A simple and efficient oxidation procedure for the synthesis of acid-sensitive epoxides

Article abstract of DOI:10.1055/s-0028-1087999

A mild and straightforward epoxidation protocol based on sodium perborate as primary oxidant and sodium dehydrocholate as organomediator under homogeneous conditions is described. In particular, geraniol, linalool, 3-carene, and a-pinene are quantitatively converted into the corresponding 6,7-epoxides and transepoxides, respectively. The bile acid salt is recovered from the reaction mixture and may be reused with unchanged efficiency and selectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087999

PAPER
1123
A Simple and Efficient Oxidation Procedure for the Synthesis of
Acid-Sensitive Epoxides
Synthesis of
A
cid-
l
S
ensitiv
g
e
Epoxidesa Bortolini,*a Giancarlo Fantin,b Marco Fogagnolo*b
a
Department of Chemistry, University of Calabria, Via Bucci 12 C, 87036 Rende (CS), Italy
Fax +39(984)493307; E-mail: o.bortolini@unical.it
b
Department of Chemistry, University of Ferrara, Via Borsari 46, 44100 Ferrara, Italy
E-mail: fgr@unife.it
Received 20 October 2008; revised 10 December 2008
particular, sodium perborate is a cyclic disubstituted per-
oxide used for the epoxidation of a,b-unsaturated
ketones20–22 and in many oxidation processes, even using
acetic acid or acetic anhydride as solvents.23 The interest-
Abstract: A mild and straightforward epoxidation protocol based
on sodium perborate as primary oxidant and sodium dehydrocholate
as organomediator under homogeneous conditions is described. In
particular, geraniol, linalool, 3-carene, and a-pinene are quantita-
tively converted into the corresponding 6,7-epoxides and trans- ing characteristics of sodium perborate, combined with
epoxides, respectively. The bile acid salt is recovered from the re-
the unlike conditions of its use, prompted us to investigate
action mixture and may be reused with unchanged efficiency and
selectivity.
alternative and more environmentally acceptable routes
for the selective epoxidation of unfunctionalized C=C
bonds with this oxidant. The mild, slightly alkaline, ep-
oxidation conditions are particularly suitable for the pro-
Key words: perborate, sodium dehydrocholate, epoxidation, orga-
nomediator, terpene oxidation
duction of acid-sensitive terpene epoxides.
During the last few years we have published a number of
There is a strong need for the development of new epoxi-
papers on the epoxidation of different alkene typologies
dation methods that employ safer oxidants and produce
using dioxirane derivatives, originating from the reaction
little waste.1,2 Molecular oxygen is the ideal oxidant,2 but
of selected bile acids such as dehydrocholic acid (3,7,12-
oxidations with oxygen are difficult to control and over-
trioxo-5b-cholan-24-oic acid, 1a) and Oxone (KHSO5).24–26
oxidation products are often associated with this transfor-
In the present case we have replaced Oxone with sodium
mation.3 Hydrogen peroxide is a very attractive oxidant,
perborate as the oxygen source, using sodium dehydro-
atom-economic, inexpensive, and easily available with
cholate (1b) as an organic catalyst (Scheme 1). Sodium
water as the sole byproduct.4,5 Activation by different
dehydrocholate (1b) is an inexpensive and commercially
metals, such as tungsten, manganese, and titanium, is re-
available bile acid, produced from cholic acid by direct
quired in this case, under homogeneous or heterogeneous
chemical or biological oxidation.27 When a solution of the
conditions; interesting solutions overcoming or reducing
alkene (0.60 mmol), sodium dehydrocholate (1b, 0.55
the drawbacks in the use of transition metals or halogenat-
mmol), and sodium perborate (NaBO3·4 H2O, 1.3 mmol)
ed solvents have been proposed in recent years.6 Further-
was simply stirred in acetonitrile–water (1:1.5, 12.5 mL)
more, activation by fluorinated alcohols has been reported
at room temperature, complete conversion of the substrate
to accelerate remarkably oxidations with hydrogen perox-
was observed in 6–18 hours, with formation of the ep-
ide, even in the absence of an additional catalyst.7–9 An al-
oxides in yields ranging from good to excellent (Table 1).
ternative to these protocols is metal-free organic catalysis,
which mediates homogeneous oxidations without the
need for metal complexes.10 Perhydrates,11 dioxiranes,12,13
O
oxaziridines,14 oxaziridinium,15 and oxammonium16,17
COO–
Na+
salts, generated from the corresponding organic catalyst
by reaction with a suitable oxygen source (H2O2, KHSO5,
NaOCl), are the most extensively employed oxidants.
