Mild deuteration method of terminal alkynes in heavy water using reusable basic resin

Article abstract of DOI:10.1039/c5ra18921g

The mild and efficient deuteration of terminal alkynes (mono-substituted alkynes) proceeded in the presence of a basic anion exchange resin, WA30, which is a polystyrene polymer bearing a tertiary amine residue on the aromatic nuclei, in heavy water (D₂O) at room temperature. WA30 could be easily removed by a simple filtration and repeatedly reused.

Full text of DOI:10.1039/c5ra18921g

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Mild deuteration method of terminal alkynes in
heavy water using reusable basic resin†
Cite this: RSC Adv., 2015, 5, 92954
*
Tsuyoshi Yamada, Kwihwan Park, Yasunari Monguchi, Yoshinari Sawama
*
and Hironao Sajiki
Received 15th September 2015
Accepted 22nd October 2015
DOI: 10.1039/c5ra18921g
www.rsc.org/advances
The mild and efficient deuteration of terminal alkynes (mono- and cheapest deuterium source without an organic co-solvent is
substituted alkynes) proceeded in the presence of a basic anion still challenging from the viewpoint of green sustainable
exchange resin, WA30, which is a polystyrene polymer bearing chemistry. We now demonstrate a clean and mild deuteration
a tertiary amine residue on the aromatic nuclei, in heavy water (D2O) at method of terminal alkynes using a reusable solid organic base
room temperature. WA30 could be easily removed by a simple filtra- in D2O at room temperature.
tion and repeatedly reused.
Various polystyrene polymer resins bearing an amine
residue within the basic skeleton are readily available, and we
have previously utilized basic and neutral resins (WA30, CR11,
CR20 and HP20 shown in Table 1) as supports of a heteroge-
neous transition metal-catalyst for coupling reactions,9 che-
moselective reductions10 and oxidations.11 We rst
investigated the effect of the substituent connected to the
polystyrene polymer backbone for the direct deuteration of 4-
ethynylanisole (1a) as a terminal alkyne (Table 1). The
deuteration of 1a (0.25 mmol: oil) using 115 weight% (wt%) of
the polystyrene WA30 resin bearing the tertiary amine residue
purchased from the Mitsubishi Chemical Corporation in D2O
smoothly proceeded to give the desired deuterated terminal
alkyne (1a-d1) with an excellent deuterium content (99% D)
and yield (93%) for 8 h (Entry 1). While AMBERLYST™ A21
possessing a structure similar to WA30 (ref. 12) and CR11
bearing the iminodiacetic acid residue as a kind of tertiary
amine were also effective (Entries 2 and 3), CR20 possessing
secondary and primary amine moieties within the molecule
was inefficient as a deuteration catalyst (Entry 4). Meanwhile,
the use of the polystyrene resin without amine moieties (HP20)
never facilitated the desired deuteration of 1a (Entry 5). WA30
possessing a physically durable structure was chosen as the
optimal basic solid catalyst to achieve the high deuterium
content of 1a-d1.
