Photoredox catalytic radical fluorosulfonylation of olefins enabled by a bench-stable redox-active fluorosulfonyl radical precursor

Sulfonyl fluorides have attracted considerable and growing research interests from various disciplines, which raises a high demand for novel and effective methods to access this class of compounds. Radical flurosulfonylation is recently emerging as a promising approach for the synthesis of sulfonyl fluorides. However, the scope of applicable substrate and reaction types are severely restricted by limited known radical reagents. Here, we introduce a solid state, redox-active type of fluorosulfonyl radical reagents, 1-fluorosulfonyl 2-aryl benzoimidazolium triflate (FABI) salts, which enable the radical fluorosulfonylation of olefins under photoredox conditions. In comparison with the known radical precursor, gaseous FSO2Cl, FABI salts are bench-stable, easy to handle, affording high yields in the radical fluorosulfonylation of olefins with before challenging substrates. The advantage of FABIs is further demonstrated in the development of an alkoxyl-fluorosulfonyl difunctionalization reaction of olefins, which forges a facile access to useful β-alkoxyl sulfonyl fluorides and related compounds, and would thus benefit the related study in the context of chemical biology and drug discovery in the future.

Among the most common methods for the synthesis of sulfonyl fluorides [1][2][3][4][34][35][36][37][38][39][40][41][42][43][44][45][46] , direct fluorosulfonylation 45-48 undoubtedly represents a concise and effective approach, and could be particularly useful in the late-stage modifications of drugs and biomolecules [1][2][3][4] . Most of the fluorosulfonylating reagents reported so far belong to the FSO 2 + -type of synthons, including the well-known sulfuryl fluoride gas (SO 2 F 2 ) 1 and other solid reagents (such as FDIT, recently reported by Sharpless, Dong et al., which exhibited high reactivity in the fluorosulfonylation of phneols and amines 47,48 . In contrast, fluorosulfonylation with the corresponding fluorosulfonyl radical (FSO 2 •) remains less investigated 4 , likely due to the instability and challenging preparation 49 . Recently, we used sulfuryl chlorofluoride (FSO 2 Cl) as a radical precursor and we reported the radical fluorosulfonylation of alkenes 50,51 , affording an effective method for the preparation of important alkenyl sulfonyl fluorides [50][51][52][53][54][55][56] . However, when we applied this reagent to the development of other transformations, e.g., the alkoxy-fluorosulfonylation reaction of styrene (Fig. 2a), we failed to obtained any desired product even after extensive optimization. Instead, undesired chloro-and styryl-sulfonyl fluorides were obtained, which were supposed to the products from a radical chain mechanism (Path I, Fig. 2b) 50 . The weak S-Cl bond in FSO 2 Cl with a highly reactive chloride renders a fast chloride atom transfer (k estimated >10 6 M −1 s −1 ) 50,57 from FSO 2 Cl to the radical intermediate Int-A; this rapid radical chain propagation (Path I) makes it difficult to trap this radical with other reagents or by single electron transfer (SET) oxidation to establish a photoredox reaction pathway (Path II). Given this challenging issue and also other limitations with FSO 2 Cl, such as: chlorination side-reactions and low/no yields with electron-rich substrates (as the chloride in FSO 2 Cl is highly electrophilic due to the electron-withdrawing effect of the FSO 2 -group) 50 , inconvenience in storage and handling due to the gaseous (b.p. 7°C) and moisture-sensitive nature, the development of a new and convenient FSO 2 radical precursor (X ≠ Cl) is highly desirable. Here, we report our efforts toward this goal, and the introduction of a solid-state, bench-stable type of reagents, 1-fluorosulfonyl 2-aryl benzoimidazolium triflate (FABI) salts, which can serve as effective redox-active FSO 2 radical precursors and enable the development of radical fluorosulfonylation of olefins via a photoredox catalytic pathway. FABI is compatible with many substrates that were not compatible or low yielding when FSO 2 Cl is used, such as electron-rich alkenes and triaryl ethylenes. Moreover, a cascade alkoxy-fluorosulfonyl difunctionalization of olefins with FABI is presented, by trapping the postulated cationic intermediate Int-B with alcohols via a photoredox pathway (Fig. 2b, c).

