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A practical protocol to simplify natural product synthesis by site selective C–H
functionalization had always been a coveted target for chemists. Most often, directing
group assisted metallacycle formation has served as an efficient strategy in ensuring
promising regioselectivity. In this regard wide variety of ortho- functionalization stands as
an archetype. Despite significant progress, directing group- assisted selective distal C–H
functionalization in arenes (at meta and para positions) had remained an unexplored
venture mainly due to the formation of a geometrically constrained metallacyclic transition
state. To address these issues, a novel class of cleavable and recyclable linker with nitrile
based templates that direct efficient functionalization of distal para- and meta-C–H bonds
are introduced. These directing templates allow the required flexibility in supporting the
formation of an oversized 12-17 membered macrocyclic pre-transition state. Using this
strategy, regioselective meta- and para-C–H functionalizations were performed on a series
of important classes of arene substrates – including phenylacetic acid, benzyl sulphonyl,
benzyl silyl and phenol systems. Applicability of these template based strategies have been
demonstrated by synthesizing various natural products and complex molecules through
post synthetic modifications. Such a benign distal C–H functionalization strategy is
expected to streamline complex molecule synthesis in pharmaceutical and polymer |