Practical Os/Cu-cocatalyzed air oxidation of allyl and benzyl alcohols at room temperature and atmospheric pressure

Article abstract of DOI:10.1021/ol025648q

(equation presented) A new protocol for the oxidation of primary and secondary allyl and benzyl alcohols at room temperature and using 1 atm of air is described. The procedure uses low loadings of copper salts and osmium tetroxide, which is activated with quinuclidine and prereduced with an alkene. Chemoselectivity for allyl and benzyl alcohols is very high, no overoxidation is observed, and the reaction takes place under neutral conditions.

Full text of DOI:10.1021/ol025648q

ORGANIC
LETTERS
2
002
Vol. 4, No. 6
043-1045
Practical Os/Cu-Cocatalyzed Air
Oxidation of Allyl and Benzyl Alcohols
at Room Temperature and Atmospheric
Pressure
1
John Muldoon and Seth N. Brown*
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall,
UniVersity of Notre Dame, Notre Dame, Indiana 46556-5670
seth.n.brown.114@nd.edu
Received January 30, 2002
ABSTRACT
A new protocol for the oxidation of primary and secondary allyl and benzyl alcohols at room temperature and using 1 atm of air is described.
The procedure uses low loadings of copper salts and osmium tetroxide, which is activated with quinuclidine and prereduced with an alkene.
Chemoselectivity for allyl and benzyl alcohols is very high, no overoxidation is observed, and the reaction takes place under neutral conditions.
Molecular oxygen is an ideal oxidant for both economic
and ecological reasons. While oxidations using air or
dioxygen are widely practiced in industry, where the scale
tion of benzylic and allylic alcohols cocatalyzed by readily
available osmium and copper complexes under neutral
conditions. This procedure is rapid and efficient and operates
at ambient temperature and pressure. In fact, it is competi-
tive with currently used stoichiometric oxidants such as
manganese dioxide in its ease, selectivity, and even ex-
pense.
1
of the reactions makes detailed optimization practical,
the lack of general, selective, easy, and safe methods has
impeded the adoption of aerobic methods for reactions
run on a smaller scale. For example, molecular oxygen is
seldom used in organic synthesis to oxidize alcohols to
aldehydes or ketones, largely because the existing aerobic
(
2) (a) Sheldon, R. A.; Arends, I. W. C. E.; Dijksman, A. Catal. Today
2
000, 57, 157-166. (b) Ben-Daniel, R.; Alsters, P.; Neumann, R. J. Org.
2
methodologies, even with notable recent improvements,
Chem. 2001, 66, 8650-8653. (c) Mark o´ , I. E.; Gautier, A.; Mutonkole,
J.-L.; Dumeunier, R.; Ates, A.; Urch, C. J.; Brown, S. M. J. Organomet.
Chem. 2001, 624, 344-347. (d) Kakiuchi, N.; Maeda, Y.; Nishimura, T.;
Uemura, S. J. Org. Chem. 2001, 66, 6620-6625. (e) Miyata, A.; Murukami,
M.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2001, 42, 6067-6070. (f)
Dijksman, A.; Marino-Gonzalez, A.; Payeras, A. M. I.; Arends, I. W. C.
E.; Sheldon, R. A. J. Am. Chem. Soc. 2001, 123, 6826-6833. (g) Ten Brink,
G. T.; Arends, I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636-1639.
require using oxygen at elevated temperatures or pressures,
3
which is inconvenient and presents a risk of explosion. Some
recent reports have described aerobic oxidations under
ambient conditions.3 However, these protocols still suffer
from low conversions or high catalyst loadings, or require
acidic media. Here we report a selective aerobic oxida-
-5
(
h) Lee, M.; Chang, S. B. Tetrahedron Lett. 2000, 41, 7507-7510. (i)
Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64,
6
750-6755. (j) Mark o´ , I. E.; Giles, P. R.; Tsukazaki, M.; Chell e´ -Regnaut,
(
1) (a) Parshall, G. W.; Ittel, S. D. Homogeneous Catalysis: The
I.; Gautier, A.; Brown, S. M.; Urch, C. J. J. Org. Chem. 1999, 64, 2433-
2439. (k) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A. Chem Commun.
1999, 1591-1592.
(3) Osborn, J. A.; Coleman, K. S.; Lorber, C. Y. Eur. J. Inorg. Chem.
