Copper-/Silver-Mediated Arylation of C(sp2)-H Bonds with 2-Thiophenecarboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.5b01560

A copper/silver-mediated arylation of (hetero)aryl C-H bonds with 2-thiophenecarboxylic acids has been achieved. The protocol features a broad substrate scope and high functional group tolerance. Preliminary mechanistic studies indicate that a cascade pro

Full text of DOI:10.1021/acs.orglett.5b01560

Letter
pubs.acs.org/OrgLett
Copper-/Silver-Mediated Arylation of C(sp2)−H Bonds with
2‑Thiophenecarboxylic Acids
Sheng Zhao, Yue-Jin Liu, Sheng-Yi Yan, Fa-Jie Chen, Zhuo-Zhuo Zhang, and Bing-Feng Shi*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
S
* Supporting Information
ABSTRACT: A copper/silver-mediated arylation of (hetero)-
aryl C−H bonds with 2-thiophenecarboxylic acids has been
achieved. The protocol features a broad substrate scope and
high functional group tolerance. Preliminary mechanistic
studies indicate that a cascade protodecarboxylation/dehydro-
genative coupling process is likely involved.
Scheme 1. Transition-Metal-Catalyzed C−H Arylation with
Aromatic Carboxylic Acids as Aryl Source
ransition-metal-catalyzed decarboxylative arylation has
Temerged as one of the most powerful and versatile
strategies for the synthesis of biaryl compounds.1 Compared to
the use of toxic and expensive organometallics as aryl source in
traditional cross-coupling reactions, this strategy employs
readily available, inexpensive, and nontoxic aromatic carboxylic
acids as coupling partners and generates gaseous CO2 instead of
toxic metal salts as waste. Since the pioneering work of Myers
and Gooßen, decarboxylative coupling of benzoic acids with
aryl halides or triflates using Pd/Cu or Pd/Ag bimetallic
catalyst systems have been extensively studied.2 In 2009, the
Liu group reported the first example of copper-catalyzed
decarboxylative coupling of potassium polyfluorobenzoates
with aryl iodides and bromides.3
Recently, transition-metal-catalyzed decarboxylative C−H
arylation has demonstrated great potential in biaryl synthesis
by taking advantage of both the high efficiency of C−H
activation and the diversity of carboxylic acids.4−12 For
example, the groups of Crabtree and Glorius first demonstrated
the synthetic potential of the tandem decarboxylation/C−H
activation process.4,5 Subsequently, Larrosa,6 Su,7 Greaney,8
and others9 demonstrated the palladium-catalyzed decarbox-
ylative arylation of activated heteroarenes, such as indoles,
thiophenes, azoles, and polyfluoroarenes (Scheme 1A). Despite
significant progress in this area, these established methods have
been limited to activated or electronically biased arenes, such as
highly C−H acidic polyfluoroarenes or azoles and electron-rich
indoles or thiophenes. To achieve decarboxylative arylation of
C(sp2)−H bonds, preinstalled directing groups have been
found to be promising. Yu and Chan reported a Pd-catalyzed
decarboxylative arylation of 2-arylpyridines using arylacylper-
oxides as aryl sources.10 Recently, Shi developed a rhodium-
catalyzed decarbonylative arylation of simple aryl C−H bonds
of 2-arylpyridines with aromatic carboxylic acids (Scheme
1B).11 However, the use of unremovable directing group, and
the need for the reactions to be conducted at high temperature
(140 °C) restrict the application of this protocol. Moreover, the
reported methods commonly rely on the use of precious
transition metals, such as Pd/Ag and Pd/Cu bimetallic catalytic
systems, or rhodium catalyst.
