Palladium-catalyzed C-H ortho arylation of benzoic acids with diaryliodonium salts in water

Full text of DOI:10.1002/cctc.201300470

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DOI: 10.1002/cctc.201300470
Palladium-Catalyzed CÀH ortho Arylation of Benzoic Acids
with Diaryliodonium Salts in Water
Zhiqing Wu,[a] Si Chen,[a] Chenxu Hu,[a] Zhengkai Li,[a] Haifeng Xiang,[a] and
Xiangge Zhou*[a, b]
Palladium-catalyzed CÀC bond-formation reactions between
aryl halides or triflates and organometallic reagents are among
the most useful methods to construct biaryls, which are usually
structural motifs found in important nature products, pharma-
ceuticals, and organic materials.[1] The corresponding organo-
metallic nucleophilic starting materials, however, are often not
commercially available and sometimes lead to the formation of
undesired side products. Over the past decade, extensive ef-
forts have been made to explore the transition-metal-catalyzed
direct arylation of CÀH bonds as ecologically and economically
friendly alternatives.[2] Furthermore, owing to the requirement
of site selectivity, directing groups such as pyridyl, acylamino,
hydroxy, and phenolic ester groups have been broadly intro-
duced into substrates.[2d] The majority of these directing
groups cannot be easily removed from the products, and
a few of them have to be deprotected by further transforma-
tions.[3] In recent years, transition-metal-catalyzed decarboxyla-
tive coupling reactions have emerged as a powerful strategy
Scheme 1. Palladium-catalyzed CÀH ortho arylation of benzoic acids.
to form carbon–carbon and carbon–heteroatom bonds from
cheap, diverse, and readily available aryl carboxylic acids.[4] The
Ac=acetyl, BQ=1,4-benzoquinone, Mes=2,4,6-trimethylphenyl,
Tf=trifluoromethanesulfonyl.
carboxylic acid group can efficiently be removed or converted
into a variety of useful functional groups, which makes the di-
rected ortho CÀH functionalization of carboxylic acids excep-
tionally practical for applications in organic synthesis.[5]
In 2007, the groups of Yu and Daugulis pioneered the direct
ortho-arylation of benzoic acids with aryl halides by using pal-
ladium as a catalyst (Scheme 1a).[6] Also, Yu and co-workers
demonstrated that phenylboronic acid esters and aryltrifluoro-
borates can be utilized as coupling partners for the ortho func-
tionalization of benzoic acids (Scheme 1b).[6a,7] Recent work
has identified that diaryliodonium salts, which are commercial-
ly available or easily synthesized, are important alternatives
that can be used as arylation reagents in palladium-catalyzed
CÀH arylation reactions.[8] However, application of diaryliodoni-
um salts in the catalytic ortho-arylation of benzoic acids has
not yet been reported.
The use of water as an environmentally benign, nonflamma-
ble, and nontoxic medium for organic transformations is
strongly desired because of green chemistry.[9,10] As part of our
continuous interest in aqueous catalysis,[11] herein we report an
efficient and practical protocol for the palladium-catalyzed
CÀH ortho arylation of benzoic acids with diaryliodonium salts
by using water as the solvent (Scheme 1c).
In our initial optimization study, m-toluic acid and
phenyl(2,4,6-trimethylphenyl)iodonium triflate (2a) were
chosen as model substrates. As illustrated in Table 1, no de-
sired product was found in the absence of catalyst by using
water as the solvent (Table 1, entry 1). Gratifyingly, the sub-
strates could be transformed into desired ortho-arylated prod-
uct 3a in 85% yield by using a catalytic amount of Pd(OAc)2
(Table 1, entry 2). Next, a variety of organic solvents were
tested; nevertheless, only a trace amount of the product was
formed (Table 1, entries 3–10). The results suggest strongly
that the choice of water as the solvent is crucial for this reac-
tion. Replacing Pd(OAc)2 by PdCl2 resulted in a slightly lower
yield of the product (78%; Table 1, entry 11). Furthermore, low
temperatures decelerated the reaction rate; product 3a was
obtained in 54% yield if the reaction was performed at 808C
(Table 1, entry 12). A symmetrical iodonium salt was also com-
patible with the reaction, and it provided a similar result
(Table 1, entry 13).
