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Article

Tetrabutylammonium Iodide–Promoted Thiolation of Oxindoles Using Sulfonyl Chlorides as Sulfenylation Reagents

by
Xia Zhao
1,*,
Aoqi Wei
1,
Xiaoyu Lu
1 and
Kui Lu
2
1
College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key laboratory of Inorganic-organic Hybrid Functional Material Chemistry, Ministry of Education, Tianjin Normal University, Tianjin 300387, China
2
College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(8), 1208; https://doi.org/10.3390/molecules22081208
Submission received: 11 July 2017 / Revised: 26 July 2017 / Accepted: 28 July 2017 / Published: 1 August 2017
(This article belongs to the Collection Heterocyclic Compounds)
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Versions Notes

Abstract

:
3-Sulfanyloxindoles were synthesised by triphenylphosphine-mediated transition-metal-free thiolation of oxindoles using sulfonyl chlorides as sulfenylation reagents. The above reaction was promoted by iodide anions, which was ascribed to the in situ conversion of sulfenyl chlorides into the more reactive sulfenyl iodides. Moreover, the thiolation of 3-aryloxindoles was facilitated by bases. The use of a transition-metal-free protocol, readily available reagents, and mild reaction conditions make this protocol more practical for preparing 3-sulfanyloxindoles than traditional methods.

Graphical Abstract

1. Introduction

Oxindoles and their derivatives have attracted increased attention as a frequently occurring structural motif of both natural products and bioactive compounds [1,2,3,4,5], with thiolation at the C-3 position imparting anticancer [6], antifungal [7], and antitubercular activities (Figure 1) [8]. Therefore, the synthesis of 3-sulfanyloxindoles has been widely investigated, including with methods such as cyclisation of sulfur-containing compounds [9,10,11,12,13,14], nucleophilic substitution reactions of 3-bromooxindoles (Scheme 1, Equation (1)) [15], electrophilic thiolation of oxindoles with sulfinothioyldibenzene (Scheme 1, Equation (2)) [16] and electrophilic thiolation of oxindoles with N-(arylthio)phthalimides (Scheme 1, Equation (3)) [17,18]. Although electrophilic thiolation is the most straightforward method, the need for strongly basic conditions and the limited availability of sulfenylation reagents limit its further application.
Recently, the use of sulfonyl chlorides as sulfenylation reagents has been reported by You (Scheme 2, Equation (1)) [19], Zheng (Scheme 2, Equation (2)) [20] and our group (Scheme 2, Equations (3) and (4)) [21]. As a part of our on-going development of new sulfenylation methods [21,22,23,24,25,26,27,28], we report here a novel tetrabutylammonium iodide-facilitated thiolation of oxindoles with sulfonyl chlorides as sulfenylation reagents (Scheme 3).

2. Results

Treatment of 3-methylindolin-2-one (1a) with 4-methylbenzenesulfonyl chloride (2a) in the presence of PPh3 in 1,4-dioxane at 80 °C afforded 3-methyl-3-(p-tolylthio)indolin-2-one (3aa) in 56% yield (Table 1, Entry 1). In agreement with our previous studies, this transformation was facilitated by iodide anions [21]. Therefore, a number of classical iodides were initially screened, including potassium iodide (KI), ammonium iodide (NH4I), and tetrabutylammonium iodide (n-Bu4NI), with the highest yield observed for n-Bu4NI (Table 1, Entries 2–4). Subsequently, other solvents, such as 1,2-dichloroethane (DCE), toluene, acetonitrile (CH3CN), and N,N-dimethylformamide (DMF) were tested, but none of them surpassed 1,4-dioxane (Table 1, Entries 5–8). Finally, the effects of temperature and concentration were examined, revealing that decreasing the reaction temperature to 70 °C or increasing it to 90 °C diminished the yield (Table 1, Entries 9 and 10), as was also observed for decreasing the concentration of 1a from 0.5 M to 0.33 M (Table 1, Entry 11). When the concentration of 1a was increased from 0.5 M to 1.0 M, the desired product was obtained in 86% yield (Table 1, Entry 12), with further concentration increases leading to diminished yields (Table 1, Entry 13). Notably, increasing the loadings of 2a and PPh3 to 1.5 and 3.0 equiv., respectively, did not significantly affect the yield (Table 1, Entry 14). Thus, the optimised reaction conditions for the thiolation of 1a were as follows: 1a (0.5 mmol), 2a (0.6 mmol), PPh3 (1.0 mmol), n-Bu4NI (0.1 mmol), and 1,4-dioxane (0.5 mL) at 80 °C.
The optimised conditions were used to investigate the substrate scope of sulfenylation. As shown in Table 2, a series of substituted 3-alkyloxindoles could be coupled with various sulfonyl chlorides to afford the corresponding oxindole thioethers in moderate to excellent yields, with 3-alkyl-(1a, 1c–1g), 3-benzyl-(1h and 1i), and 5-bromo-substituted (1b) oxindoles being well tolerated. In the case of aromatic sulfonyl chlorides, both electron-donating and electron-withdrawing groups, as well as diverse ortho-, meta-, and para-substituents (2b–2e) were tolerated. Notably, for electronic effect, aliphatic sulfonyl chlorides (2f and 2g) provided the desired thiolation products in a relatively low yield compared with aromatic sulfonyl chlorides.
To further extend the substrate scope of this reaction, we explored the thiolation of 3-aryl-substituted oxindoles with sulfonyl chlorides using 3-(p-tolyl)indolin-2-one (4a) and 3-chlorobenzenesulfonyl chloride (2h) as model substrates in the presence of PPh3 under optimised reaction conditions. However, no desired product (5ah) was obtained (Table 3, Entry 1). Fortunately, when the reaction was carried out at 60 °C, 5ah was obtained in 44% yield (Table 3, Entry 2). As a further optimisation, potassium carbonate was employed as a base to activate the substrate, affording a significantly improved yield, especially when the reaction was carried out at 40 °C (Table 3, Entries 5–8). Subsequently, other bases, base loadings, additives, thiolation reagents, and reductants were tested, with the optimal reaction condition identified as: 4a (0.25 mmol), 2h (0.3 mmol), PPh3 (0.5 mmol), n-Bu4NI (0.05 mmol), K2CO3 (0.125 mmol), and 1,4-dioxane (1.0 mL) at 40 °C.
With the new optimised conditions in hand, the generality of the thiolation reaction was examined using various 3-aryloxindoles and arylsulfonyl chlorides (Figure 2), with the desired sulfenylation products (5aa–5ca) obtained in moderate yields.

