H-D exchange reaction taking advantage of the synergistic effect of heterogeneous palladium and platinum mixed catalyst

Article abstract of DOI:10.1055/s-2008-1067017

An effective and applicable deuteration method for alkyl-substituted aromatic compounds using a heterogeneous Pd/C and Pt/C mixed catalyst in deuterium oxide in the presence of a small amount of hydrogen gas was developed. Mixing a heterogeneous palladium

Full text of DOI:10.1055/s-2008-1067017

FEATURE ARTICLE
1467
H–D Exchange Reaction Taking Advantage of the Synergistic Effect
of Heterogeneous Palladium and Platinum Mixed Catalyst
H
–DExchange Re
o
action buhiro Ito,a Tsutomu Watahiki,a Tsuneaki Maesawa,a Tomohiro Maegawa,b Hironao Sajiki*b
a
Chemical Products Research Laboratories, Wako Pure Chemical Industries, Ltd., 1633 Matoba, Kawagoe 350-1101, Japan
Fax +81(49)2337953
b
Laboratories of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
Fax +81(58)2375979; E-mail: sajiki@gifu-pu.ac.jp
Received 12 February 2008
exchange reactions. However, many of these methods in-
volve important problems such as low deuterium efficien-
cy, severe conditions for functional group tolerance, the
requirement of a large amount of catalyst, the use of spe-
Abstract: An effective and applicable deuteration method for
alkyl-substituted aromatic compounds using a heterogeneous Pd/C
and Pt/C mixed catalyst in deuterium oxide in the presence of a
small amount of hydrogen gas was developed. Mixing a heteroge-
neous palladium and platinum catalyst provides an interesting syn- cial apparatus, etc. For these reasons, it is extremely diffi-
ergistic effect in the H–D exchange reaction and leads to full H–D
cult to provide useful deuterium-labeled compounds on a
exchange results even on sterically hindered sites, which indicated
multigram scale for practical purposes. Hence, practical,
only low-deuterium efficiencies when either Pd/C or Pt/C were used
low-cost, and deuterium-efficient H–D exchange reac-
independently as a catalyst. We investigated the synergistic effect
tions have been strongly desired.
using a variety of substrates and proved the broad generality of the
heterogeneous Pd–Pt–D2O–H2 system in the H–D exchange reac-
tion. Furthermore, this system could be applied to a multigram scale
synthesis of useful deuterium-labeled compounds, such as deuteri-
um-labeled bis-aniline derivatives as raw materials for polyimides,
aryl iodides as synthetic building blocks, and biologically active
compounds.
We have recently reported a characteristic H–D exchange
reaction catalyzed by Pd/C or Pt/C using D2O in the pres-
ence of a small amount of H2 gas.15 During our effort to
achieve a quantitative deuterium efficiency, we found an
interesting synergistic effect in the H–D exchange reac-
tion using Pd/C and Pt/C mixed catalyst.16 Herein, we pro-
vide the detailed results and syntheses of practical
deuterium-labeled compounds as an application of the
heterogeneous Pd–Pt–D2O–H2 system.
Key words: H–D exchange, heterogeneous catalysis, mixed catal-
ysis, palladium, platinum
Introduction
Results and Discussion
Deuterium-labeled compounds have recently attracted a
great deal of attention in a variety of scientific fields. For
example, deuterium-labeled pharmaceuticals are recog-
nized as valuable tools in metabolic studies with the de-
velopment of quantitative analysis techniques using mass
spectrometry and they are essential for the development of
new pharmaceuticals. The uses of deuterium-labeled
compounds have been expanded not only to analytical
tools for life sciences1,2 but also to new materials for elec-
trical industries in optical communication systems.3 With
the increase in the importance of deuterium-labeled com-
pounds, the post-synthetic incorporation of deuterium by
the hydrogen isotope exchange reaction is an important
technique.4,5 Especially, H–D exchange reactions using
deuterium oxide (D2O), which is the cheapest deuterium-
labeled compound, as a deuterium source are a cost-wise
attractive method. A number of H–D exchange proce-
dures for aromatic compounds in D2O have been reported,
for example, the H–D exchange reaction catalyzed by ac-
ids,6 bases,7 or transition metals (Ir,8 Ru,9 Rh,10 Pd,11 and
Pt12) and supercritical13 or microwave-enhanced9a–c,12g,14
Typically, the reactions were carried out in a sealed tube,
as illustrated in Figure 1. After two vacuum/H2 cycles to
replace air with H2 gas in the sealed tube, a mixture of a
substrate (500 mg), heterogeneous Pd/C and Pt/C (1 wt%
of the substrate as Pd and Pt metal respectively) in D2O
(17 mL) was stirred at 180 °C [ca. 4.56 bar (4.5 atm) of in-
ner gas pressure measured by a pressure gauge by the bulk
expansion of the filled H2 gas and increased vapor pres-
sure of D2O by means of heating] for 24 hours. The deu-
SYNTHESIS 2008, No. 9, pp 1467–1478
x
x
.
x
x
.2
0
0
8
Advanced online publication: 11.04.2008
DOI: 10.1055/s-2008-1067017; Art ID: F03608SS
Figure 1 Typical reaction procedure in a sealed tube.
© Georg Thieme Verlag Stuttgart · New York

1468
N. Ito et al.
FEATURE ARTICLE
terated position and deuterium efficiency of the obtained soluble substrates were also deuterated effectively, mean-
products were determined by 1H NMR using an appropri- ing that the hydrophilicity of the substrate does not affect
2
ate internal standard and confirmed by H and 13C NMR the H–D exchange reaction.
and mass spectroscopy. It is noteworthy that even D2O in-
Biographical Sketches
Nobuhiro Ito was born in University and received his been working as a research
1971 in Aichi, Japan. He M.Sc. in 1996 under the scientist at Wako Pure
studied pharmaceutical sci- guidance of Prof. Yukio Chemical Industries, Ltd.,
ence at Gifu Pharmaceutical Masaki. Since 1996, he has Japan.
Tsutomu Watahiki was Prof. Takeshi Oriyama. Af- (2003–2004), he has been
born in 1976 in Ibaraki, Ja- ter serving as a Postdoctoral working as a research scien-
pan. He received his Ph.D. Fellow at the National Insti- tist at Wako Pure Chemical
from Ibaraki University in tute of Advanced Industrial Industries, Ltd., Japan.
2003 under the direction of Science and Technology
Tsuneaki Maesawa was ty and received his M.Sc. in as a research scientist at
born in 1967 in Osaka, Ja- 1992 under the guidance of Wako Pure Chemical Indus-
pan. He studied agricultural Prof. Ichiro Tomida. Since tries, Ltd., Japan.
science at Shinshu Universi- 1992, he has been working
Tomohiro Maegawa was He was a JSPS research fel- associate. He was promoted
born in 1976 in Mie, Japan. low during 2002–2003. He to Associate Professor in
He received his B.S. in 1998 joined Gifu Pharmaceutical 2007. His research interests
from Nagoya University University as an Assistant include the development of
and his M.S. in 2000 and Professor. He stayed at Uni- novel synthetic methods us-
Ph.D. in 2003 from Osaka versity of Pennsylvania ing heterogeneous transition
University under the direc- (Prof. A. B. Smith III, metal catalysts.
tion of Prof. Yasuyuki Kita. 2006–2007) as a research
Hironao Sajiki was born in Massachusetts Institute of fessor in 2006. His research
1959 in Nagano, Japan. He Technology (Prof. Satoru interests include develop-
received his Ph.D. from Masamune, 1991–1992) he ment of heterogeneous tran-
Gifu Pharmaceutical Uni- joined to Metasyn, Inc. (cur- sition
metal
catalysts
versity in 1989 under the di- rent Epix Pharmaceuticals), possessing novel function-
rection of Prof. Yoshifumi MA, USA as a group leader. alities, post-synthetic deu-
Maki. After serving as a In 1995, he moved to Gifu teration (tritiation) methods
Postdoctoral Fellow at the Pharmaceutical University and its pharmaceutical ap-
State University of New as an Assistant Professor. plication, and practical syn-
York at Albany (Prof. Frank He became an Associate thetic methodologies.
