Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from isopulegol and benzaldehyde over heterogeneous catalysts

Article abstract of DOI:10.1016/j.cattod.2016.03.046

Benzodioxinols, compounds with 6-membered heterocycles containing two oxygen atoms, exhibit promising analgesic activity. In the current study, synthesis of dioxinol via two-step approach including Prins cyclization of isopulegol with benzaldehyde to tetr

Full text of DOI:10.1016/j.cattod.2016.03.046

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Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic
activity from isopulegol and benzaldehyde over heterogeneous
catalysts
a
a
a
a
a
Martina Stekrova , Päivi Mäki-Arvela , Ewelina Leino , Karolina M. Valkaj , Kari Eränen
a
a
a
b,c
,
Atte Aho , Annika Smeds , Narendra Kumar , Konstantin P. Volcho
Nariman F. Salakhutdinov , Dmitry Yu. Murzin
Laboratory of Industrial Chemistry and Reaction Engineering, Åbo Akademi University, FI-20500 Turku, Finland
N. N. Vorozhtsov Institute of Organic Chemistry, Russian Academy of Sciences, Novosibirsk 630090, Russia
Novosibirsk State University, Novosibirsk 630090, Russia
,
b,c
a,∗
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzodioxinols, compounds with 6-membered heterocycles containing two oxygen atoms, exhibit
promising analgesic activity. In the current study, synthesis of dioxinol via two-step approach includ-
ing Prins cyclization of isopulegol with benzaldehyde to tetrahydropyran and its ring-rearrangement to
dioxinol was investigated. Different acidic and basic catalysts were studied in the second step and the
highest selectivity toward dioxinol was achieved using mesoporous Ce-composite material.
Received 27 October 2015
Received in revised form 1 March 2016
Accepted 4 March 2016
Available online xxx
©
2016 Elsevier B.V. All rights reserved.
Keywords:
Terpenoid
Isomerization
Zeolite
Mesoporous material
Isopulegol
Benzaldehyde
Benzodioxinols
Prins cyclization
1
. Introduction
belongs to a group of natural compounds which can be isolated
from a variety of essential oils [4] or can be synthetically prepared
by catalytic cyclization of citronellal [5].
Interesting biologically active substances are synthesized from
a variety of compounds isolated from natural sources. It has been
recently reported that compounds with benzodioxin framework
can possess promising analgesic activity [1]. The compounds with
the mentioned structure were synthesized by the reaction between
cis-verbenol oxide and aromatic aldehydes in the presence of an
excess of montmorillonite clay [1,2] or later Fe-modified Beta zeo-
lite [3]. Due to importance of the target compound, low selectivity
towards it and a very limited amount of experimental data avail-
able, there is a need to further investigate synthesis of dioxinols
with promising biological activity.
Synthesis of tetrahydropyran (Fig. 1, compounds 4 + 5) by
Prins cyclization reaction of isopulegol and benzaldehyde was
recently demonstrated by our group [6]. Different parent zeolites
as well as their metal modified forms and mesoporous materi-
als have also been used in the comparative investigation focused
on Prins cyclization of isopulegol and 3-methyl-6-(prop-1-en-2-
yl)cyclohex-3-ene-1,2-diol (diol) with benzaldehyde. It has been
discovered, that dioxinol (Fig. 1, compound 3) is formed only in
minor amounts in the above-mentioned Prins cyclization reaction,
and acidic catalysts favor the formation of tetrahydropyrans (Fig. 1,
compound 4 and 5) [6]. The highest selectivity (over 90%) toward
tetrahydropyrans was achieved using mesoporous Ce composite
material derived from MCM-41.
In the current research, synthesis of the desired dioxinol (Fig. 1,
compound 3) was investigated by the reaction between isopule-
gol and benzaldehyde. Monoterpenic alcohol, isopulegol (Fig. 1)
The aim of the current work was to synthesize dioxinol over dif-
ferent heterogeneous catalysts applying a two-step synthesis route
for the desired dioxinol, including Prins cyclization of isopulegol
and benzaldehyde for producing mainly tetrahydropyran, 4 in the
∗ Corresponding author.
E-mail address: dmurzin@abo.fi (D.Yu. Murzin).
http://dx.doi.org/10.1016/j.cattod.2016.03.046
0
920-5861/© 2016 Elsevier B.V. All rights reserved.
