Facile and convenient method of deuterium gas generation using a Pd/C-catalyzed H2-D2 exchange reaction and itsapplication to synthesis of deuterium-labeled compounds

Article abstract of DOI:10.1002/chem.200701245

The Pd/C-catalyzed H₂-D₂ exchange reaction using a H₂-D₂O combination provided a general, efficient and environmentally friendly route for the preparation of deuterium gas (D ₂). H₂ sealed

Full text of DOI:10.1002/chem.200701245

FULL PAPER
DOI: 10.1002/chem.200701245
Facile and Convenient Method of Deuterium GasGeneration Using a Pd/C-
Catalyzed H2–D2 Exchange Reaction and ItsApplication to Synthesisof
Deuterium-Labeled Compounds
Takanori Kurita, Fumiyo Aoki, Takuto Mizumoto, Toshihide Maejima, Hiroyoshi Esaki,
Tomohiro Maegawa, Yasunari Monguchi, and Hironao Sajiki*[a]
Abstract: The Pd/C-catalyzed H2–D2
exchange reaction using H2–D2O
combination provided a general, effi-
cient and environmentally friendly
route for the preparation of deuterium
lyzed one-pot reductive deuteration of
various reducible functionalities and
the chemoselective one-pot deuteroge-
nation of olefin and acetylene.Addi-
tionally, we established the capturing
method of the generated D2 in a bal-
loon, which was successfully applied to
the Pd/C-catalyzed reductive mono-N-
alkylation of a primary amine using ni-
trile as the alkylating reagent.
a
Keywords: chemoselectivity · deu-
terium gas · heterogeneous cataly-
sis · isotopic labeling · palladium
gas (D2).H sealed in a reaction flask
2
was converted into nearly pure D2,
which could be used for the Pd/C-cata-
Introduction
of D2 on a laboratory scale, the reactions of metals such as
sodium,[7] iron,[8] and magnesium[9] with D2O have been re-
ported in the literature, although a large quantity of metal
sludge was produced and drastic reaction conditions (several
hundred degrees Celsius) were required.Numerous catalytic
H2–D2 exchange reactions between H2 and D2O have also
been reported in the literature.[10–18] However, these methods
did not produce high purity D2 and also required high pres-
sure, the use of a special catalyst, and an excess amount of a
strong base or acid.Furthermore, the applications of the
generated D2 to the deuterogenation of unsaturated sub-
strates afforded the corresponding deuterated products with
low deuterium efficiencies, depending on the D2 purity.[19–21]
Therefore, efficient and catalytic preparation methods of
pure D2 via the H2–D2 exchange reaction between H2 and
D2O have not yet been developed.Consequently, the devel-
opment of an efficient and catalytic generation method of
D2 in the laboratory has been strongly desired.We have re-
cently reported a Pd/C-catalyzed regioselective H–D ex-
change reaction at the benzylic site in D2O in the presence
of a small amount of H2 at room temperature,[22] and multi-
ple deuterium-labeling methods on aromatic rings and/or
alkyl side chains under high temperature conditions (110–
1808C).[23] During the course of these investigations, we
have found that 10% Pd/C effectively catalyzed an isotope
exchange reaction between H2 and D2O, and the H2 in the
reaction flask was almost entirely replaced by D2 at room
temperature within 24 h.We have also developed a conven-
Deuterium gas (D2) has been widely utilized as a deuterium
source for the deuterium-labeling of a variety of mole-
cules,[1] since it is a non-radioactive and stable isotope.[2]
Deuterium-labeled compounds are finding increasing use as
research tools in the life, environmental, and material scien-
ces.[3,4] The catalytic deuterogenation of unsaturated hydro-
carbons, deuterodehalogenation of aryl chlorides or bro-
mides, deuterodeoxygenation of benzyl alcohols, and deuter-
ogenolysis (ring-opening reaction) of epoxides using D2 fre-
quently offer the best routes to prepare the deuterated com-
pounds with
a
high deuterium efficiency and
regioselectivity.[5] D2 is, however, very expensive since it is
commercially produced by the electrolysis of D2O using an
enormous amount of energy or the fractional distillation of
liquid hydrogen under cryogenic conditions (ca. ꢀ2508C).
The pyrolysis of UD3 was also reported as a generation
method of D2, but it is not practical because of the use of ra-
dioactive uranium metal.[6] As for the preparation methods
[a] T.Kurita, F.Aoki, T.Mizumoto, T.Maejima, H.Esaki,
Dr.T.Maegawa, Dr.Y.Monguchi, Prof.Dr.H.Sajiki
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University
Mitahora-higashi 5–6–1, Gifu 502–8585 (Japan)
Fax : (+81)58-237-5979
E-mail: sajiki@gifu-pu.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 3371 – 3379
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
3371

ient and one-pot reductive deuteration method using the
generated D2.[24] Herein, we describe the details of the Pd/C-
catalyzed H2–D2 exchange reaction, including the one-pot
reductive deuteration, chemoselective deuterium-labeling
method, D2-capturing method, and mechanistic aspects.
Results and Discussion
Pd/C-catalyzed H2–D2 exchange reaction between H2 and
D2O: In our first investigation, we conducted a H2–D2 ex-
change reaction using D2O (1.0 mL, 55 mmol) and 10% Pd/
C (10 mg, 9.4 mmol of Pd metal) in the presence of a large
quantity of H2 (balloon, ca.20. L) (Figure 1, condition A).
The course of the reaction over time was monitored by
1H NMR spectroscopy using p-methoxybenzoic acid sodium
salt as an internal standard.Figure 1 indicates the gradual
and continuous increase of the DHO signal intensity based
upon Equation (1), whereas no increase in the intensity was
observed in the absence of H2 (under Ar atmosphere, condi-
tion B) or 10% Pd/C (condition C).The H 2–D2 exchange re-
action was found to be a Pd/C-catalyzed reaction, and the
source of the hydrogen atom of DHO must be H2. D2
(63 mL, 2.6 mmol) [HD (127 mL, 5.2 mmol)] was generated
from D2O (1.0 mL, 55 mmol) after 24 h (TON=276) [HD:
TON=552] by the calculation based upon the increased
DHO.The present reaction proceeded relatively slowly, but
continuously converted H2 into D2 even under atmospheric
hydrogen pressure at room temperature.This result motivat-
ed us to more extensively examine this Pd/C-catalyzed H2–
D2 exchange reaction.
