Catalytic Meerwein-Pondorf-Verley reduction by simple aluminum complexes

Article abstract of DOI:10.1021/ol0162116

(matrix presented) Catalytic MPV reduction was successfully carried out using simple aluminum precatalysts. Alkylaluminum reagents were converted to a low-aggregation aluminum alkoxide that was highly active for the MPV reduction of several carbonyl substrates in high yield (50-99%) using ⁱPrOH as the reducing agent. A high degree of cisftrans selectivity was achieved in the reduction of 2-methylcyclohexanone (cis/trans = 20/80) by ⁱPrOH. When chiral hydride sources were utilized in the reduction of 2-chloroacetophenone, high enantioselectivity (68-80% ee) was observed.

Full text of DOI:10.1021/ol0162116

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2391-2393
Catalytic Meerwein−Pondorf−Verley
Reduction by Simple Aluminum
Complexes
E. Joseph Campbell, Hongying Zhou, and SonBinh T. Nguyen*
Department of Chemistry, Northwestern UniVersity 2145 Sheridan Road,
EVanston, Illinois 60208-3113
stn@chem.northwestern.edu
Received June 1, 2001
ABSTRACT
Catalytic MPV reduction was successfully carried out using simple aluminum precatalysts. Alkylaluminum reagents were converted to a low-
aggregation aluminum alkoxide that was highly active for the MPV reduction of several carbonyl substrates in high yield (50−99%) using
iPrOH as the reducing agent. A high degree of cis/trans selectivity was achieved in the reduction of 2-methylcyclohexanone (cis/trans ) 20/80)
by iPrOH. When chiral hydride sources were utilized in the reduction of 2-chloroacetophenone, high enantioselectivity (68−80% ee) was observed.
The Meerwein-Pondorf-Verley (MPV) reduction of car-
bonyl substrates to primary and secondary alcohols was first
reported over 70 years ago.1-3 The classical MPV reduction
involves equilibrium-driven, reversible hydride transfer from
a secondary alcohol, generally 2-propanol, to a carbonyl
substrate activated through coordination to a Lewis acidic
aluminum center.4 A ketone byproduct, acetone, is formed
as a volatile side product, and is easily removed. Although
the MPV reduction has many practical advantages, such as
being very chemoselective under mild reaction conditions
and readily adaptable for both laboratory and large-scale
synthesis, it has not found widespread utility in synthetic
organic chemistry.4 This is largely due to the fact that more
than stoichiometric amounts of aluminum alkoxides are often
required to obtain satisfactory yields of the alcohol in
reasonable time.4 Therefore, a method for the catalytic MPV
reduction of organic carbonyls using simple aluminum
complexes is highly desirable.
by protic acids5-8 and (2) “well-defined” aluminum reagents
where the aluminum centers are complexed by multidentate
ligands.9-12 Rathke’s Al(OiPr)3/acid cocatalyst system
demonstrated good catalytic activity for the reduction of
cyclohexanone to cyclohexanol.8 However, this reaction is
accompanied by significant amounts of side product forma-
tion, especially when enolizable substrates are used. The
second class of catalyst is applicable to numerous aldehydes
and ketones. Several research groups have shown that a
variety of sophisticated aluminum complexes coordinated to
multidentate ligands initiate catalytic MPV reduction in good
yields and also demonstrate highly stereoselective hydride
transfers when bulky, specialized ligands and/or chiral
hydride sources are used.10,11
In our search for a catalytic asymmetric MPV reduction
employing a chiral aluminum catalyst and 2-propanol, we
discovered that simple alkylaluminum reagents are highly
(5) Akamanchi, K. G.; Noorani, V. R. Tetrahedron Lett. 1995, 36, 5085-
5088.
(6) Gal, G.; Krasznai, I. Magyar Kem. Folyoirat 1956, 62, 155-159.
(7) Gal, G.; Krasznai, E. Acta Chim. Acad. Sci. Hung. 1958, 16, 369-
377.
(8) Kow, R.; Nygren, R.; Rathke, M. W. J. Org. Chem. 1976, 42, 826-
827.
Since the initial discovery of the MPV reduction, there
have been only a few reports in which aluminum alkoxides
are used in catalytic amounts. These examples can be divided
into two classes: (1) aluminum alkoxides that are “activated”
(1) Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925, 39, 221.
(2) Pondorf, W. Angew. Chem. 1926, 39, 138.
(3) Verley, M. Bull. Soc. Chim. Fr. 1925, 37, 871.
(4) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis
1994, 1007-1017.
(9) Ko, B.; Wu, C.; Lin, C. Organometallics 2000, 19, 1864-1869.
(10) Konishi, K.; Kazuyuki, M.; Aida, T.; Inoue, S. J. Chem. Soc., Chem.
Commun. 1988, 643-645.
(11) Ooi, T.; Miura, T.; Maruoka, K. Angew. Chem., Int. Ed. 1998, 37,
2347-2349.
10.1021/ol0162116 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/27/2001

