Manganese-Catalyzed Redox-Neutral Thiolation of Alkyl Halides with Thioformates

Significance 

The construction of carbon-sulfur (C–S) bonds is common in various biological molecules, pharmaceuticals, and materials science, highlighting the importance of efficient methods for their construction. Traditionally, noble metals have been used as the catalyst of choice for these reactions due to their high efficiency and selectivity. However, because of the high cost, scarcity, and potential environmental impact of noble metals, there is a need to search for alternative catalysts. Manganese, is third most abundant transition metal in the Earth’s crust, has emerged as a promising candidate due to its economic and environmental advantages. A new study published in Angewandte Chemie International Edition led by Prof. Dr. Liang-An Chen from Nanjing Normal University and conducted by Pan Pei, Min Zhao, Dengkai Lin, Dr. Zhan Dong, and Dr. Liangliang Song developed and validated a manganese-catalyzed redox-neutral process for the thiolation of alkyl halides using thioformates. Their work aimed at overcoming the limitations associated with the use of noble metal catalysts and the formation of C(sp3)–S bonds in transition metal-catalyzed cross-coupling reactions. The research team began with the optimization of reaction conditions to identify the most effective catalyst, solvent, temperature, and substrate ratios. Manganese was chosen as the catalyst due to its abundance, low toxicity, and diverse oxidation states, which are advantageous for redox processes. They systematically tested various manganese sources, solvent types, and temperatures to determine the optimal conditions that would yield the highest product efficiency and selectivity. Following the optimization phase, the researchers evaluated the substrate scope by testing a wide range of alkyl halides and thioformates. This was crucial for determining the method’s versatility and applicability to different molecular structures. They explored primary, secondary, and tertiary alkyl halides, alongside diverse thioformates derived from formic acid and thiols, to assess the reaction’s tolerance to different functional groups and steric environments. To demonstrate the practical utility of their method, the team conducted late-stage thiolation experiments on complex molecules, including natural products and pharmaceuticals. This step was instrumental in showcasing the method’s applicability in synthesizing biologically active compounds and modifying existing drugs to potentially improve their properties. The authors conducted mechanistic studies to elucidate the reaction pathway and the role of manganese in the catalytic cycle. These included experiments with radical scavengers like TEMPO to detect the presence of radical intermediates, and kinetic isotope effect studies to understand the nature of the bond-forming steps. Such experiments provided insights into how the manganese catalyst facilitates the formation of thiyl radicals from thioformates and their subsequent coupling with alkyl halides.

The authors reported the optimized conditions that manganese catalysis, in the absence of external ligands and strong bases, could efficiently catalyze the thiolation of a broad range of alkyl halides with thioformates. The process yielded aryl and alkyl thioethers in good to excellent yields under redox-neutral and mild conditions, highlighting the method’s efficiency and functional group tolerance. Afterward, they demonstrated broad applicability of their substrate scope evaluation method, with successful thiolation reactions across a diverse set of alkyl halides and thioformates. This included substrates with sensitive functional groups that are typically incompatible with harsher reaction conditions, underscoring the mildness and versatility of the manganese-catalyzed process. The successful late-stage thiolation of complex molecules emphasized the method’s potential in synthetic chemistry, particularly in the pharmaceutical industry. This capability allows for the modification of existing drugs and natural products, opening up possibilities for the development of new therapeutic agents and materials with enhanced properties. The researchers’ mechanistic investigations provided evidence for a radical pathway facilitated by manganese catalysis. Their experiments suggested that the reaction proceeds through the generation of thiyl radicals from thioformates, which then couple with alkyl halides to form C(sp3)–S bonds. This understanding is crucial for further methodological developments and optimization.

It is noteworthy to mention that the methodology introduced by Chen and co-workers leverages the unique properties of manganese to catalyze the thiolation of alkyl halides with thioformates. This approach is distinguished by its redox-neutral nature, avoiding the use of stoichiometric amounts of metal and enabling the reaction to proceed under comparatively mild conditions. The selection of thioformates as sulfur sources is strategic, as they are easily synthesized from readily available formic acid and thiols, and serve as practical thiyl radical precursors. This innovative use of thioformates circumvents the limitations associated with direct thiol use in cross-coupling reactions, such as catalyst deactivation and the requirement for harsh reaction conditions. Moreover, the broad substrate scope, including various aryl and alkyl thioethers, along with good to excellent yields, highlights the new method’s versatility and functional group compatibility which can open up new possibilities for the late-stage functionalization of complex molecules, including pharmaceutical compounds. Furthermore, the innovative approach avoided strong bases, external ligands, and high reaction temperatures which improved the reaction’s environmental friendliness as well as reduced the complexity and cost associated with the whole synthetic process. Therefore, the method’s efficiency and mild reaction conditions make it suitable for a wide range of applications, potentially influencing the synthesis of sulfur-containing molecules in pharmaceuticals, agrochemicals, and materials science.

In a nutshell, the research conducted by Prof. Dr. Liang-An Chen and colleagues  successfully introduced a sustainable, efficient, and versatile method for C(sp3)–S bond formation. Their findings contribute to the development of green and economical synthetic strategies and also enhance our understanding of manganese catalysis in organic synthesis.  The implications of the new study extend beyond synthetic organic chemistry, offering potential benefits in pharmaceuticals, materials science, and environmental sustainability.

Manganese-Catalyzed Redox-Neutral Thiolation of Alkyl Halides with Thioformates - Advances in Engineering

About the author

Prof. Liang-An Chen

Nanjing Normal University, China

Liang-An Chen received his PhD in organic chemistry at Xiamen University (2008-2014). Afterward, he began postdoctoral research at Columbia University (2015-2018) and then joined Indiana University Bloomington as a postdoctoral fellow (2018-2019). In 2019,  he started his independent academic career as a full professor of chemistry at Nanjing Normal University. He has received Jiangsu Specially-Appointed Professor (2020), Emerging Investigator of Organic Chemistry Frontiers (2023), and Thieme Chemistry Journals Award (2024). He was appointed Director of Organic Chemistry at Nanjing Normal University in 2023. His research interests focus on the development of practical synthetic methods and novel strategies with metal catalysis for the synthesis of functionalized molecules with an emphasis on precise and controllable selective Chemical synthesis.

Reference

Pei P, Zhao M, Lin D, Dong Z, Song L, Chen LA. Manganese-Catalyzed Redox-Neutral Thiolation of Alkyl Halides with Thioformates. Angew Chem Int Ed Engl. 2023 ;62(33):e202305510. doi: 10.1002/anie.202305510.

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