Synthesis of novel methoxyether derivative of isopulegol in a packed-bed flow reactor

Article abstract of DOI:10.1007/s00706-021-02778-8

8–Methoxymenthan–3–ol was synthesised in a packed-bed flow reactor by the reaction of isopulegol and methanol in the presence of amberlyst-15 dry hydrogen form catalyst. Key parameters that affect isopulegol conversion and 8–methoxymenthan–3–ol formation were investigated and optimised. The reaction was found to be highly temperature-dependent, and to be less dependent of isopulegol: methanol molar ratio. Higher temperatures coupled with rapid flow rates resulted in higher isopulegol conversion. The optimum working temperature in the reactor was 57 °C and a maximum yield of 51.8% of 8–methoxymenthan–3–ol was obtained in 27.4 min at a flow rate of 3.6 cm³/min. Graphic abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-021-02778-8

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-021-02778-8
ORIGINAL PAPER
Synthesis of novel methoxyether derivative of isopulegol
in a packed‑bed fow reactor
Upenyu Guyo1 · Buyiswa G. Hlangothi1 · Ben Zeelie1
Received: 15 September 2020 / Accepted: 26 April 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
8–Methoxymenthan–3–ol was synthesised in a packed-bed fow reactor by the reaction of isopulegol and methanol in the
presence of amberlyst-15 dry hydrogen form catalyst. Key parameters that afect isopulegol conversion and 8–methoxy-
menthan–3–ol formation were investigated and optimised. The reaction was found to be highly temperature-dependent,
and to be less dependent of isopulegol: methanol molar ratio. Higher temperatures coupled with rapid fow rates resulted in
higher isopulegol conversion. The optimum working temperature in the reactor was 57 °C and a maximum yield of 51.8%
of 8–methoxymenthan–3–ol was obtained in 27.4 min at a fow rate of 3.6 cm3/min.
Graphic abstract
Keywords Isopulegol · Methanol · Amberlyst-15 dry hydrogen · Packed bed fow reactor · 8–Methoxymenthan–3–ol
Introduction
industry and consumer products. While there is a signif-
cant motivation for such research from a job creation point
of view, especially in a developing region such as South-
ern Africa, there is also signifcant scientifc motivation for
undertaking a project of this nature. Thus the use of natural
feedstocks can lead to the development of environmentally
benign and sustainable materials.
Although South Africa is rich in natural resources and has a
signifcant petrochemical industry, most fne chemicals are
imported from overseas as there are very few fne chemical
industries. There is therefore a pronounced interest to use
these abundant natural resources in the development and
evaluation of a range of value-added compounds for use in
sensitive applications. The use of these natural resources
ensures economic self-sustenance as this develops a sustain-
able business concept from the cultivation of plant material
through the isolation of rich oil from the plant material, to
the conversion of the oil (or components thereof) into the
One important natural feedstock which is widely used
in the synthesis of high-value chemicals is citronellal, a
monoterpenoid aldehyde. Citronellal (1), also known as
rhodinal (3,7–dimethyloct–6–enal), is obtained from Cor-
ymbia Citriodora Hill oil, Johnson Cymbopogon Nardus
oil, and Java Citronella oil by steam distillation to give a
non-racemic mixture of R and S enantiomers [1]. Citronel-
lal is a repellent against mosquitoes and has been widely
used as an insect repellent [2]. It also works efectively as
an antifungal and has been used frequently in pharmaceu-
ticals [3]. Furthermore, it is a very versatile compound in
* Upenyu Guyo
upguyo@gmail.com
1
Nelson Mandela University, PO Box 77000,
Port Elizabeth 6031, South Africa
Vol.:(0123456789)
1 3

U. Guyo et al.
perfumery and cosmetic applications as well as a precursor
in the synthesis of several important terpenes. Moreover,
citronellal can be transformed chemically or biochemically
into important compounds such as citronellol [4–7], iso-
pulegol [8–14], menthol [15–19], and p–menthane–3,8–diol
(6) [20–22] which have numerous applications industrially
such as children’s products, pharmaceutics, insect repel-
lents, food products, cosmetics, personal care products [2,
7]. Besides being a versatile starting material for the syn-
thesis of numerous compounds, citronellal is cheap and
readily available. Together with its derivatives, it becomes
a possible suitable starting material for the production of the
essential fne chemicals.
