Carboxylic acids as traceless directing groups for formal meta-selective direct arylation

Article abstract of DOI:10.1002/anie.201103720

Without a trace: The first meta-selective direct C-H arylation that uses iodoarenes as coupling partners is reported (see scheme, EWG=electron- withdrawing group). This process utilizes carboxylic acid units as temporary directing groups that are cleaved during the reaction, leaving no trace in the resulting biaryl products.

Full text of DOI:10.1002/anie.201103720

DOI: 10.1002/anie.201103720
ꢀ
C H Arylation
Carboxylic Acids as Traceless Directing Groups for Formal meta-
Selective Direct Arylation**
Josep Cornella, Marika Righi, and Igor Larrosa*
The synthesis of biaryl compounds is of high importance as
these structures form part of numerous natural products,
pharmaceuticals, and organic materials.[1,2] The most com-
monly used method for their synthesis is the traditional cross-
coupling reaction, and this requires the use of organometallic
aryl donors. This results in large amounts of waste as well as
low atom and step economy, especially when meta-substituted
aryl donors are required as their preparation usually involves
application of this concept to the synthesis of meta-substituted
biaryl compounds has not been achieved. Herein we report
our strategy for performing direct arylation in the meta po-
sition to a variety of electron-withdrawing and electron-
donating substituents, thus bypassing any electronic prefer-
ences from such substituents (Scheme 1). Through the use of
several steps.[3] In recent years, direct C H arylation methods
ꢀ
ꢀ
have emerged, in which a simple arene is arylated at a C H
bond, thus avoiding the use of an organometallic aryl donor.[4]
However, controlling the regioselectivity of arylation in
substituted benzenes is still a great challenge. Recent
advances in this area have shown that several types of
substituents, including 2-pyridyls, amides, and carboxylic
acids among others, can act as directing groups for the
direct arylation on the ortho position.[4] meta-Selective
arylation, on the other hand, is much more difficult to
achieve. In 2009, a pioneering report by Gaunt and co-
workers described the first method for meta-selective direct
arylation.[5] This system, however, is limited exclusively to the
use of 2-oxo-substituted directing groups, and the noncom-
mercially available Ar2IOTf species as the coupling partner.
All of these strategies to control the regioselectivity of direct
arylation rely on a limited number of directing groups, which
require subsequent modification if a different substituent is
present in the target molecule. On the contrary, the ideal
direct arylation system would allow regioselective coupling
regardless of the nature of the substituents present on the
arene. This is particularly important in the case of meta-
selective direct arylations as, to date, only one class of
directing group has been reported.
Scheme 1. Tandem ortho-selective arylation/protodecarboxylation pro-
ꢀ
cess leading to formal meta-selective C H arylation.
this tandem process, ortho-substituted benzoic acid 1 becomes
a synthetic equivalent of the meta anion I, therefore allowing
the synthesis of meta-substituted biaryl compounds (4) that
would otherwise be difficult to obtain. This one-pot method is
operationally simple, requires low catalyst loadings, uses
readily available iodoarenes as coupling partners, and,
importantly, is compatible with a wide variety of substituents.
Our group, as well as Goossenꢀs, have recently reported
that a wide variety of benzoic acids can be easily proto-
decarboxylated under Ag catalysis provided that they bear an
electron-withdrawing or electron-donating substituent in the
ortho position.[8] These results place carboxylic acid substitu-
ents as the ideal candidates for our meta-selective direct
arylation strategy. Daugulis and co-workers, and Yu and co-
workers have reported two methods for the ortho-selective
direct arylation of benzoic acids with iodoarenes mediated by
a Pd/Ag system.[9] However, only one of the reported
examples contained a substituent (Me) ortho to the carboxylic
acid, thus suggesting general lack of compatibility. Despite
this potential hurdle we decided to explore the possibility of
It should be possible to access meta-substituted adducts by
the use of a strategically placed removable ortho-directing
group, a concept recently reviewed by Breit.[6] Indeed, this
approach has been successfully applied by Satoh, Miura et al.
to the formal meta olefination of arenes by ortho vinylation of
benzoic acids followed by decarboxylation.[7] However, the
[*] J. Cornella, M. Righi, Dr. I. Larrosa
School of Biological and Chemical Sciences
Queen Mary University of London, Joseph Priestley Building
Mile End Road, London, E1 4NS (UK)
ꢀ
carrying out the tandem C H arylation/protodecarboxylation
process (Scheme 1). To achieve the desired meta-selective
arylation a number of crucial challenges had to be overcome:
1) Can highly hindered adducts 3 be protodecarboxylated?
2) Can protodecarboxylation of the starting ortho-substituted
