Ni-catalyzed cross-coupling reactions of phenol-derived electrophiles

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Montana State University - Bozeman, College of Letters & Science


Herein we present in three parts our work on a variety of Ni-catalyzed cross-coupling reactions using phenol-derived electrophiles. The first part details an efficient Ni-catalyzed Stille cross-coupling of C-O electrophiles through a combination of computational and experimental methods. These allowed for the investigation of the mechanism and showed the formation of a novel 8-centered transition state involving KF. Chloride inhibits the reaction through forming a low-energy Ni(II)-chloride species during oxidative addition that has a high activation barrier towards transmetalation. This methodology was shown effective for a wide variety of C-O electrophiles and organostannanes including several difficult bond constructions. The second part explores the development of a chemoselective Ni-catalyzed Suzuki cross-coupling that is selective for C-O bonds in the presence of C-Cl bonds. This selectivity is unusual since organohalides typically undergo oxidative addition with Ni(0) and Pd(0) at similar or faster rates to phenol- derived electrophiles. We were able to pair computational and experimental investigations to develop a reliable strategy and understand the likely origin of this unique selectivity. Stoichiometric experiments showed that small phosphines, like PMe 3 and PPhMe 2 , are unique in their ability to facilitate the selective reaction at C-O bonds in the presence of C-Cl bonds. Computational investigations show the electronic and steric properties of these small ligands are crucial for a close interaction between nickel and a sulfonyl oxygen during oxidative addition, the step where selectivity is determined. The third part looked at the use of aryl methyl ethers as an electrophile under Ni-catalyzed Suzuki-Miyaura and Kumada cross-coupling conditions. Three ligands bearing chelating arms were synthesized, two known and one new, to explore the respective scopes and how these ligands compare to more commonly used ligands such as PCy 3 or ICy. We saw no success under Suzuki-Miyaura conditions but found the hydroxyphosphine ligands facilitated the Ni-catalyzed Kumada cross-coupling of Ar-OMe, which had not been reported. Further investigations proved the hydroxyphosphines had no apparent benefit over commercial ligand as far as yield, scope, or mild reaction conditions.




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