Efficient and selective Al-catalyzed alcohol oxidation via oppenauer chemistry

Article abstract of DOI:10.1021/ja063842s

A highly active and selective Al-based catalytic Oppenauer (O) oxidation is reported. Quantitative and selective oxidations of a variety of benzylic, propargylic, allylic, and aliphatic primary and secondary alcohols were achieved using nitrobenzaldehyde derivatives as the oxidant and simple aluminum compounds as precatalysts. Copyright

Full text of DOI:10.1021/ja063842s

Published on Web 09/09/2006
Efficient and Selective Al-Catalyzed Alcohol Oxidation via Oppenauer
Chemistry
Christopher R. Graves, Bi-Shun Zeng, and SonBinh T. Nguyen*
Department of Chemistry and Institute for EnVironmental Catalysis, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208-3113
Received June 1, 2006; E-mail: stn@northwestern.edu
The selective oxidation of alcohols to their corresponding
carbonyls is one of the most widely employed transformations in
Table 1. Benzaldehydes as Hydrogen Acceptors for the Catalytic
Oppenauer Oxidation of R- Butylbenzyl Alcohol
t
1
organic synthesis. Although numerous such protocols are available,
2
many employ stoichiometric heavy metal complexes or suffer from
2 2
selectivity issues when H O
or NaOCl are used as oxidants.3
Organic oxidants, such as Swern and Dess-Martin reagents, are
time
(h)
GC yield
(%)
4
5
more selective but can be either difficult to handle or hazardous.
entry
R
equiv
6
While selective catalytic oxidation methodologies have recently
become available, they draw on expensive metal complexes and/
or elevated temperatures, issues that can be circumvented with the
Oppenauer (O) oxidation. Along with the benefits of being highly
chemoselective, the O oxidation employs easily handled organic-
based oxidants and aluminum, an inexpensive and innocuous metal,
1
2
3
4
5
Ph (A)
2
2
2
2
3
2
4
4
4
25
>99
>99
90
2,6-Cl -Ph (B)
2
2,4-(NO2)2-Ph (C)
3-NO2-Ph (D)
3-NO2-Ph (D)
<0.5
>99
entries 1-9). That a readily available commercial solution of AlMe
3
7
8
as key reactants. Although discovered in the mid-1930s, only
recently have Al-based O oxidation catalysts been reported, albeit
with specialized ligated aluminum complexes and a fairly limited
in toluene can be employed effectively as the catalyst precursor in
a large-scale benchtop reaction (Table 2, entry 2) makes our protocol
very appealing to the average researcher, who may not have access
9
substrate set. Herein, we describe an Oppenauer oxidation protocol
to either a Schlenk line or a drybox. Remarkably, our protocol even
that utilizes simple organoaluminum complexes as precatalysts that
is highly active and selective for the oxidation of a diverse array
of alcohol substrates, even in the presence of nitriles, esters, amides,
halides, and tertiary alcohols. Most importantly, our protocol is
easily extendable to large-scale oxidations performed on the
benchtop with facile purification.
i
allows for the use of solid Al(O Pr)
3
as a precatalyst, albeit with
much slower kinetics (Table 2, entry 3; also see Supporting
Information). Even in the presence of excess esters, amides, nitriles,
and tertiary alcohols, the oxidation of 1 proceeds in excellent
conversion (see Supporting Information).
Our oxidation protocol was also applicable for the quantitative
oxidation of hetero-functionalized alcohols. Both furyl and thiophen-
yl substituents were tolerated (Table 2, entries 10-12), as was
pyridyl, although oxidation of R-(2-pyridyl)ethanol, 11, was not
possible (Table 2, entries 13-15), potentially due to chelative
Our recent success10 in the application of organoaluminum
compounds as precatalysts for the Meerwein-Schmidt-Ponndorf-
Verley (MSPV) reduction of ketones suggested that under the right
conditions a similarly efficient Al-based catalytic O oxidation could
be developed. As the MSPV reduction and O oxidation are mirror
11,15
inhibition of the catalyst. Importantly, the mechanistic pathway
7
processes, selecting a highly reactive aldehyde as the oxidant for
of the O oxidation does not allow for S- or N-oxidation to occur,
demonstrating its inherent chemoselectivity. Additionally, our
system was applicable for the selective oxidation of the alcohol
moiety in R,â-unsaturated alcohols (Table 2, entries 16 and 17),
comprising a chemoselective advantage over transition metal
the O oxidation of alcohol should shift the equilibrium toward the
desirable oxidation products. On the basis of relative reduction
potentials,11 a series of benzaldehyde derivatives (A-D) were
t
screened as the hydrogen acceptor in the O oxidation of R- bu-
12
tylbenzyl alcohol, a difficult-to-oxidize substrate, using only
16
catalysts that operate through metal hydride intermediates.
AlMe
3
as a precatalyst.13 Although benzaldehyde (A) gave a low
Quantitative oxidation of a variety of 2° aliphatic alcohols was
possible (Table 2, entries 18-20), including the facile oxidation
of both borneol and isoborneol to camphor (Table 2, entries 21
and 22, respectively). The appeal of our system is further
demonstrated in the smooth oxidation of the alcohol moiety in
1R,2S)-(-)-(N- butoxycarbonyl)ephedrine with no racemization of
yield (Table 1, entry 1), changing oxidant to the more active 2,6-
dichloro- (B) (Table 1, entry 2) and 2,4-dinitrobenzaldehydes (C)
t
(
Table 1, entry 3) afforded quantitative oxidation of R- butylbenzyl
