Cu(II)-mediated oxidative dimerization of 2-phenylpyridine derivatives

Article abstract of DOI:10.1016/j.tet.2008.10.053

A Cu(II)/I₂-mediated C-H bond activation is described. A variety of 2-phenylpyridine derivatives are oxidatively dimerized at the ortho-position of the phenyl ring in which a net loss of two hydrogen atoms results in the formation of a biaryl c

Full text of DOI:10.1016/j.tet.2008.10.053

Tetrahedron 65 (2009) 3085–3089
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Tetrahedron
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Cu(II)-mediated oxidative dimerization of 2-phenylpyridine derivatives
,
Xiao Chen a, Graham Dobereiner a, Xue-Shi Hao a, Ramesh Giri b, Nathan Maugel a, Jin-Quan Yu b
*
a Department of Chemistry, Brandeis University, MS015, 415 South Street, MA 02454, USA
b Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2008
Received in revised form 16 October 2008
Accepted 16 October 2008
Available online 1 November 2008
A Cu(II)/I2-mediated C–H bond activation is described. A variety of 2-phenylpyridine derivatives are
oxidatively dimerized at the ortho-position of the phenyl ring in which a net loss of two hydrogen atoms
results in the formation of a biaryl compound via a double C–H activation/C–C bond-forming process.
Moderate functional group tolerance was observed on both the aryl and the pyridyl rings. A single
electron transfer (SET) or electrophilic metalation process for iodination followed by Ullmann coupling of
the intermediate iodinated product is proposed as the operating mechanism for the dimerization
process.
Keywords:
Biaryl compounds
2-Phenylpyridine
Palladium
Ó 2008 Published by Elsevier Ltd.
Dimerization
C–H bond activation
Ullmann coupling
H
FG
1. Introduction
2
3
DG
H
DG
Ph
DG
H
Biaryl compounds have attracted remarkable attention because
of their prevalence in natural products and pharmaceuticals,1 and
pervasive utility as chiral ligands in organic synthesis.2 In recent
years, great emphasis has been placed on the development of
transition-metal catalyzed C–H bond activation/C–C bond forma-
tion as a novel approach to construct biaryl scaffolds,3 and several
metal catalysts, such as Ru, Rh, and Pd, have already been utilized
with varying degrees of success.4 This process utilizes the substrate
1 with unactivated C–H bonds, and activated molecules, such as
arylboronic acid/ester or aryl halide 2, as coupling partners
(Scheme 1, route A).5 However, from economic and environmental
perspectives, a more attractive approach would be the direct
coupling of two C–H bonds. In particular, oxidatively coupling the
two unactivated C–H bonds of the substrate 1 and the coupling
partner 3, respectively, on a metal center to form a C–C coupling
product 1a would be the most atom-efficient approach and would
involve the least number of steps for the synthesis of complex
target molecules (Scheme 1, route B).6 As such, the synthesis of
biaryl molecules using this alternative process has received sig-
nificant attention.7
[M]
route A
[M]
route B
1
1a
1
Coupling of C-H bond with
Coupling of one C-H bond
with another C-H bond
activated coupling partner
DG = directing group; FG = functional group; [M] = transition metal
Scheme 1. Biaryl synthesis via oxidative coupling of C–H bonds.
Pd(II) catalysts have frequently been used in the oxidative
coupling of two arenes via the activation of C–H bonds.8,9 In most
cases, a homodimer is obtained as the final product.10 Itahara has
shown that an oxidative coupling of quinones and heterocycles
with excess arene could be performed inter- and intramolecularly
using Pd(OAc)2 as the catalyst.11,12 Fagnou and co-workers have
recently discovered an additive effect of acetate ions and Cu(OAc)2
on the regioselective arylation of indoles with excess arenes under
Pd(II)-catalysis.13 A similar regioselective arylation of indoles and
benzofurans with excess arene has also been achieved by DeBoef
and co-workers.14 Sanford and Hull reported a moderate level of
regioselectivity by the combined effect of a directing group and
steric hindrance in the oxidative coupling of benzoquinoline with
arenes.15 A similar level of regioselectivity was also observed in the
coupling of acetanilides with arenes under Pd(II)-catalysis.16 Ex-
cellent diastereoselectivity was obtained in the oxidative coupling
of chiral ferrocenyl oxazolines with excess benzene, providing
a facile method to synthesize planar chiral aryl-substituted ferro-
cenyl oxazolines.17 Formation of unsymmetrical biaryls from simple
* Corresponding author. Tel.: þ1 858 784 7942; fax: þ1 858 784 7949.
