Highly efficient, catalytic Meerwein-Ponndorf-Verley reduction with a novel bidentate aluminum catalyst

Article abstract of DOI:10.1002/(SICI)1521-3773(19980918)37:17<2347::AID-ANIE2347>3.0.CO;2-U

Double electrophilic activation of carbonyl groups allows a modern variant of the Meerwein-Ponndorf-Verley reduction to be carried out under mild conditions with bidentate catalyst 1 (see reaction). Various carbonyl substrates can be reduced efficiently at room temperature in CH₂Cl₂ with 2-propanol or sec-phenthyl alcohol in the presence of a catalytic amount of 1. This system is also applicable to the Oppenauer oxidation of secondary alcohols to the corresponding ketones.

Full text of DOI:10.1002/(SICI)1521-3773(19980918)37:17<2347::AID-ANIE2347>3.0.CO;2-U

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[4] a) C. M. Drain, J.-M. Lehn, J. Chem. Soc.Chem. Commun. 1994,
2313 ± 2315; b) H. Yuan, L. Thomas, L. K. Woo, Inorg. Chem. 1996, 35,
2808 ± 2817; c) P. J. Stang, J. Fan, B. Olenyuk, Chem. Commun. 1997,
1453 ± 1454; d) R. V. Slone, J. T. Hupp, Inorg. Chem. 1997, 36, 5422 ±
5437.
membered transition state [A] is initiated by the activation
of the carbonyl group by coordination to the Lewis acidic
aluminum center (Scheme 1).[4] Acetone is formed as a
[5] a) C. M. Drain, D. Mauzerall, Biophys. J. 1992, 63, 1556 ± 1563; b) K.
Araki, M. J. Wagner, M. S. Wrighton, Langmuir 1996, 5393 ± 5398.
[6] K. Funatsu, A. Kimura, T. Imamura, Y. Sasaki, Chem. Lett. 1995, 765 ±
766.
[7] While coordination polymers have been known for many decades, the
formation of discrete ordered coordination arrays is enjoying a
renaissance: a) J.-M. Lehn, Angew. Chem. 1990, 102, 1347 ± 1362;
Angew. Chem. Int. Ed. Engl. 1990, 29, 1304 ± 1319; b) M. Fujita, Y. J.
Kwon, S. Washizu, K. Ogura, J. Am. Chem. Soc. 1994, 116, 1151 ± 1152;
c) R. V. Slone, J. T. Hupp, C. L. Stern, T. E. Albrecht-Schmitt, Inorg.
Chem. 1996, 35, 4096 ± 4097; d) B. Linton, A. D. Hamilton, Chem. Rev.
1997, 97, 1669 ± 1680; e)P. J. Stang, B. Olenyuk, Acc. Chem. Res. 1997,
30, 507 ± 518.
Scheme 1. MPV reduction of carbonyl compounds with Al(OiPr)3 in
iPrOH, which proceeds via transition state A.
[8] a)The UV/Vis spectra (see Figure 1 of the Supporting Information)
were measured with a 0.5mm solution in toluene (formation of
nonamer 5b from the porphyrin mixture 1 ‡ 2b ‡ 3b); Soret bands
(half-width) in nm (porphyrin mixture !5 b): 418.9 (15.3) !408.4
volatile side product, which is easily removed during the
reaction. Advantages of the MPV reduction include chemo-
selectivity, mild reaction conditions, operational simplicity,
safe handling, and ready adaptation both in the laboratory
and on a large scale.[5]
(23.2), 425.9 (18.2), 439.6 (20.4). b) The ES mass spectrum (HP-1100
1
LC/MS, direct injection at 0.1 mLmin 1, N2 carrier gas at 1 mLmin
,
ionization potential 150 kV, positive-ion mode) of 5a in CHCl3 with
0.3% acetic acid (see Figure 3 of the Supporting Information) shows
the tri- and tetra-protonated nonamer at m/z ˆ 2619 and 1965,
respectively. Additionally, it shows the loss of three and four chloride
ions at m/z ˆ 2583 and 1928, respectively. Vapor-phase osmometry
studies used toluene as solvent and were standardized with polystyr-
ene of a known average molecular weight. c) 1H NMR (300 MHz,
CDCl3; see Figure 4 of the Supporting Informtion) for nonamer 5b
formed from 1 ‡ 2b ‡ 3b: a-pyridyl (d ˆ 9.051 !9.454), b-pyridyl
(d ˆ 8.13 !8.32), tert-butyl (d ˆ 1.621 !1.627 and 1.634), pyrrole NH
(d ˆ 2.816, 2.866, 2.906 ! 2.786, 2.811, 2.840). The width at
half-height of the methyl peaks broadens from about 2 Hz to 4.2 Hz.
