Selenium dioxide-promoted selective synthesis of mono- and bis-sulfenylindoles

Abstract

A selective method for the preparation of mono- and bis-sulfenylindoles was developed using an oxidizing agent and the I₂/SeO₂ system as an efficient catalyst. The selectivity was controlled by varying the amount of SeO₂. This represents the first example of the application of SeO₂ in this type of selective chemistry.

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Introduction

Over one century after its first isolation in 1869,¹ indole still is one of the most explored building blocks in organic chemistry. Because of its extensive applicability to pharmaceutical, agrochemical, and material sciences, indole has been called “the lord of the rings” by Bandini.²

Regarding its biological importance, 3-sulfenylindole I and its derivative II have been studied as potent anti-cancer agents that inhibit tubulin polymerization in a more effective way than combretastatin-A-4.³ The fluorinated 3-sulfenylindoles III and IV showed selective COX-2-enzyme inhibition similar to etoricoxib and analogues⁴ (Fig. 1A). In addition, anti-HIV,^5a anti-allergenic,^5b and antiasthmatic^5c properties have also been attributed to sulfur-containing indole compounds.

Fig. 1 A: 3-Sulfenylindole derivatives with analogous activities to combretastatin A-4 (I and II) and etoricoxib (III and IV). B: Previous strategies for the preparation of sulfenylindoles. C: Present work.

Due to the importance of sulfur-containing scaffolds in drug development, especially sulfenylindoles, the development of methods that selectively access this class of compound has increased in the past few years.^6,7 Most of the current methodologies are limited to 3-sulfenylindoles and involve (A) the electrophilic cyclization of 2-alkynylanilines,^7a–c or (B) the direct C–H sulfenylation of the indole ring by electrophilic sulfur species, normally generated in situ.^7d–f Because it involves the use of readily available indole as the starting material, approach B is the most attractive, and efficient protocols using this strategy have been described in the past few years.

In 2012, Wey proposed a metal-free protocol for the preparation of a range of 3-sulfenylindoles using dimethyl carbonate (DMC) as a green solvent. Products were obtained in yields of up to 96% with 5 mol% I₂ as the catalyst and 3 equiv. of DMSO as the oxidant (Fig. 1B-i).⁸

Subsequently, many attempts aimed at improving this methodology have been described;^9–12 for instance through the use of microwaves (MWs) as an alternative energy source to accelerate the reaction (Fig. 1B-ii).⁹ The selective preparation of mono- and bis-sulfenylated derivatives is an important sulfenylindole-synthesis endeavor. In 2015, Wang and co-workers described the first protocol for the selective formation of mono and bis-arylsulfenylindoles directly from indoles and diaryl disulfides.¹⁰ Despite the selectivities, the need to use 50 mol% of I₂ and over-stoichiometric amounts of TBHP (2.1 equiv.) contributed to the low atom-efficiency of the reaction (Fig. 1B-iii). Very recently, Barman and Rahaman described a MW-promoted synthesis of mono- and bis-sulfenylindoles using the I₂/H₂O₂ system (Fig. 1B-iv).¹¹ The diorganyl disulfide was generated in situ from the respective sodium sulfinate (RSO₂Na) in the presence of I₂ (10–20 mol%), H₂O₂ (2.2 equiv.), and an excess of diethyl phosphite (3 equiv.). Despite these recent advances, the use of sub-equivalent amounts of oxidant during the direct, selective mono- and bis-sulfenylation of indoles remains an unsolved problem, which provides challenges for any new reaction system.

Selenium dioxide (SeO₂) was firstly introduced as an oxidizing agent in 1932 by Riley, Morlex, and Friend,¹² and to this day remains one of the most convenient reagents for allylic oxidation¹³ and oxidative-elimination reactions.¹⁴ In the past few years, only a few new protocols using SeO₂ have been reported, including the dihydroxylation and hydroxymethoxylation of alkenes,¹⁵ the syntheses of glyoxal,¹⁶ triarylethanones,¹⁷ azoxyarenes,¹⁸ and in oxidative couplings.¹⁹

With this previous work in mind, herein we describe the unprecedent use of the I₂/SeO₂ system for the preparation of mono- and bis-sulfenylindoles through the C–H sulfenylation of indoles with diaryl disulfides. The selectivity of the reaction is modulated by the amount of SeO₂ (Fig. 1C).

Results and discussion

1H-Indole (1a) (0.5 mmol) and diphenyl disulfide 2a (0.3 mmol) were chosen as model substrates during the optimization of the reaction conditions and the preparation 3-(phenylsulfenyl)indole 3aa (Table 1).

Table 1 Optimizing of the amount of SeO₂ for the selective formations of 3aa and 4aa^a

Entry	2a (mmol)	SeO2 ^b (mol%)	3aa (% conv.)	4aa (% conv.)
a Reaction conditions: 1a (0.5 mmol), glycerol (1.0 mL), and 10 mol% of I2 with respect to disulfide 2a. The progress of the reaction was followed by TLC. b Relative to indole 1a. c Conversion values obtained by GC/MS.
1	0.3	20	84	—
2	0.3	30	100	—
3	0.3	40	55	45
4	0.3	50	24	76
5	0.3	60	61	39
6	0.3	70	45	55
7	0.3	80	40	60
8	0.3	90	53	47
9	0.3	100	52	48
10	0.6	100	—	100
11	0.6	90	—	100
12	0.6	80	—	100
13	0.6	70	—	100
14	0.6	60	—	100
15	0.6	50	17	83
16	0.6	40	34	66
17	0.6	30	93	7

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In order to evaluate and optimize the amounts of catalyst and oxidant, we conducted an initial experiment using 10 mol% of I₂ and 20 mol% of SeO₂ in glycerol as the solvent. The expected product 3aa was obtained in very good conversion (84%) after heating at 100 °C for 1 h (Table 1, entry 1). Based on this result, we concentrated our efforts toward improving the yield of 3aa by gradually increasing the amount of SeO₂ to 100 mol% (Table 1, entries 2–9).

