Complete replacement of H2 by D2 via Pd/C-catalyzed H/D exchange reaction

Article abstract of DOI:10.1021/ol048591b

(Chemical Equation Presented) A general and in situ D₂ gas generation method using 10% Pd/C-catalyzed H₂-D₂ exchange reaction in a H₂-D₂O system has been developed. H ₂ gas sealed in a reac

Full text of DOI:10.1021/ol048591b

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3521-3523
Complete Replacement of H2 by D2 via
Pd/C-Catalyzed H/D Exchange Reaction
Hironao Sajiki,* Takanori Kurita, Hiroyoshi Esaki, Fumiyo Aoki,
Tomohiro Maegawa, and Kosaku Hirota*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical UniVersity,
5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
sajiki@gifu-pu.ac.jp
Received July 20, 2004
ABSTRACT
A general and in situ D2 gas generation method using 10% Pd/C-catalyzed H2−D2 exchange reaction in a H2−D2O system has been developed.
H2 gas sealed in a reaction flask was efficiently converted into nearly pure D2 gas, which can be used for the reductive deuteration of substrates
possessing reducible functionalities within the molecule.
Deuterium-labeled compounds are widely used as research
tools in the life, environmental, and material sciences.1,2
Many catalytic exchange methods with a variety of degrees
of deuterium efficiency and selectivity have been reported,1b-d
and many conventional techniques utilize D2 gas as a
deuterium source.3 Furthermore, catalytic reduction of double
and triple bonds, dehalogenation, deoxygenation at the
benzylic position, or ring-opening reaction of epoxides with
D2 gas frequently offer the best routes to the preparation of
a deuterium-labeled compound with a high specific activity.4
However, D2 gas is quite expensive and must be purchased
as a lecture bottle or cylinder charged by high-pressure D2
gas. Consequently the development of a simple and in situ
preparation method of D2 gas has been desired in the
laboratory. We have recently published a method for
(3) (a) Weil, T, A.; Friedman, S.; Wender, I. J. Org. Chem. 1974, 39,
48-50. (b) Hsiao, C. Y. Y.; Ottaway, C. A.; Wetlaufer, D. B. Lipids 1974,
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1646. (d) Maeda, M.; Ogawa, O.; Kawazoe, Y. Chem. Pharm. Bull. 1977,
25, 3329-3333. (e) Ofosu-Asante, K.; Stock, L. M. J. Org. Chem. 1986,
51, 5452-5454. (f) Takehara, D. K.; Butt, J. B.; Burwell, R. L., Jr. J. Catal.
1992, 133, 279-293. (g) Takehara, D. K.; Butt, J. B.; Burwell, R. L., Jr. J.
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Radiopharm. 1997, 39, 291-298. (m) Ellames, G. J.; Gibson, J. S.; Herbert,
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Lett. 2004, 6, 11-13.
(1) For reviews: (a) Koike, Y. Optronics 1996, 126-132. (b) Junk, T.;
Catallo, W. J. Chem. Soc. ReV. 1997, 26, 401-406. (c) Elander, N.; Jones,
J. R.; Lu, S. -Y.; Stone-Elander, S. Chem. Soc. ReV. 2000, 29, 239-249.
(d) Matsubara, S.; Yokota, Y.; Oshima, K. Chem. Lett. 2004, 33, 294-295
and references therein.
(2) For examples, see: (a) Baba, S. Radioisotopes 1982, 31, 119-126.
(b) Stevenson, D. E.; Akhtar, M.; Gani, D. Tetrahedron Lett. 1986, 27,
5661-5664. (c) Baldwin, J. E.; Adlington, R. M.; Ting, H.-H.; Arigoni,
D.; Graf, P.; Martinoni, B. Tetrahedron 1985, 41, 3339-3343. (d) Furuta,
T.; Takahashi, H.; Kasuya, Y. J. Am. Chem. Soc. 1990, 112, 3633-3636.
(e) Gardner, K. H.; Kay, L. E. J. Am. Chem. Soc. 1997, 119, 7599-7600.
(f) Raap, J.; Nieuwenhuis, S.; Creemers, A.; Hexspoor, S.; Kragl, U.;
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Durazo, A.; Abu-Omar, M. M. Chem. Commun. 2002, 66-67.
(4) For reviews, see: (a) Rylander, P, N. Hydrogenation Methods;
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Chemistry, 2nd ed.; American Chemical Society: Washington, DC, 1996.
10.1021/ol048591b CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/01/2004

