Synthesis and anticancer activity evaluation of 2(4-alkoxyphenyl)cyclopropyl hydrazides and triazolo phthalazines

Article abstract of DOI:10.1016/j.bmc.2010.02.041

A series of new 2(4-alkoxyphenyl)cyclopropyl hydrazide- and triazolo-derivatives were synthesized starting from 4-hydroxycinnamic acid (1) in a clean, mild, efficient and straightforward synthetic protocol. These compounds consisting of different alkoxy substitution, phenylcyclopropyl backbone and different heterocyclic groups were evaluated for in vitro anticancer activity against 4 cell lines displaying certain levels of resistance to pro-apoptotic stimuli and 2 cell lines sensitive to pro-apoptotic compounds. Compounds 7f and 8e were most active and displaying moderate in vitro cytostatic effect through different mechanisms. Significantly, chemically modified derivatives could be obtained in order to develop novel types of compounds aiming to combat apoptosis-resistant cancers, for example, those cancers associated with dismal prognoses.

Full text of DOI:10.1016/j.bmc.2010.02.041

Bioorganic & Medicinal Chemistry 18 (2010) 2537–2548
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and anticancer activity evaluation of 2(4-alkoxyphenyl)cyclopropyl
hydrazides and triazolo phthalazines
c
d
d
Prithwiraj De a,b, Michel Baltas a,b, , Delphine Lamoral-Theys , Céline Bruyère , Robert Kiss ,
*
Florence Bedos-Belval a,b, Nathalie Saffon e
a Université de Toulouse, UPS, LSPCMIB (Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique), 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France
b CNRS, LSPCMIB (Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique), 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France
c Laboratoire de Chimie Analytique, Toxicologie et Chimie Physique Appliquée, Institut de Pharmacie, Université Libre de Bruxelles, Boulevard du Triomphe, 1050 Bruxelles, Belgique
d Laboratoire de Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Boulevard du Triomphe,1050 Bruxelles, Belgique
e Université de Toulouse, UPS, Structure Fédérative Toulousaine en Chimie Moléculaire, FR 2599, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new 2(4-alkoxyphenyl)cyclopropyl hydrazide- and triazolo-derivatives were synthesized
starting from 4-hydroxycinnamic acid (1) in a clean, mild, efficient and straightforward synthetic proto-
col. These compounds consisting of different alkoxy substitution, phenylcyclopropyl backbone and differ-
ent heterocyclic groups were evaluated for in vitro anticancer activity against 4 cell lines displaying
certain levels of resistance to pro-apoptotic stimuli and 2 cell lines sensitive to pro-apoptotic compounds.
Compounds 7f and 8e were most active and displaying moderate in vitro cytostatic effect through differ-
ent mechanisms. Significantly, chemically modified derivatives could be obtained in order to develop
novel types of compounds aiming to combat apoptosis-resistant cancers, for example, those cancers asso-
ciated with dismal prognoses.
Received 23 November 2009
Revised 16 February 2010
Accepted 21 February 2010
Available online 1 March 2010
Keywords:
Cinnamic acid
Cyclopropyl backbone
Anticancer
Cytostatic activity
Apoptosis-resistant
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
ucts.6a Among these the ethyl ester of 3(40-geranyloxy-30-
methoxyphenyl)-2-trans propenoic acid belonging to the family
Phenolic compounds are bioactive substances with a wide-
spread occurrence in food plants.1a–c Among them, the hydroxyl
cinnamic acid family are natural products arising from the deami-
nation of the phenyl alanine; they are important constituents in
the biochemical pathway in plants leading to the lignin2a,b
polymer, the second most abundant biopolymer after cellulose,3a,b
resulting from the oxidative polymerization4 of the three hydroxy-
cinnamoyl alcohols, that is, p-coumaryl, coniferyl, sinapyl alcohols.
In recent years the phenolic compounds have attracted much
attention due to their antioxidative, anti-inflammatory, antimu-
tagenic and anticarcinogenic properties.1c,5a–d The antimutagenic
and antitumor properties5a of these compounds are related to
their ability to prevent oxidative damage in vivo by scavenging
reactive oxygen species (ROS). It is considered that they thus
prevent cellular proliferation, apoptosis and damage to DNA re-
pair enzymes or damage to DNA polymerase. The cinnamoyl
functionality is also present in a variety of secondary metabolites
of phenylpropanoid biosynthetic origin. Those containing a ses-
quiterpenyl, monoterpenyl and isopentenyl chains attached to a
4-hydroxy group represent quite a rare group of natural prod-
of Rutaceae6b showed a cancer chemopreventive effect and other
effects closely related to cancer growth.
In the light of these promising results on the antitumoral activi-
ties of families of natural cinnamoyl derivatives and in the context
of an urgentneed for the discovery and development of new antican-
cer agents, many research groups have focused their efforts on the
synthesis of non-natural cinnamic derivatives. Among them we
can mention: (i) (E)-4-[30-(1-adamentyl)-40-hydroxyphenyl]-3-
chlorocinnamic acid7 that may induce apoptosis of leukaemia cells
and may thus have a potential as a therapeutic agent for treating
acute myeloid leukaemia; (ii) the cinnamoyl benzotriazolyl amides
and related compounds such as 4-nitrocinnamoyl benzotriazolyl
amide and (E)-3-(4-nitrophenyl)-1-(pyridine-3-yl)prop-2-en-1-
one are potential transglutaminase inhibitors;8 (iii) pyrazine cin-
namoyl derivatives possessing various homopiperazine groups at-
tached to the pyrazine moiety exhibiting strong inhibitory
activities against Pim Kinases that participate in cell survival path-
ways;9 (iv) cinnamoyl substituted benzophenones such as N-[3-
benzoyl-4-[(4-methylphenyl)acetylamino]phenyl]-4-propoxy cin-
namic acid amide and N-[3-benzoyl-4-[(4-methylphenyl)acetyl-
amino]phenyl]-4-butoxy cinnamic acid amide potential farnesyl
transferase inhibitors.6a,10 Furthermore, recent results were
obtained in the field of prodrugs of anticancer agents underlying
* Corresponding author. Tel.: +33 (0) 561556289; fax: +33 (0) 561556011.
E-mail address: baltas@chimie.ups-tlse.fr (M. Baltas).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.02.041

2538
P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
the stabilizing effect towards hydrolysis of the acrylic double bond
conjugated with the aromatic ring in various cinnamoyl esters.11
In continuation of our ongoing research program, directed to-
wards design and synthesis of cinnamoylderivatives in relation with
two potential diseases (cardiovascular and tuberculosis) in the light
of increase interest of this class of compounds as anticancer agents,
we wouldlike to describe in thisreport thesynthesisof a newclass of
cinnamoyl derivatives possessing a cyclopropyl frame next to the
aromatic ring and their activities against a series of tumor cell lines.
Thecyclopropylframehasbeenchosenasitcanbeconsideredisos-
teric to the ethylenic functionality in terms of electronic sp2 character
of the carbon atoms. In addition, the phenyl cyclopropyl frame has
been reported in a series of cyclopropyl indolequinones,12 supposed
to act through ring opening of the cyclopropane ring, thus inducing
potent bioreductive cytotoxicity under hypoxic conditions.
timethylsulfoxonium iodide18 and sodium hydride in DMSO at
55 °C. Use of dry tetrahydrofuran or dry dichloromethane as sol-
vent instead of dry dimethylsulfoxide did not improve the yields
of cyclopropanated derivatives. The methyl-2(4-alkoxyphe-
nyl)cyclopropyl esters 4a–f were then saponified to the corre-
sponding carboxylic acids 5a–f using K2CO3 in aqueous methanol
as reported in Scheme 2 (yields 97–99%).
These acids 5a–f were used as starting materials for the prepa-
ration of all compounds mentioned in Scheme 3. Coupling of acids
5a–f with isoniazid was carried out using EDCꢀHCl in the presence
of HOBt and diisopropylethylamine, in acetonitrile under reflux for
24 h to afford the respective N0-isonicotinoyl-N-(2-(4-alkoxyphe-
nyl)cyclopropane carboxylhydrazides (6a–f) in excellent yields.
With same coupling agents, reaction of acids with 1-hydrazinoph-
thalazine hydrochloride in dichloromethane for 6 h at room tem-
perature (25 °C) produced 2-(4-alkoxyphenyl)-N0-(phthalazin-1-
yl)cyclopropanecarbohydrazide (7a–f) in good yields as reported
in Scheme 3. Coupling of acids 5a–f with 1-hydrazinophthalazine
hydrochloride in acetonitrile under reflux for 48 h in presence of
EDCꢀHCl, HOBt and diisopropylethylamine and concomitant cycli-
zation furnished corresponding 3-(2-(4-alkoxyphenyl)cyclopro-
2. Chemistry
The carboxylic function of 4-hydroxycinnamic acid (1) was pro-
tected first in order to introduce different alkyl chains on the phe-
nolic functionality and used as common precursor of most of the
hydrazides and phthalazides obtained. Methyl-ester of (E)-4-hy-
droxy cinnamic acid13 was prepared by refluxing in the methanol
in presence of catalytic amount of concentrated H2SO4 and 4 Å
molecular sieves for 24 h in excellent yield (95%). (E)-Methyl-4-
hydroxycinnamate (2) was then subjected to alkylation by reflux-
ing suitable alkyl halide (isopentenyl bromide, geranyl bromide,
ethyl iodide or methyl iodide) in dry acetone in presence of anhy-
drous K2CO3 and KI (used only in case of alkyl bromides) to give
corresponding phenoxy ethers 3a,14c–e in excellent yields. Owing
to the presence of trifluoromethyl functionality, similar reaction
with 2,20,200-trifluoroethyl iodide resulted in a poor yield (38%) of
(E)-methyl 4-trifluoroethoxycinnamate (3d). Therefore, we modi-
fied the reaction procedure and 3d was prepared from 2 using
2,20,200-trifluoroethyl iodide as the alkylating agent and NaH as
the base in dimethylsulfoxide at 80 °C for 24 h in 52% yield. (E)-
Methyl 4-trifluoromethoxycinnamate (3b) was obtained (89%) by
Wadworth–Emmons coupling reaction between commercially
available 4-trifluoromethoxybenzaldehyde and methyl diethyl-
phosphonoacetate under basic conditions15 (Scheme 1).
pyl)-[1,2,4]triazolo[3,4-a]phthalazine (8a–f) in good yields (65–
90%). The X-ray structure of the compound 8e, shown in Figure 1,
confirmed the formation of triazolophthalazine derivatives as well
as the phenylcyclopropyl backbone of the entire series of com-
pounds. The present reaction conditions established for the syn-
thesis of triazolo-phthalazine derivatives add to other different
methodologies available in the literature.19a–d
3. Biological evaluation and discussion
3.1. Determination of the IC50 in vitro growth inhibitory
concentrations
The origin of the cell lines used in the current study and the cul-
ture media are fully detailed in references.20a–c We made use of six
human cancer cell lines, four of which displaying certain levels of
resistance to pro-apoptotic stimuli, that is, the U373 glioblastoma
(GBM),20b,21a the A549 non-small-cell-lung cancer (NSCLC),21b the
SKMEL-28 melanoma cell line21c and the OE21 esophageal cancer
cell line.21d The two apoptosis-sensitive cancer cell lines include
the PC-3 prostate21e and the MCF-7 breast21e cancer cell lines.
As detailed in Table 1 below, we first analyzed the in vitro
antiproliferative activity of each compound under study in 3
cancer cell lines, that is, A549, PC3 and U373. If the compound
In an attempt to cyclopropanate the cinnamyl double bond, we
sonicated16 a mixture of 4-methoxy cinnamic acid (1 equiv),
samarium (6 equiv) and iodoform (5 equiv) in dry tetrahydrofuran
under argon but no reaction was observed. In a further attempt of
cyclopropanation with Mg/TiCl4 (catalytic)17 in dichloromethane-
tetrahydrofuran as solvent was of no avail. Gratefully, all these es-
ters 3a–f were converted into corresponding cyclopropyl deriva-
tives 4a–f in good yields (58–65%) when treated with
revealed itself being not active (IC50 >100 lM) in vitro in one
of these 3 cell lines, no further analysis was performed for this
compound. In contrast, if the compound revealed itself to be ac-
HO
-
a, R = CH3-
b, R = CF3
COOH
-
c, R = CH3CH2
1
d, R = CF3CH2-
e, R = (CH3)2C=CHCH2-
C.H2SO4 (Cat), MS 4A°
MeOH, 24 h.
f, R = (CH3)2C=CHCH2CH2C(CH3)=CHCH2-
CHO
HO
RO
RX, KI, K2CO3
Diethylphosphonoacetate
NaH, THF, 0°C,
Acetone, reflux, 20 h
70-95 %
COOMe
COOMe
3 h, 89 %
3a-f
2
OCF3
NaH, CF3CH2I
DMSO, 0°-80°C,
24 h, 52 %
Scheme 1. Synthesis of alkoxycinnamates.

