General method of obtaining deuterium-labeled heterocyclic compounds using neutral D2O with heterogeneous Pd/C

Article abstract of DOI:10.1016/j.tet.2006.08.088

A protocol of a versatile H-D exchange reaction of heterocyclic compounds catalyzed by heterogeneous Pd/C in D₂O is described. The reaction of various nitrogen-containing heterocycles with 10% Pd/C (10 wt % of the substrate) under hydrogen atmosphere in D₂O as a deuterium source at 110-180 °C for 24 h afforded the corresponding deuterated compounds with satisfactory efficiency of deuteration in moderate to excellent isolated yields. Furthermore, the Pd/C-H₂-D₂O system can be extended to the direct deuteration of biologically active compounds such as sulfamethazine, which is used as a synthetic antibacterial drug for fat stocks and would be applied as a general method for the preparation of the standard materials for the analysis of residual chemicals in foods and so on.

Full text of DOI:10.1016/j.tet.2006.08.088

Tetrahedron 62 (2006) 10954–10961
General method of obtaining deuterium-labeled heterocyclic
compounds using neutral D2O with heterogeneous Pd/C
Hiroyoshi Esaki,a Nobuhiro Ito,b Shino Sakai,a Tomohiro Maegawa,a
Yasunari Monguchia and Hironao Sajikia,
*
aLaboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
bChemical Products Research Laboratories, Wako Pure Chemical Industries, Ltd, 1633 Matoba, Kawagoe 350-1101, Japan
Received 13 July 2006; accepted 21 August 2006
Available online 18 September 2006
Abstract—A protocol of a versatile H–D exchange reaction of heterocyclic compounds catalyzed by heterogeneous Pd/C in D2O is described.
The reaction of various nitrogen-containing heterocycles with 10% Pd/C (10 wt % of the substrate) under hydrogen atmosphere in D2O as
a deuterium source at 110–180 ꢀC for 24 h afforded the corresponding deuterated compounds with satisfactory efficiency of deuteration in
moderate to excellent isolated yields. Furthermore, the Pd/C–H2–D2O system can be extended to the direct deuteration of biologically active
compounds such as sulfamethazine, which is used as a synthetic antibacterial drug for fat stocks and would be applied as a general method for
the preparation of the standard materials for the analysis of residual chemicals in foods and so on.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
only at the benzylic positions, but also on the non-activated
carbons.11 Since heterocyclic compounds such as indole,
pyridine, pyrimidine, and quinoline ring systems are often
seen in natural products, pharmaceuticals, veterinary medi-
cines, agrochemicals, and so on, the deuterated heterocycles
are of interest as building blocks of such bioactive materials
needed as internal standards in GC–MS or LC–MS assays.
Taking into consideration the establishment of a general deu-
teration method of heterocycles as the core nuclei of biolog-
ically active compounds using the Pd/C–H2–D2O system,
we studied the deuteration of a wide range of heterocyclic
substrates.
Deuterium-labeled compounds have found extensive appli-
cations in such research areas as pharmaceutical, bioanalyt-
ical, biological, and environmental chemistry to analyze
drug metabolism mechanisms, residual agrochemicals in
foods using mass spectrometry (MS), structure of bio-
molecules, and so on.1,2 Access to the deuterium-labeled
compounds has been facilitated by the adoption of the post-
synthetic H–D exchange reaction instead of the laborious
and costly multi-step synthetic processes starting from orig-
inally deuterium-labeled small synthons. Although a huge
number of post-synthetic H–D exchange reactions have been
reported in the literature, they usually require high tempera-
ture and pressure,3 stoichiometric reagents,4 expensive or in-
accessible reagents,5 strong bases or acids,2e,3a–c,3g–j,6 special
apparatus,2e,6f and/or deuterium atmosphere.4a–4c,5a,7 Fur-
thermore, some of the methods involve structural transforma-
tions3m,3q,8 or a low degree of deuterium-efficiency.6c,7g,7m,9
Hence, the development of new, post-synthetic, and deute-
rium-efficient H–D exchange reactions is still a challenging
subject.
2. Results and discussion
A variety of heterocyclic substrates were heated at 110–
180 ꢀC (bath temperature) in the presence of a catalytic
amount of 10% Pd/C (10% of the weight of the substrate,
Aldrich) in D2O. The reaction was carried out under ca.
1 atm H2 pressure and reflux conditions (110–160 ꢀC of
the heating head or bath temperature) using ChemiStationÔ
or reflux condenser (Dimroth type); the inner reaction tem-
perature was at ca. 104 ꢀC (boiling point of D2O). When
a sealed tube was employed as a reaction vessel, the reaction
mixture was stirred at 160 or 180 ꢀC under <2.5 atm H2
pressure (the inner gas pressure was measured by a pressure
gauge). The deuterated positions and deuterium-efficiency
of the obtained products were determined by 1H NMR
(DSS, p-anisic acid or dioxane as an internal standard),
2H NMR, and mass spectra. It is noteworthy that water
We recently developed a regioselective H–D exchange reac-
tion at the benzylic positions using Pd/C as a catalyst in deu-
terium oxide under hydrogen atmosphere (Pd/C–H2–D2O
system) at room temperature,10 and found that the applica-
tion of heat could promote the H–D exchange reaction not
* Corresponding author. Tel.: +81 58 237 8572; fax: +81 58 237 5979;
e-mail: sajiki@gifu-pu.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.088

H. Esaki et al. / Tetrahedron 62 (2006) 10954–10961
Table 1. H–D exchange reaction of pyridine derivatives in D2O catalyzed
Table 1. (continued)
10955
a
by 10% Pd/C–H2
Entry
Temp (ꢀC)b
D content (%)c
Yield (%)d
10% Pd=C; H2
ƒƒƒƒƒƒƒƒ!
