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Article

tert-Butyl Hypochlorite: A Reagent for the Synthesis of Chlorinated Oxindole and Indole Derivatives

by
Chun-Yan Liu
1,2,
Xia Chen
2,*,
Hai-Long Liu
2,
Nan Wang
1,2 and
Xiao-Yu Zhou
1,2,*
1
College of Environmental and Chemical Engineering, Dalian University, Dalian 116622, China
2
School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui 553004, China
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(1), 102; https://doi.org/10.3390/molecules30010102
Submission received: 6 December 2024 / Revised: 27 December 2024 / Accepted: 28 December 2024 / Published: 30 December 2024
(This article belongs to the Special Issue Recent Advances in Domino Reactions)
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Versions Notes

Abstract

:
tert-Butyl hypochlorite was employed as a versatile reagent for chlorooxidation of indoles, chlorination of 2-oxindoles, and decarboxylative chlorination of the indole-2-carboxylic acids. Four types of products including 2-chloro-3-oxindoles, 2,2-dichloro-3-oxindoles, 3,3-dichloro-2-oxindoles, and 2,3-dichloroindoles could be selectively obtained in moderate to excellent yields by switching the substrates. Various synthetically useful functional groups, such as halogen atoms, cyano, nitro, and methoxycarbonyl groups, remain intact during the reactions. Notable features of the approach include the universality of the starting materials, the mild reaction conditions, and the experimental simplicity.

1. Introduction

The oxindole moiety is central in a series of structurally diverse natural and man-made alkaloid products, many of which display attractive profiles for biological and pharmaceutical applications [1,2,3,4]. Chlorine-containing oxindoles are among the most prominent oxindole derivatives, owing in part to their frequent occurrence in biologically active molecules and broad application in the preparation of high-value heterocyclic molecules [5,6,7,8,9,10] (Figure 1). For example, the 3,3-dichlorooxindole scaffolds existed in caspase inhibitor, anticancer reagent, and fungicide, and 2-(2,2-dichloro-3-oxoindolin-1-yl)-3H-indol-3-one was a synthetic intermediate for the alkaloid tryptanthrin. Despite the significance of chlorine-containing oxindoles, reports on the synthesis of these compounds are still limited.
Conventional methods to access 3-oxindoles heavily rely on the transition metal (TM)-catalyzed tandem cyclization of complicated substrates [11,12,13,14,15,16,17,18]; moreover, these starting materials always require multi-step synthesis. Another approach is based on the oxidation of their aromatic precursors, indoles, by using oxodiperoxo molybdenum complexes [19], meta-chloroperoxybenzoic acid (mCPBA) [20], dimethyl dioxirane [21,22], manganese dioxide (MnO2) [23], hypervalent iodine [24], sodium periodate (NaIO4) [25] as oxidizing reagents, which represents a straightforward and practical route to obtain 2-substituted 3-oxindoles. However, the oxidation selectivity of the electron-rich indoles was still an issue, which required the installation of electron-withdrawing protective groups. Indeed, the processes always involved narrow substrate scope and low yields, and were difficult to accommodate 2-chloro-3-oxindoles preparation. As a result, it is urgent to develop convenient methods for the synthesis of 2-chloro-3-oxindoles.
For the synthesis of 2-oxindoles, the main approach is based on the cyclization of N-phenyl acrylamides [26,27,28,29]. However, the strategy is associated with drawbacks such as the requirement of expensive metals and ligands, high temperatures, and toxic radical initiators. 3,3-Dichloro-2-oxindole scaffolds widely existed in a large number of biologically active compounds, with anti-diabetic, anti-cancer, and other pharmacological activities [5,30,31,32]. Accordingly, numerous chlorination methods have been successively developed to prepare 3,3-dichloro-2-oxindoles from isatins with diverse chlorine sources, such as PCl5 [33], SO2Cl2 [34], ClSO3H [35], and WCl6 [36] (Scheme 1a). Moreover, indole-2-carboxylic acids [37,38] and indole-2,3-dicarboxylic acids [39,40] can be converted into the corresponding 3,3-dichloro-2-oxindole, respectively (Scheme 1b). Great efforts also have been devoted to developing a direct synthesis of 3,3-dichloro-2-oxindoles through chlorooxidation reaction of indoles with chlorine azide (ClN3) [41], NaCl/Oxone (2KHSO5∙KHSO4∙K2SO4) [42], sulfuryl chlorofluoride (SO2ClF) [43], and hypervalent iodine [24,44] (Scheme 1c). Although the synthesis of various 3,3-dichloro-2-oxindoles can be achieved with the use of the methods mentioned above, the use of inexpensive, and easy-to-handle feedstocks to access 3,3-dichloro-2-oxindoles is still desirable.
tert-Butyl hypochlorite (tBuOCl), a commercially available oxidating and chlorinating reagent, has been applied to various transformations like chlorination of secondary alcohols [45] and aliphatic amides [46], addition of terminal alkynes [47], and chlorooxidation of unsaturated hydrocarbons [48] and S-alkylisothiourea salts [49]. The regioselective oxidation of indoles and subsequent chlorination to construct chlorine-containing oxindoles is undoubtedly a powerful synthetic strategy because of atom economy and convenience. Herein, we would show that tBuOCl could serve as both an oxidizing reagent and chlorinating source for the controllable functionalization of protected and unprotected indoles (Scheme 2a).

