Synthesis and anticancer activity of γ-(triazolyl ethylidene)butenolides and polyfunctional pyrrolinones

Article abstract of DOI:10.1016/j.ejmech.2014.05.042

A series of novel γ-(triazolyl ethylidene)butenolides (4-23) were prepared from commercially available l-ascorbic acid in good yields. These butenolides on reaction with ethanolic ammonia/amines led to formation of respective 5-hydroxy pyrrolinones (24-33

Full text of DOI:10.1016/j.ejmech.2014.05.042

Accepted Manuscript
Synthesis and anticancer activity of γ-(triazolyl ethylidene)butenolides and
polyfunctional pyrrolinones
N. Devender , K.K.G. Ramakrishna , Hamidullah , Sanjeev K. Shukla , Rituraj
Konwar , Rama P. Tripathi
PII:
S0223-5234(14)00458-9
10.1016/j.ejmech.2014.05.042
EJMECH 7000
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 23 October 2013
Revised Date: 21 January 2014
Accepted Date: 14 May 2014
Please cite this article as: N. Devender, K.K.G. Ramakrishna, Hamidullah, S.K. Shukla, R. Konwar,
R.P. Tripathi, Synthesis and anticancer activity of γ-(triazolyl ethylidene)butenolides and polyfunctional
pyrrolinones, European Journal of Medicinal Chemistry (2014), doi: 10.1016/j.ejmech.2014.05.042.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis and anticancer activity of γ-(triazolyl ethylide
Leave this area blank for abstract info.
ne)butenolides and polyfunctional pyrrolinones
N. Devender, K. K. G. Ramakrishna, Hamidullah, Sanjeev K. Shukla, Rituraj Konwar and Rama P.
Tripathi*
Synthesis and bioevaluation of a novel γ-(triazolyl ethylidene)butenolides and consequent pyrrolinones is
reported. In which, compound 25 showed potent activity (IC = 11.3 µM) against MDA-MB-231 cells in
5
0
vitro.

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Synthesis and anticancer activity of γ-(triazolyl ethylidene)butenolides and
polyfunctional pyrrolinones
a,1
a
b,1
c,d
b,d
N. Devender , K. K. G. Ramakrishna , Hamidullah , Sanjeev K. Shukla , Rituraj Konwar *,
a,d
Rama P. Tripathi *
a
b
c
Medicinal and Process Chemistry Division, Endocrinology Division, Sophisticated Analytical
d
Instrumental Facility, CSIR-Central Drug Research Institute, Lucknow-226031, India. Academy of
Scientific and Innovative Research, New Delhi-110001, India.
*
Corresponding Author.
E-mail address: rpt.cdri@gmail.com, rp_tripathi@cdri.res.in (Rama P. Tripathi).
Tel: +91 0522 2612411. Fax: +91 522 2623405/ 2623938/2629504.
1
These authors contributed equally to this work.
Abstract: A series of novel γ-(triazolyl ethylidene)butenolides (4-23) were prepared from
commercially available L-ascorbic acid in good yields. These butenolides on reaction with
ethanolic ammonia/amines led to formation of respective 5-hydroxy pyrrolinones (24-33). The
two of these pyrrolinones on dehydration with p-toluenesulfonic acid, were transformed into γ-
(triazolyl ethylidene)pyrrolinones (34, 35). Among all the newly synthesized hybrid molecules
tested for anticancer activity in vitro, compounds 24, 25, 26, 27, 28, 30 and 32 showed
significant activity against MCF-7, MDA-MB-231, PC-3 or U-937 cells. In particular compound
2
5 (IC =11.3 µM) exhibited most potent activity against breast cancer cells and preliminary
50
studies revealed that potency of this compound is due to ROS generation, subsequent activation
of p38, leading to apoptosis and inhibition of cancer cells.
Keywords: γ-ethylidenebutenolide, 5-hydroxy pyrrolinone, γ-ethylidenepyrrolinone, 1,2,3-
triazole, anticancer activity.

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1
. Introduction
γ-Alkylidenebutenolides (γ-AIBs), an important class of naturally occurring molecules [1-4], are
endowed with a wide range of biological activities such as antibacterial, anticancer, antibiotic,
and phospholipase A2 inhibition etc [2,5-7]. Due to their biological significance, numerous
synthetic strategies have been developed and reviewed by groups of Rao [3,4], Negishi and
Kotora [8] and Bruckner [9]. The three extensive synthetic pathways known so far for γ-AIBs
are: (1) alkylidenation of five membered heterocycles, such as 2-oxyfuran [10-14], γ-lactones
[
15-18], and maleic anhydrides [19,20]; (2) cyclization of γ-hydroxy and γ-oxoacids or their
equivalents [21,22] such as γ-oxoacylpalladium complexes [23] and (3) lactonization of alk-4-
ynoic and alk-4-enoic acids [24-26]. In this endeavour yet another route for γ-AIBs from
commercially available L-ascorbic acid has been developed by our group and others [27,28].
Cochinolide (Fig. 1, A), naturally occuring γ-alkylidene bicyclic butenolide isolated from the
root bark of Homalium cochinchinensis shows antiviral activity [29]. γ-AIBs can be transformed
efficiently into pyrrolinone derivatives [30,31] and this class of compounds are wide ranging
heterocycles as several of them are biologically active compounds, potent pharmaceuticals and
natural products [32-34]. 3-Hydroxy-1H-pyrrol-2(5H)-one analogues possess various fascinating
biological activities, such as enzyme inhibition, antiviral and antibacterial activities [35-37]. One
of such pyrrolinone derivative ethyl-1-benzyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylate (Fig. 1, B) is a highly specific aldose reductase inhibitor [36]. Since the enhanced
activity of aldose reductase is accomplice with increased resistance to chemotherapeutic drugs, it
has been accounted that such compounds reinforce the cytotoxic effect of the anticancer agents,
doxorubicin and cisplatin in HeLa cervical carcinoma cells [37]. Further, pyrrole-2(5H)-one
series of compounds are known as blockers of S100 proteins, involving in regulation of the

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localization and activity of other proteins by direct protein-protein interactions and have potential
therapeutic relevance in cancer chemotherapy. One of such compound 5-(3,5-
bis(trifluoromethyl)phenyl)-3-hydroxy-1-(2-hydroxypropyl)-4-(4-methylbenzoyl)-1H-pyrrol-
2
(5H)-one (Fig. 1, C) is shown to inhibit S100A10 proteins and displays anticancer activity [38].
Insert fig. 1 here >
<
γ-Alkylidenepyrrolinones, where ring oxygen is replaced by nitrogen in γ-AIBs have distinct
biological properties particularly among various other alkylidinepyrrolinones [39-44]. 1,2,3-
Triazoles are privileged structures as they act as surrogate of peptide bond and offer intriguing
biological activities. In particularly 1,4-disubstituted 1,2,3-triazoles can effectively mimic trans-
amide bonds because of their similar size, planarity, H-bonding capabilities and dipole moment
[
45]. Keeping in view the above facts and our continuous efforts on the above mentioned
prototypes, we were prompted to synthesize small libraries of novel hybrid molecules consisting
of γ-AIBs or pyrrolinones as one pharmacophore and triazoles the other pharmacophore, and
evaluate their biological activities. Thus, the present work depicts the synthesis of azido
ethylidenebutenolides and their click reaction with different terminal alkynes to give respective
triazolyl ethylidenebutenolides. The latter on reaction with ethanolic ammonia or different
amines resulted in respective 5-hydroxy pyrrolinones in good yields. Finally, the obtained 5-
hydroxy pyrrolinones were dehydrated to the respective triazolyl ethyliedenepyrrolinones by p-
toluenesulfonic acid (p-TSA) catalyzed reaction at ambient temperature. All the newly
synthesized hybrid molecules were screened for anticancer activity in the first instance. The
ambient reaction conditions, efficient yields, environment friendly protocol and polyfunctional
nature of the compounds prepared herein are noteworthy. In addition, these prospective hybrid
molecules have inherent potential for other biological activities [46,47].

