Design, synthesis and biological evaluation of new ionone derivatives as potential neuroprotective agents in cerebral ischemia

Article abstract of DOI:10.1016/j.ejmech.2010.01.039

A new series of ionone derived allylic alcohols have been evaluated for anti-ischemic activity. Out of them, 12f and 13b decreased infarct volume to 23.98?±?4.7?mm³ and 93.98?±?24.8?mm³ as compared to ischemic group.

Full text of DOI:10.1016/j.ejmech.2010.01.039

European Journal of Medicinal Chemistry 45 (2010) 1964–1971
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and biological evaluation of new ionone derivatives as potential
neuroprotective agents in cerebral ischemia
,
Ajay Kumar Srivastava a, Preeti Dohare b, Madhur Ray b, Gautam Panda a
*
a Medicinal & Process Chemistry Division, Central Drug Research Institute, CSIR, Chattar Manzil Palace, Lucknow 226001, UP, India
b Pharmacology Division, Central Drug Research Institute, CSIR, Lucknow 226001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of ionone derived allylic alcohols have been evaluated for anti-ischemic activity. Out of
them, 12f and 13b decreased infarct volume to 23.98 ꢀ 4.7 mm3 and 93.98 ꢀ 24.8 mm3 as compared to
ischemic group.
Received 15 October 2009
Received in revised form
15 January 2010
Accepted 18 January 2010
Available online 28 January 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Ionone
Allylic alcohol
Cerebral ischemia
Stroke
1. Introduction
inflammatory agents [2–4], antiapoptotic agents [5] or antioxi-
dants [7–9].
Stroke being the major cause for cerebral ischemia, is the third
largest cause of death and disability in adults [1]. To-date there
exists only one FDA-approved treatment for ischemic stroke; i.e.,
the serine protease tissue-type plasminogen activator (t-PA,
a thrombolytic agent). Recombinant human t-PA treatment has
benefited ischemic stroke patients if given within 3–4 h of symp-
toms onset. After the focal ischemic stroke, brain tissues undergo
necrotic cell death due to the significant blood flow reduction.
During this process the nearby tissues surrounded to the necrotic
region known as ‘‘ischemic penumbra’’ remains metabolically
active and provides an opportunity for post-stroke therapy. There
are several mechanisms proposed for the neuroprotective therapy
which focus on lowering the activation of various toxic pathways
and activate the endogenous neuroprotective mechanisms [2–5].
Recently it has been established that the neurons in the ischemic
penumbra undergo apoptosis after several hours or days and thus
can be treated by antiapoptotic agents even after the onset of the
stroke [6]. Most of the reported compounds for the protection of
cerebral ischemia act as NMDA receptor antagonists, anti-
Recently some of the antioxidants like vinpocetine 1, its analog 2
[7], and curcumin 3 [10] have been reported as potential neuro-
preventive agents. Fabio et al. have reported GV150526A analogs 4
as potent glycine binding site antagonists in animal models of
cerebral ischemia [11]. Suh et al have also identified biological
activity and mechanism of quinolone analog 5 as anti-ischemic
agent [12]. MK 801; 6, {(þ)-5-methyl-10,11-dihydro-5H-diben-
zo[a,d]cyclohepten-5,10-imine maleate} is an orally active potent
NMDA receptor antagonist [13,15]. Spiromorpholone-benzopyran
derivatives 7a–b have also been found to act as anti-ischemic
activators of mitochondrial ATP-sensitive potassium channel [16].
In search of new and potent anti-ischemic agents, recently we
have reported synthesis and biological evaluation of amino-acid
based benzodiazepines 8, 9 as new class of anti-ischemic agents
(Fig. 1) [17–19]. However this series of compounds did not exhibit
very good potency in vivo. After careful searching of the literature,
we selected ionones 10, 11 as starting materials due to their
profound biological activities and wide occurrence in nature (Fig. 2)
[20–22].
Recently ionone derivatives have been reported as nuclear
hormone receptor ligands for the stimulation and/or improvement
of mammalian and particularly human skin [23]. Neuroprotection
by attenuating nitrosative [20] and oxidative stress [25,26] by
curcuma oil containing the same class of compounds is also
reported. Inspired by these findings we sought to incorporate the
* Corresponding author. Tel.: þ91 522 2364635; fax: þ91 522 2623405.
E-mail addresses: gautam_panda@cdri.res.in, gautam.panda@gmail.com (G.
Panda).
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.039

A.K. Srivastava et al. / European Journal of Medicinal Chemistry 45 (2010) 1964–1971
1965
Br
O
H
H
N
N
OH
R
N
N
R
EtO2C
Vinpocetine;
HO(H2C)O2C
OH
Mg, THF
12a-m
α-ionone; 10
1
2
O
H3CO
HO
OCH3
OH
Br
R
O
OH
Curcumin; 3
R
X
Mg, THF
NHR'
O
β-ionone; 11
NH
HN
CO2H
13 a-g
Scheme 1. Syntheses of the compounds.
N
N
(R'= alkyl, aryl,
heterocycle;
5
O
X= O, S)
NH
listed in Table 1. Curcumin; 3, a well known neuropreventive agent
[10] which is structurally similar to the synthesized compounds
was used as parent compound for biological studies. MK 801 6,
a potent NMDA receptor antagonist was used as the reference
compound for in vitro and in vivo biological evaluations.
Cl
NH
CH3
CO2Na
N
H
Cl
6
MK 801;
4
O
N
O
N
NHMs
Br
2.2. Biological studies
O
NHMs
O
2.2.1. In vitro testing of compounds
7b
7a
O
The forebrain neurons were isolated according to the method of
Dohare et al. [24]. Three groups were assigned to the isolated
neuron: (1) no treatment (2) hydrogen peroxide treated and (3)
pretreated with test compound followed by H2O2 treatment. For
H
N
O
H
N
O
(CH2)2SCH3
N
NH
9
OH
H2O2 treatment 1 ꢁ 106 cells/100
m
L were treated with equal
m
8
volume of H2O2 (concentration of 300
M) for 1 h at 37 ꢂC. For
pretreated group 1 ꢁ 106 neuronal cells/100
mL were pretreated
Fig. 1. Recently reported anti-ischemic agents.
with compound (100 m
M) for 20 min at 37 ꢂC followed by H2O2
treatment. For no treatment group, 1 ꢁ 106 neuronal cells/100
m
L
aromatic rings with various substituents in the parent
-ionones and to study them for the treatment of cerebral ischemia.