M. Hauser, 1990–1991) and Professor in 1999 and Pro-
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

FEATURE ARTICLE
H–D Exchange Reaction
1469
Table 1 Comparison of Deuterium Efficiency of 2-Propylphenol Using Various Heterogeneous Catalystsa
OH
OH
D
D
D
C5
C7
D
D
CD3
C1
C2
catalyst, H2
C6
D
D
D2O, 180 °C, 24 h
C4
D
C3
Entry Catalyst (wt%)
Additive (wt%)
Deuterium contentb (%)
Yieldc (%)
C1
99
97
99
98
99
98
99
33
63
97
C2
98
98
99
98
99
98
99
22
10
97
C3
99
97
99
98
99
98
98
62
82
97
C4
48
54
46
17
15
38
73
6
C5
98
97
99
97
98
72
96
35
9
C6
97
98
99
98
98
42
67
16
5
C7
97
97
98
97
97
28
44
9
1
2
10% Pd/C (10%)
10% Pd/C (20%)
10% Pd/C (10%)
5% Pd/C (20%)
5% Pd/C (20%)
5% Pt/C (20%)
5% Pt/C (20%)
5% Rh/C (20%)
5% Ru/C (20%)
none
none
84
80
89
79
86
62
61
89
84
55
3
activated carbon (10%)
4
none
5
activated carbon (10%)
6
none
7
activated carbon (10%)
8
none
none
none
9
6
5
10
10% Pd/C (10%) +
5% Pt/C (20%)
87
97
97
97
11
12
13
14
15
16
17
10% Pd/C (10%) +
5% Pt/C (20%)
activated carbon (10%)
98
99
98
98
98
98
16
98
99
98
98
98
98
0
98
98
98
98
98
98
9
98
97
36
26
87
92
0
99
98
98
97
98
97
0
98
98
98
98
85
82
0
98
98
97
97
65
55
0
77
84
96
81
83
83
96
5% Pd/C (20%) +
5% Pt/C (20%)
none
10% Pd/C (10%) +
5% Rh/C (20%)
none
10% Pd/C (10%) +
5% Ru/C (20%)
none
5% Pt/C (20%) +
5% Rh/C (20%)
none
5% Pt/C (20%) +
5% Ru/C (20%)
none
none
activated carbon (10%)
a Substrate (500 mg, 3.67 mmol) was used, and reactions were carried out under ordinary H2 pressure using the catalyst in D2O (17 mL) in a
sealed tube.
b Deuterium content was determined by 1H NMR.
c Isolated yield.
The deuteration results of 2-propylphenol using several rium efficiency at the C4 position (entry 2). On the other
combinations of heterogeneous catalysts are summarized hand, the use of 5% Pt/C (20 wt%) as a catalyst showed
in Table 1. Although an acidic proton such as the OH in high deuterium efficiency on the aromatic ring, except for
phenol also underwent H–D exchange, the incorporated the C4 position similarly (entry 6). An electron-rich sub-
deuterium was depleted by hydrogen during the aqueous strate such as 2-propylphenol shows relatively high H–D
workup. 2-Propylphenol and 10% Pd/C (10 wt%) in D2O exchange activity on the aromatic ring, even using either
at 180 °C under a small amount of H2 gas in a sealed tube Pd/C or Pt/C as a catalyst. However, low deuterium re-
for 24 hours leads to high deuterium efficiency on the ar- sults were observed at the C4 position, which is the ortho
omatic ring and the alkyl chain, except for the C4 position, position of the propyl group. This is probably caused by a
which was adjacent to the alkyl side chain of the aromatic steric hindrance effect, which was also reported by
ring (entry 1). Increasing the amount of 10% Pd/C (from Bergman4g and Matsubara.12g Meanwhile, when we tried
10 to 20 wt% of the substrate) did not improve the deute- to examine the reaction using 10% Pd/C (10 wt%) and 5%
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

1470
N. Ito et al.
FEATURE ARTICLE
Pt/C (20 wt%) in the same sealed tube, remarkable en- mixed catalyst, a moderate result was obtained (entry 21).
hancement of the H–D exchange activity was observed in Consequently, using a more dispersed catalyst, such as
87% deuterium efficiency even at the sterically hindered 5% Pd/C and 5% Pt/C (using 20 wt% of the substrate, re-
C4 position (entry 10). When 5% Pd/C (20 wt%) and 5% spectively) as a mixed catalyst resulted in higher deuteri-
Pt/C (20 wt%) were used as a catalyst, fully deuterated 2- um efficiency (entry 22). Furthermore, the use of 1% Pd/
propylphenol-d11 was obtained in 84% isolated yield (en- C and 1% Pt/C (using 100 wt% of the substrate, respec-
try 12). Interestingly, the addition of activated carbon (10 tively) gave excellent deuterium efficiency, and fully deu-
wt% of the substrate) to the reaction mixture of entry 10 terated 4-propylbenzoic acid-d11 was obtained (entry 23),
showed enhancement of the deuterium efficiency at the although the reduction of the catalyst amount to 10 and 1
C4 position (98%) similar to the result of entry 12 (entry wt% from 100 wt% gave disappointing results (entries 24
11). Incidentally, the activated carbon indicated very poor and 25). Other mixed catalyst systems, such as Pd/
deuteration activity (entry 17). These results indicated that alumina and Pt/alumina, gave lower deuterium efficiency
a more dispersed catalyst shows high activity in the H–D compared to that of Pd/C and Pt/C (entry 26). Interesting-
exchange reaction. It is noteworthy that the addition of ac- ly, the addition of silica gel (10 wt% of the substrate) to
tivated carbon was effective in the case of the use of Pt/C the reaction mixture of entry 26 led to an enhancement of
as a catalyst (entries 6 vs 7), although a significant effect the deuterium efficiency similar to the result of the addi-
was not observed in the case of Pd/C as a catalyst (entries tion of activated carbon (entry 27).
1 vs 3 and 5). On the other hand, other heterogeneous cat-
We have recently reported that the Pd/C-catalyzed H–D
alysts such as 5% Rh/C or 5% Ru/C showed lower H–D
exchange reaction of heterocyclic compounds including
exchange activity toward either the aromatic ring or the
the deuteration of the C3 position of nicotinic acid is ex-
alkyl chain (entries 8 and 9). Similarly, mixed catalysts of
tremely difficult.17 Therefore, we examined the mixed
Pd/C or Pt/C with Rh/C or Ru/C did not presented a sig-
catalyst system for the deuteration of nicotinic acid. Nic-
nificant synergistic effect in the H–D exchange reaction
otinic acid subjected to the deuteration condition (180 °C)
(entries 13–16).
using 10% Pd/C (10 wt%) or 5% Pt/C (20 wt%) as a cata-
Next, we investigated the deuteration efficiency of vari- lyst showed low deuterium efficiency at the C3 position
ous aromatic compounds using the Pd/C–Pt/C–D2O–H2 (entries 28 and 29). However, the use of the mixed cata-
system (Table 2). When electron-rich substrates were lyst, 10% Pd/C and 5% Pt/C or 1% Pd/C and 1% Pt/C
subjected to the deuteration condition using 10% Pd/C or caused a slight enhancement of the deuterium efficiency
5% Pt/C as a catalyst independently, the deuterium effi- at the C3 position (entries 30 and 31). On the other hand,
ciency at the ortho positions of alkyl substituents was rel- the use of 5% Pd/alumina and 5% Pt/alumina produced a
atively low similar to the previous results as shown in higher result (43%, entry 32) which was dramatically en-
Table 1. Especially, even stepwise deuteration of 5-phe- hanced to 92% deuterium content based on an average of
nylpentanoic acid with 5% Pt/C and subsequently with the whole nicotinic acid by the addition of silica gel (10
10% Pd/C-catalyzed deuteration could not produce a high wt% of the substrate) (entry 33).
deuterium efficiency at the C3 position (Table 2, entry 3).
When ethyl phenylacetate was used as a substrate, using a
As expected, mixing 10% Pd/C and 5% Pt/C led to effi-
mixture of 5% Pd/C and 5% Pt/C showed low deuterium
cient deuterium incorporation at the ortho positions of
efficiency at the aromatic ring and no deuterium incorpo-
ration into the ester moiety with a low isolated yield (entry
34). However, the use of 5% Pd/alumina and 5% Pt/
alumina as a mixed catalyst and the use of silica gel (10
wt%) as an additive gave deuterated ethyl phenylacetate-
d7 in an excellent isolated yield (entry 35). These results
alkyl substituents and highly deuterated compounds such
as 5-phenylpentanoic acid-d13, 4-propylphenol-d11, 4-pro-
pylaniline-d11, and 1,2,4,5-tetramethylbenzene-d14 were
obtained (entries 4, 7, 15, and 18). In the case of the use of
2-propylaniline as the substrate, the synergistic effect was
observed by mixing 10% Pd/C (10 wt%) with 5% Pt/C (20
suggest that the heterogeneous Pd–Pt–D2O–H2 system en-
wt%), but the deuterium efficiency of the C4 position
ables the establishment of a generally available deutera-
(59%) was not satisfactory (entry 10). The addition of ac-
tion method, and it is powerful enough to apply to the
tivated carbon (10 wt% or 20 wt%) enhanced the deuteri-
synthesis of various deuterium-labeled compounds.
um efficiency at the C4 position (83% and 97%,
We have reported the plausible reaction mechanism of the
respectively; see also Table 1) (entries 11 and 12).
