Supported ruthenium catalyst for the heterogeneous oxidation of alcohols with molecular oxygen

Article abstract of DOI:10.1002/1521-3773(20021202)41:23<4538::AID-ANIE4538>3.0.CO;2-6

Round and round it goes! A supported ruthenium catalyst, easily prepared by treatment of RuCl₃ with γ-Al₂O₃, is an efficient heterogeneous catalyst for the oxidations of alcohols with 1 atm of molecular oxygen or air without any additives (see scheme). The spent catalyst was recyclable without an appreciable loss of the catalytic activity and selectivity for the oxidation.

Full text of DOI:10.1002/1521-3773(20021202)41:23<4538::AID-ANIE4538>3.0.CO;2-6

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Pugmire, D. M. Grant, J. Magn. Reson. 1984, 56, 151; H. Miura, T.
Terao, A. Saika, J. Magn. Reson. 1986, 68, 593.
[5] M. W. Anderson, J. Klinowski, Chem. Phys. Lett. 1991, 172, 275; A. G.
Stepanov, V. N. Zudin, K. I. Zamaraev, Solid State NMR 1993, 2, 89.
[6] J. Rocha, W. Kolodziejski, J. Klinowski, Chem. Phys. Lett. 1991, 176,
395.
[7] A. Lesage, S. Steuernagel, L. Emsley, J. Am. Chem. Soc. 1998, 120,
7095.
[8] D. Sakellariou, A. Lesage, P. Hodgkinson, L. Emsley, Chem. Phys.
Lett. 2000, 319, 253.
are applicable only for the oxidation of activated benzylic and
allylic alcohols, or large quantities of additives such as
10]
NaOAc, NaOH, and K2CO3 are needed.[7
There is little
known about the oxidation of alcohols with molecular oxygen,
which could be applied to a wide range of alcohols. If these
oxidation reactions could be performed by using solid-
supported catalysts (heterogeneous catalysis), they would be
considerably cheaper and environmentally more friendly
because of the ease with which the catalysts could be
[9] D. L. VanderHart, W. L. Earl, A. N. Garroway, J. Magn. Reson. 1981,
44, 361; A. Lesage, M. Bardet, L. Emsley, J. Am. Chem. Soc. 1999, 121,
10987.
[10] R. Toreki, R. R. Schrock, W. M. Davis, J. Am. Chem. Soc. 1992, 114,
3367.
[11] N. A. Bailey, J. M. Jenkins, R. Mason, B. L. Shaw, J. Chem. Soc. Chem.
Commun. 1965, 237; S. J. LaPlaca, J. A. Ibers, Inorg. Chem. 1965, 4,
778; J. A. Ibers, Abst. Am. Crystallogr. Assoc. 1965, B10; F. A. Cotton,
T. LaCour, A. G. Stanislowski, J. Am. Chem. Soc. 1974, 96, 754; F. A.
Cotton, A. G. Stanislowski, J. Am. Chem. Soc. 1974, 96, 5074; M.
Brookhart, M. L. H. Green, J. Organomet. Chem. 1983, 250, 395.
[12] W. A. Nugent, J. M. Mayer, Metal Ligand Multiple Bond, Wiley, New
York, 1988, p. 134; R. R. Schrock, Acc. Chem. Res. 1979, 12, 98.
[13] D. G. H. Ballard, Adv. Catal. 1973, 23, 263; T. E. Lapointe, P. T.
Wolczanski, G. D. VanDuyne, Organometallics 1985, 4, 1810.
[14] http://www.ens-lyon.fr/STIM/NMR.
[15] D. Marion, K. W¸thrich, Bioch. Biophys. Res. Commun. 1983, 113,
967.
[16] A. Bielecki, A. C. Kolbert, M. H. Levitt, Chem. Phys. Lett. 1989, 155,
341; A. Bielecki, A. C. Kolbert, H. J. M. deGroot, M. H. Levitt, Adv.
Magn. Reson. 1989, 14, 111; M. H. Levitt, A. C. Kolbert, A. Bielecki,
D. J. Ruben, Solid State NMR 1993, 2, 151.
[17] E. Vinogradov, P. H. Madhu, S. Vega, Chem. Phys. Lett. 1999, 314, 443;
P. K. Madhu, X. Zhao, M. H. Levitt, Chem. Phys. Lett. 2001, 346, 142.
[18] A. E. Bennett, C. M. Rienstra, M. Auger, K. V. Lakshmi, R. G.
