A convenient and effective method for the regioselective deuteration of alcohols

Article abstract of DOI:10.1002/adsc.200800407

The convenient and regioselective deuteration of hydroxy groups on vicinal carbons was achieved by the combination of 5% ruthenium on carbon (Ru/C), hydrogen gas and deuterium oxide (D₂O).

Full text of DOI:10.1002/adsc.200800407

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DOI: 10.1002/adsc.200800407
A Convenient and Effective Method for the Regioselective
Deuteration of Alcohols
Tomohiro Maegawa,a Yuta Fujiwara,a Yuya Inagaki,a Yasunari Monguchi,a
and Hironao Sajikia,*
a
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-8585, Japan
Fax : (+81)-58-237-5979; e-mail: sajiki@gifu-pu.ac.jp
Received: July 1, 2008; Published online: September 26, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800407.
Abstract: The convenient and regioselective deuter-
ation of hydroxy groups on vicinal carbons was
achieved by the combination of 5% ruthenium on
carbon (Ru/C), hydrogen gas and deuterium oxide
(D2O).
way to obtain regioselectively deuterated alcohols
using the target compound itself as a substrate. Effi-
cient and simple methods to substitute a hydrogen
À
with a deuterium on the C H bond on carbon atoms
vicinal to hydroxy groups in carbohydrates have been
reported using Raney Ni in D2O with heat,[9] ultra-
sonication[10] and microwave irradiation.[11] Other
transition metals such as Ru[12] and Mo[13] can also cat-
alyze the regioselective deuterium incorporation at
the a-position to hydroxy groups, but these methods
often require harsh reaction conditions with an unsuf-
ficient deuterium efficiency.
Keywords: alcohols; deuteration; heterogeneous
catalysis; regioselectivity; ruthenium
Deuterium-labeled compounds are highly useful in a
We have recently established the efficient and mul-
variety of scientific fields including the analysis of me- tiple deuteration of various organic molecules cata-
tabolism, reaction mechanisms and kinetics.[1] The lyzed by a heterogeneous platinum metal group
new utilization of deuterated compounds is also in- system such as Pd/C,[14] Pt/C[15] and Rh/C[16] in D2O
creasing in the material and analytical science fields under an H2 atmosphere (Scheme 1).
such as the raw material of optical fibers[2] and the in-
During the continuous study to further improve
ternal standard for quantitative analysis.[3] According deuteration methods, we developed the regioselective
to the new demand for suitably deuterated com- deuterium incorporation method of alcohols catalyzed
pounds, the development of diverse and selective syn- by Ru/Cin the presence of H gas in D2O with a high
2
thetic methods of deuterated materials is desired.
deuterium efficiency. We now report the regioselec-
Deuterium-labeled alcohols can be widely utilized tive deuteration at the a-positions to hydroxy groups
in the biochemistry and biophysical fields,[4] especially, under mild reaction conditions.
deuterated carbohydrates and glycoconjugates play
We first examined the catalyst efficiency of several
pivotal roles in revealing the mechanisms of cell rec- activated carbon-supported metal catalysts using 2-
ognition and receptor functions.[5] Regioselectively decanol as the substrate (Table 1). Only Ru/Cwas ef-
deuterated compounds are applicable for the confor- fective for the reaction, and regiospecific and efficient
mational analysis of complex molecules using deuterium incorporation was achieved at the a-posi-
1H NMR spectroscopy because of the simplified spec- tion at room temperature in 3 h.
trum[6] and the elucidation of the chemical or enzy-
The metal content of the heterogeneous catalyst is
matic reaction pathways.[7] Conventional methods to important to achieve an efficient deuterium incorpo-
prepare regioselectively deuterated alcohols involve ration (entries 5–7) and 20 wt% (vs. substrate) of 5%
reduction with metal deuteride reagents (NaBD4 and Ru/Cgave the best result. The application of heat ac-
LiAlD4, etc.) or the deuterogenation with D2 gas of celerated the deuteration and the reaction was com-
unsaturated compounds,[8] although the construction pleted within only 1 h at 508C. Regioselective deuteri-
of the starting substrates for the reductive deuteration um incorporation on the vicinal carbon of the secon-
À
may require several steps. On the other hand, the H
dary alcohol was achieved in a nearly quantitative ef-
D exchange reaction is an easy and straightforward ficiency (Table 2, entries 1–4). Only 2-adamantanol
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Tomohiro Maegawa et al.