Recently, the elegant work by Liu has shown that the
decarboxylative coupling of potassium polyfluorobenzoates
with aryl iodides and bromides could be catalyzed by copper
only.3a As part of our ongoing research on the use of our newly
developed bidentate directing group derived from (pyridin-2-
yl)isopropyl amine (PIP-amine) for copper-catalyzed/mediated
C−H functionalization reactions,13−15 we report here the
arylation of (hetero)aryl C−H bonds with 2-thiophenecarbox-
ylic acids mediated by a Cu/Ag bimetallic catalyst system via a
hypothetic protodecarboxylation/dehydrogenative coupling
sequence (Scheme 1B). It is noteworthy that this protocol
represents the first example of protodecarboxylation/dehydro-
Received: May 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01560
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a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
[Cu] (equiv)
[Ag] (equiv)
Li2CO3 (equiv)
temp (°C)
DMF (mL)
3a (mono:di)
4
5
d
1
2
3
4
5
6
7
1.0
0.8
0.2
0.2
0.2
0.4
0.4
0.4
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
AgNO3 (4.0)
AgNO3 (4.0)
AgNO3 (4.0)
AgNO3 (4.0)
AgNO3 (4.0)
120
120
120
120
120
110
100
100
100
1.5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
3.0
43 (9.8:1)
13
11
5
16
56 (8.3:1)
49 (8.8:1)
40 (19:1)
68 (10.3:1)
19
24
6
3.0
3.0
3.0
3.0
5.0
5.0
N.D.
N.D.
14
10
8
d
73 (11.2:1)
1
4
2
d
80 (9:1)
c
d
8
93 (6.8:1)
3
c
9
N.D.
N.D.
N.D.
a
b
Reaction conditions: 1a (0.15 mmol), CuOAc (x equiv), [Ag] (y equiv), 2a (3 equiv), and Li2CO3 (z equiv) in DMF for 24 h. 1H NMR yield
c
d
using CH2Br2 as the internal standard. 2a (5 equiv). Isolated yield.
genative C−H arylation catalyzed by the inexpensive and
abundant copper catalyst.16,17
During the screening of reaction conditions for Cu-mediated
hydroxylation,13b we surprisingly obtained a trace amount of
the arylated product 3a when CuTc was used as catalyst. We
hypothesized that this may result from the decarboxylative
arylation of benzamide 1a. Therefore, we commenced to
investigate this reaction and were delighted to find that the
desired arylation product 3a can be obtained in moderate yield
in the presence of various copper salts and Ag2CO3.
Surprisingly, CuOAc was found to be the optimal catalyst
and gave 3a in 43% yield, probably via in situ generation of
Cu(II) species by the oxidation of silver carbonate (Table 1,
entry 1). The catalyst loading could be reduced to 0.2 equiv
without significantly affecting the yield (entries 2 and 3). The
addition of Li2CO3 increased both the yield and the selectivity
of 3a and avoided the unwanted byproducts 4 and 5 (entry 4).
The screening of silver salts showed that AgNO3 could
dramatically increase the yield to 68% (entry 5, mono:di =
10:1). To our delight, simply tuning the concentration of the
reaction, increasing the loading of Li2CO3, and lowering the
reaction temperature to 100 °C could dramatically inhibit the
unwanted side reactions and enhance the desired reaction
(entries 6−8, for more extensive screening, see Tables S2−
S10).18 A control experiment indicated that copper was crucial
for this reaction (entry 9). We also found that the PIP-directing
group is essential for this transformation. The use of 8-
aminoquinoline as directing group only resulted in the
formation of hydroxylation product with no trace of arylated
product (Scheme S2).18
Figure 1. Scope of benzamides. Reaction conditions: 1 (0.15 mmol),
AgNO3 (4 equiv), CuOAc (0.4 equiv), 2a (5 equiv), and Li2CO3 (5
equiv) in DMF (3 mL) at 100 °C, 24 h. Isolated yield.
the 6-position, owing to the steric interactions. On the contrary,
m-methoxybenzamide 1d gave a mixture of the arylated
products at both the 2- and 6-positions (3da and 3db),
probably due to the coordinating effect of the alkoxy
substituent. m-Fluorobenzamide 3f exclusively led to the
arylation at the kinetically more acidic C-2 position.19 It is
noteworthy that the heterocyclic substrates, such as isonicoti-
namide 3n and various substituted thiophene-2-PIP-carbox-
amides 3o−s were all tolerated under the reaction conditions,
providing an expeditious access to biologically important
(hetero)biaryl compounds. Unfortunately, the reaction does
not work with furancarboxylic acids under the optimized
conditions.
We then examined the substrate scope of various
heteroaromatic carboxylic acids (Figure 2). Generally, function-
alized thiophene-2-carboxylic acids, 2,5-dichlorothiophene-3-
carboxylic acid, and benzothiophene-2-carboxylic acid were all
suitable substrates, furnishing the desired products in good
yields (41%−84%). The halogen substituents (4b, 4d, 4h) were
compatible with this reaction.
