Synthetic scope and mechanistic studies of Ru(OH)x/Al 2O3-catalyzed heterogeneous hydrogen-transfer reactions

Article abstract of DOI:10.1002/chem.200500539

Three kinds of hydrogen-transfer reactions, namely racemization of chiral secondary alcohols, reduction of carbonyl compounds to alcohols using 2-propanol as a hydrogen donor, and isomerization of allylic alcohols to saturated ketones, are efficiently promoted by the easily prepared and inexpensive supported ruthenium catalyst Ru(OH)_x/Al₂O ₃. A wide variety of substrates, such as aromatic, aliphatic, and heterocyclic alcohols or carbonyl compounds, can be converted into the desired products, under anaerobic conditions, in moderate to excellent yields and without the need for additives such as bases. A larger scale, solvent-free reaction is also demonstrated: the isomerization of 1-octen-3-ol with a substrate/catalyst ratio of 20000/1 shows a very high turnover frequency (TOF) of 18400 h 1, with a turnover number (TON) that reaches 17200. The catalysis for these reactions is intrinsically heterogeneous in nature, and the Ru(OH)_x/Al₂O₃ recovered after the reactions can be reused without appreciable loss of catalytic performance. The reaction mechanism of the present Ru(OH)_x/Al₂O ₃-catalyzed hydrogentransfer reactions were examined with monodeuterated substrates. After the racemization of (S)-1-deuterio-1-phenylethanol in the presence of acetophenone was complete, the deuterium content at the α-position of the corresponding racemic alcohol was 91%, whereas no deuterium was incorporated into the α-position during the race mization of (S)-1-phenylethanol-OD. These results show that direct carbon-to-carbon hydrogen transfer occurs via a metal monohydride for the racemization of chiral secondary alcohols and reduction of carbonyl compounds to alcohols. For the isomerization, the α-deuterium of 3-deuterio-1-octen-3-ol was selectively relocated at the β-position of the corresponding ketones (99% D at the β-position), suggesting the involvement of a 1,4-addition of ruthenium monohydride species to the α,β-unsaturated ketone intermediate. The ruthenium monohydride species and the α,β-unsaturated ketone would be formed through alcoholate formation/β-elimination. Kinetic studies and kinetic isotope effects show that the Ru - H bond cleavage (hydride transfer) is included in the rate-determining step.

Full text of DOI:10.1002/chem.200500539

DOI: 10.1002/chem.200500539
Synthetic Scope and Mechanistic Studies of Ru(OH) /Al O -Catalyzed
x
2
3
Heterogeneous Hydrogen-Transfer Reactions
[
a, b]
[a]
[b]
[a]
Kazuya Yamaguchi,
Takeshi Koike, Miyuki Kotani, Mitsunori Matsushita,
[a, b]
[
a]
Satoshi Shinachi, and Noritaka Mizuno*
Abstract: Three kinds of hydrogen-
transfer reactions, namely racemization
of chiral secondary alcohols, reduction
of carbonyl compounds to alcohols
using 2-propanol as a hydrogen donor,
and isomerization of allylic alcohols to
saturated ketones, are efficiently pro-
moted by the easily prepared and inex-
pensive supported ruthenium catalyst
Ru(OH) /Al O . A wide variety of sub-
strates, such as aromatic, aliphatic, and
heterocyclic alcohols or carbonyl com-
pounds, can be converted into the de-
sired products, under anaerobic condi-
tions, in moderate to excellent yields
and without the need for additives such
as bases. A larger scale, solvent-free re-
action is also demonstrated: the iso-
merization of 1-octen-3-ol with a sub-
strate/catalyst ratio of 20000/1 shows a
(TON) that reaches 17200. The cataly-
mization of (S)-1-phenylethanol-OD.
These results show that direct carbon-
to-carbon hydrogen transfer occurs via
a metal monohydride for the racemiza-
tion of chiral secondary alcohols and
reduction of carbonyl compounds to al-
cohols. For the isomerization, the a-
deuterium of 3-deuterio-1-octen-3-ol
was selectively relocated at the b-posi-
tion of the corresponding ketones
(99% D at the b-position), suggesting
the involvement of a 1,4-addition of
ruthenium monohydride species to the
a,b-unsaturated ketone intermediate.
The ruthenium monohydride species
and the a,b-unsaturated ketone would
be formed through alcoholate forma-
tion/b-elimination. Kinetic studies and
kinetic isotope effects show that the
RuÀH bond cleavage (hydride transfer)
sis for these reactions is intrinsically
heterogeneous in nature, and the
Ru(OH) /Al O recovered after the re-
x
2
3
actions can be reused without apprecia-
ble loss of catalytic performance. The
reaction mechanism of the present
Ru(OH) /Al O -catalyzed
hydrogen-
x
2
3
transfer reactions were examined with
monodeuterated substrates. After the
racemization of (S)-1-deuterio-1-phe-
nylethanol in the presence of acetophe-
none was complete, the deuterium con-
tent at the a-position of the corre-
sponding racemic alcohol was 91%,
whereas no deuterium was incorporat-
ed into the a-position during the race-
x
2
3
Keywords: heterogeneous catalysis ·
isomerization
·
racemization
·
very high turnover frequency (TOF) of
is included in the rate-determining
step.
reduction · ruthenium
À1
1
8400 h , with a turnover number
Introduction
The kinetic resolution of racemic alcohols and amines is a
practical method to produce enantiomerically pure chiral
products, which are very important intermediates in the syn-
[1]
[
a] Dr. K. Yamaguchi, T. Koike, M. Matsushita, S. Shinachi,
Prof. Dr. N. Mizuno
Department of Applied Chemistry, School of Engineering
The University of Tokyo
thesis of agricultural chemicals and medicines. However,
the maximum yield is 50% based on the starting racemate
and this is still much too low. To overcome this disadvant-
age, racemization of an undesired enantiomer has been car-
7
-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
[2]
Fax : (+81)3-5841-7220
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
ried out so that this enantiomer can be recycled. Further-
more, dynamic kinetic resolution, in which the substrates
are continuously racemized with catalysts during an enzy-
matic kinetic resolution process, has been performed to
[
b] Dr. K. Yamaguchi, M. Kotani, Prof. Dr. N. Mizuno
Core Research for Evolutional Science and Technology (CREST)
Japan Science and Technology Agency
[3]
overcome this disadvantage. Although many methods for
the homogeneous racemization of secondary alcohols and
amines catalyzed by transition-metal complexes, especially
4
-1-8 Honcho, Kawaguchi, Saitama, 332-0012 (Japan)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
6574
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6574 – 6582

FULL PAPER
[
4]
ruthenium complexes, have been developed, these systems
often need additives such as hydrogen acceptors and/or
bases to promote the reaction. As far as we know, there are
only five examples of the heterogeneously catalyzed racemi-
hydrogen-transfer reactions, namely the racemization of
chiral secondary alcohols [Eq. (1)], the reduction of carbon-
yl compounds to alcohols with 2-propanol as the hydrogen
donor [Eq. (2)], and the isomerization of allylic alcohols to
saturated ketones [Eq. (3)], in the presence of Ru(OH)x/
Al O . Furthermore, we have also investigated the reaction
[2b,d,g,4j,k]
zation of alcohols.
