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

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.


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 latte yielding excellent results (>99% NMR yield) (Table 1, entries 2-5).After conducting a com prehensive 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 de creased the desired product yield, while increasing its loading had no impact on its reac tivity (      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 electronwithdrawing (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.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 yield (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 cur rent reaction system, resulting in the isolation of desired products 2t-x, with exceptiona yields.
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 chroma tography 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 oxi dants (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 deriva tives.The screening results indicated that only m-CPBA was able to undergo sequentia double oxidation in one-pot reactions, yielding the desired saccharine derivative 5a, with an 85% yield (Scheme 6a).Additionally, different kinds of N-substituted  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 chroma tography 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 oxi dants (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 deriva tives.The screening results indicated that only m-CPBA was able to undergo sequentia double oxidation in one-pot reactions, yielding the desired saccharine derivative 5a, with an 85% yield (Scheme 6a).Additionally, different kinds of N-substituted 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 H 5 IO 6 as an oxidant and CrO 3 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, H 2 O 2 , TBHP, NaIO 4 , PhI(OAc) 2 , and H 5 IO 6 ) into the benzoisothiazol-3-one-1oxide 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.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.
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.[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).Scheme 8. Proposed mechanism.

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 0.5-1.0bar.The 1 H and 13 C NMR spectra were obtained using a Bruker Avance III-300 or 400 spectrometer (Bruker Corporation, Billerica, MA, USA). 1 H 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 Scheme 8. Proposed mechanism.

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 0.5-1.0bar.The 1 H and 13 C NMR spectra were obtained using a Bruker Avance III-300 or 400 spectrometer (Bruker Corporation, Billerica, MA, USA). 1 H 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).

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 H 2 O (2 × 5 mL) and brine (5 mL), followed by drying over Na 2 SO 4 and filtration.The filtrate was concentrated in vacuo; the crude product was analyzed by 1 H NMR in CDCl 3 .The yields are based on 1a, determined by crude 1 H NMR, using dibromomethane as the internal standard.The residue did not require further purification in order to obtain product 2a.

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 H 2 O (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 H 2 O (2 × 5 mL) and brine (5 mL), followed by drying over Na 2 SO 4 and filtration.The filtrate was concentrated in vacuo to yield the product 4a.

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), H 2 O (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 H 2 O (2 × 5 mL) and brine (5 mL), followed by drying over Na 2 SO 4 and filtration.The filtrate was concentrated in vacuo, then the crude product was analyzed by 1 H NMR in CDCl 3 .The yields are based on 1a, determined by crude 1 H NMR, using dibromomethane as the internal standard.

Scheme 7 .
Scheme 7. Free radical trapping experiments.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)

Scheme 7 .Scheme 7 .
Scheme 7. Free radical trapping experiments.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) Scheme 7. Free radical trapping experiments.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 H 2 O 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 H 2 O to form the intermediate

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.

Table 1 .
Optimization of reaction conditions a .