Please cite this article in press as: M. Stekrova, et al., Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from
isopulegol and benzaldehyde over heterogeneous catalysts, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.046

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M. Stekrova et al. / Catalysis Today xxx (2016) xxx–xxx
O
O
O
+
1
2
CHO
O
OH
3
0
10
20
30
40
50
60
70
Angle 2ϴ (°)
fresh spent
O
O
+
H
H
Fig. 3. X-ray powder diffraction patterns of fresh and spent mesoporous Ce com-
OH
OH
posite.
4
5
Fig. 1. Reaction scheme of Prins cyclization of isopulegol and benzaldehyde. The
formed products are dehydration product (1) of tetrahydropyran (4, 5), dioxinol (3)
and product (2).
2
.2. Catalysts preparation
The NH4+ form of zeolites were transformed to proton forms at
◦
5
00 C in a muffle oven using a step calcination procedure.
MCM-41 (SiO /Al O ratio of 35) was synthesized in the sodium
2
1
1
5
.00E-014
.50E-014
.00E-014
.00E-015
2
2
3
weak
medium
strong
form (Na-MCM-41) using a Parr autoclave (300 mL) according to
Ref. [7] with a few modifications [8]. After synthesis of MCM-41, it
Cs-MCM-41
◦
was filtered, washed with distilled water, dried overnight at 100 C
and calcined at 450 C.
◦
Cerium, iron and cesium modified catalysts were prepared using
conventional evaporation impregnation method. Cerium, ferric and
cesium nitrates were used as metal precursors. The mixtures con-
taining the support material and an aqueous solution of metal
◦
precursor were stirred for 24 h at 60 C. The other steps of the syn-
◦
thesis were evaporation, drying at 100 C overnight and calcination
0.00E+000
◦
at 450 C for 4 h (the cesium catalyst calcination temperature was
◦
4
00 C).
-5.00E-015
Cs-Beta-25
2.3. Catalysts characterization
300
400
500
600
700
800
900 1000 1100 1200
The specific surface areas of supports and of metal modified
catalysts were determined by nitrogen adsorption using Sorptome-
Temperature (K)
Fig. 2. TPD of CO2 from Cs-MCM-41 mesoporous catalyst and Cs-Beta-25 zeolite
catalyst determined by mass spectrometry.
ter 1900 (Carlo Erba instruments). The samples were outgassed at
◦
1
50 C for 3 h before each measurement. The BET equation was used
for calculation of the specific surface area of mesoporous mate-
rials, silica and alumina and the Dubinin equation was used for
calculation of the specific surface area of microporous zeolites.
The acidity of the proton and metal modified catalysts was
measured by infrared spectroscopy (ATI Mattson FTIR) using pyri-
dine (≥99.5%) as a probe molecule for qualitative and quantitative
determination of both Brønsted and Lewis acid sites. The samples
were pressed into thin pellets (10–25 mg), which were pretreated
first step followed by its ring-rearrangement to dioxinol, 3. Since
the transformation of tetrahydropyran to dioxinol has been very
scarcely investigated [6], several types of catalysts, exhibiting only
Brønsted acidity, such as (1) ion-exchange resin Amberlite 120-H
and (2) Smopex-101, a fibrous, non- porous catalyst containing sul-
fonic groups, (3) only Lewis acidic Al O , (4), a basic MgO as well as
2
3
(
5) both Brønsted and Lewis acidic sites containing metal modified
◦
at 450 C before the measurements. Pyridine was first adsorbed
H-Beta zeolites and mesoporous materials derived from H-MCM-41
were used.
◦
for 30 min at 100 C and then desorbed by evacuation at different
temperatures. Three different temperatures were used for des-
◦
orption of pyridine. Desorption at 250–350 C corresponds to all
◦
2
. Experimental/methodology
(weak, medium and strong) sites, while 350–450 C interval reflects
medium and strong sites. Pyridine stays adsorbed after desorption
◦
2.1. Materials
at 450 C only on strong sites [9]. The amount of Brønsted and Lewis
acid sites was calculated from the intensities of the corresponding
−
1
−1
The NH -Beta-25 and NH -Beta-300 zeolites (25 and
spectral bands, 1545 cm and 1450 cm respectively, using the
molar extinction parameters previously reported by Emeis [10]. The
catalyst weights were taken into account in the calculations.
