Pd/C-Et3N-mediated catalytic hydrodechlorination of aromatic chlorides under mild conditions

Article abstract of DOI:10.1016/j.tet.2006.05.025

A mild and efficient one-pot procedure for the hydrodechlorination of aromatic chlorides using a Pd/C-Et₃N system was developed. A variety of aromatic chlorides could be dechlorinated at room temperature and under ambient hydrogen pressure. Et₃N activates the catalysis and is likely to work as a single electron donor in this system.

Full text of DOI:10.1016/j.tet.2006.05.025

Tetrahedron 62 (2006) 7926–7933
Pd/C–Et3N-mediated catalytic hydrodechlorination of aromatic
chlorides under mild conditions
*
Yasunari Monguchi, Akira Kume, Kazuyuki Hattori, Tomohiro Maegawa and Hironao Sajiki
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
Received 27 February 2006; accepted 8 May 2006
Available online 23 June 2006
Abstract—A mild and efficient one-pot procedure for the hydrodechlorination of aromatic chlorides using a Pd/C–Et3N system was devel-
oped. A variety of aromatic chlorides could be dechlorinated at room temperature and under ambient hydrogen pressure. Et3N activates the
catalysis and is likely to work as a single electron donor in this system.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
that the use of Et3N remarkably and selectively enhanced
the catalytic activity of Pd/C toward the hydrodechlorination
of aromatic chlorides,15 contrary to our expectation.16
Kaneda et al. also reported a Pd-hydroxyapatite-catalyzed
hydrodechlorination of aryl chlorides in the presence of Et3N
in 2004,17 although our highly referential communications of
hydrodechlorination published in 2002 (Refs. 16 and 18)
were not properly cited in their paper. In this paper, we
describe more details of the general procedure for the Pd/C-
catalyzed hydrodechlorination of aromatic chlorides that
operates under ambient hydrogen pressure at room tempera-
ture, together with the role of Et3N in the system.
Much study has been devoted to developing new methods for
the dehalogenation of aromatic halides from the synthetic1
and environmental2 points of view. It is well-known that
aromatic chlorides are much less reactive than aromatic bro-
mides and iodides and hence, the dechlorination of aromatic
chlorides cannot readily be achieved.3 Furthermore, the
reduction of some persistent chlorinated aromatic pollutants
such as DDT and PCB, which are difficult to degrade, has
been a global issue. Therefore, the development of efficient
dechlorination methods remains a topic of great interest.
The dechlorination of aromatic chlorides is an underdevel-
oped methodology and few effective methods are available.4
Existing techniques usually utilize hydride reduction,5 hy-
drogenation,3,6 catalytic transfer hydrogenation with formic
acid,7 formic acid salt,8 or hydrazine,9 dechlorination using
metals,10 photolysis,11 oxidation,12 electrolysis,13 or super-
critical water oxidation.14 These reactions mostly require
high heat, high pressure, radiation, stoichiometric reagents,
vast amounts of catalyst, special equipment, and/or strong
basic conditions and most of the reactions are frequently
incomplete.
2. Results and discussion
2.1. General procedure for the Pd/C–Et3N-mediated
hydrodechlorination of aromatic chlorides
A control experiment on the Pd/C-catalyzed hydrodechlori-
nation was performed using 4-chlorobiphenyl 1 as a sub-
strate, which contains no reducible functional groups
except an aromatic chloride, to investigate the effect of
Et3N as an additive. The hydrodechlorination of 1 using
commercial 10% Pd/C (3% of the weight of 1) and 1.2 equiv
of Et3N in MeOH was smoothly completed within 1 h under
ambient hydrogen pressure (balloon) at room temperature to
afford biphenyl 2 in 100% conversion yield (GC/MS) and
triethylammonium chloride, whereas the dechlorination
was incomplete even after 3 days when the reaction was car-
ried out without Et3N (Fig. 1 and Scheme 1).
We have reported that addition of a nitrogen-containing base
(e.g., NH3, pyridine, ammonium acetate) to a Pd/C-catalyzed
hydrogenation system as a weak catalyst poison chemoselec-
tively inhibited the hydrogenolysis of a benzyl ether with
smooth hydrogenation of other reducible functionalities
such as olefin, Cbz, benzyl ester, azide, and so on. During
the course of our further study on the chemoselective hydro-
genation using a variety of Pd/C–amine systems, we found
To optimize the reaction conditions, a variety of nitrogen-
containing bases were investigated (Table 1). The reaction
was carried out under ordinary hydrogen pressure (balloon)
* Corresponding author. Tel.: +81 58 237 3931; fax: +81 58 237 5979;
e-mail: sajiki@gifu-pu.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.025

Y. Monguchi et al. / Tetrahedron 62 (2006) 7926–7933
7927
H2 (balloon)
10% Pd/C
Et3N
Among the nitrogen-containing bases, which worked well
for the hydrodechlorination of 1, Et3N was selected as the
best candidate for its cost-efficiency and its non-nucleo-
philicity.
Et3N·HCl
+
Cl
MeOH, rt
1
2
The results of optimization of the solvent for the hydrodech-
lorination of aromatic chlorides are listed in Table 2. The use
of an alcoholic solvent led to the completion of the reaction
within an hour (entries 1, 3, and 4). When the reaction in
such alcoholic solvent was carried out without hydrogen,
no conversion to 2 was observed (entries 2 and 5) indicating
that the hydrogen atom of alcoholic solvents cannot be a
hydrogen source and hydrogen gas is indispensable for the
hydrodechlorination system as a hydrogen donor. Using
hexane as a solvent caused difficult stirring of the reaction
mixture due to the poor solubility of the resulting Et3N$HCl
accompanied by the reaction progress (entry 8). When H2O
was used as a solvent, no reaction took place since H2O
could not dissolve 1 at all. Therefore, MeOH was chosen
as a solvent for the hydrodechlorination.
