Practical approach to the Meerwein-Ponndorf-Verley reduction of carbonyl substrates with new aluminum catalysts

Article abstract of DOI:10.1002/1521-3773(20011001)40:19<3610::AID-ANIE3610>3.0.CO;2-L

Simple mixing of Al(OiPr)₃ with the requisite ligand 1 in CH₂Cl₂ at room temperature smoothly generates the new, powerful aluminum catalyst 2, which efficiently catalyzes Meerwein-Ponndorf-Verley (MPV) reduction of various carbonyl substrates under mild conditions (see scheme). Scale-up experiments highlight the potential of the new MPV reduction procedure for practical use.

Full text of DOI:10.1002/1521-3773(20011001)40:19<3610::AID-ANIE3610>3.0.CO;2-L

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Practical Approach to the
Meerwein ± Ponndorf ±
Verley Reduction of
Carbonyl Substrates with
New Aluminum Catalysts**
Takashi Ooi, Hayato Ichikawa,
and Keiji Maruoka*
Scheme 1. General schemes for Meerwein ± Ponndorf ± Verley reduction of carbonyl compounds and the
development of new aluminum catalysts.
The Meerwein ± Ponndorf ± Verley
(MPV) reaction, which involves a
reversible hydride transfer via a six-membered transition
state, has long-been recognized as a particularly mild reduc-
tion method that has several attractive features.[1±3] The
reaction is operationally very simple, uses inexpensive, non-
toxic, and nonhazardous reagents such as Al(OiPr)3 and
iPrOH, and is compatible with a broad range of functional
groups present in the substrate.
recovery of the starting ketone (Table 1, entry 1), and use of
salicylic acid as an aluminum ligand gave none of the desired
sec-phenethyl alcohol (Table 1, entry 2). Although the reac-
tivity was slightly enhanced by aluminum isopropoxides
derived from catechol and o-(methanesulfonylamino)phenol,
it was far from a synthetically satisfactory level (Table 1,
entries 3 and 4). However, use of the phenol possessing a
trifluoromethanesulfonamide functionality improved the
yield of sec-phenethyl alcohol (30%) and a similar result
was obtained with the 2,2'-biphenol-based catalyst (46%)
(Table 1, entries 5 and 6),[9] which led us to consider the
possibility of combining the two structural characteristics. The
synthesis of 2-hydroxy-2'-(trifluoromethanesulfonylamino)bi-
phenyl (1) was thus pursued starting from phenol. Interest-
ingly, treatment of acetophenone with 10 mol% of catalyst,
prepared from 1, Me3Al, and iPrOH, in CH2Cl2 at 258C for 5 h
produced the corresponding secondary alcohol in 65% yield
(Table 1, entry 7). Here, tuning of the perfluoroalkyl group of
the sulfonamide moiety afforded a beneficial effect on the
catalyst activity. Thus, the reaction under the influence of the
However, these advantages seem to be canceled out by the
usual need for relatively drastic reaction conditions because
of the poor reactivity of the traditional Al(OiPr)3/iPrOH
catalyst system, for which continuous removal of acetone is
necessary to shift the equilibrium and hence undesirable side
reactions seem inevitable. Accordingly, a number of modern
variants of metal alkoxide/hydride source combinations have
been elaborated to allow the classical methodology to regain
an appropriate place in organic synthesis.[4±7] Although our
recently introduced catalytic procedure with bidentate alu-
minum alkoxides certainly contributed to such an endeavor, it
unfortunately requires sec-phenethyl alcohol as a hydride
donor for smooth reduction of simple acyclic aliphatic
ketones.[8] This constitutes a major difficulty (especially in
the reduction of aromatic ketones), and prompted us to make
further effort to bring out the inherent potential in the MPV
reduction for practical use. Herein we report our preliminary
results on the development of new aluminum alkoxides that
can be employed for the efficient catalytic MPV reduction of
various ketone substrates (including aromatic ketones). These
reactions, which proceed under mild reaction conditions and
in which iPrOH functions as a convenient hydride source,
provide a simple yet practical method for carbonyl reduction.