D2O; 24 h
Substrate
Product-dn
0
COOH
37
98
15f,i
160
98
Entry
1e,f
Temp (ꢀC)b
110
D content (%)c
Yield (%)d
83k
69
N
9
97
81
99
81
99
CONH2
44
99
16f
160
100
N
97
N
NH2
N
a
Unless otherwise noted, 0.5 mmol of the substrate was used. Reactions
were carried out in a sealed tube under ordinary H2 pressure using 10%
Pd/C (10 wt % of the substrate) in D2O (2 mL) for 24 h.
Temperature of oil bath or heating head of ChemiStationÔ.
D content was determined by 1H NMR.
98
98
98
98
2f
160
180
100
100
b
c
d
e
f
98
98
98
Isolated yield, unless otherwise stated.
3g
Substrate (1 mmol) was used in D2O (4 mL).
The reaction was carried out using the ChemiStationÔ.
Substrate (500 mg) was used in D2O (17 mL).
Pd/C [10% (10 wt % of the substrate)] and Pt/C [5% (20 wt % of the
substrate)] were used.
Substrate (0.25 mmol) was used in D2O (1 mL).
Indicated as the average D content.
Determined by GC.
98
N
NH2
g
h
98
99
99
4g
180
69
98
i
j
N
NH2
98
k
98
98
5g
180
180
180
91
51
49
(D2O)-insoluble substrates are also acceptable for this H–D
exchange reaction.
98
N
NH2
98
50
91
98
6g
2.1. H–D exchange reaction of pyridine derivatives
N
NH2
98
98
As shown in Table 1, the H–D exchange reaction proceeded
well on the pyridine nucleus to give the desired multi-deuter-
ated products in satisfactory deuterium-efficiency and
isolated yields. In particular, aminopyridine and hydroxy-
pyridine derivatives showed remarkably excellent deute-
rium-efficiency at 160–180 ꢀC (entries 2–5, 7, and 8). It is
noteworthy to mention that the 5-position of 2-amino-
6-methylpyridine where the H–D exchange was inefficient
only with Pd/C could be deuterated easily by using 5% Pt/C
together with 10% Pd/C (entries 6 vs 7). In general, higher
efficiency of deuteration at the positions adjacent to the
nitrogen atoms on the pyridine rings was observed rather
than at other positions. On the other hand, lower incorpora-
tion of deuterium at the neighboring positions of a carbon
substituent (ortho-positions to the substituent) such as
CH2, CO2H, and CONH2 (entries 10–16) was observed pre-
sumably due to steric hindrance. Moreover, as shown in
entries 15 and 16, the H–D exchange reaction efficiently
proceeded even at the ortho-position to the substituent if
the position was adjacent to the nitrogen atom in the pyridine
ring. It is apparent that the nitrogen atom profoundly influ-
ences the deuteration reaction using the Pd/C–H2–D2O sys-
tem. It is expected that the Pd metal can be located in the
vicinity of the nitrogen atom of the pyridine ring since Pd
metal has a quite high affinity for the nitrogen lone pair.
This could be the reason why the 2-position of the pyridine
ring was effectively deuterated.
98
98
7g,h
N
NH2
98
8g
180
160
99
90
99
94
OH
98
N
99
71
9f
100
N
OH
99
j
97
31
5
26
j
26
j
10
11
12
160
160
160
N
88
84
80
97
5
31
26
74
97
74
97
N
N
97
74
97
74
97
96 96
97
97
97
97
97
N
N
87
96
96
87
96
96
96
87
5
13
160
160
97
99
N
N
87
87
96
2.2. H–D exchange reaction of indole derivatives
83
N
Excellent deuterium incorporation was observed at the
methyl substituents as well as at the positions adjacent to
the nitrogen atoms on the indole, azaindole, benzimidazole,
and quinoline rings, while the efficiency of the deuteration at
the neighboring positions of the methyl groups was usually
64
91
14f
COOH
(continued)

10956
H. Esaki et al. / Tetrahedron 62 (2006) 10954–10961
low compared to the position adjacent to the hydroxyl group
(Table 2, entries 1–7 and 9–11). In addition, the 7-position of
the indole and benzimidazole rings, which are regarded as the
ortho-positions to the amino groups of the benzene rings,
were deuterated efficiently (entries 1–3, 6, 7, and 10). On
the other hand, no incorporation was found at the 7-position
when 1,2-dimethylindole was used as a substrate (entry 5).
The above results also demonstrate that this deuterating
methodishighlyaffected bybothelectronicandstericfactors.
Table 2. H–D exchange reaction of indole, azaindole, benzimidazole,
quinoline derivatives in D2O catalyzed by 10% Pd/C–H2
a
10% Pd=C; H2
ƒƒƒƒƒƒƒƒ!
Substrate
Product-dn
D2O; 24 h
Entry
1
Temp (ꢀC)b
D content (%)c
Yield (%)d
80
85
95
65
70
97
160
160
160
160
N
H
2.3. H–D exchange reaction of pyrimidine
and imidazole derivatives
97
26
96
h
87
h
87
When 2-mercaptopyrimidine was used as a substrate, no
H–D exchange reaction was observed and dimerization
proceeded as a result of the formation of a disulfide linkage
(Table 3, entry 1). Probably because the sulfur atom acted as
a catalytic poison, the H–D exchange reaction was
completely suppressed. On the other hand, when the thiol
moiety was replaced with an amino group, the deuteration,
especially at the 4- and 6-positions, proceeded smoothly
with high efficiency (entry 2). When two methyl groups
were introduced to the 4- and 6-positions of 2-aminopyrimi-
dine, no deuterium incorporation at the 5-position was
observed, whereas the 5-position, which was adjacent
to the hydroxyl group, was deuterated quantitatively when
2-amino-4-hydroxy-6-methylpyrimidine was used as
2
94
98
91
85
N
H
97
53
89
99
3e,f
98
49
N
H
96
95
92
i
i
71
96
4
N
H
71
96
77
14
67
95
5f
140
160
160
95
98
99
75
N
0
86
51
71
98
HO
Table 3. H–D exchange reaction of pyrimidine, pyrazole derivatives in D2O
catalyzed by 10% Pd/C–H2
j
a
98
6
97
N
H
10% Pd=C; H2
ƒƒƒƒƒƒƒƒ!
