfonyl chlorides have been employed in excess to improve the yields of corresponding sulfenylether molecules.

Results and discussion

With our continued interest in developing a copper-catalysed sulfenylation process,¹² herein we describe our finding regarding the synthesis of aryl/alkylthioindoles by the iodine-induced reductive coupling of aryl/alkyl sulfonyl chlorides with indoles.

Initially, we chose indole 1a and p-toluenesulfonyl chloride 2a as the test substrates. At the outset, in the presence of 10 mol% of CuI in dioxane 1a (1.0 equiv.) and 2a (1.1 equiv.) reacted smoothly at 80 °C for 4 h to afford the expected 3-(p-tolyl)thioindole 3a at a 64% yield (Table 1, entry 1). As we intended to develop a metal-free sulfenylation process, we replaced CuI with iodine. With 10 mol% of I₂, the same reaction under otherwise identical conditions resulted in 3a at a 55% isolated yield (Table 1, entry 2). Under typical conditions, the molar ratios of reactants have shown considerable influence on the product yield (3a). Using 1.0 equiv. of 1a and 1.1 equiv. of 2a yielded the desired product at 55%, whereas, loading 2.0 equiv. of 1a and 1.0 equiv. of 2a improved the yield of the desired product (Table 1, entries 2 and 3, respectively). Loading 1.0 equiv. of 1a and 2.0 equiv. of 2a¹³ furnished a lower yield of 3a (Table 1, entry 4). The screening of various solvents indicated that 1,4-dioxane is the only preferable medium for this transformation (Table 1, entries 3 and 6–9).

Table 1 Evaluation of optimized conditions for the synthesis of 3-(p-tolyl)thioindole^a

Entry	Catalyst (10 mol%)	Solvent	3a (% Yield)^e
a All reactions were carried out unless otherwise stated on the 1 mmol scale using 2 mmol of 1a and 1 mmol of 2a in 3 mL of dioxane heated to 80 °C for 4 h in open air.b The reaction was carried out with 1.0 equiv. 1a and 1.1 equiv. of 2a.c The reaction was carried out with 2.0 equiv. 1a and 1.0 equiv. of 2a.d The reaction was carried out with 1.0 equiv. 1a and 2.0 equiv. of 2a.e Isolated yield, but not optimized. Yields based on the disappearance of 2a.f The reaction was carried out with 5 mol% of catalyst at 80 °C.g This reaction was also carried out at 10 mmol scale.
1	CuI	Dioxane	64
2	I2	Dioxane	54^b
3	I2	Dioxane	86^c^,^g
4	I2	Dioxane	65^d
5	I2	Dioxane	60^f
6	I2	CH3CN	64
7	I2	DMF	40
8	I2	(CH2Cl2)2	30
9	I2	DMSO	15
10	(n-Bu)4NI	Dioxane	40
11	KI	Dioxane	20
12	ICl	Dioxane	82
13	N-Iodosuccinimide	Dioxane	72

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In a brief survey of an alternative source of iodine applied as a catalyst, the yield of 3a decreased (Table 1, entry 10–13). Further, when the reaction was conducted under strict anaerobic conditions, only a trace amount of 3a was isolated (Table 1, entry 2). The reaction carried out with 5 mol% of iodine resulted in 3a at an inferior yield (Table 1, entry 5).

With the optimal conditions in hand, the scope of the substrate was surveyed. These results are shown in Table 2.

