Intramolecular hydrogen transfer reaction: Menthon from isopulegol

Article abstract of DOI:10.1021/ol500811u

The flavor menthon (isomeric mixture of (-)-menthon and (+)-isomenthon) was obtained in good yields and selectivities by a solventless ruthenium catalyzed isomerization of the homoallylic alcohol (-)-isopulegol. In contrast to most previous assumptions on such isomerization reactions, this reaction follows an intermolecular pathway, with menthol and pulegon being the central intermediates in this transformation.

Full text of DOI:10.1021/ol500811u

Letter
pubs.acs.org/OrgLett
Intramolecular Hydrogen Transfer Reaction: Menthon from
Isopulegol
Thomas Schaub,* Stefan Rudenauer, and Martine Weis
̈
BASF SE, Synthesis and Homogeneous Catalysis (GCS), 67056 Ludwigshafen, Germany
S
* Supporting Information
ABSTRACT: The flavor menthon (isomeric mixture of (−)-men-
thon and (+)-isomenthon) was obtained in good yields and
selectivities by a solventless ruthenium catalyzed isomerization of
the homoallylic alcohol (−)-isopulegol. In contrast to most
previous assumptions on such “isomerization” reactions, this
reaction follows an intermolecular pathway, with menthol and
pulegon being the central intermediates in this transformation.
enthon is a mint-like flavor and is currently available on
the market as a mixture of isomers (70% (−)-menthon,
Scheme 1. New BASF Process for for the Production of
Menthol from Citral
M
30% (+)-isomenthon). The main industrial production is based
on distillation of dementholized cornmint oil, a side stream
originating from the production of menthol from Menthe
arvensis.1 Hence, the supply and the quality of the natural
menthon are dependent on menthol production capacities as
well as on seasonal influences on crop yields. A merely
synthetical production of menthon would be able to overcome
these difficulties. From a retrosynthetical analysis, it is very
obvious that either oxidation of the natural product (L)-
menthol or hydrogenation of the aromatic precursor thymol is
the most straightforward route to menthon. Nonetheless, these
approaches impose several disadvantages. The oxidation suffers
from the use of the valuable menthol and additional oxidizers.
On the other hand, the hydrogenation of thymol with Pd/C as
the catalyst leads to an unfavorable mixture of all isomers
(mixture of rac-menthon and rac-isomenthon).2 Therefore,
isomerization of the homoallylic alcohol (−)-isopulegol would
offer the most atom-efficient approach to menthon.4 This
isomerization is also of industrial attractivity as (−)-isopulegol
is the central intermediate of the new BASF process for the
production of (L)-menthol (see Scheme 1) and therefore
available on a technical scale.5 Surprisingly, only very little
literature data are available on this reaction. To the best of our
knowledge, the only reported method for the synthesis of
menthon from isopulegol is a gas-phase reaction using a
heterogeneous copper catalyst. Nonetheless, this procedure
suffers from low selectivities due to the harsh reaction
conditions required and more than 35% of the undesired side
product thymol is formed.4 Hence, a mild and efficient
homogeneously catalyzed approach is highly attractive.
well-known with iron and ruthenium complexes.7 It is assumed
that this redox isomerization follows an intramolecular
rearrangement pathway via a 1,3-hydrogen transfer.8 In the
case of the iron catalyzed isomerization of higher unsaturated
alcohols such as 9-decen-1-ol, first a double bond isomerization
cascade is suggested, before the resulting enol tautomerizes to
the aldehyde.9,10 For the isomerization of homoallylic alcohols
to ketones very little is known,4,9a,10 and all reports refer to an
intramolecular isomerization mechanism. We achieved the
isomerization of the homoallylic alcohol (−)-isopulegol to
menthon in more than 90% yield, using a simple ruthenium
catalyst at temperatures of 130 to 170 °C (Table 1).
Only nonchiral phosphine ligands were used, as the natural
flavor menthon consists of an equilibrium isomeric mixture of
about 70% (−)-menthon and 30% (+)-isomenthon which
reequilibrates rapidly at room temperature. The absolute
configuration on the 5-position was retained, as demonstrated
by GC and the flavor properties.