alcohol in short reaction time. The use of 3-nitrobenzaldehyde (D)
(
Table 1, entry 4) as the oxidant was most appealing, as it is both
t
(
14
inexpensive and readily available. An added bonus is the easy
removal of excess D and the reduced nitrobenzyl alcohol from
reaction products for various substrates by simple filtration over
an alumina plug with hexanes eluent, even on a 10 g scale (see
Supporting Information). Gratifyingly, in the presence of 3 equiv
the R-chiral amino center (see Supporting Information).
Preliminary kinetic data show that 2° alcohols are oxidized at a
dramatically faster rate (at least 3600 times) than corresponding
1° alcohols (see Supporting Information). Nevertheless, the oxida-
tion of primary alcohols to aldehydes can still be accomplished
easily using our O oxidation protocol. While both benzylic (Table
3, entries 1-3) and allylic (Table 3, entry 4) 1° alcohols were
readily converted to their corresponding aldehydes in short reaction
times using 3-nitrobenzaldehyde, this oxidant was not an appropriate
hydrogen acceptor for the oxidation of 1° aliphatic alcohols.
However, switching the oxidant to the more active 2,4-dinitroben-
t
of 3-nitrobenzaldehyde, R- butylbenzyl alcohol was quantitatively
oxidized to butyl phenyl ketone in less than 0.5 h (Table 1, entry
t
5
).
The O oxidation of various 2° alcohols was carried out using
the established conditions of Table 1, entry 5. Excellent yields were
obtained in the oxidation of various 2° benzylic alcohols (Table 2,
12596
9
J. AM. CHEM. SOC. 2006, 128, 12596-12597
10.1021/ja063842s CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Scope the Oppenauer Oxidation of 1° Alcohols
Table 2. Scope of the Oppenauer Oxidation of 2° Alcohols
a
Isolated yield based on a 6-mmol oxidation performed using standard
b
Schlenk-line techniques with a 2 M solution of AlMe3 in toluene. Minor
loss of yield during purification (see Supporting Information).
Research Council of Canada (NSERC) PGS-D2 International
Predoctoral Fellow. B.S.Z. thanks Northwestern University for a
summer URGC research grant. We thank Dr. Daniel Appella (NIH)
and Dr. Steven Goodman (GlaxoSmithKlime) for helpful discus-
sions.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(
1) For examples, see: (a) Lee, T. V. In ComprehensiVe Organic Synthesis;
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1
991; Vol. 7, p 291. (b) Procter, G. In ComprehensiVe Organic Synthesis;
a
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b
c
Isolated yield of a 10-g scale reaction. On the benchtop, in ACS-grade
i
d
toluene, with 10 mol % of solid Al(O Pr)3 as the catalytic precursor. Minor
loss of yield during purification (see Supporting Information).
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(
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Excitingly, this is the first example of a simple Al-catalyzed O
(
oxidation that is applicable for primary aliphatic alcohols, an
unreactive substrate class for Maruoka’s (N,O)-ligated aluminum
catalyst.9 The versatility of our system is apparent through the
facile and selective oxidation of â-citronellol (27, Table 3, entry
(
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a,17
(
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7
), a sensitive primary alcohol that is known to suffer selectivity
2b,c
issues under other oxidation methods.
(
8) Oppenauer, R. V. Recl. TraV. Chim. 1937, 56, 137-144.
In conclusion, we have demonstrated a highly active Oppenauer
oxidation system comprising catalytic amounts of simple AlMe
(9) (a) Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett.
2
002, 4, 2669-2672. (b) Ooi, T.; Miura, T.; Itagaki, Y.; Ichikawa, H.;
3
Maruoka, K. Synthesis 2002, 279-291.
precursor and the inexpensive and readily available 3-nitrobenzal-
dehyde oxidant. This system is active for the selective oxidation
of a variety of benzylic, allylic, and aliphatic secondary as well as
primary alcohols. Direct comparison of this system with other
oxidation manifolds shows superior reactivity, selectivity, and cost
advantages (see Supporting Information) relative to other commonly
(
10) Campbell, E. J.; Zhou, H.; Nguyen, S. T. Org. Lett. 2001, 3, 2391-2393.
(11) (a) Adkins, H.; Cox, F. W. J. Am. Chem. Soc. 1938, 60, 1151-1159. (b)
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(
13) Although AlMe
3
is used extensively throughout this study, the less
can also be used effectively as a precatalyst without
expensive AlEt
adverse effects.
3
(
14) When purchased in bulk, 3-nitrobenzaldehyde can be bought for $0.10/g
U.S.) (Aldrich Chemical Co., 500 g scale).
utilized oxidation processes.
Acknowledgment. We gratefully acknowledge financial support
(
(
15) Cohen, R.; Graves, C. R.; Nguyen, S. T.; Martin, J. M. L.; Ratner, M. A.
J. Am. Chem. Soc. 2004, 126, 14796-14803.
from the NSF and the DOE through a grant administered by the
Institute for Environmental Catalysis (NU). S.T.N. additionally
acknowledges support from the Packard Foundation and the A. P.
Sloan Foundation. C.R.G. is a Natural Science and Engineering
(
(
16) Backvall, J.-E. J. Organomet. Chem. 2002, 652, 105-111.
t
17) Butyl aldehyde and not 3-nitrobenzaldehyde was used as the oxidant for
this O oxidation protocol.
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J. AM. CHEM. SOC.
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