2. Results

In our initial studies, ethyl 1H-indole-2-carboxylate (1a) was examined as the model substrate for chlorooxidation reaction with tBuOCl (3.0 equiv.) under an air atmosphere at 60 °C for 20 h (Table 1). Ethyl 2-chloro-3-oxoindoline-2-carboxylate (2a) was observed in 77% yield when using tetrahydrofuran (THF) as solvent (entry 1). Among the examined solvents [THF, ethyl acetate (EtOAc), 1,4-dioxane, acetonitrile (CH3CN), and toluene], EtOAc proved to be the best solvent (entries 1–5). Increased yield (99%) was observed when the loading of tBuOCl was reduced to 2.5 equivalents, while decreased yields (85% and 56%) were observed when the loading was further reduced to 2.0 and 1.5 equivalent, respectively (entries 6–8 vs. entry 2). The results obtained from the experiments of temperature screening indicated that 40 °C was the best reaction temperature (entries 6 and 9–11). Almost a quantitative yield was also obtained even though the reaction time was shortened to 16 h from 20 h (entry 12 vs. entry 10), suggesting that the target reaction could be accomplished within 16 h. Therefore, the subsequent chlorooxidation reaction of various indoles with tBuOCl (2.5 equiv.) was performed in EtOAc at 40 °C for 16 h.
With the optimized reaction conditions in hand, the scope and limitation of this reaction were explored, and the results are shown in Scheme 3. Reactions of indole substrates 1 bearing ethoxycarbonyl (-COOEt), methoxycarbonyl (-COOMe), and aryl linked on the pyrrole ring were investigated under the optimized reaction conditions. The desired products 2a–2e were obtained in excellent yields (91%–>99%). The 1-ethyl-2-phenyl-1H-indole (1f) was employed in the reaction. The desired product 2f was obtained in 65% yield, and the remaining starting material was decomposed. Notably, the reactions of indoles 1g and 1h, containing a -COOMe linked on the benzene ring, proceeded to afford the 2,2-dichloro-3-oxindole products 3g and 3h in 50% and 64% yields, respectively. That is, the absence of groups at the C2-position of indole would result in 2,2-dichloro-3-oxindole products. Reactions of indole substrates 1 bearing cyano (-CN) and nitro (-NO2) were subsequently investigated under the optimized reaction conditions. The desired products 3i and 3j were obtained in 76% and 68% yields. The suitability of indole substrates 1k–1m with halogen atoms (-F, -Cl, and -I) in the current reaction was also investigated, and moderate yields (70–73%) of the desired products 3k–3m were obtained. The functional groups, such as halogen atoms (-Cl and -I), -COOMe, -NO2, and -CN remained intact during the chlorooxidation reaction of indoles, suggesting that further manipulation may produce additional useful compounds. The N-methyl substituted indoles 1n and 1o were also employed in the reaction. The desired products 3n and 3o were obtained in 64% and 56% yields, respectively. Moreover, N-phenyl indole (1p) reacted successfully and exhibited reactivity that was similar to N-Me indole. A low yield was obtained when 1H-pyrrolo[2,3-b]pyridine (1q) was examined, and the remaining starting material was decomposed. However, the electron-donating groups, such as methyl (Me) and methoxyl (MeO), linked on the benzene ring in substrate 1 would severely hamper the chlorooxidation reaction. Only trace amounts of the desired products 3r and 3s were obtained, and most of the starting materials were decomposed. The reason behind this may be that an indole with an electron-donor group easily undergoes an oxidation reaction, leading to the decomposition of the starting materials.
Given that tBuOCl is a readily available and controllable chlorinating source, exploring its new applications is still interesting. Herein, we would further show that tBuOCl could serve as a chlorinating reagent for the functionalization of 2-oxindoles, and 3,3-dichloro-2-oxindoles were selectively formed (Scheme 2c). At the outset, we chose the simple unprotected 2-oxindole (4a) as the model substrate to investigate the reactivity of tBuOCl under the above-mentioned conditions (in EtOAc at 40 °C). The reaction parameters, including the loading of tBuOCl, temperature, and reaction time, were screened (for details, see Table S1). The substrate scope of the 2-oxindoles was investigated under optimized reaction conditions: tBuOCl (4.0 equiv.) in EtOAc (3.0 mL) at 60 °C for 16 h. The results are shown in Scheme 4.
Reactions of 2-oxindole and its derivatives bearing bromine (-Br), trifluoromethyl (-CF3), or -NO2 on the benzene ring proceeded smoothly to afford the target products 5a–5d; except for 5d (70%), good to excellent yields (86%–>99%) of the desired products were obtained. The N-phenyl substituted 2-oxindoles (4e) was employed in the reaction. The desired product 5e was obtained in a 49% yield, and the starting material was recovered. The reaction of 5-methylindolin-2-one (4f) was also examined, but only trace amounts of the desired product 5f were detected.
Reactions of indole-2-carboxylic acid derivatives 6a–6d were performed to further expand the substrate scope (Scheme 5). Interestingly, the corresponding decarboxylative chlorination products 7a–7d were obtained instead of the 2-chloro-3-oxindoles. Except for 7d, moderate yields (43%–>52%) of the products were obtained, and the remaining starting materials were decomposed. The 1-methylindole-2-carboxylic acid (6e) was also examined in the reaction. No desired product was observed, and most of the starting materials were recovered. Notably, 2,3-dichloroindoles are also prominent due to their broad application in the preparation of high-value heterocyclic molecules.
The reactions with different free radical trapping reagents, including 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), butylated hydroxytoluene (BHT), and 1,1-diphenylethylene (DPE) were performed to gain insights into the reaction pathway (Scheme 6(1),(2),(4)). Almost completely inhibited reactions were attained, clearly indicating that the chlorooxidation of indoles and the chlorination of 2-oxindoles possibly proceeded via a radical pathway. Moreover, ethyl 3-chloro-indole-2-carboxylate (8) was isolated in a 76% yield when 1a was treated in the presence of tBuOCl and TEMPO. The reason behind this may be that tBuOCl could provide Cl+ as an electrophilic reagent and undergo an electrophilic substitution reaction with 1a. On the other hand, the final product 2a was obtained in 89% yield almost as a sole product in the dry CH3CN under a N2 atmosphere, suggesting that the oxygen source in 2a possibly came from tBuOCl, rather than H2O and air (Scheme 6(3)).
On the basis of our experimental outcomes, a plausible reaction mechanism for the chlorooxidation of indoles is depicted in Scheme 7. The homolytic cleavage of the O–Cl bond of tBuOCl occurred and produced chlorine and oxygen radicals, which would react with 1 to provide the adduct A. The subsequent elimination reaction of A generated intermediate B. Acetal C was formed through the radical addition reaction of B with another tBuOCl. Elimination reaction of C would occur to furnish the desired product 2. 2-Chloro-3-oxindole and 2-oxindole, in the presence of α-H of ketone, further underwent radical chlorination to generate 2,2-dichloro-3-oxindoles (3) and 3,3-dichloro-2-oxindoles (5).

