Photoinduced Synthesis of Sulfonyl-Containing Phosphorothioates via a Three-Component Reaction

Both sulfonyl and phosphorothioate are important privileged structural motifs which are widely presented in pharmaceuticals and agrochemicals. Herein, we describe an efficient approach to synthesizing sulfonyl-containing phosphorothioates by merging photoredox and copper catalysis at room temperature. This protocol is compatible with a wide range of substrates and can be applied to the late-stage modification of complex molecules. Control experiments are conducted to demonstrate the generation of the sulfonyl radical in the transformation.

In the last few decades, the direct vicinal difunctionalization of alkenes has emerged as a powerful strategy to access complex molecules, which could introduce two functional groups into the double bond simultaneously [25][26][27][28][29][30][31][32].Accordingly, substantial efforts have been devoted to the construction of sulfonyl-containing compounds via the difunctionalization of alkenes, such as hydrosulfonation, oxysulfonation, aminosulfonylation and selenosulfonation [33][34][35].However, only limited examples have been developed for the thiosulfonylation of alkenes involving the simultaneous installation of two C-S bonds (Scheme 1a).For example, Xu et al. reported a thiosulfonylation reaction of alkenes in the presence of a dual gold/photoredox catalysis system [36,37].Lian and co-workers established a thiocyanatosulfonation of α,β-unsaturated amides/esters using TMSNCS, aryldiazonium tetrafluoroborates and sulfur dioxide to access β-thiocyanated sulfone compounds [38].Our group also disclosed an intramolecular thiosulfonylation of alkenes Molecules 2023, 28, 7869 2 of 9 to deliver sulfonated [3,1]-benzothiazepines under metal-free conditions [39].Given the importance of phosphorothioates and sulfones in organic and medicinal chemistry, we hypothesized that the introduction of these two functional groups into alkenes using the vicinal difunctionalization strategy would contribute to synthetic community and drug discovery.Herein, we describe a mild and efficient method to synthesize sulfonylcontaining phosphorothioates via the thiosulfonylation of alkenes using sulfonyl chlorides and phosphorothioic acids (Scheme 1b).In the presence of photoredox and copper catalysis, this practical reaction features a broad substrate scope and can be readily applied to the late-stage functionalization of bioactive molecules.
unsaturated amides/esters using TMSNCS, aryldiazonium tetrafluoroborates and dioxide to access β-thiocyanated sulfone compounds [38].Our group also disclo intramolecular thiosulfonylation of alkenes to deliver sulfonated [3,1]-benzothiaz under metal-free conditions [39].Given the importance of phosphorothioates and su in organic and medicinal chemistry, we hypothesized that the introduction of the functional groups into alkenes using the vicinal difunctionalization strategy contribute to synthetic community and drug discovery.Herein, we describe a mi efficient method to synthesize sulfonyl-containing phosphorothioates vi thiosulfonylation of alkenes using sulfonyl chlorides and phosphorothioic acids (S 1b).In the presence of photoredox and copper catalysis, this practical reaction fea broad substrate scope and can be readily applied to the late-stage functionaliza bioactive molecules.
Scheme 1.The development of alkene thiosulfonylation.

Results and Discussion
We began our study with the use of 4-vinylbiphenyl 1a, tosyl chloride 2a an diethyl S-hydrogen phosphorothioate 3a in the presence of Ir(ppy)3 and Cu(OTf) with K2HPO4 as the base in DCE under 30 W blue LED irradiation at room tempe Gratifyingly, we found that the desired product 4a could be obtained with an ex yield of 99% (93% isolated yield, Table 1, entry 1).The control experiments show no reaction occurred in the absence of Ir(ppy)3 or light irradiation, confirming th the photocatalyst and visible light were essential for this transformation (Table 1, 2-3).Without Cu(OTf)2 in the reaction system, the yield of 4a was diminished signifi (Table 1, entry 4).When changing the photocatatlyst to Ir(ppy)2(dtbbpy)PF corresponding product was achieved with a comparable yield (Table 1, entry 5).Sim the use of other copper catalysts such as CuCl2 and Cu(CH3CN)4PF6 also underw reaction efficiently (Table 1, entries 6-7).Replacing K2HPO4 with other bases (K K2CO3 and Na2CO3) produced inferior results (Table 1, entries 8-10).Finally, the e solvent was examined, and the reaction in THF and CH3CN resulted in moderate (Table 1, entries [11][12].

