Practical Oppenauer (OPP) oxidation of alcohols with a modified aluminum catalyst

Article abstract of DOI:10.1021/ol020094c

(Matrix presented) Modified aluminum catalyst 2 was found to be highly effective for Oppenauer (OPP) oxidation of alcohols under mild conditions. For example, oxidation of carveol in toluene with t-BuCHO (1.2 equiv) as a hydride acceptor in the presence of 2 (1 mol %) proceeded smoothly at 21°C to give carvone in 94% yield after 1 h. A practical aspect of this system was highlighted by the facile OPP oxidation of terpenoids and steroids with 1.2-3.0 equiv of acetone and 2 (3-5 mol %).

Full text of DOI:10.1021/ol020094c

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2669-2672
Practical Oppenauer (OPP) Oxidation of
Alcohols with a Modified Aluminum
Catalyst
Takashi Ooi, Hidehito Otsuka, Tomoya Miura, Hayato Ichikawa, and
Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502
maruoka@kuchem.kyoto-u.ac.jp
Received May 6, 2002
ABSTRACT
Modified aluminum catalyst 2 was found to be highly effective for Oppenauer (OPP) oxidation of alcohols under mild conditions. For example,
oxidation of carveol in toluene with t-BuCHO (1.2 equiv) as a hydride acceptor in the presence of 2 (1 mol %) proceeded smoothly at 21 °C
to give carvone in 94% yield after 1 h. A practical aspect of this system was highlighted by the facile OPP oxidation of terpenoids and steroids
with 1.2−3.0 equiv of acetone and 2 (3−5 mol %).
The oxidation of alcohols into the corresponding carbonyl
compounds is undoubtedly one of the indispensable trans-
formations in organic synthesis, and numerous studies have
been made aiming for the development of a more efficient
and milder oxidation method.1 Although stoichiometric
oxidizing agents2 such as hypochlorite,3 chromium reagents4
(PCC4c and PDC4d), active manganese oxides,5 permanga-
nate,6 Dess-Martin periodinane,7 o-iodoxybenzoic acid
(IBX),8 and activated DMSO in Swern oxidation9 have been
routinely used in laboratories, these are often toxic and
hazardous and need halogenated solvents to attain sufficient
reactivity, eventually generating noxious wastes. On the other
(3) Stevens, R. V.; Chapman, K. T.; Weller, H. N. J. Org. Chem. 1980,
45, 2030.
(4) (a) Holum, J. R. J. Org. Chem. 1961, 26, 4814. (b) Lee, D. G.; Spitzer,
U. A. J. Org. Chem. 1970, 35, 3589. (c) Corey, E. J.; Suggs, W. Tetrahedron
Lett. 1975, 2647. (d) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979,
399.
(5) Highet, R. J.; Wildman, W. C. J. Am. Chem. Soc. 1955, 77, 4399.
(6) Menger, F. M.; Lee, C. Tetrahedron Lett. 1981, 22, 1655.
(7) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (d) Meyer, S. D.; Schreiber,
S. L. J. Org. Chem. 1994, 59, 7549.
(8) (a) Frigerio, M.; Santagostino, M. Tetrahedoron Lett. 1994, 35, 8019.
(b) Mulbaier, M.; Giannis, A. Angew. Chem., Int. Ed. 2001, 40, 4393. (c)
Sorg, G.; Mengel, A.; Jung, G.; Rademann, J. Angew. Chem., Int. Ed. 2001,
40, 4395. (d) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L.
J. Am. Chem. Soc. 2002, 124, 2245.
(9) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (b) Mancuso,
A. J.; Swern, D. Synthesis 1981, 165. (c) De Luca, L.; Giacomelli, G.;
Porcheddu, A. J. Org. Chem. 2001, 66, 7907.
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of
Organic Compounds; Academic Press: New York, 1981. (b) Ley, S. V.;
Madin, A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Ley, S. V., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 251. (c) Lee, T.
V. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Ley, S.
V., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 291. (d) Procter, G. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Ley, S. V.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 305. (e) Larock, R. C. In
ComprehensiVe Organic Transformations, 2nd ed.; Wiley-VCH: New York,
1999; p 1234. (f) Smith, M. B.; March, J. March’s AdVanced Organic
Chemistry: Reactions, Mechanism, and Structure, 5th ed.; Wiley-Inter-
science: New York, 2001; p 1514.
(2) For recent examples of new oxidation methods, see: (a) Mukaiyama,
T.; Matsuo, J.; Yanagisawa, M. Chem. Lett. 2000, 1072. (b) Matsuo, J.;
Kitagawa, H.; Iida, D.; Mukaiyama, T. Chem. Lett. 2001, 150. (c) De Luca,
L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041. (d) Matano,
Y.; Nomura, H. J. Am. Chem. Soc. 2001, 123, 6443.
10.1021/ol020094c CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/09/2002

hand, many useful catalytic oxidation methods have been
elaborated,10-17 among which aerobic oxidation procedures
with transition metal catalysts have an advantage from
economic and environmental viewpoints.12-17 However, these
systems require relatively expensive metal catalysts, a large
quantity of additives, and a higher reaction temperature to
obtain satisfactory results.
Oppenauer (OPP) oxidation,18-20 the reverse process of
the Meerwein-Ponndorf-Verley (MPV) reduction (Scheme
1),19b,21 is a classical yet useful method and is widely
is still room for improvement in terms of catalytic efficiency
and substrate generality.22-26 Further, only a few examples
of aluminum-based OPP catalyst have appeared in the
literature.27 Recently, we disclosed new aluminum alkoxide
3 as a highly effective MPV reduction catalyst,28 and this
discovery prompted us to pursue the application of the
organoaluminum precatalyst 2 to OPP oxidation (Scheme
2). In this letter, we wish to report preliminary results of
Scheme 2. Application of Catalyst 2 to OPP Oxidation
Scheme 1. Opp Oxidation and MPV Reduction
employed for the synthesis of steroids and terpenoids. Despite
its operational simplicity with inexpensive and nontoxic
reagents such as Al(OBut)3 and Al(OPri)3 as well as eminent
functional group compatibility, the full synthetic potential
of this oxidation has yet to be realized mainly because of
the low reactivity of the metal alkoxides. Actually, use of 1
equiv of reagent or more with a large excess of hydride
acceptor under relatively drastic conditions is a usual recipe
but causes undesirable side reactions, i.e., dehydration of
alcohols and aldol condensations. Although some beautiful
modifications of OPP oxidation have been introduced, there
this study, providing a practical catalytic OPP oxidation
procedure.
First, we examined the reactivity of aluminum catalyst 2,
prepared in situ by mixing Me3Al and ligand 1 in CH2Cl2,28
in the OPP oxidation of carveol as a representative substrate
with 1.2 equiv of t-BuCHO as a hydride acceptor at 21 °C
for 1 h (Table 1).29 The reaction proceeded smoothly with 5
mol % of 2 to afford carvone in 90% isolated yield (entry
1). Notably, the loading of 2 can be reduced to 1 mol %
without losing the catalytic activity (entry 2).30 Needless to
(10) For recent heterogeneous catalysts, see: (a) Nishimura, T.; Kakiuchi,
N.; Inoue, M.; Uemura, S. Chem. Commun. 2000, 1245. (b) Dijksman, A.;
Arends, I. W. C. E.; Sheldon, R. A. Synlett 2001, 102. (c) Choudary, B.
M.; Kantam, M. L.; Rahman, A.; Reddy, C. V.; Rao, K. K. Angew. Chem.,
Int. Ed. 2001, 40, 763. (d) Itoh, A.; Kodama, T.; Inagaki, S.; Masaki, Y.
Org. Lett. 2001, 3, 2653. (e) Son, Y.-C.; Makwana, V. D.; Howell, A. R.;
Suib, S. L. Angew. Chem., Int. Ed. 2001, 40, 4280.