Results
Reaction optimization. We commenced our study with the screening of suitable FSO 2 radical precursors in the form of imidazolium salts under photoredox conditions (Table 1). In the beginning, we tried a sample imidazolium salt, 2a 47,58 , but it was found that 2a was unable to generate the FSO 2 radicals under this photoredox condition, delivering no any detectable formation of the desired product (entry 1). This is unexpected, as the excited fac-Ir(ppy) 3 should be reducing enough (−1.73 V vs SCE) to reduce 2a (−1.03 V vs SCE) via single electron transfer (SET). We guess the extrusion of FSO 2 radicals after accepting one electron from excited fac-Ir(ppy) 3 requires a good driving force of rearomatization (for details, see the mechanistic discussion later). Therefore, we tested the imidazolium salt 2b and 2c 58 , with a 2-substitued or a fused phenyl group, respectively. Encouragingly, we could observe a trace amount of 3aa (entry 2 and 3) Then, we combined the effects, and synthesized two 1-fluorosulfonyl 2-aryl benzoimidazolium triflate (FABI) salts: 2d and 2e. To our delight, 2d afforded a substantial improvement in the reaction efficiency (entry 4), and the yield of the desired product 3aa can be further improved to above 90% by using 2e as the precursor, together with a high E/Z ratio (94%, entry 5). In this case, the desired product can be isolated in 90% yield. For more details about the reaction optimizations, please see the Supplementary Table 1 and 2. In addition, control experiments indicated that both the photocatalyst and light are crucial to the reaction (entry 7 and 8).
Substrate scope. Having the optimized reaction conditions in hand, we moved on to investigate the reaction scope. As shown in Fig. 3, this protocol could readily accommodate a variety of styrenes (3aa-3ap) and showed a good tolerance of various functional groups, including halides (F, Cl, Br, 3ae-3ai), ester (3an), and nitrile (3ao), etc. Notably, 4-methoxystyrene is compatible with the current conditions with FABI 2e, the desired sulfonyl fluoride 3ad can be obtained in 66% yield. In sharp contrast, the previous method with FSO 2 Cl as the FSO 2 radical precursor afforded a messy reaction, and no desired product was obtained 50 . Aliphatic alkenes were less favored by this system a  Fig. 2 The development of photoredox catalytic radical fluorosulfonylation of olefins. a The development of radical alkoxy-fluorosulfonylation of styrene with alcohol as a nuleophile. b Radical fluorosulfonylation of alkenes via radical chain pathway (Path I) versus photoredox pathway (Path II). c This work: photoredox catalytic radical fluorosulfonylation of olefins enabled by redox-active radical reagent development.
(3aq-3ar), in line with the photoredox mechanism and the higher difficulty in oxidizing simple alkyl radicals than benzylic radicals 59 . Nevertheless, to our great pleasure, this FSO 2 radical reagent (2e) is well compatible with electron-rich olefins, allowing for a facile access to β-Oor N-substituted vinyl sulfonyl fluorides (3as-3bb). As shown in Fig. 3, alkyl vinyl ethers (3as-3av), phenyl vinyl ether (3aw), vinyl acetates (3ax), vinyl thioether (3ay), and N-vinyl amides (3az-3bb), were all well tolerated, which further demonstrated the usefulness and advantages of FABI reagents over FSO 2 Cl. The direct radical fluorosulfonylation of cyclic, di-and trisubstituted olefins enables the preparation of multi-substituted vinyl sulfonyl fluorides. As shown in Fig. 4, the current protocol with FABI 2e as the FSO 2 radical reagent was found very effective for the diaryl and triaryl olefins (4ad, 4ae, and 4ag-4an), delivering the corresponding products in much higher yield than that of reactions with FSO 2 Cl. For example, indene and 1,2dihydronaphthalene readily underwent the functionalization to give 5ab and 5ac in 91% and 86% yield with FABI 2e, respectively, while the yields were 68% and 63% when using FSO 2 Cl as the radical precursor 50 . In the reactions of stilbene and 1,1-diphenylethylene, 2e also exhibited good reactivity (Fig. 4, 5ae  and 5af). The superiority of this reagent was further manifested in the direct fluorosulfonylation of triarylethylenes (4ag-4an), and the desired sulfonyl fluoride products (5ag-5an) can be obtained in good to high yields (41-92%). In contrast, the previous method with FSO 2 Cl gave 5ag in a quite poor yield (18%) 50 . The low E/Z ratios in some cases probably resulted from the E/Z isomerization of the starting olefins, suggested by the tracking experiment with 4aj and 4ak (Fig. 4, b), in which both starting olefin 4aj & 4ak was found rapidly isomerized into Z/E 1:1 ratio in 10 min. Further, more examples of triarylethylenes also afforded the products (5ay-5ba, in the Supplementary Methods) in~1:1 Z/E ratios. Moreover, as shown in Fig. 4c, biorelevant molecules, such as cinnamic alcohol, menthol, ciprofibrate, thymol, galactose, abietic acid, chromene, tyrosine, estrone, and febuxosate-derived alkenes, can all be readily modified with this reagent, affording the corresponding sulfonyl fluorides (5ao-5ax) with a good functional group compatibility and high structural diversity.
