Ultrasound-Promoted Chemoselective Oxysulfonylation of Alkenes

The synthesis of organosulfur compounds experienced a tremendous growth in the last years. This is particularly true for β-keto-sulfones due to their applications in the synthesis of natural products and heterocyclic compounds as well as to their biological properties. These qualities led to the emergence of several methods for the synthesis of these compounds and strategies based on the oxidation of β-keto-sulfides, alkylation using α-halo-ketones, acylation of methyl sulfones and sulfonylation of methyl ketones using a variety of substrates were described. However, most of them have some limitations such as being non-catalytic, involving multi-step synthesis of the starting materials, or the use of harsh conditions to promote the reaction. The oxysulfonylation of alkenes or alkynes appeared as an easy alternative for the synthesis of β-keto-sulfones. The oxysulfonylation is based on the reaction of alkenes or alkynes with sulfonyl radicals. These radicals can be generated from readily available starting materials, being sulfonyl halides, sulfonylhydrazides, or the oxidation of sulfonates, the most commonly used due to the high atomic efficiency. Despite these characteristics, all these methods require long reaction times, heating and/or the use of a variety of additives to promote the reaction effectively. Accordingly, the development of a simpler method that could make the oxysulfonylation reaction more efficient in terms of yield and reaction time would be of the great interest. Lei and co-workers described the generation of sulfonyl radicals from sulfinic acids in the presence of pyridine and dioxygen for the synthesis of β-hydroxysulfones. It is also well-known that the activation of dioxygen mostly proceeded by a radical process. Within this context, the use of ultrasound as a source of hydroxyl radical and other reactive oxygen species through the formation, growth and implosive collapse of microbubbles in a liquid could result in an unusual reaction environment within and in the vicinity of bubbles. These characteristics make the use of ultrasound irradiation a common partner in a variety of areas such as organic and organometallic chemistry, materials science, aerogels, food chemistry and medicinal research. In addition, the use of ultrasound is in accordance to the principles of sustainable chemistry, while the demand for methods based on the use of less hazardous chemicals and/or solvents, and the reduction of used energy is an expanding area.


Introduction
The synthesis of organosulfur compounds experienced a tremendous growth in the last years. 1This is particularly true for β-keto-sulfones due to their applications in the synthesis of natural products 2 and heterocyclic compounds 3 as well as to their biological properties. 4These qualities led to the emergence of several methods for the synthesis of these compounds and strategies based on the oxidation of β-keto-sulfides, 5 alkylation using α-halo-ketones, 6 acylation of methyl sulfones 7 and sulfonylation of methyl ketones 8 using a variety of substrates were described.However, most of them have some limitations such as being non-catalytic, involving multi-step synthesis of the starting materials, or the use of harsh conditions to promote the reaction.
The oxysulfonylation of alkenes or alkynes appeared as an easy alternative for the synthesis of β-keto-sulfones.The oxysulfonylation is based on the reaction of alkenes or alkynes with sulfonyl radicals.These radicals can be generated from readily available starting materials, being sulfonyl halides, 9 sulfonylhydrazides, 10,11 or the oxidation of sulfonates, 12 the most commonly used due to the high atomic efficiency. 13,14Despite these characteristics, all these methods require long reaction times, heating and/or the use of a variety of additives to promote the reaction effectively.Accordingly, the development of a simpler method that could make the oxysulfonylation reaction more efficient in terms of yield and reaction time would be of the great interest.
Lei and co-workers 15 described the generation of sulfonyl radicals from sulfinic acids in the presence of pyridine and dioxygen for the synthesis of β-hydroxysulfones.It is also well-known that the activation of dioxygen mostly proceeded by a radical process. 16ithin this context, the use of ultrasound as a source of hydroxyl radical and other reactive oxygen species through the formation, growth and implosive collapse of microbubbles in a liquid could result in an unusual reaction environment within and in the vicinity of bubbles. 17These characteristics make the use of ultrasound irradiation a common partner in a variety of areas such as organic and organometallic chemistry, materials science, aerogels, food chemistry and medicinal research. 18,19n addition, the use of ultrasound is in accordance to the principles of sustainable chemistry, while the demand for methods based on the use of less hazardous chemicals and/or solvents, and the reduction of used energy is an expanding area. 20lkenes 1a-g, 1i, 1j and 1l and sodium sulfinates, 2a-d, were purchased from Aldrich Chemical Co. and used as received.Reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm E. Merck silica gel 60 plates (F254) using UV light, vanillin and p-anisaldehyde as visualizing agents. 1 H and 13 C nuclear magnetic resonance (NMR) data were recorded in CDCl 3 .The chemical shifts are reported as delta (d) units in parts per million (ppm) relative to the solvent residual peak as the internal reference. 11B NMR spectrum (128 MHz) was obtained in CDCl 3 .Spectrum was calibrated using BF 3 •Et 2 O (0.0 ppm) as external reference. 22Coupling constants (J) for all spectra are reported in hertz (Hz).The sonication was performed in an 8890E-DTH ultrasonic cleaner (with a frequency of 47 kHz and a nominal power 35 W; Cole Parmer Co.).The reaction flask was located at the maximum energy area in the cleaner, the surface of reactants was slightly lower than the level of the water.The reaction temperature was controlled by water bath.

