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Pd‐Catalyzed Regio‐ and Stereoselective sp 3 C−H Arylation of Primary Aliphatic Amines: Mechanistic Studies and Synthetic Applications
Author(s) -
Ha Hyeonbin,
Choi Ho Jeong,
Park Hahyoun,
Gwon Yunyeong,
Lee Jiin,
Kwak Jaesung,
Kim Min,
Jung Byunghyuck
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202001428
Subject(s) - chemistry , stereoselectivity , deprotonation , substituent , aryl , catalysis , selectivity , kinetic isotope effect , stereochemistry , density functional theory , regioselectivity , reaction mechanism , medicinal chemistry , reductive elimination , computational chemistry , organic chemistry , ion , alkyl , physics , deuterium , quantum mechanics
The Pd‐catalyzed γ‐position sp 3 −C−H arylation of primary amines bearing an aliphatic chain or cycloalkyl substituent and related mechanistic studies are disclosed. 3‐Bromo‐2‐hydroxybenzaldehyde plays a key role in γ‐position sp 3 −C−H arylation as a transient directing group (TDG) to assist the regio‐ and stereoselective C−H activation of a Pd catalyst, and the development of a tandem reaction to transform 1°‐amines into γ‐aryl‐substituted ketones demonstrates synthetic utility. Density functional theory (DFT)‐based calculations revealed the detailed reaction mechanism and the origins of the high selectivity (γ‐position and cis ‐only). The X‐ray crystal structure of the isolated endo‐palladacycle intermediate supported the DFT results, and a kinetic isotope experiment confirmed the results of DFT calculations indicating that the C−H activation step via simultaneous palladation and deprotonation is rate‐determining.