Oxidation of alcohols by transfer hydrogenation: driving the equilibrium with an intramolecular trap

Article abstract of DOI:10.1016/j.tetlet.2007.03.135

Levulinic acid and its esters participate in transfer hydrogenation with a range of secondary alcohols. Reduction of the levulinate leads to cyclisation into a γ-lactone, thereby acting as an oxidant for alcohols without the need for a large excess of reagents.

Full text of DOI:10.1016/j.tetlet.2007.03.135

Tetrahedron Letters 48 (2007) 3639–3641
Oxidation of alcohols by transfer hydrogenation: driving
the equilibrium with an intramolecular trap
Nicola J. Wise and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 7 March 2007; accepted 22 March 2007
Available online 25 March 2007
Abstract—Levulinic acid and its esters participate in transfer hydrogenation with a range of secondary alcohols. Reduction of the
levulinate leads to cyclisation into a c-lactone, thereby acting as an oxidant for alcohols without the need for a large excess of
reagents.
Ó 2007 Elsevier Ltd. All rights reserved.
OH
O
Transfer hydrogenation reactions between alcohols and
ketones have been catalysed by a variety of metal
complexes.1 The equilibrium position of such reactions
depends on the relative stabilities of the ketones with
respect to their corresponding alcohols, and can be
calculated from the oxidation potentials of the ketones
involved.2,3 For example, the oxidation of cyclohexanol
1 with 1 equiv of acetone 2 is expected to give a 22%
conversion into cyclohexanone 3 and isopropanol 4 at
equilibrium at 25 °C (Scheme 1).4,5
1
3
6
+
+
O
O
OH
O
OR
+
OR
ROH
O
O
7
5
Scheme 2. Lactonisation as an intramolecular trap.
In order to achieve a greater conversion of cyclohexanol
into cyclohexanone, a large excess of acetone could be
employed. However, we wanted to achieve the oxidation
of alcohols without the need for a large excess of the
acceptor ketone,6 and considered the possibility of an
intramolecular trap in order to drive the equilibrium.
A ketone with a pendant leaving group, such as a levu-
linate ester 5, would be expected to participate in trans-
fer hydrogenation to give alcohol 6, which would then
cyclise to lactone 7, driving the equilibrium to the right
hand side (Scheme 2). Ideally, the alcohol ROH released
upon cyclisation should be completely inert to oxidation
(e.g., t-BuOH or PhOH). However, we chose to use
commercially available methyl levulinate as the hydro-
gen acceptor, reasoning that the liberated methanol
would be difficult to oxidise.3 We have recently been
using Ru(PPh3)3(CO)H2 and related complexes for
transfer hydrogenation reactions,7 and herein we report
the use of this catalyst to demonstrate the viability of
using levulinates as oxidants in transfer hydrogenation
reactions.
In a preliminary experiment, 1-phenylethanol 8 was
reacted with 1.2 equiv of methyl levulinate 10 using
Ru(PPh3)3(CO)H2/diphosphine as the catalyst. We were
pleased to find that all of the alcohol had been com-
pletely converted into acetophenone 9, as judged by
OH
O
O
OH
+
+
1
78
: 22
analysis of the crude H NMR spectrum and GC trace
1
2
3
4
(Scheme 3).
Scheme 1. Equilibration in transfer hydrogenation.
Either DPE-phos8 or Xantphos9 were effective ligands,
affording a slightly faster reaction (80% conversion
in 24 h in the absence of either ligand). After 3 h, the
*
Corresponding author. E-mail: j.m.j.williams@bath.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.135