3. Discussion

Based on our previous work [21], a plausible reaction mechanism was proposed (Scheme 4), featuring the initial reduction of sulfonyl chloride 2 by PPh3 to sulfenyl chloride F via intermediates A–E. F is converted into sulfenyl iodide G in the presence of iodide anions. Finally, electrophilic thiolation of oxindoles 1 by G gives the corresponding oxindole thioethers.

4. Materials and Methods

4.1. General Methods and Material

All solvents were distilled prior to use. Unless otherwise noted, chemicals were used as received without further purification. For chromatography, 200−300 mesh silica gel was employed. 1H- and 13C-NMR spectra were recorded at 400 MHz and 100 MHz respectively. Chemical shifts are reported in ppm using tetramethylsilane as internal standard (see supplementary). HRMS was performed on an FTMS mass instrument. Melting points are reported as uncorrected.

4.2. Synthesis of Oxindoles

1c–1i were synthesized according to the literature procedures [29].

4.2.1. 5-Bromo-3-methylindolin-2-one (1b)

3-methylindolin-2-one (441 mg, 3 mmol) in acetonitrile (5 mL) was cooled to −15°C. NBS (534 mg, 3 mmol) was added. After stirring for 1 h, the reaction was diluted with water (10 mL) and extracted with EtOAc (20 mL) for three times. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography to afford compound 1b (454 mg, 67%) as a white solid.

4.2.2. 3-(p-Tolyl)indolin-2-one (4a)

Indoline-2,3-dione (1.47 g, 10 mmol) in THF (20 mL) was cooled to −15°C. NaH (60%/mineral oil, 600 mg, 15 mmol) was added. After stirring for 30 min, p-tolylmagnesium bromide (1.0 M/THF, 10 mL, 10 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1h. Then the reaction was quenched with NH4Cl (aq) (30 mL) and extracted with Et2O (50 mL) for three times. After stirring for 1 h, the reaction was diluted with water (10 mL) and extracted with EtOAc (20 mL) three times. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to afford compound 1b (454 mg, 67%) as a yellow solid.

4.3. General Procedure for the Synthesis of 3aa, 3ab, 3ac, 3ad, 3ae, 3af, 3ag, 3ba, 3ca and 3da

Oxindole (0.5 mmol), sulfonyl chloride (0.6 mmol), PPh3 (1.0 mmol), n-Bu4NI (0.1 mmol) and dry 1,4-dioxane (0.5 mL) were mixed in an oven dried sealed tube. The mixture was stirred at 80 °C for 12 h. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA = 5:1 or PE:EA = 3:1) to afford the pure product.

4.4. General Procedure for the Synthesis of 3ea, 3fa, 3ga, 3gb, 3ha and 3ia

Oxindole (0.25 mmol), sulfonyl chloride (0.3 mmol), PPh3 (0.5 mmol), n-Bu4NI (0.05 mmol) and dry 1,4-dioxane (0.25 mL) were mixed in an oven dried sealed tube. The mixture was stirred at 80 °C for 6–30 h. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA = 5:1, PE:EA = 4:1 or PE:EA = 3:1) to afford the pure product.

