An effective catalytic epoxidation of terpenes with hydrogen peroxide under organic solvent-free conditions

Article abstract of DOI:10.1055/s-0028-1088156

A catalytic system that operates well for the epoxidation of α-pinene, a very challenging substrate, at near-neutral pH and ambient temperature without organic solvent was developed. With hydrogen peroxide as a terminal oxidant, combination of Na₂WO₄, PhP(O)(OH) ₂, and [Me(n-C₈H₁₇)₃N]HSO ₄ successfully catalyzed the epoxidation of α-pinene to give α-pinene oxide in 95% selectivity at 91% conversion, while the previously published conditions that use NH₂CH₂P(O)(OH)₂ as a promoter provide no epoxide. The method is also well applicable to the epoxidation of the other acidsensitive terpenes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088156

LETTER
1095
An Effective Catalytic Epoxidation of Terpenes with Hydrogen Peroxide
under Organic Solvent-Free Conditions
Catalytic
E
poxida
t
o
ion of Terpe
s
nes hihiro Kon, Yutaka Ono, Tomohiro Matsumoto, Kazuhiko Sato*
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5 Higashi 1-1-1, Tsukuba, Ibaraki 305-8565,
Japan
Fax +81(29)8614578; E-mail: k.sato@aist.go.jp
Received 26 December 2008
successful examples that use an immobilized catalyst of
Abstract: A catalytic system that operates well for the epoxidation
polyoxometalates on mesoporous silica gel and methyltri-
of a-pinene, a very challenging substrate, at near-neutral pH and
oxorhenium catalysts have been shown to effectively cat-
ambient temperature without organic solvent was developed. With
alyze terpene epoxidation.10 Additionally, these methods
hydrogen peroxide as a terminal oxidant, combination of Na2WO4,
PhP(O)(OH)2, and [Me(n-C8H17)3N]HSO4 successfully catalyzed are not fully satisfactory because of the requirement of
the epoxidation of a-pinene to give a-pinene oxide in 95% selectiv-
ity at 91% conversion, while the previously published conditions
that use NH2CH2P(O)(OH)2 as a promoter provide no epoxide. The
method is also well applicable to the epoxidation of the other acid-
sensitive terpenes.
hazardous organic solvent and/or the complicated multi-
step preparation of catalysts using organic solvents. We
have previously reported efficient methods for the epoxi-
dation of alkenes11 under organic solvent-free conditions,
but unfortunately they did not work well for a-pinene ep-
oxidation because of the highly acidic conditions and
Key words: oxidations, catalysis, epoxides, terpenoids, green
chemistry
heating (the selectivity of a-pinene oxide was 0%).6b
A
catalytic system applicable to nearly neutral conditions
without loss of activity at ambient temperature is neces-
sary for the epoxidation of terpenes under organic-sol-
vent-free conditions. We report here a practical method
for the syntheses of terpene oxides from the epoxidation
of terpenes that can be carried out without organic solvent.
Terpenes are widely distributed in nature and are often
key raw materials in organic chemistry.1 Epoxidation of
terpenes is recognized as a particularly significant proce-
dure because the generated epoxides are important start-
ing materials with a wide variety of uses such as in
flavors, fragrances, and pharmaceuticals.1,2 Preparation of
the oxidized terpenes under current industrial methods re-
quires percarboxylic acids, which leave an equimolar
waste product after the reaction.1a,2 As a part of the green
concept, toxic oxidants are being replaced by alternative
nontoxic reagents.3 Hydrogen peroxide (H2O2) is an ideal
oxidant because water is the only side product and the
atom efficiency is excellent.4 We have therefore devel-
oped various oxidation reactions with aqueous H2O2 un-
der organic solvent-free conditions.5 Although a number
of metal-catalyzed H2O2 epoxidation reactions have been
reported thus far,6,7 the epoxidation of terpenes (especial-
ly, bicyclic terpenes) is still a challenging task due to their
sensitivity toward acidic media.1b,8 Terpenes and their ep-
oxides easily undergo ring opening, rearrangement, dou-
ble-bond migration, and hydrolysis by acid catalysis or by
application of heating.1 These reactions are due to their
isoprene units possessing trisubstituted alkenes and their
epoxides are prone to generate a stable intermediate,
namely, a tertiary carbocation through protonation or ring
opening of the epoxides during the reaction. In the case of
preparing a-pinene oxide, isomerization and/or hydrolysis
of both the reactant and the product may lead to a complex
mixture of b-pinene, 3-carene, camphene, campholenic
aldehyde, a-terpineol, etc., as shown in Scheme 1.9 Few
O
OH
O
OH
OH
Scheme 1 Compounds obtained from a-pinene and a-pinene oxide
via isomerization and/or hydolysis
a-Pinene, a most challenging terpene, was chosen as a
screening substrate. We found that at near-neutral pH
screening of phosphonic acid additives shows big differ-
ences in the catalytic reactivity. These additives for im-
proving the selectivity were tested under following
conditions: using aqueous H2O2 (60% aq, 1.3 equiv) as an
oxidant and NaOH (6 mol%) which adjust the pH to
a nearly neutral condition. The solutions were mixed
with a catalytic system consisting of Na2WO4 (8 mol% to
SYNLETT 2009, No. 7, pp 1095–1098
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Advanced online publication: 20.03.2009
DOI: 10.1055/s-0028-1088156; Art ID: U13208ST
© Georg Thieme Verlag Stuttgart · New York