P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
2539
RO
RO
K2CO3
RO
NaH, (Me)3SOI
MeOH-Water (1:1),
reflux, 3 h, quantiative
COOMe
DMSO, 55 °C, 1 h
COOMe
COOH
58-65 %
5a-f
4a-f
3a-f
Scheme 2. Synthesis of cyclopropane derivatives from alkoxycinnamates.
O
H2NHN
N
RO
O
N
H
N
CH3CN, reflux, 24 h
85-95 %
N
H
O
O
N
6a-f
NHNH2.HCl
N
RO
N
RO
N
EDC.HCl, HOBt
iPr2EtN
H
N
CH2Cl2, rt, 6 h
62-79 %
N
H
COOH
5a-f
-
a, R = CH3-
7a-f
8a-f
b, R = CF3
NHNH2.HCl
N
-
c, R = CH3CH2
d, R = CF3CH2-
RO
e, R = (CH3)2C=CHCH2-
f, R = (CH3)2C=CHCH2CH2C(CH3)=CHCH2-
N
N
N
CH3CN, reflux, 48 h
65-90 %
N
N
Scheme 3. Coupling of carboxylic acids with different hydrazine derivatives.
(Fig. 2) strongly suggest that the most active compounds within
the current series exert their anticancer activity, at least in vitro,
through mechanisms distinct of pure DNA intercalation, which is
a process known to induce cytotoxic rather than cytostatic effects.
In addition, within a series, that is, 7a–f, 8a–f, molecules with iso-
pentenyl- and geranyl- side-chains have shown better in vitro
activities compared to their saturated analogues. The role of cyclo-
propyl-part has also to be considered as the corresponding 4-alk-
oxystyryl derivatives were found to be much less active
(unpublished data; not shown) compared to their cyclopropyl ana-
logues (6a–f, 7a–f, 8a–f). Importantly, 7f and 8e are the two com-
pounds with comparable and the best in vitro anticancer activities
and particularly they are found to be active against U373 glioblas-
toma and OE21 cell lines which are known to be resistant to pro-
apoptotic stimuli.
Figure 1. X-ray structure of 8e.
tive on 3/3 cell lines, 3 additional cancer cell lines (MCF-7, OE21,
SKMEL-28) were added to the in vitro screening process of anti-
cancer activity determination.
The data in Table 1 show that when active on all six cell lines
here analyzed (IC50 <100 lM), a given compound displayed similar
in vitro anticancer activity between those cancer cell lines display-
ing certain levels of resistance to pro-apoptotic stimuli (A549,
U373, OE21, SKMEL-28) and those cell lines sensitive to pro-apop-
totic stimuli (MCF-7 and PC-3).
The data in Table 1 also reveal that of the 18 compounds under
study, there are compounds 7f and 8e that displayed the highest
in vitro anticancer activity.
3.3. Deciphering the mechanisms of action of compounds 7f
and 8e by means of quantitative videomicroscopy
Cytotoxic23 versus cytostatic24a,b activity of the two most active
compounds, 7f and 8e, was also evaluated. This has been moni-
tored in vitro by means of computer-assisted phase-contrast
microscopy (quantitative videomicroscopy). Figure 2 shows that
both compounds 7f and 8e exerted their anticancer activity
through cytostatic rather than cytotoxic effects. These experiments
have been carried out on the human U373 GBM cell line and the
morphological illustrations in Figure 2 clearly indicate that com-
pounds 7f and 8e impaired U373 tumor cell population growth
by decreasing U373 cell proliferation, thus through cytostatic ef-
fects, rather by direct killing of U373 tumor cells (which would
then correspond to cytotoxic effects). The morphological illustra-
tions in Figure 2 also reveal that the sustained cytostatic effects
occurring with 7f- and 8e-related IC50 concentrations during the
first two days of culture of U373 GBM cells in the presence of the
compounds then led to U373 cell death during the third day of cul-
ture as revealed by the apparition of numerous round-shaped cells.
3.2. Structure–activity relationship (SAR) analyses
Structure–activity relationship analyses performed with respect
to the data detailed in Table 1 suggest that 2-(4-alkoxyphenyl)-N0-
(phthalazin-1-yl)cyclopropanecarbohydrazide (7a–f) and 3-(2-(4-
alkoxyphenyl)cyclopropyl)-[1,2,4]triazolo[3,4-a]phthalazine (8a–
f) derivatives are more active compared to their isoniazid-ana-
logues (6a–f). The observed antitumor activities can be attributed
to the known ability of 1-phthalazine derivatives to behave as
DNA-intercalants22a–c and thus possible inhibition of DNA synthe-
sis of cancer cell lines. However, the fact that quantitative videomi-
croscopy demonstrated cytostatic rather than cytotoxic effects

2540
P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
Table 1
In vitro activity of 2(4-alkoxyphenyl)cyclopropyl hydrazides
Compound
Cell lines (growth inhibitory IC50 values;
l
M)
Mean SEM
C log P
First screening
PC3
Second screening
OE21
A549
U373
MCF7
SKMEL
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
>100
56
43
10
>100
78
96
87
>100
48
82
36
40
37
66
64
56
45
>100
>100
>100
44
>100
>100
64
92
94
67
81
24
29
49
>100
38
>100
37
63
19
>100
84
83
85
91
25
81
9
28
37
44
58
4
—
—
—
34
—
—
—
—
31
—
—
48
42
—
17
38
9
26
30
—
9
8
5
—
—
—
81
—
—
—
—
1.62
2.73
2.15
2.41
3.32
5.35
2.24
3.35
2.77
3.03
3.94
5.97
2.63
3.74
3.16
3.42
4.33
6.36
37 20
—
—
72
65 17
—
32
70
21
32
41
—
39 10
23
34
—
—
72
54
—
68
29
—
29
67
25
40
57
—
8
8
5
4
3
0
6
69
23
29
37
—
37
19
9
29
26
72
22
8
9
8
63
—: not determined in the second screening because at least one of three cell lines displayed an IC50 >100
lM during the run of the first screening.
Figure 2. Quantitative videomicroscopy recording of human U373 glioblastoma cell population development for three days in the absence (control) or the presence of 10
7f or 5 M 8e.
lM
l
We then made use of specific softwares that we developed in or-
der to be able to determine the levels of mitoses in cell cultures and
also the durations of mitoses.25 WhileFigure 2 strongly suggests that
both 7f and 8e exert cytostatic anticancer activity when assayed at
their IC50 in vitro growth inhibitory concentrations, Figure 3 reveals
that the cytostatic effects associated with 7f and 8e differ. Indeed,
thesecytostaticeffects seemto differ between7fand 8e: 7f couldex-
ert mitosis-dependent cytostatic effects, while 8e could exert mito-
sis-independent cytostatic ones. In other words, the data illustrated
in Figures 2 and 3 suggests that 7f and 8e could exert their cytostatic
effects through distinct signalling pathways.
while10
manU373glioblastomacells, 5
l
M 7f seemed toleadtoincrease in mitosisdurations in hu-
4. Conclusion
lM8eseemedtoleadtotheopposite
features (Fig. 3A). The 7f-induced increase in mitosis duration re-
sulted in a decrease in mitosis numbers (Fig. 3B), thus to the cyto-
static effects reported in Figure 2. The 8e-induced decrease in
mitosis duration (Fig. 3A) did not result in modifications in the mito-
sis numbers (Fig. 3B). Thus, while both compounds 7f and 8e could
exert their in vitro anticancer activity through cytostatic effects,
A series of new 2(4-alkoxyphenyl) cyclopropyl hydrazide deriva-
tives were synthesized. Clean reaction, excellent yields and mild
reaction condition are the key features of these protocols of coupling
comparedto otheravailablemethods. Thecompoundswerefoundto
exert cytostatic activity on the 6-human cancer cell-lines. Two com-
pounds, with isopentenyl-(8e) and geranyl-(7f) side-chain attached

P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
2541
try—in our case using a Biorad Model 680XR (Biorad, Nazareth, Bel-
gium) at a 570 nM wavelength (with a reference of 630 nM). Each
experiment was carried out in sextuplicate.
70
65
60
55
50
45
40
5.2. Chemical synthesis and characterization data
5.2.1. General procedure
Organic solvents were purified when necessary by methods de-
scribed by D. D. Perrin, W. L. F. Armarengo, and D. R. Perrin (Puri-
fication of Laboratory Chemicals; Pergamon: Oxford, 1986) or were
purchased from Aldrich Chemie.
Melting points (mp) were obtained on a Buchi apparatus and
are uncorrected. Infrared (IR) spectra were recorded on a Perkin–
Elmer 1725 infrared spectrophotometer and the data are reported
in cmꢁ1. Proton nuclear magnetic resonance (1H NMR) spectra
were obtained with a Bruker AC-300 spectrometer. Chemical shifts
were reported in parts per million (ppm) relative to tetramethylsil-
ane (TMS), and signals are given as follows: s, singlet; d, doublet; t,
triplet; m, multiplet. Mass spectra were recorded on an R 10–10 C
Nermag (70 eV) quadripolar spectrometer using desorption chem-
ical ionization (DCI), electrospray (ES) or fast atomic bombardment
(FAB) techniques. For better NMR data analysis, compounds were
numerated as (Fig. 4)
Ct
7f
8e
220
200
180
160
140
120
100
80
5.2.2. Preparation of (E)-methyl-3-(4-alkoxyphenyl)prop-2-
enoate (3a–f)
To compound 2 (0.5 g, 2.8 mmol, 1 equiv) in dry acetone
(15 mL), was added KI (added only in case of alkyl bromide;
0.6 g, 4.2 mmol, 1.5 equiv), K2CO3 (0.58 g, 4.2 mmol, 1.5 equiv)
and alkyl halide (4.2 mmol, 1.5 equiv). The reaction mixture was
refluxed for 20 h then cooled to room temperature and filtrated.
The filtrate was evaporated to dryness and water (20 mL) was
added into the residue and extracted with EtOAc (20 mL ꢂ 3).
The combined organic layer was dried with Na2SO4, and evapo-
rated in vacuo. The residue was purified by chromatography over
silica gel (1:4 EtOAc/petroleum ether) to afford compound 3a–f
as white solids.
60
40
Ct
7f
8e
Experimental Conditions
Figure 3. Quantitative videomicroscopy recording of mitosis duration (Fig. 3A) and
mitosis levels (Fig. 3B) in human U373 glioblastoma cell populations left untreated
(control; Ct) or treated for three days with 10 lM 7f or 5 lM 8e.
to the 4-hydroxyphenyl frame, were particularly more active than
the remaining compounds against cancer cell-lines resistant to
pro-apoptotic stimuli. The two compounds exert their cytostatic ef-
fects through distinct signalling pathways. Therefore, 7f and 8e are
considered to be hits to combat apoptosis-resistant cancers, for
example, those cancers associated with dismal prognoses. Efforts
are on to establish the mechanism of action, modify the structures
considering the lipophilicity (C log P) point of view, that is, modifica-
tion of the side-chains as well as heterocyclic part.
5.2.2.1. (E)-Methyl-3-(4-methoxyphenyl)prop-2-enoate (3a). Com-
pound 3a was prepared according to reported14 mentioned procedure
using methyl iodide in 95% yield. Spectral data matches as reported.
5.2.2.2. (E)-Methyl-3-(4-ethoxyphenyl)prop-2-enoate (3c). Com-
pound 3c was prepared from ester 2 according to procedure men-
tioned above by using ethyl iodide. White solid (0.40 g, 70%, mp
57–58 °C).
5. Experimental section
IR (KBr, m
max) cmꢁ1: 2977, 1708, 1604, 1513, 1254.
H NMR (CDCl3, 300 MHz) d ppm: 1.42 (t, 3H, J = 7.0 Hz, H2 ),
1
0
5.1. Determination of the IC50 in vitro growth inhibitory
concentrations
0
3.79 (s, 3H, H10), 4.06 (q, 2H, J = 7,0 Hz, H1 ), 6.30 (d, 1H,
J = 16.0 Hz, C8), 6.90 (d, 2H, J = 8.8 Hz, H3, H5), 7.46 (d, 2H,
J = 8.8 Hz, H2,H6), 7.64 (d, 1H, J = 16.0 Hz, H7).
We evaluated the IC50 in vitro growth inhibitory values of the
compounds under study by means of the MTT colorimetric assay
as detailed elsewhere.19a–c Briefly, the cell lines were incubated
for 24 h in 96-microwell plates (at a concentration of 10,000 to
40,000 cells/mL culture medium depending on the cell type) to en-
sure adequate plating prior to cell growth determination. The
assessment of cell population growth by means of the MTT color-
imetric assay is based on the capability of living cells to reduce
the yellow product MTT (3-(4,5)-dimethylthiazol-2-yl)-2,5-diphe-
nyltetrazolium bromide) to a blue product, formazan, by a reduc-
tion reaction occurring in the mitochondria. The number of living
cells after 72 h of culture in the presence (or absence: control) of
the various compounds is directly proportional to the intensity of
the blue, which is quantitatively measured by spectrophotome-
13C NMR (CDCl3, 75 MHz) d ppm: 14.73 (CH3), 51.57 (C10), 63.62
(CH2), 114,79 (C2, C6), 115.11 (C8), 126.93 (C4), 129.11 (C3, C5),
144.59 (C7), 160.79 (C1), 167.79 (C9).
MS (DCI, CH4, pos.) m/z: 207.1 (MH+).
5.2.2.3. (E)-Methyl-3-[4-(3-methylbut-2-enyloxy)phenyl]prop-
2-enoate (3e). Compound 3e was prepared from ester 2 according
to procedure mentioned above by using 3,30-dimethylallyl bro-
mide. White solid (0.59 g, 86%, mp 55–57 °C).
IR(KBr,
m
max) cmꢁ1: 2945, 1716, 1635, 1513, 1251, 1167, 986, 837.
1
0
H NMR (CDCl3, 300 MHz) d ppm: 1.69 (s, 3H, H4 ), 1.74 (s, 3H,
0
0
H5 ), 3.73 (s, 3H, CH3), 4.49 (d, 2H, J = 6.6 Hz, H1 ), 5.42 (th, 1H,
3J = 6.6 Hz, J = 1.5 Hz, H2 ), 6.24 (d, 1H, J = 15.9 Hz, H8), 6.84 (d,
4
0