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2
. Results and Discussion:
2
.1 Chemistry:
The synthesis of title compounds commenced from L-ascorbic acid (vitamin-C), a commercially
available inexpensive starting material as shown in Scheme 1. Allyl alcohol derivatives (Z)-3,4-
bis(benzyloxy)-5-(2-hydroxyethylidene)furan-2(5H)-one (1a) and (Z)-5-(2-hydroxyethylidene)-
3
,4-dimethoxyfuran-2(5H)-one (1b) were synthesized according to our previous reported
procedure [27]. 1a and 1b were then converted into tosylated γ-ethylidenebutenolides Z-(2)-(3,4-
bis(benzyloxy)-5-oxofuran-2(5H)-ylidine)ethyl 4-methylbenzenesulfonate (2a) and Z-(2)-(3,4-
dimethoxy-5-oxofuran-2(5H)-ylidine)ethyl 4-methylbenzenesulfonate (2b) by reacting with p-
toluenesulfonyl chloride in anhydrous CH Cl by using pyridine as a base. Reaction of 2a and 2b
2
2
with sodium azide in DMF at ambient temperature led to formation of the respective azido γ-
ethylidenebutenolides (Z)-5-(2-azidoethylidene)-3,4-bis(benzyloxy)furan-2(5H)-one (3a) and
(Z)-5-(2-azidoethylidene)-3,4-dimethoxyfuran-2(5H)-one (3b) in good yields. These
1
13
intermediates (2a, 2b, 3a and 3b) were characterized on the basis of their NMR ( H and C) and
-1
-1
HRMS data. In IR spectrum, characteristic absorption peaks at 2105 cm for 3a and 2104 cm
for 3b conform the formation of azido compounds and served as key intermediate for the
synthesis of small library of novel triazolyl γ-ethylidenebutenolides. Azido compounds 3a and
3
b on Copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction with different aliphatic,
aromatic and heteroaromatic terminal alkynes led to 1,4-disubstituted regioselective formation of
the respective (Z)-3,4-dimethoxy/benzyloxy-5-[2-(4-alkyl/aryl-1H-1,2,3-triazol-1-yl) ethylidene]
furan-2(5H)-ones (4-23) in excellent yields (scheme 1). Regioisomeric nature of the 4-
substituted triazole products were ascertained based on chemical shift value of triazole C-5 in the
above compounds appear around δ 120-125 ppm [48].

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<Insert Scheme 1 here>
In the next sequence of synthesis, some of the above synthesized triazolyl γ-ethylidine
butenolides were reacted with ethanolic ammonia or different aliphatic amines in ethanol or THF
as solvent at room temperature to obtain 3,4-dimethoxy/benzyloxy-5-[2-(1H-1,2,3-triazol-1-
yl)ethyl]-5-hydroxy-1H-pyrrol-2(5H)-ones (24-30) and 3,4-dimethoxy/benzyloxy-5-[2-(1H-
1
,2,3-triazol-1-yl)ethyl]-5-hydroxy-1-alkyl/aralkyl-1H-pyrrol-2(5H)-ones (31-33) respectively in
good yields. Reaction of the above 5-hydroxy pyrrolinones 31 and 32 with p-TSA in anhydrous
CH Cl at room temperature led to the formation of (Z)-3,4-bis(benzyloxy)-1-propyl-5-(2-(4-
2
2
propyl-1H-1,2,3-triazol-1-yl)ethylidene)-1H-pyrrol-2(5H)-one (34) and (Z)-3,4-bis(benzyloxy)-
-octyl-5-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethylidene)-1H-pyrrol-2(5H)-one (35)
respectively as dehydration products. All the newly synthesized compounds were fully
1
1
13
characterized by their IR, NMR ( H and C) and HRMS data (experimental section). In NMR
spectral data of the compounds, all proton and carbon signals were observed at their usual
1
13
chemical shift values. Complete chemical shift ( H and C NMR) assignments and connectivity
(given in supplementary data) of three different prototypes 4, 31 and 34 (4→31→34) were
carried out using COSY (correlation spectroscopy), HSQC (hetero nuclear single quantum
coherence spectroscopy) and HMBC (hetero nuclear multiple bond correlation spectroscopy).
<
Insert fig. 2 here >
All the important HMBC correlations of three ptototype compounds (4, 31 and 34) are shown in
Fig. 2. HMBC correlation of CH -9 to C-5 and CH -7 to C-4 in prototype 4 strongly established
2
2
the formation of 1,4 disubstituted regioisomer in CuAAC reaction. COSY correlations
established the four coupled systems H-3' to H-7', H-3'' to H-7'', CH -6 to CH -8 and CH -9 to
2
3
2
CH -10 in compound 4, five coupled systems H-3' to H-7', H-3'' to H-7'', CH -6 to CH -8, CH -
2
2
3
2

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1
6 to CH -18 and CH -9 to CH -10 each in compounds 31 and 34. HMBC correlation of CH -16
3
2
2
2
to C-11 and C-13 in prototype 31 conform the insertion of propyl amine into butenolide ring.
2
2
.2 Biological evaluation
.2.1 Anti-proliferative effect of compounds
All the newly synthesized compounds (4-35) were screened for anticancer activity against cancer
cell lines MCF-7 and MDA-MB-231 (breast cancer), PC-3 (prostate cancer), HCT-116
(colorectal carcinoma), U-937 (histiocytic lymphoma) and human embryonic kidney (HEK-293)
cells using MTT assay to assess cell proliferation, results are shown in Table 1. Of the analogues
tested, none of the butenolides (4-23) found active which were synthesized initially considering
IC ≤20ꢀM as active. Due to this setback, we anticipated to elaborate synthetic sequence for
5
0
modifying prototype structures in a way that, some of the butenolide derivatives were
transformed into 5-hydroxy pyrrolinones (24-33). Among the 5-hydroxypyrrolinones tested for
anticancer activity, compounds 25 (IC = 11.3ꢀM) and 27 (IC = 13.1ꢀM) showed promising
5
0
50
activity specifically against aggressive breast cancer cell lines.
Insert table 1 here >
<
Further, compounds 28, 30 and 32 exhibited potent cytotoxicity against MCF-7 cancer cell lines.
Interestingly, compound 25 was also the most active compound in a series against PC-3 cells.
Compounds 24 and 26 showed anticancer activity against majority of the cell line MCF-7,
MDA-MB-231 and U-937, but lacks high potency to any specific cell line like compound 25.
Compound 24 was found to be most active against HCT-116, but none of the compounds of this
series was found to be significantly active against this colorectal carcinoma cell line. Few
compounds of this series was found to be active against lymphoma cell line, U-937 with
compound 24 as most active in a series. Among all, compound 25 was the most active analogue

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in this series with lowest IC against MDA-MB-231 cells. In addition, compound 25 was devoid
5
0
of significant cytotoxicity against normal human embryonic kidney (HEK-293) cells suggesting
that compound 25 was the most potent and specifically active in inhibiting growth of MDA-MB-
2
31 cells.
2
.2.2 Compounds 24, 25 and 26 induces cell cycle arrest.
Data from MTT assay showed that compounds 24, 25 and 26 induces significant inhibition of
MDA-MB-231, MCF-7, PC-3, U-937 and HCT 116 cells (Fig. 3). We tried to examine this
unrevealed inhibition of cell growth by adopting cell cycle distribution analysis, treated with
compounds 24, 25 and 26. Results demonstrated that all three compounds induced cell cycle
arrest along with an increase of sub-G1 phase as compared to untreated vehicle control.
Furthermore, sub-diploid population was increased consistently in all the cell lines, indicating
apoptosis.
<
Insert fig. 3 here >
2
.2.3 Compound 25 induces apoptosis
To further confirmation, we explored whether this inhibition of cell growth and cell cycle arrest
by these compounds is associated with physiological apoptosis or non-specific necrosis by
Annexin-V-FITC and PI staining using flow cytometer. For this, we selected compound 25 as the
most potent compound of the series with IC values of 11.3 ꢀM against MDA-MB-231 cells.
5
0
Data indicated that compound 25 significantly increased the percentage of apoptotic cells
Annexin-V-positive) in dose-dependent manner, and no significant change was observed in
necrotic cells (only PI stained) as compared to untreated vehicle control at 24 h (Fig. 4)
Insert fig. 4 here >
.2.4 Compounds 12, 24, 25, 26 and 27 induces reactive oxygen species generation
(
<
2

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Reactive oxygen species (ROS) is a known mediator of apoptosis and many anti-cancer
compounds are well known to induce ROS. Therefore, we examined the production of ROS in
MDA-MB-231 cells treated with compounds 12, 24, 25, 26 and 27 for 24 h. At the end of
incubation, ROS generation was detected using ROS-sensitive probe DCFH-DA using flow
cytometer. Data indicated that treatment of compounds 12, 24, 25, 26 and 27 increases ROS
level in breast cancer cells (Fig. 5). Thus, ROS generation may be the viable explanation for
apoptosis induction and inhibition of cell proliferation by these compounds.
<
Insert fig. 5 here >
Our results corroborated with previous reports suggesting that ascorbic acid selectively kills
cancer cells but not normal cells due to generation of reactive oxygen species [49]. Interestingly,
aggressive and metastatic breast cancer model is more prone towards compound 25 mediated
killing possibly due to difference in GSH concentration [50], while no cytotoxicity was observed
in normal cells due to enrichment of antioxidant enzymes [51]. Since all the synthesised
compounds are derivatives of ascorbic acid and majority of this induced ROS generation,
probably due to ionization of compound which produces extracellular ROS as observed in
ascorbic acid. The diffusion of extra cellular ROS might be involved in mitochondrial damage,
depletion of ATP, thereby cell death [52].
2
.2.5 Compound 25 induced ROS mediate apoptosis
To further validate, whether this ROS increase by these compounds is actually responsible for
induction of apoptosis, we treated cancer cells with NAC (a well known ROS inhibitor),
followed by treatment of compound 25 for 24 h and measured percent apoptotic cells using
flowcytometry based Annexin-FITC and PI staining method. Results showed that ROS is critical
for induction of apoptosis by compound 25 in MDA-MB-231 cells as inhibition of ROS by NAC

