H-D Exchange Deuteration of Arenes at Room Temperature

Article abstract of DOI:10.1021/acs.oprd.8b00383

Arene nuclei efficiently underwent the hydrogen (H)-deuterium (D) exchange reaction catalyzed by platinum group metals on carbon in a mixed solvent of 2-propanol and D₂O at room temperature to produce deuterium-labeled arenes. Platinum on carbon (Pt/C) and iridium on carbon (Ir/C) were applicable catalysts, and the various arenes bearing a carbonyl group, fluorine, phenolic hydroxy group, amino group, or phosphonic acid on the aromatic nucleus were effectively deuterated. Nonheating conditions are valuable for the scalable industrial preparation.

Full text of DOI:10.1021/acs.oprd.8b00383

Communication
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
H−D Exchange Deuteration of Arenes at Room Temperature
Yoshinari Sawama,* Akihiro Nakano, Takumi Matsuda, Takahiro Kawajiri, Tsuyoshi Yamada,
and Hironao Sajiki*
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
S
* Supporting Information
Scheme 1. Comparison of Deuterations of Benzoic Acid
(1a) under Novel and Previous Reaction Conditions
ABSTRACT: Arene nuclei efficiently underwent the
hydrogen (H)−deuterium (D) exchange reaction cata-
lyzed by platinum group metals on carbon in a mixed
solvent of 2-propanol and D2O at room temperature to
produce deuterium-labeled arenes. Platinum on carbon
(Pt/C) and iridium on carbon (Ir/C) were applicable
catalysts, and the various arenes bearing a carbonyl group,
fluorine, phenolic hydroxy group, amino group, or
phosphonic acid on the aromatic nucleus were effectively
deuterated. Nonheating conditions are valuable for the
scalable industrial preparation.
KEYWORDS: deuteration, arene, room temperature,
platinum group metal, heterogeneous catalyst
using sealed reaction apparatus under an Ar atmosphere
(Scheme 1, eq 3).
1. INTRODUCTION
Deuterium (D)-labeled compounds are utilized in a wide
variety of scientific fields,1 such as mechanistic investigations of
organic reactions, tracers in microanalyses, elucidation of drug
metabolism, heavy drugs,2 quantitative mass spectrometry
analyses,3 etc., because of the specific property of the D atom
as a stable isotope of the H atom and the isotope effect, such as
the higher bond dissociation energy of the C−D bond in
comparison with the corresponding C−H bond. The H−D
exchange reaction is a straightforward methodology within
various synthetic methods.4,5 We have continuously developed
the platinum group metal-catalyzed H−D exchange reactions
of various organic compounds based on activation of the
catalyst metal using hydrogen gas (H2).6,7 Among them,
benzoic acid (1a) was less reactive, and comparatively harsh
reaction conditions were required to achieve excellent D
contents on its aromatic nucleus (Scheme 1, eqs 1 and 2). H2
is a key activator of Pt metal supported on carbon, and the Pt/
C-catalyzed deuteration of 1a could efficiently proceed in D2O
under H2 at atmospheric pressure at 180 °C (Scheme 1, eq
1).6b Platinum group metals on carbon, such as Pt/C, can
catalyze the dehydrogenation of secondary alcohols to ketones
accompanied by the generation of H2.8 Therefore, H2
generated in situ via the Pt/C-catalyzed dehydrogenation8 of
2-propanol (isopropanol, i-PrOH)7 as a secondary alcohol was
also utilized as an activator of Pt metal to produce deuterium-
labeled benzoic acid (1a-d5) in a mixed solvent [i-PrOH/c-
hexane (c-Hex)/D2O] at 100 °C (Scheme 1, eq 2).7b c-Hex
plays an important role as a cosolvent to increase the solubility
of 1a. Here we demonstrate that the deuteration of arenes
proceeds smoothly at room temperature under the simply
improved reaction conditions without the additional cosolvent
2. RESULTS AND DISCUSSION
Benzoic acid (1a) (0.25 mmol) underwent the 10% Pt/C (6
mol %)-catalyzed deuteration in D2O (2 mL) or a mixed
solvent (i-PrOH/D2O = 1/2 mL) under a H2 atmosphere in a
test tube connected to a H2 balloon at room temperature for
24 h to produce deuterium-labeled benzoic acid (1a-d5) with
moderate D contents in low yield (Table 1, entries 1 and 2).