E-mail address: yu200@scripps.edu (J.-Q. Yu).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.10.053

3086
X. Chen et al. / Tetrahedron 65 (2009) 3085–3089
Table 1
arenes has been achieved by Lu and co-workers under Pd-catalysis
by tuning the concentrations of arenes and trifluoroacetic acid.18
Buchwald and co-workers have arylated ortho-C–H bonds in ani-
lides with benzene derivatives (4–11 equiv) to form biphenyls via
a Pd-catalyzed twofold C–H functionalization/C–C bond-forming
process.19
Optimization of reaction conditionsa
Py
1 equiv Cu(OAc)2
1 equiv I2, air
N
Solvent, 130 °C
H
Py
4b
More recently, research activities have focused on replacing
these expensive metal catalysts with more abundant and less ex-
pensive Cu salts to execute similar C–H activation reactions.20 We
have reported a Cu(II)-catalyzed functionalization, including ami-
nation with TsNH2, of unactivated C–H bonds of 2-phenylpyridines
using O2 as the oxidant.21 Chatani and co-workers later showed
that 2-phenylpyridine could also be aminated with anilines in
moderate yields using stoichiometric amounts of Cu(OAc)2.22
Daugulis and Do have demonstrated the arylation of C–H bonds in
heterocycles and polyfluoroarenes with aryl halides using CuI as
the catalyst.23 Buchwald and Brasche have synthesized benzimid-
azoles from amidines through a Cu-catalyzed C–H activation/C–N
bond-forming process using O2 as the oxidant.24 2-Arylbenzox-
azoles have been prepared from benzanilides by a Cu-catalyzed C–
H activation/intramolecular C–O bond-forming reaction.25
Cu catalysts have also found increasing applications in the
oxidative coupling of two C–H bonds.3b,26,27 Various Cu salts have
been extensively used to synthesize racemic and chiral binaphthols
via the oxidative coupling of two aryl C–H bonds of naphthol
molecules.28,29 Herein, we report a Cu(II)-mediated oxidative di-
merization of 2-phenylpyridine derivatives in which a net loss of
two hydrogen atoms results in the formation of biaryl compounds
via a C–H activation/C–C bond-forming process.
4
Entry
Solvent
Cu(OAc)2
(equiv)
I2 (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
9
MeCN
PhI
DMF
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
0.5
85c
76c
69
Toluene
DMSO
MeCN
MeCN
MeCN
MeCN
33
14
65d
43
53
62
a
Reaction was run under air on a 0.4 mmol scale in 2.0 mL solvent at 130 ꢀC for
24 h in a sealed tube.
1H NMR yields based on dibromomethane as an internal standard.
Isolated yields from a 1.0 mmol scale reaction in 5 mL solvent.
Solvent (1.0 mL) was used.
b
c
d
with a meta-fluoro substituent on the phenyl ring also underwent
dimerization regioselectively at the less hindered C–H bond (Table
2, entry 4). Substrate 9 with a free hydroxy functional group was
also tolerated and the corresponding dimerized product 9a was
obtained in reasonable yield (Table 2, entry 5). Substrate 10 bearing
an electron-donating group on the pyridyl ring dimerized with
excellent product yield (Table 2, entry 6). 2-(Naphthalen-2-yl)pyr-
idine 11 gave a 2:1 mixture of symmetrically and unsymmetrically
homodimerized products 11a and 11b, respectively, in acceptable
yields (Table 2, entry 7).
