Efficient and selective Pt/C-catalyzed H-D exchange reaction of aromatic rings

Article abstract of DOI:10.1246/bcsj.81.278

An effective and applicable deuteration method for aromatic rings using Pt/C-D₂O-H₂ system was established. Especially, phenol was fully deuterated even at room temperature, and other electron-rich aromatic nuclei were efficiently deuterated under mild conditions. The scope and limitations of the presence method and its application to the synthesis of deuterium-labeled biologically active compounds and deuterium-labeled building blocks for practical multi-gram scale syntheses are reported. 2008 The Chemical Society of Japan.

Full text of DOI:10.1246/bcsj.81.278

278 Bull. Chem. Soc. Jpn. Vol. 81, No. 2, 278–286 (2008)
ꢀ 2008 The Chemical Society of Japan
Efficient and Selective Pt/C-Catalyzed H–D
Exchange Reaction of Aromatic Rings
Nobuhiro Ito,1 Hiroyoshi Esaki,2 Tsuneaki Maesawa,1 Eikoh Imamiya,1
ꢀ2
Tomohiro Maegawa,2 and Hironao Sajiki
1Chemical Products Research Laboratories, Wako Pure Chemical Industries, Ltd., Matoba, Kawagoe 350-1101
2Laboratories of Medicinal Chemistry, Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-8585
Received August 6, 2007; E-mail: sajiki@gifu-pu.ac.jp
An effective and applicable deuteration method for aromatic rings using Pt/C–D2O–H2 system was established.
Especially, phenol was fully deuterated even at room temperature, and other electron-rich aromatic nuclei were efficient-
ly deuterated under mild conditions. The scope and limitations of the presence method and its application to the synthesis
of deuterium-labeled biologically active compounds and deuterium-labeled building blocks for practical multi-gram
scale syntheses are reported.
Deuterium-labeled compounds are extremely useful in a va-
riety of scientific fields, such as analytical tools of drug metab-
olism, reaction mechanisms and kinetics.1 Since a large num-
ber of biologically active compounds possess aromatic rings,
post-synthetic incorporation of deuterium by hydrogen iso-
H2
Substrate
5% Pt/C
D2O
Vacuum
tope-exchange reactions on the aromatic rings is an important
technique. Especially, H–D exchange reactions using D2O as a
deuterium source are a cost-wise attractive method. A number
of H–D exchange procedures for aromatic compounds in D2O
have been reported, for example, the H–D exchange reaction
catalyzed by acids,2 bases,3 or transition metals (Ir,4 Ru,5 Rh,6
Pd,7 and Pt8) and supercritical9 or microwave-enhanced5a,5b,8g,10
exchange reactions. However, many of these methods have
problems, such as low deuterium efficiency, severe reaction
conditions that functional groups cannot tolerate, requirement
of a large amount of catalyst and/or the use of special appa-
ratuses.
Replace air with H2
React at rt, 80 °C
or 180 °C for 24 h
Fig. 1. Typical reaction procedure in a sealed tube.
strate) in D2O (17 mL) was stirred while heating from room
temperature (ca. 1 atm) to 180 ꢁC (ca. 4.5 atm by expansion
of the filled hydrogen gas and increased vapor pressure of
D2O by means of heating; the inner gas pressure was measured
by a pressure gauge) for 24 h. The deuterated position and
deuterium efficiency of the obtained products were determined
We have recently developed an efficient and chemoselective
exchange of deuterium derived from D2O with hydrogen
atoms on a benzylic carbon using Pd/C as a heterogeneous
catalyst in the presence of a catalytic amount of H2 gas at
room temperature.11 We have also found that heating increases
the catalytic activity of the Pd/C–D2O–H2 system and leads to
H–D exchange even at an inactive carbon.12 During the course
of our studies investigating the carbon-supported transition
metal-dependent catalyst efficiency of deuteration reactions,
we have found that the H–D exchange reaction on an aromatic
ring is efficiently catalyzed by Pt/C.13 Herein, we provide de-
tailed results as well as the scope and limitations of the deute-
rium incorporation into aromatic rings by the Pt/C–D2O–H2
system.
1
by using H NMR spectroscopy with an appropriate internal
2
standard and confirmed by using H NMR and mass spectros-
copy. It is noteworthy that even water (D2O)-insoluble sub-
strates were also deuterated effectively, meaning that the hy-
drophilicity of the substrate does not affect the H–D exchange
reaction.
To explore efficient heterogeneous catalysts for the H–D
exchange reaction on an aromatic ring, diphenylmethane was
chosen as a model substrate, and Table 1 summarizes a com-
parison of the deuterium efficiencies using various heterogene-
ous catalysts. The 10% Pd/C (10 wt %, 1 wt % as Pd metal)-
catalyzed reaction of diphenylmethane at room temperature
in a sealed tube lead to chemoselective and efficient deuterium
incorporation on the benzylic position within 24 h (Entry 1).
On the other hand, the use of 5% Pt/C (20 wt %, 1 wt % as
Pt metal) as a catalyst lead to good deuterium efficiency
Results and Discussion
Typically, the reactions were carried out in a sealed tube,
illustrated in Fig. 1. After two vacuum/H2 cycles to replace
air with H2 gas in the sealed tube, a mixture of the aromatic
compound (500 mg) and 5% Pt/C (100 mg, 20 wt % of the sub-
Published on the web February 12, 2008; doi:10.1246/bcsj.81.278

N. Ito et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
279
Table 1. Comparison of Deuterium Efficiency of Diphenyl-
methane Using Various Catalysts at Room Temperaturea)
as a deuterium source. Pyrocatechol was well deuterated at
room temperature, and fully deuterated pyrocatechol-d4 was
obtained at 80 ꢁC (Entries 5 and 6). In addition, 2-n-propyl-
phenol was regioselectively deuterated at C1, C2, and C3 of
the aromatic ring at room temperature (Entry 7). Similarly,
C1 of 4-n-propylphenol was deuterated quantitatively, but
low deuterium efficiency was observed at C2 not only at room
temperature but also at 80 ꢁC (Entries 9 and 10). The low deu-
terium efficiency of the ortho positions of the alkyl chain is
probably caused by the steric hindrance of the alkyl chain.15,16
The efficiency of the H–D exchange reaction seems to be
greatly enhanced at higher reaction temperatures, and fully
deuterated 2,6-dimethylphenol-d9 and o-aminophenol-d4 were
obtained at 180 ꢁC (Entries 11 and 13). A substrate possessing
an ether substituent gave lower deuterium efficiency at the po-
sitions ortho to the substituents on the aromatic ring, together
with slight deuterium incorporation at the ether methyl group
(Entries 14 and 15).
The H–D exchange reaction of aniline derivatives also oc-
curred smoothly under mild conditions as with the phenol de-
rivatives (Entries 16–26). Especially, fully deuterated aniline-
d5 and o-phenylenediamine-d4 were easily obtained, even at
80 ꢁC (Entries 17 and 19), and fully deuterated 2,6-xylidine-
d9 was afforded at 180 ꢁC (Entry 25). When 4-n-propylaniline
was used as the substrate, regioselective deuteration at C1
was observed at room temperature (Entry 22). In addition,
the NMe2 group of N,N-dimethylaniline was moderately deu-
terated at 180 ꢁC, whereas higher deuterium efficiency on
the aromatic ring was achieved (Entry 26).
D D
Catalyst, H2
D
D
D2O, rt, 24 h
Entry
Catalyst (wt %)
D content/%b)
Yieldc)
/%
Phenyl
Benzyl
1
2
3d)
4e)
5
6
7
8
10% Pd/C (10%)
5% Pt/C (20%)
5% Pt/C (20%)
5% Pt/C (20%)
PtO2 (2%)
5% Rh/C (20%)
5% Ru/C (20%)
Raney-Ni (10%)
0
51
97
20
26
0
98
24
96
14
14
0
88
72
88
100
78
44
70
0
0
0
11
80
a) Diphenylmethane 500 mg (3.0 mmol) was used, and all re-
actions were carried out under ordinary H2 pressure in D2O
(17 mL) in a sealed tube. b) Determined by using 1H NMR.
c) Isolated yield. d) The reaction was carried out at 180 ꢁC.
e) The reaction was carried out at 180 ꢁC without H2 gas
(under N2 atmosphere).
