I₂-Promoted Deoxygenative Coupling of Indolin-3-ones with Thiols for the Synthesis of 3-Sulfenylindoles

Abstract

This study aims to develop a facile and efficient synthetic method utilizing iodine as a catalyst for the deoxygenative coupling of indolin-3-one derivatives with thiols. Reaction of indolin-3-ones with a range of alkane- and arenethiols with 3 mol% iodine in 2,2,2-trifluoroethanol at room temperature or 60 °C gave 3-alkylthio- or 3-arylthio-substituted indoles in 52–98% yields while reaction with arenethiols using 10 mol% iodine, 1.2 equiv sodium hydroxide in acetonitrile gave 2-(arylthio)indoline-3-ones in moderate yields. Hence, regioselective C–S bond formation, which is produced at the C2 or C3 position of indolin-3-one, was achieved, depending on the presence or absence of a base and, advantageously, without the need for a transition metal catalyst and additional synthetic steps.

3-Sulfenyl indoles are very attractive molecules owing to their inherent biological potential.[1] The C–S bond plays a prominent role in the functional expression of natural products and biologically active small molecules. Consequently, diverse 3-sulfenyl indoles have been synthesized, with their biological activities extensively measured to identify promising good drug candidates for treating human diseases, such as heart diseases, HIV, cancer, or inhibitors of tubulin polymerization, among others. For example, Figure [1] shows several representative potential drug candidates for anti-cancer, HIV, bacterial infection, and CRTh2 antagonists.[2]

Due to their structural importance, various synthetic methods using highly reactive indole derivatives as a starting material have been developed. Consequently, many sulfenylation reagents,[3] [4] [5] [6] [7] [8] [9] such as disulfides, sulfonyl hydrazides, and sulfonyl halides, have been used for C3-selective sulfenylation of indoles under nonmetal catalytic conditions. Sulfenylation reactions utilizing a combination of iodine catalysts and disulfides have been investigated by many research groups.[3] Sulfenylation reactions using sulfonyl hydrazides, rather than disulfides, under iodine catalysis have also been independently reported by the research groups of Tian, Huang, and Deng.[4] Narayanarao and co-workers used iodine as a catalyst in conjunction with sulfonyl chloride for the 3-sulfenylation of indoles.[5] Zheng and co-workers realized a visible-light-driven 3-sulfenylation of indoles using a Ru catalyst/sulfonyl chloride combination.[6] In 2016, Sinha and co-workers introduced a cooperative cascade catalysis system employing bovine serum albumin (BSA)-iodine in water for the 3-sulfenylation of indoles.[7] On the other hand, the research group of Radosevich developed an electrophilic sulfenylation approach via deoxygenative O-atom transfer from sulfonyl chloride to organophosphine.[8] Singh and co-workers described a three-component reaction utilizing 1-aryltriazene/CS₂ as a sulfenylation source for indoles.[9]

Table 1 Optimization of Reaction Conditions^a

Entry	Variation from standard conditions	Yield (%)b of 3a′
1	10 mol% I2, toluene, 28 h	92
2	10 mol% NIS, CuI, or KI, toluene, 22 h	–c
3	toluene without I2, 18 h	–c
4	10 mol% I2, benzene, 24 h	91
5	10 mol% I2, CH3CN, 48 h	81
6	10 mol% I2, EtOAc, 20 h	93
7	10 mol% I2, EtOH, 32 h	20
8	10 mol% I2, HFIP, 5 h	46
9	10 mol% I2, PFPOH, 7 h	92
10	10 mol% I2, 3.5 h	94
11	5.0 mol% I2, 5.5 h	94
12	3.0 mol% I2, 23 h	93
13	without I2, 20 h	–c
14	1.2 equiv 2a, 45 h	82
15	1a instead of 1a′, 24 h	90 (3a)

^a Reaction conditions: 1a′ (0.1 mmol), 2a (2.0 equiv), I₂ (3.0 mol%), TFE (0.1 M), r.t., 23 h.

^b Isolated yield.

^c No reaction.

However, these strategies require toxic and unstable sulfonyl halides as well as sulfonyl hydrazides as coupling partners with indoles. Therefore, developing a new approach employing a readily available sulfur electrophiles formed in situ as reactive intermediates from thiols remains highly desirable for generating 3-sulfenyl indoles. Building on previous studies, we envisioned that indolin-3-one is a suitable substrate for the synthesis of 3-sulfenyl indoles through a deoxygenative coupling reaction. Hence, we herein report the first I₂-catalyzed deoxygenative coupling reaction of indolin-3-ones with thiols, providing an efficient method for the synthesis of valuable 3-sulfenyl indoles.

Initially, we selected tosyl-protected indolin-3-one 1a′ as the standard substrate to optimize the reaction conditions, with Table [1] showing the results. First, a reaction involving 1a′, 2.0 equiv. 2a, and 10 mol% I₂ in toluene at room temperature for 28 h, yielded 3a′ in 92% yield (entry 1). In contrast, various catalysts such as NIS, CuI, and KI were investigated, but none produced the desired product (entry 2). Furthermore, a control reaction conducted without I₂ did not afford any product (entry 3). Several solvents, such as benzene, CH₃CN, EtOAc, ethanol, hexafluoroisopropanol (HFIP), 2,2,3,3,3-pentafluoro-1-propanol (PFPOH), and 2,2,2-trifluoroethanol (TFE), were then evaluated under standard conditions (1a′, 2.0 equiv. 2a, and 10 mol% I₂). The reactions proceeded efficiently, affording 3a′ in moderate to excellent yields (46–94%, entries 4–6 and 8–10), but when ethanol was used as the solvent, 3a′ was isolated in 20% yield (entry 7). Interestingly, using TFE resulted in the shortest reaction time and the highest yield among the tested solvents. Therefore, to reduce the catalyst loading, we performed the reaction using 5 mol% or 3 mol% I₂, obtaining 3a′ in excellent yields of 94% and 93%, respectively, despite an increase in the reaction time (entries 11 and 12). Additionally, a control reaction without I₂ in TFE yielded no product (entry 13). When 1.2 equiv of 2a was used the expected deoxygenative reaction occurred forming 3a′ in 82% yield (entry 14), and replacing 1a with 1a′ led to the formation of 3a in a yield of 90% (entry 15).

With the optimized reaction conditions established, we explored the scope of the indolin-3-ones (Scheme [1]). The reaction of 1-acetyl-5-chloroindolin-3-one (1b) or 1-acetyl-5-bromoindolin-3-one (1c) proceeded well to deliver 3b and 3c in 98% and 92% yield, respectively. Analogues 1d and 1e, bearing methyl or methoxy groups at the C5 position, produced the corresponding products 3d and 3e in 95% and 98% yield, respectively. Additionally, 1-acetyl-6-fluoroindolin-3-one (1f) reacted smoothly to give the desired product 3f in 91% yield. The desired 3-sulfenyl indole 3g was generated in 96% yield after 48 h.

Next, we focused our attention on the scope of thiols as coupling partners in Scheme [2]. When the reaction of 2-mercaptoethanol was performed at 60 °C for 72 h, the target product 4a was isolated in 57% yield by column chromatography. The lower yield was attributed to nucleophilic competition even though the higher reactivity of the mercapto group compared to that of the hydroxyl group. The reaction of 1a with benzyl mercaptan worked well, affording 4b in 91% yield. In the case of cyclohexanethiol, 4c was prepared in an excellent yield of 97%, while tert-butylthiol formed 4d in 63% yield due to steric hinderance. With acetyl and tosyl protecting groups in the presence of thiophenol, the expected products 4e and 4e′ [10] were furnished in 95% and 95% yield, respectively. Similarly, the products 4f, 4g, and 4h were generated in 92%, 80%, and 85% yield, respectively, from 4-halogen-substituted thiophenols featuring fluoro, chloro, or bromo groups. The reaction with 4-methyl- and 4-methoxy-substituted thiophenols led to the corresponding products 4i and 4k [11] in 95% and 98% yield, respectively, while 2,6-dimethylphenylthio-substituted 4j was synthesized in 52% yield due to steric hindrance from the vicinal methyl groups. Additionally, the reaction of 4-substituted thiophenols, such as hydroxyl and amino, gave rise to the anticipated products 4l and 4m in 83% and 55% yield, respectively, whereas 4n was produced from naphthalene-2-thiol in 73% yield. Interestingly, the reaction of benzeneselenol worked well to produce 4o in 72% yield.