active catalyst precursors for the reduction of ketones and
aldehydes in nonpolar organic solvents in the presence of
excess 2-propanol. The resulting in situ generated, simple
aluminum catalysts show higher activities than those of
previously reported complex aluminum systems.10,11 In
addition, they demonstrate the same high level of stereo-
selectivity for hydride transfer that has been attributed solely
to the elaborate ligand frameworks of reported catalysts.
Herein, we report a remarkably efficient catalytic MPV
reduction of carbonyl substrates using simple alkylaluminum
pre-catalysts. Our results suggest that the efficiency and the
selectivity of the Al-catalyzed MPV reaction does not depend
on the presence of elaborate ligands. Rather, they are strongly
affected by the aggregation state of the aluminum catalyst.
Classical MPV reduction of carbonyl substrates typically
proceeds quite reluctantly. For example, reduction of cyclo-
accomplished efficiently using a catalytic amount of a simple
aluminum alkyl precursor. Titration studies in C6D6 using
1H NMR spectroscopy have shown that AlMe3 is completely
converted to Al(OiPr)3 under similar conditions (rt, 2 h,
i
AlMe3 at 25 µM concentration and 10 equiv of PrOH).
However, as shown in Table 1, commercial Al(OiPr)3 shows
very little catalytic activity under the same conditions. The
main difference between the two Al alkoxides is that our in
situ generated Al(OiPr)3 is completely soluble in nonpolar
organic solvents while the commercial Al(OiPr)3 is not,
presumably due to a higher degree of aggregation. The
solubility of our in situ generated Al(OiPr)3 suggests that it
exists in a lower state of aggregation than commercial
Al(OiPr)3 (vide infra).
Barron, Interrante, and co-workers have reported that
dimethylaluminum alkoxides formed in solution from tri-
methylaluminum and alcohols exist at equilibrium as a
mixture of monomer, dimer, and trimer.13,14 Several other
groups have described the time-dependent changes in the
physical properties of aluminum alkoxides, including an
increase in the melting point of solid aluminum tris(alkoxide)
over time.15,16 This was attributed to an increase in aggrega-
tion of the aluminum complexes through bridging alkoxide
ligands. It has been postulated that only nonbridging alkoxy
groups are able to transfer hydrides to the carbonyl sub-
strates.8 Therefore, highly aggregated aluminum alkoxides
would be detrimental to MPV reduction. On the basis of this,
we attribute the remarkable efficiency of our catalytic MPV
reduction to a low aggregation state of the aluminum catalyst
where very few bridging alkoxides are present. The catalyst
can be maintained in a low aggregation state in dilute solution
for an extensive period. In fact, aging the trimethylaluminum/
iPrOH catalyst mixture for 6 days before the addition of
cyclohexanone gave only a 20% decrease in the overall yield.
i
hexanone in toluene with Al(OiPr)3 (10 mol %) and PrOH
(4 equiv) at room temperature gave cyclohexanol in only
7% yield after 12 h (Table 1, entry 1d). Under similar
Table 1. Catalytic MPV Reduction Using Simple
Alkylaluminum Reagents
Interestingly, the presence of a chloride ligand diminishes
the activity of AlMe2Cl for the MPV reduction of benz-
aldehyde (Table 1, entry 2b). After the first hour, the reaction
reaches a maximum yield of only 60% benzyl alcohol.
However, the reaction can be carried to completion in neat
iPrOH (Table 1, entry 2b′).
For aromatic aldehyde and ketone substrates, the AlMe2Cl
precatalyst tends to be less active than AlMe3 (Table 1,
entries 2a,b and 3a,b). However, AlMe2Cl demonstrates
significantly better activity than AlMe3 toward the reduction
of electron-rich ketones such as 2-pentanone (Table 1, entries
5a,b). Thermodynamically, 2-pentanone is a difficult sub-
strate for MPV reduction.4,17 The enhanced activity of
AlMe2Cl toward this substrate can be attributed to the
increased Lewis acidity18 of the aluminum center in
a Reaction conditions: Al pre-catalyst in 21 µM concentration, rt, N2.
conditions, other ketone and aldehyde substrates (acetophe-
none, benzaldehyde, and 2-pentanone) were similarly un-
reactive (Table 1, entries 2d, 4d, and 5d). Contrastingly, the
use of simple alkyl aluminum reagents (dimethylaluminum
chloride or trimethylaluminum) as pre-catalysts with iPrOH
(4 equiv) at room temperature produced primary and second-
ary alcohols in good yields within 2-12 h (Table 1, entries
1a,b-5a,b). The yield could also be increased by slightly
elevating the reaction temperature (Table 1, entry 4a′).
The results of Table 1 indicate for the first time that
catalytic MPV reduction of organic carbonyls can be
(13) Sauls, F. C.; Interrante, L. V.; Jiang, Z. Inorg. Chem. 1990, 29,
2989-2996.
(14) Rogers, J. H.; Apblett, A. W.; Cleaver, W. M.; Tyler, A. N.; Barron,
A. R. J. Chem. Soc., Dalton Trans. 1992, 3179-3187.
(15) Fieggen, W.; Gerding, H. Recl. TraV. Chim. Pays-Bas. 1970, 89,
175-185.
(16) MacBeth, A. K.; Mills, J. A. J. Chem. Soc. 1949, 2646.
(17) Adkins, H.; Cox, F. W. J. Am. Chem. Soc. 1938, 60, 1151-1159.
(18) Paul, R. C.; Chandha, S. L.; Makhni, H. S. Indian J. Chem. 1971,
9, 365-367.
(12) Ooi, T.; Itagaki, Y.; Miura, T.; Maruoka, K. Tetrahedron Lett. 1999,
40, 2137-2138.
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Org. Lett., Vol. 3, No. 15, 2001

