Sustainable flow oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst

Article abstract of DOI:10.1021/ol4027107

A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 C.

Full text of DOI:10.1021/ol4027107

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5698–5701
Sustainable Flow Oppenauer Oxidation
of Secondary Benzylic Alcohols with
a Heterogeneous Zirconia Catalyst
Rajeev Chorghade,† Claudio Battilocchio,† Joel M. Hawkins,‡ and Steven V. Ley*,†
Innovative Technology Centre, Department of Chemistry, University of Cambridge,
Lensfield Road, CB2 1EW, Cambridge, U.K., and Pfizer Worldwide Research and
Development, Eastern Point Road, Groton, Connecticut 06340, United States
svl1000@cam.ac.uk
Received September 19, 2013
ABSTRACT
A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple
carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied
to a wide range of functionalized alcoholsubstrates, allowing clean andfast deliveryof ketone products within a few minutes between 40 and 100°C.
The oxidative processing of alcohols plays a fundamen-
tal role in organic synthesis leading ultimately to many of
society’s functional materials.1 Selectivity during certain
oxidative reactions can be challenging to achieve, often
requiring expensive metal catalysis and inevitably leading
to further downstream processing problems. Although
major advances have been made, there is still room for
improvement. A case in point concerns the Oppenauer
† University of Cambridge.
‡ Pfizer Worldwide Research and Development.
(1) (a) Hudlicky, M. Oxidations in Organic Chemistry; American
Chemical Society: Washington, DC, 1990. (b) Sheldon, R. A.; Kochi, J. K.
Metal-Catalyzed Oxidations of Organic Compounds; Academic Press:
New York, 1981. (c) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; Wiley-
Interscience: New York: 2001; pp 1514ꢀ1517. (d) Ley, S. V.; Norman,
J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666. (e) Marko,
I. E.; Giles, P. R.; Tsukazaki, M.; Brown, S. M.; Urch, C. J. Science 1996,
274, 2044–2046. (f) Marko, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle-
Regnaut, I.; Gautier, A.; Brown, S. M.; Urch, C. J. J. Org. Chem. 1999,
64, 2433–2439. (g) Peterson, K. P.; Larock, R. C. J. Org. Chem. 1998, 63,
3185–3189. (h) Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Science
2000, 287, 1636–1639. (i) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.;
Kozee, M. A. J. Am. Chem. Soc. 2001, 123, 7188–7189. (j) ten Brink,
G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Adv. Synth. Catal. 2002, 344,
355–369. (k) Guram, A. S.; Bei, X.; Turner, H. W. Org. Lett. 2003, 5,
2485–2487. (l) Minisci, F.; Recupero, F.; Pedulli, G. F.; Lucarini, M. J.
Mol. Catal. A: Chem. 2003, 63, 204–205. (m) Meyer, S. D.; Schreiber,
S. L. J. Org. Chem. 1994, 59, 7549–7552. (n) Ohsugia, S.-I.; Nishidea, K.;
Oonob, K.; Okuyamab, K.; Fudesakaa, M.; Kodamaa, S.; Node, M.
Tetrahedron 2003, 59, 8393–8398. (o) Zhao, M.; Li, J.; Song, Z.;
Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
Tetrahedron Lett. 1998, 39, 5323–5326.
(2) For examples of Oppenauer oxidations, see: (a) Kloetzing, R. J.;
Krasovskiy, A.; Knochel, P. Chem.;Eur. J. 2007, 13, 215–227. (b)
ꢀ
ꢀ~
´
Mello, R.; Martınze-Ferrer, J.; Asensio, G.; Gonzalez-Nunez, M. E.
J. Org. Chem. 2007, 72, 9376–9378. (c) Graves,C. R.;Zeng, B.-S.;Nguyen,
S. T. J. Am. Chem. Soc. 2006, 128, 12596–12597. (d) Ooi, T.; Otshuka, H.;
Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669–2672.
ꢁ
ꢀ
€
(e) Almeida, M. L. S.; Kocovsky, P.; Backvall, J.-E. J. Org. Chem. 1996, 61
(19), 6587–6590. (f) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org.
Chem. 2003, 68, 1601–1602. (g) Graves, C. R.; Campbell, E. J.; Nguyen, S. T.
Tetrahedron: Asymmetry 2005, 16, 3460–3468. (h) deeGraauw, C. F.; Peters,
J. A.; vanBekkum, H.; Huskens, J. Synthesis 1994, 1007–1017. (i) Wang, P.;
Shi, X.; Kataoka, K.; Maed, Y.; Kobiro, K. J. Supercrit. Fluids 2010, 52,
222–227. (j) Kamitanaka, T.; Ono, Y.; Morishima, H.; Hikida, T.; Matsuda,
T.; Harada, T. J. Supercrit. Fluids 2009, 49, 221–226. (k) Coleman, M. G.;
Brown, A. N.; Bolton, B. A.; Guan, H. Adv. Synth. Catal. 2010, 352, 967–
970. (l) Borzatta, V.; Capparella, E.; Chiappino, R.; Impala, D.; Poluzzi, E.;
Vaccari, A. Catal. Today 2009, 140, 112–116. (m) Du, W.; Wang, L.; Wu, P.;
Yu, Z. Chem.;Eur. J. 2012, 18, 11550–11554. (n) Csuk, R.; Vasileva, G.;
Barthel, A. Synthesis 2012, 44, 2840–2842. (o) Manzini, S.; Urbina-Blanco,
C. A.; Nolan, S. P. Organometallics 2013, 32, 660–664. (p) Liu, S. H.;
Chuah, G. K.; Jaenicke, S. J. Mol. Catal. A: Chem. 2004, 220,
267–274.
r
10.1021/ol4027107
Published on Web 10/25/2013
2013 American Chemical Society

