A highly para-selective copper(II)-catalyzed direct arylation of aniline and phenol derivatives

Article abstract of DOI:10.1002/anie.201004703

In short order: A copper-catalyzed Friedel-Crafts-type strategy has been developed for the title reaction. An iterative C-H arylation strategy has also been demonstrated for the functionalization of anilines by sequentially delivering different aromatic groups to the para, ortho, and meta positions (see scheme, Bn=benzyl, Piv=pivaloyl).

Full text of DOI:10.1002/anie.201004703

Communications
DOI: 10.1002/anie.201004703
À
C H arylation
A Highly Para-Selective Copper(II)-Catalyzed Direct Arylation of
Aniline and Phenol Derivatives**
Claire-Lise Ciana, Robert J. Phipps, Jochen R. Brandt, Falco-Magnus Meyer, and
Matthew J. Gaunt*
The ubiquity of the biaryl motif in natural products, medi-
cines, and novel materials ensures a constant demand for their
efficient and selective synthesis.[1] The most widespread
biaryl-forming processes are cross-coupling reactions in
which two prefunctionalized arene partners are
connected by a transition-metal catalyst. Although
selectivity in these cross-coupling reactions is not an
issue, a compromise is made on efficiency; prior
chemical transformations are required to obtain the
coupling partners as the prefunctionalization events
must be carried out regioselectively, and in some
cases this can prove a significant challenge.[2] Much
recent attention has been devoted to the develop-
Recently, we reported a C3-selective copper-catalyzed
direct arylation of indoles with diaryliodonium salts; this
selectivity would be expected from an electrophilic substitu-
tion-type (SEAr) mechanism (Figure 1).[7a] Intriguingly, we
À
ment of new concepts to utilize a C H bond in place
of one or both of the cross-coupling partners.[3] The
benefits of this strategy are considerable, but the
crucial issue of selectivity is now relocated to the
biaryl bond-forming step. Cyclometalation-based
approaches constitute the most common strategy
À
towards the arylation of C H bonds, which results Figure 1. Selectivity trends in copper-catalyzed arylation.
in functionalization ortho to a directing group.[3]
Considering the wealth of electrophilic aromatic
substitution reactions employed in synthesis, it is surprising
that few para-selective direct arylation reactions are known.
Several research groups have reported methods to achieve
direct metal-catalyzed arylation of electron-rich benzenes,
but only moderate selectivity has been observed;[4] in most
cases, all three possible isomers were obtained. Higher
selectivity was reported by Buchwald and co-workers in a
specific case during an oxidative coupling of anisole with
anilides, wherein 1:2:12 o/m/p selectivity was achieved.[5] Kita
et al. have reported a metal-free thiophenylation of some
electron-rich arenes and heteroarenes with high selectivity.[6]
discovered that we were able to override this natural
selectivity by using the coordinating ability of carbonyl
groups to effect the C2 arylation of indoles. Similarly, we
discovered that the carbonyl group of an anilide directed an
unprecedented meta-selective arylation reaction.[7b] On the
basis of these selectivity trends we speculated that electron-
rich arenes without coordinating carbonyl groups should
undergo direct arylation through a classical SEAr-type
mechanism, thereby leading to a para-selective process.
Herein, we report the development of the first highly
para-selective Friedel–Crafts-type arylation of phenol and
aniline derivatives. This versatile copper-catalyzed method
operates under mild reaction conditions, uses inexpensive
catalysts, and tolerates diverse functionality on the arene-
coupling partners (Figure 1). We have used this principle to
demonstrate an iterative arylation of aniline, which enables us
to selectively arylate the para, ortho, and then meta positions
by using only our copper-catalyzed processes.
At the outset of our studies we submitted anisole to the
standard conditions of our meta-selective pivanilide arylation
reaction and were delighted to observe the para selectivity
that we had predicted. A 62% yield of isolated para-
phenylanisole (3a) was obtained, and the balance of the
reaction consisted of separable starting material rather than
any regioisomers arising from unselective arylation
(Scheme 1). To the best of our knowledge, this represents
the first highly selective para-arylation of anisole.
[*] Dr. C.-L. Ciana, Dr. R. J. Phipps, J. R. Brandt, Dr. F.-M. Meyer,
Dr. M. J. Gaunt
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (U.K.)
Fax: (+44)1223-336-362
E-mail: mjg32@cam.ac.uk
Homepage: http://www-gaunt.ch.cam.ac.uk
[**] We gratefully acknowledge the Swiss National Science Foundation
(C.-L.C.), the Gates Cambridge Trust (J.R.B.), the DFG (F.-M.M.),
the Royal Society and Philip and Patricia Brown for a Research
Fellowship (M.J.G.), the EPSRC Mass Spectrometry Service (Uni-
versity of Swansea), and Dr. Tianyu Liu for contributions at an early
stage of this project.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004703.
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Angew. Chem. Int. Ed. 2011, 50, 458 –462