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significantly reduced percent apoptotic cell as compared compound 25 alone (Fig. 6). This
indicates that ROS generation induced by compound 25 play major role in cancer cells apoptosis.
<Insert fig. 6 here >
2
.2.6 Compound 25 induced ROS leads to p38 activation
As ROS induced apoptosis commonly involves p38 activation [53], we performed western blot
analysis of phospho-p38 in MDA-MB-231 cells after compound 25 treatment. It was found that
activation of p38 was activated dose-dependently upon 24 h treatment of compound 25 (Fig.
7
A). To confirm whether compound 25 induced ROS is leading to activation of p38, cells were
pre-treated with NAC followed by compound 25 for 24 h. The activation of p38 was completely
abolished in presence of NAC, indicating requirement of ROS for p38 activation (Fig. 7B).
<Insert fig. 7 here>
To explore the activity, we moved to transform two of the above 5-hydroxy pyrrolinones into γ-
ethylidine pyrrolinones (34, 35) and screened for anticancer activity, results showed that none of
these two compounds exhibited potent activity (IC50 = >46.2 µM). A closure look into the
structure activity relationship indicates that unsubstituted 5-hydroxy pyrrolinones (NH free)
showed significant activity, while N-substituted 5-hydroxy pyrrolinones inhibit the growth of
MCF-7 cell lines at high concentrations (IC50 = >22.3 µM). This indicates the remarkable
contribution of NH group to the activity by the unsubstituted 5-hydroxy pyrrolinones. All the γ-
ethylidenebutenolides found inactive, while corresponding γ-ethylidenepyrrolinones inhibit the
cell lines at very high concentrations (IC = >46.2 µM). Further, substitution on the triazole ring
5
0
does not showing significant contribution to the activity irrespective of the alkyne used in
synthesis.

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3
. Conclusion
In summary, a novel libraries of γ-(triazolyl ethylidene)butenolides, 5- hydroxy pyrrolinones and
γ-(triazolyl ethylidene)pyrrolinones were synthesized and characterized. All these newly
synthesized compounds were screened for anticancer activity in vitro against six cancer cell
lines. Results demonstrated that 5-hydroxy pyrrolinone analogues 24, 25, 26, 27, 28, 30 and 32
showed significant anticancer activity against MCF-7, MDA-MB-231, U-937 and PC-3 cell
lines, in particular Compound 25 exhibited most potent cytotoxic activity (IC50 = 11.3 µM)
against MDA-MB-231 cells. Environmentally benign, easily accessible synthesis and significant
activity favours these 5-hydroxy pyrrolinones to become great potential in medicinal chemistry.
4
. Experimental Section
4
.1 Chemistry
Commercially available reagent grade chemicals and solvents were used as received. All
reactions were monitored by TLC on E.Merck Kieselgel 60 F , with detection by UV light,
2
54
spraying a 20% KMnO aq. Solution or exposure to I vapours. Column chromatography was
4
2
performed on silica gel (60-120 mesh E.Merck). IR spectra were recorded as thin films or on
-1
1
KBr pellets with a PerkinElmer Spectrum RX-1 (4000-450 cm ) spectrophotometer. The H
1
3
(
400 and 300 MHz) and C NMR (100, 75 and 50 MHz) spectra were recorded on a Bruker
Avance-400, Bruker DRX-300 and Bruker DRX-200 in CDCl or DMSO-d . Chemical shift
3
6
values were reported in ppm relative to TMS (tetramethylsilane) as internal reference, unless
otherwise stated; s (singlet), d (doublet), t (triplet), dd (doublet of doublet), bs (broad singlet), m
(multiplet); J in hertz. HRMS spectra were performed using a mass spectrometer Q-TOF. Optical
rotation was recorded on Autopol III, S. No. 301, manufactured by Rudolph Research Analytical,
USA.

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4
.1.1 Typical procedure for the synthesis of intermediates 2a and 2b
To a magnetically stirred solution of the allylalcohol (1a, 1b) (1.0 mmol), pyridine (1.5 mmol) in
anhyd. CH Cl at 0°C, p-toluenesulfonyl chloride (1.2 mmol) was added in small fractions. The
2
2
resulting reaction mixture was stirred at ambient temperature for 12-15 h. After completion of
reaction the solvent was evaporated under reduced pressure to give a crude mass which was
extracted with ethylacetate and water.The organic layer was dried (anhyd. Na SO ) , evaporated
2
4
under reduced pressure to get the crude, which was chromatographed (SiO , 60-120 mesh) by
2
using hexane: ethylacetate (9.6: 0.4) as eluent to give the desired intermediates.
4
.1.1.1 Z-(2)-(3,4-bis(benzyloxy)-5-oxofuran-2(5H)-ylidine)ethyl 4-methyl benzenesulfonate (2a)
It was obtained by the reaction of allyl alcohol 1a (0.5 g, 1.4 mmol), pyridine (0.18 mL, 2.1
mmol), p-toluenesulfonyl chloride (0.34 g, 1.7 mmol) in anhydrous CH Cl (25 mL) in 62%
2
2
-1
1
yield (0.36 g) as colourless oil; IR (neat) νmax cm : 3425, 3022, 2104, 1774, 1405, 1216; H
NMR (CDCl , 400 MHz) δ: 7.96-7.94 (m, 5H, Ar), 7.44-7.37 (m, 9H, Ar), 5.50 (t, J = 8.28 Hz,
3
1
H, C=CH), 5.26 (s, 2H, OCH ), 5.21 (s, 2H, OCH ), 4.31 (d, J = 8.28 Hz, 2H, CH ), 2.51 (s,
2 2 2
13
3
H, CH ); C NMR (CDCl , 100 MHz) δ: 163.9, 147.9, 143.9, 135.8, 135.4, 129.0, 128.9, 128.8,
3 3
+
1
27.8, 123.9, 103.9, 74.2, 73.5, 36.6, 29.8; ESI-HRMS calcd for C H O S [M + H] 493.1321
27 25 7
found 493.1316.
4
.1.1.2 Z-(2)-(3,4-dimethoxy-5-oxofuran-2(5H)-ylidine)ethyl 4-methylbenzenesulfonate (2b)
It was obtained by the reaction of the allyl alcohol 1b (0.5 g, 2.6 mmol), pyridine (0.32 mL, 4.0
mmol), p-toluenesulfonyl chloride (0.61 g, 3.2 mmol) in anhyd.CH Cl (25 mL) in 59% yield as
2
2
-1
white solid (0.48 g); mp 110-112 °C; IR (KBr) νmax cm : 3432, 2931, 2400, 1648, 1332, 1049;
1
H NMR (CDCl 400 MHz) δ: 7.86 (d, J = 8.48 Hz, 2H, Ar), 7.35 (d, J = 8.52 Hz, 2H, Ar), 5.38
3,
(
t, J = 8.28 Hz, 1H, C=CH), 4.22 (d, J = 8.28 Hz, 2H, CH ), 4.07 (s, 3H, OCH ), 3.86 (s, 3H,
2 3

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13
OCH ), 2.42 (s, 3H, CH ); C NMR (CDCl , 100 MHz) δ: 163.7, 148.2, 143.8, 125.4, 103.8,
3
3
3
+
6
0.4, 59.5, 36.6; ESI-HRMS calcd for C H O S [M + H] 341.1656 found 341.1648.
15 17 7
4
.1.2 Typical procedure for the synthesis of intermediates 3a, 3b
To a magnetically stirred solution of the above synthesized allyl tosylates (2a, 2b) (1.0 mmol) in
DMF solvent, NaN (1.0 mmol) was added. The resulting mixture was stirred at ambient
3
temperature for 5-6 h. After completion, extracted the reaction mixture with ethylacetate and
water. The organic layer was dried, evaporated under reduced pressure to get the crude, which
was chromatographed (SiO , 60-120 mesh) by using hexane: ethylacetate (9.5: 0.5) as eluent to
2
give the desired intermediates.
4
.1.2.1 (Z)-5-(2-Azidoethylidene)-3,4-bis(benzyloxy)furan-2(5H)-one (3a)
It was obtained by the reaction of allyl tosylate 2a (0.5 g, 1.0 mmol), NaN (0.13 g, 2.0 mmol) in
3
-1
DMF (10 mL) in 68% yield (0.25 g) as colourless oil; IR (neat) νmax cm : 3427, 2960, 2105,
1
1
774, 1406, 1216; H NMR (CDCl , 300 MHz) δ: 7.36-7.33 (m, 8H, Ar), 7.24-7.20 (m, 2H, Ar),
3
5
.35 (t, J = 7.65 Hz, 1H, C=CH), 5.24 (s, 2H, OCH ), 5.19 (s, 2H, OCH ), 4.03 (d, J = 7.56 Hz,
2
2
13
2
H, CH ); C NMR (CDCl , 50 MHz) δ: 164.0, 147.8, 144.5, 135.8, 135.5, 129.0, 128.9, 128.8,
2 3
+
1
27.8, 123.8, 101.6, 74.2, 73.5, 45.3; ESI-HRMS calcd for C H N O [M + H] 364.1297
20 18 3 4
found 364.1292.
4
.1.2.2 (Z)-5-(2-azidoethylidene)-3,4-dimethoxyfuran-2(5H)-one (3b)
It was obtained by the reaction of allyl tosylate 2b (0.5g, 1.4 mmol), NaN (0.19 g, 2.9 mmol) in
3
-1
DMF (10 mL) as white solid in 71% yield (0.22 g); mp 108-110 °C; IR (KBr) νmax cm : 3431,
1
3
4
021, 2104, 1660, 1216, 969; H NMR (CDCl 300 MHz) δ: 5.30 (t, J = 7.68 Hz, 1H, C=CH),
3
,
1
3
.08 (s, 3H, OCH ), 3.97 (d, J = 7.65 Hz, 2H, CH ), 3.86 (s, 3H, OCH ); C NMR (CDCl , 50
3
2
3
3