Indole (1a) was quantitatively converted into the mono-sulfenylindole 3aa using 30 mol% of SeO₂ (Table 1, entry 2). On the other hand, mixtures of the mono- and bis-sulfenylated indoles 3aa and 4aa, were detected in different ratios in the presence of larger amounts of SeO₂ (40–100 mol%) (Table 1, entries 3–9).

Based on these results, we conclude that the optimal conditions for the preparation selective of mono-sulfenylindole 3aa involves stirring a mixture of 1a, 2a (1.2 equiv.), 10 mol% of I₂, and 30 mol% of SeO₂ in glycerol for 1 h at 100 °C (Table 1, entry 2).

With these interesting results in hand, our next objective involved determining the optimal amounts of SeO₂ and diphenyl disulfide 2a that lead to the selective preparation of bis-sulfenylindole 4aa (Table 1, entries 10–17).

In preliminary studies, we showed that double the amount of diphenyl disulfide 2a (0.6 mmol, instead 0.3 mmol) and 100 mol% of SeO₂ (0.5 mmol) led to the exclusive formation of 4aa (Table 1, entry 10; or Table S1,† entry 7). We performed a set of experiments in which the amount of SeO₂ varied between 100 and 30 mol%, during which we discovered that 60 mol% was optimal for the complete conversion of indole (1a) to the bis-sulfenylindole 4aa (Table 1, entries 10–17). The use of less SeO₂ resulted in an increase in the formation of 3aa, to 17, 34, and 93% with 50, 40 and 30 mol% SeO₂, respectively. These data reveal that the oxidizing agent plays a fundamental role in the selectivity of this transformation (Table 1, entries 15–17).

We subsequently studied the reaction-time-dependent effect of the amount of catalyst on conversion, as monitored by GC/MS (Fig. 2 and 3). The reaction that produced bis-(phenylsulfenyl)indole 4aa was completed in 16 min at 100 °C, while at 75 °C 50 min was required. Fig. 2 reveals that indole (1a) was entirely converted into 3aa after 4 min at 100 °C, at which point 3aa begins to be converted into 4aa.

Fig. 2 The effect of temperature on reaction. Blue line (◆): 1a, red line (■): 3aa, green line (▲): 4aa [1a (0.5 mmol), 2a (0.6 mmol), SeO₂ (60 mol%, 0.033 g), I₂ (10 mol%, 0.015 g) and glycerol (1.0 mL)].

Fig. 3 Effect of the amount of I₂ (5 mol% = 0.0075 g; 15 mol% = 0.0225 g). Blue line (◆): 1a, red line (■): 3aa, green line (▲): 4aa [1a (0.5 mmol), 2a (0.6 mmol), SeO₂ (60 mol%, 0.033 g) and glycerol (1.0 mL)].

Regarding the catalyst, we observed that 50 min was required for the complete consumption of 1a when 5 mol% of I₂ was used, which is four times longer than that required when 10 mol% was used. When 15 mol% of I₂ was used, the time required for the complete conversion to 4aa was 12 min, which does not represent a significant reduction in time compared to that required with 10 mol% of I₂ (Fig. 3).

With the best reaction conditions in hands, we explored the efficiency and generality of our methodology with other diorganyl disulfides 2 and indoles 1. The optimal conditions for the synthesis of mono-substituted sulfenylindoles 3 worked well for a range of diaryl disulfides containing electron-donating (EDG) and electron-withdrawing groups (EWG). It was not possible, however, to establish a relationship between the performance of the reaction and electronic nature of the aromatic ring in 2 (Table 2).

Table 2 Substrate scope during the synthesis of mono-sulfenylindoles 3 in glycerol^a

Entry	Indole 1	Disulfide 2 (R^2)	Time (min)	Product 3	Yield^b (%)
a Reaction conditions: Indole 1 (0.5 mmol), disulfide 2 (0.3 mmol), SeO2 (30 mol%), and I2 (10 mol%) in glycerol (1.0 mL). The reaction progress was followed by TLC. b Yields following purification by column chromatography. c A mixture of 3ac and 4ac (89 : 11) was obtained. d 20 mol% of SeO2 was used. e The conditions described in Table 1, entry 14 were used.
1			4		70
2	1a		6		76
3	1a		4		84^c
4	1a		8		71
5	1a		10		67
6	1a		18		23
7	1a		30		66
8	1a		18		80^d
9	1a		20		22 (84)^e
10	1a		7		31 (69)^e
11		2a	7		64
12		2a	18		52

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Products bearing groups such as methyl (3ab) and methoxy (3ac) were obtained in better yields than that of the neutral analogue 3aa (Table 2, entries 1–3).

The disulfide 2c (R² = 4-CH₃OC₆H₄) produced a 89 : 11 mixture of 3ac and 4ac, while halogen-substituted diaryl disulfides, as 4-fluoro- (2d), 4-chloro- (2e), and 4-bromophenyl (2f) afforded their respective products, 3ad, 3ae, and 3af, in 71, 67 and 23% yields after 8, 10 and 18 min of reaction time, respectively (Table 2, entries 4–6). Additional time (30 min) was required for the preparation of the 2-amino derivative 3ag (Table 2, entry 7), probably due to an electron-donating effect of the amino group positioned ortho to the disulfide in 2g that reduces the electrophilicity of the sulfur (see Scheme 2 for a plausible mechanism).

Dibenzyl disulfide (2i) and difurfuryl disulfide (2j), in which the sulfur atoms are attached to sp³-hybridized carbons, afforded lower yields of the respective products 3ai and 3aj (22 and 31%) under the conditions optimized for the formation of mono-sulfenylindoles.