Results and Discussion
We began our study with the use of 4-vinylbiphenyl 1a, tosyl chloride 2a and O,Odiethyl S-hydrogen phosphorothioate 3a in the presence of Ir(ppy) 3 and Cu(OTf) 2 along with K 2 HPO 4 as the base in DCE under 30 W blue LED irradiation at room temperature.Gratifyingly, we found that the desired product 4a could be obtained with an excellent yield of 99% (93% isolated yield, Table 1, entry 1).The control experiments showed that no reaction occurred in the absence of Ir(ppy) 3 or light irradiation, confirming that both the photocatalyst and visible light were essential for this transformation (Table 1, entries 2-3).Without Cu(OTf) 2 in the reaction system, the yield of 4a was diminished significantly (Table 1, entry 4).When changing the photocatatlyst to Ir(ppy) 2 (dtbbpy)PF 6 , the corresponding product was achieved with a comparable yield (Table 1, entry 5).Similarly, the use of other copper catalysts such as CuCl 2 and Cu(CH 3 CN) 4 PF 6 also underwent the reaction efficiently (Table 1, entries 6-7).Replacing K 2 HPO 4 with other bases (KHCO 3 , K 2 CO 3 and Na 2 CO 3 ) produced inferior results (Table 1, entries 8-10).Finally, the effect of solvent was examined, and the reaction in THF and CH 3 CN resulted in moderate yields (Table 1, entries 11-12).With the optimized reaction conditions established, we turned our attention to investigating the scope and generality of the three-component vicinal difunctionalization of alkenes (Figure 1 and Supplementary Materials).To verify the scalability of this protocol, the model reaction was carried out on a 6 mmol scale to obtain the product 4a with a 78% yield.In general, a range of alkenes bearing both electron-donating and electron-withdrawing substituents on the aromatic ring reacted smoothly to provide the products 4b-4l with moderate to good yields.Functional groups such as methyl, methoxy, fluoro, chloro, trifluoromethyl and ester were all well tolerated in this transformation.Notably, a heteroaromatic alkene containing a thiazole group could also be used to provide the corresponding product 4m at a 63% yield.It is worth mentioning that different types of alkenes including 1,2-dihydronaphthalene, α-methyl styrene, 1,3-enyne and 1,3diene could furnish the desired compounds 4n-4q in 48-86% yields.With the optimized reaction conditions established, we turned our attention to investigating the scope and generality of the three-component vicinal difunctionalization of alkenes (Figure 1 and Supplementary Materials).To verify the scalability of this protocol, the model reaction was carried out on a 6 mmol scale to obtain the product 4a with a 78% yield.In general, a range of alkenes bearing both electron-donating and electronwithdrawing substituents on the aromatic ring reacted smoothly to provide the products 4b-4l with moderate to good yields.Functional groups such as methyl, methoxy, fluoro, chloro, trifluoromethyl and ester were all well tolerated in this transformation.Notably, a heteroaromatic alkene containing a thiazole group could also be used to provide the corresponding product 4m at a 63% yield.It is worth mentioning that different types of alkenes including 1,2-dihydronaphthalene, α-methyl styrene, 1,3-enyne and 1,3-diene could furnish the desired compounds 4n-4q in 48-86% yields.
Then, we explored the substrate scope of commercially available aromatic and aliphatic sulfonyl chlorides.As expected, various sulfonyl chlorides with substituents on the aromatic ring underwent the reaction efficiently, giving the corresponding sulfonyl-containing phosphorothioates 5a-5h with moderate to good yields.Remarkably, the aliphatic sulfonyl chlorides were also suitable substrates to deliver the desired products 5i-5m in reasonable yields.In addition, the scope of other alkoxy-or aryloxy-substituted phosphorothioic acids was evaluated and it was found that O,O-dimethoxy, diisopropoxy and diphenoxy phosphorothioic acid reacted well to afford products 5n-5p in 57-97% yields.
Furthermore, the robustness of this three-component protocol was evaluated via the late-stage functionalization of bioactive molecules.As shown in Scheme 2, the alkenes derived from indomethacin, estrone, ciprofibrate and febuxostat were found to be compatible under the standard conditions to deliver the desired products 6a-6d in 55-94% yields.
To illustrate the mechanism for this visible-light-mediated reaction, some additional control experiments were performed (Scheme 3).First, when three equivalents of radical scavenger (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) were added to the model reaction under the standard conditions, the formation of product 4a was completely suppressed, suggesting that a free radical pathway might be involved in this reaction.Equally, a radical clock experiment was performed using vinyl cyclopropane 7, and the ring-opening product 8 was obtained with a 24% yield.Taken together, these findings support the generation of sulfonyl radicals under light irradiation.We also conducted a reaction between tosyl chloride 2a and O,O-diethyl S-hydrogen phosphorothioate 3a in the presence of K 2 HPO 4 , but the formation of benzenethiosulfonate 9 was not detected.This result indicated that both sulfonyl radicals and sulfenyl radicals were not likely generated by the homolytic cleavage of benzenethiosulfonates.Then, we explored the substrate scope of commercially available aromatic and aliphatic sulfonyl chlorides.As expected, various sulfonyl chlorides with substituents on the aromatic ring underwent the reaction efficiently, giving the corresponding sulfonylcontaining phosphorothioates 5a-5h with moderate to good yields.Remarkably, the aliphatic sulfonyl chlorides were also suitable substrates to deliver the desired products 5i-5m in reasonable yields.In addition, the scope of other alkoxy-or aryloxy-substituted phosphorothioic acids was evaluated and it was found that O,O-dimethoxy, diisopropoxy  yields.Furthermore, the robustness of this three-component protocol was evaluated late-stage functionalization of bioactive molecules.As shown in Scheme 2, the derived from indomethacin, estrone, ciprofibrate and febuxostat were foun compatible under the standard conditions to deliver the desired products 6a-6 94% yields.To illustrate the mechanism for this visible-light-mediated reaction, some ad control experiments were performed (Scheme 3).First, when three equivalents o scavenger (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) were added to the reaction under the standard conditions, the formation of product 4a was com suppressed, suggesting that a free radical pathway might be involved in this r Equally, a radical clock experiment was performed using vinyl cyclopropane 7, ring-opening product 8 was obtained with a 24% yield.Taken together, these support the generation of sulfonyl radicals under light irradiation.We also cond reaction between tosyl chloride 2a and O,O-diethyl S-hydrogen phosphorothioa the presence of K2HPO4, but the formation of benzenethiosulfonate 9 was not d This result indicated that both sulfonyl radicals and sulfenyl radicals were no generated by the homolytic cleavage of benzenethiosulfonates.To illustrate the mechanism for this visible-light-mediated reaction, some ad control experiments were performed (Scheme 3).First, when three equivalents o scavenger (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) were added to the reaction under the standard conditions, the formation of product 4a was com suppressed, suggesting that a free radical pathway might be involved in this r Equally, a radical clock experiment was performed using cyclopropane 7, ring-opening product 8 was obtained with a 24% yield.Taken together, these support the generation of sulfonyl radicals under light irradiation.We also cond reaction between tosyl chloride 2a and O,O-diethyl S-hydrogen phosphorothioa the presence of K2HPO4, but the formation of benzenethiosulfonate 9 was not d This result indicated that both sulfonyl radicals and sulfenyl radicals were no generated by the homolytic cleavage of benzenethiosulfonates.

