Nickel/Bis(oxazoline)-Catalyzed Asymmetric Negishi Arylations of Racemic Secondary Benzylic Electrophiles to Generate Enantioenriched 1,1-Diarylalkanes

Abstract

A tertiary stereogenic center that bears two different aryl substituents is found in a variety of bioactive compounds, including medicines such as Zoloft and Detrol. We have developed an efficient method for the synthesis of enantioenriched 1,1-diarylalkanes from readily available racemic benzylic alcohols. Formation of a benzylic mesylate (which is not isolated), followed by treatment with an arylzinc reagent, LiI, and a chiral nickel/bis(oxazoline) catalyst, furnishes the Negishi cross-coupling product in high ee and good yield. A wide array of functional groups (e.g., an aryl iodide, a thiophene, and an N-Boc-indole) are compatible with the mild reaction conditions. This method has been applied to a gram-scale synthesis of a precursor to Zoloft.