Table 2 Scope of sulfenylation with the functional group substituted indoles and aryl-/alkyl sulfonyl chlorides^a

Entry	R1	R2	R3	Time (h)	% Yield^b
a All reactions were carried out on the 2 mmol scale using 1a–g (2.0 equiv.), 2a–n (1.0 equiv.), I2 (10 mol%) in dioxane heated at 80 °C in open air.b Isolated yield, but not optimized.c NR = No reaction.
1	H	H	Ph	4	3b, 85
2	H	H	2,5-Me-Ph	4	3c, 85
3	H	H	4-Cl-Ph	4	3d, 81
4	H	H	3,5-Cl-4-Me-Ph	3	3e, 78
5	H	H	4-Br-Ph	4	3f, 80
6	H	H	5-F-2-Me-Ph	3	3g, 77
7	H	H	3-CF3-Ph	2	3h, 77
8	H	H	4-I-Ph	4	3i, 82
9	H	Me	4-Me-Ph	4	3j, 75
10	H	H	3-NO2-Ph	1.5	3k, 76
11	H	H	4-NO2-Ph	1	3l, 72
12	5-Bromo	H	4-Me-Ph	3	3m, 84
13	5-Iodo	H	4-Me-Ph	3	3n, 82
14	5-Methoxy	H	4-Me-Ph	3	3o, 87
15	H	H	Bn	4	3p, 76
16	H	H	Me	3	3q, 72
17	H	H	n-Bu	3	3r, 71
18	5-CN	H	4-Me-Ph	4	NR^c
19	H	Ts	4-Me-Ph	4	NR^c

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According to the results, the electron-donating and electron-withdrawing functional groups on the phenyl ring of sulfonyl chloride were compatible under the standard protocol and reacted with equal efficiency. On the other hand, the reaction efficiency was slightly sensitive to the electronic properties of the indole moiety. For instance, 5-cyanoindole failed to give the expected sulfenylation product (Table 2, entry 18), while 5-bromo- and 5-iodoindole did react under these conditions providing the desired product 3m and 3n, respectively at a very good yield, (Table 2, entry 12, and 13). Further, the halo-containing coupled product of arylthioindoles facilitates potential applications of further functionalization by a cross-coupling reaction. Remarkably, 3-NO₂-, and 4-NO₂-substituted phenylsulfonyl chlorides remain viable in this protocol disregarding the electronic effects and furnishing the desired products of 3k and 3l at high yields (Table 2, entries 10 and 11). 2-Nitrobenzenesulfonyl chloride was also reacted with indole, but the effort to isolate the product which formed failed due to rapid decomposition. Under set conditions, N-methylindole was also an effective substrate for coupling with 2a to give the sulfenylation product 3j at a high yield (Table 2, entry 9), but the N-tosyl protected indole did not undergo a coupling reaction (Table 2, entry 19).

Next, we examined the alkyl sulfonyl chlorides, as these compounds are seldom employed due to their inherent reduced reactivity and rapid decomposition. To our delight, our method gave 3-alkylthioethers 3q and 3r at a good yield using methanesulfonyl chloride 2m and butanesulfonyl chloride 2n with 1a (Table 2, entries 16 and 17). 2-Methylindole 4a was also reacted with p-toluenesulfonyl chloride 2a under typical conditions and gave the corresponding 3-thioether 5a at a high yield (72%). It was gratifying to find a reaction between the 1,3-benzenedisulfonyl chloride 2aa with 1a (2 equiv.), that provided an acceptable yield (64%) of mono-indolylsulfenyl ether 5b. on the other hand, when 2aa treated with 4 equiv. of 1a, di-indolylsulfenyl ether 5c was formed at a high yield (78%) (Table 3). Significantly, a highly polar carboxylic acid substituted arylsulfonylchloride 2ab performed well with 1a and 1b under the standard protocol, affording carboxylic acid possessing thioindole 5d and 5e at an 81% and 84% yield, respectively (Table 3). Several control experiments were carried out to understand this transformation. Indole 1a and p-toluenesulfonyl chloride 2a was heated to 80 °C for 4 h. No trace of the desired product 3a was observed and only the starting materials were recovered. In another experiment, with 10 mol% of iodine, one equiv. each of 1a and 2a were individually reacted under optimized conditions. In both cases, the recovery of the starting materials was realized, indicating the necessity of all reaction partners in order to forward the reaction. The reaction of 1a and 2a with one equivalent of TEMPO under standard protocol resulted in 3a as exclusive product and no trace of TEMPO-coupled products were observed suggesting ionic mechanism rather than radical mechanism.