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.5 In the course of our
investigation to develop efficient C-H/C-D exchange
reactions,6 we have found that 10% Pd/C effectively cata-
lyzed an isotope exchange reaction between H2 gas and D2O,
and H2 gas encapsulated into the reaction flask was almost
entirely replaced by D2 gas after stirring at room temperature
for 24 h. As an extension of this finding, we undertook a
project to develop a convenient and in situ reductive
deuteration method using a H2-D2 exchange reaction.
In our initial investigation, we conducted a H2-D2
exchange reactions using 1.0 mL (55 mmol) of D2O and 10
mg of 10% Pd/C (0.0094 mmol of Pd metal) in the presence
of large quantity of H2 gas (balloon) (conditions A). The
reactions were followed by recording 1H NMR spectra with
time using p-methoxybenzoic acid sodium salt as an internal
standard. Figure 1 indicates the gradual and continuous
Their reaction attains the equilibrium corresponding to the
total amounts of hydrogen and D2O in the reaction tube and
up to nearly 50% of the charged H2 gas was converted into
D2 gas under 2 MPa hydrogen. On the other hand, it was
found that our 10% Pd/C-catalyzed H2-D2 exchange reaction
gave a promising result of relatively slow (TOF ) 17.3 h-1)
but continuous conversion of H2 gas into D2 gas even under
atmospheric hydrogen pressure at room temperature.8 Roughly
3.9 mmol of D2 gas (87 mL) was produced from 1.0 mL
(55 mmol) of D2O after 48 h (TON ) 829).
Next, we examined the conversion of a limited amount of
H2 gas in a completely closed system. The H2-D2 exchange
efficiency after 24 h of stirring of 7.4 mg of 10% Pd/C in
5.0 mL (277 mmol) or 3.0 mL (166 mmol) of D2O using a
hydrogen-charged sealed flask (actual internal volume of the
100 mL flask is 160 mL) was determined by measurement
of the incorporation of deuterium into dihydrocinnamic acid
(2) resulting from the 10% Pd/C-catalyzed reduction of
cinnamic acid (1), added with a syringe as a methanol
solution through the septa, at room temperature for 6 h. The
results are summarized in Table 1. Almost 50% of the
Table 1. Effect of Conditions on Deuterium Efficiency of
Hydrogenation Using H2 Gas after Preliminary Stirringa,b
D content (%) of 2c
entry
1 (mmol)
H2 (mL/mmol)a
C1
C2
1d
2
3
4e
5
6
0.5
0.5
1
0.5
0.5
0.5
160/7.1
160/7.1
160/7.1
160/7.1
285/12.7
690/30.8
52
48
48
2
44
31
49
46
50
0
42
29
Figure 1. Kinetic plots of DHO ratio in D2O.
increase of the water (DHO) signal intensity based upon the
equation in Figure 1. No increase of the water signal intensity
was observed in the absence of 10% Pd/C (conditions B) or
H2 gas (under Ar atmosphere, conditions C). The H2-D2
exchange reaction was found to be a Pd-catalyzed reaction,
and the source of the water hydrogen must be charged H2
gas.
a The reaction was performed in a hydrogen-charged sealed flask.
b Cinnamic acid (1) was added as a methanol solution (0.5 mmol of 1 was
dissolved into 0.8 mL of methanol. c D content was determined by1H NMR
on the basis of the integration of the aromatic protons. d 5 mL of D2O (277
mmol) was used. e Without preliminary stirring.
Recently, Joo´ et al. reported that water-soluble Rh- and
Ru-phosphine complexes such as {RuCl2(mTPPMS)2}2
(mTPPMS ) m-sulfonatophenyl diphenylphosphine sodium
salt) showed high catalytic activity in the H2-D2 isotope
exchange reactions between H2 and D2O under elevated
hydrogen pressure (2 MPa) at room temperature (26 °C).7
deuterium was incorporated into both methylene positions
(C1 and C2) of 2 in entries 1-3. These results indicate that
the charged H2 gas (160 mL) in the sealed flask is converted
into nearly pure D2 gas. A control experiment was run
without preliminary stirring under similar reaction conditions.
(8) H2-D2 isotope exchange reaction between H2 and D2O or D2 and
H2O has often been observed during catalytic hydrogenation while the
degrees of exchange efficiency are not so high. For example: (a) Schrock,
R. R.; Osborn, J. A. Chem. Commun. 1970, 567-568. (b) Schrock, R. R.;
Osborn, J. A. J. A. Chem. Soc. 1976, 98, 2134-2143. (c) Kubas, G. J.;
Burns, C. J.; Khalsa, G. R. K.; van der Sluys, L. S.; Kiss, G.; Hoff, C. D.
Organometallics 1992, 11, 3390-3404. (d) Chan, L.; Leung, Y. S. J.
Organomet. Chem. 1994, 464, 103-106.
(5) Sajiki, H.; Hattori, K.; Aoki, F.; Yasunaga, K.; Hirota, K. Synlett
2002, 1149-1151.
(6) Sajiki, H.; Aoki, F.; Esaki, H.; Maegawa, T.; Hirota, K. Org. Lett.
2004, 6, 1485-1487.
(7) (a) Kova´cs, G.; Na´dasai, L.; Laurenczy, G.; Joo´, F. Green Chem.
2003, 5, 213-217. (b) Kova´cs, G.; Na´dasai, L.; Joo´, F.; Laurenczy, G. C.
R. Acad. Sci. Paris, Ser. IIc: Chem. 2000, 3, 601-605.
3522
Org. Lett., Vol. 6, No. 20, 2004

