Synthesis and Biological Activity of New 4-tert-Butylcyclohexanone Derivatives

Article abstract of DOI:10.1002/cbdv.201800411

In the synthesis performed in this study, derivatives of 4-tert-butylcyclohexanone 1 were obtained using typical reactions of organic synthesis. The bioactivity of the selected compounds was evaluated. 1-(Bromomethyl)-8-tert-butyl-2-oxaspiro[4.5]decan-3-o

Full text of DOI:10.1002/cbdv.201800411

DOI: 10.1002/cbdv.201800411
FULL PAPER
Synthesis and Biological Activity of New 4-tert-Butylcyclohexanone
Derivatives
Agata Kozioł,a, b Mateusz Jasnowski,a Ewa Grela,a Maryla Szczepanik,c Beata Gabryś,d
Katarzyna Dancewicz,d and Stanisław Lochyński*a, b
a
Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wyb. Wyspiańskiego 27,
50-370 Wrocław, Poland, e-mail: stanislaw.lochynski@pwr.edu.pl
Institute of Cosmetology, Wrocław College of Physiotherapy, Kościuszki 4, 50-038 Wrocław, Poland
b
c
Department of Invertebrate Zoology, Nicolaus Copernicus University, Lwowska 1, 87-100 Toruń, Poland
d
Faculty of Biological Sciences, University of Zielona Gora, Szafrana, 65-516 Zielona Góra, Poland
In the synthesis performed in this study, derivatives of 4-tert-butylcyclohexanone 1 were obtained using
typical reactions of organic synthesis. The bioactivity of the selected compounds was evaluated. 1-
(Bromomethyl)-8-tert-butyl-2-oxaspiro[4.5]decan-3-one (5) was characterized by attractant properties against
larvae and a weak feeding deterrent activity against adults of Alphitobius diaperinus PANZER. This bromolactone
was a moderate antifeedant towards Myzus persicae SULZER. In addition, ethyl (4-tert-butylcyclohexylidene)acetate
(2) and bromolactone 5 displayed antibacterial activity. The strongest bacteriostatic effect was observed against
Gram-positive strains: Bacillus subtilis and Staphylococcus aureus. The bromolactone 5 also limited the growth of
Escherichia coli strain.
Keywords: 4-tert-butylcyclohexanone, lactones, bromolactones, biological activity, antibacterial activity.
Introduction
the selected terpene derivatives was also proved in
The literature presents vast information on 4-tert- experimental tests in mice.[3] Monoterpenes – as the
butylcyclohexanone 1 – an analog of monoterpe- largest class of plant secondary metabolites – are
noids, containing the cyclohexane ring and 10 carbon generally associated with diverse biological activities,
atoms in its structure. This organic compound is including antioxidant, anti-inflammatory and vast
commonly used in the air care, perfumes and antimicrobial properties. They are known as dietary
fragrances, cosmetics and personal care products.[1] It components, pharmaceuticals and insect repellants.[4]
was also examined by testing its ability to produce Previously, derivatives with cyclohexane unit were
seizures or to inhibit seizures induced by pentylenete- used as a substrate for active compounds with high
trazol and maximal electroshock in CF-1 mice. In local anesthetic activity.[5] The same substrate was
addition, this compound was tested for its ability to subjected to the intramolecular modification of the
bind picrotoxin. Due to its interactions with the bicyclo[4.1.0]heptane system to produce the bicyclo-
inhibitory neurotransmitter γ-aminobutyric acid, picro- [3.1.0]hexane unit.[6]
toxin acts as a stimulant and convulsant and mainly
Due to the production of the undisclosed com-
impacts the central nervous system, causing seizures pounds in the 4-step synthesis reaction, we decided to
and respiratory paralysis when administered at high study their antifeedant activity against dangerous
doses.[2] Anticonvulsant and antidepressant activity of pests, lesser mealworm Alphitobius diaperinus PANZER
(Coleoptera: Tenebrionidae) and peach potato aphid
