Oxysulfonylation of Alkynes with Sodium Sulfinates to Access β-Keto Sulfones Catalyzed by BF3·OEt2

An efficient and operationally simple method for the synthesis of β-keto sulfones through the BF3·OEt2-promoted reaction of alkynes and sodium sulfinates is developed. With its facile and selective access to the targets, it features good functional group compatibility, mild conditions, easily available starting materials, and good yields. Notably, the reaction does not require metal catalysts or chemical reagents with pungent odors.


Introduction
Sulfone compounds are of considerable importance in synthetic and medicinal chemistry [1,2].For example, the introduction of sulfonyl groups into medicines can substantially influence their polarity, acidity, aqueous solubility, and other properties [3,4], so the efficient synthesis of sulfone compounds has attracted extensive attention recently [5,6].Among them, β-keto sulfone as a kind of unique sulfone compound has been extensively used in biomedicine, such as for anti-schistosomal, anti-analgesic, and antibacterial effects (Figure 1) [7][8][9].At the same time, it can also be used as a synthon and is widely used in synthetic chemistry [10][11][12].
ysulfonylation of arylpropiolic acids and sodium sulfnates to generate β-keto sulfones using only hexafluoroisopropanol (HFIP) as a solvent and oxygen as a green oxidant (Scheme 1c).
In view of this, based on our previous research on C-S bond construction [21,36], especially the sodium sulfinate reaction with BF3•OEt2 as a catalyst [34,35], herein, we hope to report a new reaction under air atmosphere to efficiently obtain β-keto sulfones via the radical pathway (Scheme 2c).This reaction is designed to synthesize β-keto sulfones without any metal catalysts and does not require the use of chemical reagents with irritating odors such as pyridine and acetic acid.Therefore, this method is more gentle and greener and its successful development is also conducive to expanding the application of BF3•OEt2 as a catalyst.In particular, the regulation and control through this organosulfur reagent and BF3•OEt2 catalyst under different reaction conditions can synthesize different products, such as thiosulfonates, β-sulfinyl alkenylsulfones, and β-keto sulfones.Thus, this strategy is of great significance in the fields of organic sulfur chemistry, BF3 chemistry, and alkyne conversion.On the other hand, BF 3 •OEt 2 exhibits strong Lewis acidity [30,31], and its excellent catalytic activity is widely used in various organic synthesis reactions [32,33].In our previous work [34], we reported a BF 3 •OEt 2 -mediated difunctionalization reaction of sodium sulfinates and alkynes to obtain β-sulfinyl alkenylsulfone (Scheme 2b).In fact, during the condition optimization for the above-mentioned work, we also unexpectedly found that if the amount of BF 3 •OEt 2 was below 1.0 equiv., the main product changed from β-sulfinyl alkenylsulfones to β-keto sulfones.
ysulfonylation of arylpropiolic acids and sodium sulfnates to generate β-keto sulfones using only hexafluoroisopropanol (HFIP) as a solvent and oxygen as a green oxidant (Scheme 1c).
In view of this, based on our previous research on C-S bond construction [21,36], especially the sodium sulfinate reaction with BF3•OEt2 as a catalyst [34,35], herein, we hope to report a new reaction under air atmosphere to efficiently obtain β-keto sulfones via the radical pathway (Scheme 2c).This reaction is designed to synthesize β-keto sulfones without any metal catalysts and does not require the use of chemical reagents with irritating odors such as pyridine and acetic acid.Therefore, this method is more gentle and greener and its successful development is also conducive to expanding the application of BF3•OEt2 as a catalyst.In particular, the regulation and control through this organosulfur reagent and BF3•OEt2 catalyst under different reaction conditions can synthesize different products, such as thiosulfonates, β-sulfinyl alkenylsulfones, and β-keto sulfones.Thus, this strategy is of great significance in the fields of organic sulfur chemistry, BF3 chemistry, and alkyne conversion.Scheme 2. Serial synthesis reactions of sodium sulfinates catalyzed by BF 3 •OEt 2 [34,35].
In view of this, based on our previous research on C-S bond construction [21,36], especially the sodium sulfinate reaction with BF 3 •OEt 2 as a catalyst [34,35], herein, we hope to report a new reaction under air atmosphere to efficiently obtain β-keto sulfones via the radical pathway (Scheme 2c).This reaction is designed to synthesize β-keto sulfones without any metal catalysts and does not require the use of chemical reagents with irritating odors such as pyridine and acetic acid.Therefore, this method is more gentle and greener and its successful development is also conducive to expanding the application of BF 3 •OEt 2 as a catalyst.In particular, the regulation and control through this organosulfur reagent and BF 3 •OEt 2 catalyst under different reaction conditions can synthesize different products, such as thiosulfonates, β-sulfinyl alkenylsulfones, and β-keto sulfones.Thus, this strategy is of great significance in the fields of organic sulfur chemistry, BF 3 chemistry, and alkyne conversion.