j
Substrate
Product-dn
D2O; 24 h
25
D3CO
55
98
24
Entry
1
Temp (ꢀC)b
D content (%)c
Yield (%)d
NAh
7f
98
0
47
N
H
0
N
160
160
0
70k
N
SH
70
92
4
4
44
55
8e
160
160
96
99
54
70k
99
N
H
56
99
70k
N
2
99
N
NH2
97
81
65
98
98
CD3 95
N
9
N
H
N
3e
110
100
0
95
D3C
N
NH2
97
93
N
97
10
160
180
99
83
OH
N
H
23
96
97
63
4e
110
160
100
81
N
96
99
D3C
N
NH2
99
99
93
99
11g
97g
CD3
97
N
98
5f
97g
D3C
N
a
Unless otherwise noted, 0.5 mmol of the substrate was used. Reactions
were carried out in a sealed tube under ordinary H2 pressure using 10%
Pd/C (10 wt % of the substrate) in D2O (2 mL).
Temperature of oil bath or heating head of ChemiStationÔ.
D content was determined by 1H NMR.
N
H
a
Unless otherwise noted, 0.5 mmol of the substrate was used. Reactions
were carried out using the ChemiStationÔ under ordinary H2 pressure
using 10% Pd/C (10 wt % of the substrate) in D2O (2 mL).
Temperature of oil bath or heating head of ChemiStationÔ.
D content was determined by 1H NMR.
b
c
d
e
f
Isolated yield.
b
c
d
e
f
Substrate (0.25 mmol) was used in D2O (1 mL).
The reaction was carried out using the ChemiStationÔ.
Substrate (500 mg) was used in D2O (17 mL).
Isolated yield.
g
The mixture was heated under reflux for 24 h.
The reaction was carried out in a sealed tube.
Indicated as the average D content.
h–k
Indicated as the average D content.
g
h
Disulfide of 2-mercaptopyrimidine was formed as a product.

H. Esaki et al. / Tetrahedron 62 (2006) 10954–10961
10957
a substrate (entries 3 vs 4). Furthermore, the use of 3,5-di-
methylpyrazole led to almost quantitative deuterium incor-
poration at the 4-position (entry 5). These results suggest
that introduction of an appropriate substituent into the
substrate may enable us to establish a regioselective H–D ex-
change reaction by taking advantage of the steric hindrance
and/or neighboring effect of the substituent.
agents, proceeded effectively (Table 4, entries 1 and 2), but
the efficiency of the deuteration at the methyl group of anti-
pirine, an analgesic agent, was seriously reduced (entry 4).
Instead, antipirine was regioselectively deuterated on the
pyrazolidinone ring (entry 4). When allopurinol, an antiuro-
lithic agent, was used as a substrate, the H–D exchange
reaction proceeded effectively (entry 3).
2.4. H–D exchange reaction of biologically
active compounds
Deuterated drugs often have different actions from the pro-
tonated forms in vivo.12 Some deuterated drugs show differ-
ent transport processes. Since many deuterated drugs are
more resistant to metabolic changes by the isotope effect
derived from bulky deuterium, it can be expected that
deuterium-labeled drugs demonstrate the feasibility of
developing new sustained-release dosage by virtue of the
isotope effect. The deuteration method we demonstrated in
this paper could be a general method for the preparation of
new prolonged drugs as well as the standard materials for
the studies of metabolism and the analysis of residual chem-
icals in the environment.
The applications of stable isotope (SI)-labeled compounds
for clinical pharmacokinetic studies and the analysis of
residual agrochemicals in the environment have rapidly
increased in recent years. Since the chemical properties of
SI-labeled compounds are similar to those of non-labeled
compounds, SI-labeled compounds are the most valuable
tracers for these studies and analyses using GC–MS or
LC–MS. In spite of the usefulness of SI-labeled isotope
tracers, there are often problems incurred in getting a desired
labeled tracer because of the difficulties in the synthesis of
SI-labeled compounds. Heating a variety of biologically ac-
tive compounds in the Pd/C–H2–D2O system led to efficient
introduction of deuterium atoms. The results are summarized
in Table 4.
3. Conclusion
In summary, we have developed an efficient and extensive
deuterium incorporation method using a heterogeneous Pd/
C–H2–D2O system for a wide range of substrates including
bioactive substances in moderate to excellent deuterium-
efficiency. The results presented here provide a deuterium
gas-free, totally catalytic, and post-synthetic deuterium
labeling method in D2O medium. The simplicity of this
method makes it an attractive new tool for medicinal,
analytical, and organic chemists.
The H–D exchange reactions at the methyl groups in sulfa-
methazine and nalidixic acid, both of which are antibacterial
Table 4. H–D exchange reaction of bioactive compounds in D2O catalyzed
by 10% Pd/C–H2
a
10% Pd=C; H2
ƒƒƒƒƒƒƒƒ!
Substrate
Product-dn
D2O; 24 h
Entry Temp (ꢀC)b
D content (%)c
Yield (%)d
4. Experimental
4.1. General
96
5
25
25
5
N
N
H2N
SO2NH
5
1
2
3
160
160
160
97
96
All the substances examined in this study were obtained
commercially and were used without further purification.
Pd/C (10%) was purchased from Aldrich Chemical Co.
and deuterium oxide (99.9% isotopic purity) was purchased
from Cambridge Isotope Laboratories.