The reaction requires 1 equiv of Cu(OAc)2 and I2 to obtain
quantitative dimerization of the substrate 4 (Table 1, entries 1 and
7–9). Based on this stoichiometry, the following reaction equation
can be drawn for the dimerization of 4 (Scheme 3).
Although we do not have concrete experimental evidence, the
following mechanistic pathway can be invoked to explain the
current Cu(II)-mediated oxidative dimerization process based on
the literature precedent and the stoichiometry of the reaction
(Scheme 4).
Iodination of aryl C–H bond using I2/Cu(OAc)2 reagent is
known.21,30 The reaction could possibly involve Cu(OAc)I species 12
generated in situ from the reaction of I2 with Cu(OAc)2 analogous to
the reaction of I2 with Hg(OAc)2 (Scheme 3, route A).31 2-Phenyl-
pyridine 4 could presumably give the intermediate iodinated
product 4a in the presence of Cu(OAc)2/I2 reagent via a single
electron transfer (SET) (Scheme 4, route A).21 The intermediate
iodinated product 4a could also be formed via the metalacycle 4f by
electrophilic metalation/iodination process (Scheme 4, route B).24
Finally, the intermediate iodinated product 4a could undergo Ull-
mann coupling to give the homodimerized product 4b. Although
the formation of the product 4b through the iodinated
intermediate 4a appears feasible, an alternative mechanism in
which 2-phenylpyridine 4 is directly homodimerized via double C–
H activation cannot also be ruled out.
2. Results and discussion
During our recent work on a Cu(II)-catalyzed functionalization
of C–H bonds with a variety of nucleophiles, we observed the dimer
4b of 2-phenylpyridine 4 when I2 was used as a nucleophile source
under a slightly modified reaction condition (Scheme 2).21 Iodine is
crucial for the dimerization reaction as no product was obtained in
its absence. Sanford and co-workers also showed an interesting
case of dimerization of 2-phenylpyridines via Pd(II)/Pd(IV)
catalysis.10c
Py
Cu(OAc)2
air, I2
PhI, 130 °C
67% yield
Cu(OAc)2
air, I2
DCE, 130 °C
61% yield
N
N
H
4
I
4a
Py
4b
Scheme 2. Cu(II)-catalyzed C–H functionalization.
The reaction was further optimized using various reaction pa-
rameters (Table 1). Substrate 4 was quantitatively dimerized to 4b
when the reaction was carried out in 2.0 mL of MeCN with stoi-
chiometric amounts of Cu(OAc)2 and I2 at 130 ꢀC under air for 24 h
(Table 1, entry 1). The reaction could also be run in iodobenzene
with similar yield (Table 1, entry 2). While the reaction carried out
in DMF provided reasonable yield, only small quantities of the
dimerized product 4b were observed in toluene or DMSO (Table 1,
entries 3–5). Decreasing the amount of either the solvent, Cu(OAc)2,
or I2 resulted in the reduction of the product yield (Table 1, entries
6–9).