Myzus persicae SULZER (Hemiptera: Aphididae). The
lesser mealworm is one of the most important and
widespread pests in commercial poultry production
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/cbdv.201800411
Chem. Biodiversity 2019, 16, e1800411
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Chem. Biodiversity 2019, 16, e1800411
around the world. In chicken house, the pest occurs in consists of the protonation of the orthoacetate groups
large numbers mainly in the bedding litter, especially in the first stage. The resulting oxonium cation is
under feeders and drinking troughs.[7] M. persicae is attached to the hydroxy group of the alcohol. Due to
extremely polyphagous, highly effective in transmit- its positive charge/protons, other alcoholic groups are
ting plant viruses, and resistant to several classes of protonated. After the reduction of the EtO groups,
insecticides.[8] These species differ in the feeding deprotonation occurs and a diene is formed in which
habits and food preferences. The lesser mealworm the final form, e.g., γ,δ-unsaturated ester 4,[17] is
possesses the chewing mouthparts and consumes produced as a result of rearrangement of the
food as a whole, while the peach potato aphid has the charges.[18,19]
sucking-piercing feeding apparatus and relies solely
on plant sap in sieve elements that can be reached to γ,δ-unsaturated carboxylic acids starts with the
only after having penetrated outer plant tissues.
protonation of the carbonyl group of ester 4,[17]
The mechanism of reduction of unsaturated esters
Additionally, screening tests were performed causing it to become more electrophilic and resulting
against three commonly chosen bacterial strains: in the subsequent nucleophilic attack of the oxygen
Gram-negative Escherichia coli and Gram-positive atom of water on the carbonyl carbon atom. The
Bacillus subtilis and Staphylococcus aureus. E. coli is a charge transfer results in the formation of a tetrahedral
known model microorganism in biological assays and, oxide ion.[19] The next step is the deprotonation of
furthermore, has pathogenic properties, most often oxygen from the water. After deprotonation of the
resulting in urinary tract infections.[9] S. aureus, another oxide ion and the removal of EtOH, a carboxy-terminal
human pathogen, may cause bacteremia, endocarditis end product is formed.[20]
and – most commonly – skin infections.[10] On the
Another reaction was the lactonization of γ,δ-
other hand, most strains of B. subtilis are associated unsaturated acid 4,[17] which consists of the formation
with food spoilage and even poisoning.[11] Due to of a positively charged halonium ion by the reaction
structural diversity of these bacteria, their juxtaposi- of bromide with the alkene group. The nucleophilic
tion serves as a convenient approach for a basic hydroxy group is involved in the process of ring
antibacterial testing.
closure, thereby forming an intra-cyclic lactone 5.[21]
The biological activity of 4-tert-butylcyclohexanone
In the presented study, the starting compound 4-
tert-butylcyclohexanone (1) was obtained from 4-(1,1- (1) derivatives is poorly described in the literature.
dimethylethyl)cyclohexan-1-ol in a reaction with bis Here, the synthesis method of novel 1-(bromomethyl)-
(quinuclidine)bromine(I) bromide.[12] The mechanism 8-tert-butyl-2-oxaspiro[4.5]decan-3-one (5)[21] was pre-
of the reaction is based on the reaction of a carbonyl sented. Its antifeedant activity was evaluated against
ketone group with an α-metal phosphonate, in this common pests. The antibacterial properties of the
case triethyl phosphonoacetate, to obtain alkenes in derivative 2 and the resulting lactone 5[21] were also
the olefin form and readily soluble phosphate esters or presented and compared to the starting compound 1.