benzoic acid (1!5) be prevented? 3) Can the alternative
decarboxylative ipso-arylation process, which would lead to
ortho-substituted adducts 6, be avoided?
E-mail: i.larrosa@qmul.ac.uk
Homepage: http://webspace.qmul.ac.uk/ilarrosa/index.html
[**] We gratefully acknowledge the Engineering and Physical Sciences
Research Council National Mass Spectrometry Service (Swansea),
and QMUL for a studentship (J.C.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103720.
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Initially, we tested the reaction of 4-bromo-2-chloroben-
zoic acid, 1a, with the ortho-arylation conditions reported by
Daugulis and co-workers,[9] and employing 3-iodotoluene, 2a,
as the coupling partner (Table 1). Perhaps unsurprisingly
owing to the lack of precedent, only 29% of the ortho-
arylated benzoic acid 3a was obtained (Table 1, entry 1).
ꢀ
Table 1: Optimization of the formal meta-selective C H arylation.
Entry[a]
Pd mol%
AgX (equiv)
T [8C]
3a [%][b]
4a [%][b]
1
2
3
4
5
10
2
1
2
AgOAc (1.3)
AgOAc (2)
AgOAc (2)
AgOAc (2)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
120
120
120
120
120
120
130
29
33
17
16
65
20
0
20
28
44
41
9
5
6[c]
7
2
2
0
73
[a] Unless otherwise noted, all reactions were carried out using Pd(OAc)2
as catalyst, a silver salt (AgX), 1.0 equiv of 1a, 3.0 equiv of 2a and
1
3.5 equiv of AcOH, for 16 h. [b] Yields were determined by H NMR
analysis using mesitylene as an internal standard. [c] 10 equiv of H2O
were added.
Scheme 2. Tandem ortho-selective arylation/protodecarboxylation pro-
ꢀ
cess leading to formal meta-selective C H arylation. Yields are of the
isolated pure material. [a] Reaction carried out at 1508C for 16 h,
followed by the addition of 1.0 equiv of Ag2CO3 in 2.5 mL of DMSO
and stirring for a further 4 h at 1708C. [b] 2.0 equiv of iodoarene were
used. [c] After 16 h, 1.0 equiv of Ag2CO3 in 2.5 mL of DMSO were
added and the reaction was stirred for 3 h.
Interestingly, 20% of 4a was also observed, thus suggesting
that the desired tandem ortho-arylation/protodecarboxyla-
tion was feasible. Optimization of this reaction showed that
lower catalyst loadings led to higher overall yield (3a + 4a),
with 2 mol% of Pd(OAc)2 being the optimum (entries 2–4).
Replacing AgOAc with Ag2CO3 further increased the overall
yield (3a + 4a), although the protodecarboxylation step was
greatly reduced (entry 5).[10] Gratifyingly, increasing the
temperature from 120 to 1308C allowed the tandem process
to occur, thus producing the meta-arylated adduct 4a in 73%
overall yield (entry 7). It is remarkable that under these
reaction conditions the protodecarboxylation step seems to
be chemoselective for 3a in the presence of 1a.
Since decarboxylative transformations are in general
highly dependent on the substitution pattern in the benzoic
acid,[11,12] our next concern was to examine the scope of this
method in regard to the acid starting material 1. Gratifyingly,
a wide range of substituents and substitution patterns are
tolerated with none or minimal changes in the reaction
not occur fully during the reaction. This problem was solved
by adding an extra equivalent of Ag2CO3 in DMSO after the
first 16 hours of the reaction.[14]
We then examined the scope of the reaction with respect
to the iodoarene coupling partner (Scheme 3). Iodoarenes
substituted with F, Cl, Me, Br, and CO2Me in para and meta
positions are compatible with the procedure, and lead to the
corresponding meta-substituted biaryl compounds in good
yields. In all cases the meta-arylated adduct was the only
regioisomer observed.
Notably most of these meta adducts 4 could not have been
ꢀ
prepared selectively by direct C H arylation of the parent
arene in the absence of the removable directing group. This is
particularly striking for the parent arenes of biaryl com-
pounds 4a–d, 4 f–g, and 4k–l, which in an electrophilic
aromatic substitution would be substituted at the ortho and/or
para positions. The inherent electronic biases of the different
substituents are therefore irrelevant with our meta-selective
arylation strategy. The only other straightforward approach to
this important class of compounds is by Suzuki coupling using
the corresponding meta-substituted aryl boronic acids. How-
ever, the synthesis of these starting materials generally
involves several steps, which is reflected in their higher cost
(ca. 500–1000 times more expensive than the equivalent
benzoic acid).[15]
ꢀ
conditions (Scheme 2). Thus, C H arylation meta to a Cl
substituent, which would offer an entry for further cross-
couplings to be performed, occurs in high yields (4b–e). Other
electron-withdrawing groups, such as F, NO2, and CF3 are also
tolerated, and lead to the corresponding meta-arylated
adducts (4 f–i). This tandem transformation is not limited to
electron-withdrawing groups in the ortho postion to the
starting benzoic acid: MeO is also compatible with our
protocol, leading to meta-substituted biaryl compounds 4k–m
in good yields. This protocol can also be applied to 1-
naphthoic acid, which selectively affords 2-aryl-naphthalene
4j.[13] In a few cases (4e and 4h–j), protodecarboxylation does
