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Article

Selective Oxidation of Benzo[d]isothiazol-3(2H)-Ones Enabled by Selectfluor

by
Qin Li
1,
Dan Yuan
1,
Chong Liu
2,
Faith Herington
2,
Ke Yang
1,* and
Haibo Ge
2,*
1
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China
2
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(16), 3899; https://doi.org/10.3390/molecules29163899
Submission received: 23 July 2024 / Revised: 10 August 2024 / Accepted: 16 August 2024 / Published: 17 August 2024
(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)
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Versions Notes

Abstract

:
A metal-free and Selectfluor-mediated selective oxidation reaction of benzo[d]isothiazol-3(2H)-ones in aqueous media is presented. This novel strategy provides a facile, green, and efficient approach to access important benzo[d]isothiazol-3(2H)-one-1-oxides with excellent yields and high tolerance to various functional groups. Furthermore, the purification of benzoisothiazol-3-one-1-oxides does not rely on column chromatography. Moreover, the preparation of saccharine derivatives has been achieved through sequential, double oxidation reactions in a one-pot aqueous media.

1. Introduction

Benzo[d]isothiazol-3(2H)-ones and their derivatives are widely used in medicine, agriculture, and the food industry [1,2,3,4,5,6,7]. Benzo[d]isothiazol-3(2H)-one-1-oxides, as important oxidative derivatives, have also attracted attention due to their promising biological properties, including antifungal, anxiolytic, and psychotropic activities [6,7]. As a result, significant efforts have been dedicated to the development of efficient methodologies [8,9,10]. The common method for synthesizing such skeletons involves the direct oxidation of benzo[d]isothiazol-3(2H)-ones. However, current oxidation approaches often require the use of unstable peroxides (H2O2 and m-CPBA) or toxic halogenated reagents (Cl2, NBS, and DBI). Moreover, the use of H2O2 and m-CPBA requires meticulous control of the oxidation temperature and reagent quantities. Notably, these methods are also constrained by their limited substrate scope, moderate yields, and considerable amounts of organic solvent usage (Scheme 1a) [10]. Therefore, seeking an ecofriendly, straightforward, and efficient method for constructing benzo[d]isothiazol-3(2H)-one-1-oxides would be of prime synthetic value.
In recent years, water has progressively been recognized as a green solvent in organic chemistry due to its advantages, such as its abundance, low cost, non-toxicity, and excellent chemical stability [11,12,13]. Meanwhile, Selectfluor [1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate)], a commercially available and exceptionally stable solid, possesses remarkable properties, including high thermal stability, excellent solubility and stability in water, as well as low toxicity [14]. Furthermore, Selectfluor not only serves as an electrophilic fluorinating reagent, but also functions as a remarkable oxidant in various organic transformations [15,16,17,18,19]. Therefore, utilizing water as the solvent and Selectfluor as the oxidant represents a sustainable strategy for achieving the direct oxidation of benzo[d]isothiazol-3(2H)-ones. As part of our continuous efforts in the field of sulfur chemistry [20,21], we herein report on the Selectfluor-mediated selective oxidation of benzo[d]isothiazol-3(2H)-ones in aqueous media to access benzo[d]isothiazol-3(2H)-one-1-oxides (Scheme 1b). In addition, the most famous sweetening agent, saccharine (benzo[d]isothiazol-3(2H)-one-1,1-dioxide) can also be prepared via one-pot, sequential, double oxidation reactions, using Selectfluor and m-CPBA in aqueous media.