acids.[13] The reaction involves the deprotonation of
the triethyl phosphonoacetate, resulting in the
carbonate of the phosphonoacetate. The ketone 1 is
attached to the phosphorus atom to form a diethyl
Results and Discussion
phosphate and ultimately is linked to the α,β-unsatu- The synthesis reaction was performed as described in
rated isomer of the ester 2. The C=O double bond is Scheme 1 and started with the modification of 4-tert-
broken, and the carbon atom adopts the tetrahedral butylcyclohexanone (1) by the Horner-Wadsworth-
form. The tetrahedral form collapses by discarding the Emmons reaction. The resulting ethyl (4-tert-butylcy-
alcoholic group ROÀ , in this case the EtO group, and clohexylidene)acetate (2) was reduced using lithium
generating an intermediate form of the aldehyde. In aluminum hydride. The reaction product was an allyl
the next step, aldehyde reduction is performed by alcohol: 2-(4-tert-butylcyclohexylidene)ethanol (3). The
LiAlH4, the C=O double bond is again broken, the next step was to convert the resulting allyl alcohol to
electrons are transferred to oxygen, and the carbon is the unsaturated ester using the Claisen-Johnson
attached to the next hydrogen atom. The last step is rearrangement reaction. The reaction product was
the simple protonation reaction of the alkoxide.[14,15]
ethyl (4-tert-butyl-1-ethenylcyclohexyl)acetate (4).[17]
The allyl alcohol 3 obtained by the reduction of the The last step was the bromolactonization[22] of the
ester was subjected to a rearrangement reaction previously obtained ester to yield the bromolactone,
described by Claisen.[16] The reaction mechanism
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Chem. Biodiversity 2019, 16, e1800411
Scheme 1. The synthesis of the bromolactone 5. Reagents and conditions: a) DBU, LiCl, THF; b) LiAlH4, THF; c) MeC(OEt)3,
MeCH2COOH; d) NBS/THF, H2O.
Table 1. Feeding deterrent activity of the lactone 5 against the lesser mealworm, A. diaperinus. The results were presented as the
mean deterrence coefficients�SD.
Compound
Deterrence coefficients[a]
Larvae
Adult stage
A
R
T
A
R
T
5
1.57�2.28
À 27.97�8.25
À 26.40�8.24
7.67�1.58
23.55�9.9
31.22�7.69
[a]
A – absolute deterrence coefficient (no-choice test). R – relative deterrence coefficient (choice test). T=A+R (total deterrence
coefficient).
Table 2. Feeding deterrent activity of the tested lactone 5 on
the peach potato aphid M. persicae (SULZER). The results were
presented as the mean number of aphids�SD.
1-(bromomethyl)-8-tert-butyl-2-oxaspiro[4.5]decan-3-
one (5).[21]
The antifeedant activity of lactone 5[21] against the
lesser mealworm varied, depending on the develop-
mental stage of the pest (Table 1). In trials with larvae,
this lactone stimulated higher food intake compared
to the control, especially in choice test, and therefore
it is defined as attractant (T=À 26.40). The obtained
total deterrence coefficient for adults (T=31.22)
indicates poor deterrence properties of the lactone 5.
Time Number of aphids
Number of aphids
on treated leaves
p
ID
[h]
on control leaves
1
2
24
5.6�0.7
6.8�1.4
6.4�1.7
2.6�0.5
1.8�0.5
2.3�1.0
0.0016 0.38
0.0036 0.59
0.0530 0.48
For comparison, the value of this coefficient for the compound 5[21] appeared to be relatively durable:
most potent antifeedant, azadirachtin, was close to aphids avoided the treated leaves for at least 24 h
200, when determined using the same method.[23]
after exposure, although the potency of the effect
The activity of the studied compound 5[21] was decreased over time (Table 2). The indices of deter-
evaluated using aphid settling bioassay. Aphids only rence were relatively high (ID 0.38–0.59).
