Ruthenium catalyzed deuterium labelling of α-carbon in primary alcohol and primary/secondary amine in D2O

Article abstract of DOI:10.1246/cl.2005.192

Primary alcohols and primary/secondary amines are labelled with D atom at α-position regioselectively by means of deuterium oxide and ruthenium catalyst. Copyright

Full text of DOI:10.1246/cl.2005.192

192
Chemistry Letters Vol.34, No.2 (2005)
Ruthenium Catalyzed Deuterium Labelling of ꢀ-Carbon in Primary Alcohol
and Primary/Secondary Amine in D2O
Masaaki Takahashi, Koichiro Oshima, and Seijiro Matsubaraꢀ
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoutodaigaku-katsura, Nishikyo-ku, Kyoto 615-8510
(Received November 11, 2004; CL-041358)
Primary alcohols and primary/secondary amines are label-
led with D atom at ꢀ-position regioselectively by means of deu-
terium oxide and ruthenium catalyst.
hols6 and primary/secondary amines.
As shown in Scheme 3, n-dodecanol (5a, 3.0 mmol) and
RuCl2(PPh3)3 were heated under reflux of deuterium oxide
(5 mL) for 60 min. Although the deuterium proportion is not
high, some regioselective deuteration at ꢀ-position (7a) was ob-
served. The longer duration of heating (24 h) improved the pro-
portion up to 85%. The ratio of deuterium content was deter-
In the field of selective oxidation of alcohol,1 the chemose-
lective oxidation of primary vs. secondary alcohol has been in-
vestigated intensively. While an electron transfer type reagent
oxidizes a secondary alcohol selectively,2 the selective oxidation
of a primary alcohol into an aldehyde was accomplished by
hydrogen transfer type oxidation using RuCl2(PPh3)3.3,4 The
reason why the RuCl2(PPh3)3 oxidizes a primary alcohol selec-
tively in the presence of a secondary one is the formation of
ruthenium alkoxide 1 as an initial reaction complex (Scheme
1). The preferential formation of alkoxide with a primary alcohol
in the presence of a secondary one explains the chemoselectivi-
ty.4 Elimination of ruthenium hydride 2 from the alkoxide 1 will
afford an aldehyde. In the case of a catalytic reaction, the hydro-
gen in 2 will be removed by oxidants or by a hydrogen acceptor
such as enone. We have reported that treatment of a primary al-
cohol with catalytic amounts of RuCl2(PPh3)3 and 3-buten-2-
one under microwave irradiation gave an aldehyde in good
yield.5 The reaction was performed without solvent. In this
non-solvent reaction, we have noticed that addition of some
water inhibited the oxidation reaction. This observation means
that the equilibrium of the reaction path in Scheme 1 inclines
to the alcohol in the presence of water.
1
2
mined by H NMR and H NMR. Use of microwave irradiation
accelerated the exchange reaction. We used Discover system
from CEM corporation,7 as the microwave system. In a 10-mL
pressure vial which can be sealed by a septum, a mixture of al-
cohol (5a, 3.0 mmol) and RuCl2(PPh3)3 (6, 0.15 mmol) in deute-
rium oxide (3.0 mL) was placed. Microwaves (100 W) irradiated
the vial while the temperature was maintaining at 150 ꢁC. The
internal pressure reached to around 10 atm. After the irradiation
was continued for 30 min, 1,1-dideuteriodecanol was obtained
quantitatively. The ratio of deuterium atom on ꢀ-position of al-
cohol was more than 99%. Other examples are shown in Scheme
4. A secondary alcohol, 2-octanol, was also examined as a sub-
strate, but it was not converted into the labelled compound. The
result was quantitative recovery of starting material after an
irradiation by microwaves for 30 min at 150 ꢁC.
The protecting group, such as a benzyl, acetyl, t-butyldi-
methylsilyl, or MOM group cannot survive the reaction condi-
tion which had been applied for the primary alcohols in Scheme
RuCl2(PPh3)2 (6, 0.15 mmol)
n-C9H19CH2OH
(5a, 3.0 mmol)
n-C9H19CD2OH
D2O (5 mL) reflux, 1 atm
7a
60 min, reflux 18%D
H
RCH
O
RCH
H
O
24 h, reflux,
85%D
+ RuL
RCH OH
n
RCH ORuL
2
2
n
RuH L
2
[Ru] H
n
RuCl2(PPh3)2 (6, 0.15 mmol)
1
n-C9H19CH2OH
(5a, 3.0 mmol)
n-C9H19CD2OH
7a, >99%D*
2
Microwaves, 150 °C,
D2O (3 mL), 10 atm, 30 min
Scheme 1. An oxidation of primary alcohols with RuCl2(PPh3)3.
(*Microwaves, 100 °C, 60 min: 89%D)
When water is replaced with deuterium oxide, an exchange
of the acidic proton in the hydroxyl group with deuterium oxide
will occur (3 and 30). Through the catalytic process shown in
Scheme 2 as a working hypothesis, ꢀ-protons of alcohol will
