Synthesis of flavonoids based novel tetrahydropyran conjugates (Prins products) and their antiproliferative activity against human cancer cell lines

Article abstract of DOI:10.1016/j.ejmech.2014.01.033

Following our previously reported Prins cyclization strategy, a series of novel and highly functionalized flavonoid based THPs (Prins products) were designed, synthesized and evaluated for their antiproliferative activity. Novel products were afforded in

Full text of DOI:10.1016/j.ejmech.2014.01.033

European Journal of Medicinal Chemistry 75 (2014) 233e246
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis of flavonoids based novel tetrahydropyran conjugates (Prins
products) and their antiproliferative activity against human cancer cell
lines
,
a
b
b
Naseem Ahmed a , Naveen Kumar Konduru , Sarfaraz Ahmad , Mohammad Owais
*
a Department of Chemistry, Indian Institute of Technology, Roorkee 247 667, Uttarakhand, India
b Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Following our previously reported Prins cyclization strategy, a series of novel and highly functionalized
flavonoid based THPs (Prins products) were designed, synthesized and evaluated for their anti-
proliferative activity. Novel products were afforded in excellent yields (72e96%) within 20e90 min at
62 C using flavonoid aldehydes, homoallylic alcohols, p-TSA$H2O (catalyst and reagent) and MS 4 A in
CHCl3. Deprotection of tosyl group was achieved with TFA (catalyst and solvent) at 140 ꢀC to obtain 4-
hydroxytetrahydropyrans and further reaction of 4-hydroxytetrahydropyrans with cinnamoyl chloride
afforded 4-cinnamate tetrahydropyrans under neat condition. Synthesized compounds evaluated against
Received 3 May 2013
Received in revised form
11 January 2014
Accepted 18 January 2014
Available online 25 January 2014
ꢀ
ꢀ
Keywords:
Prins cyclization
human cancer cell lines (Hep3
tivity in vivo. Compounds 3q and 3zb exhibited similar cytotoxicity (IC50 6.6 ꢁ 1.4, 6.9 ꢁ 1.0
respectively) to the reference drug doxorubicin (IC50 7.6 ꢁ 0.9 M) against the MCF-7 cancer cell line.
M) against the Hep3 cell
M, respec-
b
, MCF-7 and Hela), have shown moderate to good antiproliferative ac-
m
M,
Homoallylic alcohols
Flavonoids based tetrahydropyran
conjugates
Antiproliferative activity
Human cancer cell lines
m
Compound 3zb was found equally active as the standard drug (IC50 4.48 ꢁ 2.1
m
b
line and compounds 3c and 3q showed moderate cytotoxicity (IC50 10.40 ꢁ 1.1, 12.9 ꢁ 1.7
m
tively) against the HeLa cell line.
Ó 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction
derivatives that include epicalyxin F, calyxin F, epicalyxin G, calyxin
G, epicalyxin K, calyxin K, calyxin L, calyxin I (Fig.1) have previously
been isolated from the seeds of Alpinia blepharocalyx sp. These
plants are widely distributed in south-western China and their
seeds are commonly used in traditional medicine for the treatment
of various stomach disorders [3]. Many of these natural products
have shown interesting hepatoprotective activity and anti-
proliferative activity against cancer cell lines. For example, epi-
calyxin F is the most potent member of this class and is used as
Despite advances in the multimodal management of a wide
spectrum of human cancers, it remains a major global killer of
human, highlighting the need for improved and targeted specific
therapies. The discovery and development of new drugs that can be
used in the treatment of cancer remains one of the biggest chal-
lenges for the scientific community and the pharmaceutical in-
dustry. Interestingly, nature has proven to be one of the best
sources of molecules that can bind to the cancer specific targets
[1,2]. Thus, the search for new natural molecules, semi-synthetic
and synthetic compounds that display specific activity against
cancer is of great interest. For example, flavonoids based pyran
anti-cancer activity (approx. 1 mM) against human HT-1080 fibro-
sarcoma and murine 26-L5 carcinoma [4]. A high potency of epi-
calyxin F is assumed due to the adduct of flavonoid and pyran
natural moieties in a single molecule.
Functionalized THPs represent a key structural motif in different
natural products and biologically relevant molecules such as cam-
bodianin A [5], (þ)-neopeltolide [6], phorboxazole A & B, oxy-
troflavosides [7], marine toxins and pheromones [8]. They have
screened for many promising biological applications including
in vivo antinociceptive activity, in vitro anti-cancer, anti-hyperten-
sive, anti-bacterial and anti-fungal activities [9e12] as well as
cyclooxygenase-2 and tumor growth inhibitors [13]. The structural
diversity of the pyran core presence in the natural products
Abbreviations: mg, microgram; mL, microliter; mM, micromole; mL, milliliter; mg,
milligram; nm, nanometre; mmol, millimole; MTT, (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide; THP, tetrahydropyran; TFA, trifluoroacetic acid;
ꢀ
CHCl3, chloroform; DCM, dichloromethane; DMSO, dimethyl sulfoxide; MS 4 A,
ꢀ
molecular sieves 4 A.
* Corresponding author. Fax: þ91 1332 285745.
E-mail addresses: nasemfcy@iitr.ac.in, nasemfcy@iitr.ernet.in, naseem2008@
gmail.com (N. Ahmed).
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2014.01.033

234
N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
Fig. 1. Flavonoids based pyran natural products isolated from the Alpinia blepharocalyx.
moieties prompted synthetic chemists for their design and syn-
thesis. Therefore, various reaction strategies have been explored in
the stereoselective synthesis of THPs with proper functionalization.
Among them, the Prins cyclization is found to be the most impor-
tant method for the pyran ring construction in high yield under
mild reaction condition [14e19].
literature procedure [34] by the condensation of aromatic aceto-
phenones and terephthalaldehyde in alkaline ethanol at room
temperature. 4-Tosyloxy THPs were also synthesized following
literature procedure [28] using substituted flavonoid aldehydes,
ꢀ
homoallylic alcohols, p-TSA$H2O (catalyst and reagent) and MS 4 A
at 62 ꢀC in CHCl3. Generally, the products were obtained in high
yields (72e96%) within 20e90 min. Deprotection of the tosyl group
was achieved using trifluoroacetic acid (TFA) at 140 ꢀC to obtain 4-
hydroxy THPs (4aef). The reaction of 4f with cinnamoyl chloride
was achieved under neat conditions to afford 4-cinnamate THP 5, a
mimic of the natural products (þ)-neopeltolide and phorboxazole
A and B.
Similarly, flavonoid compounds occur naturally and are widely
distributed in plants such as vegetables, tea, soya beans, berries and
other fruits. They have exhibited antioxidant and chelating prop-
erties and so have many health promoting effects. Some other ac-
tivities attributed to flavonoids include anti-allergic, anti-cancer,
purely aesthetic and anti-viral properties [20,21]. Due to the bio-
logical relevance of this, we renewed our interest to synthesize
flavonoids-THP adducts via Prins cyclization and developed a ver-
satile synthetic route for the construction of functionalized 2,4,6-
trisubstituted THPs using aromatic aldehydes, homoallylic alco-
3. Pharmacology
The antiproliferative activity of the novel flavonoideTHPs (3ae
zb, 4aef, 5) were evaluated in vitro following the standard proce-
ꢀ
hols and p-TSA$H2O in the presence of MS 4 A.
In Prins cyclization, several acid catalysts (Lewis & Brønsted)
such as TFA, AcOH, Sc(OTf)3, TMSBr, AlCl3, InCl3, HBF4$OEt2, TiBr4,
Fe(III) salts and BF3$OEt2 were used. However, these catalysts were
found to be either ineffective or less effective in the case of flavo-
noids based THP 3 adducts synthesis [22e27]. In continuation of
our interest in developing new methods for the synthesis and acid
catalysis [28e33] reactions, herein we report the synthesis of
highly functionalized flavonoid based THPs and their in vitro anti-
dure
of
MTT
((3-(4,5-Dimethylthiazol-2-yl))-2,5-
diphenyltetrazolium bromide) assay [35] against three different
human cancer cell lines that include human hepatocellular carci-
noma (Hep3b), human breast adenocarcinoma (MCF-7) and human
cervical carcinoma (HeLa). These cell lines were procured from Cell
RepositoryeNational centre for Cell Science, Pune (India). Novel
synthesized compounds were found to be active against these cell
lines. Compounds 3q and 3zb exhibited similar cytotoxic activity
proliferative activity against Hep3
lines.
b, MCF-7 and HeLa cancer cell
(IC50 ¼ 6.6 ꢁ 1.4, 6.9 ꢁ 1.0
doxorubicin (IC50 ¼ 7.6 ꢁ 0.9
(Table 5). Similarly, compound 3zb was found to be equally active
m
m
M respectively) to the reference drug
M) against the MCF-7 cancer cell line
against the Hep3
(IC50 ¼ 4.1 ꢁ 1.1
b
m
cell line (IC50 value 4.48 ꢁ 2.1
mM) as doxorubicin
2. Chemistry
M, Table 5).
We tried to synthesize flavonoid based THPs following the re-
ported protocol [28]. Due to poor solubility of chalcone aldehydes
in DCM, the reaction gave a low yield even after prolonging the
reaction time (Scheme 1). To improve the solubility of chalcone
aldehydes, CHCl3 was used as the solvent at refluxed temperature.
Aromatic homoallylic alcohols (1aef) were prepared following
literature procedure [28], where aromatic aldehydes were treated
with allylic Grignard reagent at ꢂ78 ꢀC under nitrogen atmosphere
for 2 h. Similarly, chalcone aldehydes were prepared following
Scheme 1. Synthesis of (2R,4S,6S)-2-(4-chlorophenyl)-6-(4-((E)-3-(4-bromophenyl)-
3-oxopropenyl)phenyl)-4-tosyloxy THP.

