TBHP-Mediated Oxidative Cross-Coupling of Disulfides with Ethers through a C(sp3)-H Thiolation Process

Abstract A new tert-butyl hydroperoxide (TBHP)–mediated oxidative cross-coupling of disulfides with ethers is presented for the synthesis of etherified sulfides. This method is achieved by a C(sp3)-H thiolation strategy under metal-free conditions and provides a simple route to constructing the C-S bonds. GRAPHICAL ABSTRACT


INTRODUCTION
The oxidative cross-coupling reaction comprising a C-H functionalization process has emerged as one of the most important methodologies for various chemical bond constructions in organic synthesis; moreover, this reaction remains an active area of research because it is environmental benign, sustainable, and highly atom-economical because it avoids the use of halides, pseudohalides, and=or organometallic reagents. [1] Despite impressive progress in the field, examples on the construction of the C-S bond using the oxidative cross-coupling strategy are quite rare. [2,3] Recently, the group of Tang et al. established the tert-butyl hydroperoxide (TBHP)-mediated oxidative thiolation of a sp 3 C-H bond adjacent to a nitrogen atom to construct the C-S bond without the aid of metals (Scheme 1a). [2a] Herein, we report that this oxidative cross-coupling strategy could be expanded to a sp 3 C-H bond adjacent to an oxygen atom (ethers). [4] In the presence of TBHP and molecular sieve, a variety of disulfides reacted with ethers and resulted in the new C-S bond formation in moderate to good yield (Scheme 1b). Notably, etherified sulfides are important units found in organic materials, bioactive molecules, and pharmaceuticals and widely serve as valuable intermediates in synthetic chemistry. [5][6][7]

RESULTS AND DISCUSSION
As shown in Table 1, the reaction between 1,2-diphenyldisulfane (1a) and tetrahydrofuran (THF, 2a) was chosen as the model to optimize the reaction conditions. Disulfide 1a was initially treated with THF 2a and TBHP, and the target product 3aa was isolated in 21% yield (entry 1). To our delight, the presence of molecular sieve Scheme 1. Oxidative cross-coupling with disulfides.

OXIDATIVE CROSS-COUPLING OF DISULFIDES WITH ETHERS
could favor the oxidative cross-coupling reaction. [2a] The yield of product 3aa was sharply enhanced to 91% when 100 mg molecular sieve was added (entry 2). Identical results were observed at 4 equiv TBHP and 100 mg molecular sieve (entry 3). Subsequently, the effect of the reaction temperatures was examined, and the results demonstrated that the reaction at 120 C gave the best yield (entries 2, 4, and 5). Two other oxidants, di-tert-butyl peroxide (DTBP) and 2,3-dichloro-5,6-dicyano-1, 4-benzoquinone (DDQ), were also tested (entries 6 and 7). Screening revealed that DTBP was viable to mediate the reaction, albeit reducing the yield (entry 6). However, DDQ was ineffective for the reaction (entry 7). We were pleased to find that good yield was still achieved when the reaction was carried out in n BuOAc (entry 8). It is noteworthy that 3-mmol scale of substrate 1a is successfully performed, providing the desired product 3aa in 90% yield (entry 9).
With the optimal conditions in hand, we next decided to explore the scope of the oxidative cross-coupling reaction ( Table 2). In the presence of TBHP and molecular sieve, THF 1a was successfully reacted with various disulfides 1b-1g in moderate to excellent yields (entries 1-6). Gratifyingly, a number of functional groups, including Me, Cl, Br, and CO 2 Me groups, on the aryl ring of disulfides were tolerated well (entries 1-4). 1,2-Di(p-tolyl)disulfane (1b), for instance, was reacted with THF 2a, TBHP, and molecular sieve smoothly, providing the target product 3ba in 65% yield (entry 2). Importantly, halo groups, including Cl and Br groups, were also consistent with the optimal conditions, thereby facilitating possible additional modifications at the halogenated positions (entries 2 and 3). It was noted that this oxidative crosscoupling reaction method could be applied to synthesize new fipronil analog 3fa in good yields (entry 5). [14] This successful S-S bond cleavage of pyrazole disulfide followed by the sp 3 C-S bond formation would be significant for pesticide and drug design. [15] To test indoor pesticidal activities, compound 3fa was subsequently dissolved in dimethylformamide (DMF), followed by dilution with 0.1% (v=v) tween-80 distilled water. We were happy to find that this solution displayed highly pesticidal activities (Scheme 2). Notably, aliphatic disulfide, dibenzyldisulfide 1 g, was also a suitable substrate, furnishing product 3ga in moderate yield after prolonging the reaction time (entry 6).

CONCLUSION
In summary, we have illustrated a new oxidative cross-coupling of disulfides with ethers to form the C(sp 3 )-S bond through a C(sp 3 )-H thiolation strategy.
In the presence of TBHP and a molecular sieve, a variety of disulfides, including aromatic and aliphatic disulfides, were treated with ethers to afford the corresponding etherified sulfides in moderate to good yields. Notably, this method is simple and general with a wide range of disulfide compatibility, which provides a new route to the construction of the C-S bonds.

EXPERIMENTAL
NMR spectroscopy was performed on a Bruker advanced spectrometer operating at 500 MHz ( 1 H NMR) and 125 MHz ( 13 C NMR). Mass spectrometric analysis was performed on GC-MS (Shimadzu GCMS-QP2010) and ESI-Q-TOF (Bruker MicroQTOF-II) instruments.

Typical Experimental Procedure for TBHP-Mediated Oxidative Cross-Coupling of Disulfides with Ethers
To a Schlenk tube were added disulfide 1 (0.2 mmol), TBHP (2 equiv), 4-A molecular sieve (100 mg), and ether 2 (2 mL). Then the tube was charged with argon and stirred at 120 C (oil bath temperature) for the indicated time until complete consumption of starting material as monitored by thin-layer chromatography (TLC) and GC-MS analysis. After the reaction was finished, the reaction mixture was cooled to room temperature, diluted in ethyl acetate (5 mL), and washed with brine (3 Â 1 mL). The aqueous phase was extracted with ethyl acetate (3 Â 2 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuo, and the resulting residue was purified by silica-gel column chromatography (hexane=ethyl acetate ¼ 20:1) to afford product 3.

FUNDING
We thank the Natural Science Foundation of China (No. 21202121) for financial support.