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MHz) δ: 163.7, 148.2, 143.8, 125.4, 103.8, 60.4, 59.5, 36.6; ESI-HRMS calcd for C H N O [M
8
10
3
4
+
+
H] 212.0671 found 212.0672.
.1.3 Typical procedure for the synthesis of compounds 4-23
To a magnetically stirred solution of the above allyl azide (3a, 3b) (1.0 mmol) in t-BuOH: H O
4
2
(
1: 1 mL) as a solvent, at ambient temperature, CuSO .5H O (7 mg for 3a, 12 mg for 3b, 2
4 2
mol%), sodium ascorbate (13 mg for 3a, 23 mg for 3b, 5mol%), and benzoic acid (8 mg for 3a,
4 mg for 3b, 5 mol%) were sequentially added followed by addition of terminal alkyne (1.0
1
mmol). The resulting mixture was stirred for 1 h, till the completion of reaction (TLC). After
completion, reaction mixture was extracted with ethylacetate and H O, then organic layer was
2
dried (anhydrous Na SO ) and evaporated under reduced pressure to give the crude mass, which
2
4
was chromatographed (SiO , 60-120 mesh) by using hexane: ethylaceate (7: 3) as eluent to give
2
the desired products.
4
.1.3.1 (Z)-3,4-bis(benzyloxy)-5-(2-(4-ethyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-2(5H)-one (4)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 1-pentyne (0.13 mL, 1.3 mmol) in
-1
1
9
2 % yield (0.54 g) as colourless oil; IR (neat) νmax cm : 3405, 3019, 2963, 1653, 1217, 1125; H
NMR (CDCl , 400 MHz) δ: 7.39-7.33 (m, 9H, 8 Ar-H+ 1 triazolyl-H), 7.21-7.19 (m, 2H, Ar),
3
5
2
.53 (t, J = 7.64 Hz, 1H, C=CH), 5.23 (s, 2H, OCH ), 5.21 (s, 2H, OCH ), 5.16 (d, J = 7.56 Hz,
2 2
H, CH ), 2.67 (t, J = 7.56 Hz, 2H, CH ), 1.70-1.65 (m, 2H, CH ), 0.96 (t, J = 7.32 Hz, 3H,
2
2
2
1
3
CH ); C NMR (CDCl , 50 MHz) δ: 163.8, 148.8, 147.8, 144.5, 135.7, 135.2, 129.0, 129.0,
3
3
1
28.9, 128.8, 128.1, 127.8, 123.9, 120.8, 101.2, 74.2, 73.6, 44.5, 27.7, 22.7, 13.9; ESI-HRMS
+
calcd for C H N O [M + H] 432.1923 found 432.1918.
2
5
27
3
4
4
.1.3.2 (Z)-3,4-bis(benzyloxy)-5-(2-(4-ethyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-2(5H)-one (5)

ACCEPTED MANUSCRIPT
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 1-hexyne (0.16 mL, 1.3 mmol) in
-1
9
4% yield (0.57 g) as colourless oil; IR (neat) νmax cm : 3463, 2928, 1778, 1457, 1218, 1129;
1
H NMR (CDCl + DMSO-d , 300 MHz) δ: 7.83 (s, 1H, triazolyl), 7.39-7.28 (m, 10H, Ar), 5.57
3
6
(
t, J = 7.56 Hz, 1H, C=CH), 5.28 (s, 2H, OCH ), 5.14-5.11 (m, 4H, OCH + allylic CH ), 2.54 (t,
2 2 2
J = 7.44 Hz, 2H, CH ), 1.56-1.46 (m, 2H, CH ), 1.30-1.20 (m, 2H, CH ), 0.83 (t, J = 7.29 Hz,
2
2
2
1
3
3
1
H, CH ); C NMR (CDCl + DMSO-d , 50 MHz) δ: 163.5, 147.8, 143.0, 135.6, 135.3, 129.1,
3 3 6
28.7, 128.6, 128.5, 128.4, 127.8, 123.3, 121.8, 102.1, 73.9, 72.9, 43.8, 30.9, 24.5, 21.5, 13.5;
+
ESI-HRMS calcd for C H N O [M + H] 446.2080 found 446.2075.
2
6
28
3
4
4
.1.3.3 (Z)-3,4-bis(benzyloxy)-5-(2-(4-pentyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-2(5H)-one
6)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 1-heptyne (0.18 mL, 1.3 mmol) in
(
-1
1
9
2% yield (0.58 g) as colourless oil; IR (neat) νmax cm : 3444, 2929, 1777, 1652, 1218, 1129; H
NMR (CDCl + DMSO-d , 300 MHz) δ: 7.91 (s, 1H, triazolyl), 7.48-7.36 (m, 10H, Ar), 5.65 (t, J
3
6
=
7.56 Hz, 1H, C=CH), 5.36 (s, 2H, OCH ), 5.21-5.19 (m, 4H, OCH + CH ), 2.62 (t, J = 7.50
2 2 2
Hz, 2H, CH ), 1.65-1.56 (m, 2H, CH ), 1.33-1.26 (m, 4H, 2CH ), 0.89 (t, J = 6.72 Hz, 3H, CH );
2
2
2
3
1
3
C NMR (CDCl + DMSO-d , 50 MHz) δ: 163.9, 149.0, 147.8, 144.5, 135.7, 135.2, 130.2,
3
6
1
2
4
29.0, 129.0, 128.9, 128.9, 128.8, 127.9, 123.9, 120.8, 101.2, 74.2, 73.6, 44.6, 31.5, 29.8, 29.2,
+
5.7, 22.5, 14.1; ESI-HRMS calcd for C H N O [M + H] 460.2236 found 460.2212.
2
7
30
3
4
.1.3.4 (Z)-5-(2-(4-hexyl-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-dimethoxyfuran-2(5H)-one (7)
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), 1-octyne (0.33 mL, 2.3 mmol) in
-1
1
9
3% yield (0.70 g) as colourless oil; IR (neat) νmax cm : 3421, 2857, 1642, 1395, 1215, 1107; H
NMR (CDCl , 300 MHz) δ: 7.29 (s,1H, triazolyl), 5.51 (t, 1H, J = 7.56 Hz, C=CH), 5.16 (d, J =
3
7
.56 Hz, 2H, CH ), 4.12 (s, 3H, OCH ), 3.95 (s, 3H, OCH ), 2.69 (t, J = 7.47 Hz, 2H, CH ),
2 3 3 2