Herein, we report a new series of ionone derivatives with anti-
apoptotic property as neuroprotective agents for the treatment of
stroke.
a and
were maintained for 1 h and 20 min at 37 ꢂC. No treatment, H2O2
and/or compound treated neurons were re-suspended at
b
a concentration of 1 ꢁ 106 cells/100
mL in staining solution con-
taining binding buffer, FITC-labeled Annexin V and Propidium
Iodide (PI). Fluorescence was determined according to the manu-
facturer’s protocol (Calbiochem, Apoptosis Detection kit). Acquisi-
tion and analysis were performed with the Cell Quest software
package (Becton Dickinson, UK, Ltd.) [17].
2. Results and discussion
2.1. Chemistry
Representative dot plots of viable and apoptotic cell populations
of control, ischemic, MK 801 treated, curcumin treated and
compound treated groups (Fig. 3). The lower left hand quadrant
represents viable cells, lower right hand quadrant represents early
apoptosis, Upper right hand quadrant represents late apoptotic/
necrotic and upper left hand quadrant represents necrotic cells
respectively. Apoptotic population was decreased in 12f and 13b
treated group in comparison to Ischemic/Reperfusion (I/R) group.
The compounds 12a–m and 13a–g were synthesized from
reaction of appropriate Grignard reagent with
a-ionone 10 and
b
-ionone 11 respectively (Scheme 1) [27]. Substituted bromo-
benzenes were synthesized by reacting p-bromophenol with
various alkyl halides in presence of K2CO3 in acetone which was
converted into corresponding Grignard reagents on reacting with
activated Mg in dry THF. The synthesized allyl alcohols were tested
for their biological activity. In order to study the structure–activity
relationship (SAR), C Log P values of the synthesized compounds
were also calculated using chem. draw(R) programme. The struc-
tures of the prepared compounds and their biological activities are
2.2.1.1. In vitro testing results. The isolated neurons were labeled
with Annexin V-FITC and PI. Control neurons (LL) showed no FITC/
PI positive staining (1.15%/1.18%). The number of FITC positive
neurons (LR) was increased to 57.77% in ischemic neurons. 12f and
13b significantly decreased the number of FITC positive neurons to
4.31% and 4.9%, respectively. The number of viable neurons was also
increased by the treatment. In no treatment ischemic group,
viability was 30.23% (cells falling in the 4th quadrant, lower left).
Among the compounds tested, 13b and 12f increased the neurons
viability significantly to 91.9% and 82.3%. 13a and 12a showed the
neuron viability of 75.25 and 61.7% respectively. Moreover 13d, 13c,
12c showed 69.25, 66.4, 60.9% viability respectively. On the other
hand 12i, 12j, 12k, 12l, 12m and 12h showed the apoptotic
O
O
HO
R
R= alkoxy, thioalkoxy, alkyl
Designed prototype
α-ionone 10
β-ionone 11
Fig. 2. Structures of some active unsaturated ketones.

1966
A.K. Srivastava et al. / European Journal of Medicinal Chemistry 45 (2010) 1964–1971
Table 1
Synthesized compounds and their in vitro activity.
Entry
Treatment
Ionone
R
C Log P
Upper left
(Necrosis)
Upper right
(late apoptotic)
Lower left
(Normal viable)
Lower right
(Early apoptotic)
1
2
3
4
Control
Ischemia
Reference (MK-801)
Curcumin
–
–
–
–
–
–
–
–
–
–
–
–
1.02 ꢀ 0.40
0.72 ꢀ 0.37
1.96 ꢀ 0.90
1.89 ꢀ 0.67
2.22 ꢀ 0.70
11.26 ꢀ 2.36
1.56 ꢀ 3.90
7.30 ꢀ 2.80
93.66 ꢀ 2.19
30.23 ꢀ 4.21
82.45 ꢀ 2.40
79.90 ꢀ 6.50
3.09 ꢀ 1.40
57.77 ꢀ 5.40
14.9 ꢀ 5.60
24.15 ꢀ 4.65
(Parent compound)