Fortunately, the yields of 3ai and 3aj improved to 84 and 69% when the optimized conditions for the preparation of the bis-sulfenylated indoles 4 (i.e., 60 mol% of SeO₂ and 2.4 equiv. of the disulfide 2i or 2j) were used (Table 2, entries 9 and 10). On the other hand, the same effect was not observed for di(2-hydroxyethyl) disulfide 2h; the corresponding mono-sulfenylindole 3ah was obtained in 80% yield after 18 min with 20 mol% SeO₂ (Table 2, entry 8). The protocol was successfully extended to other indoles, such as 1-methyl-1H-indole (2b), which reacted with diphenyl disulfide (2a) to give the 3-phenylsulfenylindole 3ba in 64% yield after 7 min (Table 2, entry 11). 5-Bromo-1H-indole (1c) reacted with diphenyl disulfide 2a to give the corresponding 3-sulfenylindole 3ca in 52% yield after 18 min (Table 2, entry 12).

We also observed that glycerol can be replaced by H₂O without compromising the reaction yields and selectivities (Table 3). Mono-sulfenylated products 3aa–ae were obtained in almost identical yields and in similar reaction times (Table 3, entries 1–5). A better outcome was observed for the bromo-substituted sulfenylindole 3af, which was obtained in better yield in water (49%) (Table 2, entry 6 vs.Table 3, entry 5).

Table 3 Substrate scope during the synthesis of mono-sulfenylindoles 3 in water^a

Entry	Disulfide 2 (R^2)	Time (min)	Product 3	Yield^b (%)
a Reaction conditions: Indole 1a (0.5 mmol), disulfide 2 (0.3 mmol), SeO2 (30 mol%) and I2 (10 mol%) in water (1.0 mL). The reaction progress was followed by TLC. b Yields following purification by column chromatography.
1		4		70
2		2		77
3		10		63
4		12		72
5		16		49

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We next used the optimized conditions described in Table 1, entry 14 to prepare the 2,3-bis-sulfenylindoles 4, by reacting 1H-indole (1a) with several diaryl disulfides 2a–g (Table 4); consequently, 2,3-bis(phenylsulfenyl)indole 4aa was isolated in 85% yield after 16 min following the reaction of 1a with diphenyl disulfide 2a (Table 4, entry 1). Diaryl disulfides 2b and 2c, bearing EDGs (R² = 4-CH₃ and R² = 4-CH₃O), reacted with 1a to form 4ab and 4ac in 75 and 71% yields respectively in no more than 20 min (Table 4, entries 2 and 3). In the case of 4ac, the formation of the mono-substituted 3-sulfenylindole 3ac was also observed (4ac : 3ac ratio of 76 : 24). The 4-fluoro derivative 4ad was isolated in 62% yield after 19 min, while moderate yields of the chloro- and bromo-analogues 4ae (39%) and 4af (53%) were obtained (Table 4, entries 4–6). As was observed for the mono-sulfenylindole 3ag, the ortho-amino derivative 4ag was obtained in low yield (33%), even increasing the amount of SeO₂ to 80 mol% (Table 4, entry 7). An excellent yield (97%) of 4ba was obtained from the reaction of 1-methyl-1H-indole (2b) with 2a after 30 min (entry 8), while 5-bromo-1H-indole (2c) was converted to the respective 2,3-bis(phenylsulfenyl)indole 4ca in 77% yield after 18 min (Table 4, entry 9).

Table 4 Substrate scope during the synthesis of 2,3-(bis-organosulfenyl)indoles 4^a

Entry	Indole 1	Disulfide 2 (R^2)	Time (min)	Product 4	Yield^b (%)
a Reaction conditions: 1 (0.5 mmol), disulfide 2 (0.6 mmol), SeO2 (60 mol%), and I2 (10 mol%) in glycerol (1.0 mL). The reaction progress was followed by TLC. b Yields following purification by column chromatography. c A mixture of 4ac and 3ac (76 : 24) was obtained. d 80 mol% of SeO2 was used.
1			16		85
2	1a		20		75
3	1a		10		71^c
4	1a		19		62
5	1a		18		39
6	1a		23		53
7	1a		23		33^d
8		2a	30		97
9		2a	18		77

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Interestingly, dibenzyl disulfide (2i) and difurfuryl disulfide (2j) afforded the mono-substituted products 3ai and 3aj exclusively under these disulfenylation conditions, as previously discussed (Table 2, entries 9 and 10). Increasing the amount of SeO₂ to 100 mol% was ineffective at producing isolable amounts of the bis-sulfenyl partners, while di(2-hydroxyethyl) disulfide 2h afforded a complex mixture of products.

Mechanisms for the formation of mono- and bis-sulfenylindoles are already described in the literature.²⁰ Even the reaction between indole (1a) and SeO₂ has been previously described by Witkop, in 1947:²¹ this reaction gives 3,3′-bis-indolyl selenide 5, whose structure was elucidated by Wilshire in 1967 (Scheme 1, #1).²²

Scheme 1 Control experiments in the synthesis of 3aa.

However, SeO₂ has never been explored as an oxidizing agent in this specific transformation. In order to clarify the role of the I₂/SeO₂ system in the promotion and selectivity of this reaction, several control experiments were performed (Scheme 1).

Initially, we hypothesized that the 3,3′-diindolyl selenide 5 could be the key intermediate in the reaction mechanism. When we reacted indole 1a with SeO₂ in glycerol at 100 °C, 20% of 5 was obtained after 20 h (Scheme 1, control exp. #1). On the other hand, the addition of a catalytic amount of I₂ (10 mol%) to the reaction, resulted in the formation of 5 in 90% after 15 min (Scheme 1, #2).

Considering that 3,3′-diindolyl selenide 5 may be a key intermediate in the overall transformation, we reacted 5 with diphenyl disulfide (2a) (1.2 equiv.) and I₂ (30 mol%), in the absence of SeO₂, which led to the formation of 3aa in 50% yield after 1 h (Scheme 1, #3). However, 24 h was necessary in order to access 3aa in 57% yield starting from indole 1a, instead intermediate 5, (Scheme 1, #4), which demonstrates that the reactivity of intermediate 5 is significant higher than that of indole 1a.