ACCEPTED MANUSCRIPT
1
3
1
.64-1.62 (m, 2H, CH ), 1.30-1.25 (m, 6H, 3CH ), 0.87 (t, J = 5.34 Hz, 3H, CH ); C NMR
2 2 3
(
CDCl , 50 MHz) δ: 170.2, 163.3, 148.7, 147.8, 144.4, 133.1, 130.3, 130.1, 128.3, 125.2, 120.8,
3
1
00.7, 96.2, 60.1, 59.4, 44.7, 31.6, 29.4, 29.0, 25.6, 22.6, 14.2; ESI-HRMS calcd for C H N O
16 24 3 4
+
[
M + H] 322.1767 found 322.1761.
4
2
.1.3.5(Z)-5-(2-(4-(1-hydroxyhexyl)-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-dimethoxyfuran-
(5H)-one (8)
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), 1-octyne-3-ol (0.33 mL, 2.3 mmol)
-1
in 92% yield (0.73 g) as colourless oil; IR (neat) νmax cm : 3782, 2856, 1692, 1464, 1215, 995;
1
H NMR (CDCl + DMSO-d 300 MHz) δ: 7.61 (s, 1H, triazolyl), 5.48 (t, J = 7.62 Hz, 1H,
3
6,
C=CH), 5.13 (d, J = 7.53 Hz, 2H, CH ), 4.82 (bs, 1H, OH), 4.65 (t, J = 5.73, 1H, CHOH), 4.10
2
(
s, 1H, OCH ), 3.87 (s, 1H, OCH ), 1.70 (t, J = 4.92 Hz, 2H, CH ), 1.35-1.21 (m, 6H, 3CH ),
3 3 2 2
1
3
0
1
.83 (t, J = 5.28 Hz, 3H, CH ); C NMR (CDCl + DMSO-d , 50 MHz) δ: 162.0, 151.8, 146.9,
3 3 6
42.8, 123.9, 119.9, 99.9, 94.9, 65.1, 59.1, 58.3, 43.1, 36.5, 30.5, 23.9, 21.4, 13.0; ESI-HRMS
+
calcd for C H N O [M + H] 338.1716 found 338.1713.
1
6
24
3
5
4
2
.1.3.6
(5H)-one (9)
(Z)-5-(2-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-dimethoxyfuran-
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), 5-hexyne-1-ol (0.25 mL, 2.3
-1
mmol) in 94% yield (0.68 g) as colourless oil; IR (neat) νmax cm : 3782, 2935, 1778, 1363, 1218,
1
1
060; H NMR (CDCl + DMSO-d , 300 MHz) δ: 7.23 (s, 1H, triazolyl), 5.35 (t, J = 7.47 Hz, 1H,
3
6
C=CH), 5.00 (d, J = 7.47 Hz, 2H, CH ), 3.99 (s, 1H, OCH ), 3.79 (s,1H, OCH ), 3.42 (t, J = 6.09
2
3
3
1
3
Hz, 2H, CH ), 2.98 (bs, 1H, OH), 2.55 (t, J = 6.93 Hz, 2H, CH ), 1.60-1.42 (m, 4H, 2CH ); C
2
2
2
NMR (CDCl + DMSO-d , 50 MHz) δ: 162.8, 148.1, 147.5, 143.9, 124.9, 120.5, 100.5, 95.9,
3
6

ACCEPTED MANUSCRIPT
+
6
1.3, 59.8, 59.1, 44.0, 31.9, 25.4, 25.1; ESI-HRMS calcd for C H N O [M + H] 310.1403
14 20 3 5
found 310.1396.
4
2
.1.3.7 (Z)-3,4-bis(benzyloxy)-5-(2-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)ethylidene)furan-
(5H)-one (10)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 5-hexyne-1-ol (0.15 mL, 1.3
-1
mmol) in 95% yield (0.60 g) as colourless oil; IR (neat) νmax cm : 3436, 2939, 1305, 1129,
1
1
5
058; H NMR (CDCl , 300 MHz) δ: 7.38 (s, 1H, triazolyl), 5.33 (t, J = 7.62 Hz, 1H, C=CH),
3
.23 (s, 2H, OCH ), 5.21 (s, 2H, OCH ), 5.16 (d, J = 5.67 Hz, 2H, CH ), 3.66 (t, J = 4.77 Hz, 2H,
2
2
2
13
CH OH), 2.75-2.69 (m, 2H, CH ), 1.77-1.71 (m, 2H, CH ), 1.66-1.59 (m, 2H, CH ); C NMR
2
2
2
2
(
CDCl , 50 MHz) δ: 163.9, 148.5, 147.8, 144.5, 135.6, 135.2, 129.0, 128.9, 128.9, 128.8, 127.8,
3
1
23.8, 121.0, 101.0, 74.2, 73.6, 62.3, 44.6, 32.1, 25.6, 25.3; ESI-HRMS calcd for C H N O
26 28 3 5
+
[
M + H] 462.2029 found 462.2023.
4
.1.3.8 (Z)-5-(2-(4-benzyl-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-dimethoxyfuran-2(5H)-one (11)
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), 3-phenyl-1-propyne (0.28 mL, 2.3
-1
mmol) in 96% yield (0.74 g) as colourless oil; IR (neat) νmax cm : 3405, 3016, 2922, 1692, 1217,
1
1
061; H NMR (CDCl , 300 MHz) δ: 7.29-7.20 (m, 6H, 5 Ar-H+ 1 triazolyl-H), 5.49 (t, J = 7.56
3
Hz, 1H, C=CH), 5.14 (d, J = 7.53 Hz, 2H, CH ), 4.11 (s, 3H, OCH ), 4.06 (s, 2H, CH Ph), 3.93
2
3
2
1
3
(
s, 3H, OCH ); C NMR (CDCl , 50 MHz) δ: 163.5, 148.0, 147.9, 144.3, 138.9, 128.7, 128.6,
3 3
+
1
3
4
26.5, 125.2, 121.4, 100.6, 60.2, 59.4, 44.5, 32.2; ESI-HRMS calcd for C H N O [M + H]
17 18 3 4
28.1297 found 328.1286.
.1.3.9 (Z)-5-(2-(4-benzyl-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-bis(benzyloxy)furan-2(5H)-one
(12)

ACCEPTED MANUSCRIPT
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 3-phenyl-1-propyne (0.17 mL, 1.3
-1
mmol) in 95% yield (0.62 g) as colourless oil; IR (neat) νmax cm : 3422, 3069, 1777, 1497, 1217,
1
9
7
4
1
3
4
90; H NMR (CDCl , 400 MHz) δ: 7.38-7.17 (m, 16H, 15 Ar-H+ 1 triazolyl-H), 5.50 (t, J =
3
.60 Hz, 1H, C=CH), 5.21 (s, 2H, OCH ), 5.19 (s, 2H, OCH ), 5.13 (d, J = 7.56 Hz, 2H, CH ),
2
2
2
13
.06 (s, 2H, CH Ph); C NMR (CDCl , 50 MHz) δ: 163.6, 148.0, 147.6, 144.4, 138.9, 135.5,
2
3
35.1, 128.8, 128.7, 128.7, 128.6, 128.6, 127.7, 126.5, 123.8, 121.4, 100.8, 74.0, 73.4, 44.5,
+
2.2; ESI-HRMS calcd for C H N O [M + H] 480.1923 found 480.1918.
2
9
26
3
4
.1.3.10 (Z)-3,4-dimethoxy-5-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-2(5H)-one (13)
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), phenyl acetylene (0.25 mL, 2.3
-1
mmol) in 94% yield (0.69 g) as white solid; mp 115-117 °C, IR (KBr) νmax cm : 3435, 2117,
1
1
775, 1654, 1306, 1116; H NMR (CDCl , 300 MHz) δ: 7.79-7.78 (m, 3H, 2 Ar-H+ 1 triazolyl-
3
H), 7.41-7.28 (m, 3H, Ar), 5.55 (t, J = 7.71 Hz, 1H, C=CH), 5.23 (d, J = 7.62 Hz, 2H, CH ), 4.12
2
1
3
(
s, 3H, OCH ), 3.95 (s, 3H, OCH ); C NMR (CDCl , 50 MHz) δ: 163.3, 148.2, 147.9, 144.6,
3 3 3
1
30.5, 130.2, 128.9, 128.3, 125.8, 125.4, 119.7, 100.6, 96.3, 60.2, 59.5, 44.6; ESI-HRMS calcd
+
for C H N O [M + H] 314.1141 found 314.1128.
1
6
16
3
4
4
.1.3.11 (Z)-3,4-bis(benzyloxy)-5-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-2(5H)-one
14)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), phenyl acetylene (0.15 mL, 1.3
(
-1
mmol) in 96% yield (0.61 g) as colourless oil; IR (neat) νmax cm 3438, 2086, 1776, 1305, 1220,
1
1
1
125; H NMR (CDCl , 300 MHz) δ: 7.82-7.78 (m, 3H, 2 Ar-H+1 triazolyl-H), 7.39-7.28 (m,
3
1H, Ar), 7.22-7.21 (m, 2H, Ar), 5.59 (t, J = 7.62 Hz, 1H, C= CH), 5.24-5.23 (m, 6H, 2×OCH2+
1
3
CH ); C NMR (CDCl , 50 MHz) δ: 163.5, 148.3, 147.6, 144.8, 135.7, 135.2, 130.5, 130.3,
2
3