20
0
93
N
N
0
96
99
63
COOH
53
O
ChemiStationÔ is a personal organic synthesizer from
TOKYO RIKAKIKAI CO., LTD (EYELA). 1H and 2H
NMR spectra were recorded on a JEOL AL-400 spectrome-
ter or JEOL EX-400 spectrometer (1H NMR: 400 MHz, 2H
NMR: 61 MHz). Chemical shifts (d) are given in parts per
million relative to residual solvent or internal standard (3-tri-
methylsilyl-1-propanesulfonic acid sodium salt (DSS),
p-anisic acid, or dioxane). EI and FAB mass spectra were
recorded on a JEOL JMS-SX102A spectrometer. GC spectra
were recorded on a SHIMADZU GC-17A spectrometer.
Preparative thin-layer chromatography was performed using
Merk PLC plate (silica gel 60 F254).
OH
97
N
N
87
N
H
N
0
2
0
2
0
4e
160
98
N
0
O
N
91
9
a
Substrate (0.25 mmol) was used. Reactions were carried out in a sealed
tube under ordinary H2 pressure using 10% Pd/C (10 wt % of the sub-
strate) in D2O (1 mL).
Temperature of oil bath or heating head of ChemiStationÔ.
4.2. General procedure for H–D exchanges
b
c
d
e
Method A: A substrate (0.25–0.50 mmol) and 10% Pd/C
(10 wt % of the substrate) in D2O (1–2 mL) were stirred at
160 ꢀC using the ChemiStationÔ under H2 atmosphere for
D content was determined by 1H NMR.
Isolated yield.
The reaction was carried out using the ChemiStationÔ.

10958
H. Esaki et al. / Tetrahedron 62 (2006) 10954–10961
24 h. After cooling, the reaction mixture was diluted with
methanol (10 mL) and the mixture was filtered through
a membrane filter (Millipore MillexÒ-LG, 0.20 mm) to
remove the catalyst. The filtered catalyst was washed with
methanol (2ꢁ10 mL) and the filtrate was concentrated
in vacuo.
(DMSO-d6, DSS as an internal standard) d 7.97 (s, 0.03H),
6.46 (s, 0.04H), 5.96 (br s, 2H). H NMR (DMSO) d 7.96
(br s), 6.45 (br s).
2
4.2.3. [2H]-2-Aminopyridine (Table 1, entry 3). Method
C. Purification by preparative thin-layer chromatography
(silica gel, ethyl acetate) gave 2-aminopyridine-dn as a color-
less solid (100% yield). Isotope distribution (EIMS): 1% d1,
2% d2, 9% d3, 82% d4, 6% d5. 1H NMR (CD2Cl2, dioxane as
an internal standard) d 8.02 (s, 0.02H), 7.41 (s, 0.02H), 6.61
(s, 0.02H), 6.49 (s, 0.02H), 4.44 (br s, 2H). 2H NMR
(CH2Cl2) d 8.06 (br s), 7.45 (br s), 6.66 (br s), 6.54 (br s).
Method B: A substrate (0.25–0.50 mmol) and 10% Pd/C
(10 wt % of the substrate) in D2O (1–2 mL) were stirred at
160 ꢀC using the ChemiStationÔ under H2 atmosphere for
24 h. After cooling, the reaction mixture was diluted with
diethyl ether (10 mL) and the mixture was filtered through
a membrane filter (Millipore MillexÒ-LG, 0.20 mm) to
remove the catalyst. The filtered catalyst was washed with
diethyl ether (2ꢁ10 mL). The combined organic phases
were washed with H2O (2ꢁ30 mL) and brine (30 mL), dried
over MgSO4, and evaporated under reduced pressure to
afford deuterated forms.
4.2.4. [2H]-2-Amino-4-methylpyridine (Table 1, entry 4).
2-Amino-4-methylpyridine (500 mg, 4.6 mmol) and 10%
Pd/C (50 mg, 10 wt % of the substrate) in D2O (17 mL)
were stirred at 180 ꢀC under H2 atmosphere for 24 h. After
cooling, the reaction mixture was diluted with ethyl acetate
(20 mL) and the mixture was filtered through a filter paper to
remove the catalyst. The filtered catalyst was washed with
ethyl acetate (2ꢁ5 mL). The combined organic phases
were washed with H2O (20 mL), dried over MgSO4, and
concentrated in vacuo. Purification by preparative thin-layer
chromatography (silica gel, ethyl acetate) gave 2-amino-4-
methylpyridine-dn as a colorless solid (69% yield). Isotope
distribution (EIMS): 1% d3, 2% d4, 13% d5, 76% d6, 6%
d7, 2% d8. 1H NMR (CDCl3, dioxane as an internal standard)
d 7.93 (s, 0.01H), 6.48 (s, 0.01H), 6.32 (s, 0.02H), 4.35 (br s,
Method C: A substrate (500 mg, 4.6–5.3 mmol) and 10%
Pd/C (50 mg, 10 wt % of the substrate) in D2O (17 mL)
were stirred at 180 ꢀC in a sealed tube under H2 atmosphere
for 24 h. After cooling, the reaction mixture was diluted with
methanol (20 mL) and the mixture was filtered through a
filter paper to remove the catalyst. The filtered catalyst
was washed with methanol (2ꢁ5 mL) and the filtrate was
concentrated in vacuo.
2
Method D: A substrate (0.25–0.50 mmol) and 10% Pd/C
(10 wt % of the substrate) in D2O (1–2 mL) were stirred at
160 ꢀC in a sealed tube under H2 atmosphere for 24 h. After
cooling, the reaction mixture was diluted with diethyl ether
(10 mL) and the mixture was filtered through a membrane
filter (Millipore MillexÒ-LG, 0.20 mm) to remove the cata-
lyst. The filtered catalyst was washed with diethyl ether
(2ꢁ10 mL). The combined organic phases were washed
with H2O (2ꢁ30 mL) and brine (30 mL), dried over
MgSO4, and evaporated under reduced pressure to afford
deuterated forms.
