Application of Iodine as a Catalyst in Aerobic Oxidations: A Sustainable Approach for Thiol Oxidations

Iodine is a well-known oxidant that is widely used in organic syntheses. Thiol oxidation by stoichiometric iodine is one of the most commonly employed strategies for the synthesis of valuable disulfides. While recent advancements in catalytic aerobic oxidation conditions have eliminated the need for stoichiometric oxidants, concerns persist regarding the use of toxic or expensive catalysts. In this study, we discovered that iodine can be used as a cheap, low-toxicity catalyst in the aerobic oxidation of thiols. In the catalytic cycle, iodine can be regenerated via HI oxidation by O2 at 70 °C in EtOAc. This protocol harnesses sustainable oxygen as the terminal oxidant, enabling the conversion of primary and secondary thiols with remarkable efficiency. Notably, all 26 tested thiols, encompassing various sensitive functional groups, were successfully converted into their corresponding disulfides with yields ranging from >66% to 98% at a catalyst loading of 5 mol%.

Herein, we have established a novel I 2 -catalyzed aerobic oxidative thiol coupling strategy. I 2 , due to its readily available and low toxicity attributes, emerges as a highly suitable catalyst within environmentally benign processes [27][28][29][30]. The oxidation of thiols to disulfides using iodine has demonstrated a wide range of reactive groups tolerated [31]. Herein, we have established a novel I2-catalyzed aerobic oxidative thiol coupling strategy. I2, due to its readily available and low toxicity attributes, emerges as a highly suitable catalyst within environmentally benign processes [27][28][29][30]. The oxidation of thiols to disulfides using iodine has demonstrated a wide range of reactive groups tolerated [31]. Additionally, iodine has previously been employed as a catalyst in thiol oxidation combined with additives like DMSO, H2O2, and flavin [32][33][34]. This study showcases its effectiveness as a catalyst in catalyzing aerobic thiol oxidation at elevated temperatures using only 5 mol% of iodine, which is more cost-effective and environmentally friendly compared to previous studies. Notably, this green protocol exhibits good tolerance toward a diverse array of primary and secondary thiols bearing various functional groups.

Results and Discussion
This study commenced with reaction condition optimization of the iodine-catalyzed aerobic oxidation of thiols (Table 1). Dodecane-1-thiol 1a was selected as the model substrate. The initial trial of the aerobic oxidation with 10 mol% I2 gave 2a in >98% yield at 70 °C in EtOAc (Entry 1, Table 1). The high yield of 2a was maintained when the amount of I2 was reduced to 5.0 mol% (Entry 2, Table 1). However, decreasing the catalyst loading of I2 to 1.0 mol% resulted in an incomplete conversion of 1a (Entry 3, Table 1). The influence of reaction duration was investigated. Decreasing the reaction time from 4 h to 1 h resulted in a reduction in the reaction yield from >98% to 49%, which indicated extending the reaction time to 4 h can ensure the complete conversion of 1a to 2a (Entry 4, Table 1). Following the determination of optimal catalyst loading and reaction time, the impact of varying solvents on the reaction was explored. Substituting EtOAc with dichloromethane or N,N-dimethylformamide resulted in notably diminished yields (Entries 5 and 6, Table 1). This observation indicates the solvent's pronounced influence on this catalytic reaction. Subsequently, the impact of temperature was examined. The findings revealed that the reaction conducted at room temperature (r.t.) yielded 53% of 2a (Entry 7, Table 1), whereas the reaction conducted at 70 °C exhibited a significantly higher yield of >98%. Therefore, the optimal temperature for the experimental reaction was established at 70 °C. Finally, a control reaction with no catalyst was conducted. Significantly, only a trace amount of 2a was formed in the control reaction, providing compelling evidence that I2 serves as an indispensable element for the synthesis of disulfide 2a (Entry 8, Table 1).

