Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions

• Published in: Journal of the American Chemical Society Vol. 140; no. 42; pp. 13976 - 13984
• Main Authors: Thomas, Andy A, Speck, Klaus, Kevlishvili, Ilia, Lu, Zhaohong, Liu, Peng, Buchwald, Stephen L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.10.2018; Amer Chemical Soc
• Subjects: Alkenes - chemistry; Amination; Amines - chemistry; Catalysis; Chemistry; Chemistry, Multidisciplinary; Copper - chemistry; Kinetics; Ligands; Models, Molecular; Physical Sciences; Science & Technology; Thermodynamics; DENSITY FUNCTIONALS; ALKENES; PALLADIUM; ENERGY; DISPERSION; ASYMMETRIC HYDROAMINATION; CHEMISTRY; ANTI-MARKOVNIKOV HYDROAMINATION; OLEFINS; C-H BORYLATION
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.8b09565

Using a mechanically guided ligand design approach, a new ligand (SEGFAST) for the CuH-catalyzed hydroamination reaction of unactivated terminal olefins has been developed, providing a 62-fold rate increase over reactions compared to DTBM-SEGPHOS, the previous optimal ligand. Combining the respective strengths of computational chemistry and experimental kinetic measurements, we were able to quickly identify potential modifications that lead to more effective ligands, thus avoiding synthesizing and testing a large library of ligands. By optimizing the combination of attractive, noncovalent ligand–substrate interactions and the stability of the catalyst under the reaction conditions, we were able to identify a finely tuned hybrid ligand that greatly enables accelerated hydrocupration rates with unactivated alkenes. Moreover, a modular and robust synthetic sequence was devised, which allowed for the practical, gram-scale synthesis of these novel hybrid ligand structures.