As part of our overall research goals, we report herein
the synthesis of a novel ether derivative of isopulegol
using continuous fow technology. Here, we take advan-
tage of continuous fow technology which ofers chemistry
safety, processing time reduction, easy scale-up, reproduc-
ibility, and process overall yield improvement [24–28].
The synthesis method involves the etherifcation of iso-
pulegol with methanol in fow using amberlyst-15 catalyst
(Scheme 2). The ether derivatives are in the meantime
being investigated in our research group for a variety of
applications including further derivatisation.
Isopulegol (2) is a monoterpenic alcohol derived from
citronellal through a cyclisation reaction [9–14]. Cyclisa-
tion of (+)–citronellal yields four diastereoisomers namely
(−)–isopulegol, (+)–neo–isopulegol, (+)–iso–isopulegol,
and ( +)–neoiso–isopulegol, whereas, cyclisation of
(−)–citronellal yields (+)–isopulegol, (−)–neo–isopulegol,
(−)–iso–isopulegol, and (−)–neoiso–isopulegol as shown
in Scheme 1. Of the four isomers, isopulegol and neo–iso-
pulegol are the main isomers.
Scheme 2
MeOH
Catalyst,
OH
heat
OH
OMe
2
3
Isopulegol is an important material employed in the man-
ufacture of fragrances in the favour and perfume industry.
It is a useful starting material for the synthesis of three iso-
mers of 5,9–dimethylpentadecane, which are the main sex
pheromone components [23]. It is also an important inter-
mediate in the synthesis of the (−)–menthol isomer which
is employed in toothpaste, cigarettes, sweets, agrochemicals,
pharmaceutical, and personal care products.
Scheme 1
Cyclisation
O
OH
OH
(+/-)-neoisopulegol
(+/-)-citronellal
(+/-)-isopulegol
1
OH
OH
(+/-)-neoiso-isopulegol
(+/-)-iso-isopulegol
2
1 3

Synthesis of novel methoxyether derivative of isopulegol in a packed-bed fow reactor
settings used for this investigation together with the actual
Results and discussion
experimental results are shown in Table 2.
Unlike the batch reactor, it is not possible to separate
the efects of mixing and residence time in the packed-bed
reactor. The degree of mixing in the packed-bed reactor is
determined by the linear fow velocity of reagents through
the bed: as the fow rate increases so does the degree of
mixing. At the same time, however, the residence time in the
reactor is reduced. Figure 1 illustrates the efect of increas-
ing fow rate at constant temperature and MeOH: isopulegol
molar ratio.
Synthesis of 8–methoxymenthan–3–ol
in a packed‑bed reactor
The etherification of isopulegol with methanol in a
packed-bed reactor was investigated in the experimental
domain given in Table 1.
The investigation was carried out over a total of 24
experiments (Table 2). Several replicate experiments were
included in the 24 experiments to check the long-term per-
formance of the amberlyst-15 catalyst. The experimental
The results depicted in Fig. 1 clearly show that both iso-
pulegol conversion and 8–methoxy–menthan–3–ol forma-
tion decreases continuously with increasing fow rate. The
efect of increasing temperature, whilst keeping the fow
rate and the MeOH: isopulegol molar ratio constant (Fig. 2)
shows that isopulegol conversion increases with increasing
reaction temperature as expected, but the amount of 8–meth-
oxymenthan–3–ol appears to reach a maximum at approxi-
mately 56 °C before starting a declining trend.