When the standard reaction conditions used to prepare 3aa were performed under argon, a decreasing in the yield, from 70% (Table 2, entry 1) to 57% was observed, after 4 min of reaction (Scheme 1, #5). The yield of 3aa was even smaller, (10% after 24 h) in the absence of SeO₂ or air (Scheme 1, #6). Taken together, experiments #5 and #6 show that SeO₂ plays a crucial role that guarantees the efficiency of the reaction, and that atmospheric oxygen plays a role in which it acts as a co-oxidant that improves the reaction efficiency.

Finally, the reaction was performed in the absence of SeO₂ but with 1 equiv. of molecular iodine, which delivered 3aa in 99% yield after 4 min (Scheme 1, #7), which shows that the formation of an electrophilic sulfur species in the reaction medium affords an ideal reaction outcome.

Based on these experiments, we propose a mechanism for formation 3aa, which contains three catalytic cycles (Scheme 2). In Cycle A, the first step involves the reaction of 2a with I₂ to form PhSI, which then reacts with indole to form 3aa and HI; this cycle is completed by the reaction of HI with SeO₂ to form I₂. The in situ-formed selenium by-product (perhaps elemental Se reduced by HI) facilitates Cycle B by reacting with indole (1a) to form intermediate 5.²³ Intermediate I is formed after reaction with PhSI, which is generated in situ from PhSSPh (2a) and I₂.²⁴ Intermediate I then suffers disproportionation to deliver the expected product 3aa and selenone II. Nucleophilic attack of II by 1a forms more 5 and HI, which is oxidized back to I₂ by SeO₂, giving more Se (Cycle B). The formation of the bis-sulfenylated indole 4aa could follow a similar pathway to that shown in Cycle A, with the exception that the monosulfenylated indole 3aa is the starting material instead the parent 1a, as previously described (Cycle C).²⁰ This mechanism accounts for the sub-stoichiometric amounts of SeO₂ required in these reactions because it is involved in the formation of 3aa (or 4aa) in Cycle A (or Cycle C), and indirectly involved in the formation of additional 3aa through Cycle B.

Scheme 2 Proposed mechanism for the formation of 3aa and 4aa.

To provide support for the proposed mechanism, aliquots from a 3aa-forming reaction were directly injected in a high-resolution mass spectrometer equipped with an APCI source (see ESI† for experimental details). Both key intermediates 5 and I were detected as relatively intense [M + H]⁺ ions with m/z values of 313.0213 and 195.9647, respectively, along with an ion at m/z 226.0671, which corresponds to product 3aa ([M + H]⁺) (Fig. S2–S6†). A very-low intensity signal for the proposed key intermediate II was detected at m/z 421.0256; importantly the isotopic distribution is in agreement with the simulated one (Fig. S3†).

Experimental

General information

The reactions were monitored by TLC on Merk silica gel (60 F₂₅₄) visualized with UV light or with 5% of vanillin in 10% H₂SO₄ with heating. Merck silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. ¹H NMR spectra were obtained at 400 MHz on a Bruker DPX 400 spectrometer. The spectra were recorded in CDCl₃. Chemical shifts are reported in ppm, referenced against tetramethylsilane (TMS) as internal standard. ¹H coupling patterns are described as singlet (s), doublet (d), triplet (t) and multiplet (m). Coupling constants (J) are reported in Hz. ¹³C NMR spectra were obtained at 100 MHz on the above-mentioned instrument. The chemical shifts are reported in ppm, referenced to the solvent peak (CDCl₃). Low-resolution mass spectra were obtained on a Shimadzu GC-MS-QP2010 mass spectrometer. GC analyses were performed using a RESTEC RTX-5MS capillary column (30 m, 0.25 mm id, 0.25 μm film thickness) using products dissolved in ethyl acetate under the following conditions: Injected sample volume, 1.0 μL; flow rate, 54.1 mL min⁻¹; initial inlet temperature, 40 °C ramped to 72 °C at 10 °C min⁻¹ followed by a 5 °C min⁻¹ ramp to 100 °C (held for 10 min) and 10 °C min⁻¹ to 280 °C and held for 20 min (total run time: 56.8 min). High-resolution mass spectra were obtained on a Bruker Daltonics micrOTOF-Q II instrument equipped with an APCI source operating in positive mode. The samples were dissolved in HPLC-grade acetonitrile and injected into the APCI source by means of a syringe pump at a flow rate of 5.0 μL min⁻¹. The Compass 1.3 for micrOTOF-Q II software (Bruker daltonics, USA) was used for data acquisition, processing, and isotopic distribution simulations.

General procedure for the synthesis of the 3-(sulfenyl)-1H-indoles 3

The diorganyl disulfide 2a–j (0.3 mmol), indole 1a–c (0.5 mmol), SeO₂ (30 mol%, 0.016 g), I₂ (10 mol%, 0.0076 g) and glycerol (1.0 mL) were added to a round-bottomed flask. The resultant solution was stirred at 100 °C (oil bath) for the time indicated in Table 2, after which the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (3 × 10 mL), dried over MgSO₄, filtered, and concentrated under vacuum. The residue was then purified by silica-gel chromatography with hexane/ethyl acetate as the eluent.

3-(Phenylthio)-1H-indole (3aa)^7c. Yield: 0.191 g (85%); brown solid; mp 149–151 °C (lit.^7c 150–151 °C). ¹H NMR (400 MHz, CDCl₃) δ 11.02 (s, 1H), 7.55–7.41 (m, 3H), 7.17 (t, J = 7.4 Hz, 1H), 7.14–7.02 (m, 5H), 6.99 (t, J = 7.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 138.7, 136.0, 130.6, 128.1, 127.6, 124.7, 123.6, 121.3, 119.2, 117.9, 111.2, 99.6. MS (relative intensity, %) m/z: 225 (100), 193 (19), 148 (9), 121 (8), 89 (4), 77 (13), 63 (3).

