Radical C–C bond formation using sulfonium salts and light

. Sulfonium salts are playing an increasingly significant role in contemporary organic synthesis. In particular, the generation of radicals from sulfonium salts is a fundamental process in Nature and has been the subject of investigation for over 50 years. However, general synthetic methods that use sulfonium salts as radical precursors are rare. The advent of photoredox catalysis has triggered an upsurge of interest in the radical chemistry of sulfonium salts and this review surveys recent applications of aryl and alkyl sulfonium salts in light-mediated, radical C–C bond formation.


Introduction
Sulfur-containing motifs have long fascinated synthetic chemists due to their rich reactivity and their occurrence in functional molecules, such as drugs and materials. [1] The cleavage of C-S bonds is of fundamental importance. For example, in the refining of petroleum, C-S bond cleavage is key to desulfurization. [2] More recently, sulfur functionalities, such as sulfides, sulfones, sulfoxides, sulfur ylides and sulfonates, have been used in methods for cross-coupling that proceed by C-S bond cleavage. [3] Organosulfur reagents are useful alternatives to traditional cross-coupling partners (e.g. aryl halides) and their application in synthesis opens up the possibility of the late-stage modification of complex sulfur-containing molecules. The widespread use of light to drive organic chemistry is arguably the defining feature of synthesis in the 21 st century to date. [4] This approach has delivered numerous new and/or improved processes involving radical intermediates. In particular, various radical precursors have been used for C-C bond formation, including halides, diazonium salts and sulfonyl chlorides (Scheme 1). [5] The continued growth of photoredox catalysis will require the development of new methods that embrace new substrates, bearing new functional groups. Scheme 1. Light-induced radical C-C bond formation. Sulfonium salts have attracted attention in recent years as versatile reagents in organic synthesis. [3] In particular, they have found application in various C-C bond-forming reactions that involve C-S bond cleavage. [6] In this review, we focus on the application of sulfonium salts in light-promoted C-C bond formation (Scheme 1). Photochemistry opens up new possibilities for the use of sulfonium salts as radical precursors; a mode of reactivity that has received relatively little attention. We will also introduce methods for sulfonium salt preparation as this is key to their applicability in synthesis. Extensive studies on the use of sulfonium salts as trifluoromethylating agents in photoredox chemistry have recently been reviewed and will not be covered here. [7] 2 Early reports on the photochemistry of sulfonium salts

Dr Gregory J. P. Perry
The generation of radical intermediates by the homolytic cleavage of C-S bonds in sulfonium salts is a fundamental process in Nature. [8] Methods that mimic this reactivity, for example using chemistry, electrochemistry or radiolysis have been investigated for over 50 years. [9] Early reports in this area also describe the effect of light on sulfonium salts. [10] To take just one example, Hacker and colleagues observed that UV irradiation at 254 nm could trigger the rearrangement of triarylsulfonium salts (Scheme 2). [10d] A variety of products was formed in low yield, including products 3 and 4 arising from C-C bond formation. The authors suggested that these products form predominantly via heterolytic cleavage and formation of ionic intermediates, although they also suggested that a pathway involving homolytic cleavage and radical intermediates was possible. As shown here, the direct photolysis of sulfonium salts is generally an inefficient process. 11 Herein, we describe how photocatalysis has enabled the application of sulfonium salts in light-mediated transformations. In 1978, a seminal report by Kellogg and co-workers discussed the reduction of sulfonium salts 6 to give ketones 7 and sulfides 8 (Scheme 3). [12] The reaction was promoted by light and 1,4-dihydropyridines (e.g. a Hantzsch ester) were used as hydrogen atom donors. The authors suggested a mechanism involving single electron transfer (SET) reduction of the C-S bond. They also described how photocatalysts, such as meso-tetraphenylporphine, eosin Y and [Ru(bpy)3]Cl2, drastically accelerated the rate of the reduction from days to hours. Not only do these reports describe some of the first photoinitiated reductions of sulfonium salts, but they also constitute early examples of photoredox catalysis. [4] Scheme 3. The light-mediated reduction of sulfonium salts: An early report of photoredox catalysis. 1 H NMR yields shown. Hantzsch ester = Diethyl 1,4-dihydro-2,6dimethyl-3,5-pyridinedicarboxylate. light = room lighting from neon fluorescent lamp. TPP = mesotetraphenylporphine.