5
6
7
8
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
13a
13b
13c
13d
13e
13f
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
a-ionone
b-ionone
b-ionone
b-ionone
b-ionone
b-ionone
b-ionone
b-ionone
C6H4-3-OCH3
C6H4-4-OCH3
C6H4-4-OC5H11
C6H4-4-SCH3
C6H4-2-OCH3
C6H4-4-OC3H7
C6H4-4-OC2H5
C6H4-4-CF3
C6H4-4-C(CH3)3
C6H5
C6H3-2,5-CH3
C6H3-3,4-OCH3
2-thienyl
C6H4-4-OCH3
C6H4-3-OCH3
C6H4-4-SCH3
C6H4-4-OC5H11
C6H4-4-OC3H7
C6H4-4-OC2H5
C6H4-2-OCH3
5.699
5.699
7.815
6.339
5.699
6.757
6.228
6.663
7.606
5.78
6.728
5.438
5.426
5.759
5.759
6.399
7.875
6.817
6.288
5.759
3.89 ꢀ 3.30
1.14 ꢀ 0.54
0.61 ꢀ 0.41
0.58 ꢀ 0.21
0.42 ꢀ 0.15
3.00 ꢀ 2.90
1.32 ꢀ 0.80
0.057 ꢀ 0.03
0.05 ꢀ 0.02
0.05 ꢀ 0.03
0.045 ꢀ 0.02
0.065 ꢀ 0.04
0.025 ꢀ 0.009
3.42 ꢀ 2.81
7.39 ꢀ 4.10
0.21 ꢀ 0.09
0.26 ꢀ 0.21
0.52 ꢀ 0.19
0.93 ꢀ 0.40
0.32 ꢀ 0.05
9.40 ꢀ 0.96
19.72 ꢀ 6.38
12.70 ꢀ 10.39
15.43 ꢀ 0.90
15.20 ꢀ 2.70
0.70 ꢀ 0.50
16.30 ꢀ 4.20
22.23 ꢀ 1.69
30.40 ꢀ 4.93
30.47 ꢀ 4.09
38.30 ꢀ 3.60
38.50 ꢀ 9.04
42.09 ꢀ 6.60
9.06 ꢀ 1.38
5.35 ꢀ 1.42
2.5 ꢀ 0.9
61.70 ꢀ 17.30
37.75 ꢀ 12.90
60.91 ꢀ 7.60
33.43 ꢀ 14.27
44.4 ꢀ 1.60
91.90 ꢀ 4.07
50.80 ꢀ 12.70
5.09 ꢀ 2.80
7.36 ꢀ 4.20
6.50 ꢀ 3.80
6.40 ꢀ 3.60
3.90 ꢀ 2.26
6.80 ꢀ 4.60
75.25 ꢀ 1.16
82.30 ꢀ 1.70
66.40 ꢀ 6.80
69.25 ꢀ 4.90
29.00 ꢀ 15.50
33.10 ꢀ 16.4
19.00 ꢀ 8.90
25.02 ꢀ 19.70
41.37 ꢀ 17.20
25.77 ꢀ 3.18
50.55 ꢀ 14.70
39.80 ꢀ 3.80
4.31 ꢀ 0.60
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
31.40 ꢀ 14.90
72.60 ꢀ 1.50
62.10 ꢀ 5.40
62.90 ꢀ 4.70
55.10 ꢀ 7.20
57.36 ꢀ 10.90
50.90 ꢀ 3.30
12.20 ꢀ 5.30
4.95 ꢀ 4.50
30.89 ꢀ 9.80
26.48 ꢀ 7.80
53.84 ꢀ 16.30
50.34 ꢀ 18.90
66.10 ꢀ 7.50
4.02 ꢀ 1.2
16.60 ꢀ 1.80
15.62 ꢀ 2.19
14.50 ꢀ 1.40
13g
5. I/R þ pre-treatment with 13b (100 mg/Kg Body weight, i.p.)
(Figs. 4 and 5)
population of neuron of 62.1%, 62.9%, 55.1%, 57.36%, 50.9% and 72.6%
respectively and the viability was greatly decreased.
6. I/R þ pre-treatment with 12f. (100 mg/Kg Body weight, i.p.)
(Figs. 4 and 5)
2.2.2. In vivo testing
Animals: Initially all rats were evaluated for neurological deficit
according to Wang et al. [28]. Rats showing any deficit were
excluded from the study. Male Sprague–Dawley rats 21 weighing
210–250 g were housed and maintained on a 12-h light/12-h dark
cycle with access to food and water. The experiments were
approved by the Animal Ethics committee of the Institute
following strict guidelines on the care and use of experimental
animals.
The dose and route of reference compound MK 801 and curcu-
min were administered as reported earlier. The test agents used in
this study were 13b and 12f. Dose of 100 mg/Kg was given 30 min
prior to MCAO via i.p. route.
2.2.2.3. Neurological evaluation. The observation was made up to
24 h for signs of neurological deficits. An observer who was
unaware of the identity of the groups assessed neurological deficits
after 24 h of clot implant (before sacrifice) and scored as described
by the Wang et al. [28] as follows: Score 0 for no observable
neurological deficit (normal); score 1 for failure to extend left
forepaw on lifting the whole body by tail (mild); score 2 for circling
to the contralateral side (moderate); score 3 for leaning to the
contralateral side at rest or no spontaneous motor activity (severe).
2.2.2.3.1. Determination of cerebral infarct. Staining of frozen
tissue slices was done with 2,3,5-triphenyltetrazolium chloride
(TTC) [10] which is colored red by electron transport in active
mitochondria and it defines a region in which mitochondrial
function is severely compromised by not staining that region thus
differentiation can be done by color. Red color depicts the viable
tissue while the pale or white colored region depicts the dead or
infarcted tissue. 24 h after reflow all the rats were given overdose of
chloral hydrate for decapitation. Brain was quickly removed and
placed in an ice-cold saline. Seven coronal slices of 2-mm thickness
were cut and treated with 2% 2,3,5-triphenyltetrazolium chloride
(TTC) for 15 min at 37 ꢂC. The stained brain sections were fixed with
4% formalin and analyzed. The deep red and white area of each
brain slice was determined using image analyzer software [26] for
infarct area. The volume of infarction was obtained from the
product of average slice thickness (2 mm) and sum of infarction
area in all the seven slices.
2.2.2.1. Focal embolic model. Blood was drawn from the femoral
vein of a donor rat. Embolic cerebral ischemia was induced as
reported with slight modifications [29]. Briefly, the animal was
anaesthetized with chloral hydrate (400 mg/kg) intraperitoneally.
The right CCA and ECA were clamped temporarily using micro-
vascular clips. A PE 50 catheter was advanced rostrally up to
17 mm in the ICA until its tip was 1–2 mm away from the origin of
the MCA. The clot of 3 mL volume was then slowly injected into the
MCA. The clips on the right CCA and the right ECA were removed
and the incision was closed. The animal was allowed to recover
from anesthesia. The sham operated rats underwent same surgical
procedure but no clot was injected into them. The rectal temper-
ature in the animals was kept at 37 ꢂC throughout the surgical
procedure with the help of heating lamps. No significant change in
rectal temperatures was observed in all groups.
2.2.2.2. Experimental protocol. The following groups were assigned
using various test agents in vivo and in vitro neuronal study:
1. Sham operated control
2. I/R þ no treatment
3. I/R þ pre-treatment with MK 801 (Reference compound)
(1 mg/Kg Body weight, i.v.) [30].
The edema volume in each brain was determined using the
same image analyzer software. For the determination of edema
4. I/R
þ
pre-treatment with Curcumin (Parent Compound)
(300 mg/Kg Body weight, i.p.) [29]

A.K. Srivastava et al. / European Journal of Medicinal Chemistry 45 (2010) 1964–1971
1967
Fig. 3. Extent of apoptosis and necrosis in neurons by flow cytometry (Cell Quest Analysis system).
volume, the contralateral brain volume was subtracted from ipsi-
lateral brain volume. Volume of contralateral and ipsilateral brain
slice was calculated from the product of the average slice thickness
(2 mm) and the sum of areas in all seven-brain slices. Edema
correlated significantly with the neurological score.
decreased the edema volume to 28.790 ꢀ 5.90 mm3 (P < 0.001) and
41.76 ꢀ 10.6 mm3 (P < 0.001). Pre-treatment with 12f and 13b
decreased the edema volume to 13.67 ꢀ 8.64 mm3 (P < 0.001) and
32.23 ꢀ 7.34 mm3 (P < 0.001) (Fig. 6). Pre-ischemic treatment with
12f and 13b significantly reduced the edema and infarct volume.
2.2.2.4. Result
3. Conclusion
2.2.2.4.1. Pre-treatment of compound. The parent compound
Curcumin was given at the dose of 300 mg/kg and both compounds
were given through i.p. route doses of 100 mg/Kg body weight each,
while MK 801, the reference compound was given 1 mg/Kg body
weight, through the i.v. route as its effective dose via i.p. is little
higher [13–15,31,32].
This observation shows the compound offer protection by
attenuating neurological deficit.