N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
235
4. Results and discussion
(route 2, step 2) to obtain flavone and flavanone based THPs (3q, 3u,
3xez and 3za) in excellent yields (84e88%, Table 2).
4.1. Chemistry
Under optimal reaction conditions, the reaction between 1a and
2n failed to give any Prins product. Therefore, product 3zb was
synthesized by reacting homoallylic alcohol 1a with tereph-
thalaldehyde to afford 3m followed by the addition of 2-(4-oxo-2-
thioxothiazolidin-3-yl) acetic acid in a mixture of acetic acid and
sodium acetate at reflux temperature (Scheme 3).
The possible reaction mechanism for regioselective pyran ring
construction is illustrated in Scheme 4. The first step is proton-
ation of aldehyde carbonyl group with PTSA (Brønsted acid cata-
lyst). Then its reaction with homoallylic alcohol, followed by
intermolecular nucleophilic addition of tosylate group and loss of
Initially, 4-tosyloxy THPs were synthesized using chalcone
aldehyde, homoallylic alcohol, p-TSA$H2O and MS 4 A in dichloro-
ꢀ
methane (DCM) following the reported procedure [28]. However,
due to poor solubility of chalcone aldehydes in DCM, the reactions
gave low yields even after prolonging the reaction time. To improve
the solubility of reactants 1 and 2, the reaction conditions were
optimized by using different solvents (Scheme 1) and temperatures
(Table 1).
Among the solvents (THF, DCM, ACN, CHCl3 and EtOAc) used,
CHCl3 was found to be the best option for our synthetic needs
(Table 1, entry 9). Other solvents like THF, ACN and EtOAc were
equally good in solubility but afforded low yields, possibly due to
their interference with reaction intermediates. All reactions were
therefore performed under optimized reaction conditions, for
example, the tosyloxy THP (3) was obtained in excellent yields
(95%) within 25 min (Scheme 1).
a water molecule, afforded intermediate
delocalization of oxygen lone-pair electrons in
a
-tosyloxyether. The
-tosyloxyether
a
generates an oxo-carbenium ion intermediate after removal of
tosylate group. Further, the nucleophilic addition of in situ
generated tosylate group on tetrahydropyranyl cation resulted in
the formation of substituted 2-aryl-6-flavonoid-4-tosyloxy THPs
(Scheme 4).
To affirm the general applicability of this reaction, a variety of
flavonoid aldehydes (chalcone, flavone and flavanone aldehydes)
were investigated to obtain THPs (3aezb) in high diaster-
eoselectivity and yields (Table 2). It was observed that the sub-
stituents on aromatic rings play an important role on the rate of
reaction and product yields. For example, strong electron-donating
(methyl-, methoxy-, trimethoxy-) groups on homoallylic alcohols
afforded the corresponding THPs (3r, 3s, and 3t) in moderate yields
(72e80%, Table 2). Conversely, the electron-withdrawing groups
such as Cl and Br or even without substituted homoallylic alcohols
gave THPs (3aeq and 3ueza) in high yields (84e96%, Table 2). This
might be due to the fact that the electron-donating groups on ar-
omatic homoallylic alcohol stabilize the cation of oxo-carbenium
ions. Therefore, it undergoes oxonia-Cope rearrangement which
increases the possibility of side products. Conversely, the electron-
withdrawing groups destabilize the oxo-carbenium ions and so
reduced the side products [36,37]. In the case of substituents on
flavonoid aldehydes, there are no significant substituent effects in
the product yields (Table 2, products 3aec, 3e, 3hej, 3peq and 3u).
Flavone and flavanone based THPs (Table 2, products 3uev, 3xe
za) were obtained in good yield via route 2 rather than route 1
(Scheme 2). In route 1 (step 2) isomerization of 20-hydroxychalcone
THPs to flavone and flavanone THPs failed to give the desired
products. To obtain flavone and flavanone based THPs, first flavone
and flavanone aldehydes were synthesized via route 2 followed by
the reaction with homoallylic alcohols using Prins cyclization
The assigned structures of new products (3aezb) were estab-
lished from their spectroscopic data (IR, HRMS, 1H, 13C and 2D
NMR). For example, compound 3f was obtained as a yellow solid.
The IR spectrum of 3f showed absorptions at 1657, 1360, 1201, and
1181 cmꢂ1 for carbonyl, CeOeC and eSO2e bonds as symmetrical
and asymmetrical stretchings respectively. The HRMS of 3f sup-
ported a molecular composition of C34H31BrNaO5S (M þ Na)þ,
representing 19 degrees of unsaturation. In the 1H and 13C NMR
spectra of 3f, two methyl signals resonating at dH 2.4, and 2.42 and
dC 21.56 were assigned to C-11, and C-12, respectively. Two oxy-
methine groups at dH 4.56 and 4.51 and two asymmetrical
methylene group resonating at dH 1.78, and 2.30 assigned to H-2,
H-6, H-3a/H-5a, H-3e/H-5e, respectively, suggested the presence
of a THP ring [2]. The relative downfield shift of H-3e/H-5e at dH
2.30 and upfield shift of H-3a/H-5a at dH 1.78 suggested that H-3a
and H-5a are in axial orientation and H-3e and H-5e are in
equatorial. The substituents (at 2, 4, and 6 positions) orientation
and stereochemistry on THP moiety in 3f was supported by
coupling constants and 2D NMR correlations (Fig. 2). In 1H NMR
spectrum, H-3a axial proton showed doublet of triplets at
d 1.78
(3J ¼ 11.5, 10.5 Hz, 2H). The coupling constant (11.5 Hz) indicates
that H-3a coupled with H-2 and H-4 axial protons. Similarly, in H,
H-COSY spectrum H-3a/H-5a axial protons showed correlation to
H-2/H-6 (dH 4.56) and H-4 (dH 4.95) axial protons. In 1H NMR
spectrum, H-3e/H-5e equatorial protons showed triplet of triplets
at
d
2.30 (2J ¼ 11.5 Hz, 3J ¼ 2 Hz, 2H) in which the coupling
constant (11.5 Hz) indicates the geminal coupling with H-3a/H-5a
and vicinal coupling constant (2 Hz) indicates coupling with H-2/
H-6 and H-4 axial protons. In H, H-COSY spectrum, H-3e/H-5e
equatorial protons showed correlation to H-2 and H-4 axial pro-
tons. In HMBC, H-3 protons showed correlations to C-2 (dC 76.92),
Table 1
Optimization of reaction conditions.
Entrya
Solvent
Temp (ꢀC)
Time
Yield (%)b
C-4 (dC 77.51), C-5 (dC 39.66) and C-400
(dC 143.00), suggesting that
C-3 and C-5 adjacent carbons are C-2, C-4 and C-4, C-6, respec-
1
2
3
4
5
6
7
8
DCM
THF
THF
EtOAc
EtOAc
ACN
40
rt
66
rt
78
rt
82
rt
12 h
24 h
15 h
20 h
15 h
15 h
11 h
6 h
45
26
46
22
50
32
65
55
95
71
tively. The H-2 proton in 1H NMR spectrum gave doublet of dou-
blets at
showed correlation to the H-3 proton. Further, in HMBC, correla-
tions to C-3 (dC 39.73), C-400 dC 139.83), and C-300
dC 126.39)
d
4.56 (J ¼ 10.5, 1.0 Hz, 1H), and in H, H-COSY spectrum
(
(
ACN
suggested that chalcone moiety is located at C-2. The H-6 proton
showed HMBC correlations to C-10 (dC 143.00), C-20 and C-60 (dC
127.45) suggesting that para-bromophenyl moiety is located at C-
6. In 1H NMR spectrum, H-4 proton showed triplet of triplets at
CHCl3
CHCl3
CHCl3
9
62
62
25 min
1.5 h
10c
4.95 (3J ¼ 11.5 Hz, 5.0 Hz, 1H) in which the coupling constants
Bold values signify optimized conditions.
d
a
All reactions were carried out with homoallylic alcohol (1 equiv), aldehyde
11.5 Hz (trans) and 5 Hz (cis) indicate coupling with H-3a/H-5a
and H-3e/H-5e adjacent protons, suggested that the H-4 proton is
oriented in axial position. In H, H-COSY, H-4 protons showed
ꢀ
(1 equiv), PTSA (1.4 equiv) and MS 4 A (50 mg/equiv) was used.
b
Isolated yield.
MS 4 A not used.
c
ꢀ

236
N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
Table 2
Construction of flavonoid based 4-tosyloxy THPs (3aeza) (Schemes 1 and 2).a
interaction with H-3 and H-5 protons and HMBC correlations to C-
2, C-3, C-5 and C-6 suggested that C-4 is present between C-3 and
chair conformation with substituents at C-2, C-4 and C-6 equato-
rial positions (Fig. 2). All of theses assignments led to the structure
of 3f as (2R,4S,6S)-2-(4-bromophenyl)-6-(4-((E)-3-oxo-3-p-tolyl-
propenyl)phenyl)-4-tosyloxy tetrahydropyran. Similarly, the
structure of other products (3aeza, 3zb and 5) were confirmed on
their spectral data (experimental section).
For the synthesis of 4-cinnamate THPs (Scheme 6), we tried to
deprotect the tosyl group at C-4 in compound 3 following a re-
ported method with MgeMeOH at room temperature [26] but re-
action failed to give 4-hydroxy THPs. Therefore, we further
investigated different reaction conditions by varying temperature,
solvents (MeOH, acetone, THF) and acids (conc. H2SO4, TFA)
(Table 3). The best reaction efficiency in terms of yields (85e90%)
and reaction time (30 min) was obtained with TFA at 140 ꢀC
(Scheme 5, Table 4).
C-5. In 13C NMR spectrum, a peak at
d 189.18 corresponds to
carbonyl carbon (Fig. 2). The relative configuration of asymmetric
carbons was established by analyzing the coupling constants and
the NOESY spectrum (Fig. 2). In NOESY spectrum, the correlation
of H-4 (dH 4.95) with H-2 and H-6 indicated that they were located
on the same side of the ring with diaxial orientation. In 1H NMR,
the chemical shift at dH 1.78 for H-3a/H-5a protons and at dH 2.30
for H-3e/H-5e protons showed axial and equatorial orientation
respectively. The coupling constants JH-2/H-3a ¼ 11.5 Hz for H-2 and
H-3a and JH-3a/H-4 ¼ 11.5 Hz for H-3a and H-4 indicate trans-
orientation to each other. It is confirmed that protons H-3a and
H-5a are in axial orientation therefore H-2, H-4 and H-6 protons
are also axially orientated, meaning that the pyran ring exists in

N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
237
that H-3a coupled with H-2 and H-4 axial protons. Similarly, in H,
H-COSY spectrum H-3a/H-5a axial protons showed correlation to
H-2/H-6 (dH 4.66) and H-4 (dH 4.14) axial protons. In 1H NMR
spectrum, H-3e/H-5e equatorial protons showed triplet of triplets
at
d
2.30 (2J ¼ 11.5 Hz, 3J ¼ 2 Hz, 2H) in which the coupling constant
(11.5 Hz) indicates the geminal coupling with H-3a/H-5a and vicinal
coupling constant (2 Hz) indicates coupling with H-2/H-6 and H-4
axial protons. In H, H-COSY spectrum, H-3e/H-5e equatorial pro-
tons showed correlation to H-2/H-6 and H-4 axial protons. In
HMBC, H-3 protons showed correlations to C-2 (dC 77.70), C-4 (dC
69.46), C-5 (dC 40.05) and C-400 (dC 143.77) suggested that C-3 and C-
5 adjacent carbons are C-2, C-4 and C-4, C-6, respectively. The H-2
proton in 1H NMR spectrum gave triplet at
d
4.66 (J ¼ 6.5 Hz, 1H),
and in H, H-COSY spectrum showed correlation to H-3 proton.
Further, in HMBC correlations to C-3 (dC 40.05), C-400 (dC 143.77), C-
300 (dC 126.55) suggested that chalcone moiety is located at C-2. The
H-6 proton showed HMBC correlations to C-10 (dC 143.89) and C-20
and C-60 (dC 127.71) suggested that para-chlorophenyl moiety is
located at C-6. In 1H NMR spectrum, H-4 proton showed triplet of
Scheme 2. Synthesis of flavone and flavanone based 4-tosyloxy THPs.
triplets at
d
4.14 (3J ¼ 11.5 Hz, 3.0 Hz, 1H) in which the coupling
The assigned structures of 4-hydroxy THPs (4aef) were estab-
lished from their spectroscopic data (IR, HRMS, 1H, 13C and 2D
NMR). For example, (2R,4S,6S)-2-(4-chlorophenyl)-6-(4-((E)-3-(4-
fluorophenyl)-3-oxopropenyl)phenyl)-4-hydroxytetrahydropyran
(4b) obtained as a yellow semi-solid. The IR spectrum of 4b showed
absorptions at 3434 (br), and 1734 cmꢂ1 for hydroxyl and carbonyl
bonds asymm. stretching respectively. The HRMS of 4b supported a
molecular composition of C26H22ClFNaO3 (M þ Na)þ, representing
15 degrees of unsaturation. In 1H NMR spectrum, peak at dH 2.05 (s,
br, D2O exchangeable, 1H) confirms the presence of hydroxy group.
In the 1H NMR spectrum of 4b, two oxymethine groups at dH 4.66,
4.14 and two asymmetrical methylene group resonating at dH 1.78,
and 2.30 assigned to H-2/H-6, H-4, H-3a/H-5a, H-3e/H-5e, respec-
tively, suggested the presence of a THP ring. The relative downfield
shift of H-3e/H-5e at dH 2.30 and upfield shift of H-3a/H-5a at dH
1.78 suggested that H-3a and H-5a are in axial and H-3e and H-5e in
equatorial orientation. The substituents (at 2,4, and 6 positions)
orientation and stereochemistry on THP moiety in 4b was sup-
ported by coupling constants and 2D NMR correlations (Fig. 3). In
1H NMR spectrum, H-3a axial proton showed triplet of triplets at
constants 11.5 Hz (trans) and 3 Hz (cis) indicate coupled with H-3a/
H-5a and H-3e/H-5e adjacent protons, suggested that H-4 proton is
oriented in axial position. In H, H-COSY, H-4 proton showed inter-
action with H-3 and H-5 protons and HMBC correlations to C-2, C-3,
C-5 and C-6 suggested that C-4 present between C-3 and C-5. In 13
C
NMR spectrum, a peak at
d 188.84 corresponds to carbonyl carbon
(Fig. 3). The relative configurations of asymmetric carbons were
established by analyzing the coupling constants and the NOESY
spectrum (Fig. 3). In NOESY spectrum, the correlation of H-4 (dH
4.14) with H-2 and H-6 indicated that they were located on the
same side of the ring with diaxial orientation. In 1H NMR, the
chemical shift at dH 1.78 for H-3a/H-5a protons, at dH 2.30 for H-3e/
H-5e protons showed axial and equatorial orientation respectively.
The coupling constants JH-2/H-3a ¼ 11.5 Hz for H-2 and H-3a, JH-3a/H-
¼ 11.5 Hz for H-3a and H-4 indicate trans-orientation to each
4
other. It is confirmed that protons H-3a and H-5a are in axial
orientation therefore H-2, H-4 and H-6 protons are also axially
orientated. It means that the pyran ring exists in chair conforma-
tion with substituents at C-2, C-4 and C-6 is in equatorial position
(Fig. 3). All of theses assignments led to the structure of 4b as
d
1.78 (3J ¼ 11.5, 2 Hz, 2H). The coupling constant (11.5 Hz) indicates
Scheme 3. Synthesis of 2-((E)-5-(4-((2R,4S,6R)-6-(4-chlorophenyl)-4-(tosyloxy)tetrahydro-2H-pyran-2-yl)benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid.