(51%) on the aromatic ring despite lower deuterium efficiency
(24%) on the benzylic position (Entry 2). The deuterium effi-
ciency on the aromatic ring was reduced when Adam’s catalyst
(PtO2) was used (Entry 5). Other heterogeneous catalysts,
such as 5% Rh/C, 5% Ru/C, and Raney-Ni, showed no H–D
exchange activity toward the aromatic ring at room tempera-
ture (Entries 6–8). As expected, heating the reaction mixture
using 5% Pt/C as a catalyst at 180 ꢁC led to high deuterium
efficiencies on the both aromatic ring and benzylic position
(Entry 3). However, the deuterium efficiency was drastically
reduced when the reaction was performed without H2 (under
N2 atmosphere) even at 180 ꢁC, suggesting that H2 gas plays
an important role in the Pt/C-catalyzed H–D exchange reaction
(Entry 4). Consequently, we decided to study the details of the
catalyst activity of Pt/C in the H–D exchange reaction con-
cerning aromatic compounds possessing various substituents.
First, we investigated the deuteration of aromatic com-
pounds possessing an electron-donating group (Table 2). Sur-
prisingly, nearly quantitative deuterium incorporation was
observed in the case of phenol even at room temperature (ca.
20 ꢁC) (Entry 1). Although the acidic protons, such as OH in
the phenols and NH in the anilines, also underwent H–D ex-
change, the incorporated deuterium was depleted by aqueous
workup. No deuterium incorporation was observed in the
absence of hydrogen gas, i.e., under nitrogen atmosphere, or
Pt/C (Entries 2 and 3), indicating both H2 gas and Pt/C are
indispensable for the H–D exchange reaction in the present
system.11,12a,12f Moreover, when the reaction was performed
under D2 atmosphere in H2O, instead of H2 in D2O, there was
a significant decrease in the deuterium efficiency (Entry 4).
This result indicated that, although D2 gas should be generated
via the Pt/C-catalyzed H2–D2 exchange reaction between D2O
and H2 gas during the H–D exchange reaction, as we have re-
ported in the previous report,14 the formation of D2 gas did not
seem to be necessary for the presence H–D displacement. In
addition, D2O is obviously necessary for the present system
Biphenyl and n-butylbenzene were also well deuterated by
this system (Entries 27–29). Especially, Pt/C had excellent
catalytic activity toward biphenyl, and fully deuterated bi-
phenyl-d10 was obtained at 80 ꢁC (Entry 28). However, deute-
rium was hardly incorporated when thiophenol was used as
a substrate (Entry 30), probably because the sulfur atom acted
as a catalytic poison for Pt/C, thus suppressing the H–D
exchange reaction.
Next, we investigated the deuteration of the aromatic com-
pounds possessing an electron-withdrawing group (Table 3).
Although benzoic acid was not efficiently deuterated at C1 at
80 ꢁC, fully deuterated benzoic acid-d5 was obtained at higher
temperature (180 ꢁC) (Entries 1 and 2). The increase in the
number of carboxyl substituents on the aromatic ring prevent-
ed the progress of the H–D exchange reaction (compare
Entries 2, 4, and 5). In addition, 4-t-butylbenzoic acid, possess-
ing a bulky substituent, showed almost no deuterium efficiency
at C2 due to the steric hindrance of the t-butyl group (Entry 6).
It is also worth noting that the carboxylic acid and ester func-
tionalities tolerate the 5% Pt/C-catalyzed H–D exchange reac-
tion conditions even when the reaction mixture was heated up
to 180 ꢁC in the aqueous (D2O) medium (Entries 1–6).17 Nitro-
benzene possessing a strong electron-withdrawing nitro group
was scarcely deuterated even at 180 ꢁC (Entry 7). In the cases
of the H–D exchange of the phenol derivatives possessing
electron-withdrawing functionalities, such as p-nitrophenol
and o-cyanophenol, the deuterium efficiency was much lower
(Entries 8 and 9). In addition, the use of bromobenzene gave
no deuterium efficiency, which was unfortunately accompa-
nied by the partial hydrogenolysis of the bromine atom. These

280 Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
Selective Deuteration of Aromatic Rings
Table 2. Deuteration of Various Aromatic Compounds Possessing an Electron-Donating Groupa)
5% Pt/C (20 wt%), H2
D2O, Temp., 24 h
Substrate
Substrate-d
Yieldc)
/%
Entry
Substrate
D content/%b)
Temp
/ꢁC
C1
C2
C3
C4 C5 C6 C7 C8
1
rt
rt
rt
rt
97
0
98
0
97
0
63d)
100
100
65
C1 C2
2e)
3f)
4g)
HO
C3
0
0
0
5
5
5
C1
HO
C2
5
6
rt
80
81
98
98
98
64
59
HO
C4 C5
C7
C3
C2
7
8
rt
99
98
99
98
99
98
0
8
0
0
8
92
76
C6
C4
80
38 91 23
OH
C1
C2 C3
C5
9
rt
99
97
24
68
20
91
4
0
82
76
C1
10
80
31 11
HO
C3
OH
C2
11
180
98
97
98
49
C1
C1
HO
C2
C3
12
13
80
96
97
75
97
87
97
97
97
62
62
180
H2N
C4
C4 C5
C7
C8
14
15
80
29
49
99
98
99
98
35 93 23 13 16
56 97 58 29 15
42
62
C3
C2
C6
OMe
180
C1
C1 C2
16
17
rt
96
98
45
98
49
98
53
66
H2N
C3
80
C1
H2N
H2N
18
19
rt
21
98
79
98
58
66
C2
80
C4 C5
C7
20
21
rt
93
99
7
8
7
1
0
0
6
86
69
C3
C2
C6
NH2
80
98
98
38 71 16
C1
C2 C3
C5
22
23
rt
98
97
0
3
0
0
63
69
C1
C4
180
87
97
73 34
H2N
C3
C2
24
25
80
97
98
88
99
79
97
59
85
NH2
C1
180
C2 C3
26
180
98
81
98
59
36
NMe2
C4
C1
C2 C3
C3 C4
27
28
rt
86
98
85
98
33
97
73
64
C1
80
C6
C2
C1
29
30
180
160
97
97
97
97 98 86 78
73
58
C5
C7
C1 C2
<10
<10
<10
HS
C3
a) 500 mg (3.2–5.4 mmol) of the substrate was used, and reactions were carried out under ordinary H2 pres-
sure using 5% Pt/C (100 mg, 20 wt % of the substrate) in D2O (17 mL) in a sealed tube. b) D contents were
determined by using 1H NMR and confirmed by using 2H NMR and mass spectrum. c) Isolated yield. d) The
moderate isolated yield (63%) was attributed to the coincident reduction of the benzene ring. e) Without H2
gas. f) Without 5% Pt/C. g) The reaction was performed under D2 atmosphere in H2O instead of H2 in D2O.

N. Ito et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
281
Table 3. Deuteration of Various Aromatic Compounds Pos-
sessing an Electron-Withdrawing Groupa)
Table 4. Reuse of 5% Pt/C in the H–D Exchange Reaction
of 2,6-Xylidinea)
5% Pt/C (20 wt%), H2
NH2
NH2
Substrate
Substrate-d
D3C
Db
CD3
Db
5% Pt/C (20 wt%), H2
D2O, Temp., 24 h
D2O, 180 °C, 24 h
Entry
Substrate
D content/%b)
Temp
/ꢁC
Yield
/%c)
Da
C1 C2 C3 C4
Yieldc)
/%
C1 C2
C1 C2
C1
Run
D content/%b)
Db
1d)
2
80
38 98 98
97 98 98
70
66
HOOC
C3
C3
Da
CD3
180
1st
2nd
3rd
98
97
97
99
97
97
97
97
97
85
75
88
C4
MeOOC
3d)
180
180
64 99 98 19
58
51
HOOC
C2
a) 2,6-Xylidine (500 mg, 4.1 mmol) was used, and the reaction
was carried out under ordinary H2 pressure using 5% Pt/C
(100 mg) in D2O (17 mL) in a sealed tube. b) Determined by
4d)
64 99
HOOC
HOOC
C1
C2
1
COOH
using H NMR. c) Isolated yield.
5d)
180
180
22
92
HOOC
COOH
C3
Phenol
OH
H2
N2 (sparge)
C1
6d)
93
1
7
3
100
24*
9
24*
9
(1)
5% Pt/C (20 wt%)
D2O, rt, 2 h
D2O, rt, 24 h
HOOC
O2N
24*
y. 78%
C1 C2
7
8
180
180
0
2
4
64
77
* Indicate as the average D content.
