Aromatic ring favorable and efficient H-D exchange reaction catalyzed by Pt/C

Article abstract of DOI:10.1016/j.tetlet.2005.08.067

An effective and applicable Pt/C-catalyzed deuteration method of aromatic rings using D₂O as a deuterium source under hydrogen atmosphere was developed. Five percent Pt/C would lead to quite effective H-D exchange results on the aromatic ring systems. The reaction is general for a variety of aromatic compounds including biologically active compounds.

Full text of DOI:10.1016/j.tetlet.2005.08.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6995–6998
Aromatic ring favorable and efficient H–D exchange
reaction catalyzed by Pt/C
a,
b
a
b
*
Hironao Sajiki, Nobuhiro Ito, Hiroyoshi Esaki, Tsuneaki Maesawa,
a
a
Tomohiro Maegawa and Kosaku Hirota
a
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
Chemical Products Research Laboratories, Wako Pure Chemical Industries, Ltd., 1633 Matoba, Kawagoe 350-1101, Japan
b
Received 25 July 2005; revised 8 August 2005; accepted 11 August 2005
Abstract—An effective and applicable Pt/C-catalyzed deuteration method of aromatic rings using D O as a deuterium source under
2
hydrogen atmosphere was developed. Five percent Pt/C would lead to quite effective H–D exchange results on the aromatic ring
systems. The reaction is general for a variety of aromatic compounds including biologically active compounds.
Ó 2005 Elsevier Ltd. All rights reserved.
Biologically active compounds, such as drugs, pesti-
cides, and environmental pollutants, labeled with deute-
riums are widely used as research tools in life sciences.
We also recently reported that 10% Pd/C efficiently
catalyzed low (room)-temperature and chemoselective
H–D exchange at the benzylic position and high
1
12
Since a large number of drugs possess aromatic rings
within the molecule, the substitution of deuterium for
hydrogen by the hydrogen isotope exchange reaction
of aromatic compounds in the presence of a catalyst is
an attractive method for introducing deuteriums post-
synthetically into the aromatic ring. Conventional
deuterium-labeling procedures of aromatic compounds
(110–160 °C)-temperature and multi-deuterium incorpo-
ration into many different types of unactivated alkyl
1
3
chains using D O in the presence of a small amount
2
of H gas. In search of a heterogeneous catalyst that
2
could promote especially effective deuterium exchange
between aromatic ring systems and D O, we decided
2
to study the aqueous H–D exchange behavior of Pt on
carbon (Pt/C) known as highly compatible with an aro-
2
3
include H–D exchange catalyzed by acids, bases or
4
5
6
7
8
9
14
transition metals (Ir, Rh, Re, Pt, Pd, and Cr ) and
matic ring under hydrogenation conditions. We report
1
0
supercritical exchange reactions, while many such
methods include contraindication with specific function-
alities, low deuterium efficiency and/or requirement of a
vast amount of catalyst or extremely expensive deute-
rium atmosphere. Recently, Matsubara et al. developed
a notable deuterium exchange method in hydrothermal
D O (ca. 250 °C/4 MPa) using Pd/C or PtO as a cata-
here that 5% Pt/C would lead to quite effective H–D
exchange results on the aromatic ring systems better
than those of 10% Pd/C catalyst studied previously.
Typically, the reactions were carried under ordinary
hydrogen pressure using 5% Pt/C (20 wt % of the sub-
strate) in D O at room temperature to 180 °C in a sealed
2
2
2
1
1
1
lyst although only a few practical exchanges of the
deuterium incorporation into aromatic ring systems,
tube. Examination of the H NMR spectrum of the
reaction product with p-anisic acid or dioxane as an
internal standard shows quite efficient deuterium con-
tents on the aromatic ring.
1
1a
such as t-butylbenzene and biphenyl,
n-butylben-
zene,1 and sterically hindered arylsilanes
1b
11c
were re-
ported in the literature.
To explore the scope of this method, the deuteration of a
number of aromatic substrates was investigated and
Table 1 summarizes a comparison of deuterium effi-
ciency of the aromatic ring using 5% Pt/C and 10%
Pd/C as a catalyst under a variety of reaction tempera-
Keywords: H–D Exchange; Deuterium; Pt/C; Aromatic ring;
Hydrogenation.
1
5
*
Corresponding author. Tel.: +81 58 237 3931; fax: +81 58 237
979; e-mail: sajiki@gifu-pu.ac.jp
tures. Most of the substrates indicate satisfactory
deuterium incorporation into the aromatic ring and
5
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.067

