Pd/C-H2-catalysed deuterium exchange reaction of the benzylic site in D2O

Article abstract of DOI:10.1055/s-2002-32605

Pd/C is found to catalyse efficient and chemoselective exchange of deuterium derived from D₂O with hydrogens on a benzylic carbon in the presence of a catalytic amount of hydrogen at room temperature.

Full text of DOI:10.1055/s-2002-32605

LETTER
1149
Pd/C-H2-Catalysed Deuterium Exchange Reaction of the Benzylic Site in D2O
P
d/C-H -catalysed
i
D
euter
r
ium
E
xc
o
hange React
nion ao Sajiki,* Kazuyuki Hattori, Fumiyo Aoki, Kanoko Yasunaga, Kosaku Hirota*
2
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Fax +81(58)2375979; E-mail: sajiki@gifu-pu.ac.jp
Received 10 April 2002
Table 1 Assessment of Pd/C-H2-catalysed Deuterium Exchange
Reaction of Diphenylmethane in D2Oa
Abstract: Pd/C is found to catalyse efficient and chemoselective
exchange of deuterium derived from D2O with hydrogens on a
benzylic carbon in the presence of a catalytic amount of hydrogen
at room temperature.
H
H
D
D
10% Pd/C, H2
D2O (0.5 mL), rt
Ph
Ph
Ph
Ph
Key words: catalysis, chemoselectivity, deuterium exchange, deu-
(1.0 mmol)
terium labelled compounds, palladium on carbon
Entry
1
H2
Time (d)
D content (%)b
Nonec
Balloon
Balloon
Balloon
Balloon
10 mL
10 mL
1
1
1
1
3
3
5
0
66
77
81
73
95
96
Deuterium labelled compounds have been extremely use-
ful in many different branches of science, including anal-
ysis of drug metabolism, investigation of reaction
mechanisms and kinetics and so on.1,2 While various
methods are available in the literature for the preparation
of deuterium labelled compounds,1 post-synthetic and cat-
alytic displacement of hydrogen bound to the carbon of
unlabelled compounds by deuterium is efficient and great-
ly reduces effort and cost. The catalytic deuterium ex-
change reaction is an underdeveloped methodology and
existing techniques usually utilize acid,3 base4 and metal5–
2 (1st run)
3 (2nd run)d
4 (3rd run)e
5
6
7
a All reactions were carried out under ordinary pressure using 10% Pd/
C (10% of the weight of the substrate) in D2O (99.8% D content, 0.5
mL) at r.t. Unless otherwise noted, commercial diphenylmethane (168
mg, 1.00 mmol) was used as the starting substrate.
b Determined by 1H-NMR.
7
catalysed, microwave-enhanced8 and supercritical9 ex-
change reactions. Many such conventional procedures are
only applicable to the H-D exchange reactions of the aro-
matic ring, and few general methods are available for hy-
drogen bound to the aliphatic carbon.4,6,7 However, these
methods usually require high heat, high pressure, stoichi-
ometric reagents, vast amounts of catalyst, strongly basic
or acidic conditions, special apparatus and/or deuterium
atmosphere, and some of the reactions achieve only a low
c Under atmospheric air.
d The 66% deuterated diphenylmethane (the product of entry 2) was
used as the starting substrate.
e The 77% deuterated diphenylmethane (the product of entry 3) was
used as the starting substrate.
degree of deuterium efficiency and selectivity. Hence, the The Pd/C-catalysed H-D exchange reaction of diphenyl-
development of new, deuterium-efficient and post-syn- methane was carried out under several conditions
thetic H-D exchange methods remains a subjects of great (Table 1). While no exchange was observed in the ab-
interest.
sence of hydrogen gas (entry 1), hydrogen was found to
dramatically activate the reactivity of the Pd/C-catalysed
H-D exchange reaction. The initial reaction was carried
out using 168 mg (1.00 mmol) of diphenylmethane and 17
mg [10% of the weight of diphenymethane; only 1.7 mg
(0.0 16mmol) of Pd metal] of 10% Pd/C in 0.5 mL of D2O
(22.55 mmol) at room temperature under ordinary hydro-
gen atmosphere using a hydrogen balloon for 1 day. Deu-
terium incorporation of 66% at the benzylic methylene of
diphenylmethane was achieved in one reaction, but the re-
sult was less satisfactory (entry 2). With the use of the
66% deuterated product of the first reaction (entry 1) as a
substrate for the second H-D exchange reaction, the deu-
terium content (D content) of the second product was
slightly increased to 77% (entry 3) and the third reaction
gave 81% deuterated product (entry 4). Furthermore,
elongation of the reaction time (3 days) merely leads to
minimal increase of the deuterium incorporation (73%,
Herein, we describe a distinctly general procedure for the
H-D exchange reaction at the benzylic position that oper-
ates under mild conditions. Only 10% of the weight of the
substrate of 10% Pd/C, which approximately corresponds
to 1.6 mol% Pd metal, efficiently catalyses the exchange
of the deuterium derived from D2O as a solvent10 with a
substrate possessing a benzylic position, resulting in
chemoselective incorporation of deuterium in the pres-
ence of a catalytic amount of hydrogen at room tempera-
ture.
Synlett 2002, No. 7, 01 07 2002. Article Identifier:
1437-2096,E;2002,0,07,1149,1151,ftx,en;Y05502ST.pdf.
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ISSN 0936-5214