Table 3 Further scope of the sulfenylation reaction^a

Arylsulfonyl chloride	Product	% Yield^b
a All reactions were carried out on the 2 mmol scale using 1a, 1b and 4a (2.0 equiv.), 2a, 2aa and 2ab (1.0 equiv.), I2 (10 mol%) in dioxane heated at 80 °C in open air.b Isolated yield, but not optimized.
		76
		64
2aa		78
		81
2ab		84

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Considering the above results, a plausible reaction mechanism is delineated in Scheme 2, which will clearly require further experimentation. Initially, iodine induced substitution of chlorine atom of aryl-/alkyl sulfonyl chloride leads to putative intermediate [A] by eliminating ICl.¹⁴ Then, subsequent Friedel–Crafts reaction of indole with [A] followed by HI exclusion via aromatization afford sulfone [D], which can undergo deoxygenation in the presence of HI to afford the desired indolylsulfenyl ether. Eventually, HOI can be oxidized in the presence of air to give I₂ and H₂O₂ (Scheme 2).

Scheme 2 Plausible mechanism for the observed transformation.

Conclusions

In conclusion, we have demonstrated an efficient cross-coupling reaction of indole with low-cost, and readily available, stable aryl-/alkyl sulfonyl chlorides through C(sp²)–H bond activation for the syntheses of various 3-alkyl-/arylthioethers. The sulfenylation process is initiated by a catalytic amount of I₂ without any combination of radical initiator. This process is remarkable in that stoichiometric reducing trivalent phosphorous compounds are avoided. To the best of our knowledge, this is the first report on sulfenylation wherein catalytic iodine acts as a reducing agent in combination with air and avoids the creation of oxides of phosphorous. Further work is in progress to broaden the scope of this methodology.

Experimental section

General procedure

Spectra were recorded at 300, 400 & 500 MHz, and ¹³C NMR 75 & 125 MHz in CDCl₃. The J values were recorded in hertz and abbreviations used were as follows: s-singlet, d-doublet, m-multiplet, br-broad, dd-doublet of doublet. Chemical shifts (δ) are reported relative to TMS (δ = 0.0) as an internal standard. The IR (FT-IR) spectra were measured using KBr pellet or as film. Mass spectral data were compiled using MS (ESI), HRMS mass spectrometers. Column chromatography was carried out using silica gel 100–200 mesh (commercial suppliers).

The typical procedure for synthesis of 3-(p-tolylthio)-1H-indole (3a). To a stirred solution of indole 1a (2 mmol) in 1,4-dioxane (3 mL) was added sulfonylchloride, 2a (1.0 mmol) and I₂ (10 mol%) successively. The resulting reaction mixture was heated at 80 °C for 4 h in open air. Subsequently, the reaction mixture was cooled down to ambient temperature, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography, eluting with hexane/ethyl acetate (10 : 0.5 to 5 : 1) to give the thioindole, 3a at an 86% yield. White solid, yield – 206 mg (86%), m.p. 124–126 °C; ¹H-NMR (500 MHz, CDCl₃): δ 8.38 (s, br, 1H), 7.61 (d, J = 7.93 Hz, 1H), 7.47–7.42 (m, 2H), 7.27–7.24 (m, 1H), 7.17–7.14 (m, 1H), 7.04–6.96 (m, 4H), 2.25 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 136.4, 135.4, 134.6, 130.4, 129.4, 129.1, 126.2, 122.9, 120.8, 119.7, 111.5, 103.5, 20.8; IR (neat, cm⁻¹): 3405, 2922, 2853, 1892, 1490, 1453, 1088, 772, 744; HRMS (m/z): calculated for C₁₅H₁₃NS (M − H) = 239.0768 found (M − H) = 239.0775.

All other 3-aryl and alkyl thioindole were prepared employing above typical procedure.