Encouraged by these results, we examined the 2-sulfenylation of indolin-3-ones using a base, as represented in Table [2]. When 1-acetylindolin-3-one (1a) was reacted with 4-methylthiophenol (2i) in CH₃CN at 30 °C for 30 h in the presence of 10 mol% I₂ and 1.2 equiv NaOH, the desired product 5a [12] was obtained in 55% yield (entry 1). In contrast, no desired product was detected without 10 mol% I₂ (entry 2). Several solvents were evaluated, and the utility of various bases, such as K₂CO₃, TEA, or DMAP, was screened: however, 5a was either not synthesized or detected in a low yield of 11% (entries 3 and 4). Furthermore, when DBU or KOH was used as the base, 5a was formed in 12% and 34% yield, respectively (entry 5). Following the optimized reaction condition detailed in entry 1, thiophenol was successfully converted into the product 5b in 76% yield (Figure [2]). In addition, 4-fluorothiophenol was well tolerated and 5c was prepared in 78% yield after 9 h. When 1a was treated with naphthalene-2-thiol, 5d was produced in 66% yield, whereas benzeneselenol gave 5e in only 18% yield.

Based on the experimental results, we propose a possible reaction mechanism for the formation of 3a from 1a via the deoxygenative coupling reaction shown in Scheme [3].[13] The catalyst I₂ coordinates with the carbonyl group at position C3 to form intermediate I, which undergoes nucleophilic attack by the thiol. Iodide then deprotonates the sulfur in intermediate II, generating intermediate III and releasing HI. Similarly, protonation at oxygen produces intermediate IV, which converts it into 3a via hydrogen abstraction at position C2. On the other hand, generally, an electrophilic sulfenyl iodide (RS-I) intermediate is generated in situ via the reaction of thiol with I₂, followed by the release of HI. This sulfenyl iodide (RS-I) subsequently reacts with the nucleophilic C2 carbon of intermediate V formed from 1a via NaOH-mediated deprotonation yielding 5a. Thus, an alternative C–S bond formation pathway under basic conditions could lead to 2-sulfenylation formation through an enolate intermediate, inducing nucleophilic attack at the C2 position. Notably, the results confirm that acidic or basic conditions dictate whether 1a forms 3-sulfenyl indoles or 2-sulfenyl indolin-3-ones.

Table 2 2-Sulfenylation of Indolin-3-ones^a

Entry	Variation from standard conditions	Yield (%) of 5a
1	none	55
2	without I2, 8 h	–b
3	toluene, TFE, DMSO, or 1,4-dioxane	no reaction or 11
4	K2CO3, TEA, or DMAP	no reaction
5	DBU or KOH	12 or 34

^a Reaction conditions: 1a (0.2 mmol), 2i (1.2 equiv), I₂ (10 mol%), NaOH (1.2 equiv), MeCN (0.1 M), 30 °C, 30 h.

^b Not detected.

In conclusion, we have developed an I₂-catalyzed deoxygenative sulfenylation of indolin-3-ones, enabling the synthesis of 3-sulfenyl indole derivatives and 2-sulfenyl indolin-3-ones. Especially, 3-sulfenyl indole skeleton, which is widely found in pharmaceuticals and natural products, represents a valuable structural motif that necessitates facile, efficient, and general synthetic methodologies. The developed synthetic strategy leverages non-toxic, stable, commercially available thiols, operates under metal-free conditions without the need for oxidants, and exhibits broad functional group tolerance. Moreover, the acidic α-hydrogen of indolin-3-one derivatives enables 2-sulfenylation in the presence of various bases for the formation of 2-sulfenyl indolin-3-ones. Further investigations aimed at expanding the substrate scope involving heterocyclic compounds are currently underway.

Analytical thin-layer chromatography (TLC) was carried out using 0.2-mm commercial silica gel plates (silica gel 60, F254, EMD Chemical). The vials (Wheaton® Standard Scintillation Vials, 1 dram, 15 × 45 mm with PTFE lined cap attached) were purchased from DAIHAN and dried in an oven overnight. Infrared spectra were recorded on a IRPrestige-21 from SHIMADZU. High resolution mass spectra (HRMS) were obtained by a supercritical fluid chromatograph combined with Xevo G2-XS QTOF mass spectrometer (Waters, Milford, MA, USA) at the Chiral Material Core Facility Center of Sungkyunkwan University and were reported as m/z (relative intensity). Accurate masses are reported for the molecular ion [M + H]⁺, [M]⁺, or [M + Na]⁺. All chemicals were purchased from Sigma-Aldrich, TCI, or Alfa Aesar. All reactions were run in flame- or oven-dried glassware under an atmosphere of N₂ gas with dry solvents unless otherwise stated. Nuclear magnetic resonance spectra (¹H and ¹³C NMR) were recorded with a Bruker (400 MHz, ¹H at 400 MHz). For CDCl₃ or DMSO-d ₆ solutions, the chemical shifts are reported referenced to residual protium or carbon of the solvents; CDCl₃ δ_H = 7.26 or DMSO-d ₆ δ_H = 2.50 and CDCl₃ δ_C = 77.16 or DMSO-d ₆ δ_C = 39.52.

3-Sulfenylation of Indolin-3-ones at Room Temperature; General Procedure A (GPA)

A mixture of indolin-3-one 1 (0.26 mmol), I₂ (2.0 mg, 3 mol%), and thiol 2 (0.52 mmol) in TFE (2.6 mL, 0.1 M) was stirred at r.t. for 24 h. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel) to give the desired product.

1-(3-(Dodecylthio)-1H-indol-1-yl)ethan-1-one (3a)

Compound 3a was synthesized according to GPA using 1-acetylindolin-3-one (1a; 46.1 mg, 0.26 mmol) as a white solid; yield: 89.5 mg (0.25 mmol, 95%); R_f = 0.5 (EtOAc/hexane 1:6); mp 65–66 °C.

IR (film): 3137, 3049, 2921, 2851, 1718, 1445, 1375, 1312, 1143, 748 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 8.0 Hz, 1 H), 7.68–7.65 (m, 1 H), 7.45 (s, 1 H), 7.39 (td, J = 7.3, 1.3 Hz, 1 H), 7.33 (td, J = 7.5, 1.3 Hz, 1 H), 2.81 (t, J = 7.4 Hz, 2 H), 2.63 (s, 3 H), 1.60 (quin, J = 7.4 Hz, 2 H), 1.39 (quin, J = 7.0 Hz, 2 H), 1.31–1.24 (m, 16 H), 0.88 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.1, 136.0, 131.2, 127.4, 125.8, 124.0, 119.6, 116.8, 115.2, 35.0, 32.0, 29.8, 29.76, 29.74, 29.70, 29.6, 29.4, 29.2, 28.7, 24.0, 22.8, 14.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₃₄NOS: 360.2356; found: 360.2355.

3-(Dodecylthio)-1-tosyl-1H-indole (3a′)

Compound 3a′ was synthesized according to GPA using 1-tosyl-indolin-3-one (1a′; 75.6 mg, 0.26 mmol) as a white solid; yield: 120.4 mg (0.25 mmol, 97%); R_f = 0.5 (EtOAc/hexane 1:6); mp 60–61 °C.