Table 1 Experimental domain
Temperature/°C
Flow rate/cm3
min−1
MeOH: iso-
pulegol molar
ratio
Min point
Max point
30
65
2
10
2
8
The effect of increasing the amount of methanol rela-
tive to isopulegol (Fig. 3) on both the isopulegol con-
version and the amount of 8–methoxymenthan–3–ol
Table 2 Experimental settings
Entry Temperature/°C Flow
Resi-
MeOH: iso-
Isopulegol
Ether yield /% Ether
and results—packed-bed reactor
rate/cm3
dence
pulegol molar conversion
selectiv-
min−1
time/min ratio
/%
ity/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
60
48
30
48
65
60
48
48
30
35
48
35
48
48
48
48
60
60
48
35
65
48
48
35
9
2
6
6
6
3
6
6
6
3
6
3
6
6
6
10
9
3
10.95
49.27
16.42
16.42
16.42
32.85
16.42
16.42
16.42
32.85
16.42
32.85
16.42
16.42
16.42
9.85
3
5
5
2
5
7
5
8
5
7
5
3
2
8
5
5
7
3
5
3
5
5
5
7
57.9
59.4
5
42.6
52.6
2.5
38.1
38.6
43.4
38.1
28.1
4.8
69.1
83.6
47
87.3
61.2
66.3
84.4
87.5
80.3
76
41
59.3
61.6
42.5
30.2
5.6
10.8
46.3
14.7
42.5
35.5
37.8
20.7
58.4
63.2
60.6
2.6
8.7
43.1
12.8
38.1
32.6
35
19.1
49.1
38.8
48.1
2.7
87.6
82
84.4
86.2
87.3
86.5
79.1
57.7
74.8
96.3
72.6
90.7
87.4
71.5
10.95
32.85
49.27
10.95
16.42
9.85
2
9
6
10
6
56.3
25.9
46.3
2.9
43.5
25
43
16.42
10.95
9
2.2
1 3

U. Guyo et al.
Fig. 1 Efect of fow rate on isopulegol conversion a and 8–methoxymenthan–3–ol formation b; temperature=47.5 °C; MeOH: isopulegol molar
ratio=5
Fig. 2 Efect of increasing temperature on isopulegol conversion a and 8–methoxymenthan–3–ol yield b; fow rate=6 cm3/min; MeOH: iso-
pulegol molar ratio=5
formation shows that there appears to be an optimum
MeOH: isopulegol ratio at around four equivalents MeOH
to one equivalent isopulegol.
Response surface modelling
The obtained experimental data (Table 2) were ftted to the
general second-order polynomial model (Eq. (1)) following a
step-wise regression analysis using the Design Expert V 11.0
software package:
The observed decrease in isopulegol conversion and
8–methoxymenthan–3–ol formation is probably a simple
dilution effect as the two curves in Fig. 3 seem to mirror
each other.
1 3

Synthesis of novel methoxyether derivative of isopulegol in a packed-bed fow reactor
Fig. 3 Efect of increasing MeOH: isopulegol ratio on isopulegol conversion and 8–methoxymenthan–3–ol formation; temperature=47.5 °C;
fow rate=6 cm3/min
Y = ꢀ0 + ꢀ1X1 + ꢀ2X2 + ꢀ3X3
+ ꢀ4X1X2 + ꢀ5X1X3 + ꢀ6X2X3
+ ꢀ7X21 + ꢀ8X22 + ꢀ9X32,
%isopulegolconversion = 41.70 + 15.05X1
− 10.34X2 − 1.78X3
− 6.36X1X3 − 5.70X2X3
(1)
− 3.76X12 − 1.96X32,
(2)
(3)
where βi = model coefcients; X1 = temperature; X2 = fow
rate; X3 = MeOH: isopulegol mol ratio.
%8 − methoxymenthan − 3 − ol = 39.67 + 10.97X1
− 8.49X2 − 2.86X3
The results of the Analysis of Variance are summarised
in Table 3 for the conversion of isopulegol results, and in
Table 4 for 8–methoxymenthan–3–ol formation results.
All of the insignifcant terms (p value>0.05) were disre-
garded to give the fnal regression models (Eqs. (2) and (3))
in terms of coded factors:
+ 4.91X1X2 + 8.63X1X3
+ 4.33X2X3 − 6.25X12
− 1.55X22 − 2.22X32.
Table 3 ANOVA data for
Source
Sum of squares df
Mean square F value p value
isopulegol conversion
Model
X1-Temperature
X2-Flow rate
X3-MeOH: isopulegol ratio
9072.32
3401.02
1661.51
58.44
288.52
255.34
349.42
91.47
41.90
0.9864
0.9796
0.9692
36.7838
7
1
1
1
1
1
1
1
5
1296.05
3401.02
1661.51
58.44
288.52
255.34
349.42
91.47
145.32
381.34
186.30
6.55
32.35
28.63
39.18
10.26
<0.0001 Signifcant
<0.0001
<0.0001
0.0227
<0.0001
0.0001
<0.0001
0.0064
0.5157 Not signifcant
X1 X3
X22X3
X12
X3
Lack of ft
8.38
0.9092
R2
Adjusted R2
Predicted R2
Adequate precision
1 3