3-(p-Tolylthio)-1H-indole (3ab)^7c. Yield: 0.0905 g (76%); beige solid; mp 124–126 °C (lit.^7c 123–124 °C). ¹H NMR (400 MHz, CDCl₃) δ 8.11 (bs, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.29–7.22 (m, 2H), 7.16–7.10 (m, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 2.13 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 136.4, 135.4, 134.7, 130.4, 129.5, 129.1, 126.3, 122.9, 120.8, 119.6, 111.5, 103.5, 20.7. MS (relative intensity, %) m/z: 239 (100), 223 (23), 148 (11), 121 (13), 117 (5), 77 (21), 65 (10).

3-[(4-Methoxyphenyl)thio]-1H-indole (3ac)^7c. Yield: 0.1036 g (84%); brown solid; mp 111–113 °C (lit.^7c 112–114 °C). ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.57–7.46 (m, 1H), 7.32–7.20 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.08–6.96 (m, 3H), 6.64 (d, J = 8.8 Hz, 2H), 3.62 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 157.8, 136.4, 130.0, 129.5, 129.00, 128.6, 122.9, 120.7, 119.6, 114.5, 111.5, 104.6, 55.3. MS (relative intensity, %) m/z: 255 (100), 240 (42), 223 (16), 148 (6), 139 (4), 89 (4), 77 (10), 63 (6).

3-[(4-Fluorophenyl)thio]-1H-indole (3ad)^7c. Yield: 0.086 g (71%); beige solid; mp 134–137 °C (lit.^7c 133–134 °C). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1H), 7.63 (dd, J = 7.9, 1.1 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.44 (dt, J = 8.2, 0.9 Hz, 1H), 7.32–7.25 (m, 1H), 7.23–7.17 (m, 1H), 7.15–7.08 (m, 2H), 6.93–6.85 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 160.9 (d, J¹(C–F) = 244.1 Hz), 136.5, 134.0 (d, J⁴(C–F) = 3.0 Hz), 130.5, 128.8, 127.9 (d, J³(C–F) = 7.9 Hz), 123.1, 120.9, 119.5, 115.7 (d, J²(C–F) = 22.0 Hz), 111.6, 103.3. MS (relative intensity, %) m/z: 243 (100), 211 (29), 183 (11), 148 (15), 121 (17), 89 (7), 77 (16), 63 (6), 45 (9).

3-[(4-Chlorophenyl)thio]-1H-indole (3ae)^7c. Yield: 0.086 g (67%); yellow solid; mp 135–137 °C (lit.^7c 134–135 °C). ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.63 (dd, J = 7.8, 0.9 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.47 (dt, J = 8.2, 0.9 Hz, 1H), 7.35–7.30 (m, 1H), 7.25–7.20 (m, 1H), 7.18–7.14 (m, 2H), 7.11–7.02 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 137.8, 136.4, 130.7, 130.5, 128.7, 128.7, 127.1, 123.2, 121.0, 119.4, 111.6, 102.3. MS (relative intensity, %) m/z: 259 (100), 224 (66), 148 (23), 121 (19), 111 (32), 77 (31), 63 (12), 45 (17).

3-[(4-Bromophenyl)thio]-1H-indole (3af)⁸. Yield: 0.0345 g (23%); orange solid; mp 141–144 °C (lit.⁸ 144–146 °C). ¹H NMR (400 MHz, CDCl₃) δ 10.91 (s, 1H), 7.50–7.42 (m, 3H), 7.25–7.14 (m, 3H), 7.07 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 138.5, 136.3, 131.0, 130.7, 128.1, 126.6, 121.7, 119.6, 118.1, 117.1, 111.5, 99.4. MS (relative intensity, %) m/z: 305 (75), 224 (100), 148 (34), 89 (15), 77 (41), 45 (23).

2-[(1H-Indol-3-yl)thio]aniline (3ag)⁸. Yield: 0.0797 g (66%); dark brown solid; mp 94–97 °C (lit.⁸ 93–94 °C). ¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.35–7.28 (m, 2H), 7.28–7.21 (m, 2H), 7.21–7.15 (m, 1H), 7.04 (td, J = 7.9, 1.5 Hz, 1H), 6.70 (dd, J = 8.0, 1.3 Hz, 1H), 6.65 (td, J = 7.5, 1.3 Hz, 1H), 4.19 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 145.6, 136.3, 131.9, 129.0, 128.7, 128.0, 122.8, 120.8, 120.6, 119.3, 118.9, 115.4, 111.5, 104.1. MS (relative intensity, %) m/z = 240 (100), 223 (16), 148 (8), 117 (71), 90 (14), 77 (12), 45 (5).

2-[(1H-Indol-3-yl)thio]ethanol (3ah). Yield: 0.140 g (93%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 7.78–7.72 (m, 1H), 7.36–7.31 (m, 1H), 7.29–7.14 (m, 3H), 3.62 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H), 2.31 (s, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 136.4, 129.9, 129.2, 122.8, 120.6, 119.1, 111.6, 104.1, 60.5, 39.1. MS (relative intensity, %) m/z: 302 (92), 282 (13), 145 (12), 78 (100), 51 (56). HRMS (APCI-TOF) m/z: calculated for C₁₀H₁₁NOS [M + H]⁺ 194.0634, found: 194.0634.

3-(Benzylthio)-1H-indole (3ai)⁸. Yield: 0.100 g (84%); orange solid; mp 79–81 °C (lit.⁸ 84–85 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.23–7.13 (m, 5H), 7.06–7.042 (m, 2H), 6.91 (d, J = 2.6 Hz, 1H), 3.84 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 138.9, 136.1, 129.8, 129.1, 128.9, 128.1, 126.7, 122.5, 120.4, 119.2, 111.4, 105.0, 40.9. MS (relative intensity, %) m/z: 239 (78), 206 (18), 148 (100), 121 (10), 104 (8), 91 (92), 77 (16).