The reduction of carbonyl compounds to alcohols is a fun-
damental functional transformation and the Meerwein–
Ponndorf–Verley (MPV) reduction, in which a ketone is re-
duced by an alcohol in the presence of an alcoholate of a
main-group element, is a long established method. Recent-
ly, many transition-metal-catalyzed MPV-type reductions
2
3
mechanism of the present Ru(OH) /Al O -catalyzed hydro-
x
2
3
gen-transfer reactions with monodeuterated substrates.
[5]
[6]
have been developed. Enantioselective reductions have
also been achieved in extremely high enantiomeric excesses
(
ees) using transition-metal catalysts with chiral BINAP and
[7]
DuPhos ligands.
The transformation of allylic alcohols to the correspond-
ing saturated ketones has potential for use in organic syn-
thesis and is usually performed with a two-step sequential or
two-pot reaction involving dehydrogenation (or hydrogena-
tion) of allylic alcohols followed by the hydrogenation (or
dehydrogenation). However, protection and deprotection
steps are sometimes required for such a transformation.
From the standpoint of reaction efficiency, the one-pot iso-
merization of allylic alcohols to the corresponding saturated
ketones (theoretical atom economy=100%) is highly desir-
able. Many homogeneous catalytic systems have been devel-
Results and Discussion
Racemization of chiral secondary alcohols: First, the catalyt-
ic activity and selectivity for the racemization of (R)-1-phen-
ylethanol ((R)-1a) were compared for various catalysts. The
results are shown in Table 1. No racemization proceeded in
the absence of the catalyst or in the presence of Al O alone
[8]
oped for this transformation.
For example, [HRuCl-
[8a]
[8e]
(
(
PPh ) ],
[RuCp(PPh )(CH CN) ]PF ,
[RuCp-
3
3
3
3
2
6
2
3
[8b,c]
[8h]
PPh ) ]Cl/Et NPF ,
a [Cp*Ru(PN)] complex,
Shvoꢁs
(Table 1, entries 20and 21). In the case of RuCl ·nH O, the
3 2
3
2
3
6
[8d]
[8f]
diruthenium complex, and nPr NRuO /2-undecanol can
selectivity for the racemization was very low (6%) because
of the formation of 1-phenyl-1-tolylethane and 1,1’-(oxydi-
ethylidene)dibenzene as by-products (Table 1, entry 12).
Among the various ruthenium catalysts tested, Ru(OH)x/
Al O showed the highest catalytic activity for the racemiza-
4
4
catalyze the direct isomerization of allylic alcohols in the
presence of bases (in some cases). However, efficient heter-
ogeneous catalysts for the isomerization of allylic alcohols
have not been reported so far.
2
3
In the manufacture of large-scale petrochemicals as well
as in laboratory-scale syntheses, environmentally unfriendly
processes should be replaced with greener catalytic ones. In
the past few decades, many efficient catalytic hydrogen-
tion of (R)-1a, giving the corresponding alcohol 1a in
31% ee with a small amount of acetophenone (1b) (Table 1,
entry 1). The racemization rate increased with an increase in
the reaction temperature (333–383 K), and the TOF reached
[2–8]
À1
transfer reactions have been developed.
However, espe-
68 h at 383 K, while the selectivity for the racemization
cially in the case of racemization of chiral alcohols and iso-
merization of allylic alcohols, most of them are homogene-
ous systems and there are few excellent heterogeneous sys-
tems that use solid (supported) catalysts, in spite of the sig-
nificant advantages from environmental and economical
standpoints, such as easy catalyst/product separation and re-
was slightly decreased from 92% (at 353 K) to 80% (at
383 K). The TOF value was higher than that of the active
À1
homogeneous catalyst nPr NRuO (3.7 h , entry 18) and
4
4
that of the active heterogeneous catalyst Ru–hydroxyapatite
À1
[2c,12,13]
(RuHAP) (1.0h , Table 1, entry 11).
Although other
ruthenium catalysts such as [RuCl (PPh ) ], [RuCl (bpy) ],
2
3
3
2
2
[9]
cycling of catalysts. Another significant advantage of using
heterogeneous catalysts is their high thermal stability.
We have recently developed an efficient heterogeneous
and [RuCl (DMSO) ] have been reported to be active for
2 4
the racemization in the presence of bases such as NaOH
[2]
and Na CO , they were completely inactive in the absence
2
3
[
10a,c]
[10b,c]
aerobic oxidation of alcohols,
amines,
alkyl-
and hydration of ni-
by a supported ruthenium hydroxide catalyst
Ru(OH) /Al O ). In 2002, we reported that a hydrogen-
of bases under the present reaction conditions (Table 1, en-
[10e]
[10f]
[10f]
arenes,
triles
phenols
and naphthols,
tries 13–15). Similarly, K RuCl ·nH O, [Ru(acac) ], and
2
6
2
3
[
10d]
[Ru (CO) ] were completely inactive under the present
3 12
conditions (Table 1, entries 16, 17, and 19).
(
x
2
3
transfer reaction from 2-propanol to acetophenone takes
place in the presence of Ru(OH) /Al O under anaerobic
Among the solvents tested, nonpolar toluene, isooctane,
and p-xylene were found to be good solvents and gave 31,
47, and 59% ee for 1a (Table 1, entries 1–3), respectively,
for the racemization of (R)-1a under the conditions de-
scribed in Table 1. On the other hand, polar 1,4-dioxane and
x
2
3
conditions during an investigation of the mechanism of the
[10a,11]
aerobic oxidation of alcohols.
