Palladium-catalyzed regioselective homocoupling of arenes using anodic oxidation: Formal electrolysis of aromatic carbon-hydrogen bonds

Article abstract of DOI:10.1021/om500957a

Palladium-catalyzed regioselective homocoupling of arylpyridines under anodic oxidation conditions was achieved in the presence of I₂. The dimerization of meta-substituted arylpyridines proceeded selectively at less-sterically congested ortho-p

Full text of DOI:10.1021/om500957a

Note
pubs.acs.org/Organometallics
Palladium-Catalyzed Regioselective Homocoupling of Arenes
Using Anodic Oxidation: Formal Electrolysis of Aromatic
Carbon−Hydrogen Bonds
Fumito Saito, Hiroko Aiso, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa
223-8522, Japan
S
* Supporting Information
ABSTRACT: Palladium-catalyzed regioselective homocoupling of aryl-
pyridines under anodic oxidation conditions was achieved in the presence
of I2. The dimerization of meta-substituted arylpyridines proceeded
selectively at less-sterically congested ortho-positions, and the selectivity is
different from that reported for the palladium-catalyzed dimerization using
Oxone as an oxidant. The dimerization also proceeds using catalytic
amounts of both Pd(OAc)2 and I2 under the electrochemical reaction
conditions.
n search of efficient, environmentally benign syntheses,
halogenation was achieved under simple reaction systems. In these
Itransition-metal-catalyzed aromatic C−H functionalization reactions, protons are reduced to hydrogen gas at the cathode,
while generating protons by cutting off from carbon−hydrogen
bonds. Therefore, stoichiometric oxidants were not necessary for
these processes. Construction of carbon−carbon bonds by
combination of electrochemical oxidation with metal-catalyzed
C−H bond cleavage has been reported by C−H alkenylation,5 but
this type of process has rarely been explored. It should be noted
that in the absence of metal catalysts, anodic oxidation has been
employed to form carbon−carbon bonds from two aromatic C−H
bonds by using phenol derivatives6,7a or radical cation pools.7b
Here we report that palladium-catalyzed ortho-selective
homocoupling of arylpyridines proceeds under anodic oxidation
conditions in the presence of I2 (Figure 1C). The reaction can be
regarded as regioselective formal electrolysis of aromatic C−H
bonds, considering that it forms a C−C bond and an H−H bond
from two C−H bonds. The use of catalytic amounts of both a
palladium salt and I2 was also achieved.
has been extensively studied, because it may allow us to reduce
synthetic steps and chemical wastes by avoiding the installation
of reactive groups such as leaving groups and metals.1 In order to
form carbon−carbon bonds by these methods, however, most of
the reported aromatic C−H functionalization processes still
employ those groups as reaction sites in the coupling partners
(Figure 1A). In this context, much effort has been devoted to
For the palladium-catalyzed electrochemical C−H iodination
we reported previously, substrates giving high yields were
arylpyridines possessing a substituent at the ortho-position on
the aryl group or the 3-position on the pyridyl group.4b On the
other hand, 2-{3-(trifluoromethyl)phenyl}pyridine (1a) was found
to have a high tendency to dimerize under the electrochemical
reaction conditions. When the reaction of 1a was performed at
90 °C for 5.4 h at 5 mA (4.0 F/mol),8 the corresponding ortho-
dimerization product 3a was obtained in 53% yield along with 17%
yield of iodination product 2a (Table 1, entry 1). Although several
examples of ortho-selective dimerization of arylpyridines were
reported,2 the selective formation of 3a was intriguing, because
Sanford and co-workers reported that Pd(OAc)2-catalyzed
dimerization of 1a using Oxone as an oxidant gave a 1.7:1 mixture
Figure 1. Strategies for carbon−carbon bond formation via cleavage of
C−H bonds by transition metal catalysts.
development of direct coupling reactions of two carbon−
hydrogen bonds, in which significant advances have been made
in the past decade using stoichiometric amounts of oxidants
(Figure 1B).2,3
In recent years, our group has been studying the use of anodic
oxidation methods for transition-metal-catalyzed reactions,
especially for aromatic C−H functionalization reactions.4 Combin-
ing the palladium-catalyzed ortho-selective aromatic C−H bond
cleavage and anodic oxidation of halogen sources, regioselective
Received: September 19, 2014
Published: November 4, 2014
© 2014 American Chemical Society
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Organometallics
Note
Table 1. Palladium-Catalyzed Electrochemical Regioselective
a
Homocoupling of 1a
Figure 3. Our proposed reaction mechanism of the palladium-catalyzed
electrochemical homocoupling of 1a with I2.
yields (%)
entry 1a (mmol) I2 (equiv) I (mA) time (h) F/mol
2a
17
3a
may be produced by the reaction of singly chelated Pd(II) species
with I+.