1096
Y. Kon et al.
LETTER
a-pinene) and [Me(n-C8H17)3N]HSO4 (phase-transfer cat- (47%, Table 1, entry 7). The inefficiency of
alyst, 8 mol%, Equation 1). The best choice of additive as NH2CH2P(O)(OH)2 could be attributed to its amino
a cocatalyst, which binds with the tungstate center to form group. The yield of product was decreased to 54% when
a phosphonate complex,12 was found to be PhP(O)(OH)2 the epoxidation (the same conditions as entry 1) was car-
(4 mol%). The reaction of a-pinene with these catalytic ried out in the presence of n-BuNH2 (4 mol%). Though the
conditions successfully gave a-pinene oxide in 87% yield reason for this deterioration was unclear, these epoxida-
(on the basis of the starting a-pinene) after stirring at tion experiments under nearly neutral pH conditions (ad-
25 °C for 12 hours. Although the reaction preferred 60% justed by aq NaOH) eliminated the possibility for the
H2O2 as the oxidant, an epoxidation with 30% H2O2 also amines of working just as a base that alters the pH. The ad-
gave satisfactory results (75% yield of a-pinene oxide).
dition of NaOH for weakening the Brønsted acid reactiv-
ity is important to protect the generated epoxide from
hydrolysis. When the addition of NaOH was omitted (the
other conditions as same as those of entry 1), 80% of the
starting a-pinene was consumed, though the yield and se-
lectivity of a-pinene oxide were low (13% and 16%, re-
spectively).
+
60% H2O2 (1.3 equiv)
Na2WO4 (8 mol%)
O
PhP(O)(OH)2 (4 mol%)
[Me(n-C8H17)3N]HSO4 (8 mol%)
NaOH (6 mol%)
This epoxidation system using PhP(O)(OH)2 as cocatalyst
can be adopted for the epoxidation of the other various ter-
penes to generate the corresponding terpene oxides. The
results are shown in Table 2. As a model case of the sim-
ple cyclic trisubstituted alkene, 1-methyl-1-cyclohexene
was successfully converted to the epoxide (92% yield,
Table 2, entry 1). A reaction with bicyclic monoterpene,
3-carene, which is known to undergo an acid-catalyzed re-
arrangement upon treatment with peracid,1b,10d,13 also pro-
vided an excellent yield of the corresponding epoxide
(93%, Table 2, entry 4). A reaction with a-terpineol hav-
ing a hydroxy group that causes intramolecular addition
reactions in its product under acidic conditions14 also gave
the corresponding epoxide in high yield (98%, Table 2,
entry 6). A reaction with b-myrcene, with which it was
difficult to achieve regioselective epoxidation by the
former catalyst system,15 gave the 2,3-epoxide in 75%
yield (entry 7). Epoxidation of limonene and b-caryophyl-
lene, which have two alkene moieties in the molecule, was
also successfully produced the corresponding mono-
epoxides in high yields (82%, entries 8 and 9).
25 °C, 12 h
87% yield
Equation 1
Table 1 Effects of Additives on the Epoxidation of a-Pinenea
Entry Additive
Conversion
(%)b
Yield Selectivity
(%)b
(%)c
95
70
75
74
83
77
47
1
2
3
4
5
6
7
PhP(O)(OH)2
91
87
91
88
84
86
87
MeP(O)(OH)2
EtP(O)(OH)2
n-PrP(O)(OH)2
t-BuP(O)(OH)2
H3PO4
61
68
65
70
66
NH2CH2P(O)(OH)2 74
35
a Reaction conditions: a-pinene (3 mmol), 60% H2O2 (3.9 mmol),
Na2WO4 (0.24 mmol), [Me(n-C8H17)3N]HSO4 (0.24 mmol), additive
(0.12 mmol), NaOH (0.18 mmol), 25 °C, 1000 rpm, 12 h.
b Yield on the basis of a-pinene, determined by GC analysis with bi-
phenyl as internal standard.
The present method can be carried out on a hectogram
scale of terpene epoxidation. That is, with 100 g of 3-carene
as a starting material, 97.6 g of the corresponding epoxide
was obtained after distillation of the crude product (87%
yield, Equation 2 and Table 2, entry 5). Because the ep-
oxidation of 3-carene is quite exothermic, careful reaction
temperature control was found critical for a larger-scale
preparation.
c Yield/conversion (%)
The results with the other additives we examined are sum-
marized in Table 1. Alkylphosphonic acids also worked
as cocatalysts under the present reaction conditions,
although their efficiencies were somewhat lower than
that of PhP(O)(OH)2, then the epoxidations using
MeP(O)(OH)2, EtP(O)(OH)2, n-PrP(O)(OH)2, and t-
BuP(O)(OH)2 resulted in the formation of a-pinene oxide
in 61%, 68%, 65%, and 70% yield, respectively (Table 1,
entries 2–5). As well as the alkylphosphonic acids, a reac-
tion in the presence of H3PO4 gave a modest yield (66%,
Table 1, entry 6). It is noteworthy that the catalytic ability
of NH2CH2P(O)(OH)2 (previously reported as the best co-
catalyst under acidic conditions11 and as a better cocata-
lyst than PhP(O)(OH)211b) was found to be much inferior
to that of PhP(O)(OH)2. That is, the epoxidation using
NH2CH2P(O)(OH)2 gave the epoxide with less selectivity
60% H2O2
+
(1.3 equiv)
O
Na2WO4 (4 mol%)
PhP(O)(OH)2 (2 mol%)
100 g
[Me(n-C8H17)3N]HSO4 (4 mol%)
NaOH (4 mol%)
25 °C, 12 h
97.6 g
87% yield after distillation
Equation 2
Synlett 2009, No. 7, 1095–1098 © Thieme Stuttgart · New York