settle on a plant when they accept it as a food source
The antibacterial activities of compounds 1, 2 and
after having probed plant tissues with their piercing- 5[21] were evaluated (Table 3). In our research, starting
sucking mouthparts. During plant penetration with compound 1 was described with no antibacterial
their stylet-like mouthparts, aphids collect samples of activity. Ester 2 did not display bacteriostatic activity
plant sap for gustatory purposes. Chemical cues in toward E. coli and B. subtilis. However, it was effective
plant tissues determine the decision of aphids to against S. aureus, restricting the growth of the
accept or to reject the plant.[24] Aphids respond to bacterial culture by more than 60% at a 200 μg/mL
deterrents by walking away from the potential food concentration. Further incubations allowed us to
source.
calculate the minimal inhibitory concentration re-
In the present study, the application of compound quired to limit bacteria growth by 50% (MIC50) as
5[21] caused aphids to reject the treated plants as early 150 μg/mL. MIC90 was not recorded within examined
as 1 h after they had been granted access to the range of concentrations (50–250 μg/mL). Compound
treated leaves (Table 2). Thus, compound 5[21] exhib- 5[21] was not characterized as displaying strong
ited deterrent properties. The deterrent effect of bacteriostatic activity with MIC values over 250 μg/mL.
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Chem. Biodiversity 2019, 16, e1800411
contrast to the starting compound 1 that was inactive
under the standard incubation conditions. Notably,
the examined structures were more effective against
Gram-positive bacteria. Additionally, the bromolactone
5 was the only compound in the presented study that
was effective against E. coli strains.
Table 3. The antibacterial activities of compounds 1, 2 and
5.[21] Bacteria were cultured with 200 μg/mL compounds for
24 h. The assays were repeated minimum in triplicate on the
separate bacterial cultures. The results were presented as the
mean growth inhibition�SD.
Compound Growth inhibition [%][a]
Escherichia
coli
Bacillus
subtilis
Staphylococcus
aureus
PCM 2057
PCM 2021
PCM 2054
Experimental Section
1
2
5
0
0
0
0
0
Feeding Deterrent Activity
63.3�2.5
20.4�1.2
39.3�1.8
19.4�1.1
A previously described standard method employing
choice and no-choice tests was used to determine the
feeding deterrent activity of the studied compound
against A. diaperinus.[30] Oat flakes purchased from
Melvit S. A. (Warsaw, Poland) were used as the test
food. For the feeding assays, acetone solutions of the
[a]
After 24 h incubation with 200 μg/mL compound. The most
active positive control – gentamicin – limited growth of the
presented strains by 100%.
Still, it exhibited a slight antibacterial activity against test compounds were prepared at a concentration of
all examined bacterial strains with the strongest 10 mg/mL. One ml of solution or acetone alone as a
bacteriostatic activity towards B. subtilis. Here, an control was applied to one gram of flakes using a
incubation with 200 μg/mL compound 5[21] limited micropipette. After evaporation of the solvent (30 min
bacterial growth by approximately 40%. In comparison of air-drying), the flakes were weighted and placed in
to the starting compound 1 – a significant improve- Petri dishes (15 cm in diameter) together with 10
ment of the antibacterial activity was achieved. In our approximately 25–30-day-old larvae or 10 unsexed 7–
previous article, a similar enhancement of monoter- 10-day-old adults. In choice tests (insects could choose
pene antibacterial activity was observed after incorpo- either the control or treated food), control and treated
ration of bromolactone moiety into the molecule.[25] flakes were placed in Petri dishes and separated by a
Monoterpenes tend to exhibit weaker antibacterial thin glass capillary. In the no-choice test, insects were
activity towards Gram-negative strains,[26] in contrast exposed to only one type of food – treated or control.
to bromolactones that may affect the growth of both Four replicates for each type of test and each
Gram-positive and Gram-negative bacteria.[27] It is compound were conducted on insects at each life
assumed that it is the effect of the compounds stage. Dishes were maintained in the rearing chamber
°
interaction with cellular membranes, resulting in their at 29�1 C in the dark for 3 days. After this period, the
permeabilization and disruption.[4][28] Wider spectrum remaining uneaten oat flakes were reweighed and the
of bromolactone derivatives activity confirmed in our average weight of food eaten was calculated. This
studies may be the basis for a further search for novel value was the basis for calculating the deterrence
antimicrobials, as the growing drug resistance of coefficients.
