English

• 1.   Introduction

  As a prominent structural motif, the substituted indole moiety is displayed in a wide range of natural products and pharmaceutical compounds.^{[1, 2]} Among a variety of indole derivatives, 3-sulfenylindoles are currently attracting considerable attention due to their therapeutic value in diseases, such as human immunodeficiency virus (HIV), ^[3] cancer, ^[4] obesity, ^[5] bacteria, ^[6] and allergy, ^[7] virus, ^[8] as well as potential utilities in organic syntheses.^[9] Although many methods for the preparation of 3-chalcogenylindoles have been developed, ^[10] most of these protocols focus on the direct chalcogenylation at the 3-position of the indole nucleus using different chalcogenylating agents.^[10d~10i] Few reports allow simultaneous construction of the indole ring system and the installation of a sulfenyl or selenyl functionality at the 3-position of the indole nucleus.^[10j~10k] Further, these reaction are generally limited to arylalkynes bearing an amido or an equivalent group at adjacent position (Scheme 1, Paths a~c).^[10a~10c] Therefore, development of new and flexible approach to chalcogenyl-substituted indoles from different classes of starting materials is highly desirable.

  Scheme 1

  

  Scheme 1.  Synthesis of 3-chalcogenylindoles starting from indole precursors

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  Pioneering work reported in 1998 by Montevecchi and co-workers^[10a] showed that AIBN-initiated radical cycloaddition of thiols to azidoacetylene could affect the formation of 3-sulfenylindoles (Scheme 1, path a). Larock and co-workers^[10b] described a new approach to 3-chalcogenylindoles via the n-Bu₄NI-induced electrophilic cyclization of N, N-dialkyl-2-(1-alkynyl)anilines with arylsulfenyl/arylselenenyl chlorides (Scheme 1, path b). Li et al.^[10c] and our group^[11] reported that dichalcogenides could undergo the electrophilic cyclizations with 2-alkynylaniline derivatives to form 3-chalcogenylindoles (Scheme 1, path c).

  Single-pot catalysis of two different transformations holds great promise for the rapid buildup of molecular complexity.^[12] However, the development of processes that involve distinctly different sequential metal-catalyzed reactions remains a significant challenge because many transformations require very specific catalysts, ligands or conditions in order to achieve optimal yields and selectivity. Various gem-dibromovinylanilines have been reported previously to undergo the coupling/cyclization with boronic acids, which provide an efficient approach to substituted indoles.^[13] On the other hand, we have recently demonstrated a general and efficient method for catalytic chalcogenylation of indoles with dichalcogenides in the presence of CuI and air under the neutral conditions.^[14] Encouraged by these results, we were interested in the development of a synthetic strategy to incorporate gem-dibromovinylanilines, boronic acids and dichalcogenides into 3-chalcogenylindoles, in which the intermediate indole was not isolated, but immediately chalcogenylated in situ in practical, time-saving one-pot operations (Scheme 1, path d). We herein report our preliminary results on the synthesis of 3-chalcogenylindoles by the three-component reaction between gem-dibromovinylanilines, boronic acids and dichalcogenides. The sequential chalcogenylation is achieved by a key in situ switch of the catalyst and solvent.

  2.   Results and discussion

  In initial experiments Pd(OAc)₂ and CuI were employed as the catalyst fellow-actor, as they have previously exhibited distinct performance in catalytic coupling/cyclization reaction of gem-dibromovinylanilines with boronic acids^[13] and chalcogenylation of aromatic azaheterocycles, ^[14] respectively. After some experimentation, it was found that treatment of a mixture of 1a with phenylboronic acid (2a) in toluene with a catalytic system comprised of Pd(OAc)₂ (1 mol%) and 2-dicyclohexylphosphino-2', 6'-dimethoxy-1, 1'-biphenyl (S-Phos) (2 mol%) in the presence of K₃PO₄ (2.0 equiv.) followed by reacting with 1, 2-diphenyl-disulfane (3a) in dimethyl sulfoxide (DMSO) in the presence of a catalytic amount of CuI provided the desired N-benzyl-3-sulfenylindole in 68% isolated yield (4a).