[a] Z. Wu, S. Chen, C. Hu, Dr. Z. Li, Dr. H. Xiang, Prof. Dr. X. Zhou
Institute of Homogeneous Catalysis
College of Chemistry, Sichuan University
Chengdu 610064 (P.R. China)
Fax: (+86)28-8541-2026
E-mail: zhouxiangge@scu.edu.cn
[b] Prof. Dr. X. Zhou
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Soochow University
Suzhou 215123 (P.R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300470.
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Table 1. Optimization of the reaction conditions.[a]
Table 3. Scope of the diaryliodonium triflate substrate.[a]
Entry
1
Ar
Product
Yield [%][b]
85
Entry
Pd
catalyst
Solvent
T
[8C]
Yield[b]
[%]
1
2
3
4
5
6
7
8
–
H2O
H2O
100
100
100
100
100
100
100
100
100
100
100
80
0
85
0
trace
trace
trace
trace
trace
0
26
78
54
83[c]
Ph
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
1,2-dichloroethane
AcOH
MeOH
toluene
1,4-dioxane
DMF
DMSO
none
H2O
2
3
4
5
6
p-ClC6H4
p-BrC6H4
p-FC6H4
91
85
80
88
83
9
10
11
12
13
Pd(OAc)2
Pd(OAc)2
H2O
H2O
100
[a] All reactions were performed with 1a (0.25 mmol), 2a (1.5 equiv.), and
[Pd] (5 mol%) in solvent (0.5 mL) for 3 h. [b] Yield of isolated product.
[c] Ph2IOTf was used instead of 2a.
p-CH3C6H4
p-CF3C6H4
Table 2. Effect of the counteranions.[a]
7
8
9
m-CH3C6H4
m-FC6H4
80
70
75
Entry
X
Yield [%][b]
1
2
3
4
OTf
BF4
PF6
Br
83
83
79
75
m-BrC6H4
[a] All reactions were performed with 1a (0.25 mmol), 2 (1.5 equiv.), and
Pd(OAc)2 (5 mol%) in solvent (0.5 mL) for 3 h. [b] Yield of isolated prod-
uct.
[a] All reactions were performed with 1a (0.25 mmol), 2 (1.5 equiv.), and
Pd(OAc)2 (5 mol%) in H2O (0.5 mL) at 1008C for 3 h. [b] Yield of isolated
product.
We then investigated the effect of the counter anions of the
diaryliodonium salts, as summarized in Table 2. Diphenyliodoni-
um salts containing diverse anions were evaluated and all pro-
vided satisfactory yields, which demonstrated that the counter
anions did not play an important role in this aqueous CÀH
arylation reaction.
acids could be arylated smoothly with high efficacy. As shown
in Table 4, high chemoselectivity was observed, and monoaryl-
ated benzoic acids were the main products; no diarylated
products were observed. Importantly, the aqueous system is
suitable for large-scale synthesis. For example, upon perform-
ing the reaction with 10 mmol of o-toluic acid, 1.7 g of 3j was
obtained (82% yield; Table 4, entry 2). However, 3-trifluorome-
thylbenzoic acid was inert in this protocol, and this might be
the result of the highly electron-deficient nature of the sub-
strate, which is unfavorable for CÀH activation (Table 4,
entry 7).
Next, the substrate scope of the diaryliodonium salt was ex-
amined in the reaction with m-toluic acid under the optimized
reaction conditions. As shown in Table 3, diversely substituted
and readily accessible diaryliodonium salts could be successful-
ly used; exclusive transfer of the smaller aryl group to give the
desired products in moderate to good yields ranging from 70
to 91% was observed. Notably, Cl and Br substituents were
well tolerated in this protocol, which is crucial for further syn-
thetic manipulations (Table 3, entries 2, 3, and 9).
