Synthesis of allylated chalcones… Chapter 2
113
Synthesis of allylated chalcones and their derivatives with enhanced
solubility for antimalarial and pesticidal activity
Infectious diseases caused by bacteria, fungi, viruses and parasites such as malaria, tuberculosis
etc are still a major threat to public health, despite tremendous progress in medicinal chemistry.
The impact is more acute in developing countries due to non-availability of desired medicines
and emergence of widespread drug resistance. The requirement is to synthesize/semi-synthesize
novel molecules having good potential with high therapeutic index. Till date, nature has
remained an ever evolving source for the discovery and development of new compounds of
medicinal importance. Among the various natural products, chalcones (1,3-diarylprop-2-en-1-
one; Figure 1) have attracted considerable interest as potential drug candidates due to their
economical, facile, and rapid synthesis.O
R R'
A B
Figure 1
Chalcones occur mainly as petal pigments and have also been found in the heartwood, bark,
leaf, fruit, and root of a variety of trees and plants. The appeal of working with chalcones stems
from their synthetic accessibility, the various ways the core structure can be diversified
depending on the substitution pattern on the two aromatic rings (Figure 1) and their ability to
confer drug-like properties to compound libraries modeled on them [Nowakowska (2007)].
Moreover, in accordance with its privileged status, a wide range of pharmacological activities
have been identified for chalcone derivatives [Edwards et al. (1990); Mukherjee et al. (2001);
Bhat et al. (2005); Göker et al. (2005); Nielsen et al. (2005); Boeck et al. (2006); Wei et al.
(2007)]. In our pursuit to develop novel molecules having good therapeutic potential, we aimed
at the synthesis of natural chalcone analogues as antimalarial and pesticidal agents.
Synthesis of allylated chalcones… Chapter 2
114
2.1. Synthesis of allylated chalcones and their derivatives with enhanced
solubility for antimalarial activity2.1.1. Introduction
Despite years of continual efforts for its eradication, malaria still remains globally prevalent
parasitic disease; killing approximately three million people per annum mainly from
developing countries like Central- and South-America, Asia, and Sub-Saharan Africa [Phillips
(2001); Greenwood and Mutabingwa (2002); Tripathi et al. (2005)]. The British major, Ronald
Ross, discovered the transmittance of human malarial parasites by female Anopheles mosquito
more than 100 years ago. Malaria is caused by four species of parasite belonging to the genus
Plasmodium: P. falciparum, P. vivax, P. ovale and P. malariae. Among these, P. falciparum is
the parasite causing most of the deaths [Phillips (2001); Kaur et al. (2009); Kumar et al.
(2009)].
2.1.2. Pathogenesis and the life cycle of malaria parasite
The life cycle, immunological defense mechanisms, and clinical development of malaria in
humans is a complex process. Plasmodium parasites have a complex life cycle, which is shared
between a vertebrate host (human) and an insect vector (female Anopheles mosquito) [Hoffman
et al. (2002)]. The parasite enters the bloodstream in the form of sporozoites through the bite of
an infected female Anopheles mosquito. In humans, the sporozoites invade the parenchymal
cells of the liver. They remain in liver cells (safe from an immune response) for 9-16 days,
undergoing multiple asexual fission and producing merozoites. During development in the liver
the patient remains asymptomatic but after a variable period of time, 6-8 days for vivax, 9 days
for ovale, 12-16 days for malariae, and 5-7 days for falciparum, merozoites are released from
the liver [Christensen and Kharazmi (2001)]. The merozoites invade the erythrocytes, where
they feed on the haemoglobin. After proliferation, the erythrocyte rupture and the liberated
merozoites invade other erythrocytes. Some merozoites are converted into gametocytes
[Casteel (1997)]. When a mosquito takes a blood meal from an infected person it swallows
some gametocytes which undergo sexual reproduction in the digestive tract of the mosquito;
ultimately producing many sporozoites which migrate to the salivary gland for injection into
another host, beginning the cycle again (Figure 2) [Murder (2000); Christensen and Kharazmi
(2001)].
Synthesis of allylated chalcones… Chapter 2
115
Clinical malaria is characterized by periodic fever, which follows the lysis of infected
erythrocytes and caused mainly by the induction of cytokines interleukin-1 and tumor necrosis
factor. P. falciparum infection can have serious effects, for example, anemia, cerebral
complications (from coma to convulsions), hypoglycemia and glomerulonephritis. The disease
is most serious in the non-immune individuals, including children and pregnant women
[Christensen and Kharazmi (2001)].
Figure 2: Simplified presentation of the life cycle of the malaria parasite [Adapted from:
Ridley (2002)]
2.1.3. Approaches to control malaria
WHO has given malaria a high priority and a number of programmes have been initiated to
control malaria [(WHO (2010)]. Three important attempts are: a) vector control [Greenwood
(1997)], b) development of vaccine against malaria [Facer and Tanner (1997); Riley (1997);
Kumar et al. (1999)], and c) chemotherapy [Tripathi et al. (2005)]. In addition, mapping of the
genome of the parasite might reveal new possibilities for the control of malaria [Christensen
and Kharazmi (2001)].
Synthesis of allylated chalcones… Chapter 2
116
2.1.3.1. Vector Control
Vector control can be achieved either by making contact of human host and mosquito
impossible or by killing the mosquitoes through insecticides [Mitchel (1996); Tripathi et al.
(2005)]. Use of artificial barrier such as insecticidal nets, repellents, protective clothing’s by
people at risk and destruction of breeding sites and resting areas of vector mosquito by spraying
with insecticide- predominantly DDT- afforded a considerable decrease of malaria incidence in
many parts of the tropical world [Jayaraman (1997); Day (1998)]. However, development of
resistance to DDT amongst mosquitoes, together with the delirious effects of entry of
insecticides in the human food chain [Mitchel (1996)], malaria has again become one of the
three most fatal diseases in the world.
2.1.3.2. Development of vaccine against malaria
Vaccination in malaria represents one of the most important approaches that provide a cost-
effective intervention in addition to currently available malaria control strategies [Mendis et al.
(2001); Tripathi et al. (2005)]. Most of the vaccine trials have been directed against liver stages
or sporozoites, and these vaccines include completely synthetic peptides, conjugates of
synthetic peptides with proteins such as tetanus-toxoid to provide Helper T-cell, recombinant
malarial proteins, recombinant viruses, and bacteria- & DNA-based vaccines [Offman (1996)].
2.1.3.3. Chemotherapy
The efficacy of antimalarial drugs depends primarily on their ability to kill malaria parasites by
interrupting their essential life functions, leading to inhibition of multiplication and allowing
the immune system to remove damaged parasites completely from the circulation [Luzzi and
Peto (1993); White (1996); Meinnel (2000); Christensen and Kharazmi (2001)]. During its life
cycle in human erythrocytes the Plasmodium parasite requires several metabolic adaptations
and innovations which render it susceptible to chemotherapeutic attack [Ridley (2002)]. The
parasite degrades haemoglobin in its acidic food vacuole producing free heme which react with
molecular oxygen and generate reactive oxygen species as toxic by-products. A major pathway
of detoxification of heme moieties is polymerization of heme to heamazoin. Majority of
quinoline [Casteel (1997); Ridley (1997)] and peroxide [Posner et al. (1992); Robert and
Meunier (1998)] antimalarial drugs act by disturbing the polymerization (and/or the
detoxification by any other way) of heme; thus killing the parasite with its own metabolic
waste. Some drugs are reported to block biosynthesis of pyrimidines- necessary for the growth
Synthesis of allylated chalcones… Chapter 2
117
of the parasites- by inhibition of the respiratory chain of malaria mitochondria [Casteel (1997);
Olliaro and Wirth (1997); Rathod (1997)] or prevent formation of dihydrofolate reductase
[Casteel (1997)]. Tetracycline antimalarials act by inhibition of mitochondria protein synthesis
[Casteel (1997)]. A number of iron (III) chelators have antimalarial activity in vitro, apparently
through the mechanism of withholding iron from vital metabolic pathways of the
intraerythrocytic parasite [Hider and Liu (1997); Mabeza et al. (1999)]. Other iron chelators
appear to inhibit malaria parasites by forming toxic complexes with iron [Mabeza et al.
(1999)].
2.1.4. Development of new antimalarial drugs
Discovery of lead compounds is still mainly based on screening of libraries of chemicals or
plant extracts. An alternative approach, developed in the 1970s, is to examine the ability of the
compound to inhibit the growth of parasites [Trager and Jensen, (1976); Khalid et al. (1986)]
through in vitro and in vivo screening assays.
2.1.4.1. Bioassays used for antimalarial drug discovery
2.1.4.1.1. In vitro screening assays
The first step in the antimalarial drug discovery process is to evaluate the antimalarial activity
of the test compounds or plant extracts in vitro systems using well characterized strains of P.
falciparum. Usually, two strains of P. falciparum are used- a chloroquine sensitive such as 3D7
and a chloroquine resistant such as Dd2. Human peripheral blood erythrocytes are used for the
in vitro screening studies. Although several in vitro methods exist, the [3H]-hypoxanthine assay
[Desjardins et al. (1979)] is the standard test for screening potential drugs for antiplasmodial
activity or monitoring parasite sensitivity to available antimalarial drugs. However, it is an
expensive assay that requires radioactive materials which pose safety and disposal problems.
Another method is the WHO micro-test developed by Rieckmann and co-workers and adopted
by the WHO [Rieckmann et al. (1978)] with endpoint of assay evaluated microscopically.
Although inexpensive, this method is highly labor-intensive and subjective due to variation in
the expertise of the microscopists. There are other methods which are based on enzymatic
reaction and antibodies that specifically detect the presence of histidine-rich protein II or
parasite lactate dehydrogenase [Makler et al. (1993); Druilhe et al. (2001); Noedl et al. (2002)].
These assays involve multiple steps which make them not well-suited for high-throughput
antimalarial drug screening. Non-radioactive DNA stains [SYBR Green I (SG), PICO green®
Synthesis of allylated chalcones… Chapter 2
118
(PG)] have been reported for measurement of parasite growth in a short term assay using a 96-
well format [Corbett et al. (2004); Smilkstein et al. (2004); Baniecki et al. (2007)]. This
method appears to be safe, cost-effective, easily interpretable, and readily available. Its use
eliminates the challenge of appropriate disposal of radioactive waste and thus facilitates
antimalarial drug discovery process.
2.1.4.1.2. In vivo screening assays
A promising compound showing good in vitro activity (preferentially an IC50 value below 1
μM) and ready solubility in pharmaceutically suitable solvents is subjected to in vivo screening.
Different species of Plasmodium are used in these assays. The most common ones are P.
berghei K173, P. yoelii YM, P. chabaudi, and P. vinckei. These strains are lethal to animal and
kill the infected untreated animal within 7 to 12 days. In the most common assay the animals
are inoculated intraperiotoneally with 106 parasitised erythrocytes suspended in 0.2 mL saline.
Control animals receive normal saline. Chloroquine, or another drug, ought to be used as a
positive control. From day four of infection, thin blood smears are made from tail blood of the
mice for determination of parasitemia. The mortality of the mice is determined up to 28 days
following the last treatment [Peters (1980)]. In addition to mice, non-human primates, such as
Aotus lemurinus and Saimiri spp. monkeys, Macaques etc. are also used as test models for in
vivo antimalarial efficacy against infections with human parasites P. falciparum and P. vivax.
2.1.5. Natural product based antimalarial agents
The emergence and spread of strains of P. falciparum resistant to almost all available
antimalarial drugs necessitate constant monitoring of parasite susceptibility to antimalarial
drugs and concerted effort towards the search for new potent antimalarials [Bruno et al.
(1997)]. Natural products have always remained in focus for the discovery of new drug leads
[Buss and Waigh (1995); Senior (1996); Cragg et al. (1997); Pandey (1998); Shu (1998)],
especially for the treatment of human diseases [Newman et al. (2003)]. Even today, the
majority of drugs used against malaria has been developed from, or are, natural products and
form a rich source of diverse structures for optimization to obtain improved therapeutics. The
major groups of antimalarial phytochemicals can be divided into several categories that include
alkaloids, terpenoids, flavanoids, lignans, coumarins, quinones, xanthones, peptides etc. Table
1 covers a spectrum of antimalarials from natural sources.
Synthesis of allylated chalcones… Chapter 2
119
Table 1: Major groups along with representative examples of natural product based
antimalarial agents [Christensen and Kharazmi (2001); Kaur et al. (2009)]
Group Defination Representive examplesAlkaloids
O
N
NHO
Heterogeneous group of naturallyoccurring nitrogen containingcompounds derived from aminoacid precursor.
Quinine
N+
O
O
OCH3
OCH3Berberine
N
NH
NH2
H2N
HO
Cl
Girolline
N
H
CH3
Cryptoleine
Heterogeneous group of naturalproducts formed from mevalonicacid. They are characterised bythe presence of the isoprene unitin the skeleton, though this unitmight be changed byrearrangement in the molecule.
Terpenoids
O
O
OO
H
H
O
H
Artemisinin
O O
H
HO H2C
Helenalin
H OH
O
CH2
OH
O
Eudesmane
H
HNC H
H NC
H
Diisocyanoadociane
Flavanoids are a complex groupof natural products composed ofa C6C3-moiety having shikimicacid as a precursor and a C6moiety of polyketide origin.Some examples are known inwhich the two moieties havebeen alkylated might containseven carbons.
Flavanoids
O
HO OH
OCH3
CH2
Licochalcone
O
OCOCH3
OH
HO
OH O
cis-3-Acetoxy-4',5,7-trihydroxyflavanone
O
O
OH
OH
4-Hydroxy LonchocarprinO
HO
OH
OHOH
5-Prenylbutein
Synthesis of allylated chalcones… Chapter 2
120
Group Defination Representive examplesLignans
Coumarins
Quinones
HO
OH
H2C
CH2HO
CH2
OH
OCH3
NyasoleTermilignan
O
OO
H3CO
H3COO
O
OO
HO
H3CO OCH3
O
O
Ph
Dehydrodiconiferyldibenzoate
O O
OCH 3H3CO
H3COO O
H3CO
HOOCH 3
5,6,7-trimethoxycoumarin isofraxidin
O
OO
HO
O
ONewbouldiaquinone A
O
O
O
OH
OCH3Xylariaquinone A
O
OOH
Plumbagin
O
O
O
Naphthoquinoid
Xanthones Xanthones are organic compoundswith the molecular formulaC13H8O2 and are known as"adaptagens" for their uniqueability to adapt to the needs of thebody.
Quinones may either be formedvia the acetate pathway or by asequence involving shikimate andmevalonate.
The lignans are biogeneticallybuilt by dimerisation of twoC6C3-moieties originating fromshikimic acid.
O
H3CO
HO
O OH
OHCowaxanthone
O
O OH
OH
O
Calothwaitesixanthone
O
O OH
OH
H3CO
HO
Peptides
Justicidan B
The coumarins contain the2-oxobenzopyrane skeleton.
Mangostin
Peptides are short polymers ofamino acids linked by peptidebonds.
N HN
OO
NH
O
NH
O
O
NOCH3
Apicidin
Synthesis of allylated chalcones… Chapter 2
121
Among these existing antimalarial natural products, quinine has remained the drug of choice
[Rogers and Randolph (2000)] for treating the chloroquine- and multidrug- resistant falciparum
malaria; however its use is declining because of potential toxicity [Kapoor and Kumar (2005)].
At present, artemisinins-based drug is the most effective treatment for curing chloroquine-
resistant P. falciparum infections [de Vries and Dien (1996); Price et al. (1997); Kapoor and
Kumar (2005), Woodrow et al. (2005)]; however their indiscriminate use as monotherapy has
raised the concern of emerging drug resistance [Luxemburger et al. (1998); Meshnick (2002);
Alker et al. (2007); Enserink (2008); Dondorp et al. (2009)]. To slow down the resistance to
this vital class of drugs; Artemisinin based combination therapies (ACT) are being advocated
by WHO e.g. artemether-lumefantrine combination therapy [WHO (1998)]. This will also
lessen the pressure on rising artemisinin demand- a natural product in short supply and with
commercially unviable synthesis [Bhasin and Nair (2003)]. The situation demands developing
new antimalarial agents or drug combinations that are effective and support treatment at
affordable cost.
2.1.5.1. Chalcones as antimalarials
Chalcones or 1,3-diaryl-2-propen-1-ones, have drew the attention of chemists when
licochalcone A (Figure 3, IC50 4.1 µM) isolated from Chinese liquorice (Glycyrrhiza inflate)
roots was reported to exhibit potent in vivo and in vitro antimalarial activity against both
chloroquine-susceptible and chloroquine-resistant P. falciparum strains [Chen et al. (1994)].
In another report, 5-prenylbutein (Figure 3) from Erythrina abyssinica [Yenesew et al. (1994)]
and methyllinderatin (Figure 3) from Piper hostmannianum [Portet et al. (2007)] exhibiting
antimalarial activity have been reported with IC50 of 10.3 µM and 5.64 µM, respectively.
HO
OH
OCH3
OO
HO
OH
OHOH
OOH
H3CO OHH
H
Methyllinderatin5-PrenylbuteinLicochalcone
A
B
Figure 3
Since then, several natural chalcones such as xanthohumol and related chalcones, medicagenin,
crotaorixin, homobutein etc. (Figure 4) have been reported for in vitro antiplasmodial activity
Synthesis of allylated chalcones… Chapter 2
122
against the P. falciparum strains with IC50 values in the range of 10.3–16.1 µM [Stevens and
Page (2004); Frölich et al. (2005); Narender et al. (2005)].
HO
OH
OCH3
O
OH
R2O
R4OH
OR1
O
OHR3
OH
HO OH
OCH3O
HO
OH O
OH
Xanthohumol Crotaorixin Medicagenin
HomobuteinR1, R2, R3 = H, R4 = Prenyl DesmethylxanthohumalR1,R3 = H, R2, = CH3, R4 = Prenyl XanthogalenolR1, R2 = CH3, R3 = H, R4 = Prenyl 4'-O-MethylxanthohumolR1, R2 = CH3, R3 = H, R4 = Geranyl 3'-GeranylchlconaringeninR1, R2 = H, R3, R4 = Prenyl 3',5'-DiprenylchalconaringeninR1 = CH3, R2 = H, R3 , R4 = Prenyl 5'-PrenylxanthohumalR1 = R2 = CH3, R3 , R4 = Prenyl Flavokawin
OOH
HO
OCH3
OH
Figure 4
Ngameni et al. (2007) isolated bartericin A, stipulin, 4-hydroxylonchocarpin from Dorstenia
barteri var. subtriangularis (Figure 5) which were found to be active in vitro against P.
falciparum (IC50 = 2.15, 5.13 and 3.36 µM, respectively).
HO
R
OH O
OHO
O
OH
OH
Bartericin A, R =
Stipulin, R =
4-Hydroxylonchocarpin
Figure 5
Similarly, the bioassay-guided isolation of dichloromethane extract of the aerial parts of
Boronia bipinnata led to the isolation of two isoprenylated chalcones, bipinnatones A and B
Synthesis of allylated chalcones… Chapter 2
123
(Figure 6) which were found to inhibit the malarial parasite enzyme target hemoglobinase II- an
enzyme essential for the survival of the parasite [Carroll et al. (2008)].HO
OH O
OH
R
OH
Bipinnatones AR=
R = CH3 Bipinnatones B
Figure 6
However, limitations associated with these chalcones such as their low percentage in natural
resources, toxicity, low bioavailability, poor solubility and tedious total synthesis [Chen et al.
(1997); Stevens and Page (2004)] have generally restrained their use in humans. Nevertheless,
the compounds described above provide useful synthons for semisynthetic transformations of
easily available precursors into newer and modified antimalarials against not only drug-
sensitive, but also drug-resistant strains of Plasmodium [Li et al. (1995); Liu et al. (2001); Wu
et al. (2002); Go et al. (2004); Dominguez et al. (2005); Tomar et al. (2010)].
In this context, an analog of licochalcone, 2,4-dimethoxy-4'-butoxychalcone (Figure 7) was
found to exhibit potent activity against P. falciparum in vitro and the rodent parasites P.
berghei and P. yoelii in vivo [Chen et al. (1997)].
O
O OC H3
OC H3
Figure 7
Recently, a series of acetylenic chalcones were evaluated for antimalarial activity. The obtained
data series suggested that introduction of a methoxy group ortho to acetylenic group
contributed towards increasing the lipophilicity of the compounds; thus leading to growth
inhibition of the W2 strain of P. falciparum (Scheme 1) [Hans et al. (2010)].
Synthesis of allylated chalcones… Chapter 2
124
H3CO
HO
R
OH3CO
O
R
O
H3CO
O
O
R'
H3CO
OR'
O
Propagryl bromideor
K2CO3,DMFrt, 12 h
2.5 M NaOH70oC, 3 h
Methoxylatedacetophenone
or benzaldehyde
R'= 4-methoxy; 2,4-dimethoxy;2,3,4-trimethoxy
R = H, CH3R = H, CH3
Scheme 1
In a structure-activity relationship study conducted by Kumar et al. (2010) for exploring the
basic chalcone moiety for antimalarial activity, it was revealed that the presence of methoxy
substitution, particularly 2,4,5-trimethoxy substitution, on ring A of chalcone and electron
withdrawing groups at ring B significantly favors the antimalarial activity as compared to other
counterparts (Figure 8).OOCH3
H3COOCH3
Cl
OOCH3
H3COOCH3
Br
O
H3CO
OCH3
Cl
H3COOOCH3
H3CO ClOCH3
IC50 = 4 µM IC50 = 8 µM
O
H3COOCH3
OCH3
I
IC50 = 2 µM
IC50 = 4.6 µM
IC50 = 1.8 µM
Figure 8
In the context of searching novel pharmaceutically promising analogs of natural chalcones and
inspired by the Licochalcone template, we designed and synthesized a series of novel allylated
chalcones including their heterocyclic and bis derivatives for antimalarial activity.
Synthesis of allylated chalcones… Chapter 2
125
2.1.6. Results and discussion
A close scrutiny of natural antimalarial chalcones reveals that these generally possess
substituted allylated aromatic rings (prenyl or geranyl group) as an important part of their
structure [Kromann et al. (2004)]. The importance of allyl or prenyl group for enhancing the
bioactivities of flavonoids, including chalcones, is also well documented in literature
[Henderson et al. (2000); Maitrejean et al. (2000); Milligan et al. (2000); Miranda et al. (2000);
Stevens and Page (2004)]. Furthermore, the use of allyl or prenyl moiety is known to contribute
towards lipophilicity of the molecule- an important requirement for antimalarial activity
[Mukherjee et al. (2001); Hans et al. (2010)] and could be replaced by groups with comparable
lipophilic characters. Thus, the significant antiplasmodial activity of natural chalcones
prompted us to synthesize a novel series of Licochalcone A congeners for in vitro antimalarial
activity and to study their structure-activity relationship. Attention has been focused on the
modification of the aldehyde moiety (ring A, Figure 1) of Licochalcone by substituting the 1,1-
dimethyl allyl group with C- or O-allyl and prenyl groups to achieve a new antimalarial profile.