4.5. General Procedure for the Synthesis of 5aa, 5ai, 5ah, 5ba and 5ca

Oxindole (0.25 mmol), sulfonyl chloride (0.3 mmol), PPh3 (0.5 mmol), n-Bu4NI (0.05 mmol), K2CO3 (0.125 mmol) and dry 1,4-dioxane (1.0 mL) were mixed in an oven-dried sealed tube. The mixture was stirred at 40 °C for the time indicated. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA = 5:1 or PE:EA = 3:1) to afford the pure product.
3-Methyl-3-(p-tolylthio)indolin-2-one (3aa). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3aa was isolated as a white solid (116 mg, 86%); m.p. = 151–152 °C; Rf (PE:EA = 3:1) = 0.32; 1H-NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.15 (td, J = 7.7 Hz, 1.3 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.07 (td, J = 7.5 Hz, 1.0 Hz, 1H), 6.91 (d, J = 7.9 Hz, 2H), 6.70 (d, J = 7.7 Hz, 1H), 2.24 (s, 3H), 1.69 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 179.3, 139.8, 139.6, 136.3, 132.1, 129.2, 128.6, 126.4, 124.2, 122.6, 109.7, 54.9, 21.4, 21.2; HRMS (ESI) m/e calcd. for C16H15NOS (M + H)+ 270.0947, found 270.0947.
3-[(4-Methoxyphenyl)thio]-3-methylindolin-2-one (3ab). After purification by silica gel column chromatography (PE:EA = 3:1), compound 3ab was isolated as a pink solid (128 mg, 90%); m.p. = 153–154 °C; Rf (PE:EA = 3:1) = 0.27; 1H-NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.17–7.13 (m, 3H), 7.07 (td, J = 7.6 Hz, 1.0 Hz, 1H), 6.67–6.62 (m, 3H), 3.72 (s, 3H), 1.69 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 179.6, 160.7, 140.0, 137.9, 132.1, 128.6, 124.1, 122.6, 120.7, 113.9, 109.8, 55.1, 55.1, 21.1; HRMS (ESI) m/e calcd. for C16H15NO2S (M + H)+ 286.0896, found 286.0896.
3-Methyl-3-(m-tolylthio)indolin-2-one (3ac). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3ac was isolated as a pale solid (83 mg, 62%); m.p. = 106–107 °C; Rf (PE:EA = 3:1) = 0.45; 1H-NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.22 (t, J = 7.2 Hz, 2H), 7.17–7.09 (m, 3H), 7.02 (t, J = 7.5 Hz, 1H), 6.94 (td, J = 7.6 Hz, 1.1 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 2.30 (s, 3H), 1.74 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 179.6, 143.7, 139.9, 137.5, 131.9, 130.2, 129.6, 129.4, 128.7, 125.7, 124.1, 122.4, 109.9, 55.0, 21.7, 21.0; HRMS (ESI) m/e calcd. for C16H15NOS (M + H)+ 270.0947, found 270.0946.
3-((3,5-Dichlorophenyl)thio)-3-methylindolin-2-one (3ad). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3ad was isolated as a white solid (110 mg, 68%); m.p. = 176–177 °C; Rf (PE:EA = 5:1) = 0.30; 1H-NMR (400 MHz, d6-DMSO): δ 10.50 (s, 1H), 7.56 (s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 1.8 Hz, 2H), 7.03 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 1.58 (s, 3H); 13C-NMR (100 MHz, d6-DMSO): δ 177.0, 141.1, 133.9, 133.6, 133.1, 130.7, 129.3, 129.0, 124.1, 122.1, 109.7, 54.8, 21.3; HRMS (ESI) m/e calcd. for C15H11Cl2NOS (M + H)+ 324.0011, found 324.0010.
3-((4-Bromophenyl)thio)-3-methylindolin-2-one (3ae). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3ae was isolated as a white solid (136 mg, 82%); m.p. = 135–137 °C; Rf (PE:EA = 3:1) = 0.40; 1H-NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.25–7.23 (m, 2H), 7.17 (td, J = 7.7 Hz, 1.3 Hz, 1H), 7.11–7.07 (m, 3H), 6.68 (d, J = 7.7 Hz, 1H), 1.70 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 179.0, 139.8, 137.7, 131.7, 131.6, 129.0, 128.9, 124.4, 124.2, 122.8, 110.0, 55.1, 21.5; HRMS (ESI) m/e calcd. for C15H12BrNOS (M + H)+ 333.9895, found 333.9895.
