Copper(II)-catalyzed meta-selective direct arylation of α-aryl carbonyl compounds

Article abstract of DOI:10.1002/anie.201004704

Strong competition: A method for the meta-selective arylation of the highly versatile α-aryl carbonyl motif using diaryliodonium salts is described. In this Cu^II-catalyzed process the remote carbonyl group is capable of overpowering even strongly para-directing functionalities to form the elusive meta-products (see scheme). Remarkably, the arylation process can also operate under metal-free conditions.

Full text of DOI:10.1002/anie.201004704

DOI: 10.1002/anie.201004704
meta Functionalization
Copper(II)-Catalyzed meta-Selective Direct Arylation of a-Aryl
Carbonyl Compounds**
Hung A. Duong, Ruth E. Gilligan, Michael L. Cooke, Robert J. Phipps, and Matthew J. Gaunt*
Substituted arenes dominate the properties of many natural
products, medicines, and materials.[1] Therefore, the develop-
ment of new methods for direct and selective aromatic
functionalization is a persistent challenge for synthetic
chemists.[2] A particularly important class of substituted
aromatic compounds is the a-aryl carbonyl structure. These
molecules represent broadly useful starting materials for
complex molecule synthesis, and the basic structural frame-
work is present in a wide range of medicinally relevant
molecules.[3] Despite the importance of these structures,
surprisingly few direct methods are available to selectively
functionalize the arene nucleus in the absence of other
groups: aromatic substitution reactions require directing
functionality to control reactivity and selectivity; cross
coupling processes need pre-installed functional groups; and
À
while the acidity of the C H bonds between the arene and
carbonyl groups facilitates a wealth of enolate chemistry, it
precludes the use of directed ortho-lithiation reactions.[4]
A potential solution to some of these limitations has
Scheme 1. The utility of the a-aryl carbonyl framework.
À
enhanced through its compatibility with iterative C H bond
functionalization methods that will have broad utility in the
synthesis of highly functionalized arenes.
recently been presented through the development of ortho-
II
À
selective Pd -catalyzed C H bond functionalization reac-
tions.[5,6] The cyclometalation strategy employed in these
transformations, however, cannot be used to facilitate meta-
or para-functionalization of these molecules due to restrictive
geometric constraints.[7,8] The synthetic utility of the generic
a-aryl acetic acid motif would be significantly expanded by a
methodology that provides direct access to isomeric mole-
cules of potentially beneficial therapeutic value (Sche-
me 1A). Herein, we report a copper-catalyzed meta-selective
arylation of the a-aryl carbonyl scaffold with diaryliodonium
salts that is directed by a remote and versatile Weinreb amide
group (Scheme 1B). This method provides a novel synthetic
route to arenes displaying diverse substitution, benzylic
chirality and quaternary centers. Its potential is further
As part of our studies towards meta-selective functional-
ization processes,[8d] we postulated that the location of a
carbonyl group plays a key role in determining the selectivity
of our CuII-catalyzed meta-arylation of pivanilides. To test this
hypothesis, we speculated that the a-aryl carbonyl would also
provide a similar reactivity platform because the carbonyl
motif is displayed in a similar position relative to the arene
nucleus. Notably, the arene nucleophilicity of the electroni-
cally neutral a-aryl carbonyl motif is drastically different to
the electron-rich pivanilide.
To test whether a-aryl carbonyl compounds could be
functionalized at the meta-position, we prepared diethyla-
mide 1a and treated it with diphenyliodonium triflate and 20
mol% Cu(OTf)2 in dichloroethane at 708C, conditions that
are identical to those used for the arylation of pivanilides.[8d]
After reaction for 24 h we were delighted to isolate a 72%
yield of the meta-arylation product 2a, importantly this was
the only arylation product observed in the reaction (Table 1,
entry 1). Not only does this result confirm that the carbonyl
group is indeed responsible for the selectivity of this reaction,
it also demonstrates that aromatic groups that lack any strong
electronically or sterically directing substituents are still
compatible with this meta-selective process. To the best of