2542
P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
X
7
HN
6
3
NH
HN
N
4'
NH
9'
8'
5
4
3
9
1
1
2
7
1
6'
1'
8
6
5
4
5
2
3
N
N
2
O
3'
10'
5'
2'
7'
6
8
4
Figure 4.
2H, J = 8.5 Hz, H3, H5), 7.41 (d, 2H, J = 8.5 Hz, H2, H6), 7.60 (d, 1H,
5.2.2.6. (E)-Methyl-3-[4-(2,20,200-trifluoroethoxy)phenyl]prop-2-
enoate (3d). A clean dry round bottom flask (50 mL) with a stir bar
was charged with NaH (60% dispersion in mineral oil; 240 mg,
6 mmol, 1.2 equiv) under argon. Dry dimethylsulfoxide (4 mL)
was added to the reaction flask and stirred at 0 °C for 15 min. A
solution of phenol (1) (890 mg, 5 mmol, 1 equiv) in dimethylsulf-
oxide (2 mL) was slowly added to the suspension over 10 min
(1 mL DMSO was used for rinsing). It was then allowed to stir at
0 °C for 30 min when a dark yellow solution resulted. Trifluoro-
ethyl iodide (1.5 mL, 15 mmol, 3 equiv) was added to the reaction
flask. The reaction was then stirred at 80 °C for 24 h and monitored
by TLC (1:9 EtOAc/petroleum ether). A saturated NH4Cl solution
(2 mL) was added to quench the reaction. Water (20 mL) was
added and then extracted with diethyl ether (30 mL ꢂ 3). The or-
ganic layer was dried over MgSO4. The solvent was removed in va-
cuo and the residue was purified by silica gel chromatography (3%
EtOAc in petroleum ether) to afford compound 3d White solid,
(0.68 g, 52%, mp 96–98 °C).
J = 15.9 Hz, H7).
13
0
0
C NMR (CDCl3, 75 MHz) d ppm: 14.20 (C4 ), 18.22 (s, 1C, C5 ),
0
0
51.55 (CH3), 64 .91 (C1 ), 114.89 (C3, C5), 115.14 (C8), 119.22 (C2 ),
0
126.99 (s, 1C, C1), 129.70 (C2, C6), 138.66 (C3 ), 144.60 (C7),
160.74 (C4), 167.80 (C9).
MS (DCI, NH3, pos.) m/z: 247.2 (MH+), 264.2 (MNH4þ).
5.2.2.4. (E)-Methyl-3-{4-[(E)-3,7-dimethylocta-2,6-dienyloxy]-
phenyl}prop-2-enoate (3f). Compound 3f was prepared from es-
ter 2 according to procedure mentioned above by using geranyl
bromide. White solid (0.83 g, 95%, mp 72–75 °C).
IR (KBr,
m
max) cmꢁ1: 3168, 2942, 2854, 1720, 1637, 1603, 1572,
1511.
1
0
H NMR (CDCl3, 300 MHz) d ppm: 1.60 (s, 3H, CH9 ), 1.67 (s, 3H,
0
0
0
0
H4 ), 1.74 (s, 3H, H10 ), 2.10 (m, 4H, H5 and H6 ), 3.79 (s, 3H, CH3),
0
0
4.57 (d, 2H, J = 6.6 Hz, H1 ), 5.07 (m, 1H, H7 ), 5.48 (t, 1H, = 6.5 Hz,
0
H2 ), 6.31 (d, 1H, J = 15.9 Hz, H8), 6.91 (d, 2H, J = 8.9 Hz, H3, H5),
7.47 (d, 2H, J = 8.9 Hz, H2, H6), 7.64 (d, 1H, J = 15.9 Hz, H7).
IR (KBr,
830.
m
max) cmꢁ1: 2951, 1708, 1604, 1515, 1245, 1170, 974,
13
0
0
C NMR (CDCl3, 75 MHz) d ppm: 16.68 (C9 ), 25.67 (C4 ), 26.26
(C6 ), 39.17 (C10 ), 39.51 (C5 ), 51.53 (CH3), 64 .88 (C1 ), 110.03 (C8),
1H NMR (CDCl3, 300 MHz) d ppm: 3.80 (s, 3H, CH3), 4.38 (q, 2H,
J = 8.0 Hz, –OCH2), 6.34 (d, 1H, J = 16.0 Hz, H8), 6.95 (d, 2H,
J = 8.8 Hz, H2, H6), 7.50 (d, 2H, J = 8.5 Hz, H3, H5), 7.65 (d, 1H,
J = 16.0 Hz, H7).
0
0
0
0
0
0
115.11 (C3, C5), 118.84 (C2 ), 123.73 (C7 ), 126.97 (C1), 129.69 (C2,
0
0
C6), 131.83 (C8 ), 141.66 (C3 ), 144.61 (C7), 160.16 (C4), 167.78 (C9).
MS (APCI, MeOH, pos.) m/z: 315.25 (MH+).
13C NMR (CDCl3, 75 MHz) d ppm: 51.69 (CH3), 65.66 (q, 1C,
2J = 35.9 Hz, CH2), 115.18 (C2–6), 116.51 (C8), 123.15 (q, 1C,
5.2.2.5. (E)-Methyl-3-[4-trifluoromethoxyphenyl]prop-2-eno-
ate (3b). A clean dry round bottom flask (100 mL) with a stir bar was
charged with NaH (60% dispersion in mineral oil; 950 mg,
23.7 mmol, 1.5 equiv) under argon. It was then washed with petro-
leum ether (5 mL ꢂ 2). Dry THF (40 mL) was added to the reaction
flask and stirred at 0 °C (ice bath) for 15 min. Methyldiethylphos
phonoacetate (3.5 mL, 19 mmol, 1.2 equiv) was slowly added to
the suspension over 10 min. It was then allowed to stir at 0 °C for
30 min when a colorless solution resulted. A solution of 4-trifluoro-
methoxybenzaldehyde (2.3 mL, 15.8 mmol, 1 equiv) in dry THF
(12 mL)wasslowlyaddedtothereactionflaskover10 min. Thereac-
tion was then allowed to stir at room temperature (25 °C) for 20 h.
TLC was monitored using 10% ethylacetate in petroleum ether (Rf
aldehyde:0.7, product:0.6) aseluant. A saturatedNH4Cl(2 mL)solu-
tion was then added to quench the reaction. THF was removed under
reduced pressure and water (30 mL) was added to the reaction mix-
ture. It was then extracted with ethylacetate (60 mL ꢂ 3). The organ-
ic layer was dried over MgSO4. Removal of solvent gave a crude mass
(3.8 g) which was filtered through short silica gel plug (20 g) using
3% ethylacetate in petroleum ether as eluant to get pure white solid
(E)-methyl-3-[4-trifluoromethoxyphenyl]prop-2-enoate (3b, 3.3 g,
89%, mp 43–45 °C).
0
J = 277.9 Hz, C2 ), 128.90 (C4), 129.61 (C3–5), 143.87 (C7), 158.80
(C1), 167.52 (C9).
MS (DCI, CH4, pos.) m/z: Calcd. For C12H12F3O3, 261.06; found,
261.07.
5.2.3. Preparation of methyl-2-(4-alkoxyphenyl)cyclopropane-
carboxylate (4a–f): general procedure
A clean dry round bottom flask (10 mL) with a magnetic stir bar
was charged with NaH (60% suspension; 0.05 g, 1.2 mmol,
1.2 equiv) and trimethylsulfoxonium iodide (0.24 g, 1.1 mmol,
1.1 equiv) under argon. Dry dimethylsulphoxide (2 mL) was added
to the flask and stirred at room temperature (25 °C) for 40 min
when the effervescence ceased and a milky-white suspension re-
sulted. A solution of cinnamate derivative (1 mmol, 1 equiv) in
dry dimethylsulphoxide (1 mL) was then added to the reaction
mixture and stirred at 50 °C for 1 h. TLC was monitored in 5% eth-
ylacetate in petroleum ether. It was then cooled to room tempera-
ture and brine (20 mL) was added to the reaction mixture. The
quenched reaction mixture was then extracted with diethyl ether
(30 mL ꢂ 3). The combined organic layer was dried over anhydrous
MgSO4. Removal of solvent gave crude mixture. The sticky mass
was then purified over silica gel (70–200 mesh) using 3% ethylace-
tate-petroleum ether as eluant.
IR (KBr, m
max) cmꢁ1: 2951, 1708, 1604, 1515, 1245, 1170, 974, 830.
1H NMR (300 MHz, CDCl3) d ppm: 3.74 (s, 3H, –COOCH3), 6.35
(d, 1H, J = 15.9 Hz, H7), 7.17 (d, 2H, J = 9 Hz, H3, H5), 7.48 (d, 2H,
J = 9 Hz, H2, H6), 7.60 (d, 1H, J = 15.9 Hz, H8).
5.2.3.1. Methyl-2-(4-methoxyphenyl)cyclopropanecarboxylate
(4a). Compound 4a was prepared using 3a as starting material.
White solid (0.13 g, 65%, mp 51–53 °C).
13C NMR (75 MHz, CDCl3) d ppm: 51.7 (–COOCH3), 115.2 (C3,
C5), 118.6 (C8), 122.0, (q, J = 277 Hz, CF3), 129.4 (C2, C6), 132.9
(C1), 143.0 (C7), 157.1 (C4), 167.0 (C9).
IR (KBr,
m
max) cmꢁ1: 3007, 2953, 2912, 2837, 1728, 1613, 1516,
LRMS (APCI, M+H) Calcd for C13H14O3, 275.17; found, 275.14.
1443, 1339, 1340, 1293, 1254, 1202, 1177, 1029.