Table 2. Stereoselective MPV Reduction and Effect of Ligand Additives
a Reaction conditions: toluene (1 mL), 1,2,4,5-tetramethylbenzene (internal standard), N2, Al reagent (21 µmol, 10 mol %), substrate (10 equiv), either
i
chiral hydride source (1 equiv, 0 °C) or PrOH (4 equiv, rt). b Reference 10 reports a cis/trans ratio of 8/92. Al(TPP)Cl under our reaction conditions (rt)
yields a cis/trans ratio of 20/80. c Taken from ref 11; reactions carried out at 0 °C. d The absolute configuration of the major enantiomer of the product is
opposite that of the chiral hydride source. e As would be expected for a reversible reaction, the enantioselectivity of the product decreases slowly over time.
Al(OR)2Cl19 which may lead to better coordination with
electron-rich ketones20 and thus give better activity for
2-pentanone.
is not necessary for either catalyst actiVity or stereoselectiVe
hydride transfer from chiral 2o alcohol in the MPV reduction
catalyzed by aluminum alkoxides.
Building upon the initial success found with our in situ
generated catalyst, we sought to further investigate the
stereoselective hydride transfer of this catalytic system (Table
2). Aluminum porphyrins have been found to exhibit high
degrees of diastereoselectivity in the reduction of 2-methyl-
cyclohexanone.10 In addition, high degrees of catalyst activity
and enantioselectivity in the reduction of R-chloroaceto-
phenone with chiral hydride sources have been attributed to
the use of linked bis(phenoxide) ligands.11,10 As catalysts for
the reduction of carbonyl compounds with a 2° alcohol, our
simple alkylaluminum systems were found to be similar or
superior in both catalytic activity and stereoselectivity to the
aforementioned aluminum catalyst systems where elaborate
ligands were employed. For example, the use of AlMe2Cl
precatalyst yields a 20/80 cis/trans mixture of 2-methyl-
cyclohexanol independent of the presence of meso-tetra-
phenylporphyrin (Table 2, entries 1-2). Similarly, using
chirally pure 2° alcohols as the hydride source, AlMe3 alone
yields alcohol products with ee’s that are comparable to those
obtained in the presence of elaborate ligands (Table 2, entries
3-6).11 Thus, our results show that the presence of ligands
In summary, we have observed for the first time an active
and selective MPV catalyst system derived from simple
alkylaluminum complexes. Our catalyst gives superior yields
and reaction rates compared to those of other known
aluminum-based catalysts. High diastereoselectivity was
achieved in the reduction of 2-methylcyclohexanone in the
absence of a ligand. High enantioselectivity in this reaction
could also be achieved by using chiral alcohols as hydride
sources. The realization that catalytic MPV reduction can
be affected with simple alkylaluminum catalysts is significant
and will lead to further developments in this area.
Acknowledgment. Support from the Dupont Company
and the Beckman, Dreyfus, and Packard Foundations is
gratefully acknowledged. S.T.N. is an Alfred P. Sloan
research fellow. E.J.C. acknowledges the GEM and IMGIP
fellowship programs for financial support. We thank Mark
Staples for his helpful discussion.
Supporting Information Available: Experimental pro-
cedure, quantitative analysis (including typical GC traces),
and H NMR titrations. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) Mehrotra has demonstrated that chloroaluminum alkoxides in the
presence of excess alcohol at high temperatures do not hydrolyze to
aluminum tris(alkoxide). See: Mehrotra, R. C.; Mehrotra, R. K. J. Indian
Chem. Soc. 1962, 39, 23-27.
(20) Evans, D. A.; Allison, B. A.; Yang, M. G. Tetrahedron Lett. 1999,
40, 4457-4460.
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