Ruthenium-catalyzed regioselective deuteration of alcohols at the β-carbon position with deuterium oxide

Article abstract of DOI:10.1002/chem.201101542

A convenient method for regioselective H/D exchange between D₂O and alcohols at the β-carbon position using the catalytic system [(p-cymene)RuCl₂]/ethanolamine/KOH is described. This method is applicable for deuteration of both prima

Full text of DOI:10.1002/chem.201101542

DOI: 10.1002/chem.201101542
Ruthenium-Catalyzed Regioselective Deuteration of Alcohols at the
b-Carbon Position with Deuterium Oxide
Sunny Kai San Tse, Peng Xue, Christy Wai Sum Lau, Herman H. Y. Sung,
Ian D. Williams, and Guochen Jia*[a]
Abstract: A convenient method for re-
gioselective H/D exchange between
D2O and alcohols at the b-carbon posi-
tion using the catalytic system [(p-cym-
ene)RuCl2]/ethanolamine/KOH is de-
scribed. This method is applicable for
deuteration of both primary and secon-
dary alcohols. The H/D exchange reac-
tions proceed through an oxidation/
modification/reduction reaction se-
quence. Alcohols are first temporarily
oxidized to carbonyl compounds by the
hydrogen transfer catalyst. The carbon-
yl compounds then undergo deutera-
tion at the carbon adjacent to the car-
bonyl group by keto–enol tautomeriza-
tion in the presence of D2O and a cata-
lytic amount of base. The deuterated
carbonyl compounds are then reduced
to produce deuterated alcohols. In sup-
port of the reaction mechanism, a well-
defined bimetallic ruthenium complex
was isolated from the reaction of [{(p-
cymene)RuCl2}2] with ethanolamine.
The activity of this complex is similar
to that of [{(p-cymene)RuCl2}2]/etha-
nolamine.
Keywords: alcohols · deuterium ·
exchange interactions · hydrogen
transfer · isotopic labeling · rutheni-
um
Introduction
pounds using NaBD4 catalyzed by optically active metal
complexes.[7] Alcohols labeled with deuterium at other posi-
tions can be obtained by multi-step organic synthesis from
Deuterium-labeled compounds are useful for a wide range
of applications. For example, they can be used as solvents in
NMR spectroscopy, labeled drugs, probes in mass spectrom-
etry, probes for mechanistic studies in chemical and bio-
chemical processes, and raw materials for other labeled
compounds and polymers. As a result, intense research has
focused on the development of methodologies for the prepa-
ration of selectively deuterium labeled compounds.[1,2]
deuterium-labeled
synthons.[8–14]
For
example,
PhCH(OH)CD3 can be prepared from the reaction of
PhCHO with CD3MgI (prepared from CD3I and Mg)[8] or
the reaction of LiAlH4 with PhC(O)CD3 (prepared from
PhCO2H and CD3Li);[9] CH
prepared from the reaction of CH CTHNUGTRENNUNG
(CH2)5CH(OH)CDH2 can be
3A(CH2)5CH=CH2 with
BD3 THF followed by treatment with H2O2/NaOH.[11]
.
