Platinum catalyzed H-D exchange reaction of various aromatic compounds under hydrothermal condition

Article abstract of DOI:10.3987/COM-05-S(T)36

Various aromatic compounds were treated with deuterium oxide under hydrothermal conditions in the presence of a catalytic amount of platinum (IV) oxide. An efficient H-D exchange reaction was observed, which gave various deterium labeled aromatic compounds.

Full text of DOI:10.3987/COM-05-S(T)36

HETEROCYCLES, Vol. 67, No. 1, 2006
353
HETEROCYCLES, Vol. 67, No. 1, 2006, pp. 353 - 359. © The Japan Institute of Heterocyclic Chemistry
Received, 19th July, 2005, Accepted, 22nd August, 2005, Published online, 23rd August, 2005. COM-05-S(T)36
PLATINUM CATALYZED H-D EXCHANGE REACTION OF VARIOUS
AROMATIC COMPOUNDS UNDER HYDROTHERMAL CONDITION**
Mitsuru Yamamoto, Koichiro Oshima, and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto
University, Kyoudai-katsura, Nishikyo, Kyoto 615-8510, Japan
matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Abstract – Various aromatic compounds were treated with deuterium oxide
under hydrothermal conditions in the presence of a catalytic amount of platinum
(IV) oxide. An efficient H-D exchange reaction was observed, which gave
various deuterium labeled aromatic compounds.
Introduction
The H-D exchange reaction of organic compounds has been attracted attention as a method for
preparation of labeled compounds.1,2 The H-D exchange reaction in deuterium oxide has been
performed in various ways.3 For example, a base catalyzed H-D exchange reaction in supercritical or
subcritical deuterium oxide was applied for the reaction of phenol and aniline derivatives4 and an
acid-catalyzed H-D exchange reaction was applied for alkenes.5 In addition, transition metal-catalyzed
exchange reaction in deuterium oxide is a useful method.6 We have demonstrated that H-D exchange
reactions in alkanes and alkenes could be performed effectively with Pd/C catalyst in hydrothermal
deuterium oxide7a,b and those in polystyrene samples could also be performed with PtO2 catalyst in
hydrothermal deuterium oxide.7c We also demonstrated that a ruthenium-catalyzed reaction under
irradiation of microwaves in deuterium oxide could be a selective H-D exchange reaction at α-position of
alcohols and amines.8
In our findings, platinum catalyst is the most effective catalyst for H-D
exchange reaction in an aromatic ring, as shown in Table 1. The mechanism of platinum-catalyzed H-D
exchange reaction in aromatic ring may be considered to proceed via a Friedel-Crafts-type reaction.9-11
In this sense, an electron rich heterocyclic compound or a benzene ring with an electron-donating group
will show the more efficient H-D exchange reaction in hydrothermal deuterium oxide in the presence of

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HETEROCYCLES, Vol. 67, No. 1, 2006
platinum catalyst.4,6,11 Although easy deuteration is expected, the tolerances of these compounds under
the hydrothermal conditions should be kept in mind. So, we will show some systematic platinum-
catalyzed H-D exchange reactions of various heterocyclic compounds and aromatic compounds with
electron-donating groups.
a,b
Table 1. Metal salt catalyzed deuteration of butylbenzene (1) under hydrothermal condition.
1
2
3
4
C
C
C
C
H
H
H
H
D
D
D
D O (10 ml)
2
H
CH –CH –CH –CH
3
Ar
2
2
2
D
C
CD –CD –CD –CD
2
2
2
3
Catalyst (0.04 mmol)
250 °C, T h
1 (2.0 mmol)
2
D
run
1
Catalyst T/h
CAr
20%
2
C1
67%
61
C2
42%
38
C3
49%
50
C4
Pd/C
PdO
2
2
43%
42
16
5
2
3
Pd black
Raney Ni
PtO2
2
<5
3
32
14
24
4
2
28
10
13
5
2
28
65
81
96
42
26
32
30
40
56
83
6
PtO2
4
58
49
48
7
PtO2
6
75
59
65
8
PtO2
14
95
94
95
a
b
Substrate (2.0 mmol), catalyst (2 mol% Metal), and D O (20.0 g).
2
The ratios
were determined by 1H NMR, 2H NMR, and MS spectra.
Results and Discussion
As shown in Figure 1, various aromatic compounds substituted with hetero-atoms were treated with
hydrothermal deuterium oxide (250 °C) in the presence of 5 mol% of platinum(IV) oxide for 12 h, as
shown in EXPERIMENTAL
90%D 71%D 71%D 90%D
H
D
O
D
H
H
H
D
D
O
O
O
O
D
D
section. A complete H-D
e x c h a n g e r e a c t i o n w a s
observed in dibenzo-18-
crown-6. In the case of
triphenylamine, the electron-
d o n a t i n g p r o p e rt y o f a
nitrogen atom will benefit the
acceleration of the H-D
exchange reaction, but the
steric hindrance at ortho-
85%D
H
85%D
H
O
H
H
H
90%D 71%D 71%D 90%D
H
D
O
D
3b (67%)
3a (67%)
97%D 91%D
H
83%D
H
95%D
H
H
H
H
D
97%D
H
P O
H
P
D
D
N
3
3
3
H
97%D 91%D
H
H
83%D
D
H
95%D
3e (81%)
3d (67%)
3c (80%)
D
D
D
D
D
D
D
D
D
Fe
D
D D
OD
D
D
3f (68%)
3g (45%)
Figure 1. Results of H-D exchange reaction of aromatic compounds carrying
hetero-atoms (5 mol% PtO2, D2O, 250 °C, 4 MPa).