Table 1. Catalytic OPP Oxidation of Carveola with 2 in
Various Solventsb
(11) For unaerobic catalytic oxidations, see: (a) Ley, S. V.; Norman, J.;
Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639. (b) Mukaiyama, T.;
Matsuo, J.; Iida, D.; Kitagawa, H. Chem. Lett. 2001, 846. (c) Hashimoto,
K.; Kitaichi, Y.; Tanaka, H.; Ikeno, T.; Yamada, T. Chem. Lett. 2001, 922.
(12) Pd catalysts: (a) ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R.
A. Science 2000, 287, 1636. (b) Hallman, K.; Moberg, C. AdV. Synth. Catal.
2001, 343, 260. (c) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001,
123, 7725.
(13) Cu catalysts: (a) Marko, I. E.; Giles, P. R.; Tsukazaki, M.; Brown,
S. M.; Urch, C. J. Science 1996, 274, 2044. (b) Marko, I. E.; Gautier, A.;
Mutonkole, J.-L.; Dumeunier, R.; Ates, A.; Urch, C. J.; Brown, S. M. J.
Organomet. Chem. 2001, 624, 344.
(14) Ru catalysts: (a) Marko, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle-
Regnaut, I.; Urch, C. J.; Brown, S. M. J. Am. Chem. Soc. 1997, 119, 12661.
(b) Dijksman, A.; Marino-Gonzalez, A.; Mairata i Payeras, A.; Arends, I.
W. C. E.; Sheldon, R. A. J. Am. Chem. Soc. 2001, 123, 6826.
(15) Mo catalyst: Lorber, C. Y.; Smidt, S. P.; Osborn, J. A. Eur. J. Inorg.
Chem. 2000, 655.
entry
2 (mol %)
solvent
CH2Cl2
% yieldc
1
2
3
4
5
6
5
1
1
1
1
1
90
94
94
92
80d
83d
toluene
cyclohexane
THF
AcOEt
a Cis/trans ) 42:58. b Unless otherwise specified, the oxidation of carveol
was conducted with 2 as a catalyst (prepared in each solvent) and t-BuCHO
(1.2 equiv) as a hydride acceptor in various solvents (1 M substrate
concentration) at 21 °C for 1 h, and the reaction solution was directly
subjected to purification by column chromatography on silica gel without
aqueous workup. c Isolated yield. d Stirred for 5 h.
(16) V catalyst: Maeda, Y.; Kakiuchi, N.; Matsumura, S.; Nishimura,
T.; Uemura, S. Tetrahedron Lett. 2001, 42, 8877.
(17) Co catalyst: Iwahama, T.; Yoshino, Y.; Keitoku, T.; Sakaguchi,
S.; Ishii, Y. J. Org. Chem. 2000, 65, 6502.
(18) Oppenauer, R. V. Rec. TraV. Chim. 1937, 56, 137.
2670
Org. Lett., Vol. 4, No. 16, 2002

Table 2. Catalytic OPP Oxidation of Various Alcohols with 2a,b
a Unless otherwise noted, the oxidation was carried out by the successive treatment of substrate with 2 (1-3 mol %) for 0.5 h and t-BuCHO (1.2-3
equiv) in toluene (1 M substrate concentration) at 21 °C under the indicated conditions. b Reaction solution was directly subjected to purification by column
chromatography on silica gel without aqueous workup. c Isolated yield. d Reaction was performed with 1 mol % Me3Al as a catalyst. e Cis/trans ) 42:58.
f Cis/trans ) 11:89. g Substrate concentration ) 0.5 M. h Cis/trans ) 18:82. i E/Z ratio of the product. j Although the starting alcohol was consumed, homo-
and cross-Tishchenko reaction products were obtained as byproducts (decyl decanoate, 34%; neopentyl decanoate, 6%) together with the desired decanal
(3%).
