Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce-Smiles Rearrangement

Article abstract of DOI:10.1002/anie.201510236

A new benzyne transformation is described that affords versatile biaryl structures without recourse to transition-metal catalysis or stoichiometric amounts of organometallic 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. All smiles: Metal-free biaryl synthesis is achieved by adding benzyne to arylsulfonamides. A Smiles rearrangement enables C-C bond formation, thus accessing a variety of functionalized biaryls under mild reaction conditions.

Full text of DOI:10.1002/anie.201510236

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International Edition: DOI: 10.1002/anie.201510236
German Edition: DOI: 10.1002/ange.201510236
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
under http://dx.doi.org/10.1002/anie.201510236.
ꢀ 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.
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molecules for further synthesis. Whilst Smiles rearrangements
of stabilized carbanions are well known (the Truce varia-
tion),[9] the rearrangement of less-stable aryl anions as
proposed here is very rare. A seminal report from Pütter
and Waldau described an aryl Truce–Smiles reaction for
stabilized phenolate anions, and more recent work from
Quayle and co-workers described a Truce–Smiles rearrange-
ment of a-silyl-phenylsulfonate esters.[10] Further encourage-
ment for the idea came from the Motherwell biaryl synthesis,
which demonstrates an analogous process under a radical
manifold.[11] Treatment of the haloaryl sulfonamides 5 with
nBu3SnH affords 2-amino biaryls through radical ipso sub-
stitution and SO2 extrusion (Scheme 1c).
As Smiles rearrangements frequently require strongly
electron-withdrawing groups on the aryl ring to stabilize the
intermediate Meisenheimer complex 3, we began work with
the readily available 4-nitrobenzenesulfonamide (1a). We
were pleased to discover that a screen of reaction conditions
(Table 1) quickly established the reactionꢀs viability, with the
Table 1: Reaction screening data.
Entry
R
1/6 (equiv)
Fluoride (equiv)
Yield [%][a]
1
2
3
4
5
6
7
8
9
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2:1
2:1
2:1
1:2
1:2
1:1
2:1
1:1
1:1
1:1
1:1
CsF (4)
KF + 18-c-6 (4)
TBAF (1)
KF + 18-c-6 (2)
KF + 18-c-6 (2)
KF + 18-c-6 (2)
KF + 18-c-6 (2)
KF + 18-c-6 (3)
KF + 18-c-6 (4)
CsF (3)
16[b,c]
31[b]
38[b]
63
66
56
31
62[d]
59
10
11
45
Scheme 2. Substrate scope using nitro phenylsulfonamides. Yields are
those of isolated products. [a] Two equivalents of 6 used.
CsF (3)
64[c]
[a] Reaction conditions: Sulfonamide (1; 0.1 mmol), trimethylsilylphenyl
triflate (6; 0.1 mmol), fluoride source, THF (0.1m), reflux, 24 hours.
Yield is that of the isolated 4a. [b] Ambient temperature and 16 hours.
[c] Acetonitrile used as solvent. [d] Increasing scale to 1 mmol afforded
4a in a 56% yield. Tf =trifluoromethanesulfonyl, TMS=trimethylsilyl.
and nitro-substituted arylsulfonamides (1; Scheme 2). We
were pleased to observe a versatile substrate scope: 3-
methoxy and 3-phenyl arynes reacted with the expected
regioselectivity to afford the 1,2,3-substituted biaryls 4b–d.
1,2-Naphthyne was likewise productive, but with a diminished
regioselectivity of 3:1 (4e major regioisomer; X-ray). 4-
Substituted arynes gave the biaryls 4 f–i in good yields as 1:1
mixtures, thus implicating the benzyne intermediate in the
reaction mixture. Ortho substitution was well tolerated on the
sulfonamide partner (4j–l), and it was possible to switch the
nitro activating group to this position, thus giving 7a in 72%
yield. 2,6-Dichloro substitution was particularly effective,
thus giving an excellent 81% yield of 4l. Substitution adjacent
to the para-nitro group was also possible, but some attrition in
yield was observed. The bulky CF3 group produced a poor
yield of 4n and is likely a result of steric inhibition of the
resonance stabilization for the Meisenheimer intermediate.
The reaction also accommodated N-alkyl sulfonamides. In
biaryl 4a being formed upon treatment with various fluoride
sources (entries 1–4). The N-phenylated compound was
isolated in each case, thus indicating that the initial aniline
product is rapidly arylated with another equivalent of
benzyne.[12] Reaction conditions of KF in the presence of
18-crown-6 in THF at 658C were optimal, thus affording 63%
of 4a from 1a and two equivalents of the benzyne precursor
(entry 4). Using the N-phenylated sulfonamide substrate 1b
prevented the second N arylation, thus accessing 4a in