The chalcones are divided into four main types according to the substitution of A ring (Figure
1): C-allylated, O-allylated, C- and O-allylated and O-diallylated. Further, to address the
demands of green chemistry, vanillin-an easily available natural precursor, has been utilized for
the synthesis of these chalcones.
2.1.6.1. Chemistry and synthesis of chalcones
As shown, 4-allyloxy-3-methoxy benzaldehyde (1b) was obtained by refluxing vanillin (1a)
with allyl bromide in the presence of K2CO3 in dry acetone [Xu et al. (2006); Vogel and
Heilmann (2008)] (Scheme 2). Compound 1b upon microwave irradiation at 200oC underwent
Claisen reaction to yield 2b which was transformed into 3b using dimethyl sulfate as
methylating agent [Aponte et al. (2008); Srinivasan et al. (2009)] and into 4b with allyl
bromide [Aponte et al. (2008)] (Scheme 2). Claisen-Schmidt condensation of 1a, 1b-4b with
the corresponding acetophenones in the presence of aqueous NaOH [Cabrera et al. (2007);
Boumendjel et al. (2008)] gave chalcone products (1-19) which were purified by
chromatography and crystallization (Scheme 2).
Synthesis of allylated chalcones… Chapter 2
126
CHO
HOOCH3
(1b) (2b)
3b, 4b
(d)
(a)
(c)
3-8
(c)RO
OCH3
CHO
HOOCH3
CHO
HOOCH3
O
R'
R= CH3, allyl R= methyl, allylR'= Cl, Br, NO2, OCH3, OCH2O
ROOCH3
O
R'
Vanillin (1a)
O
R'OOCH3
R'= H, Cl, Br, NO2, NH2, F, I,OCH3, OCH2O etc
CHO
OOCH3
(c)
1, 2R'= OH, Cl
(b)
9-19
Scheme 2: Reagents and conditions: (a) allyl bromide, potassium carbonate, anhydrous
acetone, reflux; (b) MW at T= 200oC for 10 min; (c) 10% aq. NaOH, methanol, substituted
acetophenone, stir at rt; (d) dimethyl sulfate, NaOH, stir at rt; or allyl bromide, K2CO3 and
anhydrous acetone, reflux.
Similarly, 4-allyloxyacetophenone (5b) was formed by reacting 4-hydroxy acetophenone (2a)
with allyl bromide [Xu et al. (2006)], which was condensed with 1b in the presence of aqueous
NaOH [Cabrera et al. (2007); Boumendjel et al. (2008)] to gave corresponding chalcone 20
(Scheme 3). Likewise, corresponding allyloxy benzaldehydes (6b, 7b) were obtained by
refluxing 2-hydroxy-3-methoxy benzaldehyde (3a) and 3-hydroxy-4-methoxy benzaldehyde
(4a), respectively with allyl bromide in the presence of K2CO3 in dry acetone [Xu et al. (2006);
Vogel and Heilmann (2008)]. Compounds 6b and 7b upon Claisen-Schmidt condensation with
4-chloro acetophenone in the presence of aqueous NaOH [Cabrera et al. (2007); Boumendjel et
al. (2008)] gave chalcone products (21 and 22) which were purified by chromatography and
crystallization (Scheme 3).
Synthesis of allylated chalcones… Chapter 2
127
OH
CHO
H3COO
CHO
H3CO
OH3CO
O
Cl
CHO
OHOCH 3
CH O
OOCH3
O
O ClOCH3
O
OH
O
O
(c)
(4a)
(a)
(3a) (6b)
(a)
21
(c)
(2a) (5b)
(b)
20
(a)
(7b) 22
O
O OOCH 3
Scheme 3: Reagents and conditions: (a) allyl bromide, potassium carbonate, anhydrous
acetone, reflux; (b) 10% aq. NaOH, ethanol, 1b, stir at rt; (c) 10% aq. NaOH, methanol, 4-
chloro acetophenone, stir at rt.
Chalcone 23 was obtained by condensation of 1a with chloro acetophenone in the presence of
KOH (Scheme 4) [Cabrera et al. (2007); Boumendjel et al. (2008)]. 23 upon reaction with
prenyl bromide, 1-butyl bromide and 4-bromobenzyl bromide yielded 24, 25 and 26,
respectively (Scheme 4) [Vogel and Heilmann (2008)]. All chalcones (23-26) were purified by
chromatography and crystallization.
CHO
HOOCH3
24-26R= prenyl, butyl,
bromobenzyl(1a)
O
HOOCH3
Cl
23
ROOCH3
O
Cl
(a) (b)
Scheme 4: Reagents and conditions: (a) KOH, ethanol, 4-chloro acetophenone, stir at rt; (b)
prenyl bromide or bromobutane or 4-bromo benzyl bromide, potassium carbonate, anhydrous
acetone, reflux.
In the similar vein, syringaldehyde (5a), 4-hydroxy benzaldehyde (6a), 2-hydroxy
benzaldehyde (7a), 3-ethoxy-4-hydroxy benzaldehyde (8a) and 3,4-dihydroxy benzaldehyde
(9a) were reacted with allyl bromide in the presence of K2CO3 in dry acetone [Xu et al. (2006);
Vogel and Heilmann (2008)] to provide corresponding O-allylated benzaldehydes (8b-12b)
(Scheme 5). Compounds 8b-12b upon Claisen-Schmidt condensation with 4-chloro
acetophenone in the presence of aq. NaOH [Cabrera et al. (2007); Boumendjel et al. (2008)]
gave chalcone products (27-31) which were purified by chromatography and crystallization.
Synthesis of allylated chalcones… Chapter 2
128
Similarly, 4-allyloxy-3-methoxyacetophenone (13b) was obtained by reaction of 4-hydroxy-3-
methoxyacetophenone (10a) with allyl bromide in the presence of K2CO3 in dry acetone which
on condensation with 4-chloro benzaldehyde provided chalcone 32 (Scheme 5). 14b was
obtained by reaction of 2,4-dihydroxy acetophenone (11a) with allyl bromide in the presence of
K2CO3 in dry acetone (Scheme 5) [Xu et al. (2006); Vogel and Heilmann (2008)].
R
HOR 1
CH O R
OR 1
CH O
O
OR 1
R
Cl
O
O OH
O
HO OH
CH O
OH
CH O
O
O
O Cl
HOOC 2H 5
CH O
OOC 2H 5
CH O O
OO C 2H 5
Cl
OH
CH O
HO
O
HOOCH 3
O
OOCH 3
O
C l OOCH 3
(a)
R = O C H 3 , HR 1= O C H 3 , H
(5a , 6a )R = O C H 3 , HR 1= O C H 3 , H
(8b , 9b ) R = O C H 3 , HR 1= O C H 3 , H
27 , 28
(14 b )(11 a)
(7a ) (10 b )
(a) (b)
29
(b)(a)
(a)
( 8a ) (11b ) 30
(12 b ) 31
(b)(a)
( 9a )
(b)
(10 a ) (13 b )
(a) (c)
32
OO
CH O
OO
O
Cl
Scheme 5: Reagents and conditions: (a) allyl bromide, potassium carbonate, anhydrous
acetone, reflux; (b) 10% aq. NaOH, ethanol, 4-chloro acetophenone, stir at rt; (c) 10% aq.
NaOH, ethanol, 4-chloro benzaldehyde, stir at rt.
Chalcones 33-38 were prepared by reacting 1b with various heteroaromatic acetophenones
(Scheme 6). Compound 39 was synthesized by reaction of 18 with 4,7-dichloroquinoline in
THF in the presence of K2CO3 [Mehta and Patel (2009)] which on further reaction with allyl
bromide in presence of KOH and THF yielded 40 (Scheme 6). Similarly, compounds 41 and 42
were prepared by refluxing 9 with phenyl hydrazine [Lévai (2005)] and guanidine
Synthesis of allylated chalcones… Chapter 2
129
hydrochloride [Rahaman et al. (2009)], respectively. Bis(dimeric)chalcones 43-45 by prepared
by reacting 1,3-diacetyl benzene with 3b, 1b and 12b, respectively in the presence of base
[Khan et al. (2002)]. Compounds 46 and 47 were prepared by Claisen-Schmidt condensation of
terephthaldehyde with 5b and 14b, respectively [Pinto et al. (2003)] (Scheme 6).
OOCH3
O
NH2
O
O
OCH 3
Cl
O
OOCH 3
NH
N Cl
O
OOCH 3
N
N Cl
OOCH3
Cl
N NC6H5
O
OCH3
Cl
N N
NH 2
O O
39
(b)
1840
(c)
OO
O O
R1
OR2OR2
R1
CHO
OHC
O
O
R1
O
O
R1
OCH3
O
R= F uran-2-yl
R= 4 -hydroxy chromen-2-oneR= Chro men-2-one
R= P yrro-2-yl333435
R
O
R= meldum acidR= barbituric acid
O
CHO(a)
OCH3
(33-38)
R1= H, allylR2= CH3, allyl
(f)
43-45
(g)
R1= H, OH
46, 47
Diacetyl benzene
Teraphthaldehyde
9
41
42
(d)
(e)
36
3837
Scheme 6: Reagents and conditions: (a) aq. NaOH, ethanol, substituted heteroatomic
acetophenone stir, rt; (b) 4,7-dichloro quinoline; THF, reflux; (c) allyl bromide, KOH, THF,
CTAB, stir rt; (d) phenyl hydrazine, sodium acetate, aq. acetic acid, MW at P = 180 W for 30
min; (e) guanidine HCl, KOH, ethanol, reflux; (f) NaOH, aq. ethanol, substituted aldehyde (1b
or 3b or 12b); (g) NaOH, aq. ethanol, substituted acetophenone (5b or 14b) stir, rt.
Synthesis of allylated chalcones… Chapter 2
130
2.1.6.2. Evaluation of antimalarial activity
All the above compounds were tested for antimalarial activity against chloroquine sensitive P.
falciparum 3D7 (Pf3D7) strain (Tables 2-6) by SYBR-Green-I assay [Smilkstein et al. (2004)].
This method is based on the fact that in the mature human red blood cells (which lack DNA),
the quantitative estimation of SYBR green fluorescence acts as an index of the growth of the
malaria parasite allowing precise estimation of IC50 value for each compound.
(a) C-allylated chalcones (Hydroxy vs methoxy derivatives): Initially 3-[4-hydroxy-3-
methoxy-5-(prop-2-en-1-yl)phenyl]-1-(4-hydroxyphenyl)prop-2-en-1-one (1, Table 2) was
synthesized as an analogue of Licochalcone (Figure 3). However, the low activity of 1 (IC50:
38.5 µM) combined with the tedious synthesis due to the presence of hydroxy substituents on
both rings A and B prompted us to explore variants leading to enhanced activity, solubility as
well as ease of synthesis. Consequently, compound 2 was synthesized by replacing the hydroxy
group on ring B with isosteric chloro group. The selection of chloro group was guided by its
lipophilic nature [Mishra et al. (2008)] and several reports on antimalarial potency of
chlorinated compounds [Fu and Xiao (1991); Kesten et al. (1992); Manohar et al. (2010)].
Even so, no significant improvement was observed in activity (IC50: 28 µM, Table 2) or
solubility. Moreover, the presence of hydroxy group on ring A was still proving a holdup for
facile synthesis of molecules. Thus, protection of this hydroxy group was needed to proceed
with the synthesis. Consequently, methylation was carried out and thus obtained compound (3)
was assessed for antimalarial potency (3, Table 2). To our delight, not only the solubility but
also the activity increased almost nine folds (IC50: 3.9 µM). Thereafter, keeping the substituents
on ring A constant, we next ventured to evaluate the effect of electron withdrawing and
electron donating groups on ring B (4-7, Table 2). However, all the substitutions provided
compounds with lower activity as compared to 3 indicating the importance of chloro group on
ring B (4-7, Table 2).
(b) C- and O-allylated chalcones (Effect of allyloxy group): To make the initial template
more lipophilic, allyloxy group was introduced (8) [Aponte et al. (2008)] in place of hydroxyl
position of compound 2. It resulted in slight decrease of activity (IC50: 7.8 µM) when compared
with 3 (IC50: 3.9 µM) though it was still considerably higher than 2 (IC50: 28 µM) (8 vs 3 vs 2,
Table 2).
Synthesis of allylated chalcones… Chapter 2
131
Table 2: Antimalarial activity, resistance and therapeutic indices of C- and both C- & O-
allylated chalcones
RO
OCH3
O
R'
1. R =H, R'= 4-OH2. R= H, R'= 4-Cl3. R= CH3, R'= 4-Cl4. R= CH3, R'= 4-OCH35. R= CH3, R'= 3,4-OCH2O-6. R= CH3, R'= 4-Br7. R= CH3, R'= 4-NO28. R= allyl, R'= 4-Cl
Compd.No.
Mol. Wt IC50 (µM)Pf3D7
IC50 (µg/mL)Pf3D7 IC50 Indo/
IC50 3D7IC50 Dd2/IC50 3D7
Resistance Index Therapeutic IndexIC50 HeLa/IC50 3D7
IC50 L29/IC50 3D7
1 310.3 38.5 11.9
2 328.7 28 9.21 1.9 1.5 >3.6 3.3
3 342.8 3.9 1.34 3.6 1.2 6.9 7.4
4 338.4 4.3 1.45 3.5 0.9 12.8 12.8
5 352.3 4.7 1.65 2.0 1.2 8.5 6.4
6 387.2 5.3 2.05 2.9 0.8 3.0 10
7 353.3 12.5 4.41 - 7.88 368.8 7.8 2.87 >2.6 1.0 8.3 1.9
CQ 40 nM - 4.2 > 200 > 200319.9 -
0.6 0.6 1.5 1.4
2.2 4.6
A B
(c) O-allylated chalcones and structure-activity investigations: To appraise the effect of
removal of C-allyl group, compound 9 was prepared and evaluated against 3D7. Delightedly,
the compound exhibited profound in vitro antimalarial activity (IC50: 2.5 µM, Table 3) which
was comparable to Licochalcone and far superior to its well-reported analogue, 4-dimethoxy-4'-
butoxychalcone. Thereafter, the structure–activity studies were carried out by varying the
substitutions on ring B (10-20, Table 3). It is clear that introduction of 3,4-dichloro (10), bromo
(11), iodo (12), fluoro (13), 3-chloro (14), methoxy (15), methylenedioxy (16), nitro (17),
amino (18) or allyl (20) group at ring B (Table 3) did not lead to enhancement of activity when
compared to 9.
Synthesis of allylated chalcones… Chapter 2
132
Table 3: Antimalarial activity, resistance and selectivity indices of O-allylated chalcones
Compd.No.
Mol. Wt IC50 (µM)Pf3D7
IC50 (µg/mL)Pf3D7 IC50 Indo/
IC50 3D7IC50 Dd2/IC50 3D7
Resistance Index Therapeutic IndexIC50 HeLa/IC50 3D7
IC50 L29/IC50 3D7
9 328.8 2.5 0.82
10 363.2 10 3.63 >2 0.5
11 373.2 8.1 3.02 >2.5 0.9
12 420.2 8.5 3.57 >2.4 0.8
13
350.4 7.4 2.59 1.6 0.5 4.9 9.7
14 328.8 5.3 1.74 2.6 0.7 2.5 9.4
15 324.4 22.5 7.29
16 338.4 38.5 13.05
OCH3
O
O
4-Cl
4-Br
4-F
4-O-allyl
R
R R
4-OCH3
R
H
9
4-I
3,4-diCl 3-Cl101112 20
13141516
19
4-NO2174-NH218
3,4-OCH2O-
6.6 1.2 20.8 23.2
17 339.3 >50 -
18 309.4 36 11.1319 294.3 38 11.18
20
312.3 23 7.78
CQ 40 nM - 4.2 > 200 > 200319.9 -
>10 8.7
20.5 >12.5
13 11.8
0.6 1.3 0.8 2.9
0.6 1.1 >2.6 2.2
0.4 0.6 1.8 1.4
- - - -
0.4 0.7 1.2 2.6
0.7 0.8 1.8 2.1
A B
We next ventured to evaluate the positional importance of allyl group (ortho vs meta vs para)
on ring A (Table 4, 21, 22). The fact that activity was markedly affected by changing the
position of allyl group at the phenyl ring (21 & 22 vs 9, Table 4) emphasized the importance of
para-substitution of O-allyl group for activity. Subsequently, the effect of changing the nature
of the O-substituent (H, prenyl, C4H9 and CH2C6H4Br) was evaluated and reduced activity was
observed in each instance (23-26, Table 4). Likewise, any change in the position, nature and
number of methoxy groups at ring A markedly affected the activity (27-31, Table 4) signifying
the particular special contribution of 3-methoxy group (as revealed in compound 9) which may
be due to its orientation and binding ability with the malarial parasite proteins.
In the backdrop of a study by Liu et al. (2003), where size parameter of ring B (large,
alkoxylated) and electron deficient nature of ring A were found significant for antimalarial
activity, compound 32 was synthesized by reversal of substituents between rings A and B of 9.
However, the compound exhibited lesser antimalarial potential (IC50: 8.6 µM, Table 4) as
compared to 9 (Table 3), thus underlying the importance of enhanced electron density on ring
A of chalcone for good activity [Kumar et al. (2010)].
Synthesis of allylated chalcones… Chapter 2
133
Table 4: SAR investigation for antimalarial activity, resistance and selectivity indices of O-
allylated chalcones
Compd.No.
Mol. Wt IC50 (µM)Pf3D7
IC50 (µg/mL)Pf3D7 IC50 Indo/
IC50 3D7IC50 Dd2/IC50 3D7
Resistance Index Therapeutic IndexIC50 HeLa/IC50 3D7
IC50 L29/IC50 3D7
21 328.8 12.5 4.11
22 328.8 18 5.92 1.05
23
356.8 5.0 1.78 4.6 0.924
288.7 28 8.09
25 344.8 17 5.85
26 457.7 8.0 3.6627 358.8 3.8 1.36
28 298.8 43 12.84
R2
R1
O R=R 1=H ,R 2= OC H3,R 3= O -allyl,R'=4- Cl
R'
212223242526
2829
>1.6 0.8 1.0 3.8
29 298.8 9.0 2.6930 342.8 28 9.60
31 354.8 3.4 1.21
32 328.8 8.6 2.83
R3
R=H ,R 1= OC H3,R 2= O -a llyl,R 3=H ,R'=4- Cl
R=H ,R 1= O -pre nyl ,R 2=OC H3,R=R 3=H ,R'=4- ClR=H ,R 1= OH , R 2=OCH 3,R 3=H ,R '=4-Cl
R=H ,R 1= O -butyl , R 2=OC H3,R 3=H ,R'= 4-ClR=H ,R 1= O -CH 2C6H4Br,R 2=OC H3,R 3=H ,R'= 4-ClR=OC H3,R 1= O -allyl, R 2=OCH 3,R 3= H ,R' =4-Cl
R
R=H ,R 1= O -allyl, R 2=R3= H ,R' =4-ClR=R 1=R 2=H ,R 3= O-allyl,R '=4-Cl
30 R=H ,R 1= O -a llyl,R 2= O C2H5,R 3=H ,R'=4- Cl31 R=H ,R 1= R 2=O-allyl, R 3= H ,R' =4-Cl32 R=H ,R 1=Cl,R 2=R 3=H ,R'= 3-O-allyl,4-OCH 3
5.2 5.4
4.5 5.9 7.9 11.6
2.2 1.0
4.9 1.0 6.8 29.4
>2.3 1.3 4.1 6.0
27
- -
- -
CQ 40 nM - 4.2 > 200 > 200319.9 -
0.94 2.3 4.2
1.2 1.3 1.1 2.4
0.74 0.72 2.3 1.5
>11.1 5.60.64 0.75 1.8 2.5
(d) Effect of incorporation of heterocyclic moiety: Heteroaryl-substitution is an attractive
strategy for the development of drugs with desirable activity and several inspiring reports on
the antimalarial activity of heterocyclic chalcone derivatives [Trivedi et al. (2007)] provided us
impetus to synthesize such analogues. To begin with, we designed chalcones by the
condensation of 1b with different heterocyclic carbonyls like 2-acetyl furan (33), 3-acetyl
coumarin (34), 3-acetyl-4-hydroxy coumarin (35) [Sandeep et al. (2009)], 2-acetyl pyrrole (36),
meldrum acid (37) and barbituric acid (38). However, in each case the antimalarial potential
was found significantly reduced (33-38, Table 5). Given that the quinoline, particularly with 7-
chloro group, is considered an excellent lead prototype for the development of antimalarial
drugs [Egan et al. (2000); Kaur et al. (2010)], compound 39 was synthesized which, however,
Synthesis of allylated chalcones… Chapter 2
134
was found to be quite inactive against malarial parasites. Interestingly, N-allylation of 39
significantly improved the activity of resulting compound (40 vs 39, Table 5).
In the similar vein, cyclization of chalcones leading to the synthesis of heterocyclics, such as
pyrazoles and pyrimidines, is of great interest in drug designing because of their broad
spectrum of biological activities [Wiley (1967); Lévai (2005)]. Although, introduction of
pyrazole ring at double bond (41) had no or little effect on activity, the pyrimidine derivative
(42) displayed considerable loss of activity (Table 5).
Table 5: Antimalarial activity, resistance and selectivity indices of heterocyclic derivatives of
O-allylated chalcones
Compd.No.
Mol. Wt IC50 (µM)Pf3D7
IC50 (µg/mL)Pf3D7 IC50 Indo/
IC50 3D7IC50 Dd2/IC50 3D7
Resistance Index Therapeutic IndexIC50 HeLa/IC50 3D7
IC50 L29/IC50 3D7
33 284.3 95 26.9
35 378.3 >100 - -34 362.4 100 36.2
36 283.3 48 13.58
37
38 302.3 >100 -
39
40
470.9 75 35.33
OCH 3
O
R=F ura n-2- yl
3940
-
- -
511.0 3.5 1.7941 418.9 3.3 1.3842 367.8 >50 -
R= 4-hydroxy chrom en-2-oneR= Ch romen-2-one
R= Pyrr o-2-ylR= meldum a cidR= barb ituric acid
R=HR=a llyl 41
1.9 0.9
OOC H3
O
NR
N Cl
OOC H3
Cl
N NR
R=C6H5
OOC H3
N N
NRR'
Cl
R=R'= H42
- -
318.3 >100 - - -
- -
10.6 16.95.2 0.9 >60.6 >60.6
- -
33343536 38
- -
R
O
R
OOCH 3
37
CQ 40 nM - 4.2 > 200 > 200319.9 -
1.3 0.7 >2.1 >2.1
(e) Bis/dimeric chalcones: Among the five bischalcones (43-47) screened against chloroquine
sensitive strain, only compounds 43 and 46 showed significant activity, the order being
43>46>45>44=47. The results revealed that the type of oxygenated substituents in the phenyl
ring greatly influence the activity profile (Table 6).
