Reduction of aldehydes and ketones by transfer hydrogenation with 1,4-butanediol

Article abstract of DOI:10.1021/ol702029n

1,4-Butanediol has been used as the hydrogen donor in transfer hydrogenation reactions. The equilibrium is driven by the formation of γ-butyrolactone, and the diol is therefore not required in excess.

Full text of DOI:10.1021/ol702029n

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4387-4389
Reduction of Aldehydes and Ketones by
Transfer Hydrogenation with
1,4-Butanediol
Hannah C. Maytum,† Bahareh Tavassoli,‡ and Jonathan M. J. Williams*,†
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath, BA2 7AY,
United Kingdom, and GlaxoSmithKline Research and DeVelopment, Old Powder Mills,
Tonbridge, Kent, TN11 9AN United Kingdom
j.m.j.williams@bath.ac.uk
Received August 18, 2007
ABSTRACT
1,4-Butanediol has been used as the hydrogen donor in transfer hydrogenation reactions. The equilibrium is driven by the formation of
-butyrolactone, and the diol is therefore not required in excess.
γ
Transfer hydrogenation reactions are widely used for the
reduction of ketones and aldehydes.1 Isopropanol is often
used as a convenient hydrogen donor but is required in excess
in order to drive the reduction process. Thus, for the reduction
of a ketone with a similar oxidation potential to acetone,
the addition of 50 equiv of isopropanol will be required to
give a 1:50 ratio of ketone 1 to alcohol 2 (Scheme 1).
of 50 equiv of isopropanol to acetophenone will reach an
equilibrium position at approximately 96% conversion.2
We therefore wished to identify an alcohol which could
donate hydrogen essentially irreversibly and thereby over-
come the equilibrium problem inherent with using isopro-
panol. Alternative (nonalcoholic) hydride donors such as
triethylamine/formic acid3 and Hantzsch esters4 have been
used in the reduction of carbonyl compounds.
We have previously reported that levulinic acid (CH3-
COCH2CH2CO2H) is a good hydrogen acceptor since the
alcohol that is formed readily lactonizes, driving the equi-
librium for oxidation of alcohols.5 We chose to investigate
the use of diols as reducing agents, since they would be
expected to undergo lactol formation and further oxidation
to the lactone, as shown in Scheme 2. Although diols have
previously been oxidized to lactones using ruthenium
catalyzed transfer hydrogenation6 and dehydrogenation,7 we
Scheme 1. Equilibrium in Transfer Hydrogenation Reactions
However, for ketones with oxidation potentials that are
different from acetone, the equilibrium position is shifted in
favor of the more stable ketone. For example, the addition
(2) Adkins, H.; Elofson, R. M.; Rossow, A. G.; Robinson, C. C. J. Am.
Chem. Soc. 1949, 71, 3622.
(3) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521.
(4) Yang, J. W.; List, B. Org. Lett. 2006, 8, 5653.
† University of Bath.
(5) Wise, N. J.; Williams, J. M. J. Tetrahedron Lett. 2007, 48, 3639.
(6) (a) Murahashi, S. I.; Naota, T.; Ito, K.; Maeda, Y.; Taki, H. J. Org.
Chem. 1987, 52, 4319. (b) Lin, Y. R.; Zhu, X. C.; Zhou, Y. F. J. Organomet.
Chem. 1992, 429, 269. (c) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K.
Org. Lett. 2002, 4, 2361.
‡ GlaxoSmithKline Research and Development.
(1) (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. ReV. 1992, 92,
1051. (b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045.
(c) Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226.
10.1021/ol702029n CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/14/2007

