In situ generated HClO for the conversion of thiols and disulfides into thiosulfonates

A new, practical method for the oxidative conversion of disulfides into thiosulfonates is reported. It is based on the use of hydrogen peroxide as a green oxidant and HCl as a source of the actual catalyst, in acetonitrile as solvent at room temperature. Both disulfides and thiols are efficient substrates for this reaction that permitted the preparation of a small library of symmetrical thiosulfonates in good yields


Introduction
Thiosulfonates, the S-esters of thiosulfonic acids, are interesting organosulfur compounds displaying remarkable pharmacological properties and having synthetic applications.In particular, when introduced into organic scaffolds, such functional groups equip the molecule with the ability to block the normal metabolism of pathogenic microorganisms.The chemical mechanism behind such behavior is the ability of thiosulfonates to trigger the sulfonation of thiol groups of various enzymes, that leads to their inhibition (Figure 1). 1 Several antifungal, 2 antiviral [3][4][5] and anticancer compounds 6 having such a functional group have been reported. 7gure 1.Biologically active compounds bearing the thiosulfonate functionality.
From a synthetic perspective, thiosulfonates are particularly useful due to their ability to work as either nucleophiles or electrophiles depending on the reaction conditions.In addition, they are generally more reactive than disulfides, due to the higher polarization of the S-S bond, but, at the same time, they are easier to handle than the highly reactive sulfenyl halides.The synthetic versatility of such compounds is evident as they can transfer either the sulfenyl as well as the sulfonyl groups to the reaction partners and also the S-S bond has the propensity to break under electrochemical and photocatalytic conditions generating sulfur centered radicals. 8here are several methods for the preparation of thiosulfonates, all of them were very recently and comprehensively reviewed highlighting also the parameters associated with each synthetic procedure that make them address the green chemistry prescriptions. 8he most practical method to synthesize thiosulfonates is the direct oxidation of disulfides or thiols (Scheme 1) with m-chloroperbenzoic acid [9][10][11] or hydrogen peroxide under acidic conditions, 12 which represent the most employed reagents to perform such transformations.Among several oxidative protocols that have been reported, in the most recent, Back developed a bioinspired selenium catalyzed protocol capable of converting disulfides into the corresponding thiosulfonates in high yields, 13 while Kirihara et al. used selectfluor to perform the same transformation. 14,15In 2010, Chen and coworkers reported the use of trichloroisocyanuric acid as oxidant under mechanochemical conditions. 16Microwave heating was also implemented for the synthesis of such compounds, as demonstrated by Luu in 2015. 17Oxone in combination with KBr proved to be a valid alternative as shown by Natarajan et al. 18 Finally, molecular oxygen can be used under photoredox catalysis conditions, 19 and very recently, also an electrochemical approach has been reported to perform such chemistry allowing formation of unsymmetrical thiosulfonates. 20heme 1. Stepwise oxidation of thiols to thiosulfonates.