oxidation of alcohols to carbonyl compounds by transfer
dehydrogenation. Numerous reaction modifications have
contributed to its re-emergence as an attractive process
for oxidation;2 however, further criteria need to be met to
improve the speed and safety of the reaction to provide a
more sustainable procedure.
Scheme 1. General Flow Protocol for the Oppenauer Oxidation
of Alcohols
Given that we have recently reported a flow chemistry
method for the complementary MeerweinꢀPonndorfꢀ
Verley (MPV) reduction of carbonyl compounds using
isopropanol and hydrous zirconia3 where we demon-
strated distinct advantages over the batch reaction, it was
prudent to study a similar tactic for the oxidation process.4
The choice of hydrous zirconia makes sense in that it is
heterogeneous, cheap, recyclable, and readily packed into
flow tubes. These function especially well under the back
pressure regulated (BPR) control common to many flow
chemistry protocols and also facilitate minimal reaction
workup through simple solvent removal from the product
effluent stream.
the formation of IPA as a volatile byproduct, making the
downstream workup processing trivial. Nevertheless, the
oxidation properties of acetone are quite mild, so one can
envisage that its usefulness is limited to the oxidation of
compounds whose redox potential is lower than 90ꢀ95 mV.
In the case of substrates with higher redox potentials, a
large excess of acetone is needed to drive the reaction to
completion. This leads to further complications owing to the
formation of aldol products from the self-condensation of
acetone, which results in the difficult removal of impurities
without recourse to chromatography (a common problem
in other Oppenauer procedures).
For our initialstudy we chose R-tetralol (E0 = 80mV) as
a model substrate for the development of a sustainable
flow process. Under optimized conditions, a 0.25 M solu-
tion of the alcohol and acetone (2.5 equiv) in toluene was
reacted by passage through an Omnifit column containing
a hydrous zirconia catalyst6 (2.0 g, void volume 2.0 mL,
0.1 mL minꢀ1 flow rate)7 (Scheme 1). This reactor setup
required only short residence times of around 20 min and a
simple workup involving evaporation of the toluene sol-
vent, mild excess of acetone, and IPA byproducts to afford
nearly quantitative yields of the product.
Figure 1. Oxidation potentials (E0) of different oxidants
screened in this work.4
The selection of the necessary hydride acceptor for this
reaction was based upon the known oxidation potentials
of various ketones and aldehydes (Figure 1).5 Being a
redox process, the Oppenauer oxidation (as well as the
MPV reduction) is governed by the redox potentials of the
reacting species implying that the equilibrium of the reac-
tion might be anticipated by application of the Nernst
equation:
R-Tetralols bearing electron-donating groups underwent
oxidation even more rapidly (Table 1), with no evidence of
any byproducts being formed. Similarly a number of other
benzylic secondary alcohol substrates could be readily
oxidized under these reaction conditions (Table 1). We
were also pleased to find that the conditions were scalable
and we were able to continuously flow process compounds
on at least 15 mmol scale of product (Table 1, entry 1).
As expected, however, with certain substrates such as
1-phenylethanol, using acetone as a hydride acceptor only
35% oxidation could be realized. Neither increasing the
amount of acetone nor increasing the reaction temperature
improved the isolated yield.
log K ¼ (2=0:0592)(Eoxꢀ Ered
)
where Eox and Ered correspond to the redox potentials of
the oxidant and the reductant, respectively.
We found that the use of acetone and later cyclohex-
anone or neopentanal as hydride acceptors were particu-
larly useful. Indeed, the use of acetone is accompanied by
On the other hand, if cyclohexanone, which has a
significantly higher oxidation potential (163 mV),5 was
used as the oxidant in the flow process, we observed very
good conversions even with these difficult substrates
(Table 2).
(3) Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org. Lett. 2013, 15,
2278–2281.
(4) (a) Kuno, H.; Takahashi, K.; Shibagaki, M.; Shimazaki, K.;
Matsushita, H. Bull. Chem. Soc. Jpn. 1990, 63, 1943–1946. (b) Kuno,
H.; Shibagaki, M.; Takahashi, K.; Matsushita, H. Bull. Chem. Soc. Jpn.
1991, 64, 312–314. In our hands these procedures were not satisfactory
and led to considerable amounts of acetone aldol by products also being
formed in the process.
(5) (a) Adkins, H.; Elofson, R. M.; Rossow, A. G.; Robinson, C. C.
J. Am. Chem. Soc. 1949, 71, 3622–3629. (b) Baker, R. H.; Robinson,
C. C. J. Am. Chem. Soc. 1940, 62, 3305–3314.
(6) Hydrous zirconia was prepared starting from commercially avail-
able zirconium hydroxide (Sigma-Aldrich); calcination of zirconium
hydroxide was carried out in a Buchi TO-51 (http://www.nist.gov/ncnr/
drying-tube-buchi-to-51.cfm) at 270 °C for 24 h; we observed different
catalytic properties depending upon the level of hydration of the
catalyst.
(7) Website: http://www.omnifit.com/.
Org. Lett., Vol. 15, No. 22, 2013
5699