3-[(Furan-2-ylmethyl)thio]-1H-indole (3aj). Yield: 0.072 g (31%); brown solid; mp 77–79 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.31–7.24 (m, 2H), 7.22–7.12 (m, 2H), 7.07 (d, J = 2.5 Hz, 1H), 6.26–6.09 (m, 1H), 5.86 (d, J = 3.1 Hz, 1H), 3.85 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 152.1, 141.8, 136.3, 130.0, 129.3, 122.7, 120.5, 119.3, 111.4, 110.3, 107.6, 105.5, 33.5. MS (relative intensity, %) m/z: 229 (16), 196 (10), 148 (29), 121 (8), 81 (100), 77 (16), 53 (11). HRMS (APCI-TOF) m/z: calculated for C₁₃H₁₁NOS [M + H]⁺ 230.0634, found: 230.0634.

1-Methyl-3-(phenylthio)-1H-indole (3ba)^7c. Yield: 0.076 g (64%); yellow solid; mp 83–85 °C (lit.^7c 85–87 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.29–7.22 (m, 2H), 7.17–7.05 (m, 5H), 7.03–6.97 (m, 1H), 3.74 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 139.6, 137.5, 135.0, 129.8, 128.6, 125.7, 124.6, 122.5, 120.4, 119.7, 109.7, 100.5, 33.0. MS (relative intensity, %) m/z: 239 (100), 224 (18), 162 (10), 128 (4), 91 (2), 77 (13).

5-Bromo-3-(phenylthio)-1H-indole (3ca)^7c. Yield: 0.075 g (52%); white solid; mp 121–123 °C (lit.^7c 121–123 °C). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (bs, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.32 (dd, J = 8.6, 1.8 Hz, 1H), 7.27–7.22 (m, 1H), 7.16 (dd, J = 8.1, 6.9 Hz, 2H), 7.10–7.03 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 138.7, 135.1, 131.8, 130.9, 128.8, 126.1, 125.9, 125.0, 122.2, 114.4, 113.1, 102.8. MS (relative intensity, %) m/z: 305 (100), 224 (91), 191 (21), 165 (9), 88 (4), 77 (9).

General procedure for the synthesis of the 2,3-bis(sulfenyl)-1H-indoles 4

The diorganyl disulfide 2a–g (0.6 mmol), indole 1a–c (0.5 mmol), SeO₂ (60 mol%, 0.033 g), I₂ (10 mol%, 0.015 g) and glycerol (1.0 mL) were added to a round-bottomed flask. The resulting mixture was stirred at 100 °C (oil bath) for the time indicated in Table 3, after which the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (3 × 10 mL), dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica-gel chromatography with hexane/ethyl acetate as the eluent.

2,3-Bis(phenylthio)-1H-indole (4aa)¹⁰. Yield: 0.1421 g (85%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H), 7.31–6.92 (m, 12H). ¹³C NMR (100 MHz, CDCl₃) δ 138.1, 137.3, 135.4, 132.5, 129.6, 128.9, 128.4, 128.4, 126.3, 126.2, 124.7, 123.3, 120.5, 119.4, 111.6, 108.9. MS (relative intensity, %) m/z: 333 (54), 254 (3), 224 (100), 197 (4), 146 (5), 121 (6), 77 (8).

2,3-Bis(p-tolylthio)-1H-indole (4ab)¹⁰. Yield: 0.135 g (75%); orange oil. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (bs, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.32–7.23 (m, 4H), 7.22–7.16 (m, 1H), 7.15–7.06 (m, 4H), 7.02 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 137.6, 136.7, 134.8, 134.4, 130.5, 130.2, 130.1, 130.1, 129.4, 127.0, 123.4, 121.0, 119.7, 110.9, 108.5, 20.9, 20.8. MS (relative intensity, %) m/z: 361 (67), 238 (100), 223 (86), 205 (16), 121 (5), 91 (7), 65 (10), 40 (6). HRMS (APCI-TOF) m/z: calculated for C₂₂H₁₈NS₂ [M + H]⁺ 362.1032, found: 362.1032.

2,3-Bis[(4-methoxyphenyl)thio]-1H-indole (4ac)²⁵. Yield: 0.086 g (44%); yellow solid; mp 127–130 °C (lit.²⁵ 134–137 °C). ¹H NMR (400 MHz, CDCl₃) δ 8.20 (bs, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.30–7.13 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 6.79–6.73 (m, 2H), 3.81 (s, 3H), 3.76 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.8, 157.9, 136.6, 135.5, 133.5, 130.2, 129.3, 128.6, 123.5, 123.2, 121.0, 119.4, 115.1, 114.5, 110.8, 108.0, 55.4, 55.3. MS (relative intensity, %) m/z: 393 (45), 254 (100), 223 (60), 210 (19), 139 (10), 77 (6).

2,3-Bis[(4-fluorophenyl)thio]-1H-indole (4ad)¹⁰. Yield: 0.113 g (62%); brown oil. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.26–7.11 (m, 4H), 7.06 (t, J = 7.3 Hz, 1H), 7.02–6.92 (m, 2H), 6.83 (t, J = 8.6 Hz, 2H), 6.74 (t, J = 8.7 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 162.2 (, J¹(C–F) = 248.2 Hz), 161.0 (d, J¹(C–F) = 244.8 Hz), 136.7, 133.7, 132.8 (d, J⁴(C–F) = 3.2 Hz), 132.2 (d, J³(C–F) = 8.3 Hz), 129.8, 129.1 (d, J⁴(C–F) = 3.3 Hz), 128.7 (d, J³(C–F) = 7.9 Hz), 124.0, 121.3, 119.7, 116.5 (d, J²(C–F) = 22.2 Hz), 115.7 (d, J²(C–F) = 22.1 Hz), 111.2, 109.5. MS (relative intensity, %) m/z: 369 (52), 272 (3), 242 (100), 146 (7), 120 (8), 102 (8), 75 (7), 45 (2). HRMS (APCI-TOF) m/z: calculated for C₂₀H₁₃F₂NS₂ [M + H]⁺ 370.0530, found 370.0530.