from arylation para to the oxygen atom with exquisite
selectivity (3b–d). 2-Methylanisole was highly reactive,
although a small amount of arylation meta to the oxygen
atom was observed, presumably because of the competing
electronic influence of the methyl group (3e). Molecules
bearing two methoxy groups could also be monoarylated (3 f)
or diarylated (3g) depending on the arene substitution
pattern. The methoxy group is capable of overpowering the
meta-directing effect of the pivanilide, thereby resulting in
arylation at the para position (3h), and a synthetically useful
yield for the para arylation of phenol (3i) was observed by
using our protocol. Interestingly, blocking the para position
results in ortho selectivity (3j), and this reactivity pattern
draws instructive parallels with the classical reactivity of
anisole in standard SEAr reactions. Importantly, the methoxy
group can be used as an active functionality in nickel-
catalyzed cross-coupling reactions with arylboronic esters,
thus allowing further derivatization.[8] Diversely substituted
and readily accessed diaryliodonium salts could be success-
fully used (Scheme 2).[9] Symmetrical iodonium salts were
compatible, as were the mesityl- and tri(isopropylphenyl)-
bearing unsymmetrical iodonium salts used in our previous
studies.[7]
Scheme 1. Initial result for the para arylation of anisole.
We next investigated other phenol-derived substrates to
survey the generality of this arylation (Scheme 2). 2,3-
Dihydrobenzofuran, methoxynaphthalene, and a tetrahydro-
napthalene derivative all delivered the products resulting
To increase the generality of this para-arylation process
we next considered aniline derivatives. Numerous palladiu-
À
m(II)-catalyzed ortho-selective C H arylations on acetani-
lides have been reported,[10] and we have developed a
copper(II)-catalyzed meta-selective process.[7b] However, to
the best of our knowledge, no para-selective process exists for
anilines. We previously observed that N-methyl- and N,N-
dimethylanilines resulted in N-arylation and decomposition,
respectively, under our conditions, and that N-sulfonyl com-
pounds are unreactive.[7b] Despite this, we hypothesized that
judicious choice of an N-protecting group should permit para-
selective arylation (Scheme 1).
Accordingly, we were pleased to find that N,N-dibenzyl-
aniline was converted into the desired product 5a after
reaction at only 508C (Table 1, entry 1). Usefully, the benzyl
groups are readily removed by hydrogenolysis. Optimization
revealed the necessity of 2,6-di-tert-butylpyridine (dtbpy) as
base to capture the TfOH generated in the reaction. At high
conversions we also observed a deleterious ortho arylation of
the desired product (to give 6a; Table 1, entries 2 and 3); this
was prevented by inverting the reaction stoichiometry
(Table 1, entry 4).
Table 1: Optimization of para-selective arylation of N,N-dibenzyl-
aniline.[a]
Entry
Ph2IOTf [equiv]
Ratio 5a/6a
Conv., yield [5a, %]
1
2
3
4
1.1
1.3
1.5
0.5
9.0:1
4.2:1
2.9:1
>95:5
75, –
91, 61
95, –
85, 77
Scheme 2. Scope of the arylation of phenol derivatives. Tf=trifluoro-
methansulfonyl; DCE=1,2-dichloroethane; Piv=tBuCO.
[a] dtbpy=2,6-di-tert-butylpyridine.
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Communications
A variety of substituted anilines are compatible with this
process (Scheme 3). Meta-substituted anilines participated,
reducing conjugation of the lone pair of electrons and
“switching off” the aniline to a second arylation.
with some diarylation being responsible for lower yields
To further explore its applicability we tested the new
reaction on molecules containing complex architectures.
Accordingly, the arylation of estrone and its methylated
derivative proceeded at only 408C and included the transfer
of aryl groups capable of further functionalization, thus
demonstrating the mild and selective nature of our copper-
catalyzed transformation (Scheme 5).[11]
Scheme 5. Site-selective arylation of estrones.
We next sought to combine controllable para and ortho
arylation of anisoles into an iterative process.[12] Starting from
5-methoxytetrahydronapthalene, para-phenylation delivered
3d in 76% yield, and a second iteration added a 4-
bromophenyl group in the ortho position, to give differen-
tially diarylated product 8 (Scheme 6).
Scheme 3. Para-selective arylation of anilines.
(5b,c). Ortho-substituted anilines work best with only one
(modified) benzyl group, thus enabling electron-withdrawing
and halogen-containing substrates to undergo the para-
selective arylation process (5d,f–h). Arylation of a delicate
tetrahydroquinoline showcased the potential for the con-
struction of versatile heterocyclic biaryls (5e). The reaction
still proceeds even in the presence of a strongly electron