Herein, we report the
synthetic scope of three kinds of heterogeneously catalyzed
Chem. Eur. J. 2005, 11, 6574 – 6582
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6575

N. Mizuno et al.
[
a]
Table 1. Racemization of (R)-1-phenylethanol ((R)-1a).
Entry Catalyst
Solvent
ee
Select.
[%]
TOF
[h ]
[
b]
À1 [c]
[%]
1
2
3
4
5
6
Ru(OH)
Ru(OH)
Ru(OH)
Ru(OH)
Ru(OH)
Ru(OH)
x
x
x
x
x
x
/Al
/Al
/Al
/Al
/Al
/Al
2
O
2
O
2
O
2
O
2
O
2
O
3
3
3
3
3
3
toluene
isooctane
p-xylene
chlorobenzene 74
THF
31
47
59
92
96
94
97
96
98
23
15
11
6.0
5.5
4.7
76
79
1,2-dichloro-
ethane
7
8
9
1
1
Ru(OH)
Ru(OH)
Ru(OH)
RuHAP
x
x
x
/Al
/Al
/Al
2
2
2
O
O
O
3
3
3
1,4-dioxane
acetonitrile
water
toluene
toluene
8095
98
NR
95
4.4
98
–
98
–
0.4
1.0
[
d]
0
1
Figure 1. Effect of removal of Ru(OH)
R)-1a. Without removal of Ru(OH) /Al
removal of Ru(OH) /Al
Ru(OH) /Al (Ru: 1 mol%), toluene (3 mL), 353 K.
x
/Al
2
O
3
on the racemization of
); an arrow indicates the
RuO
drous)
RuCl ·nH
2
(anhy-
NR
(
x
2
O
3
(
&
x
2 3
O
(~). Reaction conditions: (R)-1a (1 mmol),
[
e]
12
13
14
15
16
17
18
19
20
21
3
2
O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1
6
–
–
–
–
–
–
x
2 3
O
[RuCl
[RuCl
[RuCl
2
2
2
(PPh
(bpy)
(DMSO)
3
)
3
]
NR
NR
NR
NR
NR
83
NR
NR
NR
3
]
4
]
[Ru(acac)
RuCl ·nH
nPr NRuO
[Ru (CO)12
Al
none
3
]
Table 2 shows the results of racemization of various chiral
secondary alcohols with 1 mol% of the Ru(OH) /Al O cat-
alyst at 353 K under anaerobic conditions. Ru(OH) /Al O
3
K
2
6
2
O
x
2
3
4
4
88
–
–
3.7
x
2
3
]
[
f]
has high catalytic activity for the racemization of nonactivat-
2
O
3
–
[
1
a] Reaction conditions: (R)-1a (1 mmol), Ru(OH)
mol%), solvent (3 mL), 353 K, 5 h, under 1 atm of Ar. The enantiomer-
x
/Al
2
O
3
(Ru:
Table 2. Racemization of various chiral secondary alcohols catalyzed by
Ru(OH) /Al O .
x 2 3
[
a]
ic excess of (R)-1a and selectivity for racemization were determined by
GC analysis (Rt b-CDEXM column) using an internal standard tech-
nique. The main by-product was acetophenone. Each carbon balance was
more than 95%. [b] NR=no reaction. [c] The TOF values were calculat-
Entry Substrate
1
Product
ee [%] Select. [%]
2
9
87
92
[b]
2
À1
ed by the following recursion formula: TOF [h ]={log(ee/100)}/
{
log(1À(x/100))}/t, where ee, x, and t are the enantiomeric excess [%],
amount of catalyst [mol%], and reaction time [h], respectively. [d] Pre-
pared according to the literature procedure (Ru content: 1.9 wt%,
ref. [12]). [e] 1-Phenyl-1-tolylethane and 1,1’-(oxydiethylidene)bisbenzene
3
4
5
2
86
90
94
2 3
were formed as by-products. [f] Al O (37 mg).
6
acetonitrile were found to be poor solvents (Table 1, en-
tries 7 and 8), and the racemization did not proceed at all in
water (Table 1, entry 9).
51
To verify whether the observed catalysis is due to solid
Ru(OH) /Al O or leached ruthenium species, a catalytic
6
7
1
57
65
x
2
3
racemization of (R)-1a was carried out under the conditions
described in Table 1 and then the Ru(OH) /Al O was re-
x
2
3
<1
moved from the reaction mixture by filtration at the reac-
tion temperature. The filtrate was used again for the reac-
tion. As shown in Figure 1, no racemization of (R)-1a was
observed after the removal of Ru(OH) /Al O . Furthermore,
it was confirmed by ICP-AES analysis that no ruthenium
was present in the filtrate (below detection limit of 7 ppb).
8
9
2
4
2
91
92
91
x
2
3
1
0
The Ru(OH) /Al O catalyst recovered after the racemiza-
x
2
3
x 2 3
[a] Reaction conditions: Substrate (1 mmol), Ru(OH) /Al O (Ru:
tion of (R)-1a could be recycled without appreciable loss of
the original catalytic activity (entry 2 in Table 2). These facts
rule out any contribution to the observed catalysis from
ruthenium species that leach into the reaction solution and
signify that the observed catalysis is intrinsically heterogene-
1 mol%), toluene (3 mL), 353 K, 24 h, under 1 atm of Ar. The enantio-
meric excess and selectivity to racemization were determined by GC (Rt
b-CDEXM column) or HPLC (Chiralcel-OD column) analyses using an
internal standard technique. The main by-products were the correspond-
ing ketones. Each carbon balance was more than 95%. [b] Recycling ex-
periment. The reaction conditions were the same as those for the first
run.
[
14]
ous.
6576
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6574 – 6582

Ru(OH) /Al O -Catalyzed Hydrogen-Transfer Reactions
x
2
3
FULL PAPER
[
15]
ed chiral secondary alcohols as well as activated ones. Phe-
nylethanols (R)-1a, (S)-1a, and (S)-2a were smoothly con-
verted into the corresponding racemic alcohols with good ee
values and selectivities (Table 2, entries 1, 3, and 4). On the
other hand, the racemization of (S)-3a, which contains an
electron-withdrawing substituent, was much slower than that
of (S)-2a, which contains an electron-donating substituent
conditions to those of the racemization.