100
90
80
70
60
50
40
30
20
10
0
with Et3N
without Et3N
0
2
12
24
72
Time (h)
Figure 1. Kinetics plots on the hydrodechlorination of 1 using 10% Pd/C
(3% of the weight of 1) with or without Et3N (1.2 equiv) in MeOH under
ambient hydrogen pressure at room temperature.
The use of 10% Pd/C with more than 3% weight of 1 accom-
plished completion of the hydrodechlorination of 1, although
the reduction in weight of the catalyst to 1% weight of 1
resulted in incompletion of the reaction evenafter 24 h (Table
3, entries 1 and 2). The hydrodechlorination smoothly took
place even under dark conditions (entry 3). Lowering the
reaction temperature led to drastic decrease of the reaction
efficiency (entry 4) and surprisingly, entirely no reaction was
observed under reflux conditions (Table 3, entry 5). Detailed
optimization of the reaction conditions eventually revealed
that treatment of the methanol solution of 1 with 10% Pd/C
using 1.2 equiv of an additive and 10% Pd/C (3% of the
weight of 1) in MeOH at room temperature for 1 h and the
products were analyzed by GC/MS and 1H NMR after simple
extraction. Entries 3–10 in Table 1 indicate that the addition
of relatively lipophilic amines greatly enhanced the effi-
ciency of the reaction compared with the less lipophilic
NH3 or ethylendiamine (entries 2 and 11). In addition, the
amines, which have aromatic substituents such as aniline
and N,N-diethylaniline were effective additives (entries 9
and 10), whereas the aromatized heterocyclic bases such as
pyridine or quinoline strongly suppressed the hydrodechlori-
nation and no reaction was observed (entries 12 and 13). The
addition of NaOH, an inorganic base, was also effective for
the completion of the reaction (entry 15), although concern
that the strong basicity and nucleophilicity of NaOH would
narrow the applicability of this method excluded NaOH
from the candidates.
Table 2. Assessment of solvents in the dechlorination of 1a
Entry
Solvent
Yield of 2 (%)b
1
MeOH
MeOH
EtOH
i-PrOH
i-PrOH
DMF
100
0
100
100
0
2c
3
4
5c
6
3
7
8
9
THF
Hexane
H2O
43
63
0
Table 1. Assessment of bases in the dechlorination of 4-chlorobiphenyl (1)a
a
Reactions were carried out under ordinary hydrogen pressure (balloon)
using 1.2 equiv of Et3N and 10% Pd/C (3% of the weight of 1) in a solvent
at room temperature for 1 h.
Yields were determined by GC/MS.
Reaction was performed without hydrogen.
Entry
Additive
Yield of 2 (%)b
1
2
None
NH3
24
67
b
c
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Me2NH
Me3N
Et3N
i-Pr2NEt
i-Pr3N
DBU
PhNH2
PhNEt2
H2N(CH2)2NH2
Pyridine
Quinoline
NaOH
100
100
100
100
100
100
100
100
94
0
0
100
10
17
Table 3. Assessment of amount of 10% Pd/C and temperature in the dechlo-
rination of 1a
Entry
Amount of Pd/Cb
Temperature
Yield of 2 (%)c
1
3 wt %
1 wt %
3 wt %
3 wt %
3 wt %
rt
rt
rt
100
98
100
4
2d
3e
4
ꢀ20 ꢁC
5
Reflux
0
NaOAc
Et3N$HCl
a
Reactions were carried out under ordinary hydrogen pressure (balloon)
using 1.2 equiv of Et3N and 10% Pd/C in MeOH for 1 h.
Amount of 10% Pd/C toward the weight of 1.
Yields were determined by GC/MS.
The reaction was carried out for 24 h.
Under dark conditions.
a
b
c
d
e
All reactions were carried out under ordinary hydrogen pressure (balloon)
using 1.2 equiv of additive and 10% Pd/C (3% of the weight of 1) in
MeOH at room temperature for 1 h.
b
Yields were determined by GC/MS.

7928
Y. Monguchi et al. / Tetrahedron 62 (2006) 7926–7933
(more than 3% of the weight of 1) and Et3N (1.2 equiv) at
room temperature under ordinary hydrogen pressure (bal-
loon) is the best reaction conditions for the present hydro-
dechlorination.
(entry 7), while the aromatic ketone moiety of 4-chloro-
benzophenone remained intact and the corresponding benzo-
phenone was quantitatively generated (entry 5). In addition,
some medicines (entries 9–15) were efficiently dechlori-
nated, although prolonged reaction time was required. In
the hydrodechlorination of furosemide, the furan ring was
competitively reduced to the corresponding tetrahydrofuran
ring (entry 15).
To explore the scope of this method, the hydrodechlorination
of a variety of aromatic chlorides was investigated (Table 4).