2. Results and Discussion

To begin our investigation, we explored the reaction of 2-butylbenzo[d]isothiazol-3(2H)-one (1a) with an oxidant at room temperature, in an ambient atmosphere (Scheme 2 and Table 1). To our delight, the desired product 2a was obtained with an 87% NMR yield, using a water solvent and Selectfluor oxidant (Table 1, entry 1). We subsequently explored other organic solvents, including MeOH, EtOH, DMC, and DMF, with the latter yielding excellent results (>99% NMR yield) (Table 1, entries 2–5). After conducting a comprehensive screening of the oxidants (Selectfluor II, NFSI, NFTP, NIS, NaIO4, and K2S2O8), Selectfluor achieved unmatched results (Table 1, entries 6–11). We further enhanced the yield of aqueous 2a by adding varying volumes of DMF, resulting in H2O/DMF (v/v = 9/1) being the optimal solvent ratio (Table 1, entries 12–14). It is important to note that 2a was able to be isolated with a 95% yield without column chromatography purification. Finally, the investigation of differing Selectfluor amounts indicated that reducing its loading decreased the desired product yield, while increasing its loading had no impact on its reactivity (Table 1, entries 15–17).
With the optimized conditions in hand, the substrate scope of benzo[d]isothiazol-3(2H)-ones was conducted. Various N-substituents on benzo[d]isothiazol-3(2H)-ones were initially tested, as depicted in Scheme 3. As anticipated, the introduction of different linear alkyl groups, including n-butyl, methyl, ethyl, n-propyl, n-amyl, n-hexyl, and n-nonyl, yielded the desired products 2a–g in excellent yields. Next, both iso-propyl and sec-butyl substrates provided the products 2h and 2i with 93% and 95% yields, respectively. The benzyl substrate additionally resulted in the desired product 2j, with a 96% yield. Gratifyingly, the substates 1k–o, containing diverse functional groups, such as alkenyl, alkynyl, cyano, ester, and trimethylsilyl, exhibited excellent compatibility in this protocol, affording the desired products 2k–o with high yields, ranging from 90% to 96%. The ability to convert these well-tolerated functional groups into other important moieties, further highlights the synthetic applicability of this protocol.
Subsequently, the N−H substrate 1p was efficiently converted into product 2p, with a yield of 90%, by using 2.0 equivalents of Selectfluor. Furthermore, the utilization of N-aryl substituents on benzo[d]isothiazol-3(2H)-ones resulted in excellent isolated yields (2q–s) when employing the same amount of Selectfluor. Finally, the presence of electron-withdrawing (F, Cl, Br) or electron-donating (Me, MeO) substituents on the phenyl ring at the 5- or 6- position of benzo[d]isothiazol-3(2H)-one was also compatible with the current reaction system, resulting in the isolation of desired products 2t–x, with exceptional yields.
A substrate scope of other similar sulfur-containing substrates was then studied (Scheme 4). The use of 2-methylisothiazol-3(2H)-one afforded the corresponding product 4a with a 91% yield under standard conditions. Furthermore, the desired product 4b was achieved with a yield of 90% by oxidizing 4,5-dichloro-2-octylisothiazol-3(2H)-one with 3.0 equivalents of Selectfluor at 100 °C for 12 h. Unfortunately, neither isothiazol-3(2H)-one nor 3-chlorobenzo[d]isothiazole provided the corresponding products 4c and 4d. Moreover, when benzothiazin-4-ones were employed, only the N-butyl substituted product 4e was obtained with a 92% yield; additionally, displaying the unreliability of this strategy in isolating the 2-unsubstituted product 4f.
To demonstrate the synthetic usefulness of this approach, two gram-scale reactions were conducted for the synthesis of benzo[d]isothiazol-3(2H)-one-1-oxides (Scheme 5). By slightly modifying the conditions, both products 2a and 2p were successfully obtained with 92% and 87% yields, respectively, without employing traditional column chromatography purification methods.
Saccharine derivatives have garnered extensive interest due to their well-established role as non-caloric sweetening agents [22]. The previous approach for this skeleton mainly relied on the use of H5IO6 as an oxidant and CrO3 as a catalyst in regard to the MeCN solvent [23]. Inspired by the above results, we speculated that the addition of other oxidants (m-CPBA, H2O2, TBHP, NaIO4, PhI(OAc)2, and H5IO6) into the benzoisothiazol-3-one-1-oxide system could facilitate further oxidation for constructing saccharine derivatives. The screening results indicated that only m-CPBA was able to undergo sequential double oxidation in one-pot reactions, yielding the desired saccharine derivative 5a, with an 85% yield (Scheme 6a). Additionally, different kinds of N-substituted benzo[d]isothiazol-3(2H)-ones were successfully converted into the desired saccharine derivatives 5b–e, with good yields (Scheme 6b). Finally, the isolated yield of 5a only reached 43% when exclusively employing m-CPBA (Scheme 6c).
To further explore the reaction mechanism, we performed a series of free radical trapping experiments (Scheme 7). The addition of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) suppressed the formation of product 2a, leading to the recovery of starting material 1a. These results demonstrate that Selectfluor may be utilized as a single-electron transfer (SET) oxidant in this process.
Based on the previous literature and control experiments, two plausible reaction mechanisms are proposed (Scheme 8). The nucleophilic mechanism involves the initial coordination of 1a with Selectfluor, resulting in the formation of transient fluorosulfonium salt A and chloromethyl quaternary ammonium salt B. Next, salt A reacts with H2O and salt B to form intermediate C and salt D. Subsequently, the desired product 2a is formed via the elimination of a hydrogen cation, along with a fluoride anion. Finally, m-CPBA oxidizes product 2a, leading to the formation of the subsequent product 5a (Scheme 8a) [20,24,25,26]. In addition, the presence of a radical pathway cannot be excluded at the present stage [27,28]. The single-electron transfer (SET) process between product 1a and Selectfluor provides the nitrogen radical cation E, sulfur radical cation F, and fluoride anion. Subsequently, the sulfur radical cation F reacts with H2O to form the intermediate product G. Next, the deprotonation of G, followed by a second SET process with the nitrogen radical cation E, yields the cation intermediate I. This intermediate product I can then undergo deprotonation to yield the desired product 2a (Scheme 8b).

3. Materials and Methods

3.1. General Information

All the solvents and commercially available reagents were purchased and used directly. Thin-layer chromatography (TLC) was performed on EMD precoated plates (silica gel 60 F254, Art 5715, Yantai Jiangyou Silica gel Development Co., Ltd., Yantai, China) and visualized by fluorescence quenching under UV light. Column chromatography was performed on EMD silica gel 60 (200–300 mesh, Shanghai Titan Technology Co., Ltd., Shanghai, China), using a forced flow of 0.5–1.0 bar. The 1H and 13C NMR spectra were obtained using a Bruker Avance III–300 or 400 spectrometer (Bruker Corporation, Billerica, MA, USA). 1H NMR data were reported as: chemical shift (δ ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR data were reported in terms of the chemical shift (δ ppm), multiplicity, and coupling constant (Hz). Mass (HRMS) analysis was conducted using the Agilent 6200 Accurate-Mass TOF LC/MS system (Agilent Technologies Co., LTD, Santa Clara, CA, USA), with electrospray ionization (ESI). The melting points were measured by X4-A microscopic melting point apparatus (Shanghai INESA Physico-Optical Instrument Co., Ltd., Shanghai, China).
Benzo[d]isothiazol-3(2H)-ones (1a–h, 1j–n, 1p–s, 1u–x), isothiazol-3(2H)-ones (3a–c), 3-chlorobenzo[d]isothiazole 3d, and benzothiazin-4-one 3e were purchased from Energy-chemical (Shanghai, China), BLDpharm (Shanghai, China), Chemieliva (Chongqing, China), Adamas-beta® (Shanghai, China), TCI (Shanghai, China), J&K@ (Shanghai, China), or Sigma-Aldrich (Shanghai, China). Benzo[d]isothiazol-3(2H)-ones 1i and 1o were prepared by using benzo[d]isothiazol-3(2H)-one 1p with 2-iodobutane and (iodomethyl)trimethylsilane, according to procedures in the literature [29]. Benzo[d]isothiazol-3(2H)-one 1t was prepared by using N-butyl-5-fluoro-2-(methylthio)benzamide with Selectfluor, according to procedures in the literature [20]. Benzothiazin-4-ones 3f was prepared by using N-butyl-2-(methylthio)benzamide with Selectfluor, according to procedures in the literature [21].