IR (film): 3134, 3049, 2923, 2852, 1597, 1444, 1372, 1175, 1045, 746 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.59 (s, 1 H), 7.35 (td, J = 7.8, 1.2 Hz, 1 H), 7.27 (td, J = 7.6, 1.2 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 2.77 (t, J = 7.4 Hz, 2 H), 2.31 (s, 3 H), 1.53 (quin, J = 7.4 Hz, 2 H), 1.41–1.34 (m, 2 H), 1.31–1.26 (m, 16 H), 0.89 (d, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 135.2, 135.1, 131.5, 129.9, 127.7, 126.9, 125.2, 123.5, 120.0, 115.3, 113.8, 34.8, 32.0, 29.7, 29.7, 29.61, 29.60, 29.4, 29.2, 28.6, 22.7, 21.6, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₃₇NO₂S₂Na: 494.2158; found: 494.2159.

1-(5-Chloro-3-(dodecylthio)-1H-indol-1-yl)ethan-1-one (3b)

Compound 3b was synthesized according to GPA using 1-acetyl-5-chloroindolin-3-one (1b; 55.0 mg, 0.26 mmol) as a white solid; yield: 101.6 mg (0.26 mmol, 98%); R_f = 0.5 (EtOAc/hexane 1:6); mp 62–63 °C.

IR (film): 3137, 3050, 2919, 2849, 1713, 1445, 1377, 1072, 798, 651 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.29 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 2.0 Hz, 1 H), 7.44–7.43 (m, 2 H), 2.77 (t, J = 7.4 Hz, 2 H), 2.61 (s, 3 H), 1.58 (quin, J = 7.5 Hz, 2 H), 1.39 (quin, J = 6.7 Hz, 2 H), 1.30–1.24 (m, 16 H), 0.87 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.9, 134.7, 133.1, 128.8, 128.7, 122.4, 118.3, 117.6, 114.4, 35.2, 32.0, 29.8, 29.77, 29.75, 29.71, 29.6, 29.5, 29.3, 28.7, 23.9, 22.8, 14.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₃₃ClNOS: 394.1966; found: 394.1958.

1-(5-Bromo-3-(dodecylthio)-1H-indol-1-yl)ethan-1-one (3c)

Compound 3c was synthesized according to GPA for 28 h instead of 24 h using 1-acetyl-5-bromoindolin-3-one (1c; 66.9 mg, 0.26 mmol) as a white solid; yield: 106.3 mg (0.24 mmol, 92%); R_f = 0.5 (EtOAc/hexane 1:6); mp 64–65 °C.

IR (film): 3134, 2922, 2851, 1713, 1443, 1375, 1061, 928, 647, 616 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.34 (d, J = 8.8 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H), 7.45 (s, 1 H), 7.32 (dd, J = 8.8, 1.6 Hz, 1 H), 2.77 (t, J = 7.4 Hz, 2 H), 2.61 (s, 3 H), 1.58 (quin, J = 7.4 Hz, 2 H), 1.39 (quin, J = 7.3 Hz, 2 H), 1.30–1.24 (m, 16 H), 0.87 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.9, 134.3, 132.7, 129.9, 128.8, 126.0, 119.3, 117.9, 114.5, 35.3, 32.0, 29.8, 29.76, 29.75, 29.71, 29.6, 29.5, 29.3, 28.7, 23.9, 22.8, 14.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₃₃BrNOS: 438.1461; found: 438.1452.

1-(3-(Dodecylthio)-5-methyl-1H-indol-1-yl)ethan-1-one (3d)

Compound 3d was synthesized according to GPA using 1-acetyl-5-methylindolin-3-one (1d; 49.7 mg, 0.26 mmol) as a white solid; yield: 92.5 mg (0.25 mmol, 95%); R_f = 0.5 (EtOAc/hexane 1:6); mp 60–61 °C.

IR (film): 3135, 2922, 2852, 1713, 1468, 1377, 1212, 938, 637, 619 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.28 (d, J = 8.4 Hz, 1 H), 7.44 (quin, J = 0.7 Hz, 1 H), 7.41 (s, 1 H), 7.20 (dd, J = 8.4, 1.6, 1 H), 2.80 (t, J = 9.3 Hz, 2 H), 2.61 (s, 3 H), 2.47 (s, 3 H), 1.60 (quin, J = 5.6 Hz, 2 H), 1.40 (quin, J = 5.7 Hz, 2 H), 1.31–1.24 (m, 16 H), 0.88 (t, J = 8.5 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.9, 134.1, 133.7, 131.4, 127.5, 127.2, 119.4, 116.4, 114.8, 35.0, 32.0, 29.81, 29.77, 29.75, 29.72, 29.66, 29.5, 29.3, 28.7, 23.9, 22.8, 21.5, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₃₅NOSNa: 396.2331; found: 396.2331.

1-(3-(Dodecylthio)-5-methoxy-1H-indol-1-yl)ethan-1-one (3e)

Compound 3e was synthesized according to GPA using 1-acetyl-5-methoxyindolin-3-one (1e; 53.9 mg, 0.26 mmol) as a white solid; yield: 100.5 mg (0.26 mmol, 98%); R_f = 0.5 (EtOAc/hexane 1:6); mp 52–53 °C.

IR (film): 3136, 2922, 2851, 1713, 1611, 1479, 1378, 1245, 986, 643 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.30 (d, J = 8.8 Hz, 1 H), 7.42 (s, 1 H), 7.09 (d, J = 2.8 Hz, 1 H), 6.97 (dd, J = 9.0, 2.6 Hz, 1 H), 3.88 (s, 3 H), 2.87 (t, J = 7.2 Hz, 2 H), 2.59 (s, 3 H), 1.59 (quin, J = 7.4 Hz, 2 H), 1.39 (quin, J = 7.3 Hz, 2 H), 1.30–1.23 (m, 16 H), 0.87 (d, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.7, 156.9, 132.4, 130.5, 128.3, 117.7, 114.7, 114.4, 102.0, 55.8, 35.1, 32.0, 29.8, 29.76, 29.74, 29.70, 29.66, 29.5, 29.3, 28.7, 23.8, 22.8, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₃₅NO₂SNa: 412.2281; found: 412.2281.

1-(3-(Dodecylthio)-6-fluoro-1H-indol-1-yl)ethan-1-one (3f)

Compound 3f was synthesized according to GPA using 1-acetyl-6-fluoroindolin-3-one (1f; 50.7 mg, 0.26 mmol) as a white solid; yield: 90.4 mg (0.24 mmol, 91%); R_f = 0.5 (EtOAc/hexane 1:6); mp 49–50 °C.

IR (film): 3139, 2923, 2852, 1713, 1613, 1478, 1376, 1243, 1101, 987, 633 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.17 (dd, J = 10.2, 1.4 Hz, 1 H), 7.56 (dd, J = 8.6, 5.4 Hz, 1 H), 7.40 (s, 1 H), 7.07 (td, J = 8.8, 2.4 Hz, 1 H), 2.78 (t, J = 7.4 Hz, 2 H), 2.61 (s, 3 H), 1.59 (quin, J = 7.1 Hz, 2 H), 1.38 (quin, J = 7.3 Hz, 2 H), 1.30–1.24 (m, 16 H), 0.87 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.1, 161.8 (C-F, d, ¹ J _C–F = 240.5 Hz), 136.0 (C-F, d, ³ J _C–F = 12.9 Hz). 127.48, 127.45 (C-F, d, ⁴ J _C–F = 3.7 Hz), 120.3 (C-F, d, ³ J _C–F = 10.0 Hz), 115.1, 112.3 (C-F, d, ² J _C–F = 24.1 Hz), 104.3 (C-F, d, ² J _C–F = 28.9 Hz), 35.1, 32.0, 29.8, 29.77, 29.75, 29.69, 29.6, 29.5, 29.2, 28.7, 23.9, 22.8, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₃₂FNOSNa: 400.2081; found: 400.2077.