C3
Phenol
C2
OH
NO2
C1
H2
N2
67
98
98
98
98
(2)
5% Pt/C (20 wt%)
HO
HO
D2O, rt, 2 h
D2O, 160 °C, 24 h
98
C1
y. 82%
C2
C3
9
180
160
80 38 78 10
64
56
Scheme 1. Role of H2 in the H–D exchange reaction.
NC
C4
C1 C2
0
0
0
5% Pt/C (20 wt%), H2
10
0
0
0
COOH
COOH
Br
C3
D2O, 180 °C, 24 h
0
0
5
1
a) 500 mg (2.0–4.2 mmol) of the substrate was used, and reactions
were carried out under ordinary H2 pressure using 5% Pt/C
(100 mg, 20 wt % of the substrate) in D2O (17 mL) in a sealed
tube. b) D contents were determined by using 1H NMR and con-
firmed by using 2H NMR and mass spectrum. c) Isolated yield.
d) In the case of carboxylic acids, D contents were determined
by 1H NMR after the conversion of the carboxylic acids to the
methyl esters on the basis of the integration of the methyl protons.
y. 93%
Scheme 2. H–D exchange reaction of a nonaromatic substrate.
phere for 2 h at room temperature to adsorb H2 onto the Pt
surface. Then, the tube was purged with N2 gas to replace
H2, which probably contained HD and/or D2,14 and phenol
(500 mg, 5.31 mmol) was added into the suspension. The
mixture was stirred at room temperature for 24 h (Scheme 1,
Eq. 1). The H–D exchange reaction proceeded even under
N2 atmosphere, although the deuterium efficiency of the prod-
uct was modest in comparison with the result of Table 2,
Entry 1. The deuterium efficiency greatly improved (98%)
by heating at 160 ꢁC under N2 atmosphere (Eq. 2). These re-
sults indicate that the Pt surface must be activated using H2
gas for the H–D exchange reaction to occur and the activated
Pt/C would lead to excellent deuteration by heating even
under N2 atmosphere. Furthermore, the H–D exchange reac-
tion using a nonaromatic substrate, such as octanoic acid,
afforded almost no deuterium incorporation even at 180 ꢁC
(Scheme 2).
results demonstrate that the Pt/C-catalyzed H–D exchange
reaction is affected by both electronic and steric factors.
Two of the advantages of heterogeneous catalysts is that it
is easy to separate the catalyst from the reaction mixture and
the catalyst can be reused, and so, we investigated them in
our system using 2,6-xylidine as a substrate (Table 4). The
catalyst could be recovered almost quantitatively after simple
filtration, and it could be reused without further purification.
The recovered 5% Pt/C was effective in the 2nd and 3rd runs,
and the isolated yields and deuterium efficiencies were compa-
rable to those of the first run.
Reaction Mechanism. As shown in Table 2, Entry 2, the
H–D exchange reaction does not proceed in the absence of H2
gas. To investigate the role of H2 gas, the reaction was per-
formed under N2 atmosphere after activation of 5% Pt/C by
H2. First, 5% Pt/C (100 mg, 20 wt % of phenol) was suspended
in D2O (17 mL) in a sealed tube and stirred under H2 atmos-
Although it is possible that electrophilic aromatic substitu-
tion occurs in this system, we propose the following reaction
mechanism based upon oxidative addition of the aromatic
carbon–hydrogen bond to Pd, as shown in our previous results
of H–D exchange reaction of alkyl side chains of alkyl-
substituted benzene derivatives using Pd/C as a catalyst

282 Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
Selective Deuteration of Aromatic Rings
OH
OH
92
Pt
DHO
D2O, H2
A
D2O
98
5% Pt/C, H2, D2O
98
160 °C, 24 h
99
100%
1
97 96
D
O
D
H
160 °C, 10 h
neat
59%
H3C
H2 Pt
H2 Pt
O
D
N C O
F
B
OCONHCH3
D
D
OCONHCH3
Ar
H
D
Ar D
5% Pt/C, H2, D2O
//
160 °C, 24 h
hydrolysis
D
O
D
E
C
D
D
D
D
H
H2 Pt
2
D
H2 Pt
Ar
O
D
D
Scheme 4. Synthesis of carbaryl-d7 as a surrogate compound.
R
H
D
O
D
H2 Pt
Ar
5% Pt/C, H2, D2O,160 °C, 24 h
91%
56
CH3
O
CD3
40
Scheme 3. Mechanism for the H–D exchange with the Pt/
C–D2O–H2 system.
ONa
ONa
CH3
CD3
91
O
96
54
D3C
40
4
H3C
94
100%
(Scheme 3).12a,12f First, 5% Pt/C is activated with a small
amount of H2 gas, which probably acts as a type of ligand
for Pt. Namely, the first step involves the activation of Pt0
(A) by the coordination of H2 gas and D2O to form complex
B. Oxidative addition of the Ar–H bond to activated Pt0 spe-
cies B would then take place to form a Pt–ꢀ-aryl complex
(C), followed by the formation of PtII complex D. Intramolec-
ular H–D exchange (D to E) and subsequent reductive elimina-
tion (E to F) would give the corresponding deuterated product
Ar–D. In this reaction, the formation of the Pt–ꢀ-aryl complex
(C) is probably a key step in the oxidative insertion of Pt0 into
the substrate, since a nonaromatic compound, octanoic acid,
was not deuterated (Scheme 2). In addition, the introduction
of electron-donating functionalities on the aromatic ring pro-
moted the H–D exchange activity (Table 2), whereas elec-
tron-withdrawing functionalities caused a reduction in the deu-
terium efficiency, thus supporting our proposed mechanism
(Table 3).
Synthesis of Deuterium-Labeled Compounds. Aromatic
compounds are often seen in biologically active compounds,
such as drugs, pesticides, environmental pollutants, and so
on. Therefore, such deuterated compounds are valuable as a
surrogate compound (internal standard) for clinical pharma-
cokinetic studies and the microanalysis of residual agro-
chemicals and environmental endocrine-disrupting chemicals
in the environment using GC-MS or LC-MS.18 Since surrogate
compounds should possess physical properties nearly equal to
those of the mother samples, multi-deuterated mother samples
can be employed for such purpose. Therefore, we applied the
Pt/C–D2O–H2 system to the synthesis of multi-deuterium-
labeled carbaryl (=1-naphthyl N-methylcarbamate), which is
a known bactericide in domestic animals. Carbaryl-d7 can be
applied as a surrogate compound to the microanalysis of re-
sidual carbaryl in meat. As illustrated in Scheme 4, the direct
H–D exchange of carbaryl was unsuccessful, because carbaryl
was not stable enough under the aqueous deuteration condi-
tions. Carbaryl-d7 was prepared in two steps starting from 1-
naphthol in a good chemical yield (59% two steps total yield)
and with a quantitative deuterium efficiency without signifi-
10% Pd/C
H2, D2O
160 °C, 24 h
10% Pd/C
H2, D2O
99%
160 °C, 24 h
99
96
CD3
CD3
96
CD3
97
92
CD3
ONa
ONa
97
O
97
O
29
97
99
D3C
92
D3C
96
97
97
3
5
Scheme 5. Stepwise synthesis of ibuprofen-d17.
cant over-reduction of the aromatic ring.
We have recently reported that deuterium efficiently incor-
porated into the inactive alkyl side chains of ibuprofen (=(4-
isobutylphenyl)-ꢁ-methylacetic acid), an anti-inflammatory
drug, by using the 10% Pd/C-catalyzed H–D exchange reac-
tion, whereas the deuterium efficiency of the aromatic ring
was only 29% (Scheme 5, 3).12a Consequently, we examined
the stepwise deuteration of ibuprofen as a possible application
of our system. Namely, deuteration using 5% Pt/C as a cata-
lyst lead to high deuterium efficiency (96%) on the aromatic
ring despite moderate deuterium efficiency (40%–56%) on
the alkyl side chain 4. Subsequent deuteration of intermediate
4 with 10% Pd/C gave the entirely deuterated product 5 in
excellent yield.
