CuBr/proline-catalyzed cross-coupling of unactivated benzene with aryl halides

Article abstract of DOI:10.1002/aoc.3300

Direct C-H arylation of unactivated benzene with aryl halides was achieved using a readily available copper catalyst. The reaction was carried out at 80 °C, using CuBr as catalyst, proline as ligand and t-BuOK as base. This radical cross-coupling reaction between unactivated benzene and aryl iodides proceeds via homolytic aromatic substitution and offers an efficient method for the synthesis of various biaryls in good to excellent yields.

Full text of DOI:10.1002/aoc.3300

Full Paper
Received: 16 November 2014
Revised: 7 January 2015
Accepted: 28 January 2015
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3300
CuBr/proline-catalyzed cross-coupling of
unactivated benzene with aryl halides
Wei Liu* and Fanyi Hou
Direct C–H arylation of unactivated benzene with aryl halides was achieved using a readily available copper catalyst. The reaction
was carried out at 80°C, using CuBr as catalyst, proline as ligand and t-BuOK as base. This radical cross-coupling reaction between
unactivated benzene and aryl iodides proceeds via homolytic aromatic substitution and offers an efficient method for the
synthesis of various biaryls in good to excellent yields. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: Cu catalysis; C–H activation; direct C–H arylation; unactivated arenes; aryl halides
Encouraged by these observations, we envision that Cu-
catalyzed direct C–H arylation of benzene would be possible if
Introduction
Benzene is one of the most important raw materials in chemical
syntheses. Efficient methods for assembling diversified benzenoid
motifs directly from benzene are highly economically attractive
because their derivatives are widely applied in pharmaceuticals,
agrochemicals and material sciences.
the right ligand is used (Scheme 1). Herein, we report the first
Cu-catalyzed direct arylation of benzene using proline as the ligand
and t-BuOK as the base at 80 °C.
In recent years, transition-metal-catalyzed biaryl synthesis via
direct aromatic C–H arylation of unactivated arenes (e.g. benzene)
has received significant attention.[1] In 2004, Fujita et al. first
reported the cross-coupling of unactivated benzene with aryl
iodides using a noble Ir catalyst in the presence of potassium
tert-butoxide (t-BuOK).[2] In 2006, Lafrance and Fagnou reported
the first Pd-catalyzed direct arylation of unactivated benzene
with aryl bromides.[3] Later on, other Pd-catalyst systems[4] were
developed for direct arylation of unactivated arenes (benzene,
naphthalene, etc.). And other noble metal catalyst systems (Rh,
Au, Pt and Ir/Pd co-catalysts) have been also developed for
direct C–H arylation of unactivated arenes.[5] Considering the high
cost and/or toxic ligands of noble metal catalysis, cheap and green
metal catalysts are highly desirable. In 2009, Ni-catalyzed direct
arylation of unactivated arenes (benzene, pyridine, etc.) in the pres-
ence of t-BuOK was developed by Yamakawa and co-workers.[6] In
2010, Charette and co-workers and Lei and co-workers simulta-
neously reported Fe-catalyzed direct arylation of benzene with aryl
halides through a radical process, in which combinations of
diamines/strong bases were crucial to the success of this
transformation.[7] Other cheap metal catalysts, such as Co and Mo,
have been also applied in this field.[8]
Copper is a non-noble transition metal and has rich chemis-
try and history in organic syntheses, such as Ullmann-type C–X
(X = N, O, S) coupling reactions.[9] By using a supporting ligand or
not, various authors pioneered the Cu-catalyzed direct arylation of
electron-deficient and heterocyclic arenes.[10] However, no reac-