A Philips X’Pert Pro MPD X-ray powder diffractometer was used
in the XRD measurements. The diffractometer was operated in
Bragg-Brentano diffraction mode, and the monochromatized Cu-
K␣ radiation was generated with a voltage of 40 kV and a current
of 50 mA. The primary X-ray beam was collimated with a fixed 0.25
4
4
3
00 = SiO /Al O molar ratios, Zeolyst International), Aluminum
2 2 3
oxide (UOP Inc.) and Smopex-101 (Smoptech, Johnson Matthew).
Ferric, cerium and cesium nitrates (Fluka) used as the metal
precursors, magnesium oxide, Amberlite IR-120H, benzaldehyde
(
Fluka, 99.0%), (−)-isopulegol (Aldrich, 98.9%) and toluene (anhy-
drous, 99.8%) were supplied by Sigma-Aldrich (Germany) and used
as received.
Please cite this article in press as: M. Stekrova, et al., Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from
isopulegol and benzaldehyde over heterogeneous catalysts, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.046

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3
Table 1
Main textural characteristics of the prepared H-Beta-25, Fe-Beta-300, Cs-Beta-25, Cs-MCM-41, fresh and spent mesoporous Ce composite catalysts.
2
Catalyst/support
Nominal metal content (wt%)
Specific surface area (m /g)
H-Beta-25 [11]
Fe-Beta-300 [11]
Cs-Beta-25
Cs-MCM-41
Fresh mesoporous Ce composite
Spent mesoporous Ce composite
–
2
2
10
32
32
807
587
229
642
384
666
Table 2
Brønsted and Lewis acidities of the H-Beta-25, Fe-Beta-300, Cs-MCM-41, fresh mesoporous Ce composite and spent mesoporous Ce composite catalyst determined by FTIR
using pyridine as a probe molecule.a
Catalysts
Brønsted acidity (␮mol/g)
Lewis acidity (␮mol/g)
◦
◦
◦
◦
◦
◦
450 C
250
C
350
C
450
C
250
C
350
C
H-Beta-25 [11]
Fe-Beta-300 [11]
Cs-MCM-41
Fresh mesoporous Ce composite
Spent mesoporous Ce composite
269
90
0
80
105
207
57
0
49
6
120
0
0
10
0
162
67
11
67
12
128
16
10
12
2
113
0
0
9
0
a
Acidity of Cs-Beta-25 was not measured.
divergence slit and a fixed 15 mm mask. A 0.18 parallel plate colli-
mator was used in the diffracted beam side prior to the proportional
counter. The measured 2␪ angle range was 1.0–70.0, with a step size
of 0.04 and measurement time of 2.0 s per step. The samples were
measured in Cu sample holders.
another catalyst was tested with the same reaction mixture. The
samples were taken at different time intervals and analyzed by GC
using the same method as for samples from the addition reactions.
3. Results and discussion
TPD of CO2 was performed with the following procedure using
Autochem 2910 apparatus. The catalyst, 250 mg was dried in
◦
◦
3.1. Catalysts characterization
helium flow by heating it with the rate of 30 C/min up to 300 C for
0 min. Thereafter the temperature was decreased to room tem-
1
Specific surface areas of supports and metal modified catalysts
are given in Table 1. The acidic pristine H-Beta-25 zeolite is char-
perature. The adsorption of CO2 (AGA, 99.99%) was carried out
at room temperature for 60 min followed by flushing the catalyst
for 30 min with helium flow (AGA, 99.996%). Thereafter the TPD
was performed under helium flow using the following tempera-
2
acterized by very high specific surface area >800 m /g. The specific
surface areas of the catalytic materials after the metal introduction
are lower due to partial pore blocking. Significantly lower specific
surface area was measured for Cs-Beta-25 and mesoporous Ce com-
posite catalysts. A large decrease in specific surface area in the case
of mesoporous Ce composite was caused by high loading of ceria
(32 wt.%) and by partial distortion of the mesoporous hexagonal
phase [8]. The spent mesoporous Ce composite catalyst showed
higher specific surface area than the fresh Ce-composite catalyst
(Table 1),
Loaded amounts of metals on the supports are given in Table 1. In
most cases, supports were modified by small amounts of metals in
the range 1–10 wt.%. An exception was Ce-composite derived from
MCM-41 in order to achieve 32 wt.% loading of ceria. The nominal
loading of Cs- in Cs-Beta-25 was 2 wt%.