Table 1. Oxidation of Secondary Benzylic Alcohols Using
Acetone As the Oxidant
Table 2. Oxidation of Secondary Benzylic Alcohols Using
Cyclohexanone As the Oxidant
a Optimized residence time. b 1 mmol scale reaction.
Scheme 2. General Flow Protocol for the Oppenauer Oxidation
of Secondary Aromatic Alcohols Using Cyclohexanone As
Oxidant
a Optimized residence time. b 1 mmol scale reaction. c 15 mmol scale.
d The reactionwas scaled upto 15 mmol using6 equiv of acetone. e 6 equiv
of acetone were used. f Comparative microwave reaction at 100 °C
showed 86% conversion after 1 h and 99% conversion after 1.5 h.
The only drawback of using cyclohexanone as the
oxidant is that the product stream contains cyclohexanol
which is harder to remove than the isopropanol gener-
ated when using acetone as the oxidant. Nevertheless,
the cyclohexanol can be removed by using appropriate
polymer supported scavengers (e.g., PS-isocyanates) or by
azeotropic removal of cyclohexanol and residual cyclo-
hexanone (Scheme 2).
In view of this workup problem, we switched to neo-
pentanal as the oxidant since it has an even higher redox
potential (E0 = 211 mV), it lacks R-hydrogens, and the
corresponding alcohol is water-soluble, making this mole-
cule an attractive alternative to acetone or cyclohexanone.
Using this new protocol we were able to oxidize a wide
range of other functionalized precursors employing neo-
pentanal as the oxidant (Table 3). The high redox potential
of neopentanal as the oxidant meant that reactions could
be run at remarkably low temperature without the need to
extend the residence times. Significantly, no condensation
products were observed between the neopentanal and
the ketone products. Under the standardized conditions,
a 0.25 M solution of the alcohol and neopentanal (2.0ꢀ4.0
equiv) in toluene was passed through an Omnifit glass
5700
Org. Lett., Vol. 15, No. 22, 2013

Table 3. Oxidation of Secondary Benzylic Alcohols Using
Neopentanal As the Oxidant
Scheme 3. General Flow Protocol for the Oppenauer Oxidation
of Alcohols
In conclusion, we have developed an effective flow chem-
istry procedure for the oxidation of secondary benzylic
alcohols by passage through hydrous zirconia using various
stoichiometric carbonyl compounds as the oxidants.
The procedures are mild, proceeding at as low as 40 °C,
and accommodate easy reaction workup. Electron-rich
and electron-deficient substrates are well tolerated. Improve-
ment over the batch reactions are significant (typically these
require extended reaction times of >1ꢀ1.5 h and high tem-
peratures of g100 °C) owing to the use of elevated pressure
through a back pressure control device. The catalyst could
be reused several times without apparent reduction of
the catalytic efficiency.9 Work is ongoing to improve the
scalability still further.
Acknowledgment. We gratefully acknowledge funding
from Pfizer Worldwide Research and Development (C.B.
and J.M.H.) and the BP 1702 endowment (S.V.L.). We are
also thankful to Carnegie Mellon University for study
leave (R.C.).
a Optimized residence time . b 1 mmol scale reaction.
Supporting Information Available. Characterization
data of compounds are available within the Supporting
Information.This material is available free of charge via
the Internet at http://pubs.acs.org.
column packed with hydrous zirconia operating at only
40 °C. The output stream was combined with a stream
of water and then delivered to a universal membrane
separator8 to obtain the pure product on concentration
in vacuo of the organic fraction (Scheme 3).
(9) The catalyst column was reused at least 10 times; the column was
washed with a mixture 3:1 oxidant/IPA (1 mL) in toluene (4 mL) before
and after every use.
(8) (a) http://www.biotage.com/DynPage.aspx?id=120778. (b)
Battilocchio, C.; Deadman, B. J.; Nikbin, N.; Kitching, M. O.; Baxendale,
I. R.; Ley, S. V. Chem.;Eur. J. 2013, 19, 7917–7930.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
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