The results shown in entries 1, 3, and 6 demonstrated that the
reaction could be carried out in the presence of carboxylic
acid and phenolic functionalities in the substrates. Absence
of Et3N in the reaction mixture diminished the efficiency of
the hydrodechlorination (entries 2 and 4). Competitive re-
duction of the nitro moiety of 2-chloro-4-nitrotoluene was
observed and 4-toluidine was isolated as the sole product
2.2. Mechanism analysis of the Pd/C–Et3N-mediated
hydrodechlorination of aromatic chlorides
We demonstrated that the efficiency of the hydrodechlorina-
tion was greatly affected by the nature of amine. The use of
Table 4. Ten percent Pd/C–Et3N-mediated dechlorination of aromatic chloridesa
Entry
1
ArCl
Time (h)
6
Product
CO2H
Yield (%)b
100 (99)
Cl
Cl
CO2H
CO2H
2c
3
6
3
50
CO2H
CO2H
CO2H
Cl
100 (100)
CO2H
4c
3
1
60
CO2H
Cl
O
O
5
100 (65)
Cl
Cl
OH
OH
6
7
3
2
100 (92)
100 (90)
Cl
H2N
Me
O2N
Me
Cl
8
1
100 (51)d
Me
Me
Me
Me
CH2CH2CH2N
N
CH2CH2CH2N
N
Cl
9e
24
100
S
S
Chlorpromazine
CO
Cl
CO
N
N
Me
Me
10
25
16
100 (44)
MeO
MeO
CH2CO2H
Indometacin
CH2CO2H
Cl
H
N
H
N
N
11e
100
N
H
N
Cl
N
H
Clonidine
(continued)

Y. Monguchi et al. / Tetrahedron 62 (2006) 7926–7933
7929
Table 4. (continued)
Entry
ArCl
Time (h)
27
Product
Yield (%)b
100 (71)
Me
Me
Cl
O C CO2Et
Me
O
C
CO2Et
12
13
Me
Clofibrate
H
N
H
N
Cl
H2NO2S
100 (85)f
NH
NH
O2
22
22
S
H2NO2S
S
O2
Hydrochlorothiazide
Cl
14e
100
N
H
N
H
Cl
CH2CO2Na
CH2CO2H
Dicrofenac sodium salt
CO2H
CO2H
NHCH2
NHCH2
O
O
15e
6
100
H2NO2S
H2NO2S
Cl
Furosemide
a
Reactions were carried out under ordinary hydrogen pressure (balloon) using Et3N (1.2 equiv vs the number of chlorine atoms) and 10% Pd/C (3% of the
weight of ArCl) in MeOH (ca. 1% solution of ArCl) at room temperature.
Yields were determined by GC/MS and the isolated yields are indicated in parentheses. Hundred percent yield implied that no other products were detected by
GC/MS.
The reaction was carried out without Et3N.
The low isolated yield of the product is due to the low boiling point and volatile nature.
The reaction was carried out using 10% Pd/C with 10% of the weight of ArCl.
Product was contaminated with 10% of Et3N$HCl.
b
c
d
e
f
aliphatic amines led to excellent conversion to the corre-
with the 10% Pd/C that was pre-treated without HCl af-
forded 2 in 12% yield (Table 5, entry 1). These results prove
that HCl, which forms during the hydrodechlorination, time-
dependently poisoned the commercial 10% Pd/C. Similar re-
action conditions using Et3N$HCl as an additive in place of
HCl led to no hydrodechlorination of 1 (Table 5, entry 3).
This result indicates that Et3N$HCl, which forms by neutral-
ization of HCl generated from the reaction mixture, also
sponding dechlorinated product, whereas the use of aroma-
tized heterocyclic bases led to the complete recovery of the
chlorinated starting material. As shown in entry 16 in Table
1, the presence of Et3N$HCl in the reaction mixture seemed
to delay the reaction rate rather than not to affect it in com-
parison with the absence of any additives (Table 1, entry 1).
These results led us to presume that Et3N does not work
just for the removal of the generated HCl, which is suspected
as a catalyst poison.
H2 (balloon)
10% Pd/C (3% of the weight of 1)
HCl
Cl
It is well-known that hydrogen chloride, which is generated
during the Pd/C-catalyzed hydrodechlorination of aromatic
chlorides decreases the efficiency of the reaction.19 On the
contrary, Angel and Benitez showed that the reaction rate
of the hydrodechlorination of chlorobenezene in HCl media
was boosted using their homemade Pd/C.6h To investigate
the role of Et3N in our system, we, first, studied the effect
of HCl on the Pd/C-catalyzed hydrodechlorination of
4-chlorobiphenyl (1). As shown in Figure 2, HCl dose-
dependently impeded the reaction progress. In each case, the
hydrodechlorination started with a certain reaction rate,
although the reaction rate gradually decreased as the reaction
proceeded and eventually reached a plateau. These results
suggest that Pd/C was time-dependently poisoned by the
exposure to HCl. Furthermore, after pre-stirring of 10%
Pd/C in the presence of HCl (1.2 equiv of 1) in MeOH under
hydrogen (balloon) at room temperature for 24 h, no hydro-
dechlorination of 1 was observed (Table 5, entry 2). On the
other hand, the 1-h stirring of 1 under hydrogen atmosphere
MeOH, r t
1
2
100
90
80
70
60
50
40
30
20
10
0
without HCl
with HCl (0,1 equiv)
with HCl (0.5 equiv)
with HCl (1.0 equiv)
0
4
8
12
24
48
72
Time (h)
Figure 2. The effect of HCl on the hydrodechlorination of 1.

7930
Y. Monguchi et al. / Tetrahedron 62 (2006) 7926–7933
Table 5. The effect of HCl and Et3N$HCl on the hydrodechlorination of 1a
amines such as Et3N to aromatic chlorides initiated the hy-
drodechlorination in our system and each pyridine or quino-
line may have worked as an electron acceptor to inhibit the
electron transfer to aromatic chlorides. Hydrodechlorination
of 1 using pyridine or a variety of substituted pyridines as an
additive was investigated (Fig. 3): (1) use of 2-methyl- or
4-methylpyridine caused very sluggish hydrodechlorina-
tion of 1, although use of pyridine caused no hydrodechlori-
nation; (2) use of 2,6-dimethylpyridine, 4-methoxypyridine,
or 4-tert-butylpyridine allowed the reaction to proceed at
a rate similar to that of the reaction without additives; (3)
the addition of 2,6-di-tert-butyl-4-methylpyridine (DTBMP)
expedited the reaction to completion. Tabner and Yandle re-
ported the half-wave potentials (E1/2) of a series of nitrogen-
containing heterocyclic compounds in DMF: the potentials
of quinoline, pyridine, 2-methylpyridine, 4-methylpyridine,
and 2,6-dimethylpyridine are ꢀ2.18, ꢀ2.76, ꢀ2.80, ꢀ2.86,
and ꢀ2.85 V [vs a saturated calomel electrode (SCE)], re-
spectively.20 The E1/2 of 4-chlorobiphenyl (1) in DMF was
also reported to be ꢀ2.37 V (vs SCE).13b The E1/2 of quino-
line is much greater than that of 1, while the potentials of pyr-
idine analogs are lower than that of 1 and are very close. It is,
therefore, reasonable to think quinoline accepted an electron
exclusively from Pd(0) or Et3N to block the hydrodechlorina-
tion of 1 (Table 6, entries 3 and 5).21 On the contrary, both the
comparison between pyridines and 1 and the similarity of
pyridines in E1/2 seem to make it difficult to explain our re-
sults in Figure 3 with a simple SET mechanism. We reported
that less sterically hindered pyridine inhibited more the
hydrogenolysis of aliphatic benzyl ethers22 and these results
suggested some interaction, possibly complexation, between
pyridines and palladium metal delayed the reaction rate.