1998, 1673-1675.
Applications and Chemistry of Catalysis by Soluble Transition Metal
Complexes, 2nd ed.; Wiley-Interscience: New York, 1992. (b) Marchal,
C.; Davidson, A.; Thouvenot, R.; Herv e´ , G. J. Chem. Soc., Faraday Trans.
1
993, 89, 3301-3306. (c) Ai, M.; Muneyama, E.; Kunishige, A.; Ohdan,
K. Bull. Chem. Soc. Jpn. 1994, 67, 551-556. (d) Partenheimer, W. Catal.
Today 1995, 23, 69-158. (e) Weissermal, K.; Arpe, H. J. Industrial Organic
Chemistry, 3rd ed.; VCH: Weinheim, 1997. (f) Mizuno, N.; Misono, M.
Chem. ReV. 1998, 98, 199-218.
(4) Ley, S. V.; Lenz, R. J. Chem. Soc., Perkin Trans. 1 1997, 3291-
3292.
(5) Cecchetto, A.; Fontana, F.; Minisci, F.; Recupero, F. Tetrahedron
Lett. 2001, 42, 6651-6653.
1
0.1021/ol025648q CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/21/2002

Osmium tetroxide and its amine adducts have been used
extensively in oxidation chemistry because of their rapid
reaction with alkenes to form cyclic osmate esters, which,
conversions (although isolated examples proceeded at room
temperature). Activation of the osmium by forming the
glycolate appears to significantly improve both the reactivity
and the selectivity of the system, allowing reactions to
proceed at room temperature and without any oxidation of
aliphatic alcohols (see below). Beller recently reported that
good activity for air oxidation of benzylic and secondary
aliphatic alcohols by osmium can be achieved at modestly
elevated temperature (50°) using a buffered basic aqueous/
organic biphase even in the absence of cocatalyst.11 Allyl
alcohols presumably cannot be oxidized selectively, however,
since these conditions have been reported to effect alkene
6
upon reductive or oxidative hydrolysis, yield the syn diols.
Osmylation is remarkably chemoselective; for example, allyl
alcohols have been oxidized routinely to give triols, with no
7
evidence of alcohol oxidation. We were thus surprised to
find that osmate(VI) esters derived from monosubstituted
alkenes react readily with allylic and benzylic alcohols to
give R,â-unsaturated aldehydes or ketones (eq 1). While this
reaction works best with quinuclidine-ligated glycolates
8
prepared from (C
7
H
13N)OsO
4
(1), even donor-free osmate
1
2
esters will oxidize allylic and benzylic alcohols in organic
solvents.
dihydroxylation.
Oxidation of a variety of alcohols can be carried out at
atmospheric pressure in the presence of 2 mol % of alkene-
7 4
activated (C H13N)OsO (1) and 1 mol % of copper 2-eth-
ylhexanoate (Table 1). All of the allyl and benzyl alcohols
react completely in acetonitrile within 6-18 h at room
temperature, and the products can be isolated easily using a
1
3
3
simple extractive workup. Although CH CN appears to be
the optimal solvent, other polar organic solvents such as
acetone, chloroform, THF, or DMF can be used with only a
modest decrease in activity. Use of the quinuclidine adduct
of osmium tetroxide (1) is important for achieving high
Oxidation of benzyl or allyl alcohols with osmium(VI)
diolates results in formation of only half a mole of aldehyde
or ketone relative to osmium, even when reactions are
allowed to stand for prolonged periods in the presence of
air. This suggests that the osmium is reduced to the +5
oxidation state and is then inert to further redox reactions
under these conditions. We therefore sought a cocatalyst that
could reoxidize the osmium to the +6 oxidation state using
dioxygen as the stoichiometric oxidant. Copper seemed a
logical choice for this role, given the extensive use of copper
activity, as unligated OsO
but 1 can be generated in situ by the addition of 2 equiv of
quinuclidine to OsO without any difference in performance
4
is about 10 times less reactive,
4
compared to isolated 1. While a variety of alkenes produce
reactive glycolates, the best catalyst performance is obtained
upon activation of 1 with allyl ethyl ether. Both copper(II)
2-ethylhexanoate and copper(II) acetylacetonate are effective
as cocatalysts, but copper(II) halides are less satisfactory,
presumably due to their low solubility at room temperature.