Figure 2.Effect of catalyst toward H 2–D2 exchange reaction.
10% Pd/C (7.4 mg, 10% of the substrate weight) in D2O
(1 mL, 55 mmol) in a sealed flask (160 mL: interior volume)
was stirred under a hydrogen atmosphere at room tempera-
ture for 24 h and then trans-cinnamic acid (1) was added
through a syringe attached to a needle.After 6 h, an approx-
imately 35% deuterium incorporation into both of the re-
duced methylene positions (C1 and C2) was observed by
1H NMR spectroscopy (entry 1, Table 1).The deuterium ef-
ficiency was significantly improved using 3 mL of D2O and a
nearly quantitative deuterium incorporation was achieved
(entry 2, Table 1).The D content at the benzylic site (C1 po-
sition) was slightly over 50% using 5 mL of D2O probably
due to the benzylic site selective Pd/C-catalyzed H–D ex-
change reaction (entry 3, Table 1).[22] These results indicate
at least 3 mL of D2O is necessary for the complete conver-
sion of pure H2 to pure D2 in the 160-mL flask.On the
other hand, CH3OD and CD3OD were not efficient deuteri-
um sources, and even increased amounts of CH3OD up to
13.5 mL never improved the D contents of [D]-2 (entries 4–
7, Table 1).Only acidic deuterium atoms seem to work as
deuterium sources in the present reaction since the use of
[a]
Table 1.Effect of deuterium source on the one-pot deuterogenation.
Entry Solvent (mL/mmol)
D content [%][b] Yield[c]
C1
C2
[%]
1
2
3
4
5
6
7
D2O (1/55)
D2O (3/166)
D2O (5/276)
CH3OD (3/74)
CH3OD (6.8/166)
CH3OD (13.5/332)
CD3OD (3/74)
CH3CO2D (9.7/166)
DCl in D2O [3/19 (DCl), 144 (D2O)]
36
48
52
24
24
26
28
–
35
46
49
26
25
26
28
–
87
98
100
92
95
91
90
Figure 1.Kinetic plots of DHO ratio in D 2O.
We chose to explore the utility of heterogeneous transi-
tion metal catalysts for the reaction [9.4 mmol of each cata-
lyst in D2O (1 mL) under an H2 atmosphere].As shown in
Figure 2, Rh/C indicates the highest activity and Pd/C, Ir/C,
and Pt/C are also effective.From the viewpoints of cost and
general versatility, we decided to use Pd/C as the catalyst
for the H2–D2 exchange reaction.
[d]
8
–
9[e]
–
–
–
[f]
[a] A suspension of 10% Pd/C (10 wt% of 1) in solvent was stirred under
H2 atmosphere (160 mL, 6.5 mmol) at room temperature for 24 h, trans-
cinnamic acid (1) (0.5 mmol) was added as a 0.5 mL MeOH solution, and
the reaction was quenched after 6 h.[b] D content was determined by
1H NMR spectroscopy on the basis of the integration of the aromatic
protons.[c] Yield of isolated product.[d] Starting material ( 1) was recov-
Next, we attempted the one-pot deuterogenation of an
olefin using the generated D2 (Table 1).A suspension of
ered in 71% yield.[e] 20 wt% DCl in D O solution was used.[f] Starting
2
material (1) was recovered in 85% yield.
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Chem. Eur. J. 2008, 14, 3371 – 3379

Deuterium-Labeling
FULL PAPER
CH3OD led to the nearly equal deuterium efficiency as that
of CD3OD (entry 4 vs.7, Table 1), although no desired [D]-
2 was generated when the reaction was carried out in an
acidic deuterated solvent such as CH3CO2D or 20% DCl in
D2O (entries 8 and 9, Table 1).
ever, the reaction of phenylpropiolic acid produced only a
moderate D content (72 and 76%, respectively) (entry 5,
Table 3).The displacement of the acidic proton by deuteri-
um or conversion to the corresponding sodium salt slightly
The reaction conditions of the H2–D2 exchange were opti-
Table 3.Application to catalytic deuteration of olefins and acetylenes
using Pd/C–D2O–H2 system.[a]
mized as shown in Table 2.The reductive deuteration of
1
efficiently proceeded by a 24 h pre-stirring of 10% Pd/C in
Table 2.Deuterogenation of 1 using D2 generated in situ.[a]
Entry
1
Substrate
Time
[h]
[Dn]-Product
Yield[c]
[%]
(D content,%)[b]
6
6
8
83
82
80
Entry 1 [mmol] 10% Pd/C H2
[wt%/mg] [mL/mmol] C1
D content [%][b] Yield[c]
N
G
C2
[%]
1
0.5
0.5
0.5
0.5
0.5
0.5
1.0
2.0
10/7.4
10/7.4
3/2.3
10/7.4
10/7.4
10/7.4
10/7.4
10/7.4
160/6.5
160/6.5
160/6.5
75/3.1
285/12.2
690/28.2
160/6.5
160/6.5
48
2
46
0
98
97
91
100
100
100
100
99
2
3
4
2[d]
3
37
52
44
31
48
45
36
49
42
29
50
45
4
5
6
7
8
[a] 10% Pd/C in D2O was pre-stirred under H2 atmosphere for 24 h,
trans-cinnamic acid (1) was added as a 0.5 mL MeOH solution, and the
reaction was quenched after 6 h.[b] D content was determined by
1H NMR spectroscopy on the basis of the integration of the aromatic
protons.[c] Yield of isolated product.[d] Deuterogenation was per-
formed for 6 h without pre-stirring.
6
95
5
11
11
6
98
96
D2O (3 mL) under a H2 atmosphere (160 mL, 6.5 mmol) at
room temperature (entry 1, Table 2), while almost no deute-
rium incorporation was observed without pre-stirring
(entry 2, Table 2).The efficiency of the deuterium incorpo-
ration was significantly reduced by the decreased use of the
10% Pd/C (3 wt%) (entry 3, Table 2) or an increased
amount of H2 using a larger flask (entries 5 and 6, Table 2).