common pathogens is a known matter of concern.[29]
The peach potato aphid M. persicae was used to
evaluate the deterrent potential of the bromolactone
against insects. Aphids (maintained as a multiclonal
colony) and plants (Chinese cabbage Brassica pekinen-
Conclusions
°
In the presented study, 1-(bromomethyl)-8-tert-butyl- sis) were reared in a laboratory at 20 C with 65% r.h.
2-oxaspiro[4.5]decan-3-one (5)[21] was synthesized via and a 16:8 (L/D) photoperiod. One- to seven-day-old
four step reaction. This compound was attractant for apterous female M. persicae and 3-week-old plants
larvae and a weak feeding deterrent against adults of with 4–5 fully developed leaves were used for the
A. diaperinus. Contrarily, compound 5[21] exhibited experiments. All experiments were performed under
relatively high deterrent effect (ID 0.38–0.59) against the same temperature, relative humidity, and photo-
the peach potato aphid M. persicae.
period conditions, described above. The procedures
A moderate bacteriostatic activity of derivatives 2 have been described in detail by Grudniewska et al.[8]
and 5 was observed (up to 60% bacterial growth Basically, this bioassay allows us to study aphid host
limitation at the concentration of 200 μg/mL), in the preferences under semi-natural conditions, where
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Chem. Biodiversity 2019, 16, e1800411
aphids are given a free choice between control and adjusted to 5×105 CFU/mL using 0.5 McFarland
treated leaves. Compound 5[21] was applied to one leaf standard. Stock solutions of examined compounds
of a plant by immersing it in a 0.1% ethanolic solution were prepared in ethanol and added to bacterial
of the indicated compound for 30 seconds. Control suspensions at final concentrations of 250–50 μg/mL.
leaves of similar size were immersed in 70% ethanol, Ethanol was added to the untreated control. Cultures
the solvent for compound 5.[21] Treated and control were incubated overnight at 37 C with gentle shaking.
°
leaves were placed in a Petri dish and allowed to dry The optical density was recorded at 650 nm using a
for 1 h before the start of the experiment to permit Tecan Sunrise microplate reader equipped with Magel-
the evaporation of the solvent. Next, aphids were lan software. The minimal inhibitory concentration
placed in the dish along the line that divided the (MIC50 and MIC90) was calculated as the lowest
arena into two halves and could choose between concentration that restricted the growth of micro-
treated (on one half of a Petri dish) and control leaves organism by 50% or 90%, respectively.[31]
(on the other half of the dish). Aphids that settled,
e.g., they did not move and the position of their
antennae indicated feeding, on each leaf were
Chemistry
counted at 1, 2 and 24 h intervals after the insects 4-tert-Butylcyclohexanone (1) was obtained from Sig-
were provided access to the leaf (8 replicates, 20 ma-Aldrich®. Macherey–Nagel, ALUGRAM SIL G/UV254
Viviparous apterous females/replicate). Aphids that tiles were used for the rapid analysis of thin-layer
were moving or not settled on any of the leaves were chromatography. A CombiFlash Rf+Lumen with a
not counted.
RediSept 12 gr column of silica gel flash column
chromatography or a 50 cm classical chromatography
The relative deterrence coefficient R was calculated column of Macherey-Nagel with a pore size of 0.04–
using the following formula:
0.063 mm was used to clean the compounds.