Synthesis of allylated chalcones… Chapter 2
135
Table 6: Antimalarial activity, resistance and selectivity indices of bis (dimeric) chalcones
Compd.No.
Mol. Wt IC50 (µM)Pf3D7
IC50 (µg/mL)Pf3D7 IC50 Indo/
IC50 3D7IC50 Dd2/IC50 3D7
Resistance Index Therapeutic IndexIC50 HeLa/IC50 3D7
IC50 L29/IC50 3D7
43 538.6 2.5 1.35
44 510.6 >50 - -
45 562.6 18 10.1346 450.5 >12.5 -
47 482.5 >50 -
R=R'=a llyl,R 1=R1'=R2= R2'=OCH 3434445
>8.0 1.4 11.2 8.8-
R=R'=H , R1=R1'= R2=R2'= O-allyl
O OR
R1R2
R1'R2'
R'
R=R'=H , R1=R1'=O-allyl,R 2=R 2'=O CH 3
O
O
O
O
R=R'=H4647 R=R'=OH
- -- -
- -
R'
R
CQ 40 nM - 4.2 > 200 > 200319.9 -
2.1.6.3. Evaluation of resistant index and therapeutic indices
The identified lead chalcones were also tested against chloroquine resistant Dd2 strain of P.
falciparum (Tables 2-6). Against a resistance Index (IC50 Dd2/IC50 3D7) of 4.2 for chloroquine,
the indices for the potent chalcones were found to be in the range of 0.5-5.9 (Tables 2-6).
Finally, the active compounds were analyzed for their cytotoxic behavior against two
mammalian cell lines viz. HeLa and fibroblast L29. The obtained therapeutic indices (IC50
HeLa cell line/IC50 Pf 3D7) (Tables 2-6) values indicated that the most active compounds (9,
40, 41, 43) were also relatively non-toxic.
2.1.6.4. Calculation of physical chemical properties
The molecular properties for absorption, distribution, metabolism and excretion (ADME) are
crucial to enhance the probability of success through the drug development stage [Kassel
(2004)]. Absorption is a primary focus in drug development and medicinal chemistry since the
drug must be absorbed in the body before any medicinal effects can take place. This
requirement makes lipophilicity and solubility the two major properties responsible for
absorption and bioavailability of drugs [Alavijeh et al. (2005); Bergström (2005)]. The 1-
octanol-water partition coefficient, log P, is a well known parameter to estimate lipophilicity
(or solubility in lipids) of chemical compounds [Tetko et al. (2008)]. Aqueous solubility is
usually measured as its logarithm of intrinsic or pH-dependent solubility, AlogS [Viswanadhan
et al. (2000)]. Similarly, topological polar surface area (TPSA) is a good indicator of drug
Synthesis of allylated chalcones… Chapter 2
136
absorbance in the intestines, Caco-2 monolayers penetration, and blood-brain barrier crossing
[Ertl et al. (2000)]. It has been well established that optimal lipophilicity range along with low
molecular weight and low polar surface area is the major driving force that leads to good
absorption of compounds in the intestine by passive diffusion [Mannhold. et al. (2009)]. A very
high TPSA value contributes for a low bioavailability for the molecule [Rajasekaran et al.
(2011)].
Accordingly, a computational study for prediction of ADME properties of all the molecules
was performed (Molinspiration Cheminformatics) and is presented in Table 7. TPSA was used
to calculate the percentage of absorption (%Abs) according to the equation: %Abs = 109 -
0.345 × TPSA, as reported by Zhao et al. (2002). In addition, number of rotatable bonds (n-
ROTB) and other parameters of Lipinski’s rule of five [Lipinski et al. (1997)] were also
calculated. From all the parameters, it was observed that all the active molecules exhibited a
low TPSA value when compared to Licochalcone (LC) except 43 and hence greater %Abs
ranging from 85.9 to 99.9%. Furthermore, all the active molecules violate one or none of
Lipinski’s parameters, except 43; thus making them potentially promising agents for
antimalarial therapy.
Table 7: Physical-chemical properties of compounds 1-47
TPS AID
1 310.3
2 328.73 342.84 338.4
5 352.3
6 387.2
7 353.38 368.8
Mol.wt
%Abs miLogP natoms
nrotb
nONacceptors
nOHNHdonors
ALogS Lipinski'sviolations
85.9 66.7 3.65 23 6 4 2 0-4.27
Rule <=500 <=5 <=5<=10 <=1
LC 338.4 85.9 66.7 4.84 25 6 4 2 0-4.66
92.9 46.5 4.81 23 6 3 1 096.7 35.5 5.08 24 7 3 0 193.6 44.8 4.46 25 8 4 0 090.4 54.0 4.29 26 7 5 0 0
96.7 35.5 5.21 24 7 3 0 1
80.9 81.3 4.36 26 8 6 0 0
-5.53-6.19-5.76
-5.52
-6.41
-5.92
96.7 35.5 5.73 26 9 3 0 1-6.469 328.810 363.2
96.7 35.5 4.78 23 7 3 0 096.7 35.5 5.38 24 7 3 0 1
-5.86-6.47
Synthesis of allylated chalcones… Chapter 2
137
14 328.815 324.416 338.417 339.318 309.4
19 294.3
13 312.396.7 35.5 4.75 23 7 3 0 093.5 44.7 4.15 24 8 4 0 090.3 54.0 3.99 25 7 5 0 080.9 81.3 4.06 25 8 6 0 087.7 61.5 3.17 23 7 4 2 096.7 35.5 4.10 22 7 3 0 0
96.7 35.5 4.26 23 7 3 0 0-5.83-5.35-5.26-5.62-4.82-5.18
-5.64
21 328.8
22 328.8
23 288.7
25 344.8
26 457.7
27 358.8
28 298.8
29 298.8
30 342.8
31 354.8
32 328.8
96.7 35.5 4.77 23 7 3 0 0
96.7 35.5 4.78 23 7 3 0 0
92.9 46.5 3.82 20 4 3 1 0
93.5 44.7 4.76 25 8 4 0 0
99.9 26.3 5.19 21 6 2 0 1
99.9 26.3 4.96 21 6 2 0 0
96.7 35.5 5.15 24 8 3 0 1
96.7 35.5 5.42 25 9 3 0 1
96.7 35.5 4.78 23 7 3 0 0
-5.80
-5.84
-4.71
-5.81
-5.89
-5.86
-6.05
-6.17
-5.82
96.7 35.5 5.57 24 8 3 0 1-6.18
96.7 35.5 6.54 28 7 3 0 1-7.18
33 284.334 362.4
36 283.33738 302.3
3940
470.9
510.041 418.942 367.8
318.3
92.2 48.6 3.36 21 7 4 0 0-4.26
91.2 51.6 7.43 37 11 5 0 297.2 34.1 6.22 30 7 4 0 1
91.3 51.3 3.25 21 7 4 1 084.5 71.0 3.25 23 5 6 0 074.1 101.2 0.58 22 5 7 2 0
88.2 60.4 6.98 34 9 5 1 1
-3.86
-6.56-7.01-6.70
-4.34-3.89
86.3 65.7 4.10 27 7 5 0 0-5.66
84.8 70.2 4.34 26 6 5 2 0-6.7443 538.6
44 510.6
45 562.646 450.547 482.5
84.5 71.0 6.85 40 14 6 0 2
84.5 71.0 6.24 38 14 6 0 2
90.8 52.6 7.08 34 12 4 0 176.9 93.1 6.92 36 12 6 2 1
-7.45
-6.99
-7.04-5.53
84.5 71.0 7.53 42 18 6 0 2-6.94
35 378.3 79.3 85.9 3.81 28 7 6 1 0-4.99
%Abs= percentage of absorption; TPSA= topological polar surface area; miLogP= logarithmof compound partition coefficient between n-octanol and water; ALogS = logarithm ofintrinsic or pH-dependent solubility; natoms= no. of atoms; nrotb= no. of rotatable bonds;nOHNH =no. of hydrogen bond donors; nON= no. of hydrogen bond acceptors
11 373.212 420.2
96.7 35.5 4.91 23 7 3 0 096.7 35.5 5.18 23 7 3 0 1
-5.97-6.22
20 350.4 93.5 44.7 4.80 26 10 4 0 0-5.82
24 356.8 96.7 35.5 5.81 25 7 3 0 1-5.95
Synthesis of allylated chalcones… Chapter 2
138
After testing the above chalcones for antimalarial activity, it was contemplated to screen these
for their potential as pesticidal agents.
2.2. Pesticidal activity of allylated chalcones against diamondback moth
(Plutella xylostella)2.2.1. Introduction
The diamondback moth (Plutella xylostella), also known as
cabbage moth, is one of the most destructive pests of cruciferous
crops in the world and usually feed on plants that produce
glucosinolates such as broccoli, Brussels sprouts, cabbage,
Chinese cabbage, cauliflower, kale, mustard, radish and turnip
[Talekar and Shelton (1993); Capinera (2001)]. The larvae
(Figure 9) damage the leaves, buds, flowers, and seed-buds of
cultivated cruciferous plants and cause complete removal of foliar tissue except for the leaf
veins. It is believed that absence of effective natural enemies, especially parasitoids is a major
cause of the diamondback moth’s pest status in most parts of the world [Lim (1986)].
Another reason for the lack of effective biological control in an area may be destruction of
natural enemies by the use of broad-spectrum insecticides. In 1953, the diamondback moth
became the first crop pest in the world to develop resistance to DDT [Johnson (1953); Asakawa
(1975)], and now in many countries the pest has become resistant to every basic insecticide
classes, such as organochlorides, organophosphates, and carbamates [Talekar et al. (1985); Sun
et al. (1986)]. Moreover, the non-restricted use of highly toxic insecticides for several decades
has provoked negative effects to the humans, animals and environment [Eskenazi et al. (1999)].
Thus, there is a worldwide search for alternative chemical pesticides with greater selectivity
and environmental profiles.
In the fervent research targeted for the synthesis of eco-friendly bio-pesticides, chalcones (1,3-
diaryl-2-propen-1-ones) have gained importance due to their remarkably divergent array of
bioactivities [Edwards et al. (1990); Mukherjee et al. (2001); Bhat et al. (2005); Göker et al.
(2005); Nielsen et al. (2005); Boeck et al. (2006); Wei et al. (2007)] as well as easily
degradable nature. Moreover, the molecule is viewed as a template for molecular modifications
with a view to prepare new compound libraries.
Figure 9
Synthesis of allylated chalcones… Chapter 2
139
In one report, 1,5-diphenyl-2-penten-1-one, extracted from Stellera chamaejasme, was shown
to have strong contact activity and very good antifeedant activity against Aphis gossypii and
Schizaphis graminum [Ping et al. (2001)]. Nalwar et al. also reported significant insect
antifeedant activity of twelve chalcones against the mealy bug of cotton (Phenacoccus
solanopsis) [Nalwar et al. (2009)]. Similarly, chalcone derivatives were evaluated for their
antifilarial activity on Setaria cervi using glutathione-S-transferase (GST) as a drug target
[Awasthi et al. (2009)]. In a recent report, insect antifeedant activity of substituted styryl 4'-
fluorophenyl ketones was evaluated against 4th instar larvae of Achoea janata whereby halogen
containing compounds were found to have better activity among all the tested compounds
[Thirunarayanan and Vanangamudi (2011)]. In addition, larvicidal activities have also been
reported for several chalcone derivatives [Das et al. (2005); Gautam and Chourasia (2010);
Begum et al. (2011)]. Of late, a study by Kumar et al. (2011) regarding the pesticidal activity
of chalcones against Plutella xylostella has appeared wherein, it has been revealed that
electron-withdrawing substituents, in particular chloro substitution, on ring A of chalcone
provided good pesticidal agents. Thus in view of above promising reports, it was contemplated
to screen some of the allylated chalcones (Figure 10) for pesticidal activity against
diamondback moth (Plutella xylostella) for their potential as pesticidal agents.O
R'R
A B
R= OH, OCH3, O-allyl etc.R' = Cl, Br, -OCH2O- etc.
Figure 10
2.2.2. Results and discussion
Chalcones (1-11) were prepared by Claisen-Schmidt condensation [Cabrera et al. (2007);
Boumendjel et al. (2008)] as described in section 2.1.6.1 and tested against second instar larvae
of P. xylostella after 48 h of exposure time. The preliminary screening was carried out at 1000
µg/mL and results (expressed as mortality %) is presented in Table 8. In the initial screening,
chalcone with O-allylation on ring A and 4-Cl substitution (1; electron withdrawing) and 4-O-
allylation (2; electron releasing) at ring B were subjected for pesticidal activity. Among these, 1
showed moderate pesticidal activity which was in corroboration to earlier report on well-known
pesticidal potency of chlorinated compounds [Kumar et al. (2011)]. However, replacement of
Synthesis of allylated chalcones… Chapter 2
140
Cl on ring B with more electron-withdrawing substituents i.e. 3,4-dichloro (3) exhibited lesser
activity (Table 8; entry 3 vs 1) Furthermore, the positional importance of allyl group at
different positions in terms of O-allylation (1) vs C-allylation (5), both C- and O-allylation (6),
di-O-allylation (7) and absence of allyl group (8) on ring A was evaluated with a view to
enhance the activity where compounds 5 and 7 exhibited more than 90% larval mortality in the
order 5 > 7. From the structure–activity perspective, compound 5 with mortality of 96.7% was
selected as a lead to study the effect of various substitutions on ring B. It was observed that
replacement of Cl on ring B with 3,4-dioxymethylene (9) or methoxy (10) or Br (11)
substituents showed significant reduction in activity when compared to 5. Even the reversal of
substituents of 1 did not resulted in any enhancement of pesticidal activity (4, Table 8). Thus,
the data generated (Table 8; entries 1-11) revealed that besides electronic consideration,
lipophilic and hydrophilic characteristics of various substituents are responsible for influencing
the pesticidal activity. Overall pesticidal activity of the screened chalcones was found to obey
the order: 5> 7> 9> 6> 1> 4> 8> 10> 11> 3> 2 (Table 8).
Table 8: Preliminary screening of chalcone derivatives against second instar larvae of P.
xylostella after 48 h
O
OOCH3
Cl
O
H3COOCH3
Cl
O
OOCH3
Cl
O
OOCH3
Cl
Cl
O
OOCH3
O
O
H3CO
OCH3
Br
O
H3COOCH3
OCH3
O
H3COOCH3
O
O
O
HO
OCH3
Cl
O
OO
Cl
O
ClOCH3
O
StructureS.No
1
2
3
4
5
6
7
8
9
Mortality[%]a
43.01000
75.01000
96.71000
20.01000
0.01000
23.01000
1000
1000
1000
1000
1000
26.6
86.6
36.6
93.3
40.0
Conc.(µg/mL)
Mortality[%]aStructureS.No
10
11
aData represent the mean values of the three replicates and present corrected mortality using Abbott’s formula
Conc.(µg/mL)
Synthesis of allylated chalcones… Chapter 2
141
2.3. Conclusion
A series of novel allylated Licochalcone congeners were synthesized by Claisen-Schmidt
condensation of an abundantly available precursor i.e. vanillin with various substituted
acetophenones and thus obtained compounds were evaluated for in vitro antimalarial activity
against P. falciparum 3D7 where several compounds have shown good antimalarial potential.
Compounds 9 and 43 were found to be most potent antimalarials with IC50 of 2.5 µM each.
These series of compounds showed not only promising drug-like properties but are also easy
and economical to prepare and thus might prove useful leads towards future antimalarial drug
discovery. In addition, some of the above chalcones were screened for pesticidal activity
against diamondback moth, Plutella xylostella where compound 5 was found to be most potent
among all. Though preliminary in nature, the study may prove a pivotal point in designing
compounds with comparable potency to commercial pesticides.
2.4. Experimental
2.4.1. Chemical and reagents
All the reagents were obtained from commercial sources (Merck or Acros). The solvents used
for isolation/purification of compounds were obtained from commercial sources (Merck) and
used without further purification. 1H (300 MHz) and 13C (75.4 MHz) NMR spectra were
recorded on a Bruker Avance-300 spectrometer. TMS was used as internal reference for 1H
NMR. HRMS-ESI spectra were determined using micromass Q-TOF ultima spectrometer.
2.4.2. Procedure for the synthesis of C-allylated chalcones via 1b and 2b (1-2; Table 2)
(a) Synthesis of 4-allyloxy-3-methoxybenzadehyde (1b)
To a 250-mL round bottom flask containing vanillin (1a) (1.9 mmol) in dry acetone (20 mL),
allyl bromide (2.0 mmol), and anhydrous K2CO3 (3.8 mmol) were added. The mixture was
refluxed for 6 h. After consumption of aldehyde (monitored by TLC), the mixture was filtered
to remove K2CO3. The filtrate was vacuum evaporated and washed with hexane to remove
excess of allyl bromide. The crude product was purified by silica gel column chromatography
using hexane-ethyl acetate (9:1) to provide the desired compound which was characterized by1H & 13C NMR and HRMS data.
Synthesis of allylated chalcones… Chapter 2
142
4-allyloxy-3-methoxybenzadehyde (1b)
OCH3
CHO
O
White solid (Yield 88%) m.p. 30-35°C, 1H NMR (CDCl3, 300 MHz):
9.82 (1H, s), 7.42 (2H, s), 6.97 (1H, d, J = 7.75 Hz), 6.11-6.00 (1H, m), 5.45 (1H, d, J =
17.25 Hz), 5.34 (1H, d, J = 10.47 Hz), 4.68 (2H, s), 3.91 (3H, s); 13C NMR (CDCl3, 75.4 MHz):
191.3, 153.8, 150.2, 132.6, 130.5, 127.0, 119.2, 109.5, 70.1 and 56.4. HRMS-ESI: m/z
[M+H]+ for C11H12O3, calculated 193.0996; observed 193.1011.
(b) Synthesis of 5-allyl-4-hydroxy-3-methoxybenzaldehyde (2b)
The product obtained from step (a) was taken in round bottom flask and subjected to
microwave at 150 W for 15 min at 195-205oC to undergo Claisen rearrangement. The progress
of reaction was monitor with the help of TLC. The crude product was purified by silica gel
column chromatography using hexane-ethyl acetate (9:1) to provide the desired compound
which was characterized by 1H & 13C NMR and HRMS data.
5-allyl-4-hydroxy-3-methoxybenzaldehyde (2b)
OC H3
HO
CHO
White solid (Yield 55%) m.p. 75-79°C, 1H-NMR (CDCl3, 300 MHz): δ
10.81 (1H, s), 9.72 (2H, s), 6.82 (2H, s), 5.87-5.75 (1H, m), 4.97-4.95 (1H, s), 3.76 (3H, s),
3.23 (2H, d, J = 6.63 Hz); 13C-NMR (CDCl3, 75.4 MHz): δ 191.2, 149.6, 146.9, 135.1, 128.8,
127.8, 126.1, 116.7, 107.2, 56.1 and 33.1. HRMS-ESI: m/z [M+H]+ for C11H12O3, calculated
193.0996; observed 193.0998.
(c) Synthesis of C-allylated chalcones (1 and 2)
To a solution of 2b (3 mmol) and 4-hydroxy acetophenone or 4-chloro acetophenone (3 mmol)
in methanol (20 mL), 10% aqueous NaOH (4 mmol) was added. The reaction mixture was
stirred till completion of starting material (monitored by TLC). The reaction mixture was
vacuum evaporated to remove the organic solvent and poured in cold water. The obtained
precipitates were washed with dilute HCl, excess of water, methanol, dried in air and finally
recrystallized with methanol to obtain pure chalcones (1 or 2) whose structure were confirmed
by NMR and mass spectroscopy.
Synthesis of allylated chalcones… Chapter 2
143
(2E)-3-[4-Hydroxy-3-methoxy-5-(prop-2-en-1-yl)phenyl]-1-(4-hydroxyphenyl)prop-2-en-
1-one (compound 1, Table 2) (obtained by condensation of 2b with 4-hydroxy acetophenone)O
OCH3
HO OHYellow viscous liquid (Yield 40%), 1H NMR (CDCl3, 300
MHz): 8.00 (2H, d, J = 8.64 Hz), 7.80 (1H, d, J = 15.54 Hz), 7.45 (1H, d, J = 15.54 Hz), 7.20
(2H, m), 7.01 (2H, d, J = 8.64 Hz), 6.87 (2H, d, J = 7.1 Hz), 6.12-6.01 (1H, m), 5.45 (2H, dd, J
= 17.23, 10.50 Hz), 4.66 (2H, d, J = 5.39 Hz), 3.93 (3H, s); 13C NMR (CDCl3, 75.4 MHz):
190.4, 161.8, 150.8, 149.9, 145.3, 133.6, 133.0, 131.7, 130.8, 128.5, 123.5, 120.2, 118.9, 116.2,
113.4, 70.2 and 56.4. HRMS-ESI: m/z [M+H]+ for C19H18O4, calculated 311.1458; observed
311.1442.
(2E)-1-(4-Chlorophenyl)-3-[4-hydroxy-3-methoxy-5-(prop-2-en-1-yl)phenyl]prop-2-en-1-
one (compound 2, Table 2) (obtained by condensation of 2b with 4-chloro acetophenone)O
ClOCH3
HO
Yellow viscous liquid (Yield 58%), 1H NMR (CDCl3, 300
MHz): 7.92 (2H, d, J = 8.50 Hz), 7.89 (1H, d, J = 15.30 Hz), 7.67 (1H, d, J = 15.30 Hz),
7.39-7.26 (3H, m), 7.06 (2H, d, J = 8.50 Hz), 6.01-5.92 (1H, m), 5.10 (2H, dd, J = 17.22, 10.30
Hz), 4.07 (3H, s), 3.41 (2H, d, J = 6.76 Hz); 13C NMR (CDCl3, 75.4 MHz): 191.6, 149.9,
147.4, 146.5, 135.9, 130.2, 129.4, 128.3, 126.8, 124.7, 119.4, 116.7, 116.4, 108.7, 107.6, 56.6
and 34.1. HRMS-ESI: m/z [M+H]+ for C19H17ClO3, calculated 329.5913; observed 329.5927.
2.4.3. Procedure for the synthesis of C-allylated chalcones via 3b (3-7; Table 2)
(a) Synthesis of 5-allyl-3,4-dimethoxy benzaldehyde (3b)
To the 2b (6.6 mmol; section 2.4.2) taken in round bottom flask was added sodium hydroxide
(6.6 mmol) dissolved in 2 mL of water (to increase solubility benzyltrimethylammonium
chloride (PTC) was added in a catalytic amount). The reaction mixture was stirred for 5-10
min. Thereafter, dimethyl sulfate (12.2 mmol) was added drop-wise to the above reaction
mixture at 0oC and then stirred at room temperature for 5-6 h. After the completion of reaction
(monitored by TLC), reaction mixture was acidified with dilute HCl (pH 6) and partitioned
between ethyl acetate (70 mL) and water (15 mL). The ethyl acetate layer was washed with
Synthesis of allylated chalcones… Chapter 2
144
water till neutral, dried over sodium sulfate and evaporated. The obtained residue was purified
by column chromatography (silica gel, hexane: ethyl acetate (7:3; v/v)) to afford the desired
compound whose structure was confirmed through NMR and mass spectrometry.