On the other hand, a slightly higher D content was obtained
by decreasing the amount of H2 (75 mL) in a smaller flask
(entry 4, Table 2).Therefore, these results indicate that the
D2 purity is significantly affected by the ratio between the
H2 volume and D2O amount based upon the efficiency of
the H2–D2 exchange reaction.The use of a larger amount
(1.0 and 2.0 mmol) of the substrate (1), compared with
0.5 mmol in entry 1 of Table 2, brought about the successful
deuterogenation (entries 7 and 8, Table 2), but increasing 1
caused more D2 to be consumed and induces a reduced
inner pressure in the enclosed reaction flask, which would
decrease the reaction efficiency.Therefore, the reaction con-
ditions described in entry 1 of Table 2 were used as the stan-
dard conditions for the following reactions.
6
7
100
71
8[d]
11
6
9[d]
93
10
11
6
6
90
100
[a] 10% Pd/C (10 wt% of the substrate) in D2O (3 mL, 166 mmol) was
stirred under H2 atmosphere (160 mL, 6.5 mmol) at room temperature
for 24 h, then the substrate (0.5 mmol) was added, and the reaction was
quenched after 6–11 h.[b] D content was determined by 1H NMR spec-
troscopy on the basis of the integration of the aromatic, methyl or ethyl
protons.[c] Yield of isolated product.[d] 5 mL of D 2O (276 mmol) was
used.
One-pot reductive deuteration using D2 generated in situ: A
wide variety of internal olefins and acetylenes, including
dienes and diynes were employed for the one-pot reduction
to give the corresponding deuterated products in excellent
deuterium efficiencies (entries 1–4 and 8–11, Table 3).How-
Chem. Eur. J. 2008, 14, 3371 – 3379
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3373

H.Sajiki et al.
Table 4.Application to catalytic deuteration of various substrates using Pd/C–D 2O–H2 system.[a]
improved the deuterium effi-
ciency (entries 6 and 7,
Table 3), and an excellent deu-
terium incorporation was ach-
ieved using the corresponding
Entry
1[c,d]
Substrate
Time
[h]
[Dn]-Product
Yield[c]
[%]
(D content,%)[b]
methyl ester as
a substrate
(entry 8, Table 3).These reac-
tions were very clean and virtu-
ally no competitive deuteration
on the aromatic ring or non-re-
ducible positions was observed
(confirmed by 2H NMR spec-
troscopy).
24
24
79
97
2[c,d]
The present one-pot reduc-
tive deuteration method using
the generated D2 was also ap-
plicable to the deuteration
based on the dehalogenation of
aromatic halides, deoxygena-
tion of benzylic oxygen, the
ring-opening reaction of epox-
ides and catalytic reduction of
aromatic nitriles (Table 4).The
dehalogenation of aromatic
chlorides and bromide efficient-
ly proceeded with an excellent
D content by the addition of
1.2 equivalents of triethylamine
(entries 1–5, Table 4),[25] and
the coexisting olefin functional-
ity within the molecule under-
went the quantitative deutero-
genation (entries 3 and 4,
Table 4).The Pd/C-catalyzed
ring-opening reaction of epox-
ides regioselectively proceed-
ed[26] with an efficient deuteri-
um incorporation (entries 5 and
6, Table 4).The deuterogenoly-
sis of benzyl alcohol and ester
smoothly proceeded to provide
the corresponding deuterated
and deoxygenated products
([D]-20 and [D]-21, respective-
ly; entries 7 and 8, Table 4).In
these two cases, the D content
at the methyl group (44%,
entry 7, Table 4) and benzylic
3[c–e]
24
89
4[c–e]
24
24
99
95
5[c,f]
6[g]
24
6
92
7[g]
100
8[g]
9[g,h]
10[g,i]
8
12
24
100
80
95
11[g,j]
48
77
methylene
group
(69%,
[a] 10% Pd/C (10 wt% of the substrate) in D2O (3 mL, 166 mmol) was stirred under H2 atmosphere (160 mL,
6.5 mmol) at room temperature for 24 h, then the substrate (0.5 mmol) was added, and the reaction was
quenched after 6–48 h.[b] Yield of isolated product.[c] 06. mmol of triethylamine was added together with
substrate.[d] D content was determined by 1H NMR spectroscopy after the conversion of the carboxylic acid
into the corresponding methyl ester on the basis of the integration of the methyl protons.[e] 5 mL of D 2O
(276 mmol) was used.[f] D content was determined by 1H NMR spectroscopy after the conversion of the alco-
hol into the corresponding acetate on the basis of the integration of the acetyl protons.[g] D content was de-
termined by 1H NMR spectroscopy on the basis of the integration of the aromatic protons.[h] 20 wt% of the
substrate of 10% Pd/C was used and the deuterogenation of aromatic ketone was performed at 508C.
[i] 20 wt% of the substrate of 10% Pd/C was used and 0.75 mmol of DCl (20 wt%, solution in D2O) was
added together with substrate.[j] 30 wt% of the substrate of 10% Pd/C was used and 07.5 mmol of DCl
(20 wt%, solution in D2O) were added together with substrate.
entry 8) was higher than the
theoretical D content of the
deuterogenolysis (33% and
50%, respectively), presumably
because the Pd/C-catalyzed H–
D exchange reaction proceeded
at the newly formed benzylic
site after deuterogenolysis.[22]
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Deuterium-Labeling
FULL PAPER
Table 5.Development of capturing method of generated D in situ.[a,b]
By the same token, benzophenone was also successfully em-
ployed for the deuterogenation of the aromatic ketone to
produce [D2]-diphenylmethane ([D]-22) with a 96% D con-
tent (entry 9, Table 4).Furthermore, the efficient deuteroge-
nation of aromatic nitriles cleanly proceeded in the presence
of 1.5 equivalents of DCl (as a 20 wt% D2O solution) and
efficiently deuterated benzylamine derivatives ([D]-23 and
[D]-24) were obtained without the formation of any side-
products, such as secondary and tertiary amines (entries 10
and 11, Table 4).