ðC À EÞ
R ¼
� 100
Gas chromatography measurements were per-
formed on an Agilent 7890A GC. Mass spectrometry
was performed on the Waters GCT Premier system,
consisting of a high resolution mass spectrometer with
a flight time (TOF) spectrometer. Infrared spectra were
recorded on a Bruker VERTEX 70 V equipped with ATR
Platinum and tÀh1e results were analyzed using Bruker
ðC þ EÞ
where C and E are the weights of the control and
treated foods consumed by the insects in the choice
test, respectively. The absolute deterrence coefficient
A was calculated using the same formula, but C and E
were obtained from the no-choice test. The total
coefficient of deterrence (T=A+R), which ranged
from À 200 to 200 served as the index activity.
Compounds with T-values ranging from 151 to 200 are
very good deterrents, those with values ranging from
101–150 are good deterrents, and those with values
of 51–100 are only moderate antifeedants. T-values
less than 50 indicate a weak deterrent activity.
Negative T values indicate attractant properties of the
compound.
~
OPUS; n in cm . The optical rotation was measured
with a polAAr 31 polarimeter. Measurements were
°
performed in a methanol solution at 24 C and a
wavelength of 589 nm, and the cuvette length was
100 mm. The NMR analysis was performed on a Bruker
Avance DRX 600 nuclear magnetic resonance spec-
trometer; δ in ppm relative to Me4Si as internal
standard, J in Hz. MestReNova version 6.0.2 was used
to describe the resulting NMR spectra. In the Support-
ing Information, the spectra of novel compounds 4[17]
and 5[21] were included.
Antibacterial Activity
Ethyl (4-tert-Butylcyclohexylidene)acetate (2).
The examined bacterial strains (Escherichia coli LiCl (0.0134 M) was dissolved in acetonitrile. The
PCM2057, Bacillus subtilis PCM 2021 and Staphylococ- mixture was stirred for 10 min. Then, a mixture of
cus aureus PCM2054) were obtained from the collec- triethyl phosphonoacetate (0.0133 M) and 1,8-diazabi-
tion of Polish Academy of Sciences.
cyclo[5.4.0]undec-7-ene (DBU; 0.00834 M) was dis-
solved in 15 mL of acetonitrile. The mixture was added
Tests of antibacterial activity were performed in 96- dropwise to the solution. After stirring for 40 min at
°
well microplates containing Mueller-Hinton broth. 0 C, 4-tert-butylcyclohexanone (1; 0.0063 M) in 5 mL of
Cultures were inoculated with bacterial suspensions acetonitrile was added to the mixture dropwise. The
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Chem. Biodiversity 2019, 16, e1800411
solution was mixed for 1 h in an ice bath. The reaction flash column chromatography (hexane/ethyl acetate,
was controlled by thin layer chromatography. After 4:1).
72 h, the synthesis reaction was discontinued, then
30 ml of distilled water and 40 ml of distilled hexane
1-(Bromomethyl)-8-tert-butyl-2-oxaspiro[4.5]-
were added. The product was extracted with hexane, decan-3-one (5). Ethyl (4-tert-butyl-1-ethenylcyclohex-
and then the combined organic layer was dried with yl)acetate (4; 0.001 M) in 5.5 ml of THF was mixed with
anhydrous MgSO4. The crude product was purified by 2 ml of distilled water. After 10 min of stirring, NBS
flash column chromatography (hexane/ethyl acetate, (0.025 M) was added to the mixture and then stirred at
°
4:1) to yield compound 2. IR (ATR): 3341 (m), 2953 0–5 C until the reaction was complete; the reaction
(vs), 2852 (vs), 1261 (vs), 1029 (m). H-NMR (CDCl3, was monitored by TLC. The mixture was then diluted
1
600 MHz): 1.16 (s, 9H, H-8, H-9, H-10), 1.22 (t, J=7.2, with Et2O and sequentially washed with a saturated
3H, H-3, H-4, H-5), 1.28 (t, J=3.9, 3H, H-14), 1.95–2.00 NaHCO3 solution and water. The organic layer was
(m, 2H, H-3, H-5), 2.50 (dd, J=11.7, 9.3, 4H, H-2, H-6), dried with anhydrous MgSO4. The crude product was
4.05 (q, J=4.8, 2H, H-13), 5.97 (s, 1H, H-11). 13C-NMR purified by column chromatography (hexane/isopro-
(CDCl3, 150 MHz): 14.01 (C-14), 16.20 (C-3, C-5), 20.86 panol/acetone/ethyl acetate 60:5:3:1) to yield com-
(C-8, C-9, C-10), 33.82 (C-2, C-6), 34.71 (C-7), 41.41 (C- pound 5.