Optimization of Reaction Conditions
We attempted the reaction of phenylacetylene (1a) and sodium p-tolylsulfinate (2a) as a model in dichloromethane (DCM) to systematically investigate the influences of different factors to optimize the best conditions.The results are summarized in Table 1.
Table 1.Optimization of reaction conditions [a] .

Optimization of Reaction Conditions
We attempted the reaction of phenylacetylene (1a) and sodium p-tolylsulfinate (2a) as a model in dichloromethane (DCM) to systematically investigate the influences of different factors to optimize the best conditions.The results are summarized in Table 1. [a] Reaction conditions: Usually, 1a (0.3 mmol), 2a (0.72 mmol), BF3•OEt2 (0.15 mmol), and DCE (4 mL) at room temperature (rt) for 4 h under air atmosphere. [b] Isolated yield. [c] N.D. = Not Detected.
Initially, we examined the reaction time (Entries 1-3).When the reaction time increased to 6 h, there was no improvement.When the reaction time was shortened, the yield decreased sharply.
In addition, lowering or increasing the reaction temperature did not increase the yield (Entries 4-5 vs. Entry 1).
Similarly, we also examined the amount of BF3•OEt2 used.It was found that increasing or decreasing the amount of Lewis acid did not further increase the yield (Entries 6-7 vs. Entry 1).
At the same time, the effect of solvents on the model reaction was investigated (Entries 1, 8-22).It was found that the solvent plays a significant role in the success of this Initially, we examined the reaction time (Entries 1-3).When the reaction time increased to 6 h, there was no improvement.When the reaction time was shortened, the yield decreased sharply.
In addition, lowering or increasing the reaction temperature did not increase the yield (Entries 4-5 vs. Entry 1).
Similarly, we also examined the amount of BF 3 •OEt 2 used.It was found that increasing or decreasing the amount of Lewis acid did not further increase the yield (Entries 6-7 vs. Entry 1).
At the same time, the effect of solvents on the model reaction was investigated (Entries 1, 8-22).It was found that the solvent plays a significant role in the success of this reaction.Among different solvents, e.g., ethyl acetate (EA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and N,N-dimethylformamide (DMF), using 1,2-dichloroethane (DCE) as the solvent was more favorable to the formation of 3a (Entry 8 vs. Entry 1).Therefore, we decided to choose DCE as the best solvent.
Furthermore, we investigated the ratio of reactants 1a and 2a.When the ratio of 1a:2a was 1:2.4, the best effect was achieved (Entry 8 vs. . Thus, the optimized reaction conditions were identified as using 1a (0.3 mmol), 2a (0.72 mmol), and BF 3 •OEt 2 (0.15 mmol) as the catalyst and 4.0 mL of DCE as the solvent at room temperature (rt) for 4 h.

Scope of Substrates
Under the optimized conditions, a range of alkynes 1 and sodium sulfinates 2 were applied in the transformation to establish the scope and generality of this reaction.
We first investigated various alkyne substrates 1 to explore the scope of this reaction (Table 2).
Therefore, we decided to choose DCE as the best solvent.
Furthermore, we investigated the ratio of reactants 1a and 2a.When the ratio of 1a:2a was 1:2.4, the best effect was achieved (Entry 8 vs. . Thus, the optimized reaction conditions were identified as using 1a (0.3 mmol), 2a (0.72 mmol), and BF3•OEt2 (0.15 mmol) as the catalyst and 4.0 mL of DCE as the solvent at room temperature (rt) for 4 h.

