Ni(II)-catalyzed asymmetric alkenylations of ketimines

Abstract

Chiral allylic amines are not only present in many bioactive compounds, but can also be readily transformed to other chiral amines. Therefore, the asymmetric synthesis of chiral allylic amines is highly desired. Herein, we report two types of Ni(II)-catalyzed asymmetric alkenylation of cyclic ketimines for the preparation of chiral allylic amines. When ketimines bear alkyl or alkoxycarbonyl groups, the alkenylation gives five- and six-membered cyclic α-tertiary allylic amine products with excellent yields and enantioselectivities under mild reaction conditions. A variety of ketimines can be used and the method tolerates some variation in alkenylboronic acid scope. Furthermore, with alkenyl five-membered ketimine substrates, an alkenylation/rearrangement reaction occurs, providing seven-membered chiral sulfamide products bearing a conjugated diene skeleton with excellent yields and enantioselectivities. Mechanistic studies reveal that the ring expansion step is a stereospecific site-selective process, which can be catalyzed by acid (Lewis acid or Brønsted acid).

Fig. 1

Addition of alkenylborons to imines for construction of chiral allylic amines. a Representative bioactive chiral allylic amines. b Rh-catalyzed addition of alkenylborons to ketimine. c Co-catalyzed addition of alkenylborons to aldimine. d This work: a general Ni(II)/BOX-catalyzed alkenylation and alkenylation/ring-expansion of cyclic ketimines. BOX = bisoxazoline

Fig. 2

Sterically-controlled site-selective asymmetric alkenylation/ring-expansion of ketimine 4a. The results using linear alkyl-substituted vinylboronic acids as nucleophiles reaction with 4a indicate that the asymmetric alkenylation/ring-expansion can also be controlled by steric hindrance

Fig. 3

Control experiments. These experiments indicate that the ring expansion step is an acid-promoted stereospecific process

Fig. 4

Model for explaining the origin of asymmetric induction. The alkenyl attacks the C=N bond from the Re-face to generate the products (R)-3na or (S)-7a

Fig. 5

Challenges for ring-expansion and proposed mechanism. a Challenges for ring-expansion of α,α-dialkenyl heterocyclic compounds bearing two different alkenyl groups. b Proposed mechanism for ring-expansion step

Fig. 6

Synthetic utility of alkenylation products. a Gram-scale reaction and transformations of 3ca. b Transformations of 3ta. c Further transformations of 5a