  Having demonstrated the viability of the one-pot double C—Br bond coupling and thiolation process, we investigated the generality and the scope of this transformation by variation of gem-dibromovinylanilines 1, boronic acids 2 and dichalcogenides 3. As illustrated in Table 1, treatment of a mixture of N-protected gem-dibromovinylaniline and arylboronic acid in the presence of K₃PO₄ (2.0 equiv.) and a catalytic amount of Pd(OAc)₂/S-Phos followed by reacting with 0.5 equiv. of dichalcogenides in the presence of CuI (10 mol%) in DMSO under air gave the corresponding double C—Br bond coupling/cyclization/chalcogenylation product. In general, both N-aryl- and N-alkyl-protected gem-dibromovinylanilines 1 reacted smoothly with PhB-(OH)₂ (2a) and PhSSPh (3a) to give the corresponding 3-sulfenylindoles 4b~4f in moderate to excellent yields. The introduction of an electron-withdrawing substituent on the benzene ring of N-protected benzyl substituents results in a slight increase of yields (4c~4d). It was found that the N-ethyl protected substrate (1f) gave 4f in a higher yield. The structure of 4f was also verified by X-ray diffraction analysis (Figure 1).^[15] The electronic effect of gem-dibromovinylphenyl rings has a significant impact on the yields too. For example, the presence of the electron-donating methoxyl groups led to the increase of yield (4g vs 4a), while gem-dibromovinylaniline bearing an electron-withdrawing group such as chloro 1h, afforded the corresponding product in 63% yield (4h vs. 4a).

  Table 1

  

  Table 1.  Reaction of gem-dibromovinylanilines with boronic acids and dichalcogenides^{a, b}

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  Figure 1

  

  Figure 1.  ORTEP plot of the X-ray crystal structure of 4f

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  Moreover, the effect of aryl boronic acids 2 was examined. To our delight, various substituents such as methoxyl, methyl, fluoro, chloro and trifluoro were well tolerated and the reaction proceeded smoothly to yield the corresponding products as expected. It was found that arylboronic acids containing electron-donating substituents displayed higher reactivity compared with the corresponding substrates bearing electron-withdrawing groups (4i~4m). Although the 1-position of naphthalene has been observed to be reactive to PhSSPh, ^[16] treatment of 1a with 2-naphthyl boronic acid (2g) as a partner followed by reacting with 3a under the same reaction conditions afforded only the indole thiolation product 4n in 72% yield. It was observed that heterocyclic boronic acid such as thiophen-2-ylboronic acid (2h) was also a suitable substrate, which delivered the desired product in satisfactory yield (4o). The scope with respect to disulfides was examined. Various electron-rich, electron-neutral and electron-deficient diaryl disulfides 3b~3g were also examined. The results indicated that the disulfides bearing electron-withdrawing groups were more reactive than those with electron-donating groups (4p~4u).

  These results prompted us to examine if gem-dibromovinylanilines could also undergo the similar reaction with boronic acids and diselenide under the present conditions. As expected, the reaction of gem-dibromovinylanilines with boronic acids and diselenide proceeded smoothly to give the desired 3-selenylindoles in good yields (4v~4y).

  In order to obtain further insight into the sequential coupling/cylization/chalcogenylation process, the following experiments were conducted (Scheme 2). As already mentioned, ^[13] treatment of 1f with PhB(OH)₂ in the presence of K₃PO₄ (2.0 equiv.) and a catalytic amount of Pd(OAc)₂ (1 mol%) and S-Phos (2 mol%) in toluene at 90 ℃ provided the desired N-ethyl-2-phenylindole (5f) in 92% isolated yield (Scheme 2, a). Then, the direct thiolation of indole 5f with 1, 2-diaryl disulfide (3c) under the present conditions was examined, and 93% yield of 4f was obtained (Scheme 2, b). These results indicate that the construction of the indole ring may be prior to the C—S bond formation. Furthermore, the feasibility of PhSH as an intermediate was examined. As expected, the reaction of 5f with 1 equiv. of HSC₆H₄(Me-3) (6c) in the presence of CuI (0.10 equiv.) in DMSO at 110 ℃ for 24 h under air, gave the desired product 4q in 89% yield (Scheme 2, c). In addition, the reaction of HSC₆H₄(Me-3) with air in the presence of CuI (0.10 equiv.) was carried out and 3-MeH₄C₆SSC₆H₄Me-3 (3c) was obtained in 93% (Scheme 2, d).

  Scheme 2

  

  Scheme 2.  Mechanistic studies for the formation of 3-chalcogenylindoles

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  On the basis of the above results, a plausible mechanism for the sequential coupling/cylization/chalcogenylation of gem-dibromovinylanilines with boronic acids and dichalcogenides is illustrated in Scheme 3. Firstly, gem-dibromovinylaniline 1 reacts with boronic acid 2 to form the indole-intermediate (Ⅰ) by the known palladium chemistry.^[13] Then, the regioselectively electrophilic attack of a R³E⁺cation (Ⅱ), which is generated by reaction of CuI with dichalcogenide, ^[17] on indole ring results in the formation of chalcogenonium cation (Ⅲ). Lastly, proton-exchange between Ⅲ and [R³SCuI]^－ gives the corresponding chalcogenylindole 4 and R³EH, in companying with regeneration of the copper catalyst. At the same time, the oxidation of the in situ generated R³EH by air reproduces dichalcogenide 3. Clearly, the electronic factors are favorable to the attack of R³E⁺ cation on the carbon atom at 3-position, and the indoles bearing electron-donating groups are more reactive than those with electron-withdrawing groups.