2
Entry 10% Pd/C D2O Time Pressure/H2
D content
[%][c]
Yield[d]
[%]
[mg]
[mL] [h]
G
U
C2
1
2
3
4
5
6
7
8
30
50
30
30
40
50
50
50
6
8
6
10
8
6
24
24
48
48
48
48
48
48
4/14.7
4/14.4
3/11.0
3/10.6
3/10.8
3/11.0
3/10.8
3/10.6
44
45
45
47
46
44
46
49
44
45
45
47
46
45
44
49
79
95
100
99
96
96
One-pot deuterogenation of aromatic nuclei using the gener-
ated D2: We recently reported a mild and neutral hydroge-
nation method of aromatic nuclei catalyzed by 10% Rh/C in
water.[27] Next, we applied the present method to the deuter-
ogenation of 5-phenoxy-n-valeric acid since Rh/C indicated
the efficient catalyst activity toward the H2–D2 exchange re-
action (Figure 2).The successfully reduced and efficiently
labeled cyclohexane derivative ([D]-25) was obtained as
shown in Scheme 1.
8
10
95
95
[a] Capturing Method: 10% Pd/C in D2O was stirred under H2 pressure
at room temperature using pressure-resistant Hyper-glass cylinder
a
(96 mL), the generated D2 was captured in a rubber balloon.[b] The
purity of the generated D2 was assessed by the deuterogenation of ethyl
cinnamate: a mixture of ethyl cinnamate (0.25 mmol) and 10% Pd/C
(4.4 mg, 10 wt% of the substrate weight) in cyclohexane (1 mL) were
stirred under a captured D2 atmosphere (ca.170 mL) at room tempera-
ture for 4 h.[c] D content was determined by 1H NMR on the basis of
the integration of the aromatic protons.[d] Yield of isolated product.
to the one-pot synthesis of mono-N-alkylanilines starting
from nitrobenzene.[28] The reductive N-ethylation of nitro-
benzene under a captured D2 atmosphere was investigated
using [D3]acetonirile (CD3CN, D content: 99.8%) as an al-
kylating reagent (Scheme 2).The reductive alkylation and
Scheme 1.Application to deuterogenation of aromatic nuclei using Rh/
C–D2O–H2 system.
The method of capturing the generated D2 and itsapplica-
tion to the synthesis of deuterium-labeled compounds: The
reaction conditions for the complete conversion of H2 into
D2 were investigated in a pressure-resistant reaction vessel
under medium pressure to establish an efficient capturing
method of the generated D2 because the one-pot and in situ
deuteration method was not applicable to water-sensitive
Scheme 2.Application to Pd/C-catalyzed reductive mono- N-alkylation
using CD3CN in captured D2.
substrates and reactions.The purity of the collected D in a
2
rubber balloon was assessed by the deuterium efficiency of
the Pd/C-catalyzed deuterogenation of ethyl cinnamate in
cyclohexane (Table 5).The deuterated product ([D]- 4) was
obtained with a high D content (entry 1, Table 5, C1: 44%,
C2: 44%) under the stated conditions.Although increasing
the amounts of Pd/C or D2O, the decompression of H2 and
lengthening of the reaction time were each modestly effec-
tive for the reaction efficiency (entries 2–7, Table 5), nearly
pure D2 was generated under the combined conditions
(10 mL of D2O, 50 mg of 10% Pd/C, 3 atm of H2, 96 mL of
pressure-resistant Hyper-glass cylinder, at room temperature
for 48 h) as shown in entry 8, Table 5.Roughly 170 mL of
D2 under atmospheric pressure was captured in the rubber
balloon.
simultaneous deuteration derived from the captured D2 suc-
cessfully proceeded to afford the desired N-ethylaniline with
a good D content at the a-methylene position of the nitro-
gen atom (84%).The process of generation, capture and ap-
plication of D2 was, therefore, useful for the synthesis of the
secondary amine which is regioselectively deuterated at the
a-methylene group.
Chemoselective one-pot reductive deuteration by the addi-
tion of diphenyl sulfide: We have recently developed a Pd/
C-catalyzed chemoselective hydrogenation method for ole-
fins and acetylenes without the hydrogenolysis of other re-
ducible functionalities by the addition of a very low loading
We recently reported the Pd/C-catalyzed reductive mono-
N-alkylation of anilines using nitriles as an alkylating regent
under an H2 atmosphere, and this method is also applicable
(0.01 equiv) of diphenyl sulfide (Ph2S) as a catalyst
poison.[29] The chemoselective one-pot reductive deutera-
tions of olefins and acetylenes in the presence of other re-
Chem. Eur. J. 2008, 14, 3371 – 3379
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3375

H.Sajiki et al.
Table 6.Chemoselective one-pot deuterogenation using Ph 2S as an additive.[a]
ducible functionalities were in-
vestigated as follows: a suspen-
sion of 10% Pd/C in D2O was
stirred at room temperature
under an H2 atmosphere for
24 h followed by the addition of
Ph2S (0.01 equiv) and the sub-
strate (Table 6).Selective deu-
terogenation of the olefin and
acetylene functions proceeded
with excellent deuterium effi-
ciencies without reduction of
the aromatic carbonyl (en-
tries 1, 3 and 6, Table 6), benzyl
ester, ether and alcohol (en-
tries 4, 7 and 12, Table 6), aro-
Entry
1
Substrate
[Dn]-Product
Yield[c]
[%]
(D content,%)[b]
91
88
90
85
96
2[d]
3[e]
4[f]
5[d]
matic
Table 6),
Table 6),
chloride
N-Cbz
(entry 6,
(entry 8,
ether
TBDMS
(entry 9, Table 6) and nitrile
(entries 10 and 11, Table 6), al-
though the complete reduction
of the alkene as well as aromat-
ic carbonyl (entry 2, Table 6)
and benzyl ester (entry 5,
Table 6) functions proceeded in
the absence of Ph2S.The one-
pot chemoselective deuteroge-
nation of the alkene and alkyne
moieties was achieved with a
variety of reducible functionali-
ties, including aromatic nuclei,
remaining intact.