Almost no deuterium incorporation was observed on the
reductive product (2) (entry 4). The efficiency of deuterium
incorporation was significantly reduced when the reaction
was performed using larger flask (entries 5 and 6).
We have established that the 10% Pd/C-catalyzed H2-D2
exchange reaction in a H2-D2O system can be effectively
applied as a general and in situ D2 gas preparation method
when needed (Table 2).9 The generated D2 gas is easily
5) and unsaturated hydrocarbons (entries 3 and 6) in excellent
to quantitative deuterium efficiencies. The position and
efficiency of deuterium was established by H NMR and
1
mass spectrometry. At the end of the reaction, the catalyst
can be recovered by simple filtration, and acidic deuteriums
on the carboxylic acid, alcohol, or amine were replaced by
hydrogens by treatment in aqueous solution (H2O).
At present, detailed mechanistic studies have not been
undertaken and the exact process of D2 gas generation is
unclear. We assumed that the oxidative insertion of Pd(0) A
or A′ activated by H2 or HD as a so-called ligand into D2O
to give Pd(II) species B or B′ is the key step of the catalytic
H2-D2 isotope exchange reaction in the H2-D2O system
(Scheme 1). Ligand exchange reaction of B or B′ and
Table 2. Deuterium Efficiency of the Hydrogenation Using
Various Substrates with H2 Gas and D2O after Preliminary
Stirringa
Scheme 1. Proposed Mechanism of H2-D2 Isotope Exchange
Reaction
a Substrate (0.5 mmol) and 10% Pd/C (10% of the weight of the substrate)
in D2O (3.0 mL, 166 mmol) under H2 atmosphere (160 mL, 7.1 mmol) at
room temperature, preliminary stirring for 24 h, hydrogenation for 6-24
h. b Isolated yield (100% conversion yield). c D content was determined by
1H NMR after the conversion of the carboxylic acid into corresponding
methyl ester on the basis of the integration of the methyl protons. d 5 mL
of D2O (277 mmol) was used. e D content was determined by 1H NMR
after the conversion of the alcohol into the corresponding acetate on the
basis of the integration of the acetyl protons. f D content was determined
on the basis of the integration of the aromatic protons. g D content was
determined on the basis of the integration of the ethyl protons.
subsequent reductive elimination gives the corresponding
Pd(0)-HD or D2 complex (A′ or A′′). At the end of the
reaction, D2 gas was liberated from the corresponding A′′.
In summary, we have reported a simple and effective
catalytic isotope exchange reaction between H2 gas and D2O.
H2 gas sealed in a reaction flask was efficiently converted
into nearly fine D2 gas, which can be used for the reductive
deuteration of the substrate possessing reducible function-
alities within the molecule. This H2-D2 exchange reaction
is synthetically useful as a convenient method to prepare D2
gas using a moderately inexpensive D2O in the individual
laboratory when necessary. Further modification and ap-
plication of this method are under investigation.
applicable to the catalytic reduction of functionalized aro-
matic halides (entries 1-4), epoxide (entry 4), nitrile (entry
(9) Typical Procedure. A suspension of 10% Pd/C (7.4 mg, Aldrich)
in D2O (3 mL, 166 mmol) was stirred for 24 h at room temperature in a
100 mL sealed round-bottom flask (actual internal volume of the flask is
160 mL) filled with hydrogen. To the reaction mixture were added
4-chlorobenzoic acid (78 mg, 0.5 mmol) and Et3N (83.6 µL, 0.6 mmol, to
neutralize released HCl), the mixture was stirred at room temperature for
24 h. The resulting reaction mixture was diluted with ether (10 mL) and
filtered using a membrane filter (Millex-LH, 0.25 µm). The filtrate was
diluted with ether (60 mL) and washed with water (10 mL) and brine (30
mL). The etheral layer was dried over MgSO4, filtered, and concentrated
under reduced pressure to give an analytically pure product (79%).
Deuterium content was determined by 1H NMR after the conversion of the
carboxylic acid into corresponding methyl ester on the basis of the
integration of the methyl protons.
Supporting Information Available: Spectroscopic data
of deuterated products and information on procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048591B
Org. Lett., Vol. 6, No. 20, 2004
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