Copper-Photoredox Catalyzed Enantioselective S-Alkylation of Sulfenamides
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Copper-Photocatalyzed Enantioselective S-Alkylation of Sulfenamides Enabled by Amino-Acid-Derived N,N,N-Tridentate Ligand
Xiangyu Zhuang, Xiao Sun, Yirui Zou, Jun Liu, Gang Zhao, and Hongyu Wang*
Chiral sulfinamides are valuable sulfur-stereogenic units in the pharmaceutical and agrochemical fields, serving as important precursors to drug-related compounds like sulfoximides and sulfondiimines. However, their efficient enantioselective synthesis has long been a bottleneck. Traditional methods mostly rely on the asymmetric oxidation of sulfides, requiring pre-functionalized substrates and specialized reagents. While the enantioselective S-alkylation of sulfenamides offers a complementary strategy, it has long been hindered by ionic reaction pathways. A radical pathway employing inexpensive and abundant alkyl carboxylic acids as starting materials has not been realized due to the challenge of stereocontrol at the sulfur chiral center. Addressing this research gap, the collaborative team of Prof. Hongyu Wang (China Ocean University) and Prof. Gang Zhao (Shanghai Institute of Organic Chemistry, CAS) developed an amino-acid-derived N,N,N-tridentate chiral ligand-mediated copper-photoredox catalytic system. For the first time, they achieved the enantioselective S-alkylation of sulfenamides via a radical pathway. The classic Ir(III) photocatalyst fac-Ir(dtbbpy)(ppy)2 serves as the core photocatalytic unit in this system: Upon excitation by 456 nm blue light, this photocatalyst exhibits dual properties of a strongly oxidizing excited state and a strongly reducing ground state. Its precise redox potentials enable the simultaneous oxidation of Cu(I) to Cu(II) to initiate the copper catalytic cycle, and the single-electron reduction of NHPI esters derived from alkyl carboxylic acids to generate alkyl radicals. Through efficient single-electron transfer, it perfectly couples the iridium photocatalytic cycle with the copper catalytic cycle. Ultimately, chiral sulfinamides are synthesized with high yield and high enantioselectivity. Furthermore, the strategy was extended to an XAT-induced alkyl iodide radical pathway, providing a general and efficient new method for the synthesis of sulfur-stereogenic compounds.
Condition Screening
Substrate Scope
Product Derivatization
Proposed Reaction Mechanism
Highlights of the fac-Ir(dtbbpy)(ppy)2 Metal Iridium Photocatalyst Used in This Reaction:
The selection of the fac-Ir(dtbbpy)(ppy)2 metal iridium photocatalyst is key to achieving high catalytic efficiency in this system. Its application highlights are concentrated in four dimensions: redox potential compatibility, catalytic synergy, photophysical properties, and practical economy, perfectly aligning with the requirements of copper-photoredox catalysis, as detailed below:
- Precise Redox Potential Matching Dual Electron Transfer Needs: This is the core prerequisite for realizing the catalytic cycle. The excited state of this iridium photocatalyst possesses strong oxidizing power (+0.66 V vs. SCE), enabling efficient oxidation of the L9-Cu(I)-DIPEA complex to generate the required Cu(II) active species. The reduced Ir(II) species subsequently generated exhibits strong reducing power (-1.51 V vs. SCE), capable of reducing NHPI esters with reduction potentials < -1.28 V. A single type of catalyst can accomplish the dual electron transfer tasks of "oxidizing the copper species" and "reducing the radical precursor," eliminating the need for additional oxidants or reductants and fundamentally ensuring the simplicity of the reaction.
- Excellent Photophysical Properties Adapt to Mild Reaction Conditions: This iridium photocatalyst has strong absorption in the 456 nm blue light region used in the reaction, with high photoluminescence quantum yield and excellent photostability. It shows no significant decomposition under continuous room-temperature irradiation, providing sustained redox driving force for the reaction. This allows the traditionally challenging radical-type enantioselective S-alkylation to proceed efficiently under mild visible light irradiation at room temperature, significantly lowering the operational barrier.
- High Catalytic Efficiency with Low Loading: This iridium photocatalyst requires only a very low loading (1 mol%) in the system to accomplish efficient electron transfer and dual-cycle coupling. While ensuring catalytic effectiveness, it also maintains good atom economy for the reaction and reduces the difficulty of subsequent product purification.
- Strong Compatibility, Laying the Foundation for Reaction Expansion: Its stable catalytic performance shows good compatibility with various substrates in the system, including alkyl NHPI esters with multiple functional groups, structurally diverse sulfenamides, and even complex bioactive substrates. Its catalytic activity is not lost due to changes in substrate structure. This provides crucial support for achieving a broad substrate scope and high functional group tolerance, significantly enhancing the practical application value of this catalytic system.
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Publication Details
Authors: Xiangyu Zhuang,# Xiao Sun,# Yirui Zou, Jun Liu, Gang Zhao,* and Hongyu Wang*
Title: Copper-Photocatalyzed Enantioselective S-Alkylation of Sulfenamides Enabled by Amino-Acid-Derived N,N,N-Tridentate Ligand
DOI: 10.1021/acscatal.6c01852