Late-stage C–H thiolation via sulfonium salts using β-sulnylesters as the versatile sulfur source

Organic suldes form the core scaffold of a wide range of pharmaceuticals, natural products, and materials, and serve as key intermediates in synthesis. Prior methods to organic suldes require the use of transition metal (TM) catalysts, prefunctionalized or chelating group-containing substrates, and elevated reaction temperatures. A general TM-free C–H thiolation protocol using readily accessible sulfur source is highly desirable. Herein, we disclose a direct C(sp)–, C(sp2)–, and C(sp3)–H thiolation reaction using β-sulnylesters as the versatile sulfur source. The key step of this protocol is chemoselective C–S bond cleavage of the sulfonium salts that is in situ formed from the corresponding (hetero)arenes, alkenes, alkynes, and 1,3-dicarboxyl compounds with β-sulnylesters. The successful capture of acrylate byproduct supports a retro-Michael reaction mechanism. This method is expected to be used widely because of several advantageous aspects including TM-free, mild reaction conditions, and broad substrate scope including drug molecules.


Introduction
Organic sul des have been widely found as privileged structures in pharmaceuticals, 1 natural products, 2 and materials. 3 They are also valuable precursors to sulfones-and sulfoxides-containing drugs that exhibit signi cant biological activities. 4 The most convergent approaches to these compounds are the transition metal (TM)-catalyzed C-S cross-coupling reactions of aryl/vinyl (pseudo)halogen with thiols/disul des [5][6][7][8] and the TM-catalyzed directing-group assistant C-H bond thiolations of arenes. 9,10 The requirement of prefunctionalized or chelating group-containing substrates, TM catalysts, and elevated reaction temperatures sharply limited their applications. Alternatively, the direct C-H thiolation of highly electron-rich aromatics using electrophilic thiolation reagents could proceed under TM-free conditions, which limited to deliver aryl sul des. 11 process proceeds through site-selective C-H sulfonium salt formation followed by chemoselective C-S bond cleavage under TM-free conditions with broad functional group tolerance.

Results
Reaction development. Initially, we employed methyl 3-(p-tolylsul nyl)propanoate 1a, toluene 2a as the model substrates to optimize the conditions of the TM-free C-H thiolation reaction. After extensive screening of various reaction parameters, the optimal conditions were achieved to be 1a (1.3 equiv), 2a (0.3 mmol), Tf 2 O 1.3 equiv), solvent (3 mL) under nitrogen atmosphere at room temperature for 1 h, then Et 3 N (5 equiv) at room temperature for 1 h (  (Table S1, entry 6). The yield was reduced to 30% when TFAA was used in lieu of Tf 2 O (entry 7). A similar result was obtained using ethyl ester 1b as the thiolation reagent (entry 8).
With the established optimal reaction conditions in hand, we rst investigated the substrate scope of arenes ( Table 2). A wide range of substituted benzenes could be converted to the corresponding diaryl sul des in good yields (3a-s). Functional groups including cyclopropyl, halogens, allyloxy, and ester were well tolerated in this transformation. It is noteworthy that the reactivity of this thiolation reaction was not affected by steric hindrance of the arene substrates (3q and 3s). To our delight, heteroaromatics could also be applied to the reaction system without obstacle (3t-w). Among them, indole, pyrrole, and thiophene could give the corresponding products in the excellent yields. Although quinoline derivative was less reactive under standard conditions, increasing reaction temperature slightly improved product yield (3u). Notably, this strategy was successfully applied to the late-stage C-H thiolation of a variety of drug-like molecules (3aa-af). (S)-4-benzyl-2-oxazolidinone derivative, nimesulide, bifonazole, Lphenylalanine derivative, estrone derivative and D-salicin derivative all could be modi ed by this method.
We then examined the reaction of 1,2-dimethoxybenzene 2o with a range of β-sul nylesters. Aryl sulfoxides bearing electron-donating groups or halogens had good reactivity (4a-f), whereas aryl sulfoxide with a nitro group only delivered the desired product in 26% yield (4g). In addition, pyridyl and thienyl sulfoxides were compatible, albeit the desired products were formed in low yields (4h and 4i).
Remarkably, alkyl sulfoxides including benzyl sulfoxide were applicable to the reaction system, giving the desired products in good yields (4j-l). 36 Inspired by these exciting results, we discussed the application of this strategy in the synthesis of more challenging alkenyl, alkynyl, and alkyl sul des (Table 4). Styrenes containing electron-donating andwithdrawing groups all have good adaptability (6a-j). It is worth mentioning that high E-selectivities were obtained in all cases. Vinyl sul de 6k and allyl sul de 6k` were formed in 93% combined yield using αmethylstyrene as substrate. 1,1-Diphenylethene and triphenylethene were smoothly converted to the desired alkenyl sul des in 89% and 46% yields, respectively (6l and 6m). When tetraphenylethene was subjected to the reaction system, only aryl C-H thiolation product was observed (6n). It should be noted that compounds (6l-n) were promising aggregation-induced emission luminogens. 53 Additionally, a range of aryl and alkyl sulfoxides could also donate the corresponding alkenyl sul des without obstacle (6o-y).
Next, we proceed to investigate the application of this strategy to C(sp)-H thiolation. Gratifyingly, the reaction was proved to be applicable to C(sp)-H thiolation of aryl alkynes (8a-h). Low reactivity of alkyl alkynes was observed, and only 17% yield was obtained (8i). In addition to thioarylation (8j-p), thioalkylation of C(sp)-H bond was also successful (8q and 8r).
We have carried out a gram-scale reaction of dimethyl 3,3'-sul nyldipropionate 1m and p-xylene 5m, giving the sul de 11 in 74% yield (Fig. 2a). We then sought to investigate the possibility of performing iterative C-H thiolation, wherein the newly synthesized sulfoxide 12 may serve as the starting material for an additional C-H thiolation. Delightfully, sul des 13 and 14 were formed in 72% and 73% yields from 4bromostyrene 5i and D-salicin derivative 2af, respectively (Fig. 2b). Finally, the proposed methyl acrylate byproduct could be captured via Heck reaction to give 15 and 16 in 25% and 40% yields, respectively (Fig.  2c).

Discussion
In summary, we have developed a general and practical C-H thiolation of (hetero)arenes, alkenes, alkynes, and 1,3-dicarbonyl compounds using β-sul nylesters as sulfur source that requires no preactivation of the substrates. This TM-free protocol proceeds via site-selective C-H sulfonium salt formation followed by retro-Michael reaction to give a vast number of organic sul des with broad functional group tolerance. The synthetic importance of this method was demonstrated by late-stage C-H functionalization of drug molecules, and iterative C-H thiolation. We believed that this method should have broad applications in the future. The reaction mixture was stirred for 1 h. Upon completion, Et 3 N (0.2 mL, 5.0 equiv) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum, and puri ed by preparative thin layer chromatography (PTLC) with hexane to give the corresponding product 3a (59.2 mg, 92%).

Data availability
All relevant data are available in Supplementary Information and from the authors.

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