3.2. Optimization of the Reaction Conditions

A 25 mL ordinary tube was charged with 2-butylbenzo[d]isothiazol-3(2H)-one (1a, 41.46 mg, 0.2 mmol), a solvent (2.0 mL), and an additive (0.1–0.6 mmol). The tube was sealed, and the reaction was then stirred vigorously at room temperature (25 °C) for 1 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo; the crude product was analyzed by 1H NMR in CDCl3. The yields are based on 1a, determined by crude 1H NMR, using dibromomethane as the internal standard. The residue did not require further purification in order to obtain product 2a.

3.3. Synthetic Procedures for the Synthesis of Compounds 2

A 25 mL ordinary tube was charged with N-substituted benzo[d]isothiazol-3(2H)-ones (1a-o, 0.2 mmol), Selectfluor (70.85 mg, 0.2 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at room temperature for 1 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the N-substituted benzo[d]isothiazol-3(2H)-one-1-oxides 2a–o.
  • The details for 2-Butylbenzo[d]isothiazol-3(2H)-one-1-oxide (2a). Colorless oil, 42.4 mg, 95%. 1H NMR (300 MHz, CDCl3) δ 7.94–7.91 (m, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.76–7.66 (m, 2H), 3.93–3.83 (m, 1H), 3.75–3.65 (m, 1H), 1.75–1.66 (m, 2H), 1.39–1.32 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.38, 145.56, 134.10, 133.21, 128.43, 126.11, 125.07, 41.07, 31.36, 20.09, 13.67. HRMS (ESI, m/z): calcd. for C11H14NO2S [M + H]+, 224.0740; found, 224.0737.
  • The details for 2-Methylbenzo[d]isothiazol-3(2H)-one-1-oxide (2b). White solid, 34.4 mg, 95%, m.p. = 114–115 °C. 1H NMR (300 MHz, CDCl3) δ 8.01–7.99 (m, 1H), 7.93–7.90 (m, 1H), 7.84–7.73 (m, 2H), 3.39 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 165.45, 145.47, 134.18, 133.27, 128.10, 126.07, 125.09, 26.98. HRMS (ESI, m/z): calcd. for C8H8NO2S [M + H]+, 182.0270; found, 182.0264.
  • The details for 2-Ethylbenzo[d]isothiazol-3(2H)-one-1-oxide (2c). White solid, 36.3 mg, 93%, m.p. = 80–81 °C. 1H NMR (300 MHz, CDCl3) δ 8.02–7.99 (m, 1H), 7.93–7.89 (m, 1H), 7.83–7.73 (m, 2H), 4.09–3.97 (m, 1H), 3.91–3.79 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.14, 145.54, 134.12, 133.21, 128.47, 126.05, 125.07, 36.39, 14.81. HRMS (ESI, m/z): calcd. for C9H10NO2S [M + H]+, 196.0427; found, 196.0422.
  • The details for 2-Propylbenzo[d]isothiazol-3(2H)-one-1-oxide (2d). White solid, 41.0 mg, 98%, m.p. = 55–56 °C. 1H NMR (300 MHz, CDCl3) δ 8.01–7.98 (m, 1H), 7.92–7.89 (m, 1H), 7.83–7.73 (m, 2H), 3.96–3.86 (m, 1H), 3.80–3.70 (m, 1H), 1.91–1.77 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.40, 145.55, 134.12, 133.21, 128.38, 126.10, 125.07, 42.93, 22.67, 11.37. HRMS (ESI, m/z): calcd. for C10H12NO2S [M + H]+, 210.0583; found, 210.0581.
  • The details for 2-Pentylbenzo[d]isothiazol-3(2H)-one-1-oxide (2e). Colorless oil, 43.7 mg, 92%. 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.75–7.65 (m, 2H), 3.91–3.82 (m, 1H), 3.73–3.63 (m, 1H), 1.78–1.68 (m, 2H), 1.37–1.23 (m, 4H), 0.83 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.34, 145.59, 134.07, 133.17, 128.43, 126.08, 125.05, 41.29, 28.99, 28.93, 22.23, 13.93. HRMS (ESI, m/z): calcd. for C12H15NNaO2S [M + Na]+, 260.0716; found, 260.0716.
  • The details for 2-Hexylbenzo[d]isothiazol-3(2H)-one 1-oxide (2f). Colorless oil, 45.2 mg, 90%. 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.75–7.65 (m, 2H), 3.92–3.79 (m, 1H), 3.73–3.63 (m, 1H), 1.78–1.67 (m, 2H), 1.35–1.18 (m, 6H), 0.81 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.35, 145.58, 134.08, 133.19, 128.44, 126.10, 125.06, 41.32, 31.37, 29.29, 26.51, 22.51, 14.02. HRMS (ESI, m/z): calcd. for C13H17NNaO2S [M + Na]+, 274.0872; found, 274.0866.
  • The details for 2-Nonylbenzo[d]isothiazol-3(2H)-one-1-oxide (2g). Colorless oil, 52.8 mg, 90%. 1H NMR (300 MHz, CDCl3) δ 8.00 (dd, J = 6.9, 1.7 Hz, 1H), 7.91 (dd, J = 6.8, 1.6 Hz, 1H), 7.83–7.72 (m, 2H), 3.99–3.90 (m, 1H), 3.81–3.71 (m, 1H), 1.88–1.73 (m, 2H), 1.42–1.25 (m, 12H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.35, 145.60, 134.07, 133.18, 128.46, 126.11, 125.05, 41.33, 31.83, 29.44, 29.33, 29.22, 29.17, 26.85, 22.66, 14.12. HRMS (ESI, m/z): calcd. for C16H23NNaO2S [M + Na]+, 316.1342; found, 316.1337.
