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TBAI-assisted direct C–H activation of indoles with β-E-styrene sulfonyl hydrazides: a stereoselective access to 3-styryl thioindoles

The current work describes the challenging introduction of a vinyl sulfide group by simple C–H activation on a variety of substrates. The direct C–H activation of indoles with β-(E)-styrene sulfonyl hydrazides under the sulfenylation conditions, assisted by the iodic catalyst tert-butyl ammonium iodide (TBAI), afforded a series of (E)-styrylthioindoles. Accordingly, β-(E)-styrene sulfonyl hydrazides undergo radical cross-coupling reactions with a variety of substituted indoles to afford structurally diverse indole vinyl thioethers in moderate to high yields with E-stereoselectivity. This method is metal-catalyst-free and is valuable not only because of its novelty, but also for providing a convenient synthetic pathway to a variety of (E)-styrylthioindoles with retention of the configuration. The current study paves the way for the use of β-(E)-styrene sulfonyl hydrazides as a unique styryl mercaptan source in chemical synthesis.


Introduction
One of the essential goals of modern organic synthesis is to develop efficient and environmentally friendly approaches towards the construction of valuable molecular frameworks. Vinyl suldes constitute a ubiquitous molecular framework in natural products, pharmaceuticals, and important synthetic intermediates in chemical transformations. 1 These compounds nd extensive applications in chemical and materials science, and can be used as versatile building blocks for carbonyl compounds 2 and as Michael acceptors. 3 The most popular synthetic procedures to construct such molecules involve the addition of thiols to alkynes either using transition metal catalysts, 4-12 free radicals, [13][14][15] Wittig olenation [16][17][18] or nucleophilic substitution of vinyl halides. 19,20 Nevertheless, harsh reaction conditions, expensive starting substrates and a lack of stereo-control are limitations of these methods. Consequently, a milder, more convenient, and more stereoselective protocol to obtain these signicant scaffolds would be highly desirable.
The stereoselective synthesis of (E)-vinyl suldes has been achieved by several methods. Banerjee and co-workers reported an indium-iodide-promoted one-pot synthesis of (E)-vinyl suldes via the palladium-catalyzed condensation of vinyl bromides using disuldes as a sulfur source. 21 One of the most signicant catalytic processes for the synthesis of (E)-vinyl suldes was reported by the Venkataraman group, but employs a moisture-sensitive Cu(I) catalyst, and requires a high reaction temperature. 22 Later, Cook and co-workers reported a milder protocol for the synthesis of vinyl suldes. 23 The iron-catalyzed cross-coupling reaction of alkyl vinyl halides with thiols has also been reported. 24 The triethyl-bromide-catalyzed radical addition of thiols to acetylenes results in alkenyl suldes with good stereocontrol. 25 However, all these methods require the use of either metal catalysts, base, or additives to afford the corresponding vinyl suldes. Furthermore, all these reports describe the nucleophilic addition of thiols to an unsaturated system, and none describes direct C-H activation via the addition of a vinyl sulde moiety from a single source. Fig. 1 depicts a comparison of the various synthetic methods towards E-vinyl thioethers with the current work.
The indole ring is the key structural unit of many bioactive molecules 26,27 and the development of efficient synthetic methods to access differently substituted indoles is a topic of the utmost interest in organic synthesis. 28,29 Substituted indoles, particularly thiolated indoles, constitute a signicant class of heterocyclic compounds because of their wide range of applications in medicines and biologically active molecules. [30][31][32] Consequently, considerable effort has been made to develop new synthetic routes to indole-based heterocycles. 33 3-Thiolated indoles represent one of the most important classes of bioactive molecules used in the treatment of cancer and allergies. 34 The various synthetic strategies that have been reported for the 3arylthiolation of indoles include the use of sulfonyl chlorides, 35 sodium sulnates, 36 Bunte salts, 37 sulfonyl hydrazides 38 and Nhydroxy sulfonamides 39 as thiolating agents. The only method to synthesize radio-protective vinyl thioindoles was reported by Skvortsova and co-workers and involves the nucleophilic addition of thioindoles to acetylenes. 40 The present work describes the challenging introduction of a vinyl sulde moiety by simple C-H activation on a variety of substituted indoles using b-(E)-styrene sulfonyl hydrazides (Fig. 2). Sulfonyl hydrazides are readily available, inexpensive, and stable solids that can act as sulfenylation agents. [41][42][43] Consequently, herein, we wish to report the use of b-(E)-styrene sulfonyl hydrazides as unique and direct sulfenylation agents for the synthesis of vinyl thioindoles with excellent stereocontrol under simple reaction conditions.