To gain some mechanistic insight into the reaction, the radical scavenger 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO, 2.0 equiv.) was added to the reaction mixture of 1a and 2e under standard conditions. The reaction was found completely inhibited, and no fluorosulfonylation product 3aa was observed ( Fig. 6 and Eq. 1). To further examine the involvement of FSO 2 radical in the reaction, a radical-clock experiment was conducted with cyclopropylstyrene (8), a well-known radical probe 63,64 , and the cyclization product 9 can be isolated in 21% yield. This is in accord with a redox mechanism, and suggested that fluorosulfonyl radical addition to the double bond, followed by a subsequent radical ring-opening of the three-membered cycle and radical cyclization, should be involved ( Fig. 6 and Eq. 2) 50,63,64 .
On the other hand, as demonstrated in Fig. 5, carbocationic species can be trapped by alcohols. For comparison, we also performed the reaction with FSO 2 Cl, in which no formation of 7a was observed under the same reaction conditions (Fig. 6b) Fig. 3 The scope of radical fluorosulfonylation of terminal olefins and electron-rich alkenes. The reactions were performed on 0.1 or 0.2 mmol scales, with 2 equiv. of 2e in 1,4-dioxane at room temperature for 12 h. a Yields on 1.0 mmol scale. b The yields in parentheses are the reactions with FSO 2 Cl 50 . c With 3.0 eq. of 2e. d With 1.0 eq. of K 3 PO 4 . e With 1.0 eq. of K 2 CO 3 . *Yields on 1.0 mmol scale.  Fig. 4 The scope of multi-substituted olefins and late-stage modification of natural products. a Scope of cyclic, di-and tri-substituted olefins. b Tracking the E/Z isomerization of substrate 4aj and 4ak. c Late-stage modification of natural products. a All reactions were performed on 0.1 or 0.2 mmol scales . b In parentheses are yields with FSO 2 Cl. c With 1.0 eq. of K 2 CO 3 . d With 2.0 eq. of 2e. *Reactions on 1.0 mmol scale. product 7a can be isolated in high yield, which further manifested the superiority of the newly developed FABI agents.
According to these results, a possible reaction mechanism for this radical fluorosulfonylation reaction using FABI 2e as the radical precursor is proposed in Fig. 6c. First, under the irradiation of blue LEDs, the photocatalyst (Ir III ) is excited (E 1/2 IV/III* = −1.73 V vs SCE) 65 and then undergoes a single electron transfer (SET) to the redox-active radical precursor 2e (E 1/2 red = −1.07 V vs SCE). Upon the acceptance of one electron, 2e′ would undergo a homolytic fission of the N-S bond, and give the desired FSO 2 radicals. Subsequently, the addition of FSO 2 • to styrene furnishes the key radical intermediate Int-1. Oxidation of Int-1 by Ir IV affords the cationic species Int-2, which can be deprotonated to give 3aa, while trapping Int-2 with alcohols (R'OH) could afford the difunctionalization product 7. It is worth mentioning that when FSO 2 Cl was used as FSO 2 • precursor, it was found unable to establish this redox cascade difunctionalization reaction as shown in Fig. 6B, probably due to the fast radical chain mechanism (Fig. 2B, path I) preventing the SET oxidation of the radical intermediate Int-1 50,51 . Further, considering the other reagents 2a-c have similar redox potentials (E 1/2 red = −1.03−1.09 V vs SCE, see the Supplementary Information) as 2e, the presence of both a benzo-moiety and 2-aryl group in the reagents (FABI 2d and 2e) could probably facilitate the extrusion of the desired FSO 2 radicals by enhancing the driving force of re-aromatization in the step from 2e′ to 2e″.

Discussion
In summary, 1-fluorosulfonyl benzoimidazolium triflate (FABI) salts have been demonstrated as an effective redox-active fluorosulfonyl radical precursor, featuring its solid state, bench-stable characters, convenience to handle, and good tolerance of functional groups. This radical fluorosulfonylation method allows for a facile access to various vinyl sulfonyl fluorides from olefinic substrates, with remarkable good compatibility to electron-rich substrates and triaryl ethylenes, in comparison with the methods established with the known FSO 2 radical precursor. In particular, FABI could allow the 3.0 equiv.     c Mechanistic proposal for this photoredox radical fluorosulfonylation with FABI 2e. TEMPO = 2,2,6,6-tetramethyl-1-piperidinoxyl.

Methods
General procedure. The fac-Ir(ppy) 3 (1 mol%) and FABI 2e (2.0 or 3.0 equivalents) were weighed into an oven-dried Schlenk tube, followed by the addition of anhydrous 1,4-dioxane (4.0 mL, 0.025 M) and olefin substrate (0.1 mmol) under argon. The reaction mixture was allowed to stir at room temperature under irradiation with blue LEDs for 12 h. Purification by column chromatography or preparative thin-layer chromatography on silica gel gave the desired pure product.