As described above, various deuterium-labeled aromatic
compounds, which are considered to be deuterium-labeled
building blocks of such biologically active compounds and
are not commercially available, could be obtained using the
Pt/C–D2O–H2 system. For example, 2,6-dimethylphenol-d9
(Table 2, Entry 11), o-aminophenol-d4 (Entry 13), o-phenyl-
enediamine-d4 (Entry 19), 2,6-xylidine (Entry 25), and so on.
Unfortunately, synthetically important sulfur-containing com-
pounds and aryl halides could not be deuterated directly by
our system. Consequently, we derived those derivatives from
easily deuterated synthons, in order to extend our system to
practical scale syntheses. Namely, deuteration of o-phenylene-
diamine (20 g) catalyzed by 5% Pt/C (4 g) under mild reaction
conditions (80 ꢁC under H2 atmosphere) in a 1 L autoclave
gave o-phenylenediamine-d4 (Scheme 6, 6, 13.8 g, 69%), and
subsequent cyclization with carbon disulfide gave 2-sulfanyl-

N. Ito et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
283
Merck PLC plate (silica gel 60 F254).
General Procedure for H–D Exchange Reaction Using Pt/
C–D2O–H2 System. Substrates (500 mg, 2.0–5.4 mmol) and
D
D
D
D
D
D
NH2
NH2
D
D
N
NH2
a
b
SH
5% Pt/C (100 mg, 20 wt % of the substrate) in D2O (17 mL) was
stirred at room temperature, 80 or 180 ꢁC in a sealed tube under
H2 atmosphere for 24 h. After cooling, the reaction mixture was
diluted with diethyl ether (20 mL), and the mixture was filtered
to remove the catalyst. The filtered catalyst was washed with di-
ethyl ether (5 mL ꢂ 2). The combined ether layers were washed
with H2O (20 mL), dried over MgSO4, and concentrated in vacuo.
The obtained product was purified by silica-gel column chroma-
tography, by preparative thin-layer chromatography or recrystalli-
zation. The D content (%) was determined by using 1H NMR with
dioxane, p-anisic acid, benzene, 1,2-dichloroethane, or 3-(trimeth-
ylsilyl)propanesulfonic acid sodium salt as an internal standard
N
H
NH2
6, D content: 98%
7
NH2
I
NH2
D
D
OH
D
D
OH
OH
c
d,e
D
D
D
D
8, D content: 98%
9
Scheme 6. Syntheses of 2-sulfanylbenzimidazole-d4 and
o-iodophenol-d4. Reagents and conditions: (a) 5% Pt/C
(20 wt %), H2, D2O, 80 ꢁC, 24 h, 69%; (b) CS2, KOH,
MeOH–H2O, reflux, 67%; (c) 5% Pt/C (20 wt %), H2,
D2O, 180 ꢁC, 24 h, 71%; (d) NaNO2, HCl, ꢃ2 ꢁC, 1 h;
(e) NaI, H2O, 0–10 ꢁC, 4 h, 62%.
2
and confirmed by using H NMR and mass spectrum.
[2H]-Diphenylmethane (Table 1, Entry 2): Purification by
silica-gel column chromatography (hexane) gave diphenylmeth-
ane-dn as a colorless oil (72% yield). Isotope distribution (EIMS):
3% d0, 5% d1, 8% d2, 13% d3, 17% d4, 19% d5, 16% d6, 10% d7,
5% d8, 2% d9, 1% d10; 1H NMR (acetone-d6, p-anisic acid as
an internal standard) ꢂ 7.26–7.17 (m, 4.90H), 3.96 (s, 1.53H);
2H NMR (acetone) ꢂ 7.29–7.20 (m), 3.94 (br d).
benzimidazole-d4 (7) in 67% yield, which is usable as a deute-
rium-labeled building block for the synthesis of a deuterated
proton pump inhibitor. Similarly, deuteration of o-amino-
phenol, starting from 20 g of o-aminophenol and 14.7 g (71%
yield) afforded o-aminophenol-d4 (8), and iodination via di-
azotization, using 13.5 g of 8, gave o-iodophenol-d4 (9, 16.8 g,
62% yield), which is usable as a deuterium-labeled coupling
synthon.
[2H]-Phenol (Table 2, Entry 1): Purification by preparative
thin-layer chromatography (ethyl acetate/hexane = 1/6) gave
phenol-dn as a colorless solid (63% yield). Isotope distribution
1
(EIMS): 1% d1, 1% d2, 2% d3, 16% d4, 80% d5; H NMR (ace-
tone-d6, p-anisic acid as an internal standard) ꢂ 7.18 (s, 0.05H),
2
6.83–6.81 (m, 0.09H); H NMR (acetone) ꢂ 7.20 (s), 6.85 (m).
[2H]-Pyrocatechol (Table 2, Entry 6): H–D exchange reac-
tion was carried out at 80 ꢁC for 24 h. The reaction mixture was
filtered to remove the heterogeneous catalyst, and the filtrate
was concentrated in vacuo. The residue was purified by a prepar-
ative thin-layer chromatography (ethyl acetate/hexane = 1/2) to
obtain catechol-dn as a colorless solid (59% yield). Isotope distri-
bution (EIMS): 1% d2, 11% d3, 88% d4; 1H NMR (acetone-d6, di-
oxane as an internal standard) ꢂ 6.81 (s, 0.04H), 6.67 (s, 0.04H);
2H NMR (61 MHz, acetone) ꢂ 6.84 (s), 6.70 (s).
Conclusion
In summary, we developed an effective and highly appli-
cable Pt/C-catalyzed deuteration method for aromatic rings
using D2O as a deuterium source under hydrogen atmosphere.
The results made clear the scope and limitations of the aromat-
ic ring-selective H–D exchange reaction. We showed that this
system is efficient and is applicable as a post-synthetic deuter-
ation method to prepare a variety of deuterated aromatic com-
pounds. It could be also applied to the synthesis of biologically
active compounds and deuterium-labeled building blocks for
practical multi-gram scale syntheses.
[2H]-2-n-Propylphenol (Table 2, Entry 8): H–D exchange
reaction was carried out at 80 ꢁC. Purification by silica-gel column
chromatography (ethyl acetate/hexane = 1/10) gave 2-n-propyl-
phenol-dn as a colorless oil (76% yield). Isotope distribution
(EIMS): 1% d1, 1% d2, 2% d3, 11% d4, 39% d5, 28% d6, 11% d7,
4% d8, 2% d9, 1% d10; 1H NMR (acetone-d6, dioxane as an inter-
nal standard) ꢂ 7.07 (s, 0.62H), 6.99 (s, 0.02H), 6.81 (s, 0.02H),
6.74 (s, 0.02H), 2.56 (t, 0.19H), 1.60 (m, 1.54H), 0.93 (t, 2.76H);
2H NMR (acetone) ꢂ 7.09 (br s), 7.01 (br s), 6.83 (br s), 6.77 (br s),
2.54 (br s), 1.56 (br s), 0.86 (br s).
Experimental
General Methods. All of the substances examined in this
study were obtained commercially and were used without further
purification. Pt/C (5%) was purchased from Wako Pure Chemical
Industries or Aldrich Chemical Co., and deuterium oxide (99.9%
isotopic purity) was purchased from Cambridge Isotope Labo-
[2H]-4-n-Propylphenol (Table 2, Entry 10): H–D exchange
reaction was carried out at 80 ꢁC. Purification by preparative thin-
layer chromatography (ethyl acetate/hexane = 1/10) gave 4-n-
propylphenol-dn as a pale yellow oil (76% yield). Isotope distri-
bution (EIMS): 1% d0, 2% d2, 2% d3, 5% d3, 12% d4, 26% d5,
27% d6, 13% d7, 6% d8, 3% d9, 2% d10; 1H NMR (CDCl3, p-anisic
acid as an internal standard) ꢂ 7.03 (s, 0.63H), 6.74 (s, 0.04H), 2.49
ratories. H, H, and 13C NMR spectra were recorded on a JEOL
ANM-AL400 spectrometer (1H NMR: 400 MHz, 2H NMR: 61
MHz, 13C NMR: 100 MHz). Chemical shifts (ꢂ) are given in parts
per million relative to residual solvent or tetramethylsilane as an
internal standard. The D content (%) of the substrates was esti-
mated on the basis of the integration of the 1H NMR spectra using
appropriate internal standards. Since the relative signal intensity
was found to depend on the pulse delay, the pulse delay was
adjusted to 120 s to ensure complete relaxation occurred. Mass
spectra and high-resolution mass spectra were recorded on a JEOL
JMS-SX102A spectrometer. Silica-gel column chromatography
was performed using Wakogelꢁ C-200 (Wako Pure Chemical).
