Generation of non-stabilized alkyl radicals from thianthrenium salts for C–B and C–C bond formation

Sulfonium salts bearing a positively charged sulfur atom with three organic substituents have intrigued chemists for more than a century for their unusual structures and high chemical reactivity. These compounds are known to undergo facile single-electron reduction to emerge as a valuable and alternative source of aryl radicals for organic synthesis. However, the generation of non-stabilized alkyl radicals from sulfonium salts has been a challenge for several decades. Here we report the treatment of S-(alkyl) thianthrenium salts to generate non-stabilized alkyl radicals as key intermediates granting the controlled and selective outcome of the ensuing reactions under mild photoredox conditions. The value of these reagents has been demonstrated through the efficient construction of alkylboronates and other transformations, including heteroarylation, alkylation, alkenylation, and alkynylation. The developed method is practical, and provides the opportunity to convert C–OH bond to C–B and C–C bonds.

S ulfonium salts are among the most versatile of all reactive intermediates in organic chemistry [1][2][3] . In general, the reactivity of sulfonium salts is determined by the positive charge that they contain, which is mainly located at the sulfur atom. In this context, many sulfonium salt-based reagents including Umemoto's reagent have been designed for electrophilic substitution [4][5][6][7][8][9][10] . In nature, enzymes catalyzing the generation of alkyl radicals from sulfonium salts known to date all belong to the radical S-adenosylmethionine (SAM) superfamily (Fig. 1a) [11][12][13][14][15] . In a synthetic chemistry setting, general methods that utilize sulfonium salts as radical precursors have been investigated over the past decades [16][17][18] . Recently, the emerging field of photoredox catalysis has also offered new possibilities for these single electron transfer (SET)-induced transformations under mild conditions [19][20][21] . Ritter and coworkers just reported the site-selective C-H functionalization of arenes to build S-(aryl) thianthrenium salts, which could be utilized in radical-involved transformations by photoredox catalysis (Fig. 1b) [22][23][24][25][26] . The Procter group also explored a one-pot strategy for the facile construction of (hetero)biaryl motifs with intermediate S-(aryl) dibenzothiophenium salts enabled by organic photoredox catalysts 27 . Despite these advances, the vast majority of the sulfonium salts that undergo SET process have been limited to form aryl radicals; The generation of alkyl radicals, especially the nonstabilized ones from sulfonium salts is synthetically challenging.
As precursors for S-ylides, S-(alkyl) sulfonium salts have been widely applied in cyclization 28,29 and rearrangement reactions 30 . The early studies from the Kellogg group found the reduction of S-(alkyl) sulfonium salts under photoredox catalytic conditions 31,32 . However, the reported protocols have been limited for the generation of stabilized alkyl radicals (benzyl or with α-electron-withdrawing groups) so far [33][34][35][36][37] . To mimic the radical-involved biosynthesis from SAM, here we show S-(alkyl) thianthrenium salts, which are ready to engage in diverse SETinduced fragmentations and transformations, especially by mild photoredox processes (Fig. 1c). Moreover, the formed thianthrene (TT) reagent could be recycled after the reactions. A significant observation of the reactivity of these compounds is that diverse non-stabilized alkyl radicals can be effectively generated as key intermediates in these transformations.