H–D exchange based upon the oxidative addition of Pd or
Use of electron-deficient aromatic compounds was less
Pt to the carbon–hydrogen bond of the substrate.15g,i Al-
straightforward in achieving high deuterium efficiency.15f
though it is not exactly clear why the synergistic effect
4-Propylbenzoic acid and nicotinic acid were investigated
arises with the mixed heterogeneous Pd and Pt system,
(Table 2, entries 19–33). Deuterium incorporation into the
some kind of interaction between each metal should oc-
aromatic ring catalyzed by 10% Pd/C was scarcely ob-
cur. Because the EDS analysis of the recovered mixture of
served (entry 19). Even the use of 5% Pt/C possessing
catalysts demonstrated a different dispersion of each met-
strong aromatic ring affinity showed low deuterium effi-
al, an alloy of palladium and platinum may not be formed.
ciency, especially at the C2 position (entry 20). On the
other hand, when 10% Pd/C and 5% Pt/C were used as a
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

FEATURE ARTICLE
H–D Exchange Reaction
1471
Table 2 Deuteration of Various Aromatic Compoundsa
catalyst, H2
substrate
substrate-d
D2O, 180 °C, 24 h
Entry Substrate
Catalyst (wt%)
Deuterium contentb (%)
Yieldc (%)
C1
C2
C3
C4
C5
C6
C7
1
10% Pd/C (10%)
5% Pt/C (20%)
10% Pd/C (10%)
10% Pd/C (10%) + 5% Pt/C (20%)
96
96
97
97
97
14
19
30
97
98
28
97
97
96d
8d
96d
8d
96
10
97
94
88
92
84
84
C3
C4
C6
COOH
2
97
97
97
C2
3e
C5
C7
C5
97d
97d
97d
97d
C1
4
5
6
7
10% Pd/C (10%)
5% Pt/C (20%)
10% Pd/C (10%) + 5% Pt/C (20%)
97
97
97
46
19
93
98
27
98
98
19
98
98
14
97
86
70
89
C2
C3
C1
HO
C4
8
9
10
11f
12g
10% Pd/C (10%)
5% Pt/C (20%)
10% Pd/C (10%) + 5% Pt/C (20%)
10% Pd/C (10%) + 5% Pt/C (20%)
10% Pd/C (10%) + 5% Pt/C (20%)
97
98
99
97
98
96
97
97
97
97
96
97
99
97
98
12
14
59
83
97
97
49
97
97
98
97
32
97
96
97
97
20
94
97
97
58
72
60
78
59
NH2
C5
C7
C1
C2
C6
C4
C3
C2
C3
C5
13
14
15
10% Pd/C (10%)
5% Pt/C (20%)
10% Pd/C (10%) + 5% Pt/C (20%)
98
97
97
16
87
97
99
97
97
99
73
97
98
34
97
79
69
75
C1
C4
H2N
C2
C1
C2
16
17
18
10% Pd/C (10%)
5% Pt/C (20%)
10% Pd/C (10%) + 5% Pt/C (20%)
13
75
94
97
93
97
96
92
92
19
20
21
22
23
24
25
26
10% Pd/C (10%)
5% Pt/C (20%)
3
62
78
94
97
16
0
4
17
58
92
97
4
96
15
90
96
98
57
0
93
12
83
96
94
33
0
92
11
77
95
95
23
0
64
84
88
92
72
87
94
C2
C3
C5
C1
HOOC
C4
10% Pd/C (10%) + 5% Pt/C (20%)
5% Pd/C (20%) + 5% Pt/C (20%)
1% Pd/C (100%) + 1% Pt/C (100%)
1% Pd/C (10%) + 1% Pt/C (10%)
1% Pd/C (1%) + 1% Pt/C (1%)
5% Pd/alumina (20%) +
0
73
81
96
92
90
5% Pt/alumina (20%)
5% Pd/alumina (20%) +
59
49
27h
91
96
98
98
97
5% Pt/alumina (20%)
28
29
30
31
32
10% Pd/C (10%)
5% Pt/C (20%)
10% Pd/C (10%) + 5% Pt/C (20%)
1% Pd/C (100%) + 1% Pt/C (100%) 100
5% Pd/alumina (20%) +
5% Pt/alumina (20%)
5% Pd/alumina (20%) +
5% Pt/alumina (20%)
98
99
99
98
65
98
29
98
10
11
29
3
98
54
99
88
99
96
94
92
76
95
C3
COOH
C4
C2
C1
N
99
43
33h
99
99
72
99
91
15d 15d
98d 98d
15d
98d
98
98
0
0
0
0
34
95
C3
C4
C6
34
5% Pd/C (20%) + 5% Pt/C (20%)
5% Pd/alumina (20%) +
5% Pt/alumina (20%)
O
35h
C2
C1
C5
O
a Substrate (500 mg, 2.81–4.06 mmol) was used and reactions were carried out under ordinary H2 pressure using the catalyst in D2O (17 mL) in
a sealed tube.
b Deuterium content was determined by 1H NMR.
c Isolated yield.
d Indicated as the average deuterium content.
e The product of entry 2 was used as a starting material.
f Activated carbon (10 wt% of the substrate) was added.
g Activated carbon (20 wt% of the substrate) was added.
h Silica gel (Wakogel C-200, 10 wt% of the substrate) was added.
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

1472
N. Ito et al.
FEATURE ARTICLE
um-labeled aryl halides were derived from easily deuter-
ated toluidine derivatives 6–8 by our deuteration system
on a practical scale. As depicted in Scheme 1, deuteration
Application to the Synthesis of Deuterium-Labeled
Compounds
Recently, deuterium-labeled polymers were recognized as of o-toluidine (6, 20 g) using a mixture of 5% Pd/C and
functional materials for wave guides in optical communi- 5% Pt/C and m- (7, 20 g) and p-toluidine (8, 20 g) using a
cation systems, because the replacement of hydrogen in mixture of 10% Pd/C and 5% Pt/C in a 1-L autoclave gave
the polymers with deuterium causes an enhancement of deuterium-labeled toluidine derivatives with excellent
the transparency by reduction of the C–H vibrational ab- deuterium efficiencies (9: 98% D, 13 g, 10: 98% D, 15 g,
sorption in the infrared (IR) wavelength region and its 11: 97% D, 12 g). Subsequently, the deuterated toluidines
overtones in the near IR to visible region.3 Polyimides are were subjected to iodination by diazotization and easily
important materials in the electronics industry due to their gave the corresponding iodotoluene-d7 derivatives (12: 19
superior thermostability and workability, and deuterium- g, 13: 12 g, 14: 18 g) without loss of deuterium efficiency.
labeled polyimides are being recognized as new function-
al materials.18 So we focused attention on the develop-
ment of a practical scale synthesis of deuterium-labeled
bis-aniline derivatives as raw materials for polyimides.
Reactions were performed in an autoclave using a mixture
of 10% Pd/C (10 wt%) and 5% Pt/C (20 wt%) as a catalyst
(Figure 2). As expected, bis(4-aminophenyl)methane (1),
1,2-bis(4-aminophenyl)ethane (2), 3,3¢,5,5¢-tetramethyl-
benzidine (3) and 3,3¢-dimethylbenzidine (4) achieved ex-
cellent deuterium efficiency on a multigram scale even at
sterically hindered positions (2, 2¢, 6, and 6¢ positions of 3
and 2 and 2¢ positions of 4). In particular, 137 g of bis(4-
aminophenyl) ether-d8 (5) was obtained with nearly quan-
titative deuterium efficiency (98% D content). Moderate
to good isolated yields of products 1–5 (43–79%) were at-
tributed to the coincident reduction of benzene rings and
the loss in the recrystallization process.
CD3
CD3
D
D
D
D
a or b
c, d
NH2
NH2
D
I
D
D
D
6: o-NH2
7: m-NH2
8: p-NH2
9: o-NH2, 62% yield, 98% D 12: o-I, 80% yield, 98% D
10: m-NH2, 71% yield, 98% D 13: m-I, 77% yield, 98% D
11: p-NH2, 58% yield, 97% D 14: p-I, 77% yield, 97% D
Scheme 1 Syntheses of iodotoluenes-d7. Reagents and conditions:
(a) (6 → 9) 5% Pd/C (20 wt%), 5% Pt/C (20 wt%), H2, D2O, 180 °C,
24 h; (b) (7 → 10 and 8 → 11) 10% Pd/C (10 wt%), 5% Pt/C (20
wt%), H2, D2O, 180 °C, 24 h; (c) NaNO2, concd HCl, 3 °C, 45 min;
(d) NaI, H2O, –20 to 0 °C, 30 min.
