Isomerization of bicyclic terpene epoxides into allylic alcohols without changing of the initial structure

Article abstract of DOI:10.1016/j.molcata.2013.09.016

A novel method of (1S,2R,3R,5R)-6,6-dimethyl-4-methylenebicyclo[3.1.1] heptane-2,3-diol synthesis, which is a valuable intermediate in the synthesis of a perspective potent anti-Parkinson drugs, in the presence of TiO₂ was proposed. Catalytic activity of TiO₂ in the bicyclic terpene epoxides isomerization to corresponding allylic alcohols without changing of the initial structure was demonstrated, contrary to titania-supported Au catalysts which promoted rearrangement with predominant formation of a cyclopentene α-hydroxy ketone.

Full text of DOI:10.1016/j.molcata.2013.09.016

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Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Isomerization of bicyclic terpene epoxides into allylic alcohols
without changing of the initial structure
Yu.S. Demidovaa, O.V. Ardashovb, O.A. Simakovac,d, I.L. Simakovaa, K.P. Volchob,
N.F. Salakhutdinovb, D.Yu. Murzinc,∗
a Boreskov Institute of Catalysis, pr. Lavrentieva, 5, 630090 Novosibirsk, Russia
b Novosibirsk Institute of Organic Chemistry, pr. Lavrentieva, 9, 630090 Novosibirsk, Russia
c Process Chemistry Centre, Åbo Akademi University, FI-20500 Turku/Åbo, Finland
d School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 30332-0100 Atlanta, GA, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2013
Received in revised form 30 August 2013
Accepted 11 September 2013
Available online xxx
A novel method of (1S,2R,3R,5R)-6,6-dimethyl-4-methylenebicyclo[3.1.1]heptane-2,3-diol synthesis,
which is a valuable intermediate in the synthesis of a perspective potent anti-Parkinson drugs, in the
presence of TiO2 was proposed. Catalytic activity of TiO2 in the bicyclic terpene epoxides isomerization
to corresponding allylic alcohols without changing of the initial structure was demonstrated, contrary
to titania-supported Au catalysts which promoted rearrangement with predominant formation of a
cyclopentene ␣-hydroxy ketone.
Keywords:
© 2013 Elsevier B.V. All rights reserved.
Pinene epoxide
Verbenol epoxide
Isomerization
Titania
Gold
1. Introduction
montmorillonite clays were actively studied for the synthesis of
the diol 1 [5,6], while the highest recently reported yield of this
The development of new effective medications for the med-
ical correction of the most common diseases is a challenging
topic in pharmaceutical industry. Terpenes represent a large and
diverse class of organic compounds that possess biological activity
and are widely used in the development of new drugs and vita-
mins. Recently the compound (1) in Scheme 1 synthesized from
naturally derived verbenone was demonstrated to exhibit high
anti-Parkinson’s activity in the in vivo experiments in combination
with low acute toxicity [1,2].
At the same time a set of the most probable metabolites of this
compound is of great interest for the further pharmakinetic exam-
ination, particularly triol 3. The effective way leading to compound
3 starts from two steps transformation of available verbenone to
verbenol epoxide. The key step of the triol 3 synthesis is verbenone
epoxide isomerization to compound 2 which is a valuable inter-
mediate. According to the published earlier results for this reaction
type selectivity to products can be affected by the presence of Lewis
and Brønsted acid sites as well as the reaction conditions such as
polarity and basicity of the solvent [3,4]. The application of different
compound (79%) was obtained using Fe-modified zeolite [7].
At the same time to the best of our knowledge, the compound
2 as well as the method of its synthesis has never been described
in the literature. Generally the rearrangement of epoxides to corre-
sponding allylic alcohols is an attractive approach which has been
thoroughly investigated. Different methods, including reaction
with alkylamide bases [8–11], use of organoselenium chemicals
[12] and a radical pathway ((C5H5)2TiCl) [13], are known. There are
a few examples of epoxides isomerization over heterogeneous cat-
alysts, such as Al2O3, ZrO2 and TiO2 [14,15]. However, the reaction
in the presence of these catalysts mainly proceeds extremely slow
or requires elevated temperature to form small amounts of allylic
alcohol. Recently gold catalysts were shown to be highly active in
the selective isomerization of terpene epoxides to the correspond-
ing allylic alcohols in contrast to TiO2 that was found to be inactive
without Au [16].
Nowadays special attention in the literature is deservedly
devoted to utilization of gold catalysts for fine chemical synthesis
due to its unique activity for transformations of organic com-
pounds. Many review articles concerning application of nano-gold
catalysis in organic reactions were published, including those by
Hashmi and Hutchings in 2006 [17], Corma and Garcia in 2008 [18],
Stratakis and Garcia [19] and Zhang et al. in 2012 [20]. Renewable
∗
Corresponding author. Tel.: +358 22154985.