U. Guyo et al.
Table 4 ANOVA data for
8–methoxymenthan–3–ol
formation
Source
Sum of squares df
Mean square F value p value
Model
X1-temperature
X2-fow rate
X3-MeOH: isopulegol ratio
X1 X2
X1 X3
4830.79
1613.71
942.33
102.13
180.46
422.04
125.42
855.31
54.85
9
1
1
1
1
1
1
1
1
1
2
536.75
1613.71
942.33
102.13
180.46
422.04
125.42
855.31
54.85
56.53
169.96
99.25
10.76
19.01
44.45
13.21
90.08
5.78
<0.0001 Signifcant
<0.0001
<0.0001
0.0073
0.0011
<0.0001
0.0039
<0.0001
0.0350
0.0071
X22X3
X12
X22
X3
103.16
5.08
103.16
2.54
10.87
Lack of ft
0.2300
0.7991 Not signifcant
R2
0.9788
0.9615
0.9297
Adjusted R2
Predicted R2
Adequate precision
22.1484
p Values of less than 0.05 (p = 0.0001) showed that the
models were statistically signifcant. This was further sup-
ported by higher regression coefcients of 0.9864 (iso-
pulegol conversion) and 0.979 (8–methoxymenthan–3–ol
formation). Small variations of 0.0104 (isopulegol con-
version) and 0.0318 (8–methoxymenthan–3–ol formation)
between predicted R2 and adjusted R2 are further evidence
for the signifcances of the models. In addition, the high
lack of ft F values of 0.5157 (isopulegol conversion) and
0.7991 (8–methoxymenthan–3–ol formation) implied
higher probabilities of the models ftting the data. Fur-
thermore, an adequate precision greater than 4 is desirable
as it measures the signal-to-noise ratio. Based on the above
results, adequate precision values of 36.7838 (isopulegol
conversion) and 22.1484 (8–methoxymenthan–3–ol forma-
tion) were obtained showing adequate signals.
Model validation
The normal probability plots for the residuals (observed
values − values predicted by the model) are shown in Fig. 4
for isopulegol conversion and in Fig. 5 for 8–methoxymen-
than–3–ol formation. Both these plots show that the residu-
als fall on, or nearly on a straight line, implying that the
residuals are normally distributed, hence that the observed
data are normally distributed.
Fig. 4 Normal probability plot of residuals—isopulegol conversion
model
Perturbation and three‑dimensional response
surface plots
In addition to the normal probability plots, a plot of the
predicted versus actual values shows a close agreement
between the two for the two models (Fig. S10 and S11).
Also, plots of predicted responses versus the residuals (Fig.
S12 and S13) do not show any particular trend (random dis-
tribution). These graphical tests show that the two models
do not show any abnormal behaviour and can therefore be
used for analysing the data.
Figure 6 shows the perturbation plots obtained using the
Design Expert software. The perturbation plot shows that the
temperature (X1) and fow rate (X2) had signifcant infuences
on both isopulegol conversion and 8–methoxymenthan–3–ol
formation whilst MeOH to isopulegol molar ratio (X3) had a
slight infuence on both.
Figures 7 and 8 show the 3-dimensional plots for iso-
pulegol conversion and 8–methoxymenthan–3–ol formation
1 3

Synthesis of novel methoxyether derivative of isopulegol in a packed-bed fow reactor
conversion, except that there is a clear maximum at 57
°C. This observation can probably be explained in terms
of the larger propensity for dehydration of 8–methoxy-
menthan–3–ol (3) to form the alkene 4 (Scheme 3) as the
reaction temperature increases above 57 °C.
Optimisation of the reaction parameters
The desirability function on the Design Expert software
was used to examine the optimum reaction conditions for
the synthesis of 8–methoxymenthan–3–ol in a packed-bed
fow reactor. The optimum conditions were deduced to be
a temperature of 57.9 °C, a fow rate of 3.6 cm3/min and
MeOH–isopulegol molar ratio of 3.9 for isopulegol conver-
sion of 64.0% and a temperature of 45.3 °C, a fow rate of
3.6 cm3/min and MeOH–isopulegol molar ratio of 3.2 for
an 8–methoxymenthan–3–ol yield of 51.8%.