Different ruthenium complexes are known to be suitable
homogeneous catalysts for the transfer hydrogenation of
alkenes with alcohols as the hydrogenation source, whereby
most of these reactions are intermolecular.6
In the case of formal intramolecular transfer hydrogenations,
the transition metal catalyzed isomerization of allylic alcohols is
Received: March 18, 2014
Published: April 29, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
same conditions as in the isomerization of isopulegol. Within
these experiments, menthon is formed from pulegon and
menthol under solventless conditions.12
If the temperature is raised from 170 to 180 °C, the reaction
is significantly faster with 90% conversion after 4 h compared to
20 h at the lower temperature (Figures 1 and 2). The selectivity
Table 1. Isomerization of Isopulegol to Menthon Using
Different Ruthenium Catalysts
a
isopulegol
[%]
temp
[°C]
conversion
[%]
yield
menthon [%]
catalyst [mol %]
[Ru(PnOct3)4(H)2]
15
133
58.8
47.3
b
(1)
[Ru(PnBu3) (H)2]/
15
133
62.9
42.1
b4
dcpe (1)
b
[Ru(PEt3)4(H)2] (1)
15
15
133
130
64.6
64.5
45.0
46.3
[Ru(PnOct3)4(H)2]
c
(1)
[Ru(PnOct3)4(H)2]
15
30
150
170
98.6
98.2
47.9
89.6
c
(1)
[Ru(PnOct3)4(H)2]
d
(0.5)
a
All reactions carried out under argon using xylene as solvent with a
reaction time of 20 h. Yields and selectivity were determined by GC.
b
Reaction under reflux in an open system using 10 mL of o-xylene and
c
1.8 g of isopulegol. Reaction in a glass Autoclave under inherent
pressure using 20 mL of o-xylene and 3.6 g of isopulegol. Reaction in
d
a glass Autoclave under inherent pressure using 20 mL of o-xylene and
8.6 g of isopulegol. dcpe = 1,2-bis(dicyclohexyl-phosphino)ethane was
purchased by Sigma-Aldrich, and [Ru(PR3)4(H)2]-complexes were
prepared according to the literature.11
Figure 1. Isomerization of isopulegol at 170 °C. Conditions: 21 g of
isopulegol, 0.3 mol % [Ru(PnOct3)4(H)2], no solvent, reaction in a
glass reactor under inherent pressure at 170 °C.
The experimental data also revealed some insights into the
suggested reaction mechanism. At temperatures below 150 °C,
the reaction was obviously too slow to go directly into
complete conversion, giving ∼50% selectivity of the desired
product along with ∼30% of L-menthol and pulegon in an
approximately 1:1 ratio.
Consequently, these two compounds are formed in an
intermolecular transfer hydrogenation, whereby one molecule
of isopulegol acts as a hydrogen donor and another as a
hydrogen acceptor, resulting in menthol and pulegon (Scheme
2). The pulegon is formed under these conditions instead of
Scheme 2. Intermolecular Transfer Hydrogenation with
Isopulegon and L-Menthol As Intermediates
Figure 2. Isomerization of isopulegol at 180 °C. Conditions: 21 g of
isopulegol, 0.3 mol % [Ru(PnOct3)4(H)2], no solvent, reaction in a
glass reactor under inherent pressure at 180 °C.
to menthon at 180 °C is as high as that at 170 °C (90%), and
the maximum of the two intermediates is reached after 2 h at
180 °C. The molar ratio of pulegon to menthol is
approximately 1:1 over the observed period of time.
A similar observation was made in the isomerization of the
allylic alcohol geraniol in a current work by Wu et al. When
using a ruthenium catalyst, apart from the isomerization
product citronellal, also the products from an intermolecular
hydrogen transfer, citronellol and citral, could be detected as
byproducts.13 In this work, they were not assumed as
intermediates of the isomerization.
Based on our observations, we cannot exclude that parts of
the isomerization are following an intramolecular mechanism,
but most of the product is formed by an intermolecular transfer
hydrogenation cascade.
The reaction can be carried out without any additional
solvent in pure isolpulegol just by simple addition of the
catalyst and heating in a glass reactor under a moderate
pressure of 2−3 bar (Table 2). Due to the high conversion,
excellent product concentrations in the reaction mixture can be
isopulegon due to the higher stability of the conjugated
unsaturated carbonyl compound. If the reaction is carried out
without an additional solvent and followed by GC, the amount
of these two compounds rises at the beginning and then drops
slowly whereas the amount of the desired menthon rises. This
implies that menthol and pulegon are the intermediates in this
reaction, which results in the formation of 2 equiv of the target
molecule after a second transfer hydrogenation.