R1
O
1b
R1
O
O
R3
R2
R3
R2
Sodium perborate (SPB) and sodium percarbonate (SPC),
two of the most powerful yet underused oxidants avail-
able, are solid peroxygen compounds with great storage
stability and no shock sensitivity, that function as a source
of moderately alkaline hydrogen peroxide.18,19 They are
inexpensive, safe, easy to handle, and readily available,
being present in many domestic washing formulations. In
SPB, H2O–MeCN
Scheme 1
The reaction does not require careful control of the pH,
contrary to other oxidation protocols,28 and the moderate
alkaline medium, self-buffered by sodium perborate and
1b, does not lead to decomposition of the oxidant or over-
oxidation of the bile acid (Baeyer–Villiger).
SYNTHESIS 2009, No. 7, pp 1123–1126
x
x
.
x
x
.2
0
0
9
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1087999; Art ID: T18608SS
© Georg Thieme Verlag Stuttgart · New York

1124
O. Bortolini et al.
PAPER
Table 1 Epoxidation of Unfunctionalized Alkenes with Sodium
Perborate in the Presence of Sodium Dehydrocholate 1ba
1b
Entry
Alkene
Conversionb Yieldc
(%)
97
(%)
90
SPB
H2O–MeCN
ether
O
1
2
3
NaOH
O
2
COOH
H+ (aq)
99
98
99
94
86
93
1a
3
O
O
Cl
Scheme 2
4
5
bile acid derivative. The enhanced attitude of 1b to acti-
vate sodium perborate must be ascribed to the peculiar
characteristics of the carbonyl functions within the steroid
framework, not only to the surfactant properties pertain-
ing to cholic acid derivatives. In fact, independent epoxi-
dation experiments carried out in the presence of sodium
cholate, a bile acid lacking carbonyl functions, in place of
1b, gave low epoxide yields, analogous to those obtained
in the absence of the organic catalysts.
4
5
6
7
99
97
99
95
85
92
6
7
The solvent plays an important role in our epoxidation
system. Reactions carried out in water or water–methanol
gave poor conversions (2–5%) proving that acetonitrile
serves not only as co-solvent but also as co-reactant, able
to react with sodium perborate to form a peroxygenated
species, i.e. peroxyimidic acid, capable of activating the
ketone moiety of the bile acid with formation of a diox-
irane. Similar considerations were reported by Shi et al.29
for the epoxidations mediated by a fructose-derived ke-
tone using hydrogen peroxide as the primary oxidant.
8
t-Bu
8
96
80d
9
a Reaction time 18 h.
b Based on GC analysis.
c Yield of isolated product.
d Reaction time = 22 h, only the trans-epoxide was formed.
The mildness and simplicity of this oxidation method
prompted us to extend its application to unsaturated ter-
pene derivatives, where the corresponding epoxides are
usually labile and acid-sensitive. Epoxyterpenes are im-
portant starting materials for the synthesis of fragrances,
flavors, and therapeutically active substances.30 The perti-
nent results are collected in Table 2. Several literature re-
ports described the formation of different products in the
epoxidation of geraniol (10), as a function of the oxidation
system, i.e., 2,3-epoxide, 6,7-epoxide, bis-epoxide, gera-
nial derivatives.31–35 In our case the epoxidation occurs se-
lectively on the more nucleophilic 6,7-double bond to
give 17, with formation of small amounts of the bis-ep-
oxide (10%), but no 2,3-epoxide.34,35 The advantages of
our oxidation system are particularly well illustrated in the
case of linalool (11), exclusively epoxidized at the 6,7-
double bond to give 18 in 84% yield. The documented cy-
clization of the epoxide to tetrahydrofuran and tetrahydro-
pyran derivatives is a minor reaction pathway, with
formation of the sole product, 5-(1-hydroxy-1-methyleth-
yl)-2-methyl-2-vinyltetrahydrofuran, in 12% yield.32,36
This oxidation procedure may be efficiently applied to ter-
minal and internal alkenes, possessing aryl or alkyl sub-
stituents, in cis- and trans-configurations. Of particular
interest is the epoxidation of 3-tert-butylcyclohexene
which affords the corresponding trans-epoxide only
(Table 1, entry 8). The reaction work-up is easy and
straightforward with recovery of both the epoxide and the
bile acid derivative (Scheme 2). After complete conver-
sion of the alkene, monitored by GC analysis, the reaction
mixture is diluted with water and the epoxide is extracted
with diethyl ether. The organic catalyst is quantitatively
precipitated as dehydrocholic acid (1a) from the acidified
(5% HCl) aqueous layer, recovered by filtration, and re-
used after transformation into its sodium salt 1b. We have
repeated the recovery/reuse of 1b for three cycles with no
loss of catalytic efficacy.