A
This work concerns the regioselective deuteration of alco-
hols. Convenient preparations of deuterated alcohols are de-
sirable because alcohols are readily available both syntheti-
cally and naturally and can be used as starting materials for
a variety of organic syntheses. In addition, many drugs con-
tain hydroxyl functional groups and can therefore be grossly
considered as alcohols. Several approaches have previously
been reported for the preparation of deuterium-labeled al-
cohols. a-Deuterated alcohols can be obtained through the
reduction of the corresponding aldehydes or ketones by re-
agents such as NaBD4,[3] LiAlD4,[4] SiDMe2Ph/FÀ,[5] and D2/
Raney Al.[6] Deuterated chiral primary alcohols can be pre-
pared from enantioselective reduction of carbonyl com-
more cost-effective and time-efficient approach to deuteri-
um-labeled alcohols involves metal-catalyzed direct H/D ex-
change between alcohols and an appropriate deuterium
source. For example, alcohols with deuterium labeled at the
a- and b-carbon positions could be obtained from H/D ex-
change reactions between alcohols and C6D6 at 1358C cata-
[OTf] (5 mol%).[15]
lyzed by [Cp*Ir(H)3ACHTNUTRGENNGU(PMe3)]AHCTUNGTRENNGUN
Because deuterium oxide (D2O) is safe and is the cheap-
est source of deuterium, transition-metal-catalyzed H/D ex-
change reactions between D2O and alcohols provide an at-
tractive synthetic strategy for the preparation of deuterium-
labeled alcohols. Several systems have been reported to cat-
alyze such transformations. Matsubara et al. reported that
[RuCl2ACHTNUGTRENUNG(PPh3)3] (5 mol%) can catalyze regioselective H/D
exchange reactions between primary alcohols and D2O at
the a-carbon position under microwave irradiation (1508C,
10 atm).[16] Sajiki et al. showed that Ru/C-H2 (20 wt%) can
catalyze H/D exchange between D2O and both primary and
secondary alcohols at the a-carbon position at 50–808C.[17]
Nishioka et al. observed that isopropanol and cyclohexanol
undergo H/D exchange reactions with D2O preferentially at
the a-carbon position in the presence of a b-d-glucopyrano-
side-incorporated, N-heterocyclic carbene iridium com-
[a] Dr. S. K. S. Tse, Dr. P. Xue, C. W. S. Lau, Dr. H. H. Y. Sung,
Prof. I. D. Williams, Prof. G. Jia
Department of Chemistry
Hong Kong University of Science and Technology
Clear Water Bay, Kowloon (Hong Kong)
Fax : (+852)2358-1594
E-mail: chjiag@ust.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101542.
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Chem. Eur. J. 2011, 17, 13918 – 13925

FULL PAPER
ACTHNUTRGNEUNG
plex.[18] Tyler et al. found that [Cp’2Mo(OH)(OH2)]+ (Cp’=
C5H4Me) (5 mol%) can also catalyze regioselective H/D ex-
change reactions of primary alcohols with D2O at the a-
carbon position at 80–1028C.[19] When secondary alcohols
were used in [Cp’2Mo(OH)ACHTNUTGRNEUNG
(OH2)]+-promoted reactions, H/
D exchange at both a- and b-carbon positions was ob-
served.[19] Sajiki et al. showed that Pd/C-H2 (10 wt%) can
catalyze H/D exchange between aryl-substituted alkyl alco-
hols and D2O at the aliphatic carbon positions (except for
the a-carbon position) at 1108C in a sealed tube (e.g., Ph-
(CD2)3CH2OH).[20] Under
ACHTUNGTRENNUNG(CH2)4OH is converted into PhHCATUNGTRENNUGN
Scheme 1. Working hypothesis for H/D exchange between alcohols and
D2O at the b-carbon position.
similar conditions, deuteration of secondary alcohols gives a
mixture of labeled alcohols and ketones.[21] Utilizing the
same system, primary aromatic alcohols with deuterium at
the benzylic site can be prepared at room temperature (e.g.,
RuCl2}2]/ligand[25a,30] for H/D exchange reactions of alcohols
with D2O. These systems have proved to be efficient cata-
lysts for transfer hydrogenation reactions.
Ph
ACHTUNGTRENNUNG(CH2)3OH is converted into PhCD2ACHTUNGTRENNNUG
(CH2)2OH).[22] Tilley,
(PMe3)Cl2]
Bergman, and co-workers observed that [Cp*Ir
AHCTUNGTRENNUNG
(5 mol%) is catalytically active for deuteration of the alkyl
chains of both propanol and isopropanol with D2O at
1358C.[23]
Despite the impressive progress, catalytic systems that can
efficiently catalyze regioselective H/D exchange reactions of
alcohols at the b-position are still lacking. In this work, we
report regioselective H/D exchange reactions at the b-
carbon position of primary and secondary alcohols with
D2O catalyzed by ruthenium complexes.
To evaluate the catalytic property of complexes 1 and 2,
the reaction of PhCH2CH2OH with D2O was used as a
model. The H/D exchange reaction was performed at 808C
in the presence of 3 mol% of complexes 1 or 2 and
15 mol% of KOH. The performance of complexes 1 and 2
in the catalytic reaction is shown in Scheme 2.
Results and Discussion
Selection of catalysts: Previous studies on the chemistry of
carbonyl compounds have shown that aldehydes and ke-
tones can undergo H/D exchange reactions at the carbon
adjacent to the carbonyl group in the presence of a base and
a suitable deuterium source.[24] The transformation involves
reversible deprotonation/protonation, and takes advantage
of the high acidity of the a-protons.
