Cooperative Cu/azodiformate system-catalyzed allylic C–H amination of unactivated internal alkenes directed by aminoquinoline

Abstract

Aliphatic allylic amines are common in natural products and pharmaceuticals. The oxidative intermolecular amination of C(sp3)-H bonds represents one of the most straightforward strategies to construct these motifs. However, the utilization of widely internal alkenes with amines in this transformation remains a synthetic challenge due to the inefficient coordination of metals to internal alkenes and excessive coordination with aliphatic and aromatic amines, resulting in decreasing the reactivity of the catalyst. Here, we present a regioselective Cu-catalyzed oxidative allylic C(sp3)-H amination of internal olefins with azodiformates to these problems. A removable bidentate directing group is used to control the regiochemistry and stabilize the π-allyl-metal intermediate. Noteworthy is the dual role of azodiformates as both a nitrogen source and an electrophilic oxidant for the allylic C-H activation. This protocol features simple conditions, remarkable scope and functional group tolerance as evidenced by >40 examples and exhibits high regioselectivity and excellent E/Z selectivity.

β-Silicon Effect Enables Metal-Free Site-Selective Intermolecular Allylic C–H Amination

“…Interestingly, while the installation of a bulky tert-butyl (19) or an electron-withdrawing benzyloxy (22) group at the other allylic position did not compromise the regioselectivity, other EWGs such as phenyl (20), naphthyl (21), and tert-butyl ester groups (23) did result in inferior selectivity. A broad range of secondary alkyl substituted allyl TMS silanes (24)(25)(26)(27)(28)(29)(30)(31), either cyclic or acyclic, proceeded with the desired amination smoothly. The α-allylic C−H bonds of secondary allyl silanes are potentially sterically shielded.…”

“…Allylic C–H functionalization reactions have become essential techniques in organic synthesis, facilitating the efficient construction of diverse molecules with wide-ranging applications. − However, achieving site selectivity in internal alkenes, which possess two or more sets of similar allylic protons, has long been a significant challenge compared to the well-established functionalization of alkenes with a single set of allylic protons. − Recent progress in this area has largely stemmed from advances leveraging the negative inductive effect of electron-withdrawing groups (EWGs) or the coordinating influence of heteroatoms. − …”