  • The details 2-Isopropylbenzo[d]isothiazol-3(2H)-one-1-oxide (2h). White solid, 39.0 mg, 93%, m.p. = 47–48 °C. 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.75–7.61 (m, 2H), 4.67–4.54 (m, 1H), 1.52–1.48 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 165.29, 145.59, 134.07, 133.07, 128.74, 125.96, 124.87, 46.96, 22.49, 21.87. HRMS (ESI, m/z): calcd. for C10H12NO2S [M + H]+, 210.0583; found, 210.0583.
  • The details for 2-(sec-Butyl)benzo[d]isothiazol-3(2H)-one-1-oxide (2i). Yellow oil, 42.4 mg, 95%. 1H NMR (300 MHz, CDCl3) δ 8.00–7.96 (m, 1H), 7.90–7.87 (m, 1H), 7.82–7.71 (m, 2H), 4.52–4.40 (m, 1H), 2.11–1.77 (m, 2H), 1.57–1.52 (m, 3H), 1.04–0.93 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 165.56 (d, J = 10.3 Hz), 145.67 (d, J = 6.9 Hz), 134.05, 133.05 (d, J = 1.7 Hz), 128.68 (d, J = 7.7 Hz), 126.00 (d, J = 3.3 Hz), 124.87, 52.72 (d, J = 13.2 Hz), 29.00 (d, J = 38.6 Hz), 20.23 (d, J = 35.2 Hz), 11.14 (d, J = 3.9 Hz). HRMS (ESI, m/z): calcd. for C11H14NO2S [M + H]+, 224.0740; found, 224.0738.
  • The details for 2-Benzylbenzo[d]isothiazol-3(2H)-one-1-oxide (2j). White solid, 49.4 mg, 96%, m.p. = 92–93 °C (known compound [30]). 1H NMR (300 MHz, CDCl3) δ 7.93–7.90 (m, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.72–7.62 (m, 2H), 7.35–7.18 (m, 5H), 5.20 (d, J = 15.3 Hz, 1H), 4.65 (d, J = 15.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 165.22, 145.64, 135.83, 134.28, 133.29, 128.89, 128.65, 128.24, 128.22, 126.31, 125.24, 44.33.
  • The details for 2-Allylbenzo[d]isothiazol-3(2H)-one-1-oxide (2k). Colorless oil, 39.4 mg, 95% (known compound [30]). 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.77–7.66 (m, 2H), 5.95–5.82 (m, 1H), 5.31 (d, J = 17.0 Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 4.62–4.54 (m, 1H), 4.22 (dd, J = 15.9, 6.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 165.11, 145.68, 134.26, 133.26, 131.73, 128.20, 126.24, 125.19, 119.34, 43.17.
  • The details for 2-(Prop-2-yn-1-yl)benzo[d]isothiazol-3(2H)-one-1-oxide (2l). White solid, 37.8 mg, 92%, m.p. = 142–143 °C. 1H NMR (300 MHz, CDCl3) δ 7.99–7.96 (m, 1H), 7.85–7.82 (m, 1H), 7.75–7.65 (m, 2H), 5.29–5.16 (m, 2H), 2.67 (t, J = 2.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 169.98, 154.81, 132.73, 132.39, 129.33, 125.05, 124.27, 77.00, 76.30, 57.79. HRMS (ESI, m/z): calcd. for C10H7NNaO2S [M + Na]+, 228.0090; found, 228.0090.
  • The details for 2-(1-Oxido-3-oxobenzo[d]isothiazol-2(3H)-yl)acetonitrile (2m). White solid, 38.7 mg, 94%, m.p. = 120–121 °C. 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.85–7.72 (m, 2H), 4.84 (d, J = 17.9 Hz, 1H), 4.50 (d, J = 17.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 164.57, 145.53, 135.26, 133.86, 126.79, 126.61, 125.69, 114.17, 28.04. HRMS (ESI, m/z): calcd. for C9H7N2O2S [M + H]+, 207.0223; found, 207.0223.
  • The details for Ethyl 2-(1-oxido-3-oxobenzo[d]isothiazol-2(3H)-yl)acetate (2n). Colorless oil, 45.5 mg, 90%, (known compound [31]). 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.69–7.58 (m, 2H), 5.13 (d, J = 15.7 Hz, 1H), 4.97 (d, J = 15.7 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.23, 166.54, 154.91, 132.75, 132.38, 129.12, 125.02, 124.37, 65.61, 61.90, 14.11.
  • The details for 2-((Trimethylsilyl)methyl)benzo[d]isothiazol-3(2H)-one-1-oxide (2o). Colorless oil, 48.7 mg, 96%. 1H NMR (300 MHz, CDCl3) δ 7.96–7.93 (m, 1H), 7.88–7.83 (m, 1H), 7.78–7.69 (m, 2H), 3.43 (d, J = 15.6 Hz, 1H), 3.19 (d, J = 15.6 Hz, 1H), 0.16 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 165.22, 145.49, 133.86, 133.21, 128.40, 125.93, 124.97, 32.13, -1.63. HRMS (ESI, m/z): calcd. for C11H16NO2SSi [M + H]+, 254.0666; found, 254.0666.
A 25 mL ordinary tube was charged with N-substituted benzo[d]isothiazol-3(2H)-ones (1p–s, 0.2 mmol), Selectfluor (141.70 mg, 0.4 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at room temperature for 1 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the N-substituted benzo[d]isothiazol-3(2H)-one-1-oxides 2p–s.
  • The details for Benzo[d]isothiazol-3(2H)-one-1-oxide (2p). White solid, 30.1 mg, 90%, m.p. = 158–159 °C (known compound [30]). 1H NMR (300 MHz, DMSO-d6) δ 11.52 (br, 1H), 8.13 (d, J = 7.5 Hz, 1H), 7.95–7.82 (m, 3H). 13C NMR (75 MHz, DMSO-d6) δ 167.94, 148.57, 135.18, 133.69, 127.73, 126.33, 125.91.