3-(Phenylthio)-1H-indole (3b). White solid, m.p. 150–152 °C; yield – 191 mg (85%); ¹H-NMR (500 MHz, CDCl₃): δ 8.47 (s, br, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.49–7.43 (m, 2H), 7.28–7.25 (m, 1H), 7.18–7.03 (m, 6H); ¹³C-NMR (75 MHz, CDCl₃): δ 139.2, 130.7, 128.6, 125.8, 124.7, 123.0, 120.9, 119.6, 111.5; IR (neat, cm⁻¹): 3401, 3057, 2922, 2852, 1580, 1476, 1234, 1083, 770, 739; HRMS (m/z): calculated for: C₁₄H₁₁NS (M + K) = 264.0249, found (M + K) = 264.0238.

3-((2,5-Dimethylphenyl)thio)-1H-indole (3c). White solid, m.p. 125–127 °C; yield – 215 mg (85%); ¹H-NMR (500 MHz, CDCl₃): δ 8.42 (s, br, 1H), 7.63–7.57 (m, 1H), 7.45–7.40 (m, 2H), 7.29–7.23 (m, 1H), 7.19–7.13 (m, 1H), 7.04–6.99 (m, 1H), 6.82–6.75 (m, 1H), 6.57 (s, 1H), 2.46 (s, 3H), 2.04 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃): δ 137.7, 136.5, 135.8, 131.4, 130.7, 129.7, 129.2, 125.9, 125.4, 122.9, 120.7, 119.7, 111.5, 102.4, 21.0, 19.4; IR (neat, cm⁻¹): 3412, 2926, 2857, 1896, 1520, 1456, 1075, 778, 734; HRMS (m/z): calculated for C₁₆H₁₅NS (M − H) = 252.0842, found (M − H) = 252.0846.

3-(4-Chlorophenylthio)-1H-indole (3d). White solid, m.p. 129–131 °C; yield – 210 mg (84%); ¹H-NMR (500 MHz, CDCl₃): δ 8.42 (s, br, 1H), 7.56 (dd, J = 7.93 Hz, J = 0.76 Hz, 1H), 7.46 (d, J = 2.59 Hz, 1H), 7.43 (d, J = 8.24 Hz, 1H), 7.29–7.24 (m, 1H), 7.18–7.15 (m, 1H), 7.12–7.09 (m, 2H), 7.02–6.99 (m, 2H); ¹³C-NMR (75 MHz, CDCl₃): δ 137.8, 136.5, 130.7, 130.5, 128.7, 127.1, 123.2, 121.0, 119.5, 111.6, 102.4; IR (neat, cm⁻¹): 3405, 2921, 2851, 1472, 1090, 1008, 812, 746; HRMS (m/z): calculated for C₁₄H₉NSCl (M − H) = 258.0144, found (M − H) = 258.0150.

3-((3,5-Dichloro-4-methylphenyl)thio)-1H-indole (3e). White solid, m.p. 142–145 °C; yield – 239 mg (84%); ¹H-NMR (500 MHz, CDCl₃): δ 8.51 (s, br, 1H), 7.58–7.45 (m, 3H), 7.34–7.27 (m, 1H), 7.22–7.15 (m, 1H), 6.93 (d, J = 8.51 Hz, 1H), 6.41 (d, J = 8.71 Hz, 1H), 2.50 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 137.8, 136.6, 134.5, 131.3, 131.0, 130.7, 128.8, 127.3, 123.9, 123.3, 121.2, 119.5, 111.7, 101.3, 17.7; IR (neat, cm⁻¹): 3405, 2923, 2863, 1894, 1488, 1463, 1091, 774; HRMS (m/z): calculated for C₁₅H₁₀NCl₂S (M − H) = 305.9906, found (M − H) = 305.9921.

