Thianthrene Radical Cation as a Transient SET Mediator: Photoinduced Thiocyanation and Selenocyanation of Arylthianthrenium Salts

A novel transient SET mediator approach has been developed for the photoinduced radical-radical cross coupling reaction. Using the in-situ generated thianthrene radical cation as the transient SET mediator, the thiocyanation and selenocyanation of aryl thianthrenium salts have been realized under the mild conditions in the absence of the photocatalyst or single electron donor. In comparison with the photocatalyst enabled process, the protocol features mild conditions, simple manipulation, a broad substrate scope, excellent functional group and heterocycle tolerance. Due to the feasible accessibility of aryl thianthrenium salts, this method has also been applied in the efficient synthesis of a bioactive molecule


Introduction 2
2][3] The high specificity of cross-coupling of two odd-electron partners has normally been rationalized by the persistent radical effect (PRE) [4][5][6] , and the development of efficient strategies for generating two types of radical species and facilitating the coupling reaction has attracted increasing attention over the last decade [1][2][3][4][5][6][7][8][9][10][11] .3][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The development of a process with in-situ generated endogenous transient SET mediator will be more desired due to the simple manipulation, and no extra oxidants or SET mediators are required.Here, we envisioned that the two open-shell partners could be formed via a transient single electron transfer (SET) mediator approach, that is, the transient SET mediator (in-situ generated via a homolytic cleavage of substrate A) could be further used as a SET oxidant or reductant with substrate B to afford the second radical intermediate (Figure 1a).If a suitable redox-active process is involved, an in-situ generated endogenous SET mediators could be identified to overcome the limitations in the known radical generation processes.Ideally, this novel process would enable a broadly applicable process for the new reaction development, featuring simple conditions, high efficiency, and broad functional group and heterocycle tolerance.
2][33][34] In particular, the aryl radical generation from the arylthianthrenium salts normally requires a photocatalyst via a reductive quench cycle [35][36][37][38][39][40][41][42][43][44] or requires an electron donor via EDA activation [45][46][47][48][49][50] .The homolytic cleavage of C(sp 2 )-S bond in arylthianthrenium salts for the formation of aryl radical, accompanied with the formation of a thianthrene radical cations was also feasible under strong irradiation conditions (UV-light, 254 nm, 144 w). 51,52Given the thianthrene radical cation has high oxidative potential (ETT +• /TT = 1.21 V vs. Ag/Ag + ) 53 , it might have the capability of oxidizing the reductive nucleophilic coupling partner to corresponding radical species via the SET oxidative process.Hence, we hypothesized that the thianthrene radical cations might serve as a transient SET mediator, thus enables the development of the novel coupling reaction with reductive nucleophilic coupling partners through this approach.Herein, we present the photoinduced thiocyanation and selenocyanation of arylthianthrenium salts using thianthrene radical cation as the transient SET mediator for the efficient construction of aryl thiocynates and aryl selenocyanates (Figure 1b).This reaction disclosed that the homolytic cleavage of C(sp 2 )-S bond in arylthianthrenium salts could proceed under very mild conditions (purple LEDs, 380-390 nm, 24 W).It is noteworthy that the resulting aryl thiocynates and selenocyanates, are not only one of the important chalcogen-containing compounds in the field of pharmaceutical and functional material chemistry [54][55][56][57][58][59][60] (Figure 1c), but also the versatile intermediates for the installation of other organic sulfur/selenium-containing functional groups, such as sulfides/selenides, disulfifides/diselenide, trifluoromethyl thioethers/selenoethers, etc. [61][62][63][64] Moreover, this new process leveraged the versatility, stability, and convenient availability of aryl thiantrenium salts, thus offering a sustainable approach for construction of C-S bond and for the late-stage functionalization bioactive compounds.
To shed light on the detailed mechanism of this reaction, a series of mechanistic experiments were carried out.Consideration of the photoinduced transformations of aryl thianthrenium salts via a EDA activation model have been demonstrated by Procter 45 , Molander [46][47] and other groups [48][49][50] , we first checked the UV-vis absorption spectra of the individual arylthianthrenium salts 1k, KSeCN, and the 1k/KSeCN mixture in CH3CN (0.0001 M), respectively.The results showed no red shift occurred after mixing 1k and KSeCN, which ruled out the EDA activation pathway for our reaction (Figure 2e).Interestingly, a white precipitate was observed when we mixed the solution of 1k and the solution of KSeCN in CH3CN, which has been further identified as the thianthrenium selenocyanate 1k' formed via anion exchange (Figure 2c).
The UV-vis spectroscopic analysis of 1k' evidenced a higher absorption intensity of 1k' than other species, indicating that 1k' might be the active species in this reaction (Figure 2e).This hypothesis was further proven by the same reaction rates in the first 30 minutes, when the reaction was carried out employing 1k' as the substrate or employing the 1k and KSeCN combination (Figure 2f).Moreover, the reaction could not a known bench-stable thianthrene radical cation (TT +• BF -) [65][66][67] was synthesized and reacted with SCN -in the presence of 1,1-diphenylethylene (Figure 2h).The observation of the dithiocynated product 5 implicated the formation of SCN • was initiated upon the single electron oxidation by thianthrene radical cation.In addition, the photochemical quantum yield (Φ) for selenocyanation (0.26) is less than 1, which is consistent with the radical-radical cross-coupling mechanism 7 (for more details, see Supplementary Method).
On the basis of the aforementioned mechanism experiments, a plausible reaction mechanism was described in Figure 2i.Firstly, the anion exchange between the arylsulfonium salt 1 and CuSCN or KSeCN occurred rapidly to form arylsulfonium salt 1', which underwent the homolytic cleavage of the C(sp 2 )-S bond to generate aryl radical and thianthrene radical cation under the irradiation by purple LEDs (380-390 nm, 24 W).Subsequently, the thianthrene radical cation (TT +• ) could serve as a transient SET mediator to oxidize S(Se)CN -to S(Se)CN • , followed by the formation of final products via the radical-radical crosscoupling with aryl radical.