◦
◦
◦
ture programme: 25 C–20 C/min–900 C. The mass of CO , 44 was
2
recorded with a mass spectrometry (Balzers Instruments).
2.4. Catalytic tests
Addition reactions of isopulegol and benzaldehyde over het-
erogeneous catalysts were carried out in liquid phase using a
batch-wise glass reactor. In a typical experiment the initial amounts
of isopulegol and the catalyst mass were 0.3 g each resulting in
isopulegol concentration 0.04 mol/l. The kinetic experiments were
performed in order to avoid internal and external mass transfer
limitations using catalysts particle size <90 ␮m and the stirring
speed of 390 rpm, respectively. The catalyst was activated in the
The concentrations of acid sites in the studied materials are
given in Table 2. The acidic pristine zeolite H-Beta-25 is char-
acterized by the presence of highest Lewis and Brønsted acidity.
Comparably mild Lewis and Brønsted acidity was determined for
Fe-Beta-300 and Ce-MCM-41 based composite.
◦
reactor at 250 C in an inert atmosphere for 30 min before the reac-
tion. Benzaldehyde was used in excess (VL = 50 mL) and no other
◦
solvent was applied. The reaction temperature was 70 C. The sam-
ples were taken at different time intervals and analyzed by GC with
a capillary column HP-5 (30 m x 320 ␮m x 0.5 ␮m) using the fol-
The pristine H-MCM-41 mesoporous catalyst is characterized
by very mild Lewis and Brønsted acidity being 40 and 26 ␮mol/gcat,
respectively [12]. In case of cesium modification of this material, the
Lewis acidity decreased and Brønsted acidity totally disappeared.
The complete disappearance of the Brønsted acid sites from the Cs-
MCM-41 mesoporous catalyst can be explained on the basis of the
substitution of protons present in the H-MCM-41 by basic Cs sites
(Table 2).
◦
lowing temperature program: initial temperature 100 C (held for
◦ ◦
5
min), increased at 20 C/min to 280 C and held at the final tem-
perature for 3 min. The products were confirmed by GC–MS and
NMR spectroscopy.
The catalyst after the first reaction step was filtered and obtained
reaction mixture was used in the second step of the synthe-
◦
sis. 0.3 g of catalyst was activated in the reactor at 250 C in an
inert atmosphere for 30 min before the reaction and tested in the
rearrangement reaction. Reactions were carried out at different
reaction temperatures without addition of any solvent. In some
cases, sequential reactions were carried out for the second reac-
tion step. The catalyst was filtered from the reaction mixture and
As can be seen from the comparison of concentrations of acid
sites of the fresh and the spent Ce-MCM-41 composite catalyst
(Table 2), Lewis acidity was decreased during the reaction. On the
other hand, the total concentration of Brønsted acid sites increased
and medium and strong acid sites at the same time decreased.
Please cite this article in press as: M. Stekrova, et al., Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from
isopulegol and benzaldehyde over heterogeneous catalysts, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.046

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CHO
4
Table 3
The relative amounts of CO2 from the supported Cs catalysts determined by CO2
TPD.
O
Catalyst
Weak
Medium
Strong
Total
O
OH
Cs-MCM-41
Cs-Beta-25
0.20
0.34
0.50
0.32
0.11
0.34
0.81
1
O
H
OH
4+5
3
Fig. 4. Reaction scheme for the two-step synthesis of dioxinol 3 starting from isop-
ulegol and benzaldehyde forming tetrahydropyran 4, 5 in the first step.
3
.2. Catalytic results
Relative amounts of basic sites for Cs-MCM-41 were determined
with mass spectrometry using the CO2 signal and normalizing the
results by assigning the value of 1 to Cs-Beta-25. The results pre-
sented in Table 3. It is noteworthy to mention here that although
the Cs-MCM-41 mesoporous catalyst contained 10 wt% of Cs, the
total relative amount of basic sites (0.81) was less than that of Cs-
Beta-25, with only 2 wt% of Cs. The result clearly shows the inability
of a larger amount of 10 wt% Cs to be transferred to the total active
basic sites (Table 3). The basic sites in Cs-Beta-25 were determined
Two step synthesis of the desired dioxinol (Fig. 4, compound
3), including Prins cyclization of isopulegol and benzaldehyde in
the first step and the subsequent ring-rearrangement of formed
tetrahydropyrans (Fig. 4, compounds 4 + 5), was investigated in the
current study. Besides ring-rearrangements also undesired dehy-
dration of tetrahydropyrans was detected in the previous work
[6].
