Continuous Bioinspired Oxidation of Sulfides

A simple, efficient, and selective oxidation under flow conditions of sulfides into their corresponding sulfoxides and sulfones is reported herein, using as a catalyst perselenic acid generated in situ by the oxidation of selenium (IV) oxide in a diluted aqueous solution of hydrogen peroxide as the final oxidant. The scope of the proposed methodology was investigated using aryl alkyl sulfides, aryl vinyl sulfides, and dialkyl sulfides as substrates, evidencing, in general, a good applicability. The scaled-up synthesis of (methylsulfonyl)benzene was also demonstrated, leading to its gram-scale preparation.


Introduction
Heteroatom oxidation, with particular emphasis on nitrogen and sulfur, is a process of great relevance in organic synthesis. For the oxidation of sulfides into their corresponding sulfoxides and sulfones, a number of procedures have been described, including stoichiometric reactions, chemocatalytic reactions, and bio-catalytic reactions [1]. The main goal of this kind of transformation is the selective preparation of the mono-oxygenated over the bis-oxygenated derivatives, and the result is strongly dependent on the protocol used for the oxidation, being directly correlated to the nucleophilicity of the sulfide and sulfoxide and the electrophilicity of the actual oxidizing species.
Arylsulfones and arylsulfoxides are useful synthetic intermediates and building blocks for the synthesis of a series of biologically active compounds [2,3].
A non-exhaustive panel of examples is presented in Figure 1: an arylsulfone moiety is present in drugs like Rofecoxib (I) [4], Laropiprant (II) [5], Dapson (III) [6], and Sulfamethoxazole (IV) [7], while examples of arylsulfoxides (even if less distributed due to their relative instability) can be found in Sulindac (V) a clinically used anti-inflammatory drug [8], in esomeprazole (VI), the S enantiomer of omeprazole [9], and in a recently reported compound (VII) with anti-HIV activity [10].
Over the last ten years, we have studied the applicability of selenium derivatives as catalysts in biomimetic oxidations, demonstrating that this approach presents a number of advantages in terms of eco-sustainability [11].
We demonstrated that as the selenium atom of the glutathione peroxidase enzyme catalyzes the oxidation of two molecules of glutathione using peroxides as stoichiometric oxidants, small organoselenium molecules can be biomimetically used as catalysts in the hydrogen-peroxide-mediated oxidation of thiols [12]. The same reactivity can be translated into the oxidation of carbon-carbon double bonds, affording epoxide intermediates that can be opened by a nucleophilic solvent, affording Over the last ten years, we have studied the applicability of selenium derivatives as catalysts in biomimetic oxidations, demonstrating that this approach presents a number of advantages in terms of eco-sustainability [11].
We demonstrated that as the selenium atom of the glutathione peroxidase enzyme catalyzes the oxidation of two molecules of glutathione using peroxides as stoichiometric oxidants, small organoselenium molecules can be biomimetically used as catalysts in the hydrogen-peroxidemediated oxidation of thiols [12]. The same reactivity can be translated into the oxidation of carboncarbon double bonds, affording epoxide intermediates that can be opened by a nucleophilic solvent, affording vicinal diols [13,14] or α-methoxy alcohols [14] when the reaction is carried out in water or in methanol, respectively. When the substrate is an alkenol or an alkenoic acid, the epoxydic intermediate is opened intramolecularly by the internal nucleophile, leading to oxidative cyclofunctionalization with the formation of cyclic hydroxylethers or hydroxylactones [15]. Furthermore, the same catalytic system has been used also to oxidize aldehydes into their corresponding carboxylic acids in "on water" conditions, or into their corresponding esters when the reaction medium is a primary or a secondary alcohol [16].
The possibility of performing these catalytic reactions in aqueous media or in biphasic systems and the beneficial effects on the reactivity and selectivity, as well as the reaction workup, product purification, and recovery and reuse of the catalyst, were recently reviewed [17].
Nowadays, continuous-flow transformations represent an innovative methodology which is gaining increasing interest in both academic and industrial research including in the pharmaceutical industry. Reactions performed under continuous flow are generally faster, safer, and more environmentally friendly than those realized in batches. Recently, great progress was also made in terms of flexibility and robustness for large-scale processes [18], as well as in bioorganic catalysis [19], photochemistry [20], and electrochemistry, combined with on-line analysis [21,22]. For these reasons, studies focused on the reinterpretation of old transformations with this new technology are of particular interest in order to increase the number of synthetic tools exploitable in flow chemistry.