The application of deuterium-labeled compounds for drug
metabolism studies as surrogate internal standards has
rapidly developed.2d,e,j,p,q Because the chemical properties
of surrogate compounds are quite similar to those of the
mother non-deuterated samples, surrogate compounds are
the most valuable tracers for metabolic studies using GC-
MS or LC-MS. Hence, we applied the present system to
the syntheses of deuterium-labeled surrogate compounds
(Scheme 2). Mephentermine (N,2-dimethyl-1-phenylpro-
pan-2-amine) (18, an antihypertensive agent) and ox-
98
NH2
97
99
97
98
98
H2N
98
NH2
98
98
97
98
H2N
98
98
97 97
97
98
98
98
2 (4.6 g, 43% yield)
1 (8.3 g, 79% yield)
98
98
97
97
ethazaine
{2,2¢-[(2-hydroxyethyl)imino]bis[N-(1,1-
98
98
98
98
95
95
dimethylphenethyl)-N-methylacetamide]} (20, a local an-
esthetic) are well-known drugs,19 and their deuterides are
useful as research tools for metabolic studies. First, the di-
rect H–D exchange reactions of 18 and 20 were examined;
however, unsatisfactory results were obtained. So conse-
quently, commercially available phentermine (15, 20 g),
the precursor of 18 and 20, was subjected to deuteration
conditions using a mixture of 5% Pd/C (20 wt%) and 5%
Pt/C (20 wt%) as a catalyst to give highly deuterated
phentermine (15-d, 12.3 g, average 87% D content). After
tert-butoxycarbonyl (Boc) protection of 15-d, the result-
ing 16 was methylated, and subsequent removal of the
Boc group of 17 and treatment with sulfuric acid afforded
deuterium-labeled mephentermine as its hemisulfate (18-
d, 1.2 g) in 39% (4 steps) total yield from 15. Further
transformation to chloroacetamide derivative 19, after re-
moval of the Boc group of 17 and subsequent treatment of
ethanolamine, gave deuterium-labeled oxethazaine (20-d,
6.6 g) in 67% (5 steps) total yield from 15 on a practical
scale without loss of deuterium efficiency. These deuteri-
um-labeled compounds are considered as useful tools for
H2N
NH2
H2N
NH2
97 97
97 97
98
98
3 (5.4 g, 51% yield)
4 (12.3 g, 73% yield)
98
98
O
98
H2N
98
NH2
98 98
98
98
5 (137 g, 66% yield)
Figure 2 Multigram deuteration of bis-aniline derivatives using the
10% Pd/C–5% Pt/C–D2O–H2 system (180 °C, 24 h).
Aryl halides are an important class of compounds fre-
quently used as coupling synthons, hence, deuterium-
labeled aryl halides should be useful building blocks.
However, attempted direct deuteration of aryl halides us-
ing the 5% Pt/C–D2O–H2 system gave poor results due to
concurrent dehalogenation.15i The corresponding deuteri-
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

FEATURE ARTICLE
H–D Exchange Reaction
1473
70%
D
D
D
D
D D
NH2
a
NH2
NHBoc
NBoc
96%
D5
b
c
D5
D5
D3C CD3
85%
D3C CD3
D3C CD3
15
16
17
15-d
d
e
66%
D
D
D
D
70%
D
D
D
D
N
N
96%
D5
N
N
NH
⋅ 1/2 H2SO4
95%
D5
f
Cl
D5
D3C CD3
85%
CD3
D3C
O
O
D5
D3C CD3
D3C CD3
85%
O
OH
20-d
19
18-d
Scheme 2 Syntheses of mephentermine-d and oxethazaine-d. Reagents and conditions: (a) 5% Pd/C (20 wt%), 5% Pt/C (20 wt%), H2, D2O,
180 °C, 24 h; (b) Boc2O, THF, 3 M NaOH, r.t., 30 min; (c) NaH, DMF, r.t., then MeI, r.t., 5 h; (d) 1. concd HCl, Et2O, r.t., 3 h, 2. NaOH, r.t.,
3. concd H2SO4, r.t., 39% (4 steps from 15); (e) 1. concd HCl, Et2O, r.t., 3 h, 2. Et2O, 2 M NaOH, chloroacetyl chloride, r.t., 2 h, 69% (4 steps
from 15); (f) ethanolamine, KI, THF, 3 M NaOH, reflux, 6 h, 97%.
H–D Exchange Reaction of the Heterogeneous Pd/C–Pt/
C–D2O–H2 System; General Procedure
metabolic studies. In addition, deuterated drugs often
have different actions from the protonated forms in
vivo2c,20 and have resistance to metabolic inactivation by
an isotope effect. Thus the possibility of the development
of new functional drugs that have a new action mecha-
nism is also expected.
A substrate (500 mg, 2.81–4.06 mmol), Pd/C or Pd/alumina (1 wt%
as Pd metal) and Pt/C or Pt/alumina (1 wt% as Pt metal), and, if nec-
essary, activated carbon (10 or 20 wt%) or silica gel (10 wt%) as an
additive in D2O (17 mL) was stirred at 180 °C in a sealed tube under
a H2 atmosphere for 24 h. After cooling, the mixture was diluted
with Et2O (20 mL), and the mixture was filtered to remove the het-
erogeneous catalyst. The filtered catalyst was washed with Et2O (2
× 5 mL). The combined ethereal layers were washed with H2O (20
mL), dried (MgSO4), and concentrated in vacuo. The obtained resi-
due was purified by column chromatography (silica gel), by prepar-
ative TLC, or recrystallization. The deuterium content (%) was
determined by 1H NMR using dioxane, p-anisic acid, benzene, or p-
methoxyphenol as an internal standard (as indicated) and were con-
Conclusion
We have found a synergistic effect in the H–D exchange
reaction using the heterogeneous Pd/C–Pt/C–D2O–H2
system, which efficiently incorporates deuterium into a
variety of alkyl-substituted compounds even at sterically firmed by 2H NMR, 13C NMR, and MS.
hindered sites. Moreover, a practical multigram scale deu-
[D]-2-Propylphenol (Table 1, Entry 12)
The H–D exchange reaction was carried out using 5% Pd/C (100
mg, 20 wt% of the substrate) and 5% Pt/C (100 mg, 20 wt% of the
substrate) as the catalyst. The crude product was purified by prepar-
ative TLC (EtOAc–hexane, 1:10) to give 2-propylphenol-dn as a
colorless oil (84%).
teration method based on the present system of valuable
compounds such as optical materials, building blocks,
surrogate compounds, was established.
All the substances examined in this study were obtained commer-
cially and were used without further purification. 10% Pd/C, 5% Pd/
C, 5% Pd/alumina, 5% Pt/alumina, 5% Rh/C, and 5% Ru/C were
purchased from Wako Pure Chemical Industries, Ltd. 5% Pt/C was
purchased from Wako Pure Chemical Industries, Ltd. or Aldrich
Chemical Co. 1% Pd/C and 1% Pt/C were purchased from Aldrich
Chemical Co. D2O (99.9% isotopic purity) was purchased from
Cambridge Isotope Laboratories. 1H, 2H, and 13C NMR spectra were
recorded on a JEOL ANM-AL400 spectrometer (1H NMR, 400
MHz; 2H NMR, 61 MHz; 13C NMR, 100 MHz); residual solvent or
Isotope distribution (EI-MS): 5% d9, 24% d10, 71% d11.
1H NMR (acetone-d6, dioxane): d = 8.03 (s, 1 H), 7.07 (s, 0.03 H),
6.99 (s, 0.02 H), 6.81 (s, 0.02 H), 6.74 (s, 0.02 H), 2.54 (s, 0.04 H),
1.56 (s, 0.04 H), 0.87 (s, 0.08 H).
2H NMR (acetone): d = 7.08–7.01 (br m), 6.83–6.76 (br m), 2.53 (br
s), 1.54 (br s), 0.86 (br s).
13C NMR (CDCl3): d = 153.4, 129.6*, 128.2, 126.3*, 120.0*,
114.7*, 31.1*, 21.9*, 13.1*.
TMS was used as an internal standard. Starred (*) values in the 13
C
NMR are for small peaks. The deuterium content (%) of the sub-
strates was estimated on the basis of integration of the appropriate
internal standards. Because the relative signal intensity was found
to depend on the pulse delay, the pulse delay was set to 120 s for
complete relaxation. EI-MS were recorded on a JEOL JMS-
SX102A spectrometer. APCI mass spectra were recorded on an Ag-
ilent LC/MSD TOF spectrometer. Silica gel column chromatogra-
phy was performed using Wakogel C-200 (Wako Pure Chemical
Industries, Ltd.). Preparative TLC was performed using Merck PLC
plates (silica gel 60 F254).