Scheme 2. H/D exchange reaction of PhCH2CH2OH with D2O catalyzed
by complexes 1 and 2.
On the other hand, it is known that alcohols can be used
as hydrogen donors in the catalytic transfer hydrogenation
Complex 1 was found to mediate the deuteration of 2-
phenylethanol selectively at the b-carbon position. When a
mixture of 2-phenylethanol and D2O (in a molar ratio of
1:14.6) was heated at 808C in the presence of 3 mol% 1 and
KOH (5 equiv vs. Ru) for 2 h, approximately 69% D was
found at the b-carbon of 2-phenylethanol (theoretically
90% D can be achieved at this position when the hydrogen
atoms associated with H2O, KOH, and alcohols are consid-
ered). Complex 2 was found to mediate the deuteration of
2-phenylethanol at both the a- and b-carbon positions.
When a mixture of 2-phenylethanol and D2O was heated at
808C in the presence of 3 mol% 2 and KOH (5 equiv vs.
Ru) for 2 h, approximately 83 and 82% D were found at the
a- and b-positions of 2-phenylethanol, respectively (theoreti-
cally 83.2% D can be achieved at these positions).
of ketones and aldehydes.[25] It has also been demonstrated
[26]
À
À
that transition-metal complexes can catalyze C C and C
N[27] bond-formation reactions of alcohols through an oxida-
tion/modification/reduction sequence. This redox reaction
sequence allows the modification of alcohols using carbonyl
chemistry. Thus, we envisioned that H/D exchange between
D2O and alcohols at the b-carbon position could be ach-
ieved through reversible dehydrogenation of alcohols and
hydrogenation of carbonyl compounds, and H/D exchange
reactions between D2O and carbonyl compounds generated
in situ in an alkaline medium, as illustrated in Scheme 1.
Metal complexes that catalyze hydrogen transfer reactions
were thus considered to be good candidates for the intended
H/D exchange reactions.
The catalytic properties of [{(p-cymene)RuCl2}2] in combi-
nation with fourteen ligands (see Scheme 3 for their struc-
tures) in the catalytic H/D exchange reaction of 2-phenyl-
To test the hypothesis, we began our investigation by eval-
uating the catalytic activities of [(p-cymene)RuCl-
A
N
(ampy)] (2;
ACHTUNGTRENNUNG
ampy=2-(aminomethylene)pyridine),[29] and [{(h6-arene)-
a
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13919

G. Jia et al.
tive in promoting the H/D exchange reaction (Table 1, en-
tries 9–14). The amino ligands L5–L8 were only marginally
active and the reaction produced partially deuterated 2-phe-
nylethanol with 5% or less deuterium incorporation at the
b-carbon position (Table 1, entries 5–8). The diamine ligand
L4 was more effective and promoted the reaction to give
partially deuterated 2-phenylethanol with 17% D at the b-
carbon position (Table 1, entry 4). The most effective ligands
were found to be the amino alcohol ligands L1–L3, which
promoted the reaction to give partially deuterated 2-phenyl-
ethanol with respectively 55, 60, and 44% D at the b-carbon
position (Table 1, entries 1–3).
Because ethanolamine is inexpensive and more readily
available, we further investigated the reactions catalyzed by
[{(p-cymene)RuCl2}2]/ethanolamine to establish the opti-
mum reaction conditions. We were pleased to find out that
the combination of [{(p-cymene)RuCl2}2] with ethanolamine
can effectively promote the regioselective H/D exchange re-
action of 2-phenylethanol with D2O to give partially deuter-
ated 2-phenylethanol with a deuterium content at the b-
carbon position close to the theoretical maximum. For ex-
ample, deuterated 2-phenylethanol with 84% D at the b
carbon was obtained when a mixture of 2-phenylethanol,
D2O, [{(p-cymene)RuCl2}2], KOH, and ethanolamine (in a
molar ratio of 1:14.6:0.015:0.15:0.03) was heated at 808C for
5.5 h (Scheme 4). The deuterium content of 84% at the b
carbon of 2-phenylethanol is very close to the theoretical
value of 89.3%.