2H), 2.20 (s, 0.07H). H NMR (CHCl3) d 7.94 (br s), 6.53
(br s), 6.37 (br s), 2.20 (br s).
4.2.5. [2H]-2-Amino-5-methylpyridine (Table 1, entry 5).
Method C, 91% yield as a pale yellow crystal. Isotope distri-
bution (EIMS): 1% d2, 3% d3, 18% d4, 12% d5, 61% d6, 5%
d7. 1H NMR (CD2Cl2, dioxane as an internal standard) d 7.85
(s, 0.02H), 7.25 (s, 0.02H), 6.43 (s, 0.02H), 4.32 (br s, 2H),
2.12 (s, 0.07H). 2H NMR (CH2Cl2) d 7.89 (br s), 7.30 (br s),
6.48 (br s), 2.14 (br s).
4.2.6. [2H]-2-Amino-6-methylpyridine (Table 1, entry 6).
Method C. Purification by preparative thin-layer chromato-
graphy (silica gel, ethyl acetate) gave 2-amino-6-methyl-
pyridine-dn as a pale yellow solid (51% yield). Isotope
distribution (EIMS): 1% d3, 7% d4, 48% d5, 41% d6, 3%
Method E: A substrate (0.5 mmol) and 10% Pd/C (10 wt %
of the substrate) in D2O (2 mL) were heated under reflux
for 24 h. After cooling, the reaction mixture was diluted
with methanol (10 mL) and the mixture was filtered through
a membrane filter (Millipore MillexÒ-LG, 0.20 mm) to
remove the catalyst. The filtered catalyst was washed with
methanol (2ꢁ10 mL) and the filtrate was concentrated
in vacuo.
1
d7. H NMR (CD3OD, dioxane as an internal standard)
d 7.33 (s, 0.02H), 6.45 (s, 0.50H), 6.40 (s, 0.02H), 2.26 (s,
2
0.07H). H NMR (CH3OH) d 7.35 (br s), 6.47 (br s), 6.40
(br s), 2.25 (br s).
4.2.1. [2H]-Pyridine (Table 1, entry 1). A mixture of pyr-
idine (80 mL, 1.0 mmol) and 10% Pd/C (7.9 mg, 10 wt %
of the substrate) in D2O (4 mL) was refluxed under H2 atmo-
sphere for 24 h. After cooling, the reaction mixture was fil-
tered through a membrane filter (Millipore MillexÒ-LG,
0.20 mm) to remove the catalyst. The yield was determined
by GC analysis of the crude filtrate (83% yield). Isotope dis-
tribution (EIMS): 1% d1, 2% d2, 10% d3, 30% d4, 53% d5. 1H
NMR (D2O, DSS as an internal standard) d 8.51 (s, 0.03H),
7.83 (s, 0.03H), 7.45 (s, 0.38H).
4.2.7. [2H]-2-Amino-6-methylpyridine (Table 1, entry 7).
Method C. Purification by preparative thin-layer chromato-
graphy (silica gel, ethyl acetate) gave 2-amino-6-methyl-
pyridine-dn as a pale yellow solid (49% yield). Isotope
1
distribution (EIMS): 3% d4, 17% d5, 75% d6, 5% d7. H
NMR (CDCl3, dioxane as an internal standard) d 7.31 (s,
0.02H), 6.50 (s, 0.09H), 6.30 (s, 0.02H), 4.39 (br s, 2H),
2.34 (s, 0.06H). 2H NMR (CHCl3) d 7.35 (br s), 6.53
(br s), 6.34 (br s), 2.34 (br s).
4.2.8. [2H]-2-Hydroxy-4-methylpyridine (Table 1, entry
8). Method C, 99% yield as a colorless solid. Isotope distri-
4.2.2. [2H]-4-Aminopyridine (Table 1, entry 2). Method A,
100% yield as a colorless solid. Isotope distribution
(EIMS): 4% d2, 10% d3, 79% d4, 7% d5. 1H NMR
1
bution (EIMS): 3% d4, 19% d5, 72% d6, 6% d7. H NMR
(CD2Cl2, dioxane as an internal standard) d 13.03 (br s,

H. Esaki et al. / Tetrahedron 62 (2006) 10954–10961
10959
1H), 7.24 (s, 0.01H), 6.31 (s, 0.06H), 6.11 (s, 0.10H), 2.17
(s, 0.06H). H NMR (CH2Cl2) d 7.28 (br s), 6.35 (br s),
6.17 (br s), 2.18 (br s).
an internal standard) d 9.05 (s, 0.03H), 8.72 (s, 0.01H),
8.24–8.22 (m, 0.91H), 8.19 (br s, 1H), 7.62 (br s, 1H), 7.52
2
2
(d, J¼7.81 Hz, 0.56H). H NMR (DMSO) d 9.05 (br s),
8.72 (br s), 8.23 (br s), 7.53 (br s).
4.2.9. [2H]-2-Hydroxy-6-methylpyridine (Table 1, entry
9). Method A. Boiling ethanol was used instead of methanol,
100% yield as an off-white solid. Isotope distribution
(EIMS): 3% d4, 35% d5, 56% d6, 6% d7. 1H NMR
(DMSO-d6, DSS as an internal standard) d 11.6 (br s, 1H),
7.32 (s, 0.01H), 6.13 (s, 0.02H), 5.97 (s, 0.29H), 2.14 (s,
4.2.17. [2H]-Indole (Table 2, entry 1). Method D, 80%
yield as a pale red solid. Isotope distribution (EIMS): 1%
d2, 3% d3, 10% d4, 27% d5, 36% d6, 23% d7. H NMR
(CD3OD, DSS as an internal standard) d 7.52–7.50 (m,
0.15H), 7.36–7.32 (m, 0.03H), 7.19 (s, 0.03H), 7.05 (s,
0.30H), 6.96 (s, 0.35H), 6.40 (s, 0.05H). 2H NMR
(CH3OH) d 7.56 (br s), 7.39 (br s), 7.23 (br s), 7.10 (br s),
7.01 (br s), 6.46 (br s).