Scope of Substrates
Under the optimized conditions, a range of alkynes 1 and sodium sulfinates 2 were applied in the transformation to establish the scope and generality of this reaction.
Furthermore, we investigated the ratio of reactants 1a and 2a.When the ratio of 1a:2a was 1:2.4, the best effect was achieved (Entry 8 vs. . Thus, the optimized reaction conditions were identified as using 1a (0.3 mmol), 2a (0.72 mmol), and BF3•OEt2 (0.15 mmol) as the catalyst and 4.0 mL of DCE as the solvent at room temperature (rt) for 4 h.

Scope of Substrates
Under the optimized conditions, a range of alkynes 1 and sodium sulfinates 2 were applied in the transformation to establish the scope and generality of this reaction.
In the next step, the effect of different positions of the arylalkyne ring on the yield was investigated.Due to the steric effect, for the same substituent group, when it was a meta-substituted group in the arylalkyne substrate 1, the yield was lower than that of the para-substituted group, such as 3b (58%) vs. 3j (50%), 3f (48%) vs. 3l (42%), and 3g (51%) vs. 3m (47%).

Structural Characterization Analysis
From the 1 H NMR spectra of the target compounds, it can be seen that the 1 H NMR data of the twenty compounds 3a-3t are consistent with the simulated data of the hydrogen atom in the target products.For example, the 1 H NMR spectra of the synthesized compounds 3a-3t show that there was a single peak with the integration of two units near 4.72 ppm, which was a characteristic peak caused by methylene hydrogen in the structure of the target products.
At the same time, in the 13 C NMR spectra, the single peak of the chemical shift value near 64.0 ppm was also a characteristic peak of methylene carbon.In addition, regardless of whether the product contains one fluorine atom or trifluoromethyl group, the corresponding chemical shift can be found in 19 F NMR, as anticipated.
In a word, these test results indicate that the characterization results of NMR are consistent with expectations.The tested data of the synthesized compounds 3a-3t, including the data of the melting point (m.p.), are also consistent with data in the references reported before [17,19,23,25].
Although NMR tests have proven that compounds 3a-3t have the expected structure, in order to further determine the structure of the product, we also conducted single-crystal cultivation of compound 3a.Its crystal resolution data are shown in Table 3, successfully affirming that 3a does have the expected structure [37].Accordingly, the X-ray single-crystal diffraction results of compound 3a in Figure 2 indicate that the molecule contains two benzene rings, which are connected to a carbonyl group and a sulfonyl group, respectively.Moreover, the carbonyl and sulfonyl groups are connected by a methylene group.Thus, the structure of compound 3a can also be aptly confirmed through the single crystal structure.Accordingly, the X-ray single-crystal diffraction results of compound 3a in Figure 2 indicate that the molecule contains two benzene rings, which are connected to a carbonyl group and a sulfonyl group, respectively.Moreover, the carbonyl and sulfonyl groups are connected by a methylene group.Thus, the structure of compound 3a can also be aptly confirmed through the single crystal structure.On the other hand, the molecular weights of these radicals in control experiments were obtained by high-resolution mass spectrometry (HR-MS), and the error between the tested value and the calculated value was within a reasonable range.

Mechanism Investigation
In order to understand the reaction mechanism, some control experiments were carried out.The results are shown in Scheme 3.
Initially, once 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a free radical scavenger was added under the standard reaction conditions, the formation of 3a was obviously suppressed (Scheme 3a).Importantly, the capture of the sulfonyl radical by TEMPO could be detected by HR-MS (Figure S2), indicating that a free radical pathway may be involved in this process.
Similarly, when using 1,1-diphenylethylene as a free radical scavenger, there was no normal reaction for the formation of 3a (Scheme 3b), and the capture of the sulfonyl radical by 1,1-diphenylethylene was also confirmed by HR-MS.In Figure 3, it can be seen that the theoretical calculated value of [M+H] + of intermediates is 335.1100, and the On the other hand, the molecular weights of these radicals in control experiments were obtained by high-resolution mass spectrometry (HR-MS), and the error between the tested value and the calculated value was within a reasonable range.