After a seminal study in which we demonstrated that bioinspired selenium-catalyzed reactions can be translated into continuous mode [23] some of the present authors, using a biphasic liquidliquid system, reported the continuous oxidative cyclofunctionalization of alkenoic acids. The reaction conditions were optimized for the synthesis and purification of a library of biologically relevant lactones using a fully automated flow setup [24]. We clearly observed that the flow conditions produced a sensible reduction of the reaction time (residence time) as a consequence of a The possibility of performing these catalytic reactions in aqueous media or in biphasic systems and the beneficial effects on the reactivity and selectivity, as well as the reaction workup, product purification, and recovery and reuse of the catalyst, were recently reviewed [17].
Nowadays, continuous-flow transformations represent an innovative methodology which is gaining increasing interest in both academic and industrial research including in the pharmaceutical industry. Reactions performed under continuous flow are generally faster, safer, and more environmentally friendly than those realized in batches. Recently, great progress was also made in terms of flexibility and robustness for large-scale processes [18], as well as in bioorganic catalysis [19], photochemistry [20], and electrochemistry, combined with on-line analysis [21,22]. For these reasons, studies focused on the reinterpretation of old transformations with this new technology are of particular interest in order to increase the number of synthetic tools exploitable in flow chemistry.
After a seminal study in which we demonstrated that bioinspired selenium-catalyzed reactions can be translated into continuous mode [23] some of the present authors, using a biphasic liquid-liquid system, reported the continuous oxidative cyclofunctionalization of alkenoic acids. The reaction conditions were optimized for the synthesis and purification of a library of biologically relevant lactones using a fully automated flow setup [24]. We clearly observed that the flow conditions produced a sensible reduction of the reaction time (residence time) as a consequence of a slug flow, which created local vortex fields able to increase the mass transfer rates between the organic and the aqueous phases. Here, we report our recent results in the selenium-catalyzed oxidation of sulfides under flow conditions to selectively afford sulfoxides and sulfones in line with the principles of efficiency, safety, mild reaction conditions, and overall atom economy.
The first example of a continuous oxidation of sulfides was reported by Nunez in 2010, who used silica-supported peracid and supercritical carbon dioxide and obtained a moderate level of chemoselectivity depending on the pressure [25]. In the same period, a green method was reported for the continuous and chemoselective synthesis of a few arylsulfoxides using diluted hydrogen peroxide and the sulfonic resin Amberlite 120 H [26].
More recently, a selective method based on the use of a microflow electrocell for electrochemical oxidation was reported, in which the selectivity can be tuned by changing the applied potential [27], and a method in which a solution of sulfide in dichloromethane and 15 vol. % of CF 3 COOH were fluxed in a packed-bed reactor filled with Oxone ®® . In the latter case, an example of selective mono-oxygenation of a disulfide was also described [28].
In our protocol, a bioinspired approach was implemented for the continuous and chemoselective oxidation of sulfides (1) into their corresponding sulfoxides (2) or sulfones (3) (Scheme 1). The reaction was carried out using SeO 2 as the most atom-economical Se-based pre-catalyst, in a liquid-liquid biphasic system at room temperature with hydrogen peroxide as the green oxidant. oxidation of sulfides under flow conditions to selectively afford sulfoxides and sulfones in line with the principles of efficiency, safety, mild reaction conditions, and overall atom economy.
The first example of a continuous oxidation of sulfides was reported by Nunez in 2010, who used silica-supported peracid and supercritical carbon dioxide and obtained a moderate level of chemoselectivity depending on the pressure [25]. In the same period, a green method was reported for the continuous and chemoselective synthesis of a few arylsulfoxides using diluted hydrogen peroxide and the sulfonic resin Amberlite 120 H [26].
More recently, a selective method based on the use of a microflow electrocell for electrochemical oxidation was reported, in which the selectivity can be tuned by changing the applied potential [27], and a method in which a solution of sulfide in dichloromethane and 15 vol. % of CF3COOH were fluxed in a packed-bed reactor filled with Oxone ®® . In the latter case, an example of selective monooxygenation of a disulfide was also described [28].
In our protocol, a bioinspired approach was implemented for the continuous and chemoselective oxidation of sulfides (1) into their corresponding sulfoxides (2) or sulfones (3) (Scheme 1). The reaction was carried out using SeO2 as the most atom-economical Se-based pre-catalyst, in a liquidliquid biphasic system at room temperature with hydrogen peroxide as the green oxidant.