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Scheme 1. Deuteration by the Pd/C(Pt/Cor Rh/C)-H 2-D2O system of various organic molecules.
Table 1. Effect of the catalyst.[a]
Table 2. Regioselective deuteration at the a-position to hy-
droxy groups in secondary alcohols catalyzed by Ru/Cin
D2O.[a]
Entry
Catalyst
D content [%]
1
2
3
4
5
6
7
10% Pd/C, 10 wt%
10% Rh/C, 10 wt%
10% Ir/C, 10 wt%
10% Pt/C, 10 wt%
10% Ru/C, 10 wt%
5% Ru/C, 10 wt%
5% Ru/C, 20 wt%
0
0
0
0
87
60
97
Entry Substrate
D content
[%]
Yield
[%]
1[b]
97
87
97
2[c]
100
[a]
The reaction was conducted with 0.5 mmol of the sub-
strate and catalyst in 2 mL of D2O at room temperature
under a H2 atmosphere of 1 atm for 3 h. The D content
1
2
was determined by H NMR and H NMR using an inter-
nal standard.
3
100
94
possessing a rigid basic skeleton was not affected
under these reaction conditions (entry 5). The deuter-
ated alcohols were spectromerically pure and no chro-
matographic purification was needed.
4[c]
94
0
72
We next investigated the deuteration of primary al-
cohols. The deuteration of 1-decanol selectively pro-
ceeded at the a-position to the hydroxyl group where-
as the efficiency of the deuterium incorporation was
moderate (~80%) at 508Ceven after 36 h (Table 3,
entry 1). We then attempted a further optimization of
the deuteration of primary alcohols. Consequently, an
increase in temperature to 808Cimproved the reac-
tion efficiency and a variety of primary alcohols were
regioselectively deuterated under the reaction condi-
tions with nearly quantitative deuterium efficiency
(entries 2–6).
5
N.D.[d]
[a]
The reaction was conducted with 0.25 mmol or 0.5 mmol
of the substrate and 20 wt% of 5% Ru/Cin 2 mL of D O
at 508Cunder 1 atm of H for 3 h.
The reaction was performed at room temperature.
A slight deuterium incorporation on the other carbons
was observed.
2
2
[b]
[c]
[d]
Not determined.
Furthermore, the deuteration of diol and triol de- gate the reaction mechanism. As a result, the product
rivatives in a regioselective manner is also possible, was racemized after 3 h [Eq. (1), only 1.8% ee].
and multi-deuterated products at the a-positions When the reaction with 2-decanone was performed
should be useful as deuterium-labeled synthons under the same conditions, the Ru/Ccatalyzed the re-
(Table 4).
duction of the aliphatic ketone smoothly and 2-dec-
Next, the reaction of (R)-2-decanol (97% ee) using anol was obtained in an 81:19 ratio [Eq. (2)]. Since
À
5% Ru/Cin H O under an H2 atmosphere (H H ex- the generation of a trace amount of ketones during
change reaction conditions) was conducted to investi- the deuteration of secondary alcohols could be detect-
2
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A Convenient and Effective Method for the Regioselective Deuteration of Alcohols
COMMUNICATIONS
Table 3. Regioselective deuteration at the a-position to hy-
droxy groups in primary alcohols catalyzed by Ru/Cin
D2O.[a]
Entry Substrate
D content [%] Yield [%]
1[b]
2
81
99
97
88
3[c]
100
100
95
4
100
5[c]
98
99
78
86
of various aliphatic alcohols including diol and triol
derivatives. Further applications to ethers and amines
are now underway.
6
[a]
ExperimentalSection
The reaction was conducted with 0.25 mmol or 0.5 mmol
of the substrate and 20 wt% of 5% Ru/Cin 2 mL of D O
2
GeneralProcedure for the Regioseel ctive
Deuteration of Alcohols
at 808Cunder 1 atm of H for 24 h.