3-(4-Bromophenylthio)-1H-indole (3f). White solid, m.p. 141–143 °C; yield – 242 mg (80%); ¹H-NMR (500 MHz, CDCl₃): δ 8.47 (s, br, 1H), 7.56 (d, J = 7.93 Hz, 1H), 7.50–7.44 (m, 2H), 7.30–7.15 (m, 4H), 6.97–6.93 (m, 2H); ¹³C-NMR (75 MHz, CDCl₃): δ 138.5, 136.5, 131.6, 130.7, 128.7, 127.3, 123.2, 121.0, 119.4, 118.2, 111.7, 102.1; IR (neat, cm⁻¹): 3389, 3053, 2921, 2851, 1889, 1469, 1406, 1235, 1083, 1004, 808, 744; HRMS (m/z): calculated for C₁₄H₉NSBr (M − H) = 301.9639, found (M − H) = 301.9645.

3-((5-Fluoro-2-methylphenyl)thio)-1H-indole (3g). White solid, m.p. 136–138 °C; yield – 198 mg (77%); ¹H-NMR (500 MHz, CDCl₃): δ 8.44 (s, br, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.30–7.24 (m, 2H), 7.20–7.16 (m, 1H), 6.85–6.79 (m, 1H), 6.64–6.59 (m, 1H), 2.06 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃): δ 157.6 (d, J_C–F = 241.6 Hz), 136.4, 133.8 (d, J_C–F = 2.7 Hz), 131.0, 129.2, 128.5, 127.0 (d, J_C–F = 7.3 Hz), 125.6 (d, J_C–F = 16.4 Hz), 123.1, 120.9, 119.5, 114.8 (d, J_C–F = 21.8 Hz), 111.6, 101.1, 20.7; IR (neat, cm⁻¹): 3412, 2934, 2863, 1882, 1492, 1453, 1168, 764; HRMS (m/z): calculated for C₁₅H₁₂FNS (M − H) = 256.0590, found (M − H) = 256.0592.

3-((3-(Trifluoromethyl)phenyl)thio)-1H-indole (3h). White solid, m.p. 130–132 °C; yield – 226 mg (77%); ¹H-NMR (500 MHz, CDCl₃): δ 8.47 (s, br, 1H), 7.57 (d, J = 7.93 Hz, 1H), 7.49 (d, J = 2.59 Hz, 1H), 7.44 (d, J = 8.24 Hz, 1H), 7.39 (s, 1H), 7.30–7.26 (m, 2H), 7.24–7.15 (m, 3H); ¹³C-NMR (125 MHz, CDCl₃): δ 140.9, 136.5, 131.0 (q, J_C–F = 31.8 Hz), 130.9, 129.0, 128.7, 123.8 (q, J_C–F = 272.5 Hz), 123.3, 122.3 (d, J_C–F = 3.6 Hz), 121.4 (d, J_C–F = 3.6 Hz), 121.1, 119.3, 111.7, 101.4; IR (neat, cm⁻¹); HRMS (m/z): calculated for C₁₅H₁₀F₃NS (M − H) = 292.0402, found (M − H) = 292.0411.

3-((4-Iodophenyl)thio)-1H-indole (3i). White solid, m.p. 135–137 °C; yield – 288 mg (82%); ¹H-NMR (500 MHz, CDCl₃): δ 8.44 (s, br, 1H), 7.58–7.54 (m, 1H), 7.48–7.41 (m, 4H), 7.30–7.25 (m, 1H), 7.20–7.14 (m, 1H), 6.84–6.80 (m, 2H); ¹³C-NMR (125 MHz, CDCl₃): δ 139.5, 137.5, 136.4, 130.7, 128.9, 127.6, 123.2, 121.0, 119.4, 111.6, 102.0, 88.9; IR (neat, cm⁻¹): 3312, 2876, 2753, 1882, 1496, 1455, 1076, 994, 752; HRMS (m/z): calculated for C₁₄H₁₀NIS (M − H) = 349.9495, found (M − H) = 349.9494.

