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submitted on 29.03.2019 and posted on 01.04.2019by Michael Oschmann, Linus Johansson Holm, Oscar Verho
Benzofurans are everywhere in nature and they have been extensively
studied by medicinal chemists over the years because of their chemotherapeutic
and physiological properties. Herein, we describe a strategy that can be used
to access elaborate benzo-2-carboxamide derivatives, which involves a synthetic
sequence of 8-aminoquinoline directed C–H arylations followed by transamidations.
For the directed C–H arylations, Pd catalysis was used to install a wide range
of aryl and heteroaryl substituents at the C3 position of the benzofuran
scaffold in high efficiency. Directing group cleavage and further
diversification of the C3-arylated benzofuran products were then achieved in a
single synthetic operation through the utilization of a two-step transamidation
protocol. By bocylating the 8-aminoquinoline amide moiety of these products, it
proved possible to activate them towards aminolysis with different amine
nucleophiles. Interestingly, this aminolysis reaction was found to proceed
efficiently without the need of any additional catalyst or additive. Given the
high efficiency and modularity of this synthetic strategy, it constitute a very
attractive approach for generating structurally-diverse collections of benzofuran
derivatives for small molecule screening.