Griffin, J. Chem. Phys. 1995, 103, 6951.
[19] A. Lesage, L. Duma, D. Sakellariou, L. Emsley, J. Am. Chem. Soc.
2001, 123, 5747.
14]
separated from products and recycled.[11
Examples of
solid-supported catalysts that have been tested include
tetrapropylammonium perruthenate (TPAP)/MCM-41,[15]
Ru/CeO2,[16]
Ru-hydrotalcite,[17]
Ru-hydroxyapatite,[18]
[RuCl2(p-cymene)]2/activated carbon,[19] Pd-hydrotalcite,[20]
and Pd or Pt on activated carbon.[21] However, heterogeneous
oxidation reactions are limited to activated alcohols and/or
have turn over numbers (TONs) which are very low (less
21]
than 20).[15
If oxidation reactions could be carried out
without solvents, then the system would facilitate the sepa-
ration of catalyst from products. Despite the advantage of
using solid catalysts without solvents or additives for oxida-
tion of both activated and non-activated alcohols, nothing has
been reported on the use of highly active solvent-free
heterogeneous catalysts with only molecular oxygen. Herein
we report an effective aerobic heterogeneous oxidation
reaction of both activated and non-activated alcohols, which
may have a sulfur atom, a nitrogen atom, or a carbon-carbon
double bond, by using molecular oxygen or air catalyzed by
Ru supported on alumina (Ru/Al2O3) and demonstrate the
use of solvent-free oxidation reactions [Eq. (1)]. The results
we present offer a strategy for the design of heterogeneous
alcohol-oxidation catalysts for use in conjunction with mo-
lecular oxygen.
R1
R2
R1
R2
Ru/Al2O3
H
(1)
+ 1/2O2
+ H O
2
O
OH
Supported Ruthenium Catalyst for the
Heterogeneous Oxidation of Alcohols with
Molecular Oxygen**
R1 = aryl, allyl, alkyl
R2 = H, alkyl
The Ru/Al2O3 system had high catalytic activities for the
oxidation of activated and non-activated alcohols with only
1atm of O 2 as shown in Table 1. Reaction selectivity was over
97% in all cases and all primary and secondary benzylic
alcohols were converted quantitatively into the corresponding
benzaldehydes and ketones, respectively. Primary and secon-
dary allylic alcohols afforded the corresponding enals or
enones without intramolecular hydrogen transfer or geo-
metrical isomerization of the double bonds. Additionally, the
catalytic system efficiently oxidized non-activated alcohols to
the corresponding carbonyl compounds: for the oxidation of
2-octanol, 2-octanone was produced in a 91% yield (entry 14).
Similarly, alicyclic alcohols such as cyclopentanol and cyclo-
octanol were selectively oxidized to the corresponding cyclic
ketones (entries 15 and 16). Less reactive aliphatic primary
alcohols, 1-octanol and 1-decanol, were also oxidized. How-
ever, increasing the reaction time did not improve the yields
of the aldehydes because of successive oxidation to the
corresponding carboxylic acids. The addition of a small
amount of hydroquinone (1equiv based on Ru) completely
Kazuya Yamaguchi and Noritaka Mizuno*
Although catalytic oxidation of alcohols to carbonyl com-
pounds has attracted much attention both in industrial
3]
processes and in organic syntheses,[1 alcohols are tradition-
ally oxidized by non-catalytic methods with stoichiometric
3]
oxidants such as dichromate and permanganate.[1 These
methods produce enormous amounts of metal salts as wastes.
Much effort has been made to develop homogeneous catalytic
6]
systems to solve these problems.[4 However, most systems
[*] Prof. Dr. N. Mizuno, Dr. K. Yamaguchi
Department of Applied Chemistry,
School of Engineering
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
Fax : (þ 81)3-5841-7220
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
[**] This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan.