ACCEPTED MANUSCRIPT
1
29.0, 128.9, 128.8, 128.5, 128.3, 127.9, 125.9, 123.9, 119.7, 100.8, 96.3, 74.1, 73.6, 44.7; ESI-
+
HRMS calcd for C H N O [M + H] 466.1767 found 466.1754.
2
8
24
3
4
4
2
.1.3.12 (Z)-5-(2-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-dimethoxyfuran-
(5H)-one (15)
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), 4-tert-butyl phenylacetylene (0.41
-1
mL, 2.3 mmol) in 95% yield (0.83 g) as white solid; mp 106-109 °C; IR (KBr) νmax cm : 3018,
1
1
779, 1660, 1217, 1119, 968; H NMR (CDCl , 300 MHz) δ: 7.76-7.71 (m, 3H, 2 Ar-H+ 1
3
triazolyl-H), 7.48-7.40 (m, 2H, Ar), 5.57 (t, J = 7.47 Hz, 1H, C=CH), 5.24 (d, J = 7.59 Hz, 2H,
13
CH ), 4.14 (s, 3H, OCH ), 3.97 (s, 3H, OCH ), 1.35 (s, 9H, 3CH ); C NMR (CDCl , 50 MHz)
2
3
3
3
3
δ: 163.6, 151.3, 148.3, 147.7, 144.8, 135.7, 135.3, 130.4, 129.1, 129.0, 128.9, 128.5, 127.9,
1
25.8, 125.7, 124.0, 119.4, 100.9, 96.3, 74.6, 74.1, 44.7, 34.9, 31.6, 29.9; ESI-HRMS calcd for
+
C H N O [M + H] 370.1767 found 370.1760.
20
24
3
4
4
.1.3.13
(Z)-3,4-bis(benzyloxy)-5-(2-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1yl)ethylidene)
furan-2(5H)-one (16)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 4-tert-butyl phenylacetylene (0.25
-1
mL, 1.3 mmol) in 96% yield (0.68 g) as colourless oil; IR (neat) νmax cm : 2959, 1777, 1457,
1
1
7
2
1
218, 1123, 977; H NMR (CDCl , 300 MHz) δ: 7.75-7.73 (m, 3H, 2 Ar-H+ 1 triazolyl-H), 7.45-
3
.33 (m, 10H, Ar), 7.22-7.21 (m, 2H, Ar), 5.60 (t, J = 7.62 Hz, 1H, C=CH), 5.25-5.24 (m, 6H,
13
×OCH + CH ), 1.37 (s, 9H, 3CH ); C NMR (CDCl , 50 MHz) δ: 163.2, 151.2, 148.2, 147.8,
2
2
3
3
44.6, 127.8, 125.8, 125.6, 119.4, 100.7, 96.3, 60.2, 59.5, 44.6, 34.8, 31.5; ESI-HRMS calcd for
+
C H N O [M + H] 522.2393 found 522.2384.
32
32
3
4
4
.1.3.14 (Z)-3,4-dimethoxy-5-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethylidene)furan-2(5H)-
one (17)

ACCEPTED MANUSCRIPT
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), 2-ethynyl pyridine (0.23 mL, 2.3
o
-1
mmol) in 92% yield (0.68 g) as white solid; mp 143-145 C; IR (KBr) νmax cm : 3017, 2926,
1
1
1
7
780, 1660, 1217, 1062; H NMR (CDCl + DMSO-d , 300 MHz) δ: 8.62-8.60 (m, 2H, 1 Ar-H+
3
6
triazolyl-H), 8.04-8.02 (m, 1H, Ar), 7.91-7.86 (m, 1H, Ar), 7.36-7.32 (m, 1H, Ar), 5.70 (t, J =
13
.59 Hz, 1H, C=CH), 5.31 (d, J = 7.5 Hz, 2H, CH ), 4.12 (s, 3H, OCH ), 3.85 (s, 3H, OCH ); C
2
3
3
NMR (CDCl + DMSO-d , 50 MHz) δ: 163.5, 150.2, 149.5, 148.8, 148.0, 145.0, 137.1, 125.5,
3
6
+
1
3
4
2
23.1, 122.1, 120.4, 100.1, 60.4, 59.6, 44.8, 29.8; ESI-HRMS calcd for C H N O [M + H]
15 15 4 4
15.1093 found 315.1089.
.1.3.15 (Z)-3,4-bis(benzyloxy)-5-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethylidene)furan-
(5H)-one (18)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 2-ethynyl pyridine (0.14 mL, 1.3
-1
mmol) in 94% yield (0.60 g) as colourless oil; IR (neat) νmax cm : 3436, 2925, 2141, 1776, 1125,
1
1
8
058; H NMR (CDCl + DMSO-d , 300 MHz) δ: 8.61 (s, 1H, triazolyl), 8.56-8.55 (m, 1H, Ar),
3
6
.00-7.98 (m, 1H, Ar), 7.87-7.82 (m, 1H, Ar), 7.39-7.30 (m, 11H, Ar), 5.70 (t, J = 7.53 Hz, 1H,
13
C=CH), 5.29-5.26 (m, 4H, OCH + CH ), 5.13 (s, 2H, OCH ); C NMR (CDCl + DMSO-d , 50
2
2
2
3
6
MHz) δ: 163.5, 149.5, 147.9, 143.3, 137.1, 135.6, 135.3, 128.7, 128.6, 128.5, 128.5, 128.4,
+
1
4
4
27.8, 123.3, 122.9, 119.3, 101.8, 74.0, 73.0, 44.2; ESI-HRMS calcd for C H N O [M + H]
27 23 4 4
67.1719 found 467.1714.
.1.3.16 (Z)-5-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-dimethoxyfuran-2(5H)-
one (19)
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), cyclopropyl acetylene (0.19 mL,
-
1
2
1
.3 mmol) in 95% yield (0.70 g) as colourless oil; IR (neat) νmax cm : 3436, 2854, 2078, 1779,
1
217, 1119; H NMR (CDCl + DMSO-d , 300 MHz) δ: 7.84 (s, 1H, triazolyl), 5.58 (t, J = 7.56
3
6

ACCEPTED MANUSCRIPT
Hz, 1H, C=CH), 5.14 (d, J = 7.53 Hz, 2H, CH ), 4.12 (s, 1H, OCH ), 3.85 (s, 1H, OCH ), 1.97-
2
3
3
1
3
1
.88 (m, 1H, CH), 0.91-0.85 (m, 2H, CH ), 0.72- 0.70 (m, 2H, CH ); C NMR (CDCl + DMSO-
2 2 3
d6, 50 MHz) δ: 163.7, 150.8, 148.1, 144.4, 125.4, 119.8, 114.2, 100.9, 60.4, 59.5, 44.5, 29.8, 7.8,
+
6
4
2
.7; ESI-HRMS calcd for C H N O [M + H] 278.1141 found 278.1145.
1
3
16
3
4
.1.3.17
(Z)-3,4-bis(benzyloxy)-5-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-
(5H)-one (20)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), cyclopropyl acetylene (0.12 mL,
-
1
1
1
1
.3 mmol) in 96% yield (0.56 g) as colourless oil; IR (neat) νmax cm : 3436, 3019, 2143, 1777,
1
218, 1059; H NMR (CDCl + DMSO-d , 300 MHz) δ: 7.83 (s, 1H, triazolyl), 7.42-7.33 (m,
3
6
0H, Ar), 5.59 (t, J = 7.44 Hz, 1H, C=CH), 5.32 (s, 2H, OCH ), 5.16-5.12 (m, 4H, OCH + allyl
2
2
13
CH ), 1.95-1.87 (m, 1H, CH), 0.88-0.86 (m, 2H, CH ), 0.69-0.68 (m, 2H, CH ); C NMR
2
2
2
(
CDCl + DMSO-d , 50 MHz) δ: 163.8, 150.7, 147.8, 144.5, 135.6, 135.2, 133.2, 130.1, 129.0,
3 6
1
28.9, 128.9, 128.8, 128.7, 128.4, 127.8, 123.8, 119.9, 101.1, 74.2, 73.5, 44.5, 29.7, 7.8, 6.7;
+
ESI-HRMS calcd for C H N O [M + H] 430.1767 found 430.1750.
2
5
23
3
4
4
.1.3.18 (Z)-5-(2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)ethylidene)-3,4-dimethoxyfuran- 2-
5H)-one (21)
It was obtained by the reaction of azide 3b (0.5 g, 2.3 mmol), propargyl alcohol (0.12 mL, 2.3
(
o
-1
mmol) in 90% yield (0.57 g) as white solid; mp 133-136 C; IR (KBr) ν
cm : 3395, 2922,
max
1
1
769, 1308, 1119, 992; H NMR (CDCl + DMSO-d , 300 MHz) δ: 7.63 (s, 1H, triazolyl), 5.51
3
6
(
t, J = 7.62 Hz, 1H, C=CH), 5.19 (d, J = 7.62 Hz, 2H, CH ), 4.68 (s, 2H, CH OH), 4.14 (s, 3H,
2 2
13
OCH ), 3.94 (s, 3H, OCH ); C NMR (CDCl + DMSO-d , 50 MHz) δ: 163.1, 148.5, 147.7,
3
3
3
6
+
1
2
43.9, 124.8, 121.5, 100.3, 59.9, 59.1, 55.7, 44.0; ESI-HRMS calcd for C H N O [M + H]
11 14 3 5
68.0933 found 268.0928.