Oxidation of allyl and benzyl alcohols gives only the
corresponding R,â-unsaturated aldehydes or ketones, with
the only deviations from essentially quantitative yield oc-
curring with substrates such as nerol or geraniol, which give
salts as oxygen-activating cocatalysts.3,9 Indeed, addition of
catalytic quantities of a variety of copper compounds enables
the oxidation to take place with catalytic amounts of osmium
at reasonable rates at room temperature. In fact, rates are
high enough that the reactions appear to be mass transport
2
limited when they are simply stirred under an O atmosphere,
and actual bubbling of oxygen through the solution is
required to achieve optimal rates.
This behavior contrasts with two other recent reports of
air oxidations of alcohols catalyzed by osmium. Most closely
related is a report by Osborn of aerobic oxidation of alcohols
(
10) Coleman, K. S.; Coppe, M.; Thomas, C.; Osborn, J. A. Tetrahedron
Lett. 1999, 40, 3723-3726.
(11) D o¨ bler, C.; Mehltretter, G. M.; Sundermeier, U.; Eckert, M.; Militzer,
H.-C.; Beller, M. Tetrahedron Lett. 2001, 42, 8447-8449.
(12) (a) D o¨ bler, C.; Mehltretter, G.; Beller, M. Angew. Chem., Int. Ed.
1999, 38, 3026-3028. (b) D o¨ bler, C.; Mehltretter, G. M.; Sundermeier,
U.; Beller, M. J. Am. Chem. Soc. 2000, 122, 10289-10297. (c) D o¨ bler, C.;
Mehltretter, G. M.; Sundermeier, U.; Beller, M. J. Organomet. Chem. 2001,
4
catalyzed by OsO in the presence of CuCl, pyridine, and
6
21, 70-76.
1
0
molecular sieves. Under these conditions, reaction tem-
(13) Typical experimental procedure: oxidation of 4-methoxybenzyl
alcohol. Into a 15 mL two-necked flask is added a solution of copper(II)
-ethylhexanoate (20 mg, 0.057 mmol, 1 mol %) and 4-methoxybenzyl
peratures of 100 °C were generally required to achieve high
2
alcohol (755 mg, 5.46 mmol) in 3 mL of CH3CN. Oxygen gas, which is
presaturated with CH3CN by passing it through a gas dispersion tube in a
100 mL two-neck flask filled with acetonitrile, is admitted to the reaction
vessel using a needle. Oxygen is bubbled through the reaction mixture at
a moderate rate (∼ 3 bubbles/s) and vented through a mineral oil bubbler.
In a separate vial, the osmium reagent is generated by adding allyl ethyl
ether (100 µL, 0.93 mmol, 18 mol %) to a suspension of (quinuclidine)-
OsO4 (40 mg, 0.109 mmol, 2 mol %) in 0.6 mL of CH3CN. After allowing
this osmium-containing solution to stand for 1 min after addition of the
alkene, it is added to the solution containing the substrate and copper. Upon
completion of the reaction, the reaction mixture is diluted with Et2O (10
mL) and H2O (10 mL) and the ether layer separated from the aqueous layer
and a black precipitate. The aqueous layer is washed with Et2O (2 × 10
mL), the organic layers are washed once with 7 mL of 7% aqueous Na4-
EDTA to remove copper and dried over MgSO4, and the ether is evaporated.
The product is filtered through a small plug of silica gel using Et2O/hexane
(3:1) to give pure 4-methoxybenzaldehyde (659 mg, 88%).
(
6) (a) Schr o¨ der, M. Chem. ReV. 1980, 80, 187-213. (b) Johnson, R.
A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000; Chapter 6.
(7) (a) VanNieuwenhze, M. S.; Sharpless, K. B. Tetrahedron Lett. 1994,
3
1
5, 843-846. (b) Xu, D.; Park, C. Y.; Sharpless, K. B. Tetrahedron Lett.
994, 35, 2495-2498. (c) Donohoe, T. J.; Garg, R.; Moore, P. R.
Tetrahedron Lett. 1996, 37, 3407-3410. (d) Donohoe, T. J.; Moore, P. R.;
Waring, M. J. Tetrahedron Lett. 1997, 38, 5027-5030. (e) Kallatsa, O. A.;
Koskinen, A. M. P. Tetrahedron Lett. 1997, 38, 8895-8898. (f) Donohoe,
T. J.; Waring, M. J.; Newcombe, N. J. Synlett 2000, 149-151.
(8) Cleare, M. J.; Hydes, P. C.; Griffith, W. P.; Wright, M. J. J. Chem.