Characterisation of 8–methoxymenthan–3–ol
The etherifcation of isopulegol involves the electrophilic
addition of methanol across the double bond. The identity
of the 8–methoxymenthan–3–ol product is evidenced by
the disappearance of alkene peaks on the IR spectrum of
8–methoxymenthan–3–ol (Fig. S4). The infrared spectrum
shows an O–H stretching band at 3454 cm−1 and a C–O–C
stretching band characteristic of a methoxy group at 1051
cm−1. The peak at around 1455–1367 cm−1 is character-
istic of a C–H bend showing the presence of methylene
and methyl groups and the one at 1161 cm−1 shows C–OH
stretching.
Fig. 5 Normal probability plot of residuals—8–methoxymenthan–3–
ol formation model
as a function of temperature and methanol: isopulegol molar
ratio.
The 3D response surface plots are in full agreement
with earlier observations, namely an increase in isopulegol
conversion with increasing reaction temperature, with the
MeOH: isopulegol ratio having virtually little efect on
the conversion. For 8–methoxymenthan–3–ol formation,
the general trend mirrors that observed for isopulegol
Fig. 6 Perturbation plots of the employed models, isopulegol conversion a, and 8–methoxymenthan–3–ol formation b
1 3

U. Guyo et al.
Scheme 3
+H+
-H
2O
OH
4
3
MeOH
OMe
OMe
+H+
-H
2O
OH
2
5
OH
Fig. 7 3-D response surface plot for isopulegol conversion
6
OH
8–methoxymenthan–3–ol as a singlet resonance at
δH = 3.18 ppm, and the methyl protons of the isopropyl
group were seen at 1.11 and 1.14 ppm as singlets (Fig.
S6). The H–3 proton resonated as a doublet of a triplet
at 3.57 ppm (J = 10.2 and 4.2 Hz) due to splitting by the
neighbouring protons. This proton is attached to the car-
bon atom which is bonded to an OH group and hence
its signal appears downfeld at 3.57 ppm. The 13C NMR
spectrum confrms the identity and purity of the isolated
product by the non-appearance of alkene peaks between
δC = 101.2 and 146 ppm (Fig. S7). The methoxy group
resonated at 48.5 ppm as confrmed by an HSQC NMR
spectrum (Fig. S8).
Conclusion
Synthesis in the packed-bed fow reactor was found to
depend highly on temperature and signifcantly on the fow
rate (residence time). Isopulegol conversion and 8–meth-
oxymenthan–3–ol formation decrease with an increasing
fow rate. Higher temperatures at longer residence times
resulted in higher isopulegol conversions. Several side
reactions, however, became signifcant which reduced
ether selectivity. These side reactions include dehydration
of isopulegol to 3–methyl–6–(prop–1–en–2–yl)cyclohex-
ene (5) and dehydration of 8–methoxymenthan–3–ol to
3–(2–methoxypropan–2–yl)–6–methylcyclohexene (4).
Other side reactions though not very signifcant include
Fig. 8 3-D response surface plot for 8–methoxymenthan–3–ol forma-
tion
8–Methoxymenthan–3–ol’s mass spectrum showed a
weak molecular ion peak at m/z = 187.1 corresponding to
C11H22O2+ and a base peak at m/z=73.1 corresponding to
C4H9O+ (Fig. S5). The peak at m/z = 171 corresponds to
C10H19O2 which is due to the loss of the methyl group from
the molecular ion.
1
The H NMR spectrum revealed the presence of
the new expected signals, three methyl protons of
1 3

Synthesis of novel methoxyether derivative of isopulegol in a packed-bed fow reactor
Fig. 9 Fixed-bed reactor for 8–methoxymenthan–3–ol synthesis.
1=Methanol feed; 2=Isopulegol/toluene feed; 3=Isopulegol/tolu-
ene/methanol premix; 4=HPLC pump; 5=Oil bath; 6=Reactor
packed with amberlyst-15 catalyst; 7=Heat exchanger, 8=Chilled
water out; 9=Chilled water in; 10=Pressure gauge (5 bar); 11=Heat
exchanger; 12=Reactor product
the formation of p–menthane–3,8–diol (6) from iso-
pulegol. The maximum working temperature in the reactor
before the decline of 8–methoxymenthan–3–ol formation
was 57 °C and the maximum of 51.8% was obtained at a
fow rate of 3.6 cm3/min.
mentioned otherwise, deuterated chloroform was used as a
solvent. Tetramethylsilane (TMS) was used as the internal
standard. Chemical shifts are reported in parts per million
downfield from TMS and coupling constants (J) are given
in Hz. NMR-signals multiplicities are abbreviated as fol-
lows: d = doublet; dd = doublet of doublets; dt = doublet
of triplet; m = multiplet; q = quartet; s = singlet.