Pre-ischemic treatment with MK 801 (1 mg/Kg body weight;
i.v.) and curcumin (300 mg/Kg body weight, i.p.) decreased the
In conclusion we have synthesized a new series of ionone
derived allylic alcohols with potent anti-ischemic activity. Two
compounds of the series showed significant activity in vivo. The
structure–activity relationship shows that the oxygen on aromatic
part is necessary as most of the compounds lacking this were found
to be inactive. The increase in chain length of alkoxy substituent on
benzene ring shows enhancement in activity up to three carbons.
Further increment shows loss in activity. Introduction of heteroaryl
at the place of aromatic moiety does not show any significant
change. The potential of the use of compound for treating cere-
brovascular disorder was evaluated in animal models. The delayed
death in the cortex penumbra region and the thalamus is clinically
well identified and thalamic damage is frequently associated with
aphasia and severe memory impairment in humans. Blocking of the
apoptotic damage by the compound may offer a therapeutic
window for pharmacological intervention after cerebral ischemia,
which is well observed in our experiments. Collectively, our data
infarct volumes to 78.670
ꢀ
10.10 mm3 (P
< 0.001) and
89.8700 ꢀ 12.320 mm3 (P < 0.001) as compared to the ischemic
group to 244.390 ꢀ 6.03 mm3 as shown in Fig. 6a. Pre-ischemic
treatment with 12f and 13b decreased the infarct volumes to
23.98 ꢀ 4.7 mm3 (P < 0.001) and 93.98 ꢀ 24.8 mm3 (P < 0.001) as
compared to the ischemic group to 244.390 ꢀ 6.03 mm3 as shown
in Fig. 6a. Edema volume in the ischemic animals (n ꢃ 5) was
96.89 ꢀ 12.35 mm3. Pre-treatment with MK 801 and curcumin

1968
A.K. Srivastava et al. / European Journal of Medicinal Chemistry 45 (2010) 1964–1971
Fig. 3. (continued).
suggest that combined strategies targeting apoptosis as well as
necrosis will be necessary to protect ischemic damage in the
ischemic and non-ischemic brain structures after a cerebral
ischemic insult. Further pharmacological evaluations and dose-
response studies via different route of administration are
currently underway and will be reported in due course.
4. Experimental section
4.1. General
*
7.5
*
*
All chemicals, reagents, and solvents for the synthesis of the
compounds were of analytical grade, purchased from commercial
sources and used without further purification, unless otherwise
specified. Tetrahydrofuran (THF) was dried by distillation over
sodium/benzophenone ketal and stored over molecular sieves
(3 Å). All reactions were monitored by thin layer chromatography
over silica gel coated TLC plates. The spots on TLC were visualized
by warming ceric sulphate (2% CeSO4 in 2 N H2SO4) sprayed plates
in hot plate or in an oven at about 100 ꢂC. Silica gel (60–120 mesh)
was used for column chromatography. Melting points were deter-
mined in capillary tubes on an electrically heated apparatus and
were uncorrected. IR spectra were recorded on Perkin Elmer 881 or
FT IR 820/PC instrument and values are expressed in cmꢃ1. FABMS
were recorded on a JEOL/SX-102 spectrometer and ESMS were
recorded using a Micromass LC–MS system. 1H and 13C NMR were
recorded on Brucker Advance DPX 200 MHz using TMS as an
*
*
5.0
2.5
0.0
Fig. 4. Pre-ischemic treatment with MK 801, curcumin, compound 12f and 13b
improved the neurological scores to 1.98 (S.E.M. ꢀ 0.34); 2.45 (S.E.M. ꢀ 0.78); 2.9
(S.E.M. ꢀ 0.50) and 3.27 (S.E.M. ꢀ 0.70) as compared to 5.20 (S.E.M. ꢀ 0.60); P < 0.05;
(Fig. 2) of ischemic group. Mean neurological disability scores paralleled the changes in
infarct volume in case of untreated and treated group.
internal standard (chemical shifts are expressed as
d values, J in

A.K. Srivastava et al. / European Journal of Medicinal Chemistry 45 (2010) 1964–1971
1969
solution was further stirred for 30 min and cooled to 0 ꢂC before
adding the solution of ionone in THF. The reaction mixture was
stirred for 15 min and quenched by adding saturated NH4Cl solu-
tion. The aqueous layer was extracted three times by ethyl acetate.
The combined organic layer was dried by sodium sulphate and
crude was purified by using column chromatography on silica gel.
Sham
Ischemia
MK801 (Ref Comp)
4.2.1. 2-(3-Methoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-2-enyl)-
but-3-en-2-ol (12a)
Yield 85%; IR: (neat, cmꢃ1) 3321, 3021, 2961, 2919, 2862, 2361,
1421, 1216, 761; 1H NMR (200 MHz, CDCl3):
d 7.28–7.20 (m, 1H,
ArH), 7.05–7.01 (m, 2H, ArH), 6.80–6.75 (m, 1H, ArH), 5.75 (d,
J ¼ 15.4 Hz, 1H), 5.57–5.40 (m, 2H), 3.79 (s, 3H, OCH3), 2.14 (d,
J ¼ 9.2 Hz, 1H), 1.99 (bs, 1H, OH), 1.63 (s, 3H, CH3), 1.46–1.39 (m, 2H,
CH2), 1.23–1.14 (m, 2H, CH2), 0.89 (s, 3H, CH3), 0.83 (s, 3H, CH3).
MASS (FAB): m/z (%): 283 (100, [Mþ ꢃ H2O]); Anal. Calcd for
C20H28O2: C 79.96%; H 9.39%; found: C 79.82%, H 9.26%.
Curcumin (Parent comp)
12 f
13b
***
300
***
***
***
200
100
0
4.2.2. 2-(4-Methoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-2-enyl)-
but-3-en-2-ol (12b)
Yield 87%; IR; (neat, cmꢃ1) 3392, 3020, 2961, 2910, 2856, 2361,
1461, 1216, 762; 1H NMR (200 MHz, CDCl3):
d
7.32 (d, J ¼ 8.7 Hz, 2H,
ArH), 6.79 (d, J ¼ 8.7 Hz, 2H, ArH), 5.71(d, J ¼ 15.4 Hz,1H), 5.50–5.38
(m, 2H), 3.76 (s, 3H, OCH3), 2.11 (d, J ¼ 9.2 Hz, 1H), 1.98 (bs, 1H, OH),
1.58 (s, 6H, CH3), 1.49–1.34 (m, 2H, CH2), 1.19–1.13 (m, 2H, CH2), 0.89
(s, 3H, CH3), 0.83 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3):
d 158.78,
139.97, 139.88, 139.41, 134.4, 129.46, 129.38, 126.83, 121.45, 113.79,
96.587, 74.53, 55.40, 54.40, 32.62, 32.15, 30.49, 30.36, 28.10, 27.55,
23.47. MASS (FAB): m/z (%): 283 (100, [Mþ ꢃ H2O]). Anal. Calcd for
C20H28O2: C 79.96%; H 9.39%; found: C 79.67%, H 9.19%.