◦
by CO2 desorption between 300 − 450 C analogously to Ref. [13].
3.2.1. Prins cyclization
Prins cyclization of isopulegol and benzaldehyde to synthesize
tetrahydropyran moiety, was the main task of our previous research
Comparison between the basicity data for 32 wt.% mesoporous
Ce composite catalyst reported in [8] and the values for Cs contain-
ing materials is not straightforward because in the former case TCD
[
6]. Different pristine proton (H-) zeolites as well as their metal
◦
detector was used and heating was done up to 600 C, while in the
modified forms (iron, cerium, gold) and MCM-41 mesoporous
materials have been used as catalysts in the comparative investiga-
tion. The highest activity and selectivity towards tetrahydropyran
moiety has been achieved using the mesoporous Ce composite cat-
alyst. Therefore, the Prins cyclization was performed using this
catalyst in the current study giving the results which are depicted
◦
current work TPD spectra were measured up to 900 C. Moreover,
different temperature domains were used in assignment of weak,
medium and strong sites (Fig. 2).
The phase purity and structure of the fresh and the spent meso-
porous Ce composite material were studied with X-ray powder
diffraction (Fig. 3). As has been published previously [8], neither
the major peaks which are characteristic for the MCM-41 meso-
◦
in Table 4. Complete conversion (100%) of isopulegol at 70 C was
achieved within 1 h from the beginning of the reaction and the
selectivity to tetrahydropyrans (compounds 4 + 5) was 93%. The
selectivity to dioxinol (compound 3) was at the same time only
◦
porous material (in the 2ꢀ; value of 0.2−11 ) nor the peaks which
are present in a cubic fluorite structure of CeO2 were visible in the
diffraction pattern of the fresh mesoporous Ce composite. This fact
was most likely caused by partial distortion of the MCM-41 meso-
porous structure [8]. However, the main CeO2 peaks are shown at
3
%.
3
.2.2. Ring-rearrangement
Two types of products in addition to tetrahydropyran 4
2
ꢀ; values of about 28.6, 33.1, 48 and 57 for the spent mesoporous
Ce composite catalyst (Fig. 3).
have been formed in the reaction of isopulegol with alde-
hyde, namely dehydration product of tetrahydropyran, 1 and its
ring-rearrangement product, dioxinol, 3. We suppose that the ring-
rearrangement in tetrahydropyran compounds 4 and 5 leading to
dioxinol compound 3 is possible. The reaction may start from the
protonation of hydroxy-group in 4 and 5 followed by dehydration
with formation of a tertiary cation which may turn into the cor-
responding benzylic cation (Fig. 5). It should be noted that these
cations may be also formed by protonation of dehydration prod-
ucts 1 and 2. Further interaction of benzylic cation with water and
deprotonation leads to formation of an intermediate alcohol. Com-
pound 3 may be formed by protonation of the double bond of the
The main contribution to the creation of mesoporous, an
increase of the surface area and acidity should come from MCM-41
rather than ceria having a relatively low surface area. The peaks,
shown in the X-ray powder diffraction patterns for 32 wt% Ce-
MCM-41 spent mesoporous catalyst (Fig. 3) are, however, related
not to MCM-41 mesoporous material, but CeO . The appearance of
2
◦
the peaks at 2␪ values of 28–57 in the 32 wt% Ce-MCM-41 spent
mesoporousmaterialare attributedto CeO cubic fluorite structure,
2
while most of the peaks of MCM-41 mesoporous material appear
◦
before the 2␪ value of 11 . Thus, while leaching of ceria might be
present, resulting in lower intensity of XRD peaks, it cannot as such
explain the creation of mesopores. MCM-41 mesoporous material
studied in the current work has SiO /Al O ratio of 35, hence, a sub-
2
2
3
stantial increase of Brønsted acidity can be tentatively attributed
to rearrangement of the extra-framework aluminum species, situ-
ated at octahedral positions to the tetrahedral position, leading to
an increase in the number of Brønsted acid sites from 80 ␮mol/g in
the fresh catalyst to 105 ␮mol/g in the spent one.