a similar yield under the same reaction conditions but using
only one equivalent of the benzyne precursor (entry 8).
With these simple reaction conditions in hand, we
examined the scope of the reaction for a range of arynes
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contrast to the N-aryl substrates, a second arylation with
benzyne was observed to give the tertiary biaryl aniline
products 7a–f. Restricted rotation around the biaryl axis
would be expected for some of the more hindered products,
and this was established for 4d and 7 f, by HPLC analysis
using a chiral stationary phase, thus establishing the 1:1 ratio
of atropisomers in each case.
The ortho-amino functionality in the biaryl products is
nicely disposed for additional heterocycle formation
(Scheme 3). The bromophenyl product 4o proved a good
À
substrate for C H activation, thus affording the carbazole 8a
Scheme 4. Substrate scope using other electron-deficient sulfon-
amides. Yields are those of isolated products. [a] Two equivalents of 6
used.[16]
an a-methyl benzylamine sulfonamide gave the secondary
aryl Truce–Smiles product 4x, which could be deprotected to
the primary aniline product 11.
The facility of the reaction for accessing sterically
congested, tetra-ortho-substituted biaryls is notable, and
compliments traditional metal cross-coupling methods,[15]
which are often challenged by such steric hindrance because
of the requirement for oxidative addition and/or transmeta-
lation processes of large metal–ligand complexes. In terms of
limitations, tertiary sulfonamides were unreactive under the
reaction conditions, and some degree of activation was
required on the Smiles acceptor arene; simple para-chloro,
para-bromo, and para-methyl derivatives were recovered
unchanged from the reaction.
Finally, we examined heteroarenes in the reaction. The
Smiles rearrangement of heteroaromatic sulfones is key to the
Julia–Kocienski olefination reaction, involving S!O migra-
tion, and has been demonstrated on several interesting
heteroarene substrates such as benzothiazoles, tetrazoles,
and benzimidazoles.[17] An analogous S!Csp2 rearrangement
in our system would be a new entry point into heterobiaryl
structures under metal-free conditions, something we were
keen to investigate. We were pleased to find that the
analogous heteroaromatic sulfonamides were productive
under the same reaction conditions of KF/18-c-6, and we
could prepare the arylated pyridine, pyrimidine, and benzo-
Scheme 3. Heterocycle synthesis. Yields are those of isolated products.
DMA=N,N-dimethylacetamide, HMPA=hexamethylphosphoramide,
NsCl=p-nitrophenylsulfonyl chloride.
in excellent yield on treatment with catalytic palladium(0).[13]
Alternatively, a denitrative SNAr cyclization of 4r using NaH/
HMPA gave the carbazole 8b.[14] The nitro group represents
a versatile access point for further nitrogen-based function-
ality, and we could achieve an iterative biaryl synthesis by
initial reduction, followed by sulfonamide formation with p-
nitrophenylsulfonyl chloride (NsCl). Aryne Truce–Smiles
rearrangement was then successful, thus tolerating the sub-
strate aniline, proceeding in a similar efficiency to that of the
first, and producing the extended biaryl 10 in 67% yield.
Having established the scope of the reaction for nitro-
substituted sulfonamides, we were keen to develop a more
general procedure with broad substrate scope (Scheme 4).
Pleasingly, we found that alternative electron-withdrawing
groups such as cyano and acyl were effective in the reaction
(4s and 4t), along with the triply halogenated 4-bromo-2,6-
dichloro motif (4u; X-ray). Indeed, this substrate gave higher
yields than the analogous nitro-containing compounds. Using
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In conclusion, we have demonstrated that metal-free
biaryl synthesis is possible under mild reaction conditions,
through a novel sulfonamide–benzyne addition and subse-
quent aryl Truce–Smiles rearrangement. The reaction is
notably effective for accessing sterically hindered, tri- and
tetra-ortho-substituted biaryls, which are difficult to synthe-
size using traditional cross-coupling methods. Applications of
this benzyne transformation will be the subject of future
investigations in our laboratory.
Keywords: arynes · biaryls · heterocycles · rearrangements ·
synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2450–2453
Angew. Chem. 2016, 128, 2496–2499
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Received: November 3, 2015
Published online: January 13, 2016
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