Our strategy for the development of a readily accessible,
highly active aluminum catalyst was based on the modifica-
tion of simple aluminum phenoxide through introduction of
an additional heteroatom-containing functionality on the
ortho position of the parent phenol aromatic ring as schemati-
cally illustrated in Scheme 1. Attempted reduction of aceto-
phenone as a representative substrate in the presence of
diisopropoxyaluminum phenoxide (10 mol%) (prepared in
situ from phenol, Me3Al, and iPrOH) and iPrOH as a hydride
source (5 equiv) in CH2Cl2 at 258C for 5 h resulted in total
Table 1. Catalytic MPV reduction of acetophenone with various aluminum
catalysts.[a]
Entry
R
iPrOH [equiv]
Yield [%][b]
1
2
3
4
5
H
COOH
OH
NHSO2CH3
NHSO2CF3
5
5
5
5
5
n.r.[c]
n.r.[c]
8
9
30
6
7
5
5
46
65
8
9
5
76
85
[*] Prof. K. Maruoka, Dr. T. Ooi, H. Ichikawa
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto, 606-8502 (Japan)
Fax : (‡81)75-753-4041
2
10
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[a] The MPV reduction of acetophenone was conducted with several
aluminum catalysts (10 mol%) and iPrOH (distilled from CaH2) in freshly
distilled CH2Cl2 at 258C for 5 h. [b] Yield of isolated product. [c] n.r. ˆ no
reaction.
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
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aluminum isopropoxide 3 (Scheme 2), which was derived
from 2-hydroxy-2'-(perfluorooctanesulfonylamino)biphenyl
(2), gave rise to sec-phenethyl alcohol in 76% yield and,
To gain information about the actual structure of the new
aluminum catalyst, we prepared the complex of the catalyst
precursor 4 with DMF as a model example (Scheme 3), and
Scheme 2. Efficient catalytic MPV reduction of acetophenone in the
presence of the new aluminum alkoxide 3.
eventually, the yield of the alcohol was improved to 85% by
using 10 equivalents of iPrOH (Table 1, entries 8 and 9,
respectively).[10]
Scheme 3. Preparation of the model complex 4-DMF.
A variety of ketone substrates were examined for this
optimized catalytic MPV reduction with 3 and the results are
summarized in Table 2. As expected, cyclic ketones such as
4-phenylcyclohexanone can be reduced instantaneously to
4-phenylcyclohexanol quantitatively (cis/trans ˆ 17:83) (Ta-
ble 2, entry 1). Simple aliphatic ketones were also found to be
efficiently converted to the corresponding secondary alcohols
in excellent yields (Table 2, entries 2 and 3). Moreover, the
present catalytic system based on the newly developed
aluminum catalyst allows smooth hydride transfer from
iPrOH to various aromatic ketones (Table 2, entries 4 ± 7).
the structure was determined by single-crystal X-ray diffrac-
tion analysis, which revealed a dimeric structure with unique
pentacoordinate aluminum centers (Figure 1).[11, 12] Thus, the
formation of the expected seven-membered cyclic structure
was unambiguously verified. Notably, the trifluoromethyl
moiety was found to be located away from the aluminum
center, suggesting that the introduction of the perfluoroalkyl
group essentially provides an electronic effect rather than a
steric one.
Table 2. Catalytic MPV reduction of ketone substrates with new aluminum
catalyst 3[a] and scale-up experiments with 5 g of starting ketones.[b]
Entry Substrate
Conditions Yield[c]
Scale-up reaction
[8C]
[h]
[%]
conditions
yield
[%][c]
[8C]
[h]
1
25
0.5
99[d]
25
2
99[d]
2
3
CH3(CH2)6COCH3 25
5
5
97
92
25
25
5
5
94
91
ˆ
(CH3(CH2)3)2C O 25
4
5
6
25
3.5
5
85
99
99
25
25
25
5
82
98
99
25
25
5
1
3.5
Figure 1. Structure of the 4-DMF complex (ORTEP representation).
7
25
5
97
25
9
95
Based on the results, we then conducted scale-up experi-
ments to illuminate the practical aspect of our approach, and
first examined the possibility of using Al(OiPr)3 as an
aluminum source to avoid the rather troublesome handling
of Me3Al. Fascinatingly, simple mixing of 10 mol% each of
commercially available Al(OiPr)3[13] and 2 in CH2Cl2 at room
[a] The MPV reduction of various ketone substrates was effected with 3
(10 mol%) and iPrOH (10 equiv, distilled from CaH2) in freshly distilled
CH2Cl2 (0.2m) under the indicated reaction conditions. [b] The reaction
was carried out in reagent grade CH2Cl2 (1.0m) and distilled iPrOH
(10 equiv) in the presence of 3 (5 mol%), prepared from Al(OiPr)3 and 2,
under the given conditions. [c] Yield of isolated product. [d] The cis/trans
ratio was 17:83.
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[6] Aluminum isopropoxide ± trifluoroacetic acid: a) K. G. Akamanchi,
N. R. Varalakshmy, Tetrahedron Lett. 1995, 36, 3571; b) K. G. Aka-
manchi, N. R. Varalakshmy, Tetrahedron Lett. 1995, 36, 5085; c) K. G.