This was proved independently by the reaction of pulegon
with menthol using the [Ru(PnOct3)4(H)2] catalyst under the
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Organic Letters
Letter
(7) (a) Smadja, W.; Ville, G.; Georgoulis, C. J. Chem. Soc., Chem.
Commun. 1980, 594. (b) Cowherd, F. G.; von Rosenberg, J. L. J. Am.
Chem. Soc. 1969, 91, 2157. (c) Barborak, J. C.; Herndon, J. W.; Wong,
J. W. J. Am. Chem. Soc. 1979, 101, 7430. (d) Strauss, J. U.; Ford, P. W.
Tetrahedron Lett. 1975, 33, 2917. (e) Iranpoor, N.; Mottaghinejad, E. J.
Table 2. Solventless Synthesis of Menthon and Catalyst
Recycling
a
isopulegol
[g]
conversion
[%]
menthon
[%]
menthol
[%]
isopulgeon
[%]
run
Organomet. Chem. 1992, 423, 399. (f) Backvall, J. E.; Andreasson, U.
1
2
44.0
17.4
92.6
95.1
86.5
74.3
4.9
5.7
8.0
̈
Tetrahedron Lett. 1993, 34, 5459. (g) Trost, B. M.; Kulawiec, R. J. J.
Am. Chem. Soc. 1993, 115, 2027. (h) Liu, P. N.; Ju, K. D.; Lau, C. P.
Adv. Synth. Catal. 2011, 353, 275.
14.4
a
All reactions carried out under argon. Reaction in a 50 mL glass
reactor in pure isopulegol (2 × 22 g) for 64 h at 170 °C. After distilling
of the product, fresh isopulegol was added to the catalyst containing
sump (∼13 g containing 71.3% menthon, 2.7% isopulegol, 5.1%
menthol, and 12.6% isopulegol) and the reaction was repeated for 72
h. Catalyst: 0.2 mol % [Ru(PnOct3)4(H)2].
(8) Uma, R.; Crevisy, C.; Gree, R. Chem. Rev. 2003, 103, 27.
(9) (a) Damico, R.; Logan, T. J. J. Organomet. Chem. 1967, 32, 2356.
(b) Sasson, Y.; Rempel, G. L. Tetrahedron Lett. 1974, 47, 4133.
(10) McGrath, D. V.; Grubbs, R. H. Organometallics 1994, 13, 224.
(11) Schaub, T.; Paciello, R. Angew. Chem., Int. Ed. 2011, 50, 7278.
(12) Experimental details: 8.0 g (50 mmol) of pulegon, 8.0 g (50
mmol) of menthol, and 0.36 g (0.16 mmol) of [Ru(PnOct3)4(H)2]
were added to a 50 mL glass reactor under inert conditions and stirred
for 15 h in the closed system. After the reaction, the mixture contains
78.0% menthon (35.4% (+)-menthon and 64.6%(−)-isomenthon),
9.2% pulegon, and 6.5% menthol as determined by GC.
(13) Wu, R.; Beauchamps, M. G.; Laquidara, J. M.; Sowa, J. R. Angew.
Chem., Int. Ed. 2012, 51, 2106.
achieved, resulting in a simple workup by distillation to obtain
the highly valuable menthon as the isomeric mixture, which has
the same properties as the flavor obtained from natural sources.
The active ruthenium catalyst remains in the sump of the
distillation and can simply be reused without any significant loss
in selectivity by adding fresh isopulegol and running the
reaction again.
In summary, we reported a new, simple, and highly atom-
efficient protocol for the synthesis of the flavor menthon using
the now readily available isopulegol. The isomeric mixture
obtained has identical properties to the product isolated from
natural sources. In contrast to most other reports on the
isomerization of unsaturated alcohols to the corresponding
carbonyl compound, this reaction follows an intermolecular
pathway with a transfer hydrogenation cascade.
(14) (a) Schaub, T.; Weis, M.; Ruedenauer, S. WO 2014037264,
2014. (b) Schaub, T.; Weis, M.; Ruedenauer, S. US 20140073817,
2014.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for the catalyst synthesis and the
preparation of menthon according to this method are given.
This material is available free of charge via the Internet at
http://pubs.acs.org. Parts of these results were also disclosed in
the patent applications WO 2014037264 and US 20140073817
from the same authors.14
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: thomas.schaub@basf.com.
Notes
The authors declare no competing financial interest.
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■
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