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Practical N-alkylation via homogeneous iridium-catalyzed direct reductive amination

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Abstract

Direct reductive amination (DRA) is one of the most efficient methods for amine synthesis. Herein we report a practical homogeneous DRA procedure utilizing iridium catalysis. Applying simple, readily available and inexpensive PPh3 and alike ligands along with iridium at a low loading, aldehydes and ketones reductively coupled with primary and secondary amines to efficiently form structurally and functionally diverse amine products, including a set of drugs and compounds from late-stage manipulation. The reaction conditions were exceptionally mild and additive-free, in which oxygen, moisture, polar protic groups and multiple other functional groups were tolerated. For targeted products, this methodology is especially versatile for offering multiple possible synthetic options. The 10 gram-scale synthesis further demonstrated the potential and promise of this procedure in practical amine synthesis. DFT studies reveal an “outer-sphere” H-addition pathway, in which π−π interactions and H-bonding play important roles.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21772155), the National Key R&D Program of China (2020YFA0907901), the Scientific Fund of Northwest A&F University and Postdoctoral Science Foundation of China (2019M663827). We thank HPC of Northwest A&F University for the DFT calculations carried out in this work. We also give special thanks to Dr. Xiuhuan Li of State Key Laboratory of Crop Stress Biology for Arid Areas at Northwest A&F University for her kind help on the NMR spectroscopy.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 12100, China

    Jing Wang, Wenji Wang, Xiongyu Yang, Jingwen Liu, Haizhou Huang & Mingxin Chang

  2. College of Plant Protection, Shaanxi Research Center of Biopesticide Engineering & Technology, Northwest A&F University, Yangling, 712100, China

    Mingxin Chang

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  1. Jing Wang
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  2. Wenji Wang
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  3. Xiongyu Yang
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  4. Jingwen Liu
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  5. Haizhou Huang
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  6. Mingxin Chang
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Correspondence to Mingxin Chang.

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Conflict of interest The authors declare no conflict of interest.

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Supporting information The supporting information is available online at https://chem.scichina.com and https://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Wang, J., Wang, W., Yang, X. et al. Practical N-alkylation via homogeneous iridium-catalyzed direct reductive amination. Sci. China Chem. 66, 518–525 (2023). https://doi.org/10.1007/s11426-022-1494-7

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  • DOI: https://doi.org/10.1007/s11426-022-1494-7

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