Experimental
Fixed‑bed fow reactor setup
Amberlyst-15 dry hydrogen form (Sigma-Aldrich, con-
centration of acid sites ≥ 4.7 eq/kg, nitrogen BET: surface
area 53 m2/g; average pore diameter 300 Å; total pore
volume 0.40 cc/g), isopulegol (University of Cape Town,
94.1%), methanol (Merck, 95–98%), toluene (Merck,
99.8%), n–hexane (Merck, Analytical Reagent grade),
ethyl acetate (Sigma-Aldrich, Analytical Reagent grade),
sulfuric acid (Merck). All solvents were distilled from
their respective suitable drying agents and stored under
molecular sieves.
The tubular packed-bed reactor was made from 1/4 and 1/8
inch stainless steel tubing (Fig. 9). The reactor consisted
of two HPLC pumps; one used to pump the reaction feed
and the other one to pump chilled water to cool the reactor
efuent. The reactor consisted of three compartments: (1) A
pre-heater compartment which was a coiled 1/8 inch stain-
less steel tubing to heat the feed to the required temperature
before entering the reactor compartment. A thermocouple
was connected at the end of the pre-heater compartment to
allow for monitoring of the temperature of the feed. (2) A
98.54 cm3 reactor volume compartment which was fabri-
cated using a six-metre coiled 1/4 inch outside diameter and
0.035 inch wall thickness stainless steel tubing packed with
the catalyst, amberlyst 15 dry hydrogen form (60.11 g). At
its end was another thermocouple to measure the tempera-
ture of the reactor efuent. (3) A heat exchanger at the end
of the catalyst bed was used for cooling the reactor product
stream. A pressure sensor and an automatic valve were used
to maintain the pressure of the system and were positioned
after the heat exchanger.
Gas chromatographic analyses were performed on
an Agilent Gas chromatograph, equipped with a flame
ionisation detector. Data were acquired from the detector
using a Mecer personal computer equipped with Agilent
Chemstation software for the recording and integration
of chromatograms. IR spectra were recorded on a Bruker
Platinum Tensor 27 spectrophotometer with an ATR fit-
ting. Typically 100 scans were collected for each sample.
The characteristic peaks were recorded in wavenumbers.
NMR spectra were obtained with a Bruker Ultrashield
Plus, long hold-time operating at 400 MHz. Unless
1 3

U. Guyo et al.
Typical procedure
References
1. Lenardao EJ, Botteselle GV, De Azambuja F, Perin G, Jacob RG
(2007) Tetrahedron 63:6671
The oil bath was switched on and temperature set follow-
ing the experiments specifed by a central composite design
(CCD). The chilled water bath and the high-performance
liquid chromatography (HPLC) pump which pumped the
chilled water to the heat exchanger were switched on. The
pressure was set at 5 bar for all the experiments. Isopulegol
(30.0 g, 199.66 mmol), methanol (as per CCD), and 70
cm3 toluene were mixed thoroughly by shaking to obtain a
homogenous mixture. The reactor system was frst fushed
with toluene and equilibrated to the required temperatures.
Thermocouples were used to measure temperature. The reac-
tion mixture was then pumped into the reactor system by
an HPLC pump. The fow rates used were as per CCD. The
reactor efuent was collected in a receiving container, and
the system fushed with toluene to cater for residual reaction
products remaining in the system. Toluene and unreacted
methanol were removed on a rotorvapour and a sample ana-
lysed by gas chromatography (GC). In between the indi-
vidual runs, the reactor system packed with amberlyst-15
catalyst was washed with 10% H2SO4: MeOH (100 cm3) at
a fow rate of 5 cm3/min followed by fushing with 100 cm3
toluene in preparation for the next run.