Results and Discussions
Some years ago, Drabowicz et al. reported that the synthesis of sulfoxides [29] and sulfones [30] can be achieved by starting from the corresponding sulfides, using hydrogen peroxide/selenoxide system to form peroxyselenic (IV) acid in situ as the actual stoichiometric oxidizing reagent. Even if the synthetic versatility of selenium (IV) oxide is widely reported in the literature, its use in organic synthesis, especially as a stoichiometric reagent, is often limited by its toxicity and tendency to generate volatile and malodorous side products [31]. With the aim of overcoming these limitations, we decided to explore the possibility of using SeO2 as the catalyst in a bioinspired oxidation process in the presence of hydrogen peroxide using liquid-liquid biphasic flow conditions. Preliminary investigations were carried out by following the conversion of phenylethylsulfide 1a into its sulfoxide (2a) and sulfone (3a). The effects of the flow rate and the amount of hydrogen peroxide were evaluated, looking at the conversion as well as the chemoselectivity of the reaction.
A 0.5 M solution of the substrate 1a in ethyl acetate (Solution A) and a 0.05 M solution of SeO2 in water in the presence of the different amounts of H2O2 reported in Table 1 (Solution B), were fluxed through a Y junction in a 2 mL tubular reactor, at four different flow rates corresponding to residence times of 6.5, 10, 20 and 100 min. The chemoselectivity seemed to be influenced predominantly by the amount of hydrogen peroxide (Entries 1-5 vs. Entries 6-8). In entries 3-5 the conversion yield for the formation of the sulfoxide 2a increased with the reduction of the flow rate from 0.3 mL/min to 0.1 mL/min and, in these conditions, using 2 equivalents of hydrogen peroxide, the target compound (2a) was obtained in an 85% yield and with 100% chemoselectivity. When the reaction was repeated in the same conditions but without SeO2, only the starting material was observed in the 1 H-NMR spectrum of the crude product, confirming the catalytic role of selenium. Increasing the amount of hydrogen peroxide from 2 (entry 5) to 5 (entry 7) and 10 (entries 7,8) equivalents also increased the formation of the sulfone 3a, which was quantitatively obtained as a unique reaction product when the reaction was carried out in the presence of 10 equivalents of H2O2 at both 0.1 and 0.2 mL/min (entries 7,8). The proposed mechanism for the catalytic cycle is reported in Scheme 2. Selenium (IV) oxide in water is in equilibrium with the hydrated form which is particularly prone to oxidation by hydrogen peroxide, affording the corresponding peroxyselenic (IV) acid as the actual catalyst in the formation of both the sulfoxide 2 and sulfone 3, depending on the amount of the oxidant.
The oxidation of sulfide 1 into the corresponding sulfoxide 2 and sulfone 3.