P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
2543
1H NMR (300 MHz, CDCl3) d ppm: 1.21 (m, 1H, ꢀCH2), 1.49 (m,
1H, ꢀCH2), 1.77 (m, 1H, H7), 2.43 (m, 1H, H8), 3.65 (s, 3H, –
COOCH3), 3.72 (s, 3H, –OCH3), 6.76 (d, 2H, J = 9 Hz, H3, H5), 6.97
(d, 2H, J = 9 Hz, H2, H6).
(m, 1H, H2 ), 6.77 (d, 2H, J = 9 Hz, H3, H5), 6.96 (d, 2H, J = 9 Hz, H2,
0
H6).
13
0
0
C NMR (75 MHz, CDCl3) d ppm: 14.2 (C4 ), 15.6 (C5 ), 17.1
(ꢀCH2), 22.6 (C8), 24.7 (C7), 50.8 (–COOCH3), 63.8 (–OCH2–),
113.6 (C3, C5), 118.6 (C2 ), 126.3 (C2, C6), 130.8 (C3 ), 137.1 (C1),
156.6 (C4), 175.3 (C9).
13C NMR (75 MHz, CDCl3) d ppm: 16.7 (ꢀCH2), 23.6 (C8), 25.7
(C7), 51.8 (–COOCH3), 55.3 (–OCH3), 113.9 (C3, C5), 127.4 (C2, C6),
131.9 (C1), 158.3 (C4), 174.0 (C9).
0
0
LRMS (APCI, M+Na) Calcd for C16H20O3Na, 283.14; found, 283.1
LRMS (APCI, M+Na) Calcd for C12H14O3Na, 229.09; found,
229.05.
5.2.3.6. Methyl-2-(4-((E)-3,7-dimethylocta-2,6-dienyloxy)
phenyl)cyclopropanecarboxylate (4f). Compound 4f was pre-
pared using 3f as starting material. White solid (0.19 g, 59%, mp
49–51 °C).
5.2.3.2. Methyl-2-(4-trifluoromethoxyphenyl)cyclopropane-
carboxylate (4b). Compound 4b was prepared using 3b as starting
material. Colorless oil (0.16 g, 61%).
IR (KBr, m
max) cmꢁ1: 3007, 2963, 2918, 2852, 1730, 1613, 1515,
IR (neat,
m
max) cmꢁ1: 3050, 2956, 1713, 1641, 1589, 1510, 1438,
1451, 1398, 1335, 1288, 1248, 1197, 1171, 1123, 1004, 820.
1266, 1214, 1162, 1011, 990.
1H NMR (300 MHz, CDCl3) d ppm: 1.20 (m, 1H, ꢀCH2), 1.50 (m,
1H NMR (300 MHz, acetone-d6) d ppm: 1.34 (m, 1H, ꢀCH2), 1.45
(m, 1H, ꢀCH2), 1.89 (m, 1H, H7), 2.45 (m, 1H, H8), 3.61 (s, 3H, –
COOCH3), 7.17 (d, 2H, J = 9 Hz, H3, H5), 7.25 (d, 2H, J = 9 Hz, H2, H6).
13C NMR (75 MHz, acetone-d6) d ppm: 16.9 (ꢀCH2), 23.9 (C8),
25.4 (C7), 51.9(–COOCH3), 121.0 (C3, C5), 122.1 (q, J = 284 Hz, –
CF3), 127.5 (C2, C6), 138.7 (C1), 147.8 (C4), 173.5 (C9).
LRMS (ESCl, M+Na) Calcd for C12H11F3O3Na, 283.07; found,
283.05.
1H, ꢀCH2), 1.54 (s, 3H, H9 ), 1.66 (s, 3H, H10 ), 1.66 (s, 3H, H4 ), 1.76
0
0
0
0
0
(m, 1H, H7), 2.03 (m, 4H, H5 , H6 ), 2.43 (m, 1H, H8), 3.65 (s, 3H,
0
–COOCH3), 4.46 (d, 2H, J = 6.6 Hz, –OCH2–), 5.06 (m, 1H, H7 ),
0
5.43 (m, 1H, H2 ), 6.77 (d, 2H, J = 9 Hz, H3, H5), 6.96 (d, 2H,
J = 9 Hz, H2, H6).
13
0
C NMR (75 MHz, CDCl3) d ppm: 15.63 (ꢀCH2), 15.68 (C9 ), 16.6
0
0
0
0
(C4 ), 22.6 (C8), 24.7(C6 ), 24.7 (C7), 25.2 (C5 ), 38.5 (C10 ), 50.8
0
0
(–COOCH3), 63.9 (–CH2O–), 113.7 (C3, C5), 118.4 (C2 ), 122.7 (C7 ),
0
0
126.3 (C2, C6), 130.7 (C8 ),140.1 (C3 ), 146.4 (C1), 156.6 (C4), 173.1
5.2.3.3. Methyl-2-(4-ethoxyphenyl)cyclopropanecarboxylate
(4c). Compound 4c as prepared using 3c as starting material. White
solid (0.13 g, 60%, mp 57–58 °C).
(C9).
LRMS (APCI, M+Na): Calcd for C21H28O3Na, 351.20; found,
351.1.
IR (KBr, m
max) cmꢁ1: 3007, 2979, 2957, 2926, 1732, 1612, 1515,
1454, 1434, 1398, 1340, 1288, 1250, 1199, 1174, 1049.
1H NMR (300 MHz, CDCl3) d ppm: 1.30 (m, 1H, ꢀCH2), 1.43 (t,
3H, J = 6.9 Hz, –OCH2CH3), 1.58 (m, 1H, ꢀCH2), 1.85 (m, 1H, H7),
2.51 (m, 1H, H8), 3.74 (s, 3H, –COOCH3), 4.03 (q 2H, J = 6.9 Hz, –
OCH2CH3), 6.84 (d, 2H, J = 9 Hz, H3, H5), 7.05 (d, 2H, J = 9 Hz, H2,
H6).
5.2.4. Preparation of 2-(4-alkoxyphenyl)cyclopropanecarbo
xylic acid (5a–f): general procedure
A round bottom flask (25 mL) with a magnetic stir bar was
charged with methyl-2-(4-alkoxyphenyl)cyclopropanecarboxylate
(4a–f, 1 mmol, 1 equiv). Methanol (10 mL) was added to it and stir-
red till it made a homogeneous solution. An aqueous solution
(5 mL) of K2CO3 (0.42 g, 3 mmol, 3 equiv) was added to it and stir-
red at 70 °C for 3 h when all starting material had disappeared. TLC
was monitored in 5% ethylacetate in petroleum ether. Methanol
was removed under reduced pressure and it was cooled to 0 °C
in ice bath. HCl (3 N) was then added to the reaction mixture till
pH 3 (pH paper) and a white precipitation was observed. It was
then extracted with ethylacetate (30 mL ꢂ 3). The organic layer
was dried over MgSO4. Removal of solvent gave the corresponding
carboxylic acid as white solid. The acid obtained was used for the
next reaction without further purification.
13C NMR (75 MHz, CDCl3) d ppm: 13.7 (ꢀCH2), 15.0 (–CH2CH3),
22.0 (C8), 24.1 (C7), 51.8 (–COOCH3), 61.8 (–OCH2CH3), 112.8 (C3,
C5), 125.7 (C2, C6), 130.1 (C1), 156.0 (C4), 172.4 (C9).
LRMS (APCI, M+Na) Calcd for C13H16O3Na, 243.11; found,
243.19.
5.2.3.4. Methyl-2-[4-(2,20,200-trifluoroethoxy)phenyl]cyclopro-
panecarboxylate (4d). Compound 4d was prepared using 3d as
starting material. Colorless oil (0.17 g, 63%).
IR (neat, m
max) cmꢁ1: 3047, 2979, 2956, 2924, 1714, 1639, 1589,
1510, 1438, 1266, 1214, 1162, 1011, 987.
5.2.4.1. 2-(4-Methoxyphenyl)cyclopropanecarboxylic
acid
1H NMR (300 MHz, CDCl3) d ppm: 1.22 (m, 1H, ꢀCH2), 1.52 (m,
1H, ꢀCH2), 1.78 (m, 1H, H7), 2.43 (m, 1H, H8), 3.65 (s, 3H,
–COOCH3), 4.25 (q, 2H, J = 4.8 Hz, –OCH2CF3), 6.79 (d, 2H,
J = 9 Hz, H3, H5), 6.99 (d, 2H, J = 9 Hz, H2, H6) .
(5a). Compound 5a was prepared using 4a as starting material.
White solid (0.19 g, quantitative, mp 87–89 °C).
IR (KBr, m
max) cmꢁ1: 3425, 3010, 2953, 2836, 2541, 1876, 1676,
1913, 1517, 1457, 1433, 1334, 1292, 1255, 1221, 1175, 1109, 1024,
939.
13C NMR (75 MHz, CDCl3) d ppm: 16.8 (ꢀCH2), 23.7 (C8), 25.5
(C7), 51.9 (–COOCH3), 66.1, (q, J = 35.9 Hz, –OCH2CF3), 115.0 (C3,
C5), 124.4, (q, J = 277 Hz, –CF3), 127.6 (C2, C6), 134.0 (C1), 156.1
(C4), 173.8 (C9).
1H NMR (300 MHz, CDCl3) d ppm: 1.30 (m, 1H, ꢀCH2), 1.56 (m,
1H, ꢀCH2), 1.77 (m, 1H, H7), 2.52 (m, 1H, H8), 3.73 (s, 3H, –OCH3),
6.76 (d, 2H, J = 9 Hz, H3, H5), 6.98 (d, 2H, J = 9 Hz, H2, H6).
13C NMR (75 MHz, CDCl3) d ppm: 17.2 (ꢀCH2), 23.6 (C8), 26.6
(C7), 55.3 (–OCH3), 113.9 (C3, C5), 127.5 (C2, C6), 131.4 (C1), 158.4
(C4), 179.4 (C9).
LRMS (APCI, M+H) Calcd for C13H14O3, 275.17; found, 275.14.
5.2.3.5. Methyl-2-(4-(3-methylbut-2-enyloxy)phenyl)cyclopro-
panecarboxylate (4e). Compound 4e was prepared using 3e as
starting material. White solid (0.15 g, 58%, mp 50–52 °C).
LRMS (ESꢁ, MꢁH) Calcd for C11H11O3, 191.02; found, 191.02.
IR (KBr, m
max) cmꢁ1: 3004, 2958, 2926, 2854, 1732, 1612, 1578,
1514, 1451, 1433, 1399, 1384, 1339, 1288, 1248, 1199, 1173, 1123,
5.2.4.2. 2-(4-Trifluoromethoxyphenyl)cyclopropanecarboxylic
acid (5b). Compound 5b was prepared using 4b as starting mate-
rial. White solid (0.24 g, quantitative, mp 78–80 °C).
1050, 1004, 984.
1H NMR (300 MHz, CDCl3) d ppm: 1.22 (m, 1H, ꢀCH2), 1.51 (m,
1H, ꢀCH2), 1.67 (s, 3H, H4 ), 1.71 (s, 3H, H5 ), 1.72 (m, 1H, H7), 2.42
IR (KBr,
m
max) cmꢁ1: 3410, 2926, 2650, 1697, 1514, 1459, 1436,
0
0
0
(m, 1H, H8), 3.64 (s, 3H, –COOCH3), 4.41 (d, 2H, J = 6.6 Hz, H1 ), 5.06
1336, 1256, 1198, 1164, 11.3, 1017, 937.