General Information
Unless otherwise stated, all commercial reagents were used as received.All solvents were dried and distilled according to the standard procedures.Flash column chromatography was performed using silica gel (60 Å pore size, 32-63 µm, standardgrade).Analytical thin-layer chromatography was performed using glass plates precoated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm).Thin-layer chromatography plates were visualized using exposure to ultraviolet light.The nuclear magnetic resonance (NMR) spectra were recorded in parts per million from internal tetramethylsilane on the δ scale.The 1 H, 13 C and 19 F NMR spectra were recorded in CDCl3 using a Bruker DRX 400 spectrometer (Bruker, Switzerland) operating at 400 MHz, 100 MHz and 376 MHz, respectively.All chemical shift values are quoted in ppm and coupling constants quoted in Hz.High-resolution mass spectrometry (HRMS) spectra were obtained using a micrOTOF II instrument.

General Procedure for the Synthesis of Sulfonyl-Containing Phosphorothioates
An oven-dried flask was charged with alkene 1 (0.2 mmol, 1.0 equiv), sulfonyl chloride 2 (0.4 mmol, 2 equiv), K2HPO4 (0.4 mmol, 2 equiv), Cu(OTf)2 (5 mol%) and Ir(ppy)3 (2 mol%) under a nitrogen atmosphere.Then, anhydrous DCE (2 mL) and O,Odiethyl S-hydrogen phosphorothioate 3 (0.4 mmol, 2 equiv) were added to the flask.The mixture was placed around 30 W blue LEDs at a distance of ~5 cm and stirred under blue light irradiation for 12 h at room temperature.After completion of the reaction as monitored using TLC analysis, the mixture was filtered through a celite pad, and washed using ethyl acetate; then, the filtrate was evaporated and the residue was purified using