1
2
0.04H). H NMR (DMSO) d 7.32 (br s), 6.12 (br s), 5.97
(br s), 2.09 (br s).
4.2.10. [2H]-4-Phenylpyridine (Table 1, entry 10). Method
D, 88% yield as a colorless solid. Isotope distribution
(EIMS): 5% d0, 8% d1, 24% d2, 30% d3, 21% d4, 9% d5,
4.2.18. [2H]-3-Methylindole (Table 2, entry 2). Method D,
94% yield as a pale red solid. Isotope distribution (EIMS):
1% d1, 1% d2, 5% d3, 16% d4, 29% d5, 23% d6, 16% d7,
7% d8, 1% d9. 1H NMR (CD3OD, DSS as an internal stan-
dard) d 7.46 (s, 0.74H), 7.30 (s, 0.03H), 7.06 (s, 0.15H),
1
3% d6. H NMR (DMSO-d6, DSS as an internal standard)
d 8.67–8.65 (m, 0.07H), 7.84 (d, J¼7.24 Hz, 1.91H), 7.74
(s, 1.38H), 7.58–7.51 (m, 2.23H). 2H NMR (DMSO) d 8.67
(br s), 7.73 (br s), 7.55 (br s).
2
6.97 (s, 0.26H), 2.26 (s, 0.11H). H NMR (CH3OH) d 7.31
(br s), 7.07 (br s), 6.98 (br s), 2.23 (br s).
4.2.11. [2H]-4,40-Bipyridyl (Table 1, entry 11). Method D.
Ethyl acetate was used instead of diethyl ether, 84% yield as
a colorless solid. Isotope distribution (EIMS): 1% d3, 6% d4,
14% d5, 25% d6, 30% d7, 24% d8. 1H NMR (DMSO-d6, DSS
as an internal standard) d 8.76 (s, 0.13H), 7.86 (s, 1.05H).
2H NMR (DMSO) d 8.74 (br s), 7.86 (br s).
4.2.19. [2H]-5-Methylindole (Table 2, entry 3). Method B,
98% yield as a pale red solid. Isotope distribution (EIMS):
1% d1, 1% d2, 4% d3, 14% d4, 30% d5, 24% d6, 23% d7,
1
3% d8. H NMR (CD3OD, DSS as an internal standard)
d 7.29 (s, 0.45H), 7.22–7.20 (m, 0.04H), 7.14 (s, 0.02H),
2
6.89 (s, 0.51H), 6.30 (s, 0.11H), 2.33 (s, 0.04H). H NMR
(CH3OH) d 7.27 (br s), 7.18 (br s), 6.35 (br s), 2.33 (br s).
4.2.12. [2H]-2,20-Bipyridyl (Table 1, entry 12). Method D.
Ethyl acetate was used instead of diethyl ether, 80% yield as
a colorless solid. Isotope distribution (EIMS): 1% d4, 6% d5,
4.2.20. [2H]-7-Methylindole (Table 2, entry 4). Method D,
91% yield as an off-white solid. Isotope distribution (EIMS):
1% d2, 2% d3, 9% d4, 26% d5, 25% d6, 23% d7, 11% d8, 1%
1
19% d6, 21% d7, 53% d8. H NMR (DMSO-d6, DSS as an
internal standard) d 8.72 (s, 0.07H), 8.42 (s, 0.09H), 7.98
(s, 0.06H), 7.48 (s, 0.06H). 2H NMR (DMSO) d 8.72
(br s), 8.42 (br s), 7.98 (br s), 7.49 (br s).
1
d9. H NMR (CD3OD, DSS as an internal standard) d 7.35
(s, 0.05H), 7.19 (s, 0.04H), 6.86 (s, 0.58H), 6.40 (s, 0.08H),
2
2.48–2.42 (m, 0.12H). H NMR (CH3OH) d 7.39 (br s),
7.22 (br s), 6.92 (br s), 6.45 (br s), 2.43 (br s).
4.2.13. [2H]-1,3-Di(4-pyridyl)propane (Table 1, entry 13).
Method D. Ethyl acetate was used instead of diethyl ether,
97% yield as a colorless solid. Isotope distribution (EIMS):
4.2.21. [2H]-1,2-Dimethylindole (Table 2, entry 5).
Method B, 95% yield as a wine-red solid. Isotope distribu-
tion (EIMS): 6% d4, 9% d5, 14% d6, 21% d7, 23% d8, 16%
d9, 11% d10. 1H NMR (DMSO-d6, p-anisic acid as an internal
standard) d 7.40–7.39 (m, 0.23H), 7.33 (s, 1H), 7.05–7.02
(m, 0.25H), 6.94 (s, 0.33H), 6.17 (s, 0.86H), 3.64–3.59 (m,
1
3% d10, 8% d11, 23% d12, 36% d13, 30% d14. H NMR
(DMSO-d6, p-anisic acid as an internal standard) d 8.40 (s,
0.15H), 7.29 (s, 0.51H), 2.68 (s, 0.15H), 2.00–1.96 (m,
0.27H). H NMR (DMSO) d 8.42 (br s), 7.31 (br s), 2.65
(br s), 1.93 (br s).
2
2
0.43H), 2.35 (s, 0.14H). H NMR (DMSO) d 7.43 (br s),
7.07 (br s), 6.98 (br s), 6.22 (br s), 3.60 (br s), 2.34 (br s).
4.2.14. [2H]-Picolinic acid (Table 1, entry 14). Method A,
99% yield as a colorless solid. 1H NMR (DMSO-d6, DSS as
an internal standard) d 8.73 (s, 0.09H), 8.07 (s, 0.88H), 8.03–
8.01 (m, 0.24H), 7.64 (s, 0.36H). 2H NMR (DMSO) d 8.72
(br s), 8.00 (br s), 7.64 (br s).