2544
P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
1H NMR (300 MHz, acetone-d6) d ppm: 1.33 (m, 1H, ꢀCH2), 1.62
(–CH2O–), 114.8 (C3, C5), 119.5 (C2 ), 123.8 (C7 ), 127.4 (C2, C6),
0
0
0
0
(m, 1H, ꢀCH2), 1.89 (m, 1H, H7), 2.55 (m, 1H, H8), 7.20 (d, 2H,
J = 9 Hz, H3, H5), 7.27 (d, 2H, J = 9 Hz, H2, H6).
13C NMR (75 MHz, acetone-d6) d ppm: 17.4 (ꢀCH2), 23.9 (C8),
26.3 (C7), 121.1 (C3, C5), 122.1 (q, J = 284 Hz, –CF3), 127.6 (C2, C6),
138.2 (C1), 147.9 (C4), 179.5 (C9).
131.3 (C8 ),131.8 (C3 ), 141.2 (C1), 157.7 (C4), 179.9 (C9).
LRMS (ESꢁ, MꢁH) Calcd for C20H25O3, 313.20; found, 337.24.
5.2.5. Preparation of N0-Isonicotinoyl-N-2-(4-alkoxyphenyl)
cyclopropanecarboxylhydrazide (6a–f): general procedure
A clean dry round bottom flask (10 mL) with a magnetic stir
bar was charged with carboxylic acid (5a–f, 1 mmol, 1 equiv),
isoniazide (0.20 g, 1.5 mmol, 1.5 equiv), HOBt (0.15 g, 1.1 mmol,
1.1 equiv) and EDCꢀHCl (0.21 g, 1.1 mmol, 1.1 equiv) under argon.
Dry CH3CN (5 mL) was added to it and stirred. Diisopropylethyl-
amine (0.5 mL, 3 mmol, 3 equiv) was added to the reaction mix-
ture and refluxed for 24 h. TLC was monitored in ethylacetate.
Acetonitrile was removed under reduced pressure. Ethylacetate
(60 mL) was added to the crude yellow mass and the solution
was thoroughly washed with water (30 mL ꢂ 3). The organic
layer was then dried over MgSO4. Removal of the solvent gave
a crude yellowish mass. It was the purified over silica gel (70–
200 mesh) using 80% ethylacetate in Petroleum ether to afford
6a–f.
LRMS (APCI, M+NH4) Calcd for C11H13 NF3O3, 264.08; found,
264.10.
5.2.4.3. 2-(4-Ethoxyphenyl)cyclopropanecarboxylic
acid
(5c). Compound 5c was prepared using 4c as starting material.
White solid (0.20 g, quantitative, mp 70–72 °C).
IR (KBr, m
max) cmꢁ1: 3410, 2979, 2927, 2881, 2650, 1702, 1611,
1515, 1459, 1395, 1335, 1288, 1249, 1229, 1179, 1116, 1049, 936.
1H NMR (300 MHz, CDCl3) d ppm: 1.36 (m, 1H, ꢀCH2), 1.42 (t,
3H, J = 6.9 Hz, –OCH2CH3), 1.64 (m, 1H, ꢀCH2), 1.85 (m, 1H, H7),
2.59 (m, 1H, H8), 4.03 (q, 2H, J = 6.9 Hz, –OCH2CH3), 6.84 (d, 2H,
J = 9 Hz, H3, H5), 7.06 (d, 2H, J = 9 Hz, H2, H6).
13C NMR (75 MHz, CDCl3) d ppm: 13.7 (–CH2CH3), 16.1 (ꢀCH2),
22.7 (C8), 25.6 (C7), 62.4 (–OCH2CH3), 113.5 (C3, C5), 126.4 (C2,
C6), 130.1 (C1), 156.7 (C4), 179.0 (C9).
LRMS (ES+, M+Na) Calcd for C12H14O3Na, 229.08; found, 229.11.
5.2.5.1. N0-Isonicotinoyl-N-2-(4-methoxyphenyl)cyclopropane
carboxylhydrazide (6a). Compound 6a was prepared using 5a as
starting material. White crystalline solid (0.26 g, 85%, mp.193–
195 °C).
5.2.4.4. 2-[4-(2,20,200-Trifluoroethoxy)phenyl]cyclopropanecar-
boxylic acid (5d). Compound 5d was prepared using 4d as starting
material. White solid (0.26 g, quantitative, mp 93–95 °C).
IR (KBr, m
max) cmꢁ1: 3160, 3015, 2962, 2925, 2855, 1730, 1579,
IR (KBr,
m
max) cmꢁ1: 3405, 2920, 2563, 1687, 1615, 1517, 1460,
1592, 1550, 1517, 1470, 1409, 1298, 1250, 1229, 1186, 1160, 1083,
1437, 1327, 1299, 1238, 1178, 1151, 1084, 1029, 977.
1H NMR (300 MHz, CDCl3) d ppm: 1.29 (m, 1H, ꢀCH2), 1.58 (m,
1H, ꢀCH2), 1.78 (m, 1H, H7), 2.51 (m, 1H, H8), 4.26 (q, 2H, J = 4.8 Hz,
–OCH2CF3), 6.80 (d, 2H, J = 9 Hz, H3, H5), 7.00 (d, 2H, J = 9 Hz, H2,
H6) .
1027, 993.
1H NMR (300 MHz, C6D6: DMSO-d6(5:1)) d ppm: 1.07 (m, 1H,
ꢀCH2), 1.59 (m, 1H, ꢀCH2), 2.25 (m, 1H, H7), 2.55 (m, 1H, H8),
3.39 (s, 3H, –OCH3), 6.70 (d, 2H, J = 9 Hz, H3, H5), 6.92 (d, 2H,
J = 9 Hz, H2, H6), 7.88 (m, 2H, H3, H5 py), 8.59 (m, 2H, H2, H6 py),
10.66 (br s, 1H, ꢀNH), 11.03 (br s, 1H, ꢀNH),
13C NMR (75 MHz, CDCl3) d ppm: 17.2 (ꢀCH2), 23.7 (C8), 26.4
(C7), 65.9 (q, J = 35.9 Hz, –OCH2CF3), 115.1 (C3, C5), 123.8, (q,
J = 277 Hz, –CF3), 127.6 (C2, C6), 133.5 (C1), 156.3 (C4), 179.8 (C9).
LRMS (ESꢁ, MꢁH) Calcd for C12H10F3O3, 259.06; found, 259.15.
13C NMR (75 MHz, C6D6: DMSO-d6(5:1)) d ppm: 15.8 (ꢀCH2),
24.1 (C8), 24.6 (C7), 55.0 (–OCH3), 114.2 (C3, C5), 127.6 (C2, C6),
127.61 (C3, C5 py), 133.1 (C1), 140.3 (–NH@C(O)–C€), 150.6 (C2,
C6 py), 158.5 (C4), 164.4 (–NH@C(O)–C€), 171.5 (C9).
HRMS (TOF MS CI+, M+H) Calcd for C17H18N3O3, 312.1348;
found, 312.1339.
5.2.4.5. 2-[4-(3-Methylbut-2-enyloxy)phenyl]cyclopropanecar-
boxylic acid (5e). Compound 5e was prepared using 4e as starting
material. White solid (0.24 g, 98%, mp 86–88 °C).
IR (KBr,
m
max) cmꢁ1: 3417, 2966, 2919, 2865, 2645, 2549, 1697,
5.2.5.2. N0-Isonicotinoyl-N-2-(4-trifluoromethoxyphenyl)cyclo-
propanecarboxylhydrazide (6b). Compound 6b was prepared
using 5b as starting material. White crystalline solid (0.33 g, 91%,
mp.176–177 °C).
1614, 1516, 1460, 1434, 1384, 1337, 1289, 1253, 1230, 1178, 1109,
1049, 1003, 938.
1H NMR (300 MHz, CDCl3) d ppm: 1.37 (m, 1H, ꢀCH2), 1.65 (m,
1H, ꢀCH2), 1.76 (s, 3H, H4 ), 1.82 (s, 3H, H5 ), 1.85 (m, 1H, H7), 2.59
IR (KBr, m
max) cmꢁ1: 3164, 3015, 2352, 1990, 1631, 1579, 1591,
0
0
0
0
(m, 1H, H8), 4.51 (d, 2H, J = 6.6 Hz, H1 ), 5.50 (m, 1H, H2 ), 6.87 (d,
1550, 1514, 1503, 1475, 1410, 1305, 1217, 1162, 1108, 1084, 1042,
2H, J = 9 Hz, H3, H5), 7.06 (d, 2H, J = 9 Hz, H2, H6).
994, 936.
13
1H NMR (300 MHz, C6D6: DMSO-d6(5:1)) d ppm: 1.00 (m, 1H,
ꢀCH2), 1.49 (m, 1H, ꢀCH2), 2.14 (m, 1H, H7), 2.40 (m, 1H, H8),
6.87 (m, 4H, H2, H6, H3, H5), 7.77 (m, 2H, H3, H5 py), 8.52 (m, 2H,
H2, H6 py), 10.53 (br s, 1H, ꢀNH), 10.9 (br s, 1H, ꢀNH).
13C NMR (75 MHz, C6D6: DMSO-d6(5:1)) d ppm: 16.3 (ꢀCH2),
24.1 (C8), 24.3 (C7), 114.2 (C3, C5), 127.6 (C2, C6), 127.61 (C3, C5
py), 133.1 (C1), 140.4 (–NH@C(O)–C€), 150.4 (C2, C6 py), 158.2
(C4), 164.2 (–NH@C(O)–C€), 170.8 (C9).
0
C NMR (75 MHz, CDCl3) d ppm: 16.1(ꢀCH2), 17.2 (C4 ), 22.7
0
(C8), 24.7 (C5 ), 25.6 (C7), 63.7 (–OCH2–), 113.8 (C3, C5), 118.1
0
0
(C2 ), 126.4 (C2, C6), 130.3 (C3 ), 136.8 (C1), 156.7 (C4), 179.0 (C9).
LRMS (ES+, M+Na) Calcd for C15H18O3Na, 269.14; found, 269.20.
5.2.4.6. 2-{4-[(E)-3,7-Dimethylocta-2,6-dienyloxy]phenyl}cyclo-
propanecarboxylic acid (5f). Compound 5f was prepared using 4f
as starting material. White solid (0.31 g, quantitative, mp 83–
85 °C).
19F NMR (282 MHz, DMSO-d6) d ppm: ꢁ56.86 (s, 3F)
HRMS (TOF MS CI+, M+H) Calcd for C17H15F3N3O3, 366.1066;
found, 366.1067.
IR (KBr, m
max) cmꢁ1: 3415, 2966, 2928, 2875, 2641, 1885, 1700,
1611, 1579, 1515, 1458, 1433, 1380, 1335, 1287, 1248, 1229, 1179,
1110, 1049, 996,937.
1H NMR (300 MHz, CDCl3) d ppm: 1.29 (m, 1H, ꢀCH2), 1.55 (m,
5.2.5.3. N0-Isonicotinoyl-N-2-(4-ethoxyphenyl)cyclopropane
carboxylhydrazide (6c). Compound 6c was prepared using 5c as
starting material. White crystalline solid (0.29 g, 90%, mp.195–
197 °C).
0
0
0
1H, ꢀCH2), 1.55 (s, 3H, H9 ), 1.63 (s, 3H, H10 ), 1.67 (s, 3H, H4 ), 1.76
(m, 1H, H7), 2.04 (m, 4H, H5 , H6 ), 2.51 (m, 1H, H8), 4.46 (d, 2H,
J = 6.6 Hz, –OCH2–), 5.04 (m, 1H, H7 ), 5.42 (m, 1H, H2 ), 6.78 (d,
0
0
0
0
2H, J = 9 Hz, H3, H5), 6.98 (d, 2H, J = 9 Hz, H2, H6).
IR (KBr, m
max) cmꢁ1: 3166, 3015, 2979, 1876, 1657, 1579, 1591,
13
0
C NMR (75 MHz, CDCl3) d ppm: 16.6 (C9 ), 17.2 (ꢀCH2), 17.7
1551, 1516, 1502, 1475, 1410, 1398, 1294, 1249, 1231, 1186, 1168,
1114, 1065, 1047, 994, 942.
0
0
0
0
(C4 ), 23.7 (C8), 25.7(C6 ), 26.3 (C7), 26.6 (C5 ), 39.5 (C10 ), 64.9