The results are
summarized in Table 3. The present system does not need
any bases and the reduction proceeds under relatively mild
reaction conditions with a small amount of the catalyst (typ-
ically 1–3 mol%). A major advantage of using Ru(OH)x/
Al O is its heterogeneous nature, which was confirmed by
the fact that the reaction did not proceed after removal of
the solid catalyst. Acetophenones 1b, 7b, 2b, and 8b were
smoothly converted into the corresponding 1-phenylethanols
in excellent yields (more than 88%, Table 3, entries 1–4).
Ru(OH) /Al O also catalyzes the reduction of sulfur- or ni-
trogen-containing carbonyl compounds to the corresponding
alcohols in moderate yields (Table 3, entries 7 and 8). Both
aromatic ketones and less-reactive aliphatic ketones such as
6b, 12b, and 13b could be reduced to the corresponding ali-
phatic secondary alcohols in excellent yields (more than
95%, Table 3, entries 9–11).
2
3
(
4
Table 2, entries 4 and 5). The racemization of indanols (R)-
a and (S)-4a proceeded efficiently with the formation of
indanone (Table 2, entries 6 and 7). Both aromatic alcohols
and less-reactive aliphatic alcohols such as (R)-5a, (R)-6a,
and (S)-6a could be racemized to the corresponding alco-
hols (Table 2, entries 8–10).
x
2
3
Reduction of carbonyl compounds to alcohols: The transi-
tion-metal-catalyzed hydrogen-transfer reaction from 2-
propanol to carbonyl compounds is convenient in large-scale
production processes because it is not necessary to use high-
pressure molecular hydrogen or hazardous reduction re-
agents such as LiAlH and NaBH . Various kinds of ketones
Isomerization of allylic alcohols: The scope of the present
Ru(OH) /Al O -catalyzed isomerization of various kinds of
allylic alcohols was also examined. The results are sum-
marized in Table 4. Trace amounts of the corresponding a,b-
unsaturated ketones (ca. 1%) were detected as by-products
in some cases. The aliphatic terminal allylic alcohols 14a–
4
4
x
2
3
[16]
and aldehydes could be reduced to the corresponding alco-
hols in high yields with 2-propanol as the hydrogen donor
(
solvent) in the presence of Ru(OH) /Al O under similar
x 2 3
1
8a were completely isomerized to the corresponding ali-
Table 3. Reduction of various ketones and aldehyde using 2-propanol as
a hydrogen donor catalyzed by Ru(OH) /Al O .
x 2 3
phatic saturated ketones 14b–18b at 363 K in 3 h (more
than 98%, Table 4, entries 1–5). The aromatic terminal allyl-
ic alcohols 19a–21a were also isomerized to the correspond-
ing aromatic ketones 19b–21b in high yields (more than
[
a]
Entry Substrate
1
Product
Yield [%] Select. [%]
93
98
91
>99
>99
>99
8
0%, Table 4, entries 7–9). In the case of dienol 22a, the hy-
drogen atoms were only transferred to the allylic double
bond to afford the corresponding enone 22b as the sole
product (Table 4, entry 10). In the present system, the iso-
merization of internal allylic alcohols such as 2-cyclohexen-
1-ol and 3-penten-2-ol and homoallylic alcohols such as 1-
hexen-4-ol and 4-phenyl-1-buten-4-ol did not proceed. The
Ru(OH) /Al O catalyst could be reused with the mainte-
nance of the high catalytic performance; the aliphatic allylic
alcohol 18a was converted almost quantitatively into 18b at
the same reaction rate as that for the first run (Table 4,
entry 6). The heterogeneous nature of the Ru(OH) /Al O
3
catalyst was examined by filtration experiments; no isomeri-
zation proceeded in the filtrate after removal of the catalyst.
The heterogeneous isomerization of allylic alcohols with-
out any organic solvents would be more important for indus-
2
3
[17]
x
2
3
4
88
61
>99
5
6
>99
>99
x
2
86
[
[
b]
c]
7
8
7095
try. We therefore demonstrated that Ru(OH) /Al O effi-
5099
x
2
3
ciently catalyzes the isomerization of 18a without solvents.
Thus, the solvent-free reaction of 18a was carried out at
9
1
1
96
97
95
>99
>99
>99
4
23 K with a substrate/catalyst molar ratio of 20000/1; a
[
[
b]
0
1
À1
TOF of 18400 h (determined by the initial rate) and TON
[18]
b]
(after 6 h) of 17200 were achieved [Eq. (4)].
[
a] Reaction conditions: Substrate (1 mmol), Ru(OH)
x
/Al
2
O
3
(Ru:
1
mol%), 2-propanol (3 mL), 363 K, 24 h, under 1 atm of Ar. Yields and
selectivities were determined by GC analysis (DB-WAX column) using
an internal standard technique. Each carbon balance was more than
9
5
5%. [b] Ru(OH)
mol%).
x
/Al
2
O
3
(Ru: 3 mol%). [c] Ru(OH)
x
/Al
2
O
3
(Ru:
Chem. Eur. J. 2005, 11, 6574 – 6582
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6577

N. Mizuno et al.
[
2e]
Table 4. Isomerization of various allylic alcohols catalyzed by Ru(OH)
Al O .
2 3
x
/
on the nature of the metal hydride species: a metal mono-
hydride species can be formed only from the a-hydrogen of
an alcohol substrate, while a metal dihydride species can be
formed from both the a-hydrogen and hydroxy proton of an
alcohol substrate. In the case of the monohydride mecha-
nism, the a-hydrogen is directly transferred to the carbonyl
carbon of a hydrogen acceptor (path A in Scheme 1), where-
[
a]
Entry Substrate
Product
Yield
%]
Select.
[%]
[
1
2
3
98
>99
>99
>99
99
>99
>99
99
4
5
98
96
99
99
[
[
b]
c]
6
[2e]
7
94
>99
Scheme 1. Possible pathways for hydrogen transfer.
[
c]
c]
8
8099
as two hydrogens are completely scrambled and lose their
identity in the case of the dihydride mechanism (path B in
Scheme 1).
[
9
1
89
91
>99
To clarify the origin of the hydride species, the racemiza-
tion of enantiomerically pure (S)-1-deuterio-1-phenylethan-
ol ((S)-23a) was carried out with an equimolar amount of
acetophenone (1b) according to a similar method to that re-
ported by Bäckvall and co-workers. As shown in Equa-
tion (5), the deuterium content at the a-position of the race-
mic alcohol 23a was high (91%) after complete racemiza-
tion of (S)-23a.
