Improved Process for the Palladium-Catalyzed C-O Cross-Coupling of Secondary Alcohols
Hong Zhang, Paula Ruiz-Castillo, Alexander W. Schuppe and Stephen L. Buchwald*
*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States,
Email: sbuchwalmit.edu
H. Zhang, P. Ruiz-Castillo, A. W. Schuppe, S. L. Buchwald, Org. Lett., 2020, 22, 5369-5374.
DOI: 10.1021/acs.orglett.0c01668
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Abstract
The use of a biaryl phosphine ligand was key to achieving efficient cross-coupling of (hetero)aryl chlorides with near-equimolar amounts of secondary alcohols. An unusual reactivity difference between an electron-rich aryl bromide and the analogous aryl chloride was observed.
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Details
The document discusses an improved protocol for the palladium-catalyzed C−O cross-coupling of secondary alcohols with (hetero)aryl chlorides. The key to this advancement is the use of a biaryl phosphine ligand (L2), which allows efficient coupling with only a 20% molar excess of alcohol. This method operates under mild conditions, often at room temperature, and achieves high yields. The study highlights a notable reactivity difference between electron-rich aryl bromides and chlorides, with the latter showing better performance. Deuterium-labeling experiments suggest unidentified pathways for reduction, indicating the need for further mechanistic studies. The protocol is versatile, accommodating a wide range of (hetero)aryl chlorides and secondary alcohols, including those with challenging functional groups and steric hindrance. This method represents a significant improvement over previous approaches, which required higher temperatures and larger excesses of alcohol. The research was supported by the National Institutes of Health and the Arnold and Mabel Beckman Foundation, with contributions from several authors at the Massachusetts Institute of Technology. The findings are published in the journal Organic Letters, with detailed experimental procedures and characterization data available in the supporting information.
Key Words
ID: J54-Y2020