Preparative thin-layer chromatography was performed using
1
2
2
(t, 0.17H), 1.58 (m, 1.38H), 0.92 (t, 2.68H); H NMR (CHCl3) ꢂ
7.08 (br s), 6.81 (br s), 2.50 (br s), 1.57 (br s), 0.88 (br s).
[2H]-2,6-Dimethylphenol (Table 2, Entry 11): Purification
by silica-gel column chromatography (ethyl acetate/hexane =
1/20) gave 2,6-dimethylphenol-dn as a colorless solid (49%
yield). Isotope distribution (EIMS): 1% d5, 3% d6, 16% d7, 17%
1
d8, 57% d9, 5% d10; H NMR (acetone-d6, dioxane as an internal

284 Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
Selective Deuteration of Aromatic Rings
standard) ꢂ 7.14 (s, 1H), 6.91 (s, 0.05H), 6.65 (s, 0.02H), 2.18
(m, 0.15H); H NMR (acetone) ꢂ 6.94 (s), 6.67 (s), 2.16 (s).
layer chromatography (ethyl acetate/hexane = 1/10) gave 4-n-
propylaniline-dn as a brown oil (69% yield). Isotope distribution
(EIMS): 1% d0, 1% d1, 1% d2, 2% d3, 3% d4, 7% d5, 14% d6, 19%
d7, 19% d8, 10% d9, 10% d10, 12% d11; 1H NMR (CDCl3, p-anisic
acid as an internal standard) ꢂ 6.94 (s, 0.27H), 6.64 (s, 0.06H), 5.06
(br, 2H), 2.45 (br, 0.05H), 1.56 (m, 0.54H), 0.89 (m, 1.97H);
2H NMR (CHCl3) ꢂ 7.02 (s), 6.68 (s), 2.45 (s), 1.54 (s), 0.88 (s).
[2H]-2,6-Xylidine (Table 2, Entry 25): H–D exchange reac-
tion was carried out at 180 ꢁC. Purification by preparative thin-
layer chromatography (ethyl acetate/hexane = 1/10) gave 2,6-
xylidine-dn as a pale brown oil (85% yield). Isotope distribution
(EIMS): 1% d3, 1% d4, 1% d5, 6% d6, 22% d7, 20% d8, 49% d9;
1H NMR (CDCl3, p-anisic acid as an internal standard) ꢂ 6.94 (s,
2
[2H]-o-Aminophenol (Table 2, Entry 13): H–D exchange
reaction was carried out at 180 ꢁC. Recrystallization from ethyl
acetate gave o-aminophenol-dn as a brown crystal (62% yield).
Isotope distribution (EIMS): 1% d1, 2% d2, 16% d3, 81% d4;
1H NMR (DMSO-d6, p-anisic acid as an internal standard) ꢂ
2
8.88 (br s, 1H), 6.63–6.53 (m, 0.10H), 6.39 (s, 0.03H); H NMR
(DMSO) ꢂ 6.58 (br s), 6.42 (br s).
2-n-Propylanisole (Substrate of Table 2, Entries 14 and 15):
To a stirred mixture of 2-n-propylphenol (10 g, 73.4 mmol) and
NaH (60% w/w in mineral oil, 3.5 g, 88.1 mmol) in DMF (70
mL) was added methyl iodide (12.5 g, 88.1 mmol) at room temper-
ature. The mixture was stirred at room temperature for 3 h. The
reaction mixture was diluted with H2O (100 mL) and extracted
with diethyl ether (150 mL). The ether layer was washed with
H2O (100 mL) and brine (100 mL), dried over MgSO4, and con-
centrated in vacuo. The residue was applied to a silica-gel column
chromatography (ethyl acetate/hexane = 1/40) to obtain 2-n-pro-
2
0.04H), 6.64 (s, 0.02H), 3.54 (br, 2H), 2.15 (m, 0.16H); H NMR
(CHCl3) ꢂ 7.02 (s), 6.67 (s), 2.19 (s).
[2H]-N,N-Dimethylaniline (Table 2, Entry 26): Purification
by preparative thin-layer chromatography (ethyl acetate/hexane =
1/10) gave N,N-dimethylaniline-dn as a pale brown oil (36%
yield). Isotope distribution (EIMS): 1% d2, 4% d3, 9% d4, 13%
1
1
pylanisole (11.0 g, 100% yield) as a colorless oil. H NMR (ace-
d5, 17% d6, 18% d7, 17% d8, 12% d9, 6% d10, 3% d11; H NMR
(CD2Cl2, dioxane as an internal standard) ꢂ 7.20 (s, 0.39H), 6.72–
tone-d6) ꢂ 7.16–7.10 (m, 2H), 6.91 (d, J ¼ 8:1 Hz, 1H), 6.84 (t,
J ¼ 7:3 Hz, 1H), 3.81 (s, 3H), 2.56 (t, J ¼ 7:6 Hz, 2H), 1.58 (hex,
J ¼ 7:6 Hz, 2H), 0.91 (t, J ¼ 7:6 Hz, 3H); 13C NMR (acetone-d6)
ꢂ 158.1, 131.1, 130.3, 127.5, 120.8, 111.0, 55.5; HRMS: calcd
for C10H14O: 150.1045, found: 105.1046.
2
6.67 (m, 0.06H), 2.92 (m, 2.43H); H NMR (CH2Cl2) ꢂ 7.28 (s),
6.79 (br m), 2.93 (br m).
[2H]-Biphenyl (Table 2, Entry 28): H–D exchange reaction
was carried out at 80 ꢁC. Purification by preparative thin-layer
chromatography (hexane) gave biphenyl-dn as a white solid (64%
yield). Isotope distribution (EIMS): 2% d4, 2% d5, 9% d6, 4% d7,
12% d8, 16% d9, 54% d10; 1H NMR (CDCl3, p-anisic acid as
an internal standard) ꢂ 7.60 (s, 0.14H), 7.44 (s, 0.09H), 7.35 (s,
[2H]-2-n-Propylanisole (Table 2, Entry 15): H–D exchange
reaction was carried out at 180 ꢁC. Purification by preparative
thin-layer chromatography (hexane) gave 2-n-propylanisole-dn as
a colorless oil (62% yield). Isotope distribution (EIMS): 1% d3,
5% d4, 13% d5, 20% d6, 20% d7, 15% d8, 11% d9, 8% d10, 5%
2
0.05H); H NMR (61 MHz, CHCl3): ꢂ 7.67 (s), 7.52 (s), 7.42 (s).
1
d11, 2% d12, 1% d13; H NMR (acetone-d6, dioxane as an internal
[2H]-n-Butylbenzene (Table 2, Entry 29): n-Butylbenzene-
dn was obtained as a colorless oil (73% yield) without purification.
Isotope distribution (EIMS): 1% d5, 1% d6, 1% d7, 1% d8, 3% d9,
standard) ꢂ 7.11 (s, 0.47H), 6.91 (s, 0.51H), 6.84 (s, 0.02H), 3.81
(s, 2.56H), 2.53 (br s, 0.05H), 1.55 (m, 0.84H), 0.90 (t, 2.12H);
2H NMR (acetone) ꢂ 7.18 (br d), 6.95 (br s), 6.88 (br s), 3.82
(br t), 2.52 (br s), 1.53 (br s), 0.85 (br s).
1
6% d10, 9% d11, 14% d12, 26% d13, 37% d14; H NMR (acetone-
d6, dioxane as an internal standard) ꢂ 7.26 (s, 0.05H), 7.19 (s,
0.05H), 7.15 (s, 0.03H), 2.57 (s, 0.05H), 1.54 (s, 0.04H), 1.30 (br,
[2H]-Aniline (Table 2, Entry 17): H–D exchange reaction
was carried out at 80 ꢁC. Purification by preparative thin-layer
chromatography (ethyl acetate/hexane = 1/10) gave aniline-dn
as a pale brown oil (66% yield). Isotope distribution (EIMS):
2
0.28H), 0.90 (m, 0.65H); H NMR (acetone) ꢂ 7.29–7.23 (br m),
2.57 (br s), 1.54 (br s), 1.29 (br s), 0.87 (br s).
