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revised on 03.06.2020 and posted on 04.06.2020by Vinod Landge, Justin Maxwell, Pratibha Chand-Thakuri, Mohit Kapoor, Evan Diemler, Michael Young
Mizoroki-Heck couplings are a powerful method
for elaborating alkene feedstocks. While selective functionalization of
terminal olefins has been achieved by catalyst design, selective
functionalization of internal olefins has generally required use of directing
groups except in the case of Michael acceptors. Allylamine substrates have typically
required protection to be suitable for these reactions, decreasing the step and
atom economy of these procedures. Herein we demonstrate that the addition of CO2
(dry ice) allows for the reproducible stereospecific arylation of both
secondary and primary allylamines in the presence of a PdII
catalyst. Notably, the product 3,3’-diarylallylamine motif is prevalent in a
variety of biologically-relevant structures, and this method represents the
most straightforward synthesis of these targets to date. Key features of the
method are the ability to access relatively mild conditions that facilitate a
broad substrate scope, as well as direct diarylation of terminal allylamine
substrates. In addition, several complex and therapeutically-relevant molecules
are included to demonstrate the utility of the transformation. Mechanistic
studies point to an amine-directed reaction where CO2 serves to
protect the substrate and product from degradation.
ACS Herman Frasch Foundation (830-HF17), Start-up from The University of Toledo. ETD thanks The University of Toledo - Office of Undergraduate Research for an USRCAP Fellowship in support of this work.