1-(3-(Dodecylthio)-6-methoxy-1H-indol-1-yl)ethan-1-one (3g)

Compound 3g was synthesized according to GPA for 48 h instead of 24 h using 1-acetyl-6-methoxyindolin-3-one (1g; 53.9 mg, 0.26 mmol) as a white solid; yield: 98.1 mg (0.25 mmol, 96%); R_f = 0.5 (EtOAc/hexane 1:6); mp 68–69 °C.

IR (film): 3154, 2918, 2848, 1708, 1614, 1469, 1383, 1244, 987, 642 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 1.6 Hz, 1 H), 7.51 (d, J = 8.8, 1 H), 7.31 (s, 1 H), 6.96 (dd, J = 8.8, 2.4 Hz, 1 H), 3.87 (s, 3 H), 2.79 (t, J = 7.2 Hz, 2 H), 2.60 (s, 3 H), 1.59 (quin, J = 7.4 Hz, 2 H), 1.38 (quin, J = 7.4 Hz, 2 H), 1.30–1.23 (m, 16 H), 0.87 (d, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.4, 159.0, 137.0, 125.9, 124.8, 120.0, 115.2, 113.2, 100.9, 55.8, 35.0, 32.0, 29.9, 29.78, 29.76, 29.72, 29.66, 29.4, 29.3, 28.7, 24.1, 22.8, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₃₅NO₂SNa: 412.2281; found: 412.2284.

3-Sulfenylation of Indolin-3-ones at 60 °C; General Procedure B (GPB)

A mixture of 1-acetylindolin-3-one (1a; 36.0 mg, 0.20 mmol), I₂ (1.6 mg 3 mol%), and alkanethiol or arenethiol 2 (0.40 mmol) in TFE (2.0 mL, 0.1 M) was stirred at 60 °C for 72 h. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel) to give the desired product.

1-(3-((2-Hydroxyethyl)thio)-1H-indol-1-yl)ethan-1-one (4a)

Compound 4a was synthesized according to GPB using 2-mercaptoethanol (2a′; 29 μL, 0.40 mmol) as a colorless liquid; yield: 27.6 mg (0.11 mmol, 57%); R_f = 0.5 (EtOAc/hexane 1:2).

IR (film): 3417, 3137, 3049, 2926, 2874, 1693, 1446, 1377, 1212, 983, 750, 639 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 8.4 Hz, 1 H), 7.65–7.67 (m, 1 H), 7.55 (s, 1 H), 7.40 (td, J = 7.6, 1.5 Hz, 1 H), 7.35 (td, J = 7.5, 1.3 Hz, 1 H), 3.70 (t, J = 6.0 Hz, 2 H), 2.98 (t, J = 6.0 Hz, 2 H), 2.63 (d, J = 0.4 Hz, 3 H), 1.89 (br, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.1, 136.0, 131.0, 128.9, 126.1, 124.2, 119.4, 116.9, 113.0, 60.6, 38.0, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₄NO₂S: 236.0740; found: 236.0741.

1-(3-(Benzylthio)-1H-indol-1-yl)ethan-1-one (4b)

Compound 4b was synthesized according to GPA for 8 h instead of 24 h using benzyl mercaptan (2b; 62 μL, 0.52 mmol) as a colorless liquid; yield: 67.3 mg (0.24 mmol, 91%); R_f = 0.5 (EtOAc/hexane 1:6).

IR (film): 3137, 3060, 3027, 2925, 1712, 1445, 1372, 1309, 1213, 982, 749, 699 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.44 (d, J = 8.0 Hz, 1 H), 7.64 (ddd, J = 8.0, 1.6, 0.8 Hz, 1 H), 7.41 (ddd, J = 8.8, 7.6, 1.6 Hz, 1 H), 7.35 (td, J = 7.6, 1.2 Hz, 1 H), 7.30–7.24 (m, 3 H), 7.16–7.13 (m, 3 H), 3.96 (s, 2 H), 2.47 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 138.2, 135.8, 131.1, 129.1, 128.9, 128.4, 127.3, 125.8, 124.1, 119.4, 116.8, 113.6, 39.7, 23.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆NOS: 282.0947; found: 282.0943.

1-(3-(Cyclohexylthio)-1H-indol-1-yl)ethan-1-one (4c)

Compound 4c was synthesized according to GPA using cyclohexanethiol (2c; 64 μL, 0.52 mmol) as a white solid; yield: 69.6 mg (0.25 mmol, 97%); R_f = 0.5 (EtOAc/hexane 1:6); mp 65–66 °C.

IR (film): 3135, 3048, 2927, 2851, 1713, 1526, 1445, 1372, 1213, 749, 639 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 8.0 Hz, 1 H), 7.71–7.69 (m, 1 H), 7.51 (s, 1 H), 7.39 (td, J = 7.6, 1.5 Hz, 1 H), 7.34 (td, J = 7.4, 1.2 Hz, 1 H), 2.93 (m, 1 H), 2.64 (s, 3 H), 1.98–1.94 (m, 2 H), 1.77–1.73 (m, 2 H), 1.62–1.56 (m, 1 H), 1.40–1.17 (m, 5 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 135.9, 132.2, 129.7, 125.7, 124.0, 119.9, 116.7, 113.3, 47.1, 33.8, 26.1, 25.7, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₀NOS: 274.1260; found: 274.1256.

1-(3-(tert-Butylthio)-1H-indol-1-yl)ethan-1-one (4d)

Compound 4d was synthesized according to GPB using 2-methylpropane-2-thiol (2d; 45 μL, 0.4 mmol) as a green solid; yield: 31.9 mg (0.13 mmol, 63%); R_f = 0.5 (EtOAc/hexane 1:6); mp 110–111 °C.

IR (film): 3122, 3049, 2960, 2862, 1708, 1524, 1470, 1445, 1364, 1214, 747, 641 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 8.0 Hz, 1 H), 7.75–7.72 (m, 1 H), 7.55 (s, 1 H), 7.39–7.31 (m, 2 H), 2.66 (s, 3 H), 1.32 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.3, 135.8, 133.1, 131.9, 125.6, 124.1, 120.5, 116.5, 112.7, 46.6, 31.3, 24.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₈NOS: 248.1104; found: 248.1104.

1-(3-(Phenylthio)-1H-indol-1-yl)ethan-1-one (4e)

Compound 4e was synthesized according to GPA using thiophenol (2e; 53 μL, 0.52 mmol) as a white solid; yield: 67.2 mg (0.24 mmol, 95%); R_f = 0.5 (EtOAc/hexane 1:6); mp 93–94 °C.

IR (film): 3127, 3049, 2923, 2850, 1715, 1446, 1375, 1215, 983, 749, 639 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (d, J = 8.4 Hz, 1 H), 7.75 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.30–7.24 (m, 4 H), 7.21–7.16 (m, 1 H), 2.71 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 136.4, 136.2, 130.7, 130.1, 129.1, 127.3, 126.1, 125.9, 124.3, 120.0, 116.8, 111.9, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₄NOS: 268.0791; found: 268.0786.

3-(Phenylthio)-1-tosyl-1H-indole (4e′)[10]

Compound 4e′ was synthesized according to GPA for 8 h instead of 24 h using thiophenol (2e; 53 μL, 0.52 mmol) as a white solid; yield: 95.0 mg (0.24 mmol, 95%); R_f = 0.5 (EtOAc/hexane 1:6).