This assumption relies on a concept that in general rear-
rangement of the extra framework octahedral Al species to the
tetrahedral framework in aluminosilicate type of zeolites and
mesoporous materials or re-insertion of Al in the framework may
take place not only during well-documented ex-situ catalyst pre-
treatment [14–18], but during the reaction depending upon nature
of reaction media and reaction conditions. This hypothesis requires
further elaboration, being outside of the scope of the present work.
Fig. 5. Reaction mechanism of the ring-rearrangement of tetrahydropyran, 5 to
dioxinol 3.
Please cite this article in press as: M. Stekrova, et al., Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from
isopulegol and benzaldehyde over heterogeneous catalysts, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.046

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5
Table 4
◦
Conversion of isopulegol, initial reaction rate and selectivities to different products at 100% conversion of isopulegol. The reaction temperature was 70 C.
Catalyst
Conversion after
0 min (%)
Initial reaction rate
(mol/(l min gcat))
Selectivity at total conversion (%)
6
1
3
Unidentified products
1
4 + 5
mesoporous Ce composite
100
33.5
3
3
93
100
100
◦
to 60 C. When the reaction temperature was elevated formation of
unknown products was detected over this catalyst.
3
Nearly no transformation of tetrahydropyrans (compounds
8
6
4
2
0
0
0
0
0
80
60
40
20
0
4
+ 5) was observed with only Brønsted acidic Amberlite 120H
◦
(Fig. 7, Table 5, entry 2) at lower reaction temperature (10 C) while
enhanced formation of the undesired dehydration product 1 and
unidentified products was observed at the higher temperatures.
Similarly to Amberlite 120H, tetrahydropyran transformation was
also quite minor (Table 5, entry 3) with Smopex 101 at 50 C. Unde-
sired transformation of tetrahydropyrans to unidentified products
was, however, already observed at 50 C over Smopex-101 (Table 5,
Entry 3) and at 60 C over Amberlite 120H (Table 5, Entry 2).
In addition, highly Brønsted and Lewis acidic H-Beta-25 gave at
90 C mostly unidentified products (Table 5, Entry 1) indicating
◦
◦
◦
◦
0
4
8
12
16
20
24
28
that strongly acidic catalysts are not suitable for transformation
of tetrahydropyran to dioxinol.
Time (h)
The results from the transformation of tetrahydropyran in a
sequential experiment, where Cs-Beta-25 in the step 1 and Fe-
Beta-300 in step 2 were used, are depicted in Fig. 8. Very slow
transformation of 4 + 5 to the desired 3 was observed over Cs-Beta-
Fig. 6. Transformation of tetrahydropyran over H-Beta-25 zeolite catalyst. Symbols:
tetrahydropyran (᭹), dioxinol (᭿), dehydration product 1 (open square), unknown
products (open triangle) and temperature (*).
2
8
5 without any improvement after elevation the temperature to
0 C. It should be mentioned here that the step change in the con-
◦
alcohol and subsequent heterocyclization. All these stages in prin-
ciple may be reversible.
centration of reaction compounds was caused by long storage of
the reaction mixture in the fridge (Fig. 8, before starting step 2).
No transformations of tetrahydropyrans were also observed over
a mildly acidic Fe-Beta-300 when the reaction temperature was in
Since dehydration and hydration reactions can be catalyzed
by acid and base catalysts [19], several different acidic, basic and
metal modified (Cs-, Fe-, Ce-) catalysts were tested in the ring-
rearrangement reaction of tetrahydropyran changes in the product
distribution are given in Table 5. The main focus of the inves-
tigation was to study the role of Brønsted and Lewis acid sites,
influence of basic sites and metal (Cs, Fe-, Ce) functions on the ring-
rearrangement reaction of tetrahydropyran and selectivities to the
products of dioxinol, dehydrated and other products.
◦
the range of 50–90 C.