E-mail address: dmurzin@abo.fi (D.Yu. Murzin).
1381-1169/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2013.09.016
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Scheme 1. Isomerization of verbenol epoxide.
monoterpenes conversion in the presence of gold nanoparticles
is one of the promising directions in transformation of biomass.
Some examples of unusual high activity of nanosized gold catalyst
in monoterpenes transformations were also described recently in
[21–23].
Ultimately, the main aim of this work was to synthesize
(1S,2R,3R,5R)-6,6-dimethyl-4-methylenebicyclo[3.1.1]heptane-
2,3-diol (2), which is a valuable intermediate in the synthesis of a
perspective potent anti-Parkinson compounds 3, from verbenone
epoxide using gold catalysts.
Thermo Scientific spectrometer was used in a full scan mode
(15–500 m/z, 70 eV electron impact ionization, direct sample
administration).
The epoxides isomerization was carried out at atmospheric
pressure in a glass reactor equipped with an electromagnetic
stirrer and a reflux condenser. The (-)-cis-verbenol, ␣-pinene
and verbenone epoxides were synthesized as reported previ-
ously [5,24,25]. The catalysts were additionally calcined before
the reaction. After 20 h the reaction mixture was filtered and the
solvent was removed under vacuum for identification of prod-
ucts composition by 1H NMR (CCl4–CDCl3 (1:1, v/v)). The resulting
mixture was separated by column chromatography (SiO2 (17 g,
60–200 ␮; Macherey-Nagel); hexane/Et2O 100:0 → 0:100). In the
case of the kinetic studies the aliquots were taken at appropriate
time intervals, filtered and also analyzed by 1H NMR (CCl4–CDCl3
(1:1, v/v)).
2. Experimental
2.1. Catalytic experiment
Reagents and solvents were purchased from commercial sup-
pliers and used as received. Dry solvents were obtained according
to the standard procedures. Optical rotation was measured
using polAAr 3005 spectrometer in CHCl3 solutions. 1H and
13C NMR spectra were obtained using Bruker DRX-500 appa-
ratus at 500.13 MHz (1H) and 125.76 MHz (13C) in CCl4/CDCl3
1:1 (v/v), chemical shifts ı in ppm were related to residual
CHCl3 [ı(H) 7.24, ı(C) 76.90 ppm], J in Hz. The structure of the
products was determined by analyzing the 1Н and 13C NMR
spectra, 1Н, 1Н double-resonance spectra and 13C, 1Н-type 2D-
COSY (J(C,Н) = 160 Hz). For high resolution mass spectrometry DFS
2.2. Catalyst preparation
The 2 wt.% Au/TiO2 catalyst was prepared from HAuCl4 aqueous
solution (5 × 10−4 M) by deposition-precipitation with urea at 81 ◦C
during 24 h over TiO2 (Degussa AG, Aerolyst 7708, anatase > 70%,
SBET = 45 m2/g). Obtained slurry was washed with NH4OH aqueous
solution (4 M) and deionized water. Thereafter, the catalyst was
dried at 60 ◦C for 12 h and calcined at 300 ◦C for 4 h.
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Table 1
Table 2
Verbenol epoxide isomerization over Au/TiO2 and TiO2. The reaction conditions:
␣-Pinene epoxide isomerization over Au/TiO2 and TiO2. The reaction conditions:
T = 80 ◦C, verbenol epoxide 0.4 mmol, 1,2-dicloroethane 10 ml, catalyst 35 mg.
T = 80 ◦C, ␣-pinene epoxide 0.4 mmol, 1,2-dicloroethane 10 ml, catalyst 35 mg.
Catalyst
Conversion (%)
Product selectivity (%)
Catalyst
Conversion (%)
Product selectivity (%)
1
2
4
5
6
7
8
9
Au/TiO2
TiO2 (anatase > 70%)
TiO2-a (anatase 100%)
100
100
100
25
23
20
21
40
44
43
34
30
11
4
6
Au/TiO2
TiO2 (anatase > 70%)
TiO2-a (anatase 100%)
100
100
100
32
49
36
38
25
36
22
17
18
8
9
10
3. Results
se resulted in the corresponding allylic alcohol (2) as the major
product.
In the current work, Au/TiO2 (>70% anatase) catalyst with the
Au particle size of ca. 2 nm, prepared by deposition-precipitation
method with urea, was found to promote the verbenol epoxide
isomerization with complete conversion in 15 h. The results of
experiments are presented in Fig. 1a.
Verbenol epoxide is transformed into a mixture of compounds
1, 2, 4, 5 (Scheme 1), the hydroxyl ketone 4 being the main prod-
uct with the selectivity 43% (Table 1). The desired product (2)
was formed in a yield of 21%. It should be noted that usual prod-
ucts of verbenol epoxide isomerization are only compounds 1,
4, 5, while compound 2 was never found before in the reaction
mixtures [5,6].