  Scheme 3

  

  Scheme 3.  Proposed pathway for tandem Pd(OAc)₂/CuI-mediated three-component synthesis of 3-chalcogenylindoles

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  Bearing in mind the much cheaper price of thiols compared with the corresponding disulfides and to determine the scope and limitations of the method, the utility of this method for the preparation of bridged bis(3-sulfenylindole) was explored. Significantly, treatment of a mixture of 1f with phenylboronic acid (2a) in toluene with a catalytic system comprised of Pd(OAc)₂ and S-Phos in the presence of K₃PO₄ (2.0 equiv.), followed by reacting with biphenyl-4, 4'-dithiol (6c) in DMSO in the presence of catalytic amount of CuI afforded the dicyclization product 4z in 73% yield (Scheme 4).

  Scheme 4

  

  Scheme 4.  Dicyclization of biphenyl-4, 4'-dithiol

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  3.   Conclusions

  In summary, a practical and efficient method for the synthesis of polysubstituted 3-chalcogenylindoles has been developed via a palladium-catalyzed tandem coupling/cyclization of gem-dibromovinylanilines with boronic acids and sequential CuI-catalyzed chalcogenylation of the in situ generated indoles with dichalcogenides, by which a diverse variety of 3-sulfenyl- and 3-selenenyl-indole derivatives could be obtained in moderate to excellent yields. This procedure formally allows the installation of a chalcogenyl at the 3-position and an alkyl or aryl at the 2-position, while simultaneously constructing the indole ring nucleus itself, representing the first alkene-based pathway to generate 3-sulfenyl- and 3-selenylindoles. Efforts to extend the applications of transformation in organic synthesis as well as screen for biological activity of these types of compounds are currently underway in our laboratory.

  4.   Experimental section

  4.1   Instruments and reagents

  The step (1) reactions (Table 1) for the formation of product of 4 were carried out under nitrogen atmosphere using the standard Schlenk techniques. Commercial reagents and solvents were used as received. Substrates 1, ^{[13a, 13b]} and 3^[18] were prepared according to literature methods. ¹H NMR and ¹³C NMR spectra were recorded on a JEOL ECA-400 NMR spectrometer (FT, 400 MHz for ¹H NMR; 100 MHz for ¹³C NMR) in CDCl₃ at room temperature using tetramethylsilane (δ＝0) as an internal standard. ¹³C NMR spectra were obtained by the same NMR spectrometers and were calibrated with CDCl₃ (δ＝77.00 ppm). High-resolution mass spectra (HRMS) were recorded using ESI ionization sources. X-Ray diffraction data for 4f (CCDC 861518) was collected on a SMART APEX CCD diffractometer (graphite-monochromated Mo Kα radiation, ϕ-ω-scan technique, λ＝0.071073 nm). The intensity data were integrated by means of the SAINT program. SADABS was used to perform area-detector scaling and absorption corrections. The structures were solved by direct methods and were refined against F² using all reflections with the aid of the SHELXTL package. All non-hydrogen atoms were found from the difference Fourier syntheses and refined anisotropically. The H atoms were included in calculated positions with isotropic thermal parameters related to those of the supporting carbon atoms but were not included in the refinement. All calculations were performed using the Bruker Smart program.

  4.2   General experimental procedure for reaction of gem-dibromovinylanilines 1 with boronic acids 2 and dichalcogenides 3

  To a solution of gem-dibromovinylaniline 1 (0.2 mmol) in toluene (2.0 mL) at room temperature under N₂ atmosphere were added arylboronic acid 2 (0.3 mmol), Pd(OAc)₂ (0.002 mmol, 1 mol%), S-Phos (0.004 mmol, 2 mol%) and K₃PO₄ (0.4 mmol). The mixture was heated with stirring at 90 ℃ for 4 h. Then the reaction mixture was filtered. After evaporation of the solvent, the residue was dissolved in 2.0 mL of DMSO. Then dichalcogenides 3 (0.1 mmol) and CuI (10 mol%) were added and the mixture was stirred at 110 ℃ under air atmosphere until complete consumption of starting material as monitored by thin layer chromatography (TLC, usually 24~36 h). Then the mixture was diluted by EtOAc (10 mL), washed with H₂O (25 mL), and dried over Na₂SO₄. Evaporation of the solvent followed by purification on silica gel (eluting with petroleumether/ ethylacetate, V/V＝100/1~30/1) provides the desired product 4.