withdrawing nitro group, albeit in low conversion and yield
(5g); additionally this product contains a versatile orthogo-
nally protected 1,2-diamine.
When performing the reaction on para-substituted ani-
lines, we obtained selective ortho arylation (Scheme 4).
Notably, no di-ortho-arylation occurs, a drawback of many
existing ortho-arylation procedures.[10] We speculate that the
introduction of the ortho-aromatic group causes the nitrogen
atom to twist out of plane with the aromatic ring, thus
Scheme 6. Iterative arylation of phenol derivatives.
To extend this concept further, we showed that we can use
our copper-catalyzed arylation methodology to functionalize
all three positions of anilines—ortho, meta, and para. N,N-
Dibenzylaniline first underwent para-selective arylation to 5n
(Scheme 7, step 1). The second iteration with a different
diaryliodonium salt resulted in ortho arylation and led to the
formation of differentially diarylated product 6b (step 2).
After a protecting-group switch (steps 3 and 4) from N,N-
dibenzyl to N-pivaloyl, we performed a meta-selective
arylation (step 5) by using a third diaryliodonium salt and
the conditions detailed previously.[7b] This allowed the for-
mation of the quateraryl compound 10 with exquisite control
Scheme 4. Ortho-selective arylation of anilines.
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heteroarenes, which is proposed to proceed by single-electron
transfer (SET) processes.[15] Whilst we cannot be certain that
our reaction does not proceed by a similar mechanism, we
think that it is unlikely because the phenol and aniline
substrates exhibit selectivity patterns that are absolutely
consistent with classical nucleophilic reactivity—reaction at
the para position first, as in simple Friedel–Crafts processes or
halogenation—whereas an SET mechanism would be
expected to form regioisomeric mixtures of biaryl com-
pounds.[16] This makes aryl radical cation intermediates seem
less likely, a theory that is reinforced by the observation that
radical-scavenging reagents do not affect our arylation
process.
Although it is clear that the copper salt catalyzes the
arylation reaction, the reaction in the absence of catalyst
could be explained by a thermally induced dissociation of the
counterion, thereby creating a highly electrophilic aromatic
species that undergoes attack by the electron-rich arene.
Moreover, it is possible that the copper catalyst also induces
dissociation of the triflate anion to form a similar activated
aryliodonium species.[13,17,18] This would rationalize the reac-
tivity increase upon employing copper catalysts, whilst still
delivering identical regioselectivity. Although we cannot be
certain of the exact reaction mechanism, we believe that this
transformation could be legitimately regarded as a “Friedel–
Crafts arylation” reaction based on the observed ortho/
para selectivity, and studies to elucidate the precise reaction
pathway are currently underway.
In summary, we have developed the first highly para-
selective arylation of aniline and phenol derivatives. This
copper-catalyzed Friedel–Crafts-type strategy precludes the
need for prefunctionalization of the nucleophilic arene
component and represents a significant advance in direct
arylation methodology to form valuable biaryl bonds. We
have also shown that it is possible to use this method to
iteratively functionalize arenes with exquisite selectivity,
expediting access to complex polyaryls.
Scheme 7. Iterative arylation of aniline derivatives. [a] NBn2 to NHPiv;
step 3: Pd-C, H2, MeOH then step 4; PivCl, Et3N, THF (78% yield over
2 steps). Mes=2,4,6-trimethylbenzene.
of the regioselectivity, in high chemical yield, and crucially
using only five chemical operations.
As part of our studies into the mechanism of this arylation
process we tested the reaction in the absence of the copper
catalyst.[13] Reaction occurred only at elevated temperature
and, after three days at 908C, anisole produced (3a) in 23%
yield, while aniline (4a) gave 5a in 59% yield (determined by
1H NMR spectroscopy; Table 2). In both cases this gives a
significantly lower yield than obtained with the presence of
the copper catalyst at lower temperature (Table 1).
Table 2: Copper-free arylation of electron-rich arenes.
Received: July 29, 2010
Published online: December 7, 2010
À
Keywords: aromatic substitution · C H arylation · copper ·
hypervalent iodine · synthetic methods
.
X
T [8C]
Base
Ph2IOTf [equiv]
Yield [%][a]
NBn2
NBn2
NBn2
OMe
70
80
90
90
dtbpy
dtbpy
dtbpy
–
2.0
1.3
1.3
4.0
–
–
59% (5a)[b]
23%(3a)[c]
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À
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Communications
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