[D]-5-Phenylpentanoic Acid (Table 2, Entry 4)
The H–D exchange reaction was carried out using 10% Pd/C (50
mg, 10 wt% of the substrate) and 5% Pt/C (100 mg, 20 wt% of the
substrate) as the catalyst. The deuterium content (%) was deter-
mined by 1H NMR after conversion of the carboxylic acid into the
methyl ester on the basis of integration of the methyl protons and
was confirmed by 2H and 13C NMR and MS. The procedure of es-
terification is as follows: To the stirred crude product (100 mg) in
benzene–MeOH (4:1, 4 mL) was added 10% TMSCHN2 in hexane
(1.0 mL) at r.t., the mixture was stirred for 30 min and concentrated
in vacuo. The residue was subjected to preparative TLC (EtOAc–
hexane, 1:10) to obtain methyl 5-phenylpentanoate-dn as a colorless
oil (84% in 2 steps).
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

1474
N. Ito et al.
FEATURE ARTICLE
13C NMR (CDCl3): d = 133.1, 130.3*, 18.1*.
Isotope distribution (EI-MS): 6% d11, 27% d12, 67% d13.
1H NMR (CD2Cl2): d = 7.20 (s, 0.05 H), 7.10 (s, 0.08 H), 3.56 (s, 3
H), 2.52 (s, 0.05 H), 2.22 (s, 0.12 H), 1.52 (s, 0.12 H).
[D]-4-Propylbenzoic Acid (Table 2, Entry 23)
The H–D exchange reaction was carried out using 1% Pd/C (500
mg, 100 wt% of the substrate) and 1% Pt/C (500 mg, 100 wt% of
the substrate) as the catalyst. After conversion into the methyl ester,
the crude product was purified by preparative TLC (EtOAc–hexane,
1:10) to give methyl 4-propylbenzoate-dn as a colorless oil (72% in
2 steps).
2H NMR (CH2Cl2): d = 7.26–7.17 (br m), 2.53 (br s), 2.22 (br s),
1.53 (br s).
13C NMR (CD2Cl2): d = 173.9, 142.3, 128.0*, 125.4*, 51.6, 35.1*,
33.6*, 30.2*, 24.2*.
[D]-4-Propylphenol (Table 2, Entry 7)
Isotope distribution (EI-MS): 1% d8, 5% d9 25% d10, 69% d11.
The H–D exchange reaction was carried out using 10% Pd/C (50
mg, 10 wt% of the substrate) and 5% Pt/C (100 mg, 20 wt% of the
substrate) as the catalyst. The crude product was purified by prepar-
ative TLC (EtOAc–hexane, 1:10) to give 4-propylphenol-dn as a
colorless oil (89%).
1H NMR (CD2Cl2): d = 7.93 (s, 0.06 H), 7.26 (s, 0.06 H), 3.87 (s, 3
H), 2.65 (s, 0.05 H), 1.64 (s, 0.13 H), 0.94 (s, 0.14 H).
2H NMR (CH2Cl2): d = 7.97 (s), 7.31 (s), 2.61 (s), 1.60 (s), 0.90 (s).
13C NMR (CD2Cl2): d = 167.0, 148.3, 129.2*, 128.3*, 127.9, 51.9,
37.5*, 23.6*, 13.1*.
Isotope distribution (EI-MS): 8% d9, 28% d10, 64% d11.
1H NMR (CDCl3, p-anisic acid): d = 7.03 (s, 0.13 H), 6.75 (s, 0.06
H), 2.48 (s, 0.05 H), 1.54 (s, 0.05 H), 0.86 (s, 0.08 H).
[D]-Nicotinic Acid (Table 2, Entry 33)
The H–D exchange reaction was carried out using 5% Pd/alumina
(100 mg, 20 wt% of the substrate) and 5% Pt/alumina (100 mg, 20
wt% of the substrate) as the catalyst and with silica gel (50 mg, 10
wt% of the substrate) as the additive. After the reaction, the mixture
was diluted with MeOH (100 mL), and the mixture was filtered and
washed with MeOH (2 × 10 mL). The filtrate was concentrated in
vacuo. Nicotinic acid-dn was obtained as a pale brown powder
(91%) without purification.
2H NMR (CHCl3): d = 7.26–7.17 (m), 2.53 (s), 2.22 (s), 1.53 (s).
13C NMR (CDCl3): d = 152.9, 134.4, 128.7*, 114.4*, 36.0*, 23.3*,
12.8*.
[D]-2-Propylaniline (Table 2, Entry 12)
The H–D exchange reaction was carried out using 10% Pd/C (50
mg, 10 wt% of the substrate) and 5% Pt/C (100 mg, 20 wt% of the
substrate) as the catalyst and with activated carbon (100 mg, 20 wt%
of the substrate) as the additive. The crude product was purified by
column chromatography (silica gel, EtOAc–hexane, 1:10) to give 2-
propylaniline-dn as a pale brown oil (59%).
Isotope distribution (EI-MS): 2% d5, 39% d6, 59% d7.
1H NMR (DMSO-d6, dioxane): d = 9.06 (s, 0.01 H), 8.77 (s, 0.01
H), 8.25 (s, 0.28 H), 7.53 (s, 0.01 H).
2H NMR (DMSO): d = 9.10 (br s), 8.83 (br s), 8.29 (br s), 7.58 (br
s).
13C NMR (DMSO-d6): d = 166.0, 152.5*, 149.5*, 136.5, 126.3,
123.1*.
Isotope distribution (EI-MS): 1% d8, 5% d9, 26% d10, 68% d11.
1H NMR (CDCl3, benzene): d = 7.03 (m, 0.06 H), 6.73 (s, 0.02 H),
6.67 (s, 0.02 H), 3.58 (br, 2 H), 2.43 (s, 0.04 H), 1.60 (s, 0.06 H),
0.94 (s, 0.08 H).
2H NMR (CHCl3): d = 7.09 (br s), 6.79–6.72 (m), 2.43 (s), 1.60 (s),
[D]-Ethyl Phenylacetate (Table 2, Entry 35)
0.95 (s).
The H–D exchange reaction was carried out using 5% Pd/alumina
(100 mg, 20 wt% of the substrate) and 5% Pt/alumina (100 mg, 20
wt% of the substrate) as the catalyst and with silica gel (50 mg, 10
wt% of the substrate) as the additive. The crude product was puri-
fied by preparative TLC (EtOAc–hexane, 1:2) to give ethyl phenyl-
acetate-dn as a colorless oil (95%).
13C NMR (CDCl3): d = 143.7, 127.7*, 126.3, 125.9*, 117.9*,
114.8*, 32.3*, 20.6*, 13.0*.
[D]-4-Propylaniline (Table 2, Entry 15)
The H–D exchange reaction was carried out using 10% Pd/C (50
mg, 10 wt% of the substrate) and 5% Pt/C (100 mg, 20 wt% of the
substrate) as the catalyst. The crude product was purified by prepar-
ative TLC (EtOAc–hexane, 1:10) to give 4-propylaniline-dn as a
brown oil (75%).
Isotope distribution (EI-MS): 2% d5, 15% d6, 83% d7.
1H NMR (acetone-d6, p-anisic acid): d = 7.30 (m, 0.11 H), 4.09 (q,
J = 7.1 Hz, 2 H), 3.60 (s, 0.03 H), 1.20 (t, J = 7.1 Hz, 3 H).
2H NMR (acetone): d = 7.34–7.29 (m), 3.59 (s).
13C NMR (CDCl3): d = 171.3, 133.7, 128.4*, 127.9*, 126.4*, 60.8,
40.9*, 14.2.
Isotope distribution (EI-MS): 5% d9, 25% d10, 70% d11.
1H NMR (CDCl3, p-anisic acid): d = 6.95 (s, 0.06 H), 6.67 (s, 0.02
H), 4.86 (br, 2 H), 2.44 (s, 0.06 H), 1.53 (s, 0.06 H), 0.86 (s, 0.10 H).
2H NMR (CHCl3): d = 7.02 (s), 6.68 (s), 2.45 (s), 1.54 (s), 0.88 (s).
13C NMR (CDCl3): d = 143.5, 132.3, 128.5*, 114.5*, 36.1*, 23.6*,
12.6*.