Mechanism Investigation
In order to understand the reaction mechanism, some control experiments were carried out.The results are shown in Scheme 3.
Initially, once 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a free radical scavenger was added under the standard reaction conditions, the formation of 3a was obviously suppressed (Scheme 3a).Importantly, the capture of the sulfonyl radical by TEMPO could be detected by HR-MS (Figure S2), indicating that a free radical pathway may be involved in this process.
Similarly, when using 1,1-diphenylethylene as a free radical scavenger, there was no normal reaction for the formation of 3a (Scheme 3b), and the capture of the sulfonyl radical by 1,1-diphenylethylene was also confirmed by HR-MS.In Figure 3, it can be seen that the theoretical calculated value of [M+H] + of intermediates is 335.1100, and the actual test value is 335.1096 with an error value of 0.0004, which is indeed within the reasonable range.This also indicates that there is a free radical pathway.
actual test value is 335.1096 with an error value of 0.0004, which is indeed within the reasonable range.This also indicates that there is a free radical pathway.
What is more, the control experiment also implies that Lewis acid BF3•OEt2 could be essential for this reaction (Scheme 3c).At the same time, in order to determine the source of the carboxyl oxygen atom in compound 3, an experiment in an oxygen-free atmosphere was investigated.When the What is more, the control experiment also implies that Lewis acid BF 3 •OEt 2 could be essential for this reaction (Scheme 3c).
At the same time, in order to determine the source of the carboxyl oxygen atom in compound 3, an experiment in an oxygen-free atmosphere was investigated.When the reaction was carried out in a N 2 atmosphere, the target product could not be obtained (Scheme 3d).This result shows that O 2 in the air may be the source of the carboxyl oxygen atom in the product [28].
Furthermore, when the reaction was carried out under standard conditions, β-sulfinyl alkenylsulfone and thiosulfonate were easily observed by TLC (Scheme 3e), which may be the byproducts of the reaction.
Firstly, BF 3 •H 2 O is produced in situ from BF 3 •OEt 2 in the case of a trace amount of water [34,35].Then, BF 3 •H 2 O reacts with sodium sulfinate 2, giving sulfinic acid A and Na[BF 3 OH].Subsequently, sulfinyl sulfone B is generated from sulfinic acid A, and it is easy to produce sulfonyl radical I and sulfinyl radical II from intermediate B under heating conditions [38,39].
Secondly, sulfonyl radical I is added to alkyne 1 to give intermediate C [14,23], which is then trapped by oxygen to generate intermediate D [25].Finally, intermediate D forms intermediate E [16] via the hydrogen ion and radical II, while causing radical II to generate free radical I. Intermediate E is prone to tautomerism [27][28][29], giving product 3 (Scheme 4).
Considering the preliminary experimental results (Scheme 2a and 2b) [34,35], we speculate that the amount of BF 3 •OEt 2 determines the amount of sodium sulfite involved in the reaction and less BF 3 •OEt 2 is beneficial to the reaction of less sodium sulfite (Scheme 2c).At the same time, the reaction atmosphere [35] and the presence [34] or absence [35] of acetylene substrate determine which radicals are easier to generate and react.This is why different products can be produced in similar BF 3 •OEt 2 catalytic systems (Scheme 2).At the same time, in order to determine the source of the carboxyl oxygen atom in compound 3, an experiment in an oxygen-free atmosphere was investigated.When the reaction was carried out in a N2 atmosphere, the target product could not be obtained (Scheme 3d).This result shows that O2 in the air may be the source of the carboxyl oxygen atom in the product [28].Furthermore, when the reaction was carried out under standard conditions, β-sulfinyl alkenylsulfone and thiosulfonate were easily observed by TLC (Scheme 3e), which may be the byproducts of the reaction.
Firstly, BF3•H2O is produced in situ from BF3•OEt2 in the case of a trace amount of water [34,35].Then, BF3•H2O reacts with sodium sulfinate 2, giving sulfinic acid A and Na[BF3OH].Subsequently, sulfinyl sulfone B is generated from sulfinic acid A, and it is easy to produce sulfonyl radical I and sulfinyl radical II from intermediate B under heating conditions [38,39].Secondly, sulfonyl radical I is added to alkyne 1 to give intermediate C [14,23], which is then trapped by oxygen to generate intermediate D [25].Finally, intermediate D forms intermediate E [16] via the hydrogen ion and radical II, while causing radical II to generate free radical I. Intermediate E is prone to tautomerism [27][28][29], giving product 3 (Scheme 4).
Considering the preliminary experimental results (Scheme 2a and 2b) [34,35], we speculate that the amount of BF3•OEt2 determines the amount of sodium sulfite involved in the reaction and less BF3•OEt2 is beneficial to the reaction of less sodium sulfite (Scheme 2c).At the same time, the reaction atmosphere [35] and the presence [34] or absence [35] of acetylene substrate determine which radicals are easier to generate and react.This is why different products can be produced in similar BF3•OEt2 catalytic systems (Scheme 2).
In addition, as shown in Scheme 5, sulfinyl radicals II are extremely unstable in an air atmosphere and are prone to disproportionation to form sulfonyl radicals I and thiyl radicals III [40,41], which easily couple to form thiosulfonates F (Minor path a from intermediate II) [42,43].Similarly, a small amount of β-sulfinyl alkenylsulfones G (Minor In addition, as shown in Scheme 5, sulfinyl radicals II are extremely unstable in an air atmosphere and are prone to disproportionation to form sulfonyl radicals I and thiyl radicals III [40,41], which easily couple to form thiosulfonates F (Minor path a from intermediate II) [42,43].Similarly, a small amount of β-sulfinyl alkenylsulfones G (Minor path b from intermediate II) [34] as a by-product can also be observed, which may be caused by the incomplete disproportionation of sulfinyl radicals [44].