3-(Cyclopropylthio)-3-methylindolin-2-one (3af). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3af was isolated as a white solid (48 mg, 44%); m.p. = 122–124 °C; Rf (PE:EA = 3:1) = 0.30; 1H-NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.24 (td, J = 7.6 Hz, 0.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 1.67 (s, 3H), 1.62–1.56 (s, 1H), 0.72–0.66 (s, 1H), 0.63–0.51 (m, 2H), 0.35–0.28 (m, 1H); 13C-NMR (100 MHz, CDCl3): δ 181.3, 140.1, 132.5, 128.6, 123.9, 122.8, 110.1, 52.5, 21.9, 10.1, 7.53, 5.65; HRMS (ESI) m/e calcd. for C12H13NOS (M + H)+ 220.0790, found 220.0789.
3-(Butylthio)-3-methylindolin-2-one (3ag). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3ag was isolated as a yellow liquid (66 mg, 56%); Rf (PE:EA = 3:1) = 0.42; 1H-NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.23 (td, J = 7.7 Hz, 1.2 Hz, 1H), 7.09 (td, J = 7.6 Hz, 0.7 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 2.44 (dt, J = 11.6 Hz, 7.3 Hz, 1H), 2.28 (dt, J = 11.6 Hz, 7.4 Hz, 1H), 1.67 (s, 3H), 1.41–1.36 (m, 2H), 1.32–1.25 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 180.1, 139.7, 132.3, 128.7, 124.0, 123.0, 109.8, 50.8, 30.8, 28.8, 22.4, 22.0, 13.5; HRMS (ESI) m/e calcd. for C13H17NOS (M + H)+ 236.1103, found 236.1103.
5-Bromo-3-methyl-3-(p-tolylthio)indolin-2-one (3ba). After purification by silica gel column chromatography (PE:EA = 3:1), compound 3ba was isolated as a pale solid (156 mg, 90%); m.p. = 167–168 °C; Rf (PE:EA = 3:1) = 0.33; 1H-NMR (400 MHz, CDCl3): δ 8.58 (s,1H), 7.43 (d, J = 1.9 Hz, 1H), 7.28 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 7.9 Hz, 2H), 6.60 (d, J = 8.3 Hz, 1H), 2.26 (s, 3H), 1.68 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 179.6, 139.9, 138.9, 136.2, 134.1, 131.4, 129.3, 127.2, 125.8, 115.1, 111.5, 55.0, 21.2, 21.2; HRMS (ESI) m/e calcd. for C16H14BrNOS (M + H)+ 348.0052, found 348.0052.
3-Ethyl-3-(p-tolylthio)indolin-2-one (3ca). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3ca was isolated as a white solid (106 mg, 79%); m.p. = 178–179 °C; Rf (PE:EA = 3:1) = 0.37; 1H-NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.15 (td, J = 7.6 Hz, 1.3 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.07 (td, J = 7.5 Hz, 1.0 Hz, 1H), 6.91 (d, J = 7.9 Hz, 2H), 6.67 (d, J = 7.7 Hz, 1H), 2.24 (s, 3H), 2.23–2.09 (m, 2H), 0.76 (t, J = 7.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 179.0, 140.8, 139.5, 136.4, 123.0, 129.1, 128.5, 126.0, 124.4, 122.5, 109.8, 60.0, 28.5, 21.2, 9.23; HRMS (ESI) m/e calcd. for C17H17NOS (M + H)+ 284.1103, found 284.1105.
3-Propyl-3-(p-tolylthio)indolin-2-one (3da). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3da was isolated as a pale solid (74 mg, 81%); m.p. = 152–153 °C; Rf (PE:EA = 3:1) = 0.40; 1H-NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.15 (td, J = 7.6 Hz, 1.3 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.06 (td, J = 7.5 Hz, 0.8 Hz, 1H), 6.89 (d, J = 7.9 Hz, 2H), 6.70 (d, J = 7.6 Hz, 1H), 2.22 (s, 3H), 2.17–2.01 (m, 2H), 1.20–1.05 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 178.9, 140.6, 139.5, 136.4, 130.4, 129.1, 128.5, 126.0, 124.5, 122.5, 109.7, 59.4, 37.4, 21.2, 18.3, 14.0; HRMS (ESI) m/e calcd. for C18H19NOS (M + H)+ 298.1260, found 298.1267.
3-Isopropyl-3-(p-tolylthio)indolin-2-one (3ea). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3ea was isolated as a white solid (47 mg, 63%); m.p. = 162–163 °C; Rf (PE:EA = 5:1) = 0.32; 1H-NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.14 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.07–7.03 (m, 3H), 6.85 (d, J = 7.8 Hz, 2H), 6.66 (d, J = 7.6 Hz, 1H), 2.47 (h, J = 6.8 Hz, 1H), 2.20 (s, 3H), 1.28 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 179.2, 140.8, 139.3, 136.2, 129.2, 129.1, 128.4, 126.0, 125.5, 122.2, 109.7, 64.1, 33.8, 21.1, 18.0, 17.7; HRMS (ESI) m/e calcd. for C18H19NOS (M + H)+ 298.1260, found 298.1259.