  1-Benzyl-2-phenyl-3-(phenylthio)-1H-indole   (4a): White crystalline. m.p. 147.3~149.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.06 (d, J＝9.1 Hz, 1H), 7.62~7.54 (m, 5H), 7.52~7.44 (m, 5H), 7.42 (d, J＝6.9 Hz, 1H), 7.36 (d, J＝9.2 Hz, 2H), 7.30 (d, J＝9.7 Hz, 2H), 7.24 (d, J＝8.4 Hz, 1H), 7.18 (d, J＝8.8 Hz, 2H), 5.12 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.3, 140.0, 137.7, 137.4, 130.6, 130.2, 129.1, 129.0, 128.9, 128.5, 127.6, 126.2, 125.7, 124.7, 123.2, 121.4, 120.1, 111.1, 100.7, 48.6; HRMS (ESI) calcd for C₂₇H₂₂NS [M+H]⁺ 392.1473, found 392.1472.

  1-(4-Methylbenzyl)-2-phenyl-3-(phenylthio)-1H-indole (4b): White crystalline. m.p. 120.7~123.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.65 (d, J＝7.4 Hz, 1H), 7.33~7.26 (m, 5H), 7.24~7.17 (m, 2H), 7.12 (t, J＝7.3 Hz, 3H), 7.06~6.99 (m, 5H), 6.87 (d, J＝7.5 Hz, 2H), 5.29 (s, 2H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.3, 140.1, 137.3, 137.2, 134.6, 130.6, 130.2, 129.6, 129.0, 128.8, 128.4, 126.1, 125.6, 124.6, 123.2, 121.3, 120.0, 111.1, 100.4, 48.3, 21.3; HRMS (ESI) calcd for C₂₈H₂₄NS [M+H]⁺ 406.1629, found 406.1634.

  1-(3-Fluorobenzyl)-2-phenyl-3-(phenylthio)-1H-indole (4c): White crystalline. m.p. 104.8~107.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.57 (d, J＝7.5 Hz, 1H), 7.25~7.22 (m, 5H), 7.13~7.06 (m, 4H), 7.03 (d, J＝7.3 Hz, 2H), 6.96 (d, J＝7.5 Hz, 2H), 6.92 (t, J＝7.4 Hz, 1H), 6. 80 (t, J＝7.9 Hz, 1H), 6. 65 (d, J＝7.5 Hz, 1H), 6. 56 (d, J＝9.4 Hz, 1H), 5.21 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.1, 140.3, 139.8, 137.3, 130.5, 130.4, 130.2, 129.1, 128.9, 128.5, 125.7, 124.7, 123.8, 121.8, 121.5, 120.2, 114.7, 114.5, 113.4, 113.1, 110.8, 101.1, 48.0; HRMS (ESI) calcd for C₂₇H₂₁FNS [M+H]⁺ 410.1378, found 410.1351.

  2-Phenyl-3-(phenylthio)-1-(4-(trifluoromethyl)benzyl)-1H-indole (4d): White crystalline. m.p. 124.6~127.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.57 (d, J＝7.2 Hz, 1H), 7.38 (d, J＝7.7 Hz, 2H), 7.22~7.19 (m, 5H), 7.10~7.06 (m, 3H), 7.02 (d, J＝7.2 Hz, 2H), 7.00~6.88 (m, 5H), 5.24 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.1, 141.7, 139.7, 137.2, 130.5, 130.3, 130.2, 130.1, 129.2, 128.9, 128.6, 126.5, 126.0, 125.8, 124.8, 123.5, 121.6, 120.3, 110.7, 101.4, 48.1; HRMS (ESI) calcd for C₂₈H₂₁F₃NS [M+H]⁺ 460.1347, found 460.1323.

  1, 2-Diphenyl-3-(phenylthio)-1H-indole (4e): White crystalline. m.p. 115.3~117.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.68 (d, J＝7.3 Hz, 1H), 7.37~7.28 (m, 4H), 7.23~7.21 (m, 8H), 7.16~7.14 (m, 4H), 7.07~7.03 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.1, 139.6, 138.3, 138.0, 130.9, 130.5, 130.1, 129.5, 129.4, 128.9, 128.3, 128.1, 128.0, 127.7, 125.9, 124.8, 123.5, 121.8, 120.1, 111.1, 102.1; HRMS (ESI) calcd for C₂₆H₂₀NS [M+H]⁺ 378.1316, found 378.1313.

  1-Ethyl-2-phenyl-3-(phenylthio)-1H-indole (4f): Yellow crystalline. m.p. 129.3~131.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.56 (d, J＝7.8 Hz, 1H), 7.37~7.30 (m, 6H), 7.21 (t, J＝7.4 Hz, 1H), 7.09 (t, J＝7.5 Hz, 1H), 7.03 (t, J＝7.2 Hz, 2H), 6.94~6.90 (m, 3H), 4.08 (q, J＝6.9 Hz, 2H), 1.22 (t, J＝6.9 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.7, 140.1, 136.5, 131.0, 130.5, 130.1, 128.9, 128.7, 128.4, 125.6, 124.5, 122.8, 121.0, 120.1, 110.3, 100.0, 39.7, 15.6; HRMS (ESI) calcd for C₂₂H₂₀NS [M+H]⁺ 330.1316, found 330.1302.