It was surprisingly observed that titanium oxide per se, which
was used for the catalyst preparation, also catalyzed the verbenol
epoxide isomerization with a comparable reaction rate (Fig. 1b). In
the presence of TiO2 the total conversion of verbenol epoxide was
attained for 20 h resulting in the target product (2) with selectivity
40% (Table 1), as well as in nearly the same selectivity to hydroxyl
ketone 4 and diol 1.
Unexpectedly the data obtained in the current study did not cor-
relate with that reported in [16], where gold nanoparticles were
shown to predominantly catalyze the isomerization of epoxides to
corresponding allylic alcohols. However in this case of titania the
catalytic activity can strongly depend on its allotropic forms, which
was also demonstrated for different reaction types [26–29]. It is
well known titanium dioxide occurs in the following main forms:
rutile, anatase and brookite. For the gold catalyst preparation TiO2
powder containing more than 70% of anatase was used in this work
(Degussa AG, Aerolyst 7708). In order to specify the eventual influ-
ence of titania phase, the 100% anatase form TiO2 (designated as
TiO2-a) was also tested in the verbenol epoxide isomerization. The
anatase form of titania afforded complete conversion giving a simi-
lar product distribution as a mixed phase titania (Table 1). Therefore
the data obtained demonstrate that TiO2 activity in epoxides isom-
erization is unlikely to be strongly connected with its allotropic
form.
In order to explore the role of gold in the epoxide transfor-
mations, gold on titania and titania per se were evaluated in the
isomerization of terpene epoxides with different molecular struc-
tures such as ␣-pinene epoxide which was used in [16] as one of
the substrate as well as verbenone epoxide. trans-Pinocarveol (6),
campholenic aldehyde (7) and pinocamphone (8) were found to
be the products of ␣-pinene epoxide isomerization in the pres-
ence of gold on titania in a ratio 65:25:10 [16]. In our experiments
␣-pinene epoxide was transformed to trans-pinocarveol (6), cam-
pholenic aldehyde (7), pinocamphone (8) and trans-carveol (9) as
shown in Scheme 2.
Similar types of products as for verbenol epoxide were observed
in the case of ␣-pinene epoxide for both Au catalyst and TiO2
(Table 2).
The activity of Au/TiO2 was comparable with TiO2. Au/TiO2 cat-
alyst was shown to promote mainly formation of campholenic
aldehyde (7) with selectivity of 38% and pinocarveol (6) with selec-
tivity of 32%. At the same time TiO2 containing more than 70% of
anatase resulted in pinocarveol (6) with 49% selectivity, while in the
presence of 100% anatase form of titania (TiO2-a) the equal amounts
(36% each) of pinocarveol (6) and campholenic aldehyde (7) were
obtained. These experiments confirm that Au nanoparticles play a
minor role in the formation of the corresponding allylic alcohol, and
titania as such can be applied in transformations of verbenol and
␣-pinene epoxides. It should be noted that at the present moment
it is too premature to assume applicability of pristine titania for
transformations of other epoxides to allylic alcohols. This would
require a special study with a broader base of polycyclic terpene
epoxides.
It is interesting that verbenone epoxide reacted neither over
Au/TiO2 nor TiO2 and its conversion was zero after 20 h. At the
moment, it can be only speculated that the peculiarities of molecule
coordination on the catalyst surface or the effect of the functional
group are responsible for these results.
Based on these results in the presence of TiO2 the concerted
mechanism of the epoxides isomerization, presented in the Fig. 2
for verbenol epoxide, can be envisaged. The epoxide molecule is
coordinated first to the catalyst Lewis sites following by the rapid
proton transfer. In the case of Au/TiO2 catalyst the mechanism of the
epoxide isomerization was proposed to be initiated by the coordi-
nation of oxygen atom in the epoxide to the Au␦+ species, inducing
It is important to note again that although titania per se
can catalyze rearrangements of verbenol epoxide, the presence
of gold nanoparticles supported on titania had an influence on
reaction selectivity. For instance primarily hydroxyl ketone 4
was formed over Au/TiO2, while the reaction over titania per
α
Scheme 2. Isomerization of ␣-pinene epoxide.
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a
b
verbenol epoxide
100
100
verbenol epoxide
1
1
2
4
5
2
80
80
60
40
20
4
5
60
40
20
0
0
0
5
10
15
20
0
5
10
15
20
Time, h
Time, h
Fig. 1. Product distribution as a function of the reaction time during verbenol epoxide isomerization over Au/TiO2 (a) and TiO2 (b). The reaction conditions: T = 80 ◦C, verbenol
epoxide 0.4 mmol, 1,2-dicloroethane 10 ml, catalyst 35 mg.
Fig. 2. Proposed mechanism for the isomerization of verbenol epoxide over TiO2.
the ring opening and followed by subsequent or concerted alkyl
shifts.
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