Results and Discussion
This work describes the use of ultrasound irradiation for the chemo-and regioselective synthesis of β-ketosulfones based on the type reaction of alkenes and sodium salts of organosulfinic acids.In the course of developing milder reaction conditions, the effect of the solvent to promote the reaction was first examined.Thus, styrene, 1a (0.25 mmol), and benzenesulfinic acid sodium salt, 2a (0.375 mmol), were used as model compounds and treated at room temperature with FeCl 3 (20 mol%) using different solvents.The progress of the reaction was monitored by TLC and the results are depicted in Table 1.
From Table 1, it can be observed that mixtures of the corresponding β-keto-sulfone (3a) and β-hydroxy-sulfone (4a) were obtained in all cases with ratios depending on the type of solvent.When dichloromethane was used, a good conversion from 1a to the products and a lower selectivity to the desired compound 3a were observed (Table 1, entry 1).When water or tetrahydrofuran (THF) were used, lower conversions were also observed in both cases, probably due to the low solubility of starting materials in these solvents (Table 1, entries 2 and 3).Better results were observed when acetone or acetonitrile were used after 24 h of reaction (Table 1, entries 4 and 5).A dramatic effect occurred when the reaction was performed under sonication (Table 1, entries 6 to 8).When acetone or acetonitrile were used as the reaction solvent, an increment in both conversion and selectivity was observed, however, when a 2:1 mixture of acetonitrile and water was used, 3a was obtained in better conversions and selectivities (Table 1, entry 8).The most evident effect of the use of ultrasound in the reaction was the reduction of the time from 24 h to only 1 h.
Next, the minimal amount of FeCl 3 necessary to promote the reaction under sonication was screened.The results are described on Table 2. Smaller amounts of catalyst favored the formation of β-hydroxy-sulfone (4a, Table 2, entries 1-3), however, an improvement in both conversion and selectivity was observed when the amount of FeCl 3 was increased to 20 and 30 mol% with no significant changes in the product ratio (Table 2, entries 4 and 5).Nonetheless, the increment in the amount of FeCl 3 to 40 mol% led to a decrease in both conversion and selectivity due to the formation of several by-products in the reaction (Table 2, entry 6).Therefore, the control of the amount of FeCl 3 used in the reaction is fundamental because it is directly related to the conversion and selectivity of the formed products.
As mentioned before, ultrasound irradiation can be used as a source of hydroxyl radical and other reactive oxygen species. 16The combination of ultrasound irradiation and persulfate has been proved to be effective for removing several kinds of pollutants through the generation of both HO • and SO 4 •-. 25Thus, it would be expected that by using the combination of ultrasound irradiation and persulfate, an increment not only in the formation of radicals would be observed, but also in the selectivity favoring the formation of 3a.7][28][29][30][31][32][33] The results are described in Table 3.
Initially, the efficacy of the reaction was investigated using 20 mol% of ammonium persulfate [(NH 4 ) 2 S 2 O 8 ] as the oxidant, without FeCl 3 .After 1 h, the reaction was not complete with much of the remaining starting material being observed together with a conversion of 39% to product 3a and only traces of 4a (Table 3, entry 2).The best result was observed when 20 mol% of (NH 4 ) 2 S 2 O 8 and 20 mol% of FeCl 3 were used, where excellent conversions and selectivities to the β-keto-sulfone 3a were observed after 1 h (Table 3, entry 3).Additional increment in the amount of oxidant to 40 mol% resulted in 84% conversion to 3a (Table 3, entry 4).Noteworthy, the corresponding thiosulfonate ( 5) was obtained as a byproduct in the reaction in a small amount.This result was later confirmed by increasing the amount of (NH 4 ) 2 S 2 O 8 and FeCl 3 to 100 mol%, where 4a was obtained as the major product in the reaction together with the corresponding thiosulfonate 5 (Table 3, entry 5).Finally, a reaction under stirring using the optimized conditions was performed in order to compare the efficacy of ultrasound in the oxysulfonylation of styrene, 1a.Using these conditions 3a was obtained as the major product after 24 h reaction (Table 3, entry 6).
The optimized reaction conditions namely: 1a (0.25 mmol), 2a (0.375 mmol), FeCl 3 (20 mol%) and (NH 4 ) 2 S 2 O 8 (20 mol%) in MeCN:H 2 O [3 mL (2:1)] under sonication for 1 h were then applied to different substrates in order to explore the scope of the method, as well as the electronic effects of the substituents on the reaction yields.The results are described on Table 4, where it can be seen that the method was efficient for most of the substrates used.When compounds 1a and 1b were used as substrates together with the sulfinate 2a, the desired products were obtained in good yields, being observed better selectivities when 1a was used as substrate (Table 4, entries 1 and 2).When 1c was used, the corresponding β-hydroxysulfone 4c was obtained in 90% yield as the exclusive reaction product (Table 4, entry 3).The use of trans-stilbene (1d), a 1,2-disubstituted alkene, led to a complex mixture of products, and the isolation of 3d and 4d was not possible in this case (Table 4, entry 4).