Scheme 3. Structures of ligands used in the screening experiments.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1:11.74:0.015:0.15:0.03) was heated at 808C for 2 h in an
NMR tube. The deuterium content of the products were
then determined by using 1H NMR spectroscopic analysis.
The results are summarized in Scheme 3 and Table 1.
As in the case of transfer hydrogenation, the ligand was
found to play an important role in determining the activity
and selectivity of the H/D exchange reaction. As shown in
Table 1, many of the tested ligands (L9–L14) were ineffec-
Scheme 4. Deuteration with the [{(p-cymene)RuCl2}2]/ethanolamine
system in D2O.
Table 1. Effect of the ligand on the H/D exchange reaction of 1-phenyl-
ACHTUNGTRENNUNG
ethanol with D2O mediated by [{(p-cymene)RuCl2}2]/ligand.[a]
Ligand
Dinc [%][b]
a-position b-position
Scope of substrates: We explored the scope of substrates in
the H/D exchange reactions between D2O and alcohols cata-
lyzed by the [{(p-cymene)RuCl2}2]/ethanolamine/KOH
system. In most cases, the H/D exchange reactions were per-
formed in the presence of 1.5 mol% [{(p-cymene)RuCl2}2],
3 mol% ethanolamine, and 15 mol% KOH. The molar ratio
of substrate and D2O was chosen such that the theoretical
percentage of deuterium incorporation at the b-carbon was
approximately 90%. The results of the catalytic reactions
are shown in Table 2.
As shown in Table 2, a variety of primary and secondary
alcohols that were deuterated at the b-position were readily
prepared by the present ruthenium-catalyzed H/D exchange
reactions. For example, the reaction of 1-phenylethanol
under the standard conditions for 5.5 h gave deuterated 1-
phenylethanol with 84% deuterium at the b-carbon position
(theoretically ca. 90% deuteration can be achieved). The
potentially coordinating alcohols 1-(2-pyridinyl)ethanol
(S10) and 1-(4-pyridinyl)ethanol (S9) also underwent H/D
1
2
3
4
5
6
7
8
9
ethanolamine (L1)
(S)-(+)-2-amino-3-methyl-1-butanol (L2)
ACHTUNGTRENNUNG(1R,2S)-(+)-cis-1-amino-2-indanol (L3)
N-methylethylenediamine (L4)
benzylamine (L5)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
55
60
44
17
5
2
2
1
0
0
0
0
0
0
0
aniline (L6)
2-(aminomethyl)pyridine (L7)
ethylenediamine (L8)
butylamine (L9)
10 dihexylamine (L10)
11 N,N’-diisopropylethylenediamine (L11)
12 2-pyridinyl-propanol (L12)
13 l-threonine (L13)
14 2,4,6-triaminopyrimidine (L14)
15 none
[a] Reagents and conditions (reaction performed in an NMR tube): [{(p-
cymene)RuCl2}2] (1.5 mol%), ligand (3 mol%), KOH (15 mol%), N2,
808C, 2 h. Dtheo (the statistical percentage of D considering the hydrogen
atoms associated with H2O, KOH and alcohols) was set to be approxi-
mately 90%. [b] Dinc is the percentage of deuterium incorporation deter-
1
mined experimentally by H NMR spectroscopic analysis.
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Chem. Eur. J. 2011, 17, 13918 – 13925

Regioselective Deuteration of Alcohols
FULL PAPER
Table 2. H/D exchange reactions of alcohols with D2O catalyzed by the [{(p-cymene)RuCl2}2]/ethanolamine/
methane at room temperature
for 27 h afforded [{(p-cymene)-
RuCl}2(m-NH2CH2CH2O·H·O-
CH2CH2NH2)]Cl (3), which was
isolated as a yellow solid in
83% yield (Scheme 6).
The structure of 3 was con-
firmed by X-ray diffraction
analysis. As shown in Figure 1,
complex 3 is a bimetallic com-
KOH system.[a]
Substrate
Dtheo
t
Products
[%][b]
[h]
Dinc [%][c]
1
2
2-phenylethanol (S1)
90.0
90.0
5.5
N-(2-hydroxyethyl)morpholine (S2)
9.25
3
4
5
1-phenylethanol (S3)
89.9
90.0
90.0
5.5
9.25
6
À
plex with an O H···O linkage
in the solid state. The short
O1A···O1B distance (2.397 ꢁ)
1,1’-(1,4-phenylene)diethanol (S4)
1-phenylpropanol (S5)
indicates
a strong hydrogen
bond between the two oxygen
atoms. Each ruthenium center
is ligated with an N,O-ligand.