[9] Fluorescence quenching (supramolecular array/porphyrin mixture at
the same optical density): 5a (ca. 87% in toluene, ca. 93% in CCl4), 5b
(>90% in CHCl3 or mineral oil), 9a (14% in toluene), 10a (18% in
toluene). The complete photophysical characterization of these
systems will be reported elsewhere.
Nonetheless, there are several practical problems with the
MPV reduction such as the need for an excess of alcohol as
hydride source, low reaction rate, formation of condensation
products, and need for higher reaction temperatures so that
the concurrent removal of acetone shifts the equilibrium
towards the formation of alcohol. The most important side
reactions are the aldol condensation and the Tishchenko
reaction; the latter leads to the formation of carboxylic esters,
especially in the case of the more reactive aldehydes.[6]
Accordingly, various modifications of the MPV reduction
have been developed in order to overcome these disadvan-
tages. The more recent improvements are the use of catalyti-
cally active lanthanide alkoxides,[7] microwave irradiation,[8]
and the addition of CF3CO2H to Al(OiPr)3 to accelerate the
reduction.[9] Herein we report the highly accelerated MPV
reduction of carbonyl substrates with a bidentate aluminum
catalyst. The realization of this modern MPV reduction is
crucially dependent on the effective use of our recently
developed bidentate Lewis acid chemistry.[10]
The typical MPV reduction of carbonyl substrates proceeds
quite reluctantly. For example, reduction of benzaldehyde in
CH2Cl2 with Al(OiPr)3 (1 equiv) at room temperature for 1 h
gave rise to benzyl alcohol in 34% yield.[11] When the reaction
was carried out in CH2Cl2 with iPrOH (1 equiv) and a
catalytic amount of Al(OiPr)3 (10 mol%) at room temper-
ature for 2 h, benzyl alcohol was obtained in only 10% yield
(Table 1). Under similar reduction conditions, ketone sub-
strates (e.g., 4-phenylcyclohexanone and 2-undecanone) were
totally unreactive, and most of the starting material was
recovered. In marked contrast, however, use of the bidentate
aluminum catalyst 1 in the reduction of benzaldehyde
produced the benzyl alcohol at room temperature instanta-
neously and almost quantitatively (Scheme 2). Catalyst 1 is
generated in situ from 2,7-dimethyl-1,8-biphenylenediol,
Me3Al (2 equiv), and iPrOH (4 equiv). Moreover, even with
5 mol% of 1 the reduction proceeds quite smoothly at room
temperature to furnish benzyl alcohol in 81% yield after 1 h.
This remarkable efficiency can be ascribed to the double
[10] a) A. D. Adler, F. R. Longo, W. Shergalis, J. Am. Chem. Soc. 1964, 86,
3145 ± 3148; b) C. M. Drain, X. Gong, Chem. Commun. 1997, 2117 ±
2118.
Highly Efficient, Catalytic
Meerwein ± Ponndorf ± Verley Reduction
with a Novel Bidentate Aluminum Catalyst**
Takashi Ooi, Tomoya Miura, and Keiji Maruoka*
The Meerwein ± Ponndorf ± Verley (MPV) reaction, named
after the independent originators, involves the chemoselective
reduction of carbonyl substrates with aluminum alkoxides,
generally Al(OiPr)3, as catalyst and iPrOH as hydride
source.[1±3] In the MPV reduction, a reversible hydride transfer
from the alcoholate to a carbonyl acceptor via a six-
[*] Prof. K. Maruoka, Dr. T. Ooi, T. Miura
Department of Chemistry, Graduate School of Science
Hokkaido University
Sapporo, 060 ± 0810 (Japan)
Fax: (‡81)11-746-2557
E-mail: maruoka@sci.hokudai.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and
Culture, Japan.
Angew. Chem. Int. Ed. 1998, 37, No. 17
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Table 1. Catalytic MPV reduction of carbonyl substrates with 1 or 2.