Combining the substituent effect on the pyridine ring as a
catalyst poison with the SET mechanism, the results in
Figure 3 could be rationally explained: (1) pyridine inter-
acted with palladium metal to block the hydrogenation and
even in the presence of Et3N as an additive (the deactivation
of catalysis was observed, Table 6, entry 1 vs entry 4);
(2) mono-substituted pyridines such as 2-methyl- and
H
2 (balloon)
Additive (1.2 equiv)
MeOH, rt, 24 h
H2 (balloon)
1 h
10% Pd/C
2
Cl
1
Entry
Additive
Conversion (%)b
1
2
3
None
HCl
Et3N$HCl
12
0
0
a
All reactions were carried out by stirring 10% Pd/C (3% of the weight of
1) with 1.2 equiv of additive in MeOH under ordinary hydrogen pressure
(balloon) at room temperature for 24 h followed by the addition of 1,
reintroduction of hydrogen (balloon), and stirring the mixture for 1 h.
Yields were determined by GC/MS.
b
suppresses the catalyst activity of Pd/C. It, therefore, seems
sure that the great acceleration of the hydrodechlorination of
aromatic chlorides by the addition of a certain amine is not
achieved by just neutralization of HCl with the amine.
We described that the addition of pyridine or quinoline
instead of Et3N completely blocked the hydrodechlorination
(Table 1, entries 12 and 13 or Table 6, entries 2 and 3).
Furthermore, addition of either pyridine or quinoline to the
Pd/C–Et3N system suppressed the hydrodechlorination effi-
ciency (Table 6, entries 4 and 5), and no reaction was ob-
served when quinoline was added to the reaction mixture
(entry 5). There is little doubt that Et3N is not only an
HCl scavenger but also plays some vital role as a strong
accelerator in the Pd/C-catalyzed hydrodechlorination pro-
cess. Moreover, addition of TCNE (tetracyanoethylene) or
TCNQ (7,7,8,8-tetracyanoquinodimethane), a single elec-
tron capture, to the hydrodechlorination reaction mixture
in the presence of Et3N thoroughly suppressed the reaction
(entries 6 and 7), suggesting the participation of a single
electron transfer (SET) mechanism in the simple catalytic
process.
H2 (balloon)
10% Pd/C (3% of the weight of 1)
Et3N has been reported as an initiator (single electron donor)
of the photochemical dechlorination of aryl chlorides.11a–f It
seems reasonable to consider that an SET from aliphatic
Additive (1.2 equiv)
Cl
MeOH, rt
1
2
Table 6. The effect of additional additive on the hydrodechlorination of 1a
100
90
80
70
60
50
40
30
20
10
0
H2 (balloon)
10% Pd/C (3% of the weight of 1)
Additive (1.2 equiv)
Cl
MeOH, rt, 1 h
1
2
Entry
Additive
Yield of 2 (%)b
1
2
3
4
5
6
7
Et3N
Pyridine
Quinoline
Et3N+pyridine
Et3N+quinoline
Et3N+TCNE
Et3N+TCNQ
100
0
0
90
0
0
0
0.5
1
Time (h)
2
0
pyridine ( ), 2-methylpyridine ( ), 4-methylpyridine ( ), 2,6-dimethylpyridine ( ),
(
a
All reactions were carried out under ordinary hydrogen pressure (balloon)
using 1.2 equiv of additive and 10% Pd/C (3% of the weight of 1) in
MeOH at room temperature for 1 h.
4-methoxypyridine ( ), 4-tert-butylpyridine (
DTBMP ( ), without additive (
)
Figure 3. The effect of substituted pyridine as an additive on the hydro-
dechlorination of 1.
b
Yields were determined by GC/MS.

Y. Monguchi et al. / Tetrahedron 62 (2006) 7926–7933
7931
4-methylpyridinescouldinteractwith palladium metalandde-
activated Pd/C less than pyridine; (3) bulky pyridines such as
2,6-dimethylpyridine, 4-methoxypyridine, and 4-tert-butyl-
puridine were hard to interact with palladium metal and did
not interfere in the catalyst activity for the hydrodechlorina-
tion; (4) the bulkiest DTBMP never interacts with palladium
metal, but acts as an electron donor, as well as Et3N.
the Mass Spectrometry Laboratory at Gifu Pharmaceutical
University.