238
N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
Scheme 5. Deprotection of tosyl group.
dissolved into a colored solution by the addition of a suitable sol-
vent and the absorbance of the colored solution was measured.
Each experiment was performed in triplicate and the data is re-
ported as average value in Fig. 4. The potency of the drugs (com-
pounds 3e5 series) in causing cell death was obtained through the
production of doseeresponse curves when the amount of purple
formazan produced by untreated control cells was taken into
consideration. Experiments revealed that there was substantial
increase in cytotoxicity in cells with increasing exposure to drug
concentration.
Scheme 4. Proposed mechanism for synthesis flavonoid based THPs.
(2R,4S,6S)-2-(4-chlorophenyl)-6-(4-((E)-3-(4-fluorophenyl)-3-
oxopropenyl)phenyl)-4-hydroxytetrahydropyran. Similarly, the
structure of other products (4a, 4cef) was confirmed on their
spectral data (Experimental section).
Further, reaction of 4f with cinnamoyl chloride was performed
at 140 ꢀC to give 4-cinnamate THP 5 under neat conditions and the
structural formula was confirmed on the basis of their spectral
analysis (IR, 1H, 13C NMR, and HRMS). Similarly, the assigned
structural formulas of flavonoid based aldehydes (2ael and 2n)
were confirmed on the basis of their spectral analysis (IR, 1H, 13C
NMR, and HRMS) (Experimental section).
The results revealed that all synthesized compounds have
antiproliferative activities by inhibiting cell growth with IC50 values
varying from 4.48 to 56
cell line, some compounds exhibited IC50 values upto 46
the majority of the reported compounds inhibited IC50 values
below 20 M. Compound 3zb was found the most potent with high
cytotoxicity (IC50 4.48 ꢁ 2.1 M) similar to the reference drug
Doxorubicin (IC50 4.1 ꢁ 1.1 M) against the Hep3 cell line. Com-
pounds 3c, 3oeq and 5 showed moderate cytotoxicity against the
Hep3
cell line with IC50 values: 10.40 ꢁ 1.1, 11.1 ꢁ 1.1, 14.1 ꢁ 1.3,
12.9 ꢁ 1.7 and 11.3 ꢁ 1.0 M respectively. Against the MCF-7 cell
line, all compounds exhibited IC50 values upto 56 M, but the
majority of the reported compounds inhibited IC50 values below
15 M. Compounds 3q and 3zb were found the most potent which
mM against all tested cell lines. In the Hep3
b
mM, but
m
m
4.2. Antiproliferative activity
m
b
All synthesized Prins products (3aezb, 4aef, 5) were evaluated
for their in vitro antiproliferative activity against three human
cancer cell lines namely; human hepatocellular carcinoma (Hep3b),
b
m
m
human breast adenocarcinoma (MCF-7) and human cervical car-
cinoma (HeLa) following the standard procedure of MTT ((3-(4,5-
Dimethylthiazol-2-yl))-2,5-diphenyltetrazolium bromide) assay.
Each compound was tested in concentration (dose)e% cell viability
(response) experiments; varying the concentration by dilution to
define potency. In the MTT (colorimetric) assay, the cytotoxicity of
potential drugs and other toxic compounds were measured by the
reduction of cellular growth that reduces the tetrazolium yellow
dye (MTT) to its insoluble formazan (purple color) by mitochondrial
dehydrogenases of living cells. IC50 (concentration required to
achieve 50% inhibition of tumor growth) values of tested com-
m
exhibiting similar cytotoxicity (IC50 6.6 ꢁ 1.4, 6.9 ꢁ 1.0
mM
respectively) to the reference drug doxorubicin (IC50 7.6 ꢁ 0.9
mM)
against the MCF-7 cell line. Compounds 3f, 3g, 3i, and 3s exhibited
moderate cytotoxicity (IC50 < 11
Against the HeLa cell line, some compounds exhibited IC50 values
upto 36 M, but the majority of the reported compounds inhibited
IC50 values below 20 M. Compound 3c was found the most potent
with IC50 value 12.5 ꢁ 1.7 M against the HeLa cells. Compounds 3q
and 3v demonstrated better cytotoxicity with IC50 values 14.4 ꢁ 1.9
and 15.1 ꢁ 2.8 M respectively against the HeLa cells.
mM) against the MCF-7 cell line.
m
m
m
pounds are reported in
mM against the above cell lines and sum-
m
marized in Table 5. The insoluble purple formazan product was
Fig. 2. Selected 1He1H COSY (blue arrows), HMBC (pink arrows), NOE (green arrows) correlations for compound 3f. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)

N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
239
Scheme 6. Synthesis of 4-cinnamate THPs.
On the basis of the cytotoxicity results, the flavonoid (chalcone,
flavone and flavonone) based pyrans envisaged remarkable anti-
Hep3
b
cells (IC50 value 11.3 ꢁ 1.0
m
M). Overall, the substituent ef-
fects of different C-4 substituted THPs were observed as 4-tosyloxy
proliferative activity against the Hep3
b
and the MCF-7 cell lines as
THPs > 4-cinnamate THPs > 4-Hydroxy THPs for cytotoxicity.
compared to the HeLa cell line. The para-chlorophenyl substituted
at C-6 of pyran derivatives (3bee, 3n, 3u, 3v, 3x, 3zb) for example,
compound 3zb a rhodanine-3-acetic acid chalcone containing py-
5. Conclusion
ran derivative showed excellent cytotoxicity against the Hep3
the MCF-7 cell lines (IC50 ꢃ 6.9 ꢁ 1.0 M). It was also observed that
the chloro-substituents on chalcone (e.g., 3c) enhanced cytotoxicity
against the Hep3 M) and
the methyl-substituents on chalcone (e.g., 3v) enhanced cytotox-
icity against the MCF-7 and the HeLa cell lines
b and
In conclusion, we have reported a new strategy for the synthesis
of highly diastereoselective and functionalized 2-flavonoid-6-aryl-
4-tosyloxy THPs via Prins cyclization in excellent yields (72e96%)
within 20e90 min. Deprotection of tosyl group in 4-tosyloxy THPs
with TFA and then reaction with cinnamoyl chloride gave 4-
cinnamate THPs under neat conditions. Novel products show good
m
b
and the HeLa cell lines (IC50 ꢃ 12.5 ꢁ 1.7
m
(IC50 ꢃ 15.1 ꢁ 2.8
showed moderate cytotoxicity against these cancer lines
M). The para-bromophenyl substituted pyran
mM). Other substituents such as F, Br and SMe
antiproliferative activities against human cancer cell lines (Hep3
MCF 7 and HeLa). Compounds 3q and 3zb have shown similar po-
tency IC50 6.6 ꢁ1.4, 6.9 ꢁ1.0 M respectivelyagainst the MCF-7 cells
compared to the reference drug doxorubicin. Compound 3zb
M) against the Hep3
b,
(IC50 ꢃ 17.8e34.8
m
m
derivatives at C-6 (e.g., 3fek, 3y and 3za), and naphthalene chal-
cone pyran derivative 3g at C-2 demonstrated good cytotoxicity
showed equal cytotoxicity (IC50 4.48 ꢁ 2.1
m
b
(IC50 ꢃ 8.85 ꢁ 1.8
substituted chalcones showed better cytotoxicity against the MCF-7
cells (IC50 ꢃ 11.2 ꢁ 1.2 M). However, 3j, and 3h substituted chal-
M) against the
mM) against the MCF-7 cells. Similarly, 3f and 3i
cells compared to the reference drug doxorubicin. Compounds 3c,
3o and 5 showed moderate cytotoxicity (IC50 10.40 ꢁ 1.1, 11.1 ꢁ 1.1,
m
11.3 ꢁ 1.0
mM respectively) against the Hep3b cells. Compounds 3a,
cones decreased cytotoxicity (IC50 ꢃ 37.0 ꢁ 1.6
m
3f, 3g, 3i, and 3s showed moderate cytotoxicity (IC50 10.6 ꢁ 1.7,
10.9 ꢁ 2.3, 8.85 ꢁ 1.8, 11.2 ꢁ 1.2, 9.43 ꢁ 2.1 M respectively) against
the MCF-7 cells and compounds 3c and 3q showed moderate cyto-
M respectively) against the HeLa
MCF-7 cells. In compounds having no substitution on phenyl ring at
m
C-6 of pyran derivatives (e.g., 3a, 3lem, 3oeq, 3z) and compound
3q showed the maximum cytotoxicity (IC50 6.6e14.4
these cell lines. Whereas flavanone moiety compound 3z decreased
the cytotoxicity (IC50 45.7 ꢁ 1.3 M). Further, 3a and 3p substituted
chalcones enhanced cytotoxicity (IC50 ꢃ 10.6e16.4 M) against all
cancer cell lines and the 3o substituted chalcone also increased
cytotoxicity (IC50 11.1 ꢁ1.1 M) against the Hep3 cells. Similarly, 3l
M)
mM) against
toxicity (IC50 10.40 ꢁ1.1,12.9 ꢁ1.7
m
cells. The present work provides strong incentive for future devel-
m
opment of flavonoid based THPs as potential antitumor agents.
m
m
b
Table 4
substituted chalcone enhanced cytotoxicity (IC50 15.3 ꢁ 1.5
m
Preparation of flavonoid based 4-hydroxy pyran derivatives.
against the MCF-7 cells. However, 3m substituted chalcone
decreased cytotoxicity against these cancer cell lines (Table 5). But,
3s substituted at C-6 showed excellent cytotoxicity (IC50
9.43 ꢁ 2.1
mM) against the MCF-7 cells. In total, the cytotoxicity of
C-2 substituted chalcones and flavones on pyran ring have shown
better activity against tested cancer cell lines. We also observed
that the pyrans substituted at C-4 with hydroxyl group decreased
cytotoxicity compared to the tosyl group. However, the introduc-
tion of cinnamoyl group at C-4 showed high cytotoxicity against the
Table 3
Optimization of reaction conditions for deprotection of tosyl group.
Entry
Reagent
Temp (ꢀC)
Yield (%)
1
2
3
4
5
6
MgeMeOH
MgeMeOH
Conc. H2SO4
25
66
25
25
25
e
e
e
e
e
90
1 M NaOH/EtOH þ Acetone
TFA
TFA
140

