Oxidant-free oxidation: Ruthenium catalysed dehydrogenation of alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.09.083

The oxidation of alcohols has been achieved using Grubbs' catalyst or a ruthenium p-cymene complex without the presence of an added oxidant.

Full text of DOI:10.1016/j.tetlet.2005.09.083

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8233–8235
Oxidant-free oxidation: ruthenium catalysed dehydrogenation
of alcohols
Gareth R. A. Adair and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 5 August 2005; revised 7 September 2005; accepted 14 September 2005
Available online 6 October 2005
Abstract—The oxidation of alcohols has been achieved using Grubbsꢀ catalyst or a ruthenium p-cymene complex without the pres-
ence of an added oxidant.
Ó 2005 Elsevier Ltd. All rights reserved.
Table 1. Study of ruthenium catalysts for oxidation of alcohol 1
We have recently demonstrated that alcohols can be
Ruthenium complexa
Conversion (%)c
used as substrates for C–C and C–N bond formation,
using both ruthenium and iridium catalysts.1,2 In these
reactions, the alcohol undergoes dehydrogenation to
give a carbonyl compound, which undergoes in situ con-
version into the corresponding alkene or imine, followed
by return of the ꢁborrowed hydrogenꢀ to provide the
product alkane or amine. In some cases, we have
observed a net oxidation, with product remaining at
the alkene/imine oxidation level, suggesting a competing
hydrogen loss process.
CpRuCl(PPh3)2
(Indenyl)RuCl(PPh3)2
[(Benzene)RuCl2]2
[(p-Cymene)RuCl2]2
PhCH = Ru(PCy3)2Cl2
Ru(IMes)(PPh3)2CO(H)2
16
22
24
58
71
17
b
a 5 mol % Ru, 5 mol % KOH, PhMe, 110 °C, 24 h, flow of Ar.
b No base added for this catalyst.
c Conversion was determined from analysis of the 1H NMR spectra.
Herein, we report the development of conditions, which
exploit this oxidation process, involving the catalysed
dehydrogenation of an alcohol into a ketone with the
concomitant loss of hydrogen gas. There is some litera-
ture precedent for ruthenium catalysed dehydrogena-
tion, with a very recent example being reported by
Junge and Beller.3 Ruthenium hydride complexes have
also been used by Morton and Cole-Hamilton4 in the
generation of hydrogen and other workers have used
the Shvo and Robinson catalysts.5,6 Our focus was on
the development of a process using commercially avail-
able catalysts that would lead to alcohol oxidation reac-
tions, potentially allowing for further in situ conversion
into alkenes, imines or asymmetric reduction back into
alcohols.
ruthenium catalysts. As shown in Table 1, this survey
identified Grubbsꢀ catalyst, PhCH = Ru(PCy3)2Cl2,
and the ruthenium precursor to Noyoriꢀs transfer hydro-
genation catalyst, [(p-cymene)RuCl2]2/PPh3, as promis-
ing systems under the conditions that we employed—
5 mol % (in Ru) catalyst, 5 mol % KOH, toluene,
110 °C, 24 h. It is clear that many ruthenium complexes
have the ability to oxidise alcohols in the absence of an
oxidant. Reactions were performed under a gentle flow
of argon, in order to remove hydrogen gas formed.
We assume that in each case a ruthenium hydride species
is formed.7
Optimisation experiments of the reaction shown
in Scheme 1 were then performed for each of these
Preliminary studies investigated the oxidation of phen-
ethyl alcohol 1 into acetophenone 2 using a variety of
OH
Me
O
Ru Catalyst
Base, PhMe
+
H2
Ph
Ph
Me
Keywords: Ruthenium oxidation Grubbs catalyst.
1
2
*
Corresponding author. Tel.: +44 01225 323942; fax: +44 01225
386231; e-mail: chsjmjw@bath.ac.uk
Scheme 1. Ruthenium catalysed dehydrogenation of alcohol 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.083