1-Methyl-3-(p-tolylthio)-1H-indole (3j). White solid, m.p. 86–88 °C; yield – 190 mg (83%); ¹H-NMR (500 MHz, CDCl₃): δ 7.46 (d, J = 8.4 Hz, 2H), 7.26–7.21 (m, 5H), 7.14 (d, J = 8.1 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 144.5, 142.0, 140.4, 136.5, 130.2, 129.3, 127.6, 124.6, 29.7, 21.5; IR (neat, cm⁻¹): 3412, 2946, 2845, 1894, 1490, 1463, 1088, 772; HRMS (m/z): calculated for C₁₁H₁₈O₃NS (M + H) = 253.0925, found (M + H) = 253.0931.

3-((3-Nitrophenyl)thio)-1H-indole (3k). White solid, m.p. 135–137 °C; yield – 205 mg (84%); ¹H-NMR (500 MHz, CDCl₃): δ 8.57 (s, br, 1H), 7.93–7.86 (m, 2H), 7.57–7.54 (m, 2H), 7.48 (d, J = 8.24 Hz, 1H), 7.36 (d, J = 7.93 Hz, 1H), 7.32–7.26 (m, 2H), 7.21–7.16 (m, 1H); ¹³C-NMR (75 MHz, CDCl₃): δ 136.4, 135.4, 134.6, 130.4, 129.4, 129.1, 126.2, 122.9, 120.8, 119.7, 111.5, 103.5, 20.8; IR (neat, cm⁻¹): 3506, 2923, 2873, 1867, 1556, 1490, 1454, 1353, 1088, 782, 762; HRMS (m/z): calculated for C₁₄H₉O₂N₂S (M − H) = 269.0379, found (M − H) = 269.0390.

3-((4-Nitrophenyl)thio)-1H-indole (3l). Yellow solid, m.p. 174–175 °C; yield – 194 mg (84%); ¹H-NMR (500 MHz, CDCl₃): δ 8.92 (s, br, 1H), 7.95 (d, J = 9.0 Hz, 2H), 7.52–7.46 (m, 3H), 7.28 (t, J = 8.1 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H); ¹³C-NMR (75 MHz, CDCl₃): δ 150.0, 144.6, 136.5, 131.3, 128.3, 124.9, 123.7, 123.3, 121.2, 118.9, 112.0, 99.6; IR (neat, cm⁻¹): 3605, 3422, 2753, 1892, 1553, 1464, 1346, 1078, 784; ESI-MS (m/z): calculated for C₁₄H₁₀O₂N₂S = 270, found (M − H) = 269.

5-Bromo-3-(p-tolylthio)-1H-indole (3m). White solid, m.p. 126–128 °C; yield – 266 mg (84%); ¹H-NMR (300 MHz, CDCl₃ + DMSO): δ 8.70 (s, br, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.32–7.29 (m, 1H), 7.26–7.24 (m, 1H), 7.01–6.96 (m, 4H), 2.25 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 135.0, 134.8, 133.9, 132.1, 130.3, 128.8, 125.4, 124.4, 120.8, 113.1, 112.8, 100.5, 20.2; IR (neat, cm⁻¹): 3744, 3611, 2922, 2852, 1696, 1509, 1454, 1219, 772, 657; HRMS (m/z): calculated for C₁₅H₁₁NSBr (M − H) = 315.9795, found (M − H) = 315.9782.

5-Iodo-3-(p-tolylthio)-1H-indole (3n). White solid, m.p. 132–134 °C; yield – 299 mg (82%); ¹H-NMR (500 MHz, CDCl₃): δ 8.46 (s, br, 1H), 7.51 (dd, J = 6.9 Hz, J = 1.7 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.0 (s, 4H), 2.26 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 135.5, 134.9, 134.8, 131.6, 131.4, 131.2, 129.6, 128.4, 126.2, 113.5, 102.9, 84.7, 20.8; IR (neat, cm⁻¹): 3645, 2924, 2853, 1692, 1512, 1453, 1098, 772, 646; HRMS (m/z): calculated for C₁₅H₁₁NIS (M − H) = 363.9651, found (M − H) = 363.9665.