Sulfonium salts in C-C bond formation
The value of aryl sulfonium salts in light-mediated C-C bond formation: In 2013, Fensterbank, Goddard, Ollivier et al. reported visible lightmediated C-C bond formation using triarylsulfonium salts 9 and alkenes (Scheme 4). [13] A range of allyl sulfones and chlorides 10 underwent the radical addition reaction in moderate to good yield, furnishing substituted allyl arenes (13a-d). 2-Arylacrylates 11 and 1,1-diphenylethylene 12 were also suitable radical acceptors that provided products 14 and 15. The electronic nature of the aryl substituents on either substrate had little effect on the reaction outcome in these cases (14a-c, 15a-c). By contrast, other olefins, such as styrenes, methacrylate, acrylonitriles and tert-butyl vinyl ether, proved to be  Accepted Manuscript

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ineffective aryl radical traps in this process and gave products in low yield (<10%). Finally, the effect of the counter anion in the sulfonium salt 9 on the preparation of 15c revealed that triflate (70%), tetrafluoroborate (72%), and hexafluorophosphate (65%) anions give similar results, whereas a bromide counter anion gave a lower yield (42%). To our knowledge, this is the first report of a general photoredox process involving sulfonium salts. A proposed mechanism for this transformation is provided in Scheme 5. The photoredox catalyst, Ru(bpy)3Cl2, is first excited under visible light irradiation. A standard light bulb was used in this instance, though blue LEDs are often used for performing photoredox chemistry with Ru(bpy)3Cl2 (max = 452 nm). [4a,b] The photoexcited state of the catalyst (E1/2 *II/I = +0.77 V vs SCE) [4a,b] is then susceptible to single electron reduction by the amine additive. This reductive quenching process forms a Ru(I) species (E1/2 II/I = -1.33 V vs SCE), [4a,b] which is capable of reducing the sulfonium salt 9 (E red = -1.2 V vs MSE) [13] to give an aryl radical. Trapping of the aryl radical with the olefin (e.g. 12) and subsequent hydrogen abstraction from the amine radical cation provides the desired product (e.g. 15).
Scheme 4. Photocatalytic reduction of sulfonium salts for radical C-C bond formation.

Scheme 6. Preparation of benzylsulfonium salts.
The preparation of benzylsulfonium salts and their reactivity in light-mediated C-C bond formation: Benzylsulfonium salts 17/18 can also participate in light-mediated C-C bond-forming reactions. The salts were prepared from the corresponding benzyl bromides 16 by a simple substitution reaction (Scheme 6). [14] To increase the stability of these salts, the bromide counterion can be exchanged for hexafluorophosphate. [15] Yorimitsu and co-workers reported a visible lightmediated radical alkenylation using benzylsulfonium salts 17 as benzyl radical precursors (Scheme 7). [16] The reaction tolerates various functionalities on the phenyl ring of the sulfonium salt, including ortho, meta, and para-substitution, and electrondonating/electron-withdrawing substituents (19a-f). Similarly, good functional group tolerance was observed with respect to substituents on the phenyl ring of 1,1-diarylethylenes (19g, 19h). Unsymmetrical 1,1-disubstituted alkenes were also tolerated in the reaction, however, a geometric mixture of products was obtained (19i, 19j). By switching the counter ion of the sulfonium salt to triflate and carrying out the reaction in co-solvent quantities of water or MeOH, the reactivity was extended to the synthesis of oxygenated products (19k, 19l). The reaction was proposed to proceed by SET reduction of the benzyl sulfonium 17 salt (E red = -1.48 V vs SCE) [16] by the excited state of the photoredox catalyst (E1/2 IV/*III = -1.73 V vs SCE, Scheme 8). [4a,b] The photoexcited state of the catalyst, fac-Ir(ppy)3 (max = 375 nm), [4a,b] was accessed through irradiation with blue LEDs. This generates a benzylic radical that is trapped by the olefin (e.g. 12).

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Another single electron transfer event involving the photoredox catalyst (E1/2 IV/III = +0.77 V vs SCE) provides the desired product 19 and closes the catalytic cycle. This mechanism is similar to that shown in Scheme 5, however, alkenyl products 19 are formed in this case as no terminal reductant (e.g. the radical cation of i-Pr2NEt) is present.
Building on this work, Novák and co-workers recently reported a metallaphotoredox coupling of benzylsulfonium salts 18 with N-Boc protected prolines (Scheme 9). [15] Various electron-deficient and electron-rich benzyl sulfonium salts underwent cross-coupling to provide the desired products in moderate to good yields (20a-d). However, substrates bearing ortho-substituents on the aromatic core gave lower yields suggesting that steric hindrance plays a crucial role in the reaction efficiency (20a, 20b).

The direct preparation of arylsulfonium salts for light-mediated C-C bond formation:
An ideal route to arylsulfonium salts is through direct sulfenylation of C-H bonds (Scheme 10). This reactivity, often termed an interrupted Pummerer reaction, first found widespread application for the preparation of trifluoromethylating agents. [17] Towards the turn of the century, Balenkova and Nenajdenko began investigating the generality of this method. [18] More recently, several groups have contributed to establishing intermolecular C-H sulfenylation using sulfoxides as a facile means for accessing sulfonium salts. [19,20] Within these reports, sulfonium salts have proved effective electrophilic partners in transition-metal catalysed C-C crosscouplings. [3, 6, 19, 20c-f, 20m] In particular, formal C-H cross-couplings can occur when C-H sulfenylation and C-C bond formation are carried out in one pot. [20f] Scheme 9. Metallaphotoredox-catalysed radical alkylation of benzyl sulfonium salts.