The complex has a +1 overall
charge with a chloride ion as
the counter anion. The rutheni-
um center adopts a piano-stool
geometry with chloride and
ethanolamine serving as the
6
1,2,3,4-tetrahydronaphthalen-1-ol (S6)
90.0
6
7
8
2-buthanol (S7)
89.9
90.0
5.5
8
cyclohexanol (S8)
À
legs. The Ru N (2.111(6) ꢁ for
À
Ru1A N1A and 2.120(7) ꢁ
9
1-(pyridin-4-yl)ethanol (S9)
1-(pyridin-2-yl)ethanol (S10)
90.0
89.9
9.25
9.25
À
À
for
Ru1B N1B),
Ru Cl
À
(2.422(2) ꢁ for Ru1A Cl1A
10
À
and 2.418(2) ꢁ for Ru1B
Cl1B), and Ru O (2.079(6) ꢁ
for Ru1A O1A and 2.094(5) ꢁ
for Ru1B O1B) bond lengths,
À
[a] Reagents and conditions: [{(p-cymene)RuCl2}2] (1.5 mol%), ethanolamine (3 mol%), KOH (15 mol%), N2,
808C in a Schlenk tube. [b] Dtheo is the statistical percentage of D considering the hydrogen atoms associated
with water, KOH, ethanolamine, and substrates. [c] Dinc is the percentage of deuterium incorporated, deter-
À
À
À
as well as the Ru C
N
1
2
mined experimentally by H and D NMR spectroscopic analyses.
exchange smoothly to give the corresponding deuterated
pyridinylethanols.
Alcohols with more than 90% deuterium at the b-carbon
position can be obtained by repeating the H/D exchange re-
action. For example, PhCD2CH2OH with 91%D was ob-
tained in the following way. A mixture of [{(p-cymene)-
ACHTUNGTRENNUNGRuCl2}2] (36.8 mg, 0.06 mmol), 2-phenylethanol (480 mL,
4.0 mmol), ethanolamine (72 mL, 1.66m in D2O, 120 mmol),
D2O (716 mL), and KOH in D2O (178 mL, 3.38m, 0.6 mmol)
was heated at 808C for 4 h. The product was isolated and
the reaction was repeated one more time. With a similar
procedure, other alcohols with more than 90% deuterium at
the b-carbon position can be obtained, as exemplified in
Scheme 5.
Scheme 5. Deuterated alcohols obtained by carrying out the H/D ex-
change reaction twice.
Preparation and characterization of a bimetallic ruthenium
complex from the reaction of [{(p-cymene)RuCl2}2] with
ethanolamine: To gain a better understanding of the nature
of the active species in the catalytic reactions, we attempted
to prepare well-defined metal complexes from the reaction
of [{(p-cymene)RuCl2}2] with ethanolamine.
Scheme 6. Synthesis of complex 3.
distances (2.15–2.42 ꢁ) are comparable to those found in re-
lated complexes such as [(p-cymene)RuCl
amino-1,2-diphenylethanolato}],[31]
[(p-cymene)RuCl
N,N-(1S,2S)-TsDPEN}] (N,N-(1S,2S)-TsDPEN=(1S,2S)-N-
p-toluenesulfonyl-1,2-diphenylethyl
enediamine),[32] and [(p-
{h2-N,O-
ACHUTGTNRENNUG ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Reaction of [{(p-cymene)RuCl2}2] with two equivalents of
ethanolamine in the presence of triethylamine in dichloro-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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13921

G. Jia et al.
[(p-cymene)RuCl(NH2CH2CH2O)]. In our view, conversion
of 3 into only the mononuclear complex [(p-cymene)R-
uCl(NH2CH2CH2OH)] in a neutral aprotic solvent such as
dichloromethane is unlikely because addition of a proton is
required for the process. On the other hand, we cannot rule
out the possibility that there is a fast equilibrium between
complex 3 and the two monomeric complexes [(p-cyme-
ne)RuCl(NH2CH2CH2OH)]+
(NH2CH2CH2O)] in solution.
and
[(p-cymene)RuCl-
H/D exchange reactions with complex 3: With complex 3 in
hand, we examined its catalytic performance in the H/D ex-
change reaction of phenethyl alcohol with D2O. The H/D
exchange reaction was performed neat at 808C in the pres-
ence of 3 mol% of the complex. Consistent with the screen-
ing results discussed above, complex 3 was found to be cata-
lytically active for the regioselective H/D exchange reaction.