4), 60.23 (C-13), 114.00 (C-11), 165.71 (C-1), 170.94 (C-
12). HR-TOF-MS (pos.): 224.1845 (M+; calc. 225.1850).
Acknowledgements
2-(4-tert-Butylcyclohexylidene)ethanol (3). Ethyl
(4-tert-butylcyclohexylidene)acetate (2; 0.0044 M) was English editing was funded by the Wroclaw Centre of
dissolved in 10 mL of anhydrous THF. A 10% solution Biotechnology Program, The Leading National Re-
of ester in solvent was placed in an ice bath and search Centre (KNOW) for the years 2014–2018
°
stirred slowly to a temperature of 0–2 C. After 15 min, (know.wroc.pl).
LiAlH4 (0.0087 M) was added to the flask. The reaction
was conducted for 80 min. The solution from the
precipitate was decanted by adding 6 mL of distilled
water and the product was extracted with hexane. The
Author Contribution Statement
organic phase was dried with anhydrous MgSO4. A. K. and M. J. synthesized the 4-tert-butylcyclohexa-
Product 3 was purified by flash column chromatog- none derivatives. E. G. performed the antibacterial
raphy (hexane/ethyl acetate, 4:1). IR (ATR): 3341 (m), studies. M. S., B. G. and K. D. evaluated the feeding
2953 (vs), 2852 (vs), 1261 (vs), 1029 (m). 1H-NMR deterrent activity. A. K., E. G. and S. L. wrote the article.
(CDCl3, 600 MHz): 0.91 (s, 9H, H-8, H-9, H-10), 0.97– A. K. obtained the funding for the English editing.
1.02 (m, 2H, H-3, H-5), 1.16–1.21 (m, 1H, H-4), 1.16–
1.21 (m, 2H, H-3, H-4), 1.51–1.61 (m, 2H, H-3, H-5),
1.63–1.75 (m, 2H, H-2, H-6), 1.76–1.88 (m, 2H, H-2, H- References
6), 2.08 (s, 1H, OH), 4.20–4.31 (m, 2H, H-12), 5.31–5.35
[1] S. Telalović, A. Ramanathan, J. F. Ng, R. Maheswari, C.
(m, 1H, H-11). 13C-NMR (CDCl3, 150 MHz): 22.71 (C-3, C-
Kwakernaak, F. Soulimani, H. C. Brouwer, G. K. Chuah, B. M.
5), 29.05 (C-8, C-9, C-10), 29.34 (C-2), 31.91 (C-6), 31.95
(C-7), 42.34 (C-4), 59.46 (C-12), 122.93 (C-11), 141.45 (C-
1). HR-TOF-MS (pos.): 183.1400 (M+; calc. 183.1670).
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Ethyl (4-tert-Butyl-1-ethenylcyclohexyl)acetate
(4). Compound 3 (0.00158 M) was charged in a solution
containing 14.5 mL of triethyl orthoacetate and
0.05 mL of propanoic acid. The reaction was per-
°
formed for 5 h at 135 C, and TLC (hexane/acetone
4:1) was used to monitor the reaction. After 5 h, the
reaction was removed from heat and allowed to
proceed for an additional 19 h. The synthesis reaction
was terminated after 24 h and triethyl orthoacetate
was distilled off. The crude product 4 was purified by
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Received August 16, 2018
Accepted November 27, 2018
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