Substrate scope
With the understanding the reaction mechanism, we set out to evaluate the generality of the reaction.
The selenocyanation of the arylthianthrenium salts was firstly examined.As summarized in Figure 3, the reaction proceeded smoothly under photocatalyst-free conditions.Various thianthrenium salts 68 bearing different substituents at ortho-, meta-or para-positions (1a-l) are all suitable substrates for this reaction, providing the desired products in moderate to good yields.The compatible with the bulky ortho-substituents (1b-d) are noteworthy, as they are normally troublesome in transition metal catalyzed coupling reaction.
To further demonstrate the scalability of this process, the gram-scale reaction for thiocyanation was conducted using 1k as the model substrate, providing the desired product in 67% isolated yield and recovered thianthrene in 94% yield (Figure 5a).Notably, the late-stage introduction of the thiocyanate and selenocyanate groups into marketed drugs was further demonstrated via the electrophilic thianthrenation and sequential photoinduced thiocyanation and selenocyanation.As shown in Figure 5b, the regioselective thiocyanation and selenocyanation of fenofibrate (6a) and boscalid (6b) were realized in synthetically useful yields.Our methodology could also facilitate the rapid synthesis of bioactive molecules.
Selenocyanated product 7c', a potent trypanocidal activity against amastigotes and trypomastigotes of Trypanosoma cruzi strains, 69 could be readily prepared in 51% yield using N-phenyl 4trifluoromethylbenzamide (6c) as the starting material.Its thiocyanated analogue 7c could also be accessed in 60% yield, which might possess similar bioactivities (Figure 5c).
Boscalid-derived selenocyanate 7b' was treated with sodium borohydride to unmask selenium nucleophile that engaged the glycosyl halide, providing the glycosylselenide 8b' in 81% yield.And aryl selenocyanate 7b' could also be attacked by nucleophile, such as sulfone α-carbanion, to get selenide 9b' in 74% yield.In summary, we have developed a transient SET mediator approach for the generation of two radical species, enabling the efficient synthesis of aryl thio/selenocyanates via photoinduced thiocyanation and selenocyanation of a wide range of thianthrenium salts.The process features the wide substrate scope, good functional group tolerance and mild conditions.Further investigations toward new reaction developments with this novel strategy are undergoing in our laboratory.

Methods
General procedure for photoinduced selenocyanation of arylthianthrenium salts.A 10 mL Schlenk tube were charged with arylthianthrenium salts 1 (0.1 mmol, 1.0 equiv), KSeCN (43.2 mg, 0.3 mmol, 3.0 equiv) and MeCN (1.0 mL) under a nitrogen atmosphere.The tube was irradiated with purple LEDs (380-390 nm, 24 W) at 25°C for 24 h.Subsequently, the mixture was passed through a pad of Celite with DCM as the eluent to remove the insoluble precipitate.The resulting solution was concentrated and purified by preparative thin-layer chromatography to afford the desired product 2. Full experimental details and characterization of new compounds can be found in the Supplementary Information.