H2 could facilitate the hydrogenation of the aromatic nucleus
to produce cyclohexanecarboxylic acid as a byproduct,
resulting in the low yield of 1a-d5. The deuteration in other
mixed solvents (i-PrOH/c-Hex/D2O = 0.1/0.9/2 mL, entry 3;
i-PrOH/D2O = 1/2 mL, entry 4) under an Ar atmosphere
using an Ar balloon proceeded inefficiently, although the arene
reduction as a side reaction was significantly suppressed.
Surprisingly, the H−D exchange reaction proceeded smoothly
in a test tube tightly sealed with a septum in i-PrOH/D2O (1/
2 mL) under an Ar atmosphere, and the D contents were
dramatically improved (entry 5). Meanwhile, the reactions in a
sealed test tube enclosed with H2 or air resulted in low D
contents (entries 6 and 7). H2 gas is known to react with O2 in
the presence of the platinum group metals to produce H2O2,
which is instantaneously degraded to H2O in the presence of
the platinum group metal catalyst.9 Therefore, the slight
amount of H2 generated by the Pt/C-catalyzed dehydrogen-
ation of i-PrOH was rapidly consumed in the presence of O2 in
Special Issue: Japanese Society for Process Chemistry
Received: November 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00383
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Table 1. Optimization of the H−D Exchange Reaction of
Benzoic Acid (1a)
Table 2. Catalyst Efficiency
D contents (%)
b
D contents (%)
entry
catalyst
a
c
yield (%)
entry
conditions
a
b
c
yield (%)
1
2
3
10% Pt/C
5% Pt/C
95
94
95
2
0
4
94
94
93
0
0
0
86
58
70
0
0
0
0
94
93
94
b
>99
97
>99
(>99)
(>99)
b
a
d
1
H2 balloon
H2 balloon
Ar balloon
Ar balloon
81
96
23
77
95
66
16
94
80
95
17
58
94
63
11
94
53
78
10
20
86
48
6
27
18
98
96
>99
55
a
d
2
3
a
10% Pt/C
10% Pd/C
10% Au/C
10% Rh/C
10% Ru/C
10% Ir/C
10% Ir/C
10% Ir/C
c
a
d
4
5
6
7
8
a
4
5
6
7
8
d
e
sealed under Ar
sealed under H2
sealed under air
under Ar bag
d
(>99)
e
7
4
>99
>99
>99
89
e
98
>99
95
95
94
95
94
94
f
87
b
9
c
a
The reaction was carried out in an 18 mL test tube connected to a
rubber balloon filled with H2 or Ar. The reaction was performed in
only D2O (2 mL) without i-PrOH. i-PrOH/c-Hex/D2O (0.1/0.9/2
mL) was used as a mixed solvent. The formation of cyclo-
hexanecarboxylic acid as a byproduct was observed. The reaction was
carried out in an 18 mL test tube that was tightly sealed with a septum
after the replacement of the inside air with the corresponding gas. A
10
b
a
c
Sodium benzoate (1b) was used as the substrate. The reaction was
carried out in a 30 mL sealed glass tube under an Ar atmosphere, and
the inside pressure was maintained at ca. 1.0 bar during the 24 h
reaction. 5 mmol of 1a was used in a 200 mL tightly sealed round-
bottom flask. Recovery of the nonlabeled substrate (1a).
d
e
c
d
f
gas collecting bag (1 L) was used instead of a rubber balloon.
Table 3. Cosolvent Effect
air to give the low D contents (entry 7). The sealed conditions
could avoid contamination with O2 by the invasion of O2 into
the reaction tube (entry 5), while O2 gas could pass through
the rubber balloon material to deactivate the deuteration
process under the Ar atmosphere using the Ar balloon (entries
3 and 4). The use of a gas collecting bag, in which the inside
gas tightly remains, instead of a rubber balloon, also gave high
D contents (entry 8). (Photographs of the reaction apparatuses
using the rubber balloon, sealed test tube, and gas collecting
bag are shown in the Supporting Information.)