Results and Discussion
This study commenced with reaction condition optimization of the iodine-catalyzed aerobic oxidation of thiols (Table 1). Dodecane-1-thiol 1a was selected as the model substrate. The initial trial of the aerobic oxidation with 10 mol% I 2 gave 2a in >98% yield at 70 • C in EtOAc (Entry 1, Table 1). The high yield of 2a was maintained when the amount of I 2 was reduced to 5.0 mol% (Entry 2, Table 1). However, decreasing the catalyst loading of I 2 to 1.0 mol% resulted in an incomplete conversion of 1a (Entry 3, Table 1). The influence of reaction duration was investigated. Decreasing the reaction time from 4 h to 1 h resulted in a reduction in the reaction yield from >98% to 49%, which indicated extending the reaction time to 4 h can ensure the complete conversion of 1a to 2a (Entry 4, Table 1). Following the determination of optimal catalyst loading and reaction time, the impact of varying solvents on the reaction was explored. Substituting EtOAc with dichloromethane or N,N-dimethylformamide resulted in notably diminished yields (Entries 5 and 6, Table 1). This observation indicates the solvent's pronounced influence on this catalytic reaction. Subsequently, the impact of temperature was examined. The findings revealed that the reaction conducted at room temperature (r.t.) yielded 53% of 2a (Entry 7, Table 1), whereas the reaction conducted at 70 • C exhibited a significantly higher yield of >98%. Therefore, the optimal temperature for the experimental reaction was established at 70 • C. Finally, a control reaction with no catalyst was conducted. Significantly, only a trace amount of 2a was formed in the control reaction, providing compelling evidence that I 2 serves as an indispensable element for the synthesis of disulfide 2a (Entry 8, Table 1).  Based on the comprehensive investigation of reaction conditions, we concluded that 5.0 mol% of I2 in EtOAc at 70 °C for a duration of 4 h was suitable for the substrate scope investigation ( Figure 2). The substrate scope demonstrated that the I2-catalyzed aerobic oxidation protocol can convert all 23 tested primary and secondary thiols into disulfides in good to excellent yields. Notably, the aerobic oxidation process demonstrated a notable capacity to overcome the inherent challenges typically associated with secondary thiols, as exemplified by the good efficacy observed in the transformation of 1d to 2d. A variety of thiols with various functional groups were tested for the synthesis of symmetrical disulfides. Aryl thiols bearing both electron-withdrawing groups, including fluoride (2e, 2j), chloride (2f, 2g, and 2k), and bromide (2l, 2m, and 2n), as well as electron-donating functional groups such as methoxyl (2o, 2p, and 2q), isopropyl (2r), methyl (2s), and amide (2t), afforded the corresponding disulfides in good to excellent yields. Extending the scope beyond the aforementioned substrates, the protocol effectively facilitated the conversion of ploy-aromatic (2u) and heteroaromatic (2v and 2w) thiols into their respective disulfides. To underscore the practical utility of this approach, we have employed it in the oxidation of bioactive thiols, namely N-(tert-butoxycarbonyl)-L-cysteine methyl ester 1x and N-acetyl-L-cystine 1y (Figure 3), which have been used as treatments for acute paracetamol toxicity and peptide synthesis, respectively [35,36]. This resulted in the formation of the corresponding disulfides 2x and 2y in 66% and 98% yields, respectively. In addition, this method has also been applied to the oxidation of dithiol, dithiothreitol 1z ( Figure 4). The exclusive formation of the cyclized disulfide 2z was achieved with an impressive yield of 98%, and there was no observed formation of the dimerized by-product. Notably, the formed trans-4,5-dihydroxy-1,2-dithiane 2z is an inducer of ER stress proteins, which protects the kidney from chemical stress in vivo [37]. These results not only emphasize the method's effectiveness but also highlight its potential for synthesizing intricate bioactive disulfides. Based on the comprehensive investigation of reaction conditions, we concluded that 5.0 mol% of I 2 in EtOAc at 70 • C for a duration of 4 h was suitable for the substrate scope investigation ( Figure 2). The substrate scope demonstrated that the I 2 -catalyzed aerobic oxidation protocol can convert all 23 tested primary and secondary thiols into disulfides in good to excellent yields. Notably, the aerobic oxidation process demonstrated a notable capacity to overcome the inherent challenges