Substrate
Al reagent
(mol%)
Hydride source
(equiv)
t[h]
Yield
[%][a]
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCH(CH2)4C O
PhCH(CH2)4C O
PhCH(CH2)4C O
PhC(O)CH2Cl
PhC(O)CH2Cl
PhC(O)CH2Cl
PhC(O)CH2Cl
CH3(CH2)8COCH3 Al(OiPr)3 (100)
CH3(CH2)8COCH3 1 (5)
CH3(CH2)8COCH3 2 (5)
CH3(CH2)8COCH3 2 (5)
CH3(CH2)8COCH3 2 (5)
Al(OiPr)3 (100)
Al(OiPr)3 (10)
1 (100)
1 (5)
1 (5)
Al(OiPr)3 (100)
1 (5)
1 (5)
Al(OiPr)3 (100)
1 (5)
1 (5)
±
1
2
34
10
iPrOH (1)
±
iPrOH (1)
iPrOH (3)
±
iPrOH (1)
iPrOH (1)
±
iPrOH (1)
iPrOH (1)
PhMeCHOH (1)
±
iPrOH (3)
PhMeCHOH (1)
PhMeCHOH (3)
PhMeCHOH (6)
iPrOH (1)
PhMeCHOH (6)
(5 min) 99
1
1
1
1
2
2
2
10
2
5
5
5
5
5
5
5
81
96
(trace)
91
ˆ
ˆ
ˆ
99
[b]
±
75
89
99
2 (5)
Scheme 3. Enantioselective MPV reduction with chiral secondary alcohols
as hydride source.
[b]
±
50
73
89
99
31[c]
70[c]
ketones. For example, sequential addition of a 1m solution in
hexane of Me3Al (10 mol%) and carveol (8) to 2,7-dimethyl-
1,8-biphenylenediol (5 mol%) in CH2Cl2 at room temper-
ature in the presence of 4-Š molecular sieves and subsequent
treatment with pivalaldehyde (3 equiv) at room temperature
for 5 h provided carvone (9) in 91% yield. Under similar
oxidation conditions, cholesterol (10)[18] was converted into 4-
cholesten-3-one (11) in 75% yield (91% yield with 5 equiv of
tBuCHO, Scheme 4).
ˆ
PhCH CHCOCH3 1 (5)
ˆ
PhCH CHCOCH3 2 (5)
[a] Yield of isolated product. [b] No reaction. [c] Yield of 1,2-reduction product.
Scheme 2. Catalytic MPV reduction of aldehydes and ketones with 1 or 2.
electrophilic activation of carbonyl groups by the bidentate
aluminum catalyst.[12]
Other selected examples are listed in Table 1. In addition to
aldehydes, both cyclic and acyclic ketones can be reduced
equally well. sec-Phenethyl alcohol (4, R ˆ Ph) is a more
effective hydride source than iPrOH. This finding prompted
us to examine the enantioselective MPV reduction of unsym-
metrical ketones with chiral alcohols in the presence of
catalyst 2 (Scheme 3).[13] Indeed, treatment of 2-chloroaceto-
phenone (6) with optically pure (R)-(‡)-sec-phenethyl alco-
hol (1 equiv) under the influence of 2 at 08C for 10 h afforded
(S)-(‡)-2-chloro-1-phenylethanol (7) with moderate asym-
metric induction (82% yield, 54% ee).[14] Switching chiral
alcohols from (R)-(‡)-sec-phenethyl alcohol to (R)-(‡)-a-
methyl-2-naphthylmethanol and (R)-(‡)-sec-o-bromophen-
ethyl alcohol further enhanced the optical yields of 7 to 70
and 82% ee, respectively.[14, 15]
Scheme 4. Catalytic Oppenauer oxidation of secondary alcohols with
bidentate aluminum catalyst/pivalaldehyde system.
Experimental Section
MPV reduction of 4-phenylcyclohexanone: 2,7-Dimethyl-1,8-biphenylene-
diol (10.7 mg, 0.05 mmol) and predried, powderized 4-Š molecular sieves
(ca. 60 ± 70 mg) were placed in a dry two-neck flask with a stirring bar under
argon, and freshly distilled CH2Cl2 (5 mL) was introduced. The suspension
was carefully degassed and a 1m solution of Me3Al (100 mL, 0.1 mmol) in
hexane was added dropwise at room temperature. After the reaction
mixture was stirred for 30 min, iPrOH (92 mL, 1.2 mmol) was added, and
the stirring was continued for an additional 30 min. The resulting mixture
was then treated with a solution of 4-phenylcyclohexanone (174 mg,
1.0 mmol) in CH2Cl2 and stirred at room temperature for 1 h. The reaction
was quenched with 1n HCl, and the mixture was extracted with diethyl
ether. The combined organic extracts were then dried over Na2SO4.