Soc., Dalton Trans. 1977, 941-944.
(
9) (a) Tsuji, J. Synthesis 1984, 369-384. (b) Lorber, C. Y.; Smidt, S.
P.; Osborn, J. A. Eur. J. Inorg. Chem. 2000, 655-658. (c) Michaelson, R.
C.; Austin, R. G. U.S. Patent 4,390,739 (June 28, 1983). (d) Austin, R. G.;
Michaelson, R. C.; Myers, R. S. U.S. Patent 4,824,969 (April 25, 1989).
1044
Org. Lett., Vol. 4, No. 6, 2002

the oxidation. While many catalytic air oxidations proceed
more rapidly with allylic and benzylic substrates, the
essentially complete chemoselectivity observed here is very
unusual and is not shared even by other osmium-catalyzed
Table 1. Os/Cu-Cocatalyzed Oxidations of R,â-Unsaturated
Alcohols
1
0,11
processes.
In contrast to simple aliphatic alcohols,
alcohols flanked by electron-withdrawing groups such as
esters and ketones are oxidized catalytically by osmium/
copper. However, their rates of oxidation are much slower
than those of allylic and benzylic alcohols. Cyclopro-
panemethanol is also oxidized very slowly and cleanly forms
cyclopropanecarboxaldehyde without any sign of ring-opened
products, indicating that long-lived radicals are not involved
in the oxidation.
The presence of water has no effect on the reaction, with
equal rates observed in wet acetonitrile or in the presence
of molecular sieves. Oxidation is, however, completely
inhibited in the presence of 1,2- or 1,3-diols. This may
indicate that diol dissociates from the osmium(VI) glycolate
to form the catalytically active species or may simply be
due to conversion of the active monoglycolate complex to
1
4
an inactive bis(diolate) complex.
The standard reagent currently used for selective oxidation
of allylic and benzylic alcohols is manganese dioxide.15
While MnO shows excellent chemoselectivity, there are
2
sometimes problems associated with the generation and
storage of active material, and the universal need to employ
a large excess of the reagent results in the generation of
substantial quantities of inorganic waste. The aerobic protocol
2
described here is as chemoselective as MnO , and since it
uses commercially available reagents and operates at room
temperature and atmospheric pressure, it is as convenient to
employ. Despite the use of the relatively expensive osmium,
the low catalyst loadings mean that it is actually economically
competitive with the obligate use of superstoichiometric
2
MnO , while generating far less waste. For these reasons,
we envision this procedure supplanting the use of manganese
dioxide for this class of oxidations and substantially further-
ing the use of air as a stoichiometric oxidant in lab-scale
organic synthesis.
a
1
Yields determined by H NMR; values in parentheses indicate isolated
b
yields. Product contains 4% geranial.
a small amount (<5%) of double bond isomerization.
Overoxidation to the carboxylic acid is never observed.
Alkenes are not dihydroxylated under these conditions, and
even easily oxidized functional groups such as sulfides are
tolerated, as are acid-sensitive groups such as acetals. Most
remarkably, as long as the gas is bubbled through the reaction
solution rapidly enough to prevent mass transfer limitations,
the reaction can be performed as effectively using air as it
can with pure oxygen.
The oxidation is highly chemoselective, with only allylic
and benzylic alcohols reacting at appreciable rates. Simple
aliphatic primary and secondary alcohols are completely inert
to osmium(VI), and their presence does not interfere with
Acknowledgment. Support from a DuPont Young Pro-
fessor Award, from the Camille and Henry Dreyfus Founda-
tion (New Professor Award), and from the Dow Chemical
Company (Innovation Recognition Program) is gratefully
acknowledged.
OL025648Q
(
14) Collin, R.; Griffith, W. P.; Phillips, F. L.; Skapski, A. C. Biochim.
Biophys. Acta 1974, 354, 152-154.
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(
Organic Compounds; Academic Press: New York, 1981. (b) Hudlicky, M.
Oxidations in Organic Chemistry; American Chemical Society: Washington,
DC, 1990. (c) Procter, G. In ComprehensiVe Organic Synthesis; Ley, S.
V., Ed.; Pergamon: Oxford, 1991; Vol. 7, p 305.
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