D contents (%)
entry
cosolvent
i-PrOH
MeOH
t-BuOH
none
acetone
a
b
c
yield (%)
1
2
3
4
5
6
7
95
12
0
0
0
95
9
0
0
0
94
8
0
0
0
>99
99
(>99)
(>99)
(98)
a
a
It was found that 5% Pt/C instead of 10% Pt/C was also
applicable, although the D content at the ortho position of 1a
was moderately lower (Table 2, entry 1 vs 2). Sodium
benzoate (1b) was effectively deuterated in the presence of
10% Pt/C without any influence of the solubility (entry 3). A
variety of platinum group metal on carbon catalysts were
investigated next. While 10% Pd/C, Au/C, Rh/C, and Ru/C
were ineffective (entries 4−7), 10% Ir/C also indicated an
excellent catalytic activity to give 1a-d5 with excellent D
contents and yield (entry 8). The difference in the catalytic
activities of these catalysts was not clearly examined. The
deuteration could effectively proceed without any increase of
inside pressure (1.0 bar) (entry 9), and the generation of a
slight amount of H2 gas could be detected from the inside gas
by GC-TCD analysis during the deuteration. During the
present deuteration (entry 1), a slight amount of H2 can be
generated to activate the platinum metal and promote the
deuteration under strictly maintained inactive inside gas (Ar)
conditions at room temperature. In particular, inflammable H2
did not accumulate in the reaction apparatus. Additionally, the
5 mmol scale reaction of 1a could be accomplished (entry 10).
The use of MeOH or t-BuOH instead of i-PrOH hardly
facilitated the desired deuteration (Table 3, entry 1 vs 2 and
3), and the deuteration never proceeded in only D2O without
i-PrOH (entry 4). The addition of acetone (1 mL), which is a
product of the dehydrogenation of i-PrOH, as a cosolvent of
D2O was also ineffective (entry 5). The use of i-PrOD-d8 as a
a
i-PrOD-d8
1,4-butanediol
86
0
60
0
64
17
>99
96
a
Recovery yield of nonlabeled substrate.
cosolvent gave lower deuteration efficiency compared with the
use of i-PrOH (entry 6), and 1,4-butanediol was also
ineffective. The Ir/C-catalyzed dehydrogenation of i-PrOH
smoothly proceeded to generate H2 for the activation of Ir/C
without any byproducts except acetone,8 while the dehydro-
genation of i-PrOD-d8 was slower because of the isotope effect.
The efficient incorporation of deuterium into 1a was
performed within 12 h (Table 4, entry 1 vs 2), and moderate
D incorporation was obtained even after 6 h (entry 3).
Although the reduction of the Ir/C loading to 3 mol % also
maintained the efficient D contents of 1a-d5 (entry 1 vs 4), an
Ir/C loading of 1 mol % resulted in significantly decreased
deuteration efficiency (entry 5). The reduction of the usage of
i-PrOH and D2O to half or quarter could also produce 1a-d5
without significant loss of the D contents (entries 6 and 7).
Additionally, the 5 g scale deuteration could be accomplished
in the presence of 3 mol % Ir/C to give the desired 1a-d5 with
high D contents and quantitative isolated yield (eq 4).
The scope of substrates, including fluorinated compounds,10
for the present deuteration was examined using 10% Pt/C
B
DOI: 10.1021/acs.oprd.8b00383
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Organic Process Research & Development
Communication
Table 4. Effects of Reaction Time, Catalyst Loading, and
Solvent Concentration
Scheme 2. Scope of Substrates for Pt/C-Catalyzed
a
Deuteration
D contents (%)
entry
X
Y
Z
time (h)
a
b
c
yield (%)
1
2
3
4
5
6
7
6
6
6
3
1
6
6
1
1
1
1
1
2
2
2
2
2
1
0.5
24
12
6
24
24
24
24
95
94
71
94
63
92
90
95
94
44
94
62
90
86
94
92
56
91
58
81
75
>99
98
97
99
>99
97
0.5
0.25
96
(Scheme 2).11,12 o- or p-Fluorobenzoic acid (1c, 1d) were also
efficiently deuterated. Substrates bearing a hydroxy group
within the molecule (1e−h) were applicable, and an indole
derivative (1i) could be deuterated with moderate D contents.
Acetophenone derivatives (1j−m) bearing various functional
groups on the aromatic nucleus also underwent the desired
deuteration, and benzamides (1n and 1o) and phenyl-
phosphonic acid (1p) were also deuterium-labeled. Addition-
ally, O-tert-butyldimethylsilylphenol (1q) effectively under-
went the deuteration without deprotection. Chlorobenzene,
bromobenzene, and iodobenzene derivatives could not be
applied, as they mainly produced the reduced products.