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Table 1. Results of oxidations of various alcohols catalyzed by Ru/Al2O3 with molecular oxygen.[a]
Entry
Substrate
Product
t [h]
Conv. [%]
Selectivity [%]
1
1
> 99
> 99
2
3
1
1
> 99
> 99
> 99
> 99
4
5
1
3
> 99
> 99
> 99
97
6
7
1
1
> 99
> 99
> 99
> 99
8
1.5
6
> 99
98
9[b]
84
> 99
10
6
89
97
98
11[b,c]
12[b,c]
C7H15CH2OH
C9H19CH2OH
C7H15CHO
C9H19CHO
4
4
87
7199
13
5
2
8
90
91
92
> 99
> 99
> 99
14
15[b]
16[b]
17
6
81
> 99
93
> 99
> 99
> 99
1.5
2
18[b]
[a] Reaction conditions were as follows: alcohol (1mmol), Ru/Al 2O3 (Ru: 2.5 mol%),PhCF3 (1.5 mL), 356 K, under 1 atm of O2: conversion and selectivity
were determined by gas chromatography with an internal standard. [b] Ru/Al2O3 (Ru: 5 mol%). [c] Hydroquinone (1equiv based on Ru) was added.
suppressed the over-oxidation, which afforded only aliphatic
aldehydes in fairly good yields. Ru/Al2O3 catalyzed the
oxidation of alcohols also containing nitrogen or sulfur atoms
to the corresponding aldehydes in high yields (entries 17
and 18), while monomeric Ru complexes cannot affect
catalytic oxidation of these alcohols because of the strong
coordination to the metal center.[10]
Among various Ru catalysts tested, Ru/Al2O3 showed the
highest catalytic activity for the oxidation of benzyl alcohol at
356 K. Ru(OH)3¥nH2O gave benzaldehyde in a 29% yield
(TON ¼ 12) after 20 h and other Ru compounds of RuCl3¥n-
H2O, [RuCl2(PPh3)3]2, [RuCl2(p-cymene)], and RuO2 showed
no catalytic activity.
The heterogeneous oxidation of alcohols without solvents
would be more feasible for industrialized processes. The Ru/
Al2O3 catalyst system efficiently facilitated the oxidation of
non-activated 2-octanol and activated 1-phenylethanol with-
out the use of solvents. The solvent-free oxidation of 2-
octanol, and 1-phenylethanol at 423 K had turn over frequen-
cies (TOFs) of 300 hꢀ1 and 340 hꢀ1, and TONs of 950 and 980,
respectively [Eq. (2)]. These TOFs and TONs are higher than
those reported for the aerobic oxidation of 2-octanol by other
Ru catalysts: ([RuCl2(PPh3)3]/TEMPO (TON and TOF, 466
and 104 hꢀ1),[10] Ru/quinone/Co salen (194, 97 hꢀ1),[8] TPAP
(20, 6 hꢀ1),[15] Ru/CeO2 (30, 5 hꢀ1),[16] Ru Co hydrotalcite (9,
5 hꢀ1),[17] and Ru hydroxyapatite (6, 1h ꢀ1
)
[18]). Furthermore,
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gave a Hammett 1 value of ꢀ0.461( r2 ¼
0.99; Figure 2), which suggests that hydride
abstraction from II to form the carbocation-
type intermediate is involved in the oxida-
tion path.
The number of moles of water produced
was equivalent to that of acetone produced
for the oxidation of 2-propanol (19.6 mmol,
at 343 K) by using Ru/Al2O3 and molecular
yield 98%
TOF 340 h-1
TON 980
O
OH
Ru/Al2O3 (Ru: 0.1 mol%),
(2)
423 K, O2 (1 atm)
(solvent free)
OH
O
yield 95%
TOF 300 h-1
TON 950
air can be used instead of molecular oxygen in the present
system without changes in conversion and selectivity values.