3-Isopentyl-3-(p-tolylthio)indolin-2-one (3fa). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3fa was isolated as a white solid (64 mg, 78%); m.p. = 159–160 °C; Rf (PE:EA = 5:1) = 0.30; 1H-NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.14 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.10–7.05 (m, 3H), 6.90 (d, J = 7.9 Hz, 2H), 6.65 (d, J = 7.6 Hz, 1H), 2.23 (s, 3H), 2.20–2.04 (m, 2H), 1.51–1.44 (m, 1H), 1.09–0.86 (m, 2H), 0.81 (d, J = 6.6 Hz, 6H), 0.80 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 178.9, 140.6, 139.5, 136.4, 130.4, 129.1, 128.4, 126.0, 124.4, 122.5, 109.7, 59.4, 33.5, 33.2, 28.1, 22.4, 22.2, 21.2; HRMS (ESI) m/e calcd. for C20H23NOS (M + H)+ 326.1573, found 326.1570.
3-Cyclohexyl-3-(p-tolylthio)indolin-2-one (3ga). After purification by silica gel column chromatography (PE:EA = 4:1), compound 3ga was isolated as a white solid (56 mg, 67%); m.p. = 216–217 °C; Rf (PE:EA = 3:1) = 0.47; 1H-NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H), 7.00–6.93 (m, 5H), 6.58 (d, J = 7.6 Hz, 1H), 2.19 (s, 3H), 2.04 (d, J = 12 Hz, 1H), 1.96 (d, J = 11.8 Hz, 1H), 1.76 (d, J = 12.2 Hz, 1H), 1.59–1.53 (m, 3H), 1.35–1.10 (m, 3H), 1.04–0.97 (m, 1H), 0.86–0.76 (m, 1H); 13C-NMR (100 MHz, d6-DMSO): δ 176.5, 141.8, 138.7, 135.7, 129.2, 129.0, 128.4, 126.0, 125.1, 121.4, 109.1, 63.2, 43.3, 27.6, 27.2, 25.9, 25.7, 25.7, 20.6; HRMS (ESI) m/e calcd. for C21H23NOS (M + H)+ 338.1573, found 338.1572.
3-Cyclohexyl-3-((4-methoxyphenyl)thio)indolin-2-one (3gb). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3gb was isolated as a white solid (52 mg, 65%); m.p. = 198–199 °C; Rf (PE:EA = 3:1) = 0.42; 1H-NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.13 (td, J = 7.6 Hz, 1.1 Hz, 1H), 7.08–7.04 (m, 3H), 6.60 (d, J = 7.7 Hz, 1H), 6.57 (d, J = 8.8 Hz, 2H), 3.68 (s, 3H), 2.21 (m, 2H), 1.83 (d, J = 12.6 Hz, 1H), 1.64 (d, J = 10.6 Hz, 2H), 1.42–1.22 (m, 4H), 1.13–0.88 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ 179.0, 160.4, 140.7, 137.9, 129.9, 128.3, 125.6, 122.2, 120.0, 113.7, 109.6, 64.3, 55.0, 43.7, 28.3, 27.8, 26.5, 26.2, 26.1; HRMS (ESI) m/e calcd. for C21H23NO2S (M + H)+ 354.1522, found 354.1522.
4-((2-Oxo-3-(p-tolylthio)indolin-3-yl)methyl)benzonitrile (3ha). After purification by silica gel column chromatography (PE:EA = 3:1), compound 3ha was isolated as a white solid (56 mg, 60%); m.p. = 238–239 °C; Rf (PE:EA = 3:1) = 0.26; 1H-NMR (400 MHz, d6-DMSO): δ 10.17 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 7.0 Hz, 1H), 7.11 (d, J = 8.2 Hz, 4H), 7.07–7.03 (m, 3H), 7.00 (td, J = 7.5 Hz, 0.8 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 3.52 (d, J = 12.9 Hz, 1H), 3.35 (d, J = 12.9 Hz, 1H), 2.24 (s, 3H); 13C-NMR (100 MHz, d6-DMSO): δ 175.8, 141.3, 141.2, 139.4, 136.1, 131.6, 130.9, 129.2, 128.9, 128.1, 125.6, 125.0, 121.5, 118.5, 109.6, 109.4, 59.2, 39.9, 20.7; HRMS (ESI) m/e calcd. for C23H18N2OS (M + H)+ 371.1212, found 371.1213.
3-(4-Chlorobenzyl)-3-(p-tolylthio)indolin-2-one (3ia). After purification by silica gel column chromatography (PE:EA = 5:1), compound 3ia was isolated as a white solid (75 mg, 79%); m.p. = 217–218 °C; Rf (PE:EA = 3:1) = 0.50; 1H-NMR (400 MHz, d6-DMSO): δ 10.1 (s, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.07–7.02 (m, 3H), 6.97 (t, J = 6.7 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 7.6 Hz, 1H), 3.40 (d, J = 13.0 Hz, 1H), 3.26 (d, J = 13.0 Hz, 1H), 2.24 (s, 3H); 13C-NMR (100 MHz, d6-DMSO): δ 176.1, 141.5, 139.4, 136.1, 134.4, 131.7, 131.5, 129.0, 128.8, 128.5, 127.8, 125.8, 125.05, 121.5, 109.3, 59.4, 39.5, 20.8; HRMS (ESI) m/e calcd. for C22H18ClNOS (M + H)+ 380.0870, found 380.0870.
