Oppenauer oxidation of secondary alcohols with 1,1,1-trifluoroacetone as hydride acceptor

Article abstract of DOI:10.1021/jo7016422

(Chemical Equation Presented) 1,1,1-Trifluoroacetone (2a) reacts as a hydride-acceptor in the Oppenauer oxidation of secondary alcohols (1) in the presence of diethylethoxyaluminum. The oxidant allows for selective oxidation of secondary alcohols in the presence of primary alcohols.

Full text of DOI:10.1021/jo7016422

SCHEME 1. Oppenauer Oxidation Reaction Mechanism
Oppenauer Oxidation of Secondary Alcohols with
1,1,1-Trifluoroacetone as Hydride Acceptor
Rossella Mello, Jaime Mart´ınez-Ferrer,
Gregorio Asensio,* and Mar´ıa Elena Gonza´lez-Nu´n˜ez
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
AVda. V. Andre´s Estelle´s s/n, 46100-Burjassot (Valencia), Spain
gregorio.asensio@uV.es
ReceiVed July 26, 2007
potentials are suitable oxidants in Oppenauer oxidations and
most of the recently described procedures use aromatic and
aliphatic aldehydes as hydride acceptors (Scheme 1, R3 ) H,
R4 ) alkyl, aryl).
On the other hand, it is known that introduction of fluorine
substituents in ketones (2) enhances the electrophilic reactivity
of the carbonyl group, reduces their Lewis basicity, and increases
the stability of their addition products.3 Thus, the chemical
reactivity of perfluorinated ketones significantly differs from
that of their hydrogenated counterparts. For instance, it has been
described3 that hexafluoroacetone reacts with tertiary amines
via hydride abstraction from the carbon atom at the R-position
to result in the corresponding iminium salt and 1,1,1,2,2,2-
hexafluoro-2-propanol. However, this enhanced hydride-acceptor
ability of fluorinated ketones has not yet been tested in the
Oppenauer reaction.
1,1,1-Trifluoroacetone (2a) reacts as a hydride-acceptor in
the Oppenauer oxidation of secondary alcohols (1) in the
presence of diethylethoxyaluminum. The oxidant allows for
selective oxidation of secondary alcohols in the presence of
primary alcohols.
The Oppenauer oxidation of alcohols (1) is a highly selective
reaction that can be performed with simple organic molecules
as oxidants and easily accessible and inexpensive metal alkox-
ides as catalysts under mild conditions.1 This reaction is
performed with Lewis acids derived from aluminum, magne-
sium, or boron, either in solution or on solid support, and
employs aldehydes as suitable oxidants. The research for more
efficient catalysts and reaction conditions allowed the synthetic
applications of this oxidation method, which can presently be
efficiently applied at preparative scale, to be extended.2
We report herein that 1,1,1-trifluoroacetone (2a) is a suitable
reagent to perform the oxidation of secondary alcohols (1) to
ketones (2) in the presence of diethylethoxyaluminium under
mild conditions (eq 1). Moreover, the oxidation is selective and
It is generally accepted1 that Oppenauer oxidation proceeds
via a complex in which both the hydride-acceptor carbonyl
group and the alcohol (1) are bound to the metal ion (Scheme
1). The carbonyl group, which is activated upon coordination
with the metal ion, initiates the hydride abstraction process from
the alkoxide ligand via a concerted six-membered transition
state. The reaction is reversible and the equilibrium position is
determined by the reduction potentials of the carbonyl com-
pounds involved.1 Carbonyl compounds with low reduction
primary alcohols remain unchanged under the reaction condi-
tions. 1,1,1-Trifluoroacetone (2a) and 1,1,1-trifluoro-2-propanol
(1a) are volatile compounds removed from the reaction mixture
by evaporation thus simplifying the workup and isolation of
the products.