Results and Discussions
Some years ago, Drabowicz et al. reported that the synthesis of sulfoxides [29] and sulfones [30] can be achieved by starting from the corresponding sulfides, using hydrogen peroxide/selenoxide system to form peroxyselenic (IV) acid in situ as the actual stoichiometric oxidizing reagent. Even if the synthetic versatility of selenium (IV) oxide is widely reported in the literature, its use in organic synthesis, especially as a stoichiometric reagent, is often limited by its toxicity and tendency to generate volatile and malodorous side products [31]. With the aim of overcoming these limitations, we decided to explore the possibility of using SeO 2 as the catalyst in a bioinspired oxidation process in the presence of hydrogen peroxide using liquid-liquid biphasic flow conditions. Preliminary investigations were carried out by following the conversion of phenylethylsulfide 1a into its sulfoxide (2a) and sulfone (3a). The effects of the flow rate and the amount of hydrogen peroxide were evaluated, looking at the conversion as well as the chemoselectivity of the reaction.  Table 1 (Solution B), were fluxed through a Y junction in a 2 mL tubular reactor, at four different flow rates corresponding to residence times of 6.5, 10, 20 and 100 min. The chemoselectivity seemed to be influenced predominantly by the amount of hydrogen peroxide (Entries 1-5 vs. Entries 6-8). In entries 3-5 the conversion yield for the formation of the sulfoxide 2a increased with the reduction of the flow rate from 0.3 mL/min to 0.1 mL/min and, in these conditions, using 2 equivalents of hydrogen peroxide, the target compound (2a) was obtained in an 85% yield and with 100% chemoselectivity. When the reaction was repeated in the same conditions but without SeO 2 , only the starting material was observed in the 1 H-NMR spectrum of the crude product, confirming the catalytic role of selenium. Increasing the amount of hydrogen peroxide from 2 (entry 5) to 5 (entry 7) and 10 (entries 7,8) equivalents also increased the formation of the sulfone 3a, which was quantitatively obtained as a unique reaction product when the reaction was carried out in the presence of 10 equivalents of H 2 O 2 at both 0.1 and 0.2 mL/min (entries 7,8). The proposed mechanism for the catalytic cycle is reported in Scheme 2. Selenium (IV) oxide in water is in equilibrium with the hydrated form which is particularly prone to oxidation by hydrogen peroxide, affording the corresponding peroxyselenic (IV) acid as the actual catalyst in the formation of both the sulfoxide 2 and sulfone 3, depending on the amount of the oxidant.  From these preliminary data, the reaction conditions reported in Entry 5 and Entry 8 were selected as the best ones for the evaluation of the scope. A set of sulfides (Compounds 1a-g, Table 2) was converted into the corresponding sulfoxides 2a-f and sulfones 3a-g.
The results obtained for the synthesis of sulfoxides 2a-g are summarized in Table 2. All the tested aryl sulfides 1a-f afforded the corresponding mono-oxygenated derivatives 2a-f in very high yields and with complete chemoselectivity. Only in the case of the naphtylethylsulfide 1d was it necessary to use diluted solutions, due to a lower solubility leading to poor conversion into the target compound 2d (20%). In order to increase the yield, we decided to use 5 equivalents of hydrogen peroxide. In these new conditions, 1d was quantitatively converted in an 80:20 mixture of 2d/3d, from which 2d was isolated in a 75% yield after chromatographic purification by flash chromatography. In the case of the aliphatic tetrahydrothiofene 1g, it was impossible to optimize the conditions for the synthesis and purification of sulfoxide 2g, and a mixture of 1g, 2g, and 3g was obtained that proved to be neither separable by chromatography nor unequivocally quantifiable by 1   From these preliminary data, the reaction conditions reported in Entry 5 and Entry 8 were selected as the best ones for the evaluation of the scope. A set of sulfides (Compounds 1a-g, Table 2) was converted into the corresponding sulfoxides 2a-f and sulfones 3a-g.
