Angewandte
Communications
Chemie
Biaryls
Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce–Smiles
Rearrangement
Catherine M. Holden, Shariar M. A. Sohel, and Michael F. Greaney*
Abstract: A new benzyne transformation is described that
affords versatile biaryl structures without recourse to transi-
tion-metal catalysis or stoichiometric amounts of organome-
tallic building blocks. Aryl sulfonamides add to benzyne upon
fluoride activation, and then undergo an aryl Truce–Smiles
rearrangement to afford biaryls with sulfur dioxide extrusion.
The reaction proceeds under simple reaction conditions and
has excellent scope for the synthesis of sterically hindered
atropisomeric biaryl amines.
T
he biaryl motif is fundamental to chemistry, as it is widely
represented in natural products, materials, pharmaceuticals,
and agrochemicals. Synthesis of these ubiquitous structures is
often carried out using transition-metal catalysis and stoi-
chiometric amounts of metallated arenes, which enable the
coupling of two sp2-carbon centers via organometallic inter-
mediates.[1] The drive for sustainable synthetic methods which
avoid both the use of expensive and scarce transition metals,
and the separate preparation of aryl metal reactants, has
stimulated efforts to develop metal-free biaryl syntheses.[2–4]
Achieving the controlled union of two arene fragments
without organometallic assistance is very challenging, and
current methods are often forced to employ harsh reaction
conditions and/or operationally complex protocols. Recent
examples include UV photochemistry to generate aryl cations
from electron-rich arenes,[3a] oxidative coupling of electron-
rich arenes in the presence of strong Lewis acids,[3b–d] and
base-mediated coupling of aryl iodides with simple arenes
through electron transfer.[4] This latter approach has received
significant attention in recent literature and uses the combi-
nation of an alkali metal base and an electron-rich ligand to
generate aryl radicals through a single-electron transfer.
Subsequent SArH substitution and oxidation lead to biaryl
formation (Scheme 1a). The method is impressively simple,
but requires high temperatures, up to 20-fold excess of the
arene coupling partner, and produces regioisomeric mixtures
of substituted biaryls. The discovery of a mild, metal-free
Scheme 1. Proposed aryne addition/Truce–Smiles rearrangement for
biaryl synthesis. AIBN=2,2’-azobis(2-methylpropionitrile), EWG=elec-
tron-withdrawing group.
biaryl synthesis with broad substrate scope would therefore
be a significant development in the field.
We were interested in applying the reactive intermediate
benzyne to this problem. Arynes are versatile intermediates
in biaryl synthesis, with their addition to aryl organometallics
being a well-described method, known since the earliest days
of aryne chemistry.[5,6] Cross-coupling with simple arenes,
however, in the absence of organometallic species, has rarely
been reported as a synthetic method.[7]
[*] C. M. Holden, Dr. S. M. A. Sohel, Prof. M. F. Greaney
School of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
Given that arynes undergo smooth addition to hetero-
atom nucleophiles,[8] we wondered if this feature could be
exploited in a metal-free biaryl synthesis through addition/
rearrangement chemistry. Our synthetic plan is set out in
Scheme 1b. Starting with readily available aryl sulfonamides
(1), addition of a benzyne [generated from a 2-trimethylsilyl-
(phenyl) triflate precursor upon treatment with fluoride]
should give the adduct 2. This intermediate could then
undergo a Smiles-type ipso substitution with SO2 extrusion,
thus affording a 2-amino-biaryls 4, which are versatile
E-mail: michael.greaney@manchester.ac.uk
Supporting information for this article is available on the WWW
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
2450
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 2450 –2453