3-(p-Tolyl)-3-(p-tolylthio)indolin-2-one (5aa). After purification by silica gel column chromatography (PE:EA = 5:1), compound 5aa was isolated as a white solid (37 mg, 42%); m.p. = 196–197 °C; Rf (PE:EA = 3:1) = 0.41; 1H-NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 7.16–7.10 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 6.64 (d, J = 7.6 Hz, 1H), 2.34 (s, 3H), 2.22 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 177.8, 140.3, 139.6, 138.0, 136.2, 133.2, 130.8, 129.3, 129.1, 128.6, 127.9, 126.5, 126.3, 122.5, 110.1, 62.8, 21.2, 21.0; HRMS (ESI) m/e calcd. for C22H19NOS (M + H)+ 346.1260, found 346.1260.
4-((2-Oxo-3-(p-tolyl)indolin-3-yl)thio)benzonitrile (5ai). After purification by silica gel column chromatography (PE:EA = 5:1), compound 5ai was isolated as a pale solid (37 mg, 41%); m.p. = 178–181 °C; Rf (PE:EA = 3:1) = 0.36; 1H-NMR (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.24–7.19 (m, 3H), 7.12 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 2.35 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 177.0, 139.9, 138.7, 137.1, 135.5, 132.3, 131.7, 129.8, 129.6, 129.35, 127.72, 126.3, 123.0, 118.2, 112.5, 110.3, 62.6, 21.1; HRMS (ESI) m/e calcd. for C22H16N2OS (M + H)+ 357.1056, found 357.1058.
3-((3-Chlorophenyl)thio)-3-(p-tolyl)indolin-2-one (5ah). After purification by silica gel column chromatography (PE:EA = 5:1), compound 5ah was isolated as a white solid (65 mg, 71%); m.p. = 192–193 °C; Rf (PE:EA = 3:1) = 0.40; 1H-NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 7.3 Hz, 1H), 7.22–7.12 (m, 5H), 7.19 (d, J = 7.8 Hz, 2H), 7.00 (t, J = 7.9 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 2.35 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 177.3, 140.1, 138.4, 135.7, 134.1, 133.7, 132.5, 131.9, 130.1, 129.6, 129.4, 129.3, 129.1, 127.9, 126.4, 122.8, 110.2, 62.8, 21.1; HRMS (ESI) m/e calcd. for C21H16ClNOS (M + H)+ 366.0713, found 366.0711.
5-Bromo-3-(p-tolyl)-3-(p-tolylthio)indolin-2-one (5ba). After purification by silica gel column chromatography (PE:EA = 3:1), compound 5ba was isolated as a white solid (51 mg, 48%); m.p. = 213–215 °C; Rf (PE:EA = 3:1) = 0.32; 1H-NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 7.9 Hz, 2H), 6.55 (d, J = 8.3 Hz, 1H), 2.35 (s, 3H), 2.23 (s, 3H); 13C-NMR (100 MHz, d6-DMSO): δ 175.2, 140.5, 139.7, 137.8, 135.7, 133.0, 132.5, 131.7, 129.4, 129.3, 128.5, 127.5, 126.2, 113.4, 111.8, 62.2, 20.8, 20.7; HRMS (ESI) m/e calcd. for C22H18BrNOS (M + H)+ 424.0365, found 424.0363.
3-(3-Methoxyphenyl)-3-(p-tolylthio)indolin-2-one (5ca). After purification by silica gel column chromatography (PE:EA = 5:1), compound 5ca was isolated as a white solid (35 mg, 39%); m.p. = 175–176 °C; Rf (PE:EA = 3:1) = 0.33; 1H-NMR (400 MHz, CDCl3): δ 7.93 (s, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.31–7.11 (m, 4H), 7.11–7.07 (m, 3H), 6.86 (d, J = 7.6 Hz, 3H), 6.66 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H), 2.21 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 177.1, 159.7, 140.1, 139.8, 137.7, 136.2, 130.6, 129.5, 129.2, 128.7, 126.4, 122.6, 120.4, 114.1, 113.7, 109.9, 62.8, 55.3, 55.3, 21.2; HRMS (ESI) m/e calcd. for C22H19NO2S (M + H)+ 362.1209, found 362.1208.