6996
H. Sajiki et al. / Tetrahedron Letters 46 (2005) 6995–6998
Table 1. Comparison of deuterium efficiency of aromatic compounds
using 5% Pt/C and 10% Pd/C as a catalyst
Table 1 (continued)
a,b,c
Entry
5% Pt/C
10% Pd/C
Catalyst, H2
Substrate
Substrate-dn
10% Pd/C
CO H
CO H
CO H
2
2
2
D2O, 24 h
3
8
38
97
98
97
2
2
Entry 5% Pt/C
d
9
1
98
98
98
98
70
70
OH
OH
OH
98
87
8
0 ˚C (70%) 180 ˚C (66%)
180 ˚C (90%)
9
7
8
97
98
85
81
85 98
81 98
98
98
1
CO2Me 19
CO Me 2
9
2
97
85
98
64
64
1
1
rt (63%)
80 ˚C (60%) 180 ˚C (40%)
0
99
99
70
70
87
9
9
OH
OH
8
0
71
0
180 ˚C (58%)
180 ˚C (57%)
9
8
9
2
0
0
0
2
64
0
9
0
0
CO H
CO H
2
9
9
9
2
10
10
99
3
d
rt (92%)
rt (92%)
11
9
CO H
CO H
2
2
64
0
OH
OH
1
80 ˚C (100%)
180 ˚C (98%)
91
8
98
80
9
8
8
74
94
23
97
24
9
38
29
98
97
5
1
51
97
1
2
—
8
0 ˚C (76%)
80 ˚C (61%)
NH2
NH2
rt (72%)
NH2
NH2
96
96
98
98
98
93
30
93 98
30 98
98
98
3
4
96
45
45
98
21
97
49
98
97
8
0 ˚C (54%) 180 ˚C (48%)
—
rt (53%)
80 ˚C (59%)
1
80 ˚C (88%)
NH2
NH2
NH
7
9
79 97
97
98
2 98 98
NH2
98
31
85
33 33
85
85
88
88
99
99
5
5
31
97
98
48
98
86
98
86
98
1
3
—
—
8
0 ˚C (85%) 180 ˚C (73%)
8
0 ˚C (79%) 180 ˚C (85%)
85
33 33
rt (73%)
5
9
8
96
4
9
98
47
98
97
H2N
9
8
8
97 97
98
98
8
86
99
5
9
9
5
H2N
9
97
9
97 97
8
0 ˚C (69%)
80 ˚C (88%)
80 ˚C (88%)
a
8
7
97
34
16
99
98
5
00 mg (3.0–5.4 mmol) of the substrate was used and reactions were
carried out under ordinary H pressure using 5% Pt/C (20 wt % of
the substrate) or 10% Pd/C (10 wt % of the substrate) in D O (99.9%
D content, 17 mL) in a sealed tube and isolated yields were indicated
in parentheses.
D contents were determined by H NMR and confirmed by H NMR
and mass spectrum and indicated in small figures in the table.
Deuterium efficiency was indicated as the average D content in the
case of a symmetrical structure.
97
98
7
3
2
87
16
2
H N
H N
2
2
9
7
98
1
80 ˚C (69%)
180 ˚C (79%)
b
c
1
2
OH
OH
OH 98
81 98
OH
8
1
8
6
7
8
—
9
98
d
1
D contents were determined by H NMR after the conversion of
carboxylic acid into the corresponding methyl ester on the basis of
the integration of the methyl protons.
98
98
rt (64%)
80 ˚C (59%)
NH2
NH2
NH2
OH
NH2
OH
OH
OH
9
7
7
97
97
90
28
97
97
5
% Pt/C-catalyzed reaction conditions always gave
8
96
97
67
30
80 ˚C (60%)
97
75
97
97
apparently better deuterium efficiency on the aromatic
ring at the same or lower temperature. The efficiency
into the side alkyl chain (propyl, entries 2and 5; methyl,
entry 4) was indicated to be better under the 10% Pd/C-
catalyzed conditions. Even at room temperature (ca.
20 °C) nearly quantitative incorporation was observed
8
0 ˚C (62%) 180 ˚C (62%)
180 ˚C (63%)
NH2
NH2
NH2
NH2
NH2 98
21 98
rt (58%)
NH2
NH2
NH2
98
2
1
1
7
98
98
7
9
98
1
1
17
98
16
79
98
80 ˚C (66%)
in phenol although 10% Pd/C required 180 °C to ac-
quire the equivalent result (entry 1). In addition, 2-pro-
8
0 ˚C (60%)
180 ˚C (100%)