8234
G. R. A. Adair, J. M. J. Williams / Tetrahedron Letters 46 (2005) 8233–8235
Table 4. Oxidation of other alcohols
Table 2. Optimisation of the Grubbs catalyst oxidation reaction
Base useda
Conversion (%)d
Entry
R
R0 Grubbsꢀ catalysta [(p-Cymene)RuCl2]2
b
Conversion (%)c Conversion (%)c
No base
K2CO3
Cs2CO3
DBU
6
23
75
72
85
1
2
3
4
5
6
7
Ph
p-FC6H4
p-MeOC6H4 Me 100
Ph
Ph
Ph(CH2)2
Tetralol
Me 100
Me 100
100
100
100
3
LiOH
H
2
LiOHb
LiOHc
100
100
Ph 54
Me 58
100
100
91
100
a 15 mol % base, 5 mol % Grubbsꢀ catalyst, PhMe, 110 °C, 24 h.
b Reaction performed over 48 h.
a PhCH = Ru(PCy3)2Cl2.
b With PPh3 (20 mol %).
c Reaction performed using second generation Grubbsꢀ catalyst.
d Conversion was determined from analysis of the 1H NMR spectra.
c Conversion was determined from analysis of the 1H NMR spectra.
48 h, whilst maintaining a gentle flow of argon in order
to remove hydrogen gas.
Table 3. Optimisation of [(p-cymene)RuCl2]2/PPh3 for oxidation
PPh3 equivalentsa
Conversion (%)b
Both catalytic systems were effective for the oxidation of
secondary alcohols, although the more hindered alco-
hol, benzhydrol (entry 5), was oxidised more slowly by
Grubbsꢀ catalyst. The alcohol remote from the phenyl
ring, 4-phenyl-2-butanol (entry 6), also underwent a
slower oxidation, as expected.8 A representative sample
of ketones was isolated by column chromatography
showing isolated yields to be broadly comparable to
the conversion attained. For example, p-methoxyphen-
ethyl alcohol (entry 3) was isolated in 84% and 97%
yields using the Grubbs and ruthenium p-cymene cata-
lyst systems, respectively. In the presence of excess base,
small amounts (typically 5–10%) of reduced aldol con-
densation products were observed, presumably formed
by self aldol condensation of the ketone, followed by
alkene hydrogenation.
0
1
2
3
4
5
6
24
45
62
81
83
85
90
a 2.5 mol % dimer (5 mol % in Ru), 15 mol % LiOH, PhMe, 110 °C,
24 h.
b Conversion was determined from analysis of the 1H NMR spectra.
catalysts, as shown in Table 2 for Grubbsꢀ catalyst and
Table 3 for the ruthenium p-cymene complex. Caesium
carbonate, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
and lithium hydroxide were all found to be suitable
bases using the Grubbs catalyst.
The attempted oxidation of the primary alcohol, benzyl
alcohol 5 is noteworthy, since both catalysts essentially
fail in this case. We thought that the initially formed
benzaldehyde might de-activate the catalyst via the for-
mation of a ruthenium carbonyl complex.9 We therefore
performed an experiment where both benzyl alcohol 5
and phenethyl alcohol 1 were present, anticipating the
benzyl alcohol or benzaldehyde formed to deactivate
the catalyst, thus preventing the oxidation of the phen-
ethyl alcohol. Interestingly, all of the benzyl alcohol
and phenethyl alcohol were consumed during the course
of the reaction, however, no benzaldehyde or acetophe-
none was detected. Instead, the products formed were
ketone 8 and alcohol 9 (Scheme 3).
In the case of the ruthenium p-cymene complex, the
addition of triphenylphosphine was found to be benefi-
cial, as shown in Table 3. In subsequent reactions, we
employed four equivalents of phosphine as a compro-
mise between reactivity and the requirement for excess
phosphine.
The oxidation of a range of alcohols was then performed
using both the Grubbs catalyst and the [(p-cym-
ene)RuCl2]2/PPh3 system using the optimised conditions
(Scheme 2). The alcohols were successfully oxidised to
the corresponding ketones in moderate to quantitative
conversion as shown in Table 4.
Using the catalyst PhCH = Ru(PCy3)2Cl2, ketone 8 and
alcohol 9 were formed in 26% and 74% yield, whilst for
the catalyst [(p-cymene)RuCl2]2 the ratio was 52% to
48%.
In a typical experiment, alcohol (3 mmol), ruthenium
catalyst (0.15 mmol in Ru) and LiOHÆH2O (0.45 mmol,
18.9 mg) were heated at reflux in toluene (3 mL) for
We assume that during the oxidation reaction, the benz-
aldehyde and acetophenone formed react together via
an aldol condensation, a process which serves to remove
the aldehyde thus discouraging the catalyst deactivation.
The aldol condensation product is then reduced as out-
lined in Scheme 3. Cho, Shim and co-workers have
reported a related reaction involving the coupling of
primary and secondary alcohols, which required the
OH
R'
O
a,b
5 mol% Ru Catalyst
+
H2
R
R
R'
15 mol% LiOH
PhMe, 48 h, reflux
3
4
Flow of Ar
Scheme 2. Oxidation of other alcohols with ruthenium catalysts.
a5 mol% in Ru. b20 mol % PPh3 employed with [(p-cymene)RuCl2]2.

