Redox-active benzimidazolium sulfonamides as cationic thiolating reagents for reductive cross-coupling of organic halides |
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| Authors: | Weigang Zhang Mengjun Huang Zhenlei Zou Zhengguang Wu Shengyang Ni Lingyu Kong Youxuan Zheng Yi Wang Yi Pan |
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| Institution: | State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Collaborative Innovation Center of Advanced Microstructures, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023 China, |
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| Abstract: | Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C–S bond coupling. The IMDN-SO2R reagent provides a bench-stable cationic precursor to generate a portfolio of highly active N–S intermediates, which can be successfully applied in cross-electrophilic coupling with various organic halides. The employment of an electrophilic sulfur source solved the problem of catalyst deactivation and avoided odorous thiols, featuring practical conditions, broad substrate scope, and excellent tolerance.Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C–S bond coupling.The high frequency of sulfur-containing moieties in natural products,1 bioactive molecules,2 pharmaceuticals,3 organic materials,4 fragrances5 and asymmetric catalysis as chiral catalysts/ligands6 has triggered the best endeavours for the selective construction of C–S bonds. The conventional cross-coupling of thiols with aryl halides generally relies on the conversion of mercaptans to thiolates by means of transition-metal catalysis7 (such as Pd,8 Cu,9 and Ni10) and other metals,11 although these efforts were plagued by several drawbacks. The strong coordination of thiolates to metals often leads to catalyst deactivation and displays low efficiencies. Therefore, high catalyst loading, specific ligands, excessive heating and strong bases are often required to facilitate this transformation (, left). Recent development using photochemical12 and electrochemical13 induced thiol radicals as a sulfur source could avoid the problem of catalyst poisoning, although restricted substrate scope was displayed (, middle). Despite the progress made for C–S bond construction,14 the longstanding issues that exist in the above-mentioned strategies should not be overlooked.Open in a separate windowOrigin of the reaction design. (a) C–S formation from organic halides. (b) The preparation of the electrophilic thiolating reagent (R–S+). (c) This work: cationic active reagent for cross electrophilic coupling.Compared to classical cross-coupling processes, the nickel-catalyzed reductive cross-coupling of two electrophilic partners has emerged as a powerful tool for the replacement of air- and moisture-sensitive organometallic reagents.15 The cross electrophilic coupling for the construction of C–S bonds is more challenging due to the lack of sulfur sources and homo-coupling of organic halides (, right). Several examples of reductive thiolation16 have been described using thiol derivatives as S+ sources (). We speculated that readily accessible sulfonyl chloride as an electrophilic sulfur source could avoid the use of highly toxic thiols and significantly the substrate scope.17 However, the direct reduction of sulfonyl chloride inevitably resulted in dimerization to disulfide.17b Putatively, activated by an electron-deficient heterocycle such as imidazole, sulfonyl chloride could be assembled into a bench-stable cationic reagent (). Benzimidazolium sulfonamides would be better electron acceptors18 and easily reduced by PPh3 to generate a highly reactive N–S+ species in situ. The positive charge of this intermediate is delocalized on both nitrogens of imidazole. Followed by the cleavage of the weak N–S bond (BDE ≈ 70 kcal mol−1),19 the electrophilic sulfur species can be captured by metal catalysts for cross-coupling. Herein, we have described a redox-active benzimidazolium sulfonamide reagent (IMDN-SO2R) for Ni-catalyzed reductive coupling of organic halides for a portfolio of C(sp)–S, C(sp2)–S and C(sp3)–S bond formations (). This strategy avoids the formation of disulfide by-products and the use of organometallic reagents, which facilitates purification and enhances the functionality tolerance.To determine the suitable conditions for the reductive coupling of the cationic reagent with organic halides, we first studied the reductive thiolation of p-iodo-methoxybenzene (2a) and 1a (2 equiv.) with a survey of Ni catalysts in the presence of dtbbpy (20 mol%), PPh3 (2.5 equiv.), Zn powder (3.0 equiv.) and MgCl2 (2.0 equiv.) in DMA at 60 °C ( | Open in a separate windowThe generality of the reductive thiolation was evaluated under the optimized conditions (). A wide range of aryl iodides containing either electron-withdrawing or electron-donating functionality were tolerated, delivering products with methoxy (3a, 3c), trifluoromethoxy (3b), methyl (3d), acetyl (3e), ester (3f), boronate (3g), and phenyl (3h) groups in good to excellent yields (63–94%). 