Open AccessEntry to 1,2,3,4-Tetrasubstituted Arenes through Addressing the “Meta Constraint” in the Palladium/Norbornene Catalysis
Author(s) -
Jianchun Wang,
Yun Zhou,
Xiaolong Xu,
Peng Liu,
Guangbin Dong
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b12355
Subject(s) - chemistry , norbornene , aryl , palladium , substituent , electrophile , regioselectivity , nucleophile , metalation , combinatorial chemistry , catalysis , amide , stereochemistry , organic chemistry , monomer , polymer , alkyl
Arenes with four different contiguous substituents, i.e. 1,2,3,4-tetrasubstituted arenes, are commonly found in bioactive compounds, but they are nontrivial to access via conventional methods. Through addressing the " meta constraint" in the palladium/norbornene (Pd/NBE) cooperative catalysis, which is the difficulty of tolerating a sizable meta substituent in aryl halide substrates, here a modular and regioselective approach is realized for preparing 1,2,3,4-tetrasubstituted arenes. One key is the use of a C2-amide-substituted NBE, and a combined experimental and computational study reveals its role in promoting the NBE insertion and the ortho C-H metalation steps. The scope is broad: a variety of electrophiles and nucleophiles could be introduced to the ortho and ipso positions, respectively, with 1,4-disubstituted aryl halides, leading to diverse unsymmetrical contiguous tetrasubstituted arenes. Application of this approach has been demonstrated in streamlined syntheses of several bioactive compounds.