  1-Benzyl-5, 6-dimethoxy-2-phenyl-3-(phenylthio)-1H-indole (4g): Yellow crystalline. m.p. 168.8~170.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.30~7.27 (m, 5H), 7.26~7.23 (m, 3H), 7.15 (d, J＝7.2 Hz, 2H), 7.07~7.05 (m, 3H), 7.00 (t, J＝8.4 Hz, 3H), 6.70 (s, 1H), 5.30 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.8, 146.3, 144.6, 140.1, 137.7, 131.4, 130.8, 130.5, 129.0, 128.8, 128.7, 128.4, 127.5, 126.1, 125.4, 124.5, 123.2, 101.1, 99.9, 94.4, 56.4, 48.6; HRMS (ESI) calcd for C₂₉H₂₆NO₂S [M+H]⁺ 452.1684, found 452.1666.

  1-Benzyl-5-chloro-2-phenyl-3-(phenylthio)-1H-indole (4h): White crystalline. m.p. 151.6~153.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (s, 1H), 7.39~7.32 (m, 5H), 7.27~7.22 (m, 3H), 7.18~7.14 (m, 4H), 7.06~7.02 (m, 3H), 6.95 (d, J＝6.6 Hz, 2H), 5.32 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.6, 139.5, 137.2, 135.6, 131.4, 130.4, 130.0, 129.3, 129.0, 128.9, 128.5, 127.7, 127.2, 126.0, 125.6, 124.8, 123.5, 119.4, 112.20, 100.4, 48.7; HRMS (ESI) calcd for C₂₇H₂₁ClNS [M+H]⁺ 426.1083, found 426.1079.

  1-Benzyl-2-(4-methoxyphenyl)-3-(phenylthio)-1H-indole (4i): Yellow crystalline. m.p. 128.9~131.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.56 (d, J＝7.2 Hz, 1H), 7.16~7.14 (m, 4H), 7.09 (d, J＝7.7 Hz, 2H), 7.04 (t, J＝7.3 Hz, 3H), 6.97 (d, J＝7.4 Hz, 2H), 6.94~6.84 (m, 4H), 6.76 (d, J＝7.4 Hz, 2H), 5.24 (s, 2H), 3.65 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 146.3, 140.1, 137.8, 137.3, 131.8, 130.2, 129.0, 128.9, 127.5, 126.1, 125.6, 124.6, 123.0, 122.7, 121.3, 119.9, 114.0, 111.0, 100.1, 55.4, 48.5; HRMS (ESI) calcd for C₂₈H₂₄NOS [M+H]⁺ 422.1578, found 422.1581.

  1-Benzyl-2-(3, 5-dimethylphenyl)-3-(phenylthio)-1H-indole (4j): White crystalline. m.p. 143.0~145.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.66 (d, J＝7.3 Hz, 1H), 7.26~7.15 (m, 6H), 7.12 (d, J＝7.5 Hz, 2H), 7.07 (d, J＝7.8 Hz, 2H), 7.02~6.98 (m, 4H), 6.97~6.89 (m, 2H), 5.30 (s, 2H), 2.11 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.7, 140.2, 138.0, 137.8, 137.3, 130.8, 130.3, 130.2, 128.8, 128.8, 128.4, 127.5, 126.3, 126.0, 124.6, 123.0, 121.2, 120.0, 110.9, 100.6, 48.6, 21.4; HRMS (ESI) calcd for C₂₉H₂₆NS [M+H]⁺ 420.1786, found 420.1787.

  1-Benzyl-2-(4-fluorophenyl)-3-(phenylthio)-1H-indole (4k): White crystalline. m.p. 170.1~172.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.67 (d, J＝7.4 Hz, 1H), 7.26~7.20 (m, 7H), 7.16 (d, J＝7.4 Hz, 1H), 7.13 (d, J＝7.3 Hz, 2H), 7.05~6.99 (m, 5H), 6.96 (d, J＝6.8 Hz, 2H), 5.31 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.1, 139.8, 137.5, 137.3, 132.4, 132.4, 130.0, 129.0, 128.9, 127.6, 126.0, 125.6, 124.7, 123.3, 121.4, 120.1, 115.7, 115.5, 110.9, 101.0, 48.4; HRMS (ESI) calcd for C₂₇H₂₁FNS [M+H]⁺ 410.1378, found 410.1386.