2,3-Bis[(4-chlorophenyl)thio]-1H-indole (4ae). Yield: 0.0782 g (39%); yellow solid; mp 68–72 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (bs, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.23–7.14 (m, 1H), 7.13–6.96 (m, 7H), 6.90 (d, J = 8.8 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 136.8, 136.4, 133.4, 132.9, 132.8, 131.0, 130.7, 129.7, 129.4, 128.8, 127.9, 124.3, 121.5, 119.8, 111.3, 109.6. MS (relative intensity, %) m/z: 401 (19), 258 (19), 223 (100), 178 (4), 120 (6), 102 (6), 75 (7), 69 (3). HRMS (APCI-TOF) m/z: calculated for C₂₀H₁₃Cl₂NS₂ [M + H]⁺ 401.9940, found 401.9940.

2,3-Bis[(4-bromophenyl)thio]-1H-indole (4af). Yield: 0.130 g (53%); beige solid; mp 109–112 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (bs, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.42–7.16 (m, 7H), 7.08 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 137.1, 136.8, 133.6, 132.6, 132.4, 131.7, 130.8, 129.7, 128.2, 124.3, 121.6, 121.3, 119.9, 118.9, 111.3, 109.6. MS (relative intensity, %) m/z: 491 (3), 303 (3), 255 (4), 223 (100), 146 (4), 120 (4), 76 (5). HRMS (APCI-TOF) m/z: calculated for C₂₀H₁₃Br₂NS₂ [M + H]⁺ 491.8906, found 491.8908.

1-Methyl-2,3-bis(phenylthio)-1H-indole (4ba). Yield: 0.171 g (99%); beige solid. mp 92–94 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.0 Hz, 1H), 7.47–7.37 (m, 2H), 7.29–7.14 (m, 8H), 7.14–7.07 (m, 3H), 3.85 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 138.4 (2C), 135.8, 134.2, 129.1, 128.6, 127.3, 126.5, 126.1, 124.9, 123.9, 121.0, 120.3, 111.0, 110.1, 31.0. MS (relative intensity, %) m/z: 347 (100), 238 (92), 223 (83), 205 (5), 165 (4), 121 (4), 77 (11). HRMS (APCI-TOF) m/z: calculated for C₂₁H₁₇S₂N₁ [M]⁺ 347.0802, found: 347.0801.

5-Bromo-2,3-bis(phenylthio)-1H-indole (4ca). Yield: 0.1589 g (77%); brown solid; mp 151–152 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.28 (dd, J = 8.6, 1.9 Hz, 2H), 7.25–7.09 (m, 7H), 7.07–6.96 (m, 3H). Missing one signal, N–H̲. ¹³C NMR (100 MHz, CDCl₃) δ 136.6, 134.9, 133.7, 133.3, 129.8, 127.8, 127.4, 127.1, 125.3, 124.6, 123.7, 119.9, 112.5, 112.3, 106.0. MS (relative intensity, %) m/z: 413 (23), 303 (4), 255 (5), 223 (100), 207 (10), 119 (4), 77 (5). HRMS (APCI-TOF) m/z: calculated for C₂₀H₁₄BrNS₂ [M + H]⁺ 411.9825, found 411.9824.

Conclusions

In summary, we describe herein an easy, inexpensive, rapid, and efficient method for the controlled preparation of 3-sulfenylindoles and 2,3-bis-sulfenylindoles using I₂/SeO₂ as catalyst/oxidizing agent and glycerol as the solvent. This new protocol uses readily available diorganyl disulfides and indoles as starting materials and involves S–S bond cleavage and the formation of new S–C_sp² (indole) bonds. The products were selectively obtained in good yields in only a few minutes in air and with good substituent tolerance on both the disulfide and the indole.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank FAPERGS, CNPq, and CAPES for financial support. CNPq is also acknowledged for Fellowships to G. P., D. A., and E. J. L. University of Perugia is acknowledged for an “accordi quadro” Fellowship to B. M. and financial support through “Ricerca di Base 2017” to C. S. The work described in this manuscript is part of the scientific activity of the international multidisciplinary “SeS Redox and Catalysis” network.