H. Sajiki et al. / Tetrahedron Letters 46 (2005) 6995–6998
6997
pylphenol was regioselectively deuterated at the 4, 5,
5% Pt/C, H , D O, 160 °C, 24 h
2
2
and 6 positions of the aromatic ring at room tempera-
ture using 5% Pt/C as a catalyst (entry 2). Electron-suf-
ficient aromatic compounds were well deuterated by
using 5% Pt/C (entries 1–8). For electronically neutral
and electron-deficient aromatic compounds, the desired
H–D exchange reaction is less straightforward and rela-
tively higher reaction temperature is necessary to
9
1%
CH3
CD 56
3
4
0
3
ONa
ONa
CH3
CD
91
9
6
54
O
O
B
H C
D C
3
3
40
9
4
1
0% Pd/C
10% Pd/C
H , D O
99%
CD 99
100% H , D O
2 2
2
2
1
60 °C, 24 h
160 °C, 24 h
1
7
achieve satisfactory results (entries 9–12) although it
is difficult to determine exactly the reason for the lower
CD 96
3
3
9
2
96
ONa
ONa
1
8
4l,11a,11c
reactivity (electronic or steric hindrance
effect).
CD3
97
CD3
97
2
9
97
9
9
97
On the other hand, 10% Pd/C-catalyzed H–D exchange
reaction of electron-deficient aromatic rings reveals
quite low deuteration efficiency even at 180 °C (entries
O
O
D C
D C
3
3
96
97
97
92
A
C
9
–11). It is worth noting that the 5% Pt/C and 10%
Scheme 2. Stepwise synthesis of ibuprofen-d17.
Pd/C-catalyzed deuterations tolerate carboxylic acid
1
9
(
entries 9 and 11) and ester (entry 10) although the
reaction mixture was heated up to 180 °C in the aqueous
medium. Moreover, 5% Pt/C exerts excellent catalytic
activity toward deuterium incorporation of a biphenyl
and the throughly deuterated biphenyl-d10 was obtained
even at 80 °C (entry 13). The catalyst could be recovered
almost quantitatively after simple filtration and it could
be reused. The recovered 5% Pt/C was also effective in
the 2nd and the 3rd reactions, and the isolated yields
and deuterium efficiency of the 2nd and 3rd runs were
comparable to those of the first run.
We recently reported the excellent deuterium incorpora-
tion into the inactivated alkyl side chains of ibuprofen,
an antiinflammatory drug, by 10% Pd/C-catalyzed H–
D exchange reaction while the deuterium efficiency of
the aromatic ring was only 29% (Scheme 2, A). A use-
ful application of 5% Pt/C and 10% Pd/C-catalyzed deu-
teration methods is to transform an aromatic compound
possessing an alkyl side chain, such as ibuprofen, into an
entirely deuterated product (C) via 5% Pt/C-catalyzed
aromatic ring favorable deuteration of a mother aro-
matic compound with accompanying subsequent 10%
Pd/C-catalyzed aliphatic side chain favorable deutera-
tion of intermediary B as shown in Scheme 2.
1
3
To reliably identify the residual pesticides, pharmaceuti-
cals, environmental pollutants and so on in foods,
water, atmospheric air, etc., using Mass or GC–mass
spectrometry, analytical samples should be fortified with
2
0
In summary, we have developed a method for effective
and applicable Pt/C-catalyzed deuteration of aromatic
surrogate compounds (internal standards). Since sur-
rogate compounds should possess nearly equal physical
properties to those of analytical mother samples, multi-
deuterated mother samples may be employed for such
purpose. As illustrated in Scheme 1, 5% Pt/C-catalyzed
deuteration process can also be useful for deuteration
of carbaryl as a bactericide of domestic animals and car-
rings using D O as a deuterium source under hydrogen
2
atmosphere. The reaction is general for a variety of aro-
matic compounds including biologically active com-
pounds. Further investigations directed toward
elucidation of the detailed scope and limitation of those
reactions are in progress.
baryl-d can be applied to the microanalysis of residual
7
carbaryl of meat as a surrogate compound. Carbaryl-d7
was prepared in two steps starting from a-naphthol with
good chemical yield (59% two steps total yield) and deu-
terium efficiency without significant overreduction of the
aromatic ring, because carbaryl was not stable enough
under the aqueous deuteration conditions.
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7
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