Fig. 5. Upper Panel showing the representative TTC stained Brain sections of sham,
ischemic, 12f and 13b treated group of rats (n ꢃ 5). The pale or white colored area
shows the dead tissue and red area depicts the viable tissue. There is a significant
decrease in the infarct volume in compound treated group of rats. (For interpretation
of the references to colour in this figure legend, the reader is referred to the web
version of this article.).
4.2.3. 2-(4-Pentyloxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-2-enyl)-
but-3-en-2-ol (12c)
Yield 78%; IR; (neat, cmꢃ1) 3431, 3022, 2962, 2920, 2862, 2361,
1441, 1216, 762; 1H NMR (200 MHz, CDCl3):
d
7.36 (d, J ¼ 8.7 Hz, 2H,
hertz). Elementary analysis was carried out on Carlo ERBA-1108
analyzer. The purity of the synthesized compounds was deter-
ArH), 6.85 (d, J ¼ 8.7, 2H, ArH), 5.75 (d, J ¼ 15.4 Hz, 1H), 5.54–5.39
(m, 2H), 3.94 (t, J ¼ 6.5 Hz, 2H, OCH2), 2.13 (d, J ¼ 9.3 Hz, 1H), 1.99
(bs, 1H, OH), 1.82–1.74 (m, 2H), 1.62 (s, 3H, CH3), 1.58 (s, 3H, CH3),
1.49–1.40 (m, 6H), 1.19–1.12 (m, 2H, CH2), 0.96–0.92 (m, 3H, CH3),
0.89 (s, 3H, CH3), 0.83 (s, 3H, CH3). MASS (FAB): m/z (%): 339 [100,
(Mþ ꢃ H2O)]. Anal. Calcd for C24H36O2: C 80.85%; H 10.18%; found: C
80.64%, H 10.02%.
mined by LichroCART Chiradex column (250 ꢁ 4 mm, 5
mm) column
using water and methanol as eluent at 25 ꢂC and in all cases the
extent of purity was >95%.
4.2. General procedure for the preparation of compounds
4.2.4. 2-(4-Methylsulfanyl-phenyl)-4-(2,6,6-trimethyl-cyclohex-
2-enyl)-but-3-en-2-ol (12d)
To a suspension of activated Mg in dry THF catalytic amount of
iodine was added and stirred for 15 min. To this a solution of bromo
compound in THF was added and stirred until the temperature of
vessel rises indicating the formation of Grignard reagent. The
Yield 92%; IR; (neat, cmꢃ1) 3430, 3020, 2962, 2920, 2862, 2361,
1441, 1216, 762; 1H NMR (200 MHz, CDCl3):
d
7.34 (d, J ¼ 8.7 Hz, 2H,
ArH), 7.18 (d, J ¼ 8.7 Hz, 2H, ArH), 5.71 (d, J ¼ 15.4 Hz, 1H), 5.52–5.38
(m, 2H), 2.46 (s, 3H, SCH3), 2.10 (d, J ¼ 9.3 Hz, 1H), 1.99 (bs, 1H, OH),
1.59 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.45–1.38 (m, 2H, CH2), 1.19–1.12
(m, 2H, CH2), 0.89 (s, 3H, CH3), 0.81 (s, 3H, CH3). 13C NMR (50 MHz,
150
***
***
***
***
CDCl3):
d 144.69, 138.97, 137.11, 134.24, 129.95, 129.85, 126.92,
126.18, 121.57, 96.58, 74.63, 54.39, 32.62, 32.11, 30.49, 30.35, 28.11,
27.52, 23.45, 16.35. MASS (FAB): m/z (%): 316 (75, [Mþ]), 299 (100,
[Mþ ꢃ H2O]). Anal. Calcd for C20H28OS: C 75.90%; H 8.92%; found: C
75.84%, H 8.72%.
100
50
0
4.2.5. 2-(2-Methoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-2-enyl)-
but-3-en-2-ol (12e)
Yield 93%; IR; (neat, cmꢃ1) 3592, 3430, 3010, 2959, 2915, 2862,
2358, 1451, 1216, 762; 1H NMR (200 MHz, CDCl3):
d 7.32–7.18 (m,
2H, ArH), 6.95–6.83 (m, 2H, ArH), 5.71 (d, J ¼ 15.4 Hz,1H), 5.33–5.25
(m, 2H), 3.84 (s, 3H, OCH3), 2.08 (d, J ¼ 9.5 Hz, 1H), 1.95 (bs, 1H, OH),
1.63 (s, 3H, CH3), 1.55 (s, 3H, CH3), 1. 54–1.43 (m, 2H, CH2), 1.17–1.12
(m, 2H, CH2), 0.86 (s, 3H, CH3), 0.72 (s, 3H, CH3). 13C NMR (50 MHz,
Fig. 6. Bar chart showing the edema volume in sham, ischemic, MK 801, curcumin, 12f
and 13b treated group of rats (n ꢃ 5). There is a significant decrease in the edema
volume in compound treated group of rats. (P < 0.001).

1970
A.K. Srivastava et al. / European Journal of Medicinal Chemistry 45 (2010) 1964–1971
CDCl3):
d
157.22, 139.55, 134.97, 134.73, 134.62, 128.64, 128.52,
5.48 (m, 1H), 5.43 (s, 1H), 2.16 (d, J ¼ 9.3 Hz, 1H), 2.02 (bs, 1H, OH),
1.67 (s, 3H, CH3), 1.61 (s, 3H, CH3), 1.47–1.43 (m, 2H, CH2), 1.22–1.17
(m, 2H, CH2), 0.92 (s, 3H, CH3), 0.85 (s, 3H, CH3). MASS (ESI MS): m/z
(%): 253 (100, [Mþ ꢃ H2O]). Anal. Calcd for C19H26O: C 84.39%; H
9.69%; found: C 84.04%, H 9.37%.
126.88, 121.22, 121.15, 121.06, 111.19, 96.58, 74.78, 55.50, 54.246,
32.57, 32.34, 32.27, 28.40, 27.60, 23.45, 23.30. MASS (FAB): m/z (%):
283 (100, [Mþ ꢃ H2O]). Anal. Calcd for C20H28O2: C 79.96%; H 9.39%;
found: C 79.64%, H 9.19%.