It was confirmed by induced coupled plasma techniques
(ICP) that the Ru content of the used Ru/Al2O3 catalyst was
the same as that of the fresh catalyst and that no Ru was in the
filtrate. In addition, the oxidation of benzyl alcohol was
completely stopped by the removal of Ru/Al2O3 from the
reaction solution. These results indicate that any Ru species
that leached into the reaction solution is not an active
homogeneous catalyst and that the observed catalysis is truly
heterogeneous in nature.[22] The Ru/Al2O3 catalyst system is
reusable (Figure 1). When the oxidation of benzyl alcohol was
repeated seven times with the same sample of catalyst,
benzaldehyde was quantitatively produced at the same rate as
that of the first run.
oxygen. This 1:1 stoichiometry suggests that the simple
dehydrogenation does not proceed. Under anaerobic condi-
tions, the number of moles of acetone produced was
approximately the same as those of Ru loaded on Al2O3,
Figure 2. Hammett plots for the aerobic oxidation of p-substituted benzyl
alcohols by using Ru/Al2O3 catalyst. Reaction conditions were as follows:
alcohol (1mmol), Ru/Al 2O3 (1mol%), PhCF 3 (1.5 mL), 333K, under 1 atm
O2..
and water produced. When acetophenone (1m) was treated in
2-propanol under Ar, almost equimolar amounts of acetone
and 1-phenylethanol were produced, which shows that trans-
fer hydrogenation takes place [Eq. (3)].[25] These facts suggest
that a Ru-H species III is formed. On the basis of all the
results, Scheme 1is proposed: Ru alcoholate species II is
formed by ligand exchange between Ru hydroxide I then, an
alcohol undergoes typical b elimination to afford the corre-
sponding carbonyl compound and III. The hydride species is
then reoxidized by molecular oxygen.[26]
Figure 1. Recycling of Ru/Al2O3 catalyst for the oxidation of benzyl
alcohol. Reaction conditions were as follows: benzyl alcohol (1mmol), Ru/
Al2O3 (Ru: 2.5 mol%), PhCF3 (1.5 mL), 356 K, under 1 atm of O2, 1 h.
The conversion and selectivity were not changed by the
addition of a free-radical trap, for example, 2,6-di-tert-butyl-4-
methylphenol, and hydroquinone. The skeletal isomerization
of a cyclopropyl ring used as a radical clock did not proceed at
all. This evidence shows that a radical is not involved in the
oxidation reaction. Primary alcohols were selectively oxidized
even in the presence of secondary ones, an equimolar mixture
of benzyl alcohol and 1-phenylethanol gave a mixture of
benzaldehyde and acetophenone in 90% and 24% yields,
respectively. Similarly, competitive oxidations of 1-octanol
and 4-octanol showed 84 and 8% conversions, respectively.
These faster oxidations of primary alcohols show that Ru
alcoholate II (see scheme 1) is formed as an intermediate,
since the formation of metal alcoholate species is well known
for such selective oxidation of primary hydroxy groups.[23,24]
Competitive oxidations of para-substituted benzyl alcohols
Ru/Al2O3 (Ru: 1 mol%), iPrOH (2 mL),
O
OH
(3)
343 K, 12 h, Ar atmosphere
93% yield
The rate did not change with a decrease in oxygen partial
pressure (PO ) from 1.0 to 0.2 atm (air). Kinetic data could
2
well be expressed by the Michaelis-Menten type equation.[27]
The kinetic isotope effects (kH/kD) were 5.0 and 2.4 for the
intramolecular competitive oxidation of a-deuterio-p-meth-
ylbenzyl alcohol and for the intermolecular competitive
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0.101 g of pure benzaldehyde (95% yield). The separated Ru/Al2O3 was
washed with an aqueous solution of NaOH (1.0m) and water (30 mL), and
dried in vacuo before recycling.
1/2O2
R2
R1
H
HO
Run+
I
OH
step 4
Received: July 16, 2002 [Z19744]
step 1
HOO
H2O
Run+
[1] R. A. Sheldon, J. K. Kochi, MetalCataylzed Oxidations of Organic
Compound, Academic Press, New York, 1981.
[2] C. L. Hill in Advances in Oxygenated Processes, Vol. 1 (Eds.: A. L.
Baumstark), JAI, London, 1988, p. 1 .
[3] M. Hudlucky, Oxidations in Organic Chemistry, ACS Monograph
Series, American Chemical Society, Washington, 1990.