[
d]
0
99
[
1
a] Reaction conditions: Substrate (1 mmol), Ru(OH)
x
/Al
2
O
3
(Ru:
[2e]
mol%), toluene (3 mL), 363 K, 3 h, under 1 atm of Ar. Yields and se-
lectivities were determined by GC analysis (DB-WAX column) using an
internal standard technique. Traces of the a,b-unsaturated ketones
<1%) were detected in some cases. Each carbon balance was more
than 95%. [b] Recycling experiment. The reaction conditions were the
same as those for the first run. The reaction rate for the recycling experi-
ment was almost the same as that for the first run with new catalyst.
(
[
x 2 3 8
c] 393 K. [d] 22a (0.5 mmol), Ru(OH) /Al O (Ru: 2 mol%), [D ]tolu-
ene (1.5 mL), 393 K, 15 h. Yield and selectivity were determined by GC
1
and H NMR analysis.
The TOF and TON values are higher than those reported
Furthermore, when racemization of (S)-24a was carried
out with an equimolar amount of 1b, no deuterium was
found at the a-position of the racemic alcohol 24a and the
deuterium content in the hydroxy group was high (>80%)
[Eq. (6)].
to date for the isomerization of allylic alcohols:
À1
[
Cp*Ru(PN)]/KOtBu (19a, TOF and TON of 2500 h and
[
8h]
1
2
1
00, respectively),
[RuCp(PPh )(CH CN) ]PF
(18a,
Shvoꢁs diruthenium complex (18a,
3
3
2
6
À1
[8e]
000 h , 100),
À1
[8d]
À1
[8a]
000 h , 500),
[HRuCl(PPh ) ] (18a, 287 h , 287),
Fe(CO) /hn (18a, 95 h , 95),
3
3
À1
[8g]
[RuCp(PPh ) ]Cl/Et NPF
3 2 3 6
5
À1
[8b,c]
(
20a, 8 h , 16),
reported, 17).
and n-Pr NRuO /2-undecanol (19a, not
4 4
[8f]
Mechanism of racemization and reduction of carbonyl com-
[
2e,f]
pounds to alcohols: According to the literature,
the race-
These results show that the a-hydrogen atom of the alco-
hol is transferred to the carbonyl carbon atom and that the
hydroxy proton is transferred to the carbonyl oxygen in the
present Ru(OH) /Al O -catalyzed hydrogen-transfer reac-
mization of chiral secondary alcohols and reduction of car-
bonyl compounds to alcohols can proceed through the one
of two mechanisms. The first is a direct hydrogen transfer,
which involves a six-membered cyclic transition state and is
reported to occur in the case of main-group elements,
and the other is the metal hydride mechanism using transi-
Since the detailed mechanistic
studies of Ru(OH) /Al O -catalyzed aerobic oxidation of al-
cohols suggest the formation of a ruthenium hydride,
x
2
3
tions.
[2,3,19]
On the basis of these results, we can propose a possible
reaction mechanism for this Ru(OH) /Al O -catalyzed race-
x
2
3
[2,3,7c]
tion-metal catalysts.
mization (Scheme 2a). Initially, the ruthenium alcoholate
species B is formed by ligand exchange between ruthenium
hydroxide A and the alcohol (step 1). The alcoholate B then
undergoes b-hydride elimination to afford the corresponding
carbonyl compound and the ruthenium monohydride species
C (step 2). The direct formation of the ketone–hydride inter-
x
2
3
[10a,c]
the present racemization and reduction probably proceed by
the metal hydride mechanism. Two different pathways have
been reported for the metal hydride mechanism depending
6578
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6574 – 6582

Ru(OH) /Al O -Catalyzed Hydrogen-Transfer Reactions
x
2
3
FULL PAPER
mediate D from B may be pos-
sible (step 2’). The re-addition
of the hydride species C to the
carbonyl carbon gives the iso-
meric alcoholate species
E
(
steps 3 and 4). Finally, inter-
molecular ligand exchange be-
tween the alcoholate E and the alcohol leads to the racemic
alcohol (step 5). When the reduction of 1b was carried out
using 2-deuterio-2-propanol under similar conditions to
those described in Table 3, the a-deuterium of 2-deuterio-2-
propanol was transferred to the carbonyl carbon of 1b to
give racemic 1-deuterio-1-phenylethanol (23a) as the main
product (88% yield, 91% D at a-position) [Eq. (7)].
This fact suggests that the reduction of carbonyl com-
pounds to alcohols using 2-propanol also proceeds by the
same mechanism as that for the racemization.
A kinetic isotope effect (k /k ) of 3.3 was observed for
H
D
[20]
the racemization of (S)-1a and (S)-23a at 353 K. On the
other hand, no kinetic isotope effect (k /k =1.0) was ob-
H
D
served for the racemization of (S)-1a and (S)-24a. These ki-
netic isotope effects show that the OÀH bond cleavage is
not part of the rate-determining step and that the CÀH (b-
elimination) or RuÀH bond cleavage (hydride transfer) is
part of the rate-determining step. The Arrhenius plots for
the racemization of (R)-1a (the pseudo-first-order rate con-
À1
stant kapp versus T between 333 and 383 K) are shown in
Figure 2. The good linearity of these plots gives the follow-
À1
°
353
ing activation parameters: E =11.9 kcalmol , DH
=
a
À1
°
°
À1
1
1.2 kcalmol , DS =À46.5 eu, and DG =27.5 kcalmol .
3
53
353
°
The large negative value of the activation entropy (DS353)
suggests that a bimolecular transition state, where two mole-
cules (or more) are converted into a single transition state
molecule, is probably included in the rate-determining
[21]
step.
Therefore, we conclude that RuÀH bond cleavage
hydride transfer, step 4) is the rate-determining step for
(
this racemization.
Figure 2. Arrhenius plots for the racemization of (R)-1a. The apparent
pseudo-first-order rate constants (kapp) were determined from the initial
part of the reactions. Reaction conditions: (R)-1a (1 mmol), Ru(OH)
Al (Ru: 1 mol%), toluene (3 mL), 333–383 K. Line fit: ln(kapp)=7.1–
5977.1/T (R =0.99). The following activation parameters were obtained
x
/
2
O
3
2
x 2 3
Scheme 2. Proposed reaction mechanisms for the Ru(OH) /Al O -cata-
lyzed racemization of chiral secondary alcohols (a) and isomerization of
allylic alcohols (b).
