Photoredox-Catalyzed Synthesis of 3-Sulfonylated Pyrrolin-2-ones via a Regioselective Tandem Sulfonylation Cyclization of 1,5-Dienes

A mild, visible-light-induced, regioselective cascade sulfonylation-cyclization of 1,5-dienes with sulfonyl chlorides through the intermolecular radical addition/cyclization of alkenes C(sp2)-H was developed. This procedure proceeds well and affords a mild and efficient route to a range of monosulfonylated pyrrolin-2-ones at room temperatures.

Considering the significance of pyrrolinones and the importance of sulfone moieties in organic synthesis. Herein, we aimed to develop an unprecedented visible-light-induced photoredox-catalyzed reaction of linear 1,5-dienes with sulfonyl chlorides via regioselective sulfonylation and 5-endo cyclization to produce important pyrrolinones (Scheme 1b). However, three challenges hinder the successful development of such a process: (i) The selective addition of the sulfone radical between two carbon-carbon double bonds is challenging. (ii) 6-Exo cyclization competes with the desired reaction and needs to be restricted. (iii) The C=C bond in the target product continues to react with the sulfonyl radical to afford 3,4-disulfonated pyrrolin-2-ones.
Considering the significance of pyrrolinones and the importance of sulfone moieties in organic synthesis. Herein, we aimed to develop an unprecedented visible-light-induced photoredox-catalyzed reaction of linear 1,5-dienes with sulfonyl chlorides via regioselective sulfonylation and 5-endo cyclization to produce important pyrrolinones (Scheme 1b). However, three challenges hinder the successful development of such a process: (i) The selective addition of the sulfone radical between two carbon-carbon double bonds is challenging. (ii) 6-Exo cyclization competes with the desired reaction and needs to be restricted. (iii) The C=C bond in the target product continues to react with the sulfonyl radical to afford 3,4-disulfonated pyrrolin-2-ones.

Results and Discussion
After obtaining the optimal reaction conditions, we embarked upon exploring the substrate scope of 1,5-dienes. Different R 1 , R 2 , R 3 and R 4 groups of 1,5-dienes were tested with p-toluenesulfonyl chloride 2a; the results are shown in Figure 2. Substrates with halogen atoms (F, Cl, Br, and I) and electron-donating groups (Me and MeO) at the parapositions of the benzene ring proceeded well to give target products 3b-3g and 3g-3h in medium to good yields. Gratifyingly, the CO2Et group at the para-position of the benzene ring furnished product 3f in an acceptable yield. The reactivity of substituents at the metaor ortho-position was also tested, achieving yields of products 3i-3l from 46% to 82%. Notably, substrates with an ethyl group at the β-position of the enamide moiety or an nbutyl group at the α-position of the acrylamide moiety smoothly converted to the corresponding product 3m or 3n in 85% yield or 62% yield. In addition, using propionyl or