The utility of deuterium-labeled compounds is widely recog-
nized in various scientic elds, such as human metabolic,
reaction mechanistic, analytic and material studies.1,2 Among
them, deuterated terminal alkynes were also utilized for
mechanistic reaction studies3 and as useful building blocks to
construct deuterium labeled materials (e.g., deuterated alkene-
s3a,b,h,4 by hydrogenation, 1,2,3-triazole5 by Huisgen cycloaddi-
tion with azido compounds, and aromatics3f,g by Lewis acid-
catalyzed intra or intermolecular annulation and aromatiza-
tion, etc.). The deuterated terminal alkynes are traditionally
prepared via an acetylide, generated by the stoichiometric use of
organolithium,3a,b,c,g Grignard reagents3f or Na metal3h in a non-
protic solvent, and subsequent quench using deuterium sour-
ces, such as D2O and CD3OD, in association with the production
of a large amount of metal sludge. Additionally, the deuteration
using the silver salt/CD3CO2D combination6 or tri-
azabicyclodecene (TBD)7 and N-heterocyclic carbene8 in CDCl3
has also been reported. Bew et al. recently developed a mild
deuteration method of terminal alkynes under basic reaction
conditions in the presence of K2CO3 in a D2O/CH3CN mixed-
solvent.5 We have also reported a deuteration method using
Et3N as an organic base in a D2O/THF mixed-solvent at nearly
the same time.4 However, the development of the deuterium-
labeled method using a reusable catalyst in D2O as a neutral
We next examined the efficiency based on the WA30 usage
(Table 2). The deuterium contents of 1a increased in tandem
with the WA30 usage (Entries 1, 3 and 5). The efficient
deuterium incorporation of 1a to 1a-d1 was never achieved
using 10 or 50 wt% WA30 (Entries 2 and 4). Although 115 wt%
of WA30 versus 1a was required to obtain the quantitative
deuterium efficiency for the shorter reaction time (Entries 4
vs. 5), it is remarkable that WA30 could be reused at least 5
Laboratory of Organic 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; Fax: +81-58-230-8109; Tel: +81-58-230-8109
† Electronic supplementary information (ESI) available: Details of the general
procedure for deuteration, and NMR spectral data of the products. See DOI:
10.1039/c5ra18921g
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Table 1 Effect of resina
times without any deactivation and technical loss to accom-
plish the excellent D contents and isolated yield of 1a-d1
(Table 3).
The present reaction efficiencies were signicantly affected
by the physical state of the substrates (oil or solid, Table 3 vs.
eqn (1) and Table 4). An oily substrate, such as 1a, smoothly and
efficiently underwent the deuteration in D2O (Table 3). While 1-
ethynyl-4-phenylbenzene (1b) as a solid-state substrate was
never deuterated in D2O (eqn (1)), the addition of a small
amount of toluene as a co-solvent to dissolve the substrate
dramatically improved the deuterium content to give the
quantitatively deuterated 1b-d1 (the effect of other organic
solvents are described in the ESI†). Furthermore, WA30 used in
a D2O/toluene mixed-solvent could also be repeatedly reused
(see ESI†).
Entry
Resin
D content (%)
Yielda (%)
1
2
3
4
5
WA30
AMBERLYST™ A21
CR11
CR20
HP20
99
93
98
34
0
93
86
93
96
100
a
WA30, CR11, CR20 and HP20 were commercially available from
Mitsubishi Chemical Corporation. AMBERLYST™ A21 was
commercially available from the ORGANO Corporation. All resins
were washed with water and methanol, then dried in vacuo before
using them.
(1)
Various mono aryl- and alkyl-substituted alkynes could be
efficiently deuterated to give the corresponding mono-
deuterium labeled alkynes (Table 4). 2-Methoxy (1c) and tri-
uoromethyl (1d) ethynylbenzene as oily substrates were
smoothly deuterated with excellent deuterium efficiencies in
D2O (1c-d1 and 1d-d1) (Entries 1 and 2). The oily propargyl
alcohol derivatives (1e–g) were also efficiently deuterated in
quantitative deuterium contents (1e-d1, 1f-d1, 1g-d1) accom-
panied without hydrolysis of the ester (1e) or decomposition of
the benzyl ether (1f) and sulde moiety (1g) under the present
reaction conditions (Entries 3–5). Dodecyne (1h) as an oily
aliphatic terminal alkyne was effectively deuterated in D2O by
heating at 50 ꢀC (Entry 6). Although the 4-amino (1i) and nitro
(1j) ethynylbenzenes and a naphthalene derivative (1k) as
solid-state substrates were inefficiently deuterated in D2O
(Entries 7, 9 and 11), the addition of toluene as a co-solvent
facilitated the deuteration of 1i, 1j and 1k to give the corre-
sponding deuterium-labeled alkynes, respectively (1i-d1, 1j-d1
and 1k-d1) (Entries 8, 10 and 12). On the other hand, the
deuteration of the solid-state N-(propargyloxy)-phthalimide
(1l) resulted in the low deuterium incorporation regardless
of the addition of toluene as a co-solvent (1l-d1) for some
unaccountable reason (Entries 13 and 14). Ethynylestradiol
(1m), which is crucial medicinal compound as the solid-state
substrate, never underwent the deuteration in D2O. The
addition of AcOEt as a co-solvent facilitated the deuteration of
1m (Entries 15 vs. 16), while the addition of toluene was
ineffective (see ESI†).
