Direct Deuteration of Acrylic and Methacrylic Acid Derivatives Catalyzed by Platinum on Carbon in Deuterium Oxide

Article abstract of DOI:10.1002/adsc.201800170

The platinum on carbon (Pt/C)-catalyzed deuteration of acrylic and methacrylic acid derivatives in deuterium oxide (D₂O) efficiently proceeded to give the corresponding acrylic acid-d₃ and methacrylic acid-d₅ derivatives. The olefinic functionality, as well as the methyl group on the unsaturated functionality of the substrate, were satisfactorily deuterated via the hydrogen (H)-deuterium (D) exchange reaction. The obtained deuterated compounds are useful building blocks and efficiently converted to the corresponding desired products including a polymer without the degradation of the original deuterium contents. (Figure presented.).

Full text of DOI:10.1002/adsc.201800170

Title: Direct Deuteration of Acrylic and Methacrylic Acid Derivatives
Catalyzed by Platinum on Carbon in Deuterium Oxide
Authors: Kwihwan Park, Takumi Matsuda, Tsuyoshi Yamada, Yasunari
Monguchi, Yuka Sawama, Naoki Doi, yasushi Sasai, Shin-ichi
Kondo, Yoshinari Sawama, and Hironao Sajiki
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800170
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10.1002/adsc.201800170
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Direct Deuteration of Acrylic and Methacrylic Acid Derivatives
Catalyzed by Platinum on Carbon in Deuterium Oxide
Kwihwan Park,a Takumi Matsuda,a Tsuyoshi Yamada,a Yasunari Monguchi,a Yuka
Sawama,b Naoki Doi,b Yasushi Sasai,b Shin-ichi Kondo,b Yoshinari Sawama,*a Hironao
Sajiki*a
a Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
b Laboratory of Pharmaceutical Physical Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196,
Japan
E-mail: sawama@gifu-pu.ac.jp, sajiki@gifu-pu.ac.jp
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
platinum group metal on carbon-catalyzed H-D
deuteration of acrylic and methacrylic acid derivatives in exchange reactions of various organic frameworks in
Abstract. The platinum on carbon (Pt/C)-catalyzed
deuterium oxide (D2O) efficiently proceeded to give the
corresponding acrylic acid-d3 and methacrylic acid-d5
derivatives. The olefinic functionality, as well as the methyl
group on the unsaturated functionality of the substrate,
were satisfactorily deuterated via the hydrogen (H)-
deuterium (D) exchange reaction. The obtained deuterated
compounds are useful building blocks and efficiently
converted to the corresponding desired products including a
polymer without the degradation of the original deuterium
contents.
deuterium oxide (D2O) in the presence of H2 gas or 2-
propanol as an in situ hydrogen source based on the
dehydrogenation reaction.[1c,7,8] We now report the
deuterium-labeling of acrylic and methacrylic acid
derivatives, which are easily transformed into various
products by the Mizoroki-Heck reaction,[9] Micheal
addition[10], polymerization[11,12] etc. (Scheme 1, top).
While the direct deuteration method limited to ethyl
acrylate as a substrate has been reported using the
homogeneous ruthenium catalyst in D2O with room
for improvement of the D efficiencies (Scheme 1,
bottom),[6c] there is no report about the direct
preparation method of the deuterated methacrylic
acid derivative.[13]
Keywords: deuteration; deuterium oxide; platinum on
carbon; hydrogenation free; deuterated polymer
Deuterium (D) is a stable isotope of hydrogen (H),
and the carbon (C)-D bonds are found to be stable in
comparison to C-H bonds. Therefore, the deuterium-
labeled compounds are utilized in various scientific
research fields on the basis of such a small difference
in the physical properties between the D and H, for
examples, the elucidation of organic reaction
mechanisms, microanalysis and pharmacokinetic
studies.[1] Heavy drugs, deuterium-labeled drugs, are
recently spotlighted due to their important role in the
expression of the long-lasting effects of drugs based
on the retarded metabolism by the isotopic effect.[2]
Since olefins are useful building blocks to be
transformed to various functional groups, deuterium-
labeled olefins are also powerful tools to synthesize
deuterium-labeled functional materials. While the
semi-deuterogenation of alkynes using gaseous D2 in
the presence of heterogeneous Pd catalysts, such as
the Lindlar catalyst[3] and Pd/boron nitride (BN)[4],
provides the deuterated olefins, the H-D exchange
reaction on alkene functionalities straightforwardly
produces the desirable deuterium-labeled olefins.[5,6]
We have continuously developed heterogeneous
Scheme 1. H-D exchange reaction of acrylic acid
derivatives (the deuterium contents are indicated in red
numbers).
The catalyst efficiency was first examined for the
H-D exchange reaction of n-dodecyl acrylate (1a) as
a substrate in the combined solvents of i-PrOH (0.5
mL) and D2O (2 mL) at 120 °C for 24 h in a test tube
(Table 1). H2 is an important activator for the
platinum on carbon to facilitate the desired H-D
exchange reaction,[1c,7] and the platinum group metal-
catalyzed dehydrogenation[14] of i-PrOH can supply
the appropriate amount of H2, which sufficiently
activates the metal surface (active sites).[8,15]
Although 10% Pd/C, Rh/C, Ir/C or Ru/C (each 8
1
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10.1002/adsc.201800170
Advanced Synthesis & Catalysis
mol%) exhibited a low or no catalyst activity for the
deuteration of 1a (entries 3-6), 10% Pt/C (8 mol%)
selectively catalyzed the desirable H-D exchange
reaction only on the unsaturated carbons of 1a to
form the deuterated n-dodecyl acrylate (1a-d3) with
72% (-position) and 96 and 97% (-positions)
deuterium contents (entry 1). The increased use of
5
6
7
―
25
20
28
28
29
45
33
32
74
79
77
MeOH (0.2 mL)
t-BuOH (0.2 mL) 23
[a] Determined by 1H and 2H NMR.
All the reactions in Tables 1 and 2 were carried
out in a glass test tube equipped with an argon
balloon. Meanwhile, the Pt/C-catalyzed H-D
exchange reaction of 1a in i-PrOH/D2O (0.2 / 2 mL)
in a sealed tube effectively proceeded to give 1a-d3
with quantitative D contents at the , both
unsaturated carbons, however, the isolated yield was
quite low due to the polymerization of 1a and 1a-d3
(Scheme 2, top). The addition of the catalytic
hydroquinone as a polymerization inhibitor[16] could
improve the yield (73%) of the desired 1a-d3 with
excellent D contents (Scheme 2, bottom reaction
formula) along with a trace amount of hydrogenated
product (dodecyl propanoate) (See Supporting
Information). Although alkanes were also multi
deuterated under Pt/C-catalyzed analogous conditions
in i-PrOH/D2O[8c], the dodecyl group (aliphatic side
chain) of 1a was never deuterated under the present
reaction conditions. Meanwhile, the deuteration of
dodecyl propanoate as a substrate proceeded at all
methyl and methylene groups, while the deuterium
efficiency was low (eq. 1). It is worth noting that the
H-D exchange reaction at the dodecyl group of 1a
may be inhibited in the presence of the ,-
unsaturated carbonyl moiety.
10% Pt/C (10 mol%) could make
a slight
improvement in the D content at the -position of 1a-
d3 (78%D, entry 2). Under the present reaction
conditions, the sterically hindered -position of 1a
seems to be less reactive.
Table 1. Catalyst efficiency
D content (%)[a]
yield
entry catalyst
(%)
-1
96
96
34
75
38
0
-2
97
97
16
75
20
0