3. Conclusions

In summary, we have disclosed that tBuOCl plays a dual role as an oxidizing reagent and chlorinating source for the chlorooxidation of indoles and chlorination of 2-oxindoles. This approach enables access to various 2-chloro-3-oxindoles, 2,2-dichloro-3-oxindoles, and 3,3-dichloro-2-oxindoles in a controllable manner by choosing different substrates. The decarboxylative chlorination of indole-2-carboxylic acids with tBuOCl also proceeded smoothly to produce 2,3-dichloroindoles in moderate yields. Different groups, including synthetically useful functional groups -F, -Cl, -Br, -CO2Me, -CN, and -NO2 are well tolerated under the reactions. The mild conditions, simplicity, and universality of the starting materials and the experimental simplicity make the present methodology highly useful in the synthesis of chlorinated oxindoles and indoles.

4. Materials and Methods

4.1. General Information

Unless otherwise noted, all reactions were carried out in oven-dried 25 mL Schlenk tubes under an air atmosphere. IKA plate was used as the heat source. All reagents and solvents were of pure analytical grade. Thin layer chromatography (TLC) was performed on HSGF254 silica gel, pre-coated on glass-backed plates coated with 0.2 mm silica and revealed with either a UV lamp (λmax = 254 nm). The products were purified by flash column chromatography on silica gel 200–300 mesh. 1H, 13C, and 19F NMR spectra were recorded on a Bruker Avance NEO 600M NMR Spectrometer (600 MHz for 1H, 151 MHz for 13C, 565 MHz for 19F), a Bruker Avance III HD 500M NMR Spectrometer (500 MHz for 1H, 126 MHz for 13C, 471 MHz for 19F), using CDCl3 or d6-DMSO as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. The chemical shifts are reported in ppm downfield (δ) from TMS, and the coupling constants J are given in Hz. The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High-resolution mass spectra were recorded on either a Q-TOF mass spectrometry or an LTQ Orbitrap XL mass spectrometry. Unless otherwise noted, starting materials are commercially available. Unless otherwise noted, starting materials are commercially available.