5-allyl-3,4-dimethoxy benzaldehyde (3b)
OCH3
CHO
H3CO
Pale yellow viscous liquid (Yield 80%), 1H NMR (CDCl3, 300 MHz):
9.88 (1H, s), 7.34 (2H, d, J = 4.24 Hz ), 6.03-5.93 (1H, m), 5.12-5.06 (2H, m), 3.93 (6H, s),
3.46 (2H, d, J = 5.43 Hz); 13C NMR (CDCl3, 75.4 MHz): 191.4, 153.4, 152.8, 136.5, 134.5,
132.4, 126.6, 116.4, 109.3, 60.9, 56.6 and 34.1. HRMS-ESI: m/z [M+H]+ for C12H14O3,
calculated 207.1152; observed 207.1164.
(b) Synthesis of C-allylated chalcones (3-7)
To a solution of 3b (3 mmol) and appropriate acetophenone (3 mmol) in methanol (20 mL),
10% aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that
described in step (c) of section 2.4.2. The desired compounds obtained after recrystallization
were characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-Chlorophenyl)-3-[3,4-dimethoxy-5-(prop-2-en-1-yl)phenyl]prop-2-en-1-one
(compound 3, Table 2) (obtained by condensation of 3b with 4-chloro acetophenone)O
OC H3
H3CO Cl
Yellow solid (Yield 72%) m.p. 65-69°C, 1H NMR (CDCl3, 300
MHz): 7.97 (2H, d, J = 7.70 Hz), 7.77 (1H, d, J = 15.57 Hz), 7.48 (2H, d, J = 7.70 Hz), 7.33
(1H, d, J = 15.57 Hz), 7.10 (1H, s), 7.06 (1H, s), 6.03-5.94 (1H, m), 5.12 (2H, d, J = 11.77 Hz),
3.92 (3H, s), 3.87 (3H, s), 3.45 (2H, d, J = 6.39 Hz); 13C NMR (CDCl3, 75.4 MHz): 191.6,
153.4, 150.1, 145.8, 139.4, 137.1, 134.8, 130.8, 130.3, 130.1, 129.3, 123.7, 121.0, 116.5, 110.7,
61.2, 56.3 and 34.5. HRMS-ESI: m/z [M+H]+ for C20H19ClO3, calculated 343.6069; observed
343.6072.
Synthesis of allylated chalcones… Chapter 2
145
(2E)-3-[3,4-Dimethoxy-5-(prop-2-en-1-yl)phenyl]-1-(4-methoxyphenyl)prop-2-en-1-one
(compound 4, Table 2) (obtained by condensation of 3b with 4-methoxy acetophenone)O
OC H3H3CO OC H3
Yellow solid (Yield 70%) m.p. 64-66°C, 1H NMR (CDCl3,
300 MHz): 7.88 (2H, d, J = 6.19 Hz), 7.57 (1H, d, J = 15.56 Hz), 7.27 (1H, d, J = 15.56 Hz),
6.93 (1H, s), 6.88 (1H, s), 6.82 (2H, d, J = 6.27 Hz), 5.84-5.78 (1H, m), 4.94 (2H, d, J = 12.67
Hz), 3.75 (3H, s), 3.64 (6H, s), 3.27 (2H, d, J = 6.27 Hz); 13C NMR (CDCl3, 75.4 MHz):
189.4, 163.9, 153.5, 149.9, 144.6, 137.4, 134.9, 131.8, 131.3, 123.8, 123.6, 121.6, 116.6, 114.4,
110.8, 61.3, 56.4, 56.0 and 34.6. HRMS-ESI: m/z [M+H]+ for C21H22O4, calculated 339.1770;
observed 339.1738.
(2E)-1-(1,3-Benzodioxol-5-yl)-3-[3,4-dimethoxy-5-(prop-2-en-1-yl)phenyl]prop-2-en-1-one
(compound 5, Table 2) (obtained by condensation of 3b with 3,4-dioxymethylene
acetophenone)O
OC H3
H3CO O
O
Pale yellow solid (Yield 71%) m.p. 88-92°C, 1H NMR (CDCl3,
300 MHz): 7.88 (2H, d, J = 6.19 Hz), 7.54 (1H, s), 7.45 (1H, d, J = 15.56 Hz), 7.11 (2H, d, J
= 6.20 Hz), 6.90 (1H, s) 6.08 (2H, s), 6.06-5.94 (1H, m), 5.13 (2H, d, J = 14.64 Hz), 3.93 (3H,
s), 3.45 (3H, s), 3.46 (2H, d, J = 5.72 Hz); 13C NMR (CDCl3, 75.4 MHz): 188.7, 153.4, 151.9,
149.7, 148.7, 144.7, 137.2, 134.7, 133.5, 131.1, 125.0, 123.4, 121.2, 116.4, 110.6, 108.9, 108.3,
102.2, 61.2, 56.3 and 34.5. HRMS-ESI: m/z [M+H]+ for C21H20O5, calculated 353.1608;
observed 353.1631.
(2E)-1-(4-Bromophenyl)-3-[3,4-dimethoxy-5-(prop-2-en-1-yl)phenyl]prop-2-en-1-one
(compound 6, Table 2) (obtained by condensation of 3b with 4-bromo acetophenone)O
OC H3
H3CO Br
Yellow solid (Yield 70%) m.p. 58-60°C, 1H NMR (CDCl3, 300
MHz): 7.90 (2H, d, J = 8.29 Hz), 7.77 (1H, d, J = 15.61 Hz), 7.67 (2H, d, J = 8.29 Hz), 7.38
Synthesis of allylated chalcones… Chapter 2
146
(1H, d, J = 15.61 Hz), 7.11 (1H, s), 7.06 (1H, s), 6.04-5.95 (1H, m), 5.13 (2H, d, J = 11.40 Hz),
3.94 (3H, s), 3.93 (3H, s), 3.46 (2H, d, J = 6.38 Hz); 13C NMR (CDCl3, 75.4 MHz): 191.9,
153.5, 150.1, 146.0, 136.8, 136.7, 134.9, 132.4, 130.8, 130.5, 128.7, 123.8, 120.9, 116.6, 110.6,
61.3, 56.3 and 34.3. HRMS-ESI: m/z [M+H]+ for C20H19 BrO3, calculated 388.0582; observed
388.0597.
(2E)-3-[3,4-Dimethoxy-5-(prop-2-en-1-yl)phenyl]-1-(4-nitrophenyl)prop-2-en-1-one
(compound 7, Table 2) (obtained by condensation of 1b with 4-nitro acetophenone)O
OC H3
H3CO NO2
Bright yellow solid (Yield 68%) m.p. 93-96°C, 1H NMR
(CDCl3, 300 MHz): 8.38 (2H, d, J = 8.20 Hz), 8.16 (2H, d, J = 8.20 Hz), 7.80 (1H, d, J =
15.62 Hz), 7.39 (1H, d, J = 15.62 Hz), 7.13 (1H, s), 7.08 (1H, s), 6.03-5.92 (1H, m), 5.13 (2H,
d, J = 11.69 Hz), 3.94 (3H, s), 3.89 (3H, s), 3.46 (2H, d, J = 6.13 Hz); 13C NMR (CDCl3, 75.4
MHz): 189.6, 153.5, 150.4, 150.3, 147.4, 143.7, 136.9, 134.9, 130.3, 130.2, 129.8, 124.2,
124.0, 120.8, 116.7, 61.3, 56.3 and 34.5. HRMS-ESI: m/z [M+H]+ for C20H19NO5, calculated
354.1561; observed 354.1579.
2.4.4. Procedure for the synthesis of C-allylated chalcone via 4b (8; Table 2)
(a) Synthesis of 5-allyl-4-allyloxy-3-methoxy benzaldehyde (4b)
To a 250-mL round bottom flask containing 2b (1.9 mmol; section 2.4.2) in dry acetone (20
mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol) were added. The remaining
procedure was similar to that described in step (a) of section 2.4.2. The desired compound
obtained after column chromatography over silica gel with hexane-ethyl acetate (9:1) was
characterized by 1H & 13C NMR and HRMS data.
5-allyl-4-allyloxy-3-methoxy benzaldehyde (4b)
OCH3
CHO
O
Pale yellow viscous liquid (Yield 84%), 1H NMR (CDCl3, 300 MHz):
9.81 (1H, s), 7.27 (2H, s), 6.02-5.90 (2H, m), 5.31 (1H, d, J = 17.16 Hz), 5.18 (1H, d, J =
10.35 Hz), 5.05-5.00 (2H, m), 4.54 (2H, s), 3.86 (3H, s), 3.41 (2H, s); 13C NMR (CDCl3, 75.4
MHz): 191.6, 153.6, 151.7, 136.7, 134.9, 134.2, 133.1, 126.8, 118.2, 116.7, 109.4, 74.2, 56.2
and 34.5. HRMS-ESI: m/z [M+H]+ for C14H16O3, calculated 233.1308; observed 233.1321.
Synthesis of allylated chalcones… Chapter 2
147
(b) Synthesis of C-allylated chalcones (8)
To a solution of 4b (3 mmol) and 4-chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-Chlorophenyl)-3-[3-methoxy-5-(prop-2-en-1-yl)-4-(prop-2-en-1-yloxy)phenyl]
prop-2-en-1-one (compound 8, Table 2)O
OOCH3
Cl
Yellow solid (Yield 74%) m.p. 69-71°C, 1H NMR (CDCl3, 300
MHz): 8.02 (2H, d, J = 8.30 Hz), 7.71 (1H, s), 7.54-7.33 (3H, m), 7.15 (2H, d, J = 8.30 Hz ),
6.11-5.99 (2H, m), 5.42-5.09 (4H, m), 4.59 (2H, d, J = 5.44 Hz), 3.93 (3H, s), 3.47 (2H, d, J =
6.50 Hz); 13C NMR (CDCl3, 75.4 MHz): 189.7, 153.4, 148.8, 145.8, 139.4, 137.1, 137.0,
135.0, 134.5, 130.8, 130.3, 129.3, 123.7, 121.0, 118.0, 116.8, 110.6, 74.3, 56.3 and 34.6.
HRMS-ESI: m/z [M+H]+ for C22H21ClO3, calculated 369.6225; observed 369.6257.
2.4.5. Procedure for the synthesis of O-allylated chalcones (9-19; Table 3)
To a solution of 1b (3 mmol) and appropriate acetophenone (3 mmol) in methanol (20 mL),
10% aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that
described in step (c) of section 2.4.2. The desired compounds obtained after recrystallization
was characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 9, Table 3) (obtained by condensation of 1b with 4-chloro acetophenone)O
O
OCH3
Cl
Pale yellow solid (Yield 85%) m.p. 90-93°C, 1H NMR (CDCl3,
300 MHz): 7.97 (2H, d, J = 8.45 Hz), 7.79 (1H, d, J = 15.56 Hz), 7.48 (2H, d, J = 8.45 Hz),
7.37 (1H, d, J = 15.56 Hz ), 7.22-7.17 (2H, m), 6.92 (1H, d, J = 8.43 Hz), 6.15-6.03 (1H, m),
5.47 (2H, dd, J = 17.25, 10.45 Hz), 4.68 (2H, d, J = 5.27 Hz), 3.95 (3H, s); 13C NMR (CDCl3,
75.4 MHz): 189.6, 151.1, 150.1, 145.9, 139.3, 137.2, 133.1, 130.2, 129.3, 128.3, 123.5,
Synthesis of allylated chalcones… Chapter 2
148
119.9, 118.9, 113.4, 111.1, 70.2 and 56.5. HRMS-ESI: m/z [M+H]+ for C19H17ClO3, calculated
329.5913 observed 329.5945.
(2E)-1-(3,4-Dichlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 10, Table 3) (obtained by condensation of 1b with 3,4-dichloro acetophenone)O
O
OCH3
Cl
Cl
Light yellow solid (Yield 80%) m.p. 80-82°C, 1H NMR
(CDCl3, 300 MHz): 8.10 (1H, s), 7.86-7.77 (2H, m), 7.60 (1H, d, J = 8.00 Hz), 7.33-7.17
(3H, m), 6.93 (1H, d, J = 8.08 Hz), 6.15-6.04 (1H, m), 5.48 (2H, dd, J = 17.27, 10.46 Hz), 4.70
(2H, d, J = 4.17 Hz), 3.97 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 188.4, 151.2, 150.0, 146.7,
138.5, 137.4, 133.6, 133.0, 131.1, 130.8, 128.0, 127.9, 123.8, 119.2, 118.9, 113.3 110.9, 70.2
and 56.5. HRMS-ESI: m/z [M+H]+ for C19H16Cl2O3, calculated 364.0962; observed 364.0928.
(2E)-1-(4-Bromophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 11, Table 3) (obtained by condensation of 1b with 4-bromo acetophenone)O
O
OCH3
Br
Yellow solid (Yield 80%) m.p. 100-103°C, 1H NMR
(CDCl3, 300 MHz): 7.90 (2H, d, J = 10.83 Hz), 7.79 (1H, d, J = 15.59 Hz), 7.66 (2H, d, J =
10.83 Hz), 7.36 (1H, d, J = 15.59 Hz), 7.23-7.16 (2H, m), 6.92 (1H, d, J = 8.30 Hz), 6.15-6.04
(1H, m), 5.47 (2H, dd, J = 17.26, 10.48 Hz), 4.69 (2H, d, J = 5.30 Hz), 3.96 (3H, s); 13C NMR
(CDCl3, 75.4 MHz): 189.8, 151.0, 150.0, 145.9, 137.6, 133.0, 132.3, 130.4, 128.3, 128.0,
123.5, 119.8, 118.9, 113.3, 111.0, 70.2 and 56.5. HRMS-ESI: m/z [M+H]+ for C19H17O2Br,
calculated 374.0426; observed 374.0453.
(2E)-1-(4-Iodophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 12, Table 3) (obtained by condensation of 1b with 4-iodo acetophenone)O
O
OC H3
I
Pale orange solid (Yield 78%) m.p. 95-97°C, 1H NMR
(CDCl3, 300 MHz): δ 7.88-7.85 (2H, m), 7.79-7.70 (3H, m), 7.35 (1H, d, J = 15.59 Hz), 7.23-
Synthesis of allylated chalcones… Chapter 2
149
7.16 (2H, m), 6.92 (1H, d, J = 8.30 Hz), 6.17-6.04 (1H, m), 5.48 (2H, dd, J = 17.26, 10.47 Hz),
4.69 (2H, d, J = 5.31 Hz), 3.96 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 190.1, 151.0, 150.0,
145.9, 138.3, 138.2, 133.1, 130.3, 128.3, 123.5, 119.9, 118.9, 113.3, 111.0, 100.7, 70.2 and
56.5. HRMS-ESI: m/z [M+H]+ for C19H17O2I, calculated 421.0431; observed 421.0418.
(2E)-1-(4-Fluorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 13, Table 3) (obtained by condensation of 1b with 4-fluoro acetophenone)O
O
OCH3
F
Bright yellow solid (Yield 82%) m.p. 96-99°C, 1H NMR
(CDCl3, 300 MHz): 8.08 (2H, d, J = 8.40 Hz), 7.79 (1H, d, J = 15.56 Hz), 7.40 (1H, d, J =
15.56 Hz ), 7.22-7.15 (4H, m), 6.92 (1H, d, J = 8.41 Hz), 6.15-6.04 (1H, m), 5.47 (2H, dd, J =
17.24, 10.49 Hz), 4.69 (2H, d, J = 5.28 Hz), 3.96 (3H, s); 13C NMR (CDCl3, 75.4 MHz):
189.3, 150.9, 150.0, 145.6, 135.2, 133.1, 131.3, 128.4, 123.4, 119.9, 118.8, 116.2, 115.9, 113.4,
111.0, 70.2 and 56.4. HRMS-ESI: m/z [M+H]+ for C19H17FO3, calculated 313.1370 observed
313.1343.
(2E)-1-(3-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 14, Table 3) (obtained by condensation of 1b with 3-chloro acetophenone)O
OOC H3
Cl
Yellow solid (Yield 83%) m.p. 80-84°C, 1H NMR (CDCl3,
300 MHz): 6.76 (1H, s), 6.66 (1H, d, J = 6.48 Hz), 6.58 (1H, dd, J = 5.44, 15.58 Hz), 6.31
(1H, d, J = 4.74 Hz), 6.23 (1H, d, J = 5.96 Hz), 6.13 (1H, dd, J = 5.44, 15.58 Hz), 6.00-5.93
(2H, m), 5.70 (1H, t, J = 5.34 Hz), 4.92-4.79 (1H, m), 4.27-4.08 (2H, m), 3.45 (2H, s), 2.73
(3H, s); 13C NMR (CDCl3, 75.4 MHz): 188.3, 149.9, 148.8, 145.0, 139.3, 134.0, 131.8, 131.6,
129.1, 127.7, 126.9, 125.7, 122.4, 118.6, 117.7, 112.1, 109.7, 68.9 and 55.2. HRMS-ESI: m/z
[M+H]+ for C19H17ClO3, calculated 329.5913; observed 329.5938.
Synthesis of allylated chalcones… Chapter 2
150
(2E)-1-(4-Methoxyphenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 15, Table 3) (obtained by condensation of 1b with 4-methoxy acetophenone)O
O
OC H3
OC H3
Light orange solid (Yield 77%) m.p. 62-64°C, 1H NMR
(CDCl3, 300 MHz): 8.06 (2H, d, J = 8.68 Hz), 7.79 (1H, d, J = 15.55 Hz), 7.44 (1H, d, J =
15.55 Hz ), 7.22-7.18 (2H, m), 7.00 (2H, d, J = 8.68 Hz ), 6.89 (1H, d, J = 4.93 Hz), 6.16-6.03
(1H, m), 5.47 (2H, dd, J = 17.26, 10.47 Hz), 4.68 (2H, d, J = 5.24 Hz), 3.95 (3H, s), 3.89 (3H,
s); 13C NMR (CDCl3, 75.4 MHz): 189.2, 163.7, 150.7, 149.9, 144.5, 133.2, 131.7, 131.1,
128.7, 123.1, 120.3, 118.8, 114.2, 113.4, 111.0, 70.1, 56.4 and 55.9. HRMS-ESI: m/z [M+H]+
for C20H20O4, calculated 325.1614; observed 325.1647.
(2E)-1-(1,3-benzodioxol-5-yl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 16, Table 3) (obtained by condensation of 1b with 3,4-dioxymethylene
acetophenone)O
OOCH3
O
O
Creamish solid (Yield 79%) m.p. 86-89°C, 1H NMR
(CDCl3, 300 MHz): 7.76 (1H, d, J = 15.52 Hz), 7.66 (1H, d, J = 8.26 Hz), 7.52 (1H, s), 7.37
(1H, d, J = 15.52 Hz), 7.20-7.15 (2H, m), 6.90 (2H, d, J = 8.26 Hz), 6.13-6.02 (3H, m ), 5.46
(2H, dd, J = 15.20, 10.47 Hz), 4.67-4.65 (2H, m), 3.94 (3H, s); 13C NMR (CDCl3, 75.4 MHz):
188.7, 151.9, 150.7, 149.9, 148.6, 144.8, 133.6, 133.2, 128.6, 124.9, 123.2, 120.1, 118.8, 113.3,
110.9 108.8, 108.3, 102.2, 70.1 and 56.4. HRMS-ESI: m/z [M+H]+ for C20H18O5, calculated
339.1452; observed 339.1418.
(2E)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]-1-(4-nitrophenyl)prop-2-en-1-one
(compound 17, Table 3) (obtained by condensation of 1b with 4-nitro acetophenone)O
O
OC H3
NO 2
Orange solid (Yield 72%) m.p. 107-112°C, 1H NMR
(CDCl3, 300 MHz): 8.37 (2H, d, J = 8.60 Hz), 8.16 (2H, d, J = 8.60 Hz), 7.83 (1H, d, J =
Synthesis of allylated chalcones… Chapter 2
151
15.56 Hz ), 7.37 (1H, d, J = 15.56 Hz), 7.28-7.18 (2H, m), 6.94 (1H, d, J = 8.29 Hz), 6.15-6.04
(1H, m), 5.48 (2H, dd, J = 17.24, 10.45 Hz), 4.70 (2H, d, J = 5.25 Hz), 3.96 (3H, s); 13C NMR
(CDCl3, 75.4 MHz): 189.4, 151.5, 150.3, 150.1, 147.4, 143.8, 132.9, 129.7, 127.9, 124.2,
123.9, 119.7, 118.9, 113.3, 111.1, 70.2 and 56.5. HRMS-ESI: m/z [M+H]+ for C19H17NO5,
calculated 340.1416; observed 340.1451.
(2E)-1-(4-aminophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 18,Table 3) (obtained by condensation of 1b with 4-amino acetophenone)O
O
OC H3
NH 2
Bright yellow solid (Yield 70%) m.p. 103-107°C, 1H NMR
(CDCl3, 300 MHz): 8.38 (1H, d, J = 8.25 Hz), 8.11 (2H, d, J = 8.25 Hz), 7.82 (1H, d, J =
15.20 Hz ), 7.62 (1H, s), 7.48 (1H, d, J = 15.20 Hz), 7.34-7.21 (3H, m), 6.98-6.72 (2H, m),
6.12-6.09 (1H, m), 5.48 (2H, dd, J = 17.20, 10.25 Hz), 4.70 (2H, d, J = 5.30 Hz), 3.96 (3H, s);13C NMR (CDCl3, 75.4 MHz): 188.6, 151.7, 150.5, 149.9, 143.6, 133.2, 131.4, 128.9, 122.9,
120.5, 118.7, 114.3, 114.1, 113.5, 111.1, 70.2 and 56.4. HRMS-ESI: m/z [M+H]+ for
C19H19NO3, calculated 310.1573; observed 310.1544.
(2E)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]-1-phenylprop-2-en-1-one (compound 19,
Table 3) (obtained by condensation of 1b with acetophenone)O
OCH3
O
Yellow solid (Yield 88%) m.p. 78-81°C, 1H NMR (CDCl3, 300
MHz): 8.04 (2H, d, J = 8.15 Hz), 7.80 (1H, d, J = 15.63 Hz), 7.59-7.49 (3H, m ), 7.43 (1H, d,
J = 15.63 Hz ), 7.22-7.81 (2H, m), 6.93 (1H, d, J = 8.15 Hz), 6.15-6.04 (1H, m), 5.48 (2H, dd, J
= 17.26, 7.17 Hz), 4.69-4.66 (2H, m), 3.96 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 191.0,
150.9, 150.1, 145.4, 138.9, 133.2, 132.9, 128.9, 128.8, 128.5, 123.3, 120.6, 118.8, 113.4, 111.1,
70.2 and 56.5. HRMS-ESI: m/z [M+H]+ for C19H18O3, calculated 295.1464; observed
295.1438.