Reactions were carried out by adding 1,1,1-trifluoroacetone
(2a) to a mixture of the starting alcohol (1) and diethylethoxy-
aluminum in dichloromethane (molar ratio 1:2a:(CH3CH2)2-
AlOEt 1:2:0.3) (eq 1). The mixture was allowed to react at room
temperature in a tightly closed flask. The aluminum alkoxides
were hydrolyzed by treatment with the stoichiometric amount
of water, the mixture was dried with anhydrous sodium sulfate,
and the resulting ketones were isolated by vacuum evaporation
of solvent. The results are shown in Table 1.
(1) (a) Graves, C. R.; Campbell, E. J.; Nguyen, S. T. Tetrahedron:
Asymmetry 2005, 16, 3460. (b) deGraauw, C. F.; Peters, J. A.; vanBekkum,
H.; Huskens, J. Synthesis 1994, 1007.
(2) (a) Kloetzing, R. J.; Krasovskiy, A.; Knochel, P. Chem. Eur. J. 2007,
13, 215. (b) Graves, C. R.; Zeng, B.-S.; Nguyen, A. T. J. Am. Chem. Soc.
2006, 128, 12596. (c) Hanasaka, F.; Fujita, K.; Yamaguchi, R. Organo-
metallics 2006, 25, 4643. (d) Zhu, Y.; Chuah, G.; Jaenicke, S. J. Catal.
2004, 227, 1. (e) Gauthier, S.; Scopelliti, R.; Severin, K. Organometallics
2004, 23, 3769. (f) Meijer, R. H.; Ligthart, G. B. W. L.; Meuldijk, J.;
Vekemans, J. A. J. M.; Hulshof, L. A.; Mills, A. M.; Kooijman, H.; Spek,
A. L. Tetrahedron 2004, 60, 1065. (g) Hon, Y.-S.; Chang, C.-P.; Wong,
Y.-C. Tetrahedron Lett. 2004, 45, 3313. (h) Suzuki, T.; Morita, K.; Tsuchida,
M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601. (i) Ooi, T.; Otsuka, H.; Miura,
T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669. (j) Ishihara, K.;
Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 5664. (k) Akamanchi,
K. G.; Chaudri, B. A. Tetrahedron Lett. 1997, 38, 6925. (l) Byrne, B.;
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Collin, J.; Kagan, H. B. J. Org. Chem. 1984, 49, 2045.
Oxidations take place efficiently for secondary alcohols 1 in
the presence of CdC double bonds (entries 1-7, Table 1).
Primary allylic alcohols (entry 9, Table 1) and primary aliphatic
alcohols do not react efficiently under these reaction conditions.
Reactions performed at 40 °C in a sealed vial led to slower
(3) Gambaryan, N. P.; Rokhlin, E. M.; Zeifman, Y. V.; Ching-Yun, C.;
Knunyants, I. L. Angew. Chem., Int. Ed. Engl. 1966, 5, 947 and references
cited therein.
10.1021/jo7016422 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/02/2007
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J. Org. Chem. 2007, 72, 9376-9378

TABLE 1. Oppenauer Oxidation of Alcohols 1 with
1,1,1-Trifluoroacetone 2aa
FIGURE 1. Transition states for the oxidation of exo and endo-
norbornanol (1e) and axial and equatorial trans-1-decalol (1i).
The reactions are more efficient for cyclic, polycyclic, and
rigid substrates than for their alycyclic counterparts (entries 1
and 7, Table 1). This result indicates that for linear substrates
it is difficult to achieve the highly ordered structure required
for the hydride transfer process to take place.
When 1,1,1-trifluoroacetone (2a) is the hydride acceptor either
a methyl or trifluoromethyl substituent is placed in the pseudo-
axial position in the transition state structure, with a significant
steric interaction with one of the substituents of the secondary
alcohol (Scheme 1). A comparison between the reactivity of
1-decalol (1i) and the structurally related alcohols cyclohexanol
(1b), 2-adamantanol (1f), or norbornanol (1e) shows the effect
of the steric hindrance on the oxidation rate.