4.2. Synthetic Procedures

4.2.1. The Typical Procedure for Chlorooxidation of Indoles with tBuOCl

To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, indole substrate 1 (0.5 mmol, 1.0 equiv.), tBuOCl (1.25 mmol, 2.5 equiv.) or tBuOCl (2.0 mmol, 4.0 equiv.), and EtOAc (3.0 mL) were added and sealed under an air atmosphere. The reaction mixture was stirred at 40 °C for 16 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford the desired product 2 or 3.
ethyl 2-chloro-3-oxoindoline-2-carboxylate (2a): Yield: 99%, 118.6 mg, white solid, mp 121–123 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (600 MHz, CDCl3) δ 9.28 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.38–7.35 (m, 1H), 7.15–7.12 (m, 1H), 7.03 (d, J = 7.8 Hz, 1H), 4.35–4.23 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.4, 165.0, 140.9, 131.4, 127.0, 125.0, 123.8, 111.2, 64.7, 63.8, 13.9. HRMS (ESI) m/z: [M+H]+ Calcd for C11H11ClNO3+ 240.0422; Found 240.0425.
methyl 2-chloro-3-oxoindoline-2-carboxylate (2b): Yield: 91%, 102.6 mg, white solid, mp 117–119 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (600 MHz, CDCl3) δ 9.31 (brs, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.39–7.36 (m, 1H), 7.15–7.13 (m, 1H), 7.03 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.3, 165.6, 140.9, 131.5, 126.8, 125.1, 123.9, 111.3, 64.6, 54.4. HRMS (ESI) m/z: [M+H]+ Calcd for C10H9ClNO3+ 226.0265; Found 226.0267.
2-chloro-2-phenylindolin-3-one (2c): Yield: >99%, 121.0 mg, yellow solid, mp 130–132 °C, purified using petroleum ether/ethyl acetate (10:1~5:1). 1H NMR (600 MHz, CDCl3) δ 8.53–8.45 (m, 2H), 7.76 (d, J = 7.4 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.62–7.56 (m, 3H), 7.51–7.49 (m, 1H), 7.43–7.38 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.9, 149.3, 139.8, 132.1, 131.6, 129.5, 128.7, 128.6, 127.9, 122.7, 121.6, 80.2. HRMS (ESI) m/z: [M+H]+ Calcd for C14H11ClNO+ 244.0524; Found 244.0526.
2-chloro-2-(4-fluorophenyl)indolin-3-one (2d): Yield: >99%, 130.5 mg, yellow solid, mp 123–125 °C, purified using petroleum ether/ethyl acetate (10:1~5:1). 1H NMR (600 MHz, CDCl3) δ 8.50–8.47 (m, 2H), 7.75 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.51–7.48 (m, 1H), 7.43–7.37 (m, 1H), 7.28–7.21 (m, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 170.8, 165.1 (d, JC-F = 254.9 Hz), 149.2, 139.7, 131.8 (d, JC-F = 8.7 Hz), 131.6, 127.9, 124.9 (d, JC-F = 3.2 Hz), 122.8, 121.5, 115.9 (d, JC-F = 22.1 Hz), 80.1. 19F NMR (565 MHz, CDCl3) δ -106.2 (s, 1F). HRMS (ESI) m/z: [M+H]+ Calcd for C14H10ClFNO+ 262.0429; Found 262.0431.
ethyl 2,4-dichloro-5-methoxy-3-oxoindoline-2-carboxylate (2e): Yield: 93%, 142.1 mg, white solid, mp 130–132 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (600 MHz, CDCl3) δ 9.17 (1H), 6.95–6.91 (m, 2H), 4.38–4.28 (m, 2H), 3.91 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.3, 163.4, 152.0, 134.9, 126.9, 121.2, 113.9, 109.6, 65.8, 64.1, 56.8, 14.0. HRMS (ESI) m/z: [M+H]+ Calcd for C12H12Cl2NO4+ 304.0138; Found 304.0141.
2-chloro-1-ethyl-2-phenylindolin-3-one (2f): Yield: 65%, 88.6 mg, white solid, mp 90–92 °C, purified using petroleum ether. 1H NMR (500 MHz, CDCl3) δ 7.65–7.53 (m, 5H), 7.53–7.44 (m, 3H), 7.27 (d, J = 1.9 Hz, 1H), 4.45 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 139.4, 130.6, 129.6, 129.4, 129.31, 129.26, 128.7, 126.0, 124.5, 117.5, 116.8, 104.6, 41.0, 17.1. HRMS (ESI) m/z: [M+H]+ Calcd for C16H15ClNO+ 272.0837; Found 272.0841.
methyl 2,2-dichloro-3-oxoindoline-6-carboxylate (3g): Yield: 50%, 65.6 mg, white solid, mp 178–180 °C, purified using petroleum ether/ethyl acetate (2:1). 1H NMR (500 MHz, d6-DMSO) δ 11.56 (s, 1H), 7.90–7.68 (m, 2H), 7.44 (s, 1H), 3.87 (s, 3H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.2, 165.6, 140.0, 133.5, 125.6, 125.2, 111.8, 74.6, 53.1. HRMS (ESI) m/z: [M+H]+ Calcd for C10H8Cl2NO3+ 259.9876; Found 259.9878.
methyl 2,2-dichloro-3-oxoindoline-4-carboxylate (3h): Yield: 64%, 82.7 mg, light yellow solid, mp 136–138 °C, purified using petroleum ether/ethyl acetate (2:1). 1H NMR (500 MHz, d6-DMSO) δ 11.55 (s, 1H), 7.89–7.58 (m, 2H), 7.25–7.23 (m, 1H), 3.92 (s, 3H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.6, 164.6, 141.2, 133.2, 128.0, 127.6, 125.3, 116.1, 75.3, 52.8. HRMS (ESI) m/z: [M+H]+ Calcd for C10H8Cl2NO3+ 259.9876; Found 259.9877.