5-Iodobenzod]1,3]dioxole and 2-iodofluorene also furnished the corresponding adducts (3i, 3j) in 91% and 82% yields, respectively. Notably, aryl iodides bearing sensitive groups such as amine (3k) and hydroxyl (3l) were engaged in the cross-coupling to forge the C–S bond in good yields. Aryl bromides (3a, 3m) were also found compatible. The scope of the heteroaryl halide coupling partner was also explored. Various five- and six-membered heterocycles, including thiophene (3n), pyrazole (3o), quinoline (3p), carbazole (3q), indole (3r), isothiazole (3s), benzofuran (3t), benzothiophene (3u), benzothiazole (3v), pyrimidine (3w), pyrazine (3x), and pyridine (3y, 3z) derived heteroaryl bromides and iodides were treated with 1a to produce the corresponding sulfides in good yields. In the cases of relatively unreactive organic chlorides, the corresponding coupling products (3aa–3cc) could be obtained in low yields under the standard conditions. Subsequently, we assessed the scope of aryl sulfonamides. Reagents 1c–1k containing electron-withdrawing and electron-donating substitutions on the benzene ring afforded the desired products in good to excellent yields (3dd–3ll). Sterically hindered imidazolium sulfonamides 2,4,6-trimethylated 1j and 2,4,6-triisopropylated 1k showed good compatibility in this reaction to give the corresponding products 3kk and 3ll in high yields.Open in a separate windowSubstrate scope of (hetero)aryl and benzimidazolium sulfonamides. aReaction was performed at 80 °C.The more challenging aliphatic halides have also been examined with the redox-active reagent 1a (). Primary and secondary alkyl halides yielded alkyl sulfides (5a–5k and 5l) in good to excellent yields. No dimerization side-product was observed. Functionalities including esters (5b, 5i, and 5j), sulfide (5c), alkene (5f), acetal (5h) and ether (5k) are tolerated. Some sensitive functional groups including silyl ether (5e) and organoboronate (5g) were well tolerated, provided in 75% and 57% yields, respectively. Alkenyl halides were also tolerated to afford 7a and 7b in good yields. In addition, alkynyl bromides were employed for reductive thiolation with benzimidazolium sulfonamides 1a and 1c–1i to afford the corresponding C(sp)–S bond coupling products (9a–9h) in moderate to good yields.Open in a separate windowSubstrate scope of alkyl, alkenyl and alkynyl bromide. aNi(PCy3)2Cl2 instead of Ni(OTf)2 and without dtbbpy. b4-(Trifluoromethyl)pyridine (0.2 mmol) and THF (2 mL) were used instead of dtbbpy and DMA.To demonstrate the synthetic potential of this cross-electrophile coupling, a gram scale reaction was performed with 1a and p-iodo-methoxybenzene 2a under the standard conditions (). The reductive thiolation was also applied in the late-stage modification of biologically active molecules and synthesis of pharmaceutically active molecules. d-Glucose (10a), (+)-α-tocopherol (10b), rosin amine (10c), and 17a-methyl-drostanolone-derived (10d) alkyl halides were compatible to afford thiolated products in good yields (). Treating benzimidazolium sulfonamide 1n with piperazine-derived iodobenzene 11 generated the thiolated intermediate 12 and deprotection with TFA afforded anti-depressive vortioxetine 13 (ref. 20) in 50% overall yields ().Open in a separate windowFurther transformations. (a) Gram-scale experiment. (b) Late-stage modification of natural products. (c) The synthesis of vortioxetine using our protocol.To investigate the mechanism for this reductive thiolation, a series of control experiments have been carried out. First, the treatment of benzimidazolium sulfonamide 1a with PPh3 furnished the key N–S+ intermediate Int-I and Ph3P = O, which were confirmed by 1H NMR, HRMS data and 31P NMR (, see the ESI†). A mixture of Int-I and 2a was able to afford 3a in 80% yield under the standard conditions, indicating that the reaction did go through this route (). Furthermore, the key nickel-complex 14 was prepared and reacted with Int-I to furnish thioether 3d in 15% yield (). Finally, sulfone 15 was used in the absence of benzimidazolium sulfonamide 1a and 2a under standard conditions. No reduced product 3a was detected, which indicates that the PPh3 reduction occurs before the cross-coupling (). On the basis of the experimental results and previous reports,16c,g a plausible mechanism for the reductive thiolation of organic halides is proposed (). Initially, the reduction of the Ni(ii) salt by zinc affords the active Ni(0) catalyst A, which undergoes oxidative addition into the C–X bond of organic halides to give the intermediate R–Ni(ii)X B. The following reduction of B forms R–Ni(i) intermediate C.15b,16g Then C and Int-I undergo stepwise single-electron transfer with the possibility of radical trapping within a solvent cage to afford intermediate D before the generation of R–Ni(iii)-SAr E and benzoimidazole residue 16. Finally, the reductive elimination of E furnishes the desired thioether product and Ni(i) species F which is reduced by zinc to facilitate the next catalytic cycle.Open in a separate windowMechanistic studies and proposed mechanism. |