5-Methoxy-3-(p-tolylthio)-1H-indole (3o). Brown oil; yield – 234 mg (87%); ¹H-NMR (500 MHz, CDCl₃): δ 8.31 (s, br, 1H), 7.35 (d, J = 2.7 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 7.03–6.99 (m, 2H), 6.98–6.95 (m, 2H), 3.76 (s, 3H), 2.23 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃): δ 155.0, 135.6, 134.5, 131.3, 131.1, 129.9, 129.4125.9, 113.5, 112.3, 102.7, 100.8, 55.7, 20.8; IR (neat, cm⁻¹): 3455, 2923, 2893, 1887, 1495, 1463, 1296, 1098, 772, 744; HRMS (m/z): calculated for C₁₅H₁₃NS (M − H) = 253.0556, found (M − H) = 253.0561.

3-(Benzylthio)-1H-indole (3p). Yellow solid, m.p. 81–82 °C; yield – 182 mg (76%); ¹H-NMR (500 MHz, CDCl₃): δ 8.39 (s, br, 1H), 7.72–7.67 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.25–7.14 (m, 5H), 7.10–7.04 (m, 2H), 6.95 (s, 1H), 3.85 (s, 2H); ¹³C-NMR (75 MHz, CDCl₃): δ 139.0, 136.2, 129.9, 129.2, 128.1, 126.7, 122.4, 120.3, 119.1, 111.5, 105.0, 40.9; IR (neat, cm⁻¹): 3406, 2872, 1902, 1560, 1463, 1078, 736; ESI-MS (m/z): calculated for C₁₅H₁₃NS = 239, found (M − H) = 238.

3-(Methylthio)-1H-indole (3q). Colorless oil; yield – 117 mg (72%); ¹H-NMR (500 MHz, CDCl₃): δ 8.21 (s, br, 1H), 7.77 (d, J = 7.63 Hz, 1H), 7.36 (d, J = 8.10 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.26–7.18 (m, 2H), 2.37 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 134.2, 129.2, 127.8, 122.9, 121.0, 1118.9, 110.7, 105.1, 19.0; IR (neat, cm⁻¹): 3386, 2853, 1876, 1490, 1451, 1058, 776, 754; ESI-MS (m/z): calculated for C₉H₉NS = 163, found (M − H) = 162.

3-(Butylthio)-1H-indole (3r). Yellow oil; yield – 145 mg (71%); ¹H-NMR (500 MHz, CDCl₃): δ 8.26 (s, br, 1H), 7.77 (d, J = 7.93 Hz, 1H), 7.47–7.42 (m, 2H), 7.27–7.24 (m, 1H), 7.17–7.14 (m, 1H), 7.04–6.96 (m, 4H), 2.25 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ IR (neat, cm⁻¹): 3345, 2934, 2835, 1876, 1478, 1433, 1068, 762, 745; HRMS (m/z): calculated for C₁₂H₁₄NS (M − H) = 204.0842, found (M − H) = 204.0844.

2-Methyl-3-(p-tolylthio)-1H-indole (5a). White solid, m.p. 93–96 °C; yield – 192 mg (76%); ¹H-NMR (500 MHz, CDCl₃): δ 8.21 (s, br, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.19–7.15 (m, 1H), 7.13–7.09 (m, 1H), 6.95 (m, 4H), 2.49 (s, 3H), 2.23 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃): δ 140.9, 135.6, 135.3, 134.2, 130.2, 129.4, 125.7, 122.0, 120.5, 118.9, 110.6, 99.6, 20.8, 12.0; IR (neat, cm⁻¹): 3415, 2892, 2763, 1952, 1560, 1463, 1078, 784, 753; HRMS (m/z): calculated for C₁₅H₁₃NS = 239.0768, found = 239.0775.