Results and Discussion
After obtaining the optimal reaction conditions, we embarked upon exploring the substrate scope of 1,5-dienes. Different R 1 , R 2 , R 3 and R 4 groups of 1,5-dienes were tested with p-toluenesulfonyl chloride 2a; the results are shown in Figure 2. Substrates with halogen atoms (F, Cl, Br, and I) and electron-donating groups (Me and MeO) at the parapositions of the benzene ring proceeded well to give target products 3b-3g and 3g-3h in medium to good yields. Gratifyingly, the CO 2 Et group at the para-position of the benzene ring furnished product 3f in an acceptable yield. The reactivity of substituents at the meta-or ortho-position was also tested, achieving yields of products 3i-3l from 46% to 82%. Notably, substrates with an ethyl group at the β-position of the enamide moiety or an n-butyl group at the α-position of the acrylamide moiety smoothly converted to the corresponding product 3m or 3n in 85% yield or 62% yield. In addition, using propionyl or isobutyryl as the nitrogen-protecting groups was viable for this reaction to give target products 3o and 3p in considerable yields.
isobutyryl as the nitrogen-protecting groups was viable for this reaction to give target products 3o and 3p in considerable yields. Next, we moved on to explore the generality of various sulfonyl chlorides ( Figure 3). Arylsulfonyl chlorides bearing electron-rich (Me, MeO, and t-Bu) groups at different positions worked well, giving corresponding sulfones 4b-4e in 66%-84% yield. Electronpoor arylsulfonyl chlorides, such as Br, I, CN, CF3, and NO2 groups on the benzene ring, allowed the formation of product 4f-4j in 41% to 78% yield with the need for 20 W white LEDs as the light source. It is noteworthy that arylsulfonyl chlorides having substituents at the ortho-position were inferior to those at the para-or meta-position, mainly because of the large steric hindrance of the ortho-position (4b vs. 4e and 4k vs. 4l). Remarkably, 2thiophenesulfonyl chloride survived under the current conditions to achieve product 4m in 62% yield. Moreover, alkyl-substituted sulfonyl chlorides, such as cyclopropyl and ethyl, were applicable for this reaction and transferred to 4n and 4o in 68% and 62% yield, respectively. Next, we moved on to explore the generality of various sulfonyl chlorides (Figure 3). Arylsulfonyl chlorides bearing electron-rich (Me, MeO, and t-Bu) groups at different positions worked well, giving corresponding sulfones 4b-4e in 66-84% yield. Electron-poor arylsulfonyl chlorides, such as Br, I, CN, CF 3 , and NO 2 groups on the benzene ring, allowed the formation of product 4f-4j in 41% to 78% yield with the need for 20 W white LEDs as the light source. It is noteworthy that arylsulfonyl chlorides having substituents at the ortho-position were inferior to those at the para-or meta-position, mainly because of the large steric hindrance of the ortho-position (4b vs. 4e and 4k vs. 4l). Remarkably, 2-thiophenesulfonyl chloride survived under the current conditions to achieve product 4m in 62% yield. Moreover, alkyl-substituted sulfonyl chlorides, such as cyclopropyl and ethyl, were applicable for this reaction and transferred to 4n and 4o in 68% and 62% yield, respectively. In order to further expand the practicality of the reaction, a gram scale reaction and removal of OAc group of compound 4a were conducted. We were delighted to obtain the sulfonylated pyrrolinone 4a in 78% yield with a prolonged time when the reaction was taken on 1 mmol scale (Scheme 2, (1)). Furthermore, with the addition of n-BuLi in THF at −78 °C, the compound 4a could smoothly remove the OAc group, which generated the product 4aa in 84% yield (Scheme 2, (2)).  In order to further expand the practicality of the reaction, a gram scale reaction and removal of OAc group of compound 4a were conducted. We were delighted to obtain the sulfonylated pyrrolinone 4a in 78% yield with a prolonged time when the reaction was taken on 1 mmol scale (Scheme 2, (1)). Furthermore, with the addition of n-BuLi in THF at −78 • C, the compound 4a could smoothly remove the OAc group, which generated the product 4aa in 84% yield (Scheme 2, (2)).  In order to further expand the practicality of the reaction, a gram scale reaction and removal of OAc group of compound 4a were conducted. We were delighted to obtain the sulfonylated pyrrolinone 4a in 78% yield with a prolonged time when the reaction was taken on 1 mmol scale (Scheme 2, (1)). Furthermore, with the addition of n-BuLi in THF at −78 °C, the compound 4a could smoothly remove the OAc group, which generated the product 4aa in 84% yield (Scheme 2, (2)). To shed the possible mechanism of this visible-light-induced sulfonylation-cyclization of 1,5-dienes, some control experiments were carried out (Scheme 3). When 2.0 equivalents of TEMPO or 1,1-diphenylethylene was added to the reaction of 1,5-diene and p-toluenesulfonyl chloride under standard conditions, the transformation was completely suppressed, suggesting that a free-radical pathway may be involved in this sulfonylationcyclization reaction. In addition, visible-light irradiation on/off experiments were performed on the model reaction, and the results show that a long-chain process was unlikely to be involved in this reaction (see Supplementary Materials).
Molecules 2023, 28, 5473 6 of 14 To shed the possible mechanism of this visible-light-induced sulfonylation-cyclization of 1,5-dienes, some control experiments were carried out (Scheme 3). When 2.0 equivalents of TEMPO or 1,1-diphenylethylene was added to the reaction of 1,5-diene and ptoluenesulfonyl chloride under standard conditions, the transformation was completely suppressed, suggesting that a free-radical pathway may be involved in this sulfonylationcyclization reaction. In addition, visible-light irradiation on/off experiments were performed on the model reaction, and the results show that a long-chain process was unlikely to be involved in this reaction (see Supplementary Materials). According to the above experimental results and previous literature reports [13][14][15][16][17][18], we propose a possible mechanism for visible-light-induced regioselective cascade sulfonylation-cyclization of 1,5-dienes (Scheme 4). First, the photocatalyst [fac-Ir(ppy)3] under visible light irradiation is excited to form the strongly reducing state *[fac-Ir(ppy)3]. A single electron transfer between *[fac-Ir(ppy)3] and p-toluenesulfonyl chloride produces the p-toluenesulfonyl radical and oxidation state [fac-Ir(ppy)3] + . Second, the p-toluenesulfonyl radical was selectively added to the terminal carbon-carbon double bond of acrylamide of 1,5-diene, followed by a 5endo cyclization to produce radical species II [58,59]. Although 5-endo cyclizations are often less favorable kinetically than their 4-exo cyclizations, the switch from 4exo to 5-endo mode can be achieved through specific properties of the Ts radical [60,61]. The high regioselectivity can be explained by the reason that the rate of sulfonyl radical addition to the carbo-carbon double bond of acrylamide is much greater than to the enamine carbon-carbon double bond. Third, radical species II loses an electron by the oxidation of photocatalyst [fac-Ir(ppy)3] + to forge tertiary cation intermediate III and to regenerate photocatalyst [fac-Ir(ppy)3] for the next turnover. Last, deprotonation of cation intermediate III occurs in the presence of K3PO4, giving sulfonylated pyrrolinone 3a. However, since the presence of base is important for the reaction, it cannot be ruled out that the radical II is directly deprotonated by the base to form radical anion, which is oxidized by the photocatalyst [fac-Ir (ppy)3] + [62]. It is notable that arylsulfonyl radicals are prone to loss of SO2 to form aryl radicals, which could induce the cyclization of 1,5-dienes in the same way as arylsulfonyl radicals, but the corresponding products have not been found in this system [63][64][65][66][67][68]. According to the above experimental results and previous literature reports [13][14][15][16][17][18], we propose a possible mechanism for visible-light-induced regioselective cascade sulfonylationcyclization of 1,5-dienes (Scheme 4). First, the photocatalyst [fac-Ir(ppy) 3 ] under visible light irradiation is excited to form the strongly reducing state *[fac-Ir(ppy) 3 ]. A single electron transfer between *[fac-Ir(ppy) 3 ] and p-toluenesulfonyl chloride produces the ptoluenesulfonyl radical and oxidation state [fac-Ir(ppy) 3 ] + . Second, the p-toluenesulfonyl radical was selectively added to the terminal carbon-carbon double bond of acrylamide of 1,5-diene, followed by a 5-endo cyclization to produce radical species II [58,59]. Although 5-endo cyclizations are often less favorable kinetically than their 4-exo cyclizations, the switch from 4-exo to 5-endo mode can be achieved through specific properties of the Ts radical [60,61]. The high regioselectivity can be explained by the reason that the rate of sulfonyl radical addition to the carbo-carbon double bond of acrylamide is much greater than to the enamine carbon-carbon double bond. Third, radical species II loses an electron by the oxidation of photocatalyst [fac-Ir(ppy) 3 ] + to forge tertiary cation intermediate III and to regenerate photocatalyst [fac-Ir(ppy) 3 ] for the next turnover. Last, deprotonation of cation intermediate III occurs in the presence of K 3 PO 4 , giving sulfonylated pyrrolinone 3a. However, since the presence of base is important for the reaction, it cannot be ruled out that the radical II is directly deprotonated by the base to form radical anion, which is oxidized by the photocatalyst [fac-Ir (ppy) 3 ] + [62]. It is notable that arylsulfonyl radicals are prone to loss of SO 2 to form aryl radicals, which could induce the cyclization of 1,5-dienes in the same way as arylsulfonyl radicals, but the corresponding products have not been found in this system [63][64][65][66][67][68].