The relative reaction rates found for the oxidation of endo-
and exo-norbornanol (1e) (kendo/kexo ) 16.6) and 1-decalol (1i)
(kax/keq ) 2.4) can be attributed to the differences in steric
crowding at the corresponding diastereomeric transition states
(Figure 1) and also to the release of torsional strain in the alcohol
cyclic systems on going from an sp3 to an sp2 carbon atom in
the ketone.
a Reactions performed in dichloromethane/toluene at rt with initial molar
ratio 1:2a:Et2AlOEt 1:2:0.3. b Substrate conversion was complete for all
cases except where noted. c Isolated product yield was >99% in all cases
except where noted. d Initial molar ratio 1:2a:Et2AlOEt 1:2:0.1. e Substrate
conversion was 26%. f Initial molar ratio 1j:2a:Et2AlOEt 1:2:0.5, substrate
conversion 46%. g Initial molar ratio 1k:2a:Et2AlOEt 1:5:0.3, substrate
conversion >99%.
Primary alcohols were unreactive under our standard reaction
conditions indicating that in these conditions the reduction
potential of 1,1,1-trifluoroacetone (2a) (Eo ) -1.3 V)4 lies
red
between those of simple dialkyl ketones and aliphatic aldehydes.
This characteristic of 1,1,1-trifluoroacetone prompted us to
attempt the selective oxidation of secondary alcohols in the
presence of a primary alcohol. Effectively, the reaction of an
equimolar mixture of cyclohexanol (1b) and n-heptanol (1l) with
2 equiv of 1,1,1-trifluoroacetone (2a) and 30% diethylethoxy-
aluminum in dichloromethane/toluene at room temperature
allowed for the complete conversion of 1b, while the primary
alcohol remained unchanged. The competition reaction per-
formed between cyclohexanol (1b) and trans-2-hexenol (1j) led
to 73% conversion of 1b and 27% conversion of 1j. This
indicates that the unsaturated aldehyde 2j has a reduction
potential more negative than the aliphatic aldehyde 2l. This
enables the allylic alcohol 1j to compete more efficiently with
cyclohexanol (1b) in the hydride transfer process to 1,1,1-
trifluoroacetone. On the other hand, the oxidation of endo-2-
norbornanol (1e), which is more reactive than cyclohexanol (1b)
(entries 1 and 4, Table 1), can be performed selectively in the
presence of an equimolar amount of benzyl alcohol under the
same reaction conditions (eq 2). Therefore, for the oxidation of
reactions and lower conversion values. This observation was
attributed to the high vapor pressure of 1,1,1-trifluoroacetone
(2a) (13.2 psi at 20 °C), which favors the oxidant to escape to
the vapor phase and results in a lower availability in solution.
The data show that, despite the electron-withdrawing effect of
the trifluoromethyl group, 1,1,1-trifluoroacetone is basic enough
to coordinate with the aluminum Lewis acid (Scheme 1). On
the other hand, the oxidation of 2-adamantanol (1f) and benzyl
alcohol with acetone under our reaction conditions led to only
4% conversion of the substrates after 15 h, indicating that the
fluorine substituents significantly enhance the hydride abstrac-
tion ability of the carbonyl group.
The corresponding magnesium alkoxides led to lower sub-
strate conversions. For instance, the reaction of cyclohexanol
(1b) with 1.1 equiv of methylmagnesium bromide in toluene/
THF followed by treatment with 1.5 equiv of 1,1,1-trifluoro-
acetone at room temperature for 5 h allowed a 63% yield of
the corresponding ketone (2b) to be obtained. The reaction with
magnesium alkoxides derived from other alcohols led to
complex mixtures of undefined materials with partial recovery
of the reactants.
(4) Adam, W.; Asensio, G.; Curci, R.; Gonza´lez-Nu´n˜ez, M. E.; Mello,
R. J. Am. Chem. Soc. 1992, 114, 8345-8349.
J. Org. Chem, Vol. 72, No. 24, 2007 9377

SCHEME 2. Oxidation of 1,5-Hexanediol with
1,1,1-Trifluoroacetone and (CH3CH2)2AlOEt
a secondary alcohol with 1,1,1-trifluoroacetone (2a) to be
selective in the presence of a primary alcohol, it is necessary
that the reduction potentials of the corresponding carbonyl
compounds are different enough to allow for a favorable
equilibrium under our reaction conditions.