typically associated with secondary thiols, as exemplified by the good efficacy observed in the transformation of 1d to 2d. A variety of thiols with various functional groups were tested for the synthesis of symmetrical disulfides. Aryl thiols bearing both electron-withdrawing groups, including fluoride (2e, 2j), chloride (2f, 2g, and 2k), and bromide (2l, 2m, and 2n), as well as electron-donating functional groups such as methoxyl (2o, 2p, and 2q), isopropyl (2r), methyl (2s), and amide (2t), afforded the corresponding disulfides in good to excellent yields. Extending the scope beyond the aforementioned substrates, the protocol effectively facilitated the conversion of ploy-aromatic (2u) and heteroaromatic (2v and 2w) thiols into their respective disulfides. To underscore the practical utility of this approach, we have employed it in the oxidation of bioactive thiols, namely N-(tert-butoxycarbonyl)-L-cysteine methyl ester 1x and N-acetyl-Lcystine 1y (Figure 3), which have been used as treatments for acute paracetamol toxicity and peptide synthesis, respectively [35,36]. This resulted in the formation of the corresponding disulfides 2x and 2y in 66% and 98% yields, respectively. In addition, this method has also been applied to the oxidation of dithiol, dithiothreitol 1z ( Figure 4). The exclusive formation of the cyclized disulfide 2z was achieved with an impressive yield of 98%, and there was no observed formation of the dimerized by-product. Notably, the formed trans-4,5-dihydroxy-1,2-dithiane 2z is an inducer of ER stress proteins, which protects the kidney from chemical stress in vivo [37]. These results not only emphasize the method's effectiveness but also highlight its potential for synthesizing intricate bioactive disulfides.
In order to explore the possible mechanism of this reaction, a series of control reactions was conducted in Scheme 1. In the control reaction using 5 mol% HI to replace 5 mol% I 2 , 2a was also formed in >98% yield (Scheme 1(AI)). This result indicated that the catalyst iodine was regenerated from the oxidation of HI by oxygen. In the presence of TEMPO, a powerful free radical scavenger, the oxidation of thiols by stoichiometric iodine remained unaffected (Scheme 1(AII,AIII)). Interestingly, TEMPO completely halted the iodine-catalyzed aerobic oxidation of thiols (Scheme 1(AIV)). This observation strongly suggests that the oxidation of thiols might follow a distinct pathway within the catalytic cycle, contrasting with the oxidation process involving stoichiometric iodine.   In order to explore the possible mechanism of this reaction, a series of control reactions was conducted in Scheme 1. In the control reaction using 5 mol% HI to replace 5 mol% I2, 2a was also formed in >98% yield (Scheme 1A(I)). This result indicated that the catalyst iodine was regenerated from the oxidation of HI by oxygen. In the presence of TEMPO, a powerful free radical scavenger, the oxidation of thiols by stoichiometric iodine remained unaffected (Scheme 1A(II,III)). Interestingly, TEMPO completely halted the iodine-catalyzed aerobic oxidation of thiols (Scheme 1A(IV)). This observation strongly   In order to explore the possible mechanism of this reaction, a series of control reactions was conducted in Scheme 1. In the control reaction using 5 mol% HI to replace 5 mol% I2, 2a was also formed in >98% yield (Scheme 1A(I)). This result indicated that the catalyst iodine was regenerated from the oxidation of HI by oxygen. In the presence of TEMPO, a powerful free radical scavenger, the oxidation of thiols by stoichiometric iodine remained unaffected (Scheme 1A(II,III)). Interestingly, TEMPO completely halted the iodine-catalyzed aerobic oxidation of thiols (Scheme 1A(IV)). This observation strongly   In order to explore the possible mechanism of this reaction, a series of control reactions was conducted in Scheme 1. In the control reaction using 5 mol% HI to replace 5 mol% I2, 2a was also formed in >98% yield (Scheme 1A(I)). This result indicated that the catalyst iodine was regenerated from the oxidation of HI by oxygen. In the presence of TEMPO, a powerful free radical scavenger, the oxidation of thiols by stoichiometric iodine remained unaffected (Scheme 1A(II,III)). Interestingly, TEMPO completely halted the iodine-catalyzed aerobic oxidation of thiols (Scheme 1A(IV)). This observation strongly suggests that the oxidation of thiols might follow a distinct pathway within the catalytic cycle, contrasting with the oxidation process involving stoichiometric iodine.

