Palladium-catalyzed aromatic C-H halogenation with hydrogen halides by means of electrochemical oxidation

Article abstract of DOI:10.1021/ja9049228

(Chemical Equation Presented) A new strategy for catalytic functionalization of C-H bonds by means of electrochemical oxidation is described. Combination of palladium-catalyzed aromatic C-H bond cleavage and halogenation with electrochemically generated h

Full text of DOI:10.1021/ja9049228

Published on Web 07/28/2009
Palladium-Catalyzed Aromatic C-H Halogenation with Hydrogen Halides by
Means of Electrochemical Oxidation
Fumitoshi Kakiuchi,* Takuya Kochi, Hitoshi Mutsutani, Noboru Kobayashi, Seiya Urano, Mitsuo Sato,
Shigeru Nishiyama, and Takamasa Tanabe
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama, Kanagawa 223-8522, Japan
Received June 16, 2009; E-mail: kakiuchi@chem.keio.ac.jp
Table 1. Palladium-Catalyzed Regioselective Chlorination of
With the ever-increasing need for sustainable chemical processes,
tremendous attention has been paid to efficient, atom-economical
methods for production of organic molecules.1 Direct, selective,
catalytic functionalization of C-H bonds, which are ubiquitous in
organic molecules, is one of the most recognized strategies for this
purpose because it allows for the introduction of functional groups
using all parts of the substrate except for one hydrogen atom.2-9
A variety of functional groups have been directly introduced by
cross-coupling with preactivated partners2-6 or oxidative coupling
with unactivated reagents using external oxidants.7-9 We envisioned
that transition-metal-catalyzed oxidative C-H functionalization
without oxidants could be achieved by the application of techniques
used in electroorganic synthesis, a promising candidate as a green-
sustainable process.10,11
Arenes by Means of Electrochemical Oxidationa
Recently, transition-metal-catalyzed regioselective halogenations
of aromatic C-H bonds have been developed as a new synthetic
tool using several halogenating agents.5-7 However, separation of
the remaining oxidants and the byproducts is unavoidable in the
purification process. Therefore, we examined the halogenations
using two of the simplest halogen sources, aqueous HCl and HBr,
under electrochemical oxidation conditions, because they would
enable direct C-H halogenation without generating organic
byproducts.
Herein we report palladium-catalyzed halogenation of aromatic
C-H bonds with hydrogen halides by means of electrochemical
oxidation. The required reagents for this reaction are an arene and
an aqueous hydrogen halide as substrates, a palladium salt as a
catalyst, and an organic solvent. No further additives such as
electrolytes, oxidants, or ligands are necessary to achieve effective
catalytic activity. Several remarkable advantages of the use of the
electrochemical method are also described.
a Conditions: arene (0.25 mmol), PdCl2 (10 mol %), DMF (10 mL)
(anode), and 2 M HCl (10 mL) (cathode) in an H-type divided cell with
two platinum electrodes and an anion-exchange membrane, 90 °C, 20
mA. b Performed at 100 °C. c Using 15 mol % PdCl2.
First, the chlorination was performed with benzo[h]quinoline (1)
in DMF under ambient atmosphere using 2 mol % PdCl2.12 When
the reaction was carried out for 5 h at 90 °C under constant-current
electrolysis conditions at 20 mA, the 10-position of 1 was
chlorinated regioselectively to afford 2 in a quantitative yield (eq
1): The reaction was complete within 2 h in the presence of 10
proceeds without supporting electrolyte because hydrogen halide
can also act as the electrolyte, whereas the need for a large amount
of supporting electrolyte is considered to be the major drawback
of electroorganic synthesis.13
The results for the chlorination of arenes are shown in Table 1.
In all cases, the arenes were completely consumed, and excellent
isolated yields were achieved. Predominant dichlorination was
observed for 2-phenylpyridine (3) to afford 4 in 94% yield (entry
1), while 2-(2-methylphenyl)pyridine (5) provided monochlorination
product 6 in 93% yield (entry 2). The chlorination of arylpyridines
bearing meta substituents took place selectively at the less hindered
ortho position, and both electron-donating and -withdrawing groups
were tolerated (entries 3-6). Arylpyrimidines were also applicable