Experimental Procedure for Compounds 3a-3t
As shown in Scheme 8, the mixture of alkyne compound 1 (0.30 mmol, 1.0 equiv.),sodium sulfinate 2 (0.72 mmol, 2.4 equiv.), and BF 3 •OEt 2 (0.15 mmol, 0.5 equiv.) in DCE (4 mL) under an air atmosphere was stirred at room temperature for 4 h.After the completion of the reaction, ethyl acetate (EA) (15 mL) was poured into the reaction mixture.The organic layers were extracted with a saturated sodium chloride solution (3 × 15 mL).Then, the organic layer was dried over anhydrous Na 2 SO 4 .Finally, after the filtration and evaporation of the solvents under reduced pressure, the crude product was purified by column chromatography on silica gel to afford the desired product 3.
According to the literature [22,26,46], the mixture of arylsulfonyl chloride (10 mmol), sodium sulfite 2 (20 mmol), and sodium bicarbonate (20 mmol) in H2O (15 mL) was stirred at 80 °C for 4 h.Water was removed by a rotary evaporator.Then, the remaining solid was extracted and recrystallized by ethanol to obtain the required compound 2.

Experimental Procedure for Compounds 3a-3t
As shown in Scheme 8, the mixture of alkyne compound 1 (0.30 mmol, 1.0 equiv.),sodium sulfinate 2 (0.72 mmol, 2.4 equiv.), and BF3•OEt2 (0.15 mmol, 0.5 equiv.) in DCE (4 mL) under an air atmosphere was stirred at room temperature for 4 h.After the completion of the reaction, ethyl acetate (EA) (15 mL) was poured into the reaction mixture.The organic layers were extracted with a saturated sodium chloride solution (3 × 15 mL).Then, the organic layer was dried over anhydrous Na2SO4.Finally, after the filtration and evaporation of the solvents under reduced pressure, the crude product was purified by column chromatography on silica gel to afford the desired product 3. Scheme 8. Synthesis route for Compounds 3a-3t.
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Figure 3 .
Figure 3.The HR-MS of the capture of sulfonyl radical by scavenger 1,1-diphenylethylene in the control experiment.

Figure 3 .
Figure 3.The HR-MS of the capture of sulfonyl radical by scavenger 1,1-diphenylethylene in the control experiment.

Figure 3 .
Figure 3.The HR-MS of the capture of sulfonyl radical by scavenger 1,1-diphenylethylene in the control experiment.

Table 1 .
Optimization of reaction conditions[a]

Table 3 .
X-ray crystal data and structure refinement for compound 3a.