4.2. General procedure (Fig. 1)
After two vaccum/H2 cycles to remove air from a round-
bottom flask, a suspension of 4-chlorobiphenyl (100 mg,
0.53 mmol), 10% Pd/C (3.0 mg), and Et3N (89 mL,
0.64 mmol) in MeOH (10 mL) was vigorously stirred using
a stir bar under hydrogen atmosphere (balloon) at ambient
temperature (ca. 20 ꢁC). At a given time point, the reaction
mixture (1 mL) was sampled using a syringe, filtered through
a 0.2-mL Millipore membrane filter (Millipore), and concen-
trated invacuo. The residue was partitioned between hexanes
(10 mL) and H2O (10 mL) and the organic layer was washed
with brine (10 mL), dried (MgSO4), and filtered. An aliquot
(1 mL) was taken from the filtrate, diluted with hexanes
(19 mL), and analyzed by a Hewlett Packard 5891 series II
gas chromatograph equipped with a Hewlett Packard 5972
mass-selective detector (Hewlett Packard) and a Neutra-
bond-5 capillary column (30 mꢂ0.25 m, 0.4 mm film thick-
ness; GL Science). Helium was employed as carrier gas with
a flow rate of 1.0 mL/min. Injector and detector temperatures
were 230 and 250 ꢁC, respectively. The column temperature
was programmed to ramp from 150 ꢁC (5 min hold) to
250 ꢁC (3 min hold) at a rate of 5 ꢁC/min. The retention times
of 4-chlorobiphenyl and biphenyl were 8.86 min and
4.81 min, respectively. The products were identified by their
retention times on GC/MS or their 1H NMR spectra in com-
parison with those of commercial authentic samples.
These experimental results suggest that an SET mechanism
is involved in the dechlorination using the Pd/C–Et3N sys-
tem (Scheme 1). Initial single electron transfer from Et3N
to the palladium-activated chlorobenzene ring of A affords
an anion radical B, which then could be converted to the
dechlorinated benzene ring of C by the elimination of the
chloride anion and subsequent hydrogenation of the corre-
sponding benzene radical.
Cl
Cl
–
H
Pd
e–
A
B
C
Cl–
Cl
H2/Pd
HCl
Et3N
Et3N+
Et3N
e–
Et3N·HCl
Scheme 1. Proposed mechanism of the hydrodechlorination of aromatic
chlorides.
4.2.1. Optimization of base for the hydrodechlorination
of 4-chlorobiphenyl (1) (Table 1). According to the general
procedure, the reaction was carried out for 1 h using another
base in place of Et3N. The reaction mixture was filtered
through a 0.2-mL Millipore membrane filter and concen-
trated in vacuo. The residue was partitioned between hex-
anes (10 mL) and H2O (10 mL) and the organic layer was
washed with brine (10 mL), dried (MgSO4), and filtered.
The filtrate was concentrated in vacuo. An aliquot (1 mg)
was taken from the residue, dissolved in hexanes (20 mL),
and analyzed as described in Section 4.2.
3. Conclusion
We have developed a mild and efficient one-pot method for
the hydrodechlorination of aromatic chlorides that proceeds
at room temperature and under ordinary hydrogen pressure.
The presence of Et3N is crucial for the reaction and Et3N
works not only as a scavenger of hydrogen chloride but
also as an electron donor to expedite the reaction. The reac-
tion is general for a variety of aromatic chlorides. The sim-
plicity and reliability of this method make it an attractive
tool for organic and environmental chemists.
4.2.2. Optimization of solvent for the hydrodechlorina-
tion of 1 (Table 2). According to the general procedure,
the reaction was carried out for 1 h using another solvent
in place of MeOH. The reaction mixture was treated and
analyzed in the same manner as described in Table 1.
4. Experimental23
4.1. General
Pd/C (10%) was purchased from Sigma–Aldrich (cat. no.
205699) and Et3N was purchased from Wako Pure Chemical
Industries, Ltd. Analytical thin-layer chromatography (TLC)
was carried out on pre-coated Silica Gel 60 F254 plates
(Merck, Art 5715) and visualized with UV light. Column
chromatography was accomplished using Merck Silica Gel
60 (230–400 mesh). For reversed phase column chromato-
4.2.3. Optimization of amount of Pd/C and temperature
for the hydrodechlorination of 1 (Table 3). According to
the general procedure, the reaction was carried out for 24 h
using 1 mg of 10% Pd/C (1% weight of 1) in place of 3 mg
of 10% Pd/C or the reaction was carried out for 1 h at
ꢀ20 ꢁC or reflux in place of room temperature. Aluminum
foil was used for the reaction under dark conditions. The re-
action mixture was treated and analyzed in the same manner
as described in Table 1.
1
graphy Waters Sep-PakÒ C18 cartridge was used. H NMR
spectra were recorded on a JOEL JNM EX-400 NMR spec-
trometer (400 MHz). Chemical shifts (d) are expressed in
parts per million and are internally referenced (0.00 ppm
for tetramethylsilane—CDCl3, 4.79 ppm for D2O, or
3.31 ppm for CD3OD). Mass spectra and high-resolution
mass spectra were taken on a JMS-SX 102A spectrometer at
4.3. Hydrodechlorination of aromatic chlorides (Table 4)
According to the general procedure, the reaction was carried
out using 100 mg of a substrate. After the starting chloride

7932
Y. Monguchi et al. / Tetrahedron 62 (2006) 7926–7933
disappeared, the reaction mixture was filtered through a
0.2-mL Millipore membrane filter and concentrated in vacuo.
The residue was partitioned between Et2O (10 mL) and H2O
(10 mL) and the organic layer was washed with brine
(10 mL), dried (MgSO4), and filtered. If necessary, the resi-
due was purified by silica gel column chromatography or
reversed phase column chromatography.
4.4. Hydrodechlorination of 1 in the presence of HCl
(Fig. 2)
According to the general procedure, the reaction was carried
out using 0.1 M HCl in MeOH (0, 0.1, 0.5, or 1.0 equiv) in
place of Et3N and analyzed.
4.5. Hydrogenation of 1 after pre-treatment of Pd/C with
additive (Table 5)
4.3.1. 10-[3-(Dimethylamino)propyl]phenothiazine [CAS
Registry Number 58-40-2] (entry 9).24 1H NMR (CDCl3)
d 2.19 (5H, m), 2.42 (6H, s), 2.76 (2H, t, J¼6.4 Hz), 4.00
(2H, t, J¼6.4 Hz), 6.89–6.96 (4H, m), 7.17 (4H, m); MS
(EI) m/z 284 (M+), 58 (83), 198 (45), 238 (42), 284 (100);
HRMS (EI) Calcd for C17H20N2S (M+) 284.1347; Found
284.1356.