Notes and references

1. A. Baeyer and A. Emmerling, Ber. Dtsch. Chem. Ges., 1869, 2, 679.
2. M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608.
3. G. La Regina, R. Bai, W. M. Rensen, E. Di Cesare, A. Coluccia, F. Piscitelli, V. Famiglini, A. Reggio, M. Nalli, S. Pelliccia, E. Da Pozzo, B. Costa, I. Granata, A. Porta, B. Maresca, A. Soriani, M. L. Iannitto, A. Santoni, J. Li, M. M. Cona, F. Chen, Y. Ni, A. Brancale, G. Dondio, S. Vultaggio, M. Varasi, C. Mercurio, C. Martini, E. Hamel, P. Lavia, E. Novellino and R. Silvestri, J. Med. Chem., 2013, 56, 123.
4. J. A. Campbell, V. Bordunov, C. A. Broka, M. F. Browner, J. M. Kress, T. Mirzadegan, C. Ramesha, B. F. Sanpablo, R. Stabler, P. Takahara, A. Villasenor, K. A. M. Walker, J.-H. Wang, M. Welch and P. Weller, Bioorg. Med. Chem. Lett., 2004, 14, 4741.
5. (a) R. Silvestri, G. D. Martino, G. La Regina, M. Artico, S. Massa, L. Vargiu, M. Mura, A. G. Loi, T. Marceddu and P. La Colla, J. Med. Chem., 2003, 46, 2482; (b) P. C. Unangst, D. T. Connor, S. R. Stabler, R. J. Weikert, M. E. Carethers, J. A. Kennedy, D. O. Thueson, J. C. Chestnut, R. L. Adolphson and M. C. Conroy, J. Med. Chem., 1989, 32, 1360; (c) C. D. Funk, Nat. Rev. Drug Discovery, 2005, 4, 664.
6. For reviews, see: (a) M. Feng, B. Tang, S. H. Liang and X. Jiang, Curr. Top. Med. Chem., 2016, 16, 1200; (b) H. Liu and X. Jiang, Chem. – Asian J., 2013, 8, 2546.
7. (a) H. Du, R. Tang, C. Deng, Y. Liu, J. Li and X. Zhang, Adv. Synth. Catal., 2011, 353, 2739; (b) Y. Chen, C. Cho, F. Shi and R. C. Larock, J. Org. Chem., 2009, 74, 6802; (c) Y. Chen, C. Cho, F. Shi and R. C. Larock, Org. Lett., 2009, 11, 173; (d) E. G. Zimmermann, S. Thurow, C. S. Freitas, S. R. Mendes, G. Perin, D. Alves, R. G. Jacob and E. J. Lenardão, Molecules, 2013, 18, 4081; (e) C. C. Silveira, S. R. Mendes, L. Wolf, G. M. Martins and L. von Mühlen, Tetrahedron, 2012, 68, 10464; (f) X. Fang, R. Tang, P. Zhong and J. Li, Synthesis, 2009, 4183.
8. W. Ge and Y. Wei, Green Chem., 2012, 14, 2066.
9. J. B. Azeredo, M. Godoi, G. M. Martins, C. C. Silveira and A. L. Braga, J. Org. Chem., 2014, 79, 4125.
10. H. Zhang, X. Bao, Y. Song, J. Qu and B. Wang, Tetrahedron, 2015, 71, 8885.
11. R. Rahaman and P. Barman, Eur. J. Org. Chem., 2017, 6327.
12. (a) H. L. Hiley, J. F. Morley and N. A. C. Friend, J. Chem. Soc., 1932, 1875; (b) H. L. Hiley and N. A. C. Friend, J. Chem. Soc., 1932, 2342.
13. (a) D. Chen, W.-D. Xu, H.-M. Liu, M.-M. Li, Y.-M. Yan, X.-X. Li, Y. Li, Y.-X. Cheng and H.-B. Qin, Chem. Commun., 2016, 52, 8561; (b) R. M. Patel, V. G. Puranik and N. P. Argade, Org. Biomol. Chem., 2011, 9, 6312; (c) U. Kauhl, L. Andernach, S. Weck, L. P. Sandjo, S. Jacob, E. Thines and T. Opatz, J. Org. Chem., 2016, 81, 215.
14. (a) Y. Wang, B. Zhu, Q. Xu, Q. Zhu and L. Yu, RSC Adv., 2014, 4, 49170; (b) B. A. Sousa and A. A. dos Santos, Eur. J. Org. Chem., 2012, 3431.
15. C. Santi, R. D. Lorenzo, C. Tidei, L. Bagnoli and T. Wirth, Tetrahedron, 2012, 68, 10530.
16. R. M. Young and M. T. Davies-Coleman, Tetrahedron Lett., 2011, 52, 4036.
17. B. M. Laloo, H. Mecadon, M. R. Rohman, I. Kharbangar, I. Kharkongor, M. Rajbangshi, R. Nongkhlaw and B. Myrboh, J. Org. Chem., 2012, 77, 707.
18. M. R. Rohman, I. Kharkongor, M. Rajbangshi, H. Mecadon, B. M. Laloo, P. R. Sahu, I. Kharbangar and B. Myrboh, Eur. J. Org. Chem., 2012, 320.
19. C. Gebhardt, B. Priewisch, I. Irran and K. Rück-Braun, Synthesis, 2008, 1889.
20. (a) K. J. Anzai, Heterocycl. Chem., 1979, 16, 567; (b) R. Plate, H. C. J. Ottenheijm and R. J. F. Nivard, J. Org. Chem., 1984, 49, 540; (c) R. Plate, H. C. J. Ottenheijm and R. J. F, Tetrahedron, 1986, 42, 4511; (d) P. Hamel and P. Préville, J. Org. Chem., 1996, 61, 1573; (e) P. Hamel, Tetrahedron Lett., 1997, 38, 8473; (f) P. Hamel, Y. Girard and J. G. Atkinson, J. Chem. Soc., Chem. Commun., 1989, 63.
21. B. Witkop, Ann., 1947, 558, 106.
22. J. F. K. Wilshire, Aust. J. Chem., 1967, 20, 359.
23. We speculate that SeO₂ is reduced to Se by HI (SeO₂ + 4HI → Se + 2I₂ + 2H₂O). The in situ-formed Se then acts as an electrophile for indole (1a) to form a selenide (RSe⁻) that may react with I₂ to form RSeI, and then with another equivalent of 1a to form 5. HI has been reported to be an efficient reducing agent in organic synthesis; for reviews, see: (a) I. D. Entwistle and W. W. Wood, Hydrogenolysis of Allyl and Benzyl Halides and Related Compounds, in Comprehensive Organic Synthesis: selectivity, strategy and efficiency in modern organic chemistry, ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, vol. 8, pp. 955–982; (b) G. W. Breton, P. J. Kropp and R. G. Harvey, Hydrogen Iodide, in Encyclopedia of Reagents for Organic Synthesis, ed. L. Paquette, J. Wiley & Sons, New York, 2004,  DOI:10.1002/047084289X.rh039.
24. When equimolar amounts of 3,3′-diindolyl selenide 5 and PhSSPh 2a were mixed in MeOD-d3, after 12 h it was observed in the ⁷⁷Se-NMR the incipient formation of a product having a chemical shift of 556 ppm that can be speculated to be due to intermediate I. This is in agreement also to the data reported in literature for some selenoketals. See: H. Duddeck, P. Wagner and A. Biallab, Magn. Reson. Chem., 1991, 29, 248.
25. C. D. Prasad, S. Kumar, M. Sattar, A. Adhikary and S. Kumar, Org. Biomol. Chem., 2013, 11, 8036.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and figures of NMR spectra. See DOI: 10.1039/c8qo00360b

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