tivity was found for the direct arylation of unactivated benzene
using their catalyst systems.[11] The recent breakthrough in
transition-metal-free coupling between unactivated arenes and
aryl halides was mediated by strong bases and special
ligands.[12]
Results and Discussion
Inspired by many efforts using green and cheap amino acids, such
as proline, as ligands in copper-catalyzed coupling reactions,[9c] the
coupling between 4-iodoanisole (1a) and benzene was chosen as a
model reaction to investigate the reaction conditions (Table 1). We
find that a catalytic amount of CuBr (10 mol%) combined with pro-
line (20 mol%) in the presence of t-BuOK base (3 equiv.) can effi-
ciently arylate benzene under rather mild conditions (80 °C) and
affords the corresponding arylation product 3a in a 74% yield
(Table 1, entry 3). Interestingly, other strong bases (t-BuOLi and t-
BuONa) or potassium bases (K3PO4 and K2CO3) are not as effective
as t-BuOK (Table 1, entries 1, 2 and 4, 5). Other amino acids, such as
phenylalanine, valine, leucine and alanine, were tested and are
found to be not appropriate ligands for this aromatic C–H transfor-
mation (9–46% yields; Table 1, entries 6–9). Copper sources (CuBr,
CuI and CuCl) were also examined, but they do not make a signifi-
cant difference to the reaction conversions (74, 72 and 71% yields;
Table 1, entries 10 and 11). And the control experiments show that
CuBr or t-BuOK alone do not promote such coupling between 1a
and benzene (Table 1, entries 12 and 13). In the absence of CuBr,
proline ligand alone shows less efficiency at 80°C (29% yield;
Table 1, entry 14).[13] Increasing the amount of benzene can favor
the conversion of 1a. When the reaction is carried out in 4 ml of
benzene (45 mmol, 90 equiv.), the yield of 3a can be up to 89%
*
Correspondence to: Wei Liu, College of Food Science and Technology, Henan
University of Technology, Lianhua Street, Zhengzhou 450001, Henan, PR China.
E-mail: liuwei307@hotmail.com
College of Food Science and Technology, Henan University of Technology,
Lianhua Street, Zhengzhou 450001, Henan, PR China
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.

W. Liu and F. Hou
Table 2. Direct arylation of benzene with a variety of aryl halidesa
Entry
Aryl halides (1)
Yield (%)b
Scheme 1. Transition-metal-catalyzed direct arylation of benzene with aryl
halides.
1
4-MeOPhI (1a)
4-MeOPhBr (1a′)
4-MeOPhCl (1a″)
PhI (1b)
90
14
<5
91
89
84
45
65
85
75
40
0
2
3
Table 1. Optimization of reaction conditions for copper-catalyzed
4
direct arylation of benzene with 4-iodoanisolea
5
4-MePhI (1c)
3-MePhI (1d)
2-MePhI (1e)
2-MeOPhI (1f)
4-PhPhI (1 g)
4-FPhI (1 h)
6
7
8
9
Entry Catalyst. (mol%)
Ligand (mol%)
Base
Yield (%)
10
11
12
4-CNPhBr (1i)
4-NO2PhI (1j)
1
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuI (10)
CuCl (10)
—
Proline (20)
Proline (20)
Proline (20)
Proline (20)
Proline (20)
t-BuOLi
t-BuONa
t-BuOK
K3PO4
0
0
2
aReactions were carried out with 0.5 mmol of 1 in 4 ml of benzene for
48 h.
bIsolated yield.
3
74
0
4
5
K2CO3
0
6
Phenylalanine (20) t-BuOK
22
9
7
Valine (20)
Leucine (20)
Alanine (20)
Proline (20)
Proline (20)
—
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
8
46
27
72
71
0
benzene generates the targeted arylation product (3 h) in 75% yield
(Table 2, entry 10). However, no conversion is observed when nitro-
or ester-substituted aryl iodides are examined as the substrates
(Table 2, entry 12). Electron-rich aryl bromides, such as 4-MeOC6H4Br
(1a′), give 14% yield of direct arylated product (3a) due to low con-
version under the same reaction conditions (Table 2, entry 2). When
electron-deficient 4-CNC6H4Br (1i) is used, a 40% yield of direct C–H
arylation product 3i is obtained (Table 2, entry 11).