À1
°
from the line fit of the Arrhenius plots: E
a
=11.9 kcalmol , DH3
=
53
À1
°
53
°
353
À1
11.2 kcalmol , DS3 =À46.4 eu, and DG =27.5 kcalmol
.
Chem. Eur. J. 2005, 11, 6574 – 6582
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6579

N. Mizuno et al.
Mechanism of isomerization of allylic alcohols: The isomeri-
zation of the allylic acetate of 3-acetoxy-1-octene and homo-
allylic alcohols such as 1-hexen-4-ol and 4-phenyl-1-buten-4-
ol does not proceed under the same conditions as those de-
scribed in Table 4. In addition, the hydrogen-transfer reac-
tion does not take place at the isolated double bond in the
case of a dienol (entry 10in Table 4). Therefore, both an al-
lylic hydroxy function and a double bond are necessary for
the present isomerization. When 1 mol% of Ru(OH) /Al O
3
Conclusion
Ru(OH) /Al O acts as an efficient heterogeneous catalyst
x
2
3
for three kinds of hydrogen-transfer reactions. This ability
raises the prospect of using this type of simple supported
catalyst for organic syntheses and industrial processes be-
cause of 1) its applicability to a wide range of substrates, 2)
its high turnover frequency and turnover number, 3) simple
workup procedures, that is, product/catalyst separation, and
4) its reusability. The mechanistic investigations using mono-
deuterated substrates have shown that the ruthenium mono-
hydride species formed from an alcohol and a ruthenium hy-
droxide species on the catalyst is a key intermediate for
these Ru(OH) /Al O -catalyzed hydrogen-transfer reactions,
x
2
was used for the isomerization of 18a, the corresponding
a,b-unsaturated ketone was initially produced and the yield
was less than 1% in the conversion range 0–99%.
A monodeuterated allylic alcohol, namely 3-deuterio-1-
[
8c,h]
octen-3-ol (25a), was used as a mechanistic probe.
The
x
2
3
isomerization of 25a for 12 h under similar conditions of
for which RuÀH bond cleavage (hydride transfer) is includ-
Table 4 gave a monodeuterated saturated ketone (MS: m/z
ed in the rate-determining step.
+
1
29.20[ M ], 7.25% of base peak). The deuterium is only
present at the b-position of this ketone [Eq. (8)], therefore,
the present Ru(OH) /Al O can distinguish between the hy-
x
2
3
drogen in the hydroxy group and from the a-hydrogen,
probably because of their relocation at the a- and b-carbon
[22]
atoms of the corresponding ketone.
Experimental Section
General: NMR spectra were recorded on a JEOL JNM-EX-270spec-
1
13
trometer. H and C NMR spectra were measured at 270and 67.8 MHz,
respectively, in [D ]chloroform or [D ]acetonitrile with TMS as an inter-
nal standard. H NMR spectra were measured at 41.25 MHz using
]benzene as an external standard. GC analyses were performed on a
1
3
2
[
D
6
Shimadzu GC-17 A using a flame ionization detector equipped with an
Rt b-CDEXM capillary column (internal diameter=0.25 mm, length=
On the basis of the above results, we can propose the fol-
lowing reaction mechanism for this Ru(OH) /Al O -cata-
3
0m) or a DB-WAX capillary column (internal diameter =0.25 mm,
x
2
3
length=30m). HPLC analyses were performed on Shimadzu LC-10A
with a UV detector equipped with a Chiralcel-OD column (internal di-
ameter=46 mm, length=25 cm) and with n-hexane/2-propanol (95/5 v/v)
as the eluent. Mass spectra were recorded on a Shimadzu GCMS-
QP2010 equipped with a DB-WAX capillary column (internal diameter=
lyzed isomerization of allylic alcohols (Scheme 2b). The ini-
tial two steps (steps 1 and 2) are probably the same as those
for the racemization and reduction: the ruthenium alcohol-
ate species F is formed by ligand exchange between rutheni-
um hydroxide A and an allylic alcohol (step 1), followed by
the formation of the ruthenium monohydride species C and
the corresponding a,b-unsaturated ketone by b-hydride
elimination (step 2). The direct formation of the enone–hy-
dride intermediate G from F may also be possible (step 2’).
Then, 1,4-addition of C to the a,b-unsaturated ketone gives
0
.25 mm, length=30m) at an ionization voltage of 70eV. Reagents, sol-
vents, and substrates, except for 21a, 22a, (S)-23a, (S)-24a, 25a, and 26a,
which were synthesized according to the literature procedures (see Sup-
[
8c,25–27]
porting Information),
were purchased from Tokyo Kasei, Aldrich,
and Fluka (reagent grade) (the solvents in particular must be carefully
2
À1
purified). Alumina (KHS-24, BET surface area: 160m g ) was supplied
by Sumitomo Chemical Co., Ltd. All products were identified by compar-
1
13
ison of their GC retention time, mass spectra, and H and C NMR spec-
tra with authentic samples. The Ru(OH) /Al O catalyst was prepared ac-
[8f,23]
the s-enolate intermediate H (steps 3 and 4).
Finally, in-
x
2
3
termolecular ligand exchange between H and the allylic al-
cohol leads to the corresponding saturated ketone (step 5).
A kinetic isotope effect (k /k ) of 2.5 was observed for
cording to a procedure reported previously (See Supporting Informa-
[
10]
tion).
Procedure for the Ru(OH)
All operations were carried out in a glove box under argon. A typical
procedure is as follows. Ru(OH) /Al (Ru: 1 mol%), (R)-1a (1 mmol),
x
2 3
/Al O -catalyzed hydrogen-transfer reactions:
H
D
the isomerization of 18a and 25a at 353 K, whereas no ki-
netic isotope effect (k /k =1.0) was observed for the iso-
x
2 3
O
H
D
and toluene (3 mL) were successively placed into a Pyrex-glass vial. A
Teflon-coated magnetic stir-bar was then added, and the reaction mixture
was vigorously stirred (800 rpm) at 353 K under 1 atm of argon. After
24 h, the catalyst and the product(s) were separated by filtration (or cen-
trifugation), and the solid mixture was washed with toluene. Then, di-
phenyl (internal standard, 0.3 mmol) was added to the combined organic
solution and the solution was analyzed by chiral GC. The separated
merization of 18a and deuterated 1-octen-3-ol (26a). For
°
the isomerization of 18a, an activation entropy (DS 63) of
3
[24]
À30.5 eu was observed, which suggests that a bimolecular
[21]
transition state is included in the rate-determining step.