Results
Synthesis of S-(alkyl) thianthrenium salts. Instead of the known methods to access S-(alkyl) thianthrenium salts by using alkylmercurial and alkyl-tin reagents in the 1990s 38,39 , they were easily prepared by an alternative method from the corresponding alcohols and TT in one-pot on the gram scale (for an example of 1a, Fig. 2). A crystal of the substrate 1a was generated and subjected to X-ray crystallographic analysis (see Supplementary Data 1).
Scope of the methodology. With the optimized conditions in hand, the scope of the thianthrenium salts was explored under photo-and thermoinduced conditions (Fig. 4). Desulfurative borylation of primary alkyl-substituted thianthrenium salts with alkyl chains (2-4a), methoxy (5a), ester (6a), cyano (7a), halides (F, Cl, Br and I, 8-12a), heterocycles (thiophene, benzofuran, oxazole and carbazole, 13-16a), alkenes (17a) and alkynes    (18-19a) were converted into the corresponding pinacol boronic esters 2-19c in good to high yields. Secondary alkyl-substituted substrates, either appended to the acyclic chain (20-21a) or to a variety of rings (cyclohexyl, cyclo cyclododecyl and adamantan-2y, 22-24a), underwent smooth borylation under the two developed reaction conditions. Benzylic-substituted thianthrenium salt 25a was also compatible under photoinduced conditions, but only trace amount of the desired product 25c was observed under thermoinduced conditions. Borylation of thianthrenium salt 26a containing a perfluoroalkyl chain was facile to form desired product 26c. Thianthrenium salt 27a, which is derived from αlinolenic acid with three cis double bonds, was compatible with excellent configuration retention. The functional group tolerance of both reaction systems was further tested with complex molecules 28-30a. Among them, idebenone derivative 30a was an eligible substrate to provide 30c in a modest yield with visible light irradiation, but it did not work under the Lewis base system. In addition, substrate 31a containing two sulfonium salt motifs could undergo double borylation in both reaction systems. In most of the above examples, the photochemical process showed better reactivity than that using the Lewis base. In the case of a thianthrenium salt 32a with an aromatic C-I bond, the thermal reaction conditions showed excellent chemoselectivity for desulfurative borylation; however, the choice of the photochemical setup led to poor compatibility 52 .
Synthetic applications. We next turned our attention to improve the practicability and operability of this transformation (Fig. 5). Although using a catalytic amount of TT in our reaction remains challenging at this stage, this compound could, nevertheless, be recycled (Fig. 5a). After the reaction of 1a, TT reagent was formed accompanying with the main product 1c. The reaction mixture was then separated by flash column chromatography on silica gel affording the product 1c in a good yield and regenerating TT reagent in nearly quantitative recovery. To further demonstrate the potential of this transformation to simplify synthesis, one-pot reactions were conducted. For example, the one-pot sulfonation and thianthrenation with alcohol I followed by borylation under irradiation conditions led to the generation of alkylboronate 1c in 67% yield (Fig. 5b). The secondary alkyl-substituted thianthrenium salt 33 bearing a chloride group was not stable and difficult to prepare. Notably, one-pot transformation of formyloxy 34 could provide a convenient way toward the corresponding product 35 (Fig. 5c).

Discussion
Several mechanistic experiments were then performed to gain insight into the mechanism of this transformation (Fig. 6). We tested the CV of phenethyl-containing thianthrenium salt 1a, Katritzky salt II and NHPI ester III (Fig. 6a). Thianthrenium salt 1a showed irreversible reduction profiles, with E red = −1.28 V (versus Ag/AgNO 3 ) in DMA, which is more prone to be reduced than Katritzky salt II (E red = −1.33 V, versus Ag/AgNO 3 ) and NHPI ester III (E red = −1.30 V, versus Ag/AgNO 3 ). Then, the absorption spectra of 1a, B 2 cat 2 , and a mixture of 1a and B 2 cat 2 were obtained (Fig. 6b). A bathochromic shift of the mixture proves the strong evidence for the existence of an electron-donoracceptor (EDA) complex 60,63-65,68-71 . Furthermore, using TEMPO or 1,1-diphenylethylene as radical scavengers in the reactions with visible light irradiation, trapped products 36 and 37 were detected and isolated (Fig. 6c). In addition, desulfurative borylation of 38 could form major product 39 accompanied by cyclization product 40 (Fig. 6d) 72 . These results indicate that alkyl radicals are formed during the reaction. In addition, "light/dark" experiments further showed that visible light was a necessary component of the transformation. Finally, the quantum yield of the transformation to form 1c was determined to be Ф = 46, indicating that a radical chain process was operative (for details, see Supplementary Information) 73 .
Based on the above observations, a proposed mechanism is shown in Fig. 7. Photoexcitation of EDA complex A derived from S-(alkyl) thianthrenium salts and B 2 cat 2 ·DMA adduct initiates the radical chain reaction, forming alkyl radical B, DMA·Bcat adduct C, DMA-stabilized boron-centered radical D, and TT. Then, propagation of the desulfurative borylation probably proceeds through reaction of alkyl radical B with the B 2 cat 2 ·DMA adduct to produce radical complex E. Cleavage of the B-B bond generates borylated products b and boryl radical D, which can further reduce substrates a to form DMA·Bcat adduct C and regenerate alkyl radical B (for the proposed mechanism of thermoinduced borylation, see the Supplementary Information).
In addition to desulfurative borylation under metal-free conditions, the reaction of thianthrenium salts with several different coupling partners can also be carried out by photoredox catalysis at ambient temperature (Fig. 8). For example, Giese radical addition of thianthrenium salt 1a with electron-deficient olefins 41a-b can be accessed to provide products 42-43 using Hantzsch ester as a reductant with a catalytic amount of Ir[(ppy) 2 dtbpy]PF 6 under irradiation with a blue LED 74 . With the same photocatalyst, an   efficient and mild defluorinative alkylation of α-trifluoromethyl alkene 41c using thianthrenium salt 1a as a radical precursor could produce gem-difluoroalkene 44 in a 65% yield 75 . Under the same reaction conditions, we also developed alkyl radical olefination (45) and alkynylation (46) reactions with secondary thianthrenium salt 23a with sulfone reagents 41d-e 76 . The photoredox Minisci-type functionalization of isoquinoline (41 f) and 9-methyl-9H-purine (41 g) with 1a efficiently led to alkylation products 47-48 with catalytic amounts of Ir[dF(CF 3 )ppy] 2 (dtbpy)PF 6 and triflate acid in DMA under a blue LED 77,78 . Treatment of 1,1-diphenylethylene with substrate 23a with visible light irradiation could provide the trapped products 49 in 67% yield. Moreover, direct cross-coupling of C(sp 3 )−H bonds in N-aryl tetrahydroisoquinoline 41 h with thianthrenium salt 1a by visible-light photoredox system could generate product 50 in an excellent yield 79 . In addition, S-(alkyl) thianthrenium salt can also serve as an electrophile reagent to provide an alkyl source with nucleophiles 80 . For example, when a complex molecule atorvastatin (51) with several possible reactive sites was examined with thianthrenium salt 1a, the reaction showed excellent selectivity for esterification product 52 in a good yield. In conclusion, the challenges associated with sulfonium salts forming nonstabilized alkyl radicals could be efficiently solved by using S-(alkyl) thianthrenium salts in SET-induced fragmentations and transformations, especially under mild photoredox systems. These thianthrenium salts bearing a large range of functional groups are suitable electrophiles for borylation, heteroarylation, alkylation, alkenylation, and alkynylation under photochemical conditions. Given the ready availability of alcohols, our approach provides an efficient way to stepwise conversion of OH group to other functional groups, and especially, one-pot manners can be performed with the almost complete recovery of the TT reagent. Extending the developed sulfonium salts to other challenging and useful transformations is currently being explored in our laboratory.

