Sulfinyl Sulfone Chemistry
Inspired by the reductive cross-coupling of C-C (X) bonds in the literature, the authors speculated whether sulfinyl sulfones could be used in nickel-catalyzed coupling reactions of organohalides to obtain products of sulfoxide transfer. Previous studies have shown that the sulfinyl sulfone is rapidly oxidized to sulfonic anhydride in air and undergoes a slow disproportionation reaction even after 36 h in a nitrogen atmosphere. In addition, due to its unique structure, the sulfinyl sulfone may be
sensitive to Lewis acids or Lewis bases. This catalytic reductive transformation of the sulfinyl sulfone attempted by the authors may be accompanied by its thermodynamic instability and the challenge of unknown reductive transformations (Fig. 1B below). Cross-electrophilic coupling of 4-methoxyiodobenzene with preactivated phenylsulfinic acid in the presence of NiCl2-6H2O/o-phenanthroline and zinc powder, however, led the authors to unexpectedly obtain the sulfide etherification product (RSR’), suggesting that the in situ generated sulfinyl sulfone may undergo a smooth reductive sulfidation reaction in this system. Since sulfoxide and sulfone compounds are readily reduced or deoxygenated to important sulfides in the literature, however, no reductive transformations of structurally unique sulfinyl sulfones have been reported. Based on cyclic voltammetry experiments, the starting reduction potential of sulfinyl sulfone was measured to be -0.08 V vs SHE (standard hydrogen electrode); considering the reduction potential of zinc to be -0.762 V vs SHE, the authors concluded that zinc is capable of reducing sulfinyl sulfone in this system.
A bifunctional nickel catalyst and a bifunctional reducing agent, zinc, generate in situ redox-active sulfinyl sulfones that can be reductively coupled with a variety of organic halides to obtain thioether compounds rather than sulfoxide compounds (Fig. 1C). The key to achieving this chemical transformation is the redox-active sulfinyl sulfone due to its cationic nature of an electron-withdrawing leaving group (-SO2R), which facilitates the in situ generation of electrophilic sulfur reagents through the assistance of a zinc reductant and a nickel catalyst, which is also compatible with the subsequent nickel-catalyzed reductive coupling reaction. The authors suggest that this strategy may open new avenues for metal-catalyzed transformations of redox-active sulfinyl sulfones in organic synthesis. The strategy is highlighted by its good tolerance to a wide range of organic halides and functional groups, and has great potential for application in the derivatization and synthesis of meso-substituted functional diaryl sulfides, C-S modification of complex bioactive molecules, and drug discovery of sulfide-containing ethers.
Screening of activators
Systematic optimization of nickel sulfinylsulfoxide-catalyzed transformations
After observing the remarkable reactivity with the sulfinic acid activator 2o, the authors set out to optimize the system for this cross-coupling. As shown in Fig. 3, the optimized conditions used NiCl2-6H2O (2.5 mol%)/phen (L4, 3.0 mol%) as the catalytic system and 2.5 equiv. of Zn as the reductant, and the reaction was carried out for 9 h at 60 °C in THF, resulting in an 89% yield of the target product 4aa (entry 1). As a comparison, this cross-coupling does not occur when the nickel catalyst is not present; the yields of the corresponding diaryl sulfides were 67-80% when anhydrous NiCl2, NiBr2, and Ni(acac)2 were employed (entries 2-3). Commonly used nickel catalysts including NiBr2-dilyme, NiBr2-DME, and NiCl2-DME were also able to promote this reductive cross-coupling (entry 4). In addition, the authors’ attempts to use ligands L1 or L2 containing bipyridine backbones may have resulted in a decrease in the yield of the aryl thioether product (entries 5-6). However, when 2,9-dimethyl substituted phenanthroline L3 was used as ligand, the yield was only 5% (entry 7). In addition, the silane reductant (Et3SiH) did not give the expected cross-coupling product 4aa (entry 8), probably due to incompatibility with the nickel-catalyzed C-S reduction coupling reaction. When the authors used manganese powder as a reducing agent, they were unable to obtain any of the desired products, and the starting material was recovered in high yield (entry 9). In contrast, the organic reductant Ph3P gave the target product in low yield, suggesting that the system may not have involved an organic zinc reagent (entry 10). In addition, polar solvents such as DMF, DMA, acetone, and DCM can successfully facilitate reductive cross-coupling, albeit in low yields. In addition, considering the thermodynamic instability of the sulfinyl sulfone, the authors attempted reductive coupling at lower temperatures (10 °C and RT), and the conversion of phenylsulfinic acid to diaryl sulfides with 3aa was still achieved in yields up to 75-83% (entries 14-15). Replacing phenylsulfinic acid with sodium phenylsulfinate still resulted in satisfactory yields of the reductive coupling product (entry 16). It is noteworthy that when 1.5 equiv. of phenylsulfinic acid is used, the