6
7
90
92
8
9
59
84
90
Reaction mechanism: A plausi-
ble mechanism of the Pd/C-cat-
alyzed H2–D2 exchange reaction
is illustrated in Scheme 3.We
assumed that the oxidative ad-
dition of the H2-adsorbed (acti-
vated) Pd0 (A) to D2O would
give a PdII species (B), and the
subsequent exchange reaction
between D derived from D2O
10
and H from H2 followed by the 11[g]
reductive elimination would
afford the corresponding Pd0–
HD (C) and DHO.The libera-
83
86
12[h]
tion of D2 and regeneration of
Pd0 should be achieved by fol-
lowing
through D and E.
a
similar
process
[a] 10% Pd/C (10 wt% of the substrate) in D2O (3 mL, 166 mmol) was stirred under H2 atmosphere (160 mL,
6.5 mmol) at room temperature for 24 h, the substrate (0.5 mmol) and Ph2S (0.01 equiv) were added, and the
reaction was quenched after 24 h.[b] D content was determined by 1H NMR spectroscopy on the basis of the
integration of the aromatic protons.[c] Yield of isolated product.[d] Without Ph 2S.[e] 30 wt% of the substrate
of 10% Pd/C and 5 mL of D2O (276 mmol) were used.[f] 20 wt% of the substrate of 10% Pd/C was used.
[g] 0.25 mmol of substrate, 0.02 equivalents of Ph2S, 30 wt% of the substrate of 10% Pd/C, and 5 mL of D2O
(276 mmol) were used.[h] 02.5 mmol of substrate, 30 wt% of the substrate of 10% Pd/C and 5 mL of D 2O
(276 mmol) were used.
It is noteworthy that the H2–
D2 exchange efficiency was
drastically decreased using the
low-purity D2O as the deuteri-
um source (Table 7, see also
3376
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Chem. Eur. J. 2008, 14, 3371 – 3379

Deuterium-Labeling
FULL PAPER
complex D’, but virtually no reaction would proceed by the
favorable H–H exchange on D’ [Eq.(6)] .Similarly, the ex-
istence of H2O would result in no reaction after the com-
plexation by oxidative addition of Pd species A or/and C
followed by the intramolecular H–H exchange.The use of
excess D2O compared with the H2 volume should be re-
quired for the efficient generation of pure D2.
Scheme 3.Proposed mechanism.
Scheme 3).Only 30% and 26% deuterium efficiencies were
observed at the C1 and C2 positions, respectively, in 90%
D2O (entry 2, Table 7), and 50% D2O led to virtually no in-
corporation of deuterium (entry 4, Table 7).Since a decrease
in the purity of D2O caused a significant drop in the H2–D2
exchange efficiency, an excess amount of D2O (3 mL,
166 mmol) might be required to circumvent the drastic deg-
radation of the D2O purity.
Table 7.Change of H 2–D2 exchange efficiency using low-purity D2O.[a]
Entry
D2O
[mL]
H2O
[mL]
D content [%][b]
C2
Yield[c]
[%]
C1
1
2
3
4
5
3.0
2.
2.
1.5
0.9
0
48
0.
0.
5
46
3
9
6
0
93
7
1
30
13
26
12
98
94
Conclusion
1.5
2.1
98
95
0
We have demonstrated the Pd/C-catalyzed H2–D2 exchange
reaction between D2O and H2 and its application to the
preparation of deuterium-labeled compounds.H sealed in
the reaction flask was efficiently converted into pure D2,
which can be used for the one-pot reductive deuteration of
a variety of reducible functionalities.Furthermore, the che-
moselective deuterogenation of olefins and acetylenes was
accomplished by the addition of a trace amount of Ph2S
with retention of the various other reducible functionalities.
A method of capturing the generated D2 gas was also devel-
[a] 10% Pd/C (10 wt% of 1) in mixed solvents (3 mL) of H2O and D2O
was stirred under H2 atmosphere (160 mL, 6.5 mmol) at room tempera-
ture for 24 h, trans-cinnamic acid (1) (0.5 mmol) was added, and the reac-
tion was quenched after 6 h.[b] D content was determined by 1H NMR
spectroscopy on the basis of the integration of the aromatic protons.
[c] Yield of isolated product.
2
These results were also considered from a mechanistic
point of view based on the isotope effect between H and D.
The oxidative addition of Pd to DHO should proceed pref-
erably and H–Pd–OD would predominantly form via inser-
oped.The significant features of the H –D2 exchange reac-
2
tion are efficiency, inexpensiveness, environmental friendli-
ness and convenience.These novel methodologies related to
the D2 generation should contribute to many chemistry
fields.
ꢀ
ꢀ
tion to the O H bond rather than the O D bond [Eq.(2)] .
Similarly, complex B’ could be generated by the oxidative
addition of the H2-activated Pd0 (A, Scheme 3) to DHO and
virtually no reaction was observed as a result of the “possi-
ble” H–H exchange of B’ [Eq.(3)] . Therefore, the forma-
tion of complex B derived from D2O and A (Scheme 3, A
! B) should be necessary to generate HD [Eq.(4)] . The
oxidative addition of the HD-activated Pd0 (C, Scheme 3)
with D2O (Scheme 3, C ! D) gave the complex D, which
would undergo the intramolecular H–D exchange, leading
to D2 generation via complex D’’ [Eq.(5)] . On the other
hand, the oxidative addition of C to DHO would give the
Experimental Section
General: 10% Pd/C was purchased from Sigma-Aldrich Co.(Lot.
05718BC).D 2O (>99.9% D atom) was obtained from Cambridge Iso-
tope Laboratories, Inc.or Spectra Gases, Inc.All other reagents were
purchased from commercial sources and used without further purifica-
tion.Analytical thin-layer chromatography (TLC) was carried out on
pre-coated Silica Gel 60 F254 plates (Merck, Art 5715) and visualized with
Chem. Eur. J. 2008, 14, 3371 – 3379
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
3377

H.Sajiki et al.