our knowledge, only Ir-catalyzed borylation of 1,3-disubsti-
tuted arenes[8b,c] is capable of achieving this type of trans-
formation.
[*] Dr. H. A. Duong, R. E. Gilligan, M. L. Cooke, Dr. R. J. Phipps,
Dr. M. J. Gaunt
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)01223-336362
E-mail: mjg32@cam.ac.uk
Homepage: http://www-gaunt.ch.cam.ac.uk
[**] We gratefully acknowledge the Marie Curie Foundation for a
Fellowship (H.A.D.), St John’s College and Cambridge Trusts for a
Scholarship (R.E.G.), GSK and EPSRC for Industrial Case Award
(M.L.C.), the Royal Society and Philip and Patricia Brown for a
Research Fellowship (M.J.G.), Novartis for financial support, and
the EPSRC Mass Spectrometry Service (University of Swansea). We
are grateful to Matej Janacek for the preparation of 7d.
Having identified this new reactivity of a-aryl acetamides,
we next assessed the nature of the carbonyl moiety by testing
a range of substrates with our standard CuII-catalyzed
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004704.
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Table 1: Optimization of the meta-selective arylation reaction.[a]
Table 2: Aryl transfer in the meta-arylation of a-arylacetamides.[a]
Entry
R1
Cu(OTf)2
NMR Yield
(yield[b]) [%]
1
2
3
4
5
6
NEt2 (1a)
OH (1b)
OEt (1c)
N(OMe)Me (1d)
N(OMe)Me (1d)
N(OMe)Me (1d)
20 mol%
20 mol%
20 mol%
20 mol%
10 mol%
5 mol%
75 (72)
–
40 (38)
76
80
93 (84)
84%, 2e[b]
52%, 2 f[b]
70%, 2g[b]
78%, 2h[c]
[a] DCE=1,2-dichloroethane, Tf=trifluoromethanesulfonyl. [b] Isolated
yield after chromatography.
arylation conditions. We found that while a-arylacetic acid 1b
gave a complex mixture of undesired products, ester 1c gave a
moderate yield of arylated compound (2c) and was com-
pletely selective for the meta-position (Table 1, entries 2,
3).[5a] However, the superior performance of a-aryl acet-
amides (1a) led us to consider other amide functions, and we
found that using Weinreb amide 1d improved the yield in the
arylation process (entries 4, 5). Using mild optimized reaction
conditions, treatment of 1d with 2 equivalents of diphenylio-
donium triflate (3a) and 5 mol% Cu(OTf)2 gave 2d in 84%
yield (Table 1, entry 6). Notably, the Weinreb amide motif
also offers significant synthetic versatility in further trans-
formations.
The improved reactivity of the a-aryl Weinreb amides
may arise from the increased electron density on the carbonyl
oxygen as a result of the a-heteroatom effect.[10] Indeed, a
competition experiment between Weinreb amide 1d and
pivanilide 4 shows a preference for the formation of 2d over 5
(Scheme 2). This is remarkable considering the drastically
different electronic properties of these arenes and underlines
the importance of the carbonyl group in this reaction.
71%, 2i[c]
79%, 2j[c]
81%, 2k[c]
35%, 2l[c]
[a] R1 =N(OMe)Me. [b] Ar1 =Ar2. [c] Ar2 =mesityl.
cantly, functionally diverse aryl groups displaying electron-
rich (2e,f), electron-deficient (2h–j) and halogen-containing
substituents (2g,h,k) were transferred in good yield; these
latter groups can facilitate subsequent chemoselective pro-
cesses.
The nature of the a-arylacetamide could also be varied.
Alkyl groups are tolerated in all positions on the aromatic
ring, with selective meta-arylation delivering complex 1,2,4-
and 1,3,5-trisubstitued arenes (Table 3). When strongly elec-
Table 3: Scope of the meta-arylation of a-arylacetamides.[a]
84%, 2d
61%, 2o
68%, 2m
86%, 2p
68%, 2n
60%, 2q
Scheme 2. Competition experiment between 1d and 4. Ratio of 5:2d
1
determined by H NMR spectroscopy.
43%, 2r
60%, 2s
65%, 2t
We next explored the capacity of this useful meta-selective
CuII-catalyzed arylation process (Table 2). Pleasingly, a range
of aryl groups could be transferred through symmetrical or
unsymmetrical diaryliodonium triflates in good yield with
exquisite meta-selectivity. These salts are readily prepared in
a one-step process from commercial materials.[11] Signifi-
58%, 99% ee, 2u
63%, 98% ee, 2v[b]
58%, 2w
[a] R1 =N(OMe)Me. [b] 10 mol% Cu(OTf)2, 508C.
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tron-donating substituents are located on the arene, the
remote carbonyl group overrides these para-directing motifs
to generate the isomer with the aryl group meta to both
substituents (2n,o). The reaction tolerates molecules possess-
ing orthogonal functionalities allowing access to complex
arenes (2r), albeit in reduced yield due to incomplete