When 1,4-diiodobenzene (1 k) is used under the same reac-
tion conditions, bis-arylation takes place efficiently and affords
p-terphenyl (3 g) as the main product in 85% yield (Scheme 2).
To our surprise, other haloiodoarenes, such as 4-BrC6H4I (1 l)
and 4-ClC6H4I (1 m), also undergo bis-arylation with benzene
and afford p-terphenyl (3 g) in 79 and 77% yields, respectively
(Scheme 2). Based on these above results (Table 2 and Scheme 2),
the C–Br or even C–Cl bonds in the haloiodoarene substrates can
be activated and take place in direct arylation as efficiently as the
active C–I bonds, which suggests that aryl radical anion intermedi-
ates are involved in this reaction process.[12b,14]
9
10
11
12
13
14
15b
16c
17d
18b
CuBr (10)
—
—
<5
29
89
78
70
78
Proline (20)
Proline (20)
Proline (20)
Proline (20)
Proline (20)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
aReactions were carried out with 0.5 mmol of 1a in 3 ml of benzene for
48 h. Yields were determined by GC.
bIn 4 ml of benzene.
cIn 5 ml of benzene.
dIn 6 ml of benzene.
eIn dry air.
It is noteworthy that no regioisomers are observed from the
direct arylation of benzene with aryl halides under our reaction
conditions (Tables 1 and 2), which clearly rules out the benzyne
mechanism.[15] Considering recent reports of strong base-mediated
radical cross-coupling between aryl halides and unactivated
arenes,[12] we propose that such coupling goes through a radical
pathway. Radical-trapping experiments were conducted using
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a typical radical
scavenger to verify the existence of radical intermediates (Scheme 3).
(Table 1, entry 14). Further increasing the amount of benzene
(5–6 ml) leads to 78 and 70% yields of coupling products, re-
spectively (Table 1, entries 16 and 17). It is very interesting that
the reaction is not air sensitive, and 78% yield of targeted
product 3a is obtained when the reaction is carried out in dry
air (Table 1, entry 18).
With the optimized reaction conditions in hand, the scope of
substrate was investigated (Table 2). In general, under the standard
conditions (10 mol% of CuBr, 20 mol% of proline, 4 ml of benzene,
3.0 equiv. of t-BuOK, 80 °C), the reactions of direct C–H arylation
of benzene proceed smoothly and the obtained yields of the de-
sired products are good to excellent for most tested aryl iodides.
4-MeOC6H4I (1a), PhI (1b) and 4-MeC6H4I (1c) can generate the cor-
responding direct arylated products (3a, 3b and 3c) in 90, 91 and
89% yields, respectively (Table 2, entries 1–5). Ortho-substituted aryl
iodides, such as 2-MeC6H4I (1e) and 2-MeOC6H4I (1f), can react with
benzene smoothly and give moderate yields (45 and 65%; Table 2,
entries 7 and 8). And the reaction between 4-FC6H4I (1 h) and
Scheme 2. Bis-arylation of haloiodoarenes with benzene.
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2015)

Cu-catalyzed cross-coupling of unactivated benzene with aryl halides
good yields. Radical trapping experiments revealed that radical
intermediates were involved in this reaction process. This
CuBr/proline catalysis system will provide a useful and cheap
alternative for biaryl synthesis.
Scheme 3. Radical trapping effect in the cross-coupling of 4-iodoanisole
with benzene.
Experimental
General
Aryl halides, copper salts, t-BuOK and other reagents were
purchased from commercial sources and used without prior
treatments. Benzene was dried and distilled from sodium/
benzophenone immediately prior to use under a nitrogen atmo-
sphere. All other reagents and solvents were used as received from
commercial sources. Unless otherwise noted, all other com-
pounds have been reported in the literature or are commercially
available. Thin-layer chromatography employed 0.25 mm glass
silica gel plates. Flash chromatography columns were packed
with 200–300 mesh silica gel in hexane. 1H NMR and 13C NMR
data were recorded in CDCl3 solutions with Varian Mercury spec-
trometers (300 MHz) using tetramethylsilane as the internal stan-
dard. Analytical gas chromatography (GC) was performed using
an Agilent 6890 gas chromatograph fitted with a flame ioniza-
tion detector.