2
[b]
[c]
The reaction was performed at 508Cfor 36 h.
A slight deuterium incorporation on the other carbons
was observed.
A suspension of 5%Ru/C(20 wt% of substrate), substrate
(0.25 or 0.5 mmol) and D2O (2 mL) in a test-tube was stirred
at the appropriate temperature under a hydrogen atmos-
phere. After completion, the mixture was cooled to room
temperature and filtered using a membrane filter (Millipore,
Millexꢁ-LH, 0.45 mm). The filtrate was extracted with dieth-
yl ether (2”10 mL), washed with water (2”30 mL) and
brine (30 mL) and dried with Mg2SO4 followed by concen-
tration under reduced pressure to furnish the deuterated al-
cohol. The details of experiments and the data (1H and
2H NMR and mass spectra) are available in the Supporting
Information.
ed, a redox reaction is more likely the mechanism for
the present deuteration, while the direct C H inser-
tion cannot be entirely ruled out.
In conclusion, we have developed a convenient and
efficient method for the regiospecific deuteration at
the a-positions to hydroxy moieties. The reaction pro-
ceeded with a high deuterium efficiency and regiose-
lectivity. This method is applicable to the deuteration
À
Table 4. Regioselective deuteration at the a-position to hydroxy groups in diols and triols catalyzed by Ru/Cin D O.[a]
2
Entry
Substrate
Product
D content [%]
Yield [%]
1
97
89
2[b]
82
75
90
89
3
4
98
100
[a]
The reaction was conducted with 0.25 mmol or 0.5 mmol of the substrate and 20 wt% of 5% Ru/Cin 2 mL of D O at
2
808Cunder 1 atm of H for 24 h.
A slight deuterium incorporation on the other carbons was observed.
2
[b]
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Tomohiro Maegawa et al.
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[7] J. E. G. Barnett, D. L. Corina, Adv. Carbohyd. Chem.
1972, 27, 127.
Acknowledgements
[8] a) C. Sreekumar, C. N. Pillai, Synthesis 1974, 498;
b) E. J. Corey, J. O. Link, Tetrahedron Lett. 1989, 30,
6275.
We thank N.E.Chemcat for the gift of the catalysts.
[9] a) H. J. Koch, R. S. Stuart, Carbohydr. Res. 1977, 59,
C1; b) H. J. Koch, R. S. Stuart, Carbohydr. Res. 1978,
67, 341; c) H. J. Koch, R. S. Stuart, Carbohydr. Res.
1978, 64, 127.
[10] E. A. Cioffi, J. H. Prestegard, Tetrahedron Lett. 1986,
27, 415; E. A. Cioffi, W. S. Willis, S. L. Suib, Langmuir
1988, 4, 697; E. A. Cioffi, W. S. Willis, S. L. Suib, Lang-
muir 1990, 6, 404; E. A. Cioffi, Tetrahedron Lett. 1996,
37, 6231.
References
[1] a) D. E. Stevenson, M. Akhtar, D. Gani, Tetrahedron
Lett. 1986, 27, 5661; b) T. Furuta, H. Takahashi, Y.
Kasuya, J. Am. Chem. Soc. 1990, 112, 3633; c) D. J.
Porter, F. L. Boyd, J. Biol. Chem. 1992, 267, 3205; d) S.
Murray, A. M. Lynch, M. G. Knize, M. J. Gooderham,
J. Chromatogr. 1993, 616, 211; e) M. Okazaki, N.
Uchino, N. Nozaki, K. Kubo, Bull. Chem. Soc. Jpn.
1995, 68, 1024; f) K. H. Gardner, L. E. Kay, J. Am.
Chem. Soc. 1997, 119, 7599; g) T. Junk, W. J. Catallo,
Chem. Soc. Rev. 1997, 26, 401; h) K. Liu, J. Williams, H.