G. R. A. Adair, J. M. J. Williams / Tetrahedron Letters 46 (2005) 8233–8235
8235
Acknowledgements
Ru
Ru
RuH
RuH
2
OH
Me
O
We wish to thank the EPSRC for funding (to G.R.A.A.).
Ph
Ph
Ph
Me
Aldol
O
O
1
2
Ph
Ph
OH
Ph
7
References and notes
5
6
2
RuH
2
1. (a) Edwards, M. G.; Williams, J. M. J. Angew. Chem., Int.
Ed. 2002, 41, 4740; (b) 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.
2. (a) Cami-Kobeci, G.; Williams, J. M. J. Chem. Commun.
2004, 1072; (b) Cami-Kobeci, G.; Slatford, P. A.; Whit-
tlesey, M. K.; Williams, J. M. J. Bioorg. Med. Chem. Lett.
2005, 15, 535.
Ru
Ru
RuH
2
OH
O
Ph
Ph
Ph
Ph
9
8
3. Junge, H.; Beller, M. Tetrahedron Lett. 2005, 46, 1031.
4. Morton, D.; Cole-Hamilton, D. J. J. Chem. Soc., Chem.
Commun. 1988, 1154.
Scheme 3. Oxidation of phenethyl alcohol in the presence of benzyl
alcohol.
5. Choi, J. H.; Kim, N.; Shin, Y. J.; Park, J. H.; Park, J.
Tetrahedron Lett. 2004, 45, 4607.
6. Ligthart, G. B. W. L.; Meijer, R. H.; Donners, M. P. J.;
Meuldijk, J.; Vekemans, J. A. J. M.; Hulshof, L. A.
Tetrahedron Lett. 2003, 35, 1507.
use of an alkene to act as a hydrogen acceptor, and the
solvent used, dioxane, as a hydrogen source.10
7. Chowdhury, R. L.; Backvall, J.-E. J. Chem. Soc., Chem.
Commun. 1991, 1063.
8. Adkins, H.; Elofson, R. M.; Rossow, A. G.; Robinson,
C. C. J. Am. Chem. Soc. 1949, 71, 3622.
9. Dinger, M. B.; Mol, J. C. Organometallics 2003, 22,
1089.
10. Cho, C. S.; Kim, B. T.; Kim, H.-S.; Kim, T.-J.; Shim, S. C.
Organometallics 2003, 22, 3608.
In summary, ruthenium complexes can be employed for
the oxidation of alcohols in the absence of an oxidant.
In some cases, oxidation is coupled with C–C bond for-
mation, and the development of this and related pro-
cesses provides an opportunity for additional domino
reactions to be addressed. This use of the Grubbs cata-
lyst adds to the number of reactions that this complex
catalyses which do not involve alkene metathesis.11
11. Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1259.