1
2
3
4
0.25
0.5
2
2
2
1
5
10
20
20
5.4
5.4
5.4
3.5
4.0
4.0
4.0
1.3
53
67
80
82
8
4
Based on the speculated mechanism, examination of the
concentration of the substrate was conducted, because a higher
concentration of the substrate may increase the concentration of
the doubly chelated Pd(II) species. Indeed, when we increased
the amount of substrate to 0.5 mmol with keeping the use of
10 mol % of Pd(OAc)2 and 2 equiv of I2, the yield of 3a was
improved to 67% while the yield of iodoarene 2a was reduced to
8% (Table 1, entry 2). Further increase of the amount of 1a to
1 mmol enhanced the yield of 3a to 80% with reducing the yield of
2a to 4% (entry 3). After optimization of the reaction conditions,
the use of 2 mmol of 1a with 1 equiv of I2 allowed us to decrease
the electrochemical equivalents to 1.3 F/mol (entry 4).
Under the optimized reaction conditions, the generality of
the substrate was examined (Table 2). Arylpyridines having meta
1.0
2.0
trace
a
Reaction conditions: 1a, Pd(OAc)2 (10 mol %), I2, MeCN (10 mL)
[anode], and 2 M H2SO4 aq [cathode] in an H-type divided cell with
two platinum electrodes and an anion-exchange membrane, 90 °C.
of dimers 3a and 4a.2b The major product 3a was formed by
carbon−carbon bond formation at the less-sterically congested
ortho-positions, while the minor product 4a was formed by
connecting the less-sterically congested ortho-position with the
more conjested one. They studied the reaction mechanism and
proposed that the dimerization proceeds via regioselective C−H
bond cleavage by a Pd(II) species (path a in Figure 2) and
Table 2. Palladium-Catalyzed Electrochemical Regioselective
a
Homocoupling of Arylpyridines
entry
1
R
I (mA) time (h)
F/mol
yield (%)
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
m-CO2Me
m-Ph
20
20
20
10
10
20
10
20
20
3.5
3.5
2.0
4.0
4.0
2.0
4.0
1.0
1.0
1.3
1.3
0.7
0.7
0.7
0.7
0.7
0.4
0.4
80
56
70
65
60
50
65
66
62
m-Me
p-CF3
p-CO2Me
p-Br
1g
1h
1i
p-Ph
p-Me
1j
H
Figure 2. Reaction mechanism of the palladium-catalyzed homocou-
pling of 1a with Oxone proposed by Sanford and co-workers.
a
Reaction conditions: 1, Pd(OAc)2 (10 mol %), I2 (1 equiv) MeCN
(10 mL) [anode], and 2 M H2SO4 aq [cathode] in an H-type divided
cell with two platinum electrodes and an anion-exchange membrane,
90 °C.
oxidation of the Pd(II) species to Pd(IV) species with Oxone,
followed by unselective cleavage of the ortho C−H bond of
another molecule of 1a by the Pd(IV) species and reductive elimi-
nation (path b in Figure 2). Sanford and co-workers also described
that C−H bond cleavage by Pd(IV) species may be less selective
compared to that by Pd(II) species.9 The complete regioselectivity
of the dimer formation in our reaction led us to speculate that
the reaction may proceed by a different mechanism(Figure 3). The
ortho C−H bond cleavage mayfirst occur on a Pd(II) species twice
to form a doubly chelated Pd(II) species which then oxidized by
electrochemically generated I+ species.10,11 The other product 2a
substituents were first investigated. The reactions of arylpyridines
with methoxycarbonyl and phenyl groups (1b and 1c) gave
80% and 56% yields, respectively (entries 1 and 2). In the case of
2-(3-methylphenyl)pyridine (1d), the reaction for 2 h instead of
3.5 h gave a higher yield of dimer 3d, probably due to the undesired
iodination of 3d (entry 3). The reactions of para-substituted
arylpyridines were also performed. Arylpyridines with electron
withdrawing groups such as trifluoromethyl, methoxycarbonyl, and
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Organometallics
Note
with a solution of arypyridine, I2 (1 equiv), and palladium acetate
(10 mol %) in CH3CN (10 mL). A 2 M aqueous solution (10 mL) of
sulfuric acid was introduced into the cathodic chamber. An electric field
was applied at 90 °C under a constant current condition and the mixture
in the anodic chamber was stirred. After the reaction, the mixture was
quenched with an aqueous solution of K2CO3 and was extracted twice
with EtOAc. The obtained organic portions were washed with saturated
Na2S2O3, and then with brine. The resulting solution was dried over
anhydride Na2SO4 and concentrated. The product was isolated by flash
column chromatography.