  1-Benzyl-2-(4-chlorophenyl)-3-(phenylthio)-1H-indole (4l): White crystalline. m.p. 108.3~110.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (d, J＝7.5 Hz, 1H), 7.22~7.11 (m, 9H), 7.07 (t, J＝7.4 Hz, 3H), 6.96 (d, J＝7.5 Hz, 3H), 6.88 (d, J＝6.8 Hz, 2H), 5.23 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 144.9, 139.7, 137.4, 135.2, 131.8, 130.1, 129.0, 128.9, 128.7, 127.7, 126.0, 125.6, 124.8, 123.5, 121.5, 120.1, 111.0, 101.1, 48.5; HRMS (ESI) calcd for C₂₇H₂₁ClNS [M+H]⁺ 426.1083, found 426.1092.

  1-Benzyl-3-(phenylthio)-2-(4-(trifluoromethyl)phenyl)-1H-indole (4m): White crystalline. m.p. 60.2~62.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.60 (d, J＝7.6 Hz, 1H), 7.49 (d, J＝7.7 Hz, 2H), 7.34 (d, J＝7.7 Hz, 2H), 7.19~7.14 (m, 4H), 7.10 (t, J＝7.3 Hz, 2H), 7.05 (d, J＝7.1 Hz, 2H), 6.96 (d, J＝7.5 Hz, 3H), 6.87 (d, J＝6.8 Hz, 2H), 5.24 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 144.4, 139.5, 137.6, 137.3, 134.2, 130.9, 130.0, 129.1, 129.0, 127.7, 126.0, 125.7, 125.4, 125.4, 124.9, 123.8, 121.6, 120.3, 111.1, 101.7, 48.6; HRMS (ESI) calcd for C₂₈H₂₁F₃NS [M+H]⁺ 460.1347, found 460.1387.

  1-Benzyl-2-(naphthalen-2-yl)-3-(phenylthio)-1H-indole (4n): Yellow crystalline. m.p. 60.5~62.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71~7.67 (m, 3H), 7.61 (d, J＝7.4 Hz, 1H), 7.54 (d, J＝7.6 Hz, 1H), 7.38~7.32 (m, 3H), 7.20~7.07 (m, 6H), 7.03 (d, J＝7.3 Hz, 2H), 7.00 (d, J＝7.5 Hz, 2H), 6.94 (d, J＝6.7 Hz, 1H), 6.89 (d, J＝6.9 Hz, 2H), 5.27 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.2, 140.0, 137.7, 137.5, 133.3, 132.9, 130.4, 130.3, 129.0, 128. 9, 128.5, 128.1, 127.9, 127.9, 127.8, 127.6, 126.9, 126.5, 126.2, 125.8, 124.7, 123.3, 121.4, 120.1, 111.1, 101.1, 48.7; HRMS (ESI) calcd for C₃₁H₂₄NS [M+H]⁺ 442.1629, found 442.1686.

  1-Benzyl-3-(phenylthio)-2-(thiophen-2-yl)-1H-indole (4o): White crystalline. m.p. 127.8~129.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.68 (d, J＝7.6 Hz, 1H), 7.40 (s, 1H), 7.32~7.24 (m, 5H), 7.22~7.15 (m, 3H), 7.08 (d, J＝8.4 Hz, 2H), 7.05~7.04 (m, 5H), 5.48 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 139.7, 138.9, 137.6, 137.5, 130.4, 130.1, 129.7, 129.0, 128.8, 128.4, 127.6, 127.3, 126.0, 125.8, 124.7, 123.6, 121.5, 120.1, 110.8, 102.5, 48.5; HRMS (ESI) calcd for C₂₅H₂₀NS₂ [M+H]⁺ 398.1037, found 398.1065.

  1-Benzyl-2-phenyl-3-(p-tolylthio)-1H-indole (4p): White crystalline. m.p. 119.3~121.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.66 (d, J＝7.3 Hz, 1H), 7.27~7.39 (m, 5H), 7.24~7.19 (m, 4H), 7.17~7.14 (m, 2H), 6.82~7.05 (m, 6H), 5.32 (s, 2H), 2.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.1, 137.7, 137.3, 136.3, 134.3, 130.6, 130.2, 129.6, 129.0, 128.9, 128.4, 127.5, 126.1, 125.9, 123.1, 121.3, 120.2, 111.0, 101.2, 48.5, 21.0; HRMS (ESI) calcd for C₂₈H₂₄NS [M+H]⁺ 406.1629, found 406.1665.