ACCEPTED MANUSCRIPT
4
.1.3.19 (Z)-3,4-bis(benzyloxy)-5-(2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-2(5H)-one
(22)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 4-ethynyl toluene (0.17 mL, 1.3
-1
mmol) in 92% yield (0.60 g) as colourless oil; IR (neat) νmax cm : 3401, 3018, 1778, 1366, 1215,
1
8
48; H NMR (CDCl , 400 MHz) δ: 7.68-7.64 (m, 3H, 2 Ar-H+ 1 triazolyl-H), 7.36-7.29 (m, 9H,
3
Ar), 7.18-7.16 (m, 4H, Ar), 5.54 (t, J = 5.73 Hz, 1H, C=CH), 5.20-5.17 (m, 6H, 2×OCH + CH ),
2
2
1
3
2
1
.35 (s, 3H, CH ); C NMR (CDCl , 50 MHz) δ: 163.5, 148.4, 147.6, 144.8, 137.9, 135.7, 135.2,
3 3
29.6, 129.1, 129.0, 128.9, 128.8, 127.9, 125.8, 124.0, 119.3, 100.8, 96.3, 74.1, 73.6, 44.6, 21.5;
+
ESI-HRMS calcd for C H N O [M + H] 480.1923 found 480.1918.
2
9
26
3
4
4
2
.1.3.20
(Z)-3,4-bis(benzyloxy)-5-(2-(4-cyclohexenyl-1H-1,2,3-triazol-1-yl)ethylidene)furan-
(5H)-one (23)
It was obtained by the reaction of azide 3a (0.5 g, 1.3 mmol), 1-ethynyl cyclohexene (0.16 mL,
-
1
1
1
.3 mmol) in 95% yield (0.61 g) as colourless oil; IR (neat) νmax cm : 3386, 2933, 1777, 1216,
1
057, 922; H NMR (CDCl , 400 MHz) δ: 7.37-7.30 (m, 9H, 8 Ar-H+ 1 triazolyl-H), 7.18-7.17
3
(
m, 2H, Ar), 6.46 (t, J = 6.3 Hz, 1H), 5.51 (t, J = 7.64 Hz, 3H, C=CH), 5.21 (s, 2H, OCH ), 5.20
2
(
s, 2H, OCH ), 5.16 (d, J = 7.60 Hz, 2H, CH ), 2.36-2.34 (m, 2H, CH ), 2.18-2.17 (m, 2H, CH ),
2
2
2
2
1
3
1
1
2
4
.78-1.62 (m, 4H, 2CH ), C NMR (CDCl , 50 MHz) δ: 163.3, 147.4, 144.4, 135.5, 135.1,
2 3
33.2, 128.8, 128.7, 128.6, 128.3, 127.7, 123.7, 100.8, 96.1, 73.9, 73.4, 44.5, 26.2, 25.3, 22.4,
+
2.2; ESI-HRMS calcd for C H N O [M + H] 470.2080 found 470.2074.
2
8
28
3
4
.1.4 Typical procedure for the synthesis of compounds 24-30
A solution of the above synthesized triazole compound (1.0 mmol) in ethanolic ammonia (10-15
mL) was magnetically stirred at ambient temperature for 6-10 h in a sealed vessel. The excess of
ammonia and solvent were evaporated under reduced pressure, then extracted the crude with

ACCEPTED MANUSCRIPT
ethylacetate, H O. The organic layer was dried (anhydrous Na SO ), evaporated under reduced
2
2
4
pressure, then chromatographed (SiO , 60-120 mesh) by using hexane: ethylacetate (6: 4) as
2
eluent to give the desired products.
4
.1.4.1 5-hydroxy-3,4-dimethoxy-5-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)-1H-pyrrol-2(5H)-
one (24)
It was obtained by using the compound 13 (0.5 g, 1.59 mmol) in 92% yield (0.48 g), as white
-1
25
solid; mp 145-147 °C; IR (KBr) νmax cm : 3360, 2856, 1766, 1642, 1250, 1035; [α] 4.00° (c
D
1
0
.05, CH OH); H NMR (CDCl + DMSO-d , 300 MHz) δ: 8.56 (s, 1H, NH), 8.14 (s, 1H,
3
3
6
triazolyl), 7.83-7.81 (m, 2H, Ar), 7.46-7.31 (m, 3H, Ar), 6.24 (s, 1H, OH), 4.40 (t, J = 6.78 Hz
1
3
2
H, CH ), 3.87 (s, 3H, OCH ), 3.69 (s, 3H, OCH ), 2.31-2.28 (m, 2H, CH ); C NMR (CDCl +
2 3 3 2 3
DMSO-d , 50 MHz) δ: 167.9, 153.6, 146.3, 130.8, 128.9, 127.8, 125.1, 124.8, 121.5, 81.4, 60.2,
6
+
5
8.5, 45.2, 36.9; ESI-HRMS calcd for C H N O [M + H] 331.1406 found 331.1401.
1
6
19
4
4
4
.1.4.2 5-hydroxy-3,4-dimethoxy-5-(2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethyl)-1H-pyrrol-2(5H)-
one (25)
It was obtained by using compound 15 (0.4 g, 1.08 mmol) in 95% yield (0.39 g) as colourless oil;
-1
25
1
IR (neat) νmax cm : 3362, 2959, 1680, 1216, 1085, 761; [α] 8.38° (c 0.05, CHCl ); H NMR
D
3
(
CDCl , 400 MHz) δ: 7.83 (s, 1H, triazolyl), 7.70-7.68 (m, 2H, Ar), 7.50 (bs, NH), 7.40-7.37 (m,
3
2
2
1
H, Ar), 4.51 (t, J = 7.08 Hz, 2H, CH ), 3.93 (s, 3H, OCH ), 3.69 (s, 3H, OCH ), 2.59-2.43 (m,
2 3 3
1
3
H, CH ), 1.30 (s, 9H, 3CH ); C NMR (CDCl , 50 MHz) δ: 168.5, 153.5, 150.3, 146.7, 127.4,
2
3
3
25.1, 124.8, 124.7, 119.6, 95.5, 81.4, 60.0, 58.4, 45.1, 36.8, 34.1, 30.8, 29.1; ESI-HRMS calcd
+
for C H N O [M + H] 387.2032 found 387.2027.
2
0
27
4
4
4
2
.1.4.3
3,4-bis(benzyloxy)-5-hydroxy-5-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)-1H-pyrrol-
(5H)-one (26)

ACCEPTED MANUSCRIPT
It was obtained by using compound 14 (0.5 g, 1.07 mmol) in 90% yield (0.46 g) as white solid;
-1
25
mp 151-153 °C; IR (KBr) νmax cm : 3429, 3019, 2400, 1706, 1424, 1215; [α] 8.34° (c 0.05,
D
1
CH OH); H NMR (CDCl + DMSO-d , 300 MHz) δ: 8.10 (s, 1H, triazolyl), 7.75-7.29 (m, 2H,
3
3
6
Ar), 7.35-7.21 (m, 13H, Ar), 6.23 (bs, 1H, NH), 5.12-4.97 (m, 4H, 2×OCH ), 4.36-4.31 (m, 2H,
2
13
NCH ), 2.40-2.21 (m, 2H, CH ); C NMR (CDCl + DMSO-d , 50 MHz) δ: 167.4, 152.1, 145.7,
2
2
3
6
1
8
4
4
35.5, 135.1, 129.6, 127.5, 127.4, 127.2, 127.0, 127.0, 126.6, 126.4, 124.2, 122.3, 119.6, 94.7,
+
0.7, 72.4, 71.3, 44.3, 36.2; ESI-HRMS calcd for C H N O [M + H] 483.2032 found
2
8
27
4
4
83.2026.
.1.4.4
3,4-bis(benzyloxy)-5-(2-(4-cyclohexenyl-1H-1,2,3-triazol-1-yl)ethyl)-5-hydroxy-1H-
pyrrol-2(5H)-one (27)
It was obtained by using compound 23 (0.4 g, 0.85 mmol) in 92% yield (0.38 g) as colourless oil.
-1
25
1
IR (neat) νmax cm : 3401, 2926, 1677, 1454, 1216, 1155; [α] 8.32° (c 0.05, CH OH); H NMR
D
3
(
CDCl + DMSO-d , 300 MHz) δ: 7.30-7.17 (m, 11H, 10 Ar-H+ 1 triazolyl-H), 6.71 (bs, 1H,
3 6
NH), 6.37 (bs, 1H, OH), 5.61 (t, J = 6.9 Hz, 1H), 5.09-4.98 (m, 4H, 2×OCH ), 4.24-4.11 (m, 2H,
2
NCH ), 2.28-2.24 (m, 2H, CH ), 2.12-2.08 (m, 2H, CH ), 1.67-1.57 (m, 4H, 2×CH ), 0.80-0.75
2
2
2
2
1
3
(
m, 2H, CH ); C NMR (CDCl + DMSO-d , 50 MHz) δ: 168.9, 153.4, 136.5, 136.1, 128.7,
2 3 6
1
28.4, 128.3, 128.2, 127.6, 124.7, 118.7, 82.0, 73.8, 72.8, 45.2, 37.3, 29.5, 26.2, 25.1, 22.3, 22.1;
+
ESI-HRMS calcd for C H N O [M + H] 487.2345 found 487.2340.
2
8
31
4
4
4
2
.1.4.5
3,4-bis(benzyloxy)-5-hydroxy-5-(2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethyl)-1H-pyrrol-
(5H)-one (28)
It was obtained by using compound 22 (0.3 g, 0.62 mmol) in 95% yield (0.29 g) as white solid;
-1
25
mp 159-161 °C; IR (KBr) νmax cm : 3407, 3020, 1684, 1405, 1215, 924; [α]
8.90° (c 0.05,
D
1
CH OH); H NMR (CDCl + DMSO-d , 300 MHz) δ: 8.29-8.22 (m, 2H, 1 triazolyl-H+ 1 Ar-H),
3
3
6