bromo groups were converted to the corresponding dimerization
products 3e-g in 50−65% yields using 0.7 F/mol of electricity
(entries 4−6). The reaction of 2-(4-phenylphenyl)pyridine (1h)
also gave dimer 3h in 65% yield (entry 7). However, in the case of
2-(4-methylphenyl)pyridine and 2-phenylpyridine (1i and 1j), the
reaction using 0.4 F/mol of electricity gave 66% and 62% yields of
dimerization products 3i and 3j, which indicates that the
dimerization should proceed without applying electric current to
some extent.
2-(2-Iodo-5-trifluoromethylphenyl)pyridine (2a). The general
procedure was followed with 56.2 mg (0.252 mmol) of 2-{3-
(trifluoromethyl)phenyl}pyridine (1a), except that a 0.2 M aqueous
solution (10 mL) of sulfuric acid was introduced into the cathodic
chamber, and the reaction was carried out under a 5 mA constant current
condition for 5.4 h. Column chromatography (Chromatorex NH, hexane)
afforded 19.7 mg of 2a (0.0564 mmol, 22% yield) as an yellow oil: 1H
NMR (400 MHz, CDCl3): δ 7.32−7.37 (m, 2H), 7.53 (d, J = 7.8 Hz, 1H),
7.70 (s, 1H), 7.81 (td, J = 7.8, 1.2 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.73
(d, J = 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): 101.0, 119.6, 123.1,
123.8 (q, J = 272.5 Hz), 126.1 (q, J = 3.8 Hz), 126.9 (q, J = 3.8 Hz), 130.9
(q, J = 32.9 Hz), 136.3, 140.4, 145.8, 149.5, 159.5; HRMS (ESI-TOF)
calcd for [M + H]+ (C12H8F3IN) m/z 349.9654. Found 349.9650.
2,2′-{4,4′-Bis(trifluoromethyl)-1,1′-biphenyl-2,2′-diyl}-
bispyridine (3a). The general procedure was followed with 446 mg
(2.00 mmol) of 2-{3-(trifluoromethyl)phenyl}pyridine (1a) and the
reaction was carried out under a 20 mA constant current condition
for 3.5 h. Column chromatography (Chromatorex NH, hexane, then
30:1 hexane/EtOAc) afforded 363 mg of 3a (0.817 mmol, 82% yield) as
a white solid. 1H NMR spectroscopic data are in good agreement with
those reported in literature.2b
The progress of the dimerization of 1a was then monitored
with or without applying electric current (eq 1, Figure 4). As a
Figure 4. Plots of GC yield of 3a versus time for the reactions with or
without applying electric current.
2,2′-{4,4′-Bis(methoxycarbonyl)-1,1′-biphenyl-2,2′-diyl}-
bispyridine (3b). The general procedure was followed with 427 mg
(2.00 mmol) of 2-{3-(methoxycarbonyl)phenyl}pyridine (1b) and the
reaction was carried out under a 20 mA constant current condition for
3.5 h. Column chromatography (silica gel 60N, 5:1 hexane/EtOAc, then
2:1 hexane/EtOAc) afforded 338 mg of 3b (0.796 mmol, 80% yield) as a
white solid: δ 3.92 (s, 6H), 6.86 (d, J = 7.8 Hz, 2H), 7.07 (ddd, J = 7.8,
4.9, 1.0 Hz, 2H), 7.38 (td, J = 7.8, 2.0 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H),
8.07 (dd, J = 7.8, 2.0 Hz, 2H), 8.21 (d, J = 2.0 Hz, 2H), 8.35 (ddd, J = 4.9,
2.0, 1.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): 52.1, 121.7, 124.2,
129.4, 129.8, 131.2, 131.3, 135.6, 140.0, 143.9, 149.2, 157.0, 166.6;
HRMS (ESI-TOF) calcd for [M + H]+ (C26H21N2O4) m/z 425.1501.