The bile acid derivative takes an active part in the epoxi-
dation. In the absence of the bile acid, in fact, only small
amounts of epoxide are found, ca. 7% after 18 hours.
Moreover, in the presence of 1b a moderate enantiomeric
excess, up to 35% in the epoxidation of 4, was found that
may be unquestionably associated with the chirality of the
The method may be successfully expanded to other ter-
pene substrates such as (+)-3-carene (12) and (–)-a-
pinene (13). In both cases the respective epoxides 19 and
Synthesis 2009, No. 7, 1123–1126 © Thieme Stuttgart · New York

PAPER
Synthesis of Acid-Sensitive Epoxides
1125
Table 2 Epoxidation of Unsaturated Terpenes and Functionalized
Alkenes with Sodium Perborate in the Presence of Sodium Dehydro-
cholate 1b
hept-5-en-2-one, 15) and sulcatol (6-methylhept-5-en-2-
ol, 16), which were transformed into the corresponding
epoxides 22 and 23 in 93% and 86% yield, respectively.
No rearrangement products of sulcatone oxide (22) to
1,3,3-trimethyl-2,7-dioxabicyclo[2.2.1]heptane, usually
found in the epoxidation with peracids, was detected.38
Entry Substrates
Time Conversiona Product
Yieldb
(%)
(h)
(%)
In summary, we have shown that the epoxidation of dif-
ferent unfunctionalized alkenes may be obtained in homo-
geneous conditions using inexpensive, safe, and
commercially available reagents such as sodium perbo-
rate and sodium dehydrocholate at ambient temperature.
Both the products and the bile acid organic mediator are
easily recovered and the latter may be reused without loss
of efficiency. The procedure is particularly recommended
for the production of acid-sensitive or labile epoxides
such as those obtained from the oxidation of unsaturated
terpenes. At the present time neither the reagents nor the
reduction product (borate) are regarded as posing an envi-
ronmental hazard.
OH
OH
1
9
97
80
O
10
17
OH
OH
2
9
98
99
84
97
O
11
18
19
O
3
18
All the epoxides are known compounds, characterized by compari-
12
1
son of their H NMR spectra with literature data. ESI-MS spectra
and elemental analysis were carried out to further confirm identity
and purity.
4
18
18
97
99
91
O
13
20
21
Epoxidation with Sodium Perborate/Sodium Dehydrocholate
(1b); General Procedure
5
50c
The alkene (0.60 mmol), sodium dehydrocholate (1b, 233 mg, 0.55
mmol), and NaBO3·4 H2O (Fluka, 200 mg, 1.3 mmol) were simply
stirred in MeCN–H2O (1:1.5, 12.5 mL) at r.t. The reaction was fol-
lowed by GC analysis and stopped when the conversion of the sub-
strate was complete or when the conversion remained constant for
two successive analyses. The mixture was diluted with H2O (15
mL) and extracted with Et2O (2 × 15 mL). The organic phase was
dried (anhyd Na2SO4), concentrated, and the epoxide rapidly puri-
fied by chromatography (deactivated silica gel, 1% Et3N in the elu-
ent during packing of the column). In the cases of substrates 10, 11,
and 14 the second product was also isolated by column chromatog-
raphy. The aqueous phase, containing the organic catalyst, was
acidified (5% HCl) with the consequent precipitation of the bile
acid derivative as dehydrocholic acid (1a), this was recovered by
filtration and transformed into its sodium salt 1b by treatment with
aq NaOH and reused without loss of catalytic efficiency.