Scheme 10. The direct preparation of sulfonium salts from C-H bonds via an interrupted Pummerer reaction.
Building on this precedent, Ritter and colleagues have developed a highly para-selective C-H sulfenylation of arenes. [21] The resulting tetrafluorothianthrene (TFT) sulfonium salts 21/22  were then engaged in photoredox and transition metal catalysed processes (Scheme 11). [21] For example, a derivative of the insecticide pyriproxyfen 21 underwent cyanation to give 23 and a Minisci-type C-H arylation converted 22 into 24. Other lightmediated processes were used to introduce a range of useful functionalities, for example; Bpin, (O)P(OPh)2, SCF3, and halogens. An intermediate aryl radical is likely formed from the sulfonium salts 21/22 in these processes. Similarly, TFT and thianthrene (TT) salts 25 were used for site-selective trifluoromethylation. [22] Ritter and co-workers utilised a trifluoromethyl copper species, formed in situ, as the trifluoromethylating agent under the photoredoxcatalysed conditions (Scheme 12). The sequence tolerates a number of functional groups; for example, aldehydes, ketones, esters, alcohols, halides and pseudohalides. Notably, the method can be used for the late-stage functionalisation of medicinally and agrochemically important compounds (26e, 26f). In 2020, Procter et al. developed a one-pot, formal C-H/C-H (hetero)biaryl coupling (Scheme 13). [23] The process uses commercially available dibenzothiophene S-oxide (DBTSO) to achieve selective sulfonium salt formation, via an interrupted Pummerer reaction, before an organic photoredox catalyst (10-phenylphenothiazine, PTH) mediates the desired radical cross-coupling. The sulfonium salts were isolable, however, the formal C-H/C-H crosscouplings were generally performed in one pot to improve overall efficiency. A range of heteroaromatics were coupled with the sulfonium salt derived from arene 27a, including furan (29a), indole (29b) and pyridine (29c). Sulfonium salts derived from phenol and aniline derivatives also provided good overall yields (29d), however, limitations arose when substrates with free amine and alcohol groups were used. Drug molecules were also subjected to late stage arylation, for example, in the derivatization of the anti-arrhythmic drug mexiletine 29f. Synthesis of the natural product pseudilin 30 was also described; the formal C-H/C-H coupling of 27b and 28b gave the key intermediate biaryl 29g (Scheme 14a).

12.
Photoredox-catalysed radical trifluoromethylation of sulfonium salts. This method was also applicable to the crosscoupling of aryl sulfonium salt 31 and olefin 12 to give 32 (Scheme 14b). This result is complementary to the report of Fensterbank, Goddard and Ollivier, in which alkyl products were observed (Scheme 4), and Yorimitsu, who used benzylsulfoniums (Scheme 7). A mechanism for the cross-coupling is provided in Scheme 15. Photoexcitation of the catalyst, PTH (E1/2 red* = -2.1 V vs SCE) [4c] , enabled SET reduction of the sulfonium salt 31 (E red = -1.1 V vs SCE) [23] to generate an aryl radical. The excited state of the photoredox catalyst (max <300 nm) [4c] was accessed through irraditation with blue LEDs. This radical is then trapped by the arene 28 (or olefin 12), before subsequent single electron oxidation by PTH (E1/2 ox = +0.68 V vs SCE) [4c] and deprotonation provides the desired product 29. Stern-Volmer quenching experiments and the measurement of the quantum yield ( = 0.18) supports the proposed catalytic cycle.

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Conclusion
While investigations into the radical chemistry of sulfonium salts reach back over several decades, it is only recently that this reactivity has found application in mainstream synthesis. Developments in the synthesis of sulfonium salts, particularly methods that allow salts to be accessed directly by C-H sulfenylation using sulfoxides, have played a key role in making highly functionalised salts available. These new methods for the efficient preparation of sulfonium salts, combined with the discovery of new reactivity, is allowing teams to reveal the synthetic potential of these reagents. The marriage of sulfonium salts and light-activation is proving a particularly useful strategy for the invention of new radical C-C bond-forming reactions. As access to this underexplored functional group grows, we look forward to the discovery of new reactivity, new processes, and new applications driven by the chemistry of sulfonium salts.

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REVIEW Radical C-C bond formation using sulfonium salts and light
The chemistry of sulfonium salts has grown significantly in recent years. In this review, we discuss recent applications of sulfonium salts as radical precursors for light-mediated C-C bond formation.