Atroposelective Pd(0)-Catalyzed Direct Intermolecular C─H Arylation of Thiazole N-Oxides Provides Access to
Vitalii Smal1, Nicolai Cramer1
1Institute of Chemical Sciences and Engineering (ISIC), EPFL SB ISIC LCSA, Lausanne, Switzerland.
Abstract:
Despite the importance of heteroaryl atropisomers in medicinal chemistry and catalysis, straightforward access to these motifs via direct enantioselective C─H heteroaryl-aryl coupling remains challenging. We report an enantioselective Pd(0)-catalyzed arylation at the C4-position of thiazole N-oxides, forging the critical atropochiral axis. A designer point- and axially chiral monodentate phosphine is instrumental to enable high reactivities along with tight stereocontrol. A broad range of substrate combinations is coupled in high enantioselectivities, including two different heteroarenes. The enantioenriched thiazole N-oxides are amenable to derivatizations around the substituents contributing to the stability of the chiral axis, including a reduction of the N-oxide moiety without racemization.
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