General Considerations
All the reagents purchased from Leyan company were directly used. 1 H-NMR and 13 C-NMR spectra of the products were recorded on a Bruker FT-NMR 400M or 600M spectrometer (Bruker Beijing Scientific Technology Co., Ltd, Beijing, China). Chemical shifts spectra are given as δ in the units of parts per million (ppm) with reference to tetramethylsilane (TMS). Multiplicities were indicated as follows: d (doublet); s (singlet); t (triplet); q (quartet); m (multiplets); etc. Coupling constants are reported as a J value in Hz. High-resolution mass spectral analysis (HRMS) of the products were collected on an Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS (ESI) instrument (Beijing Agilent Technologies Co., Ltd, Beijing, China).

Procedure for the Synthesis of the Coupling Product 4aa
n-BuLi (2.5 M, 0.24 mmol) was slowly added to the solution of compound 4a (0.2 mmol) and THF (8 mL) at −78 °C. After 15 min, the reaction increased to room temperature. After completing, 8 mL water was added to quench the reaction and the mixture was extracted with 10 mL dichloromethane 3 times. The combined dichloromethane phases were dried over CaCl2, concentrated in vacuo and purified by flash column chromatography (30-40% EtOAc/petroleum ether) to furnish the desired product 4aa as a white solid (84% yield).

General Considerations
All the reagents purchased from Leyan company were directly used. 1 H-NMR and 13 C-NMR spectra of the products were recorded on a Bruker FT-NMR 400M or 600M spectrometer (Bruker Beijing Scientific Technology Co., Ltd., Beijing, China). Chemical shifts spectra are given as δ in the units of parts per million (ppm) with reference to tetramethylsilane (TMS). Multiplicities were indicated as follows: d (doublet); s (singlet); t (triplet); q (quartet); m (multiplets); etc. Coupling constants are reported as a J value in Hz. High-resolution mass spectral analysis (HRMS) of the products were collected on an Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS (ESI) instrument (Beijing Agilent Technologies Co., Ltd, Beijing, China).

Procedure for the Synthesis of the Coupling Product 4aa
n-BuLi (2.5 M, 0.24 mmol) was slowly added to the solution of compound 4a (0.2 mmol) and THF (8 mL) at −78 • C. After 15 min, the reaction increased to room temperature. After completing, 8 mL water was added to quench the reaction and the mixture was extracted with 10 mL dichloromethane 3 times. The combined dichloromethane phases were dried over CaCl 2 , concentrated in vacuo and purified by flash column chromatography (30-40% EtOAc/petroleum ether) to furnish the desired product 4aa as a white solid (84% yield).