R2
step 3
R1
O
H
O2
H
Run+
Run+
III
II
[4] CuCl/Phen/K2CO3[5] and Pd(OAc)2/bathophenanthroline disulfonate/
NaOAc[6] systems are reported to be efficient examples. In the former
system, the turnover number (TON, moles of product per mol of
catalyst) and turnover frequency (TOF, TON hrꢀ1) for the oxidation
of 2-undecanol are 9 and 5 hꢀ1, respectively. In the latter system, the
step 2
R2
R1
O
TON and TOF for the oxidation of 2-pentanol are 400 and 100 hꢀ1
,
Scheme 1.
respectively. Even in these systems, large quantities of additives such
as NaOAc, NaOH, or K2CO3 (0.05 2 equivalents based on alcohol)
are needed to acheive high yields of carbonyl conpounds. In addition,
the Pd(OAc)2/PhenS*/NaOAc system can not oxidize sulfur, nitrogen,
carbon carbon double-bond-containing alcohols because of the
strong coordination to the metal center.
oxidation of benzyl alcohol and benzyl [D7]alcohol
(C6D5CD2OH) at 333K, respectively. The apparent activation
energies for steps 1(alcoholate formation) and 2 ( b elimina-
tion) were 40.0 and 54.9 kJmolꢀ1, respectively. On the basis of
these facts, step 2 is rate-determining.
[5] I. E. MarkÛ, P. R. Giles, M. Tsukazaki, S. M. Brown, C. J. Urch,
Science 1996, 274, 2044.
[6] G.-J. ten Brink, I. W. C. E. Arends, R. A. Sheldon, Science 2000, 287,
1636.
In summary, Ru/Al2O3 can act as an efficient heterogeneous
catalyst for the oxidation of alcohols with 1atm of molecular
oxygen or air, without additives. The high activity of, and ease
with which, the catalyst can be recovered and reused raise the
prospect of using this type of simple supported catalyst for
organic syntheses and the industrial oxidation of alcohols. The
catalyst would be considerably cheaper than organometallic
and inorganic compounds.
[7] Some Ru compounds have high catalytic activity for the oxidation of
alcohols with molecular oxygen by use of hydrogen/electron transfer
agents: hydroquinone and 2,2’,6,6’-tetramethylpyperidine N-oxyl
10]
(TEMPO).[8
[8] G. Csjernyik, A. H. Ell, L. Fadini, B. Pugin, J.-E. B‰ckvall, J. Org.
Chem. 2002, 67, 1657.
[9] A. Hanyu, E. Takezawa, S. Sakaguchi, Y. Ishii, Tetrahedron Lett. 1998,
39, 5557.
[10] A. Dijksman, A. Marino-Gonzµlez, A. M.
i Payeras, I. W. C. E.
Arends, R. A. Sheldon, J. Am. Chem. Soc. 2001, 123, 6826.
[11] R. A. Sheldon, I. W. C. E. Arends, A. Dijksman, Catal. Today 2000, 57,
157.
[12] J. M. Thomas, R. Raja, G. Sankar, Nature 1999, 398, 227.
[13] A. Corma, L. T. Nemeth, M. Renz, S. Valencia, Nature 2001, 412, 423.
[14] J. T. Rhule, W. A. Neiwert, K. I. Hardcastle, B. T. Do, C. L. Hill, J. Am.
Chem. Soc. 2001, 123, 12101.
[15] A. Bleloch, B. F. G. Johnson, S. V. Ley, A. J. Price, D. S. Shephard,
A. W. Thomas, Chem. Commun. 1999, 907.
[16] F. Vocanson, Y. P. Guo, J. L. Namy, H. B. Kagan, Synth. Commun.
1998, 28, 2577.
[17] T. Matsushita, K. Ebitani, K. Kaneda, Chem. Commun. 1999, 265.
[18] K. Yamaguchi, K. Mori, T. Mizugaki, K. Ebitani, K. Kaneda, J. Am.
Chem. Soc. 2000, 122, 7144.
[19] E. Choi, C. Lee, Y. Na, S. Chang, Org. Lett. 2002, 4, 2369.
[20] N. Kakiuchi, Y. Maeda, T. Nishimura, S. Uemura, J. Org. Chem. 2001,
66, 6620.
[21] T. Mallat, A. Baiker, Catal. Today 1994, 19, 247.
[22] R. A. Sheldon, M. Wallau, I. W. C. E. Arends, U. Schuchardt, Acc.
Chem. Res. 1998, 31, 485.
