Direct Asymmetric α-C-H Addition of N-unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis
Direct Asymmetric α-C-H Addition of N-unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis
复制标题
DOI：
10.1002/anie.202206111
复制
发表时间：
2022-10-26
影响因子：
16.6
通讯作者：
Zhao, Baoguo
中科院分区：
文献类型：
--
作者：
Ji, Pengwei;Liu, Xiaopei;Zhao, Baoguo
由于α-C-H键的低酸性（pK（a）约为42.6）和亲核NH 2基团的中断，N-未保护的炔丙基胺的惰性α-C-H键的直接不对称官能化是有机化学中的一个巨大挑战。以手性吡哆醛为羰基催化剂，成功地实现了N-未保护的炔丙胺与三氟甲基酮的直接不对称α-C-H加成反应，以54- 84%的产率合成了一系列手性炔基β-氨基醇，立体选择性高达20：1dr和99%ee。炔丙基胺的α C-H键被吡哆醛催化剂通过形成亚胺中间体大大活化，导致酸度增加高达10（22）倍（从pK（a）42.6到pK（a）20.1），其变得足够酸性以在温和条件下脱质子化用于不对称加成。这项工作提出了一个令人印象深刻的例子，惰性C-H键的不对称官能化的有机催化剂。
Direct asymmetric functionalization of the inert alpha C-H bonds of N-unprotected propargylic amines is a big challenge in organic chemistry, due to the low acidity (pK(a)approximate to 42.6) of the alpha C-H bonds and interruption of the nucleophilic NH2 group. By using a chiral pyridoxal as carbonyl catalyst, we have successfully realized direct asymmetric alpha-C-H addition of N-unprotected propargylic amines to trifluoromethyl ketones, producing a broad range of chiral alkynyl beta-aminoalcohols in 54-84 % yields with excellent stereoselectivities (up to 20 : 1 dr and 99 % ee). The alpha C-H bonds of propargylic amines are greatly activated by the pyridoxal catalyst via the formation of an imine intermediate, resulting in the increase of acidity by up to 10(22) times (from pK(a) 42.6 to pK(a) 20.1), which become acidic enough to be deprotonated under mild conditions for the asymmetric addition. This work presented an impressive example for asymmetric functionalization of inert C-H bonds enabled by an organocatalyst.