4.2.22. [2H]-5-Hydroxyindole (Table 2, entry 6). Method
D, 98% yield as a brown solid. Isotope distribution
(EIMS): 3% d2, 18% d3, 38% d4, 33% d5, 7% d6, 1% d7.
1H NMR (DMSO-d6, DSS as an internal standard) d 10.8
(br s, 1H), 8.60 (s, 1H), 7.22 (s, 0.02H), 7.19 (s, 0.02H),
4.2.15. [2H]-Nicotinic acid (Table 1, entry 15). Method A.
Boiling water was used instead of methanol, 98% yield as
a colorless solid. Isotope distribution (EIMS): 1% d0, 15%
2
6.86 (s, 0.29H), 6.61 (s, 0.03H), 6.23 (s, 0.49H). H NMR
(DMSO) d 7.21 (br s), 6.87 (br s), 6.62 (br s), 6.26 (br s).
1
d1, 46% d2, 34% d3, 4% d4. H NMR (DMSO-d6, DSS as
an internal standard) d 13.4 (br, 1H), 9.10 (s, 0.31H), 8.79
(s, 0.02H), 8.30–8.28 (m, 1H), 7.57 (d, J¼7.82 Hz, 0.63H).
2H NMR (DMSO) d 9.08 (br s), 8.81 (br s), 7.57 (br s).
4.2.23. [2H]-5-Methoxylindole (Table 2, entry 7). Method
B, 99% yield as a brown solid. Isotope distribution (EIMS):
12% d3, 34% d4, 27% d5, 17% d6, 7% d7, 2% d8, 1% d9. 1H
NMR (CD3OD, DSS as an internal standard) d 7.23 (s,
0.02H), 7.16 (s, 0.02H), 7.03 (s, 0.45H), 6.73 (s, 0.53H),
6.33 (s, 0.76H), 3.78 (s, 2.26H). H NMR (CH3OH) d 7.26
(br s), 7.18 (br s), 7.06 (br s), 6.76 (br s), 6.37 (br s), 3.89–
3.67 (m).
4.2.16. [2H]-Nicotinamide (Table 1, entry 16). Method A.
Boiling ethanol was used instead of methanol, 100% yield as
a colorless solid. Isotope distribution (EIMS): 2% d1, 38%
2
1
d2, 50% d3, 9% d4, 1% d5. H NMR (DMSO-d6, DSS as

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H. Esaki et al. / Tetrahedron 62 (2006) 10954–10961
4.2.24. [2H]-2-Phenylindole (Table 2, entry 8). Method D,
96% yield as a yellow solid. Isotope distribution (EIMS): 2%
d0, 5% d1, 9% d2, 11% d3, 12% d4, 13% d5, 16% d6, 16% d7,
solid. Isotope distribution (EIMS): 1% d2, 14% d3, 77%
d4, 8% d5. 1H NMR (DMSO-d6, DSS as an internal standard)
d 10.7 (br s, 1H), 6.49 (br s, 2H), 5.40 (s, 0.04H), 1.97 (s,
0.11H). 2H NMR (DMSO) d 5.40 (br s), 1.92 (br s).
1
12% d8, 3% d9, 1% d10. H NMR (DMSO-d6, DSS as an
internal standard) d 11.5 (br s, 1H), 7.89 (s, 1.93H), 7.56–
7.54 (m, 0.31H), 7.50–7.41 (m, 0.92H), 7.33 (s, 0.46H),
7.12–7.10 (m, 0.45H), 7.04–7.00 (m, 0.57H), 6.92 (s,
0.08H). 2H NMR (DMSO) d 7.48 (br s), 6.98 (br).
4.2.31. [2H]-3,5-Dimethylpyrazole (Table 3, entry 5).
Method D, 81% yield as a yellow solid. Isotope distribution
(EIMS): 1% d1, 1% d3, 7% d4, 34% d5, 13% d6, 41% d7, 3%
d8. H NMR (DMSO-d6, p-anisic acid as an internal stan-
dard) d 12.3 (br s, 1H), 5.72 (s, 0.03H), 2.07 (s, 0.17H). 2H
NMR (DMSO) d 5.75 (br s), 2.06 (br s).
1
4.2.25. [2H]-7-Azaindole (Table 2, entry 9). Method A. The
reaction was carried out in a sealed tube, 99% yield as a pale
yellow solid. Isotope distribution (EIMS): 1% d1, 2% d2,
1
12% d3, 41% d4, 39% d5, 5% d6. H NMR (DMSO-d6,
DSS as an internal standard) d 11.6 (br s, 1H), 8.24–8.20
4.2.32. [2H]-Sulfamethazine (Table 4, entry 1). Method A.
The reaction was carried out in a sealed tube, 97% yield as
a colorless solid. Isotope distribution (FABMS, Gly): 1%
d2, 1% d3, 2% d4, 9% d5, 29% d6, 33% d7, 17% d8, 6% d9,
(m, 0.02H), 7.98–7.96 (m, 0.03H), 7.47 (s, 0.08H), 7.06 (s,
0.35H), 6.46 (s, 0.19H). H NMR (CH3OH) d 8.20 (br s),
7.95 (br s), 7.46 (br s), 7.05 (br s), 6.44 (br s).
2
1
2% d10. H NMR (CD3OD, DSS as an internal standard)
d 7.74–7.71 (m, 1.89H), 6.67 (s, 0.95H), 6.61 (d,
4.2.26. [2H]-5-Methylbenzimidazole (Table 2, entry 10).
Method A. The reaction was carried out in a sealed tube,
99% yield as a colorless solid. Isotope distribution
(EIMS): 2% d2, 11% d3, 28% d4, 24% d5, 27% d6, 7% d7,
J¼9.28 Hz, 1.51H), 2.25 (s, 0.22H). H NMR (CH3OH)
2
d 6.66 (br s), 2.24 (br s).