[2H]-Thiophenol (Table 2, Entry 30): Thiophenol-dn was
1
1
2% d2, 18% d4, 80% d5; H NMR (acetone-d6, dioxane as an in-
ternal standard) ꢂ 7.03 (s, 0.04H), 6.64 (s, 0.05H), 6.56 (s, 0.02H),
obtained as a colorless oil (58% yield). H NMR (acetone-d6, p-
anisic acid as an internal standard) ꢂ 7.38–7.14 (m, 4.48H), 4.26
2
2
4.51 (br s, 2H); H NMR (CH3OH) ꢂ 7.09 (s), 6.73 (m).
(br s, 1H); H NMR (acetone) ꢂ 7.26 (br s).
[2H]-o-Phenylenediamine (Table 2, Entry 19): H–D ex-
change reaction was carried out at 80 ꢁC. Ethyl acetate was used
instead of diethyl ether. Recrystallization from ethyl acetate/
hexane gave o-phenylenediamine-dn as a pale brown crystal (66%
yield). Isotope distribution (EIMS): 2% d0, 3% d1, 4% d2, 22% d3,
[2H]-Benzoic Acid (Table 3, Entry 2): H–D exchange reac-
tion was carried out at 180 ꢁC. D content (%) was determined after
conversion of the carboxylic acid to the methyl ester. The proce-
dure was as follows: To a stirred crude product (100 mg) in ben-
zene/methanol (4/1) (4 mL) was added 10% TMSCHN2 in hex-
ane (1.0 mL) at room temperature. The mixture was stirred for
30 min at room temperature and concentrated in vacuo. The resi-
due was applied to a preparative thin-layer chromatography (ethyl
acetate/hexane = 1/10) to obtain methyl benzoate-dn as a color-
less oil (66% 2 steps yield). Isotope distribution (EIMS): 4% d3,
11% d4, 85% d5; 1H NMR (acetone-d6) ꢂ 8.02 (s, 0.06H), 7.64
(s, 0.02H), 7.51 (s, 0.04H), 3.89 (s, 3H); 2H NMR (acetone) ꢂ 8.04
(s), 7.66 (s), 7.54 (s).
[2H]-Methyl Benzoate (Table 3, Entry 3): Purification by
preparative thin-layer chromatography (ethyl acetate/hexane =
1/10) gave methyl benzoate-dn as a colorless oil (58% yield). Iso-
tope distribution (EIMS): 2% d2, 18% d3, 39% d4, 35% d5, 6% d6;
1H NMR (acetone-d6, dioxane as an internal standard) ꢂ 8.02 (s,
0.73H), 7.63 (s, 0.01H), 7.51 (s, 0.02H), 3.89 (s, 2.44H); 2H NMR
(acetone) ꢂ 8.04 (br s), 7.66 (br s), 7.54 (br s), 3.88 (br s).
1
69% d4; H NMR (DMSO-d6, dioxane as an internal standard) ꢂ
6.48 (s, 0.05H), 6.36 (s, 0.05H), 4.34 (br s, 4H); 2H NMR (DMSO)
ꢂ 6.52 (br s), 6.40 (br s).
[2H]-2-n-Propylaniline (Table 2, Entry 21): H–D exchange
reaction was carried out at 80 ꢁC. Purification by preparative thin-
layer chromatography (ethyl acetate/hexane = 1/10) gave 2-n-
propylaniline-dn as a pale brown oil (69% yield). Isotope distri-
bution (EIMS): 2% d2, 9% d3, 25% d4, 33% d5, 20% d6, 7% d7,
3% d8, 1% d9; 1H NMR (CDCl3, p-anisic acid as an internal
standard) ꢂ 7.04 (s, 0.64H), 6.74 (s, 0.02H), 6.68 (s, 0.01H),
5.65 (br, 2H), 2.45 (m, 0.58H), 1.65 (m, 1.68H), 1.00 (t, 2.83H);
2H NMR (CHCl3) ꢂ 7.18 (br s), 6.88 (br s), 6.85 (br s), 2.56 (br
s), 1.73 (br s), 1.07 (br s).
[2H]-4-n-Propylaniline (Table 2, Entry 23): H–D exchange
reaction was carried out at 180 ꢁC. Purification by preparative thin-

N. Ito et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
285
[2H]-Phthalic Acid (Table 3, Entry 4): After conversion
to the methyl ester, purification by preparative thin-layer chroma-
tography (ethyl acetate/hexane = 1/8) gave dimethyl phthalate-
dn as a colorless oil (51% 2 steps yield). Isotope distribution
filter (Millipore Millexꢁ-LG). The filtered catalyst was washed
with ether (20 mL ꢂ 2). The combined ether layers were washed
with H2O (50 mL) and brine (30 mL), dried over MgSO4 and con-
centrated in vacuo to give 1-naphthol-d7 (72 mg, 100% yield) as a
light brown powder. Isotope distribution (EIMS): 1% d3, 1% d4,
9% d5, 31% d6, 58% d7; 1H NMR (CD3OD, 3-(trimethylsilyl)pro-
panesulfonic acid sodium salt as an internal standard) ꢂ 8.16 (s,
0.08H), 7.73 (s, 0.03H), 7.40 (s, 0.04H), 7.38 (s, 0.04H), 7.30 (s,
1
(EIMS): 17% d2, 41% d3, 42% d4; H NMR (CDCl3) ꢂ 7.73 (s,
0.72H), 7.54 (s, 0.02H), 3.91 (s, 6H); 2H NMR (CHCl3) ꢂ 7.76
(br s), 7.57 (br s).
[2H]-Pyromellitic Acid (=1,2,4,5-Benzenetetracarboxylic
Acid) (Table 3, Entry 5): After conversion to the methyl ester,
purification by preparative thin-layer chromatography (ethyl ace-
tate/hexane = 1/3) gave tetramethyl pyromellitate-dn as a white
solid (92% 2 steps yield). Isotope distribution (EIMS): 59% d0,
32% d1, 9% d2; 1H NMR (CDCl3) ꢂ 8.07 (s, 1.56H), 3.94 (s, 12H);
2H NMR (CHCl3) ꢂ 8.09 (br s).
2
0.05H), 6.70 (s, 0.20H); H NMR (DMSO) ꢂ 8.16 (br s), 7.73 (br
s), 7.50–7.20 (br m), 6.79 (br s).
[2H7]-Carbaryl (Scheme 4, 2): The mixture of 1 (53 mg,
0.35 mmol) and N-methyl isocyanate (118 mL, 2.0 mmol) was
stirred at 160 ꢁC in a sealed tube under Ar atmosphere for 10 h.
The reaction mixture was diluted with ether (50 mL) and washed
with H2O (50 mL) and brine (30 mL), dried over MgSO4 and con-
centrated in vacuo. The residue was purified by column chroma-
tography on silica gel (ether/hexane = 1/10) to afford carbaryl-
d7 (37 mg, 59% yield) as colorless needles. 1H NMR (CDCl3) ꢂ
7.96 (s, 0.09H), 7.86 (s, 0.03H), 7.72 (s, 0.07H), 7.52–7.45 (m,
0.07H), 7.29 (s, 0.18H), 5.17 (br s, 1H), 2.97 (d, J ¼ 5:3 Hz, 3H);
2H NMR (CHCl3) ꢂ 7.90 (br s), 7.81 (br s), 7.67 (br s), 7.44–7.42
(m), 7.24 (br s); HRMS: calcd for C12H4D7O2N: 208.1229, found:
208.1237.
[2H]-4-t-Butylbenzoic Acid (Table 3, Entry 6): After con-
version to the methyl ester, purification by preparative thin-layer
chromatography (ethyl acetate/hexane = 1/10) gave methyl 4-t-
butylbonzoate-dn as a colorless oil (100% 2 steps yield). Isotope
distribution (EIMS): 4% d0, 5% d1, 58% d2, 19% d3, 7% d4, 5%
1
d5, 2% d6; H NMR (CD2Cl2) ꢂ 7.94 (d, 0.13H), 7.48 (s, 1.99H),
3.87 (s, 3H), 1.34 (s, 8.38H); 2H NMR (CH2Cl2) ꢂ 7.99 (br s), 7.52
(br s), 1.32 (br s).
[2H]-Nitrobenzene (Table 3, Entry 7): Purification by pre-
parative thin-layer chromatography (ethyl acetate/hexane = 1/10)
[2H17]-Ibuprofen (Scheme 5, 5):
Ibuprofen (sodium salt,
1
gave nitrobenzene-dn as a pale yellow oil (64% yield). H NMR
(acetone-d6) ꢂ 8.26 (d, 2H), 7.85 (t, 0.97H), 7.69 (t, 1.96H);
2H NMR (acetone) ꢂ 7.86 (br s), 7.72 (br s).