  • The details for 2-Phenylbenzo[d]isothiazol-3(2H)-one-1-oxide (2q). White solid, 44.8 mg, 92%, m.p. = 136–137 °C (known compound [30]). 1H NMR (400 MHz, CDCl3) δ 8.11–8.09 (m, 1H), 7.98–7.95 (m, 1H), 7.89–7.79 (m, 2H), 7.53–7.43 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 164.54, 145.51, 134.65, 133.90, 133.48, 129.79, 128.94, 128.25, 127.42, 126.80, 125.26.
  • The details for 2-(p-Tolyl)benzo[d]isothiazol-3(2H)-one-1-oxide (2r). White solid, 46.3 mg, 90%, m.p. = 169–170 °C (known compound [30]). 1H NMR (400 MHz, CDCl3) δ 8.10–8.07 (m, 1H), 7.97–7.94 (m, 1H), 7.88–7.78 (m, 2H), 7.41–7.38 (m, 2H), 7.32–7.30 (m, 2H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.66, 145.57, 139.19, 134.57, 133.42, 131.04, 130.42, 128.29, 127.45, 126.73, 125.24, 21.31.
  • The details for 2-(4-Bromophenyl)benzo[d]isothiazol-3(2H)-one-1-oxide (2s). White solid, 61.2 mg, 95%, m.p. = 100–101 °C. 1H NMR (400 MHz, CDCl3) δ 8.11–8.09 (m, 1H), 7.98–7.96 (m, 1H), 7.91–7.81 (m, 2H), 7.66–7.62 (m, 2H), 7.45–7.41 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 164.37, 145.39, 134.81, 133.60, 133.10, 132.94, 128.74, 128.02, 126.87, 125.30, 122.81. HRMS (ESI, m/z): calcd. for C13H9BrNO2S [M + H]+, 321.9532; found, 321.9529.
A 25 mL ordinary tube was charged with N-substituted benzo[d]isothiazol-3(2H)-ones (1t–x, 0.2 mmol), Selectfluor (106.28 mg, 0.3 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at room temperature for 1 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the N-substituted benzo[d]isothiazol-3(2H)-one-1-oxides 2t–x.
  • The details for 2-Butyl-5-fluorobenzo[d]isothiazol-3(2H)-one-1-oxide (2t). White solid, 45.0 mg, 93%, m.p. = 82–83 °C. 1H NMR (300 MHz, CDCl3) δ 7.83 (dd, J = 8.5, 4.3 Hz, 1H), 7.58 (dd, J = 7.4, 2.4 Hz, 1H), 7.44–7.37 (m, 1H), 3.91–3.82 (m, 1H), 3.74–3.64 (m, 1H), 1.76–1.66 (m, 2H), 1.41–1.29 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.65 (d, J = 256.5 Hz), 164.12 (d, J = 3.0 Hz), 141.09 (d, J = 3.1 Hz), 131.59 (d, J = 9.2 Hz), 127.33 (d, J = 9.3 Hz), 121.45 (d, J = 23.9 Hz), 113.32 (d, J = 24.5 Hz), 41.33, 31.25, 20.04, 13.60. 19F NMR (282 MHz, CDCl3) δ -103.42. HRMS (ESI, m/z): calcd. for C11H13FNO2S [M + H]+, 242.0646; found, 242.0648.
  • The details for 2-Butyl-5-chlorobenzo[d]isothiazol-3(2H)-one-1-oxide (2u). Colorless oil, 47.4 mg, 92%. 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J = 1.9, 0.5 Hz, 1H), 7.77 (dd, J = 8.2, 0.6 Hz, 1H), 7.68 (dd, J = 8.2, 1.9 Hz, 1H), 3.91–3.81 (m, 1H), 3.74–3.64 (m, 1H), 1.76–1.65 (m, 2H), 1.41–1.29 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 164.14, 143.64, 140.08, 134.12, 130.37, 126.29, 126.27, 41.31, 31.26, 20.05, 13.61. HRMS (ESI, m/z): calcd. for C11H13ClNO2S [M + H]+, 258.0350; found, 258.0343.
  • The details for 6-Bromo-2-butylbenzo[d]isothiazol-3(2H)-one-1-oxide (2v). White solid, 57.4 mg, 95%, m.p. = 97–98 °C. 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.90–7.83 (m, 1H), 3.98–3.88 (m, 1H), 3.81–3.72 (m, 1H), 1.86–1.73 (m, 2H), 1.48–1.36 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 164.61, 147.12, 136.50, 128.84, 128.31, 127.35, 127.20, 41.24, 31.27, 20.06, 13.61. HRMS (ESI, m/z): calcd. for C11H13BrNO2S [M + H]+, 301.9845; found, 301.9840.
  • The details for 2-Butyl-5-methylbenzo[d]isothiazol-3(2H)-one-1-oxide (2w). White solid, 42.7 mg, 90%, m.p. = 100–101 °C. 1H NMR (300 MHz, CDCl3) δ 7.71–7.68 (m, 2H), 7.51 (d, J = 7.8 Hz, 1H), 3.91–3.81 (m, 1H), 3.72–3.62 (m, 1H), 2.45 (s, 3H), 1.76–1.65 (m, 2H), 1.41–1.29 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.50, 144.33, 142.77, 134.75, 128.68, 126.37, 124.84, 41.03, 31.35, 21.67, 20.08, 13.64. HRMS (ESI, m/z): calcd. for C12H15NNaO2S [M + Na]+, 260.0716; found, 260.0716.
  • The details for 2-Butyl-6-methoxybenzo[d]isothiazol-3(2H)-one-1-oxide (2x). White solid, 45.6 mg, 90%, m.p. = 139–140 °C. 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.21 (dd, J = 8.5, 2.2 Hz, 1H), 3.95–3.87 (m, 4H), 3.79–3.70 (m, 1H), 1.83–1.72 (m, 2H), 1.46– 1.39 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.21, 164.54, 147.86, 127.43, 120.44, 119.56, 109.51, 56.19, 41.08, 31.42, 20.07, 13.64. HRMS (ESI, m/z): calcd. for C12H16NO3S [M + H]+, 254.0845; found, 254.0666.