2. Kim K-J, Kang C-S, Lee J-K, Kim Y-R, Han H-Y, Yun HK (2005)
Entomol Res 35:117
3. Nakahara K, Alzoreky NS, Yoshihashi T, Nguyem HTT, Trakoon-
tivakorn G (2003) Japan Agric Res Q 37:249
4. Corey E, Ensley HE, Suggs WJ (1976) J Org Chem 41:39
5. Kaur S, Rana S, Pal H, Rani D (2011) Z Naturforsch C J Biosci
66:260
6. Brito RG, Guimaraes AG, Quintans JSS, Santos MRV, De Sousa
DP, Badaue-Passos D Jr, de Lucca JW, Brito FA, Barreto EO,
Quintans LJ Jr (2012) J Nat Med 66:637
7. Katsukawa M, Nakata R, Koeji S, Hori K, Takahashi S, Inoue H
(2011) Biosci Biotechnol Biochem 75:1010
8. Jacob RG, Perin G, Loi LN, Pinno CS, Lenardao EJ (2003) Tet-
rahedron Lett 44:3605
9. Yongzhong Z, Yuntong N, Jaenicke S, Chuah G (2005) J Catal
229:404
10. Mäki-arvela P, Kumar N, Nieminen V, Sjöholm R, Salmi T, Yu D
(2004) J Catal 225:155
11. Coman SM, Patil P, Wuttke S, Kemnitz E (2009) Chem Commun
460
12. Fuentes M, Magraner J, Las Pozas CD, Roque-Malherbe R (1989)
Appl Catal 47:367
13. Kozhevnikova EF, Kozhevnikov IV, Gusevskaya EV (2004) Catal
Commun 5:425
14. Chuah GK, Liu SH, Jaenicke S, Harrison LJ (2001) J Catal
200:352
15. Cirujano F, Xamena LF, Corma A (2012) Dalton Trans 41:4249
16. Cortés CB, Galván VT, Pedro SS, García TV (2011) Catal Today
172:21
8–Methoxymenthan–3–ol (3, C11H22O2) FT-IR: ꢀ = 3454,
1
2926–2868, 1054, 906, 731 cm−1; H NMR (400 MHz,
17. Trasarti AF, Marchi AJ, Apesteguía CR (2004) J Catal 224:484
18. Oertling H, Reckziegel A, Surburg H, Bertram H (2007) Chem
Rev 107:2136
CDCl3): δ = 0.83 (3H, d, J = 4.0 Hz, C7H3), 0.87—0.93
(3H, m, C6HH, C5H, C2HH), 1.11, 1.14 (6H, 2 × s, C9H3,
C10H3), 1.16–1.26 (2H, m, C1H, C4H), 1.45–1.62 (2H, m,
C5HH, C6HH), 1.89 (1H, br t, C2HH), 3.18 (3H, s, OC11H3),
3.57 (1H, dt, J = 10.2, 4.2 Hz, C3H) ppm; 13C NMR (100
MHz, CDCl3): δ=19.8, 23.4 (C–9, C–10), 22.0 (CH3), 26.6,
34.7 (C–5, C–6), 30.9 (C–1), 43.8 (C–2), 48.3 (OCH3), 50.2
(C–4), 71.9 (C–3), 80.6 (C–8) ppm.
19. Nie Y, Jaenicke S, Chuah G (2009) Chem Eur J 15:1991
20. Yuasa Y, Tsuruta H, Yuasa Y (2000) Org Process Res Dev 4:1999
21. Vanek T, Novotny M, Podlipna R, David S, Valterova I (2003) J
Nat Prod 66:1239
22. Cheng H, Meng X, Liu R, Hao Y, Yu Y, Cai S, Zhao F (2009)
Green Chem 11:1227
23. Moreira JA, Corre AG (2003) Tetrahedron Asymmetry 14:3787
24. Porta R, Benaglia M, Puglisi A (2016) Org Process Res Dev 20:2
25. De Souza ROMA, Watts P (2017) J Flow Chem 7:146
26. Akwi F, Watts P (2018) Chem Commun 54:13894
27. Hughes DL (2018) Org Process Res Dev 22:13
28. Sagandira CR, Watts P (2019) Beilstein J Org Chem 15:2577
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s00706-021-02778-8.
Acknowledgements In loving memory of Professor Ben Zeelie†. The
authors would like to thank InnoVenton, and Nelson Mandela Univer-
sity Research Ofce for fnancial support.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
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