Benzyne in synthesis: a search for palladium catalysed three-component couplings
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Date
2008Author
Henderson, Jaclyn
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Abstract
It is over 100 years since scientists first postulated the existence of arynes as reactive
intermediates. Their use in organic synthesis is now well-established and
investigations into novel methods for their generation and utility in carbon-carbon
bond forming reactions continue to this day. In 1983 Kobayashi and co-workers
introduced a novel method of generating benzyne under mild conditions, using a
fluoride induced decomposition of 2-(trimethylsilyl)phenyl triflate 1. This
development has opened the door to employing arynes in a variety of transitionmetal
mediated carbon-carbon bond forming processes. Intermolecular
carbopalladation, in particular, stands out as a powerful methodology for the
construction of diverse 1,2-functionalised arenes through multi-component coupling
processes. Initial benzyne carbopalladation with an organopalladium species
produces the arylpalladium intermediate 3, which can then undergo a second
coupling to any one of the vast numbers of nucleophiles that have been demonstrated
to work in palladium cross coupling. Presented herein are investigations towards the realisation of such methodology.
Initial efforts focussed on its application to the Heck reaction, using acryates as the
nucleophilic component. The chemistry has been developed to incorporate a variety
of organo-halides in order to generate a variety of molecular architectures; the
resultant 1,2-substituted diaryls being useful in the synthesis of both natural products
and medicinal chemistry targets. Following successful development of the Heck
reaction, investigations of other palladium catalysed couplings were also undertaken,
in particular the Buchwald reaction. Initial mechanistic studies are also discussed.