HETEROCYCLES, Vol. 67, No. 1, 2006
355
position of triphenylamine makes the exchange reaction difficult. Selective H-D exchange at ortho-
position of triphenylphosphine can be explained by coordination of phosphorous-atom with platinum
catalyst.
In the case of heterocycles containing nitrogen-atoms, the H-D exchange reaction proceeded smoothly.
As shown in Figure 2, efficient H-D exchange reactions were observed in all cases.
D
D
D
D
D
D
D
D
D
N
D
D
D
D
D
D
D
D
D
D
D
D
D
D
N
N
D
N
N
D
D
D
91% (4a, 250 °C, 24 h) 72% (4b, 250 °C, 12 h) 84% (4c, 250 °C, 24 h)
99% (4d, 250 °C, 4 h)
D
D
53%D
53%D
D
D
D
D
D
D
D
CH
H C
3
3
N
D
N
D
D
D
D
N
N
D
D
D
N
D
D
D
D
D
D
D
D
N
D
N
D
D
D
80% (4e, 250 °C, 8 h)
96% (4f, 250 °C, 4 h)
87% (4g, 250°C, 16 h)
87% (4h, 250 °C, 8 h)
Figure 2. Results of H-D exchange reaction of N-atom containing heterocycles in deuterium oxide in the
presence of 5 mol% platinum(IV) oxide (in parentheses, reaction temperature and reaction
period).
A substrate in Scheme 1, 1,3-bis(4-pyridyl)propane, has three methylene groups between two nitrogen
atom containing heterocycles. In this case, the use of a palladium catalyst instead of a platinum one
gave the corresponding fully deuterated product. The reaction with platinum(IV) catalyst could not
exchange the protons on the center methylene group perfectly.
H
N
H
H
N
H
H
H
H
H
D
D
D
N
D
D
D
5 mol% Pd on Carbon (10 wt%)
(CH2)3
N
(CD2)3
D O, 250 °C, 4 MPa, 12 h
2
D
4i (93%)
D
Scheme 1.
Thus, transition metal catalyzed H-D exchange reactions under hydrothermal deuterium oxide can be
applied to various aromatic compounds and heterocycles. Although the hydrothermal condition means
that the reaction is performed under 200~250 °C / 1.5~5 MPa, the surrounding water (or D2O) also
prevents the decomposition of organic compounds. The hydrothermal reaction is different from direct
heating.

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HETEROCYCLES, Vol. 67, No. 1, 2006
EXPERIMENTAL
The H-D exchange reactions were performed as follows. The vessel in Figure 3 is designed to release
the internal overpressure.7a It is commercially available from Shikokurika Co., Ltd., Kochi, Japan. In a
teflon vessel, platinum(IV) oxide (22.7 mg, 0.1 mmol), deuterium oxide (15 mL), and aromatic
compound (2.0 mmol) were added. After the vessel was placed in autoclave and sealed, the whole was
placed in oven (250 °C). After the autoclave was heated for the period indicated in the text, it was
cooled to rt.
mixture was extracted with
chloroform. Teflon vessel
The obtained
Bolt
Spring
Holder
Autoclave cap (SUS 316)
absorbs organic compounds. To
extract the product completely,
Reaction vessel (cap, teflon)
Autoclave (SUS 316)
Reaction vessel (30 ml, teflon)
Sample
12 cm
the
vessel
washed
with
chloroform and water using ultra
sonic cleaner for 15 min each.
These solvents used for wash
were extracted with chloroform.
The combined organic layers
Figure 3. 30mL Teflon© lined autoclave
were dried over Na2SO4 and concentrated in vacuo. The obtained product was purified by a short silica-
gel column chromatography. Instead of the vessel in Figure 1, glass sealed tube is also possible. In the
sealed tube case, however, the reaction should be taken care concerning about explosion, as the internal
1
2
pressure is quite high. The deuteration ratio was determined by H and H NMR spectrum using an
internal standard (CHBr3 for 1H NMR spectrum and CDCl2-CDCl2 for 2H NMR spectrum).
Deuterated Dibenzo-18-Crown-6 (3a)
2
1H-NMR (300 MHz, CDCl3): δ 4.25-3.6 (m, 16H); H-NMR (40 MHz, CHCl3): δ 7.4-6.8 (m, 8D); MS:
368 (M+).
Deuterated Diphenyl ether (3b)
1H-NMR (300 MHz, CDCl3): δ 7.25 (m, 0.4H), 6.99 (m, 0.3H), 6.95 (m, 1.16H); 2H-NMR (40 MHz,
CHCl3): δ 7.25 (m, 3.6H), 6.9 (m, 4.5H).
Deuterated Triphenylamine (3c)
2
1H-NMR (300 MHz, CDCl3): δ 7.05 (m, 0.3H); H-NMR (40 MHz, CHCl3): δ 7.7-7.0 (m, 14.7D); MS:
260 (M+).