for the chlorination. The use of 2-phenyl- and 2-(2-methylphe-
nyl)pyrimidines (15 and 17) led to chlorination products 16 and
18 in excellent yields (entries 7 and 8). Naphthalene derivatives
were also chlorinated regioselectively, and the reactions of naph-
mol % catalyst. No reaction was observed in the absence of either
the catalyst or the electric current. Our new chlorination protocol
provided 2 with higher efficiency than the reported palladium-
catalyzed chlorination of 1 with chlorinating agents (95% isolated
yield in 3 days with NCS, 81% and 85% GC yields in ∼12 h with
CuCl2 and Chloramine-T).5 It is noteworthy that our reaction
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11310 J. AM. CHEM. SOC. 2009, 131, 11310–11311
10.1021/ja9049228 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Regioselective Halogenation by Controlling the Electric
Current
Scheme 2. Proposed Reaction Pathway
We believe that our C-H functionalization protocol employing
a combination of transition-metal-catalyzed C-H bond cleavage
and electrochemical oxidation offers a new environmentally benign
tool for introduction of functional groups on aromatic rings in an
efficient, selective manner. Further investigation of catalytic C-H
functionalization via dual activation by transition-metal catalysts
and electrochemical oxidation is currently in progress.
thylpyridine 19 and naphthylpyrimidine 21 provided 20 and 22,
respectively, in >95% yield (entries 9 and 10).14
The bromination of C-H bonds was also successful. The
reactions of 5 and 11 with hydrobromic acid using PdBr2 as a
catalyst afforded the corresponding products 23 and 24 in 94 and
83% isolated yields, respectively (eq 2):
Acknowledgment. This work was supported in part by a Grant-
in-Aid for Scientific Research on Priority Areas (“Advanced
Molecular Transformations of Carbon Resources”) from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan, and by The Science Research Promotion Fund. We are
grateful to Prof. Kyoko Nozaki (the University of Tokyo).
Supporting Information Available: Experimental procedures,
spectroscopic data for new compounds, and X-ray crystallographic data
for 20 and 22 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
The regioselectivity in the halogenations of 2-(2-methoxylphe-
nyl)pyridine (25) was controlled by tuning the electric current to
an appropriate level (Scheme 1). The regioselective chlorination
of 25 was problematic because chlorination at the para position of
the methoxy group took place even in the absence of the palladium
catalyst. In fact, partial chlorination at the para position was
observed with a 20 mA electric current. However, simple reduction
of the electric current to 10 mA led to exclusive formation of the
desired product 28 in 92% yield. The electrochemical method allows
for facile control over the rate of reactive chloronium ion generation
to suppress the side reactions caused by an excess amount of
chloronium ion. Similarly, the regioselectivity of the bromination
was also controlled by tuning the electric current to 10 mA, and
the bromination product was obtained in 94% yield.
One of the most appealing features of the present halogenation
is that complete conversion to the product may significantly
facilitate the purification process. Generation of the halonium ions
can be stopped by turning off the electric current. The only organic
materials present in the mixture are the product and the solvent.
Therefore, a simple extraction process may afford the halogenation
product in a pure form. In fact, product 2 was isolated in an
analytically pure form (as determined by 1H and 13C NMR spectra
and elemental analysis) simply by neutralization of the reaction
mixture with aqueous K2CO3 followed by extraction with ether.
Our proposed reaction pathway for the present palladium-
catalyzed C-H halogenation is shown in Scheme 2. Coordination
of a nitrogen atom in the substrate to the palladium center yields
complex 30, and electrophilic palladation at the ortho C-H bond
gives palladacycle 31. Reaction of intermediate 31 with a halonium
ion generated by electrochemical oxidation of a halide ion provides
the C-X bond at the ortho position to form complex 32.
Dissociation of the product from the palladium center affords the
product and regenerates the catalyst.
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