UV light.Flash column chromatography was accomplished using a Silica
Gel 60 (Merck; 230–400 mesh) or Silica Gel 60N (Kanto Chemical Co.,
Inc.; 63–210 mm, spherical, neutral).The 1H, 2H and 13C NMR spectra
were recorded by a JEOL AL 400 spectrometer or a JEOL EX 400 spec-
trometer.The chemical shifts ( d) are expressed in ppm and are internally
referenced to tetramethylsilane or residual solvents (7.27 ppm/CHCl3,
3.30 ppm/CH3OH, 4.75 ppm/H2O and 1.93 ppm/MeCN for 2H NMR).El-
emental analyses were performed using a YANACO CHN CORDER
MT-5 instrument.The EI and FAB mass spectra were taken by a JEOL
JMS-SX102 A instrument at the Mass Spectrometry Laboratory of the
Gifu Pharmaceutical University.The pressurized reactions were carried
out using a Hyper-glass cylinder (purchased from Taiatsu Techno Co.). In
the mass spectra data, M(D2) indicates the molecular ion peak of deuter-
ated product with two deuterium atoms, and M(D0) indicates the peak of
non-deuterated product.
determined by 1H NMR spectroscopy on the basis of the integration of
the aromatic protons.No deuterium incorporation at the aromatic ring
was confirmed by H NMR spectroscopy.
2
1
Data for [D]-26: H NMR (400 MHz, CD3OD): d=1.15 (m, 0.03H), 3.06
(d, J=7.2 Hz, 0.33H), 6.59–6.64 (m, 3H), 7.08 ppm (m, 2H); 2H NMR
(60.7 MHz, CH3OH): d=1.15 (br s), 3.04 ppm (br s); MS (EI): m/z (%):
126 (44) [M(D5)]+, 125 (36) [M(D4)]+, 124 (12) [M(D3)]+, 123 (17)
[M(D2)]+, 122 (8) [M(D1)]+, 121 (13) [M(D0)]+, 108 (100), 107 (56).
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Re-
search (No.18590009) from the Japan Society for the Promotion of Sci-
ence and the Sasakawa Scientific Research Grant from The Japan Sci-
ence Society.TK. .acknowledges the Research Fellowships of the Japan
Society for the Promotion of Science for Young Scientists.
The procedure for the one-pot reductive deuteration using the Pd/C–
D2O–H2 system: Table 2, entry 1; 10% Pd/C (7.4 mg, 10 wt% of 1) and
D2O (3 mL, 166 mmol) were placed in a 100 mL round-bottom flask
(actual internal volume of the flask is 160 mL).The system was sealed
with a septum and filled with H2 using five vacuum/H2 cycles.The mix-
ture was stirred at room temperature for 24 h and trans-cinnamic acid (1)
(74.1 mg, 0.5 mmol) as a 0.5 mL MeOH solution was added. The mixture
was stirred at room temperature for 6 h, diluted with Et2O (10 mL) and
passed through a membrane filter (Millex-LH, 0.45 mm).The filtrate was
separated into two layers.The aqueous layer was extracted with Et 2O
(2”15 mL) and the combined ethereal layers were washed with brine
(30 mL), dried over MgSO4, filtered and concentrated in vacuo to give
the analytically pure dideuterocinnamic acid ([D]-2; 73.5 mg, 98%) as a
colorless oil.The D content was determined by 1H NMR spectroscopy on
the basis of the integration of the aromatic protons.No deuterium incor-
[1] a) E.K.Barefield, G.W.Parshall, F.N.Tebbe,
J. Am. Chem. Soc.
1970, 92, 5234–5235; b) T.A.Weil, S.Friedman, I.Wender, J. Org.
Chem. 1974, 39, 48–50; c) C.Y.Hsiao, C.A.Ottaway, D.B.Wetlau-
fer, Lipids 1974, 9, 913–915; d) M.Maeda, Y.Kawazoe, Tetrahedron
Lett. 1975, 16, 1643–1646; e) M.Maeda, O.Ogawa, Y.Kawazoe,
Chem. Pharm. Bull. 1977, 25, 3329–3333; f) K.Ofosu-Asante, L.M.
Stock, J. Org. Chem. 1986, 51, 5452–5454; g) D.K. Takehara, J.B.
Butt, R.L.Burwell Jr., J. Catal. 1992, 133, 279–293; h) D.K.Take-
hara, J.B.Butt, R.L.Burwell Jr.,
Heys, J. Chem. Soc. Chem. Commun. 1992, 680–681; j) J.R. Heys,
A.Y.L.Shu, S.G.Senderoff, N.M.Phillips, J. LabelledCompd. Ra-
diopharm. 1993, 33, 431–438; k) J.Azran, M.Shimori, O.Buchman,
J. Catal. 1992, 133, 294–308; i) R.
2
poration at the aromatic ring was confirmed by H NMR spectroscopy.
Data for [D]-2: 1H NMR (400 MHz, CD3OD): d=2.47 (m, 1.07H), 2.79
(m, 1.01H), 7.05–7.18 ppm (m, 5H, Ph); 2H NMR (60.7 MHz, CH3OH):
d=2.56 (br s), 2.87 ppm (br s); MS (EI): m/z (%): 152 (50) [M(D2)]+,
151 (15) [M(D1)]+, 150 (2) [M(D0)]+, 106 (60), 92 (100).
J. Catal. 1994, 148, 648–653; l) D.Hesk, P.R.Das, B.Evans,
J. La-
belled Compd. Radiopharm. 1995, 36, 497–502; m) W.Chan, K.T.
Garnes, S.H. Levinson, D. Saunders, S.G. Senderoff, A.Y.L. Shu,
A.J. Villani, J.R. Heys, J. Labelled Compd. Radiopharm. 1997, 39,
291–298; n) G.J. Ellames, J.S. Gibson, J.M. Herbert, W.J. Kerr,
A.H. McNeill, Tetrahedron Lett. 2001, 42, 6413–6416; o) M.J.