4.2.6. 2-(4-Propoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-2-enyl)-
but-3-en-2-ol (12f)
4.2.11. 2-(2,5-Dimethyl-phenyl)-4-(2,6,6-trimethyl-cyclohex-
2-enyl)-but-3-en-2-ol (12k)
Yield 85%; IR; (neat, cmꢃ1) 3523, 3320, 2965, 2920, 2761, 2361,
Yield 91%; IR; (neat, cmꢃ1) 3423, 3021, 2972, 2359, 1655, 1216,
1441, 1210, 760; 1H NMR (300 MHz, CDCl3):
d
7.30 (d, J ¼ 8.7 Hz, 2H,
1045, 761, 671; 1H NMR (300 MHz, CDCl3):
d 7.38 (s, 1H, ArH), 7.08–
ArH), 6.78 (d, J ¼ 8.7 Hz, 2H, ArH), 5.72 (d, J ¼ 15.4 Hz, 1H), 5.50–
5.37 (m, 2H), 3.89 (t, J ¼ 6.5 Hz, 2H, OCH2CH2CH3), 2.03 (d,
J ¼ 9.3 Hz, 1H), 1.99 (bs, 1H, OH), 1.80 (m, 2H, OCH2CH2CH3), 1.57 (s,
6H, CH3), 1.45–1.38 (m, 2H, CH2), 1.21–1.12 (m, 2H, CH2), 1.04 (t,
7.03 (m, 2H, ArH), 5.84 (d, J ¼ 15.6 Hz, 1H), 5.43–5.40 (m, 2H), 2.45
(s, 3H, CH3), 2.35 (s, 3H, CH3), 2.18 (d, J ¼ 12.8 Hz, 1H), 2.00 (bs, 1H,
OH), 1.82–1.80 (m, 1H), 1.73 (s, 3H, CH3), 1.62 (s, 3H, CH3), 1.50–1.38
(m, 2H, CH2), 1.21–1.12 (m, 1H, CH2), 0.92 (s, 3H, CH3), 0.83 (s, 3H,
J ¼ 7.3 Hz, 3H, OCH2CH2CH3), 0.89 (s, 3H, CH3), 0.81 (s, 3H, CH3). 13
C
CH3). 13C NMR (75 MHz, CDCl3):
d 142.65, 137.56, 133.47, 132.68,
NMR (50 MHz, CDCl3):
d
158.36, 139.43, 134.40, 129.44, 126.76,
131.65, 130.89, 128.62, 126.47, 125.27, 119.90, 73.95, 52.72, 31.07,
30.40, 28.24, 26.48, 25.79, 21.79, 20.13, 19.93. MASS (ESI MS): m/z
(%): 281 (100, [Mþ ꢃ H2O]). Anal. Calcd for C21H30O C 84.51%; H
10.13%; found: C 84.45%, H 10.03%.
121.45, 114.36, 96.58, 74.55, 69.69, 54.39, 32.63, 32.14, 30.51, 28.10,
27.55, 23.46, 23.07, 11.05. MASS (FAB): m/z (%): 311 (100,
[Mþ ꢃ H2O]). Anal. Calcd for C22H32O2: C 80.44%; H 9.82%; found: C
80.34%, H 9.63%.
4.2.12. 2-(3,4-Dimethoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-
2-enyl)-but-3-en-2-ol (12l)
4.2.7. 2-(4-Ethoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-2-enyl)-
but-3-en-2-ol (12g)
Yield 83%; IR; (neat, cmꢃ1) 3670, 3220, 2962, 2872, 2859, 2361,
Yield 74%; IR: (neat, cmꢃ1) 3631, 3420, 2896, 2921, 2865, 2361,
1421, 1216, 762; 1H NMR (300 MHz, CDCl3):
d 7.04–6.99 (m, 1H,
1431, 1206, 761; 1H NMR (300 MHz, CDCl3):
d
7.30 (d, J ¼ 8.7 Hz, 2H,
ArH), 6.90–6.82 (m, 2H, ArH), 5.75 (d, J ¼ 15.4 Hz,1H), 5.57–5.48 (m,
1H), 5.42 (s, 1H), 3.90 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 2.16(d,
J ¼ 9.3 Hz, 1H), 2.00 (bs, 1H, OH), 1.65 (s, 3H, CH3), 1.61 (s, 3H, CH3),
1.47–1.40 (m, 2H, CH2), 1.22–1.17 (m, 2H, CH2), 0.93 (s, 3H, CH3),
0.86 (s, 3H, CH3). MASS (ESI MS): m/z (%): 313 (100, [Mþ ꢃ H2O]).
Anal. Calcd for C21H30O3: C 76.33%; H 9.15%; found: C 76.34%, H
9.10%.
ArH), 6.77 (d, J ¼ 8.7 Hz, 2H, ArH), 5.70 (d, J ¼ 15.4 Hz, 1H), 5.49–
5.37 (m, 2H), 3.98 (q, J ¼ 6.9 Hz, 2H, OCH2CH3), 2.10 (d, J ¼ 9.3 Hz,
1H), 1.99 (bs, 1H, OH), 1.57 (s, 6H, CH3), 1.39 (t, J ¼ 6.9 Hz, 3H,
OCH2CH3) 1.45–1.38 (m, 2H, CH2), 1.21–1.12 (m, 2H, CH2), 0.89 (s,
3H, CH3), 0.81 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3):
d 158.74,
158.15, 147.88, 139.81, 139.73, 139.47, 135.21, 134.43, 133.50, 133.40,
129.45, 129.31, 126.82, 121.43, 114.34, 114.04, 96.59, 74.52, 63.56,
55.19, 54.41, 32.91, 32.63, 32.33, 32.17, 30.46, 30.32, 28.09, 27.56,
23.48, 15.34, 14.67. MASS (FAB): m/z (%): 297 (100, [Mþ ꢃ H2O]).
Anal. Calcd for C21H30O2: C 80.21%; H 9.62%; found: C 80.02%, H
9.38%.