240
N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
chamber. The column chromatography was performed using silica
gel 100e200 mesh size (SD Fine-Chem Limited) with ethyl acetate/
hexane mixture as eluent. Melting points were recorded on perfit
apparatus and are uncorrected. The IR spectrum was recorded with
KBr on a Thomso Nicolet FT-IR spectrophotometer. 1H and 13C NMR
spectra were obtained in CDCl3 on a Bruker Spectrospin-500/
125 MHz spectrometer using TMS as internal standard. Chemical
shifts of 1H NMR spectra were given in parts per million with
respect to TMS, and the coupling constant J was measured in Hz.
Datas are reported as follows: chemical shifts, multiplicity
(s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet,
dd ¼ doublet of doublets). HRMS were recorded on Bruker
instrument.
6.1.2. General procedure for the synthesis of flavonoid based 4-
tosyloxy THP (3aezb)
Fig. 3. Selected 1He1H COSY (blue arrows), HMBC (pink arrows), NOE (green arrows)
correlations for compound 4b. (For interpretation of the references to color in this
figure legend, the reader is referred to the web version of this article.)
ꢀ
To a stirred solution of aldehyde (1 mmol), MS 4 A and p-tol-
uenesulfonic acid (1.4 mmol) at 62 ꢀC in chloroform (5 mL) was
added aromatic homoallylic alcohol (1 mmol, dissolved in 2 mL
CHCl3) dropwise and the reaction mixture stirred for the required
time at the same temperature. TLC monitoring, the reaction
mixture was cooled and then added to an aqueous NaHCO3 solu-
tion. The product was extracted with chloroform (3 ꢄ 10 mL). The
combined organic layer was washed with brine (5 mL) and water
(5 mL) followed by drying on anhydrous Na2SO4. Upon evaporation
of solvent under vacuo, pure product was obtained. In some cases,
purification was performed by silica gel column chromatography
using hexane: EtOAc (4:1) mixture as eluent.
6. Experimental section
6.1. Chemistry
6.1.1. Material and methods
Organic solvents were dried by standard methods when
necessary. Commercially available reagents were used without
further purification unless mentioned. All reactions were moni-
tored by TLC using pre-coated silica gel aluminum plates. Visuali-
zation of TLC plates was accomplished with a UV lamp or in iodine
6.1.2.1. (2R,4R,6S)-2-Phenyl-6-(4-((E)-3-oxo-3-p-tolylpropenyl)
phenyl)-4-tosyloxytetrahydropyran (3a). Yellow solid, mp 80 ꢀC;
Table 5
IC50 values of flavonoid based THPs on the growth of human cancer cell lines.a
yield 90%. 1H NMR (500 MHz, CDCl3):
d
1.84 (dq, J ¼ 12 Hz, 2H), 2.30
S.No
Drug
Hep3
b
MCF 7
HeLa
16.4 2.1
(m, 2H), 2.43 (s, 3H), 2.45 (s, 3H), 4.55 (dd, J ¼ 11.5 Hz, 1 Hz, 1H),
4.58 (dd, J ¼ 12 Hz, 1 Hz, 1H), 4.98 (tt, J ¼ 11 Hz, 4.5 Hz, 1H), 7.30 (d,
J ¼ 8 Hz, 3H), 7.34e7.38 (m, 4H), 7.42 (d, J ¼ 8 Hz, 2H), 7.52 (d,
J ¼ 15.5 Hz, 1H), 7.62 (d, J ¼ 8 Hz, 2H), 7.69 (s, 1H), 7.78 (d,
J ¼ 15.5 Hz,1H), 7.83 (d, J ¼ 8.5 Hz, 2H), 7.93 (d, J ¼ 8 Hz, 2H), 7.96 (d,
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
14.7 1.5
31.8 ꢁ 1.6
10.40 1.1
19.4 ꢁ 1.2
24.8 ꢁ 1.9
19.4 ꢁ 1.1
22.2 ꢁ 1.1
24.6 ꢁ 0.8
15.1 ꢁ 1.1
45.9 ꢁ 3.1
35.6 ꢁ 1.1
46.1 ꢁ 1.9
24.5 ꢁ 2.5
26.3 ꢁ 1.1
11.1 1.1
14.1 1.3
12.9 1.7
26.3 ꢁ 1.1
17.0 ꢁ 0.8
14.7 ꢁ 3.2
31.3 ꢁ 1.6
18.1 ꢁ 1.7
37.7 ꢁ 1.1
35.6 ꢁ 1.1
29.8 ꢁ 1.5
38.9 ꢁ 5.0
36.9 ꢁ 1.2
4.48 2.1
14.9 ꢁ 0.9
15.6 ꢁ 3.7
16.5 ꢁ 1.8
37.5 ꢁ 1.5
33.5 ꢁ 0.5
29.8 ꢁ 1.5
11.3 1.0
4.1 ꢁ 1.1
10.6 1.7
56.4 ꢁ 3.2
26.0 ꢁ 1.2
41.4 ꢁ 1.3
20.8 ꢁ 1.3
10.9 2.3
8.85 1.8
24.62 ꢁ 0.7
11.2 1.2
37.0 ꢁ 1.6
30.5 ꢁ 2.1
15.3 ꢁ 1.5
19.7 ꢁ 1.1
17.8 ꢁ 2.1
27.7 ꢁ 1.1
15.3 1.3
6.6 1.4
17.8 ꢁ 2.1
9.43 2.1
28.7 ꢁ 2.7
27.9 ꢁ 1.9
14.6 1.8
43.2 ꢁ 1.6
30.5 ꢁ 2.1
37.1 ꢁ 4.1
34.4 ꢁ 3.1
42.5 ꢁ 3.2
6.9 1.0
34.8 ꢁ 1.2
12.5 1.7
26.6 ꢁ 3.1
34.6 ꢁ 2.1
30.4 ꢁ 2.1
27.8 ꢁ 3.1
25.3 ꢁ 1.2
23.23 ꢁ 2.1
35.2 ꢁ 1.9
21.5 ꢁ 2.1
23.8 ꢁ 0.9
25.2 ꢁ 0.9
23.4 ꢁ 4.1
29.1 ꢁ 2.3
16.12 0.8
14.4 1.9
23.4 ꢁ 4.1
43.1 ꢁ 1.9
24.2 ꢁ 1.8
36.2 ꢁ 3.2
15.1 2.8
32.3 ꢁ 2.5
21.5 ꢁ 2.1
33 ꢁ 1.3
J ¼ 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3):
d 21.58, 39.83, 76.96,
77.49, 77.87, 122.05, 125.76, 126.30, 127.51, 127.86, 128.42, 128.56,
128.82, 129.25, 129.84, 134.17, 134.46, 135.50, 140.70, 143.28, 143.57,
143.78, 144.79, 189.86. IR (KBr): 3024, 2953, 2841, 1683, 1612, 1345,
1201, 1131, 853 cmꢂ1. HRMS (ESIMS) for C34H32NaO5S (M þ Na)þ
Anal. calcd. 575.1868; found 575.1856.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
6.1.2.2. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-(4-
m e t h y l m e r c a p t o p h e n y l ) - 3 - o x o p r o p e n y l ) p h e n y l ) - 4 -
tosyloxytetrahydropyran (3b). Yellow semi-solid, yield 96%. 1H NMR
(500 MHz, CDCl3):
d 1.75 (m, 2H), 2.26e2.34 (m, 2H), 2.44 (s, 3H),
2.51 (s, 3H), 4.54 (ddd, J ¼ 20 Hz, 11.5 Hz, 1 Hz, 2H), 4.96 (tt,
J ¼ 11 Hz, 5 Hz, 1H), 7.29e7.32 (m, 5H), 7.34 (d, J ¼ 8 Hz, 2H), 7.40 (d,
J ¼ 8 Hz, 2H), 7.50 (d, J ¼ 15.5 Hz, 1H), 7.61 (d, J ¼ 16 Hz, 2H), 7.76e
7.83 (m, 3H), 7.94e7.96 (m, 3H). 13C NMR (125 MHz, CDCl3):
d 14.82,
21.71, 39.81, 39.90, 76.84, 77.35, 77.63, 121.90, 125.11, 126.40, 127.24,
127.63, 128.61, 128.67, 128.98, 129.98, 133.67, 134.21, 134.37, 134.64,
139.33, 143.18, 143.90, 144.99, 145.79, 189.10. IR (KBr): 3024, 2953,
2841, 1683, 1612, 1345, 1201, 1131, 853 cmꢂ1. HRMS (ESIMS) for
3y
3z
41.1 ꢁ 1.1
45.7 ꢁ 1.3
33.6 ꢁ 3.1
19.1 ꢁ 4.1
22.1 ꢁ 1.9
20.7 ꢁ 1.9
24.32 ꢁ 1.5
33.2 ꢁ 1.1
33 ꢁ 1.3
3za
3zb
4a
4b
4c
4d
4e
4f
C
34H31ClNaO5S2 (M þ Na)þ Anal. calcd. 641.1199; found 641.1184.
23.4 ꢁ 5.1
24.4 ꢁ 3.8
20.1 ꢁ 0.90
38.2 ꢁ 2.1
26.8 ꢁ 5
6.1.2.3. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-(4-chlorophenyl)-
3-oxopropenyl)phenyl)-4-tosyloxytetrahydropyran
(3c). Yellow
1.84 (qd,
semi-solid, yield 94%. 1H NMR (500 MHz, CDCl3):
d
37.1 ꢁ 4.1
27.9 ꢁ 3.2
7.6 ꢁ 0.9
J ¼ 24 Hz, 12 Hz, 2H), 2.34 (dd, 12.5 Hz, 4 Hz, 2H), 2.45 (s, 3H), 4.55
(ddd, J ¼ 23.5 Hz, 11.5 Hz, 1.5 Hz, 2H), 4.99 (tt, J ¼ 5 Hz, 1H), 7.29e
7.31 (m 4H), 7.35 (d, J ¼ 8 Hz, 2H), 7.41 (d, J ¼ 8 Hz, 2H), 7.45e7.48
(m, 3H), 7.61 (d, J ¼ 8 Hz, 2H), 7.77e7.83 (m, 3H), 7.95 (d, J ¼ 8.5 Hz,
5
23.3 ꢁ 1.4
5.3 ꢁ 1.2
Doxorubicin
a
Values were means of three experiments, each done in duplicate. IC50 values are
m. Hep3 , MCF-7 and Hela cells IC50 values are expressed in m.
expressed in
m
b
m

N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
241
Fig. 4. MTT assay graph of selected compounds.

242
N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
2H). 13C NMR (125 MHz, CDCl3):
d
21.70, 39.83, 39.88, 76.92, 77.17,
6.1.2.8. (2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-oxo-3-(2,4,6-
77.58, 121.63, 126.45, 127.24, 127.63, 128.68, 128.71, 128.98, 129.94,
129.98, 133.71, 134.19, 134.37, 136.46, 139.29, 143.48, 144.76, 145.00,
trimethoxyphenyl) propenyl)phenyl)-4-tosyloxytetrahydropyran
(3h). Yellow semi-solid, yield 85%. 1H NMR (500 MHz, CDCl3):
189.12. IR (KBr): 3001, 2946, 1678, 1614, 1350, 1200, 1114, 862 cmꢂ1
.
d 1.76e1.83 (m, 2H), 2.25e2.33 (m, 2H), 2.44 (s, 3H), 3.93 (s, 9H),
HRMS (ESIMS) for
629.0932; found 629.0921.
C
33H28Cl2NaO5S (M
þ
Na)þ Anal. calcd.
4.53 (dd, J ¼ 30 Hz, 10 Hz, 2H), 4.96 (tt, J ¼ 11 Hz, 3 Hz, 1H), 7.23 (d,
J ¼ 8 Hz, 2H), 7.27e7.28 (m, 2H), 7.34 (d, J ¼ 8 Hz, 2H), 7.40 (d,,
J ¼ 8 Hz, 2H), 7.44e7.46 (m, 2H), 7.50 (s, 1H), 7.62e7.63 (m, 2H), 7.77
(d, J ¼ 8 Hz, 1H), 7.81 (d, J ¼ 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3):
6.1.2.4. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-(naphthalen-2-
d
21.73, 39.86, 56.45, 61.03, 72.90, 77.19, 77.64, 106.20, 121.97,
yl)-3-oxopropenyl)phenyl)-4-tosyloxytetrahydropyran
(3d).
1.77 (q,
126.45, 127.61, 127.64, 128.68, 130.03, 131.64, 133.48, 134.23, 134.60,
139.91, 142.61, 143.33, 144.18, 144.48, 145.03, 1553.21, 189.18. IR
Yellow semi-solid, yield 96%. 1H NMR (500 MHz, CDCl3):
d
J ¼ 12 Hz, 2H), 2.30 (td, J ¼ 16.5 Hz, 2 Hz, 2H), 2.43 (s, 3H), 4.53 (dd,
J ¼ 27.5 Hz, 10.5 Hz, 2H), 4.97 (tt, J ¼ 11 Hz, 3 Hz, 1H), 7.28e7.34 (m,
4H), 7.39e7.41 (d, J ¼ 8 Hz, 2H), 7.54e7.68 (m, 6H), 7.81e7.91 (m,
(KBr): 2921, 2847, 1660, 1605, 1421, 1326, 1213, 1173, 817 cmꢂ1
.
HRMS (ESIMS) for C36H35BrNaO8S (M þ Na)þ Anal. calcd. 729.1134;
found 729.1108.
6H), 7.97 (d, J ¼ 8 Hz, 1H), 8.08 (d, J ¼ 8.5 Hz, 1H), 8.52 (s, 1H). 13
C
NMR (125 MHz, CDCl3):
d 21.79, 39.92, 40.01, 76.95, 77.26, 77.74,
6.1.2.9. (2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-(4-
methoxyphenyl)-3-oxopropenyl) phenyl)-4-tosyloxytetrahydropyran
(3i). Yellow semi-solid, yield 88%. 1H NMR (500 MHz, CDCl3):
122.33, 124.58, 126.52, 126.94, 127.34, 127.72, 127.96, 128.55, 128.77,
129.66, 130.08, 132.68, 133.76, 134.35,134.73, 135.61, 139.45, 143.38,
144.27, 144.27, 145.07, 190.27. IR (KBr): 3013, 2942, 1681, 1604, 1331,
1241, 1126, 880 cmꢂ1. HRMS (ESIMS) for C37H31ClNaO5S (M þ Na)þ
Anal. calcd. 645.1478; found 645.1481.
d
1.80 (q, J ¼ 11.5 Hz, 2H), 2.29 (t, J ¼ 12 Hz, 2H), 2.44 (s, 3H), 3.88 (s,
3H), 4.50 (d, J ¼ 12 Hz, 1H), 4.55 (d, J ¼ 11.5 Hz, 1H), 4.95 (m, 1H),
6.97 (m, 3H), 7.23 (d, J ¼ 7 Hz, 1H), 7.34 (d, J ¼ 8 Hz, 2H), 7.39 (d,
J ¼ 7 Hz, 2H), 7.46 (d, J ¼ 6.5 Hz, 2H), 7.53 (d, J ¼ 15.5 Hz, 1H), 7.57e
7.60 (m, 2H), 7.76 (d, J ¼ 15 Hz, 1H), 7.81 (d, J ¼ 6.5 Hz, 1H), 8.02e
6.1.2.5. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-(4-fluorophenyl)-
3-oxopropenyl)phenyl)-4-tosyloxytetrahydropyran
(3e). Yellow
1.76e1.83 (m,
8.05 (m, 3H). 13C NMR (125 MHz, CDCl3):
d 21.81, 39.89, 39.96,
semi-solid, yield 95%. 1H NMR (500 MHz, CDCl3):
d
55.63, 77.02, 77.29, 77.74, 122.13, 126.48, 127.68, 127.73, 128.65,
129.00, 130.09, 130.96, 131.72, 134.30, 134.86, 139.97, 142.91, 143.10,
143.48, 145.10, 163.60, 188.75. IR (KBr): 2960, 2921, 2850, 1661,
1600, 1355, 1172, 818 cmꢂ1. HRMS (ESIMS) for C34H31BrNaO6S
(M þ Na)þ Anal. calcd. 669.0922; found 669.0900.
2H), 2.25e2.33 (m, 2H), 2.43 (s, 3H), 4.54 (dddd, J ¼ 33.5 Hz, 22 Hz,
12 Hz, 2 Hz, 2H), 4.96 (tt, J ¼ 11 Hz, 4.5 Hz, 1H), 7.33 (d, J ¼ 8 Hz, 2H),
7.39 (dd, J ¼ 8.5 Hz, 3 Hz, 3H), 7.47 (d, J ¼ 15.5 Hz, 2H), 7.60 (dd,
J ¼ 8 Hz, 2.5 Hz, 4H), 7.75 (d, J ¼ 5 Hz, 1H), 7.78 (d, J ¼ 5 Hz, 1H), 7.81
(d, J ¼ 8.5 Hz, 1H), 8.02e8.05 (m, 4H). 13C NMR (125 MHz, CDCl3):
d
21.79, 39.80, 39.86, 76.90, 77.36, 77.65, 121.28, 126.49, 127.26,
6.1.2.10. .(2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-(2-
hydroxyphenyl)-3-oxopropenyl) phenyl)-4-tosyloxytetrahydropyran
(3j). Yellow semi-solid, yield 87%. 1H NMR (500 MHz, CDCl3):
127.62, 128.62, 128.68, 130.00, 131.10, 131.17, 133.65, 133.89, 134.10,
134.38, 139.32, 143.42, 144.80,146.92, 164.60, 188.85.IR (KBr): 3000,
2945, 1678, 1614, 1354, 1208, 1130, 865 cmꢂ1. HRMS (ESIMS) for
d
1.81 (q, J ¼ 11.5 Hz, 2H), 2.32 (dd, J ¼ 26.5 Hz, 8 Hz, 2H), 2.46 (s,
C
33H28ClFNaO5S (M þ Na)þ Anal. calcd. 613.1228; found 613.1220.
3H), 4.52 (d, J ¼ 11.5 Hz, 1H), 4.92e5.01 (m, 1H), 4.58 (d, J ¼ 11 Hz,
1H), 6.96 (t, J ¼ 7.5 Hz, 1H), 7.03 (d, J ¼ 8.5 Hz, 1H), 7.25 (dd, J ¼ 9 Hz,
1 Hz, 1H), 7.36 (d, J ¼ 7.5 Hz, 2H), 7.43 (d, J ¼ 7 Hz, 2H), 7.48 (d,
J ¼ 8.5 Hz, 2H), 7.52 (d, J ¼ 8 Hz, 1H), 7.65 (d, J ¼ 8.5 Hz, 3H), 7.73 (d,
J ¼ 13 Hz, 1H), 7.82 (J ¼ 6.5 Hz, 2H), 7.89e7.93 (m, 2H), 11.59 (s, br,
6.1.2.6. (2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-oxo-3-p-tolylpro-
penyl)phenyl)-4-tosyloxytetrahydropyran (3f). Yellow solid, mp
75 ꢀC; yield 90%. 1H NMR (500 MHz, CDCl3):
d
1.78 (dt, J ¼ 11.5,
D2O exchangeable, 1H). 13C NMR (125 MHz, CDCl3):
d 21.86, 39.97,
10.5 Hz 2H), 2.30 (tt, J ¼ 11.5, 2 Hz, 2H), 2.4 (s, 3H), 2.42 (s, 3H), 4.51
(dd, J ¼ 10.5 Hz, 1 Hz, 1H), 4.56 (dd, J ¼ 10.5, 1 Hz, 1H), 4.95 (tt,
J ¼ 11.5, 5 Hz, 1H), 7.22e7.39 (m, 8H), 7.44e7.53 (m, 3H), 7.56e7.60
(m, 2H), 7.75e7.82 (m, 3H), 7.92 (d, J ¼ 8 Hz, 2H). 13C NMR
77.12, 77.32, 77.68, 118.83, 119.06, 120.43, 122.00, 126.62, 127.72,
127.79, 129.01, 129.41, 129.82, 130.13, 131.80, 134.33, 134.43, 136.65,
139.92, 143.80, 145.04, 145.16, 163.77, 193.83. IR (KBr): 3045, 2926,
2852, 1695, 1655, 1600, 1324, 1179, 1121, 850 cmꢂ1. HRMS (ESIMS)
for C33H29BrNaO6S (M þ Na)þ Anal. calcd. 655.0766; found
655.0753.
(125 MHz, CDCl3):
d 21.56, 39.66, 39.73, 76.74, 76.99, 77.51, 121.64,
122.13, 126.25, 127.45, 127.49, 128.45, 128.55, 128.81, 129.25, 129.86,
131.47, 134.12, 134.54, 135.47, 139.76, 143.00, 143.65, 144.85, 189.77.
IR (KBr): 2960, 2917, 2848, 1657, 1602, 1360, 1181, 818 cmꢂ1. HRMS
(ESIMS) for C34H31BrNaO5S (M þ Na)þ Anal. calcd. 653.0973; found
653.0962.
6.1.2.11. (2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-(4-
bromophenyl)-3-oxopropenyl) phenyl)-4-tosyloxytetrahydropyran
(3k). Yellow semi-solid, yield 95%. 1H NMR (500 MHz, CDCl3):
d
1.77 (q, J ¼ 11 Hz, 2H), 2.29 (dd, J ¼ 24 Hz,12.5 Hz, 2H), 2.43 (s, 3H),
6.1.2.7. (2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-(naphthalen-2-
4.52 (dd, J ¼ 28 Hz, 10 Hz, 2H), 4.95 (tt, J ¼ 6.5 Hz, 3 Hz, 1H), 7.22 (d,
J ¼ 8.5 Hz, 1H), 7.33 (d, J ¼ 8 Hz, 1H), 7.39e7.46 (m, 6H), 7.60 (dd,
J ¼ 10.5 Hz, 8.5 Hz, 6H), 7.86 (dd, J ¼ 8.5 Hz, 2 Hz, 4H). 13C NMR
yl)-3-oxopropenyl)phenyl)-4-tosyloxytetrahydropyran
(3g).
1.70 (q,
Yellow semi-solid, yield 95%. 1H NMR (500 MHz, CDCl3):
d
J ¼ 12 Hz, 2H), 2.22 (dd, J ¼ 19 Hz, 12 Hz, 2H), 2.35 (s, 3H), 4.44 (dd,
J ¼ 29.5 Hz, 11 Hz, 2H), 4.88 (tt, J ¼ 5 Hz, 1 Hz, 1H), 7.15 (d, J ¼ 8 Hz,
2H), 7.25 (d, J ¼ 8 Hz, 2H), 7.35 (dd, J ¼ 27 Hz, 7.5 Hz, 4H), 7.48 (d,
J ¼ 7 Hz, 1H), 7.51 (d, J ¼ 7 Hz, 1H), 7.54e7.60 (m, 3H), 7.73e7.91 (m,
6H), 8.00 (d, J ¼ 7.5 Hz, 1H), 8.44 (s, 1H). 13C NMR (125 MHz, CDCl3):
(125 MHz, CDCl3): d 21.55, 39.65, 72.70, 76.73, 77.43, 118.61, 121.03,
126.33, 127.42, 127.46, 128.50, 129.90, 131.46, 131.78, 133.67, 133.91,
136.75, 139.67, 143.35, 146.84, 189.18. IR (KBr): 3000, 2945, 1678,
1614, 1347, 1234, 1128, 840 cmꢂ1
.
HRMS (ESIMS) for
C
33H28Br2NaO5S (M þ Na)þ Anal. calcd. 716.9922; found 716.9900.
d
21.57, 39.71, 76.70, 76.96, 77.50, 121.69, 122.18, 124.38, 126.31,
126.72, 127.45, 127.52, 127.75, 128.34, 128.56, 129.44, 129.86, 131.52,
132.48, 133.95, 134.17, 134.56, 135.42, 139.75, 143.14, 144.06, 144.86,
6.1.2.12. (2R,4R,6S)-2-Phenyl-6(4-((E)-3-(4-methylmercaptophenyl)-
3-oxopropenyl) phenyl)-4-tosyloxytetrahydropyran (3l). Yellow
190.11. IR (KBr): 3000, 2945, 1678, 1625, 1350, 1205, 1121, 868 cmꢂ1
.
semi-solid, yield 97%. 1H NMR (500 MHz, CDCl3):
d 1.79e1.89 (m,
HRMS (ESIMS) for C37H31BrNaO5S (M þ Na)þ Anal. calcd. 689.0973;
2H), 2.29e2.35 (m, 2H), 2.45 (s, 3H), 2.53 (s, 3H), 4.56 (td, J ¼ 9 Hz,
found 689.0978.
4 Hz, 2H), 4.98 (tt, J ¼ 5 Hz, 1H), 7.28e7.36 (m, 8H), 7.42 (d, J ¼ 8 Hz,