Hickey, J.R. Jones, L.P. Kingston, W.J.S. Lockley, A.N. Mather,
B.M. McAuley, D.J. Wilkinson, Tetrahedron Lett. 2003, 44, 3959–
Table 4, entry 1: 10% Pd/C (7.8 mg, 10 wt% of 4-chlorobenzoic acid)
and D2O (3 mL, 166 mmol) were placed in a 100 mL round-bottom flask
(actual internal volume of the flask is 160 mL).The system was sealed
with a septum and filled with H2 using five vacuum/H2 cycles.The mix-
ture was stirred at room temperature for 24 h and 4-chlorobenzoic acid
(78.0 mg, 0.5 mmol) as a 0.5 mL MeOH solution and Et3N (83.6 mL,
0.6 mmol) were added. The mixture was stirred at room temperature for
24 h, diluted with Et2O (10 mL), and passed through a membrane filter
3961; p) MB. .Skaddan, CM. .Yung, RG. .Bergman,
Org. Lett.
2004, 6, 11–13; q) M.J. Hickey, J.R. Jones, L.P. Kingston, W.J.S.
Lockley, A.N.Mather, D.J.Wilkinson,
8621–8623.
Tetrahedron Lett. 2004, 45,
(Millex-LH, 0.45 mm).The filtrate was neutralized using a 5% NaHSO
4
[2] The Merck Index, 12th ed,. (Eds:. S.Budavari, MJ..OꢁNeil, A.
Smith, P.E. Heckelman, J.F. Kinneary), Merck & Co., Ink., New
Jersey, 1996, pp.2983.
[3] For reviews: a) Y.Koike, OPTRONICS 1996, 126–132; b) T.Junk,
W.J. Catallo, Chem. Soc. Rev. 1997, 26, 401–406, and references
therein.
[4] For examples: a) S.Baba, Radioisotopes 1982, 31, 119–126; b) D.E.
Stevenson, M.Akhtar, D.Gani, Tetrahedron Lett. 1986, 27, 5661–
5664; c) J.E. Baldwin, R.M. Adlington, H-.H. Ting, D. Arigoni, P.
Graf, B.Martinoni, Tetrahedron 1985, 41, 3339–3343; d) T.Furuta,
H.Takahashi, Y.Kasuya, J. Am. Chem. Soc. 1990, 112, 3633–3636;
aqueous solution and extracted with Et2O (2”15 mL).The ethereal
layers were washed successively with water (10 mL) and brine (30 mL),
dried over MgSO4, filtered, and concentrated in vacuo to give an analyti-
cally pure 4-deuterobenzoic acid ([D]-14; 48.4 mg, 79%) as a colorless
solid.The D content was determined by 1H NMR of the corresponding
methyl ester on the basis of the integration of the methyl protons.
Data for methyl ester of [D]-14: 1H NMR (400 MHz, CD3OD): d=3.93
(s, 3H), 7.49 (d, J=5.9 Hz, 2H), 7.62 (m, 0.060H), 8.04 ppm (d, J=
5.9 Hz, 2H); MS (EI): m/z (%): 137 (42) [M(D1)]+, 136 (9) [M(D0)]+,
106 (100), 78 (54).
The method of capturing the generated D2 in situ and the application to
the reductive mono-N-alkylation using nitrile: Scheme 2; A suspension of
10% Pd/C (50.0 mg) in D2O (10 mL, 553 mmol) in a 96 mL Hyper-glass
cylinder was stirred under 3 atm of H2 pressure (internal H2 is ca.
260 mL under atmospheric pressure) at room temperature for 48 h.The
generated D2 gas was captured using a rubber balloon (ca.170 mL).A
mixture of nitrobenzene (61.6 mg, 0.5 mmol) and 10% Pd/C (12.3 mg, 20
wt% of the nitrobenzene) in CD3CN (D content: 99.8%, 0.75 mL,
14.4 mmol) in a test tube was stirred under the captured D2 (balloon) at
room temperature for 24 h.The reaction mixture was diluted with Et 2O
(30 mL), and passed through a membrane filter (Millex-LH, 0.45 mm).
The filtrate was concentrated in vacuo.The residue was purified by flash
silica gel column chromatography (hexane:Et2O = 20:1) to give [D5]-N-
ethylaniline ([D]-26; 48.1 mg, 79%) as a colorless oil. The D content was
e) K.H. Gardner, L.E. Kay,
J. Am. Chem. Soc. 1997, 119, 7599–
7600; f) J.Raap, S.Nieuwenhuis, A.Creemers, S.Hexspoor, U.
Kragl, J.Lugtenburg, Eur. J. Org. Chem. 1999, 2609–2621; g) M.-Y.
Chou, A.B. Mandal, M.-K. Leung, J. Org. Chem. 2002, 67, 1501–
1505; h) A.Durazo, M.M.Abu-Omar,
67.
Chem. Commun. 2002, 66–
[5] For reviews: a) P.N.Rylander in Hydrogenation Methods, Academic
Press, New York, 1985; b) M.Hudlicky in Reduction in Organic
Chemistry, 2nd ed., American Chemical Society, Washington, DC,
1996.
[6] Inorganic Isotopic Synthesis, (Ed.: R. H. Herber), Benjamin, New
York, 1962.
[7] W.B.Mann, W.C.Newell,
397–403.
Proc. R. Soc. London Ser. A 1973, 158,
3378
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Chem. Eur. J. 2008, 14, 3371 – 3379

Deuterium-Labeling
FULL PAPER
[8] J.B.M.Coppock, Trans. Faraday Soc. 1935, 31, 913–914.
T.Maegawa, K.Hirota, Tetrahedron Lett. 2005, 46, 6995–6998; c) T.
[9] J.W.Knowlton, F.D.Rossini,
J. Res. Natl. Bur. Stand. 1937, 19, 605–
Maegawa, A.Akashi, H.Esaki, F.Aoki, H.Sajiki, K.Hirota,
Synlett
612.
2005, 845–847; d) H.Sajiki, H.Esaki, F.Aoki, T.Maegawa, K.
Hirota, Synlett 2005, 1385–1388; e) H.Esaki, F.Aoki, T.Maegawa,
K.Hirota, H.Sajiki, Heterocycles 2005, 66, 361–369; f) N.Ito, T.
[10] A.Farkas, L.Farkas, J.Yudkin,
379.