[D]-Bis(4-Aminophenyl)methane (1); Typical Procedure
Bis(4-aminophenyl)methane (10 g, 50.4 mmol), 10% Pd/C (1 g, 10
wt% of the substrate), and 5% Pt/C (2 g, 20 wt% of the substrate) in
D2O (340 mL) were stirred at 180 °C in a 500-mL autoclave under
a H2 atmosphere for 24 h. After cooling, the mixture was diluted
with EtOAc (400 mL), and the mixture was filtered and washed
with EtOAc (2 × 20 mL). The combined organic layers were washed
with H2O (200 mL), dried (MgSO4), and concentrated in vacuo. The
residue was subjected to column chromatography (silica gel,
EtOAc–hexane, 1:2 to 1:1) to give bis(4-aminophenyl)methane-dn
(8.3 g, 79%) as a pale brown solid.
[D]-1,2,4,5-Tetramethylbenzene (Table 2, Entry 18)
The H–D exchange reaction was carried out using 10% Pd/C (50
mg, 10 wt% of the substrate) and 5% Pt/C (100 mg, 20 wt% of the
substrate) as the catalyst. The crude product was purified by prepar-
ative TLC (EtOAc–hexane, 1:5) to give 1,2,4,5-tetramethylben-
zene-dn as a white solid (92%).
Isotope distribution (EI-MS): 1% d10, 4% d11, 13% d12, 29% d13,
53% d14.
1H NMR (CDCl3, dioxane): d = 6.90 (s, 0.13 H), 2.16 (s, 0.37 H).
2H NMR (CHCl3): d = 6.97 (s), 2.19 (s).
Isotope distribution (EI-MS): 1% d4, 1% d5, 2% d6, 6% d7, 23% d8,
19% d9, 48% d10.
1H NMR (acetone-d6, benzene): d = 6.87 (s, 0.12 H), 6.56 (s, 0.09
H), 4.34 (br, 4 H), 3.62 (s, 0.04 H).
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

FEATURE ARTICLE
H–D Exchange Reaction
1475
2H NMR (acetone): d = 6.89 (s), 6.58 (s), 3.60 (s).
13C NMR (acetone-d6): d = 146.6, 130.9, 129.3*, 114.6*, 40.9*.
centrated in vacuo. The residue was dissolved in 1 M HCl (1.72 L)
and MeOH (0.78 L) to prepare the hydrochloride of 5, and activated
carbon (7.8 g) was then added. The mixture was stirred at r.t. for 1
h and filtered to remove activated carbon. A soln of 1 M NaOH
(2.34 L) was added to the filtrate to crystallize the desired product.
The resultant slurry was filtered, and the obtained solid was washed
with H2O (1.5 L), then dried in vacuo to afford bis(4-aminophenyl)
ether-dn (137 g, 66%) as a pale brown solid.
[D]-1,2-Bis(4-aminophenyl)ethane (2)
1,2-Bis(4-aminophenyl)ethane (10 g, 47.1 mmol), 10% Pd/C (1 g,
10 wt% of the substrate), and 5% Pt/C (2 g, 20 wt% of the substrate)
in D2O (340 mL) were stirred at 180 °C in a 500-mL autoclave un-
der a H2 atmosphere for 24 h. The mixture was worked up according
to the procedure for 1. The residue was recrystallized (EtOAc–hex-
ane) to give 1,2-bis(4-aminophenyl)ethane-dn (4.6 g, 43%) as a pale
brown solid.
Isotope distribution (EI-MS): 2% d6, 16% d7, 82% d8.
1H NMR (acetone-d6, dioxane): d = 6.88 (s, 0.08 H), 6.62 (s, 0.07
H), 4.34 (br, 4 H).
Isotope distribution (EI-MS): 2% d6, 2% d7, 7% d8, 3% d9, 4% d10,
19% d11, 63% d12.
1H NMR (DMSO-d6, dioxane): d = 6.83 (s, 0.08 H), 6.46 (s, 0.08
H), 4.76 (s, 4 H), 2.55 (s, 0.12 H).
2H NMR (DMSO): d = 6.90 (br s), 6.54 (br s), 2.59 (br s).
13C NMR (DMSO-d6): d = 145.8, 128.4, 127.9*, 113.3*, 36.0*.
2H NMR (acetone): d = 6.71 (br s), 6.65 (br s).
13C NMR (acetone-d6): d = 150.2, 144.2, 119.3*, 115.5*.
H–D Exchange Reaction of Toluidine in a 1-L Autoclave
(Scheme 1); General Procedure
Toluidine (20 g, 187 mmol), 10% Pd/C (2 g, 10 wt% of the sub-
strate), 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 mixture was diluted with EtOAc (300 mL),
and the mixture was filtered and washed with EtOAc (2 × 20 mL).
The combined organic layers were washed with H2O (150 mL),
dried (MgSO4), and concentrated in vacuo. The obtained product
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 1:20 to 1:4).
[D]-3,3¢,5,5¢-Tetramethylbenzidine (3)
3,3¢,5,5¢-Tetramethylbenzidine (10 g, 41.6 mmol), 10% Pd/C (1 g,
10 wt% of the substrate), and 5% Pt/C (2 g, 20 wt% of the substrate)
in D2O (340 mL) were stirred at 180 °C in a 500-mL autoclave un-
der a H2 atmosphere for 24 h. The mixture was worked up according
to the procedure for 1. The residue was subjected to column chro-
matography (silica gel, EtOAc–hexane, 1:4 to 1:1) to give 3,3¢,5,5¢-
tetramethylbenzidine-dn (5.4 g, 51%) as a pale yellow solid.
[D]-o-Toluidine (9)
5% Pd/C (4 g, 20 wt% of the substrate) was used instead of 10% Pd/
C; o-toluidine-dn (13.2 g, 62%) was obtained as a brown oil.
Isotope distribution (EI-MS): 1% d13, 8% d14, 29% d15, 62% d16.
1H NMR (CDCl3, benzene): d = 7.13 (s, 0.08 H), 3.54 (s, 4 H), 2.19
(s, 0.29 H).
2H NMR (CHCl3): d = 7.19 (br s), 2.22 (br s).
13C NMR (CDCl3): d = 141.1, 131.3, 126.0*, 121.6, 17.0*.
Isotope distribution (EI-MS): 1% d2, 1% d3, 6% d4, 33% d5, 19% d6,
40% d7.
1H NMR (CDCl3, benzene): d = 7.04–7.03 (m, 0.04 H), 6.70 (s, 0.03
H), 3.57 (br, 2 H), 2.13 (s, 0.07 H).
2H NMR (CHCl3): d = 7.14 (br s), 6.81–6.77 (br m), 2.19 (br s).
[D]-3,3¢-Dimethylbenzidine (4)
3,3¢-Dimethylbenzidine (16 g, 75.4 mmol), 10% Pd/C (1.6 g, 10
wt% of the substrate), and 5% Pt/C (3.2 g, 20 wt% of the substrate)
in D2O (540 mL) were stirred at 180 °C in a 1-L autoclave under a
H2 atmosphere for 24 h. After cooling, the mixture was diluted with
EtOAc (600 mL) and the mixture was filtered and washed with
EtOAc (2× 30 mL). The combined organic layers were washed with
H2O (300 mL), dried (MgSO4), and concentrated in vacuo. The res-
idue was subjected to column chromatography (silica gel, EtOAc–
hexane, 1:2 to 1:1) to give 3,3¢-dimethylbenzidine-dn (12.3 g, 73%)
as a pale brown solid.
13C NMR (CDCl3): d = 144.3, 129.8*, 126.3*, 121.9, 118.0*,
114.4*, 16.5*.
[D]-m-Toluidine (10)
m-Toluidine-dn (15.2 g, 71%) was obtained as a brown oil.
Isotope distribution (EI-MS): 1% d2, 1% d3, 9% d4, 31% d5, 19% d6,
39% d7.
1H NMR (CDCl3, benzene): d = 7.04 (s, 0.03 H), 6.58 (s, 0.02 H),
6.51–6.49 (m, 0.04 H), 3.48 (br, 2 H), 2.23 (s, 0.04 H).
Isotope distribution (EI-MS): 1% d9, 7% d10, 26% d11, 66% d12.
1H NMR (acetone-d6, dioxane): d = 7.18 (s, 0.09 H), 7.12 (s, 0.05
H), 4.32 (s, 4 H), 2.13 (s, 0.16 H).
2H NMR (acetone): d = 7.17 (br m), 6.70 (br s), 2.12 (br s).
13C NMR (acetone-d6): d = 145.0, 131.2, 128.0*, 124.4*, 122.2,
115.0*, 16.7*.
2H NMR (CHCl3): d = 7.12 (br s), 6.66–6.58 (br m), 2.26 (br s).
13C NMR (CDCl3): d = 146.0, 138.6, 128.5*, 118.9*, 115.5*,
111.7*, 20.6*.
