Letter
Ambient-Temperature Ortho C−H Arylation of Benzoic Acids with
Aryl Iodides with Ligand-Supported Palladium Catalyst
Changlei Zhu, Yuanfei Zhang, Jian Kan, Huaiqing Zhao,* and Weiping Su*
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences,
Yangqiao West Road 155, Fuzhou, Fujian 350002, People’s Republic of China
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* Supporting Information
ABSTRACT: The ambient-temperature ortho C−H arylation of
electron-deficient benzoic acids with aryl iodides has been
achieved by using an Ac-Ile-OH-supported Pd catalyst. A wide
range of unactivated benzoic acids could cross-couple an array of
aryl iodides in moderate to excellent yields. The choice of HFIP
as a solvent is crucial to realizing the mild C−H arylation, and the beneficial effect of the ligand on the reaction likely stems from
the accelerated C−H activation process and the improved catalyst lifetime.
ver 20 years of efforts has led to great progress in the
development of metal-catalyzed direct C−H functionali-
mild C−H functionalization of benzoic acids has been reported.
In fact, in view of the ready availability and great diversity of
substituted benzoic acids, metal-catalyzed transformations of
benzoic acids have been investigated intensely.9−12 Yu and co-
workers demonstrated that Pd-catalyzed cross-coupling of
benzoic acids with organic boron reagents led to ortho C−H
arylation10a and alkylation.8c Satoh and Miura achieved a series of
carboxyl-directed C−H functionalization reactions of benzoic
acids with various coupling partners using Pd,11a Rh,11b Ru and
Ir11c catalysts. Daugulis10b and Larrosa10d,c independently
developed the Pd-catalyzed ortho arylation of benzoic acid
with aryl iodides that necessitated elevated temperatures, which
led to a decrease in reaction selectivity, forming a mixture of
monosubstituted and disubstituted products or protodecarbox-
ylation side products.
The investigation of the ambient-temperature ortho C−H
arylation of benzoic acids stemmed from our continuing interest
in the reactivity of benzoic acids.12 When treating benzoic acid
(1a) with 2 equiv of 4-iodoanisole (2a) in the presence of 1 equiv
of Ag2CO3 and 1 equiv of Li2CO3 in 1 mL of hexafluor-
oisopropayl alcohol (HFIP)13 for 24 h, we were surprised to find
that the ortho arylation of benzoic acid could occur at ambient
temperature (30 °C), albeit in a moderate yield (entry 1, Table
1). Using other bases in place of Li2CO3 improved the yields
(entries 2−6). Among the bases used, Cs2CO3 gave the best
result (entry 4). Interestingly, the positive effect of alkali-metal
carbonates as bases on the yields increased with an increase in
cation radius (entries 1−4), which might result from the
difference in solubility or in the interaction of metal ions with
benzoate substrate among those tested bases.14 Prolonging the
reaction time up to 36 h had no effect on the yield (entry 7),
indicating that the catalyst lost its activity after 24 h. Inspired by
Yu’s pioneering work on ligand-accelerated C−H activation
reactions,8 we screened a variety of monoprotected amino acid
O
zation.1 As a result of the high dissociation energies of the
breaking C−H bonds, the vast majority of these established
reactions occur at high temperatures (often above 100 °C). As is
well-known, mild reaction conditions such as ambient-temper-
ature reactions are very beneficial to reaction selectivity control
and functional group tolerance. In the context of mild C−H
functionalization reactions,1c,2−6 Fujiwara and co-workers
reported the first example of mild C−H functionalization
reactions in 1995.2 Since this pioneering work, several elegant
studies demonstrated that the in situ generation of electron-
deficient metal−catalyst intermediates by using an acid as a
solvent or an additive3 or by abstracting anionic ligand from a
metal−catalyst precursor4a−g,i,l was an effective strategy to
achieve mild C−H functionalization reactions. The C−H
transformations involving oxidation of the metal−catalyst to
high-oxidation-state intermediates were shown to allow C−H
functionalization to occur under mild conditions.5 In these
transformations, the high-oxidation-state metal−catalyst inter-
mediates favor the C−H bond metalation step and also the
subsequent reductive elimination step of new bond forma-
tions,5b,d especially when the reductive elimination has difficulty
in proceeding. Despite the significant advances, mild C−H
functionalization reactions are mainly limited to specific
substrates, including electron-rich aromatic heterocycles,3b,e,f,5d,e
arenes bearing electron-donating substituents3a,c,d,g−i,4e,5f and
arenes containing an acidic C−H bond6 such as pyridine N-
oxides and their analogues,6a,b,e and polyfluoroarenes.6c The
achievement of mild C−H functionalization of electronically
unbiased substituted arenes remains a challenge.7 Herein, we
report a ligand-supported palladium-catalyst system8 that
enables ortho C−H arylation of electron-deficient benzoic
acids with aryl iodides as arylating reagents at ambient
temperature in high yield and selectivity.
Owing to the inherent electron deficiency of the benzene ring
of benzoic acids, activation of aromatic C−H bonds of benzoic
acids is difficult at ambient temperature. To date, no example of
Received: May 13, 2015
© XXXX American Chemical Society
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Org. Lett. XXXX, XXX, XXX−XXX