A suspension of 10% Pd/C (3 mg) and an additive
(0.64 mmol) was stirred under hydrogen (balloon) for 24 h.
4-Chlorobiphenyl (100 mg, 0.53 mmol) was added and the
mixture was stirred under hydrogen (balloon) for 1 h. The re-
action mixture was treated and analyzed in the same manner
as described in Table 1.
4.3.2. 1-Benzoyl-5-methoxy-2-methylindole-3-acetic acid
[CAS Registry Number 1601-19-0] (entry 10).25 1H NMR
(CDCl3) d 2.38 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 6.65 (1H, d,
J¼9.3 Hz), 6.87 (1H, d, J¼9.3 Hz), 6.95 (1H, s), 7.49 (2H, t,
J¼7.6 Hz), 7.62 (1H, t, J¼7.6 Hz), 7.70 (2H, d, J¼7.6 Hz);
MS (EI) m/z 357 (M+), 77 (61), 105 (100), 158 (25), 323
(76); HRMS (EI) Calcd for C19H17NO4 (M+) 323.1158;
Found 323.1146.
4.6. Hydrogenation of 1 in the presence of Et3N and an
additional additive (Table 6)
According to the general procedure, the reaction was carried
out for 1 h in the presence of Et3N (89 mL, 0.64 mmol) and
an additive (0.64 mmol). The reaction mixture was treated
and analyzed in the same manner as described in Table 1.
4.3.3. 2-(Phenylamino)imidazoline [CAS Registry
Number 1848-75-5] (entry 11).26 1H NMR (D2O) d 3.62
(4H, s), 7.18 (2H, s), 7.26 (1H, t, J¼7.3 Hz), 7.36 (2H, t,
J¼7.3 Hz); MS (EI) m/z 161 (M+), 77 (29), 104 (33), 160
(40); HRMS (EI) Calcd for C9H11N3 (M+) 161.0953; Found
161.0949.
4.7. Hydrogenation of 1 in the presence of pyridine
analog (Fig. 3)
According to the general procedure, the reaction was carried
out using a substituted pyridine (0.64 mmol) in place of Et3N
and analyzed.
4.3.4. Ethyl 2-methyl-2-phenoxypropanoate [CAS Regis-
try Number 18672-04-3] (entry 12).27 1H NMR (CDCl3)
d 1.25 (3H, t, J¼7.1 Hz), 1.60 (6H, s), 4.23 (2H, q,
J¼7.1 Hz), 6.84 (2H, d, J¼8.0 Hz), 6.98 (1H, t, J¼8.0 Hz),
7.24 (2H, t, J¼8.0 Hz); MS (EI) m/z 208 (M+), 77 (18), 94
(100), 135 (54); HRMS (EI) Calcd for C12H16O3 (M+)
208.1099; Found 208.1101.
Acknowledgements
We thank N. E. Chemcat Corp. for the Pd leaching assay.
This work was supported by a Grant-in Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and
Culture of the Japanese Government (No. 13672222), the
Research Foundation for Pharmaceutical Sciences, and the
Research Foundation for the Electrotechnology of Chubu.
4.3.5. 7-Sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine
1,1-dioxide [CAS Registry Number 23141-82-4] (entry
13).28 1H NMR (CD3OD) d 3.46 (2H, s), 4.89 (2H, s), 7.01
(1H, d, J¼8.9 Hz), 7.85 (1H, d, J¼8.9 Hz), 8.14 (1H, s);
MS (EI) m/z 263 (M+), 171 (58), 187 (36); HRMS (EI) Calcd
for C7H9N3O4S2 (M+) 263.0034; Found 263.0038.
References and notes
1. For reviews, see: (a) Pinder, A. R. Synthesis 1980, 425–452; (b)
Hudlicky, M. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 895–922;
(c) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102,
4009–4091.
2. For review, see: Hitchman, M. L.; Spackman, R. A.; Ross,
N. C.; Agra, C. Chem. Soc. Rev. 1995, 423–430.
3. For review, see: Urbano, F. J.; Marinas, J. M. J. Mol. Catal. A
2001, 173, 329–345.
4.3.6. 2-(Phenylamino)benzeneacetic acid [CAS Registry
Number 70172-33-7] (entry 14).29 1H NMR (CD3OD)
d 3.53 (2H, s), 6.70 (1H, t, J¼7.6 Hz), 6.77 (2H, d,
J¼7.6 Hz), 6.87 (1H, t, J¼7.6 Hz), 7.05–7.10 (3H, m),
7.13–7.17 (2H, m); MS (EI) m/z 227 (M+), 167 (10), 180
(100), 209 (54); HRMS (EI) Calcd for C14H13NO2 (M+)
227.0946; Found 227.0956.
4. Hara, R.; Sato, K.; Sun, W.-H.; Takahashi, T. Chem. Commun.
1999, 845–846.
4.3.7. 5-Sulfamoyl-N-(tetrahydrofurfuryl)anthranilic
acid [CAS Registry Number 4818-84-2] (entry 15).30 1
5. (a) Bosin, T. R.; Raymond, M. G.; Buckpitt, A. R. Tetrahedron
Lett. 1973, 14, 4699–4700; (b) Roth, J. A.; Dakoji, S. R.;
Hughes, R. C.; Carmody, R. E. Environ. Sci. Technol. 1994,
28, 80–87; (c) Liu, Y.; Schwartz, J.; Cavallaro, C. L. Environ.
Sci. Technol. 1995, 29, 836–840; (d) Liu, Y.; Schwartz, J.