The use of 10% Ir/C instead of 10% Pt/C improved the
deuterium efficiencies in some cases (Scheme 3).11 Benzamide
(1r), acetanilides (1s−u), acetophenone derivatives (1v), and
methyl salicylate (1w) were more efficiently deuterated. The
aromatic nuclei of 1-naphthol (1x) and 4,4′-bis(fluorophenyl)-
methane (1y) were also deuterated. Although the variability of
the deuteration-position-dependent deuterium efficiencies
cannot be clearly explained, it could depend on the steric
hindrance and/or electronic properties of the substrates.
The deuteration of salicylic acid (2-hydroxybenzoic acid, 1z)
also proceeded effectively in the presence of 10% Ir/C or 10%
Pt/C (6 mol %) at room temperature to give multiple
deuterium-labeled products (1z-d4) (eq 5). The deuteration
efficiency at the 5-position of 1z in the 10% Ir-catalyzed
reaction was slightly lower, while the D content at the 6-
position was somewhat unsatisfactory under the 10% Pt/C-
catalyzed conditions. On the other hand, the mixed use4c,6d of
10% Ir/C and 10% Pt/C (each 3 mol %) obviously improved
the D contents at the 5- and 6-positions to give the desired 1z-
d4 with over 90% D at all of the aromatic carbons. The
deuterium-labeling efficiencies of acetanilide derivatives (1t
and 1u) and 1-naphthol (1x) could be also improved by the
concurrent use of 10% Pt/C and 10% Ir/C (Scheme 3 vs eq
6). The details of the synergic effect using Pt/C and Ir/C are
unclear.
a
The reactions were carried out using 10% Pt/C in an 18 mL test
b
tube that was tightly sealed with a septum under Ar gas. The
defluorinated product (9%) was obtained as a byproduct.
hydrol (1h). As shown in Scheme 1, the desired deuterated
product (1h-d8) was obtained under 10% Pt/C-catalyzed
reaction conditions in i-PrOH/D2O at room temperature with
high deuteration efficiency and yield. On the other hand, the
Pt/C-catalyzed deuteration under atmospheric H2 at 180 °C6b
provided only moderate deuterium contents in low yields
(10%) as a result of the significant hydrogenolysis of the
fluorine and hydroxyl group (eq 7). Furthermore, the use of
the mixed solvent (i-PrOH/c-Hex/D2O) at 100 °C7b resulted
in lower deuterium incorporation (eq 8).
3. CONCLUSION
We have developed the efficient Pt/C- or Ir/C-catalyzed
deuteration of aromatic nuclei bearing various functional
An advantage of the present deuteration method at room
temperature is shown by the deuteration of 4,4′-difluorobenz-
C
DOI: 10.1021/acs.oprd.8b00383
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Organic Process Research & Development
Communication
Scheme 3. Scope of Substrates for Ir/C-Catalyzed
a
Deuteration
labeled without defluorination. D2O is an inexpensive
deuterium source, and the heterogeneous 10% Pt/C or 10%
Ir/C can be removed from the reaction mixture by simple
filtration. Therefore, the present deuteration is expected to be
an alternative for the preparation of useful deuterium-labeled
functional materials and useful for the industrial preparation
without heating conditions.
4. EXPERIMENTAL SECTION
As a representative example, “10% Pt/C (6 mol %)” has the
following meaning: 10% w/w platinum on carbon equivalent to
6 mol % as the platinum amount versus the amount of
substrate used.
a
The reactions were carried out using 10% Ir/C in an 18 mL test tube
Typical Procedure Using Pt/C or Ir/C. Arene (0.25
mmol), 10% Pt/C (29.3 mg, 0.015 mmol, 6 mol %) or 10% Ir/
C (28.9 mg, 0.015 mmol, 6 mol %), i-PrOH (1 mL), and D2O
(2 mL) were added to an 18 mL test tube, which was sealed
with a septum, and the inside gas was immediately replaced by
Ar using a vacuum pump. The reaction mixture was stirred at
room temperature for 24 h and then filtered through a
membrane filter (Millipore Millex-LH, 0.45 μm) together with
AcOEt (20 mL) and H2O (5 mL) to remove the catalyst. The
combined filtrates were extracted with AcOEt (20 mL × 3),
and the organic layers were dried over Na2SO4 and then
concentrated in vacuo. The residue was purified by silica gel
column chromatography if necessary.