2,2-dichloro-3-oxoindoline-5-carbonitrile (3i): Yield: 76%, 86.7 mg, brown solid, mp 212–214 °C, purified using petroleum ether/ethyl acetate (2:1). 1H NMR (500 MHz, d6-DMSO) δ 11.86 (s, 1H), 8.24 (s, 1H), 7.86 (d, J = 4.9 Hz, 1H), 7.13 (d, J = 5.5 Hz, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.4, 143.8, 137.7, 130.2, 129.3, 118.6, 112.8, 106.4, 73.9. HRMS (ESI) m/z: [M+H]+ Calcd for C9H5Cl2N2O+ 226.9773; Found 226.9772.
2,2-dichloro-5-nitroindolin-3-one (3j): Yield: 68%, 84.2 mg, yellow solid, mp 154–156 °C, purified using petroleum ether/ethyl acetate (2:1). 1H NMR (500 MHz, d6-DMSO) δ 12.04 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 7.17 (s, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.7, 145.6, 143.8, 129.8, 129.3, 120.9, 112.5, 73.8. HRMS (ESI) m/z: [M+H]+ Calcd for C8H5Cl2N2O3+ 246.9672; Found 246.9675.
2,2-dichloro-5-fluoroindolin-3-one (3k): Yield: 73%, 80.3 mg, white solid, mp 156–158 °C, purified using petroleum ether/ethyl acetate (10:1~5:1). 1H NMR (500 MHz, CDCl3) δ 9.54 (s, 1H), 7.37 (dd, J = 7.2, 2.5 Hz, 1H), 7.14–7.10 (m, 1H), 7.03 (dd, J = 8.6, 4.1 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 171.45, 159.7 (d, JC-F = 244.9 Hz), 133.9 (d, JC-F = 2.3 Hz), 130.8 (d, JC-F = 8.6 Hz), 118.9 (d, JC-F = 23.8 Hz), 112.8 (d, JC-F = 29.1 Hz), 112.7 (d, JC-F = 4.6 Hz), 74.3. 19F NMR (471 MHz, CDCl3) δ -116.8 (s, 1F). HRMS (ESI) m/z: [M+H]+ Calcd for C8H5Cl2FNO+ 219.9727; Found 219.9730.
2,2,5,6-tetrachloroindolin-3-one (3l): Yield: 73%, 98.5 mg, yellow solid, mp 200–202 °C, purified using petroleum ether/ethyl acetate (10:1~5:1). 1H NMR (500 MHz, d6-DMSO) δ 11.64 (s, 1H), 8.04 (s, 1H), 7.20 (s, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.2, 139.6, 135.3, 129.5, 127.3, 126.2, 113.7, 74.1. HRMS (ESI) m/z: [M+H]+ Calcd for C8H4Cl4NO+ 269.9042; Found 269.9041.
2,2-dichloro-5-iodoindolin-3-one (3m): Yield: 70%, 114.9 mg, yellow solid, mp 230–232 °C, purified using petroleum ether/ethyl acetate (10:1~5:1). 1H NMR (500 MHz, d6-DMSO) δ 11.46 (s, 1H), 7.97 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.0, 141.4, 139.3, 133.4, 131.4, 114.1, 86.6, 74.6. HRMS (ESI) m/z: [M+H]+ Calcd for C8H5Cl2INO+ 327.8787; Found 327.8789.
2,2-dichloro-1-methyl-5-nitroindolin-3-one (3n): Yield: 64%, 83.0 mg, yellow solid, mp 184–186 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H), 8.40–8.35 (m, 1H), 7.06 (d, J = 8.7 Hz, 1H), 3.38 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 168.7, 146.0, 144.4, 129.9, 128.4, 120.9, 109.4, 72.4, 27.6. HRMS (ESI) m/z: [M+H]+ Calcd for C9H7Cl2N2O3+ 260.9828; Found 260.9827.
2,2-dichloro-1-methylindolin-3-one (3o): Yield: 56%, 60.3 mg, white solid, mp 76–78 °C, purified using petroleum ether/ethyl acetate (10:1). 1H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 7.2 Hz, 1H), 7.45–7.42 (m, 1H), 7.23–7.20 (m, 1H), 6.89 (d, J = 7.9 Hz, 1H), 3.30 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.0, 140.7, 131.9, 129.3, 124.8, 124.3, 109.2, 74.3, 27.1. HRMS (ESI) m/z: [M+H]+ Calcd for C9H8Cl2NO+ 215.9977; Found 215.9978.
2,2-dichloro-1-phenylindolin-3-one (3p): Yield: 46%, 64.2 mg, white solid, mp 86–88 °C, purified using petroleum ether/ethyl acetate (10:1). 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 7.6 Hz, 1H), 7.60–7.57 (m, 2H), 7.5 –7.45 (m, 3H), 7.38–7.35 (m, 1H), 7.29–7.24 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.1, 140.8, 133.0, 131.8, 129.8, 129.0, 128.9, 126.3, 125.1, 124.6, 110.3, 74.5. HRMS (ESI) m/z: [M+H]+ Calcd for C14H10Cl2NO+ 278.0134; Found 278.0136.
2,2-dichloro-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-one (3q): Yield: 20%, 20.8 mg, white solid, mp 160–162 °C, purified using petroleum ether/ethyl acetate (2:1). 1H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 8.35 (d, J = 4.2 Hz, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.21–7.18 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 168.8, 153.3, 149.5, 133.8, 125.0, 119.8, 73.1. HRMS (ESI) m/z: [M+H]+ Calcd for C7H5Cl2N2O+ 202.9773; Found 202.9776.