The results obtained for the synthesis of sulfoxides 2a-g are summarized in Table 2. All the tested aryl sulfides 1a-f afforded the corresponding mono-oxygenated derivatives 2a-f in very high yields and with complete chemoselectivity. Only in the case of the naphtylethylsulfide 1d was it necessary to use diluted solutions, due to a lower solubility leading to poor conversion into the target compound 2d (20%). In order to increase the yield, we decided to use 5 equivalents of hydrogen peroxide. In these new conditions, 1d was quantitatively converted in an 80:20 mixture of 2d/3d, from which 2d was isolated in a 75% yield after chromatographic purification by flash chromatography. In the case of the aliphatic tetrahydrothiofene 1g, it was impossible to optimize the conditions for the synthesis and purification of sulfoxide 2g, and a mixture of 1g, 2g, and 3g was obtained that proved to be neither separable by chromatography nor unequivocally quantifiable by 1  From these preliminary data, the reaction conditions reported in Entry 5 and Entry 8 were selected as the best ones for the evaluation of the scope. A set of sulfides (Compounds 1a-g, Table 2) was converted into the corresponding sulfoxides 2a-f and sulfones 3a-g.
The results obtained for the synthesis of sulfoxides 2a-g are summarized in Table 2. All the tested aryl sulfides 1a-f afforded the corresponding mono-oxygenated derivatives 2a-f in very high yields and with complete chemoselectivity. Only in the case of the naphtylethylsulfide 1d was it necessary to use diluted solutions, due to a lower solubility leading to poor conversion into the target compound 2d (20%). In order to increase the yield, we decided to use 5 equivalents of hydrogen peroxide. In these new conditions, 1d was quantitatively converted in an 80:20 mixture of 2d/3d, from which 2d was isolated in a 75% yield after chromatographic purification by flash chromatography. In the case of the aliphatic tetrahydrothiofene 1g, it was impossible to optimize the conditions for the synthesis and purification of sulfoxide 2g, and a mixture of 1g, 2g, and 3g was obtained that proved to be neither separable by chromatography nor unequivocally quantifiable by 1 H NMR.             3 Not determined (a non-resolvable mixture of 1g, 2g, and 3g was obtained, and it was not possible to calculate the corresponding ratio from the 1 H-NMR spectrum of the crude product).
Excellent results were also obtained for the synthesis of the sulfones 3a-g, (Table 3). In all the cases, the desired products were obtained pure and in quantitative yield simply by the separation of the organic layers and the removal under vacuum of the solvent, without the need for any other purification. In the cases of substrate 1d, we used a 0.25 M solution of the starting material and a 0.025 M solution of the catalyst to overcome the solubility issues of the corresponding sulfone 3d, without any detrimental effect on the yield.
In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy.  3 Not determined (a non-resolvable mixture of 1g, 2g, and 3g was obtained, and it was not possible to calculate the corresponding ratio from the 1 H-NMR spectrum of the crude product).
Excellent results were also obtained for the synthesis of the sulfones 3a-g, (Table 3). In all the cases, the desired products were obtained pure and in quantitative yield simply by the separation of the organic layers and the removal under vacuum of the solvent, without the need for any other purification. In the cases of substrate 1d, we used a 0.25 M solution of the starting material and a 0.025 M solution of the catalyst to overcome the solubility issues of the corresponding sulfone 3d, without any detrimental effect on the yield.
In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy.  M solution of the catalyst to overcome the solubility issues of the corresponding sulfone 3d, without any detrimental effect on the yield. In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy. purification. In the cases of substrate 1d, we used a 0.25 M solution of the starting material and a 0.025 M solution of the catalyst to overcome the solubility issues of the corresponding sulfone 3d, without any detrimental effect on the yield. In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy. purification. In the cases of substrate 1d, we used a 0.25 M solution of the starting material and a 0.025 M solution of the catalyst to overcome the solubility issues of the corresponding sulfone 3d, without any detrimental effect on the yield. In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy. any detrimental effect on the yield. In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy. any detrimental effect on the yield. In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy. In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy. In these conditions, the aliphatic substrate 1g was quantitatively converted into the corresponding sulfone 3g, which was isolated and characterized using 1 H and 13 C-NMR spectroscopy. It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3 affording, in 200 min, quantitatively a 91:9 mixture of 3b/2b corresponding to a processing rate of 10.16 gd −1 for 3b. (See Supplementary Materials).