Synthesis of allylated chalcones… Chapter 2
152
2.4.6. Procedure for the synthesis of O-allylated chalcone via 5b (20; Table 3)
(a) Synthesis of 4-allyloxyacetophenone (5b)
To a 250-mL round bottom flask containing 4-hydroxy acetophenone (2a) (1.9 mmol) in dry
acetone (20 mL), allyl bromide (2.0 mmol), and anhydrous K2CO3 (3.8 mmol) were added. The
remaining procedure was similar to that described in step (a) of section 2.4.2. The desired
compound obtained after column chromatography over silica gel was characterized by 1H &13C NMR and HRMS data.
4-allyloxyacetophenone (5b)
O
CH3
O
Colorless viscous liquid (Yield 85%), 1H NMR (CDCl3, 300 MHz):
7.86 (2H, d, J = 8.66 Hz), 6.88 (2H, d, J = 8.66 Hz), 6.02-5.91 (1H, m), 5.39 (2H, dd, J =
17.26, 10.84 Hz), 4.52 (2H, d, J = 4.87 Hz), 2.46 (3H, s); 13C NMR (CDCl3, 75.4 MHz):
197.0, 162.8, 132.9, 130.9, 130.7, 118.4, 117.7, 69.2 and 26.7. HRMS-ESI: m/z [M+H]+ for
C11H12O2, calculated 177.0996; observed 177.0984.
(a) Synthesis of O-allylated chalcone (20)
To a solution of 5b (3 mmol) 10% aqueous NaOH (4 mmol) was added. Thereafter, 1b (3
mmol) dissolved in 20 mL of methanol was added drop wise. The remaining procedure was
similar to that described in step (c) of section 2.4.2. The desired compound obtained after
recrystallization was characterized by 1H & 13C NMR and HRMS data.
(2E)-3-[3-Methoxy-4-(prop-2-en-1-yloxy)phenyl]-1-[4-(prop-2-en-1-yloxy)phenyl]prop-2-
en-1-one (compound 20, Table 3)O
OOCH3
O
Light yellow solid (Yield 87%) m.p. 73-76°C, 1H NMR
(CDCl3, 300 MHz): 8.06 (2H, d, J = 8.85 Hz), 7.79 (1H, d, J = 15.56 Hz), 7.44 (1H, d, J =
15.56 Hz ), 7.22-7.17 (2H, m), 7.02 (2H, d, J = 8.85 Hz), 6.92 (1H, d, J = 8.22 Hz), 6.15-6.04
(2H, m), 5.48 (4H, dd, J = 16.20, 10.26 Hz), 4.68 (4H, d, J = 5.45 Hz), 3.96 (3H, s); 13C NMR
(CDCl3, 75.4 MHz): 189.1, 162.7, 150.7, 149.9, 144.5, 133.2, 132.9, 131.8, 131.1, 128.7,
123.1, 120.3, 118.8, 118.6, 114.9, 113.4, 110.9, 70.2, 69.3 and 56.4. HRMS-ESI: m/z [M+H]+
for C22H22O4, calculated 351.1770; observed 351.1739.
Synthesis of allylated chalcones… Chapter 2
153
2.4.7. Procedure for the synthesis of chalcones (21-32; Table 4)
2.4.7.1. Procedure for the synthesis of chalcone 21 via 6b
(a) Synthesis of 2-allyloxy-3-methoxy benzaldehyde (6b)
To a 250-mL round bottom flask containing 2-hydroxy-3-methoxy benzaldehyde (3a) (1.9
mmol) in dry acetone (20 mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol)
were added. The remaining procedure was similar to that described in step (a) of section 2.4.2.
The desired compound obtained after column chromatography over silica gel with hexane-ethyl
acetate (9:1) was characterized by 1H & 13C NMR and HRMS data.
2-allyloxy-3-methoxy benzaldehyde (6b)
OC H3
CHO
O
Bright yellow viscous liquid (Yield 80%), 1H NMR (CDCl3, 300 MHz): δ
10.38 (1H, s), 7.33 (1H, d, J = 6.87 Hz ), 7.10 (2H, dd, J = 7.68, 7.92 Hz), 6.06-5.95 (1H, m),
5.32 (1H, d, J = 17.13 Hz), 5.21 (1H, d, J = 10.24 Hz), 4.60 (2H, d, J = 5.85 Hz), 3.83 (3H, s);13C NMR (CDCl3, 75.4 MHz): 190.3, 152.9, 151.1, 133.1, 129.9, 123.9, 118.8, 118.3, 77.4,
75.0 and 55.9. HRMS-ESI: m/z [M+H]+ for C11H12O3, calculated 193.0996; observed
193.0998.
(b) Synthesis of chalcone (21)
To a solution of 6b (3 mmol) and 4-chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-chlorophenyl)-3-[3-methoxy-2-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 21, Table 4)O
OC H3
ClO
Light yellow solid (Yield 77%) m.p. 70-75°C, 1H NMR (CDCl3, 300
MHz): 8.14 (1H, d, J = 15.89 Hz), 7.98 (2H, d, J = 8.54 Hz), 7.60 (1H, d, J = 15.89 Hz ), 7.50
(2H, d, J = 6.70 Hz), 7.29 (1H, d, J = 7.80 Hz), 7.14 (1H, t, J = 8.03 Hz), 7.01 (1H, d, J = 8.10
Hz), 6.16-6.05 (1H, m), 5.41 (2H, dd, J = 17.15, 10.31 Hz), 4.59 (2H, d, J = 5.90 Hz), 3.90
Synthesis of allylated chalcones… Chapter 2
154
(3H, s); 13C NMR (CDCl3, 75.4 MHz): 190.1, 153.7, 148.1, 141.2, 139.4, 137.0, 134.2, 130.4,
129.6, 129.3, 124.6, 123.7, 120.4, 118.5, 114.8, 74.8 and 56.3. HRMS-ESI: m/z [M+H]+ for
C19H17ClO3, calculated 329.5913; observed 329.5936.
2.4.7.2. Procedure for the synthesis of chalcone 22 via 7b (Table 4)
(a) Synthesis of 3-allyloxy-4-methoxy benzaldehyde (7b)
To a 250-mL round bottom flask containing 3-hydroxy-4-methoxy benzaldehyde (4a) (1.9
mmol) in dry acetone (20 mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol)
were added. The remaining procedure was similar to that described in step (a) of section 2.4.2.
The desired compound obtained after column chromatography over silica gel with hexane-ethyl
acetate (9:1) was characterized by 1H & 13C NMR and HRMS data.
3-allyloxy-4-methoxy benzaldehyde (7b)
O
C H O
H 3 C O
Colorless viscous liquid (Yield 78%), 1H NMR (CDCl3, 300 MHz): 9.81
(1H, s), 7.45-7.38 (2H, m), 6.98 (1H, d, J = 8.19 Hz), 6.11-6.00 (1H, m), 5.45 (2H, dd, J =
17.20, 10.40 Hz), 4.65 (2H, d, J = 5.36 Hz), 3.93 (3H, s); 13C NMR (CDCl3, 75.4 MHz):
191.2, 155.2, 148.9, 132.9, 130.4, 127.1, 118.9, 111.3, 111.1, 70.1 and 56.5. HRMS-ESI: m/z
[M+H]+ for C11H12O3, calculated 193.0996; observed 193.0989.
(b) Synthesis of chalcone (22)
To a solution of 7b (3 mmol) and chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-chlorophenyl)-3-[4-methoxy-3-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 22, Table 4)O
H3COO
Cl
Light yellow solid (Yield 84%) m.p. 80-83°C, 1H NMR (CDCl3,
300 MHz): 7.99 (2H, d, J = 8.31 Hz), 7.73 (1H, d, J = 15.31 Hz), 7.51 (2H, d, J = 8.31 Hz),
Synthesis of allylated chalcones… Chapter 2
155
7.35-7.19 (3H, m), 6.94 (1H, d, J = 15.31 Hz), 6.13-6.04 (1H, m), 5.48-5.29 (2H, m), 4.72 (2H,
d, J = 10.29 Hz), 3.94 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 189.6, 152.5, 148.7,
145.4,139.4, 137.2, 133.4, 130.2, 129.3, 128.0, 123.9, 119.8, 118.8, 113.0, 112.0, 70.4 and
56.4. HRMS-ESI: m/z [M+H]+ for C19H17ClO3, calculated 329.5913; observed 329.5941.
2.4.7.3. Procedure for the synthesis of chalcone 23 (Table 4)
To the solution of vanillin (3 mmol) and chloro acetophenone (3 mmol) in ethanol (20 mL),
KOH (4 mmol) was added. The remaining procedure was similar to that described in step (c) of
section 2.4.2. The desired compound obtained after recrystallization was characterized by 1H &13C NMR and HRMS data.
(2E)-1-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one (compound 23,
Table 4)O
ClOC H3
HO
Bright yellow solid (Yield 60%) m.p. 110-115°C, 1H NMR
(CDCl3, 300 MHz): 7.98 (2H, d, J = 8.50 Hz), 7.79 (1H, d, J = 15.57 Hz), 7.49 (2H, d, J =
8.50 Hz), 7.36 (1H, d, J = 15.57 Hz), 7.24 (1H, dd, J = 1.30, 1.27 Hz), 7.13 (1H, s), 6.99 (1H,
d, J = 8.20 Hz), 6.11 (1H, s), 3.97 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 189.7, 148.9, 147.3,
146.2, 139.4, 137.2, 130.2, 129.3, 127.7, 123.9, 119.6, 115.4, 110.5 and 56.4. HRMS-ESI: m/z
[M+H]+ for C16H13ClO3, calculated 289.5601; observed 289.5627.
2.4.7.4. Procedure for the synthesis of chalcone 24 (Table 4)
To a 250 mL round bottom flask containing 1-(4-chlorophenyl)-3-(4-hydroxy-3-
methoxyphenyl)prop-2-en-1-one (23) (1.9 mmol) in dry acetone (20 mL), prenyl bromide (2.0
mmol) and anhydrous K2CO3 (3.8 mmol) were added. The remaining procedure was similar to
that described in step (a) of section 2.4.2. The desired compound obtained after column
chromatography over silica gel with hexane-ethyl acetate (9:1) was characterized by 1H & 13C
NMR and HRMS data.
Synthesis of allylated chalcones… Chapter 2
156
(2E)-1-(4-chlorophenyl)-3-{3-methoxy-4-[(3-methylbut-2-en-1-yl)oxy]phenyl}prop-2-en-1-
one (compound 24, Table 4)
Cl
O
OC H3
OYellow solid (Yield 62%) m.p. 71-74°C, 1H NMR (CDCl3, 300
MHz): 7.79-7.95 (2H, m), 7.82 (1H, dd, J = 7.79, 15.52 Hz ), 7.50-7.46 (2H, m), 7.39 (1H,
dd, J = 7.80, 15.55 Hz), 7.29-7.16 (2H, m), 6.93 (1H, s), 5.52 (1H, s), 4.66 (2H, s), 3.96 (3H, d,
J = 4.85 Hz), 1.78 (6H, s); 13C NMR (CDCl3, 75.4 MHz): 189.7, 151.4, 150.0, 146.1, 139.3,
137.2, 130.7, 130.3, 129.3, 127.9, 123.6, 119.7, 113.0, 112.0, 110.7, 66.2, 56.4, 26.3 and 18.7.
HRMS-ESI: m/z [M+H]+ for C21H21ClO3, calculated 357.6212; observed 357.6235.
2.4.7.5. Procedure for the synthesis of chalcone 25 (Table 4)
To a 250 mL round bottom flask containing 1-(4-chlorophenyl)-3-(4-hydroxy-3-
methoxyphenyl)prop-2-en-1-one (23) (1.9 mmol) in dry acetone (20 mL), 1-bromo butane (2.0
mmol) and anhydrous K2CO3 (3.8 mmol) were added. The remaining procedure was similar to
that described in step (a) of section 2.4.2. The desired compound obtained after column
chromatography over silica gel with hexane-ethyl acetate (9:1) was characterized by 1H & 13C
NMR and HRMS data.
(2E)-3-(4-butoxy-3-methoxyphenyl)-1-(4-chlorophenyl)prop-2-en-1-one (compound 25,Table 4)
O
OCH3O Cl
Yellow solid (Yield 81%) m.p. 47-50°C, 1H NMR (CDCl3, 300
MHz): 7.99 (2H, d, J = 8.44 Hz), 7.81 (1H, d, J = 15.60 Hz), 7.50 (2H, d, J = 8.43 Hz), 7.37
(1H, d, J = 15.55 Hz), 7.26-7.18 (2H, m), 6.93 (1H, d, J = 8.30 Hz), 4.11 (2H, t), 3.95 (3H, s),
1.89-1.83 (2H, m), 1.57-1.49 (2H, m), 1.01 (3H, t); 13C NMR (CDCl3, 75.4 MHz): 189.7,
151.8, 149.9, 146.1, 139.3, 137.2, 130.2, 129.3, 127.9, 123.8, 119.7, 112.8, 111.1, 69.1, 56.5,
31.5, 19.6 and 14.2. HRMS-ESI: m/z [M+H]+ for C20H21ClO3, calculated 345.6225; observed
345.6203.
2.4.7.6. Procedure for the synthesis of chalcone 26 (Table 4)
To a 250 mL round bottom flask containing 1-(4-chlorophenyl)-3-(4-hydroxy-3-
methoxyphenyl)prop-2-en-1-one (23) (1.9 mmol) in dry acetone (20 mL), 4-
Synthesis of allylated chalcones… Chapter 2
157
bromobenzylbromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol) were added. The
remaining procedure was similar to that described in step (a) of section 2.4.2. The desired
compound obtained after column chromatography over silica gel with hexane-ethyl acetate
(9:1) was characterized by 1H & 13C NMR and HRMS data.
(2E)-3-{4-[(4-bromobenzyl)oxy]-3-methoxyphenyl}-1-(4-chlorophenyl)prop-2-en-1-one
(compound 26, Table 4)O
ClOC H3
O
Br Creamish solid (Yield 75%) m.p. 115-120°C, 1H NMR
(CDCl3, 300 MHz): 7.98 (2H, d, J = 8.47 Hz), 7.78 (1H, d, J = 15.57 Hz), 7.53-7.46 (4H, m),
7.37-7.28 (3H, m), 7.18 (2H, d, J = 5.46 Hz), 6.89 (1H, d, J = 8.77 Hz), 5.15 (2H, s), 3.96 (3H,
s); 13C NMR (CDCl3, 75.4 MHz): 189.6, 150.8, 150.2, 145.7, 139.4, 137.1, 135.9, 132.2,
130.3, 129.3, 128.7, 123.3, 122.4, 120.1, 113.9, 111.3, 70.6 and 56.4. HRMS-ESI: m/z [M+H]+
for C23H18ClBrO3, calculated 458.5031; observed 458.5054.
2.4.7.7. Procedure for the synthesis of chalcone 27 via 8b (Table 4)
(a) Synthesis of 4-allyloxy-3,5-dimethoxy benzaldehyde (8b)
To a 250 mL round bottom flask containing syringaldehyde (5a) (1.9 mmol) in dry acetone (20
mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol) were added. The remaining
procedure was similar to that described in step (a) of section 2.4.2. The desired compound
obtained after column chromatography over silica gel with hexane-ethyl acetate (9:1) was
characterized by 1H & 13C NMR and HRMS data.
4-allyloxy-3,5-dimethoxy benzaldehyde (8b)
OCH3
CHO
O
H3CO
White solid (Yield 70%) m.p. 45-47oC, 1H NMR (CDCl3, 300 MHz):
9.87 (1H, s), 7.31 (2H, s), 6.10-6.04 (1H, m), 5.36 (2H, dd, J = 17.15, 10.24 Hz), 4.64(2H, d, J
= 6.07 Hz), 3.93 (6H, s); 13C NMR (CDCl3, 75.4 MHz): 191.5, 154.3, 142.7, 134.3, 132.2,
118.7, 107.1, 74.6 and 56.6. HRMS-ESI: m/z [M+H]+ for C12H14O4, calculated 223.1146;
observed 223.1147.
Synthesis of allylated chalcones… Chapter 2
158
(b) Synthesis of chalcone (27)
To a solution of 8b (3 mmol) and 4-chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-chlorophenyl)-3-[3,5-dimethoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 27, Table 4)O
ClO
H3CO
OCH3 Yellow solid (Yield 76%) m.p. 120-123°C, 1H NMR (CDCl3, 300
MHz): 7.99 (2H, d, J = 8.53 Hz), 7.52 (1H, d, J = 15.60 Hz), 7.50 (2H, d, J = 8.53 Hz ), 7.38
(1H, d, J = 15.60 Hz ), 6.86 (2H, s), 6.16-6.06 (1H, m), 5.37-5.20 (2H, m), 4.61 (2H, d, J =
5.20 Hz), 3.91 (6H, s); 13C NMR (CDCl3, 75.4 MHz): 189.6, 154.1, 145.9, 139.7, 139.5,
136.9, 134.5, 130.6, 130.3, 129.3, 121.2, 118.5, 106.2, 74.7 and 56.6. HRMS-ESI: m/z [M+H]+
for C20H19ClO4, calculated 359.6063; observed 359.6042.
2.4.7.8. Procedure for the synthesis of chalcone 28 via 9b (Table 4)
(a) Synthesis of 4-allyloxy benzaldehyde (9b)
To a 250 mL round bottom flask containing 4-hydroxy benzaldehyde (6a) (1.9 mmol) in dry
acetone (20 mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol) were added. The
remaining procedure was similar to that described in step (a) of section 2.4.2. The desired
compound obtained after column chromatography over silica gel with hexane-ethyl acetate
(9:1) was characterized by 1H & 13C NMR and HRMS data.
4-allyloxy benzaldehyde (9b)CHO
O Pale yellow viscous liquid (Yield 80%), 1H NMR (CDCl3, 300
MHz): 9.89 (1H, s), 7.86 (2H, d, J = 8.32 Hz), 7.07 (2H, d, J = 8.32 Hz), 6.11-6.02 (1H, m),
5.48 (2H, dd, J = 17.32, 10.35 Hz), 4.65 (2H, d, J = 5.21 Hz); 13C NMR (CDCl3, 75.4 MHz):
191.2, 164.0, 132.7, 132.4, 130.5, 118.7, 115.4 and 69.6. HRMS-ESI: m/z [M+H]+ for
C10H10O2, calculated 163.0846; observed 163.0853.
Synthesis of allylated chalcones… Chapter 2
159
b) Synthesis of chalcone (28)
To a solution of 9b (3 mmol) and 4-chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-chlorophenyl)-3-[4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one (compound 28,
Table 4)
Cl
O
O Light yellow solid (Yield 90%) m.p. 101-104°C, 1H NMR
(CDCl3, 300 MHz): 7.99 (2H, d, J = 8.73 Hz), 7.82 (1H, d, J = 15.60 Hz), 7.62 (2H, d, J =
8.73 Hz ), 7.50 (2H, d, J = 8.73 Hz ), 7.40 (1H, d, J = 15.60 Hz), 6.99 (2H, d, J = 8.73 Hz),
6.14-6.01 (1H, m), 5.47 (2H, dd, J = 18.78, 10.5 Hz), 4.61-4.59 (2H, m); 13C NMR (CDCl3,
75.4 MHz): 189.6, 161.3, 145.6, 139.3, 137.2, 133.1, 130.7, 130.2, 129.3, 127.9, 119.7,
118.5, 115.6 and 51.2. HRMS-ESI: m/z [M+H]+ for C18H15ClO2, calculated 299.5763;
observed 299.5738.
2.4.7.9. Procedure for the synthesis of chalcone 29 via 10b (Table 4)
(a) Synthesis of 2-allyloxy benzaldehyde (10b)
To a 250 mL round bottom flask containing 2-hydroxy benzaldehyde (7a) (1.9 mmol) in dry
acetone (20 mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol) were added. The
remaining procedure was similar to that described in step (a) of section 2.4.2. The desired
compound obtained after column chromatography over silica gel with hexane-ethyl acetate
(9:1) was characterized by 1H & 13C NMR and HRMS data.
2-allyloxy benzaldehyde (10b)CHO
O Yellow viscous liquid (Yield 72%), 1H NMR (CDCl3, 300 MHz): δ 10.73
(1H, s), 8.04 (1H, s), 7.73 (1H, d, J = 7.72 Hz), 7.19 (2H, d, J = 8.4 Hz), 6.32-6.21 (1H, m),
5.65 (1H, dd, J = 8.32, 8.30 Hz), 5.54 (1H, m), 4.85 (2H, s); 13C NMR (CDCl3, 75.4 MHz):
189.8, 161.1, 135.9, 132.5, 128.4, 125.2, 120.9, 118.1, 113.0 and 69.3. HRMS-ESI: m/z
[M+H]+ for C10H10O2, calculated 163.0846; observed 163.0858.
Synthesis of allylated chalcones… Chapter 2
160
(b) Synthesis of chalcone (29)
To a solution of 10b (3 mmol) and 4-chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-chlorophenyl)-3-[2-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one (compound 29,
Table 4)O
ClOCreamish solid (Yield 78%) m.p. 91-93°C, 1H NMR (CDCl3, 300
MHz): 8.19 (1H, d, J = 15.39 Hz), 7.99 (2H, d, J = 6.80 Hz), 7.68 (2H, d, J = 6.87 Hz), 7.50
(2H, d, J = 6.87 Hz), 7.41 (1H, d, J = 15.39 Hz), 7.05-6.95 (2H, m), 6.18-6.08 (1H, m), 5.51
(2H, dd, J = 17.23, 10.45 Hz), 4.66 (2H, s); 13C NMR (CDCl3, 75.4 MHz): 190.5, 158.6,
141.7, 139.7, 137.6, 133.5, 132.6, 130.7, 130.4, 129.6, 124.7, 123.2, 121.7, 118.8 113.3 and
69.9. HRMS-ESI: m/z [M+H]+ for C18H15ClO2, calculated 299.5685; observed 299.5746.
2.4.7.10. Procedure for the synthesis of chalcone 30 via 11b (Table 4)
(a) Synthesis of 3-ethoxy-4-allyloxy benzaldehyde (11b)
To a 250 mL round bottom flask containing 3-ethoxy-4-hydroxy benzaldehyde (8a) (1.9 mmol)
in dry acetone (20 mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol) were
added. The remaining procedure was similar to that described in step (a) of section 2.4.2. The
desired compound obtained after column chromatography over silica gel with hexane-ethyl
acetate (9:1) was characterized by 1H & 13C NMR and HRMS data.