Table 2 Effect of resin usage
Entry
X
Time (h)
D content (%)
1
2
3
4
5
13.2 (10 wt%)
13.2 (10 wt%)
66.1 (50 wt%)
66.1 (50 wt%)
152 (115 wt%)
8
24
8
12
8
23
45
75
94
99 (93a)
a
Isolated yield.
Table 3 Reuse test
Recovery yield
of WA30 (%)
Try
D content (%)
Yield (%)
1st
99
99
99
99
98
95
96
97
97
97
99
>99
99
99
2nd
3rd
4th
5th
Conclusions
Quant.
We have developed a mild and efficient deuteration method of
terminal alkynes by using a heterogeneous basic polystyrene
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Table 4 Scope of substrates
groups (e.g., nitro, propargyl ester, sulde, benzyl ether, etc.)
could be tolerant under the present mild reaction conditions.
WA30 could be repeatedly used without any loss of catalyst
activity. The present clean deuteration method of terminal
alkynes is expected to be utilized in not only laboratories, but
also industrial elds as an economic and eco-friendly reaction.
D content (%)
[yield (%)]
Entry
Product
Co-solvent
Time (h)
Oily substrates
Notes and references
1
—
—
8
8
96 [95]
99 [59]
1 Review: (a) J. Atzrodt, V. Derdau, T. Fey and J. Zimmermann,
Angew. Chem., Int. Ed., 2007, 46, 7744–7765; (b) Y. Sawama,
Y. Monguchi and H. Sajiki, Synlett, 2012, 23, 959–972; (c)
J. M. Herbert, J. Labelled Compd. Radiopharm., 2010, 53,
658–661.
2
2 Our recent H/D exchange reactions using heterogeneous
platinum metal on carbon; (a) Y. Sawama, Y. Yabe,
H. Iwata, Y. Fujiwara, Y. Monguchi and H. Sajiki, Chem.–
Eur. J., 2012, 18, 16436–16442; (b) Y. Sawama, T. Yamada,
Y. Yabe, K. Morita, K. Shibata, M. Shigetsura, Y. Monguchi
and H. Sajiki, Adv. Synth. Catal., 2013, 355, 1529–1534; (c)
T. Yamada, Y. Sawama, K. Shibata, K. Morita, Y. Monguchi
and H. Sajiki, RSC Adv., 2015, 5, 13727–13732.
3 (a) J. M. Brown and G. C. Lloyd-Jones, J. Am. Chem. Soc., 1994,
116, 866–878; (b) J. E. Baldwin and R. C. Burrell, J. Org.
Chem., 1999, 64, 3567–3571; (c) J.-C. Cintrat, F. Pillon and
B. Rousseau, Tetrahedron Lett., 2001, 42, 5001–5003; (d)
M.-Y. Chou, A. B. Mandal and M.-k. Leung, J. Org. Chem.,
2002, 67, 1501–1505; (e) C. H. Oh, H. H. Jung, K. S. Kim
and N. Kim, Angew. Chem., Int. Ed., 2003, 42, 805–808; (f)
A. S. K. Hashmi, M. Rudolph, H.-U. Siehl, M. Tanaka,
J. W. Bats and W. Frey, Chem.–Eur. J., 2008, 14, 3703–3708;
(g) T. Tsuchimoto, H. Matsubayashi, M. Kaneko, Y. Nagase,
T. Miyamure and E. Shirakawa, J. Am. Chem. Soc., 2008,
130, 15823–15835; (h) G. Zhang, L. Cui, Y. Wang and
L. Zhang, J. Am. Chem. Soc., 2010, 132, 1474–1475.
4 Y. Yabe, Y. Sawama, Y. Monguchi and H. Sajiki, Chem.–Eur.
J., 2013, 19, 484–488.