Scheme 4. Kinetic isotopic effects experiment.
General Procedure for Direct Arylation of Benzene
with Aryl Halides
A Schlenk tube was charged with aryl halides (0.5mmol), proline
(11.5 mg, 0.1 mmol), CuBr (7.2mg, 0.05 mmol) and t-BuOK
(168mg, 1.5mmol) under an atmosphere of nitrogen at room
temperature, and then benzene (4.0 ml) was added. The resulting
mixture was stirred at 80 °C for 48h. After cooling to room temper-
ature, the reaction mixture was quenched and extracted with ethyl
acetate (3 × 10 ml). The organic layers were combined, dried over
Na2SO4 and concentrated under reduced pressure, and then puri-
fied using silica gel chromatography (hexane–ethyl acetate, 200:1)
to yield the desired biaryl product. All isolated products were char-
acterized using 1H NMR and 13C NMR spectra. The spectral data of
known compounds are consistent with those reported.
Figure 1. Proposed mechanism.
The coupling reaction is completely inhibited by adding 1 equiv.
of TEMPO, which suggests that this coupling involves radical
intermediates.
Furthermore, a competition experiment was also conducted
using an equimolar amount of benzene along with benzene-d6 to
estimate the rate-determining step in this aromatic C–H arylation
reaction (Scheme 4). The observed low KH/KD value (1.1) indicates
that the rate-determining step does not involve C–H bond cleavage.
Based on the above observations, we propose that this aromatic
C–H arylation proceeds via a radical pathway (Fig. 1), which is sim-
ilar to a recently reported base-promoted homolytic aromatic
substitution.[8b,12d] Aryl halide radical anion is generated through
single-electron transfer from the CuBr/proline catalyst, followed
by the formation of an aryl radical via the dissociation of C–X bond
to give up a halogen anion. The aryl radical then reacts with arene
to form biaryl radical. In the presence of t-BuOK, the resulting biaryl
radical is deprotonated to give biaryl radical anion. The highly
reductive biaryl radical anion then transfers an electron to the
oxidized catalyst to afford the final biaryl product and fulfilling
the catalytic cycle.
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (grant no. 21102036), Science and Technology
Research Project of Department of Education in Henan Province
(grant no. 14B550006) and Plan for Scientific Innovation Talent of
Henan University of Technology (grant no. 11CXRC02).
References
[1] a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174; b)
G. P. McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009, 38, 2447; c)
A. Lei, W. Liu, C. Liu, M. Chen, Dalton Trans. 2010, 39, 10352.
[2] K. Fujita, M. Nonogawa, R. Yamaguchi, Chem. Commun. 1926, 2004.
[3] M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496.
[4] a) C. X. Qin, W. J. Lu, J. Org. Chem. 2008, 73, 7424; b) J. J. Mousseau,
F. Vallée, M. M. Lorion, A. B. Charette, J. Am. Chem. Soc. 2010, 132,
14412; c) W. K. Hong, Y. Qiu, Z. Yao, Z. Wang, S. Jiang, Tetrahedron
Lett. 2011, 52, 4916.
[5] a) S. Proch, R. Kempe, Angew. Chem. Int. Ed. 2007, 46, 3135; b) M. Li,
R. Hua, Tetrahedron Lett. 2009, 50, 1478; c) A. M. Wagner,
A. J. Hickman, M. S. Sanford, J. Am. Chem. Soc. 2013, 135, 15710; d)
L. J. Durak, J. C. Lewis, Organometallics 2014, 33, 620.
Conclusions
In summary, we have reported the first copper-catalyzed direct C–H
arylation of unactivated benzene with aryl halides in the presence
of t-BuOK base and a catalytic amount of proline ligand at 80°C.