Akamanchi, N. R. Varalakshmy, B. A. Chaudhari, Synlett 1997, 371.
[7] For other examples, see: a) D. Barbry, S. Torchy, Tetrahedron Lett.
1997, 38, 2959; b) P. S. Kumbhar, J. Sanchez-Valente, J. Lopez, F.
Figueras, Chem. Commun. 1998, 535; c) R. Anwander, C. Palm, G.
Gerstberger, O. Groeger, G. Engelhardt, Chem. Commun. 1998, 1811;
d) B.-T. Ko, C.-C. Wu, C.-C. Lin, Organometallics 2000, 19, 1864.
[8] T. Ooi, T. Miura, K. Maruoka, Angew. Chem. 1998, 110, 2524; Angew.
Chem. Int. Ed. 1998, 37, 2347. See also: T. Ooi, Y. Itagaki, T. Miura, K.
Maruoka, Tetrahedron Lett. 1999, 40, 2137; T. Ooi, T. Miura, K.
Takaya, K. Maruoka, Tetrahedron Lett. 1999, 40, 7695.
temperature, followed by treatment with iPrOH (10 equiv)
and acetophenone at 258C for 5 h resulted in the formation of
sec-phenethyl alcohol in 82% yield,[14, 15] indicating the
intervention of extremely facile ligand exchange.[16] With this
simple yet efficient process in hand, the reactions with 5 g of
the starting ketones were undertaken with a lower catalyst
loading (5 mol%), which scarcely affect the outcome of the
catalysis. The results included in Table 2 demonstrate the
potential utility of the present method.[17] Importantly, these
product yields were achieved at high substrate concentration
(1.0m) with reagent grade CH2Cl2, which also simplifies the
operations of this MPV reduction procedure.
[9] Attempted reduction of acetophenone with previously reported (2,7-
dimethyl-1,8-biphenylenedioxy)bis(diisopropoxyaluminum)[8]
In summary, we have devised an essentially new aluminum
alkoxide that exerts high catalytic activity with iPrOH as a
hydride donor in the MPV reduction of various ketone
carbonyl groups. This is the most reactive aluminum-based
catalyst reported so far and has remarkable potential for
practical use. Further improvement of the reactivity and
development of an asymmetric version of the reaction are
currently under investigation in our laboratory.
(10 mol%) as a catalyst under otherwise identical conditions pro-
duced sec-phenethyl alcohol in 35% yield.
[10] The requisite aluminum ligand 2 can be readily prepared from phenol
in five steps: 1) NaH, methoxymethyl chloride (MOMCl), THF
‡
(99%); 2) BuLi, ether, then B(OMe)3, H3O (85%); 3) 2-bromoani-
line, Pd(OAc)2, PPh3, K2CO3, DME (70%); 4) BuLi, N,N,N',N'-
tetramethyl-1,2-ethylenediamine (TMEDA), C8F17SO2F, diethyl ether
(50% with recovery of the starting material); 5) HCl, MeOH (99%).
Spectroscopic characterization of 2: 1H NMR (CDCl3, 400 MHz): d ˆ
7.92 (s, 1H; NH), 7.65 (dd, J ˆ 1.6, 8.0 Hz, 1H; ArH), 7.32 ± 7.47 (m,
4H; ArH), 7.26 (dd, J ˆ 1.6, 8.0 Hz, 1H; ArH), 7.09 (dt, J ˆ 1.2, 7.6 Hz,
1H; ArH), 6.95 (dd, J ˆ 1.0, 8.2 Hz, 1H; ArH), 5.44 (s, 1H; OH); IR
(KBr): nÄ ˆ 3476, 3194, 1489, 1440, 1408, 1356, 1269, 1232, 1213, 1205,
Experimental Section
‡
1182, 1155, 1065, 935, 835, 752 cm 1; MS: m/z (%): 667 [M ], 184
Scale-up reaction with acetophenone: 2-Hydroxy-2'-(perfluorooctanesul-
fonylamino)biphenyl (1.39 g, 2.1 mmol) and Al(OiPr)3 (0.43 g, 2.1 mmol)[13]
were placed in a dry, two-neck flask with a Teflon-coated stirring bar under
argon, and CH2Cl2 (42 mL, reagent grade purchased from Wako Chemical
Co., Ltd.) was introduced. The resulting mixture was stirred for 15 min at
room temperature and then 2-propanol (31.3 mL, 412 mmol) distilled from
CaH2 was introduced at the same temperature and stirring was continued
for an additional 15 min. Freshly distilled acetophenone (5 g, 41.6 mmol)
was added at 258C and the reaction solution was stirred for 5 h. This
solution was poured into 1n HCl and extracted three times with diethyl
ether. The ethereal extracts were washed with brine and dried over
Na2SO4. Evaporation of solvents and purification of the residual oil by
column chromatography on silica gel (H ˆ 12 cm, Æ ˆ 7 cm, acetone/
hexane ˆ 1:9 as eluant) gave sec-phenethyl alcohol (4.15 g, 34.0 mmol;
82% yield). The ligand, 2-hydroxy-2'-(perfluorooctanesulfonylamino)bi-
phenyl, can be recovered by subsequent elution with ethyl acetate. In
addition, purification of the reduction product by vacum distillation is also
recommended.
