Site-Selective and Stereoselective C−H Functionalization of N-Cyclopropylamides via a Directed Remote Metalation Strategy

Maryia Barysevich

Tallinn University of Technology, Tallinn, Estonia

The cyclopropane ring strain and orbital hybridization offer the consequence, inter alia, of increased acidity of C−H bonds (pK_a ≈ 46), which thereby provides a convenient route to densely substituted cyclopropane scaffolds via functionalization of simple cyclopropane precursors. Herein we present a new methodology for site-selective and stereoselective C−H functionalization of aminocyclopropanes via directed remote lithiation.¹ Treatment of N-directing group (DG = pivaloyl, tetramethylsuccinimidoyl) arylcyclopropanes with t-BuLi results in a clean β-lithiation and, following quench with electrophiles, leads to a range of cyclopropane derivatives. Sequential double lithiation − methylation to give a dimethylated cyclopropane has been achieved. X-ray, NMR, and computational studies allow rationalization of syn-DG β-deprotonation selectivity via a DG-lithium base coordinated complex.

Reference:

Ermolovich, Y.; Barysevich, M. V.; Adamson, J; Rogova, O.; Kaabel, S.; Järving, I.; Gathergood, N.; Snieckus, V.; Kananovich, D. G.; Site-Selective and Stereoselective C–H Functionalization of N-Cyclopropylamides via a Directed Remote Metalation Strategy Lett. 2019, 21 (4), 969-973