Haloiodoarenes can form bis-arylation products with benzene in
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

W. Liu and F. Hou
[6] a) O. Kobayashi, D. Uraguchi, T. Yamakawa, Org. Lett. 2009, 11, 2679; b)
G. Xie, T. Li, X. Qu, J. Mao, J. Mol. Catal. A 2011, 340, 48.
[7] a) F. Vallee, J. J. Mousseau, A. B. Charette, J. Am. Chem. Soc. 2010,
132, 1514; b) W. Liu, H. Cao, A. Lei, Angew. Chem. Int. Ed. 2010,
49, 2004.
[8] a) W. Liu, H. Cao, J. Xin, L. Jin, A. Lei, Chem. Eur. J. 2011, 17, 3588; b) H. Li,
C. Sun, M. Yu, D. Yu, B. Li, Z. Shi, Chem. Eur. J. 2011, 17, 3593; c) C. T. To,
T. L. Chan, B. Z. Li, Y. Y. Hui, T. Y. Kwok, S. Y. Lam, K. S. Chan, Tetrahedron
Lett. 2011, 52, 1023.
[9] a) S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400; b)
G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054; c)
D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450; d) Q. Liao, X. Yang, C. Xi,
J. Org. Chem. 2014, 79, 8507.
H. Zhang, K. H. Chung, C. He, H. B. Wang, F. Y. Kwong, A. W. Lei, J. Am.
Chem. Soc. 2010, 132, 16737; c) E. Shirakawa, K. Itoh, T. Higashino,
T. Hayashi, J. Am. Chem. Soc. 2010, 132, 15537; d) A. Studer,
D. P. Curran, Angew. Chem. Int. Ed. 2011, 50, 5018; e) S. Yanagisawa,
K. Itami, ChemCatChem 2011, 3, 827; f) T. L. Chan, Y. Wu, P. Y. Choy,
F. Y. Kwong, Chem. Eur. J. 2013, 19, 15802; g) C.-L. Sun, Z.-J. Shi,
Chem. Rev. 2014, 114, 9219.
[13] It has been reported recently that proline (20 mol%) can promote di-
rect C–H arylations of benzene with aryl iodides in good yields under
harsh conditions (150°C), and less efficiency has been also observed
at 120°C. For more details, see: K. Tanimoro, M. Ueno, K. Takeda,
M. Kirihata, S. Tanimori, J. Org. Chem. 2012, 77, 7844.
[14] J. F. Bunnett, X. Creary, J. Org. Chem. 1974, 39, 3611.
[10] a) H. Q. Do, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 12404; b) H. Q. Do,
O. Daugulis, J. Am. Chem. Soc. 2008, 130, 1128; c) H. O. Do, R. M. K. Khan,
O. Daugulis, J. Am. Chem. Soc. 2008, 130, 15185; d) R. J. Phipps,
N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130, 8172; e)
R. J. Phipps, M. J. Gaunt, Science 2009, 323, 1593; f) D. B. Zhao,
W. H. Wang, F. Yang, J. B. Lan, L. Yang, G. Gao, J. S. You, Angew. Chem.
Int. Ed. 2009, 48, 3296.
[15] G. B. Bajracharya, O. Daugulis, Org. Lett. 2008, 10, 4625.
Supporting Information
Additional supporting information may be found in the online
version of this article at the publisher’s web-site.
[11] O. Daugulis, H. Q. Do, D. Shabashov, Acc. Chem. Res. 2009, 42,
1074.
[12] a) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou, X. Y. Lu, K. Huang, S. F. Zheng,
B.-J. Li, Z.-J. Shi, Nat. Chem. 2010, 2, 1044; b) W. Liu, H. Cao, H. Zhang,
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2015)