7
24
Chemistry Letters Vol.36, No.6 (2007)
Preparation of Cyclohexene-d by H/D-Exchange Reaction
1
0
Ã
Kenichi Ishibashi and Seijiro Matsubara
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoutodaigaku-katsura, Nishikyo-ku, Kyoto 615-8510
(Received March 8, 2007; CL-070249; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp)
Preparation of fully deuterium-labeled cyclohexene by H/
[
Ru]
D-exchange reaction was performed efficiently in the presence
of ruthenium catalyst under irradiation of microwaves. The
reaction proceeds via a repetition of hydroruthenation and ꢀ-
elimination.
+ [Ru-D]
[Ru] − [Ru-H]
D − [Ru-H]
+
[Ru-D]
D
D
D
D D
D
D
D
D
D2O
D
[Ru-H]
[Ru-D]
(1)
D
D
D
D D
As shown in Table 1, the irradiations of microwaves to
mixtures of cyclohexene, D2O, and ruthenium catalyst were
examined in the presence of various additives. An addition of
While regio- and stereospecifically deuterium-labeled com-
pounds have been used as fundamental research tools for biolog-
ical, pharmaceutical, environmental, and mechanistic studies,
fully deuterium-labeled compounds have also been important
for analytical chemistry including NMR and neutron scattering
Table 1. The effect of additives on the ruthenium-catalyzed
exchange reaction of cyclohexene
1
studies. In addition, recently, these compounds receive much at-
2
5
mol % RuCl (PPh )
2 3 3
tention as new materials. The H/D-exchange reaction using
additives
Dn
+
deuterium oxide as an isotopic source is one of the most practical
methods for the preparation of the fully deuterium-labeled com-
pounds, considering its cost and low toxicity. The reaction has
been performed in various ways. For example, a base catalyzed
H/D-exchange reaction in supercritical or subcritical deuterium
D O, Microwaves
2
1
2
3
Distribution
c
Run
Additivea
Conditionb
3
of D in 2
ꢀ
40 C,
0.34 MPa, 1 h
1
oxide was applied for the reaction of phenol and aniline deriva-
tives,3 and an acid-catalyzed H/D-exchange reaction was
1
2
none
0
0
ꢀ
4
185 C,
applied for alkenes. The transition metal-catalyzed exchange
reaction in hot deuterium oxide is also a useful method. The
methods can be applied not only for unsaturated hydrocarbons
none
30%D 5%
1
1
.0 MPa, 1 h
ꢀ
40 C,
3
MeOH (20 mol %)
MeOH (20 mol %)
EtOH (20 mol %)
EtOH (20 mol %)
SDS (10 mol %)
SDS (10 mol %)
SDS (10 mol %)
0
65%D
13%D
0
5
0
5
0.34 MPa, 1 h
but also for saturated ones. Although these methods have been
ꢀ
1
1
1
0
85 C,
.0 MPa, 1 h
applied to many compounds, cyclohexene-d10, which is one of
the most useful perdeuterated hydrocarbon, cannot be obtained
from cyclohexene efficiently by the existing methods. The only
example of a direct H/D-exchange reaction of cyclohexene was
4
ꢀ
40 C,
.34 MPa, 1 h
5
ꢀ
ꢀ
4a
185 C,
Werstiuk’s acid-catalyzed reaction in D2O at 225 C; but it
gave 1-methylcyclopentene-d10 as a major product. As far as
the reaction is acid-catalyzed, such skeletal rearrangement
cannot be avoided. In the cases of transition metal-catalyzed
H/D-exchange reactions, the formation of benzene is the major
pathway of the reaction, as the dehydrogenation reaction from
cyclohexene is also catalyzed by these metals to afford a stable
aromatized product. One of the crucial intermediary compounds
for dehydrogenation is supposed to be an allylic metal com-
pound. Thus, some new reaction, which does not contain such
an intermediate, should be designed for conversion from cyclo-
hexene into cyclohexene-d10.
6
95%D 10
1
1
0
1
0
1
0
.0 MPa, 1 h
ꢀ
40 C,
.34 MPa, 1 h
7
97%D
96%D
90%D
96%D
0
0
0
0
ꢀ
40 C,
.34 MPa, 15 min
8
ꢀ
20 C,
.14 MPa, 1 h
9
ꢀ
EtOH (20 mol %) 140 C,
10
SDS (10 mol %)
EtOH (20 mol %) 185 C,
SDS (10 mol %) 1.0 MPa, 1 h
0.34 MPa, 1 h
ꢀ
11
96%D 15
a
b
During the course of our study of ruthenium-catalyzed
reactions in water under irradiation of microwaves, we have
found a rapid repetition of hydrometallation and ꢀ-elimination,
which makes the isomerization of !-alkenol into saturated
alkanone possible.6 As the exchange reaction on ruthenium
SDS: Sodium dodecylsulfate. Microwaves were irradiated us-
ing a Biotage InitiatorÔ in 10 mL vial. Power varied automati-
cally between 0–100 W to maintain the temperature. The internal
pressure was measured at the indicated temperature. Cyclohex-
ene (1.0 mmol), Ru catalyst (0.05 mmol), D2O (3 mL), and addi-
tives (as indicated in Table) are used. During the irradiation, the
mixture was stirred by an electronic stirrer which is equipped in
7
hydride in deuterium oxide was also known, the reaction may
be applied to the conversion of cyclohexene into cyclohexene-
d10. Moreover, the intermediate is considered to be a saturated
cyclohexyl–metal compound, which does not have a step for
formation of benzene (eq 1).
c
the Biotage machine. Yields of the deuterated cyclohexene were
8
0–96%. The ratio of D-atom distribution was determined by
2
1
H and H NMR using CHBr3 and CDCl –CDCl as internal
2
2
standard individually.
Copyright Ó 2007 The Chemical Society of Japan