Evaporation of solvents and purification of the residual oil by column
The present approach is applicable to the reverse reaction
of the MPV reduction, that is, the Oppenauer oxidation.[16, 17]
We have successfully developed a highly accelerated Oppe-
nauer oxidation system using a bidentate aluminum catalyst
of type 1 and 2. This modified, catalytic system effectively
oxidizes a variety of secondary alcohols to the corresponding
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chromatography on silica gel (CH2Cl2 as eluant) gave a cis/trans mixture of
4-phenyl-1-cyclohexanol (159 mg, 0.91 mmol, 91% yield; cis:trans ˆ
23:77).
The Family Approach to the Resolution of
Racemates **
Ton Vries,* Hans Wynberg,* Erik van Echten,
Jan Koek, Wolter ten Hoeve, Richard M. Kellogg,
Quirinus B. Broxterman,* Adri Minnaard, Bernard
Kaptein, Sietse van der Sluis,* Lumbertus Hulshof, and
Jaap Kooistra
Received: March 31, 1998 [Z11667IE]
German version: Angew. Chem. 1998, 110, 2524 ± 2526
Keywords: aluminum ´ asymmetric synthesis ´ homogene-
ous catalysis ´ oxidations ´ reductions
A cornerstone of stereochemistry is the resolution of
tartaric acid by Louis Pasteur.[1, 2] This conversion of a
racemate with a chiral resolving agent and subsequent
separation of the mixture of diastereomers formed is known
as the ªclassical method of resolutionº,[3] and remains, 150
years after Pasteur, a paradigm of trial and error.[4] Despite
many attempts,[3] neither computer-assisted modeling,[5] de-
tailed examination of the crystal structure data of diastereo-
meric salts,[6] study of the energy differences of diastereomeric
salts,[7] nor empirical correlations[8] have led to a hypothesis,
let alone a theory, on which to base a predictable resolution
technique.
All too aware of these problems on the basis of long ex-
perience and motivated by a need to develop fast and reliable
protocols, we considered the combinatorial approach, a recent
technique that has shown promise in the search for lead com-
pounds in drug design.[9] A rudimentary application of such
methodology led to the remarkable results reported here.
The standard technique for the resolution of a racemate
entails the addition of one chiral resolving agent to a racemate
followed by a suitable waiting period in order to observe
crystallization of one diastereomeric salt. We hoped that the
simultaneous addition of several resolving agents might
shorten the time required for the hit-and-miss method of
finding a resolving agent. The addition of more than one
resolving agent could result in the precipitation of the least
soluble diastereomeric salt, thus obviating the need for
repetition of the process of resolution with one resolving
agent at a time. To our great surprise, the simultaneous
addition of more than one member of a ªfamilyº of resolving
agents (for a definition, see below) to a solution of a racemate
usually causes very rapid precipitation of a crystalline
diastereomeric salt in good to high enantiomeric purity and
yield. The results from some of the more than two hundred
successful experiments carried out during the past year[10] are
listed in Tables 1 and 2. In virtually all cases examined both
the yields and enantiomeric excesses (ee) were superior to
those obtained by the classical approach (compare entry 55
with entry 53).
[1] H. Meerwein, R. Schmidt, Justus Liebigs Ann. Chem. 1925, 444, 221.
[2] a) A. Verley, Bull. Soc. Chim. Fr. 1925, 37, 537; b) A. Verley, Bull. Soc.
Chim. Fr. 1925, 37, 1871; c) A. Verley, Bull. Soc. Chim. Fr. 1927, 41, 788.
[3] W. Ponndorf, Angew. Chem. 1926, 39, 138.
[4] Reviews: a) A. L. Wilds, Org. React. 1944, 2, 178; b) R. M. Kellogg in
Comprehensive Organic Synthesis, Vol.
8 (Eds.: B. M. Trost, I.
Fleming), Pergamon Press, Oxford, 1991, p. 88.