5. Conclusions

We have developed a new synthesis of oxindole thioethers by triphenylphosphine-mediated deoxygenation-thiolation of oxindoles with sulfonyl chlorides as sulfenylation reagents. The above reaction was facilitated by iodide anions, possibly due to the in situ conversion of sulfenyl chlorides to the more reactive sulfenyl iodides. Sulfenylation of 3-aryloxindoles required the presence of a base. The use of a transition-metal-free protocol, readily available reagents, and mild reaction conditions allow this protocol more practical to prepare 3-sulfanyloxindoles than traditional methods. This study demonstrated the potential of sulfonyl chlorides as novel, readily accessible, and environmentally friendly sulfenylation reagents for direct thiolation of electron-rich heterocycles.

Supplementary Materials

The following are available online, 1H-NMR and 13C-NMR of compound 3aa–3gb and 5aa–5ca.

Acknowledgments

The authors sincerely thank the financial support from National Science Foundation of China (Grants 21572158).

Author Contributions

X.Z. and K.L. designed the experiments and wrote the paper; A.W. and X.L. performed the experiments and analyzed the data.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availabilty: Samples of the compounds 3aa–3gb and 5aa–5ca are available from the authors.
Molecules 22 01208 g001 550
Figure 1. Bioactive oxindoles with thiolation at the C-3 position.
Figure 1. Bioactive oxindoles with thiolation at the C-3 position.
Molecules 22 01208 g001
Molecules 22 01208 sch001 550
Scheme 1. Previously reported syntheses of 3-sulfanyloxindoles.
Scheme 1. Previously reported syntheses of 3-sulfanyloxindoles.
Molecules 22 01208 sch001
Molecules 22 01208 sch002 550
Scheme 2. Thiolation of electron-rich aromatics using sulfonyl chlorides as sulfenylation reagents.
Scheme 2. Thiolation of electron-rich aromatics using sulfonyl chlorides as sulfenylation reagents.
Molecules 22 01208 sch002
Molecules 22 01208 sch003 550
Scheme 3. Present Results for Thiolation of oxindoles by sulfonyl chlorides in the presence of PPh3.
Scheme 3. Present Results for Thiolation of oxindoles by sulfonyl chlorides in the presence of PPh3.
Molecules 22 01208 sch003
Molecules 22 01208 g002 550
Figure 2. Thiolation of 3-aryloxindoles with sulfonyl chlorides in the presence of PPh3.a
Figure 2. Thiolation of 3-aryloxindoles with sulfonyl chlorides in the presence of PPh3.a
Molecules 22 01208 g002
Molecules 22 01208 sch004 550
Scheme 4. Proposed reaction mechanism.
Scheme 4. Proposed reaction mechanism.
Molecules 22 01208 sch004
Table
Table 1. Optimisation of 3-methylindolin-2-one (1a) thiolation by 4-methylbenzenesulfonyl chloride (2a) in the presence of PPh3. a
Table 1. Optimisation of 3-methylindolin-2-one (1a) thiolation by 4-methylbenzenesulfonyl chloride (2a) in the presence of PPh3. a
Molecules 22 01208 i001
EntryAdditive/eq.Temperature (°C)Solvent/Volume (mL)Yield (%) b
1-801,4-dioxane/1.056
2KI/0.2801,4-dioxane/1.056
3NH4I/0.2801,4-dioxane/1.073
4n-Bu4NI/0.2801,4-dioxane/1.082
5n-Bu4NI/0.280DCE/1.075
6n-Bu4NI/0.280toluene/1.066
7n-Bu4NI/0.280CH3CN/1.046
8n-Bu4NI/0.280DMF/1.045
9n-Bu4NI/0.2701,4-dioxane/1.079
10n-Bu4NI/0.2901,4-dioxane/1.028
11n-Bu4NI/0.2801,4-dioxane/1.568
12n-Bu4NI/0.2801,4-dioxane/0.586
13n-Bu4NI/0.2801,4-dioxane/0.374
14n-Bu4NI/0.2801,4-dioxane/0.586 c