General Information
Reagents and solvents were purchased from commercial suppliers and used directly without further purification, unless otherwise noted. All water was deionized before use. Unless otherwise noted, the glassware employed in the reactions was dried in an oven overnight before use. The oxygen purity used in the experiment is 99.999%.
NMR data were measured with a Bruker Avance NOE 500 and manipulated directly from the spectrometer or via a networked PC with appropriate software. Reference values for residual solvent were taken as δ = 7.27 (CDCl3) and δ = 2.50 (DMSO-d6) for 1 H NMR; δ = 77.1 (CDCl3) and δ = 39.5 (DMSO-d6) for 13 C{ 1 H} NMR. Multiplicities for coupled signals were designated using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br = broad signal, and are given in Hz. Thin-layer chromatography was performed on SIL G/UV254 silica-glass plates, and the plates were visualized using ultra-violet light (254 nm) and KMnO4 solution. For flash column chromatography, silica gel (60, 35-70 μm) was used.

General Information
Reagents and solvents were purchased from commercial suppliers and used directly without further purification, unless otherwise noted. All water was deionized before use. Unless otherwise noted, the glassware employed in the reactions was dried in an oven overnight before use. The oxygen purity used in the experiment is 99.999%.
NMR data were measured with a Bruker Avance NOE 500 and manipulated directly from the spectrometer or via a networked PC with appropriate software. Reference values for residual solvent were taken as δ = 7.27 (CDCl 3 ) and δ = 2.50 (DMSO-d 6 ) for 1 H NMR; δ = 77.1 (CDCl 3 ) and δ = 39.5 (DMSO-d 6 ) for 13 C{ 1 H} NMR. Multiplicities for coupled signals were designated using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br = broad signal, and are given in Hz. Thin-layer chromatography was performed on SIL G/UV254 silica-glass plates, and the plates were visualized using ultra-violet light (254 nm) and KMnO 4 solution. For flash column chromatography, silica gel (60, 35-70 µm) was used.

Calculation of the Yield by Internal Standard Using 1 H NMR
The determination of yields by 1 H NMR was according to the equation below: Yield = Area product Area internal standard n internal standard n theoretical product × 100% Area product means the integration of the product peak; Area internal standard means the integration of the internal standard peak; n internal standard means the number of moles of the internal standard; n theoretical product means the theoretical number of moles of the product. (Table 1) To a round bottom flask were added I 2 (0-7.61 mg, 0-10.0 mol%), dodecane-1-thiol (60.7 mg, 0.300 mmol, 1.00 equiv), and anhydrous EtOAc (8.00 mL). The flask was filled with an oxygen balloon (0.3 MPa), and the reaction mixture was stirred at 70 • C for a duration of 1-4 h. Subsequently, the reaction mixture was cooled to r.t. The reaction mixture was diluted with EtOAc (10.0 mL) and washed with HCl solution (15.0 mL, 0.100 M, aq). The aqueous layer was extracted with EtOAc (3 × 15.0 mL). Organic layers were combined, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by flash chromatography (silica, 0-12.5% EtOAc/Hexane). The sample was then analyzed by 1 H NMR (CDCl 3 , 500 MHz) to obtain the yield using the internal standard (1,1,2,2-tetrachloroethane) and comparison with corresponding samples.

