Unique salt effect on the high yield synthesis of acid-labile terpene oxides using hydrogen peroxide under acidic aqueous conditions

Article abstract of DOI:10.1055/s-0031-1289860

Acid-labile epoxides such as -pinene oxide are (effectively) synthesized in high yield from the epoxidation of terpenes with aqueous H₂O ₂ catalyzed by Na₂WO₄, [Me(n-C ₈H₁₇)₃N]HSO₄, and PhP(O)(OH) ₂ in the presence of Na₂SO₄ as an auxiliary additive under organic solvent-free conditions at ambient temperature. Origin of the salt effect is considered that the addition of a saturated amount of Na₂SO₄ to aqueous H₂O₂ strongly inhibited the undesired hydrolysis of the acid-labile epoxide products, despite the highly acidic reaction conditions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289860

LETTER
2819
Unique Salt Effect on the High Yield Synthesis of Acid-Labile Terpene Oxides
Using Hydrogen Peroxide under Acidic Aqueous Conditions
a
a
a
b
b
b
U
H
nique Salt Effect
o
onthe
H
igh
u
-
Yield Synth
j
esis of
i
Acid-L
n
abile Terpene
O
xid
H
es achiya, Yoshihiro Kon,* Yutaka Ono, Kiyoshi Takumi, Naoki Sasagawa, Yoichiro Ezaki,
a
Kazuhiko Sato*
a
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5 Higashi 1-1-1, Tsukuba, Ibaraki 305-8565,
Japan
Fax +81(29)8614670; E-mail: y-kon@aist.go.jp
Arakawa Chemical Industries, Ltd., Tsukuba Okubo 5, Tsukuba, Ibaraki 300-33, Japan
b
Received 18 August 2011
and PhP(O)(OH) was effective for the epoxidation of
2
Abstract: Acid-labile epoxides such as a-pinene oxide are (effec-
tively) synthesized in high yield from the epoxidation of terpenes
with aqueous H O catalyzed by Na WO , [Me(n-C H ) N]HSO ,
a-pinene at 25 °C. But this process required as much as
0
.08 equivalents of catalysts and intractable 60% H O for
2 2
2
2
2
4
8
17 3
4
the reaction to proceed. Based on these results, we have
and PhP(O)(OH) in the presence of Na SO as an auxiliary additive
2
2
4
under organic solvent-free conditions at ambient temperature. Ori- developed another synthetic approach that effectively
gin of the salt effect is considered that the addition of a saturated protects the generated a-pinene oxide from hydrolysis un-
amount of Na SO to aqueous H O strongly inhibited the undesired
2
4
2
2
der acidic conditions and under organic solvent-free con-
ditions, maintaining the intrinsic catalyst reactivity at the
same time. We here report the effective and convenient
tungsten-catalyzed H O epoxidation of terpenes by the
hydrolysis of the acid-labile epoxide products, despite the highly
acidic reaction conditions.
Key words: oxidation, catalysis, epoxides, terpenoids, green chem-
2
2
istry
simple addition of inorganic salts to give the acid-labile
epoxides in good to excellent yields. This process re-
quired as much as 0.02 equivalents of tungsten, 0.02
equivalents of phase transfer catalyst, 0.01 equivalents of
phenyl phosphonic acid, and commercially available 30%
H O aqueous solution for the reaction to proceed under
Epoxides are a versatile class of compounds for the labo-
ratory and industrial manufacturing of a wide variety of
useful chemicals. While various oxidants are now being
1
2
2
2
used for epoxidation, they often give equimolar amounts
organic solvent-free biphasic conditions of substrate (oil
phase) and aqueous H O (acidic water phase).
of the deoxygenated compounds as waste. Hydrogen per-
oxide (H O ) is an ideal oxidant because water is the only
2
2
2
2
Table 1 Effect of Additives on Epoxidation of 1 under Acidic Con-
3
4
side product and the atom efficiency is excellent. Al-
though a number of metal-catalyzed H O epoxidation re-
ditions in the Presence of Saltsa
2
2
5
,6
30% H O2 (1.0 equiv)
2
actions have been reported thus far, the chemical
processes using organic solvent and halide compounds
should be converted to organic solvent- and halide-free
processes from both an industrial perspective, taking costs
into account, and an environmental perspective. We have
developed various epoxidation reactions of olefins includ-
ing terminal aliphatic olefins with aqueous H O under or-
ganic solvent-free conditions. This oxidation process
gives the corresponding epoxides in good yield catalyzed
by highly active tungsten peroxide species that are effec-
tively formed at 90 °C under acidic conditions. Howev-
er, terpene oxides such as a-pinene oxide were not
obtained under these reaction conditions because the gen-
erated epoxides easily underwent ring opening, rearrange-
ment, and hydrolysis by acid catalysis or by application of
Na2WO4 (0.02 equiv)
[Me(n-C8H17)3N]HSO4 (0.02 equiv)
PhP(O)(OH)2 (0.01 equiv)
O
salt
5 °C, 16 h
2
1
2
b
b
Entry Salt (equiv)
Conversion (%) Yield (%) Selectivity (%)c
2
2
7
1
2
3
4
5
6
7
8
none (0)
55
3
1
0
2
0
NaHCO (0.6)
3
7
b
NaCl (0.6)
20
31
89
73
57
15
0
75
0
NaNO (0.6)
3
Na SO (0.3)
89
40
6
100
55
11
60
43
2
4
8
Li SO (0.3)
heating. Therefore, to avoid the decomposition of a-
pinene oxide under organic solvent-free conditions, the
epoxidation of a-pinene under weak acidic conditions at
room temperature was employed. It was also revealed
2
4
K SO (0.3)
2
4
9
(NH
)
SO
(0.3) 74
MgSO (0.3) 69
4
44
30
4
2
4
that the combination of Na WO , [Me(n-C H ) N]HSO ,
2
4
8
17 3
4
9
a
Reaction conditions: 1 (1.0 equiv), 30% H O (1.0 equiv), Na WO
2
2
2
4
SYNLETT 2011, No. 19, pp 2819–2822
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289860; Art ID: U06011ST
x
x
.x
x
.2
0
1
1
(0.02 equiv), [Me(n-C
8
H
17
)
3
N]HSO
4
(0.02 equiv), PhP(O)(OH)
2
(0.01
equiv), salt, 25 °C, 1000 rpm, 16 h.
b
Determined by GC analysis with decane as an internal standard.
Yield/conversion (%).
c
©
Georg Thieme Verlag Stuttgart · New York