With the optimized reaction conditions in hand, we first
tested the substrate scope of different benzamides 1. As shown
in Figure 1, both electron-donating and electron-withdrawing
benzamides were well tolerated, and moderate to good yields of
the corresponding substituted 2-(thiophene-2-yl)benzamides
3a−m were obtained. A broad range of functional groups, such
as fluoro (3b and 3f), chloro (3c and 3i), methoxy (3d and
3m), bromo (3g), trifluoromethyl (3h), methoxycarbonyl (3j),
and acetyl (3l), were compatible with this protocol. Notably,
meta-methylbenzamide 1e gave arylated product exclusively at
The decarboxylative arylation reaction could be conducted
on gram scale, and the desired product 3a was obtained in 90%
B
DOI: 10.1021/acs.orglett.5b01560
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sequence, we conducted additional experiments. The reaction
of 1a with 5-deuterated 2-thiophenecarboxylic acid (d1-2a)
gave the products 3a and d1-3a in a 1:1 ratio (eq 1). When 3-
Figure 2. Scope of carboxylic acids. Reaction conditions: 1a (0.15
mmol), AgNO3 (4 equiv), CuOAc (0.4 equiv), 2 (5 equiv), and
Li2CO3 (5 equiv) in DMF (3 mL) at 100 °C, 24 h. Isolated yield. Note
a: Ag2CO3 was used instead of AgNO3.
yield (Scheme 2, 1.31 g). Furthermore, the PIP group of
compound 3a can be readily removed in 88% yield via a
thiophenecarboxylic acid 2i was used under the standard
conditions, 3a was obtained as the sole product and no 13 was
observed (eq 2). In addition, the reaction of 1a with thiophene
11 under the standard conditions was conducted, affording 3a
in 50% yield (eq 3). These results indicated that thiophene
might be formed in situ through the protodecarboxylation, and
subsequent dehydrogenative arylation afforded the desired
product.21,22
Scheme 2. Gram-Scale Synthesis and Removal of the
Directing Group
In conclusion, we have developed the first copper-catalyzed
arylation of C(sp2)−H bonds with 2-thiophenecarboxylic acids
as aryl source. This reaction is scalable and tolerates a wide
range of functional groups, providing a valuable synthetic entry
to biaryl compounds. Preliminary mechanistic studies reveal
that a cascade protodecarboxylation/dehydrogenative arylation
process is probably involved.
nitrosylation/hydrolysis sequence, affording 2-(thiophene-2-
yl)benzoic acid 7 in 88% yield.13a Compound 7 can be
transferred to the corresponding biaryl lactone 8 in 72% yield
as reported by Wang.20
The synthetic versatility of this protocol can be further
demonstrated by a set of PIP-directed sequential C−H
functionalization reactions developed by our group recently
(Scheme 2). For example, the decarboxylative C−H arylation
product 3a can undergo copper-mediated C−H alkynylation to
give the 2-(thiophene-2-yl)-6-((triisopropylsilyl)ethynyl)-
benzamide 9 in 65% yield.13 Similarly, copper-mediated C−H
hydroxylation of 3a using our previous established conditions
provided 2-hydroxy-6-(thiophen-2-yl)benzamide 10 in 41%
yield.13d
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectral data for all new compounds.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01560.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bfshi@zju.edu.cn.
Notes
The authors declare no competing financial interest.
To gain further insight into the course of the reaction, we
conducted a series of competition and radical-trapping
experiments.18 The intermolecular KIE for decarboxylative
C−H arylation is 3.0, while the intramolecular KIE is 2.3. These
data suggest that C−H cleavage is either the turnover-limiting
step or the turnover-limiting step occurs prior to C−H
cleavage. Addition of 1 equiv of radical scavengers, such as
1,4-dinitrobenzene and 1,1-diphenylethylene, did not inhibit
the reaction. Addition of 1 equiv of TEMPO substantially
reduced the yield but still did not completely suppress the
reaction. These observations suggest that the transformation
does not proceed via radical intermediates.
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (2015CB856600) and the NSFC (21422206, 21272206)
is gratefully acknowledged.
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