say, however, use of CH2Cl2 as a solvent is not recom-
mended, and thus we investigated the applicability of other
solvents in this reaction. Fascinatingly, comparable reactivity
was attained in toluene and cyclohexane with 1 mol % of 2
(entries 3 and 4). It was of interest that the reaction proceeded
even in THF and AcOEt to furnish carvone in good yields
after stirring for 5 h (entries 5 and 6). On the basis of the
results, we selected toluene as the most suitable solvent.31
The scope and limitations of this optimized catalytic OPP
oxidation with 2 were explored with various alcohols, and
the results are summarized in Table 2. Secondary aliphatic
alcohols as well as secondary allylic and benzylic alcohols
were smoothly oxidized into the corresponding ketones in
good to excellent yields in the presence of 1-2 mol % of 2
(entries 1 and 3-6), and the yield could be improved by
increasing the amount of t-BuCHO (entry 7). The use of Me3-
Al itself as a catalyst, however, gave a poor result even after
18 h of stirring (entry 2), indicating the significant rate-
acceleration effect of ligand 1 as previously observed in MPV
reduction.28 Secondary propargylic alcohol was also ef-
ficiently converted to the corresponding ketone with 3 mol
(19) Reviews: (a) Djerassi, C. Org. React. 1951, 6, 207. (b) de Graauw,
C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007.
(20) For alkali metal alkoxide-catalyzed OPP oxidation, see: (a) Wood-
ward, R. B.; Wendler, N. L.; Brutschy, F. J. J. Am. Chem. Soc. 1945, 67,
1425. (b) Warnhoff, E. W.; Reynolds-Warnhoff, P. J. Org. Chem. 1963,
28, 1431.
(21) (a) Meerwein, H.; Schmidt, R. Liebigs Ann. Chem. 1925, 444, 221.
(b) Verley, A. Bull. Soc. Chim. Fr. 1925, 37, 537. (c) Ponndorf, W. Angew.
Chem. 1926, 39, 138. (d) Wilds, A. L. Org. React. 1944, 2, 178.
(22) For the use of borinic acid as an OPP catalyst, see: Ishihara, K.;
Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 5664.
(23) Zirconium alkoxide: Krohn, K.; Knauer, B.; Kupke, J.; Seebach,
D.; Beck, A. K.; Hayakawa, M. Synthesis 1996, 1341.
(24) Zirconocene complexes: (a) Ishii, Y.; Nakano, T.; Inada, A.;
Kishigami, Y.; Sakurai, K.; Ogawa, M. J. Org. Chem. 1986, 51, 240. (b)
Nakano, T.; Terada, T.; Ishii, Y.; Ogawa, M. Synthesis 1986, 774. (c)
Nakano, T.; Ishii, Y.; Ogawa, M. J. Org. Chem. 1987, 52, 4855.
Org. Lett., Vol. 4, No. 16, 2002
2671

% of 2 (entry 8). Moreover, the present method was found
to be applicable to the oxidation of primary allylic and
benzylic alcohols in a successful manner (entries 9-13). In
the case of geraniol, E/Z isomerization was completely
suppressed by starting the reaction at 0 °C (entries 10 and
11). Unfortunately, the reaction of simple primary aliphatic
alcohols suffered from the Tishchenko reaction32 of the
desired aldehydes, furnishing the corresponding dimer
together with the products of mixed Tishchenko reaction with
t-BuCHO (entry 14). An additional characteristic feature of
this oxidation protocol was demonstrated in the reactions
involving both acid- and base-labile compounds. For ex-
ample, exposure of monotrimethylsilyl ether of 1,4-benzene-
dimethanol to this OPP oxidation condition resulted in almost
quantitative formation of the corresponding monoaldehyde
without Si-O bond cleavage, and none of the undesired
terephthalaldehyde was obtained (entry 15).2a On the other
hand, the alcohol bearing a â-aryl substituent such as
3-phenyl-2-propanol underwent smooth oxidation to give
enolizable benzyl methyl ketone in good yield (entry 16).2b
To further improve this catalytic system as a practical
oxidation method, we examined acetone as a more general
and convenient hydride acceptor.19a Surprisingly, the oxida-
tion of carveol with only 1.2 equiv of acetone in the presence
of 5 mol % of 2 in toluene at 21 °C for 2 h gave rise to
carvone in 83% yield without any aldol byproducts (Scheme
3). This observation is in sharp contrast to the common
situation with the previous aluminum-based OPP oxidation
system, where a 50-200-fold amount of acetone and
continuous heating were required to obtain synthetically
satisfactory results.19a As also illustrated in Scheme 3,
R-ionone was readily accessible by the present procedure
and a steroid such as allocholesterol was converted to the
corresponding ketones in excellent yield with 3 equiv of
acetone under otherwise similar conditions.