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steric factors.[17] Notably PdII salts have only been reported to
mediate the protodecarboxylation of highly electron-rich
benzoic acids,[18] whereas our system seems to be independent
of the electronic nature of the initial ortho substituent. To
further explore this new hypothesis, we attempted the meta-
arylation protocol on ortho-toluic acid (1t) which, lacking a
strong electron-withdrawing or electron-donating ortho sub-
stituent, does not decarboxylate with either Ag or Pd
catalysts. To our delight, after 16 hours at 1308C, 56% of
the corresponding meta-substituted biaryl compound 4t was
obtained (Scheme 5), thus showing that the scope of this
ꢀ
Scheme 3. Scope of the formal meta-selective C H arylation of a
variety of arenes. Yields are of the isolated pure material. [a] After 16 h,
1.0 equiv of Ag2CO3 in 2.5 mL DMSO were added and the reaction
stirred for further 3 h. [b] After 16 h, 0.25 equiv of Ag2CO3 in 2.5 mL
DMSO were added and the reaction was stirred for further 3 h.
[c] 7.0 equiv of AcOH were used.
Scheme 5. meta-Selective arylation of o-toluic acid (1t).
method is not limited to the traditional activating ortho
groups for Ag- or Pd-mediated decarboxylation.[12] Further
mechanistic studies to explore the effect of the ortho-aryl
group on the decarboxylation step are under way and will be
reported in due course.
This process is likely to proceed by a tandem ortho-
arylation/protodecarboxylation, as depicted in Scheme 1. To
explain the high selectivity displayed for the protodecarbox-
ylation step (1 versus 3) we hypothesized that the decarbox-
ylation of the more-hindered 3 is much faster than that of 1.
Surprisingly, when a mixture of 1a and 3n was treated under
our previously reported Ag-mediated protodecarboxylation
conditions (10 mol% Ag2CO3 in DMSO),[8] the opposite
trend was observed: 1a decarboxylates more than three times
faster than 3n (Scheme 4). Furthermore, when AcOH was
In summary, we have reported the first method for the
ꢀ
formal meta-selective direct C H arylation using iodoarenes
as coupling partners. This process, which is compatible with a
wide range of meta substituents, utilizes carboxylic acids as
traceless directing groups to afford exquisite control upon the
ꢀ
regioselectivity of the direct C H arylation. Benzoic acids are
cheap and readily available starting materials, and provide an
efficient alternative to the sometimes prohibitively expen-
sive Suzuki couplings, to access meta-substituted biaryl
compounds. Furthermore, we have demonstrated that Pd
salts (and not Ag) are able to perform the decarboxylation
of ortho-arylated disubstituted benzoic acids under the
reported reaction conditions. Notably this decarboxylation
occurs with complete chemoselectivity over the starting
ortho-monosubstituted benzoic acids.
Scheme 4. Attempts at protodecarboxylation of 1a and 3n. DMSO=dime- Experimental Section
thylsulfoxide.
Representative meta-selective direct arylation of 4b (Scheme 1): A
mixture of Pd(OAc)2 (2.2 mg, 0.01 mmol), Ag2CO3 (138 mg,
0.5 mmol), 2,4-dichlorobenzoic acid (96.0 mg, 0.5 mmol), and 2b
(0.218 mL, 0.75 mmol) in 0.1 mL of AcOH was heated at 1308C for
16 h. The reaction mixture was filtered through a plug of celite with
CH2Cl2. The filtrate was washed with 5% aqueous KOH and
extracted with CH2Cl2 (2 ꢁ 10 mL). The organic layers were
combined, dried over anhydrous Na2SO4, filtered, and evaporated
to dryness. The crude product was purified by flash column
chromatography on silica gel (hexanes) to afford 3,5-dichloro-3’,5’-
dimethyl-1,1’-biphenyl (4b) as a white solid (98 mg, 78%).
used as the solvent, no protodecarboxylation was observed
for either substrate, suggesting that Ag is not responsible for
the decarboxylation step in this process. On the other hand,
when 1a and 3n were treated with 2 mol% of Pd(OAc)2 in
AcOH, protodecarboxylation of 3n was observed with
complete selectivity.[16] This remarkable selectivity suggests
that electronics are not the only factor controlling the Pd-
mediated decarboxylation of benzoic acids. Based on compu-
tational studies, Su, Lin, and Xue have previously hypothe-
sized that Pd-mediated decarboxylation may be influenced by
Received: May 31, 2011
Published online: August 30, 2011
Angew. Chem. Int. Ed. 2011, 50, 9429 –9432
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9431

Communications
ꢀ
b) H. A. Chiong, Q.-N. Pham, O. Daugulis, J. Am. Chem. Soc.
2007, 129, 9879.
Keywords: arylation · C H functionalization ·
homogeneous catalysis · palladium · silver
.
[10] One should be cautious when employing “aged” Ag2CO3 as we
have found that lower yields can be obtained in this case. We
attribute this effect to the presence of variable amounts of water
in the silver salt; this water seems to enhance the protodecar-
boxylation rate in the benzoic acid starting material. No acid
starting material 1a was recovered when a standard reaction in
the presence of 10 equiv of H2O was carried out (Table 1,
Entry 6).
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ꢀ
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