ORGANIC
LETTERS
2011
Vol. 13, No. 21
5713–5715
Oxidative CꢀH Homodimerization of
Phenylacetamides
Didier G. Pintori and Michael F. Greaney*
School of Chemistry, University of Edinburgh, Joseph Black Building, King’s Buildings,
West Mains Road, Edinburgh EH9 3JJ, U.K.
Received August 15, 2011
ABSTRACT
A range of secondary and tertiary phenylacetamides undergo oxidative homodimerization to afford biaryls. The reaction proceeds under
palladium catalysis in the presence of a copper cocatalyst and oxygen and is most effective for electron-rich substrates.
The biaryl motif is integral to a large number of biolo-
gically active molecules, making biaryl synthesis one of the
most studied and applied areas of synthetic methodology.
Current methods are dominated by transition metal (TM)
catalyzed coupling, which has recently expanded toinclude
CꢀH activation mechanisms. Oxidative biaryl formation,
where two CꢀH bonds react to form the key CꢀC bond,
represents a particularly powerful approach.1,2 Requiring
no prefunctionalization at the inchoate biaryl bond, TM
catalysis is used to selectively activate two separate arene
CꢀH bonds. A stoichiometric oxidant is then required to
ensure catalyst turnover.
bonds underwent intramolecular coupling to form biaryls
tethered with seven- and eight-membered rings.3 As part of
this study, we prepared substrate 1a as a possible nine-
membered ring precursor (Scheme 1). The compound proved
recalcitrant to intramolecular cyclization but did afford sig-
nificant amounts of intermolecular homodimerization prod-
uct 2, under Pd/Cu-based oxidative coupling conditions in
trifluoroethanol (TFE). Given the current interest in inter-
molecular CꢀH oxidative processes, we were interested in
examining the scope of this reaction for biaryl synthesis.4 We
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We recently established an oxidative coupling reaction
for medium ring synthesis, whereby indole and arene CꢀH
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r
10.1021/ol202212f
2011 American Chemical Society
Published on Web 10/06/2011