P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
2545
1H NMR (300 MHz, C6D6: DMSO-d6(5:1)) d ppm: 1.03 (m, 1H,
ꢀCH2), 1.03 (t, 3H, J = 6.9 Hz, –OCH2CH3), 1.55 (m, 1H, ꢀCH2), 2.20
(m, 1H, H7), 2.49 (m, 1H, H8), 3.60 (q, 2H, J = 6.9 Hz, –OCH2CH3),
6.65 (d, 2H, J = 9 Hz, H3, H5), 6.87 (d, 2H, J = 9 Hz, H2, H6), 7.82
(m, 2H, H3, H5 py), 8.52 (m, 2H, H2, H6 py), 10.60 (br s, 1H, ꢀNH),
10.98 (br s, 1H, ꢀNH).
H6), 7.81 (m, 2H, H3, H5 py), 8.52 (m, 2H, H2, H6 py), 10.56 (br s,
1H, ꢀNH), 10.95 (br s, 1H, ꢀNH).
13C NMR (75 MHz, C6D6: DMSO-d6(5:1)) d ppm: 15.8 (ꢀCH2),
0
0
0
0
16.5(C9 ), 17.3 (C4 ), 24.1 (C8), 24.6 (C7), 25.7(C6 ), 26.5 (C5 ), 39.5
0
0
(C10 ), 64.9 (–OCH2–), 115.0 (C3, C5), 121.8 (C2 ), 122.0 (C-3, C-5
0
0
0
py),124.2 (C7 ), 127.51(C2, C6), 127.59 (C8 ),128.8 (C3 ), 133.0 (C1),
140.1 (–NH@C(O)–C€), 150.6 (C-2, C-6 py), 157.9 (C4), 164.4 (–
NH@C(O)–C€), 171.5 (C9).
13C NMR (75 MHz, C6D6: DMSO-d6(5:1)) d ppm: 14.6 (–CH2CH3),
15.6 (ꢀCH2), 23.8 (C8), 24.4 (C7), 63.0 (–OCH2CH3), 114.5 (C3, C5),
121.8 (C3, C5 py), 127.3 (C2, C6), 132.8 (C1), 140.1 (–NH@C(O)–
C€), 150.4 (C2, C6 py), 157.6 (C4), 164.2 (–NH@C(O)–C€), 171.3 (C9).
HRMS (TOF MS CI+, M+H) Calcd for C18H20N3O3, 326.1505;
found, 326.1503.
HRMS (TOF MS CI+, M+H) Calcd for C26H32N3O3, 434.2444;
found, 434.2449.
5.2.5.7. Preparation of
2-(4-alkoxyphenyl)-N0-(phthalazin-1-
yl)cyclopropanecarbohydrazide (7a–f): general procedure. A
clean dry round bottom flask (10 mL) with a magnetic stir bar
was charged with carboxylic acid (5a–f, 1 mmol), 1-hydrazinoph-
thalazine hydrochloride (0.294 g, 1.5 mmol, 1.5 equiv), HOBt
(0.15 g, 1.1 mmol, 1.1 equiv) and EDCꢀHCl (0.21 g, 1.1 mmol,
1.1 equiv) under argon. Dry dichloromethane (5 mL) was added
to it and stirred. Diisopropylethylamine (0.7 mL, 4 mmol, 4 equiv)
was added to the reaction mixture and stirred at room tempera-
ture for 6 h. TLC was monitored in ethylacetate. Dichloromethane
was removed under reduced pressure. Ethylacetate (60 mL) was
added to the crude yellow mass and the solution was thoroughly
washed with water (30 mL ꢂ 3). The organic layer was then dried
over MgSO4. Removal of the solvent gave a crude yellowish mass.
It was the purified over silica gel (70–200 mesh) using 80% ethyl-
acetate in Petroleum ether to afford 7a–f.
5.2.5.4. N0-Isonicotinoyl-N-2-[4-(2,20,200-trifluoroethoxy)phenyl]
cyclopropanecarboxylhydrazide (6d). Compound 6d was pre-
pared using 5d as starting material. White crystalline solid
(0.35 g, 93%, mp.198–200 °C).
IR (KBr, m
max) cmꢁ1: 3163, 3008, 2365, 1654, 1590, 1551, 1518,
1502, 1477, 1411, 1281, 1249, 1251, 1183, 1163, 1113, 1084, 1003,
974.
1H NMR (300 MHz, C6D6: DMSO-d6(5:1)) d ppm: 0.99 (m, 1H,
ꢀCH2), 1.69 (m, 1H, ꢀCH2), 2.31 (m, 1H, H7), 2.60 (m, 1H, H8),
3.76 (q, 2H, J = 4.8 Hz, –OCH2CF3), 6.53 (d, 2H, J = 9 Hz, H3, H5),
6.77 (d, 2H, J = 9 Hz, H2, H6), 7.81 (m, 2H, H3, H5 py), 8.52 (m, 2H,
H2, H6 py), 10.73 (br s, 1H, ꢀNH), 10.99 (br s, 1H, ꢀNH).
13C NMR (75 MHz, C6D6: DMSO-d6(5:1)) d ppm: 15.9 (ꢀCH2),
24.1 (C8), 24.5 (C7), 65.8 (q, J = 35.9 Hz, –O H2CF3), 115.1 (C3, C5),
122.0 (C3, C5 py), 127.6 (C2, C6), 135.2 (C1), 140.2 (–NH@C(O)–
C€), 150.6 (C2, C6 py), 156.1 (C4), 164.3 (–NH@C(O)–C€), 171.3 (C9).
19F NMR (282 MHz, DMSO-d6) d ppm: ꢁ72.51 (t, J = 8.4 Hz, 3F).
HRMS (TOF MS CI+, M+H) Calcd for C18H17F3N3O3, 380.1222;
found, 380.1226.
5.2.5.8. 2-(4-Methoxyphenyl)-N0-(phthalazin-1-yl)cyclopropa-
necarbohydrazide (7a). Compound 7a was prepared using 5a as
starting material. Yellow solid (0.22 g, 65%, mp.188–190 °C
decomposes).
IR (KBr, m
max) cmꢁ1: 3363, 3317, 3272, 3179, 3006, 2924, 2837,
2360, 1674, 1640, 1611, 1580, 1514, 1455, 1431, 1339, 1301, 1245,
1181, 1139, 1109, 1032, 946.
5.2.5.5. N0-Isonicotinoyl-N-2-[4-(3-methylbut-2-enyloxy)phe-
nyl]cyclopropanecarboxylhydrazide (6e). Compound 6e was pre-
pared using 5e as starting material. White crystalline solid (0.32 g,
90%, mp.188–190 °C).
1H NMR (300 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: 1.31 (m, 1H, ꢀCH2), 1.38 (m, 1H, ꢀCH2), 1.94
(m, 1H, C7), 2.68 (m, 1H, C8), 3.64 (s, 3H, –OCH3), 6.81 (d, 2H,
J = 9 Hz, H3, H5), 7.06 (d, 2H, J = 9 Hz, H2, H6), 8.17 (m, 3H, H3, H4,
H5 phthalazine), 8.55 (m, 1H, H6 phthalazine), 9.07 (s, 1H, H8
phthalazine).
IR (KBr, m
max) cmꢁ1: 3159, 3008, 2967, 2929, 2861, 1591, 1550,
1515, 1502, 1473, 1410, 1385, 1294, 1246, 1186, 1160, 1111, 1083,
1044, 1013, 941.
1H NMR (300 MHz, C6D6: DMSO-d6(5:1)) d ppm: 1.00 (m, 1H,
13C NMR (75 MHz, C6D6: DMSO-d6(5:1) + few drops of
0
0
ꢀCH2), 1.38 (s, 3H, H4 ), 1.45 (s, 3H, H5 ), 1.54 (m, 1H, ꢀCH2), 2.20
CF3COOD)
d ppm: 16.3 (–CH2–), 25.1 (C8), 26.5 (C7), 55.2
0
(m, 1H, H7), 2.49 (m, 1H, H8), 4.25 (d, 2H, J = 6.6 Hz, H1 ), 5.32 (m,
(–OCH3), 114.2, 114.3 (C3, C5), 118.5 (C-phthalazine), 124.4 (CH-
phthalazine), 127.5, 127.6 (C2, C6), 128.1 (C1), 130.2 (CH-phthal-
azine), 132.5 (C-phthalazine), 135.5 (CH-phthalazine), 136.7 (CH-
phthalazine), 145.9 (–N@CH–), 151.8 (C4), 157.4 (–NH–C@N–),
172.5 (C9).
0
1H, H2 ), 6.70 (d, 2H, J = 9 Hz, H3, H5), 6.87 (d, 2H, J = 9 Hz, H2,
H6), 7.83 (m, 2H, H3, H5 py), 8.52 (m, 2H, H2, H6 py), 10.60 (br s,
1H, ꢀNH), 10.98 (br s, 1H, ꢀNH).
13C NMR (75 MHz, C6D6: DMSO-d6(5:1)) d ppm: 15.6(ꢀCH2),
0
0
17.8 (C4 ), 23.9 (C8), 24.4 (C7), 25.3 (C5 ), 64.6 (–OCH2–), 114.7
HRMS (TOF MS CI+, M+H) Calcd for C19H17N4O, 351.1508;
found, 351.1508.
0
0
(C3, C5), 120.4 (C3, C5 py), 121.8 (C2 ), 127.3 (C2, C6), 132.8 (C3 ),
136.6 (C1), 140.1 (–NH@C(O)–C€), 150.4 (C2, C6 py), 157.6 (C4),
164.2 (–NH@C(O)–C€),171.3 (C9).
5.2.5.9. 2-(4-Trifluoromethoxyphenyl)-N0-(phthalazin-1-yl)cy-
clopropanecarbohydrazide (7b). Compound 7b was prepared
using 5b as starting material. Yellow solid (0.26 g, 67%, mp.184–
186 °C decomposes).
HRMS (TOF MS CI+, M+H) Calcd for C21H24N3O3, 366.1818;
found, 366.1812.
5.2.5.6. N0-Isonicotinoyl-N-2-{4-[(E)-3,7-dimethylocta-2,6-die-
nyloxy]phenyl} cyclopropanecarboxylhydrazide (6f). Compound
6f was prepared using 5f as starting material. White crystalline so-
lid (0.41 g, 95%, mp.186–188 °C).
IR (KBr, m
max) cmꢁ1: 3210, 3061, 2926, 1728, 1630, 1605, 1580,
1548, 1511, 1481, 1452, 1410, 1371, 1344, 1259, 1225, 1164, 1085,
1038, 1018.
1H NMR (300 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: 1.34 (m, 1H, ꢀCH2), 1.46 (m, 1H, ꢀCH2), 2.19
(m, 1H, H7), 2.64 (m, 1H, H8), 7.17 (m, 4H, H2, H3, H5, H6), 8.12
(m, 3H, H3, H4, H5 phthalazine), 8.59 (m, 1H, H6 phthalazine),
9.02 (s, 1H, H8 phthalazine).
IR (KBr, m
max) cmꢁ1: 3166, 3019, 2968, 2920, 1591, 1551, 1515,
1474, 1410, 1389, 1293, 1246, 1186, 1160, 1110, 1083, 997.
1H NMR (300 MHz, C6D6: DMSO-d6(5:1)) d ppm: 1.00 (m, 1H,
0
0
0
ꢀCH2), 1.36 (s, 3H, H9 ), 1.42 (s, 3H, H10 ), 1.47 (s, 3H, H4 ), 1.48
13C NMR (75 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: 16.6 (–CH2–), 24.9 (C8), 26.2 (C7), 118.4 (C-
phthalazine), 120.9 (C3, C5), 124.4 (CH-phthalazine), 128.2 (C2,
0
0
(m, 1H, ꢀCH2), 1.92 (m, 4H, H5 , H6 ), 2.18 (m, 1H, H7), 2.48 (m,
1H, H8), 4.28 (d, 2H, J = 6.6 Hz, –OCH2–), 4.96 (m, 1H, H7 ), 5.36
0
0
(m, 1H, H2 ), 6.69 (d, 2H, J = 9 Hz, H3, H5), 6.87 (d, 2H, J = 9 Hz, H2,