Found 425.1493.
2,2′-(4,4′-Diphenyl-1,1′-biphenyl-2,2′-diyl)bispyridine (3c).
The general procedure was followed with 463 mg (2.00 mmol) of
2-(3-phenylphenyl)pyridine (1c) and the reaction was carried out under
a 20 mA constant current condition for 3.5 h. Column chromatography
(silica gel 60N, 5:1 hexane/EtOAc, then 1:1 hexane/EtOAc) afforded
259 mg of 3c (0.562 mmol, 56% yield) as a pale brown solid: δ 6.92
(d, J = 7.9 Hz, 2H), 7.06 (dd, J = 7.2, 4.9 Hz, 2H), 7.32−7.41 (m, 4H),
7.44 (t, J = 7.6 Hz, 4H), 7.49 (d, J = 7.9 Hz, 2H), 7.66−7.71 (m, 6H),
7.81 (d, J = 2.0 Hz, 2H), 8.38 (d, J = 4.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3): 121.3, 124.5, 127.0, 127.1, 127.4, 128.7, 128.8, 131.9, 135.4,
138.6, 140.3, 140.3, 140.4, 149.1, 158.1; HRMS (ESI-TOF) calcd for
[M + H]+ (C34H25N2) m/z 461.2018. Found 461.2036.
result, the reaction with no electric current gave the product but
with less efficiency. The formation of 3a was slower from the
beginning, and the GC yield of 3a after 5 h was 31%, which ismuch
lower than that obtained with 20 mA of electric current (85%).
The dimerization can be considered as formal electrolysis
of carbon−hydrogen bonds at ortho-positions of arylpyridines,
which means that I2 only acts as a redox mediator for this reaction
and theoretically the amount of I2 can be used as a catalyst.
Therefore, the use of 10 mol % of I2 was examined and when the
reaction was conducted for 9 h, dimerization product 3a was
obtained in 59% yield (eq 2).
In conlusion, palladium-catalyzed regioselective homocou-
pling of arylpyridines under anodic oxidation conditions was
achieved in the presence of I2. The reaction can be considered as
formal electrolysis of aromatic C−H bonds. The dimerization of
meta-substituted arylpyridines proceeded selectively at less-
sterically congested ortho-positions. The dimerization can also
proceed using catalytic amounts of both Pd(OAc)2 and I2. The
results described here showed that the palladium-catalyzed
formation of biaryl frameworks is possible, and further studies on
metal-catalyzed electrochemical carbon−carbon bond formation
are underway.
2,2′-(4,4′-Dimethyl-1,1′-biphenyl-2,2′-diyl)bispyridine (3d).
The general procedure was followed with 338 mg (2.00 mmol) of
2-(3-methylphenyl)pyridine (1d) and the reaction was carried out
under a 20 mA constant current condition for 2 h. Column chromato-
graphy (silica gel 60N, 15:1 hexane/EtOAc, then 2:1 hexane/EtOAc)
1
afforded 234 mg of 3d (0.696 mmol, 70% yield) as a white solid. H
NMR spectroscopic data are in good agreement with those reported in
literature.2e
2,2′-{5,5′-Bis(trifluoromethyl)-1,1′-biphenyl-2,2′-diyl}-
bispyridine (3e). The general procedure was followed with 446 mg
(2.00 mmol) of 2-{4-(trifluoromethyl)phenyl}pyridine (1e) and the
reaction was carried out under a 10 mA constant current condition for
4 h. Column chromatography (silica gel 60N, 4:1 hexane/EtOAc, then
1:1 hexane/EtOAc) afforded 288 mg of 3e (0.648 mmol, 65% yield) as a
EXPERIMENTAL SECTION
■
General Procedure for Palladium-Catalyzed Electrochemical
Homocoupling of Arylpyridines. The reaction was carried out in an
H-type divided cell (anion-exchange membrane) equipped with two
platinum electrodes (1.7 × 1.7 cm2). The anodic chamber was charged
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Organometallics
Note
1
white solid. H NMR spectroscopic data are in good agreement with
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bispyridine (3f). The general procedure was followed with 427 mg
(2.00 mmol) of 2-{4-(methoxycarbonyl)phenyl}pyridine (1f) and the
reaction was carried out under a 10 mA constant current condition for
4 h. Column chromatography (silica gel 60N, 5:1 hexane/EtOAc, then
2:1 hexane/EtOAc) afforded 257 mg of 3f (0.605 mmol, 60% yield) as a
pale brown solid: δ 3.97 (s, 6H), 6.70 (d, J = 7.6 Hz, 2H), 7.05 (ddd,
J = 7.6, 4.9, 0.9 Hz, 2H), 7.34 (td, J = 7.6, 1.8 Hz, 2H), 7.59 (d, J = 8.1 Hz,
2H), 8.10 (dd, J = 8.1, 1.8 Hz, 2H), 8.21 (d, J = 1.8 Hz, 2H), 8.35 (ddd,
J = 4.9, 1.8, 0.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): 52.3, 121.8,