be replaced with D atom (4 and 40). Here, we wish to report a cat-
alytic process for the labelling of the ꢀ-position of primary alco-
Scheme 3. Regioselective H–D exchange of 5a with RuCl2(PPh3)3.
RuCl2(PPh3)3 (6, 0.15 mmol)
RCH2OH
RCD2OH
Microwaves, 150 °C,
D2O (3 ml), 10 atm, 30 min
(5, 3.0 mmol)
7
n-C9H19CD2OH
CH2CD2OH
7a, 150 °C, 10 atm, 30 min,
H
RC
(>99%D, 98%)
7b, 150 °C, 10 atm, 30 min,
DH
H
O
(98%D, 96%)
RCH2OD
RCHDOH
RCH2ORuLn
RCHDORuLn
CD2OH
N
CD2OH
4
3
RuHDLn
DOH
D2O
RCH2OH
D2O
7c, 150 °C, 10 atm, 30 min,
(97%D, 90%)
RuLn
RuLn
7d, 150 °C, 10 atm, 30 min,
DOH
D
RC
HO CD2 (CH2)8 CD2 OH
(94%D, 62%)
H
D
O
7e, 150 °C, 10 atm, 30 min,
RCD2OH
(98%D, 79%)
RCD2ORuLn
RCHDOD
RCHDORuLn
RuHDLn
In the parentheses: (the ratio of D-atom contribution at -carbon, isolated yield)
α
4'
3'
Scheme 2. Working hypothesis for H–D exchange reaction of
primary alcohol with D2O and RuCl2(PPh3)3.
Scheme 4. Regioselective H–D exchange of primary alcohols under
microwave irradiation.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.2 (2005)
193
H
RC
RuCl2(PPh3)2 (6, 0.15 mmol)
DD
DH
ND
RCH2OH
RCD2OH
Microwaves, 100 °C,
1M NaOD (3 mL), 1.5 atm, 60 min
RCHDNHD
D2O
RCH2ND2
DOH
D2O
RCH2NH2
RCH2NRuLn
RCHDNRuLn
(5, 3.0 mmol)
7
RuHDLn
CD2 OH
t-BuMe2SiO CH2 (CH2)8
CD2 OH
PhCH2O CH2 (CH2)8
RuLn
RuLn
DOH
RCHDND2
D
RC
7f, 100 °C, 1.5 atm, 60 min,
7g, 100 °C, 1.5 atm, 60 min,
DH
ND
DD
(87%D, 82%)
(>99%D, 68%)
RCD2NH2
RCD2NRuLn
RCHDONRuLn
RuHDLn
CD2 OH
MOMO CH2 (CH2)8
CD2 OH
AcO CH2 (CH2)8
7h, 100 °C, 1.5 atm, 60 min,
7i, 0.02 M, NaOD (3 ml)
100 °C, 1.5 atm, 60 min,
(92%D, 85%)
Scheme 7. Working hypothesis for H–D exchange reaction of
primary amine with D2O and RuCl2(PPh3)3.
(92%D, 85%)
In the parentheses: (the ratio of D-atom contribution at
α−carbon, isolated yield)
RCH2NH2
RCD2ND(H)2
Scheme 5. Regioselective H–D exchange of primary alcohols in
basic condition under microwave irradiation.
RuCl2(PPh3)3 (6, 0.09 mmol)
or
or
(RCH2)2NH
(RCD2)2ND(H)
Microwave, 150 °C, D2O (3 ml)
10 atm, 30 min
(12, 3.0 mmol)
13
(CH3CH2CH2CH2CH2CD2)2ND
13b, 92%D at -position, 85%
4, because a mixture of deuterium oxide and 6 generates DCl.
When the reactions were operated in basic deuterium oxide,
these groups were intact and H–D exchange on the ꢀ-carbon
of alcohol proceeded selectively, as shown in Scheme 5.
n-C7H15CD2ND(H)2
13a, 94%D at -position, 79%
α
α
D
D
ND(H)
D
CD2
(CH2)4
CD2 ND(H)2
(H)D2N
Optically active primary alcohols with the stereogenic cen-
ter at ꢁ-position were also examined for this exchange reaction.
As shown in Scheme 6, (1S, 2S, 5S)-(–)-myrtanol (8) and (R)-2-
phenylpropanol were treated with RuCl2(PPh3)3 (6) and deuteri-
um oxide at 150 ꢁC under microwave irradiation. The exchange
proceeded in both cases to give the labelled alcohol, but some
epimerisation at ꢁ-position was observed. In these cases, a par-
tial deuteration was also observed at ꢁ-position (9: 38%D, 11:
30%D). Tuning the reaction temperature solved this racemiza-
tion problem. The reaction below 100 ꢁC with microwaves (in-
ternal pressure 1.5 atm) did not cause the epimerisation. When
the substrate was treated with the catalyst 6 in refluxing deuteri-
um oxide (bp. 101.4 ꢁC, 1.0 atm) for 1 h by simple external heat-
ing, only slight deuteration on ꢀ-carbon was observed (12%).
Irradiation by microwaves is different from simple external
heating, because polar species such as catalyst 6 and ruthenium
alkoxide are heated selectively by microwave irradiation.8,9
D
13c, 90%D at
α
-position, 64%
13d, 91%D at
α
-position, 68%
Scheme 8. Regioselective ruthenium catalyzed H–D exchange of
primary/secondary amines.
pounds based on transition metal-catalyzed direct C–H activa-
tion have been reported.11,12 The present method may also be
classed a catalytic C–H activation, but one should recognize that
the reaction proceeds as a result of transition metal catalyzed re-
dox equilibrium of primary alcohols in water. The method may
be applied for the regioselective labelling for more complex
compounds such as sugar or DNA. This is now underway.
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OH
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T°C
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Scheme 4.
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Published on the web (Advance View) January 15, 2005; DOI 10.1246/cl.2005.192