with respect to propiophenone 3. With no R-hydrogens, tert-
butanol is totally unsuccessful as a reducing agent. However,
the diols were all more successful than the use of a primary
alcohol, with 1,4-butanediol providing a promising conver-
sion under these conditions. The presence of unreacted diol
and lactone was observed in the 1H NMR spectrum, although
there was no evidence of the presumed intermediate lactol.
Scheme 2. 1,4-Butanediol as a Hydrogen Donor
We then applied the use of 1,4-butanediol as a reducing
agent to the conversion of a range of carbonyl compounds
(Scheme 4, Table 2). The use of (o-Ph2PC6H4)2O (DPEphos)
Scheme 4. Reduction of Other Carbonyl Compounds with
1,4-Butanediol
are unaware of the use of diols as the stoichiometric reducing
agent for a range of carbonyl compounds.
We have recently been using Ru(PPh3)3(CO)H2 in the
presence of bidentate phosphine ligands to catalyze transfer
hydrogenation reactions.8 We therefore chose to use this
catalyst to assess the viability of diols as reducing agents.
and potassium tert-butoxide as additives provided a slightly
more reactive catalyst.
Scheme 3. Reduction of Propiophenone by Transfer
Hydrogenationa
Table 2. Alcohols Formed by Reduction of the Carbonyl
Compound with 1,4-Butanediol
a Ru cat. ) Ru(PPh3)3(CO)H2.
In preliminary experiments, we examined the reduction of
propiophenone 3 to 1-phenylpropanol 4 using Ru(PPh3)3-
(CO)H2 with a variety of diols in comparison with alcohols
(Scheme 3, Table 1).
Table 1. Diols and Alcohols Used in the Reduction of
Propiophenone
entry
diol/alcohol
conversion (%)a
1
2
3
4
5
6
n-butanol
tert-butanol
1,3-propanediol
1,4-butanediol
1,5-pentanediol
1,6-hexanediol
6
0
9
96
50
26
1
a Determined from the H NMR spectrum.
As expected, the use of n-butanol (entry 1) led to a low
conversion in the reduction of propiophenone 3. The equi-
librium is disfavored by the relatively low stability of butanal
a Reactions were carried out using Ru(PPh3)3(CO)H2 (2.5 mol %),
DPEphos (2.5 mol %), t-BuOK (5 mol %) with 1,4-butanediol (1 equiv)
on a 1 mmol scale in 1 mL of toluene at reflux for 24 h. Isolated yields are
given in parentheses. b 48 h. c We assume that the lower isolated yield is
due to the volatility of cyclohexanol.
(7) (a) Ichikawa, N.; Sato, S.; Takahashi, R.; Sodesawa, T.; Inui, K. J.
Mol. Catal. A: Chem. 2004, 212, 197. (b) Zhao, J.; Hartwig, J. F.
Organometallics 2005, 24, 2441.
(8) Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J. Tetrahedron
Lett. 2006, 47, 6787.
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Org. Lett., Vol. 9, No. 21, 2007

All of the ketones were successfully reduced using 1,4-
butanediol, even tetralone (entry 1) and p-methoxyacetophe-
none (entry 2) which are particularly stable, although longer
reaction times were required to achieve reduction. Other aryl
alkyl ketones (entries 3-5), dialkyl ketones (entries 6-8),
and aldehydes (entries 9-11) were also successfully reduced.
Although isolation of the alcohols by column chromatog-
raphy was convenient, we have also demonstrated that the
alcohol can be purified by treatment with aqueous sodium
hydroxide. 1,4-Butanediol is water soluble, and treatment
of γ-butyrolactone with 2 M NaOH led to hydrolysis, leaving
only the alcohol behind in the organic solvent. Using this
method, benzyl alcohol and cyclohexanol were recovered
unchanged from a 1:1:1 mixture of alcohol, γ-butyrolactone
and 1,4-butanediol.
Scheme 6. Transfer Hydrogenation with Noyori Catalysta
We were interested in combining the use of 1,4-butanediol
as a reducing agent with the use of methyl levulinate as an
oxidant, and this process led to the formation of the lactones
5 and 6 as shown in Scheme 5.
a Ru* ) [Ru(p-cymene)Cl2]2/(S,S)-TsDPEN/KOH (1:4:8).
process, the reaction rate was significantly lower than with
isopropanol (Scheme 6). With 50 equiv of isopropanol, we
achieved an 82% conversion in 14 h, whereas with one
equivalent of isopropanol, only 24% conversion was achieved,
even after 72 h. Increasing the catalyst loading and temper-
ature led to almost complete reduction of 3-chloroacetophe-
none but with a reduced enantioselectivity, presumably due
to the higher temperature employed.
Scheme 5. Combined Use of 1,4-Butanediol with Methyl
Levulinate Leading to Two Lactonesa
We assume that the slower rate observed with 1,4-
butanediol is a consequence of the initial oxidation of a
primary alcohol to the aldehyde, which is less favorable than
oxidation of a secondary alcohol to a ketone.
In summary, we have demonstrated that 1,4-butanediol can
be used for the reduction of carbonyl compounds by transfer
hydrogenation. An excess of this reagent is not required due
to the formation of γ-butyrolactone. We are currently
exploring the scope of this process with alternative catalysts.
a Ru cat. ) Ru(PPh3)3(CO)H2, DPEphos, t-BuOK (1:1:2).
Having established that 1,4-butanediol could be success-
fully used as the stoichiometric reducing agent in transfer
hydrogenation reactions, we wished to evaluate the use of
this reagent in asymmetric transfer hydrogenation. The
Noyori catalyst derived from [Ru(p-cymene)Cl2]2 and (S,S)-
TsDPEN is known to be highly selective for the reduction
of ketones using isopropanol in excess as the reducing agent.9
We found that, although 1,4-butanediol could be used in this
Acknowledgment. We thank GlaxoSmithKline and
EPSRC for the award of an industrial CASE studentship.
Supporting Information Available: Experimental pro-
cedures and compound characterization are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Hashiguchi, S.; Fujii, A.; Takahara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562.
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