3-ethoxy-4-allyloxy benzaldehyde (11b)CHO
OC2H5
O
Pale yellow viscous liquid (Yield 80%), 1H NMR (CDCl3, 300 MHz):
9.82 (1H, s), 7.42 (2H, d, J = 7.48 Hz), 6.98 (1H, d, J = 8.66 Hz), 6.12-6.02 (1H, m), 5.47 (2H,
dd, J = 17.26, 10.54 Hz), 4.70 (2H, d, J = 5.21 Hz), 4.19 (2H, q, J = 7.00 Hz), 1.50 (3H, t, J =
7.0 Hz); 13C NMR (CDCl3, 75.4 MHz): 191.3, 154.2, 149.6, 132.8, 130.6, 126.7, 118.6, 112.7,
Synthesis of allylated chalcones… Chapter 2
161
111.2, 70.1, 64.9 and 15.0. HRMS-ESI: m/z [M+H]+ for C14H16O3, calculated 207.1152;
observed 207.1158.
(b) Synthesis of chalcone (30)
To a solution of 11b (3 mmol) and 4-chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(4-chlorophenyl)-3-[3-ethoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 30, Table 4)O
OC2H5
O ClLight yellow solid (Yield 88%) m.p. 85-89°C, 1H NMR (CDCl3,
300 MHz): 7.89 (2H, d, J = 8.23 Hz), 7.78 (1H, d, J = 15.52 Hz), 7.36 (2H, d, J = 8.23 Hz),
7.31 (1H, d, J = 15.52 Hz), 7.21 (2H, d, J = 7.67 Hz), 6.92 (1H, s), 6.11-6.05 (1H, m), 5.47-
5.31 (2H, m), 5.31 (2H, s), 4.18 (2H, d, J = 6.82 Hz), 1.53 (3H, t); 13C NMR (CDCl3, 75.4
MHz): 189.6, 151.5, 149.4, 145.9, 139.3, 137.2, 133.3, 130.2, 129.3, 128.3, 123.5, 119.8,
118.4, 113.9, 113.0 70.2, 65.2 and 15.2. HRMS-ESI: m/z [M+H]+ for C20H19ClO3, calculated
343.5991; observed 343.6034.
2.4.7.11. Procedure for the synthesis of chalcone 31 via 12b (Table 4)
(a) Synthesis of 3,4-diallyloxy benzaldehyde (12b)
To a 250 mL round bottom flask containing 3,4-dihydroxy benzaldehyde (9a) (1.9 mmol) in
dry acetone (20 mL), allyl bromide (4 mmol) and anhydrous K2CO3 (3.8 mmol) were added.
The remaining procedure was similar to that described in step (a) of section 2.4.2. The desired
compound obtained after column chromatography over silica gel with hexane-ethyl acetate
(9:1) was characterized by 1H & 13C NMR and HRMS data.
3,4-diallyloxy benzaldehyde (12b)
O
CHO
O
Pale yellow viscous liquid (Yield 80%), 1H NMR (CDCl3, 300 MHz): δ
9.82 (1H, s), 7.42 (2H, d, J = 8.28 Hz ), 6.97 (1H, d, J = 7.93 Hz), 6.11-6.02 (2H, m), 5.44 (2H,
Synthesis of allylated chalcones… Chapter 2
162
d, J = 17.25 Hz), 5.32 (2H, dd, J = 6.18, 7.19 Hz), 4.67 (4H, m); 13C NMR (CDCl3, 75.4
MHz): 191.3, 154.2, 149.2, 133.0, 132.7, 130.4, 127.0, 118.7, 118.5, 112.6, 111.7, 77.7 and
70.1. HRMS-ESI: m/z [M+H]+ for C13H14O3, calculated 219.1152; observed 219.1167.
(b) Synthesis of chalcone (31)
To a solution of 12b (3 mmol) and 4-chloro acetophenone (3 mmol) in methanol (20 mL), 10%
aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that described in
step (c) of section 2.4.2. The desired compound obtained after recrystallization was
characterized by 1H & 13C NMR and HRMS data.
(2E)-3-[3,4-bis(prop-2-en-1-yloxy)phenyl]-1-(4-chlorophenyl)prop-2-en-1-one (compound
31,Table 4)O
OO Cl
Light yellow solid (Yield 90%) m.p. 72-75°C, 1H NMR (CDCl3, 300
MHz): 7.99 (2H, d, J = 7.83 Hz), 7.79 (1H, d, J = 15.54 Hz), 7.51 (2H, d, J = 6.16 Hz), 7.37
(1H, d, J = 15.54 Hz), 7.20 (2H, d, J = 7.83 Hz), 6.94 (1H, s), 6.13-6.09 (2H, m), 5.50-5.33
(4H, m), 4.69 (4H, s); 13C NMR (CDCl3, 75.4 MHz): 189.6, 151.6, 149.0, 145.8, 139.6,
137.2, 133.5, 133.2, 130.2, 129.3, 128.3, 123.8, 119.9, 118.5 118.4, 113.9, 113.7, 70.5 and
70.1. HRMS-ESI: m/z [M+H]+ for C21H19ClO3, calculated 355.5991; observed 355.6069.
2.4.7.12. Procedure for the synthesis of chalcone 32 (Table 4)
(a) Synthesis of 4-allyloxy-3-methoxyacetophenone (13b)
To a 250 mL round bottom flask containing 4-hydroxy-3-methoxy acetophenone (10a) (1.9
mmol) in dry acetone (20 mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol)
were added. The remaining procedure was similar to that described in step (a) of section 2.4.2.
The desired compound obtained after column chromatography over silica gel with hexane-ethyl
acetate (9:1) was characterized by 1H & 13C NMR and HRMS data.
OOCH3
CH3
O
White solid (Yield 80%) m.p. 39-41oC, 1H NMR (CDCl3, 300 MHz):
7.49 (2H, d, J = 4.57 Hz), 6.86 (1H, s), 6.10-5.97 (1H, m), 5.42-5.26 (2H, m), 4.64 (2H, s), 3.89
(3H, s), 2.52 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 197.1, 152.7, 149.6, 132.9, 130.9, 123.4,
Synthesis of allylated chalcones… Chapter 2
163
118.9, 111.9, 110.8, 70.0, 56.3 and 26.5. HRMS-ESI: m/z [M+H]+ for C12H14O3, calculated
207.1152; observed 207.1171.
(b) Synthesis of chalcone (31)
To a solution of 13b (3 mmol), 10% aqueous NaOH (4 mmol) was added. Thereafter, 4-chloro
benzaldehyde (3 mmol) dissolved in 20 mL of methanol was added drop wise. The remaining
procedure was similar to that described in step (c) of section 2.4.2. The desired compound
obtained after recrystallization was characterized by 1H & 13C NMR and HRMS data.
(2E)-3-(4-chlorophenyl)-1-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 32, Table 4)O
O
OCH3
Cl Light yellow solid (Yield 80%) m.p. 120-123°C, 1H NMR
(CDCl3, 300 MHz): 7.79 (1H, d, J = 15.63 Hz), 7.67-7.64 (2H, m), 7.59-7.55 (3H, m), 7.40
(2H, d, J = 8.18 Hz ), 6.95 (1H, d, J = 8.18 Hz), 5.49-5.18 (1H, m), 5.49 (2H, dd, J = 17.25,
10.47 Hz), 4.73-4.70 (2H, m), 3.98 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 188.6, 152.8,
150.0, 142.8, 136.6, 133.9, 132.9, 131.7, 129.9, 129.6, 123.3, 122.5, 119.0, 112.0, 111.5, 70.2
and 56.5. HRMS-ESI: m/z [M+H]+ for C19H17ClO3, calculated 329.5913; observed 329.5929.
2.4.8. General procedure for the synthesis of heterocyclic chalcone derivatives (33-38;
Table 5)
To a solution of 1b (3 mmol) and appropriate aceto derivatives (3 mmol) in methanol (20 mL),
10% aqueous NaOH (4 mmol) was added. The remaining procedure was similar to that
described in step (c) of section 2.4.2. The desired compounds obtained after recrystallization
was characterized by 1H & 13C NMR and HRMS data.
(2E)-1-(furan-2-yl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-en-1-one
(compound 33, Table 5)O
OOCH3
O
Light yellow solid (Yield 70%) m.p. 132-135°C, 1H NMR (CDCl3,
300 MHz): 7.82 (1H, d, J = 15.81 Hz), 7.29-7.11 (5H, m), 6.91 (1H, d, J = 8.36 Hz ), 6.38
(1H, d, J = 5.80 Hz), 6.13-6.02 (1H, m), 5.46 (2H, dd, J = 17.26, 10.47 Hz), 4.67 (2H, d, J =
5.20 Hz), 3.95 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 179.5, 150.6, 150.0, 142.7, 133.7,
Synthesis of allylated chalcones… Chapter 2
164
133.3, 128.7, 126.0, 122.9, 120.6, 118.7, 116.7, 113.5, 111.3, 111.2, 70.2 and 56.5. HRMS-ESI:
m/z [M+H]+ for C17H16O4, calculated 285.1302; observed 285.1345.
3-{(2E)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-enoyl}-2H-chromen-2-one
(compound 34, Table 5)O
OOCH3
O O
Yellow solid (Yield 70%) m.p. 148-151°C, 1H NMR (CDCl3,
300 MHz): 8.58 (1H, s), 7.82 (2H, s), 7.69 (2H, d, J = 7.44 Hz), 7.41-7.33 (2H, m), 7.27 (2H,
d, J = 8.58 Hz), 6.91(1H, d, J = 7.44 Hz), 6.14-6.07 (1H, m), 5.47 (2H, dd, J = 17.22, 10.26
Hz), 4.68 (2H, s), 3.95 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 186.6, 159.8, 155.6, 151.2,
149.9, 148.2, 145.7, 134.5, 133.1, 130.2, 128.5, 126.0, 125.3, 124.1, 122.3, 119.0, 118.9, 117.0,
113.2, 111.1, 70.1 and 56.4. HRMS-ESI: m/z [M+H]+ for C22H18O5, calculated 363.1452;
observed 363.1433.
4-hydroxy-3-{(2E)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]prop-2-enoyl}-2H-
chromen-2-one (compound 35, Table 5)O
O
OH
OOCH3
OOrange solid (Yield 68%) m.p. 150-153°C, 1H NMR
(CDCl3, 300 MHz): 8.30 (1H, d, J = 15.34 Hz), 8.10 (1H, d, J = 7.62 Hz), 8.00 (1H, d, J =
15.34 Hz), 7.68-7.63 (1H, m), 7.42-7.23 (4H, m), 6.91 (1H, d, J = 8.15 Hz), 6.14-6.07 (1H, m),
5.47 (2H, dd, J = 17.20, 10.25 Hz), 4.72 (2H, d, J = 5.20 Hz), 3.96 (3H, s), 3.09 (1H, s); 13C
NMR (CDCl3, 75.4 MHz): 181.7, 161.6, 154.9, 151.6, 150.1, 147.2, 145.5, 135.8, 133.0,
128.5, 126.2, 124.7, 124.6, 121.5, 118.9, 117.8, 117.3, 113.2, 111.4, 101.3, 70.2 and 56.4.
HRMS-ESI: m/z [M+H]+ for C22H18O6, calculated 379.1446; observed 379.1426.
Synthesis of allylated chalcones… Chapter 2
165
(2E)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(compound 36, Table 5)O
OC H3
O
NH
Light yellow solid (Yield 63%) m.p. 132-135°C, 1H NMR (CDCl3,
300 MHz): 9.81 (1H, s), 7.84 (1H, d , J = 15.85 Hz), 7.29-7.12 (5H, m), 6.91 (1H, d, J = 8.40
Hz ), 6.36-6.33 (1H, m ), 6.15-6.03 (1H, m), 5.46 (2H, dd, J = 17.26, 10.47 Hz), 4.67 (2H, d, J
= 5.31 Hz), 3.95 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 179.5, 150.6, 150.0, 142.7, 133.7,
133.2, 128.7, 125.9, 125.9, 120.5, 118.7, 116.7, 113.5, 111.2, 70.2 and 56.5. HRMS-ESI: m/z
[M+H]+ for C17H17NO3, calculated 284.1417; observed 284.1442.
5-[3-methoxy-4-(prop-2-en-1-yloxy)benzylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione
(compound 37, Table 5)
OCH3
O O
O
O
O
Fluorescent yellow solid (Yield 91%) m.p. 128-133°C, 1H
NMR (CDCl3, 300 MHz): 8.34 (1H, s), 8.29 (1H, s), 7.63 (1H, d, J = 8.52 Hz ), 6.95 (1H, d, J
= 8.52 Hz ), 6.08-6.03 (1H, m), 5.46-5.33 (2H, m), 4.74 (2H, d, J = 5.37 Hz), 3.95 (3H, s), 1.79
(6H, s); 13C NMR (CDCl3, 75.4 MHz): 164.6, 161.0, 158.6, 154.2, 149.4, 132.7, 132.4, 125.5,
119.4, 116.5, 112.4, 111.0, 104.6, 70.2, 56.4 and 27.8. HRMS-ESI: m/z [M+H]+ for C17H18O6,
calculated 319.1446; observed 319.1479.
5-[3-methoxy-4-(prop-2-en-1-yloxy)benzylidene]pyrimidine-2,4,6(1H,3H,5H)-trione
(compound 38, Table 5)
OCH3
O NH
NH
O
OO
Bright yellow solid (Yield 90%) m.p. 250-256°C, 1H NMR
(DMSO-d6, 300 MHz): 9.99 (1H, s), 9.87 (1H, s), 7.06 (1H, s), 6.91 (1H, s), 6.49 (1H, d, J =
8.32 Hz), 5.78 (1H, d, J = 8.36 Hz), 4.12-3.97 (1H, m), 4.12-3.97 (2H, m), 3.37 (2H, d, J =
3.39 Hz), 2.31 (3H, s); 13C NMR (DMSO-d6, 75.4 MHz): 164.2, 162.4, 155.9, 152.7, 150.4,
Synthesis of allylated chalcones… Chapter 2
166
148.0, 132.9, 131.7, 125.4, 118.6, 116.9, 115.2, 112.3, 69.1 and 55.6. HRMS-ESI: m/z [M+H]+
for C15H14N2O5, calculated 303.1172; observed 303.1149.
2.4.9. General procedure for the synthesis of heterocyclic chalcone derivative (39;
Table 5)
To a solution of 4,7-dichloro quinoline (2.5 mmol) in tetrahydrofuran (20 mL), compound 18
(2.75 mmol; section 2.4.5.) was added and the mixture was refluxed for 8 h. Thereafter the
reaction mixture was cooled and thus formed precipitates were filtered, washed with water,
diethyl ether and recrystallized from alcohol. The desired compound obtained after
recrystallization was characterized by 1H & 13C NMR and HRMS data.
(E)-3-(4-(allyloxy)-3-methoxyphenyl)-1-(4-((7-chloroquinolin-4-yl)amino)phenyl)prop-2-
en-1-one (compound 39, Table 5)O
OCH3
O
N Cl
NH
Yellow solid (Yield 76%) m.p. 168-171°C, 1H NMR
(CDCl3 + DMSO-d6, 300 MHz): 7.35 (2H, d, J = 8.41 Hz), 6.93 (2H, d, J = 7.83 Hz), 6.78
(1H, s), 6.60 (1H, s), 6.50-6.29 (4H, m), 6.08 (1H, s), 6.02 (1H, d, J = 7.8 Hz), 5.92 (1H, d, J =
4.82 Hz), 5.71 (1H, d, J = 8.42 Hz ), 4.84-4.76 (1H, m), 4.20 (2H, dd, J = 15.34, 10.52 Hz),
3.39 (2H, d, J = 5.10 Hz), 2.68 (3H, s); 13C NMR (CDCl3 + DMSO-d6, 75.4 MHz): 188.8,
151.5, 150.9, 150.1, 149.6, 147.9, 145.1, 144.9, 143.9, 137.9, 135.1, 133.4, 130.8, 128.5, 127.5,
125.7, 124.1, 123.9, 122.7, 120.2, 118.6, 113.7, 111.5, 103.4, 69.9 and 56.6. HRMS-ESI: m/z
[M+H]+ for C28H23ClN2O3, calculated 471.6449; observed 471.6421.
2.4.10. General procedure for the synthesis of heterocyclic chalcone derivative (40;
Table 5)
To the solution of compound 39 (2.7 mmol; section 2.4.9) in dry tetrahydrofuran (15 mL),
potassium hydroxide (13.5 mmol), allyl bromide (5.5 mmol) and cetyltrimethylammonium
bromide (CTAB) (0.7 mmol) was added. The contents were stirred at room temperature for 12-
14 h till the starting disappeared (monitored by TLC). After the completion of reaction, the
reaction mixture was partitioned between ethyl acetate (70 mL) and water (15 mL). The ethyl
acetate layer was washed with water till neutral, dried over sodium sulfate and evaporated. The
Synthesis of allylated chalcones… Chapter 2
167
obtained residue was purified by column chromatography (silica gel, hexane: ethyl acetate (7:3
v/v) to afford the desired compound whose structure was confirmed through NMR and mass
spectrometry.
(E)-1-(4-(allyl(7-chloroquinolin-4-yl)amino)phenyl)-3-(4-(allyloxy)-3-methoxyphenyl)
prop-2-en-1-one (compound 40, Table 5)
N
N
O
Cl
OC H 3
O
Orange-yellow viscous liquid (Yield 61%), 1H
NMR (CDCl3, 300 MHz): 7.40 (2H, d, J = 8.30 Hz), 6.92 (2H, d, J = 7.80 Hz), 6.73 (1H, s),
6.56 (1H, s), 6.49-6.30 (4H, m), 6.06 (1H, s), 6.05 (1H, d, J = 7.80 Hz), 5.90 (1H, d, J = 4.85
Hz), 5.70 (1H, d, J = 8.40 Hz ), 4.80-4.75 (2H, m), 4.19-4.02 (4H, m), 3.40 (2H, d, J = 5.10
Hz), 3.30 (2H, d, J = 5.11 Hz), 2.60 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 188.9, 151.4,
151.0, 150.0, 149.5, 147.7, 145.0, 144.7, 143.7, 137.6, 136.0, 135.0, 133.6, 130.7, 128.6, 127.7,
125.1, 124.0, 123.7, 122.7, 120.2, 118.4, 116.2, 113.7, 111.5, 103.4, 70.0, 56.3 and 44.5.
HRMS-ESI: m/z [M+H]+ for C31H27ClN2O3, calculated 511.6759; observed 511.6782.
2.4.11. General procedure for the synthesis of heterocyclic chalcone derivative (41;
Table 5)
In a 100 mL round bottom flask, mixture of 9 (1.5 mmol), phenylhydrazine hydrochloride (4.5
mmol) and sodium acetate (0.25 mmol) was taken. To this mixture, added 15 mL of aq. acetic
acid (HAc/H2O; 2:1) and refluxed the contents for 8-10 hrs till the starting was consumed
(monitored by TLC). Thereafter the reaction mixture was cooled and poured in ice cold water.
The obtained precipitates were filtered, washed with water till neutral pH and recrystallized
from alcohol to afford the desired compound whose structure was confirmed through NMR and
mass spectrometry.
Synthesis of allylated chalcones… Chapter 2
168
5-(4-(allyloxy)-3-methoxyphenyl)-3-(4-chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole
(compound 41, Table 5)
NN
ClOOCH3 Creamish solid (Yield 60%) m.p. 116-121°C, 1H NMR
(CDCl3, 300 MHz): 7.68 (2H, dd, J = 1.69, 1.70 Hz), 7.38 (2H, dd, J = 1.71, 1.67 Hz), 7.24-
7.18 (2H, m), 7.11 (2H, d, J = 8.22 Hz), 6.86 (4H, d, J = 6.03 Hz), 6.17-6.06 (1H, m), 5.44-5.28
(2H, m), 4.62 (2H, d, J = 4.46 ), 3.83 (3H, s), 3.17 (1H, t, J = 1.50 Hz), 1.60 (2H, s); 13C NMR
(CDCl3, 75.4 MHz): 150.5, 147.9, 146.1, 145.3, 135.7, 134.7, 133.7, 131.7, 129.3, 129.2,
127.3, 119.9, 118.4, 114.0, 109.5, 70.3, 65.2, 56.4 and 43.9. HRMS-ESI: m/z [M+H]+ for
C25H23ClN2O2, calculated 419.6449; observed 419.6456.
2.4.12. General procedure for the synthesis of heterocyclic chalcone derivative (42; Table
5)
In a 100 mL round bottom flask, mixture of 9 (1.5 mmol), guanidine hydrochloride (1.5 mmol)
and potassium hydroxide (5 mmol) was taken in ethanol (25 mL). The contents were refluxed
for 6 h till the starting was consumed (monitored by TLC). Thereafter, the organic layer was
evaporated in vacuo and the product was recrystallized from hexane-alcohol system whose
structure was confirmed through NMR and mass spectrometry.
4-(4-(allyloxy)-3-methoxyphenyl)-6-(4-chlorophenyl)pyrimidin-2-amine (compound 42,
Table 5)
N N
ClOOCH3
NH2
Creamish solid (Yield 82%) m.p. 184-186°C, 1H NMR
(CDCl3, 300 MHz): 8.02 (2H, d, J = 7.73 Hz), 7.72 (1H, s), 7.61 (1H, d, J = 8.43 ), 7.49 (2H,
d, J = 7.73 Hz ), 7.38 (1H, s), 6.99 (1H, d, J = 8.31 Hz), 6.17-6.06 (1H, m), 5.48-5.29 (4H, m),
4.71 (2H, d, J = 4.46 Hz), 4.01 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 166.3, 165.1, 163.9,
150.7, 150.0, 136.9, 136.7, 133.3, 130.9, 129.4, 128.8, 120.4, 118.8, 113.2, 110.7, 103.7, 70.2
Synthesis of allylated chalcones… Chapter 2
169
and 56.5. HRMS-ESI: m/z [M+H]+ for C20H18ClN3O2, calculated 368.6090; observed
368.6063.
2.4.13. General procedure for the synthesis of bis(dimeric) chalcones (43-45; Table 6)
To a solution of diacetyl benzene (1.5 mmol) in ethanol, sodium hydroxide (2 mmol) was
added and the contents were stirred for 3-5 min. Thereafter, substituted aldehyde (1b or 3b or
12b; 3 mmol) in ethanol (10 mL) was added drop wise. The reaction mixture was stirred at
40oC for 6-8 h till completion of starting material (monitored by TLC). The reaction mixture
was vacuum evaporated to remove the organic solvent and poured in cold water. The obtained
precipitates were washed with dilute HCl, excess of water, methanol, dried in air and finally
recrystallized with methanol to obtain pure chalcones whose structures were confirmed by
NMR and mass spectroscopy.