114 mg, 0.5 mmol) and 5% Pt/C (11 mg, 10 wt % of the substrate)
in D2O (2.0 mL) were stirred at 160 ꢁC in a sealed tube under H2
atmosphere for 24 h. The reaction mixture was filtered using a
membrane filter (Millipore Millexꢁ-LG). The filtered catalyst
was washed with boiling water (50 mL) and concentrated in vacuo
to give the multi-deuterated product, ibuprofen-dn (4) (104.7 mg,
91% yield) as a white powder.
[2H]-p-Nitrophenol (Table 3, Entry 8): Purification by pre-
parative thin-layer chromatography (ethyl acetate/hexane = 1/3)
gave p-nitrophenol-dn as a pale yellow solid (77% yield). Isotope
1
distribution (EIMS): 11% d0, 42% d1, 42% d2, 4% d3; H NMR
(acetone-d6, dioxane as an internal standard) ꢂ 9.76 (br s, 1H),
Ibuprofen-dn (4) (50 mg, ca. 0.2 mmol) and 10% Pd/C (5 mg,
10 wt % of the substrate) in D2O (1.0 mL) were stirred at 160 ꢁC
in a sealed tube under H2 atmosphere for 24 h. The reaction mix-
ture was filtered using a membrane filter (Millipore Millexꢁ-LG).
The filtered catalyst was washed with boiling water (50 mL)
and concentrated in vacuo to give the multi-deuterated product,
ibuprofen-d17 (5) (50 mg, 100% yield) as a white powder. Isotope
distribution (EIMS): 1% d13, 4% d14, 14% d15, 34% d16, 41% d17,
2
8.16 (s, 1.92H), 7.03 (d, 0.66H); H NMR (acetone) ꢂ 8.20 (br s),
7.05 (br s).
[2H]-o-Cyanophenol (Table 3, Entry 9): Purification by pre-
parative thin-layer chromatography (ethyl acetate/hexane = 1/2)
gave o-cyanophenol-dn as a colorless solid (64% yield). Isotope
distribution (EIMS): 3% d0, 23% d1, 46% d2, 25% d3, 3% d4;
1H NMR (acetone-d6, dioxane as an internal standard) ꢂ 9.76 (s,
1H), 7.59 (d, 0.90H), 7.51 (s, 0.62H), 7.08 (d, 0.20H), 7.00 (t,
1
6% d18; H NMR (D2O, p-anisic acid sodium salt as an internal
2
0.22H); H NMR (acetone) ꢂ 7.60 (s), 7.52 (s), 7.10 (s), 7.02 (s).
standard) ꢂ 7.13 (s, 0.07H), 7.07 (s, 0.07H), 3.46 (s, 0.03H), 2.31
(s, 0.06H), 1.64 (s, 0.03H), 1.22 (s, 0.12H), 0.69 (s, 0.24H);
2H NMR (H2O) ꢂ 7.22 (br s), 7.18 (br s), 3.50 (br s), 2.35 (br s),
1.68 (br s), 1.26 (br s), 0.74 (br s).
[2H]-Bromobenzene (Table 3, Entry 10): Bromobenzene-d0
was obtained as a pale brown oil (56% yield) without purification.
1H NMR (acetone-d6, p-anisic acid as an internal standard) ꢂ 7.55
2
(d, 2H), 7.34 (m, 3H); H NMR (acetone) No peak was detected.
[2H4]-o-Phenylenediamine (Scheme 6, 6): o-Phenylenedi-
amine (20 g, 0.185 mol) and 5% Pt/C (4 g, 20 wt % of the sub-
strate) in D2O (680 mL) were stirred at 80 ꢁC in a 1 L autoclave
under H2 atmosphere for 24 h. After cooling, the reaction mixture
was diluted with ethyl acetate (600 mL), and the mixture was
filtered to remove 5% Pt/C. The filtered catalyst was washed with
ethyl acetate (40 mL ꢂ 2), and the separated aqueous layer was
extracted with ethyl acetate (100 mL ꢂ 3). The combined organic
phases were dried over MgSO4 and concentrated in vacuo. The
residue was recrystallized from ethyl acetate–hexane to obtain 6
(13.8 g, 69% yield) as pale brown crystal. 1H NMR (400 MHz,
DMSO-d6, dioxane as an internal standard) ꢂ 6.48 (s, 0.05H), 6.36
5% Pt/C Reuse Procedure (Table 4): 2,6-Xylidine (500 mg,
4.1 mmol) and 5% Pt/C (100 mg, 20 wt % of the substrate) in
D2O (17 mL) were stirred at 180 ꢁC in a sealed tube under H2
atmosphere for 24 h. After cooling, the reaction mixture was dilut-
ed with ether (20 mL), and the mixture was filtered to remove 5%
Pt/C. The filtered catalyst was washed with ether (5 mL ꢂ 2) and
then reused for the 2nd run without further purification. The com-
bined ether layers were washed with H2O (20 mL), dried over
MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/hexane =
1/10) to afford 2,6-xylidine-d9 (423 mg, 85% yield) as a pale
brown oil.
2
(s, 0.05H), 4.34 (br s, 4H); H NMR (DMSO) ꢂ 6.52 (br s), 6.40
[2H7]-1-Naphthol (Scheme 4, 1): 1-Naphthol (72 mg, 0.5
mmol) and 5% Pt/C (7 mg, 10 wt % of the substrate) in D2O
(2.0 mL) were stirred at 160 ꢁC in a sealed tube under H2 atmos-
phere for 24 h. After cooling, the reaction mixture was diluted
with ether (10 mL), and the mixture was filtered using a membrane
(br s).
[2H4]-2-Sulfanylbenzimidazole (Scheme 6, 7): To a stirring
mixture of 6 (3.0 g, 25.8 mmol), KOH (1.64 g, 29.2 mmol), and
H2O (4 mL) in MeOH (22 mL) was added carbon disulfide (2.22 g,
29.2 mmol) at room temperature. The mixture was refluxed for

286 Bull. Chem. Soc. Jpn. Vol. 81, No. 2 (2008)
Selective Deuteration of Aromatic Rings
6 h. After cooling, the reaction mixture was added acetic acid
(12 mL) and cooled to 4 ꢁC. The precipitate was collected by
filtration, washed with cold EtOH, and recrystallized from EtOH
to obtain 7 (2.67 g, 67% yield) as a pale brown crystal. Isotope
distribution (EIMS): 1% d2, 9% d3, 90% d4; 1H NMR (DMSO-d6,
dioxane as an internal standard) ꢂ 12.50 (s, 2H), 7.14 (s, 0.02H),
T. D. Tilley, R. G. Bergman, J. Am. Chem. Soc. 2002, 124, 2092.
e) M. J. Hickey, J. R. Jones, L. P. Kingston, W. J. S. Lockley,
A. N. Mather, B. M. McAuley, D. J. Wilkinson, Tetrahedron Lett.
2003, 44, 3959.
5
a) M. Takahashi, K. Oshima, S. Matsubara, Chem. Lett.
2005, 34, 192. b) K. Ishibashi, M. Takahashi, Y. Yokota, K.
Oshima, S. Matsubara, Chem. Lett. 2005, 34, 664. c) M. H. G.
Prechtl, M. Holscher, Y. Ben-David, N. Theyssen, R. Loschen,
D. Milstein, W. Leitner, Angew. Chem., Int. Ed. 2007, 46, 2269.
2
7.11 (s, 0.02H); H NMR (DMSO) ꢂ 7.12 (br s).
[2H4]-o-Aminophenol (Scheme 6, 8): o-Aminophenol (20 g,
0.183 mol) and 5% Pt/C (4 g, 20 wt % of the substrate) in D2O
(680 mL) were stirred at 180 ꢁC in a 1 L autoclave under H2
atmosphere for 24 h. After cooling, the reaction mixture was dilut-
ed with MeOH (600 mL), and the mixture was filtered to remove
5% Pt/C. The filtered catalyst was washed with MeOH (40 mL ꢂ
2) and the mother liquid was concentrated in vacuo. The residue
was recrystallized form ethyl acetate to obtain 8 (14.7 g, 71%
6
a) M. R. Blake, J. L. Garnett, I. K. Gregor, W. Hannan, K.