N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
243
2H), 7.50 (dd, J ¼ 15.5 Hz, 3 Hz, 1H), 7.61 (d, J ¼ 8 Hz, 2H), 7.77e7.83
2.44 (s 3H), 4.51e4.57 (m, 2H), 4.95 (tt, J ¼ 4.5 Hz, 3 Hz, 1H), 6.90 (s,
1H), 7.25e7.31 (m, 4H), 7.34 (d, J ¼ 8 Hz, 2H), 7.39 (d, J ¼ 8.5 Hz, 2H),
7.50 (d, J ¼ 16 Hz, 1H), 7.61 (d, J ¼ 8 Hz, 2H), 7.77 (d, J ¼ 16 Hz, 1H),
7.81 (d, J ¼ 8.5 Hz, 2H), 7.91e7.97 (m, 3H). 13C NMR (125 MHz,
(m, 3H), 7.95 (d, J ¼ 8.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d 14.71,
21.55, 39.83, 76.91, 77.16, 77.83, 121.73, 125.01, 125.74, 126.29,
127.50, 127.86, 128.38, 128.43, 128.84, 129.81, 134.18, 134.31, 134.43,
140.67, 143.31, 143.87, 144.77, 145.59, 189.04. IR (KBr): 3024, 2953,
2841, 1683, 1612, 1345, 1201, 1131, 853 cmꢂ1. HRMS (ESIMS) for
CDCl3):
d 21.77, 40.05, 77.41, 77.70, 78.05, 100.24, 115.94, 121.68,
125.97, 126.55, 127.71, 128.08, 128.61, 128.72, 130.06, 131.18, 131.25,
134.39,134.59,144.64,145.02,157.02,164.69,188.84. IR (KBr): 2999,
2852, 1654, 1602, 1418, 1324, 1201, 1163, 821 cmꢂ1. HRMS (ESIMS)
for C33H28NaO6S (M þ Na)þ Anal. calcd. 575.1504; found 575.1531.
C
34H32NaO5S2 (M þ Na)þ Anal. calcd. 607.1589; found 607.1569.
6.1.2.13. (2R,4R,6S)-2-Phenyl-6-(4-((E)-3-oxo-3-(2,4,6-
trimethoxyphenyl) propenyl) phenyl)-4-tosyloxytetrahydropyran
(3m). Yellow semi-solid, yield 84%. 1H NMR (500 MHz, CDCl3):
6.1.2.18. (2R,4R,6S)-2-p-Tolyl-6-(4-((E)-3-(naphthalen-2-yl)-3-
d
1.76 (q, J ¼ 11.5 Hz, 2H), 2.22 (dd, J ¼ 12.5 Hz, 4.5 Hz, 2H), 2.37 (s,
oxopropenyl)phenyl)-4-tosyloxytetrahydropyran (3r). Yellow semi-
3H), 3.88 (s, 3H), 3.89 (s, 6H), 4.23 (t, J ¼ 6.5 Hz, 1H), 4.46 (d,
J ¼ 10.5 Hz, 1H), 4.86e4.93 (m. 1H), 7.19e7.30 (m, 10H), 7.52 (d,
J ¼ 15.5 Hz, 1H), 7.65 (d, J ¼ 3 Hz, 1H), 7.72e7.78 (m, 4H), 7.86e7.88
solid, yield 80%. 1H NMR (500 MHz, CDCl3): 1H NMR (500 MHz,
d
CDCl3):
d
1.69 (q, J ¼ 24.5 Hz, 14 Hz, 2H), 2.22 (dd, J ¼ 19 Hz, 11 Hz,
2H), 2.35 (s, 6H), 4.45 (dd, J ¼ 29.5 Hz,11H, 2H), 4.88 (m,1H), 7.15 (d,
J ¼ 8 Hz, 2H), 7.25 (d, J ¼ 8 Hz, 2H), 7.32 (d, J ¼ 7 Hz, 2H), 7.38 (d,
J ¼ 7 Hz, 2H), 7.47e7.56 (m, 5H), 7.72e7.91 (m, 6H), 8.00 (d,
(d, J ¼ 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3):
d 22.86, 40.19, 56.61,
61.19, 77.72, 78.42, 106.38, 124.60, 126.03, 127.76, 128.02, 128.60,
129.03, 130.08, 130.39, 131.09, 132.85, 133.17, 137.42, 140.74, 141.12,
142.95, 144.99, 153.40, 191.64. IR (KBr): 2954, 2912, 2850, 1653,
1599, 1345, 1172, 830 cmꢂ1. HRMS (ESIMS) for C36H36NaO8S
(M þ Na)þ Anal. calcd. 651.2029; found 651.2041.
J ¼ 7.5 Hz, 1H), 8.44 (s, 1H). 13C NMR (125 MHz, CDCl3):
d 21.31,
21.38, 39.95, 77.06, 77.32, 77.74, 121.94, 122.42, 124.62, 126.55,
126.97, 127.69, 127.76, 127.99, 128.55, 128.81, 129.68, 130.10, 131.76,
132.72, 134.19, 134.41, 134.80, 135.67, 139.99, 143.38, 144.31, 145.10,
190.35. IR (KBr): 3056, 2920, 2847, 1698, 1660, 1601, 1324, 1179,
1125, 857 cmꢂ1. HRMS (ESIMS) for C38H34NaO5S (M þ Na)þ Anal.
calcd. 625.2025; found 625.2031.
6.1.2.14. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-(4-
bromophenyl)-3-oxopropenyl) phenyl)-4-tosyloxytetrahydropyran
(3n). Yellow semi-solid, yield 94%. 1H NMR (500 MHz, CDCl3):
d
1.84 (q, J ¼ 12 Hz, 2H), 2.34 (dd, J ¼ 11.5 Hz, 7 Hz, 2H), 2.46 (s, 3H),
6.1.2.19. (2R,4S,6S)-2-(3,4,5-Trimethoxyphenyl)-6-(4-((E)-3-(4-
bromophenyl)-3-oxopropenyl)phenyl)-4-tosyloxytetrahydropyran
(3s). Yellow semi-solid, yield 72%. 1H NMR (500 MHz, CDCl3):
4.60 (d, J ¼ 11 Hz, 2H), 4.99 (tt, J ¼ 4.5 Hz, 1H), 7.36 (d, J ¼ 8 Hz. 2H),
7.43e7.48 (m, 5H), 7.62e7.66 (m, 5H), 7.78e7.82 (m, 3H), 7.88 (dd,
J ¼ 7 Hz, 2 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d
21.60, 39.72, 39.77,
d 1.76e1.83 (m, 2H), 2.25e2.33 (m, 2H), 2.44 (s, 3H), 3.93 (s,
76.73, 77.24, 77.48, 121.49, 126.34, 127.14, 127.52, 128.57, 128.60,
128.76, 129.88, 129.94, 131.86, 133.59, 134.09, 134.24, 136.77, 139.19,
143.40, 144.71, 144.89, 189.18. IR (KBr): 3045, 2926, 2852, 1695,
9H),4.53 (dd, J ¼ 30 Hz, 10 Hz, 2H), 4.96 (tt, J ¼ 11 Hz, 3 Hz, 1H), 7.23
(d, J ¼ 8 Hz, 2H), 7.27e7.28 (m, 2H), 7.34 (d, J ¼ 8 Hz, 2H), 7.40 (d,,
J ¼ 8 Hz, 2H), 7.44e7.46 (m, 2H), 7.50 (s, 1H), 7.62e7.63 (m, 2H), 7.77
(d, J ¼ 8 Hz, 1H), 7.80e7.82 (m, 2H). 13C NMR (125 MHz, CDCl3):
1655, 1600, 1324, 1221, 1179, 850 cmꢂ1
. HRMS (ESIMS) for
C
33H28BrClNaO5S (M þ Na)þ Anal. calcd. 673.0427; found 673.0400.
d 21.73, 39.86, 56.45, 61.03, 72.90, 77.19, 77.64, 106.20, 121.97,
126.45, 127.61, 127.64, 128.68, 130.03, 131.64, 133.48, 134.23, 134.60,
139.91, 142.61, 143.33, 144.18, 144.48, 145.03, 153.21, 189.78. IR
6.1.2.15. (2R,4R,6S)-2-Phenyl-6-(4-((E)-3-(4-fluorophenyl)-3-
oxopropenyl)phenyl)-4-tosyloxytetrahydropyran (3o). Yellow semi-
(KBr): 3001, 2851, 1666, 1601, 1432, 1325, 1200, 1121, 825 cmꢂ1
.
solid, yield 95%. 1H NMR (500 MHz, CDCl3):
d
1.81 (q, J ¼ 11.5 Hz,
HRMS (ESIMS) for C36H35BrNaO8S (M þ Na)þ Anal. calcd. 729.1134;
2H), 2.30 (dd, J ¼ 24.5 Hz, 14.5 Hz, 2H), 2.43 (s, 3H), 4.50e4.58 (m,
2H), 4.96 (t, J ¼ 5 Hz, 1H), 7.15 (d, J ¼ 8 Hz, 3H), 7.23e7.41 (m, 8H),
7.59 (t, J ¼ 8 Hz, 2H), 7.76e7.82 (m, 3H), 8.03e8.04 (m, 3H). 13C NMR
found 729.1139.
6.1.2.20. (2R,4S,6S)-2-(4-Methoxyphenyl)-6-(4-((E)-3-(4-
bromophenyl)-3-oxopropenyl) phenyl)-4-tosyloxytetrahydropyran
(3t). Yellow semi-solid, yield 77%. 1H NMR (500 MHz, CDCl3):
(125 MHz, CDCl3):
d 21.77, 39.80, 40.05, 77.41, 77.70, 78.05, 115.77,
121.68, 125.97, 126.55, 127.71, 128.08, 128.61, 128.72, 130.06, 131.18,
131.25, 134.39, 134.59, 140.89, 143.77, 144.64, 145.02, 166.72, 188.84.
d
1.80 (q, J ¼ 11.5 Hz, 2H), 2.29 (t, J ¼ 12 Hz, 2H), 2.44 (s, 3H), 3.88 (s,
IR (KBr): 2921, 2847, 1660, 1605, 1421, 1326, 1213, 1173, 817 cmꢂ1
.
3H), 4.50 (d, J ¼ 12 Hz, 1H), 4.55 (d, J ¼ 11.5 Hz, 1H), 4.95 (m, 1H),
7.23 (d, J ¼ 7 Hz,1H), 7.34 (d, J ¼ 8 Hz, 2H), 7.39 (d, J ¼ 7 Hz, 2H), 7.40
(m, 3H), 7.46 (d, J ¼ 6.5 Hz, 2H), 7.53 (d, J ¼ 15.5 Hz, 1H), 7.57e7.60
(m, 2H), 7.76 (d, J ¼ 15 Hz,1H), 7.81 (d, J ¼ 6.5 Hz,1H), 8.02e8.05 (m,
HRMS (ESIMS) for C33H29FNaO5S (M þ Na)þ Anal. calcd. 579.1617;
found 579.1613.
6.1.2.16. (2R,4R,6S)-2-Phenyl-6-(4-((E)-3-(3,4-dimethylphenyl)-3-
3H). 13C NMR (125 MHz, CDCl3):
d 21.81, 39.89, 39.96, 55.63, 77.02,
oxopropenyl)phenyl)-4-tosyloxytetrahydropyran (3p). Yellow semi-
77.29, 77.74, 122.13, 126.48, 127.68, 127.73, 128.65, 129.00, 130.09,
130.96, 131.72, 134.30, 134.86, 139.97, 142.91, 143.10, 143.48, 145.10,
163.60, 188.75. IR (KBr): 3012, 2952, 1654, 1602, 1418, 1324, 1201,
1163, 821 cmꢂ1. HRMS (ESIMS) for C34H31BrNaO6S (M þ Na)þ Anal.
calcd. 669.0922; found 669.0912.
solid, yield 86%. 1H NMR (500 MHz, CDCl3):
d
1.83 (q, J ¼ 11.5 Hz,
2H), 2.32 (m, 9H), 2.35 (m, 2H), 2.42 (d, J ¼ 9 Hz, 2H), 4.53e4.57 (m,
2H), 4.95e4.98 (m, 1H), 7.24 (d, J ¼ 7.5 Hz, 2H), 7.31e7.35 (m, 3H),
7.40e7.42 (m, 3H), 7.48e7.53 (m, 1H), 7.60e7.61 (m, 2H), 7.66 (d,
J ¼ 9 Hz.1H), 7.75e7.80 (m, 6H). 13C NMR (125 MHz, CDCl3):
d 19.94,
20.18, 21.77, 40.03, 77.20, 77.68, 78.09, 122.35, 125.95, 126.37,
126.49, 127.70, 128.06, 128.60, 129.79, 129.95, 130.06, 134.34,
134.70, 136.09, 137.16, 140.92, 142.56, 143.45, 143.82, 145.00, 190.27.
6.1.2.21. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-(4-oxochromanyl)
phenyl)-4-tosyloxytetrahydropyran (3u). Yellow semi-solid, yield
85%. 1H NMR (500 MHz, CDCl3):
d
1.80 (q, J ¼ 11 Hz, 2H), 2.30 (t,
IR (KBr): 3056, 2920, 2847, 1698, 1660, 1601, 1324, 1179, 815 cmꢂ1
.
J ¼ 13 Hz, 2H), 2.44 (s 3H), 2.89e3.12 (m, 2H), 4.51e4.57 (m, 2H),
4.95 (tt, J ¼ 4.5 Hz, 3 Hz, 1H), 5.55e5.65 (m, 1H), 7.25e7.31 (m, 4H),
7.34 (d, J ¼ 8 Hz, 2H), 7.39 (d, J ¼ 8.5 Hz, 2H), 7.50 (d, J ¼ 16 Hz, 1H),
7.61 (d, J ¼ 8 Hz, 2H), 7.77 (d, J ¼ 16 Hz, 1H), 7.81 (d, J ¼ 8.5 Hz, 2H),
HRMS (ESIMS) for C35H34KO5S (M þ K)þ Anal. calcd. 605.1764;
found 605.1775.
6.1.2.17. (2R,4R,6S)-2-Phenyl-6-(4-(4-oxo-2-chromenyl)phenyl)-4-
7.91e7.97 (m, 2H). 13C NMR (125 MHz, CDCl3):
d 21.45, 39.95, 44.5,
tosyloxytetrahydropyran (3q). Yellow semi-solid, yield 84%. 1H NMR
77.40, 77.70, 78.05, 85.01, 116.34, 125.68, 125.97, 126.54, 127.91,
128.08, 128.77, 129.71, 130.06, 131.18, 131.25, 135.39, 136.59, 144.88,
(500 MHz, CDCl3):
d
1.80 (q, J ¼ 11 Hz, 2H), 2.30 (t, J ¼ 13 Hz, 2H),