LETTER
Catalytic Epoxidation of Terpenes
1097
Table 2 H2O2 Epoxidation of Terpenes and Inner Olefina
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Entry
Alkene
Product
Yield (%)b
O
Acknowledgment
1
92
This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular Transformation
of Carbon Resources’ from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We are grateful to Prof.
Dr. Akira Sekiguchi in Department of Chemistry, Graduate School
of Pure and Applied Sciences, University of Tsukuba for the helpful
cooperation.
O
O
2
87
75
3c
4
93
5d
87e
References and Notes
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O
a Reaction conditions: alkene (3.0 mmol), 60% H2O2 (3.9 mmol),
Na2WO4 (0.24 mmol), [Me(n-C8H17)3N]HSO4 (0.24 mmol),
PhP(O)(OH)2 (0.12 mmol), NaOH (0.18 mmol), 25 °C, 1000 rpm, 12 h.
b Yield on the basis of alkene, determined by GC analysis with biphe-
nyl as internal standard.
c 30% H2O2 was used instead of 60% H2O2.
d The reaction was run using 100 g of 3-carene, 1.3 equiv of 60%
H2O2, 4 mol% of Na2WO4, 2 mol% of PhP(O)(OH)2, 4 mol% of
[Me(n-C8H17)3N]HSO4, 4 mol% of NaOH.
e Isolated yield after distillation.
In summary, we have developed a green and practical
method for terpene epoxidation using aqueous H2O2 as an
oxidant under organic solvent-free conditions. The cata-
lytic system, which consists of Na2WO4, PhP(O)(OH)2,
and [Me(n-C8H17)3N]HSO4, having high activity under
nearly neutral pH conditions at ambient temperature,
achieved the excellent yield and selectivity for epoxida-
tion of very challenging acid-sensitive terpenes. The ap-
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products, for example, styrene oxide derivatives, is now
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Synlett 2009, No. 7, 1095–1098 © Thieme Stuttgart · New York

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LETTER
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