O
14
O
6
18
98
90
93
86
O
O
15
22
23
O
7
6
OH
OH
16
trans-3-tert-Butyl-1,2-epoxycyclohexane39 (Table 1, Entry 8)
Purified by column chromatography (cyclohexane–CH2Cl2, 7:3).
IR (neat): 2995, 1445, 1250 cm–1.
a Based on GC analysis.
b Yield of isolated products.
c Ratio trans/cis 1.5 from 1H NMR analysis.
1H NMR (300 MHz, CDCl3): d = 0.94 (m, 1 H), 0.98 (s, 9 H), 1.25–
1.70 (m, 5 H), 2.10 (m, 1 H), 3.04 (d, J = 3.7 Hz, 1 H), 3.15 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 17.9, 22.8, 25.1, 27.4, 32.7, 44.8,
53.2, 54.1.
20 are formed in greater than 90% yield, with formation
of the trans derivatives only.36 Rearrangement products,
reportedly formed in the epoxidation of 13, were not de-
tected.37 Unexpected was the selectivity found with li-
monene (14), that afforded a mixture of mono- 21 and bis-
epoxides in similar amounts (55:45). Since this epoxida-
tion method is not particularly efficient with terminal
alkyl-substituted alkenes, we may conclude that the ep-
oxidation of the internal double bond somehow activates
the terminal one.
MS (ESI): m/z = 155 [M + H]+.
Anal. Calcd for C10H18O: C, 77.86; H, 11.76. Found: C, 77.52; H,
11.71.
trans-3,4-Epoxycarene40 (19)
No purification was needed prior to analysis.
IR (neat): 2987, 1423, 1254 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.46 (ddd, J = 2.1, 8.8, 9.0 Hz, 1
H), 0.54 (ddd, J = 2.2, 8.8, 9.0 Hz, 1 H), 0.74 (s, 3 H), 1.02 (s, 3 H),
1.27 (s, 3 H), 1.50 (dd, J = 2.1, 16.1 Hz, 1 H), 1.65 (dt, J = 2.2, 16.3
As additional examples for the epoxidation of alkenes
yielding acid-sensitive epoxides, we have considered the
cases of two non-terpenic substrates, sulcaton (6-methyl-
Synthesis 2009, No. 7, 1123–1126 © Thieme Stuttgart · New York

1126
O. Bortolini et al.
PAPER
(14) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.
Hz, 1 H), 2.15 (dd, J = 9.0, 16.1 Hz, 1 H), 2.31 (ddd, J = 1.8, 8.8,
16.3 Hz, 1 H), 2.85 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.7, 14.5, 15.8, 15.9, 19.0, 23.2,
23,4, 26.6, 56.0, 58.2.
(15) Bohe, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999, 55,
141.
(16) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H.
Synthesis 1996, 1153.
(17) Sheldon, R. A.; Arends, I. W. C. E.; Ten Brink, G.-J.;
Dijksman, A. Acc. Chem. Res. 2002, 35, 774.
(18) McKillop, A.; Sanderson, W. R. Tetrahedron 1995, 51,
6145.
(19) Muzart, J. Synthesis 1995, 1325.
(20) Sharifi, A.; Bolourtchian, M.; Mohsenzadeh, F. J. Chem.
Res., Synop. 1998, 668.
(21) Savizky, R. M.; Suzuki, N.; Bové, J. L. Tetrahedron:
Asymmetry 1998, 9, 3967.
MS (ESI): m/z = 153 [M + H]+.
Anal. Calcd for C10H16O: C, 78.89; H, 10.59. Found: C, 78.32; H,
11.02.
trans-a-Pinene Oxide40 (20)
Purified by column chromatography (cyclohexane–CH2Cl2, 7:3).
IR (neat): 2980, 1447, 1378 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95 (s, 3 H), 1.31 (s, 3 H), 1.35
(s, 3 H), 1.63 (d, J = 11.5 Hz, 1 H), 1.74 (m, 1 H), 1.94–2.09 (m, 4
H), 3.09 (d, J = 3.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.2, 22.5, 25.9, 26.8, 27.8, 39.7,
40.5, 45.1, 56.8, 60.3.
(22) Lasterra-Sanchez, M. E.; Felfer, U.; Mayon, P.; Roberts, S.