3.4. Synthetic Procedures for the Synthesis of Compounds 4

A 25 mL ordinary tube was charged with 2-methylisothiazol-3(2H)-one (3a, 23.03 mg, 0.2 mmol), Selectfluor (70.85 mg, 0.2 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at room temperature for 1 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the product 4a.
  • The details for 2-Methylisothiazol-3(2H)-one-1-oxide (4a). White solid, 24.0 mg, 91%, m.p. = 81–82 °C. 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J = 6.5 Hz, 1H), 6.83 (d, J = 6.4 Hz, 1H), 3.25 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 166.06, 148.19, 130.66, 26.57. HRMS (ESI, m/z): calcd. for C4H6NO2S [M + H]+, 132.0114; found, 132.0111.
A 25 mL ordinary tube was charged with 4,5-dichloro-2-octylisothiazol-3(2H)-one (3b, 56.44 mg, 0.2 mmol), Selectfluor (212.56 mg, 0.6 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at 100 °C for 12 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the product 4b.
  • The details for 4,5-Dichloro-2-octylisothiazol-3(2H)-one-1-oxide (4b). Colorless oil, 53.7 mg, 90%. 1H NMR (300 MHz, CDCl3) δ 3.80–3.59 (m, 2H), 1.71–1.62 (m, 2H), 1.31–1.18 (m, 10H), 0.81 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 159.92, 148.68, 130.86, 42.85, 31.72, 29.08, 29.07, 29.00, 26.66, 22.60, 14.07. HRMS (ESI, m/z): calcd. for C11H18Cl2NO2S [M + H]+, 298.0430; found, 298.0416.
A 25 mL ordinary tube was charged with 3-butyl-2,3-dihydro-4H-benzo[e][1,3]thiazin-4-one (3e, 44.26 mg, 0.2 mmol), Selectfluor (70.85 mg, 0.2 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at room temperature for 1 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the product 4e.
  • The details for 3-Butyl-2,3-dihydro-4H-benzo[e][1,3]thiazin-4-one-1-oxide (4e). Colorless oil, 43.7 mg, 92%. 1H NMR (300 MHz, CDCl3) δ 8.14–8.11 (m, 1H), 7.70–7.56 (m, 3H), 4.67 (d, J = 13.0 Hz, 1H), 4.48 (d, J = 13.0 Hz, 1H), 3.61 (t, J = 7.4 Hz, 2H), 1.64–1.54 (m, 2H), 1.39–1.28 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 162.05, 140.88, 132.84, 132.56, 130.42, 127.51, 127.00, 65.22, 48.87, 29.80, 19.95, 13.77. HRMS (ESI, m/z): calcd. for C12H15NNaO2S [M + Na]+, 260.0716; found, 260.0714.

3.5. Synthetic Procedures for Gram-Scale Reactions

A 50 mL round-bottom flask was charged with 2-butylbenzo[d]isothiazol-3(2H)-one (1a, 1.04 g, 5 mmol), Selectfluor (1.77 g, 5 mmol), DMF (2 mL), and H2O (18 mL). The reaction was then stirred vigorously at room temperature for 3 h. After the reaction was finished, ethyl acetate (20 mL) was added. The organic phase was subjected to washing with H2O (2 × 15 mL) and brine (15 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the 2-butylbenzo[d]isothiazol-3(2H)-one-1-oxide 2a (1.03 g, 92%).
A 50 mL round-bottom flask was charged with benzo[d]isothiazol-3(2H)-one (1p, 1.51 g, 10 mmol), Selectfluor (7.09 g, 20 mmol), DMF (3 mL), and H2O (27 mL). The reaction was then stirred vigorously at room temperature for 3 h. After the reaction was finished, ethyl acetate (40 mL) was added. The organic phase was subjected to washing with H2O (2 × 25 mL) and brine (25 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo to yield the benzo[d]isothiazol-3(2H)-one-1-oxide 2p (1.45 g, 87%).