(2E,2'E)-1,1'-(1,3-phenylene)bis(3-(3-allyl-4,5-dimethoxyphenyl)prop-2-en-1-one
(compound 43, Table 6)
OCH3
OCH3OCH3
H3CO
OO
Yellow viscous liquid (Yield 68%), 1H
NMR (CDCl3, 300 MHz): 8.63 (1H, s), 8.24 (2H, d, J = 7.73 Hz), 7.83 (2H, d, J = 15.69 Hz),
7.68 (1H, t, J = 7.73 Hz), 7.49 (2H, d, J = 15.69 Hz), 7.13 (4H, d, J = 7.70 Hz), 6.04-5.95 (2H,
m), 5.12-5.07 (4H, m), 3.94 (6H, s), 3.88 (6H, s), 3.45 (4H, d, J = 6.50 Hz); 13C NMR (CDCl3,
75.4 MHz): 190.3, 153.4, 150.1, 146.2, 139.2, 137.1, 134.8, 132.7, 130.7, 129.4, 128.6,
124.0, 121.0, 116.5, 110.6, 61.2, 56.3 and 34.5. HRMS-ESI: m/z [M+H]+ for C34H34O6,
calculated 539.2694; observed 539.2683.
(2E,2'E)-1,1'-(1,3-phenylene)bis(3-(4-(allyloxy)-3-methoxyphenyl)prop-2-en-1-one
(compound 44, Table 6)
OCH3
OOCH3
O
OO
Bright yellow solid (Yield 71%), m.p. 63-
65°C, 1H NMR (CDCl3, 300 MHz): 8.64 (1H, s), 8.25 (2H, s), 7.86 (2H, dd, J = 5.68, 5.70
Hz), 7.66 (1H, t, J = 7.71 Hz ), 7.49 (2H, dd, J = 5.70, 5.73 Hz), 7.29-7.20 (4H, m), 6.95 (2H, t,
Synthesis of allylated chalcones… Chapter 2
170
J = 7.68 Hz ), 6.17-6.05 (2H, m), 5.49-5.33 (4H, m), 4.70 (4H, s), 3.99 (6H, s); 13C NMR
(CDCl3, 75.4 MHz): 190.3, 151.1, 150.1, 146.3, 139.3, 133.1, 132.6, 129.4, 128.6, 128.3,
123.7, 120.0, 118.9, 113.4, 111.1, 70.2 and 56.5. HRMS-ESI: m/z [M+H]+ for C32H30O6,
calculated 511.2382; observed 511.2347.
(2E,2'E)-1,1'-(1,3-phenylene)bis(3-(3,4-bis(allyloxy)phenyl)prop-2-en-1-one (compound
45, Table 6)OO
OOO
O
Yellow solid (Yield 75%) m.p. 189-190°C, 1H
NMR (CDCl3, 300 MHz): 8.62 (1H, s), 8.22 (2H, d, J = 7.66 Hz), 7.83 (2H, d, J = 15.56 Hz),
7.68 (1H, t), 7.45 (2H, d, J = 15.56 Hz), 7.28-7.23 (4H, m), 6.94 (2H, d, J = 8.11 Hz), 6.82-6.04
(4H, m), 5.50 (4H, dd, J = 6.86, 6.87 Hz), 5.35 (4H, d, J = 10.46 Hz), 4.68 (8H, s); 13C NMR
(CDCl3, 75.4 MHz): 190.2, 151.6, 149.1, 146.2, 139.3, 133.5, 133.2, 132.6, 129.4, 128.6,
128.2, 123.9, 120.0, 118.5, 118.4, 113.8, 113.7, 70.5 and 70.1. HRMS-ESI: m/z [M+H]+ for
C36H34O6, calculated 563.2694; observed 563.2651.
2.4.14. General procedure for the synthesis of bis(dimeric) chalcone (46; Table 6)
To a solution of terephthaldehyde (1.5 mmol) in ethanol, sodium hydroxide (2 mmol) was
added and the contents were stirred for 3-5 min. Thereafter, substituted acetophenone (8b; 3
mmol) in ethanol (10 mL) was added drop wise. The reaction mixture was stirred at 40oC till
for 6-8 h completion of starting material (monitored by TLC). The reaction mixture was
vacuum evaporated to remove the organic solvent and poured in cold water. The obtained
precipitates were washed with dilute HCl, excess of water, methanol, dried in air and finally
recrystallized with methanol to obtain pure chalcone whose structure was confirmed by NMR
and mass spectroscopy.
Synthesis of allylated chalcones… Chapter 2
171
(2E,2'E)-3,3'-(1,4-phenylene)bis(1-(4-(allyloxy)phenyl)prop-2-en-1-one (compound 46,
Table 6)
O
O
O
O
Yellow solid (Yield 68%) m.p. 208-210°C,1H NMR (CDCl3, 300 MHz): 8.09 (2H, d, J = 8.89 Hz), 8.07 (2H, d, J = 8.90 Hz), 7.96 (2H,
d, J = 8.87 ), 7.83 (1H, d, J = 15.67 Hz), 7.69 (2H, d, J = 5.58 Hz), 7.58-7.49 (3H, m), 7.04
(2H, d, J = 8.87 Hz), 6.97 (2H, d, J = 8.89 Hz), 6.11-6.01 (2H, m), 5.36-5.32 (4H, m), 4.65
(4H, d, J = 4.46 Hz); 13C NMR (CDCl3, 75.4 MHz): 189.1, 163.5, 145.9, 133.5, 132.7, 130.9,
128.9, 126.7, 122.2, 118.7, 114.9 and 69.3. HRMS-ESI: m/z [M+H]+ for C30H26O4, calculated
451.2082; observed 451.2058.
2.4.15. General procedure for the synthesis of bis(dimeric) chalcone via 14b (47; Table
6)
a) Synthesis of 4-allyloxy-2-hydroxyacetophenone (14b)
To a 250 mL round bottom flask containing 2,4-dihydroxy acetophenone (11a) (1.9 mmol) in
dry acetone (20 mL), allyl bromide (1.9 mmol) and anhydrous K2CO3 (3.8 mmol) were added.
The remaining procedure was similar to that described in step (a) of section 2.4.2. The desired
compound obtained after column chromatography over silica gel with hexane-ethyl acetate
(9:1) was characterized by 1H & 13C NMR and HRMS data.
4-allyloxy-2-hydroxyacetophenone (14b)
O OH
O
Pale yellow viscous liquid (Yield 65%), 1H NMR (CDCl3, 300 MHz):
12.73 (1H, s), 7.65 (1H, d, J = 8.85 Hz), 6.48-6.42 (2H, m), 6.08-5.99 (1H, m), 5.46-5.30
(2H, m), 4.58-4.56 (2H, m), 2.56 (3H, s); 13C NMR (CDCl3, 75.4 MHz): 202.9, 165.6, 165.4,
132.7, 132.6, 118.7, 114.4, 108.4, 102.1, 69.3 and 26.6. HRMS-ESI: m/z [M+H]+ for C11H12O3,
calculated 193.0996; observed 193.0984.
(b) Synthesis of chalcone (47)
To a solution of terephthaldehyde (1.5 mmol) in ethanol, sodium hydroxide (2 mmol) was
added and the contents were stirred for 3-5 min. Thereafter, substituted acetophenone (14b; 3
Synthesis of allylated chalcones… Chapter 2
172
mmol) in ethanol (10 mL) was added drop wise. The reaction mixture was stirred at 40oC till
for 6-8 h completion of starting material (monitored by TLC). The reaction mixture was
vacuum evaporated to remove the organic solvent and poured in cold water. The obtained
precipitates were washed with dilute HCl, excess of water, methanol, dried in air and finally
recrystallized with methanol to obtain pure chalcone whose structure was confirmed by NMR
and mass spectroscopy.
(2E,2'E)-3,3'-(1,4-phenylene)bis(1-(4-(allyloxy)-2-hydroxyphenyl)prop-2-en-1-one
(compound 47, Table 6)
O
O
HO O
OHO
Bright yellow solid (Yield 70%)
m.p. 192-194°C, 1H NMR (CDCl3, 300 MHz): 13.38 (2H, s), 7.93-7.85 (4H, m), 7.72-7.62
(6H, m), 6.57-6.51 (4H, m), 6.14-6.00 (2H, m), 5.44 (4H, dd, J = 17.26, 10.49 Hz), 4.63 (4H, d,
J = 5.31 Hz); 13C NMR (CDCl3, 75.4 MHz): 191.9, 167.1, 165.8, 143.5, 137.3, 132.5, 131.6,
129.5, 121.9, 118.9, 114.6, 108.7, 102.4 and 69.5. HRMS-ESI: m/z [M+H]+ for C30H26O6,
calculated 483.2070; observed 483.2049.
2.5. References
Alaoui, M.A., Gayral, P. and Kirkiacharian, S. (1993). Research of antiparasitic agents:
1(nitrophenyl)-3-(methyl-3-indolyl)-prop-2-ene-1-ones (nitroindolylchalcones). Annales
pharmaceutiques françaises 51: 260-65.
Alavijeh, M.S., Chishty, M., Qaiser, M.Z. and Palmer A.M. (2005). Drug metabolism and
pharmacokinetics, the blood-brain barrier and central nervous system drug discovery. The
Journal of the American Society for Experimental NeuroTherapeutics 2: 554-71.
Alker, A.P., Lim, P., Sem, R., Shah, N.K., Yi, P., Bouth, D.M., Tsuyuoka, R., Maguire, J.D.,
Fandeur, T., Ariey, F., Wongsrichanalai, C. and Meshnick, S.R. (2007). Pfmdr1 and in vivo
resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border.
The American Journal of Tropical Medicine and Hygiene 76: 641-47.
Synthesis of allylated chalcones… Chapter 2
173
Aponte, J.C., Verástegui, M., Málaga, E., Zimic, M., Quiliano, M., Vaisberg, A.J., Gilman,
R.H. and Hammond, G.B. (2008). Synthesis, cytotoxicity, and anti-Trypanosoma cruzi
activity of new chalcones. Journal of Medicinal Chemistry 51: 6230-34.
Asakawa, M. (1975). Current status of insecticide resistance of agricultural insect pests (in
Japanese). Plant Protection 29: 257-61.
Awasthi, S.K., Mishra, N., Dixit, S.K., Singh, A., Yadav, M., Yadav, S.S. and Rathaur, S.
(2009). Antifilarial activity of 1,3-diarylpropen-1-One: Effect on glutathione-S-transferase,
a phase II detoxification enzyme. The American Society of Tropical Medicine and Hygiene
80: 764-68.
Baniecki, M.L., Wirth, D.F. and Clardy, J. (2007). High-throughput Plasmodium falciparum
growth assay for malaria drug discovery. Antimicrobial Agents and Chemotherapy 51: 716-
23.
Begum, N.A., Roy, N., Laskar, R.A. and Roy, K. (2011). Mosquito larvicidal studies of some
chalcone analogues and their derived products: structure–activity relationship analysis.
Medicinal Chemistry Research 20: 184-91.
Bergström, C.A.S. (2005). In silico predictions of drug solubility and permeability: Two rate-
limiting barriers to oral drug absorption. Basic and clinical pharmacology and toxicology
96: 156-61.
Bhasin, V.K. and Nair, L. (2003). Act now—with caution—for malaria treatments. The Lancet
Infectious Diseases 3: 609.
Bhat, B.A., Dhar, K.L., Puri, S.C., Saxena, A.K., Shammugravel, M. and Qazi, G.N. (2005).
Synthesis and biological evaluation of chalcones and their derived pyrazoles as potential
cytotoxic agents. Bioorganic and Medicinal Chemistry Letters 15: 3177-80.
Boeck, P., Falcão, C.A.B., Leal, P.C., Yunes, R.A., Filho, V.C., Terres-Santos, E.C. and Rossi-
Bergman, B. (2006). Synthesis of chalcone analogues with increased antileishmanial
activity. Bioorganic and Medicinal Chemistry 14: 1538-45.
Boumendjel, A., Boccard, J., Carrupt, P.A., Nicolle, E., Blanc, M., Geze, A., Choisnard, L.,
Wouessidjewe, D., Matera, E.L. and Dumontet, C. (2008). Antimitotic and antiproliferative
activities of chalcones: Forward structure-activity relationship. Journal of Medicinal
Chemistry 51: 2307-10.
Synthesis of allylated chalcones… Chapter 2
174
Bruno, J.M., Feachmen, R., Godal, T., Nchinda, T., Ogilvie, B., Mons, B., Mshana, R., Radda,
G., Samba, E., Schwartz, M., Varmus, H., Diallo, S., Doumbo, O., Greenwood, B., Kilama,
W., Miller, L.H. and Dasilva, L.P. (1997). The spirit of Dakar: A call for action on malaria.
Nature 386: 541.
Buss, A.D. and Waigh, R.D. (1995). Natural products as leads for new pharmaceuticals. In:
Wolff, M.E. (ed.) Burger’s medicinal chemistry and drug discovery. pp 983-1033. John
Wiley and Sons, New York.
Cabrera, M., Simoens, M., Falchi, G., Lavaggi, M.L., Piro, O.E., Castellano, E.E., Vidal, A.,
Azqueta, A., Monge, A., Lopez de Cerain, A., Sagrera, G., Seoane, G., Cerecetto, H. and
Gonzalez, M. (2007). Synthetic chalcones, flavanones, and flavones as antitumoral agents:
Biological evaluation and structure-activity relationships. Bioorganic and Medicinal
Chemistry 15: 3356-67.
Capinera, J.L. (2001). Handbook of vegetable pests. pp 729. Academic Press, New York.
Carroll, A.R., Fechner, G.A., Smith, J., Guymer, G.P. and Quinn R.J. (2008). Prenylated
dihydrochalcones from Boronia bipinnata that inhibit the malarial parasite enzyme target
hemoglobinase II. Journal of Natural Products 71: 1479-80.
Casteel, D.A. (1997). Antimalarial agents. In: Wolff, M.E. (ed). Burger’s medicinal chemistry
and drug discovery. pp 3-91. John Wiley and Sons, New York.
Chen, M., Christensen, S.B., Zhai, L., Rasmussen, M.H., Theander, T.G., Frøkjaer, S.,
Steffansen, B., Davidsen, J. and Kharazmi, A. (1997). The novel oxygenated chalcone, 2,4-
dimethoxy-4'-butoxychalcone, exhibits potent activity against human malaria parasite
Plasmodium falciparum in vitro and rodent parasites Plasmodium berghei and Plasmodium
yoelii in vivo. Journal of Infectious Diseases 176: 1327-33.
Chen, M., Theander, T.G., Christensen, S.B., Hviid, L., Zhai, L. and Kharazmi, A. (1994).
Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria
parasite Plasmodium falciparum and protects mice from P. yoelii infection. Antimicrobial
Agents and Chemotherapy 38: 1470-75.
Christensen, S.B. and Kharazmi, A. (2001). Antimalarial natural products. In: Tringali, C. (ed).
Bioactive compounds from natural sources. pp 379-432. Taylor and Francis, London.
Corbett, J., Herrera, L., Gonzalez, J., Cubilla, L., Capson, T.L., Coley, P.D., Kursar, T.A.,
Romero, L.I. and Ortega-Barria, E. (2004). A novel DNA based microfluorometric method
Synthesis of allylated chalcones… Chapter 2
175
to evaluate antimalarial drug activity. The American Journal of Tropical Medicine and
Hygiene 70: 119-24.
Cragg, G.M., Newmann, D.J. and Snader, K.M. (1997). Natural products in drug discovery and
development. Journal of Natural Products 60: 52-60.
Das, B.P., Begum, N.A., Choudhury, D.N. and Banerji, J. (2005). Larvicidal studies of
chalcones and their derivatives. Journal of Indian Chemical Society 82: 161-64.
Day, K.P. (1998). Malaria: A global threat. In: Krause, R.M. (ed). Emerging infections. pp 463-
97. Academic Press, New York.
de Vries, P.J. and Dien, T.K. (1996). Clinical pharmacology and therapeutic potential of
artemisinin and its derivatives in the treatment of malaria. Drugs 52: 818-36.
Desjardins, R.E., Canfield, C.J., Haynes, J.D. and Chulay, J.D. (1979). Quantitative assessment
of antimalarial activity in vitro by a semiautomated micro dilution technique. Antimicrobial
Agents and Chemotherapy 16: 710-18.
Dominguez, J.N., Leon, C., Rodrigues, J., De Dominguez, N.G., Gut, J. and Rosenthal, P.J.
(2005). Synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives.
Journal of Medicinal Chemistry 48: 3654-58.
Dondorp, A.M., Nosten, F., Yi, P., Das, D., Phyo, A.P., Tarning, J., Lwin, K.M., Ariey, F.,
Hanpithakpong, W., Lee, S.J., Ringwald, P., Silamut, K., Imwong, M., Chotivanich, K.,
Lim, P., Herdman, T., An, S.S., Yeung, S., Singhasivanon, P., Day, N.P.J., Lindegardh, N.,
Socheat, D. and White, N.J. (2009). Artemisinin resistance in Plasmodium falciparum
malaria. The New England Journal of Medicine 361: 455-67.
Druilhe, P., Moreno, A., Blanc, C., Basseur, P.H. and Jacquier, P. (2001). A colorimetric in
vitro drug sensitivity assay for Plasmodium falciparum based on a highly sensitive double-
site lactate dehydrogenase antigen-capture enzyme-linked immunosorbent assay. The
American Journal of Tropical Medicine and Hygiene 64: 233-41.
Edwards, M.L., Stemerick, D.M. and Sunkara, P.S. (1990). Chalcones: a new class of
antimitotic agents. Journal of Medicinal Chemistry 33: 1948-54.
Egan, T.J., Hunter, R., Kinchella, C.H., Marques, H.M., Misplon, A. and Walden, J.C. (2000).
Structure-function relationships in aminoquinolines: Effect of amino and chloro groups on
quinoline−hematin complex formation, inhibition of β-hematin formation and
antiplasmodial activity. Journal of Medicinal Chemistry 43: 283-91.
Synthesis of allylated chalcones… Chapter 2
176
Enserink, M. (2008). Malaria: signs of drug resistance rattle experts, trigger bold plan. Science
322: 1776.
Ertl, P., Rohde, B. and Selzer, P. (2000). Fast calculation of molecular polar surface area as a
sum of fragment based contributions and its application to the prediction of drug transport
properties. Journal of Medicinal Chemistry 43: 3714-17.
Eskenazi, B., Bradman, A. and Castorina, R. (1999) Exposures of children to organophosphate
pesticides and their potential adverse health effects. Environmental Health Perspectives
107: 409-13.
Facer, C.A. and Tanner, M. (1997). Clinical trials of malaria vaccines: Progress and prospects.
Advances in Parasitology 39: 2-68.
Frölich, S., Schubert, C., Bienzle, U. and Jenett-Siems, K. (2005). In vitro antiplasmodial
activity of prenylated chalcone derivatives of hops (Humulus lupulus) and their interaction
with haemin. Journal of Antimicrobial Chemotherapy 55: 883-87.
Fu, S. and Xiao, S.H. (1991). Pyronaridine: A new antimalarial drug. Parasitology Today 7:
310-13.
Gautam, N. and Chourasia, O.P. (2010). Synthesis, antimicrobial and insecticidal activity of
some new cinnoline based chalcones and cinnoline based pyrazoline derivatives. Indian
Journal of Chemistry B 49: 830-35.
Go, M.L., Liu, M., Wilairat, P., Rosenthal, P.J., Saliba, K.J. and Kirk, K. (2004).
Antiplasmodial chalcones inhibit sorbitol-induced hemolysis of Plasmodium falciparum
infected erythrocytes. Antimicrobical Agents and Chemotherapy 48: 3241-45.
Göker, H., Boykin, D.W. and Yildiz, S. (2005). Synthesis and potent antimicrobial activity of
some novel 2-phenyl or methyl-4H-1-benzopyran-4-ones carrying amidinobenzimidazoles.
Bioorganic and Medicinal Chemistry 13: 1707-14.
Greenwood, B.M. (1997). Malaria transmission and vector control. Parasitology Today 13: 90-
91.
Greenwood, B. and Mutabingwa, T. (2002). Malaria in 2002. Nature 415: 670-72.
Hans, R.H., Guantai, E.M., Lategan, C., Smith, P.J., Wan, B., Franzblau, S.G., Gut, J.,
Rosenthal, P.J. and Chibale, K. (2010). Synthesis, antimalarial and antitubercular activity of
acetylenic chalcones. Bioorganic and Medicinal Chemistry Letters 20: 942-44.
Synthesis of allylated chalcones… Chapter 2
177
Henderson, M.C., Miranda, C.L., Stevens, J.F., Deinzer, M.L. and Buhler, D.R. (2000). In vitro
inhibition of human P450 enzymes by prenylated flavonoids from hops, Humulus lupulus.
Xenobiotica 30: 235-51.
Hider, R.C. and Liu, Z.D. (1997). The treatment of malaria with iron chelators. Journal of
Pharmacy and Pharmacology 49: 59-64.
Hoffman, S.L., Subramanian, M.G., Collins, F.H. and Venter, J.C. (2002). Plasmodium, human
and Anopheles genomics and malaria. Nature 415: 702-09.
Jain, A.C., Lal, P. and Seshadri, T.R. (1970). A study of nuclear prenylation of β-
resacetophenone—II: Synthesis of bavachalcone, 4′-O-methylbavachalcone and bavachin.
Tetrahedron 26: 2631-35.
Jayaraman, K.S. (1997). India plans $200 million attack on malaria. Nature 386: 536.
Johnson, D.R. (1953). Plutella maculipennis resistance to DDT in Java. Journal of Economic
Entomology 46: 176-76(1)
Kapoor, V.K. and Kumar, K. (2005). Recent advances in the search of newer antimalarial
agents. In: King, F.D. and Lawton, G. (eds) Progress in medicinal chemistry. Vol 43. pp
189-237. Elsevier.
Kassel, D.B. (2004). Applications of high-throughput ADME in drug discovery. Current
Opinion in Chemical Biology 8: 339-45.
Kaur, K., Jain, M., Kaur, T. and Jain R. (2009). Antimalarials from nature. Bioorganic and
Medicinal Chemistry 17: 3229-56.
Kaur, K., Jain, M., Reddy, R.P. and Jain, R. (2010). Quinolines and structurally related
heterocycles as antimalarials. European Journal of Medicinal Chemistry 45: 3245-64.
Kesten, S.J., Degnan, M.J., Hung, J., McNamara, D.J., Ortwine, D.F., Uhlendorf, S.E. and
Werbel, L. (1992). Antimalarial drugs. Synthesis and antimalarial properties of 1-imino
derivatives of 7-chloro-3-substituted-3,4-dihydro-1,9(2H,10H)-acridinediones and related
structures. Journal of Medicinal Chemistry 35: 3429-47.
Khalid, S.A., Friedrichsen, G.M., Kharazmi, A., Theander, T.G., Olsen, C.E. and Christensen,
S.B. (1998). Limonoids from Khaya senegalensis. Phytochemistry 49: 1769-72.