that was tightly sealed with a septum under Ar gas, unless otherwise
noted. The defluorinated product (4%) was obtained as a byproduct.
b
Typical Procedure Using Pt/C and Ir/C. Arene (0.25
mmol), 10% Pt/C (14.6 mg, 0.0075 mmol, 3 mol %) and 10%
Ir/C (14.4 mg, 0.0075 mmol, 3 mol %), i-PrOH (1 mL), and
D2O (2 mL) were added to an 18 mL test tube, which was
sealed with a septum, and the inside gas was immediately
replaced by Ar using a vacuum pump. The reaction mixture
was stirred at room temperature for 24 h and then filtered
through a membrane filter (Millipore Millex-LH, 0.45 μm)
together with AcOEt (20 mL) and H2O (5 mL) to remove the
catalyst. The combined filtrates were extracted with AcOEt (20
mL × 3), and the organic layers were dried over Na2SO4 and
then concentrated in vacuo. The residue was purified by silica
gel column chromatography if necessary.
Scaled-Up Reaction. 1a (5g, 41.0 mmol), 10% Ir/C (2.36
g, 1.23 mmol), i-PrOH (82 mL), and D2O (164 mL) were
added to a 500 mL flask, which was sealed with a septum, and
the inside gas was immediately replaced by Ar using a vacuum
pump. The reaction mixture was stirred at room temperature
for 24 h and then filtered through a Celite pad together with
AcOEt (300 mL) and H2O (50 mL) to remove the catalyst.
The combined filtrates were extracted with AcOEt (300 mL ×
3), and the organic layers were dried over Na2SO4 and then
concentrated in vacuo. Consequently, 1a-d5 (5.15 g, 40.7
mmol) was obtained in 99% yield.
groups in a mixed solvent of i-PrOH and D2O at room
temperature. The concurrent use of Pt/C and Ir/C was newly
developed to improve deuteration efficiencies. Many biochemi-
cally useful fluorinated compounds could also be deuterium-
D
DOI: 10.1021/acs.oprd.8b00383
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Communication
2007, 119, 7890−7911; Angew. Chem., Int. Ed. 2007, 46, 7744−7765.
(b) Herbert, J. M. Deuterium Exchange Promoted by Iridium
Complexes Formed in situ. J. Labelled Compd. Radiopharm. 2010, 53,
658−661. (c) Sawama, Y.; Monguchi, Y.; Sajiki, H. Efficient H−D
Exchange Reactions Using Heterogeneous Platinum-Group Metal on
Carbon−H2−D2O System. Synlett 2012, 23, 959−972. (d) Atzrodt, J.;
Derdau, V.; Kerr, W. J.; Reid, M. C-H Functionalisation for Hydrogen
Isotope Exchange: Angew. Chem., Int. Ed. 2018, 57, 3022−3047.
(e) Sawama, Y.; Park, K.; Yamada, T.; Sajiki, H. New Gateways to the
Platinum Group Metal-Catalyzed Direct Deuterium-Labeling Method
Utilizing Hydrogen as a Catalyst Activator. Chem. Pharm. Bull. 2018,
66, 21−28.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00383.
■
S
Synthetic procedures and spectroscopic data for the
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: sawama@gifu-pu.ac.jp.
*E-mail: sajiki@gifu-pu.ac.jp.
ORCID
■
(5) For selected papers on arene deuteration, see: (a) Prechtl, M. H.
̈
G.; Holscher, M.; Ben-David, Y.; Theyssen, N.; Loschen, R.; Milstein,
D.; Leitner, W. H/D Exchange at Aromatic and Heteroaromatic
Hydrocarbons Using D2O as the Deuterium Source and Ruthenium
Dihydrogen Complexes as the Catalyst. Angew. Chem., Int. Ed. 2007,
46, 2269−2272. (b) Duttwyler, S.; Butterfield, A. M.; Siegel, J. S.
Arenium Acid Catalyzed Deuteration of Aromatic Hydrocarbons. J.
Org. Chem. 2013, 78, 2134−2138. (c) Ma, S.; Villa, G.; Thuy-Boun, P.