Thus, deuterated 2-phenylethanol with 80% D at the b-
carbon was obtained when a mixture of 2-phenylethanol,
D2O, KOH, and 3 (in a molar ratio of 1:7.24:0.15:0.03) was
heated at 808C for 5.5 h. The deuterium content of 80%
found at the b-carbon of 2-phenylethanol was very close to
the theoretical maximum value of 82.1% (Table 3, entry 1).
To further demonstrate that complex 3 behaves in a simi-
lar way to the species generated in situ, H/D exchange reac-
tions between D2O and several other alcohols were investi-
gated. The reactions were conducted with 3 mol% 3 and
15 mol% KOH, neat at 808C. As shown in Table 3, the per-
formance of catalyst 3 was similar to that of the catalytic
system [{(p-cymene)RuCl2}2]/ethanolamine.
Figure 1. ORTEP drawing of 3. Thermal ellipsoids are shown at the 40%
probability level. The chloride anion and acetonitrile are not shown. Se-
À
lected bond lengths [ꢁ] and angles [8]: average Ru1A C (p-cymene)
À
À
À
2.165, average Ru1B C (p-cymene) 2.172, Ru1A Cl1A 2.422(2), Ru1B
À
À
À
Cl1B 2.418(2), Ru1A N1A 2.111(6), Ru1B N1B 2.120(7), Ru1A O1A
À
À
À
2.079(6), Ru1B O1B 2.094(5), O1A Ru1A N1A 79.1(2), O1B-Ru1B-
N1B 78.6(2), C11A-N1A-Ru1A 109.5(5), C11B-N1B-Ru1B 109.5(5),
C12A-O1A-Ru1A 114.5(5), C12B-O1B-Ru1B 113.6(5), O1A···O1B
2.397.
cymene)RuClACHTUNGTRENNUNG CAHTUNGTRNE(NUGN 1S,2R)-N-(4-biphenylmethyl)nore-
{h2-N,O-
phedrine}].[33] The N-Ru-O bond angle (around Ru1A,
79.1(2)8; around Ru1B, 78.6(2)8) also closely resemble the
reported values of 78.3(2)8 in [(p-cymene)RuCl
(1S,2R)-amino-1,2-diphenylethanol
ato)][30] and 80.6(8)8 in
(1S,2R)-N-(4-biphenylmethyl)nor-
(h2-N,O-
ACHTUNGTRENNUGN ACHTUGN-
T
G
Mechanistic considerations: A plausible pathway for the H/
D exchange reactions catalyzed by [{(p-cymene)RuCl2}2]/
ethanolamine/KOH is shown in Scheme 7, using 1-phenyle-
[(p-cymene)RuClACHTUNGTRENNUNG ACTHUNGTRENNNUG
(h2-N,O-
ephedrine)].[33]
Consistent with the structure,
the 1H NMR spectrum of
3
Table 3. The H/D exchange reactions of alcohols with D2O catalyzed by 3.[a]
showed four ethylene proton
signals of the ethanolamine
group at d=2.34, 2.62, 3.16, and
3.35 ppm. The 13C{1H} NMR
spectrum showed two signals at
d=63.1 and 45.6 ppm for the
Substrate
Dtheo
t
Product
[%][b]
[h]
Dinc [%][c]
1
2-phenylethanol (S1)
82.1
5.5
ethanolamine
group.