Hoa, M. A. Long, J. Chem. Soc., Chem. Commun. 1975, 930. b) D.
Hesk, J. R. Jones, W. J. S. Lockley, J. Labelled Compd. Radio-
pharm. 1990, 28, 1427. c) D. Hesk, J. R. Jones, W. J. S. Lockley,
J. Pharm. Sci. 1991, 80, 887.
7
a) C. Hardacre, S. E. J. McMath, J. D. Holbrey, Chem.
1
yield) as a brown crystal. H NMR (DMSO-d6, benzene as an in-
ternal standard) ꢂ 8.88 (br s, 1H), 6.63 (s, 0.02H), 6.58 (s, 0.02H),
Commun. 2001, 367. b) S. Matsubara, K. Yokota, K. Oshima,
Chem. Lett. 2004, 33, 294. c) V. Derdau, J. Atzrodt, Synlett
2006, 1918.
2
6.53 (s, 0.02H), 6.39 (s, 0.02H); H NMR (DMSO) ꢂ 6.58 (br s),
6.42 (br s).
8
a) W. G. Brown, J. L. Garnett, J. Am. Chem. Soc. 1958, 80,
[2H4]-o-Iodophenol (Scheme 6, 9): To a stirring solution of 8
(13.5 g, 0.122 mol) in acetone (210 mL) was dropped conc. HCl
(31.6 g, 0.304 mol) below 10 ꢁC. A solution of NaNO2 (8.41 g,
0.122 mol) in H2O (22 mL) was added dropwise to the stirred
reaction mixture at 0 ꢁC during 30 min. The mixture was stirred
at ꢃ2 ꢁC for 1 h. To the diazonium solution was then added a
solution of NaI (36.6 g, 0.244 mol) in H2O (40 mL) at ꢃ10 ꢁC over
15 min, and the mixture was stirred at 0–10 ꢁC for 4 h. The mix-
ture was extracted with ethyl acetate (280 mL). The extract was
washed with H2O (100 mL), a solution of NaHSO3 (6 g) in H2O
(100 mL), and H2O (100 mL), dried over MgSO4, and concentrat-
ed in vacuo. The residue was applied to a silica-gel column chro-
matography (acetone/hexane = 1/20) to obtain 9 (16.8 g, 62%
yield) as a pale red solid. Isotope distribution (EIMS): 8% d3,
92% d4; 1H NMR (DMSO-d6, 1,2-dichloroethane as an internal
standard) ꢂ 10.22 (br s, 1H), 7.66 (s, 0.02H), 7.19 (s, 0.02H),
6.89 (s, 0.02H), 6.58 (s, 0.02H); 2H NMR (DMSO) ꢂ 7.68 (br
s), 7.22 (br s), 6.91 (br s), 6.61 (br s).
5272. b) R. R. Fraser, R. N. Renaud, J. Am. Chem. Soc. 1966, 88,
4365. c) J. L. Garnett, R. J. Hodges, J. Am. Chem. Soc. 1967, 89,
4546. d) E. Buncel, O. Clement, J. Chem. Soc., Perkin Trans. 2
1995, 1333. e) M. H. P. Van Genderen, M. Pfaadt, C. Moller, S.
Valiyaveettil, H. W. Spiess, J. Am. Chem. Soc. 1996, 118, 3661.
f) M. Yamamoto, Y. Yokota, K. Oshima, S. Matsubara,
Chem. Commun. 2004, 1714. g) M. Yamamoto, K. Oshima,
S. Matsubara, Org. Lett. 2004, 6, 5015. h) M. Yamamoto, K.
Oshima, S. Matsubara, Heterocycles 2006, 67, 353.
9
a) T. Junk, W. J. Catallo, L. D. Civils, J. Labelled Compd.
Radiopharm. 1997, 39, 625. b) T. Junk, W. J. Catallo, Tetrahedron
Lett. 1996, 37, 3445. c) T. Junk, W. J. Catallo, J. Elguero, Tetra-
hedron Lett. 1997, 38, 6309.
10 a) S. Vaidyanathan, B. W. Surber, Tetrahedron Lett. 2005,
46, 5195. b) U. Hakala, K. Wahala, J. Org. Chem. 2007, 72, 5817.
¨ ¨ ¨
11 H. Sajiki, K. Hattori, F. Aoki, K. Yasunaga, K. Hirota,
Synlett 2002, 1149.
12 a) H. Sajiki, F. Aoki, H. Esaki, T. Maegawa, K. Hirota,
Org. Lett. 2004, 6, 1485. b) T. Maegawa, A. Akashi, H. Esaki,
F. Aoki, H. Sajiki, K. Hirota, Synlett 2005, 845. c) H. Sajiki,
H. Esaki, F. Aoki, T. Maegawa, K. Hirota, Synlett 2005, 1385.
d) H. Esaki, F. Aoki, T. Maegawa, K. Hirota, H. Sajiki, Hetero-
cycles 2005, 66, 361. e) H. Esaki, N. Ito, S. Sakai, T. Maegawa,
Y. Monguchi, H. Sajiki, Tetrahedron 2006, 62, 10954. f) H. Esaki,
F. Aoki, M. Umemura, M. Kato, T. Maegawa, Y. Monguchi, H.
Sajiki, Chem. Eur. J. 2007, 13, 4052.
13 For preliminary communication, see: H. Sajiki, N. Ito,
H. Esaki, T. Maesawa, T. Maegawa, K. Hirota, Tetrahedron Lett.
2005, 46, 6995.
14 H. Sajiki, T. Kurita, H. Esaki, F. Aoki, T. Maegawa, K.
Hirota, Org. Lett. 2004, 6, 3521.
This work was supported in part by a Grant-in-Aid for
Scientific Research (No. 18590009) from the Japan Society
for the Promotion of Science.
References
1
2
T. Junk, W. J. Catallo, Chem. Soc. Rev. 1997, 26, 401.
a) J. L. Garnett, R. J. Hodges, J. Am. Chem. Soc. 1967, 89,
4546. b) J. L. Garnett, R. J. Hodges, Chem. Commun. 1967, 1001.
c) G. P. Bean, C. D. Johnson, A. R. Johnson, A. R. Katritzky, B. J.
Ridgewell, A. M. White, J. Chem. Soc. B 1967, 1219. d) M. A.
Long, J. L. Garnett, R. F. W. Vining, T. Mole, J. Am. Chem.
Soc. 1972, 94, 8632. e) N. H. Werstiuk, T. Kadai, Can. J. Chem.
1974, 52, 2169.
15 N. Ito, T. Watahiki, T. Maesawa, T. Maegawa, H. Sajiki,
Adv. Synth. Catal. 2006, 348, 1025.
3
a) M. Tashiro, K. Nakayama, G. Fukata, J. Chem. Soc.,
16 M. B. Skaddan, C. M. Yung, R. G. Bergman, Org. Lett.
2004, 6, 11.
17 Matsubara et al. reported an interesting decarboxylative
deuteration method using Pd/C as a catalyst in D2O under hydro-
thermal conditions (250 ꢁC, 4 MPa), see: S. Matsubara, Y. Yokota,
K. Oshima, Org. Lett. 2004, 6, 2071.
Perkin Trans. 1 1983, 2315. b) G. Y. Iranzo, J. Elguero, J.
Labelled Compd. Radiopharm. 1990, 28, 967. c) M. Okazaki, N.
Uchino, N. Nozaki, K. Kubo, Bull. Chem. Soc. Jpn. 1995, 68,
1024.
4
a) J. L. Garnett, M. A. Long, A. B. McLaren, K. B.
Peterson, J. Chem. Soc., Chem. Commun. 1973, 749. b) J. R. Heys,
A. Y. L. Shu, S. G. Senderoff, N. M. Phillips, J. Labelled Compd.
Radiopharm. 1993, 33, 431. c) C. A. Lukey, M. A. Long, J. L.
Garnett, Aust. J. Chem. 1995, 48, 79. d) S. R. Klei, J. T. Golden,
18 a) R. G. Lewis, C. R. Fortune, R. D. Willis, D. E. Camann,
J. T. Antley, Environ. Health Perspect. 1999, 107, 721. b) R. A.
Rudel, D. E. Camann, J. D. Spengler, L. R. Korn, J. G. Brody,
Environ. Sci. Technol. 2003, 37, 4543.