Optimization of the reaction conditions
Scheme 1 outlines the synthetic pathway and conditions adopted for the preparation of the target molecules. We started with the reaction of b-(E)-styrene sulfonyl hydrazide (1a) with indole (2a) in the presence of 10 mol% of iodine at 70 C in a sealed tube for 12 hours, but the desired product was formed in only 25% yield ( Table 1, entry 1). To our delight, the yield was increased to 46% by increasing the temperature to 100 C (entry 2). Further screening of various solvents afforded the product in moderate yields (entries [3][4][5] and an improved yield of 65% was obtained using 1,4-dioxane (entry 6). Conducting the reaction under an inert atmosphere to avoid the formation of byproducts enhanced the yield to 71% (entry 7). Next, the catalytic effect of various iodic reagents in this transformation was studied (entries [8][9][10][11][12][13], and the best result was obtained by using TBAI in 1,4-dioxane at 100 C for 12 hours under an N 2 atmosphere (entry 10). Repeating the reaction with a decreased temperature of 90 C resulted in a slight decrease in the yield of the product (entry 14), and was thus found to be optimum temperature for this conversion. In contrast, further increasing the temperature to 120 C dropped the yield to 69% (entry 15). A decrease or increase in catalyst loading (5 mol% & 20 mol%) also resulted in a decrease in the yield of the product (entries 16 and 17).
Attempts to decrease in reaction time from 8 to 10 h resulted in lower consumption of the starting materials and thus low yields of the product.

Scope and limitations of substrates
Scope with respect to substituted indoles. With the optimized conditions in hand, we next studied the scope of substituted indoles for this catalytic transformation. In the presence of 10 mol% of TBAI, a range of substituted indoles having both electron-donating and electron-withdrawing groups on the indole ring underwent sulfenylation with b-(E)styrene sulfonyl hydrazides to give structurally diverse 3-styryl thioindoles in good to high yields (66-88%) with excellent stereoselectivity (Scheme 2).
Effect of the nature of the substituents (electron donating/ withdrawing) on the indole ring. Under the optimized conditions, the reaction was repeated with an electron-donating (2h) or an electron-withdrawing group (2k) on the indole ring, and the results summarized in the scheme below clearly depict the enhanced yield due to the presence of the electron-donating group. that the desired transformation had successfully been carried out.

Proposed mechanistic pathway
To elucidate the mechanism of this reaction, we turned our attention to some control experiments. The reaction of indole with b-(E)-styrene sulfonyl hydrazide (1) under the optimal conditions in the presence of the radical inhibitor 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO, 1.2 equiv.) completely inhibited the formation of the desired product, suggesting the involvement of a sulfonyl radical during the reaction (Scheme 4A). The reaction of (1) with indole in the absence of TBAI also results in product formation, but in a very low yield (Scheme 4B). In the absence of indole, a mixture of the products 3s (major) and 3t (minor) was obtained (detected via GC-MS and EI-MS), indicating that (1a) is converted into these species before reacting with indole to give the styryl thioether (Scheme 4C).
In addition, during the course of the reaction, we noticed a change in the color of the reaction mixtures from light brown to purple black, indicating the formation of iodine during this reaction. On the basis of experiment and observations, the following reaction mechanism can be suggested for this radical cross-coupling reaction. Initially, disulde compound 3s is generated from b-E-styrene sulfonyl hydrazide 1 in the presence of TBAI, and then reacts with iodine to produce PhCH]CHSI (II). Nucleophilic attack of the indole on III produces radical intermediate IV and an iodine radical. Extrusion of HI leads to the formation of the nal product, thioether 3. The produced HI reacts with TBAOH to remove a water molecule, and the regenerated TBAI can react with sulfonyl hydrazide to produce disulde again (Scheme 5).
The proposed mechanism is based on reports in the literature; the free-radical pathway was conrmed by the control experiment (A) and the formation of the major intermediate 3s was conrmed by EI-MS analysis (ESI S-48 †).

Materials and instruments
Indole and its derivatives were purchased from Sinopharm Chemical Reagent Co., Meryer, Acros, Alfa Aesar, and TCI, and were used without further purication. b-(E)-Styrene sulfonyl chlorides and their derivatives were prepared according to literature procedures. 9 Melting points were determined in open glass capillaries using a Stuart SMP3 (UK) melting point apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded using a Bruker AC-400 FT spectrometer (400 MHz and 100 MHz, respectively) using TMS as an internal standard. NMR multiplicities are abbreviated as follows: Chemical shis (d) were recorded using an LC-TOF spectrometer (Micromass). Electron spray ionization (ESI) mass spectrometry data are expressed in ppm, while coupling constants (J) are expressed in Hz. High resolution mass spectra (HRMS) were obtained using a Thermo LTQ Orbitrap XL instrument equipped with an ESI source and controlled by the soware Xcalibur. Elemental analyses were conducted using a LECO-183 CHNS analyzer.

General procedure for the preparation of b-(E)-styrene sulfonyl hydrazides
Hydrazine monohydrate (50 mg, 1 mmol, 2.5 equiv.) was added dropwise to a solution of b-(E)-styrene sulfonyl chloride Scheme 1 Synthetic pathway and optimization of the reaction conditions. (0.4 mmol, 1 equiv.) in THF (2 mL) at 0 C under an N 2 atmosphere. The mixture became brown due to the formation of a white precipitate of hydrazine hydrochloride during the addition of hydrazine. The reaction mixture was stirred at 0 C for 30 to 45 minutes, diluted with ethyl acetate (10 mL), washed with brine (2 Â 10 mL), dried over sodium sulfate, and ltered. The ltrate was slowly added to stirred hexane (10 mL) over 5 min. Aer being stirred for 10 min, the mixture was ltered and then dried under vacuum to obtain the b-(E)-styrene sulfonyl hydrazides as a brown solid.

Conflicts of interest
There are no conicts to declare.