2
820
H. Hachiya et al.
LETTER
We examined the H O epoxidation of a-pinene (1), as Na SO (0.3 equiv) without any other catalysts at 25 °C
2
2
2
4
shown in Table 1. The reaction was conducted with 30% for 16 hours (Table 2). As a result, the hydrolysis of 2 was
H O (1.0 equiv to 1), Na WO (0.02 equiv), [Me(n- observed in only 5% yield with the addition of 0.3 equiv-
2
2
2
4
C H ) N]HSO (0.02 equiv), and PhP(O)(OH) (0.01 alents Na SO to a stirred biphasic mixture of 2 with 30%
8
17 3
4
2
2
4
equiv) at 25 °C for 16 hours with vigorous stirring. As H O (Table 2, entry 4). On the other hand, the hydrolysis
2
2
shown in Table 1 (entry 1), the epoxidation reaction in the of 2 occurred completely in the absence of Na SO , and
2
4
absence of any additional salts proceeded moderately, but the hydrolysis of 2 to give 3 was observed in 62% yield
8
the produced epoxide 2 decomposed under the acidic con- (Table 2, entry 1). The amount of the added salts is also
ditions (55% conversion of 1 and 1% yield of 2). The ad- crucial to effectively protect the generated epoxides from
dition of 0.6 equivalents NaHCO to the aqueous phase hydrolysis. Table 2 shows the results of the investigation
3
created an alkaline solution (pH 9.0), and as a result the regarding the relationship between the conversion of 2
H O epoxidation did not proceed (Table 1, entry 2). The and the amount of Na SO in the biphasic reaction. The
2
2
2
4
addition of 0.6 equivalents NaCl to the epoxidation reac-
tion afforded only 20% conversion of 1 and 15% yield of Table 3 H O Epoxidation of Terpenes with Acidic Conditions in
2
2
a
the Presence or Absence of Na SO
4
2
(Table 1, entry 3). The addition of 0.6 equivalents
2
NaNO did not give 2 at all (Table 1, entry 4). One of the
3
Yield (%)b
Entry
Alkene
Product
reasons for the low conversion of 1 (Table 1, entries 1–4),
is that the formation of sobrerol (3) by the hydrolysis of 2
might be chelated with tungstate metal at the 1,2-diol moi-
O
O
1
2
89
1
c
1
0
ety of 3, which would prohibit any possibility of the ep-
oxidation proceeding. It is noteworthy that Na WO ,
2
4
[
Me(n-C H ) N]HSO , and PhP(O)(OH) catalyzed the
8 17 3 4 2
H O epoxidation of 1 with 0.3 equivalents Na SO as di-
2
2
2
4
3
4
90
90
valent neutral salts, which displayed excellent efficiency
c
despite the acidic conditions (pH 2.0) and produced 2 in
8
9% yield and 100% selectivity (Table 1, entry 5). The
catalytic H O epoxidation of 1 with sulfates of other cat-
2
2
O
+
+
2+
ion species such as Li , NH , and Mg proceeded mod-
4
5
6
67
34
erately to give 40%, 44%, and 30% yields of 2 with
selectivity of 55%, 60%, and 43%, respectively (each 0.3
equiv, Table 1, entries 6, 8, and 9). In contrast, the reac-
tion in the presence of 0.3 equivalents K SO afforded 2
c
OH
OH
O
2
4
in only 6% yield (Table 1, entry 7).
7
8
82
65
c
Table 2 Effect of Na SO on the Hydrolysis of 2 in the Presence of
2
4
a
3
0% H O2
OH
OH
2
O
OH
3
0% H2O2 (1.0 equiv)
with or without
9
0
97
87
Na2SO4 (0–0.4 equiv)
5 °C, 16 h
c
1
1
OH
OH
OH
2
O
O
2
3
b
Entry
Na SO (equiv) Decomposition of 2 (%) Yield of 3 (%)b
2 4
1
12
89
83
c
1
2
3
4
0
100
59
11
5
62
22
11
5
0.1
0.2
0.3
0.4
O
O
O
O
1
1
3
4
50 (41:9)
52 (45:7)
c
5
4
4
O
a
Reaction conditions: 2 (1.0 equiv), 30% H O (1.0 equiv), Na SO ,
2
2
2
4
2
5 °C, 1000 rpm, 16 h.
Determined by GC analysis with decane as an internal standard.
a
Reaction conditions: terpenes (1.0 equiv), 30% H O (1.0 equiv),
2
2
b
Na WO (0.02 equiv), [Me(n-C H ) N]HSO (0.02 equiv),
2
4
8
17 3
4
PhP(O)(OH) (0.01 equiv), Na SO (0.3 equiv), 25 °C, 1000 rpm,
2
2
4
1
6 h.
To clarify the effect of the addition of salt on H O epoxi-
b
2
2
Determined by GC analysis with decane or biphenyl as an internal
standard.
dation, we produced a simple hydrolysis reaction of 2 with
c
aqueous 30% H O (1.0 equiv to 2) in the presence of
The reaction was run in the absence of Na SO .
2
2
2
4
Synlett 2011, No. 19, 2819–2822 © Thieme Stuttgart · New York