3-((1H-Indol-3-yl)thio)benzene-1-sulfonyl chloride (5b). White solid, m.p. 156–159 °C; yield – 207 mg (64%); ¹H-NMR (500 MHz, CDCl₃): δ 8.62 (s, br, 1H), 7.75–7.72 (m, 1H), 7.70–7.66 (m, 1H), 7.56–7.53 (m, 2H), 7.48 (d, J = 8.21 Hz, 1H), 7.36–7.28 (m, 3H), 7.21–7.17 (m, 1H); ¹³C-NMR (75 MHz, CDCl₃): δ 144.7, 143.3, 136.5, 131.7, 131.2, 129.7, 128.3, 123.5, 123.2, 122.7, 121.4, 119.1, 111.9, 100.3; IR (neat, cm⁻¹): 3505, 3312, 2921, 2845, 1553, 1370, 1290, 1092, 776; EI-MS (m/z): calculated for: C₁₄H₁₀ClO₂NS₂ (M⁺) = 323, found (M⁺) = 323.

1,3-Bis((1H-indol-3-yl)thio)benzene (5c). White solid, m.p. 210–212 °C; yield – 290 mg (78%); ¹H-NMR (300 MHz, CDCl₃ + DMSO): δ 10.84 (s, br, 2H), 7.56 (s, 2H), 7.50–7.43 (m, 2H), 7.36 (d, J = 2.5 Hz, 2H), 7.24–7.16 (m, 2H), 7.11–7.03 (m, 2H), 6.89 (t, J = 7.7 Hz, 1H), 6.83–6.79 (m, 1H), 6.72–6.66 (m, 2H); ¹³C-NMR (75 MHz, CDCl₃ + DMSO): δ 139.7, 136.1, 130.9, 128.2, 128.0, 121.7, 121.6, 121.3, 119.5, 118.2, 111.4, 99.5; IR (neat, cm⁻¹): 3412, 2932, 2863, 1967, 1872, 1530, 1462, 1098, 792, 767; HRMS (m/z): calculated for C₂₂H₁₆N₂S₂ (M + H) = 373.0828, found (M + H) = 373.0826.

3-((1H-Indol-3-yl)thio)benzoic acid (5d). White solid, m.p. 183–186 °C; yield – 218 mg (81%); ¹H-NMR (300 MHz, CDCl₃ + DMSO): δ 10.94 (s, br, 1H), 7.81 (s, 1H), 7.73–7.61 (m, 1H), 7.55–7.45 (m, 3H), 7.24–7.04 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃ + DMSO): δ 167.3, 139.7, 136.3, 131.2, 130.8, 129.1, 128.2, 127.9, 126.2, 125.4, 121.7, 119.6, 118.2, 111.6, 99.4; IR (neat, cm⁻¹): 3402, 2978, 2876, 1887, 1753, 1492, 1443, 1068, 768, 744; HRMS (m/z): calculated for C₁₅H₁₁O₂NS (M − H) = 268.0426, found (M − H) = 268.0427.

3-((1-Methyl-1H-indol-3-yl)thio)benzoic acid (5e). White solid, m.p. 142–146 °C; yield – 238 mg (84%); ¹H-NMR (300 MHz, CDCl₃ + DMSO): δ 7.84–7.59 (m, 2H), 7.56–7.38 (m, 3H), 7.33–7.08 (m, 4H), 3.88 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃ + DMSO): δ 167.2, 139.5, 136.9, 134.7, 130.8, 129.1, 128.8, 127.9, 126.2, 125.4, 121.9119.8, 118.5, 109.3, 98.8, 32.5; IR (neat, cm⁻¹): 3305, 2972, 2845, 1892, 1745, 1490, 1453, 1413, 1294, 1076, 773; ESI-MS (m/z): calculated for C₁₆H₁₃O₂NS = 283, found (M − H) = 282.

Acknowledgements

Financial support was provided by the DST, New Delhi, India (Grant no. SR/S1/OC-08/2011), ORGIN (CSC-0108) programme CSIR (New Delhi) of XII Five year plan is gratefully acknowledged. Also, UGC & CSIR (New Delhi) is acknowledged for awarding the fellowships to R.R. and V.N.R.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectras. See DOI: 10.1039/c5ra00646e

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