Scheme 3. Catalytic OPP Oxidation of Terpenoids and
Steroids with 2 Using Acetone as a Hydride Acceptor
transformations. Further improvement in the OPP oxidation
of aliphatic primary alcohols and application to the synthesis
of natural products, including a steroid or terpenoid skeleton,
are under intensive investigation in our laboratory.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
T.M. is grateful to the Japan Society for the Promotion of
Science for Young Scientists for a research fellowship.
In summary, a practical and mild OPP oxidation procedure
has been devised by taking advantage of the high activity of
aluminum catalyst 2. With acetone as a hydride acceptor,
the present system should meet the recent economical and
environmental requirements for fundamental functional group
Supporting Information Available: Spectroscopic char-
acterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL020094C
(25) For ruthenium- or iridium-catalyzed OPP-type oxidation, see: (a)
Almeida, M. L. S.; Kocovsky, P., Backvall, J.-E. J. Org. Chem. 1996, 61,
6587. (b) Ajjou, A. N. Tetrahedron Lett. 2001, 42, 13.
(26) Lanthanide alkoxides: Namy, J. L.; Souppe, J.; Collin, J.; Kagan,
H. B. J. Org. Chem. 1984, 49, 2045.
(27) For recent modifications of aluminum alkoxide, see: (a) Akamanchi,
K. G.; Chaudhari, B. A. Tetrahedron Lett. 1997, 38, 6925. (b) Ooi, T.;
Miura, T.; Maruoka, K. Angew. Chem., Int. Ed. 1998, 37, 2347. (c) Ooi,
T.; Miura, T.; Itagaki, Y.; Ichikawa, H.; Maruoka, K. Synthesis 2002, 279.
(28) Ooi, T.; Ichikawa, H.; Maruoka, K. Angew. Chem., Int. Ed. 2001,
40, 3610.
(29) Since 2 is treated with carveol for 0.5 h before the addition of
t-BuCHO, the in situ-derived aluminum alkoxide is the actual catalyst in
the present system.31
(31) The following procedure is representative (entry 3, Table 2):
2-Hydroxy-2′-(perfluorooctanesulfonylamino)biphenyl (33.4 mg, 0.05 mmol)
was placed in a dry, two-neck flask with a Teflon-coated stirring bar under
argon, and toluene (5 mL) distilled from sodium metal was introduced.
The resulting mixture was degassed, and a 0.5 M toluene solution of Me3-
Al (100 µL, 0.05 mmol) was added, followed by stirring for 15 min at 21
°C. Freshly distilled carveol (795 µL, 5.0 mmol) was introduced at the same
temperature, and stirring was continued for an additional 30 min. Freshly
distilled pivalaldehyde (652 µL, 6.0 mmol) was added at the same
temperature, and the reaction solution was stirred for 1 h. Direct purification
of this solution without aqueous workup by column chromatography on
silica gel (1:18 ethyl acetate/hexane as an eluant) gave carvone (708 mg,
4.71 mmol; 94% yield). The ligand, 2-hydroxy-2′-(perfluorooctanesulfo-
nylamino)biphenyl, can be recovered by subsequent elution with ethyl
acetate.
(30) Although we found that the oxidation of carveol with 3 (1 mol %),
prepared by simple mixing of Al(OPri)3 [purchased from Aldrich Chemical
Co., Ltd. (99.99% purity)] and 1, under otherwise similar conditions
furnished carvone in 88% yield, use of CH2Cl2 as a solvent was a
prerequisite.28
(32) (a) Tischtschenko, W. Chem. Zentralbl. 1906, 77, I, 1309. (b) Ooi,
T.; Miura, T.; Takaya, K.; Maruoka, K. Tetrahedron Lett. 1999, 40, 7695.
(c) Deacon, G. B.; Gitlits, A.; Roesky, P. W.; Burgstein, M. R.; Lim, K.
C.; Skelton, B. W.; White, A. H. Chem. Eur. J. 2001, 7, 127.
2672
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