LETTER
Unique Salt Effect on the High Yield Synthesis of Acid-Labile Terpene Oxides
2821
amount of Na SO increased from 0 to 0.4 equivalents, NH + with sulfate anion SO42–, Na is the most effective
+
2
4
4
and the decomposition rate of 2 decreased from 100% to salt for the salting-out process under biphasic condi-
1
6
4
% (Table 2, entries 1 and 5). These results suggest that tions. However, the findings regarding hydrolysis inhi-
the addition of Na SO clearly enhanced the inhibition of bition in the biphasic epoxidation reaction cannot simply
2
4
the hydrolysis of 2. But in comparing entries 4 and 5 explain the reactivity due to the interaction between the
Table 2), the addition of more than 0.3 equivalents substrate 2 and cations as well as the catalyst species and
(
Na SO seems less effective because the aqueous H O
anions.
2
4
2
2
solution was saturated by the addition of 0.3 equivalents
Na SO . The results clearly showed that the addition of a
In summary, we have demonstrated the effective and se-
lective salt effect on the high yield synthesis of acid-labile
epoxides using H O2 with the Na WO , [Me(n-
2
4
saturated amount of Na SO effectively inhibited the hy-
2
4
2
2
4
drolysis of 2 in the H O epoxidation reaction conditions
2
2
C H ) N]HSO , and PhP(O)(OH) catalysts under not
8
17 3
4
2
at room temperature without deactivation of the tungsten
peroxide species.
only organic solvent-free but also acidic aqueous biphasic
conditions. The simple addition of a saturated amount of
This epoxidation reaction using Na SO as an additive in Na SO strongly promotes the production of a-pinene ox-
2
4
2
4
the biphasic conditions can be adopted for various other ide due to the suppression of hydrolysis without deactiva-
terpenes to generate the corresponding terpene oxides. tion of the catalytic H O2 epoxidation system. We
2
These results are summarized in Table 3. A reaction with consider the present synthetic improvement by the salt ad-
a bicyclic monoterpene, 3-carene, which is known to un- dition will be quite promising for the practical preparation
dergo an acid-catalyzed rearrangement upon treatment of a variety of acid-labile epoxides using H O .
2
2
1
1
with peracid, also provided an excellent yield of the cor-
responding epoxides under the acidic conditions (90%,
Table 3, entry 3). The reaction with a-terpineol and ter-
pinen-4-ol, having a hydroxy group that causes intramo-
lecular addition reactions in its product under acidic
conditions, also gave the corresponding epoxides in
good to high yield (67% and 82%, respectively, Table 3,
entries 5 and 7). On the other hand, a reaction with isop-
ulegol gave the corresponding epoxides in excellent yield
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
1
2
Acknowledgment
This work was partially supported by the New Energy and Industri-
al Technology Development Organization (NEDO), Japan. We are
grateful to Dr. Masaru Yoshida at the Nanosystem Research Insti-
tute, National Institute of Advanced Industrial Science and Techno-
(
97%, Table 3, entry 9). The epoxidation of limonene,
which has two alkene moieties in the molecule, also suc- logy (AIST) for helpful cooperation.
cessfully produced the corresponding monoepoxides in
high yield (89%, Table 3, entry 11). Meanwhile, it should
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