Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium‐Catalyzed Enantio‐, Chemo‐ and Diastereoselective Methylene C(sp<sup>3</sup>)−H arylation
Ye‐Qiang Han, Yang Xu, Ke‐Xin Kong, Yao‐Ting Deng, Le‐Song Wu, Yi Ding, Bing‐Feng Shi
Abstract
Abstract The enantioselective desymmetrizing C−H activation of α‐ gem ‐dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp 3 )−H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo‐ and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,β‐contiguous stereogenic centers via Pd II ‐catalyzed asymmetric arylation of unbiased methylene C(sp 3 )−H, in good yields and with high levels of enantio‐, chemo‐ and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem ‐dialkyl groups with two different aryl iodides, giving a range of β‐Ar 1 ‐β′‐Ar 2 ‐aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.