¹H NMR (400 MHz, CDCl₃): δ = 8.02 (d, J = 8.4 Hz, 1 H), 7.83 (s, 1 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.23–7.15 (m, 3 H), 7.13–7.09 (m, 3 H), 2.36 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.5, 136.3, 135.5, 135.0, 131.1, 130.9, 130.1, 129.0, 127.3, 127.1, 125.9, 125.5, 123.9, 120.5, 113.9, 111.9, 21.7.

1-(3-((4-Fluorophenyl)thio)-1H-indol-1-yl)ethan-1-one (4f)

Compound 4f was synthesized according to GPA using 4-fluorothiophenol (2f; 56 μL, 0.52 mmol) as a white solid; yield: 69.0 mg (0.24 mmol, 92%); R_f = 0.5 (EtOAc/hexane 1:6); mp 109–111 °C.

IR (film): 3118, 3053, 2921, 2849, 1713, 1446, 1376, 1311, 1214, 984, 749, 640 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.45 (d, J = 8.4 Hz, 1 H), 7.67 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.39 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.27 (ddd, J = 8.0, 7.2, 1.2 Hz, 1 H), 7.23–7.18 (m, 2 H), 6.95–6.89 (m, 2 H), 2.66 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 161.6 (C-F, d, ¹ J _C–F = 244.4 Hz), 136.3. 131.2 (C-F, d, ⁴ J _C–F = 3.0 Hz), 130.5, 129.7 (C-F, d, ³ J _C–F = 8.0 Hz), 126.2, 124.3, 119.8, 116.9, 116.2 (C-F, d, ² J _C–F = 22.0 Hz), 112.4, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₃FNOS: 286.0697; found: 286.0695.

1-(3-((4-Chlorophenyl)thio)-1H-indol-1-yl)ethan-1-one (4g)

Compound 4g was synthesized according to GPA for 48 h instead of 24 h using 4-chlorothiophenol (2g; 76.1 mg, 0.52 mmol) as a white solid; yield: 63.2 mg (0.21 mmol, 80%); R_f = 0.5 (EtOAc/hexane 1:6); mp 180–181 °C.

IR (film): 3143, 2922, 2850, 1723, 1529, 1472, 1311, 1211, 982, 751, 638 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H), 7.71 (s, 1 H), 7.44–7.38 (m, 2 H), 7.27 (t, J = 7.4 Hz, 1 H), 7.19–7.09 (m, 4 H), 2.67 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 136.3, 135.1, 131.8, 130.4, 130.3, 129.2, 128.5, 126.3, 124.4, 119.9, 116.9, 111.3, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₃ClNOS: 302.0401; found: 302.0399.

1-(3-((4-Bromophenyl)thio)-1H-indol-1-yl)ethan-1-one (4h)

Compound 4h was synthesized according to GPA at 60 °C instead of r.t. using 4-bromothiophenol (2h; 99.5 mg, 0.52 mmol) as a white solid; yield: 77.9 mg (0.22 mmol, 85%); R_f = 0.5 (EtOAc/hexane 1:6); mp 200–201 °C.

IR (film): 3140, 2926, 1722, 1442, 1372, 1310, 1210, 1082, 981, 750, 638 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H), 7.71 (s, 1 H), 7.44–7.38 (m, 2 H), 7.33–7.25 (m, 3 H), 7.04 (dt, J = 9.1, 2.2 Hz, 2 H), 2.67 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 136.3, 135.8, 132.1, 130.4, 128.7, 126.3, 124.4, 119.9, 119.6, 116.9, 111.1, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₃BrNOS: 345.9896; found: 345.9897.

1-(3-(p-Tolylthio)-1H-indol-1-yl)ethan-1-one (4i)

Compound 4i was synthesized according to GPA using 4-methylthiophenol (2i; 65.3 mg, 0.52 mmol) as a white solid; yield: 70.3 mg (0.24 mmol, 95%); R_f = 0.5 (EtOAc/hexane 1:6); mp 120–121 °C.

IR (film): 3135, 3049, 3017, 2919, 2851, 1714, 1445, 1374, 1214, 982, 749, 641 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H), 7.65 (s, 1 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 2.65 (s, 3 H), 2.28 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 136.2, 136.1, 132.5, 130.7, 129.9, 129.5, 128.0, 126.0, 124.2, 120.0, 116.8, 112.8, 24.0, 21.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆NOS: 282.0947; found: 282.0940.

1-(3-((2,6-Dimethylphenyl)thio)-1H-indol-1-yl)ethan-1-one (4j)

Compound 4j was synthesized according to GPB for 48 h instead of 72 h using 2,6-dimethylthiophenol (2j; 54 μL, 0.52 mmol) as a white solid; yield: 31.1 mg (0.14 mmol, 52%); R_f = 0.5 (EtOAc/hexane 1:6); mp 100–101 °C.

IR (film): 3135, 3051, 2922, 2852, 2359, 1708, 1446, 1374, 1213, 980, 745, 639 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.48 (d, J = 6.8 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.45 (ddd, J = 8.0, 6.8, 0.8 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.30–7.23 (m, 3 H), 6.92 (s, 1 H), 2.61 (s, 6 H), 2.58 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.8, 143.0, 136.0, 130.4, 129.9, 129.1, 128.7, 125.8, 123.8, 122.0, 119.3, 117.2, 116.7, 24.0, 22.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₈NOS: 296.1104; found: 296.1100.

1-(3-((4-Methoxyphenyl)thio)-1H-indol-1-yl)ethan-1-one (4k)[11]

Compound 4k was synthesized according to GPA for 8 h instead of 24 h using 4-methoxythiophenol (2k; 54 μL, 0.52 mmol) as a white solid; yield: 77.3 mg (0.25 mmol, 98%); R_f = 0.5 (EtOAc/hexane 1:6).

¹H NMR (400 MHz, CDCl₃): δ = 8.43 (d, J = 8.0 Hz, 1 H), 7.58 (s, 1 H), 7.49 (dt, J = 7.7, 1.1 Hz, 1 H), 7.37 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.27–7.23 (m, 3 H), 6.79 (dt, J = 9.6, 2.7 Hz, 2 H), 3.76 (s, 3 H), 2.63 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 158.8, 136.2, 130.8, 130.6, 128.6, 126.1, 126.0, 124.2, 119.9, 116.8, 114.8, 114.2, 55.4, 24.0.

1-(3-((4-Hydroxyphenyl)thio)-1H-indol-1-yl)ethan-1-one (4l)

Compound 4l was synthesized according to GPB at r.t. for 8 h instead of 60 °C for 72 h using 4-hydroxythiophenol (2l; 41 μL, 0.40 mmol) as a white solid; yield: 48.1 mg (0.22 mmol, 83%); R_f = 0.5 (EtOAc/hexane 1:1); mp 211–212 °C.

IR (film): 3284, 2921, 2850, 1714, 1445, 1377, 1265, 1211, 984, 750, 641 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.57 (s, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 8.19 (s, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 7.20 (dt, J = 9.5, 2.4 Hz, 2 H), 6.71 (dt, J = 9.3, 2.5 Hz, 2 H), 2.68 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.4, 156.6, 135.4, 131.2, 130.9, 130.2, 125.4, 123.8, 123.2, 119.2, 116.2, 111.6, 23.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₄NO₂S: 284.0740; found: 284.0737.

1-(3-((4-Aminophenyl)thio)-1H-indol-1-yl)ethan-1-one (4m)

Compound 4m was synthesized according to GPA at 80 °C instead of r.t. using 4-aminothiophenol (2m; 58 μL, 0.52 mmol) as a yellow solid; yield: 40.9 mg (0.15 mmol, 55%); R_f = 0.5 (EtOAc/hexane 1:1); mp 140–141 °C.