The
2
3
N-(2-hydroxyethyl)morpholine (S2)
N-(3-hydroxypropyl)morpholine (S11)
89.9
88.2
9.25
8
proton signal of the bridging
hydrogen could not be located
in the spectrum, presumably
due to the exchange of this
proton with those of water in
solution. The solution NMR
data are also consistent with
4
5
6
1-phenylethanol (S3)
82.7
89.2
90.5
6.5
6
1,2,3,4-tetrahydronaphthalen-1-ol (S6)
tetrahydrofuran-3-ol (S12)
the
mononuclear
complex
[(p-cymene)RuCl(NH2CH2CH2-
OH)] or the situation that there
is a fast equilibrium between
complex 3 and the two mono-
meric complexes [(p-cymene)R-
8.5
[a] Reagents and conditions: complex 3 (1.5 mol%), KOH (15 mol%), N2, 808C in a Schlenk tube. [b] Dtheo is
the statistical percentage of D considering the hydrogen atoms associated with water, KOH and alcohols.
uCl(NH2CH2CH2OH)]+
and [c] Dinc is the percentage of deuterium determined experimentally by 1H and 2D NMR spectroscopic analysis.
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Chem. Eur. J. 2011, 17, 13918 – 13925

Regioselective Deuteration of Alcohols
FULL PAPER
Consistent with the mechanism, the rate for deuterium in-
corporation into the substrates is closely related to the acidi-
ty of protons of the corresponding carbonyl compounds. H/
D exchange occurs less readily when an electron-donating
group is attached to the b-carbon of the substrate alcohol.
For example, 1-phenylethanol (Table 2, entry 3) underwent
H/D exchange reaction more readily than cyclohexanol
(Table 2, entry 8). The order of reactivity was determined to
be the same as the order of acidity of the corresponding car-
bonyl compounds (Scheme 8).[34]
Conclusion
Scheme 7. Proposed mechanism for the H/D exchange reaction of alco-
hols.
We have developed a convenient method for regioselective
H/D exchange between D2O and alcohols at the b-carbon
position using the catalytic system [{(p-cymene)RuCl2}2]/
ethanolamine/KOH.
The present H/D exchange reactions proceed through an
oxidation/modification/reduction reaction sequence. Alco-
hols are first temporarily oxidized to carbonyl compounds
by the hydrogen transfer catalyst. The carbonyl compounds
then undergo deuteration at the carbon adjacent to the car-
bonyl group by keto–enol tautomerization in the presence
of D2O and a catalytic amount of base. The deuterated car-
bonyl compounds are then reduced to produce deuterated
alcohols.
thanol as an example. Because 3, which can be isolated from
the reaction of [{(p-cymene)RuCl2}2] with ethanolamine, has
a performance similar to that of [{(p-cymene)RuCl2}2]/etha-
nolamine in the catalytic reactions, we believe complex 3 is
generated as a precatalyst in the reaction mixture. Complex
3 can react with KOH to give the alkoxyamido species 3A
as the true catalyst. Complex 3A reacts with 1-phenyletha-
nol to give hydride complex 3B and acetophenone through
a six-membered cyclic transition state such as A, which is a
generally accepted pathway for hydrogen transfer reactions.
Acetophenone then undergoes H/D exchange with D2O in
the presence of KOH through keto–enol tautomerization.
The deuterated acetophenone is then reduced by complex
3B to give deuterated 1-phenylethanol and the active spe-
cies 3A is regenerated for the next reaction cycle.
This method is applicable for deuteration of both primary
and secondary alcohols. A well-defined bimetallic ruthenium
precatalyst 3 was isolated from the reaction of [{(p-cyme-
ne)RuCl2}2] with ethanolamine. The activity of this complex
is similar to that of [{(p-cymene)RuCl2}2]/ethanolamine.
In agreement with the proposed mechanism, acetophe-
none regioselectively deuterated at the b-carbon position
was readily obtained by heating a mixture of acetophenone
and D2O in the presence of 20.7 mol% KOH at 808C. The
result indicates that a H/D exchange reaction through keto–
enol tautomerization can indeed proceed in the presence of
a catalytic amount of KOH. The observation that tertiary al-
cohols do not undergo H/D exchange reactions also sup-
ports the proposed hydrogen transfer mechanism and elimi-
Experimental Section
All manipulations were carried out under a nitrogen atmosphere using
standard Schlenk techniques unless otherwise stated. Solvents were dis-
tilled under nitrogen from sodium/benzophenone (n-hexane, diethyl
ether, THF), sodium (benzene), or calcium hydride (dichloromethane).