1
2[b]
10% Pt/C
10% Pt/C
10% Pd/C
10% Rh/C
10% Ir/C
10% Ru/C
72
78
27
42
7
91
84
91
63
53
88
3
4
5
6
0
[a] Determined by 1H and 2H NMR.
[b] 10 mol% of 10% Pt/C was used.
Because i-PrOH might act as a hydrogen source
and facilitate the undesirable decreasing of the
deuterium contents of 1a-d3 by the deterioration of
D2O resulted by the deuteration of a large amount of
the acidic-OH group of i-PrOH, the reduced use of i-
PrOH versus D2O (2 mL) was next investigated
(Table 2). While the decrease in i-PrOH from 0.5 to
0.3 or 0.2 mL slightly improved the deuterium
content of the -position of 1a-d3 (entries 1 vs. 2 and
3), the further reduction of i-PrOH use (0.1 mL)
produced insufficient D contents at the , positions
of both unsaturated carbons (entry 4). The
independent use of D2O and the addition of MeOH or
t-BuOH instead of i-PrOH as a co-solvent hardly
facilitated the H-D exchange reaction (entries 5-7).
Namely, i-PrOH mainly plays the role of the in situ
H2 source for the activation of the catalyst and a
solubilization agent for the substrate.
Scheme 2. H-D exchange reaction in a sealed tube and the
effect of hydroquinone as a polymerization inhibitor.
We next examined the substrate applicability of
the Pt/C-catalyzed H-D exchange reaction in i-PrOH
and D2O in the presence of hydroquinone.[17] The
olefin moiety of benzyl acrylate (1b) was effectively
deuterated to give 1b-d3 with nearly quantitative
deuterium contents in 80% yield, while no
deuteration of the aromatic nucleus was confirmed.
The N-dodecyl acrylamide (1c) and 4-hydroxybutyl
acrylate (1d) also underwent the deuteration to give
the corresponding deuterium-labeled products (1c-d3
and 1d-d3). α-Fluoroacrylate derivatives are useful as
intermediates in the synthesis of peptidomimetics[18]
and medicines[19]. The H-D exchange reaction of
dodecyl α-fluoroacrylate (1e) gave 1e-d2 without the
loss of fluorine. Since the undesirable polymerization
Table 2. Solvent efficiency.
D content (%)[a]
co-solvent
yield
(%)
entry
(X mL)
-1
96
97
99
84
-2
97
98
99
86