These results show that the RuÀH bond cleavage (hydride
transfer, step 4) is the rate-determining step for this isomeri-
zation.
Ru(OH)
and water, and then dried in vacuo before being recycled.
Procedure for the Ru(OH) /Al -catalyzed deuterium transfer reac-
x 2 3
/Al O was washed with an aqueous solution of NaOH (1m)
x
2 3
O
tions: The reactions of (S)-23a, (S)-24a, and 25a were carried out follow-
ing the same procedure as for the hydrogen-transfer reactions. The loca-
1
tion and content of deuterium in the products were determined by H,
2
13
H, and C NMR analyses (see Supporting Information).
6580
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6574 – 6582

Ru(OH) /Al O -Catalyzed Hydrogen-Transfer Reactions
x
2
3
FULL PAPER
Acknowledgements
M. M. Kirchhoff, T. C. Williamson, Catal. Today 2000, 55, 11; c) J. H.
Clark, Green Chem. 1999, 1, 1; d) R. A. Sheldon, Green Chem. 2000,
2
, G1; e) R. A. Sheldon, H. van Bekkum, Fine Chemicals through
This work was supported by the Core Research for Evolutional Science
and Technology (CREST) program of the Japan Science and Technology
Agency (JST) and Grants-in-Aid for Scientific Research ((A) and Priori-
ty Area “Molecular Nano Dynamics”) from the Ministry of Education,
Culture, Sports, Science, and Technology.
Heterogeneous Catalysis, Wiley, Weinheim, 2001.
[10] a) K. Yamaguchi, N. Mizuno, Angew. Chem. 2002, 114, 4720; Angew.
Chem. Int. Ed. 2002, 41, 4538; b) K. Yamaguchi, N. Mizuno, Angew.
Chem. 2003, 115, 1517; Angew. Chem. Int. Ed. 2003, 42, 1479; c) K.
Yamaguchi, N. Mizuno, Chem. Eur. J. 2003, 9, 4353; d) K. Yamagu-
chi, M. Matsushita, N. Mizuno, Angew. Chem. 2004, 116, 1602;
Angew. Chem. Int. Ed. 2004, 43, 1576; e) K. Kamata, J. Kasai, K. Ya-
maguchi, N. Mizuno, Org. Lett. 2004, 6, 3577; f) M. Matsushita, K.
Kamata, K. Yamaguchi, N. Mizuno, J. Am. Chem. Soc. 2005, 127,
[
1] a) R. A. Sheldon, Chirotechnology, Industrial Synthesis of Optically
Active Compounds, Dekker, New York, 1993; b) C. H. Wang,
G. M. Whitesides, Enzymes in Synthetic Organic Chemistry, Elsevi-
er, Amsterdam, 1994.
6
632.
11] During the preparation of this manuscript, Park and co-workers re-
ported the racemization of secondary alcohols with a Ru(OH)
Al catalyst. See reference [2b].
[
[
2] a) J. H. Koh, H. M. Jeong, J. Park, Tetrahedron Lett. 1998, 39, 5545;
b) W.-H. Kim, R. Karvembu, J. Park, Bull. Korean Chem. Soc. 2004,
x
/
2
O
3
2
5, 931; c) S. Wuyts, D. E. De Vos, F. Verpoort, D. Depla, R. De -
[
12] K. Yamaguchi, K. Mori, T. Mizugaki, K. Ebitani, K. Kaneda, J. Am.
Chem. Soc. 2000, 122, 7144.
13] Ikariya and co-workers have reported an efficient homogeneous rac-
emization using [Cp*RuCl(cod)] as the catalyst. In the presence of
Gryse, P. A. Jacobs, J. Catal. 2003, 219, 417; d) U. T. Strauss, U.
Felfer, K. Faber, Tetrahedron: Asymmetry 1999, 10, 107; e) O.
Pàmies, J.-E. Bäckvall, Chem. Eur. J. 2001, 7, 5052; f) D. Klomp, T.
Maschmeyer, U. Hanefeld, J. A. Peters, Chem. Eur. J. 2004, 10,
[
Ph
2
P(CH
2
)
2
NH
2
and KOtBu as base, the turnover frequency for the
2
088; g) D. W. House, US Patent, 5,476,964, 1995.
À1
racemization of (R)-1a reached 479 h . See reference [4l].
14] R. A. Sheldon, M. Wallau, I. W. C. E. Arends, U. Schuchardt, Acc.
Chem. Res. 1998, 31, 485.
15] The reduction of 1b in methanol, ethanol, and 2-propanol was car-
ried out under the conditions of Table 3 and gave the corresponding
alcohol 1a in 1, 5, and 93% yield, respectively.
16] The catalytic activity and selectivity for this isomerization were com-
pared for various catalysts in the absence of bases using 18a as a
model substrate. The effect of solvents was also examined. See
Table S1 in the Supporting information.
17] It has been reported that the reactivity of internal allylic alcohols
decreases with an increase in the steric constraints of the catalysts
because the steric hindrance around the double bond of internal al-
lylic alcohols imposes a steric barrier to coordination to the metal
center(s). See reference [8].
[
3] a) O. Pàmies, J.-E. Bäckvall, Chem. Rev. 2003, 103, 3247; b) F. F.
Huerta, A. B. E. Minidis, J.-E. Bäckvall, Chem. Soc. Rev. 2001, 30,
[
[
3
21.
[
4] a) B. A. Persson, A. L. E. Larsson, M. Le Ray, J.-E. Bäckvall, J. Am.
Chem. Soc. 1999, 121, 1645; b) O. Pàmies, A. H. Éll, J. S. M. Samec,
N. Hermanns, J.-E. Bäckvall, Tetrahedron Lett. 2002, 43, 4699; c) O.
Pàmies, J.-E. Bäckvall, J. Org. Chem. 2002, 67, 1261; d) J. H. Koh,
H. M. Jung, M.-J. Kim, J. Park, Tetrahedron Lett. 1999, 40, 6281;
e) J. H. Choi, Y. H. Kim, S. H. Nam, S. T. Shin, M.-J. Kim, J. Park,
Angew. Chem. 2002, 114, 2479; Angew. Chem. Int. Ed. 2002, 41,
[
[
2
372; f) M.-J. Kim, Y. Chung, Y. K. Choi, H. K. Lee, D. Kim, J.