3. Conclusions
A variety of 2-phenylpyridine derivatives bearing substituents
on either rings were oxidatively dimerized in reasonable to excel-
lent yields under the optimized reaction conditions. 2-Phenyl-
pyridine derivatives 5–8 containing both electron-donating and
electron-withdrawing substituents on the phenyl ring were
dimerized in reasonable yields (Table 2, entries 1–4). Substrate 8
2-Phenylpyridine derivatives are oxidatively dimerized at the
ortho-position of the phenyl ring in which the loss of two hydrogen
atoms results in the formation of a biaryl compound via a Cu(OAc)2-
promoted C–H activation/C–C bond formation. A small range of
functional groups are tolerated on both the aryl and the pyridyl

X. Chen et al. / Tetrahedron 65 (2009) 3085–3089
3087
Table 2
Route A
Cu(II)-mediated oxidative dimerization of 2-phenylpyridinesa
+
I2
+
Cu(OAc)I
IOAc
Cu(OAc)2
Entry
Substrate
Product
Me
Yield (%)b
SET
Py
N
N
N
N
Py
CuI
CuII
I
CuI(OAc)
OAc
I
4c
I
4d
OAc
1
68
4a
Py
Me
Me
Py
5
Route B
5a
CF3
Py
N
SEAr
I2
CuII(OAc)I
N
CuII
CuII
2
58
HOAc
OAc
I
OAc
AcO
Py
Py
CF3
4e
4f
4a
CF3
Py
6
6a
Ullmann coupling
Py
F
F
F
CuI(OAc)
IOAc
N
F
F
3
4
24
44
N
CuI
I
4a
7
7a
4g
Py
Py
N
Ullmann coupling
I
4a
Py
F
8
8a
CH2OH
N
Py
N
Py
CuIII
N
I
5
40
N
CuII
Py
CH2OH
CH2OH
9a
9
4b
4h
Scheme 4. Possible mechanisms of Cu(II)-mediated oxidative dimerization of 2-
phenylpyridine.
N
N
Me
Me
4. Experimental
6
88
Me
Py
4.1. General experimental
N
10
Solvents were obtained from Acros and used directly without
further purification. 1H and 13C NMR spectra were recorded on
a Varian instrument (400 MHz and 100 MHz, respectively) and
internally referenced to the SiMe4 signal. Exact mass spectra for
new compounds were recorded on a VG 7070 high resolution mass
spectrometer. Substrates 4, 5, and 7 were purchased from Aldrich.
10a
Py
Py
7
42
Py
Py
4.2. Preparation of 2-phenylpyridine substrates
11
11a
(2:1)
11b
a
Other substrates (6 and 8–11) were prepared via Suzuki cou-
pling of the corresponding boronic acid and 2-bromopyridine using
a literature procedure.32
Reactions were run under air on a 0.4 mmol scale in 2.0 mL MeCN at 130 ꢀC for
24 h in a sealed tube.
b
Isolated yields.
rings. A single electron transfer (SET) or electrophilic metalation
process for iodination followed by Ullmann coupling of the in-
termediate iodinated product is proposed as the operating mech-
anism for the dimerization process.
4.3. General procedure for Cu(II)-mediated dimerization of 2-
phenylpyridines
In a 20 mL reaction tube, the substrate (0.4 mmol), Cu(OAc)2
(72.8 mg, 0.4 mmol), and I2 (101.6 mg, 0.4 mmol) were dissolved in
2 mL of MeCN under atmospheric air. The reaction tube was sealed
with a Teflon lined cap and the reaction mixture was stirred at
130 ꢀC for 24 h. The reaction mixture was diluted with 20 mL of
CH2Cl2 and then treated with saturated aqueous solutions of
Na2S2O3 (5 mL) and Na2S (5 mL) sequentially. The mixture was
Py
Py
+ 2Cu(OAc)2 2I2
+ + +
2CuI 2HOAc 2IOAc
2
+
Py
4b
4
Scheme 3. Balanced reaction equation for the dimerization of 4.

3088
X. Chen et al. / Tetrahedron 65 (2009) 3085–3089
filtered through a pad of Celite and the filtrate was washed twice
with brine. The organic layer was dried over Na2SO4 and concen-
trated under vacuum. The residue was purified by column chro-
matography on silica gel with hexane/ether (1:1 to 0:1 ratio) to give
the dimerized products.
4.3.7. 2,20-Bis(3-methylpyridin-2-yl)biphenyl (10a)
Substrate 10 was dimerized following the general procedure.
After purification by column chromatography, 10a was obtained as
a brown oil (60.2 mg, 89% yield). 1H NMR (400 MHz, CDCl3)
d
8.45
(d, J¼4.5 Hz, 2H), 7.85 (d, J¼8.0 Hz, 2H), 7.59–6.86 (m, 12H), 1.89 (s,
6H); 13C NMR (100 MHz, CDCl3)
161.2, 147.2, 145.6, 139.2, 138.2,
d
4.3.1. 2,20-Bis(pyridin-2-yl)biphenyl (4b)
131.6, 129.4, 128.5, 128.1, 123.3, 122.3, 19.4; HRMS (EI) calcd for
C24H20N2 (Mþ) 336.1627, found 336.1624.