  1-Ethyl-2-phenyl-3-(m-tolylthio)-1H-indole (4q): White crystalline. ¹H NMR (400 MHz, CDCl₃) δ: 7.83 (s, 1H), 7.62~7.50 (m, 6H), 7.45 (d, J＝5.8 Hz, 1H), 7.33 (d, J＝5.5 Hz, 1H), 7.19~7.03 (m, 2H), 6.96 (d, J＝5.5 Hz, 2H), 4.31 (q, J＝5.1 Hz, 2H), 2.35 (s, 3H), 1.45 (t, J＝5.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.6, 139.8, 138.3, 136.5, 131.0, 130.5, 130.1, 128.8, 128.6, 128.4, 126.3, 125.4, 122.7, 122.6, 120.9, 120.1, 110.2, 100.2, 39.6, 21.5, 15.5.

  1-Benzyl-3-[(4-methoxyphenyl)thio]-2-phenyl-1H-indole (4r): Yellow crystalline. m.p. 128.3~130.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d, J＝7.4 Hz, 1H), 7.34 (m, 5H), 7.24~7.15 (m, 6H), 7.03 (d, J＝7.7 Hz, 2H), 6.96 (d, J＝6.9 Hz, 2H), 6.71 (d, J＝7.9 Hz, 2H), 5.31 (s, 2H), 3.70 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 157.6, 145.8, 137.7, 137.2, 130.7, 130.4, 130.1, 128.9, 128.9, 128.4, 128.1, 127.5, 126.1, 123.0, 121.2, 120.0, 114.6, 110.9, 102.2, 55.4, 48.4; HRMS (ESI) calcd for C₂₈H₂₄NOS [M+H]⁺ 422.1578, found 422.1621.

  1-Benzyl-3-[(4-chlorophenyl)thio]-2-phenyl-1H-indole (4s): White crystalline. m.p. 113.2~115.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.54 (d, J＝7.2 Hz, 1H), 7.26~7.22 (m, 5H), 7.18~7.06 (m, 6H), 7.00 (d, J＝7.4 Hz, 2H), 6.87 (d, J＝7.5 Hz, 4H), 5.23 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.4, 138.6, 137.5, 137.3, 130.5, 130.3, 129.9, 129.2, 128.9, 128.5, 127.6, 126.9, 126.1, 123.3, 121.5, 119.8, 111.3, 100.2, 48.5; HRMS (ESI) calcd for C₂₇H₂₁ClNS [M+H]⁺ 426.1083, found 426.1123.

  1-Benzyl-3-[(4-bromophenyl)thio]-2-phenyl-1H-indole (4t): White crystalline. m.p. 120.3~122.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.54 (d, J＝7.3 Hz, 1H), 7.26 (d, J＝6.4 Hz, 2H), 7.22~7.19 (m, 3H), 7.16~7.14 (m, 6H), 7.11~7.07 (m, 2H), 6.88 (d, J＝6.9 Hz, 2H), 6.82 (d, J＝7.4 Hz, 2H), 5.24 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.4, 139.3, 137.5, 137.3, 131.8, 130.5, 130.3, 129.8, 129.2, 128.9, 128.5, 127.6, 127.2, 126.1, 123.3, 121.5, 119.8, 118.1, 111.1, 100.0, 48.5; HRMS (ESI) calcd for C₂₇H₂₁BrNS [M+H]⁺ 470.0578, found 470.0615.

  1-Benzyl-3-(naphthalen-1-ylthio)-2-phenyl-1H-indole (4u):White crystalline. m.p. 133.7~135.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.68 (d, J＝7.4 Hz, 2H), 7.61 (d, J＝8.6 Hz, 1H), 7.52 (d, J＝7.7 Hz, 1H), 7.42 (s, 1H), 7.35~7.28 (m, 6H), 7.25~7.18 (m, 6H), 7.15 (t, J＝7.5 Hz, 2H), 6.98 (d, J＝6.9 Hz, 2H), 5.34 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.5, 137.8, 137.7, 137.5, 134.0, 131.4, 130.6, 130.3, 129.1, 129.0, 128.5, 128.4, 127.9, 127.6, 127.1, 126.5, 126.2, 125.1, 124.8, 123.3, 123.1, 121.5, 120.1, 111.1, 100.5, 48.6; HRMS (ESI) calcd for C₃₁H₂₄NS [M+H]⁺ 442.1629, found 442.1698.

  1-Benzyl-2-phenyl-3-(phenylselanyl)-1H-indole (4v): White crystalline. m.p. 145.3~147.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d, J＝7.0 Hz, 1H), 7.34~7.31 (m, 5H), 7.23~7.16 (m, 8H), 7.12~7.06 (m, 3H), 6.96 (d, J＝6.9 Hz, 2H), 5.33 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.3, 137.7, 137.5, 134.6, 131.3, 131.0, 130.8, 129.0 128.9, 128.9, 128.5, 128.3, 127.5, 126.1, 125.4, 123.1, 121.2, 120.9, 110.9, 97.5, 48.6; HRMS (ESI) calcd for C₂₇H₂₂NSe [M+H]⁺ 440.0917, found 440.0965.