2546
P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
C6), 129.2 (CH-phthalazine), 135.0 (CH-phthalazine), 136.2 (C-
phthalazine), 136.8 (CH-phthalazine), 140.3 (C1), 146.0 (–N@CH–
), 148.1 (C4), 152.5 (–NH–C@N–), 172.1 (C9).
13C NMR (75 MHz, DMSO-d6 + few drops of CF3COOD) d ppm:
0
0
0
16.3 (ꢀCH2), 18.0 (C4 ), 24.4 (C8), 25.1 (C7), 25.5 (C5 ), 64.6 (C1 ),
0
115.1 (C3, C5), 118.6 (C-phthalazine), 120.5 (C2 ), 124.6 (HC-phthal-
19F NMR (282 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: ꢁ53.15 (s, 3F)
azine), 127.5, 127.6 (C2, C6), 128.3 (C3 ), 130.1 (HC-phthalazine),
0
132.6 (C1), 134.9 (HC-phthalazine), 135.5 (HC-phthalazine), 137.2
(C-phthalazine), 146.1 (C8 phthalazine), 152.5 (C4), 157.5 (HN@C–
N), 172.6 (C9).
HRMS (TOF MS CI+, M+H) Calcd for C19H16F3N4O2, 389.1225;
found, 389.1245.
HRMS (TOF MS CI+, M+H) Calcd for C23H25N4O2, 389.1978;
found, 389.1986.
5.2.5.10. 2-(4-Ethoxyphenyl)-N0-(phthalazin-1-yl)cyclopropane-
carbohydrazide (7c). Compound 7c was prepared using 5c as
starting material. Yellow solid (0.21 g, 62%, mp.191–193 °C
decomposes).
5.2.5.13. 2-{4-[(E)-3,7-Dimethylocta-2,6-dienyloxy]phenyl}-N0-
(phthalazin-1-yl) cyclopropanecarbohydrazide (7f). Compound
7f was prepared using 5f as starting material. Yellow solid
(0.36 g, 79%, mp.184–186 °C decomposes).
IR (KBr, m
max) cmꢁ1: 3338, 3220, 2978, 1636, 1609, 1551, 1514,
1478, 1447, 1406, 1339, 1290, 1235, 1177, 1142, 1115, 1083, 1047.
1H NMR (300 MHz, DMSO-d6 + few drops of CF3COOD) d ppm:
1.22 (t, 3H, J = 6.9 Hz, –CH3), 1.27 (m, 1H, ꢀCH2), 1.38 (m, 1H,
ꢀCH2), 1.95 (m, 1H, H7), 2.28 (m, 1H, H8), 3.90 (q, 2H, J = 6.9 Hz,
IR (KBr, m
max) cmꢁ1: 3424, 3214, 3029, 2920, 1640, 1608, 1573,
1551, 1513, 1448, 1407, 1373, 1340, 1290, 1234, 1178, 1145, 1083,
1003, 908.
0
H1 ), 6.77 (d, 2H, J = 9 Hz, H3, H5), 7.03 (d, 2H, J = 9 Hz, H2, H6),
1H NMR (300 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: 1.28 (m, 1H, ꢀCH2), 1.40 (m, 1H, ꢀCH2), 1.45 (s,
8.16 (m, 3H, H3, H4, H5 phthalazine), 8.56 (d, 1H, J = 8.4 Hz, H6
phthalazine), 9.05 (s, 1H, H8 phthalazine).
0
0
0
3H, H9 ), 1.51 (s, 3H, H10 ), 1.58 (s, 3H, H4 ), 2.30 (m, 1H, H7), 2.69
13C NMR (75 MHz, DMSO-d6 + few drops of CF3COOD) d ppm:
(m, 1H, H8), 4.41 (d, 2H, J = 6.6 Hz, H1 ), 4.96 (m, 1H, H7 ), 5.30
0
0
0
0
14.2 (–OCH2CH3), 15.7 (–CH2–), 23.8 (C8), 24.6 (C7), 62.8 (C1 ),
(m, 1H, H3 ), 6.77 (d, 2H, J = 9 Hz, H3, H5), 7.03 (d, 2H, J = 9 Hz, H2,
114.2 (C3, C5), 118.0 (C-phthalazine), 123.9 (CH-phthalazine),
127.0 (C2, C6), 127.6 (C-phthalazine), 128.6 (CH-phthalazine),
131.8 (C1), 134.4 (CH-phthalazine), 136.2 (CH-phthalazine), 145.4
(–N@CH–), 152.0 (C4), 157.1 (–NH–C@N–), 172.0 (C9).
HRMS (TOF MS CI+, M+H) Calcd for C20H21N4O2, 349.1665;
found, 349.1651.
H6), 8.14 (m, 3H, H3, H4, H5 phthalazine), 8.56 (m, 1H, H6 phthal-
azine), 9.03 (s, 1H, H8 phthalazine).
13C NMR (125 MHz, C6D6: DMSO-d6(5:1) + few drops of
0
0
CF3COOD) d ppm: 15.6 (C9 ), 16.2 (–CH2–), 17.4 (C4 ), 25.1 (C8),
0
0
25.4 (C7), 26.14 (ꢀCH2), 26.17 (ꢀCH2), 39.6 (C10 ), 64.7 (C1 ),
0
115.09, 115.00 (C3, C5), 118.6 (C-phthalazine), 120.1 (C2 ), 124.0
0
0
(C8 ), 124.4 (CH-phthalazine), 124.6 (C3 ), 127.6, 127.4 (C-2, C-6),
5.2.5.11. 2-[4-(2,20,200-Trifluoroethoxy)phenyl]-N0-(phthalazin-
1-yl)cyclopropanecarbohydrazide (7d). was prepared using 5d
as starting material. Yellow solid (0.29 g, 73%, mp.188–190 °C
decomposes).
128.1 (C-phthalazine), 130.0 (CH-phthalazine), 131.3 (C7 ) 132.4
0
(C1), 134.8 (CH-phthalazine), 136.7 (CH-phthalazine), 145.8 (–
N@CH–), 157.6 (C4), 157.9 (–NH–C@N–),172.5 (C9).
HRMS (TOF MS CI+, M+H) Calcd for C28H33N4O2, 457.2604;
found, 457.2580.
IR (KBr, m
max) cmꢁ1: 3348, 3262, 2322, 1669, 1636, 1556, 1516,
1477, 1455, 1432, 1338, 1287, 1239, 1156, 1139, 1110, 1083, 976.
1H NMR (300 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: 1.40 (m, 1H, ꢀCH2), 1.65 (m, 1H, ꢀCH2), 2.28
(m, 1H, H7), 2.62 (m, 1H, H8), 4.60 (q, 2H, J = 8.1 Hz, –OCH2CF3),
6.93 (d, 2H, J = 9 Hz, H3, H5), 7.11 (d, 2H, J = 9 Hz, H2, H6), 8.17
(m, 3H, H3, H4, H5 phthalazine), 8.55 (m, 1H, H6 phthalazine),
9.07 (s, 1H, H8 phthalazine).
5.2.6. Preparation of 3-(2-(4-alkoxyphenyl)cyclopropyl)-[1, 2,
4]triazolo[3, 4-a]phthalazine (8a–f): General Procedure
A clean dry round bottom flask (10 mL) with a magnetic stir bar
was charged with carboxylic acid (5a–f, 1 mmol, 1 equiv), 1-hydra-
zinophthalazine hydrochloride (0.294 g, 1.5 mmol, 1.5 equiv),
HOBt (0.15 g, 1.1 mmol, 1.1 equiv) and EDCꢀHCl (0.21 g, 1.1 mmol,
1.1 equiv) under argon. Dry acetonitrile (5 mL) was added to it and
stirred. Diisopropylethylamine (0.7 mL, 4 mmol, 4 equiv) was
added to the reaction mixture and refluxed for 48 h. TLC was mon-
itored in ethylacetate. Acetonitrile was removed under reduced
pressure. Ethylacetate (60 mL) was added to the crude yellow mass
and the solution was thoroughly washed with water (30 mL ꢂ 3).
The organic layer was then dried over MgSO4. Removal of the sol-
vent gave a crude yellowish mass. It was then purified over silica
gel (70–200 mesh) using 80% ethylacetate in Petroleum ether to af-
ford 8a–f.
13C NMR (75 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: 15.8 (–CH2–), 23.9 (C8), 24.5 (C7), 64.5 (q,
J = 37.5 Hz, –CH2CF3), 114.8 (C3, C5), 118.0 (C-phthalazine), 123.9
(CH-phthalazine), 127.2 (C2, C6), 127.6 (C-phthalazine), 128.7(CH-
phthalazine), 133.9 (C1),134.5 (CH phthalazine), 136.3 (CH phthal-
azine), 146.2 (–N@CH–), 155.64 (C4), 158.9 (–NH–C@N–),171.9
(C9).
19F NMR (282 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: ꢁ68.37 (t, J = 9.3 Hz, 3F)
HRMS (TOF MS CI+, M+H) Calcd for C20H18F3N4O2, 403.1382;
found, 403.1397.
5.2.6.1. 3-[2-(4-Methoxyphenyl)cyclopropyl]-[1, 2, 4]triazolo[3,
4-a]phthalazine (8a). Compound 8a was prepared using 5a as
starting material. White crystalline solid (0.23 g, 74%, mp.187–
5.2.5.12. 2-[4-(3-Methylbut-2-enyloxy)phenyl]-N0-(phthalazin-
1-yl)cyclopropanecarbohydrazide (7e). Compound 7e was pre-
pared using 5e as starting material. Yellow solid (0.26 g, 68%,
mp.185–187 °C decomposes).
189 °C).
IR (KBr, m
max) cmꢁ1: 3435, 3056, 3016, 3002, 2949, 2832, 1898,
IR (KBr,
m
max) cmꢁ1: 3202, 3031, 2970, 2915, 1640, 1608, 1572,
1610, 1579, 1513, 1456, 1440, 1354, 1302, 1281, 1249, 1180, 1141,
1552, 1513, 1447, 1407, 1372, 1338, 1290, 1229, 1176, 1144, 1107,
1118, 1034, 993, 977.
1083, 1039, 1001, 908.
1H NMR (300 MHz, CDCl3) d ppm: 1.57 (m, 1H, ꢀCH2), 1.98 (m,
1H, ꢀCH2), 2.65 (m, 1H, H7), 2.77 (m, 1H, H8), 3.74 (s, 3H, –OCH3),
6.82 (d, 2H, J = 9 Hz, H3, H5), 7.13 (d, 2H, J = 9 Hz, H2, H6), 7.73
(m, 1H, H3 phthalazine), 7.85 (m, 2H, H4, H5 phthalazine), 8.53 (s,
1H, H6 phthalazine), 8.59 (m, 1H, H8 phthalazine).
1H NMR (300 MHz, C6D6: DMSO-d6(5:1) + few drops of
CF3COOD) d ppm: 1.28 (m, 1H, ꢀCH2), 1.39 (m, 1H, ꢀCH2), 1.56 (s,
0
0
3H, H4 ), 1.58 (s, 3H, H5 ), 2.30 (m, 1H, H7), 2.68 (m, 1H, H8), 4.38
0
0
(d, 2H, J = 6.6 Hz, H1 ), 5.29 (m, 1H, H2 ), 6.75 (d, 2H, J = 9 Hz, H3,
H5), 7.01 (d, 2H, J = 9 Hz, H2, H6), 8.08 (m, 3H, H3, H4, H5 phthal-
azine), 8.56 (m, 1H, H6 phthalazine), 8.98 (s, 1H, H8 phthalazine),
13C NMR (75 MHz, CDCl3) d ppm: 15.9 (C8), 16.6 (ꢀCH2), 26.0
(C7), 55.3 (–OCH3), 113.9 (C3, C5), 123.2 (C-phthalazine), 123.7