Substrate 4 was dimerized following the general procedure.
After purification by column chromatography, 4b was obtained as
a yellow solid (47.7 mg, 77% yield). 1H NMR (400 MHz, CDCl3)
d
8.32
4.3.8. 3,30-Di(pyridin-2-yl)-2,20-binaphthyl (11a) and 2,20-(1,20-
binaphthyl-2,30-diyl)dipyridine (11b)
Substrate 11 was dimerized following the general procedure.
After purification by column chromatography, 11a was obtained as
a yellow solid (21.2 mg, 26% yield) and 11b was obtained as a white
solid (13.3 mg, 16% yield).
(d, J¼4.8 Hz, 2H), 7.54 (d J¼7.6 Hz, 1H), 7.41–7.36 (m, 6H), 7.30 (t,
J¼8.0 Hz, 2H), 6.99 (dd, J¼7.6, 4.8 Hz, 1H), 6.76 (d, J¼7.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d 158.2, 149.2, 140.1, 140.1, 135.4, 131.5,
130.2, 128.8, 128.0, 124.6, 121.4; HRMS (EI) calcd for C22H16N2 (Mþ)
308.1314, found 308.1310.
Compound 11a: 1H NMR (400 MHz, CDCl3)
d
8.30 (d, J¼4.2 Hz,
4.3.2. 2,20-(5,50-Dimethylbiphenyl-2,20-diyl)dipyridine (5a)
Substrate 5 was dimerized following the general procedure.
After purification by column chromatography, 5a was obtained as
2H), 8.14 (s, 2H), 8.03 (s, 2H), 7.96 (d, J¼7.8 Hz, 2H), 7.91 (d, J¼7.8 Hz,
2H), 7.50–7.55 (m, 4H), 7.27–7.19 (m, 2H), 7.08–6.93 (m, 2H), 6.71 (d,
J¼7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 157.8,149.2,138.5,135.5,
133.6, 133.1, 130.8, 129.7, 128.6, 127.9, 126.9, 126.6, 124.6, 121.5;
a yellow solid (45.4 mg, 68% yield). 1H NMR (400 MHz, CDCl3)
d
8.27
(d, J¼4.8 Hz, 2H), 7.48–7.19 (m, 8H), 6.99–6.90 (m, 2H), 6.68 (d,
HRMS (EI) calcd for C30H20N2 (Mþ) 408.1627, found 408.1627.
J¼7.9 Hz, 2H), 2.43 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
158.1, 149.0,
Compound 11b: 1H NMR (400 MHz, CDCl3)
d
8.37 (d, J¼4.8 Hz,
139.9, 138.7, 137.4, 135.3, 132.1, 130.1, 128.7, 124.5, 121.1, 21.5; HRMS
(EI) calcd for C24H20N2 (Mþ) 336.1627, found 336.1623.
1H), 8.33 (d, J¼4.9 Hz, 1H), 8.22 (s, 1H), 7.94 (m, 5H), 7.81–7.87 (m,
2H), 7.73 (d, J¼8.5 Hz, 1H), 7.56–7.49 (m, 3H), 7.41–7.38 (m, 1H), 7.19
(m, 2H), 7.00–6.92 (m, 2H), 6.85 (d, J¼7.9 Hz, 1H), 6.71 (d, J¼8.0 Hz,
4.3.3. 2,20-(5,50-Bis(trifluoromethyl)biphenyl-2,20-diyl)-
dipyridine (6a)
Substrate 6 (0.2 mmol) was reacted with Cu(OAc)2 (36.4 mg,
0.2 mmol) and I2 (50.8 mg, 0.2 mmol). The general procedure was
followed to give product 6a as a brown solid (26.0 mg, 58% yield).