S.; Homs, A.; Yu, J.-Q. Palladium- Catalyzed ortho-Selective C-H
Deuteration of Arenes: Evidence for Superior Reactivity of Weakly
Coodinated Palladacycles. Angew. Chem., Int. Ed. 2014, 53, 734−737.
(d) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-
catalysed tritiation of pharmaceuticals. Nature 2016, 529, 195−199.
(e) Liang, X.; Duttwyler, S. Efficient Brønsted-Acid-Catalyzed
Deuteration of Arenes and Their Transformation to Functionalized
Deuterated Products. Asian J. Org. Chem. 2017, 6, 1063−1071.
(6) For examples using additional H2 as an activator of metals, see:
(a) Sajiki, H.; Ito, N.; Esaki, H.; Maesawa, T.; Maegawa, T.; Hirota, K.
Aromatic ring favorable and efficient H−D exchange reaction
catalyzed by Pt/C. Tetrahedron Lett. 2005, 46, 6995−6998. (b) Ito,
N.; Esaki, H.; Maesawa, T.; Imamiya, E.; Maegawa, T.; Sajiki, H. Pt/
C-catalyzed efficient H−D exchange reaction of aromatic rings and its
scope and limitations. Bull. Chem. Soc. Jpn. 2008, 81, 278−286.
(c) Ito, N.; Watahiki, T.; Maesawa, T.; Maegawa, T.; Sajiki, H. H−D
Exchange Reaction Taking Advantage of a Synergistic Effect of a
Heterogeneous Pd and Pt Mixed Catalyst. Synthesis 2008, 2008,
1467−1478. (d) Maegawa, T.; Ito, N.; Oono, K.; Monguchi, Y.;
Sajiki, H. Bimetallic Palladium−Platinum on Carbon Catalyzed H−D
Exchange Reaction: Synergistic Effect on Multiple Deuterium
Incorporation. Synthesis 2009, 2009, 2674−2678. (e) Sajiki, H. In
New Horizons of Process Chemistry: Scalable Reactions and Technologies;
Tomioka, K., Shioiri, T., Sajiki, H., Eds.; Springer Nature, 2017; pp
29−40.
(7) For examples using in situ-generated H2 as an activator of metals,
see: (a) Sawama, Y.; Yabe, Y.; Shigetsura, M.; Yamada, T.; Nagata, S.;
Fujiwara, Y.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Platinum on
Carbon-Catalyzed Hydrodefluorination of Fluoroarenes Using
Isopropyl Alcohol-Water-Sodium Carbonate Combination. Adv.
Synth. Catal. 2012, 354, 777−782. (b) Sawama, Y.; Yamada, T.;
Yabe, Y.; Morita, K.; Shibata, K.; Shigetsura, M.; Monguchi, Y.; Sajiki,
H. Platinum on Carbon-Catalyzed H−D Exchange Reaction of
Aromatic Nuclei Due to Isopropyl Alcohol-Mediated Self-Activation
of Platinum Metal in deuterium oxide. Adv. Synth. Catal. 2013, 355,
1529−1534. (c) Sawama, Y.; Mori, M.; Yamada, T.; Monguchi, Y.;
Sajiki, H. Hydrogen Self-Sufficient Arene Reduction to Cyclohexane
Derivatives Using a Combination of Platinum on Carbon and 2-
Propanol. Adv. Synth. Catal. 2015, 357, 3667−3670.
Yoshinari Sawama: 0000-0002-9923-2412
Tsuyoshi Yamada: 0000-0002-6048-5578
Hironao Sajiki: 0000-0003-2792-6826
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the N.E. CHEMCAT Corp. for the kind gift of the
catalysts. This study was partially supported by the Research
Foundation for Pharmaceutical Sciences (to Y.S.), a Grant-in-
Aid for Scientific Research (C) from the Japan Society for the
Promotion of Science (JSPS) (16K08169 to Y.S.), and a
Grant-in-Aid from JSPS (15J01556 to T.Y.).
REFERENCES
■
(1) For reviews, see: (a) Allen, P. H.; Hickey, M. J.; Kingston, L. P.;
Wilkinson, D. J. Metal−catalysed Isotopic Exchange Labelling: 30
Years of Experience in Pharmaceutical R&D. J. Labelled Compd.
Radiopharm. 2010, 53, 731−738. (b) Lockley, W. J. S.; Heys, J. R.
Metal−catalysed Hydrogen Isotope Exchange Labelling: a brief
overview. J. Labelled Compd. Radiopharm. 2010, 53, 635−644.