P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
2547
(HC-phthalazine), 127.4 (C2, C6), 128.0 (HC-phthalazine), 131.0
(HC-phthalazine), 132.5 (C1), 134.1 (HC-phthalazine), 142.2 (C-
phthalazine), 147.6 (C8 phthalazine), 152.2 (N@C–N), 158.3 (C4),
164.5 (N@C–N).
HRMS (TOF MS Cl+, M+H) Calcd for C19H17N4O, 317.1402;
found, 317.1404.
133.9 (HC-phthalazine), 134.9 (C1), 147.4 (C8 phthalazine),151.8
(C-phthalazine),156.1 (N@C–N), 158.4 (C4),169.5 (N@C–N).
19F NMR (282 MHz, CDCl3) d ppm: ꢁ73.94 (t, J = 7.9 Hz, 3F).
HRMS (TOF MS Cl+, M+H) Calcd for C20H16F3N4O, 385.1276;
found, 385.1258.
5.2.6.5. 3-{2-[4-(3-Methylbut-2-enyloxy)phenyl]cyclopropyl}-
[1, 2, 4]triazolo[3, 4-a]phthalazine (8e). Compound 8e was pre-
pared using 5e as starting material. White crystalline solid
5.2.6.2. 3-[2-(4-Trifluoromethoxyphenyl)cyclopropyl]-[1, 2, 4]
triazolo[3, 4-a]phthalazine (8b). Compound 8b was prepared
using 5b as starting material. White crystalline solid (0.30 g, 81%,
(0.24 g, 65%, mp.187–189 °C).
IR (KBr, m
max) cmꢁ1: 3427, 3057, 3018, 2965, 2923, 2870, 1979,
mp.191–193 °C).
IR (KBr, m
max) cmꢁ1: 3431, 3059, 1904, 1630, 1591, 1561, 1531,
1899, 1728, 1677, 1630, 1611, 1578, 1512, 1471, 1456, 1415, 1382,
1354, 1300, 1279, 1241, 1178, 1141, 1118, 1080, 1052, 1003, 992,
975.
1511, 1458, 1420, 1353, 1289, 1204, 1166, 1115, 1079, 1054, 1018,
993, 976.
1H NMR (300 MHz, CDCl3) d ppm: 1.57 (m, 1H, ꢀCH2), 1.68 (s,
1H NMR (300 MHz, CDCl3) d ppm: 1.59 (m, 1H, ꢀCH2), 2.04 (m,
1H, ꢀCH2), 2.73 (m, 1H, H7), 2.84 (m, 1H, H8), 7.11 (d, 2H, J = 9 Hz,
H3, H5), 7.21 (d, 2H, J = 9 Hz, H2, H6), 7.74 (m, 1H, H3 phthalazine),
7.87 (m, 2H, H4, H5 phthalazine), 8.55 (s, 1H, H6 phthalazine), 8.62
(m, 1H, H8 phthalazine),
0
0
3H, H4 ), 1.74 (s, 3H, H5 ), 2.00 (m, 1H, ꢀCH2), 2.68 (m, 1H, H7),
0
0
2.78 (m, 1H, H8), 4.44 (d, 2H, J = 6.6 Hz, H1 ), 5.44 (m, 1H, H2 ),
6.83 (d, 2H, J = 9 Hz, H3, H5), 7.12 (d, 2H, J = 9 Hz, H2, H6), 7.77
(m, 1H, H3 phthalazine), 7.88 (m, 2H, H4, H5 phthalazine), 8.56 (s,
13C NMR (75 MHz, CDCl3) d ppm: 16.3 (C8), 17.0 (ꢀCH2), 25.8
(C7), 121.1 (C3, C5), 123.1(C-phthalazine), 123.4 (HC-phthalazine),
127.6 (C2, C6), 128.1 (HC-phthalazine), 130.9 (HC-phthalazine),
130.9 (C1), 134.1 (HC-phthalazine), 139.4 (C-phthalazine), 147.4
(C4), 147.6 (C8 phthalazine), 152.2 (N@C–N), 164.5 (N@C–N).
19F NMR (282 MHz, CDCl3) d ppm: ꢁ57.90 (s, 3F)
1H, H6 phthalazine), 8.65 (m, 1H, H8 phthalazine).
13
0
C NMR (75 MHz, CDCl3) d ppm: 15.9 (C4 ), 16.5 (ꢀCH2), 18.2
0
0
0
(C8), 25.85 (C7), 25.87 (C5 ), 64.8 (C1 ), 114.7 (C3, C5), 119.7 (C2 ),
0
123.10 (HC-phthalazine), 123.18 (C-phthalazine), 123.7 (C3 ),
127.4 (C2, C6),130.5 (HC-phthalazine), 132.7 (C1), 133.8 (HC-
phthalazine), 138.1 (C-phthalazine), 142.7 (N@C–N), 147.2 (C8
phthalazine),152.1 (C4), 157.5 (N@C–N).
HRMS (TOF MS Cl+, M+H) Calcd for C23H23N4O, 371.1872;
found, 371.1869.
HRMS (TOF MS Cl+, M+H) Calcd for C19H14F3N4O, 371.1110;
found, 371.1110
5.2.6.3. 3-[2-(4-Ethoxyphenyl)cyclopropyl]-[1, 2, 4]triazolo[3, 4-
5.2.6.6. 3-{2-(4-[(E)-3,7-Dimethylocta-2,6-dienyloxy]phenyl)
cyclopropyl}-[1, 2, 4]triazolo[3, 4-a]phthalazine (8f). Compound
8f was prepared using 5f as starting material. White crystalline so-
a
]phthalazine (8c). Compound 8c was prepared using 5c as start-
ing material. White crystalline solid (0.29 g, 90%, mp.187–189 °C).
IR (KBr,
max) cmꢁ1: 3441, 3059, 3017, 2976, 2926, 1897, 1628,
m
lid (0.33 g, 75%, mp.187–189 °C).
1610, 1580, 1514, 1478, 1456, 1416, 1395, 1353, 1300, 1281, 1247,
1181, 1141, 1114, 1047, 992, 977.
IR (KBr, m
max) cmꢁ1: 3436, 3057, 3018, 3003, 2964, 2917, 2854,
1H NMR (300 MHz, CDCl3) d ppm: 1.34 (t, 3H, J = 6.9 Hz, –CH3),
1.54 (m, 1H, ꢀCH2), 1.97 (m, 1H, ꢀCH2), 2.65 (m, 1H, H7), 2.68 (m,
1H, H8), 3.96 (q, 2H, J = 6.9 Hz, –OCH2–), 6.79 (d, 2H, J = 9 Hz, H3,
H5), 7.12 (d, 2H, J = 9 Hz, H2, H6), 7.73 (m, 1H, H3 phthalazine),
7.86 (m, 2H, H4, H5 phthalazine), 8.52 (s, 1H, H6 phthalazine),
8.60 (m, 1H, H8 phthalazine).
2359, 1979, 1729, 1673, 1629, 1611, 1579, 1514, 1456, 1416, 1379,
1354, 1301, 1279, 1265, 1246, 1179, 1141, 1119, 1052, 1002, 992,
975.
1
0
H NMR (300 MHz, CDCl3) d ppm: 1.63 (s, 3H, H9 ), 1.65 (m, 1H,
0
0
ꢀCH2), 1.69 (s, 3H, H10 ), 1.75 (s, 3H, H4 ), 2.05 (m, 1H, ꢀCH2), 2.12
0
0
(m, 4H, H5 , H6 ), 2.75 (m, 1H, H7), 2.85 (m, 1H, H8), 4.55 (d, 2H,
13C NMR (75 MHz, CDCl3) d ppm: 14.9 (–CH3), 16.4 (C8), 16.6
0
0
0
J = 6.6 Hz, H1 ), 5.11 (m, 1H, H7 ), 5.50 (m, 1H, H2 ), 6.90 (d, 2H,
J = 9 Hz, H3, H5), 7.19 (d, 2H, J = 9 Hz, H2, H6), 7.80 (m, 1H, H3
phthalazine), 7.95 (m, 2H, H4, H5 phthalazine), 8.61 (s, 1H, H6
0
(ꢀCH2), 25.9 (C7), 63.4 (C1 ), 114.5 (C3, C5), 123.3 (C-phthalazine),
123.7 (HC-phthalazine), 127.6 (C2, C6), 128.0 (HC-phthalazine),
130.6 (HC-phthalazine), 132.6 (C1), 133.9 (HC-phthalazine),142.8
(C-phthalazine), 147.4 (C8 phthalazine), 152.1 (N@C–N), 157.8
(C4), 164.1 (N@C–N).
phthalazine), 8.68 (m, 1H, H8 phthalazine).
13
0
C NMR (75 MHz, CDCl3) d ppm: 15.9 (C9 ), 16.61 (ꢀCH2), 16.67
0
0
0
0
0
0
(C4 ), 17.71(C6 ), 25.7 (C8 ), 25.9 (C7 ), 26.3 (C5 ), 39.5 (C10 ), 64.9
0
0
0
(C1 ), 114.7 (C3, C5), 119.5 (C7 ), 123.1 (C-phthalazine), 123.2 (C2 ),
HRMS (TOF MS Cl+, M+H) Calcd for C20H19N4O, 331.1559;
found, 331.1554.
0
123.7 (HC-phthalazine), 123.8 (C8 ), 127.4 (C2, C6), 128.0 (HC-
0
phthalazine), 130.6 (HC-phthalazine), 131.8 (C3 ), 132.6 (C1),
133.9 (HC-phthalazine), 142.1 (C-phthalazine), 142.6 (N@C–N),
147.2 (C8 phthalazine), 152.1 (C4), 157.5 (N@C–N).
HRMS (TOF MS Cl+, M+H) Calcd for C28H31N4O, 439.2498;
found, 439.2503.
5.2.6.4. 3-{2-[4-(2,20,200-Trifluoroethoxy)phenyl]cyclopropyl}-
[1, 2, 4]triazolo[3, 4-a]phthalazine (8d). Compound 8d was pre-
pared using 5d as starting material. White crystalline solid
(0.32 g, 83%, mp.177–179 °C).
IR (KBr, m
max) cmꢁ1: 3427, 3059, 3016, 2953, 1906, 1628, 1610,
5.2.7. X-ray data
1532, 1514, 1475, 1459, 1421, 1353, 1299, 1245, 1178, 1157, 1119,
Crystal data for (8e): C23H22N4O, M = 370.45, monoclinic, Pc,
a = 19.0593(6) Å, b = 7.6970(3) Å, c = 6.6124(2) Å, b = 94.911(2)°,
V = 966.47(6) Å3, Z = 2, T = 193(2) K. 13083 reflections (3839 inde-
pendent, Rint = 0.0389) were collected at low temperatures using
an oil-coated shock-cooled crystal on a Bruker-AXS SMART APEX
1079, 1056, 994, 977.
1H NMR (300 MHz, CDCl3) d ppm: 1.55 (m, 1H, ꢀCH2), 1.99 (m,
1H, ꢀCH2), 2.67 (m, 1H, H7), 2.80 (m, 1H, H8), 4.28 (q, 2H, J = 8.1 Hz,
0
H1 ), 6.84 (d, 2H, J = 9 Hz, H3, H5), 7.15 (d, 2H, J = 9 Hz, H2, H6), 7.72
(m, 1H, H3 phthalazine),7.86 (m, 2H, H4, H5 phthalazine), 8.53 (s,
1H, H6 phthalazine), 8.58 (m, 1H, H8 phthalazine).
II diffractometer with MoKa radiation (k = 0.71073 Å). The struc-
ture was solved by direct methods (SHELXS-97, G. M. Sheldrick, Acta
Crystallogr. 1990, A46, 467–473) and all non-hydrogen atoms were
refined anisotropically using the full-matrix least-squares method
13C NMR (75 MHz, CDCl3) d ppm: 16.1 (C8), 16.6 (ꢀCH2), 25.6
(C7), 65.8 (q, J = 37.5 Hz, –OCH2–), 115.1 (C3, C5), 123.1 (C-phthal-
azine), 123.2 (HC-phthalazine), 123.6 (q, J = 278.0 Hz, –CF3),
127.7 (C2, C6), 128.0 (HC-phthalazine), 130.6 (HC-phthalazine),
on F2
(SHELXL-97, Program for Crystal Structure Refinement, G. M.
Sheldrick, University of Göttingen, 1997). Largest electron density

2548
P. De et al. / Bioorg. Med. Chem. 18 (2010) 2537–2548
11. Do, Q.; Tian, W.; Yougnia, R.; Gaslonde, T.; Pfeiffer, B.; Pierré, A.; Léonce, S.;
residue: 0.350 e Åꢁ3, R1 (for I > 2
r
R
(I)) = 0.0544 and wR2 = 0.1445
Kraus-Berthier, L.; David-Cordonnier, M.-H.; Depauw, S.; Lansiaux, A.;
Mazinghien, R.; Koch, M.; Tillequin, F.; Michel, S.; Dufat, H. Bioorg. Med.
Chem. 2009, 17, 1918.
(all data) with R1 =
R
||Fo| ꢁ |Fc||/
|Fo| and wR2 = (
R
w (F2o ꢁ F2c )2/
R
w(F2o)2)0.5. CCDC 755182 contains the supplementary crystallo-
12. Moody, C.; Norton, C.; Slawin, A.; Taylor, S. Anticancer Drug Des. 1998, 13, 611.
13. Percec, V.; Peterca, M.; Sienkowska, M. J.; Ilies, M. A.; Aquad, E.; Smidrkal, J.;
Heiney, P. A. J. Am. Chem. Soc. 2006, 128, 3324.
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk).
14. Andrus, M. B.; Song, C.; Zang, J. Org. Lett. 2002, 4, 2079.
15. Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001, 123, 12168.
16. Concellón, J. M.; Rodríguez-Solla, H.; Simal, C. Org. Lett. 2007, 9, 2685.
17. Tsai, C.-C.; Hsieh, I.-H.; Cheng, T.-T.; Tsai, P.-K.; Lin, K.-W.; Yan, T.-H. Org. Lett.
2006, 8, 2261.
Acknowledgements
18. Corey, E. J.; Chaykovosky, M. J. Am. Chem. Soc. 1965, 87, 1353.
19. (a) Akbarzadeh, T.; Tabatabai, S. A.; Khoshnoud, M. J.; Shafaghi, B.; Shafiee, A.
Bioorg. Med. Chem. 2003, 11, 769; (b) Borioni, A.; Mustazza, C.; Sestili, I.;
Sbraccia, M.; Turchetto, L.; Giudice, M. R. D. Arch. Pharm. Chem. Life Sci. 2007,
340, 17; (c) Francis, J. E.; Cash, W. D.; Barbaz, B. S.; Bernard, P. S.; Lovell, R. A.;
Mazzenga, G. C.; Friedmann, R. C.; Hyun, J. L.; Braunwalder, A. F.; Loo, P. S.;
Bennette, D. A. J. Med. Chem. 1991, 34, 281; (d) Zimmer, H.; Kokosa, J. M.; Shah,
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We thank the European Community. Thanks are also due to the
CNRS (France), ‘Université Paul Sabatier’ (Toulouse, France), ITAV (Tou-
louse, France) and Fonds Yvonne Boël (Brussels, Belgium) for financial
support. R.K. is a director of research with the FNRS (Belgium).
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