[D]-p-Toluidine (11)
p-Toluidine-dn (12.4 g, 58%) was obtained as a pale brown solid.
Isotope distribution (EI-MS): 1% d2, 1% d3, 8% d4, 43% d5, 14%
d6, 33% d7.
[D]-Bis(4-Aminophenyl) Ether (5)
Bis(4-aminophenyl) ether (200 g, 1.0 mol), 10% Pd/C (20 g, 10
wt% of the substrate), and 5% Pt/C (40 g, 20 wt% of the substrate)
in D2O (6.8 L) were stirred at 180 °C in a 13-L autoclave under a H2
atmosphere for 24 h. After cooling, the mixture was filtered to col-
lect the product and heterogeneous catalysts. To the collected mix-
ture, acetone (8 L) was added to dissolve the product and the
mixture was filtered to remove the heterogeneous catalyst. The col-
lected catalyst was washed with acetone (3 × 500 mL), and the fil-
trate was concentrated in vacuo to a volume of 6.5 L. The resultant
mixture was filtered through a pad of silica gel (500 g), and the sil-
ica gel was washed with acetone (3 × 500 mL). The filtrate was con-
1H NMR (CDCl3, benzene): d = 6.96 (m, 0.06 H), 6.60 (m, 0.05 H),
3.41 (br, 2 H), 2.20 (s, 0.08 H).
2H NMR (CHCl3): d = 7.02 (br m), 6.67 (br m), 2.21 (br s).
13C NMR (CDCl3): d = 143.5, 129.2*, 127.3, 114.7*, 19.6*.
Synthesis of Iodotoluene-dn from Toluidine-dn (Scheme 1); Gen-
eral Procedure
To a stirred soln of toluidine-dn (12.5 g, 0.103 mol) in acetone (210
mL) was added dropwise concd HCl (26.9 g, 0.259 mol) below 10
°C. A soln of NaNO2 (7.32 g, 0.106 mol) in H2O (20 mL) was added
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

1476
N. Ito et al.
FEATURE ARTICLE
dropwise to the stirred mixture at 5 °C over 30 min. The mixture
was stirred at 3 °C for 45 min. To the diazonium soln was then add-
ed dropwise a soln of NaI (30.9 g, 0.206 mol) in H2O (35 mL) at
–30 °C over 20 min. The mixture was stirred at –20 °C for 80 min,
at –20–0 °C for 30 min, and then allowed to come up to 20 °C within
15 min. A soln of NaOAc (4.8 g, 0.06 mol) in H2O (50 mL) was add-
ed to the mixture, which was then concentrated in vacuo. To the res-
idue was added a soln of NaHSO3 (2 g) in H2O (50 mL) and the
mixture was extracted with hexane (200 mL). The extract was
washed with NaHSO3 (0.5 g) in H2O (50 mL), 2% aq NaOH (50
mL), and H2O (2 × 50 mL), dried (MgSO4), and concentrated in vac-
uo. The obtained product was purified by column chromatography
(silica gel, hexane).
TLC (EtOAc–hexane, 1:2) to obtain N-acetylphentermine-dn as a
white solid (48% in 2 steps).
Isotope distribution (TOF-MS): 1% d7, 2% d8, 5% d9, 10% d10, 22%
d11, 33% d12, 27% d13.
1H NMR (CD2Cl2): d = 7.28 (s, 0.08 H), 7.22 (s, 0.04 H), 7.13 (s,
0.09 H), 5.12 (br, 1 H), 3.01 (d, 0.60 H), 1.85 (s, 3 H), 1.29–1.24 (m,
0.89 H).
2H NMR (CH2Cl2): d = 7.32–7.18 (br m), 3.01 (br s), 1.26 (br s).
13C NMR (CD2Cl2): d = 169.6, 138.3*, 130.3*, 127.6*, 125.8*,
44.4*, 27.2*, 24.7.
[D]-N-(tert-Butoxycarbonyl)-2-methyl-1-phenylpropan-2-
amine (16)
[D]-o-Iodotoluene (12)
o-Iodotoluene-dn (18.6 g, 80%) was obtained as a colorless oil.
To a stirred mixture of 15-d (9 g, 60.3 mmol) in THF (36 mL) and
3 M NaOH (21 mL) was added dropwise a soln of Boc2O (13.8 g,
63.3 mmol) in THF (14 mL) at r.t. and the mixture was stirred for
30 min. The mixture was diluted with EtOAc (100 mL) and the lay-
ers were separated. The organic layer was washed with H2O (100
mL) and brine (100 mL) and dried (MgSO4). Concentration of the
soln in vacuo afforded crude 16 (16 g), which was used in the next
step without purification.
1H NMR (CD2Cl2): d = 7.26 (s, 0.06 H), 7.21 (s, 0.03 H), 7.14 (s,
0.07 H), 4.28 (br, 1 H), 2.93 (d, 0.53 H), 1.44 (s, 9 H), 1.23–1.19 (m,
1.09 H).
Isotope distribution (EI-MS): 2% d5, 17% d6, 81% d7.
1H NMR (DMSO-d6, p-methoxyphenol): d = 7.82 (s, 0.03 H), 7.33–
7.30 (m, 0.06 H), 6.93 (s, 0.03 H), 2.33 (s, 0.08 H).
2H NMR (DMSO): d = 7.87 (br s), 7.38 (br m), 7.00 (br s), 2.35 (br
s).
13C NMR (CDCl3): d = 141.0, 138.4*, 129.2*, 127.5*, 126.7*,
100.9, 27.3*.
[D]-m-Iodotoluene (13)
2H NMR (CH2Cl2): d = 7.34–7.22 (br m), 2.97 (br s), 1.23 (br s).
13C NMR (CD2Cl2): d = 154.7, 138.4, 130.4*, 127.6*, 126.0*, 85.5,
52.7, 44.9*, 28.8, 27.1*.
Following the general procedure for the preparation of iodotoluene,
except for the following operation; to the diazonium soln was added
dropwise NaI in H2O at 0 °C over 40 min. The mixture was stirred
at 0 °C for 2 h, at 10 °C for 1 h and then allowed to come up to 15
°C within 15 min. m-Iodotoluene-dn (11.9 g, 77%) was obtained as
a pale yellow oil.
[D]-N-tert-Butoxycarbonyl-N,2-dimethyl-1-phenylpropan-2-
amine (17)
To a stirred mixture of 16 (15 g, 61.2 mmol) and NaH (60% w/w in
mineral oil, 7.2 g, 181 mmol) in DMF (150 mL) was added MeI
(42.7 g, 301 mmol) at r.t. and the mixture was stirred for 5 h. The
mixture was diluted with H2O (200 mL) and extracted with EtOAc
(150 mL). The organic layer was washed with H2O (3 × 100 mL)
and brine (100 mL) and dried (MgSO4). Concentration of the soln
in vacuo afforded the crude 17 (15 g), which was used in the next
step without purification. A small portion of the crude product was
purified by preparative TLC (EtOAc–hexane, 1:20), and 17 was ob-
tained as a colorless oil.
1H NMR (CD2Cl2): d = 7.26 (s, 0.08 H), 7.20 (s, 0.04 H), 7.14 (s,
0.09 H), 3.06 (d, 0.64 H), 1.52 (s, 9 H), 1.36–1.32 (m, 0.89 H).
2H NMR (CH2Cl2): d = 7.31–7.20 (br m), 3.07 (br s), 1.34 (br s).
13C NMR (CD2Cl2): d = 155.9, 139.0, 130.1*, 127.5*, 125.6*, 79.3,
44.6*, 32.5, 28.9, 27.7*.
Isotope distribution (EI-MS): 2% d5, 18% d6, 80% d7.
1H NMR (CDCl3, dioxane): d = 7.55 (s, 0.03 H), 7.49 (s, 0.03 H),
7.13 (s, 0.03 H), 6.98 (s, 0.02 H), 2.27 (s, 0.06 H).
2H NMR (CHCl3): d = 7.61 (br s), 7.56 (br s), 7.19 (br s), 7.05 (br
s), 2.29 (br s).
13C NMR (CDCl3): d = 139.8, 137.6*, 133.9*, 129.3*, 127.8*, 94.0,
20.2*.
[D]-p-Iodotoluene (14)
p-Iodotoluene-dn (18.2 g, 77%) was obtained as a colorless oil.
Isotope distribution (EI-MS): 2% d5, 16% d6, 82% d7.
1H NMR (DMSO-d6, p-methoxyphenol): d = 7.59 (s, 0.05 H), 7.01
(s, 0.06 H), 2.21 (s, 0.08 H).
2H NMR (DMSO): d = 7.65 (br s), 7.07 (br s), 2.24 (br s).
13C NMR (CDCl3): d = 137.0, 136.6*, 130.6*, 89.8, 20.3*.