Khan, M.S.Y., Sharma, S. and Husain, A. (2002). Synthesis and antibacterial evaluation of new
flavonoid derivatives from 4,6-diacetyl resorcinol. Science Pharmacy 70: 287-94.
Synthesis of allylated chalcones… Chapter 2
178
Kromann, H., Larsen, M., Boesen, T., Schønning, K. and Nielsen, S.F. (2004). Synthesis of
prenylated benzaldehydes and their use in the synthesis of analogues of licochalcone A.
European Journal of Medicinal Chemistry 39: 993-1000.
Kumar, R., Mohanakrishnan, D., Sharma, A., Kaushik, N.K., Kalia, K., Sinha, A.K. and Sahal,
D. (2010). Reinvestigation of structure-activity relationship of methoxylated chalcones as
antimalarials: Synthesis and evaluation of 2,4,5-trimethoxy substituted patterns as lead
candidates derived from abundantly available natural β-asarone. European Journal of
Medicinal Chemistry 45: 5292-301.
Kumar, R., Sharma, P., Shard, A., Tewary, D.K., Nadda, G. and Sinha, A.K. (2011). Chalcones
as promising pesticidal agents against diamondback moth (Plutella xylostella): microwave-
assisted synthesis and structure–activity relationship. Medicinal Chemistry Research DOI
10.1007/s00044-011-9602-8.
Kumar, S., Kaslow, D.C. and Hoffman, S.L. (1999). An overview of malaria vaccine
development efforts. Vaccines 133: 397-442.
Kumar V., Mahajan, A. and Chibale, K. (2009). Synthetic medicinal chemistry of selected
antimalarial natural products. Bioorganic and Medicinal Chemistry 17: 2236-75.
Lévai, A. (2005). Synthesis of chlorinated 3,5-diaryl-2-pyrazolines by the reaction of
chlorochalcones with hydrazines. Arkivoc ix: 344-52.
Li, R., Kenyon, G.L., Cohen, F.E., Chen, X.W., Gong, B.Q., Dominguez, J.N., Davidson, E.,
Kurzban, G., Miller, R.E. and Nuzum, E.O. (1995). In vitro antimalarial activity of
chalcones and their derivatives. Journal of Medicinal Chemistry 38: 5031-37.
Lim, G.S. (1986). Biological control of diamondback moth. In: Talekar, N.S. and Griggs, T.D.
(eds) Diamondback Moth Management. pp 159-71. Proceedings of the First International
Workshop, Asian Vegetable Research and Development Center, Shanhua, Taiwan.
Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (1997). Experimental and
computational approaches to estimate solubility and permeability in drug discovery and
development settings. Advanced Drug Delivery Reviews 23: 3-25.
Liu, M., Wilairat, P. and Go, M.L. (2001). Antimalarial alkoxylated and hydroxylated
chalcones: Structure-activity relationship analysis. Journal of Medicinal Chemistry 44:
4443-52.
Synthesis of allylated chalcones… Chapter 2
179
Liu, M., Wilairat, P., Croft, S.L., Tan, A.L.C. and Go, M.L. (2003). Structure–activity
relationships of antileishmanial and antimalarial chalcones. Bioorganic and Medicinal
Chemistry 11: 2729-38.
Luxemburger, C., Brockman, A., Silamut, K., Nosten, F., van Vugt, M., Gimenez, F.,
Chongsuphajaisiddhi, T. and White, N.J. (1998). Two patients with falciparum malaria and
poor in vivo responses to artesunate. Transactions of the Royal Society of Tropical Medicine
and Hygiene 92: 668-69.
Luzzi, G.A. and Peto, T.E.A. (1993). Adverse effects of antimalarials: An update. Drug Safety
8: 295-311.
Mabeza, G.F., Loyevsky, M., Gordeuk, V.R. and Weiss, G. (1999). Iron chelation therapy for
malaria: A review. Pharmacology and Therapeutics 81: 53-75.
Maitrejean, M., Comte, G., Barron, D., El Kirat, K., Conseil, G. and Di Pietro, A. (2000). The
flavanolignan silybin and its hemisynthetic derivatives, a novel series of potential
modulators of p-glycoprotein. Bioorganic and Medicinal Chemistry Letters 10: 157-60.
Makler, M.T., Ries, J.M., Williams, J.A., Bancroft, J.E., Piper, R.C., Gibbins, B.L. and
Hinrichs, D.J. (1993). Parasite lactate dehydrogenase as an assay for Plasmodium
falciparum drug sensitivity. The American Journal of Tropical Medicine and Hygiene 48:
739-41.
Mannhold, R., Poda, G.I., Ostermann, C. and Tetko, I.V. (2009). Calculation of molecular
lipophilicity: State-of-the-art and comparison of logP methods on more than 96,000
compounds. Journal of Pharmaceutical Sciences 98: 861-93.
Manohar, S., Khan, S.I. and Rawat, D.S. (2010). Synthesis, antimalarial activity and
cytotoxicity of 4-aminoquinoline–triazine conjugates. Bioorganic and Medicinal Chemistry
Letters 20: 322-25.
Mehta, A.G. and Patel, A.A. (2009). Studies on novel N4-[4,6-diaryl-2-pyrimidinyl]-7-chloro-
4-quinolinamine and their microbicidal efficacy. E-Journal of Chemistry 6(S1): S406-12
(http://www.e-journals.net).
Meinnel, T. (2000). Peptide deformylase of eukaryotic protists: A target for new antiparasitic
agents? Parasitology Today 16: 165-68.
Synthesis of allylated chalcones… Chapter 2
180
Mendis, K.N., Sina, B.J., Marchesini, P. and Carter, R. (2001). The neglected burden of
Plasmodium vivax malaria. The American Journal of Tropical Medicine and Hygiene 64:
97-106.
Meshnick, S.R. (2002). Artemisinin: mechanisms of action, resistance and toxicity.
International Journal for Parasitology 32: 1655-60.
Milligan, S.R., Kalita, J.C., Pocook, V., Van de Kauter, V., Stevens, J.F., Deinzer, M.L., Rong,
H. and De Keukeleire, D. (2000). The endocrine activities of 8-prenylnaringenin and related
hop (Humulus lupulus L.) flavonoids. The Journal of Clinical Endocrinology and
Metabolism 85: 4912-15.
Miranda, C.L., Aponso, G.L., Stevens, J.F., Deinzer, M.L. and Buhler, D.R. (2000). Prenylated
chalcones and flavanones as inducers of quinone reductase in mouse Hepa 1c1c7
cells. Cancer Letters 149: 21-29.
Mishra, N., Arora, P., Kumar, B., Mishra, L.C., Bhattacharya, A., Awasthi, S.K. and Bhasin,
V.K. (2008). Synthesis of novel substituted 1,3-diaryl propenone derivatives and their
antimalarial activity in vitro. European Journal of Medicinal Chemistry 43: 1530-35.
Mitchel, C.J. (1996). Environmental management for vector control. In: Beaty and Marquardt,
W.C. (eds) The Biology of disease Vectors. pp 492. University of Colorado, Colorado.
Molinspiration Cheminformatics. http://www.molinspiration.com/services/properties.html.
Mukherjee, S., Kumar, V., Prasad, A.K., Raj, H.G., Bracke, M.E., Olsen, C.E., Jain, S.C. and
Parmar, V.S. (2001). Synthetic and biological activity evaluation studies on novel 1,3-
diarylpropenones. Bioorganic and Medicinal Chemistry 9: 337-45.
Murder, M.J. (2000). Magic and medicine. 2nd edn. Oxford University Press, Oxford.
Nalwar, Y.S, Sayyed, M.A., Mokle, S.S., Zanwar, P.R. and Vibhute, Y.B. (2009). Synthesis
and insect antifeedant activity of some new chalcones against Phenacoccus solanopsis.
World Journal of Chemistry 4:123-26.
Narender, T., Shweta, T.K., Rao, M.S., Srivastava, K. and Puri, S.K. (2005). Prenylated
chalcones isolated from Crotalaria genus inhibits in vitro growth of the human malaria
parasite Plasmodium falciparum. Bioorganic and Medicinal Chemistry Letters 15: 2453-55.
Newman, D.J., Cragg, G.M. and Snader, K.M. (2003). Natural products as sources of new
drugs over the period 1981-2002. Journal of Natural Products 66: 1022-37.
Synthesis of allylated chalcones… Chapter 2
181
Nielsen, S.F., Larsen, M.T., Schønning, B.K. and Kromann, H. (2005). Cationic chalcone
antibiotics. Design, synthesis and mechanism of action. Journal of Medicinal Chemistry 48:
2667-77.
Ngameni, B., Watchueng, J., Boyom, F.F., Keumedjio, F., Ngadjui, B.T., Gut, T.J., Abegaz,
B.M. and Rosenthal, P.J. (2007). Antimalarial prenylated chalcones from the twigs of
Dorstenia barteri var. subtriangularis. Arkivoc (xiii): 116-23.
Noedl, H., Werndorfer, W.H., Miller, R.S. and Wongsrichanalai, C. (2002). Histidine rich
protein II, a novel approach to antimalarial drug susceptibility testing. Antimicrobial Agents
and Chemotherapy 46: 1658-64.
Nowakowska, Z. (2007). A review of anti-infective and anti-inflammatory chalcones.
European Journal of Medicinal Chemistry 42: 125-37.
Offman, S.L. (1996). Malaria vaccine development: A multi-immune response approach. ASM
Press, Washington DC.
Olliaro, P. and Wirth, D. (1997). New targets for antimalarial drug discovery. Journal of
Pharmacy and Pharmacology 49: 29-33.
Pandey, R.C. (1998). Prospecting for potentially new pharmaceuticals from natural sources.
Medicinal Research Reviews 18: 333-46.
Peters, W. (1980). In: Kreier, J.P. (ed). Malaria. Vol. 1. pp 160-61. Academic Press, New
York.
Phillips, R.S. (2001). Current status of malaria and potential for control. Clinical Microbiology
Reviews 14: 208-26.
Ping, G., Taiping, H., Rong, G., Qiu C. and Shigui L. (2001). Activity of the botanical
aphicides 1,5-diphenyl-1-pentanone and 1,5-diphenyl-2-penten-1-one on two species of
Aphididnae. Pest Management Science 57: 307-10.
Pinto, D.C.G.A., Silva, A.M.S., Cavaleiro, J.A.S. and Elguero, J. (2003). New bis(chalcones)
and their transformation into bis(pyrazoline) and bis(pyrazole) derivatives. European
Journal of Organic Chemistry 2003: 747-55.
Portet, B., Fabre, N., Roumy, V., Gornitzka, H., Bourdy, G., Chevalley, S., Sauvain, M.,
Valentin, A. and Moulis, C. (2007). Activity-guided isolation of antiplasmodial
dihydrochalcones and flavanones from Piper hostmannianum var. berbicense.
Phytochemistry 68: 1312-20.
Synthesis of allylated chalcones… Chapter 2
182
Posner, G.H., Oh, C.H., Gerena, L. and Milhous, W.K. (1992). Extraordinarily potent
antimalarial compounds. New structurally simple, easily synthesized, tricyclic 1,2,4-
trioxanes. Journal of Medicinal Chemistry 35: 2459-67.
Price, R.N., Nosten, F., Luxemburger, C., van Vugt, M., Phaipun, L., Chongsuphajaisiddhi, T.
and White, N.J. (1997). Artesunate/mefloquine treatment of multi-drug resistant falciparum
malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 91: 574-77.
Rahaman, Sk.A., Pasad, Y.R., Kumar, P. and Kumar, B. (2009). Synthesis and anti-histaminic
activity of some novel pyrimidines. Saudi Pharmaceutical Journal 17: 259-64.
Rajasekaran, S., Rao, G.K., Pai, P.N.S. and Ranjan, A. (2011). Design, synthesis, antibacterial
and in vitro antioxidant activity of substituted 2H benzopyran-2-one derivatives.
International Journal of ChemTech Research 3: 555-59.
Rathod, P.K. (1997). Antimalarial agents directed at thymidylate synthase. Journal of
Pharmacy and Pharmacology 49: 65-69.
Ridley, R.G. (1997). Haemoglobin degradation and haem polymerization as antimalarial drug
targets. Journal of Pharmacy and Pharmacology 49: 43-48.
Ridley, R.G. (2002). Medical need, scientific opportunity and the drive for antimalarial drugs.
Nature 415: 686-93.
Rieckmann, K.H., Campbell, G.H., Sax, L.J. and Mrema, J.E. (1978). Drug sensitivity of
Plasmodium falciparum: an in vitro micro technique. Lancet I: 22-23.
Riley, E. (1997). Malaria vaccines: Current status and future prospects. Journal of Pharmacy
and Pharmacology 49: 21-27.
Robert, A. and Meunier, B. (1998) Alkylating properties of antimalarial artemisinin derivatives
and synthetic trioxanes when activated by a reduced heme model. Chemistry-A European
Journal 4: 1287-96.
Rogers, D.H. and Randolph, S.E. (2000). The global spread of malaria in a future, warmer
world. Science 289: 1763-66.
Sandeep, G., Ranganath, Y.S., Bhasker S. and Rajkumar. N. (2009). Synthesis and biological
screening of some novel coumarin derivatives. Asian Journal of Research Chemistry 2: 46-
48.
Senior, K. (1996). Pharmaceuticals from plants: promise and progress. Molecular Medicine
Today 2: 60-64.
Synthesis of allylated chalcones… Chapter 2
183
Shu, Y.Z. (1998). Recent natural products based drug development: A pharmaceutical industry
perspective. Journal of Natural Products 61: 1053-71.
Smilkstein, M., Sriwilaijaroen, N., Kelly, J.X., Wilairat, P. and Riscoe, M. (2004). Simple and
inexpensive fluorescence-based technique for high throughput antimalarial drug screening.
Antimicrobial Agents and Chemotherapy 48:1803-06.
Srinivasan, B., Johnson, T.E., Lad, R. and Xing. C. (2009). Structure-activity relationship
studies of chalcone leading to 3-hydroxy-4,3',4',5'-tetramethoxychalcone and its analogues
as potent nuclear factor KB inhibitors and their anticancer activities. Journal of Medicinal
Chemistry 52: 7228-35.
Stevens, J.F. and Page, J.E. (2004). Xanthohumol and related prenylflavonoids from hops and
beer: To your good health! Phytochemistry 65: 1317-30.
Sun, C.N., Wu, T.K., Chen, J.S. and Lee, W.T. (1986). Insecticide resistance in diamondback
moth management. In: Talekar, N.S. and Griggs, T.D. (eds). Diamondback moth
management. pp 359-71. Proceedings of the First International Workshop, Asian Vegetable
Research and Development Center, Taiwan.
Talekar, N.S. and Shelton, A.M. (1993). Biology, ecology and management of the
diamondback moth. Annual Review of Entomology 38: 275-301.
Talekar, N.S., Yang, H.C., Lee, S.T., Chen, B.S. and Sun, L.Y. (1985). Annotated bibliography
of diamondback Moth. pp 469. Asian Vegetable Research and Development Center,
Shanhua, Taiwan.
Tetko, I.V., Jaroszewicz, I., Platts, J.A. and Kuduk-Jaworska, J. (2008). Calculation of
lipophilicity for Pt (II) complexes: Experimental comparison of several methods. Journal of
Inorganic Biochemistry 102: 1424-37.
Thirunarayanan, G. and Vanangamudi, G. (2011). Synthesis, spectral studies, antimicrobial and
insect antifeedant activities of some substituted styryl 4'-fluorophenyl ketones. Arabian
Journal of Chemistry doi:10.1016/j.arabjc.2010.10.034.
Tomar, V., Bhattacharjee, G., Kamaluddin, Rajakumar, S., Srivastava, K. and Puri, S.K.
(2010). Synthesis of new chalcone derivatives containing acridinyl moiety with potential
antimalarial activity. European Journal of Medicinal Chemistry 45: 745-51.
Trager, W. and Jensen, J.B. (1976). Human malaria parasites in continuous culture. Science
193: 673-75.
Synthesis of allylated chalcones… Chapter 2
184
Tripathi, R.P., Mishra, R.C., Dwivedi, N., Tewari, N. and Verma, S.S. (2005). Current status of
malarial control. Current Medicinal Chemistry 12: 2643-59.
Trivedi, J.C., Bariwal, J.B., Upadhyay, K.D., Naliapara, Y.T., Joshi, S.K., Pannecouque, C.C.,
De Clercq, E. and Shah, A.K. (2007). Improved and rapid synthesis of new coumarinyl
chalcone derivatives and their antiviral activity. Tetrahedron Letters 48: 8472-74.
Viswanadhan, V.N. Ghose, A.K. and Wendoloski, J.J. (2000). Estimating aqueous solvation
and lipophilicity of small organic molecules: A comparative overview of atom/group
contribution methods. Perspectives in Drug Discovery and Design 19: 85-98.
Vogel, S. and Heilmann J. (2008). Synthesis, cytotoxicity, and antioxidative activity of minor
prenylated chalcones from Humulus lupulus. Journal of Natural Products 71: 1237-41.
Wei, B.L., Teng, C.H., Wang, J.P., Won, S.J. and Lin, C.N. (2007). Synthetic 2′,5′-
dimethoxychalcones as G2/M arrest-mediated apoptosis-inducing agents and inhibitors of
nitric oxide production in rat macrophages. European Journal of Medicinal Chemistry 42:
660-68.
Wiley, R.H. (1967). Pyrazoles, pyrazolines, pyrazolidines, indazoles and condensed rings. In:
Weissberger, A. (ed) The chemistry of heterocyclic compounds. Vol 22. pp 180.
Interscience Publishers, New York.
White, J.J.N. (1996). The treatment of malaria. New England Journal of Medicine 335: 800-06.
WHO. (1998). The use of artemisinin and its derivatives as anti-malarial drugs. Report of a
joint CTD/DMP/TDR Informal Consultation. Geneva, 10–12 June. Geneva.
WHO (2010). World malaria report. http://www.who.int/malaria/en.
Woodrow, C.J., Haynes, R.K. and Krishna, S. (2005). Artemisinins. Postgraduate Medical
Journal 81: 71-78.
Wu, X., Wilairat, P. and Go, M.L. (2002). Antimalarial activity of ferrocenyl chalcones.
Bioorganic and Medicinal Chemistry Letters 12: 2299-302.
Xu, B., Pelish, H., Kirchhausen, T. and Hammond, G.B. (2006). Large scale synthesis of the
Cdc42 inhibitor secramine A and its inhibition of cell spreading. Organic and Biomolecular
Chemistry 4: 4149-57.
Yenesew, A., Induli, M., Derese, S., Midiwo, J.O., Heydenreich, M., Peter, M.G., Akala, H.,
Wangui, J., Liyala, P. and Waters, N.C. (2004). Anti-plasmodial flavonoids from the stem
bark of Erythrina abyssinica. Phytochemistry 65: 3029-32.
Synthesis of allylated chalcones… Chapter 2
185
Zhao, Y., Abraham, M.H., Lee, J., Hersey, A., Luscombe, N.C., Beck, G., Sherborne, B. and
Cooper, I. (2002). Rate-limited steps of human oral absorption and QSAR studies.
Pharmaceutical Research 19: 1446-57.
Synthesis of allylated chalcones… Chapter 2
i
NMR spectra of some compoundsO
O
OCH3
Cl
3456789 ppm
1H NMR (in CDCl3) spectrum of (2E)-1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-
yloxy)phenyl]prop-2-en-1-one (9, Table 3)
220 200 180 160 140 120 100 80 60 40 20 ppm
13C NMR (in CDCl3) spectrum of (2E)-1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-
yloxy)phenyl]prop-2-en-1-one (9, Table 3)
Synthesis of allylated chalcones… Chapter 2
ii
12345678910 ppm1H NMR (in CDCl3) spectrum of 5-[3-methoxy-4-(prop-2-en-1-yloxy)benzylidene]-2,2-dimethyl-1,3-
dioxane-4,6-dione (37, Table 5)
220 200 180 160 140 120 100 80 60 40 20 ppm
13C NMR (in CDCl3) spectrum of 5-[3-methoxy-4-(prop-2-en-1-yloxy)benzylidene]-2,2-dimethyl-1,3-
dioxane-4,6-dione (37, Table 5)
OC H3
O O
O
O
O
Synthesis of allylated chalcones… Chapter 2
iii
O
OC H3
O
N C l
N H
10 9 8 7 6 5 4 3 2 1 ppm
1H NMR (in CDCl3 + DMSO-d6) spectrum of E)-3-(4-(allyloxy)-3-methoxyphenyl)-1-(4-((7-
chloroquinolin-4-yl)amino)phenyl)prop-2-en-1-one (39, Table 5)
220 200 180 160 140 120 100 80 60 40 20 ppm
13CNMR (in CDCl3 + DMSO-d6) spectrum of E)-3-(4-(allyloxy)-3-methoxyphenyl)-1-(4-((7-
chloroquinolin-4-yl)amino)phenyl)prop-2-en-1-one (39, Table 5)
5.05.56.06.57.07.58.08.59.09.5 ppm
Synthesis of allylated chalcones… Chapter 2
iv
NN
ClOOCH3
123456789 ppm1H NMR (in CDCl3) spectrum of 5-(4-(allyloxy)-3-methoxyphenyl)-3-(4-chlorophenyl)-1-phenyl-4,5-
dihydro-1H-pyrazole (41, Table 5)
180 160 140 120 100 80 60 40 20 ppm
13C NMR (in CDCl3) spectrum of 5-(4-(allyloxy)-3-methoxyphenyl)-3-(4-chlorophenyl)-1-phenyl-4,5-
dihydro-1H-pyrazole (41, Table 5)
Synthesis of allylated chalcones… Chapter 2
v
N N
ClOOCH3
NH2
3456789 ppm
1H NMR (in CDCl3) spectrum of 4-(4-(allyloxy)-3-methoxyphenyl)-6-(4-chlorophenyl)pyrimidin-2-
amine (42, Table 5)
220 200 180 160 140 120 100 80 60 40 20 ppm
13C NMR (in CDCl3) spectrum of 4-(4-(allyloxy)-3-methoxyphenyl)-6-(4-chlorophenyl)pyrimidin-2-
amine (42, Table 5)
Synthesis of allylated chalcones… Chapter 2
vi
OCH3
OCH3OCH3
H3CO
OO
23456789 ppm
1H NMR (in CDCl3) spectrum of (2E,2'E)-1,1'-(1,3-phenylene)bis(3-(3-allyl-4,5-
dimethoxyphenyl)prop-2-en-1-one (43, Table 6)
220 200 180 160 140 120 100 80 60 40 20 ppm
1H NMR (in CDCl3) spectrum of (2E,2'E)-1,1'-(1,3-phenylene)bis(3-(3-allyl-4,5-
dimethoxyphenyl)prop-2-en-1-one (43, Table 6)