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [32] Analytical thinlayer chromatography (TLC) was performed on silica-gel-precoated (60F-254) aluminum foil sheets It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [ It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [ It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [ It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [ It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3 affording, in 200 min, quantitatively a 91:9 mixture of 3b/2b corresponding to a processing rate of 10.16 gd −1 for 3b. (See Supplementary Materials).

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [ It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3 affording, in 200 min, quantitatively a 91:9 mixture of 3b/2b corresponding to a processing rate of 10.16 gd −1 for 3b. (See Supplementary Materials).

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [ It was observed that in the case of vinyl sulfide 1e, the proposed methodology afforded only the oxidation of the sulfur atom, and in both conditions for the synthesis of the sulfoxide 2d or the sulfone 3d, the C=C was not oxidized.
Finally, in order to test the scalability of the process, 10 mmol of sulfide 1b was processed using the conditions reported in Table 3 affording, in 200 min, quantitatively a 91:9 mixture of 3b/2b corresponding to a processing rate of 10.16 gd −1 for 3b. (See Supplementary Materials).

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [

Materials and Methods
Solvents and reagents were purchased from Sigma-Aldrich (St Louis, MS, USA), Alfa Aesar (Kandel, Germany), and VWR (Milano, Italy), and used as received unless otherwise noted. Compound 1d was prepared according to the procedure reported in literature. [32] Analytical thin-layer chromatography (TLC) was performed on silica-gel-precoated (60F-254) aluminum foil sheets (Merck, Darmstadt, Germany), using short-wave UV light (TUV T8 HO 95W G13 UVC, Philips, Milano, Italy) as the visualizing agent. NMR spectroscopic (Bruker, Fällanden, Switzerland) experiments were conducted at 25 • C on Bruker DPX and DRX spectrometers operating at the specified frequencies. 1 H and 13 C chemical shifts (δ) are reported in parts per million (ppm), relative to TMS (δ = 0.0 ppm) and the residual solvent peak of CDCl 3 (δ = 7.27 and 77.00 ppm in 1 H and 13 C NMR, respectively). Data are reported as chemical shift (multiplicity, coupling constants where applicable, number of hydrogen atoms). Abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), dt (double of triplet), tt (triplet of triplet), m (multiplet), br. s (broad signal). Coupling constants (J) are quoted in Hertz (Hz) to the nearest 0.1 Hz. Melting points were measured using a Kofler hot-stage-microscope Thermovar (Reichert, Vienna, Austria) and are reported as uncorrected data.

Synthesis of Sulfoxides 2a-f
In a 2 mL volumetric flask, ethyl acetate was added to sulfides 1a-c,e-g (1.0 mmoL) or sulfide 1d (0.5 mmoL) to make up the required volume. (Solution A: 0.5 M (1a-c,e-g). In the case of 1d the concentration was optimized at 0.25 M.) Into a 2 mL volumetric flask, 0.1 mmoL of SeO 2 (11 mg) and H 2 O 2 30 wt. % (2 mmoL, 205 µL) were poured, and then water was added until the desired volume was reached. (Solution B: 0.05 M (SeO 2 ) and 1 M (H 2 O 2 ). In the case of 1d, a different concentration was optimized at 0.025 M (SeO 2 ) and 1.25 M (H 2 O 2 )).
Solutions A and B were fluxed at the same flow rate through a multi-syringe pump apparatus (Chemyx Fusion 100, Stafford, TX, USA) equipped with two syringes (2 mL), and they were mixed in a Y-junction and flowed at 0.100 mL/min through a tubularPTFE reactor coil with internal diameter of 1 mm and internal volume of 2 mL (Bohlender GmbH, Grünsfeld, Germany) at room temperature. The system was washed with 4 mL of ethyl acetate, and the aqueous and organic layers were collected in a flask, quenched with an aqueous solution of Na 2 S 2 O 3 10% (w/v) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure, affording the target sulfoxides. When required, the unreacted starting material was removed under vacuum, and in the case of 2d, it was separated from the corresponding sulfone (3d) by flash chromatography on a silica gel column using EtOAc/petroleum ether (2:98) as eluent.

Synthesis of Sulfones 2a-g
In a 2 mL volumetric flask, ethyl acetate was added to sulfides 1a-c,e-g (1.0 mmoL) or sulfide 1d, (0.5 mmoL) to make up the required volume. (Solution A: 0.5 M (1a-c,e-g). In the case of 1d, the concentration was optimized at 0.25 M) In a 2 mL volumetric flask, 0.1 mmoL of SeO 2 (11 mg) and H 2 O 2 30 wt. % (10 mmoL, 1.025 mL) were poured, and then water was added until the desired volume was reached. (Solution B: 0.05 M (SeO 2 ) and 5 M (H 2 O 2 ). In the case of 1d, a different concentration was optimized at 0.025 M (SeO 2 ) and 2.5 M (H 2 O 2 )).
Solutions A and B were fluxed at the same flow rate through a multi-syringe pump apparatus equipped with two syringes (2 mL), and they were mixed in a Y-junction and flowed at 0.200 mL/min through a tubular PTFE reactor coil with internal diameter of 1 mm and internal volume of 2 mLat room temperature. The system was washed with 4mL of ethyl acetate, and the aqueous and organic layers were collected in a flask, quenched with an aqueous solution of Na 2 S 2 O 3 10% (w/v), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure affording the target sulfones without further purification.