[5] C. De Graauw, J. Peters, H. Van Bekkum, J. Huskens, Synthesis 1994,
1007.
[6] W. Tischtschenko, Chem. Zentralbl. 1906, 77, 1309.
[7] a) H. Kagan, J. Namy, Tetrahedron 1986, 42, 6573; b) J. Huskens, C.
De Graauw, J. Peters, H. Van Bekkum, Recl. Trav. Chim. Pays-Bas
1994, 1007.
[8] D. Barbry, S. Torchy, Tetrahedron Lett. 1997, 38, 2959.
[9] a) K. G. Akamanchi, N. R. Varalakshmy, Tetrahedron Lett. 1995, 36,
3571; b) K. G. Akamanchi, N. R. Varalakshmy, Tetrahedron Lett. 1995,
36, 5085; c) K. G. Akamanchi, N. R. Varalakshmy, B. A. Chaudhari,
Synlett 1997, 371.
[10] a) T. Ooi, M. Takahashi, K. Maruoka, J. Am. Chem. Soc. 1996, 118,
11307; b) T. Ooi, E. Tayama, M. Takahashi, K. Maruoka, Tetrahedron
Lett. 1997, 38, 7403; c) T. Ooi, A. Saito, K. Maruoka, Tetrahedron Lett.,
in press.
[11] The reduction of benzaldehyde with Al(OiPr)3 (1 equiv) in 2-propanol
did not proceed at room temperature.
[12] Our system surely takes advantage of the lower susceptibility of both
acetone and acetophenone toward the MPV reduction with the
reduction products as a hydride source. Indeed, attempted reaction of
acetone with 4-phenylcyclohexanol (1 equiv) in the presence of 1
(5 mol%) in CH2Cl2 at room temperature for 1 h gave rise to 4-
phenylcyclohexanone in only 8% yield.
[13] J. D. Morrison, H. S. Mosher, Asymmetric Organic Reactions, Amer-
ican Chemical Society, Washington, DC, 1976, p. 160. Evans et al.
reported the first catalytic and highly enantioselective MPV reduction
with a chiral Sm complex: D. A. Evans, S. G. Nelson, M. R. Gagne,
A. R. Muci, J. Am. Chem. Soc. 1993, 115, 9800.
[14] The enantiomeric excess of 7 was determined by comparison of the
optical rotation with that of commercially available 7 (98% ee). In the
reaction with (R)-(‡)-sec-o-bromophenethyl alcohol the ee value was
measured after conversion into the corresponding styrene oxide: H. C.
Kolb, K. B. Sharpless, Tetrahedron 1992, 48, 10515.
[15] Unfortunately, the asymmetric MPV reduction of dialkyl ketones
gave unsatisfactory results in terms of reactivity and selectivity. For
example, reaction of 2-undecanone under similar conditions with (R)-
(‡)-sec-o-bromophenethyl alcohol afforded 2-undecanol in 11% yield
with less than 25% ee.
[16] R. V. Oppenauer, Recl. Trav. Chim. 1937, 56, 137.
[17] For a recent modification, see K. G. Akamanchi, B. A. Chaudhari,
Tetrahedron Lett. 1997, 38, 6925.
[18] Commercially available cholesterol was further dried according to the
literature procedure: J. F. Eastham, R. Teranishi, Org. Synth. Coll. Vol.
1963, 4, 192.
[*] Dr. T. Vries, Prof. Dr. H. Wynberg, E. van Echten, J. Koek,
Dr. W. ten Hoeve, Prof. Dr. R. M. Kellogg
Syncom BV
Nijenborgh 4, NL-9747 AG Groningen (The Netherlands)
Fax: (‡31)50-363-4875
E-mail: t.vries@chem.rug.nl
Dr. Q. B. Broxterman, Dr. A. J. Minnaard, Dr. B. Kaptein
Organic Chemistry & Biotechnology Section, DSM Research
P.O. Box 18, 6160 MO Geleen (The Netherlands)
Dr. S. van der Sluis, Prof. Dr. L. Hulshof, Dr. J. Kooistra
P.O. Box 81, 5900 AB Venlo (The Netherlands)
[**] Dr. Ton Vries is the discoverer of this new method.
Angew. Chem. Int. Ed. 1998, 37, No. 17
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1433-7851/98/3717-2349 $ 17.50+.50/0
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