General Information
Unless otherwise stated, all commercial reagents were used as received.All solvents were dried and distilled according to the standard procedures.Flash column chromatography was performed using silica gel (60 Å pore size, 32-63 µm, standard-grade).Analytical thin-layer chromatography was performed using glass plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm).Thin-layer chromatography plates were visualized using exposure to ultraviolet light.The nuclear magnetic resonance (NMR) spectra were recorded in parts per million from internal tetramethylsilane on the δ scale.The 1 H, 13 C and 19 F NMR spectra were recorded in CDCl 3 using a Bruker DRX 400 spectrometer (Bruker, Fallanden, Switzerland) operating at 400 MHz, 100 MHz and 376 MHz, respectively.All chemical shift values are quoted in ppm and coupling constants quoted in Hz.High-resolution mass spectrometry (HRMS) spectra were obtained using a micrOTOF II instrument.

General Procedure for the Synthesis of Sulfonyl-Containing Phosphorothioates
An oven-dried flask was charged with alkene 1 (0.2 mmol, 1.0 equiv), sulfonyl chloride 2 (0.4 mmol, 2 equiv), K 2 HPO 4 (0.4 mmol, 2 equiv), Cu(OTf) 2 (5 mol%) and Ir(ppy) 3 (2 mol%) under a nitrogen atmosphere.Then, anhydrous DCE (2 mL) and O,O-diethyl S-hydrogen phosphorothioate 3 (0.4 mmol, 2 equiv) were added to the flask.The mixture was placed around 30 W blue LEDs at a distance of ~5 cm and stirred under blue light irradiation for 12 h at room temperature.After completion of the reaction as monitored using TLC analysis, the mixture was filtered through a celite pad, and washed using ethyl acetate; then, the filtrate was evaporated and the residue was purified using flash column chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to give the corresponding product.

General Procedure for the Scale-Up Experiment
An oven-dried flask was charged with 4-vinyl-1,1 -biphenyl 1a (6 mmol, 1.0 equiv), 4-methylbenzenesulfonyl chloride 2a (12 mmol, 2 equiv), K 2 HPO 4 (12 mmol, 2 equiv), Cu(OTf) 2 (5 mol%) and Ir(ppy) 3 (2 mol%) under a nitrogen atmosphere.Then, anhydrous DCE (60 mL) and O,O-diethyl S-hydrogen phosphorothioate 3a (6 mmol, 2 equiv) were added to the flask.The mixture was placed around 30 W blue LEDs at a distance of ~5 cm and stirred under blue light irradiation for 12 h at room temperature.After completion of the reaction as monitored using TLC analysis, the mixture was filtered through a celite pad, and washed with ethyl acetate; then, the filtrate was evaporated and the residue was puri-fied using flash column chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to give the corresponding product 4a with a 78% yield (2.342 g).

Conclusions
In conclusion, we have developed a visible-light-mediated three-component reaction of alkenes, sulfonyl chlorides and phosphorothioates under blue LED irradiation at room temperature.This efficient protocol shows a broad substrate scope, high functional group tolerance and excellent chemoselectivity.Under the mild reaction conditions, a variety of sulfonyl-containing phosphorothioates were obtained with moderate to good yields.Moreover, the gram-scale synthetic capability and late-stage functionalization of the bioactive molecules demonstrated the applicability of this methodology.

Scheme 3 .Scheme 3 .
Scheme 3. Control experiments.Scheme 3. Control experiments.On the basis of the above results and the literature reports, a plausible mechanism for this three-component protocol is depicted in Scheme 4. Initially, the visible-lightexcited Ir(III)* undergoes single-electron transfer with sulfonyl chloride 2 to generate the sulfonyl radical A, which then adds to the double bond of alkene 1 to form the alkyl radical intermediate B. Meanwhile, the reaction of the copper catalyst with phosphorothioic acid 3 affords the Cu I complex C, followed by single-electron oxidation with Ir (IV) to give the Cu II intermediate D and regenerate the photocatalyst.Subsequently, the alkyl radical intermediate B is captured by the Cu II intermediate D to form the Cu III species E. Finally, the desired product is delivered via the reductive elimination of E, along with releasing the Cu I catalyst.

Table 1 .
Optimization of the reaction conditions a .

Table 1 .
Optimization of the reaction conditions a .