Lewis acidic alumina, did not catalyze any transformation of
◦
tetrahydropyrans despite temperature increase to 80 C (Fig. 9, step
1
), indicating that Lewis acidity does not catalyze the rearrange-
ment of tetrahydropyrans to dioxinol (Table 5, Entry 5a, Fig. 9). The
obtained results with Fe-Beta-300 and Al O at relatively high tem-
peratures with minor conversion of tetrahydropyran are also in line
with the calculated total energies of tetrahydropyrans and dioxinol,
being 95.7 kJ/mol and 118.6 kJ/mol, respectively, showing that the
2
3
Transformation of tetrahydropyrans over highly acidic H-Beta-
2
5 containing Brønsted and Lewis acidity is depicted in Fig. 6.
Interestingly, no transformation was observed over H-Beta-25 up
1
00
100
80
60
40
20
0
80
60
40
20
0
0
5
10
15
20
25
30
35
40
45
Time (h)
Fig. 7. Transformation of tetrahydropyran over Amberlite 120H. Symbols: tetrahydropyran (᭹), dioxinol (᭿), dehydration product 1 (ᮀ), unknown 1 (open triangle), unknown
2
(solid triangle) and temperature (*).
Please cite this article in press as: M. Stekrova, et al., Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from
isopulegol and benzaldehyde over heterogeneous catalysts, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.046

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6
Table 5
The change in molar fractions in percentage (consumed—negative values, formed—positive value) with solid acidic catalysts H-Beta-25, Amberlite 120H, Smopex 101,
Fe-Beta-300, Lewis acidic Al2O3, basic Cs-Beta-25, MgO, and mesoporous catalysts Cs-MCM-41 and Ce-MCM-41.
◦
Entry Catalyst
Temperature ( C) Time (h) Tetrahydropyran (mol%) 4, 5
Dehydrated product 1 (mol%) Dioxinol 3 (mol%) Other products (mol%)
1
2
3
4
4
5
5
5
6
H-Beta-25
Amberlite 120H
Smopex-101
Cs-Beta-25
Fe-Beta-300
Al2O3
MgO
Cs-MCM-41
mesoporous Ce composite 70
90
60
50
55
50–90
80
50
1
−16
1
10
1
1
0
−1
−2
−2
2
16
7
4
0
<1
24
20
2
29
3
3.5
15
0.5
−15
−3
a
b
a
b
c
−3
0
<−1
No reaction
7
2
13
1
−11
−2
9
2
5
−1
100
−16
−9
Table 6
Selectivities to different products after ring-rearrangement over Ce-MCM-41 mesoporous catalyst.
◦
Catalyst
Temperature ( C)
Time (h)
Mol-% of different compounds
1
3
Unidentified products
4 + 5
Initial reaction mixture
mesoporous Ce composite (0.3 g)
–
70
90
–
2
1
24
0.5
3
3
3
3
3
1
5
6
8
8
10
12
93
89
54
59
46
50
45
+
+
+
fresh mesoporous Ce composite (0.1 g)
fresh mesoporous Ce composite (0.1 g)
fresh mesoporous Ce composite (0.1 g)
11
11
10
10
9
30
21
36
29
34
90
90
90
90
1
Step 1
Step 2
Step 2
Step 1
Step 3
1
00
100
80
60
40
20
0
1
00
100
8
6
4
2
0
0
0
0
0
8
6
4
2
0
0
0
0
0
80
60
40
20
0
0
5
10
15
20
25
30
0
6
12
18
24
30
36
Time (h)
Time (h)
Fig. 8. Transformation of tetrahydropyran over Cs-Beta-25 (step 1) and Fe-Beta-
00 (step 2). Symbols: tetrahydropyran (᭹), dioxinol (᭿), dehydration product 1
ᮀ), unknown 1 (open triangle), unknown 2 (solid triangle) and temperature (*).
Fig. 9. Transformation of tetrahydropyran over Al2O3 (step 1), MgO (step 2) and Cs-
MCM-41 mesoporous catalyst (step 3). Symbols: tetrahydropyran (᭹), dioxinol (᭿),
dehydration product 1 (ᮀ), unknown 1 (open triangle), unknown 2 (solid triangle)
and temperature (*).
3
(
tetrahydropyrans are more stable compounds. An important obser-
vation was the backward transformation of dioxinol (compound 3)
to tetrahydropyrans (compounds 4 + 5) catalyzed by a purely basic
catalyst, magnesium oxide (Table 5, entry 5b, Fig. 9, step 2).