Park, J. Am. Chem. Soc. 2003, 125, 11494; g) R. J. Kazlauskas,
A. N. E. Weissfloch, A. T. Rappaport, L. A. Cuccia, J. Org. Chem.
1
991, 56, 2656; h) P. M. Dinh, J. A. Howarth, A. R. Hudnott, J. M. J.
Williams, W. Harris, Tetrahedron Lett. 1996, 37, 7623; i) A. Dijks-
man, J. M. Elzinga, Y.-X. Li, I. W. C. E. Arends, R. A. Sheldon, Tet-
rahedron: Asymmetry 2002, 13, 879; j) M. T. Reetz, K. Schimossek,
Chimia 1996, 50, 668; k) S. Wuyts, K. De Temmerman, D. De Vos, P.
Jacobs, Chem. Commun. 2003, 1928; l) M. Ito, A. Osaku, S. Kita-
hara, M. Hirakawa, T. Ikariya, Tetrahedron Lett. 2003, 44, 7521.
5] a) H. Meerwein, R. Schmidt, Justus Liebigs Ann. Chem. 1925, 444,
[
18] We confirmed that no reaction proceeded under the same reaction
conditions without the Ru(OH)
19] a) W. N. Molton, R. E. Van Atta, R. R. Rich, J. Org. Chem. 1960, 25,
x 2 3
/Al O catalyst.
[
2
1
90; b) V. J. Shiner, D. Whittaker, J. Whittaker, J. Am. Chem. Soc.
969, 91, 394.
[
[
[
H D
20] A kinetic isotope effect (k /k ) of 5.3 was observed for the reduc-
[
tion of 1b in 2-propanol and 2-deuterio-2-propanol.
21] K. A. Connors, Chemical Kinetics, The Study of Reaction Rates in
Solution, VCH Publishers: New York, 1990.
2
21; b) A. Verley, Bull. Soc. Chim. Fr. 1925, 37, 537; c) W. Ponndorf,
Angew. Chem. 1926, 38, 138; d) K. Nishida, M. Noda, Chirality 2002,
4, 759; e) J. F. de Graauw, J. A. Peters, H. van Bekkum, J. Huskens,
1
22] In the reaction of a 1:1 mixture of the two allylic alcohols 25a and
Synthesis 1994, 1007, and references therein.
1
2
7a with Ru(OH)
x 2 3
/Al O , an equimolar mixture of ketones 18b,
[
6] a) G. Zassinovich, G. Mestroni, S. Gladiali, Chem. Rev. 1992, 92,
5b, 17b, and 27b was obtained [Eq. (9)], thus showing the intermo-
1
2
051; b) T. Naota, H. Takaya, S.-I. Murahashi, Chem. Rev. 1998, 98,
599; c) J.-E. Bäckvall, R. L. Chowdhury, U. Karlsson, J.
lecularity of the present hydrogen transfer.
Chem. Soc. Chem. Commun. 1991, 473; d) A. Aranyos, G.
Csjernyik, K. J. Szabꢂ, J.-E. Bäckvall, Chem. Commun. 1999,
3
51.
[
[
7] a) R. Noyori, Chem. Soc. Rev. 1989, 18, 187; b) R. Noyori,
Science 1990, 248, 1194; c) R. Noyori, H. Takaya, Acc. Chem.
Res. 1990, 23, 345; d) R. Noyori, S. Hashiguchi, Acc. Chem.
Res. 1997, 30, 97; e) M. J. Palmer, M. Will, Tetrahedron:
Asymmetry 1999, 10, 2045, and references therein.
8] a) Y. Sasson, G. L. Rempel, Tetrahedron Lett. 1974, 15, 4133;
b) B. M. Trost, R. J. Kulawiec, Tetrahedron Lett. 1991, 32,
[
23] For a related 1,4-addition of ruthenium species to a,b-unsaturated
ketones, see: a) Y. Ishii, K. Osakada, T. Ikariya, M. Saburi, S. Yoshi-
kawa, J. Org. Chem. 1986, 51, 2034; b) R. Guo, R. H. Morris, D.
Song, J. Am. Chem. Soc. 2005, 127, 516; c) M. Watanabe, K. Murata,
T. Ikariya, J. Am. Chem. Soc. 2003, 125, 7508; d) T. Ikariya, H.
Wang, M. Watanabe, K. Murata, J. Organomet. Chem. 2004, 689,
3
1
3
039; c) B. M. Trost, R. J. Kulawiec, J. Am. Chem. Soc. 1993,
15, 2027; d) J.-E. Bäckvall, U. Andresson, Tetrahedron Lett. 1993,
4, 5459; e) C. Slugovc, E. Ruba, R. Schmid, K. Kirchner, Organo-
metallics 1999, 18, 4230; f) I. E. Markꢂ, A. Gautier, M. Tsukazaki,
A. Llobet, E. Plantalech-Mir, C. J. Urch, S. M. Brown, Angew.
Chem. 1999, 111, 2126; Angew. Chem. Int. Ed. 1999, 38, 1960; g) H.
Cherkaoui, M. Soufiaoui, R. Grꢃe, Tetrahedron 2001, 57, 2379;
h) M. Ito, S. Kitahara, T. Ikariya, J. Am. Chem. Soc. 2005, 127, 6172.
9] a) P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Prac-
tice, Oxford University Press, 1998; b) P. T. Anastas, L. B. Bartlett,
1
4
377; e) H. Wang, M. Watanabe, T. Ikariya, Tetrahedron Lett. 2005,
6, 963.
[
24] The Arrhenius plots for the isomerization of 18a (333–373 K) are
[
shown in Figure S1 in the Supporting Information. The following ac-
Chem. Eur. J. 2005, 11, 6574 – 6582
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6581

N. Mizuno et al.
tivation parameters were obtained from the line fit of the Arrhenius
[27] A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli, J.
Org. Chem. 1997, 62, 6974.
À1
°
À1
°
plots: E
a
=16.5 kcalmol , DH3 =15.8 kcalmol , DS =À30.5 eu,
63
363
°
63
À1
and DG3 =26.8 kcalmol
.
[
[
25] C. Spino, N. Barriault, J. Org. Chem. 1999, 64, 5292.
26] H. L. Holland, F. M. Brown, M. Conn, J. Chem. Soc. Perkin Trans. 2
990, 1651.
Received: May 16, 2005
Published online: August 10, 2005
1
6582
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6574 – 6582