4.2.33. [2H]-Nalidixic acid (Table 4, entry 2). Method D.
Chloroform was used instead of diethyl ether, 96% yield
as a colorless solid. Isotope distribution (EIMS): 4% d0,
3% d1, 7% d2, 12% d3, 18% d4, 28% d5, 16% d6, 8% d7,
1
1% d8. H NMR (CD3OD, DSS as an internal standard)
d 8.06 (s, 0.03H), 7.48–7.46 (m, 0.03H), 7.38 (s, 0.03H),
7.08–7.07 (m, 0.77H), 2.44–2.40 (m, 0.22H). 2H NMR
(CH3OH) d 8.07 (br s), 7.47 (br s), 7.40 (br s), 7.09 (br s),
2.38 (br s).
1
4% d8. H NMR (DMSO-d6, DSS as an internal standard)
d 9.23 (s, 1H), 8.66–8.64 (m, 0.47H), 7.64–7.63 (m,
0.37H), 4.67 (q, J¼7.08 Hz, 2H), 2.71 (s, 0.22H), 1.45 (t,
4.2.27. [2H]-Quinoline (Table 2, entry 11). Quinoline
(500 mg, 3.9 mmol) and 10% Pd/C (50 mg, 10 wt % of the
substrate) in D2O (17 mL) were stirred at 180 ꢀC under H2
atmosphere for 24 h. After cooling, the reaction mixture
was diluted with ethyl acetate (20 mL) and the mixture
was filtered through a filter paper to remove the catalyst.
The filtered catalyst was washed with ethyl acetate
(2ꢁ5 mL). The combined organic phases were washed
with H2O (20 mL), dried over MgSO4, and concentrated in
vacuo. Purification by preparative thin-layer chromato-
graphy (silica gel, ethyl acetate–hexane, 1:4 v/v) gave quin-
oline-dn as pale yellow oil (83% yield). Isotope distribution
(EIMS): 1% d2, 1% d3, 5% d4, 12% d5, 39% d6, 42% d7. 1H
NMR (CDCl3, dioxane as an internal standard) d 8.93 (s,
0.01H), 8.17 (s, 0.02H), 8.12 (s, 0.01H), 7.83 (s, 0.37H),
J¼7.08 Hz, 2.40H). H NMR (DMSO) d 8.62 (br s), 7.63
2
(br s), 2.65 (br s), 1.36 (br s).
4.2.34. [2H]-Allopurinol (Table 4, entry 3). Allopurinol
(68.1 mg, 0.5 mmol) and 10% Pd/C (6.8 mg, 10 wt % of
the substrate) in D2O (2 mL) were stirred at 160 ꢀC under
H2 atmosphere for 24 h. After cooling, the reaction mixture
was diluted with boiling water (10 mL) and the mixture
was filtered through
a membrane filter (Millipore
MillexÒ-LG, 0.20 mm) to remove the catalyst. The filtered
catalyst was washed with boiling water (2ꢁ10 mL) and the
filtrate was concentrated in vacuo, 99% yield as an off-
white solid. Isotope distribution (EIMS): 8% d0, 19% d1,
1
65% d2, 8% d3. H NMR (DMSO-d6, DSS as an internal
standard) d 13.7 (br, 1H), 12.1 (br, 1H), 8.15 (br s,
0.13H), 8.03 (s, 0.03H). 2H NMR (DMSO-d6) d 8.11
(br s), 8.00 (br s).
2
7.73 (s, 0.01H), 7.58–7.52 (m, 0.07H), 7.40 (s, 0.01H). H
NMR (CHCl3) d 9.01 (br s), 8.26 (br s), 7.92 (br s), 7.82
(br s), 7.65 (br s), 7.47 (br s).
4.2.35. [2H]-Antipirine (Table 4, entry 4). Method A,
98% yield as a pale yellow solid. Isotope distribution
(EIMS): 17% d0, 65% d1, 15% d2, 5% d3. 1H NMR
(DMSO-d6, p-anisic acid as an internal standard) d 7.48–
7.44 (m, 1.97H), 7.31–7.24 (m, 3H), 5.27 (s, 0.09H), 3.03
(s, 3H), 2.22 (s, 2.73H). 2H NMR (DMSO-d6) d 5.31
(br s), 2.17 (br s).
4.2.28. [2H]-2-Aminopyrimidine (Table 3, entry 2).
Method A, 99% yield as a colorless solid. Isotope distribu-
1
tion (EIMS): 4% d1, 31% d2, 52% d3, 13% d4. H NMR
(CD3OD, p-anisic acid as an internal standard) d 8.16 (s,
2
0.03H), 6.54 (s, 0.42H). H NMR (CH3OH) d 8.26 (br s),
6.67 (br s).
4.2.29. [2H]-2-Amino-4,6-dimethylpyrimidine (Table 3,
entry 3). Method E, 100% yield as a colorless solid. Isotope
distribution (EIMS): 3% d4, 16% d5, 72% d6, 8% d7, 1% d8.
1H NMR (CD3OD, p-anisic acid as an internal standard)
d 6.37 (s, 1H), 2.17–2.13 (m, 0.28H). H NMR (CH3OH)
d 2.22 (br s).
Acknowledgements
This work was supported in part by a Grant-in Aid for Sci-
entific Research (No. 18590009) from the Japan Society
for the Promotion of Science, and by the Research Founda-
tion of Gifu Pharmaceutical University. H.E. is grateful for
the Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists.
2
4.2.30. [2H]-2-Amino-4-hydroxy-6-methylpyrimidine
(Table 3, entry 4). Method E, 100% yield as a colorless

H. Esaki et al. / Tetrahedron 62 (2006) 10954–10961
10961
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