Proc. Roy. Soc. B 1934, 115, 373–
[11] H.E.von Hahn, E.Peters, J. Phys. Chem. 1971, 75, 571–579.
Watahiki, T.Maesawa, T.Maegawa, H.Sajiki,
Adv. Synth. Catal.
[12] N.Palibroda, E.Grecu, P.M¼rginean, Isotopenpraxis 1986, 22, 435–
2006, 348, 1025–1028; g) H.Esaki, N.Ito, S.Sakai, T.Maegawa, Y.
Monguchi, H.Sajiki, Tetrahedron 2006, 62, 10954–10961; h) H.
438.
[13] F.A.El-Nour, N.Belacy, M.Abdel-Khalik, T.Khalil, H.F.Aly,
topenpraxis 1990, 26, 529–531.
[14] H.Mochizuki, S.Noda, T.Morishima, Radioisotopes 1987, 36, 163–
Iso-
Esaki, R.Ohtaki, T.Maegawa, Y.Monguchi, H.Sajiki,
Chem. 2007, 72, 2143–2150; i) H.Esaki, F.Aoki, M.Umemura, M.
Kato, T.Maegawa, Y.Monguchi, H.Sajiki, Chem. Eur. J. 2007, 13,
4052–4063; j) T.Kurita, K.Hattori, S.Seki, T.Mizumoto, F.Aoki.
J. Org.
168.
[15] A.Baba, M.Nishikawa, T.Eguchi, J. Nucl. Mater. 1997, 250, 29–35.
Y.Yamada, K.Ikawa, T.Maegawa, Y.Monguchi, H.Sajiki,
Eur. J. 2008, 14, 664–673.
Chem.
[16] T.Yoshida, T.Okano, K.Saito, S.Otsuka,
Inorg. Chim. Acta 1980,
44, L135–L136.
[24] Preliminary results were reported on a communication: H.Sajiki, T.
[17] J.P.Collman, P.S.Wagenknecht, R.T.Hembre, N.S.Lewis,
J. Am.
Kurita, H.Esaki, F.Aoki, T.Maegawa, K.Hirota,
Org. Lett. 2004, 6,
Chem. Soc. 1990, 112, 1294–1295.
3521–3523.
[18] P.V.Grundler, O.V.Yazyev, N.Aebischer, L.Helm, G.Laurenczy,
A.E.Merbach, Inorg. Chim. Acta 2006, 359, 1795–1806.
[19] W.-C. Chan, C.-P. Lau, L. Cheng, Y.-S. J. Leung, J. Organomet.
Chem. 1994, 464, 103–106.
[25] a) H.Sajiki, A.Kume, K.Hattori, K.Hirota,
Tetrahedron Lett. 2002,
43, 7247–7250; b) H.Sajiki, A.Kume, K.Hattori, H.Nagase, K.
Hirota, Tetrahedron Lett. 2002, 43, 7251–7254; c) Y.Monguchi, A.
Kume, K.Hattori, T.Maegawa, H.Sajiki,
Tetrahedron 2006, 62,
Tetrahedron 2006,
[20] J.Bakos, R.Karaivanov, M.Laghmari, D.Sinou,
Organometallics
7926–7933; d) Y.Monguchi, A.Kume, H.Sajiki,
1994, 13, 2951–2956.
62, 8384–8392; e) A.Kume, Y.Monguchi, K.Hattori, H.Nagase, H.
Sajiki Appl. Catal. B-Environ. 2008, in press..
[26] a) W.Whitmore, A.Gelbhart, J. Am. Chem. Soc. 1942, 64, 912–917;
[21] a) F.Joꢂ, P.Csiba, A.Bꢃnyei, J. Chem. Soc. Chem. Commun. 1993,
1602–1604; b) F.Joꢂ, L.Nꢄdasdi, A.C.Bꢃnyei, D.J.Darensbourg,
J. Organomet. Chem. 1996, 512, 45–50; c) L.Nꢄdasdi, F.Joꢂ, Inorg.
Chim. Acta 1999, 293, 218–222; d) G.Kovꢄcs, L.Nꢄdasdi, F.Joꢂ, G.
Laurenczy, C. R. Acad. Sci. Paris, SØrie IIc, Chem. 2000, 3, 601–605;
b) M.S.Newman, G.Underwood, M.Renold,
J. Am. Chem. Soc.
1949, 71, 3362–3363; c) F.Gordon, BE Pat,. Serial Code: 663808,
1965.
e) G.Kovꢄcs, L.Nꢄdasdi, G.Laurenczy, F.Joꢂ,
5, 213–217; f) G.Kovꢄcs, G.Schubert, F.Joꢂ, I.Pꢄpai, Organometal-
lics 2005, 24, 3059–3065.
Green Chem. 2003,
[27] T.Maegawa, A.Akashi, H.Sajiki, Synlett 2005, 1440–1442.
[28] H.Sajiki, T.Ikawa, K.Hirota, Org. Lett. 2004, 6, 4977–4980.
[29] a) A.Mori, Y.Miyakawa, E.Ohashi, T.Haga, T.Maegawa, H.
Sajiki, Org. Lett. 2006, 8, 3279–3281; b) A.Mori, T.Mizusaki, Y.
Miyakawa, E.Ohashi, T.Haga, T.Maegawa, Y.Monguchi, H.
Sajiki, Tetrahedron 2006, 62, 11925–11932.
[22] H.Sajiki, K.Hattori, F.Aoki, K.Yasunaga, K.Hirota,
1149–1151.
[23] We have recently reported the multiple deuterium-labeling methods
of inactive alkyl chains, aromatic rings, aliphatic secondary alcohols,
ketones, phenylalanine derivatives and nucleosides under high tem-
perature conditions using the Pd/C (and/or Pt/C)-D2O-H2 system,
Synlett 2002,
Received: August 10, 2007
Revised: November 18, 2007
see: a) H.Sajiki, F.Aoki, H.Esaki, T.Maegawa, K.Hirota,
Org.
Lett. 2004, 6, 1485–1487; b) H.Sajiki, N.Ito, H.Esaki, T.Maesawa,
Published online: February 13, 2008
Chem. Eur. J. 2008, 14, 3371 – 3379
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
3379