Methods
General procedures I. A 10.0 mL Schlenk tube with a stirring bar was added with alkyl sulfonium 1a (0.4 mmol, 1.0 equiv), B 2 cat 2 (190.3 mg, 0.8 mmol, 2.0 equiv) and DMA (1.0 mL) under argon. The resulting mixture was stirred at room temperature under blue LED irradiation for 12 h. Then pinacol (189.1 mg, 1.6 mmol, 4.0 equiv) was dissolved in Et 3 N (1.0 mL), added to the reaction mixture and stirred for 1 h. The mixture was cooled to 0°C to precipitate thianthrene, which was removed by filtration. Then water was added, and the reaction mixture was extracted with EtOAc, dried over MgSO 4, and concentrated under reduced pressure. The crude product 1c was purified by flash column chromatography.
General procedures II. A 10.0 mL Schlenk tube with a stirring bar was added with alkyl sulfonium 1a (0.4 mmol, 1.0 equiv), B 2 cat 2 (190.3 mg, 0.8 mmol, 2.0 equiv), B1 (26.0 mg, 30.0 mol %) and DMA (1.0 mL) under argon. The resulting mixture was stirred at 80°C under Ar for 3 h. The mixture was cooled to room temperature. Pinacol (189.1 mg, 1.6 mmol, 4.0 equiv) was dissolved in Et 3 N (1.0 mL), added to the reaction mixture, and stirred for 1 h. The mixture was cooled to 0°C to precipitate thianthrene, which was removed by filtration. Then water was added, and the reaction mixture was extracted with EtOAc, dried over MgSO 4, and concentrated under reduced pressure. The crude product 1c was purified by flash column chromatography.

Data availability
All data supporting the findings of this study are available within the article and Supplementary Information file or from the corresponding author upon reasonable request. The crystallography data have been deposited at the Cambridge Crystallographic Data Center (CCDC) under accession number CCDC: 2047564 (1a) and can be obtained free of charge from www.ccdc.cam.ac.uk/data_request/cif. Received: 18 February 2021; Accepted: 24 June 2021;