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), PPh3 (1.0 mmol), and additive (0–0.1 mmol)) in an appropriate solvent (0.3–1.5 mL) for 12 h at the indicated temperature. b Yield of product isolated after silica gel chromatography. c 2 (0.75 mmol) and PPh3 (1.25 mmol) were used.
Table
Table 2. Thiolation of 3-alkyloxindoles with sulfonyl chlorides in the presence of PPh3. a
Table 2. Thiolation of 3-alkyloxindoles with sulfonyl chlorides in the presence of PPh3. a
Molecules 22 01208 i002
EntryOxindoleR1R2 Sulfonyl ChlorideR3 ProductYield (%)
11aHMe2bp-MeOC6H43ab90
21aHMe2cm-MeC6H43ac62
31aHMe2d3,5-Cl2C6H33ad68
41aHMe2ep-BrC6H43ae82
51aHMe2fcyclopropyl3af44
61aHMe2gn-Butyl3ag56
71bBrMe2ap-MeC6H43ba90
81cHEt2ap-MeC6H43ca79
91dHPr2ap-MeC6H43da81
101eHi-Pr2ap-MeC6H43ea63 b
111fHi-Bu2ap-MeC6H43fa78 b
121gHcyclohexyl2ap-MeC6H43ga67 b
131gHcyclohexyl2bp-MeOC6H43gb65 b
141hHp-NCC6H4CH22ap-MeC6H43ha60 b
151iHp-ClC6H4CH22ap-MeC6H43ia79 b
a Reaction conditions: 1a–1d (0.5 mmol), 2a–2g (0.6 mmol), PPh3 (1.0 mmol), n-Bu4NI (0.1 mmol), 1,4-dioxane (0.5 mL), 80 °C, 12 h. b 1e–1i (0.25 mmol), 2a–2g (0.3 mmol), PPh3 (1.5 mmol), n-Bu4NI (0.05 mmol), 1,4-dioxane (0.25 mL), 80 °C, 6-30 h.
Table
Table 3. Optimisation of 3-(p-tolyl)indolin-2-one (4a) thiolation by 3-chlorobenzenesulfonyl chloride (2h) in the presence of PPh3. a
Table 3. Optimisation of 3-(p-tolyl)indolin-2-one (4a) thiolation by 3-chlorobenzenesulfonyl chloride (2h) in the presence of PPh3. a
Molecules 22 01208 i003
EntryBase/eq.Temperature (°C)Reaction Time (h)Solvent/Volume (mL)Yield (%) b
1-80151,4-dioxane/0.50
2-60151,4-dioxane/0.544
3-60141,4-dioxane/1.048
4-60201,4-dioxane/1.539
5K2CO3/0.560151,4-dioxane/1.054
6K2CO3/0.550341,4-dioxane/1.045
7K2CO3/0.540381,4-dioxane/1.071
8K2CO3/0.5251141,4-dioxane/1.068
9Na2CO3/0.540341,4-dioxane/1.070
10Cs2CO3/0.540391,4-dioxane/1.026
11K2CO3/1.040111,4-dioxane/1.070
12K2CO3/0.540211,4-dioxane/1.066 c
13K2CO3/0.540511,4-dioxane/1.027 c
14K2CO3/0.540321,4-dioxane/1.044 d
a Reaction conditions: 4a (0.25 mmol), 2 h (0.3 mmol), PPh3 (0.5 mmol), and n-Bu4NI (0.05 mmol) in 1,4-dioxane (0.5–1.5 mL) for indicated time and at specified temperature. b Yield of product isolated after silica gel chromatography. c n-Bu4NI (0.125 mmol) was used. d2h (0.375 mmol) and PPh3 (0.75 mmol) were used.

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Zhao, X.; Wei, A.; Lu, X.; Lu, K. Tetrabutylammonium Iodide–Promoted Thiolation of Oxindoles Using Sulfonyl Chlorides as Sulfenylation Reagents. Molecules 2017, 22, 1208. https://doi.org/10.3390/molecules22081208

AMA Style

Zhao X, Wei A, Lu X, Lu K. Tetrabutylammonium Iodide–Promoted Thiolation of Oxindoles Using Sulfonyl Chlorides as Sulfenylation Reagents. Molecules. 2017; 22(8):1208. https://doi.org/10.3390/molecules22081208

Chicago/Turabian Style

Zhao, Xia, Aoqi Wei, Xiaoyu Lu, and Kui Lu. 2017. "Tetrabutylammonium Iodide–Promoted Thiolation of Oxindoles Using Sulfonyl Chlorides as Sulfenylation Reagents" Molecules 22, no. 8: 1208. https://doi.org/10.3390/molecules22081208

APA Style

Zhao, X., Wei, A., Lu, X., & Lu, K. (2017). Tetrabutylammonium Iodide–Promoted Thiolation of Oxindoles Using Sulfonyl Chlorides as Sulfenylation Reagents. Molecules, 22(8), 1208. https://doi.org/10.3390/molecules22081208

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