HETEROCYCLES, Vol. 67, No. 1, 2006
357
Deuterated Triphenylphosphine (3d)
2
1H-NMR (300 MHz, CDCl3): δ 7.8-7.1 (m, 10H); H-NMR (40 MHz, CHCl3): δ 7.7-7.0 (m, 4.9D). The
regio of deuteration was determined after conversion into triphenylphosphine oxide by oxone.
1
Deuterated triphenylphosphine oxide: H-NMR (300 MHz, CDCl3): δ 7.8-7.7 (m, 1H), 7.65-7.3 (m, 9H);
2H-NMR (40 MHz, CHCl3): δ 7.8-7.7 (m, 5D).
Deuterated Triphenylphosphine oxide (3e)
2
1H-NMR (300 MHz, CDCl3): δ 7.8-7.7 (m, 0.6H), 7.65-7.3 (m, 0.27H); H-NMR (40 MHz, CHCl3):
δ 7.8-7.0 (m, 14.1D).
Deuterated Phenol (3f)
2
1H-NMR (300 MHz, CDCl3): no signal; H-NMR (40 MHz, CHCl3): δ 7.2 (br s, 2D), 6.9 (br s, 1D),
6,8 (br s, 2D).
Deuterated Ferrocene (3g)
1H-NMR (300 MHz, CDCl3): no signal; 2H-NMR (40 MHz, CHCl3): δ 4.1 (br s, 10D).
Deuterated Isoquinoline (4a)
2
1H-NMR (300 MHz, CDCl3): no signal; H-NMR (40 MHz, CHCl3): δ 9.2 (br s, 1D), 8.5 (br s, 1D),
7.9 (br s, 1D), 7.7 (br s, 1D), 7.6-7.3 (br s, 3D); MS: 136 (M+).
Deuterated Quinoxaline (4b)
2
1H-NMR (300 MHz, CDCl3): no signal; H-NMR (40 MHz, CHCl3): δ 8.9 (br s, 2D), 8.2 (br s, 2D),
7.8 (br s, 2D); MS: 136 (M+).
Deuterated Quinoline (4c)
1H-NMR (300 MHz, CDCl3): no signal; 2H-NMR (40 MHz, CHCl3): δ 8.9 (br s, 1D), 8,15 (br s, 1D),
8.1 (br s, 1D), 7.8 (br s, 1D), 7.7 (br s, 1D), 7.5 (br s, 1D), 7.3 (br s, 1D); MS: 136 (M+).
Deuterated Indole (4d)
2
1H-NMR (300 MHz, CDCl3): no signal; H-NMR (40 MHz, CHCl3): δ 7.8 (br s, 1D), 7.6 (br s, 1D), 7.5-
7.0 (m, 4D), 6.6 (br s, 1D); MS: 124 (M+).
Deuterated 4,4’-Dipyridyl (4e)
1H-NMR (300 MHz, CDCl3): no signal; 2H-NMR (40 MHz, CHCl3): δ 8.7 (br s, 4D), 7.5 (br s, 4D); MS:
164 (M+).
Deuterated Carbazole (4f)
2
1H-NMR (300 MHz, CDCl3): no signal; H-NMR (40 MHz, CHCl3): δ 7.95 (br s, 2D), 7.45 (br s, 3D),
7.15 (br s, 2D); MS: 176 (M+).
Deuterated 2,2’-Dipyridyl (4g)

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HETEROCYCLES, Vol. 67, No. 1, 2006
2
1H-NMR (300 MHz, CDCl3): no signal; H-NMR (40 MHz, CHCl3): δ 8.6 (br s, 2D), 8.4 (br s, 2D),
7.7 (br s, 2D), 7.2 (br s, 2D); MS: 164 (M+).
Deuterated 4-(Dimethylamino)pyridine (4h)
1H-NMR (300 MHz, CDCl3): δ 3.0 (m, 2.8H); 2H-NMR (40 MHz, CHCl3): δ 8.2 (br s, 2D), 6.5 (br s, 2D),
2.9 (br s, 3.2D).
Deuterated 4,4'-Trimethylenedipyridine (4i)
2
1H-NMR (300 MHz, CDCl3): no signal; H-NMR (40 MHz, CHCl3): δ 8.5 (br s, 4D), 7.1 (br s, 4D),
2.6 (br s, 4D), 1.9 (br s, 2D); MS: 212 (M+).
ACKNOWLEDGEMENTS
This work was supported financially by Kyoto University, International Innovation Centre. The
financial support by Chugai Pharmaceutical Co., Ltd. and Takahashi Industrial and Economical research
foundation are also acknowledged.
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**This paper is dedicated to Professor Dr. Barry M. Trost as we celebrate his 65th birthday.