244
N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
145.02, 164.69, 188.84. IR (KBr): 3021, 2960, 1678, 1602, 1421, 1346,
1201, 1154, 845 cmꢂ1. HRMS (ESIMS) for C33H29ClNaO6S (M þ Na)þ
Anal. calcd. 611.1271; found 611.1261.
HRMS (ESIMS) for C30H26ClNNaO7S3 (M þ Na)þ Anal. calcd.
666.0458; found 666.0442.
6.1.3. General procedure for the synthesis of flavonoid based 4-
hydroxy THPs (4aef)
6.1.2.22. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-oxo-3-p-tolyl-
propenyl)phenyl)-4-tosyloxytetrahydropyran (3v). Yellow semi-
In a flame dried round bottom flask under N2 atmosphere,
flavonoid based 4-tosyloxy THP (0.5 mmol) dissolved in trifluoro-
acetic acid (0.5 mL) heated to 140 ꢀC and reaction kept for 30 min
on same temperature. After cooling, the reaction mixture poured in
ice cold water and extracted with ethyl acetate (3 ꢄ 10 mL). The
combined organic layer was washed with brine and water and
dried on anhydrous Na2SO4. Upon evaporation of solvent in vacuo,
which gave pure flavonoid based 4-hydroxy THPs.
solid, yield 90%. 1H NMR (500 MHz, CDCl3):
d
1.83 (q, J ¼ 12 Hz,
2H), 2.33 (dd, J ¼ 12 Hz, 3 Hz, 2H), 2.43 (s, 3H), 2.45 (s, 3H), 4.58 (d,
J ¼ 11 Hz, 2H), 5.00 (tt, J ¼ 11 Hz, 5 Hz,1H), 7.30 (d, J ¼ 8 Hz, 3H), 7.35
(d, J ¼ 8 Hz,1H), 7.42 (d, J ¼ 8.5 Hz, 2H), 7.53 (d, J ¼ 15.5 Hz, 2H), 7.62
(d, J ¼ 8.5 Hz, 3H), 7.68 (s, 1H), 7.77 (s, 1H), 7.80 (t, J ¼ 9 Hz, 1H), 7.83
(d, J ¼ 8 Hz, 1H), 7.93 (d, J ¼ 8.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d
21.64, 21.66, 39.74, 39.85, 76.72, 77.03, 77.68, 118.41, 121.66,
122.08, 127.23, 127.57, 128.65, 129.34, 129.97, 133.52, 134.14, 134.23,
134.54, 135.49, 139.38, 143.17, 143.70, 143.79, 144.11, 144.95, 189.83.
6.1.3.1. (2R,4R,6S)-2-Phenyl-6-(4-((E)-3-(4-fluorophenyl)-3-
oxopropenyl)phenyl)-4-hydroxytetrahydropyran (4a). Yellow semi-
IR (KBr): 2921, 2847, 1660, 1605, 1421, 1326, 1213, 1173, 817 cmꢂ1
.
HRMS (ESIMS) for C34H31ClNaO5S (M þ Na)þ Anal. calcd. 609.1478;
solid, yield 90%. 1H NMR (500 MHz, CDCl3):
d
1.60 (q, J ¼ 11.5 Hz,
found 609.1501.
2H), 2.22 (s, br, D2O exchangeable,1H), 2.29 (dt, J ¼ 12 Hz, 2 Hz, 2H),
3.97 (tt, J ¼ 4.5 Hz, 11 Hz, 1H), 4.52 (dd, J ¼ 26 Hz, 7 Hz, 2H), 7.23 (d,
J ¼ 7 Hz, 1H), 7.34 (d, J ¼ 8 Hz, 2H), 7.39 (d, J ¼ 7 Hz, 2H), 7.46 (d,
J ¼ 6.5 Hz, 2H), 7.53 (d, J ¼ 15.5 Hz, 1H), 7.57e7.60 (m, 3H), 7.75e
7.82 (m, 3H), 8.03 (d, J ¼ 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3):
6.1.2.23. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-formylphenyl)-4-
tosyloxytetrahydropyran (3w). Yellow semi-solid, yield 90%. 1H
NMR (CDCl3, 500 MHz):
d
1.96 (q, J ¼ 11.5 Hz, 2H), 2.41 (dd, J ¼ 3 Hz,
2 Hz, 2H), 2.57 (s, 3H), 4.66 (d, J ¼ 10 Hz, 2H), 5.08 (tt, J ¼ 11.5 Hz,
6.5 Hz, 1H), 7.40e7.41 (m, 2H), 7.43e7.50 (m, 8H), 7.94 (d, J ¼ 8 Hz,
2H), 10.00 (s, 1H). IR (KBr): 3010, 2990, 2885, 1701, 1405, 1325, 1205,
1125, 843 cmꢂ1. HRMS (ESIMS) for C25H23ClNaO5S (M þ Na)þ Anal.
calcd. 493.0852; found 493.0810.
d 39.71, 68.01, 76.70, 77.50, 124.38, 127.75, 128.34, 128.56, 129.44,
129.86, 131.52, 132.48, 134.17, 143.14, 144.06, 144.86, 168.56, 190.11.
IR (KBr): 3433.8, 2965.2, 2921.7, 2852.1, 1634.8, 1452.1, 1265.2,
1156.5, 1065.2, 900.0, 760.87, 700 cmꢂ1
. HRMS (ESIMS) for
C
26H23FNaO3 (M þ Na)þ Anal. calcd. 425.1529; found 425.1545.
6.1.2.24. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-(4-oxo-2-chromenyl)
6.1.3.2. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-(4-fluorophenyl)-
3-oxopropenyl) phenyl)-4-hydroxytetrahydropyran (4b). Yellow
phenyl)-4-tosyloxytetrahydropyran (3x). Yellow semi-solid, yield
88%. 1H NMR (500 MHz, CDCl3):
d
1.87 (q, J ¼ 11 Hz, 2H), 2.32 (t,
semi-solid, yield 90%. 1H NMR (500 MHz, CDCl3):
d 1.73e1.84 (m,
J ¼ 13 Hz, 2H), 2.47 (s 3H), 4.57 (d, J ¼ 11.5 Hz, 2H), 4.99 (tt,
2H), 2.046 (s, br, D2O exchangeable, 1H), 2.22e2.85 (m, 2H), 4.14 (tt,
J ¼ 11 Hz, 3 Hz, 1H), 4.66 (t, J ¼ 3 Hz, 2H), 7.01 (d, J ¼ 9 Hz, 2H), 7.36
(d, J ¼ 8.5 Hz, 2H), 7.41 (d, J ¼ 9 Hz, 2H), 7.48 (d, J ¼ 8 Hz, 2H), 7.59 (d,
J ¼ 9 Hz, 3H), 7.95 (d, J ¼ 8 Hz, 2H), 8.18 (d, J ¼ 8 Hz, 1H). 13C NMR
J ¼ 4.5 Hz, 3 Hz, 1H), 7.25e7.41 (m, 16H), 7.85 (d, J ¼ 8 Hz, 1H). 13
C
NMR (125 MHz, CDCl3): d 21.64, 40.00, 77. 24, 77. 97, 78.05, 100. 45,
116.64, 123.68, 125.70, 126.55, 127.75, 128.85, 128.91, 129.72, 130.06,
131.14, 131.25, 134.39, 135.61, 144.71, 146.02, 157.02, 164.69, 188.84.
(125 MHz, CDCl3):
d 40.05, 69.46, 77.70, 78.05, 115.94, 121.68,
IR (KBr): 3011, 2995, 2872, 1701, 1614, 1415, 1365, 1212, 1163 cmꢂ1
.
125.97, 126.55, 127.71, 128.72, 130.06, 131.25, 134.39, 134.59, 140.89,
143.77, 144.64, 164.69, 166.72, 188.84. IR (KBr): 3434, 3010, 2922,
2843, 1734, 1626, 1456, 1256, 1069, 808.8 cmꢂ1. HRMS (ESIMS) for
HRMS (ESIMS) for C33H27ClNaO6S (M þ Na)þ Anal. calcd. 609.1115;
found 609.1132.
C
26H22ClFNaO3 (M þ Na)þ Anal. calcd. 459.1139; found 459.1150.
6.1.2.25. (2R,4R,6S)-2-Phenyl-6-(4-(4-oxochromanyl)phenyl)-4-
tosyloxytetrahydropyran (3z). Yellow semi-solid, yield 84%. 1H NMR
6.1.3.3. (2R,4S,6S)-2-(4-Chlorophenyl)-6-(4-((E)-3-oxo-3-p-tolylpro-
(500 MHz, CDCl3):
d
1.81 (q, J ¼ 11 Hz, 2H), 2.28 (t, J ¼ 13 Hz, 2H),
penyl)phenyl)-4-hydroxytetrahydropyran (4c). Yellow semi-solid,
2.35 (s, 3H), 2.90e3.15 (m, 2H), 4.49e4.54 (m, 2H), 4.93 (tt,
J ¼ 4.5 Hz, 3 Hz, 1H), 5.55e5.65 (m, 1H), 7.25e7.35 (m, 4H), 7.37 (d,
J ¼ 8 Hz, 2H), 7.41 (d, J ¼ 8.5 Hz, 2H), 7.50 (d, J ¼ 16 Hz, 1H), 7.61 (m,
2H), 7.77 (d, J ¼ 16 Hz, 1H), 7.85 (d, J ¼ 8.5 Hz, 2H), 7.91e7.97 (m,
yield 88%. 1H NMR (500 MHz, CDCl3): 1H NMR (500 MHz,
d
CDCl3):
d
1.63e1.72 (m, 2H), 2.12e2.25 (dd, J ¼ 12.5 Hz, 4 Hz, 2H),
2.35 (s, 3H), 3.91 (tt, J ¼ 10.5 Hz, 3 Hz,1H), 4.45 (d, J ¼ 32 Hz,11.5 Hz,
2H), 7.11e7.15 (m. 2H), 7.16e7.19 (m, 2H), 7.23 (d, J ¼ 8 Hz, 2H),
7.28e7.32 (m, 2H), 7.33e7.36 (m, 2H), 7.52 (d, J ¼ 8 Hz, 2H), 7.71 (d,
2H). 13C NMR (125 MHz, CDCl3):
d 21.41, 39.74, 39.85, 43.51, 76.72,
77.03, 77.68, 84.31, 116.34, 121.94, 122.42, 124.62, 126.55, 126.97,
127.69, 128.81, 129.68, 130.10, 131.76, 132.72, 134.19, 144.88, 146.02,
165.32, 189.21. IR (KBr): 3026, 2965, 1679, 1612, 1436, 1356, 1200,
1145 cmꢂ1. HRMS (ESIMS) for C33H30O6NaS (M þ Na)þ Anal. calcd.
577.1661; found 577.1673.
J ¼ 8 Hz, 2H). 13C NMR (125 MHz, CDCl3):
d 21.57, 40.07, 69.24, 76.94,
78.10, 125.99, 126.53, 128.09, 128.65, 128.79, 129.06, 129.48, 130.08,
134.41, 134.69, 135.73, 143.51, 143.81, 145.03, 190.10. IR (KBr):
3447.1, 2960.87, 2886, 1652, 1543, 1088, 804 cmꢂ1. HRMS (ESIMS)
for C27H25ClNaO3 (M þ Na)þ Anal. calcd. 455.1390; found 455.1392.
6.1.2.26. 2-((E)-5-(4-((2S,4S,6R)-6-(4-Chlorophenyl)-4-
tosyloxytetrahydropyran-2-yl)ben zyliden e)-4 -o xo-2-
thioxothiazolidin-3-yl)acetic acid (3zb). Yellow semi-solid, yield
6.1.3.4. (2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-(2-
h y d r o x y p h e n y l ) - 3 - o x o p r o p - 1 - e n y l ) p h e n y l ) - 4 -
hydroxytetrahydropyran (4d). Yellow semi-solid, yield 85%. 1H
70%. 1H NMR (500 MHz, d-DMSO):
d
1.81 (q, J ¼ 11 Hz, 2H), 2.30 (dd,
NMR (500 MHz, CDCl3):
d
1.79 (q, J ¼ 11.5 Hz, 2H), 2.19 (s, br, D2O
J ¼ 25 Hz, 15 Hz, 2H), 2.41 (s, 3H), 4.51e4.56 (m, 2H), 4.77 (s, 2H),
4.95e4.97 (m, 1H), 7.15 (d, J ¼ 8 Hz, 2H), 7.19e7.41 (m, 6H), 7.66 (d,
J ¼ 10.5 Hz, 1H), 7.76e7.82 (m, 2H), 8.03e8.04 (m, 2H). 13C NMR
exchangeable, 1H), 2.40 (dd, J ¼ 11 Hz, 2H), 4.02 (tt, J ¼ 15.5 Hz,
8.5 Hz, 1H), 4.55 (dd, J ¼ 32 Hz, 11.5 Hz, 2H), 6.94e7.04 (m, 1H), 7.03
(d, J ¼ 8.5 Hz, 1H), 7.35 (d, J ¼ 7.5 Hz, 2H), 7.42e7.52 (m, 4H), 7.64 (t,
J ¼ 8.5 Hz, 3H), 7.74e7.79 (m, 1H), 7.81e7.89 (m, 2H). 13C NMR
(125 MHz, CDCl3):
d 21.81, 39.89, 39.96, 46.63, 77.01, 77.46, 77.74,
114.00, 127.68, 127.73, 128.65, 129.00, 130.09, 130.96, 131.72, 134.30,
134.86, 139.97, 142.91, 143.10, 143.48, 145.10, 165.60, 168.75, 193.97.
(125 MHz, CDCl3): d 40.08, 68.56, 77.22, 77.42, 118.93, 120.26,
120.53, 121.66, 122.10, 126.72, 127.82, 127.89, 129.12, 129.92, 130.23,
131.90, 136.75, 143.90, 145.14, 163.88, 193.93. IR (KBr): 3440, 2943,
IR (KBr): 2921, 2847, 1660, 1605, 1421, 1326, 1213, 1173, 817 cmꢂ1
.