(c) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Deuterium− and
Tritium−Labelled Compounds: Applications in the Life Sciences.
Angew. Chem., Int. Ed. 2018, 57, 1758−1784.
(2) (a) Nelson, S. D.; Trager, W. F. The Use of Deuterium Isotope
Effects to Probe the Active Site Properties, Mechanism of
Cytochrome P450-catalyzed Reactions, and Mechanisms of Metabol-
ically Dependent Toxicity. Drug Metab. Dispos. 2003, 31, 1481−1498.
(b) Schneider, F.; Hillgenberg, M.; Koytchev, R.; Alken, R.-G.
Enhanced Plasma Concentration by Selective Deuteraion of
Rofecoxib in Rats. Arzneim. Forsch. 2006, 56, 295−300. (c) Maltais,
F.; Jung, Y. C.; Chen, M.; Tanoury, J.; Perni, R. B.; Mani, N.; Laitinen,
L.; Huang, H.; Liao, S.; Gao, H.; Tsao, H.; Block, E.; Ma, C.; Shawgo,
R. S.; Town, C.; Brummel, C. L.; Howe, D.; Pazhanisamy, S.;
Raybuck, S.; Namchuk, M.; Bennani, Y. L. In Vitro and In Vivo
Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced
Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats. J.
Med. Chem. 2009, 52, 7993−8001. (d) Sanderson, K. Big interest in
heavy drugs. Nature 2009, 458, 269. (e) Meanwell, N. A. Synopsis of
Some Recent Tactical Application of Bioisosteres in Drug Design. J.
Med. Chem. 2011, 54, 2529−2591. (f) Gant, T. G. Using Deuterium
in Drug Discovery: Leaving the Label in the Drug: J. Med. Chem.
2014, 57, 3595−3611.
(8) (a) Sawama, Y.; Morita, K.; Yamada, T.; Nagata, S.; Yabe, Y.;
Monguchi, Y.; Sajiki, H. Direct Deuteration of Acrylic and
Methacrylic Acid Derivatives Catalyzed by Platinum on Carbon in
Deuterium Oxide. Green Chem. 2014, 16, 3439−3443. (b) Sawama,
Y.; Morita, K.; Asai, S.; Kozawa, M.; Tadokoro, S.; Nakajima, J.;
Monguchi, Y.; Sajiki, H. Palladium on Carbon-Catalyzed Aqueous
Transformation of Primary Alcohols to Carboxylic Acids Based on
Dehydrogenation under Mildly Reduced Pressure: Adv. Synth. Catal.
2015, 357, 1205−1210.
(3) (a) Stokvis, E.; Rosing, H.; Beijnen, J. H. Stable Isotopically
Labeled Internal Standards in Quantitative Bioanalysis using Liquid
Chromatography/Mass Spectrometry: Necessity or Not? Rapid
Commun. Mass Spectrom. 2005, 19, 401−407. (b) Hewavitharana,
A. K. Matrix Matching in Liquid Chromatography−Mass Spectrom-
etry with Stable Isotope Labelled Internal Standards−Is It Necessary?
J. Chromatogr. A 2011, 1218, 359−361.
(4) For reviews, see: (a) Atzrodt, J.; Derdau, V.; Fey, T.;
Zimmermann, J. The Renaissance of H/D Exchange. Angew. Chem.
E
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Organic Process Research & Development
Communication
(9) Monguchi, Y.; Ida, T.; Maejima, T.; Yanase, T.; Sawama, Y.;
Sasai, Y.; Kondo, S.; Sajiki, H. Palladium on Carbon-catalyzed Gentle
and Quantitative Combustion of Hydrogen at Room Temperatures.
Adv. Synth. Catal. 2014, 356, 313−318.
(10) Chloro-, bromo-, and iodoarene derivatives were inapplicable.
Deuterium-labeled products with low D contents and/or hydro-
genated byproducts were generated.
(11) 10% Ir/C was applicable to some substrates that were less
reactive under the 10% Pt/C-catalyzed conditions. The comparison of
the catalytic activities of 10% Pt/C and 10% Ir/C is described in the
Supporting Information.
(12) Defluorinated byproducts were generated in some reactions
(see the Supporting Information). Heating conditions facilitate
defluorination of aromatic fluorides (see ref 7a).
F
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