3.6. Synthetic Procedures for the Synthesis of Compounds 5

A 25 mL ordinary tube was charged with N-substituted benzo[d]isothiazol-3(2H)-ones (1, 0.2 mmol), Selectfluor (70.85 mg, 0.2 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at room temperature for 1 h. Next, m-CPBA (103.54 mg, 0.6 mmol) was added to the reaction system, then stirred vigorously at room temperature for 6 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was treated with NaOH aqueous solution (10 wt%), followed by washing with H2O (2 × 5 mL) and brine (5 mL), then dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to yield the N-substituted benzo[d]isothiazol-3(2H)-one-1,1-dioxides 5a–d.
  • The details for 2-Butylbenzo[d]isothiazol-3(2H)-one-1,1-dioxide (5a). White solid, 40.7 mg, 85%, m.p. = 42–43 °C (known compound [32]). 1H NMR (300 MHz, CDCl3) δ 8.00–7.96 (m, 1H), 7.87–7.72 (m, 3H), 3.70 (t, J = 7.4 Hz, 2H), 1.82–1.72 (m, 2H), 1.44–1.31 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 158.96, 137.74, 134.65, 134.27, 127.48, 125.09, 120.88, 39.23, 30.43, 20.05, 13.52.
  • The details for 2-Ethylbenzo[d]isothiazol-3(2H)-one-1,1-dioxide (5b). White solid, 34.2 mg, 81%, m.p. = 93–94 °C (known compound [32]). 1H NMR (300 MHz, CDCl3) δ 7.99–7.96 (m, 1H), 7.86–7.72 (m, 3H), 3.78 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 158.71, 137.78, 134.67, 134.29, 127.50, 125.08, 120.88, 34.50, 13.98.
  • The details for 2-Benzylbenzo[d]isothiazol-3(2H)-one-1,1-dioxide (5c). White solid, 45.4 mg, 83%, m.p. = 110–111 °C (known compound [32]). 1H NMR (300 MHz, CDCl3) δ 7.97–7.94 (m, 1H), 7.85–7.69 (m, 3H), 7.42 (dd, J = 7.6, 1.9 Hz, 2H), 7.30–7.17 (m, 3H), 4.82 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 158.93, 137.75, 134.85, 134.51, 134.38, 128.75, 128.72, 128.30, 127.30, 125.26, 121.06, 42.69.
  • The details for 2-((Trimethylsilyl)methyl)benzo[d]isothiazol-3(2H)-one-1,1-dioxide (5d). Colorless oil, 45.8 mg, 85% (known compound [33]). 1H NMR (300 MHz, CDCl3) δ 8.03–8.00 (m, 1H), 7.92–7.89 (m, 1H), 7.86–7.77 (m, 2H), 3.13 (s, 2H), 0.19 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 159.02, 137.75, 134.45, 134.33, 127.79, 124.98, 120.99, 29.12, -1.54.
A 25 mL ordinary tube was charged with 1p (30.24 mg, 0.2 mmol), Selectfluor (141.70 mg, 0.4 mmol), DMF (0.2 mL), and H2O (1.8 mL). The reaction was then stirred vigorously at room temperature for 1 h. Next, m-CPBA (103.54 mg, 0.6 mmol) was added to the reaction system, then stirred vigorously at room temperature for 6 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was treated with NaOH aqueous solution (10 wt%), followed by washing with H2O (2 × 5 mL) and brine (5 mL), then dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, the residue was purified by flash chromatography on silica gel, using EtOAc/MeOH (v/v = 10/1) as the eluent, to yield the product 5e.
  • The details for Benzo[d]isothiazol-3(2H)-one-1,1-dioxide (5e). White solid, 27.5 mg, 75%, m.p. = 227–228 °C (known compound [34]). 1H NMR (300 MHz, DMSO-d6) δ 12.36 (br, 1H), 8.19–8.15 (m, 1H), 8.04–7.92 (m, 3H). 13C NMR (75 MHz, DMSO-d6) δ 161.30, 139.74, 136.01, 135.22, 127.92, 125.31, 121.64.

3.7. Procedures for Free Radical Trapping Experiments

A 25 mL ordinary tube was charged with 2-butylbenzo[d]isothiazol-3(2H)-one (1a, 41.46 mg, 0.2 mmol), Selectfluor (141.70 mg, 0.4 mmol), DMF (0.2 mL), H2O (1.8 mL), and TEMPO (0.1, 0.2, or 0.4 mmol). The tube was sealed, and the reaction was then stirred vigorously at room temperature for 1 h. After the reaction was finished, ethyl acetate (5 mL) was added. The organic phase was subjected to washing with H2O (2 × 5 mL) and brine (5 mL), followed by drying over Na2SO4 and filtration. The filtrate was concentrated in vacuo, then the crude product was analyzed by 1H NMR in CDCl3. The yields are based on 1a, determined by crude 1H NMR, using dibromomethane as the internal standard.

4. Conclusions

In summary, we have developed Selectfluor-mediated, selective oxidation of benzo[d]isothiazol-3(2H)-ones, in the aqueous phase. This strategy demonstrated broad tolerance towards assorted functional groups, producing a variety of benzo[d]isothiazol-3(2H)-one-1-dioxides with excellent yields, without column chromatography purification. Furthermore, other similar sulfur-containing substrates, including N-substituted isothiazol-3(2H)-ones and benzothiazin-4-ones, proved suitable for this strategy. Lastly, saccharine derivatives were also synthesizable via sequential, one-pot, double oxidation using Selectfluor and m-CPBA in aqueous media.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29163899/s1, Figure S1: benzo[d]isothiazol-3(2H)-ones; Figure S2: isothiazol-3-ones, isothiazoles, and benzothiazin-4-ones; Figures S3–S67: 1H, 19F, and 13C NMR spectra.

Author Contributions

Synthesis and characterization, Q.L. and D.Y.; data curation, Q.L. and K.Y.; writing—original draft preparation, C.L., F.H., K.Y. and H.G.; writing—review and editing, C.L., F.H., K.Y. and H.G.; funding acquisition, Q.L., K.Y. and H.G. All authors have read and agreed to the published version of the manuscript.