M.; Thornton, S. R.; Todd, C. J. J. Chem. Soc., Perkin Trans.
1 1996, 343.
(23) McKillop, A.; Sanderson, W. R. J. Chem. Soc., Perkin
Trans. 1 2000, 471.
MS (ESI): m/z = 153 [M + H]+.
(24) Bortolini, O.; Fogagnolo, M.; Fantin, G.; Maietti, S.; Medici,
A. Tetrahedron: Asymmetry 2001, 12, 1113.
(25) Bortolini, O.; Fantin, G.; Fogagnolo, M.; Forlani, R.;
Maietti, S.; Pedrini, P. J. Org. Chem. 2002, 67, 5802.
(26) Bortolini, O.; Fantin, G.; Fogagnolo, M.; Mari, L.
Tetrahedron 2006, 62, 448.
(27) Bortolini, O.; Medici, A.; Poli, S. Steroids 1997, 62, 564.
(28) Shi, Y. Acc. Chem. Res. 2004, 37, 488; and references
therein.
Anal. Calcd for C10H16O: C, 78.89; H, 10.59. Found: C, 78.39; H,
11.01.
Acknowledgment
This work was supported by MIUR (Italy) PRIN 2006 and Univer-
sities of Calabria and Ferrara.
(29) Shi, Y.; Shu, L. Tetrahedron 2001, 57, 5213.
(30) de Villa, P. A. L.; De Vos, D. E.; de Montes, C. C.; Jacobs,
P. A. Tetrahedron Lett. 1998, 39, 8521.
References
(1) Sheldon, R. A. Green Chem. 2007, 9, 1273.
(2) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev.
2005, 105, 2329.
(3) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of
Organic Compounds; Academic Press: New York, 1981.
(4) Conte, V.; Bortolini, O. The Chemistry of Peroxides, Vol. 2;
Rapoport, Z., Ed.; J. Wiley & Sons: Chichester, 2006, Chap.
13, 1053.
(31) Fringuelli, F.; Germani, R.; Pizzo, F.; Santinelli, F.; Savelli,
G. J. Org. Chem. 1992, 57, 1198.
(32) Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1996,
61, 5307.
(33) Martins, R. R. L.; Neves, M. G. P. M. S.; Silvestre, A. J. D.;
Simões, M. M. Q.; Silva, A. M. S.; Toméa, A. C.; Cavaleiro,
J. A. S.; Tagliatesta, P.; Crestini, C. J. Mol. Catal. A: Chem.
2001, 172, 33.
(5) Grigoropoulou, G.; Clark, J. H.; Elings, J. A. Green Chem.
2003, 5, 1.
(6) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977.
(7) Neimann, K.; Neumann, R. Org. Lett. 2000, 2, 2861.
(8) van Vliet, M. C. A.; Arens, I. W. C. E.; Sheldon, R. A.
Synlett 2001, 248.
(34) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.
(35) Grocock, E. L.; Marples, B. A.; Toon, R. C. Tetrahedron
2000, 56, 989.
(36) Villa, A. L.; Sels, B. F.; De Vos, D. E.; Jacobs, P. A. J. Org.
Chem. 1999, 64, 7267.
(37) Kunkeler, P. J.; van der Waal, J. C.; Bremmer, J.; Zuurdeeg,
B. J.; Downing, R. S.; van Bekkum, H. Catal. Lett. 1998, 53,
135.
(9) Berkessel, A.; Adrio, J. A. J. Am. Chem. Soc. 2006, 128,
13412.
(10) Adam, W.; Saha-Möller, C. R.; Ganeshpure, P. A. Chem.
Rev. 2001, 101, 3499.
(11) Ganeshpure, P. A.; Adam, W. Synthesis 1996, 179.
(12) Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989,
22, 205.
(38) Anderson, W. K.; Veysoglu, T. J. Org. Chem. 1973, 38,
2267.
(39) Murray, R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M.
J. Org. Chem. 1996, 61, 1830.
(40) Saladino, R.; Andreoni, A.; Neria, V.; Crestini, C.
Tetrahedron 2005, 61, 1069.
(13) Murray, R. W. Chem. Rev. 1989, 89, 1187.
Synthesis 2009, No. 7, 1123–1126 © Thieme Stuttgart · New York