1
2
3
4
i-PrOH (0.5 mL)
i-PrOH (0.3 mL)
i-PrOH (0.2 mL)
i-PrOH (0.1 mL)
78
81
83
36
91
71
83
86
2
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10.1002/adsc.201800170
Advanced Synthesis & Catalysis
[c]
of 1e preferentially proceeded in a sealed tube, the
reaction was performed in a glass test tube. Sodium
acrylate (1f) was also efficiently deuterated, and the
product was isolated as n-dodecyl acrylate-d3 (1a-d3)
by esterification using 1-dodecanol (See Supporting
Information). Benzyl cinnamate (1g) possessing a
benzyl acrylate core had a lower reactivity toward the
deuteration, and the aromatic rings preferentially
underwent the H-D exchange reaction (50%D) rather
than the olefin site. The difference of the H-D
exchange reactivity between each benzyl group of 1b
and 1g could not be clearly explained. 1,10-Dodecyl
diacrylate (1h) was also effectively labeled by
deuteriums to give 1h-d6 with high D contents. The
H-D exchange reaction of acrylic acid (1i) as a free
acid also effectively proceeded to give 1i-d3 with high
D contents. Furthermore, methacrylic acids (2a-2c)
were also efficiently deuterated to give the
corresponding methacrylic acid-d5 derivatives. Both
an olefin and a methyl group were effectively
deuterated via the Pt/C-catalyzed H-D exchange
reaction on the olefin site and simultaneous
isomerization[6c] between the olefin and methyl
groups. In the case of the H-D exchange reaction of
diethyl fumarate (3a), the olefin moiety was
moderately deuterated. Meanwhile, dimethyl maleate
(3b) was smoothly deuterated to give dimethyl
fumarate (3c-d2) along with the isomerization of the
cis-isomer into the trans-olefin.
A trace amount of the hydrogenated product was
contaminated. The yield and D contents were determined
after isolation via esterification with 1-dodecanol. See
Supporting Information.
[d]
Since the direct determination of the yield was difficult,
the yield of 1i-d3 was confirmed as dodecyl acrylate (1a-
d3) after esterification by the use of 1-dodecanol via the
corresponding sodium salt. See Supporting Information.
[e] 0.5 mL of i-PrOH and 3 mL of D2O were used.
[f] Dimethyl maleate (3b) was used as a substrate.
An eight-fold scale-up of H-D exchange reaction
of 1b (2.0 mmol) also provided the desired 1b-d3
with excellent D contents in 83% yield, and the
obtained 1b-d3 could be transformed into a wide
variety of organic compounds maintaining the D
contents (Scheme 3). The site-selectively-deuterated
benzyl cinnamate derivative (4a-d2) was constructed
by the Pd/HP20[20]-catalyzed Mizoroki-Heck reaction
using 4-iodotoluene. The copper-catalyzed β-
borylation[21] with bis(pinacolate)diboron (Pin2B2) in
D2O gave the corresponding borylated product (4b-
d4), while the deuterium contents at the -position of
the benzyl ester function drastically decreased to ca.
50%D by the use of H2O instead of D2O. The
deuterium-labeled cyclohexene derivative (4c-d3) was
also obtained by the Diels-Alder reaction of 2,3-
dimethyl-1,3-butadiene and 1c-d3 as a dienophile.
Furthermore, β-monodeuterium-labeled α-bromo-β-
aminoacrylate derivative (4d-d1) could be synthesized
by the addition of N-bromosuccinimide (NBS).[22]
The 1,2,3-triazole derivatives are widely employed as
intermediates of biologically active materials.[23]
Benzyl -fluoro-β,β-dideuterated acrylate (1e-d2) was
coupled with NaN3 to give the deuterated 1,2,3-
triazole derivative (4e-d1).[24] The deuterated
methacrylate (2c-d5) efficiently underwent the
benzoyl peroxide (BPO)-mediated polymerization to
provide the multi-deuterated polymethacrylic acid
benzyl ester (4f-dn) in moderate yield.
Table 3. The scope of substrates.
[a] The reaction was performed in a glass test tube instead
of a sealed tube.
[b] 15 mol% of 10% Pt/C was used.
3
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10.1002/adsc.201800170
Advanced Synthesis & Catalysis
for Scientific Research (C) from the Japan Society for the
Promotion of Science (JSPS: 16K08169 for Y.S.) and a Grant-in-
Aid from JSPS (15J01556 to T.Y.).
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methacrylic acid derivatives in D2O with high D
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mmol), 10% Pt/C (10 mol%) and hydroquinone (10 mol%)
in i-PrOH (0.2 mL) and D2O (2 mL) was heated with
stirring at 120 °C for 24 h in a 6 mL stainless-steel sealed
tube. The reaction mixture was cooled to room temperature
and filtered through a membrane filter (Milipore, Millex®-
LH, 0.2 µm) together with Et2O (10 mL) and H2O (10 mL)
to remove the catalyst, and the combined filtrates were
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chromatography to give the deuterated product.
Acknowledgments
We thank the N.E. ChemCat Corporation for the kind gift of the
catalysts. This work was partially supported by the Research
Foundation for Pharmaceutical Sciences for Y. S., Grant-in-Aid
4
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10.1002/adsc.201800170
Advanced Synthesis & Catalysis
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10.1002/adsc.201800170
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