4.2.13. 2-Thiophen-3-yl-4-(2,6,6-trimethyl-cyclohex-2-enyl)-but-
3-en-2-ol (12m)
Yield 67%; IR; (neat, cmꢃ1); 3777, 3620, 3430, 3020, 2966, 2359,
1664, 1426, 1216, 1044, 761; 1H NMR (300 MHz, CDCl3):
d 7.23 (d,
J ¼ 4.9 Hz,1H, ArH), 7.08–6.96 (m, 2H, ArH), 6.28 (d, J ¼ 15.4 Hz,1H),
5.90–5.81 (m, 1H), 5.44 (s, 1H), 2.18 (d, J ¼ 9.3 Hz, 1H), 2.02 (bs, 1H,
OH), 1.75 (s, 3H, CH3), 1.65 (s, 3H, CH3), 1.48–1.43 (m, 2H, CH2), 1.23–
1.13 (m, 2H, CH2), 0.95 (s, 3H, CH3), 0.87 (s, 3H, CH3). 13C NMR
4.2.8. 2-(4-Trifluoromethyl-phenyl)-4-(2,6,6-trimethyl-cyclohex-
2-enyl)-but-3-en-2-ol (12h)
Yield 77%; IR; (neat, cmꢃ1) 3404, 3020, 2961, 2922, 2862, 2361,
1618, 1449, 1327, 1216, 1166, 1127, 1074, 759; 1H NMR (300 MHz,
(50 MHz, CDCl3):
d 142.02, 139.06, 134.03, 130.02, 125.80, 123.20,
CDCl3):
d
7.60 (s, 4H, ArH), 5.77 (d, J ¼ 15.4 Hz, 1H), 5.60–5.50 (m,
119.93, 71.73, 53.42, 52.50, 31.18, 30.49, 29.48, 28.42, 26.34, 25.78,
21.79. MASS (ESI MS): m/z (%): 259 (100, [Mþ ꢃ H2O]). Anal. Calcd
for C17H24OS: C 73.86%; H 8.75%; found: C 73.80%, H 8.47%.
1H), 5.44(s, 1H), 2.16 (d, J ¼ 9.3 Hz, 1H), 2.01 (bs, 1H, OH), 1.67 (s, 3H,
CH3), 1.60 (s, 3H, CH3), 1.45–1.40 (m, 2H, CH2), 1.24–1.18 (m, 2H,
CH2), 0.95 (s, 3H, CH3), 0.91 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3):
d
150.05, 136.52, 132.34, 129.38, 124.32, 123.84, 120.13, 73.12, 52.69,
4.2.14. 2-(4-Methoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-1-enyl)-
but-3-en-2-ol (13a)
30.92, 30.29, 28.81, 26.50, 25.68, 21.73. MASS (ESI MS): m/z (%): 321
(100, [Mþ ꢃ H2O]). Anal. Calcd for C20H25F3O: C 70.98%; H 7.45%;
found: C 70.78%, H 7.29%.
Yield 87%; IR; (neat, cmꢃ1) 3691, 3468, 3120, 2351, 1435, 1216,
761; 1H NMR (200 MHz, CDCl3):
d
7.40 (d, J ¼ 8.7 Hz, 2H, ArH), 6.87
(d, J ¼ 8.7 Hz, 2H, ArH), 6.43–6.20 (m, 1H), 5.76–5.71 (m, 1H), 3.81
(s, 3H, OCH3), 2.16–2.13 (m, 2H),1.98 (bs, 1H, OH), 1.85–1.84 (m, 2H),
1.67–1.44 (m, 2H), 1.34 (s, 6H, CH3), 0.98 (s, 6H, CH3). MASS (FAB):
m/z (%): 282 (100, [Mþ ꢃ H2O]). Anal. Calcd for C20H28O2: C 79.96%;
H 9.39%; found: C 79.74%, H 9.37%.
4.2.9. 2-(4-tert-Butyl-phenyl)-4-(2,6,6-trimethyl-cyclohex-2-enyl)-
but-3-en-2-ol (12i)
Yield 84%; IR; (neat, cmꢃ1) 3689, 3412, 3021, 2352, 1415, 1208,
761; 1H NMR (300 MHz, CDCl3):
d 7.46–7.37 (m, 4H, ArH), 5.82 (d,
J ¼ 15.4 Hz, 2H), 5.62–5.53 (m, 1H), 5.45 (s, 1H), 2.20 (d, J ¼ 9.4 Hz,
1H), 2.04 (bs,1H, OH),1.67 (s, 3H, CH3),1.65 (s, 3H) 1.50–1.41 (m, 2H,
CH2), 1.36 (s, 9H), 1.26–1.15 (m, 2H, CH2), 0.95 (s, 3H, CH3), 0.89 (s,
3H, CH3). MASS (ESI MS): m/z (%): 309 (100, [Mþ ꢃ H2O]). Anal.
Calcd for C23H34O: C 84.60%; H 10.50%; found: C 84.54%, H 10.37%.
4.2.15. 2-(3-Methoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-1-enyl)-
but-3-en-2-ol (13b)
Yield 87%; IR; (neat, cmꢃ1) 3581, 3388, 3023, 2358, 1395, 1216,
761, 671; 1H NMR (200 MHz, CDCl3):
d 7.26–7.21 (m, 1H, ArH), 7.09–
7.05 (m, 2H, ArH), 6.81–6.77 (m, 1H, ArH), 6.13 (d, J ¼ 16.1 Hz, 1H),
5.73 (d, J ¼ 16.1 Hz, 1H), 3.80 (s, 3H, OCH3), 1.99–1.93 (m, 3H, CH2
and OH), 1.68 (s, 3H, CH3), 1.65 (s, 3H, CH3), 1.60–1.56 (m, 2H, CH2),
1.47–1.41 (m, 2H, CH2), 0.99 (s, 6H, CH3). 13C NMR (50 MHz, CDCl3):
4.2.10. 2-Phenyl-4-(2,6,6-trimethyl-cyclohex-2-enyl)-but-3-en-
2-ol (12j)
Yield 81%; IR; (neat, cmꢃ1) 3691, 3408, 3020, 2358, 1435, 1216,
761; 1H NMR (300 MHz, CDCl3):
d
7.51–7.48 (m, 2H, ArH), 7.38–7.33
d
159.9,149.4,140.5,137.1,129.6,128.9,126.4,118.1,112.8,111.4, 75.3,
(m, 2H, ArH), 7.28–7.26 (m, 1H, ArH), 5.80 (d, J ¼ 15.4 Hz, 1H), 5.57–
55.6, 39.8, 34.5, 33.1, 30.3, 29.2, 21.8, 19.7. MASS (FAB): m/z (%): 283

A.K. Srivastava et al. / European Journal of Medicinal Chemistry 45 (2010) 1964–1971
1971
[100, (Mþ ꢃ H2O)]. Anal. Calcd for C20H28O2 C 79.96%; H 9.39%;
(FAB): m/z (%): 283 (100, [Mþ ꢃ H2O]). Anal. Calcd for C20H28O2: C
found: C 79.84%, H 9.27%.
79.96; H 9.39; found: C 79.54%, H 9.47%.