N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
245
2814, 1701, 1606, 1401, 1256, 1069, 801 cmꢂ1. HRMS (ESIMS) for
C
6.1.4.4. (E)-4-(3-(Naphthalen-2-yl)-3-oxopropenyl)benzaldehyde
26H23BrNaO4 (M þ Na)þ Anal. calcd. 501.0677; found 501.0683.
(2d). Light yellow solid; yield 90%; 1H NMR (CDCl3, 500 MHz):
d
7.60 (td, J ¼ 1.5 Hz, 8.5 Hz, 1H), 7.64 (td, J ¼ 1.5 Hz, 8 Hz, 1H), 7.79
(d, J ¼ 12 Hz, 1H), 7.84 (d, J ¼ 7 Hz, 1H), 7.88 (d, J ¼ 13 Hz, 2H), 7.92
(m,1H), 7.96e7.98 (m, 2H), 8.02 (d, J ¼ 9.5 Hz,1H), 8.12 (dd, J ¼ 2 Hz,
9 Hz, 1H), 10.07 (s, 1H). IR (KBr): 3021, 2945, 2882, 1712, 1646,
1402 cmꢂ1. HRMS (ESIMS) for C20H14NaO2 (M þ Na)þ Anal. calcd.
309.0891; found 309.0880.
6.1.3.5. (2R,4R,6S)-2-Phenyl-6-(4-(4-oxo-4H-chromenyl)phenyl)-4-
hydroxy tetrahydropyran (4e). Yellow semi-solid, yield 85%. 1H
NMR (500 MHz, CDCl3):
d 1.68e1.77 (m, 2H), 2.15e2.22 (m, 2H),
3.90 (tt, J ¼ 11 Hz, 3 Hz, 1H), 4.40 (t, J ¼ 11.5 Hz, 2H), 6.79 (dd,
J ¼ 6.5 Hz, 3 Hz, 2H), 6.92 (s, 1H), 7.15 (d, J ¼ 8.5 Hz, 2H), 7.17e7.21
(m, 3H), 7.27 (d, J ¼ 8.5 Hz, 2H), 7.37 (dd, J ¼ 6 Hz, 3 Hz, 2H), 7.74 (d,
J ¼ 8 Hz, 2H). 13C NMR (125 MHz, CDCl3):
d
39.78, 39.85, 65.07,
6.1.4.5. (E)-4-(3-(4-Fluorophenyl)-3-oxopropenyl)benzaldehyde (2e).
76.92, 77.19, 121.80, 122.23, 126.39, 127.57, 127.63, 128.60, 128.69,
129.38, 129.99, 131.62, 134.16, 135.56, 139.83, 156.09, 163.07, 190.04.
IR (KBr): 3446, 2971, 2880, 1652, 1513, 1208, 799 cmꢂ1. HRMS
(ESIMS) for C26H21NaO4 (M þ Na)þ Anal. calcd. 421.1416; found
421.1441.
Light yellow solid; yield 89%; 1H NMR (CDCl3, 500 MHz):
d 7.18 (d,
J ¼ 8.5 Hz, 2H), 7.58e7.61 (m, 1H), 7.68 (m, 1H), 7.79e7.85 (m, 2H),
7.94 (d, J ¼ 8 Hz, 2H), 8.07e8.10 (m, 2H), 10.04 (s, 1H). 13C NMR
(CDCl3, 125 MHz):
d 115.58, 115.67, 115.76, 115.86, 124.11, 128.69,
128.84, 130.07, 131.01, 131.08, 137.17, 142.87, 191.26. IR (KBr): 3027,
2991, 2801, 1743, 1656, 1414 cmꢂ1. HRMS (ESIMS) for C16H11FNaO2
(M þ Na)þ Anal. calcd. 277.0641; found 277.0630.
6.1.3.6. (2R,4S,6S)-2-(4-Bromophenyl)-6-(4-((E)-3-(4-
bromophenyl)-3-oxopropenyl) phenyl)-4-hydroxytetrahydropyran
(4f). Yellow semi-solid, yield 90%. 1H NMR (500 MHz, CDCl3):
6.1.4.6. (E)-4-(3-(4-Bromophenyl)-3-oxopropenyl)benzaldehyde (2f).
d
1.77e1.86 (m, 2H), 2.20 (s, br, D2O exchangeable, 1H), 2.30e2.35
Light yellow solid; yield 85%; 1H NMR (CDCl3, 500 MHz):
d 7.58 (d,
(m, 2H), 4.07 (tt, J ¼ 10.5 Hz, 3 Hz, 1H), 4.45 (d, J ¼ 32 Hz, 11.5 Hz,
J ¼ 15.5 Hz, 1H), 7.66 (dd, J ¼ 6.5 Hz, 1.5 Hz, 2H), 7.79 (d, J ¼ 8 Hz,
2H), 7.31e7.32 (m, 2H), 7.35 (d, J ¼ 8 Hz, 2H), 7.47 (s, 1H), 7.61e7.66
2H), 7.83 (d, J ¼ 15.5 Hz, 1H), 7.90 (dd, J ¼ 7 Hz, 2 Hz, 2H), 7.93 (d,
(m, 4H), 7.78 (s,1H), 7.82 (d, J ¼ 8.5 Hz, 2H), 7.88 (d, J ¼ 8 Hz, 2H). 13
C
J ¼ 8 Hz, 2H), 10.05 (s, 1H). 13C NMR (125 MHz, CDCl3):
d 124.30,
NMR (125 MHz, CDCl3):
d
39.83, 67.21, 77.49, 77.87, 122.05, 125.75,
128.58, 129.09, 130.24, 130.41, 132.26, 136.62, 137.57, 140.49, 143.55,
126.29, 127.50, 127.86, 128.41, 128.55, 129.24, 129.84, 134.17, 134.45,
135.49,140.70,143.77,189.86. IR (KBr): 3454, 2961, 2878,1651,1541,
1091, 801 cmꢂ1. HRMS (ESIMS) for C26H22Br2NaO3 (M þ Na)þ Anal.
calcd. 562.9833; found 562.9853.
188.99, 191.60. IR (KBr): 3020, 2985, 2881, 1711, 1654, 1426 cmꢂ1
.
HRMS (ESIMS) for C16H11BrNaO2 (M þ Na)þ Anal. calcd. 336.9840;
found 336.9834.
6.1.4.7. (E)-4-(3-Oxo-3-(2,4,6-trimethoxyphenyl)propenyl)benzalde-
6.1.4. General procedure for synthesis of chalcone based aldehyde
(2aen)
hyde (2g). Light yellow solid; yield 80%; 1H NMR (CDCl3, 500 MHz):
d
3.95 (s, 3H), 3.96 (s, 6H), 7.29 (s, 2H), 7.52e7.60 (m, 1H), 7.71 (s,
Substituted ketone (5 mmol) and NaOH (0.2 g, 5 mmol) were
dissolved in ethanol (20 mL) in Erlenmeyer flask and stirred at
room temperature for 10 min. Aldehyde (3 mmol, 5 mL) was added
and the mixture was stirred at room temperature. TLC monitoring,
cold aq. 2 M HCl added in the reaction mixture to neutralize it. In
most cases, the product was obtained as a pale yellow precipitate
after neutralization followed by filtration under vacuum and
recrystallized from ethanol.
1H), 7.79e7.82 (m, 2H), 7.84- (d, J ¼ 5.5 Hz, 1H), 7.94 (d, J ¼ 8 Hz,
1H). IR (KBr): 3033, 2955, 2888, 1717, 1636, 1413, 1253 cmꢂ1. HRMS
(ESIMS) for C19H18NaO5 (M þ Na)þ Anal. calcd. 349.1052; found
349.1055.
6.1.4.8. (E)-4-(3-(4-Methoxyphenyl)-3-oxopropenyl)benzaldehyde
(2h). Light yellow solid; yield 78%; 3.92 (s, 3H), 7.01 (d, J ¼ 9 Hz,
2H), 7.60e7.70 (m, 2H), 7.80 (d, J ¼ 8 Hz, 2H), 7.95 (d, J ¼ 8 Hz, 2H),
8.07 (d, J ¼ 8.5 Hz, 2H), 10.06 (s, 1H). 13C NMR (125 MHz, CDCl3):
6.1.4.1. (E)-4-(3-Oxo-3-p-tolylpropenyl)benzaldehyde
(2a).
2.45 (s,
d 55.71, 114.15, 124.81, 128.92, 130.36, 131.11, 137.28, 140.98, 142.14,
Light yellow solid; yield 84%; 1H NMR (CDCl3, 500 MHz):
d
142.94, 163.90, 188.25, 191.67. IR (KBr): 3027, 2991, 2801, 1743, 1656,
1414 cmꢂ1. HRMS (ESIMS) for C17H14NaO3 (M þ Na)þ Anal. calcd.
289.0841; found 289.0816.
3H), 7.32 (d, J ¼ 7.5 Hz, 2H), 7.57e7.69 (m, 2H), 7.79 (d, J ¼ 8 Hz, 2H),
7.94 (d, J ¼ 8.5 Hz, 4H), 10.05 (s, 1H). IR (KBr): 3014, 2961, 2878,
1708, 1641, 1421 cmꢂ1. HRMS (ESIMS) for C17H14NaO2 (M þ Na)þ
Anal. calcd. 273.0891; found 273.0883.
6.1.4.9. (E)-4-(3-(2-Hydroxyphenyl)-3-oxopropenyl)benzaldehyde
(2i). Light yellow solid; yield 75%; 1H NMR (CDCl3, 500 MHz):
6.1.4.2. (E)-4-(3-(4-Methylmercaptophenyl)-3-oxopropenyl)benzal-
d
6.97 (t, J ¼ 7.5 Hz, 1H), 7.05 (d, J ¼ 8.5 Hz, 1H), 7.53 (d, J ¼ 7.5 Hz,
2H), 7.82 (d, J ¼ 7.5 Hz, 2H), 7.92e7.96 (m, 4H),10.06 (s,1H),12.66 (s,
D2O exchangeable, 1H). 13C NMR (CDCl3, 125 MHz):
118.80, 119.05,
dehyde (2b). Light yellow solid; yield 85%; 1H NMR (CDCl3,
500 MHz):
d
2.56 (s, 3H), 7.33 (d, J ¼ 8.5 Hz, 2H), 7.63 (d, J ¼ 16 Hz,
d
1H), 7.79 (d, J ¼ 8 Hz, 2H), 7.83 (d, J ¼ 16 Hz, 1H), 7.94 (d, J ¼ 8.5 Hz,
119.87, 123.08, 129.06, 129.70, 130.28, 136.87, 137.49, 140.22, 143.45,
163.71, 191.43, 193.28. IR (KBr): 3021, 2945, 2882, 1712, 1646, 1402,
1205 cmꢂ1. HRMS (ESIMS) for C16H12NaO3 (M þ Na)þ Anal. calcd.
275.0684; found 275.0687.
2H), 7.97 (d, J ¼ 8.5 Hz, 2H), 10.05 (s, 1H). 13C NMR (125 MHz,
CDCl3): d 14.93, 124.65, 12.26, 128.98, 129.18, 130.38, 134.09, 137.38,
140.83, 142.65, 146.52, 188.74, 191.64. IR (KBr): 3021, 2945, 2882,
1712, 1646, 1402, 1205 cmꢂ1. HRMS (ESIMS) for C17H14NaO2S
(M þ Na)þ Anal. calcd. 305.0612; found 305.0604.
6.1.4.10. (E)-4-(3-(3,4-Dimethylphenyl)-3-oxopropenyl)benzalde-
hyde (2j). Light yellow solid; yield 78%; 1H NMR (CDCl3, 500 MHz):
6.1.4.3. (E)-4-(3-(4-Chlorophenyl)-3-oxopropenyl)benzaldehyde (2c).
d
2.35 (s, 6H), 7.63e7.69 (m, 2H), 7.78e7.79 (m, 5H), 7.92 (m, 2H),
Light yellow solid; yield 83%; 1H NMR (CDCl3, 500 MHz):
d
7.50 (d,
10.05 (s, 1H). 13C NMR (CDCl3, 125 MHz):
d
20.01, 20.28, 123.26,
J ¼ 8.5 Hz, 2H), 7.70 (d, J ¼ 11 Hz, 1H), 7.81 (t, J ¼ 8.5 Hz, 3H), 7.94 (d,
J ¼ 8 Hz, 2H), 7.98 (d, J ¼ 8.5 Hz, 2H), 10.06 (s, 1H). IR (KBr): 3020,
2985, 2881, 1711, 1654, 1426 cmꢂ1. HRMS (ESIMS) for C16H11ClNaO2
(M þ Na)þ Anal. calcd. 293.0345; found 293.0388.
125.11, 126.51, 128.97, 129.07, 129.89, 130.13, 130.37, 137.32, 137.41,
140.96, 142.39, 143.11, 190.01, 191.67. IR (KBr): 2943, 2814, 1701,
1606, 1401, 1256, 1069, 801 cmꢂ1. HRMS (ESIMS) for C18H16NaO2
(M þ Na)þ Anal. calcd. 287.1048; found 287.1032.