[23] K. B. Sharpless, K. Akashi, K. Oshima, Tetrahedron Lett. 1976, 17,
2503.
ExperimentalSection
The Ru/Al2O3 catalyst was prepared by the modification of a literature
preparation of Ru(OH)3¥nH2O:[28] g-Al2O3 (2.0 g, JRC-ALO-4, BET
surface area: 174 m2 gꢀ1) was vigorously stirred with an aqueous solution
of RuCl3 (60 mL, 8.3 î 10ꢀ3 m) for 15 min at room temperature. The initially
brown aqueous phase became lighter, and the alumina powder turned dark
gray. The solid was separated by filtration and washed with a large amount
of water, then dried in vacuo. This solid was added to deionized water
(30 mL), the pH of the solution was adjusted to 13.2 by the addition of an
aqueous solution of NaOH (1.0m) and the resulting slurry was stirred for
24 h. During this period, the powder changed from dark gray to dark green.
The solid was separated by filtration and copiously washed with water, then
dried in vacuo to afford 2.1g of Ru/Al 2O3 as a dark green powder. The
contents of ruthenium and chloride was 1.4 and 0 wt%, respectively, and
the BET surface area was 182 m2 gꢀ1. The ESR spectrum had a signal at g ¼
2.11, which is assigned to Ru3þ with low-spin d5 electron configuration.[29]
The XRD pattern was the same as that of the g-Al2O3 support and no
signals arising from ruthenium metal or dioxide were observed. Particles of
ruthenium metal or dioxide were not detected by TEM. The IR spectrum
showed a very broad n(OH) band in the range of 2900 3700 cmꢀ1. These
facts suggest that ruthenium(iii) hydroxide is highly dispersed on g-Al2O3.
Thus, the Ru/Al2O3 catalyst can be easily prepared in a quantitative yield
and the content of Ru can be controlled.
[24] S. Kanemoto, S. Matsubara, K. Takai, K. Oshima, K. Utimoto, H.
Nozaki, Bull. Chem. Soc. Jpn. 1988, 61, 3607.
Oxidations of alcohols were typically carried out as follows. A suspension
of Ru/Al2O3 (0.11 g, Ru: 2.5 mol%) in trifluorotoluene (1.5 mL) was stirred
for 5 min. Benzyl alcohol (0.108 g, 1 mmol) was added to the reaction
mixture and the suspension was purged with molecular oxygen. The
resulting mixture was heated at 356 K for 1h, and benzaldehyde was
produced in > 99% yield determined by GC. After the reaction, the
catalyst was separated by filtration (or centrifugation) and was further
washed with acetone. The filtrate was evaporated in vacuo, and the crude
product was purified by column chlomatography on silica gel, which gave
[25] R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 2001, 66, 7932.
[26] While step 3 may proceed via the formation of hydrogen peroxide, the
filtrate for the oxidation of benzyl alcohol with molecular oxygen
showed a negative peroxide test (Quantofix test stick, detection limit
1mgL ꢀ1 hydrogen peroxide). The catalytic oxidation of benzyl
alcohol with hydrogen peroxide hardly proceeded because of the
rapid decomposition of hydrogen peroxide, in agreement with the
rapid decomposition of Runþ-OOH without contributing to the
oxidation of alcohols in Scheme 1.
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[27] The catalytic rate (R) of the oxidation of benzyl alcohol was expressed
by R ¼ k2[C]/{1 þ k2/(k1[A])}, where [C] and [A] are the amount of Ru/
Al2O3 and the concentration of benzyl alcohol, respectively, and k1
and k2 are the rate constants for step 1and step 2, respectively, and at
356 K these were 38 hꢀ1 gꢀ1 and 42m hꢀ1 gꢀ1, respectively.
[28] J. W. Mellor, A Comprehensive Treatise on Inorganic and Theoretical
Chemistry, Vol. XV, Longmans & Green, London, 1936, pp. 498 544.
[29] B.-Z Wan, J. H Lunsford, Inorg. Chim. Acta 1982, 65, 29; M. G.
Cattania, A. Gervasini, F. Morazzoni, P. Scotti, D. Strumolo, J. Chem.