Results and Discussion
Acetonitrile was selected as the most suitable solvent to convert the model substrate, dibenzyldisulfide 2a, into the corresponding thiosulfonate derivative 4a in the presence of a catalytic amount of copper salts, which were selected as it is known that they are useful in oxidative transformations. 31Different combinations of catalysts, amounts of catalysts and amounts of hydrogen peroxide were tested monitoring the reactions at different times.The most relevant results are collected in Table 1.While cuprous nitrite and iodide proved to be ineffective, even after a reaction time of 72 hours (not shown), both copper chlorides (I) and (II) showed an appreciable catalytic capability.In particular, CuCl is able to almost completely convert the starting material in the presence of three equivalents of oxidant after eight hours (Table 1, entry 4).Unfortunately, the reaction is not selective, since, beside the target compound 4a, several other overoxidized products were detected in the crude reaction mixture.Cupric chloride, is a weaker catalyst, indeed, to reach a conversion of 53%, 31 hours were needed, but this helped the selectivity, indeed the desired thiosulfonate 4a was the main reaction product (entry 1).Increasing the reaction time, as well as the amount of hydrogen peroxide did not improve the outcome of the reaction.
In order to understand if the catalytic activity is exerted by the metal or its counter-anion, experiments using catalytic amounts of NaCl or KCl were performed (Table 2).a stoichiometric amounts were used, b a stoichiometric amount of 37% (w/w) aqueous hydrochloric acid was used, c calculated by 1 H NMR of the crude reaction mixture on the consumption of 2a, d yield calculated by 1 H NMR, e isolated yield.
Using these alkaline metals chlorides the reaction reached completion in a time ranging from 55 h to 45 h and the formation of overoxidized products is almost completely abolished, thus the thiosulfonate 4a was formed as the main reaction product (Table 2, entries 1 and 2).Comparative reactions were carried out replacing the metal catalysts with stoichiometric amounts of HCl.The reactions in the presence of hydrochloric acid are faster if compared to those catalyzed by alkaline metals chlorides, and if compared to those catalyzed by the copper salts, they are more efficient as lower amounts of oxidant are needed to make the reaction complete.Thiosulfonate 4a was the only compound obtained from the reaction and only traces of side products, removed after a fast and easy chromatographic purification, were observed.With the best conditions in hands, the scope of the reaction was briefly explored starting from a small library of aromatic and aliphatic disulfides and aromatic thiols (Tables 3 and 4).The presence of an electron-donating or -withdrawing group in the phenyl ring did not influence the outcome of the reaction, indeed p-tolyldisulfide 2b and 2c p-fluorophenyl disulfide were straightforwardly converted into the corresponding thiosulfonates in excellent yields, in reaction times ranging from 8 to 9 hours.Diphenyldisulfide 2d was converted into the target compound after 42 h in fair yield.The aliphatic diallyldisulfide 2e showed a reduced reactivity when subjected to the oxidation protocol using either three or four equivalents of hydrogen peroxide, yielding S-allyl prop-2-ene-1-sulfonothioate 4e in fair yields (entry 4) which were slightly improved by prolonging the reaction times to 16 hours.
The flexibility of the proposed protocol was tested by using thiols as starting materials.From a stoichiometric standpoint, three equivalents of hydrogen peroxide were enough for both the formation of the disulfide link as well as for the oxidation to thiosulfonate (Table 4).
Meta-methylphenyl thiol 1f gave the corresponding thiosulfonate in excellent yield (entry 1) after 24 hours of reaction time.The use of its ortho regioisomer 1g gave a very similar result.(entry 2).Compound 1h was converted into the thiosulfonate 4h in lower yield (entry 3).In this specific case the formation of p-Brbenzensulfonic acid as an overoxidation and undesired product was observed.The naphthyl derivative 4i was prepared in good yield but a longer reaction time was required (entry 4).Based on literature evidence, 32,33 a reaction mechanism can be suggested (Scheme 2).Initially, the oxidation of HCl into hypochlorous acid takes place.Then, HClO reacts with the thiol leading to disulfides that in turn are converted into 7. Intermediate 7 decomposes to the elusive thiosulfinate 3 which is in turn further oxidized to the target thiosulfonate 4 via the intermediate gem disulfoxide 8.

Conclusions
In the present paper a novel process for the synthesis of thiosulfonates has been developed, including screening of copper and alkali metal chlorides as catalysts.While the reactions catalyzed by copper chloride were unselective, the use of alkali metal chlorides, such as NaCl and KCl, avoided the formation of overoxidation products, thus obtaining the target thiosulfonates.The use of stoichiometric amounts of HCl shortened the reaction time while maintaining the same chemoselectivity and this allowed the preparation of a small library of thiosulfonates potentially useful for other purposes.This also sugests that in the reaction catalyzed by copper and alkali metal chlorides, it is reasonable to suppose that they act as precursors of HCl and thus of HClO.

Experimental Section
General.Reactions were conducted in round bottom flasks and were stirred with Teflon-coated magnetic stirring bars.Solvents and reagents were used as received unless otherwise noted.The starting materials are commercially available.Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 precoated aluminum foil sheets and visualized by UV irradiation or by iodine staining.Sigma Aldrich silica gel (230-400 mesh) was used for flash chromatography and silica gel Kieselgel 60 (70-230 mesh) was used for column chromatography.NMR measurements were conducted at 25 °C on a Bruker Avance 400 spectrometer operating at 400 MHz for 1 H, 100.62 MHz for 13 C and 376 MHz for 19 F experiments. 1 H and 13 C chemical shifts (δ) are reported in parts per million (ppm) and they are relative to TMS 0.0 ppm and the residual solvent peak of CDCl3 at δ 7.26 and δ 77.00 in 1 H and 13 C NMR, respectively. 19F spectra were referenced to CFCl3 resonating at 0 ppm.Data are reported as follows: chemical shift (multiplicity, number of hydrogens, coupling constants where applicable, and assignment where possible).Abbreviations are as follows: 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 constant (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.

Table 2 .
Evaluation of alkaline metal chlorides

Table 3 .
Scope of the reaction: disulfides

Table 4 .
Scope of the reaction: thiols