4.2.16. 2-(4-Methylsulfanyl-phenyl)-4-(2,6,6-trimethyl-cyclohex-
1-enyl)-but-3-en-2-ol (13c)
Acknowledgments
Yield 68%; IR; (neat, cmꢃ1) 3690, 3412, 3020, 2358, 1651, 1435,
The authors wish to acknowledge Mr. A. L. Vishwakarma and
Mr. Ramesh Chandra for their technical assistance. Ajay and Preeti
thank Council of Scientific and Industrial Research (CSIR) for
providing fellowship. This manuscript bear CDRI communication
number 7721.
1116, 761; 1H NMR (200 MHz, CDCl3):
d 7.43–7.36 (m, 2H, ArH), 7.21
(d, J ¼ 7.9 Hz, 2H, ArH), 6.11 (d, J ¼ 16.1 Hz, 1H,), 5.70 (d, J ¼ 16.1 Hz,
1H), 2.47 (s, 3H, CH3), 2.16 (bs, 1H, OH) 1.96–1.93 (m, 2H, CH2), 1.65
(s, 3H, CH3), 1.64 (s, 3H, CH3), 1.60–1.55 (m, 2H, CH2), 1.46–1.33 (m,
2H, CH2), 0.99 (s, 6H, CH3). Mass (FAB): m/z (%): 298 [100,
(Mþ ꢃ H2O)]. Anal. Calcd for C20H28OS: C 75.90%; H 8.92%; found: C
75.68%, H 9.67%.
Appendix. Supplementary material
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.ejmech.2010.01.039.
4.2.17. 2-(4-Pentyloxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-
1-enyl)-but-3-en-2-ol (13d)
Yield 79%; IR; (neat, cmꢃ1) 3691, 3345, 3400, 3028, 2345, 1415,
References
1214, 761; 1H NMR (300 MHz, CDCl3):
d
7.36 (d, J ¼ 8.7 Hz, 2H, ArH),
6.85 (d, J ¼ 8.7 Hz, 2H, ArH), 6.85–6.20 (m, 1H), 5.75–5.54 (m, 1H),
3.94 (t, J ¼ 6.5 Hz, 2H, OCH2CH2CH2CH2CH3), 2.16–2.13 (m, 3H), 1.99
(bs, 1H, OH), 1.80–1.74 (m, 2H), 1.68–1.61 (m, OCH2CH2CH2CH2CH3),
1.56–1.51 (m, 2H, CH2), 0.96–0.92 (m, 3H, CH3), 1.43 (s, 3H,
OCH2CH2CH2CH2CH3), 1.34 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.93 (s,
3H, CH3). MASS (FAB): m/z (%): 339 [100, (Mþ ꢃ H2O)]. Anal. Calcd
for C24H36O2: C 80.85%; H 10.18%; found: C 80.68%, H 9.97%.
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but-3-en-2-ol (13e)
´
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Yield 74%; IR; (neat, cmꢃ1) 3408, 3320, 2358, 1435, 1216, 761; 1H
NMR (200 MHz, CDCl3):
d
7.36 (d, J ¼ 8.7 Hz, 2H, ArH), 6.80 (d,
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54–62.
J ¼ 8.7 Hz, 2H, ArH), 6.06 (d, J ¼ 15.4 Hz, 1H), 5.69 (d, J ¼ 15.4 Hz,
1H), 3. 89 (t, J ¼ 6.5 Hz, 2H, OCH2CH2CH3), 1.97–1.94 (m, 3H, CH2
and OH), 1.82–1.75 (m, 2H, OCH2CH2CH3), 1.57(s, 6H, CH3), 1.45–
1.38 (m, 2H, CH2), 1.21–1.12 (m, 2H, CH2), 1.04 (t, 3H, J ¼ 7.35 Hz,
OCH2CH2CH3), 0.89 (s, 3H, CH3), 0.81(s, 3H, CH3). 13C NMR (50 MHz,
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CDCl3):
d 158.36, 130.90, 126.97, 114.67, 96.563, 69.72, 41.16, 29.48,
28.43, 26.52, 23.05, 22.24, 15.93, 11.04. MASS (FAB): m/z (%): 311
(100, [Mþ ꢃ H2O]). Anal. Calcd for C22H32O2: C 80.44%; H 9.82%;
found: C 80.04%, H 9.67%.
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4.2.19. 2-(4-Ethoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-1-enyl)-
but-3-en-2-ol (13f)
Yield 78%; IR; (neat, cmꢃ1) 3691, 3514, 2920, 2298, 1435, 1212,
762; 1H NMR (200 MHz, CDCl3):
d
7.32 (d, J ¼ 8.7 Hz, 2H, ArH), 6.82
(d, J ¼ 8.7 Hz, 2H, ArH), 6.43–6.20 (m, 1H), 5.76–5.71 (m, 1H), 3.98
(q, 2H, J ¼ 6.9 Hz, OCH2CH3), 2.14–2.11 (m, 2H), 1.98 (bs, 1H, OH),
1.71–1.38 (m, 4H), 1.51 (t, J ¼ 6.9 Hz, 3H, OCH2CH3), 1.38 (s, 6H, CH3),
0.98 (s, 6H, CH3). MASS (FAB): m/z (%): 297 (100, [Mþ ꢃ H2O]). Anal.
Calcd for C21H30O2: C 80.21%; H 9.62%; found: C 79.34%, H 9.37%.
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4.2.20. 2-(2-Methoxy-phenyl)-4-(2,6,6-trimethyl-cyclohex-
1-enyl)-but-3-en-2-ol (13g)
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180–185.
Yield 88%; IR; (neat, cmꢃ1) 3691, 3408, 3120, 2358, 1395, 1216,
761; 1H NMR (200 MHz, CDCl3):
d 7.35–7.17 (m, 2H, ArH), 6.96–6.84
(m, 2H, ArH), 5.82 (d, J ¼ 15.9 Hz, 1H), 5.67 (d, J ¼ 15.9 Hz, 1H), 3.86
(s, 3H, OCH3), 1.95–1.89 (m, 2H, CH2), 1.68 (s, 3H, CH3), 1.61 (s, 3H,
CH3), 1.58–1.51 (m, 2H, CH2), 1.43–1.28 (m, 2H, CH2), 0.94 (s, 3H,
CH3), 0.91 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3):
d 157.17, 144.91,
136.09, 135.48, 134.80, 131.21, 129.58, 128.24, 127.89,126.92, 126.36,
122.38, 121.06, 120.63, 118.80, 111.32, 96.58, 55.67, 41.17, 37.56,
35.30, 29.35, 28.46, 25.95, 25.51, 24.23, 23.33, 22.22, 17.51. MASS