Soc. Faraday Trans. 1 1987, 83, 3619.
cally pure, C2-symmetric chiral quaternary ammonium salt
1[14] as a phase-transfer catalyst (Scheme 1). This approach
provides a practical and environmentally benign chemical
process for the synthesis of optically active b-hydroxy-a-
amino acids.
Initially, we examined the direct asymmetric aldol reaction
of prochiral glycine Schiff base 2 and 3-phenylpropanal as a
representative acceptor under phase-transfer conditions.
Thorough optimization of the catalyst structure and reaction
conditions revealed that treatment of 2 with 3-phenylpropanal
(2 equiv) in toluene/aqueous NaOH (1%) (v/v 1.25:1; 2 equiv
of base for 2) in the presence of chiral quaternary ammonium
Direct Asymmetric Aldol
Reactions of Glycine Schiff Base
with Aldehydes Catalyzed by
Chiral Quaternary Ammonium
Salts**
Takashi Ooi, Mika Taniguchi,
Minoru Kameda, and Keiji Maruoka*
As naturally occurring a-amino acids as
well as components of many complex bio-
logically active cyclic peptides and enzyme
inhibitors, optically active b-hydroxy-a-amino
acids are extremely important chiral units,
especially from the pharmaceutical view-
point.[1] Furthermore, they are useful chiral
building blocks in organic synthesis[2] as
exemplified by their transformation into b-
lactams,[3] b-halo-a-amino acids,[4] and aziri-
dines.[5] Accordingly, numerous methods for
the asymmetric synthesis of b-hydroxy-a-
Scheme 1. Direct catalytic asymmetric aldol reaction of glycine Schiff base 2 with aldehydes in
the presence of 1 under phase-transfer conditions. a) (R,R)-1 (2 mol%), toluene/aqueous
NaOH (1%), 0 8C, 2 h; b) HCl (1n)/THF.
amino acids have been elaborated, most of
which unfortunately involve multistep proce-
dures and/or the inevitable use of a stoichio-
8]
metric amount of chiral auxiliaries.[6 In this
regard, the construction of their primary structure with the
correct stereochemistry by the direct catalytic asymmetric
aldol reaction of a glycine donor with aldehyde acceptors has
been considered to be an ideal protocol.[9] However, there
have been few successful examples to date,[10,11] except for the
chemoenzymatic process with glycine-dependent aldola-
ses.[9b,12] We report herein an efficient and direct asymmetric
aldol reaction of glycine Schiff base 2[13] with aldehydes under
organic/aqueous biphasic conditions by using enantiomeri-
salt (R,R)-1a (2 mol%)[14d] at 08C for 2 h and subsequent
hydrolysis with HCl (1n) in THF resulted in the formation of
the corresponding b-hydroxy-a-amino ester
3
(R ¼
PhCH2CH2) in 76% yield with the anti/syn ratio of 3.3:1.
The enantiomeric excess of the major anti isomer was
determined to be 91% by chiral HPLC analysis (Table 1,
entry 1). Significantly, use of (R,R)-1b (which contains a 3,5-
bis(3,5-bis(trifluoromethyl)phenyl)phenyl substituent) as a
catalyst enhanced both diastereo- and enantioselectivities in
this system (anti/syn 12:1; 96%ee for anti isomer) (Table 1,
entry 2).[15]
[*] Prof. K. Maruoka, Dr. T. Ooi, M. Taniguchi, M. Kameda
Department of Chemistry
A variety of aldehydes were examined for this direct
asymmetric aldol reaction with (R,R)-1 and the results are
listed in Table 1. Generally, the reaction proceeded smoothly
at 08C for 2 h to afford the anti isomer predominantly, with
excellent enantioselectivity. Heptanal, an aliphatic aldehyde
with a long hydrocarbon chain, was found to be a good
candidate (Table 1, entry 3), thus indicating the feasibility of
direct asymmetric synthesis of a variety of lipo b-hydroxy-a-
amino acids, a useful component for the preparation of
lipophilic peptides and glycopeptides with characteristic high
Graduate School of Science, Kyoto University
Sakyo, Kyoto, 606-8502 (Japan)
Fax : (þ 81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. M.K. is grateful to the Japan Society for the
Promotion of Science for Young Scientists for a Research Fellowship.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
4542
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4123-4542 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 23