4.2.2. The Typical Procedure for Chlorination of 2-Oxindoles with tBuOCl

To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, indole substrate 4 (0.5 mmol, 1.0 equiv.), tBuOCl (2.0 mmol, 4.0 equiv.), and EtOAc (3.0 mL) were added and sealed under an air atmosphere. The reaction mixture was stirred at 60 °C for 24 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford the desired product 5.
3,3-dichloroindolin-2-one (5a): Yield: 86%, 87.3 mg, white solid, mp 176–178 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (500 MHz, d6-DMSO) δ 11.47 (s, 1H), 7.74 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.3, 138.5, 132.8, 130.9, 128.0, 125.3, 113.4, 74.8. HRMS (ESI) m/z: [M+H]+ Calcd for C8H6Cl2NO+ 201.9821; Found 201.9822.
5-bromo-3,3-dichloroindolin-2-one (5b): Yield: >99%, 140.1 mg, white solid, mp 198–200 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (500 MHz, d6-DMSO) δ 11.49 (s, 1H), 7.87 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.2, 138.9, 135.6, 131.2, 128.0, 115.4, 113.9, 74.7. HRMS (ESI) m/z: [M+H]+ Calcd for C8H5BrCl2NO+ 279.8926; Found 279.8925.
3,3-dichloro-6-(trifluoromethyl)indolin-2-one (5c): Yield: 97%, 131.4 mg, white solid, mp 156–158 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (500 MHz, d6-DMSO) δ 11.73 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.2, 140.6, 133.1, 132.7 (q, JC-F = 30.2 Hz), 126.3, 123.8 (q, JC-F = 273.4 Hz), 121.0 (q, JC-F = 3.9 Hz), 108.4 (q, JC-F = 4.0 Hz), 74.2. 19F NMR (471 MHz, d6-DMSO) δ -61.8 (s, 3F). HRMS (ESI) m/z: [M+H]+ Calcd for C9H5Cl2F3NO+ 269.9695; Found 269.9693.
3,3-dichloro-5-nitroindolin-2-one (5d): Yield: 70%, 86.5 mg, yellow solid, mp 172–174 °C, purified using petroleum ether/ethyl acetate (5:1). 1H NMR (500 MHz, d6-DMSO) δ 12.04 (s, 1H), 8.45 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H). 13C{1H} NMR (126 MHz, d6-DMSO) δ 169.7, 145.6, 143.8, 129.8, 129.4, 121.0, 112.5, 73.8. HRMS (ESI) m/z: [M+H]+ Calcd for C8H5Cl2N2O3+ 246.9672; Found 246.9673.
3,3-dichloro-1-phenylindolin-2-one (5e): Yield: 49%, 67.5 mg, yellow oil, purified using petroleum ether/ethyl acetate (10:1). 1H NMR (500 MHz, CDCl3) δ 7.78–7.69 (m, 1H), 7.60–7.57 (m, 2H), 7.52–7.44 (m, 3H), 7.39–7.31 (m, 1H), 7.26–7.23 (m, 1H), 6.82 (dd, J = 26.8, 8.2 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 168.1, 131.8, 130.1, 129.9, 129.2, 129.0, 126.4, 126.3, 125.5, 125.2, 124.7, 111.6, 110.4, 74.6. HRMS (ESI) m/z: [M+H]+ Calcd for C14H10Cl2NO+ 278.0134; Found 278.0135.