1H); 13C NMR (100 MHz, CDCl3)
d 158.7, 157.7, 149.1, 149.1, 139.6,
137.7, 136.8, 135.4, 135.4, 135.0, 133.7, 133.2, 133.1, 133.0, 132.3,
129.9, 128.7, 128.3, 127.9, 127.2, 126.9, 126.8, 126.7, 126.6, 126.3,
125.2, 124.0, 121.6, 121.4; HRMS (EI) calcd for C30H20N2 (Mþ)
408.1627, found 408.1626.
1H NMR (400 MHz, CDCl3)
d
8.36 (d, J¼4.6 Hz, 2H), 7.66 (s, 4H), 7.59
(s, 2H), 7.42 (t, J¼7.7 Hz, 2H), 7.10 (dd, J¼7.5, 4.9 Hz, 2H), 6.86 (d,
Acknowledgements
J¼7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 156.6, 149.6, 143.4,
139.5, 135.9, 130.9, 128.2, 125.4, 125.1, 124.5, 122.7, 122.3; HRMS (EI)
We thank The Scripps Research Institute, Brandeis University
and the U.S. National Science Foundation (NSF CHE-0615716) for
financial support, and the Camille and Henry Dreyfus Foundation
for a New Faculty Award.
calcd for C24H14F6N2 (Mþ) 444.1061, found 444.1060.
4.3.4. 2,20-(3,30-Difluorobiphenyl-2,20-diyl)dipyridine (7a)
Substrate 7 was dimerized following the general procedure.
After purification by column chromatography, 7a was obtained as
a brown oil (17.1 mg, 25% yield). 1H NMR (400 MHz, CDCl3)
d 8.47 (d,
References and notes
J¼4.9 Hz, 2H), 7.51 (dt, J¼7.8, 1.5 Hz, 2H), 7.34–6.80 (m, 12H); 13C
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d
160.3 (d, JC–F¼246.0 Hz), 153.6, 149.2,
141.9, 135.8, 129.1 (d, JC–F¼9.0 Hz), 127.2 (d, JC–F¼4.0 Hz), 126.3,
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found 344.1127.
4.3.5. 2,20-(4,40-Difluorobiphenyl-2,20-diyl)dipyridine (8a)
Substrate 8 (0.25 mmol) was reacted with Cu(OAc)2 (72.8 mg,
0.4 mmol) and I2 (101.6 mg, 0.4 mmol). The general procedure was
followed to give product 8a as a brown solid (19.4 mg, 43% yield).
1H NMR (400 MHz, CDCl3)
d
8.38 (t, J¼4.8 Hz, 2H), 7.46–7.31 (m,
4H), 7.29–7.24 (m, 2H), 7.14–7.05 (m, 4H), 6.95 (dd, J¼7.9, 6.7 Hz,
2H); 13C NMR (100 MHz, CDCl3)
d
160.7 (d, JC–F¼245.0 Hz), 159.4,
157.0, 149.2, 142.9, 135.7, 130.1 (d, JC–F¼9.0 Hz), 125.7, 123.9, 122.0,
115.4; HRMS (EI) calcd for C22H14F2N2 (Mþ) 344.1125, found
344.1121.
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After purification by column chromatography, 9a was obtained as
a brown oil (33.3 mg, 44% yield). 1H NMR (400 MHz, CDCl3)
d 8.45
(d, J¼4.5 Hz, 2H), 7.85 (d, J¼8.0 Hz, 2H), 7.51–7.41 (m, 2H), 7.39–7.30
(m, 2H), 7.20–7.08 (m, 4H), 7.00 (t, J¼7.7 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d 157.4, 149.9, 141.9, 138.9, 137.1, 128.4, 127.5,
127.3, 122.6, 122.4, 120.8, 65.1; HRMS (EI) calcd for C24H20N2O2
(Mþ) 368.1525, found 368.1528.

X. Chen et al. / Tetrahedron 65 (2009) 3085–3089
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