Funding

H.G. acknowledges NSF (CHE-2029932), the Robert A. Welch Foundation (D-2034-20230405), and Texas Tech University for financial support. K.Y. is grateful for financial support from Changzhou University, Advanced Catalysis and Green Manufacturing Collaborative Innovation Center (ACGM2022-10-10), and Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110). Q.L. is grateful for the financial support from the Postgraduate Research and Practice Innovation Program of Jiangsu Province (SJCX24_1603).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

We acknowledge the analytical testing support from the Analysis and Testing Center, NERC Biomass at Changzhou University.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

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Molecules 29 03899 sch001
Scheme 1. The direct oxidation of benzo[d]isothiazol-3(2H)-ones for benzoisothiazol-3-one-1-oxides.
Scheme 1. The direct oxidation of benzo[d]isothiazol-3(2H)-ones for benzoisothiazol-3-one-1-oxides.
Molecules 29 03899 sch001
Molecules 29 03899 sch002
Scheme 2. Selectfluor-mediated selective oxidation of 2-butylbenzo[d]isothiazol-3(2H)-one.
Scheme 2. Selectfluor-mediated selective oxidation of 2-butylbenzo[d]isothiazol-3(2H)-one.
Molecules 29 03899 sch002
Molecules 29 03899 sch003
Scheme 3. Scope of benzo[d]isothiazol-3(2H)-ones. Reaction conditions: 1a (0.2 mmol), Selectfluor (0.2 mmol), H2O/DMF (2.0 mL, v/v = 9:1), room temperature (25 °C), 1 h, air. Isolated yields. a Selectfluor (0.4 mmol). b Selectfluor (0.3 mmol).
Scheme 3. Scope of benzo[d]isothiazol-3(2H)-ones. Reaction conditions: 1a (0.2 mmol), Selectfluor (0.2 mmol), H2O/DMF (2.0 mL, v/v = 9:1), room temperature (25 °C), 1 h, air. Isolated yields. a Selectfluor (0.4 mmol). b Selectfluor (0.3 mmol).
Molecules 29 03899 sch003
Molecules 29 03899 sch004
Scheme 4. Scope of isothiazol-3-ones, isothiazoles, and benzothiazin-4-ones. Reaction conditions: 1a (0.2 mmol), Selectfluor (0.2 mmol), H2O/DMF (2.0 mL, v/v = 9:1), room temperature (25 °C), 1 h, air. Isolated yields. a Selectfluor (0.6 mmol), 100 °C and 12 h.
Scheme 4. Scope of isothiazol-3-ones, isothiazoles, and benzothiazin-4-ones. Reaction conditions: 1a (0.2 mmol), Selectfluor (0.2 mmol), H2O/DMF (2.0 mL, v/v = 9:1), room temperature (25 °C), 1 h, air. Isolated yields. a Selectfluor (0.6 mmol), 100 °C and 12 h.
Molecules 29 03899 sch004
Molecules 29 03899 sch005
Scheme 5. Gram-scale synthesis of benzo[d]isothiazol-3(2H)-one-1-oxides.
Scheme 5. Gram-scale synthesis of benzo[d]isothiazol-3(2H)-one-1-oxides.
Molecules 29 03899 sch005
Molecules 29 03899 sch006
Scheme 6. Sequential, one-pot, double oxidation reactions for the synthesis of saccharine derivatives.
Scheme 6. Sequential, one-pot, double oxidation reactions for the synthesis of saccharine derivatives.
Molecules 29 03899 sch006
Molecules 29 03899 sch007
Scheme 7. Free radical trapping experiments.
Scheme 7. Free radical trapping experiments.
Molecules 29 03899 sch007
Molecules 29 03899 sch008
Scheme 8. Proposed mechanism.
Scheme 8. Proposed mechanism.
Molecules 29 03899 sch008
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
EntryOxidant (Eq.)Solvent (v/v, mL)Yield (%)
1Selectfluor (1.0)H2O87
2Selectfluor (1.0)MeOHtrace
3Selectfluor (1.0)EtOH0
4Selectfluor (1.0)DMC0
5Selectfluor (1.0)DMF>99
6Selectfluor II (1.0)H2O82
7NFSI (1.0)H2O80
8NFTP (1.0)H2O0
9NIS (1.0)H2O0
10NaIO4 (1.0)H2O0
11K2S2O8 (1.0)H2O0
12Selectfluor (1.0)H2O/DMF (v/v = 4/1)>99
13Selectfluor (1.0)H2O/DMF (v/v = 9/1)>99[95] b
14Selectfluor (1.0)H2O/DMF (v/v = 19/1)90
15Selectfluor (0.5)H2O/DMF (v/v = 9/1)48
16Selectfluor (2.0)H2O/DMF (v/v = 9/1)>99
17Selectfluor (3.0)H2O/DMF (v/v = 9/1)>99
a Reaction conditions: 1a (0.2 mmol), oxidant (0.1–0.6 mmol), solvent (2.0 mL), room temperature (25 °C), 1 h, air. Yields are based on 1a, determined by 1H-NMR using dibromomethane as the internal standard. b Isolated yields. Selectfluor =1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate). Selectfluor II = 1-fluoro-4-methyl-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate). NFSI = N-fluorobenzenesulfonamide. NFTP = 1-fluoropyridinium triflate. NIS = N-iodosuccinimide. DMC =dimethyl carbonate. DMF = N,N-dimethylformamide.
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Li, Q.; Yuan, D.; Liu, C.; Herington, F.; Yang, K.; Ge, H. Selective Oxidation of Benzo[d]isothiazol-3(2H)-Ones Enabled by Selectfluor. Molecules 2024, 29, 3899. https://doi.org/10.3390/molecules29163899

AMA Style

Li Q, Yuan D, Liu C, Herington F, Yang K, Ge H. Selective Oxidation of Benzo[d]isothiazol-3(2H)-Ones Enabled by Selectfluor. Molecules. 2024; 29(16):3899. https://doi.org/10.3390/molecules29163899

Chicago/Turabian Style

Li, Qin, Dan Yuan, Chong Liu, Faith Herington, Ke Yang, and Haibo Ge. 2024. "Selective Oxidation of Benzo[d]isothiazol-3(2H)-Ones Enabled by Selectfluor" Molecules 29, no. 16: 3899. https://doi.org/10.3390/molecules29163899

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