IR (film): 3135, 3049, 3017, 2919, 2851, 1714, 1445, 1374, 1214, 982, 749, 641 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H), 7.65 (s, 1 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 2.65 (brs, 2 H), 2.28 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 136.2, 136.1, 132.5, 130.7, 129.9, 129.5, 128.0, 126.0, 124.2, 120.0, 116.8, 112.8, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₅N₂OS: 283.0900; found: 282.0897.

1-(3-(Naphthalen-2-ylthio)-1H-indol-1-yl)ethan-1-one (4n)

Compound 4n was synthesized according to GPA using naphthalene-2-thiol (2n; 84.3 mg, 0.52 mmol) as a white solid; yield: 61.4 mg (0.19 mmol, 73%); R_f = 0.5 (EtOAc/hexane 1:6); mp 119–120 °C.

IR (film): 3131, 3050, 1713, 1445, 1378, 1215, 983, 745, 637 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 8.4 Hz, 1 H), 7.77–7.74 (m, 2 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.64–7.62 (m, 2 H), 7.49 (ddd, J = 8.0, 1.6, 0.8 Hz, 1 H), 7.45–7.38 (m, 3 H), 7.33 (dd, J = 8.6, 1.8 Hz, 1 H), 7.24 (ddd, J = 8.0, 7.2, 0.8 Hz, 1 H), 2.67 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.3, 136.3, 133.8, 131.8, 130.7, 130.1, 128.7, 127.8, 127.1, 126.7, 126.1, 125.7, 125.6, 125.4, 124.3, 120.0, 116.8, 111.9, 24.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₁₅NOSNa: 340.0766; found: 340.0763.

1-(3-(Phenylselanyl)-1H-indol-1-yl)ethan-1-one (4o)

Compound 4o was synthesized according to GPA using benzeneselenol (2o; 58 μL, 0.52 mmol) as a white solid; yield: 59.6 mg (0.19 mmol, 72%); R_f = 0.5 (EtOAc/hexane 1:6); mp 74–75 °C.

IR (film): 3135, 3050, 2925, 2851, 1713, 1577, 1443, 1373, 1211, 968, 749, 633 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H), 7.69 (s, 1 H), 7.52 (ddd, J = 7.6, 1.2, 0.4 Hz, 1 H), 7.40 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.33–7.27 (m, 3 H), 7.21–7.15 (m, 3 H), 2.66 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 136.0, 131.7, 131.4, 130.9, 129.8, 129.2, 126.5, 125.9, 124.2, 120.7, 116.6, 106.9, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₄NOSe: 316.0235; found: 316.0227.

2-Sulfenylation of Indolin-3-ones; General Procedure C

A mixture of 1-acetylindolin-3-one (1a; 36 mg, 0.2 mmol), NaOH (9.8 mg, 0.24 mmol), I₂ (5.2 mg, 10 mol%), and thiophenol 2 (0.24 mmol) in CH₃CN (2.0 mL, 0.1 M) was stirred at 30 °C for 30 h. After completion of the reaction, the mixture was quenched by H₂O and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel) to give the desired product.

1-Acetyl-2-(p-tolylthio)indolin-3-one (5a)[12]

Compound 5a was synthesized according to GPC using 1-acetylindolin-3-one (1a; 36 mg, 0.2 mmol) as a white solid; yield: 33.9 mg (0.11 mmol, 55%); R_f = 0.5 (EtOAc/hexane 1:2).

¹H NMR (400 MHz, CDCl₃): δ = 8.27 (s, 1 H), 7.50–7.45 (m, 2 H), 7.24–7.21 (m, 2 H), 7.04–6.99 (m, 1 H), 6.89 (d, J = 6.8 Hz, 2 H), 5.12 (s, 1 H), 2.60 (s, 3 H), 2.16 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 194.4, 169.0, 152.6, 140.3, 137.2, 136.2, 129.6, 124.2, 123.8, 123.2, 118.1, 68.3, 24.8, 21.2.

1-Acetyl-2-(phenylthio)indolin-3-one (5b)

Compound 5b was synthesized according to GPC for 27 h instead of 30 h using thiophenol (2e; 25 μL, 0.24 mmol) as a white solid; yield: 43.3 mg (0.15 mmol, 76%); R_f = 0.5 (EtOAc/hexane 1:2); mp 164–165 °C.

IR (film): 2954, 1721, 1671, 1607, 1587, 1462, 1352, 1301, 1175, 1004, 766 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.27 (d, J = 5.2 Hz, 1 H), 7.49–7.45 (m, 2 H), 7.37–7.35 (m, 2 H), 7.18–7.13 (m, 1 H), 7.10–7.06 (m, 2 H), 7.00 (t, J = 7.4 Hz, 1 H), 5.17 (s, 1 H), 2.62 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 194.3, 168.9, 152.7, 137.3, 136.3, 130.0, 128.9, 126.8, 124.3, 123.8, 118.1, 68.2, 24.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₄NO₂S: 284.0740; found: 284.0740.

1-Acetyl-2-((4-fluorophenyl)thio)indolin-3-one (5c)

Compound 5c was synthesized according to GPC for 9 h instead of 30 h using 4-fluorothiophenol (2f; 26 μL, 0.24 mmol) as a white solid; yield: 47.3 mg (0.16 mmol, 78%); R_f = 0.5 (EtOAc/hexane 1:2); mp 114–115 °C.

IR (film): 3090, 2947, 1720, 1681, 1588, 1488, 1345, 1225, 1156, 1005, 921, 828 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.25 (d, J = 7.6 Hz, 1 H), 7.47 (ddd, J = 8.8, 7.6, 1.6 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.34–7.29 (m, 2 H), 7.01 (t, J = 7.6 Hz, 1 H), 6.75 (tt, J = 8.9, 2.2 Hz, 2 H), 5.14 (s, 1 H), 2.60 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 194.1, 168.9, 163.9 (C-F, d, ¹ J _C–F = 250.0 Hz), 152.6, 138.6 (C-F, d, ³ J _C–F = 8.5 Hz), 137.5, 124.4, 123.7, 121.7, 118.0, 116.1 (C-F, d, ² J _C–F = 21.8 Hz), 68.1, 24.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₃FNO₂S: 302.0646; found: 302.0645.

1-Acetyl-2-(naphthalen-2-ylthio)indolin-3-one (5d)

Compound 5d was synthesized according to GPC for 22 h instead of 30 h using naphthalene-2-thiol (2n; 39.4 mg, 0.24 mmol) as a white solid; yield: 44.5 mg (0.13 mmol, 66%); R_f = 0.5 (EtOAc/hexane 1:2); mp 153–154 °C.

IR (film): 3052, 2924, 2852, 1722, 1682, 1606, 1461, 1378, 1342, 1300, 1259, 814, 756 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.23 (d, J = 8.0 Hz, 1 H), 7.90 (d, J = 1.6 Hz, 1 H), 7.67–7.64 (m, 2 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.44–7.33 (m, 5 H), 6.88 (t, J = 7.4 Hz, 1 H), 5.23 (s, 1 H), 2.64 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 194.2, 169.0, 152.5, 137.2, 136.2, 133.2, 133.1, 131.8, 128.5, 127.9, 127.5, 127.3, 126.6, 124.4, 124.2, 123.7, 123.6, 118.0, 68.3, 24.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₁₅NO₂SNa: 356.0715; found: 356.0717.

1-Acetyl-2-(phenylselanyl)indolin-3-one (5e)

Compound 5e was synthesized according to GPC for 9 h instead of 30 h using benzeneselenol (2o; 26 μL, 0.24 mmol) as a white solid; yield: 12.1 mg (0.04 mmol, 18%); R_f = 0.5 (EtOAc/hexane 1:2); mp 127–128 °C.