Experimental Section
However, the presence of both primary and secondary
hydroxy functionalities in the same molecule can lead to
alternative oxidation pathways. Thus, the selective oxidation
of the secondary alcohol moiety in 1,4-hexanediol with 1,1,1-
trifluoroacetone (2a) and diethylethoxyaluminum failed. The
reaction was extremely slow and led to a mixture of 5-methyl-
2-oxotetrahydropirane and 2-ethoxy-5-methyltetrahydropirane
as the main products (Scheme 2) by oxidation of the primary
alcohol of the substrate. Perhaps, as the hydride transfer process
in the Oppenauer oxidation is reversible, the reaction is
channeled toward the corresponding lactone through the forma-
tion of an intermediate aldehyde followed by the highly favored
oxidation of the cyclic hemiacetal (Scheme 2). On the other
hand, complexation of 1,4-hexanediol with aluminum and/or
formation of a cyclic acetal with 1,1,1-trifluoroacetone (2a)
might hinder the hydride-transfer process from the secondary
alcohol.
Then it seems that the selective oxidation of the secondary
alcohol moiety in diols is not possible if both alcohols can
simultaneously coordinate the metal ion. Effectively, the oxida-
tion of 2-[4-(1-hydroxyethyl)phenoxy]ethanol (1k) with 1,1,1-
trifluoroacetone (2a) in the presence of diethylethoxyaluminium
(initial molar ratio 1:5:0.3) for 10 h led exclusively to the
oxidation of the secondary benzylic hydroxy group (entry 10,
Table 1).
Oxidation of 2-Adamantanol (1f). General Procedure. A
stirred solution of 0.24 g of 2-adamantanol (1f) (1.6 mmol) in 10
mL of dichloromethane was treated with 0.1 mL of a 1.6 M solution
of diethylethoxyaluminum in toluene (0.1 equiv) at room temper-
ature. After 5 min, 0.3 mL of 1,1,1-trifluoroacetone (3.2 mmol)
was added at once. Commercial 1,1,1-trifluoroacetone was used
without further purification. The flask was tightly closed and
allowed to stand at room temperature for 1 h. The reaction mixture
was treated for 15 min with 0.25 mL of water and then with MgSO4.
The solution was filtered and the solvent was removed under
vacuum to yield 0.24 g of 2-adamantanone (2f) as a white solid.
Competition Experiments. A stirred solution of 50 mg of
cyclohexanol (1b) (0.5 mmol) and 58 mg of n-heptanol (1l) (0.5
mmol) in 3 mL of dichloromethane was treated with 0.188 mL of
a 1.6 M solution of diethylethoxyaluminum in toluene (0.3 mmol)
at room temperature. After 2 min, 0.18 mL of commercial 1,1,1-
trifluoroacetone (2 mmol) was added at once. The flask was tightly
closed and allowed to stand at room temperature. The reaction
advance was monitored by treating 0.1 mL samples diluted with
0.5 mL of dichloromethane for 5 min with 3 µL of water and then
dried with MgSO4.
Acknowledgment. Financial support by the Spanish Direc-
cio´n General de Investigacio´n, CTQ2006-28333-E and Con-
solider Ingenio 2010 (CSD2007-00006), and the Generalitat
Valenciana GV06217 is gratefully acknowledged. J.M.-F. thanks
the Spanish Ministerio de Educacio´n y Ciencia for a fellowship.
We acknowledge SCSIE (Universidad de Valencia) for access
to the instrumental facilities.
To summarize, we have described the Oppenauer oxidation
of secondary alcohols (1) promoted by 1,1,1-trifluoroacetone
(2a) in the presence of diethylethoxyaluminum. This protocol
enables the selective oxidation of secondary alcohols in the
presence of primary alcohols and, with some restrictions, the
selective oxidation of the secondary alcohol moiety in mixed
primary/secondary diols.
Supporting Information Available: GC-MS spectra of the
crude reaction mixtures. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO7016422
9378 J. Org. Chem., Vol. 72, No. 24, 2007