  1, 2-Diphenyl-3-(phenylselanyl)-1H-indole (4w): White crystalline. m.p. 111.8~113.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (d, J＝7.3 Hz, 1H), 7.33~7.29 (m, 4H), 7.27~7.20 (m, 10H), 7.13~7.05 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.1, 138.5, 138.2, 134.3, 131.3, 131.2, 131.0, 129.6, 129.8, 129.2, 128.8, 128.3, 128.2, 127.9, 127.6, 125.6, 123.5, 121.7, 121.0, 111.0, 99.0; HRMS (ESI) calcd for C₂₆H₂₀NSe [M+H]⁺ 426.0761, found 426.0742.

  1-Benzyl-5, 6-dimethoxy-2-phenyl-3-(phenylselanyl)-1H-indole (4x): Yellow crystalline. m.p. 143.7~145.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.39~7.12 (m, 14H), 7.05~7.04 (d, J＝4.0 Hz, 2H), 6.77 (s, 1H), 5.36 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.7, 146.3, 144.6, 137.7, 134.7, 131.5, 130.7, 129.0, 128.8, 128.6, 128.3, 128.2, 127.4, 126.1, 125.3, 124.1, 102.2, 96.9, 94.3, 56.4, 48.7; HRMS (ESI) calcd for C₂₉H₂₆NO₂Se [M+H]⁺ 500.1129, found 500.1183.

  1-Benzyl-5-chloro-2-phenyl-3-(phenylselanyl)-1H-indole (4y): White crystalline. m.p. 144.2~146.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.67 (s, 1H), 7.38~7.28 (m, 5H), 7.24~7.20 (m, 3H), 7.13~7.08 (m, 7H), 6.91 (d, J＝6.5 Hz, 2H), 5.30 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.6, 137.3, 135.8, 134.2, 132.3, 130.8, 130.7, 129.2, 129.0, 128.5, 128.4, 127.7, 127.1, 126.1, 125.7, 123.4, 120.3, 112.1, 97.2, 48.7; HRMS (ESI) calcd for C₂₇H₂₁ClNSe [M+H]⁺ 474.0527, found 474.0596.

  4, 4'-Bis[(1-ethyl-2-phenyl-1H-indol-3-yl)thio]-1, 1'-biphenyl (4z): Yellow solid. m.p. 201.0~203.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.72~7.89 (m, 1H), 7.54~7.37 (m, 7H), 7.29~7.26 (m, 1H), 7.14~7.11 (m, 2H), 7.02~6.98 (m, 2H), 4.24 (q, J＝2.0 Hz, 2H), 1.39 (t, J＝2.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.7, 139.4, 136.5, 131.4, 131.3, 130.6, 130.4, 129.9, 128.9, 128.4, 126.3, 122.9, 121.0, 119.9, 110.3, 99.6, 39.6, 15.5.

  4.3   Gram-scale experiment for the formation of 4x

  The reaction can be synthesized in large scale. To a solution of gem-dibromovinylaniline 1x (2.5 mmol) in toluene (20 mL) at room temperature under N₂ atmosphere were added arylboronic acid 2a (3.75 mmol), Pd(OAc)₂ (0.025 mmol, 1 mol%), S-Phos (0.05 mmol, 2 mol%) and K₃PO₄ (5 mmol), the mixture was heated with stirring at 90 ℃ for 4 h. Then the reaction mixture was filtered. After evaporation of the solvent, the residue was dissolved in 25 mL of DMSO. Then PhSeSePh 3 (1.25 mmol) and CuI (10 mol%) were added, and the mixture was stirred at 110 ℃ under air atmosphere until complete consumption of starting material as monitored by TLC (36 h). The mixture was diluted by EtOAc (100 mL), washed with H₂O (250 mL), and dried over Na₂SO₄, evaporation of the solvent followed by purification on silica gel (eluting with petroleumether/ethylacetate, V/V＝50/1) provides the desired product 4x (85% yield).

  Supporting Information    ¹H NMR and ¹³C NMR spectra of compounds 4a~4z. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
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  Scheme 1  Synthesis of 3-chalcogenylindoles starting from indole precursors

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  Figure 1  ORTEP plot of the X-ray crystal structure of 4f

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  Scheme 2  Mechanistic studies for the formation of 3-chalcogenylindoles

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  Scheme 3  Proposed pathway for tandem Pd(OAc)₂/CuI-mediated three-component synthesis of 3-chalcogenylindoles

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  Scheme 4  Dicyclization of biphenyl-4, 4'-dithiol

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  Table 1.  Reaction of gem-dibromovinylanilines with boronic acids and dichalcogenides^{a, b}

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