General Procedure for the Oxidative Coupling of Thiols
To a round bottom flask were added I 2 (3.81 mg, 5.00 mol%), thiol (0.300 mmol, 1.00 equiv), and EtOAc (8.00 mL). The flask was filled with an oxygen balloon (0.3 MPa), and the reaction mixture was stirred at 70 • C for a duration of 4 h. Subsequently, the reaction mixture was cooled to r.t. The reaction mixture was diluted with EtOAc (10.0 mL) and washed with HCl solution (15.0 mL, 0.100 M, aq). The aqueous layer was extracted with EtOAc (3 × 15.0 mL). Organic layers were combined, dried over MgSO 4 , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography (silica, 0-12.5% EtOAc/Hexane). Notably, 1 H NMR and 13 C{ 1 H} NMR data of 2a-2z were presented at Supporting Information.

Procedure for Control Experiments (Scheme 1)
Scheme 1(AI): To a round bottom flask were added 55 wt% HI (3.49 mg, 5.00 mol%), dodecane-1-thiol (60.7 mg, 0.300 mmol, 1.00 equiv), and anhydrous EtOAc (8.00 mL). The flask was filled with an oxygen balloon (0.3 MPa), and the reaction mixture was stirred at 70 • C for a duration of 4 h. Subsequently, the reaction mixture was cooled to r.t. The reaction mixture was diluted with EtOAc (10.0 mL) and washed with HCl solution (15.0 mL, 0.100 M, aq). The aqueous layer was extracted with EtOAc (3 × 15.0 mL). Organic layers were combined, dried over MgSO 4 , filtered, and concentrated. The crude product was then analyzed by 1 H NMR (CDCl 3 , 500 MHz) to obtain the yield using the internal standard (1,1,2,2-tetrachloroethane) and comparison with corresponding samples. Scheme 1(AII): To a round bottom flask were added I 2 (38.1mg, 50.0 mol%), dodecane-1-thiol (60.7 mg, 0.300 mmol, 1.00 equiv), and anhydrous EtOAc (8.00 mL). The flask was filled with an oxygen balloon (0.3 MPa), and the reaction mixture was stirred at 70 • C for a duration of 4 h. Subsequently, the reaction mixture was cooled to r.t. The reaction mixture was diluted with EtOAc (10.0 mL) and washed with HCl solution (15.0 mL, 0.100 M, aq). The aqueous layer was extracted with EtOAc (3 × 15.0 mL). Organic layers were combined, dried over MgSO 4 , filtered, and concentrated. The crude product was then analyzed by 1 H NMR (CDCl 3 , 500 MHz) to obtain the yield using the internal standard (1,1,2,2-tetrachloroethane) and comparison with corresponding samples. Scheme 1(AIII): To a round bottom flask were added I 2 (38.1 mg, 50.0 mol%), dodecane-1-thiol (60.7 mg, 0.300 mmol, 1.00 equiv), TEMPO (1.00 equiv), and anhydrous EtOAc (8.00 mL). The flask was filled with an oxygen balloon (0.3 MPa), and the reaction mixture was stirred at 70 • C for a duration of 4 h. Subsequently, the reaction mixture was cooled to r.t. The reaction mixture was diluted with EtOAc (10.0 mL) and washed with HCl solution (15.0 mL, 0.100 M, aq). The aqueous layer was extracted with EtOAc (3 × 15.0 mL). Organic layers were combined, dried over MgSO 4 , filtered, and concentrated. The crude product was then analyzed by 1 H NMR (CDCl 3 , 500 MHz) to obtain the yield using the internal standard (1,1,2,2-tetrachloroethane) and comparison with the corresponding sample.

Conclusions
In summary, we have established a cost-effective and environmentally friendly I 2 -catalyzed aerobic oxidative coupling of thiols for the synthesis of valuable disulfide. In contrast to reported catalytic aerobic oxidation methods, this protocol circumvented the need for transition-metal catalysts and reagents that are not commercially available. This novel method tolerates both primary and secondary alkyl thiols, as well as aryl thiols. All 26 tested substrates with various functional groups resulted in good yields, which highlighted the exceptional functional group compatibility of this approach. This sustainable methodology holds promise for widespread applicability across both academic and industrial realms.