246
N. Ahmed et al. / European Journal of Medicinal Chemistry 75 (2014) 233e246
6.1.4.11. (E)-2-(5-(4-Formylbenzylidene)-4-oxo-2-thioxothiazolidin-
Acknowledgments
3-yl)acetic acid (2n). Light yellow solid; yield 70%; 1H NMR (CDCl3,
500 MHz):
d
4.75 (s, 2H), 7.88e7.90 (m, 2H), 7.94e7.97 (m, 1H),
Authors are grateful to BRNS, BARC Mumbai and DST New Delhi
for financial support and NKK for fellowship from Council of Sci-
entific and Industrial Research (CSIR), New Delhi, India. The re-
viewers are highly appreciated for their valuable suggestions/
comments in improving the manuscript.
8.03e8.07 (m, 2H), 10.07 (s, 1H). IR (KBr): 3475, 3072, 2923, 2852,
1701, 1443, 1262, 1094, 1030, 804, 781 cmꢂ1. HRMS (ESIMS) for
C
13H9NNaO4S2 (M þ Na)þ Anal. calcd. 329.9871; found 329.9888.
6.1.5. General procedure for the synthesis of flavone based aldehyde
(2k)
To a solution of the 20-hydroxychalcone aldehyde 2i (1 equiv) in
DMSO (5.0 mL/mmol) was added I2 (0.01 equiv). The mixture was
heated at 110 ꢀC for 1 h. Then, the reaction mixture was cooled to
room temperature and poured into ice cold water to precipitate,
washed with aqueous sodium thiosulphate solution to remove
excess I2, then washed with water and dried to get pure flavone
based aldehyde.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.01.033.
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solid; yield 80%; 1H NMR (CDCl3, 500 MHz):
d 6.90 (s, 1H), 7.44 (t,
J ¼ 7.5 Hz, 1H), 7.59 (d, J ¼ 9 Hz, 1H), 7.73 (td, J ¼ 8.5 Hz, 1 Hz, 1H),
8.03 (d, J ¼ 8.5 Hz, 2H), 8.09 (d, J ¼ 8.5 Hz, 2H), 8.22 (d, J ¼ 7 Hz, 1H).
13C NMR (CDCl3, 125 MHz):
d 109.13, 118.17, 123.93, 125.63, 125.82,
126.90, 130.17, 134.23, 137.08, 138.09, 156.23, 161.70, 178.27, 191.33.
IR (KBr): 3021, 2945, 2882, 1712, 1646, 1402, 1205 cmꢂ1. HRMS
(ESIMS) for C16H10NaO3 (M þ Na)þ Anal. calcd. 273.0528; found
273.0514.
6.1.6. General procedure for the synthesis of flavanone based
aldehyde (2l)
20-Hydroxychalcone aldehyde 2i (1 mmol) and sodium acetate
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mixture was then allowed to cool to room temperature and poured
into ice-water (30 mL) and extracted with CH2Cl2 (3 ꢄ 15 mL). The
combined organic layer was washed with brine, dried over anhyd.
Na2SO4, and concentrated under vacuo. The residue was column
chromatographed on silica gel, eluting with mixture of ethyl ace-
tate/hexane 1:4, to afford flavanone aldehyde.
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6.1.6.1. 4-(4-Oxochromanyl)benzaldehyde (2l). Light yellow solid;
yield 81%; 1H NMR (CDCl3, 500 MHz):
d 2.92e3.07 (m, 2H), 5.57 (dd,
J ¼ 13.5 Hz, 3.5 Hz, 1H), 7.07e7.10 (m, 2H), 7.54 (td, J ¼ 7 Hz, 1.5 Hz,
1H), 7.67 (d, J ¼ 8 Hz, 2H), 7.93e7.97 (m, 3H), 10.05 (s, 1H). IR (KBr):
3100, 2934, 2847, 1731, 1623,1460,1421,1330,1239,1060, 834 cmꢂ1
.
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6.2. MTT assay
Hep3b, MCF-7 and HeLa cell lines were maintained in RPMI
1640 culture medium supplemented with 10% heat-inactivated
fetal calf serum. The cells were plated at a density of 5 ꢄ 103
cells/well in a 96-well plate, and cultured for 24 h at 37 ꢀC. The cells
were subsequently exposed to drugs. The plates were incubated for
48 h and cell proliferation was measured by adding 20 mL of MTT
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were incubated for a further 4 h at 37 ꢀC in a humidified chamber
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absorbance was recorded at 570 nm. The results values were
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