3
—
—
—
—
8
99 [quant.]
99 [90]
4
8
5
8
95 [93]
6a
16
93 [65]
Solid-state substrates
7
8
—
Toluene
8
12
15 [91]
97 [97]
9
10
—
8
12
18 [94]
94 [97]
Tolueneb
11
12
—
Toluene
8
12
19 [98]
96 [quant.]
5 S. P. Bew, G. D. Hiatt-Gipson, J. A. Lovell and C. Poullain, Org.
Lett., 2012, 14, 456–459.
13
—
Toluene
8
12
19 [86]
35 [89]
6 G. S. Lewandos, J. W. Maki and J. P. Ginnebaugh,
Organometallics, 1982, 1, 1700–1705.
14a
7 C. Sabot, K. A. Kumar, C. Antheaume and C. Mioskowski, J.
Org. Chem., 2007, 72, 5001–5004.
8 F. Perez, Y. Ren, T. Boddaert, J. Rodriguez and Y. Coquerel, J.
Org. Chem., 2015, 80, 1092–1097.
15
—
AcOEtb
8
24
0 [84]
92 [94]
16a
9 (a) Y. Kitamura, K. Taniguchi, T. Maegawa, Y. Monguchi,
Y. Kitade and H. Sajiki, Heterocycles, 2009, 77, 521–532; (b)
Y. Monguchi, K. Sakai, K. Endo, Y. Fujita, M. Niimura,
M. Yoshimura, T. Mizusaki, Y. Sawama and H. Sajiki,
ChemCatChem, 2012, 4, 546–558; (c) Y. Monguchi,
K. Nozaki, T. Maejima, Y. Shimoda, Y. Sawama,
Y. Kitamura, Y. Kitade and H. Sajiki, Green Chem., 2013,
15, 490–495; (d) Y. Monguchi, Y. Sawama and H. Sajiki,
Heterocycles, 2015, 91, 239–264; (e) Y. Monguchi,
T. Ichikawa, M. Netsu, T. Hattori, T. Mizusaki, Y. Sawama
and H. Sajiki, Synlett, 2015, 26, 2014–2018.
a
At 50 ꢀC. b 0.5 mL of the co-solvent was added.
resin (WA30) in D2O under mild conditions. It is noteworthy
that oily substrates smoothly underwent the direct deuteration
in D2O, while the deuteration of solid substrates could be
facilitated by the addition of a small quantity of a co-solvent,
such as toluene and AcOEt. A wide variety of functional
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10 (a) Y. Monguchi, Y. Fujita, K. Endo, S. Takao, M. Yoshimura, 12 Although WA30 and AMBERLYST™ A21 both partially
Y. Takagi, T. Maegawa and H. Sajiki, Chem.–Eur. J., 2009, 15,
834–837; (b) Y. Monguchi, T. Ichikawa, K. Nozaki, K. Kihara,
Y. Yamada, Y. Miyake, Y. Sawama and H. Sajiki, Tetrahedron,
2015, 71, 6499–6505.
possess tert-amino functionalities on the polystyrene
backbone, the apparent density and total ion-exchange
capacity should be different. Nevertheless, both catalysts
possess similar high catalyst activities.
11 Y. Monguchi, F. Wakayama, H. Takada, Y. Sawama and
H. Sajiki, Synlett, 2015, 26, 700–704.
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