IR (film): 3068, 2960, 2925, 1714, 1681, 1606, 1461, 1379, 1344, 1300, 1259, 780, 740 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.20 (d, J = 8.0 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.47 (ddd, J = 8.8, 7.2, 1.6 Hz, 1 H), 7.45–7.41 (m, 2 H), 7.18 (tt, J = 7.4, 1.7 Hz, 1 H), 7.09–7.02 (m, 3 H), 5.46 (s, 1 H), 2.58 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 194.9, 168.6, 151.9, 137.6, 136.9, 129.8, 129.0, 124.4, 124.2, 123.9, 123.3, 118.3, 61.3, 24.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₃NO₂SeNa: 354.0004; found: 354.0004.

Scale-Up Synthesis of 3a

A mixture of 1-acetylindolin-3-one (1a; 180 mg, 1.0 mmol), I₂ (7.8 mg, 3 mol%), and dodecane-1-thiol (2a; 492 μL, 2.05 mmol) in TFE (10.2 mL, 0.1 M) was stirred at r.t. for 24 h. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel) to give the desired 1-(3-(dodecylthio)-1H-indol-1-yl)ethan-1-one (3a; 354 mg, 0.96 mmol, 96%) as a white solid.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1a La Regina G, Edler MC, Brancale A, Kandil S, Coluccia A, Piscitelli F, Prosperi E, Lavecchia A, Novellino E, Artico M, Silvestri R. J. Med. Chem. 2007; 50: 2865
  PubMedSearch in Google Scholar
• 1b Unangst PC, Connor DT, Stabler SR, Weikert RJ, Carethers ME, Kennedy JA, Thueson D, Chestnut JC, Adolphson RL, Conroy MC. J. Med. Chem. 1989; 32: 1360
  CrossrefPubMedSearch in Google Scholar
• 2a Silvestri R, De Martino G, La Regina G, Artico M, Massa S, Vargiu L, Mura M, Loi AG, Marceddu T, La Colla P. J. Med. Chem. 2003; 46: 2482
  CrossrefPubMedSearch in Google Scholar
• 2b Ragno R, Coluccia A, La Regina G, De Martino G, Piscitelli F, Lavecchia A, Novellino E, Bergamini A, Ciaprini C, Sinistro A, Maga G, Crespan E, Artico M, Silvestri R. J. Med. Chem. 2006; 49: 3172
  PubMedSearch in Google Scholar
• 2c Ragno R, Artico M, De Martino G, La Regina G, Coluccia A, Di Pasquali A, Silvestri R. J. Med. Chem. 2005; 48: 213
  PubMedSearch in Google Scholar
• 2d De Martino G, Edler MC, La Regina G, Coluccia A, Barbera MC, Barrow D, Nicholson RI, Chiosis G, Brancale A, Hamel E, Artico M, Silvestri R. J. Med. Chem. 2006; 49: 947
  CrossrefPubMedSearch in Google Scholar
• 2e De Martino G, La Regina G, Coluccia A, Edler MC, Barbera MC, Brancale A, Wilcox E, Hamel E, Artico M, Silvestri R. J. Med. Chem. 2004; 47: 6120
  CrossrefPubMedSearch in Google Scholar
• 2f La Regina G, Bai R, Rensen W, Coluccia A, Piscitelli F, Gatti V, Bolognesi A, Lavecchia A, Granata I, Porta A, Maresca B, Soriani A, Iannitto ML, Mariani M, Santoni A, Brancale A, Ferlini C, Dondio G, Varasi M, Mercurio C, Hamel E, Lavia P, Novellino E, Silvestri R. J. Med. Chem. 2011; 54: 8394
  PubMedSearch in Google Scholar
• 2g Luker T, Bonnert R, Brough S, Cook AR, Dickinson MR, Dougall I, Logan C, Mohammeda RT, Paine S, Sanganee HJ, Sargent C, Schmidt JA, Teague S, Thom S. Bioorg. Med. Chem. Lett. 2011; 21: 6288
  PubMedSearch in Google Scholar
• 2h Funk CD. Nat. Rev. Drug Discovery 2005; 4: 664
  PubMedSearch in Google Scholar
• 2i Cianchi F, Cortesini C, Magnelli L, Fanti E, Papucci L, Schiavone N, Messerini L, Vannacci A, Capaccioli S, Perna F, Lulli M, Fabbroni V, Perigli G, Bechi P, Masini E. Mol. Cancer Ther. 2006; 5: 2716
  PubMedSearch in Google Scholar
• 3a Fang X.-L, Tang R.-Y, Zhong P, Li J.-H. Synthesis 2009; 4183
• 3b Zhang S, Qian P, Zhang M, Hu M, Cheng J. J. Org. Chem. 2010; 75: 6732
  PubMedSearch in Google Scholar
• 3c Ge W, Wei Y. Synthesis 2012; 934
• 3d Ge W, Wei Y. Green Chem. 2012; 14: 2066
  CrossrefSearch in Google Scholar
• 3e Browder CC, Mitchell MO, Smith RL, el-Stdayman G. Tetrahedron. Lett. 1993; 34: 6245
  Search in Google Scholar
• 3f Sang P, Chen Z, Zou J, Zhang Y. Green Chem. 2013; 15: 2096
  CrossrefSearch in Google Scholar
• 3g Huang D, Chen J, Dan W, Ding J, Liu M, Wu H. Adv. Synth. Catal. 2012; 354: 2123
  CrossrefSearch in Google Scholar
• 3h Dong D.-Q, Hao S.-H, Yang D.-S, Li L.-X, Wang Z.-L. Eur. J. Org. Chem. 2017; 6576
• 3i Zhang H, Wang H, Jiang Y, Cao F, Gao W, Zhu L, Yang Y, Wang X, Wang Y, Chen J, Feng Y, Deng X, Lu Y, Hu X, Li X, Zhang J, Shi T, Wang Z. Chem. Eur. J. 2020; 26: 17289
  CrossrefPubMedSearch in Google Scholar
• 4a Yang F.-L, Tian S.-K. Angew. Chem. Int. Ed. 2013; 52: 4929
  CrossrefPubMedSearch in Google Scholar
• 4b Kang X, Yan R, Yu G, Pang X, Liu X, Xiang L, Huang G. J. Org. Chem. 2014; 79: 10605
  CrossrefPubMedSearch in Google Scholar
• 4c Xiao F, Xie H, Liu S, Deng G.-J. Adv. Synth. Catal. 2014; 356: 364
  CrossrefSearch in Google Scholar
• 5 Kumaraswamy G, Raju R, Narayanarao V. RSC Adv. 2015; 5: 22718
  CrossrefPubMedSearch in Google Scholar
• 6 Chen M, Huang Z.-T, Zheng Q.-Y. Chem. Commun. 2012; 48: 11686
  CrossrefPubMedSearch in Google Scholar
• 7 Saima, Equbal D, Lavekar AG, Sinha AK. Org. Biomol. Chem. 2016; 14: 6111
  PubMedSearch in Google Scholar
• 8 Ghosh A, Lecomte M, Kim-Lee S.-H, Radosevich AT. Angew. Chem. Int. Ed. 2019; 58: 2864
  CrossrefPubMedSearch in Google Scholar
• 9 Pandey AK, Chand S, Singh R, Kumar S, Singh KN. ACS Omega 2020; 5: 7627
  CrossrefPubMedSearch in Google Scholar
• 10a Yamashiro T, Abe T, Tanioka M, Kamino S, Sawada D. Chem. Commun. 2021; 57: 13381
  Search in Google Scholar
• 10b Hostier T, Ferey V, Ricci G, Pardo DG, Cossy J. Chem. Commun. 2015; 51: 13898
  CrossrefPubMedSearch in Google Scholar
• 11 Dodds AC, Sutherland A. J. Org. Chem. 2021; 86: 5922
  CrossrefPubMedSearch in Google Scholar
• 12 Zou C, Wu H, He J, Hu Y, Deng W, Li X, Hu J, Li Y, Huang Y. J. Org. Chem. 2022; 87: 1335
  PubMedSearch in Google Scholar
• 13 Mitsudo K, Habara N, Kobashi Y, Kurimoto Y, Mandai H, Suga S. Synlett 2020; 31: 1947
  Search in Google Scholar