The most significant dehydration of tetrahydropyrans to prod-
uct 1 was observed in the case of testing of Cs-MCM-41 mesoporous
3, however, was transformed back to tetrahydropyrans 4 + 5 and
unidentified products.
This is also a reason for seemingly apparent contradiction
between data in Table 5 (entry 6) after 30 min and the second entry
from Table 6, where after 2 h, the dioxinol 3 selectivity remained at
3%.
◦
catalyst at 100 C (Table 5, Entry 5c, Fig. 9, step 3) while no trans-
formations of tetrahydropyrans were seen using this catalyst at a
lower temperature, 50 C (Fig. 9, step 3).
Significant formation of the desired dioxinol 3 was observed
over mesoporous Ce composite (Table 5, entry 6), which contains
mild Brønsted and Lewis acid sites (Table 2) and also mild basic sites
An analogous formation of dioxinol from tetrahydropyran and
the reverse reaction was repeated when another portion of the
fresh ceria catalyst was added. This effect may be explained by
fast deactivation of catalytic centers responsible for formation of
dioxinol while centers leading to formation of tetrahydropyran
compounds remain to be active. The highest achieved selectivity
to the desired product with dioxinol framework (calculated based
on initial isopulegol conversion) was 36% using mesoporous Ce
composite catalyst.
◦
(
see Section 3.1). On the other hand, only dioxinol 3 was formed
from tetrahydropyrans over mesoporous Ce composite catalyst at
◦
7
0 C (Table 5, Entry 6) similarly to our previous results [6]. As it
can be seen from Table 6 addition of the fresh mesoporous Ce com-
posite catalyst caused initially a fast transformation of products
The currently presented results are in line with those already
published [6], where it was shown that pyran products 4 + 5 were
4
+ 5 to the desired product 3. After some time, the desired dioxinol
Please cite this article in press as: M. Stekrova, et al., Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from
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M. Stekrova et al. / Catalysis Today xxx (2016) xxx–xxx
7
transformed to dehydration product 1 over a catalyst contain-
ing high concentration of Brønsted acid sites, such as proton
forms of Beta zeolites, Au-Beta-25 and Fe-Beta-150, and ring-
rearrangement of 4 + 5 to 3 occurred in the case of using mildly
acidic catalysts and mainly in the reaction catalyzed by meso-
porous Ce composite mesoporous catalyst [6]. When starting the
reaction from isopulegol and benzaldehyde using mesoporous Ce
of the fresh ceria catalyst even if after some time, dioxinol was
transformed back to tetrahydropyran and to unidentified prod-
ucts. The highest achieved selectivity to the desired dioxinol was
36% over mesoporous Ce composite catalyst significantly improv-
ing the previously reported values for direct synthesis of dioxinol
from isopulegol and benzaldehyde.
◦
composite as a catalyst at 70 C, it was observed [6] that the
Acknowledgement
maximum amount of tetrahydropyran, 92 mol%, was formed with
isopulegol conversion of 96%. Thereafter the conversion of tetrahy-
dropyran was 24% within 120 min, out of which about 8 mol% was
converted to dioxinol in addition to the formation of other prod-
ucts, such as dehydration product [6]. In the two-step synthesis
method, the addition of 0.1 g of fresh mesoporous Ce compos-
ite facilitated a rapid transformation of tetrahydropyran and its
conversion in 30 min was 23% corresponding to the formation of
dioxinol about 15 mol%. In the current study, highly acidic cat-
alysts, such as H-Beta-25, Amberlite 120H and Smopex-101, did
not catalyze the desired ring-rearrangement of tetrahydropyran to
dioxinol. Moreover, formation of unidentified products and dehy-
dration of tetrahydropyrans were observed using these catalysts at
higher reaction temperatures.
This work is part of the activities at the Johan Gadolin Process
Chemistry Centre, a Centre of Excellence financed by Åbo Akademi
University.
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4
The desired ring-rearrangement, transforming tetrahydropyran
to dioxinol was observed in the reaction catalyzed by mesoporous
Ce composite catalyst, which exhibited both, mild acidic and basic
properties. Dioxinol formation was also observed after addition
Please cite this article in press as: M. Stekrova, et al., Two-step synthesis of monoterpenoid dioxinols exhibiting analgesic activity from
isopulegol and benzaldehyde over heterogeneous catalysts, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.046