4.2.3. The Typical Procedure for Decarboxylative Chlorination of Indole-2-Carboxylic Acids

To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, indole-2-carboxylic acid substrate 6 (0.5 mmol, 1.0 equiv.), tBuOCl (1.5 mmol, 3.0 equiv.), and EtOAc (3.0 mL) were added and sealed under an air atmosphere. The reaction mixture was stirred at 60 °C for 24 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford the desired product 7.
2,3-dichloro-5-fluoro-1H-indole (7a): Yield: 52%, 52.5 mg, white solid, mp 131–133 °C, purified using petroleum ether/ethyl acetate (10:1). 1H NMR (600 MHz, CDCl3) δ 8.14 (brs, 1H), 7.27–7.18 (m, 2H), 7.03–7.00 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 158.5 (d, JC-F = 238.1 Hz), 129.6, 126.1 (d, JC-F = 10.7 Hz), 121.7, 112.0 (d, JC-F = 20.9 Hz), 111.9 (d, JC-F = 3.7 Hz), 103.9 (d, JC-F =4.5 Hz), 103.3 (d, JC-F = 25.8 Hz). 19F NMR (565 MHz, CDCl3) δ -121.7. HRMS (ESI) m/z: [M+H]+ Calcd for C8H5Cl2FN+ 203.9778; Found 203.9780.
2,3,5-trichloro-1H-indole (7b): Yield: 43%, 47.0 mg, white solid, mp 148–150 °C, purified using petroleum ether/ethyl acetate (10:1). 1H NMR (600 MHz, CDCl3) δ 8.18 (brs, 1H), 7.54 (s, 1H), 7.24–7.19 (m, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 131.5, 127.1, 126.5, 123.9, 121.5, 117.5, 112.0, 103.5. HRMS (ESI) m/z: [M+H]+ Calcd for C8H5Cl3N+ 219.9482; Found 219.9485.
6-Bromo-2,3-dichloro-1H-indole (7c): Yield: 49%, 64.0 mg, white solid, mp 183–185 °C, purified using petroleum ether/ethyl acetate (10:1). 1H NMR (600 MHz, CDCl3) δ 8.15 (brs, 1H), 7.47 (d, J = 1.4 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.33 (dd, J = 8.5, 1.5 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 133.7, 124.6, 124.5, 120.7, 119.2, 117.0, 113.8, 104.2. HRMS (ESI) m/z: [M+H]+ Calcd for C8H5BrCl2N+ 263.8977; Found 263.8978.

4.3. Control Experiments

4.3.1. The Effect of Radical Scavenger TEMPO on the Reaction

To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, 1a (0.5 mmol, 1.0 equiv.), tBuOCl (1.25 mmol, 2.5 equiv.), TEMPO (1.5 mmol, 3.0 equiv.), and EtOAc (3.0 mL) were added and sealed under an air atmosphere. The reaction mixture was stirred at 40 °C for 16 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford the chlorination product 8 (84.9 mg, 76% yield).
ethyl 3-chloro-1H-indole-2-carboxylate (8): Yield: 76%, 84.9 mg, white solid, mp 138–140 °C, purified using petroleum ether/ethyl acetate (10:1). 1H NMR (500 MHz, CDCl3) δ 9.35 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.45–7.36 (m, 2H), 7.26–7.23 (m, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 161.3, 134.9, 126.6, 126.2, 122.4, 121.3, 120.2, 112.4, 112.2, 61.5, 14.4.

4.3.2. The Effect of Radical Scavenger BHT and DPE on the Reaction

To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, 1a (0.5 mmol, 1.0 equiv.), tBuOCl (1.25 mmol, 2.5 equiv.), BHT or DPE (1.5 mmol, 3.0 equiv.), and EtOAc (3.0 mL) were added and sealed under an air atmosphere. The reaction mixture was stirred at 40 °C for 16 h, and then cooled to room temperature. The corresponding reaction mixture was analyzed by TLC.

4.3.3. The Effect of Water and Air on the Reaction

Method A: To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, 1a (0.5 mmol, 1.0 equiv.), tBuOCl (1.25 mmol, 2.5 equiv.), and CH3CN (3.0 mL) were added and sealed under an air atmosphere. The reaction mixture was stirred at 40 °C for 16 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford the desired product 2a (104.2 mg, 87% yield).
Method B: To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, 1a (0.5 mmol, 1.0 equiv.), tBuOCl (1.25 mmol, 2.5 equiv.), and CH3CN (dry, 3.0 mL) were added under an N2 atmosphere. The reaction mixture was stirred at 40 °C for 16 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford the desired product 2a (106.6 mg, 89% yield).
Method C: To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar, 1a (0.5 mmol, 1.0 equiv.), tBuOCl (1.25 mmol, 2.5 equiv.), H2O (2.0 mmol, 4.0 equiv.), and CH3CN (dry, 3.0 mL) were added under an N2 atmosphere. The reaction mixture was stirred at 40 °C for 16 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford the desired product 2a (100.6 mg, 84% yield).

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30010102/s1. Crystallographic data and copies of NMR spectra [43,50].