‡
(100), 156, 154; HRMS calcd for C20H10F17NO3S: 667.0109 [M ],
‡
found: 667.0106 [M ]; elemental analysis calcd (%) for
C20H10F17NO3S: C 36.00, H 1.51, F 48.40, N 2.10; found: C 35.71, H
1.35, F 48.32, N 2.40.
[11] Crystal structure data for the complex 4-DMF collected at 123 K:
C34H36Al2F6N4S2O8, Mr ˆ 860.75, monoclinic, space group P21/c, a ˆ
9.4834(7), b ˆ 9.4378(7), c ˆ 21.375(1) Š, b ˆ 97.856(3)8, Vˆ
1895.2(2) Š3, Z ˆ 2, 1calcd ˆ 1.508 gcm 3, R1 ˆ 0.063. Crystallographic
data (excluding structure factors) for the structure reported in this
paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-165945. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
[12] Shibasaki, Sasai, and co-workers have reported the structure of the
pentacoordinate aluminum complex [(CH3)2Al2(binaphthoxi-
de)2(thf)2]. T. Arai, H. Sasai, K. Yamaguchi, M. Shibasaki, J. Am.
Chem. Soc. 1998, 120, 441.
[13] Purchased from Aldrich Chemical Co., Ltd. (99.99% purity).
[14] This simple method resulted in a slight decrease of the chemical yield
probably due to the incomplete catalyst formation, which is techni-
cally inevitable at present.
Received: March 9, 2001
Revised: June 27, 2001 [Z16743]
[15] Attempted use of other representative metal alkoxides as catalyst
under similar reaction conditions gave the following results: 58% with
Gd(OiPr)3; 51% with Sm(OiPr)3; 0% with Zr(OR)4 (R ˆ iPr, tBu).
[16] As expected, attempted reduction of acetophenone with Al(OiPr)3
(10 mol%) and iPrOH (10 equiv) in CH2Cl2 at 258C for more than 5 h
showed no evidence of the product formation.
[1] a) H. Meerwein, R. Schmidt, Liebigs Ann. Chem. 1925, 444, 221; b) A.
Verley, Bull. Soc. Chim. Fr. 1925, 37, 537; A. Verley, Bull. Soc. Chim.
Fr. 1925, 37, 1871; A. Verley, Bull. Soc. Chim. Fr. 1927, 41, 788; c) W.
Ponndorf, Angew. Chem. 1926, 39, 138.
[2] 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. Flem-
ing), Pergamon, Oxford, 1991, p. 88.
[17] For the result of the scale-up reaction with acetophenone, see
Experimental Section.
[3] C. F. de Graauw, J. A. Peters, H. van Bekkum, J. Huskens, Synthesis
1994, 1007.
[4] Lanthanide alkoxides: a) J. L. Namy, J. Souppe, J. Collin, H. B. Kagan,
J. Org. Chem. 1984, 49, 2045; b) H. B. Kagan, J. L. Namy, Tetrahedron
1986, 42, 6573; c) T. Okano, M. Matsuoka, H. Konishi, J. Kiji, Chem.
Lett. 1987, 181; d) A. Lebrun, J. L. Namy, H. B. Kagan, Tetrahedron
Lett. 1991, 32, 2355; e) D. A. Evans, S. G. Nelson, M. R. Gagne, A. R.
Muci, J. Am. Chem. Soc. 1993, 115, 9800; f) J. Huskens, C. F.
de Graauw, J. A. Peters, H. van Bekkum, Recl. Trav. Chim. Pays-Bas
1994, 1007; g) Y. Nakano, S. Sakaguchi, Y. Ishii, Tetrahedron Lett.
2000, 41, 1565.
[5] Zirconium alkoxides: a) B. Knauer, K. Krohn, Liebigs Ann. 1995, 677;
b) K. Krohn, B. Knauer, Liebigs Ann. 1995, 1347.
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