We next sought to demonstrate that the carboxyl group
could be removed, which would allow the regioselective syn-
thesis of biaryls. 2-Chloro-6-phenylbenzoic acid (3k) was decar-
boxylated by using known methods to afford 3-chlorobiphenyl
in 81% yield, as shown in Scheme 2.[12]
Also, the aromatic acid substrates were investigated. We
were delighted to observe that different substituted benzoic
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conditions. This result demonstrated that the aryl iodide,
which may come from the decomposition of the diaryliodoni-
um salt, is not the actual arylating species in this reaction. We
suspected that the addition of silver salts could promote the
CÀH arylation with iodobenzene in water.[13] After extensive
screening, we found that the reaction between m-toluic acid
and iodobenzene provided the arylated product in a moderate
61% yield in the presence of water-soluble AgSbF6.
Table 4. Scope of the aromatic acid substrate.[a]
Entry
1
Substrate
Product
Yield [%][b]
85
On the basis of the work of Sanford and co-workers, who
suggested that palladium-catalyzed CÀH arylation with diaryl-
iodonium salts might proceed through a high-valent palladium
pathway,[8e,h] a proposed mechanism is shown in Scheme 4.
88
82[c]
2
3
4
5
70
75
70
Scheme 4. Proposed catalytic cycle.
The carboxyl-directed insertion of PdII into the CÀH bond af-
fords PdII species A, which is subsequently oxidized to PdIV in-
termediate B by the diaryliodonium salt. Following reductive
elimination, the arylated product is produced and the PdII spe-
cies is regenerated to complete the catalytic cycle.[14]
6
7
76
0
In summary, we have disclosed an efficient and practical pro-
tocol for the CÀH ortho arylation of benzoic acids by using
water as an environmentally benign, nontoxic reaction
medium. Remarkably, the diaryliodonium salts were first uti-
lized as arylating reagents for CÀH arylation of benzoic acids.
The choice of water as the solvent is crucial for this reaction,
which sets the stage for the broad application of aqueous con-
ditions in CÀH functionalization reactions. Overall, this simple
catalytic system represents an important complement to previ-
ous reports for the preparation of biaryls. Further investiga-
tions of this system for use in other reactions as well as the
study of a detailed mechanism are currently ongoing in our
laboratory.
[a] All reactions were performed with 1 (0.25 mmol), 2a (1.5 equiv.), and
Pd(OAc)2 (5 mol%) in H2O (0.5 mL) at 1008C for 3 h. [b] Yield of isolated
product. [c] Reaction was performed on a 10 mmol scale.
Scheme 2. Protodecarboxylation of a carboxylic acid. DMA=dimethylacet-
amide.
Experimental Section
General experimental procedure for the CÀH arylation of
benzoic acids with diaryliodonium salts
Benzoic acid (0.25 mmol), [Mes-I-Ar]OTf (0.375 mmol), and Pd(OAc)2
(0.0125 mmol) were combined in water (0.5 mL) in a 10 mL vial.
The vial was sealed with a Teflon-lined cap, and the reaction mix-
ture was stirred in a 1008C oil bath for 3 h without an inert gas at-
mosphere. After cooling to room temperature, the mixture was
acidified with 2n HCl (2 mL) and extracted with ethyl acetate (3ꢁ
10 mL). The organic layer was dried with Na2SO4, and the solvent
was removed under reduced pressure. The residue was purified by
Scheme 3. Arylation with iodobenzene.
To gain some insight into the reaction process, comparative
experiments were performed (Scheme 3). The reaction be-
tween m-toluic acid and iodobenzene provided
a trace
amount of the desired product under the optimized aqueous
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Acknowledgements
We are grateful to the Natural Science Foundation of China (Nos.
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0581) for financial support. We also acknowledge the Analytical
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Keywords: biaryls · CÀH activation · diaryliodonium salts ·
palladium · water chemistry
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Received: June 18, 2013
Published online on August 9, 2013
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