The presence of deactivating groups such as the fluorine atom on the aromatic ring led preferentially to the β-keto-  4, entry 5).Moreover, when 4-methoxyvinylbenzene (1f) was used as substrate, a decrease in yield and in the selectivity of the reaction was observed, where the desired product 3f was obtained in 52% yield in a ratio of 67:33 (Table 4, entry 6).These results indicate that the electronic effects can influence both the yield and the selectivity of the reaction and that the presence of donor groups in the starting alkene would favor the formation of β-hydroxysulfone.This observation was confirmed when 4-vinylaniline (1g) was subjected to the same reaction conditions, where the corresponding products 3g and 4g were obtained in 89% yield as an inseparable mixture, being the β-hydroxysulfone (4g) the major product (Table 4, entry 7).When amide 1h was used as substrate, a complex mixture of products was obtained (Table 4, entry 8).When 4-(diphenylphosphino)-styrene (1i) was used in the reaction, the expected products 3i and 4i were not observed, and the only product obtained in the reaction was the corresponding phosphinoxide (Table 4, entry 9).This fact indicated that the presence of some functionalities containing a Lewis base character in the starting material would be troublesome when performing the reaction.
A study of the behavior of the reaction in the presence of Lewis acids, such as boronic acid 1j, was also performed.In this case, a complex mixture of products was observed in the reaction (Table 4, entry 10).When the corresponding boronic ester 1k was used in the oxysulfonylation reaction, the only product observed was the boronic acid 1j, probably due to the presence of water and FeCl 3 in the reaction medium (Table 4, entry 11).This result is in agreement with the literature, 34 where it is described that the hydrolysis of some boron compounds can occur in the presence of FeCl 3 .Finally, when 1-pentene (1l) was used as the substrate, the desired product 3l was not observed (Table 4, entry 12).Isolated yield; b determined by gas chromatography (GC) analysis; c the reaction was sonicated for 2 h; d a complex mixture of products was obtained; e the yield refers to the mixture of compounds 3g and 4g; f the corresponding phosphinoxide was obtained as product; g the corresponding boronic acid 1j was obtained as product.The use of different sodium sulfinates in the oxysulfonylation of alkenes promoted by ultrasound was also evaluated.When styrene 1a and sodium sulfinate 2b were used, similar yields and selectivities were observed (Table 4, entries 1 and 13).However, when sodium methanesulfinate 2d was used, the corresponding product 3n was obtained in only 40% yield with a high selectivity, favoring the β-keto-sulfone (Table 4, entry 14).Finally, when sodium hydroxymethanesulfinate 2c was used, the corresponding products were not observed (Table 4, entry 15).
In an attempt to obtain some information about the mechanism of the reaction, some additional experiments were performed.First, the optimized conditions were applied for the reaction of 1a and 2a under argon atmosphere using only anhydrous acetonitrile as solvent (Table 5, entry 1).In this case, 3a was obtained in a low conversion together with the corresponding vinyl sulfone, 6.
Next, the reaction was performed in presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), a radical scavenger (Table 5, entry 2).In this specific case, the desired product 3a was not observed and only the starting materials were recovered.The results described in Table 5 indicated that the presence of oxygen is important for the oxysulfonylation reaction and are in agreement with those previously described in the literature. 16oteworthy, when the reaction was carried out using the β-hydroxysulfone 4a as the substrate under the optimized reaction conditions, the corresponding β-keto-sulfone 3a was not observed indicating that 4a was not the intermediate in the reaction (Scheme 1).
The suggested reaction mechanism was proposed by Huang and co-workers 35 and Yadav and co-workers, 36 which is based on the generation of an oxygen-centered radical and its resonance structure sulfonyl radical A (Scheme 2).The capture of this radical by the appropriate alkene would lead to a carbon-centered radical B, which would be trapped by O 2 to give the corresponding peroxyl radical C. Further reaction with radical B to generate the oxyl radical D followed by hydrogen radical abstraction would give the β-keto sulfone (Scheme 2).

Conclusions
In summary, we have demonstrated the ultrasoundassisted oxysulfonylation of different alkenes using sodium salts of organosulfinic acids under air atmosphere in a very chemo-and regioselective way.The corresponding β-keto-sulfones were obtained in short reaction time when compared to other procedures described in the literature, high yield and purity.The method is simple, fast and general, allowing further applications in the synthesis of more complex compounds.

Table 3 .
Oxysulfonylation of styrene, 1a, using benzenesulfinic acid sodium salt, 2a, using different amounts of FeCl 3 and (NH 4 ) 2 S 2 O 8 a Reaction conditions: reactions were performed using 1a (0.25 mmol), 2a (0.375 mmol) and the appropriate amount of FeCl 3 and (NH 4 ) 2 S 2 O 8 in MeCN:H 2 O (3 mL) at 25 °C under sonication for 1 h; b determined by gas chromatography (GC) analysis; c the reaction was performed under stirring for 24 h.

Table 4 .
Oxysulfonylation of different alkenes promoted by ultrasound sulfone (3e) in moderate yield (Table