124.3, 129.2, 130.3, 130.4, 132.4, 135.5, 139.2, 144.0, 149.2, 156.6,
166.7; HRMS (ESI-TOF) calcd for [M + H]+ (C26H21N2O4) m/z
425.1501. Found 425.1520.
2,2′-(5,5′-Dibromo-1,1′-biphenyl-2,2′-diyl)bispyridine (3g).
The general procedure was followed with 468 mg (2.00 mmol) of
2-(4-bromophenyl)pyridine (1g) and the reaction was carried out under
a 20 mA constant current condition for 2 h. Column chromatography
(silica gel 60N, 1:1 hexane/EtOAc) afforded 231 mg of 3g (0.496 mmol,
50% yield) as a pale brown solid: δ 6.70 (d, J = 7.9 Hz, 2H), 7.05 (ddd,
J = 7.4, 4.9, 0.9 Hz, 2H), 7.34−7.39 (m, 4H), 7.56 (dd, J = 8.3, 2.0 Hz,
2H), 7.62 (d, J = 2.0 Hz, 2H), 8.29 (d, J = 4.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3): 121.6, 122.7, 124.1, 131.2, 131.7, 133.6, 135.5,
138.7, 140.3, 149.1, 156.5; HRMS (ESI-TOF) calcd for [M + H]+
(C22H15Br2N2) m/z 464.9602. Found 464.9604.
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2,2′-(5,5′-Diphenyl-1,1′-biphenyl-2,2′-diyl)bispyridine (3h).
The general procedure was followed with 463 mg (2.00 mmol) of
2-(4-phenylphenyl)pyridine (1h) and the reaction was carried out under
a 10 mA constant current condition for 4 h. Column chromatography
(silica gel 60N, 4:1 hexane/EtOAc, 1:1 hexane/EtOAc, then 1:2
hexane/EtOAc) afforded 299 mg of 3h (0.649 mmol, 65% yield) as a
1
white solid. H NMR spectroscopic data are in good agreement with
those reported in literature.2e
2,2′-(5,5′-Dimethyl-1,1′-biphenyl-2,2′-diyl)bispyridine (3i).
The general procedure was followed with 339 mg (2.00 mmol) of
2-(4-methylphenyl)pyridine (1i) and the reaction was carried out under
a 20 mA constant current condition for 1 h. Column chromatography
(silica gel 60N, 1:10 hexane/ether) afforded 224 mg of 3i (0.666 mmol,
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1
66% yield) as a white solid. H NMR spectroscopic data are in good
agreement with those reported in literature.2d,e
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S. R. Chem.Eur. J. 2011, 17, 14164.
2,2′-(1,1′-Biphenyl-2,2′-diyl)bispyridine (3j). The general pro-
cedure was followed with 311 mg (2.00 mmol) of 2-phenylpyridine (1j)
and the reaction was carried out under a 20 mA constant current
condition for 1 h. Column chromatography (silica gel 60N, 1:1 hexane/
EtOAc, then EtOAc) afforded 193 mg of 3j (0.626 mmol, 62% yield) as a
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Fischer, A.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2010, 49, 971.
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51, 7259.
1
white solid. H NMR spectroscopic data are in good agreement with
those reported in literature.2a
(8) These reaction conditions were employed in our previous
palladium-catalyzed C−H iodination using I2 by electrochemical anodic
oxidation.
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ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C{1H} NMR spectra and IR data of new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
* E-mail: kakiuchi@chem.keio.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported, in part, by a Grant-in-Aid for Scientific
Research on Priority Areas “Organic Synthesis Based on
Reaction Integration” from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
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dx.doi.org/10.1021/om500957a | Organometallics 2014, 33, 6704−6707