Author Contributions

Conceptualization, X.-Y.Z.; methodology, C.-Y.L., X.C., H.-L.L., N.W. and X.-Y.Z.; investigation, C.-Y.L., X.C., H.-L.L., N.W. and X.-Y.Z.; writing—original draft preparation, X.C.; writing—review, and editing, X.C. and X.-Y.Z.; supervision, X.C. and X.-Y.Z.; project administration, X.C. and X.-Y.Z.; funding acquisition, X.C. and X.-Y.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (Nos. 22262019 and 22062012), and the Natural Science Foundation of Guizhou Province (No. qiankehejichu-ZK [2023]zhongdian048) for their financial support. This work was also supported by the Foundation of Guizhou Educational Committee (No. qianjiaoji [2023]088) and Liupanshui Normal University Scientific Research & Cultivation Projects (No. LPSSYLPY202326).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data obtained in this project are contained within this article and are available upon request from the authors.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 00102 g001
Figure 1. Some chlorine-containing oxindoles.
Figure 1. Some chlorine-containing oxindoles.
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Molecules 30 00102 sch001
Scheme 1. Methods for chlorinated oxindoles synthesis.
Scheme 1. Methods for chlorinated oxindoles synthesis.
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Molecules 30 00102 sch002
Scheme 2. tert-Butyl hypochlorite for the synthesis of chlorinated oxindoles and indoles: (a) chlorooxidation of indoles; (b) decarboxylative chlorination of the indole-2-carboxylic acids; (c) chlorination of 2-oxindoles.
Scheme 2. tert-Butyl hypochlorite for the synthesis of chlorinated oxindoles and indoles: (a) chlorooxidation of indoles; (b) decarboxylative chlorination of the indole-2-carboxylic acids; (c) chlorination of 2-oxindoles.
Molecules 30 00102 sch002
Molecules 30 00102 sch003
Scheme 3. Substrate scope. Reaction conditions: 1 (0.5 mmol) and tBuOCl (2.5 equiv.) in EtOAc (3.0 mL) at 40 °C for 16 h, and isolated yield. a 4.0 equivalent of tBuOCl was used. b The reaction was performed at 60 °C.
Scheme 3. Substrate scope. Reaction conditions: 1 (0.5 mmol) and tBuOCl (2.5 equiv.) in EtOAc (3.0 mL) at 40 °C for 16 h, and isolated yield. a 4.0 equivalent of tBuOCl was used. b The reaction was performed at 60 °C.
Molecules 30 00102 sch003
Molecules 30 00102 sch004
Scheme 4. Substrate scope. Reaction conditions: 4 (0.5 mmol) and tBuOCl (4.0 equiv.) in EtOAc (3.0 mL) at 60 °C for 24 h, and isolated yield. a The reaction was performed at 80 °C.
Scheme 4. Substrate scope. Reaction conditions: 4 (0.5 mmol) and tBuOCl (4.0 equiv.) in EtOAc (3.0 mL) at 60 °C for 24 h, and isolated yield. a The reaction was performed at 80 °C.
Molecules 30 00102 sch004
Molecules 30 00102 sch005
Scheme 5. Substrate scope. Reaction conditions: 6 (0.5 mmol) and tBuOCl (3.0 equiv.) in EtOAc (3.0 mL) at 60 °C for 24 h, and isolated yield.
Scheme 5. Substrate scope. Reaction conditions: 6 (0.5 mmol) and tBuOCl (3.0 equiv.) in EtOAc (3.0 mL) at 60 °C for 24 h, and isolated yield.
Molecules 30 00102 sch005
Molecules 30 00102 sch006
Scheme 6. The control experiments.
Scheme 6. The control experiments.
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Scheme 7. The plausible reaction mechanism.
Scheme 7. The plausible reaction mechanism.
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Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 30 00102 i001
EntrytBuOCl (x Equiv.)SolventTemp. (°C)Yield (%) b
13.0THF6077
23.0EtOAc6091
33.01,4-dioxane6061
43.0CH3CN6087
53.0toluene6053
62.5EtOAc6094
72.0EtOAc6085
81.5EtOAc6056
92.5EtOAc5097
102.5EtOAc4099
112.5EtOAc3092
12 c2.5EtOAc4099
13 d2.5EtOAc4088
a Reaction conditions: 1a (0.5 mmol) and tBuOCl (x equiv.) in solvent (3.0 mL) at heating for 20 h. b Isolated yield. c The reaction was performed for 16 h. d The reaction was performed for 12 h.
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MDPI and ACS Style

Liu, C.-Y.; Chen, X.; Liu, H.-L.; Wang, N.; Zhou, X.-Y. tert-Butyl Hypochlorite: A Reagent for the Synthesis of Chlorinated Oxindole and Indole Derivatives. Molecules 2025, 30, 102. https://doi.org/10.3390/molecules30010102

AMA Style

Liu C-Y, Chen X, Liu H-L, Wang N, Zhou X-Y. tert-Butyl Hypochlorite: A Reagent for the Synthesis of Chlorinated Oxindole and Indole Derivatives. Molecules. 2025; 30(1):102. https://doi.org/10.3390/molecules30010102

Chicago/Turabian Style

Liu, Chun-Yan, Xia Chen, Hai-Long Liu, Nan Wang, and Xiao-Yu Zhou. 2025. "tert-Butyl Hypochlorite: A Reagent for the Synthesis of Chlorinated Oxindole and Indole Derivatives" Molecules 30, no. 1: 102. https://doi.org/10.3390/molecules30010102

APA Style

Liu, C.-Y., Chen, X., Liu, H.-L., Wang, N., & Zhou, X.-Y. (2025). tert-Butyl Hypochlorite: A Reagent for the Synthesis of Chlorinated Oxindole and Indole Derivatives. Molecules, 30(1), 102. https://doi.org/10.3390/molecules30010102

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