Tetrahedron 1995, 51, 4471–4482; (e) Yang, C.; Pittman, C. U.,
H
NMR (CD3OD) d 1.80–1.93 (1H, m), 1.99–2.10 (2H, m),
3.42–3.49 (2H, m), 3.86 (1H, m), 4.01 (1H, m), 4.23 (1H,
m), 6.86 (1H, d, J¼8.8 Hz), 7.81 (1H, d, J¼8.8 Hz), 8.51
(1H, s); MS (EI) m/z 300 (M+), 71 (57), 81 (73), 211
(100), 229 (42); HRMS (EI) Calcd for C12H16N2O5S (M+)
300.0780; Found 300.0785.
´
Jr. Tetrahedron Lett. 1997, 38, 6561–6564; (f) Lassova, L.;
Lee, H. K.; Hor, T. S. A. J. Org. Chem. 1998, 63, 3538–3543;

Y. Monguchi et al. / Tetrahedron 62 (2006) 7926–7933
7933
(g)Pittman, C.U., Jr.;Yang,C. J. Hazard.Mater. 2001, B82, 299–
311; (h) Lipshutz, B. H.; Tomioka, T.;Sato, K. Synlett2001, 970–
973; (i) Lipshutz, B. H.; Tomioka, T.; Pfeiffer, S. S. Tetrahedron
Lett. 2001, 42, 7237–7740; (j) Maleczka, R. E., Jr.; Rahaim, R. J.,
Jr.; Teixeira, R. R. Tetrahedron Lett. 2002, 43, 7087–7090; (k)
Rahaim, R. J., Jr.; Maleczka, R. E., Jr. Tetrahedron Lett. 2002,
43, 8823–8826.
Zhang, P.-C.; Scrudato, R. J.; Pagano, J. J.; Roberts, R. N.
Chemosphere 1993, 26, 1213–1223; (h) Hu, C.; Yue, B.;
Yamase, T. Appl. Catal. A 2000, 194–195, 99–107.
12. Sedlak, D. L.; Andren, A. W. Environ. Sci. Technol. 1991, 25,
1419–1427.
13. (a) Connors, T. F.; Rustling, J. F. J. Electrochem. Soc. 1983,
130, 1120–1121; (b) Connors, T. F.; Rustling, J. F.; Owlia, A.
Anal. Chem. 1985, 57, 170–174; (c) Zhang, S.; Rustling, J. F.
Environ. Sci. Technol. 1993, 27, 1375–1380; (d) Huang, Q.;
Rustling, J. F. Environ. Sci. Technol. 1995, 29, 98–103; (e)
Miyoshi, K.; Kamegaya, Y.; Matsumura, M. Chemosphere
2004, 56, 187–193.
6. (a) Lunin, V. V.; Lokteva, E. S. Russ. Chem. Bull. 1996, 45,
1519–1534. See also: (b) Kammerer, H.; Horner, L.; Beck, H.
¨
Chem. Ber. 1958, 91, 1376–1379; (c) Marques, C. A.; Selva,
M.; Tundo, P. J. Org. Chem. 1993, 58, 5256–5260; (d)
Marques, C. A.; Selva, M.; Tundo, P. J. Org. Chem. 1994, 59,
3830–3837; (e) Schach, T.; Papenfuhs, T. Eur. Pat. Appl. EP
14. Weber, R.; Yoshida, S.; Miwa, K. Environ. Sci. Technol. 2002,
36, 1839–1844.
667,328, 1995; Chem. Abstr. 1995, 123, 285486. (f) Schuth,
¨
C.; Reinhard, M. Appl. Catal. B 1998, 18, 215–221; (g) Moon,
D. J.; Moon, J. C.; Park, K. Y.; Hong, S. I. Appl. Catal. A
1998, 168, 159–170; (h) Angel, G. D.; Benitez, J. L. J. Mol.
15. Rousseau et al. reported chemoselective hydrodeiodination us-
ing a Pd/C–Et3N system, but the effect of Et3N on the reaction
was not described in detail. Ambroise, Y.; Mioskowski, C.;
´
Catal. A: Chem. 2001, 165, 9–13; (i) Aramendıa, M. A.;
Burch, R.; Garcıa, I. M.; Marinas, A.; Marinas, J. M.;
´
Djega-Mariadassou, G.; Rousseau, B. J. Org. Chem. 2000,
65, 7183–7186.
´
Southward, B. W. L.; Urbano, F. J. Appl. Catal. B 2001, 31,
163–171; (j) Janiak, T.; Blazejowski, J. Appl. Catal. A 2004,
271, 103–108; (k) Evdokimova, G.; Zinovyev, S.; Perosa, A.;
Tundo, P. Appl. Catal. A 2004, 271, 129–136; (l) Wu, W.;
Xu, J. Catal. Commun. 2004, 5, 591–595; (m) Hashimoto, Y.;
Uemichi, Y.; Ayame, A. Appl. Catal. A 2005, 287, 89–97; (n)
Bovkun, T. T.; Sasson, Y.; Blum, J. J. Mol. Catal. A: Chem.
2005, 242, 68–73; (o) Amorim, C.; Yuan, G.; Patterson, P. M.;
Keane, M. A. J. Catal. 2005, 234, 268–281.
16. Sajiki, H.; Kume, A.; Hattori, K.; Hirota, K. Tetrahedron Lett.
2002, 43, 7247–7250.
17. Hara, T.; Mori, K.; Oshiba, M.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Green Chem. 2004, 6, 507–509.
18. Sajiki, H.; Kume, A.; Hattori, K.; Nagase, H.; Hirota, K.
Tetrahedron Lett. 2002, 43, 7251–7254.
19. Nishimura, S. Handbook of Heterogeneous Catalytic
Hydrogenation for Organic Synthesis; Wiley-Interscience:
New York, NY, 2001.