[D]-Mephentermine Hemisulfate (18-d)
To a soln of 17 (3 g, 11.4 mmol) in Et2O (30 mL) was added drop-
wise concd HCl (5.7 g, 68.4 mmol) at r.t. and the mixture was stirred
for 3 h. The aqueous layer was then separated and Et2O (30 mL) was
added and followed by aq NaOH until the pH reached 11. After sep-
aration of the organic layer, concd H2SO4 (ca. 250 mg) was added
dropwise to the organic layer. The resultant slurry was filtered and
the solid was washed with Et2O (10 mL). Drying in vacuo afforded
18-d (1.2 g, 39% from 15).
[D]-Phentermine (15-d)
Phentermine (15, 20 g, 134 mmol), 5% Pd/C (4 g, 20 wt% of the
substrate), 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 a H2 atmo-
sphere for 24 h. After cooling, the mixture was diluted with EtOAc
(680 mL) and filtered to remove the heterogeneous catalyst. The fil-
tered catalyst was washed with EtOAc (2 × 20 mL). The combined
organic layers were washed with brine (200 mL), dried (MgSO4),
and concentrated in vacuo. Phentermine-dn was obtained and used
for the next step without further purification. The deuterium content
(%) was determined after conversion of the N-acetyl derivative. The
procedure is as follows: To a stirred crude product (160 mg) in Et2O
(7.5 mL) and 4 M NaOH (6 mL) was added Ac2O (20 drops) at r.t.
and the mixture was stirred for 30 min. The layers were then sepa-
rated and the organic layer was washed with H2O (6 mL) and then
concentrated in vacuo. The residue was subjected to preparative
Isotope distribution (TOF-MS): 1% d6, 1% d7, 2% d8, 5% d9, 12%
d10, 23% d11, 31% d12, 25% d13.
1H NMR (D2O): d = 7.33 (s, 0.09 H), 7.29 (s, 0.04 H), 7.22 (s, 0.10
H), 2.87 (d, 0.62 H), 2.58 (s, 3 H), 1.22–1.18 (m, 0.88 H).
2H NMR (H2O): d = 7.32–7.22 (br m), 2.81 (br s), 1.13 (br s).
13C NMR (D2O): d = 135.0, 131.2*, 128.9*, 127.8*, 59.9, 44.3*,
27.3, 22.1*.
Synthesis 2008, No. 9, 1467–1478 © Thieme Stuttgart · New York

FEATURE ARTICLE
H–D Exchange Reaction
1477
[D]-N-(Chloroacetyl)-N,2-dimethyl-1-phenylpropan-2-amine
(19)
Oka, H. J. Chromatogr., B 1999, 732, 55. (m) Oba, Y.;
Kato, S.; Ojika, M.; Inouye, S. Tetrahedron Lett. 2002, 43,
2389. (n) Pavlik, J. W.; Laohhasurayotin, S. Tetrahedron
Lett. 2003, 44, 8109. (o) Babu, B. S.; Balasubramanian, K.
K. Carbohydr. Res. 2005, 340, 753. (p) Liu, H.-X.; Yao, Z.-
J. Tetrahedron Lett. 2005, 46, 3525. (q) Morrison, J. J.;
Botting, N. P. Tetrahedron Lett. 2007, 48, 1891.
To a soln of 17 (11.8 g, 44.9 mmol) in Et2O (118 mL) was added
dropwise concd HCl (27 g, 269 mmol) at r.t. and the mixture was
stirred for 3 h. To the resultant mixture was then added aq NaOH
until the pH reached 11. To the separated organic layer was added
2 M NaOH (71 mL, 141 mmol). Chloroacetyl chloride (7.7 g, 68.2
mmol) was added dropwise to the resultant mixture, and the mixture
was stirred at r.t. for 2 h. The separated organic layer was washed
with H2O (2 × 20 mL), brine (2 × 20 mL), and dried (MgSO4). Con-
centration of the soln in vacuo afforded the crude 19 (7.6 g, 69%
from 15), which was used in the next step without purification.
(3) (a) Koshino, A.; Tagawa, T. J. Appl. Polym. Chem. Sci.
1965, 9, 117. (b) Miller, M. S.; Klotz, I. M. J. Am. Chem.
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B.; Maier, W. F. J. Am. Chem. Soc. 1986, 108, 1601.
(b) Heys, R. J. Chem. Soc., Chem. Commun. 1992, 680.
(c) Hesk, D.; Das, P. R.; Evans, B. J. Labelled Compd.
Radiopharm. 1995, 36, 497. (d) Chen, W.; Garnes, K. T.;
Levinson, S. H.; Saunders, D.; Senderoff, S. G.; Shu, A. Y.
L.; Villani, A. J.; Heys, J. R. J. Labelled Compd.
Isotope distribution (TOF-MS): 2% d6, 2% d7, 4% d8, 9% d9, 12%
d10, 19% d11, 29% d12, 23% d13.
1H NMR (CD2Cl2): d = 7.26 (s, 0.07 H), 7.21 (s, 0.03 H), 7.14 (s,
0.07 H), 4.06 (s, 2 H), 3.15 (d, 0.57 H), 2.56 (s, 3 H), 1.42–1.37 (m,
0.85 H).
2H NMR (CH2Cl2): d = 7.31–7.18 (br m), 3.16 (br s), 1.39 (br s).
Radiopharm. 1997, 39, 291. (e) Shu, A. Y. L.; Saunders, D.;
Levinson, S. H.; Landvatter, S. W.; Mahoney, A.; Senderoff,
S. G.; Mack, J. F.; Heys, J. R. J. Labelled Compd.
Radiopharm. 1999, 42, 797. (f) Hickey, M. J.; Jones, J. R.;
Kingston, L. P.; Lockley, W. J. S.; Mather, A. N.; McAuley,
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13C NMR (CD2Cl2): d = 166.8, 138.3, 130.4*, 127.6*, 125.9*, 60.4,
45.1, 43.2*, 33.7, 30.0*.
[D]-Oxethazaine (20-d)
A mixture of ethanolamine (0.85 g, 13.85 mmol), KI (0.46 g, 2.8
mmol), THF (52 mL), and 3 M NaOH (21.2 mL, 63.7 mmol) was
heated to 60 °C; then a soln of crude 19 (7.0 g, 27.7 mmol) in THF
(35 mL) was added dropwise to the mixture at the same tempera-
ture. The resultant mixture was refluxed for 6 h. After cooling, the
mixture was diluted with EtOAc (90 mL). The separated organic
layer was washed with H2O (2 × 35 mL) and brine (35 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, CH2Cl2–MeOH, 20:1) to afford
20-d (6.6 g, 97%) as a pale yellow solid.
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C. P.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 1999,
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Ridgewell, B. J.; White, A. M. J. Chem. Soc. B 1967, 1219.
(d) Long, M. A.; Garnett, J. L.; Vining, R. F. W.; Mole, T. J.
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Isotope distribution (TOF-MS): 2% d17, 2% d18, 4% d19, 7% d20,
11% d21, 14% d22, 17% d23, 17% d24, 16% d25, 10% d26.
1H NMR (CD2Cl2): d = 7.24 (s, 0.18 H), 7.20 (s, 0.08 H), 7.12 (s,
0.20 H), 5.12 (br 1 H), 3.54 (m, 6 H), 3.16 (d, 0.1.36 H), 2.92 (t, 2
H), 2.49 (s, 6 H), 1.41–1.36 (m, 1.84 H).
2H NMR (CH2Cl2): d = 7.30 (br m), 3.19 (br s), 1.40 (br s).
13C NMR (CD2Cl2): d = 172.2, 138.8, 130.1*, 127.6*, 125.8*, 60.3,
59.9, 59.2, 58.4, 43.5*, 32.2, 27.0*.
(8) (a) Garnett, J. L.; Long, M. A.; McLaren, A. B.; Peterson, K.
B. J. Chem. Soc., Chem. Commun. 1973, 749. (b) Heys, J.
R.; Shu, A. Y. L.; Senderoff, S. G.; Phillips, N. M. J.
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(d) Klei, S. R.; Golden, J. T.; Tilley, T. D.; Bergman, R. G.
J. Am. Chem. Soc. 2002, 124, 2092.
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(c) Ishibahsi, K.; Matsubara, S. Chem. Lett. 2007, 36, 724.
(d) Prechtl, M. H. G.; Holscher, M.; Ben-David, Y.;
Theyssen, N.; Loschen, R.; Milstein, D.; Leitner, W. Angew.
Chem. Int. Ed. 2007, 46, 2269.
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Hoa, K.; Long, M. A. J. Chem. Soc., Chem. Commun. 1975,
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