Corresponding Author

Publication History

Received: 21 February 2025

Accepted after revision: 09 April 2025

Accepted Manuscript online:
09 April 2025

Article published online:
12 May 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• References

• 1a La Regina G, Edler MC, Brancale A, Kandil S, Coluccia A, Piscitelli F, Prosperi E, Lavecchia A, Novellino E, Artico M, Silvestri R. J. Med. Chem. 2007; 50: 2865
  PubMedSearch in Google Scholar
• 1b Unangst PC, Connor DT, Stabler SR, Weikert RJ, Carethers ME, Kennedy JA, Thueson D, Chestnut JC, Adolphson RL, Conroy MC. J. Med. Chem. 1989; 32: 1360
  CrossrefPubMedSearch in Google Scholar
• 2a Silvestri R, De Martino G, La Regina G, Artico M, Massa S, Vargiu L, Mura M, Loi AG, Marceddu T, La Colla P. J. Med. Chem. 2003; 46: 2482
  CrossrefPubMedSearch in Google Scholar
• 2b Ragno R, Coluccia A, La Regina G, De Martino G, Piscitelli F, Lavecchia A, Novellino E, Bergamini A, Ciaprini C, Sinistro A, Maga G, Crespan E, Artico M, Silvestri R. J. Med. Chem. 2006; 49: 3172
  PubMedSearch in Google Scholar
• 2c Ragno R, Artico M, De Martino G, La Regina G, Coluccia A, Di Pasquali A, Silvestri R. J. Med. Chem. 2005; 48: 213
  PubMedSearch in Google Scholar
• 2d De Martino G, Edler MC, La Regina G, Coluccia A, Barbera MC, Barrow D, Nicholson RI, Chiosis G, Brancale A, Hamel E, Artico M, Silvestri R. J. Med. Chem. 2006; 49: 947
  CrossrefPubMedSearch in Google Scholar
• 2e De Martino G, La Regina G, Coluccia A, Edler MC, Barbera MC, Brancale A, Wilcox E, Hamel E, Artico M, Silvestri R. J. Med. Chem. 2004; 47: 6120
  CrossrefPubMedSearch in Google Scholar
• 2f La Regina G, Bai R, Rensen W, Coluccia A, Piscitelli F, Gatti V, Bolognesi A, Lavecchia A, Granata I, Porta A, Maresca B, Soriani A, Iannitto ML, Mariani M, Santoni A, Brancale A, Ferlini C, Dondio G, Varasi M, Mercurio C, Hamel E, Lavia P, Novellino E, Silvestri R. J. Med. Chem. 2011; 54: 8394
  PubMedSearch in Google Scholar
• 2g Luker T, Bonnert R, Brough S, Cook AR, Dickinson MR, Dougall I, Logan C, Mohammeda RT, Paine S, Sanganee HJ, Sargent C, Schmidt JA, Teague S, Thom S. Bioorg. Med. Chem. Lett. 2011; 21: 6288
  PubMedSearch in Google Scholar
• 2h Funk CD. Nat. Rev. Drug Discovery 2005; 4: 664
  PubMedSearch in Google Scholar
• 2i Cianchi F, Cortesini C, Magnelli L, Fanti E, Papucci L, Schiavone N, Messerini L, Vannacci A, Capaccioli S, Perna F, Lulli M, Fabbroni V, Perigli G, Bechi P, Masini E. Mol. Cancer Ther. 2006; 5: 2716
  PubMedSearch in Google Scholar
• 3a Fang X.-L, Tang R.-Y, Zhong P, Li J.-H. Synthesis 2009; 4183
• 3b Zhang S, Qian P, Zhang M, Hu M, Cheng J. J. Org. Chem. 2010; 75: 6732
  PubMedSearch in Google Scholar
• 3c Ge W, Wei Y. Synthesis 2012; 934
• 3d Ge W, Wei Y. Green Chem. 2012; 14: 2066
  CrossrefSearch in Google Scholar
• 3e Browder CC, Mitchell MO, Smith RL, el-Stdayman G. Tetrahedron. Lett. 1993; 34: 6245
  Search in Google Scholar
• 3f Sang P, Chen Z, Zou J, Zhang Y. Green Chem. 2013; 15: 2096
  CrossrefSearch in Google Scholar
• 3g Huang D, Chen J, Dan W, Ding J, Liu M, Wu H. Adv. Synth. Catal. 2012; 354: 2123
  CrossrefSearch in Google Scholar
• 3h Dong D.-Q, Hao S.-H, Yang D.-S, Li L.-X, Wang Z.-L. Eur. J. Org. Chem. 2017; 6576
• 3i Zhang H, Wang H, Jiang Y, Cao F, Gao W, Zhu L, Yang Y, Wang X, Wang Y, Chen J, Feng Y, Deng X, Lu Y, Hu X, Li X, Zhang J, Shi T, Wang Z. Chem. Eur. J. 2020; 26: 17289
  CrossrefPubMedSearch in Google Scholar
• 4a Yang F.-L, Tian S.-K. Angew. Chem. Int. Ed. 2013; 52: 4929
  CrossrefPubMedSearch in Google Scholar
• 4b Kang X, Yan R, Yu G, Pang X, Liu X, Xiang L, Huang G. J. Org. Chem. 2014; 79: 10605
  CrossrefPubMedSearch in Google Scholar
• 4c Xiao F, Xie H, Liu S, Deng G.-J. Adv. Synth. Catal. 2014; 356: 364
  CrossrefSearch in Google Scholar
• 5 Kumaraswamy G, Raju R, Narayanarao V. RSC Adv. 2015; 5: 22718
  CrossrefPubMedSearch in Google Scholar
• 6 Chen M, Huang Z.-T, Zheng Q.-Y. Chem. Commun. 2012; 48: 11686
  CrossrefPubMedSearch in Google Scholar
• 7 Saima, Equbal D, Lavekar AG, Sinha AK. Org. Biomol. Chem. 2016; 14: 6111
  PubMedSearch in Google Scholar
• 8 Ghosh A, Lecomte M, Kim-Lee S.-H, Radosevich AT. Angew. Chem. Int. Ed. 2019; 58: 2864
  CrossrefPubMedSearch in Google Scholar
• 9 Pandey AK, Chand S, Singh R, Kumar S, Singh KN. ACS Omega 2020; 5: 7627
  CrossrefPubMedSearch in Google Scholar
• 10a Yamashiro T, Abe T, Tanioka M, Kamino S, Sawada D. Chem. Commun. 2021; 57: 13381
  Search in Google Scholar
• 10b Hostier T, Ferey V, Ricci G, Pardo DG, Cossy J. Chem. Commun. 2015; 51: 13898
  CrossrefPubMedSearch in Google Scholar
• 11 Dodds AC, Sutherland A. J. Org. Chem. 2021; 86: 5922
  CrossrefPubMedSearch in Google Scholar
• 12 Zou C, Wu H, He J, Hu Y, Deng W, Li X, Hu J, Li Y, Huang Y. J. Org. Chem. 2022; 87: 1335
  PubMedSearch in Google Scholar
• 13 Mitsudo K, Habara N, Kobashi Y, Kurimoto Y, Mandai H, Suga S. Synlett 2020; 31: 1947
  Search in Google Scholar

• Supplementary Material