7. Pandey, P. N.; Purkayastha, M. L. Synthesis 1982, 876–878.
8. (a) Anwer, M. K.; Spatola, A. F. Tetrahedron Lett. 1985, 26,
1381–1384; (b) Rajagopal, S.; Spatola, A. F. J. Org. Chem.
1995, 60, 1347–1355; (c) Kang, R.; Ouyang, X.; Han, J.;
Zhen, X. J. Mol. Catal. A: Chem. 2001, 175, 153–159; (d)
Arcadi, A.; Cerichelli, G.; Chiarini, M.; Vico, R.; Zorzan, D.
Eur. J. Org. Chem. 2004, 3404–3407; (e) Selvam, P.;
Sonavane, S. U.; Mohapatra, S. K.; Jayaram, R. V.
Tetrahedron Lett. 2004, 45, 3071–3075; (f) Nakao, R.; Rhee,
H.; Uozumi, Y. Org. Lett. 2005, 7, 163–165; (g) Logan,
M. E.; Oinen, M. E. Organometallics 2006, 25, 1052–1054.
20. Tabner, B. J.; Yandle, J. R. J. Chem. Soc. A 1968, 381–388.
21. In the absence of Et3N, quinoline may not accept an electron
from Pd(0) but interact with palladium metal to block the
hydrodechlorination of 1.
22. Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981–13996.
23. The residual palladium assay of biphenyl: after two vaccum/H2
cycles to replace air inside a round-bottom flask with H2,
a solution of 4-chlorobiphenyl (1.89 g, 10 mmol), 10% Pd/C
(56.7 mg), and Et3N (1.67 mL, 12 mmol) in MeOH (35 mL)
was vigorously stirred using a stir bar under hydrogen atmo-
sphere (balloon) at ambient temperature (ca. 20 ꢁC) for 24 h.
Simple filtrations of the reaction mixture using Millipore
membrane filters (0.45 mL MillexÒ-LH and then 0.20 mL
MillexÒ-LG) without any rinse with additional MeOH gave
Pd/C-free filtrate. The filtrate was concentrated in vacuo and
the resulting white solid (1.34 g) was assayed. Residual palla-
dium (3.5 ppm) was detected by an ICP-MS (Agilent 7500CE,
Agilent Technologies). The leaching of palladium into the
reaction mixture in the presence of Et3N was reported:
Zhao, F.; Bhanage, B. M.; Shirai, M.; Arai, M. Chem.—Eur. J.
2000, 6, 843–848.
´
9. (a) Rodrıgues, J. G.; Lafuente, A. Tetrahedron Lett. 2002, 43,
9645–9647; (b) Cellier, P. P.; Spindler, J.-F.; Taillefer, M.;
Cristau, H.-J. Tetrahedron Lett. 2003, 44, 7191–7195.
10. (a) Sakai, M.; Lee, M.-S.; Yamaguchi, K.; Kawai, Y.; Sasaki,
K.; Sakakibara, Y. Bull. Chem. Soc. Jpn. 1992, 65, 1739–
1740; (b) Chuang, F.-W.; Larson, R. A.; Wessman, M. S.
Environ. Sci. Technol. 1995, 29, 2460–2463; (c) Grittini, C.;
Malcomson, M.; Fernando, Q.; Korte, N. Environ. Sci.
Technol. 1995, 29, 2898–2900; (d) Wang, C.-B.; Zhang, W.-X.
Environ. Sci. Technol. 1997, 31, 2154–2156; (e) Ukisu, Y.;
Kameoka, S.; Miyadera, T. Appl. Catal. B 1998, 18, 273–279;
(f) Yak, H. K.; Wenclawiak, B. W.; Cheng, I. F.; Doyle, J. G.;
Wai, C. M. Environ. Sci. Technol. 1999, 33, 1307–1310;
(g) Jackman, S. A.; Knowles, C. J.; Robinson, G. K.
Chemosphere 1999, 38, 1889–1900; (h) Ukisu, Y.; Kameoka,
S.; Miyadera, T. Appl. Catal. B 2000, 27, 97–104.
24. Schmolka, S. J.; Zimmer, H. Synthesis 1984, 29–31.
25. Maguire, A. R.; Plunkett, S. J.; Papot, S.; Clynes, M.;
O’Connor, R.; Touhey, S. Bioorg. Med. Chem. 2001, 9,
745–762.
26. Servi, S.; Genc, M.; Gur, S.; Koca, M. Eur. J. Med. Chem. 2005,
40, 687–693.
¨
11. (a) Ohashi, M.; Tsujimoto, K.; Seki, K. J. Chem. Soc., Chem.
Commun. 1973, 384; (b) Bunce, N. J. J. Org. Chem. 1982,
47, 1948–1955; (c) Ohashi, M.; Tsujimoto, K. Chem. Lett.
1983, 423–426; (d) Beecroft, R. A.; Davidson, R. S.;
Goodwin, D. Tetrahedron Lett. 1983, 24, 5673–5676; (e)
Tanaka, Y.; Uryu, T.; Ohashi, M.; Tsujimoto, K. J. Chem.
Soc., Chem. Commun. 1987, 1703–1704; (f) Epling, G. A.;
Wang, Q.; Qiu, Q. Chemosphere 1991, 22, 959–962; (g)
27. Tanaka, N.; Tamai, T.; Mukaiyama, H.; Hirabayashi, A.;
Muranaka, H.; Ishikawa, T.; Akahane, S.; Akahane, M.
Bioorg. Med. Chem. 2001, 9, 3265–3271.
28. Ulvi, V.; Tammilehto, S. Acta Pharm. Nord. 1989, 1, 195–200.
29. Wadia, M. S.; Patil, D. V. Synth. Commun. 2003, 33, 2725–
2736.
30. Siedel, W.; Sturm, K.; Scheurich, W. Chem. Ber. 1966, 99,
345–352.