Other solvents were purged with nitrogen for 10 min before use. [(p-cym-
ene)RuCl(NH2CH2CH2NTs)]Cl (1),[28] [RuCl
2ACHTNUTRGENN(UG PPh3)2AHCUTNGTREN(NUGN ampy)] (2; ampy=
À
2-(aminomethylene)pyridine),[29] and [{(h6-arene)RuCl2}2][35] were synthe-
sized according to reported procedures. Deuterium oxide (99.9 atom%
D), was purchased from Aldrich Chemical Co. and used as received. All
other reagents were used as purchased from Aldrich Chemical Co.,
Acros Organics, International Laboratory USA, or Kodak. 1H and
13C{1H} NMR spectra were recorded with a Bruker ARX 300 MHz spec-
trometer or a Bruker AV 400 MHz spectrometer. 2D NMR spectra were
recorded with a Bruker AV 400 MHz spectrometer.
nates a direct C H bond activation mechanism.
General procedure for the H/D exchange reactions between alcohols and
D2O in the screening experiments (in NMR tubes): A mixture of ligand
(2 equiv relative to [{(p-cymene)RuCl2}2]), [{(p-cymene)RuCl2}2] (9.2 mg,
15 mmol), KOH in D2O (5.07m, 29.5 mL, 0.15 mmol), phenylethanol
(120 mL, 1.0 mmol), and D2O (210 mL, 11.7 mmol) was heated at 808C for
2 h. The resulting solution was analyzed by 1H NMR spectroscopy using
CDCl3 as the solvent.
General procedure for H/D exchange reactions between alcohols and
D2O catalyzed by [{(p-cymene)RuCl2}2]/KOH/ethanolamine conducted
on a preparative scale: Ethanolamine (36 mL, 1.66m in D2O, 60 mmol),
Scheme 8. Correlation between the activity of alcohols towards H/D ex-
change reactions and the acidity of the protons of the corresponding car-
bonyl compound at the carbon adjacent to the carbonyl group.
D2O (397.5 mL, total D2O added=397.5
+
36
+
89=522.5 mL,
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13923

G. Jia et al.
29.2 mmol) and KOH in D2O (89 mL, 3.38m, 0.3 mmol) were added to a
Schlenk tube charged with [{(p-cymene)RuCl2}2] (18.4 mg, 0.03 mmol)
and 2-phenylethanol (240 mL, 2.0 mmol). The mixture was heated at
808C for a defined period of time. The progress of the reaction was
monitored by 1H NMR spectroscopic analysis. When the reaction was
complete, the product was extracted with diethyl ether, washed with
water, and purified by column chromatography.
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formula
Mr
l [ꢁ]
C28H47Cl3N4O2Ru2
780.19
0.71073
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T [K]
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
100(2)
triclinic
¯
P1
10.379 (2)
12.367 (3)
14.172 (3)
97.136 (5)
97.748 (4)
107.608 (4)
1691.6(6)
4
1.532
796
0.25ꢃ0.10ꢃ0.08
1.47 to 26.50
9656
a [8]
b [8]
g [8]
V [ꢁ3]
Z
1calcd [MgmÀ3
]
F
N
crystal size [mm3]
q range [8]
reflns collected
independent reflns
final R indices [I>2s(I)]
R indices (all data)
largest diff. peak/hole [eꢁÀ3
6709 [RACTHNGUTERN(UNG int)=0.0661]
R1 =0.0631, wR2 =0.1388
R1 =0.1386, wR2 =0.1700
1.211/À1.320
]
General procedure for the preparative scale H/D exchange reactions be-
tween alcohols and D2O catalyzed by complex 3: D2O (0.17 mL,
9.38 mmol) and KOH in D2O (2.0m, 0.13 mL, 0.26 mmol) were added in
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a Schlenk tube charged with complex 3 (20.0 mg,
25.9 mmol) and 1-phenylethanol (200 mL, 1.66 mmol). The mixture was
heated at 808C for a defined period of time. During the reaction, the
progress was monitored by H NMR spectroscopic analysis. When the re-
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washed with water, and purified by column chromatography.
1
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Acknowledgements
This work was supported by the Hong Kong Research Grant Council
(Project Nos. HKUST 601709 and HKU1/CRF/08).
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Chem. Eur. J. 2011, 17, 13918 – 13925

Regioselective Deuteration of Alcohols
FULL PAPER
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Received: May 19, 2011
Published online: November 3, 2011
Chem. Eur. J. 2011, 17, 13918 – 13925
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13925