3640
N. J. Wise, J. M. J. Williams / Tetrahedron Letters 48 (2007) 3639–3641
O
was not essential, although reactions proceeded slightly
more quickly in its presence.10
OMe
OH
Me
O
(1.2 equiv.)
10
O
Methyl levulinate was then used for the oxidation of
other alcohols, providing high conversions under these
reaction conditions (see Table 1). Separation of the
product ketones from lactone 7 was achieved by column
chromatography with reasonable isolated yields. In the
case of the oxidation of the primary alcohol (entry 8),
the main product was the ester, with minor impurities
visible in the crude NMR spectrum. Even cyclohexanol
could be oxidised with almost complete conversion,
despite the relatively high reduction potential of this
ketone (entry 9). The use of ethyl levulinate as the
oxidant was less satisfactory, affording 88% conversion
for the oxidation of alcohol 8 into ketone 9. This may
be due to the easier oxidation of ethanol in comparison
with methanol.3
Ph
Ph
Me
2.5 mol% Ru(PPh ) (CO)H
3 3
2
8
9
2.5 mol% diphosphine
5 mol% KOtBu, toluene, reflux, 24 h
>99.5% conversion
or
O
O
PPh
PPh
2
2
PPh
PPh
2
2
DPE-phos
Xantphos
Scheme 3. Complete oxidation of 1-phenylethanol.
reaction with DPE-phos had reached 98% conversion,
whereas the reaction with Xantphos had only reached
64% conversion.
Levulinic acid itself could also be used as the oxidant,
and was applied to the oxidation of the secondary alco-
hols identified in Table 2.
Since the ruthenium complex was already in the acti-
vated dihydride form, the addition of base (KOt-Bu)
Table 1. Oxidation of other alcohols
O
OMe
O
OH
(1.2 equiv.)
O
R
R'
R
R'
2.5 mol% Ru(PPh3)3(CO)H2
2.5 mol% diphosphine
5 mol% KOtBu, toluene, reflux, 24 h
Entry
Ligand
R
R0
Conv. (%)a
1
2
3
4
5
6
7
8
9
DPE-phos
Xantphos
DPE-phos
DPE-phos
DPE-phos
DPE-phos
Xantphos
DPE-phos
DPE-phos
Ph
Ph
Ph
Me
Me
Et
Me
Me
Me
Me
H
100 (81)
100
100 (88)
99.5 (68)
99.4
100 (83)
95.6b
(60)c
Ph(CH2)2
3-(F3C)Ph
2-Furyl
PhOCH2
Ph(CH2)3
Cyclohexanol
98.6
a Isolated yields in parentheses.
b 48 h.
c The isolated product was the ester Ph(CH2)3O2C(CH2)2Ph.
Table 2. Oxidation of alcohols with levulinic acid
O
OH
O
OH
(1.2 equiv.)
O
R
R'
R
R'
2.5 mol% Ru(PPh ) (CO)H
3 3
2
2.5 mol% diphosphine
toluene, reflux, 24 h
Entry
Ligand
R
R0
Conv. (%)
1
2
3
4
Xantphosa
DPE-phos
Xantphosa
DPE-phos
Ph
Ph
3-(F3C)Ph
Ph(CH2)2
Me
Et
Me
Me
100
98
100
100
a Reaction performed with 1.25 mol % catalyst.

N. J. Wise, J. M. J. Williams / Tetrahedron Letters 48 (2007) 3639–3641
3641
of the oxidation potentials of over 90 carbonyl
compounds.
In summary, levulinic acid and its methyl ester can be
used as oxidants in a transfer hydrogenation reaction.
An excess of this reagent is not required due to the sub-
sequent cyclisation, which drives the equilibrium.
4. The equilibrium constant K for two carbonyl compounds
A and B can be calculated from E0(A) ꢀ E0(B) = (RT/
NF)lnK. The ratio of ketones at equilibrium is given by
p
K:1. The ketone with the lower oxidation potential will
be the major component.
Acknowledgement
5. The equilibrium position at 110 °C is predicted to be 27%
cyclohexanone.
We wish to thank the Engineering and Physical Sciences
Research Council for funding a studentship (to N.J.W.).
6. Adair, G. R. A.; Williams, J. M. J. Chem. Commun. 2005,
5578.
7. (a) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.;
Shermer, D. J.; Whittlesey, M. K.; Williams, J. M. J.;
Edney, D. D. Chem. Commun. 2004, 90; (b) Slatford, P.
A.; Whittlesey, M. K.; Williams, J. M. J. Tetrahedron Lett.
2006, 47, 6787.
8. Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J.
Organometallics 1995, 14, 3081.
References and notes
1. Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226.
2. Adkins, H.; Elofson, R. M.; Rossow, A. G.; Robinson, C.
C. J. Am. Chem. Soc. 1949, 71, 3622.
3. Representative oxidation potentials, E0, include: aceto-
phenone (118 mV); 2-acetylfuran (122 mV); acetone
9. Freixa, Z.; van Leeuwen, P. W. N. M. Dalton Trans. 2003,
1890.
(129 mV);
cyclohexanone
(162 mV);
acetaldehyde
10. Ba¨ckvall, J.-E. J. Organomet. Chem. 2002, 652, 105.
(226 mV); formaldehyde (270 mV). Ref. 2 provides a list