conversion. The process works well for substrates displaying
a-substitution (2o–q) providing the meta-arylated products in
good yield. Moreover, enantiopure (S)-ibruprofen and (S)-
naproxen derivatives underwent selective meta-arylation to
2u and 2v in 58% and 63% yield, respectively, leading to
potential analogues of known nonsteroidal antiinflammatory
drugs (NSAIDs). The mild reaction forms the product
without loss of chiral integrity at the benzylic center, a
result that rules out a mechanism involving enolization of the
amide. a,a-Disubstitution can also be accommodated (2t),
providing access to functionalized aryl motifs embedded
within molecules that contain all carbon quaternary benzylic
centers. An indole-containing substrate is tolerated under the
mild reaction conditions and meta-arylation delivers the
functionally rich 1,3,5-trisubstituted arene 2w.
The meta-directing power of the remote carbonyl group
was probed through the arylation of a-aryl ketones 6, thereby
significantly expanding the scope and generality of the
process. Pleasingly, under our standard reaction conditions,
methyl ketone 6a underwent meta-arylation in reasonable
yield to 7a (Table 4). We also showed that a range of simple
alkyl substituted a-arylketones work well in the meta-
arylation, demonstrating the application of this transforma-
tion to even less reactive systems.
À
Scheme 3. Iterative metal-catalyzed C H bond functionalization.
À
strate the potential of iterative metal-catalyzed C H bond
functionalization for the rapid assembly of complex mole-
cules.
As part of our ongoing studies to elucidate the origin of
the meta-arylation reaction, we tested whether the selectivity
was compromised at higher temperatures than our optimal
conditions (Scheme 4), and we were extremely surprised to
Table 4: Scope of the meta-arylation of a-arylketones.
Scheme 4. Metal-free meta-selective arylation reaction.
find that the meta-arylated product was still formed with the
exquisite selectivity in the absence of the copper catalyst,
albeit in moderate yield. A closer inspection of this result
revealed an extremely narrow threshold temperature range
for the copper-free reaction. While we observed reaction at
908C and 808C, no product was observed at 708C (our
original operating temperature) in the absence of copper
catalyst (Scheme 4). This suggests that the meta-selectivity
may not be the result of a CuIII–aryl intermediate that we had
previously hypothesized in our original working model.[13]
However, it does suggest that the copper salt must still be
facilitating the reaction at 708C through an interaction with
the diaryliodonium salt. In light of these observations, we are
currently investigating the mechanism of this remarkable
metal-free meta-arylation process, and these results will be
published in due course.[14]
50%, 7a
79%, 7d
47%, Ar=4-BrC6H4, 7b
60%, 7c
84%, 7 f
66%, 7e
We next tested whether our new meta-arylation process
could provide access to complex arene products through
À
iterative metal-catalyzed C H bond functionalization meth-
ods (Scheme 3).[12] For example, starting from arylacetic acid
II
À
8, Yuꢀs ortho-selective Pd -catalyzed C H arylation would
In conclusion, we have developed a method for the meta-
selective arylation of the highly versatile a-aryl carbonyl
motif with diaryliodonium salts. In this CuII-catalyzed process
the remote carbonyl group is capable of overpowering even
strongly directing functionalities to form the elusive meta-
deliver 9.[5a] Conversion to the Weinreb amide 1x, followed by
our CuII-catalyzed meta-selective arylation (65%) resulted in
complex phenylacetic acid derivative 2x in just three steps
from a commercial building block. Such methods demon-
Angew. Chem. Int. Ed. 2011, 50, 463 –466
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465

Communications
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be linked with other cross coupling reactions through iterative
À
C H bond functionalization methods. We also discovered
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À
[8] For metal-catalyzed meta-selective C H bond functionalization,
Received: July 29, 2010
Published online: October 22, 2010
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À
Keywords: arylation · C H functionalization · copper ·
.
hypervalent iodine · meta substitution
À
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