Lee, M. M. Fitzgerald, G. M. Jensen, D. B. Goodin,
A. E. McDermott, J. Am. Chem. Soc. 1998, 120, 10199;
i) H. Nakazawa, S. Ino, K. Kato, T. Watanabe, Y. Ito,
H. Oka, J. Chromatogr. B Biomed. Sci. Appl. 1999, 732,
55; j) B. Chandramouli, D. Harvan, S. Brittain, R. Hass,
Organohalogen Compd. 2004, 66, 244; k) D. M. Marcus,
M. J. Hayman, Y. M. Blau, D. R. Guenther, J. O. Ehres-
mann, P. W. Kletnieks, J. F. Haw, Angew. Chem. 2006,
118, 1967; Angew. Chem. Int. Ed. 2006, 45, 1933; l) J.
Atzrodt, V. Derdau, T. Fey, J. Zimmermann, Angew.
Chem. 2007, 119, 7890; Angew. Chem. Int. Ed. 2007, 46,
7744.
[11] E. A. Cioffi, R. H. Bell, B. Le, Tetrahedron: Asymmetry
2005, 16, 471.
[12] M. Takahashi, K. Oshima, S. Matsubara, Chem. Lett.
2005, 34, 192.
[13] C. Balzarek, D. R. Tyler, Angew. Chem. 1999, 111,
2563; Angew. Chem. Int. Ed. 1999, 38, 2406; C. Balzar-
ek, T. J. R. Weakley, D. R. Tyler, J. Am. Chem. Soc.
2000, 122, 9427.
[14] H. Sajiki, F. Aoki, H. Esaki, T. Maegawa, K. Hirota,
Org. Lett. 2004, 6, 1485; H. Esaki, F. Aoki, T. Maega-
wa, K. Hirota, H. Sajiki, Heterocycles 2005, 66, 361; T.
Maegawa, A. Akashi, H. Esaki, F. Aoki, H. Sajiki, K.
Hirota, Synlett 2005, 845; H. Sajiki, H. Esaki, F. Aoki,
T. Maegawa, K. Hirota, Synlett 2005, 1385; H. Esaki, N.
Ito, S. Sakai, T. Maegawa, Y. Monguchi, H. Sajiki, Tet-
rahedron 2006, 62, 10954; H. Esaki, F. Aoki, M. Ume-
mura, M. Kato, T. Maegawa, Y. Monguchi, H. Sajiki,
Chem. Eur. J. 2007, 13, 4052; H. Esaki, R. Ohtaki, T.
Maegawa, Y. Monguchi, H. Sajiki, J. Org. Chem. 2007,
72, 2143.
[15] H. Sajiki, N. Ito, H. Esaki, T. Maesawa, T. Maegawa,
K. Hirota, Tetrahedron Lett. 2005, 46, 6995; N. Ito, T.
Watahiki, T. Maesawa, T. Maegawa, H. Sajiki, Adv.
Synth. Catal. 2006, 348, 1025; N. Ito, H. Esaki, T. Mae-
sawa, E. Imamiya, T. Maegawa, H. Sajiki, Bull. Chem.
Soc. Jpn. 2008, 81, 278.
[2] T. Kaino, K. Jinguji, S. Nara, Appl. Phys. Lett. 1983, 42,
567.
[3] a) R. G. Lewis, C. R. Fortune, R. D. Willis, D. E.
Camann, J. T. Antley, Environ. Health Perspect. 1999,
107, 721; b) R. A. Rudel, D. E. Camann, J. D. Spengler,
L. R. Korn, J. G. Brody, Environ. Sci. Technol. 2003, 37,
4543; c) E. Stokvis, H. Rosing, J. H. Beijnen, Rapid
Commun. Mass Spectrom. 2005, 19, 401; d) Y. Suzuki,
T. Korenaga, Y. Chikaraishi, Chem. Lett. 2006, 35, 532.
[4] D. G. Cameron, A. Martin, H. H. Mantsch, Science
1983, 219, 180.
[5] A. P. Tulloch, Prog. Lipid Res. 1983, 22, 235.
[6] a) C. P. Rao, S. P. Kaiwar, Carbohydr. Res. 1992, 237,
195; b) B. S. Babu, K. K. Balasubramanian, Carbohydr.
Res. 2005, 340, 753.
[16] T. Maegawa, Y. Fujiwara, Y. Inagaki, H. Esaki, Y.
Monguchi, H. Sajiki, Angew, Chem. 2008, 120, 5474;
Angew. Chem. Int. Ed. 2008, 47, 5394.
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