1150
H. Sajiki et al.
LETTER
entry 5). The efficiency of the H-D exchange reaction can
be greatly enhanced by reduction in the volume of hydro-
gen. The exchange reaction proceeded dramatically using
only 10 mL of hydrogen (ca. 0.45 mmol; 0.45 equiv vs.
diphenylmethane) instead of a hydrogen balloon (ca. 2000
mL) for 3 days at room temperature to provide 1,1-diphe-
nyl-1,1-D2-methane with 95% D content in 88% isolated
yield (entry 6). While elongation of the reaction time to 5
days led to no significant change, subsequent experiments
were carried out in the presence of 10 mL of hydrogen for
3 days at room temperature.11
Table 2 Results of 10% Pd/C-H2-catalysed Deuterium Exchange
Reaction of Benzylic Site in D2Oa
D
R1
R2
H
R1
R2
D
D
H
H
10% Pd/C, H2 (10 mL)
D2O (0.5 mL), rt, 3 days
or
or
Ph
Ph
Ph
R
Ph
R
(1.0 mmol)
Entry Substrate
D content (%)b
Yield (%)c
1
2
PhCH2Ph
95
97
88
73d
Ph
Ph
Table 2 shows the results of H-D exchange reaction of
various substrates. The reactions were very clean and no
chromatographic separation was required to obtain spec-
trally pure products. No side products were isolated from
any reaction and virtually no competitive deuteration on
the aromatic ring was observed. For the substrates in
Table 2, methoxy and hydroxy substituents on the aromat-
ic ring or side chain apparently do not have any influence
on the course of the H-D exchange reaction (entries 3 and
4). The incorporation of deuterium into the branched ben-
zylic position (methine) also proceeded without any prob-
lems (entries 9 and 10). The reaction using 4-ethylbenzoic
acid or methyl 4-ethylbenzoate as a substrate gave only
moderate D content (entry 5 or 6) while the reaction using
4-ethylbenzoic acid sodium salt gave nearly quantitative
D content (entry 7). The failure of 4-ethylbenzoic acid and
methyl 4-ethylbenzoate to undergo full labeling may be
rationalized by invoking coordination of palladium with
the carboxylic acid or ester oxygen leading to a less reac-
tive catalyst (complex).
3
4
92
96
98
OH
40d
Et
OMe
5
6
7
61
74
98
>99
74d
Et
Et
CO2H
CO2Me
>99
Et
CO2Na
CO2Na
8
9
90
98
97
Ph
55d
10
PhCH(Me)Et
93
20d
In the same manner, the H-D exchange reaction of Ibupro-
fen, a nonsteroidal antiinflammatory medicine, was also
attempted under the same conditions (Figure). Castell et
al. previously reported12 a base-catalysed deuterium label-
ing of Ibuprofen using D2O-NaOH under reflux condi-
tions. Although the benzylic methylene of their product
was not deuterated, the benzylic methine connected to the
carboxylic acid was labelled with ca. 50% D content On
the other hand, the benzylic methylene was highly deuter-
ated (97% D content) under our reaction conditions while
the deuterium efficiency of the benzylic methine was
somehow not attractive (Figure).
a All reactions were carried out under ordinary hydrogen pressure (10
mL) using 10% Pd/C (10% of the weight of the substrate) in D2O
(99.8% D content, 0.5 mL) at r.t. for 3 d.
b Determined by 1H-NMR.
c Yields refer to those of pure isolated products, fully characterized by
spectral and analytical data.
d The low isolated yield of the deuterated product is due to low boiling
point and the volatile nature.
In summary, we have developed a mild and totally cata-
lytic one-pot method for the chemoselective H-D ex-
change reaction at the benzylic position in very high D
content. Less than 2 mol% of palladium metal in the pres-
ence of a catalytic amount of hydrogen can carry out effi-
cient H-D exchange at room temperature under ordinary
pressure. The reaction is general for a variety of sub-
strates. The simplicity of this method makes it an attrac-
tive new tool for the post-synthetic deuterium labeling to
a wide variety of disciplines.
Pr
Me
D
D
D
CO2Na
D content 17%
Ibuprofen Na
D content 97%
Figure
The reaction mechanism is not clear yet for our specific
H-D exchange reaction. It has been proposed that a cata-
lytic amount of hydrogen gas is an obvious activator of the
Pd/C-catalysed H-D exchange reaction. Since equilibrium
is an apparent state between H-D and D-H exchange, the
amount of hydrogen gas is significant for the deuterium
efficiency of the product.
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Synlett 2002, No. 7, 1149–1151 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Pd/C-H2-Catalysed Deuterium Exchange Reaction of the Benzylic Site in D2O
1151
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Synlett 2002, No. 7, 1149–1151 ISSN 0936-5214 © Thieme Stuttgart · New York