ACCEPTED MANUSCRIPT
7
4
.70-7.67 (m, 2H, Ar), 7.37-7.18 (m, 11H, Ar), 6.27 (s, 1H, NH), 5.06-5.04 (m, 4H, 2×CH2),
13
.37-4.34 (m, 2H, CH ), 2.33-2.31 (m, 5H, CH + CH ); C NMR (CDCl + DMSO-d , 50 MHz)
2
2
3
3
6
δ: 166.5, 151.4, 144.9, 135.3, 135.1, 134.7, 127.6, 126.8, 126.6, 126.4, 125.9, 123.5, 121.8,
+
1
19.1, 80.1, 71.7, 70.5, 43.6, 35.5, 19.3; ESI-HRMS calcd for C H N O [M + H] 497.2189
2
9
29
4
4
found 497.2183.
4
2
.1.4.6
5-(2-(4-benzyl-1H-1,2,3-triazol-1-yl)ethyl)-3,4-bis(benzyloxy)-5-hydroxy-1H-pyrrol-
(5H)-one (29)
It was obtained by using compound 12 (0.5 g, 1.0 mmol) in 93% yield (0.48 g) as white solid;
-1
25
mp 121-123 °C; IR (KBr) νmax cm : 3290, 3018, 1679, 1388, 1216, 1095; [α] -2.94° (c 0.05,
D
1
CHCl ), H NMR (CDCl , 400 MHz) δ: 7.32-7.17 (m, 16H, 15 Ar-H+ 1 triazolyl), 7.06 (s, 1H,
3
3
NH), 7.01(s, 1H, OH), 5.14-4.99 (m, 4H, 2×OCH ), 4.26-4.12 (m, 2H, NCH ), 3.97 (s, 2H,
2
2
1
3
CH Ph), 2.45-2.23 (m, 2H, CH ); C NMR (CDCl , 50 MHz) δ: 169.8, 154.1, 147.6, 139.0,
2
2
3
1
7
4
1
36.4, 136.1, 129.0, 128.8, 128.7, 128.7, 128.6, 128.5, 127.8, 126.6, 123.6, 122.2, 82.7, 74.3,
+
3.1, 45.4, 36.9, 32.2; ESI-HRMS calcd for C H N O [M + H] 497.2189 found 497.2183.
2
9
29
4
4
.1.4.7 3,4-bis(benzyloxy)-5-(2-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)-5-hydroxy-
H-pyrrol-2(5H)-one (30)
It was obtained by using compound 16 (0.4 g, 0.76 mmol) in 94% yield (0.39 g) as white solid;
-1
25
mp 147-149 °C; IR (KBr) νmax cm : 3366, 2973, 1672, 1441, 1212, 1114; [α] -5.36° (c 0.05,
D
1
CH OH); H NMR (CDCl + DMSO-d , 400 MHz) δ: 7.83 (s, 1H, triazolyl), 7.71-7.64 (m, 3H,
3
3
6
Ar), 7.42-7.26 (m, 11H, Ar), 6.15 (bs, 1H, NH), 5.15-5.11 (m, 4H, 2×OCH ), 4.40-4.39 (m, 2H,
2
1
3
NCH ), 2.45-2.38 (m, 2H, CH ), 1.34 (s, 9H, 3CH ); C NMR (CDCl + DMSO-d , 50 MHz) δ:
2
2
3
3
6
1
67.8, 152.4, 149.8, 146.0, 135.7, 135.3, 127.6, 127.4, 127.2, 127.2, 126.7, 124.6, 124.2, 119.4,

ACCEPTED MANUSCRIPT
+
9
5
4
5.0, 81.05, 72.7, 71.6, 44.5, 36.3, 33.5, 30.3; ESI-HRMS calcd for C H N O [M + H]
32
35
4
4
39.2658 found 539.2652.
.1.5 Typical procedure for the synthesis of compounds 31-33
To a magnetically stirred solution of triazole compound (1.0 mmol) in ethanol or THF as a
solvent at ambient temperature, alkyl amine (1.0 mmol) was added. The resulting mixture was
stirred for overnight at same temperature until completion of starting material (TLC). After
completion, solvent was evaporated under reduced pressure, then extracted with ethylacetate,
H O. The organic layer was dried (anhyd.Na SO ), evaporated under reduced pressure to get the
2
2
4
crude, which was chromatographed (SiO , 60-120 mesh) by using hexane: ethylacetate (6: 4) as
2
eluent to give the desired products.
4
.1.5.1
(Z)-3,4-bis(benzyloxy)-1-propyl-5-(2-(4-propyl-1H-1,2,3-triazol-1-yl)ethylidene)-1H-
pyrrol-2(5H)-one (31)
It was obtained by the reaction of compound 4 (0.2 g, 0.46 mmol), n-propylamine (0.19 mL, 0.46
-1
mmol) in ethanol (10 mL) in 94% yield (0.21 g) as colourless oil: IR (neat) νmax cm : 3368,
2
5
1
3
7
017, 2875, 1683, 1550, 1216; [α]
3.03° (c 0.05, CHCl ); H NMR (CDCl , 400 MHz) δ:
D 3 3
.40-7.24 (m, 10H, 10 Ar), 6.95 (s, 1H, triazolyl), 5.29 (d, J = 11.2 Hz, 1H, OCH ), 5.18 (s, 2H,
2
OCH ), 5.09 (d, J = 11.2 Hz, 2H, OCH ), 3.93-3.75 (m, 2H, NCH ), 3.26-3.08 (m, 2H, NCH of
2
2
2
2
propylamine), 2.60 (t, J = 7.48 Hz, 2H, CH ), 2.50-2.42 (m, 2H, CH ), 1.65-1.60 (m, 4H, 2CH ),
2
2
2
1
3
0
5
8
.93 (t, J = 7.32 Hz, 3H, CH of propylamine), 0.88 (t, J = 7.36 Hz, 3H, CH ); C NMR (CDCl ,
3 3 3
0 MHz) δ: 167.6, 151.0, 148.0, 136.6, 136.3, 129.2, 128.7, 128.6, 128.5, 127.9, 124.2, 121.0,
5.5, 73.8, 73.1, 45.1, 39.9, 35.0, 27.6, 22.9, 22.7, 13.8, 11.8; ESI-HRMS calcd for C H N O
4
2
8
35
4
+
[
M + H] 491.2658 found 491.2653.

ACCEPTED MANUSCRIPT
4
1
.1.5.2 (Z)-3,4-bis(benzyloxy)-1-propyl-5-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethylidene)-
H-pyrrol-2(5H)-one (32)
It was obtained by the reaction of compound 18 (0.4 g, 0.85 mmol), n-octylamine (0.14 mL, 0.85
-1
mmol) in ethanol (15 mL) in 92% yield (0.46 g) as colourless oil: IR (neat) νmax cm : 3407,
2
5
1
3
8
9
4
018, 1682, 1312, 1112, 993; [α] 6.33° (c 0.05, CHCl ); H NMR (CDCl , 400 MHz) δ: 8.45-
D 3 3
.44 (m, 1H, Ar), 8.22-8.18 (m, 2H, 1Ar-H+ 1 triazolyl-H), 7.83-7.79 (m, 1H, Ar), 7.35-7.24 (m,
H, Ar), 7.07-7.05 (m, 2H, Ar), 5.30 (d, J = 11.16 Hz, 1H, OCH ), 5.08-5.03 (m, 2H, OCH ),
2
2
.95 (d, J = 11.52 Hz, 1H, OCH ), 4.04-3.73 (m, 2H, CH ), 3.37-3.14 (m, 2H, CH ), 2.38-2.04
2
2
2
(
m, 2H, CH ), 1.68-1.63 (m, 2H, CH ), 1.32-1.25 (m, 10H, 5CH ), 0.86 (t, J = 7.04 Hz, 3H,
2 2 2
1
3
CH ); C NMR (CDCl , 50 MHz) δ: 167.4, 151.0, 150.0, 148.9, 147.7, 137.6, 136.5, 135.8,
3
3
1
29.3, 128.7, 128.6, 128.2, 124.0, 123.2, 122.8, 120.6, 96.2, 85.2, 73.8, 73.3, 45.4, 38.4, 35.2,
+
3
1.9, 29.9, 29.4, 29.4, 27.6, 22.7, 14.2; ESI-HRMS calcd for C H N O [M + H] 596.3237
3
5
42
5
4
found 596.3231.
4
.1.5.3 (Z)-3,4-bis(benzyloxy)-5-(2-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1-yl)ethylidene)-1-
phenethyl-1H-pyrrol-2(5H)-one (33)
It was obtained by the reaction of compound 16 (0.5 g, 0.95 mmol), phenethylamine (0.12 mL,
.95 mmol) in ethanol (20 mL) in 93% yield (0.57 g) as white solid; mp 131-133 °C; IR (KBr)
0
-1
25
1
νmax cm : 3316, 3065, 1695, 1356, 1250, 1018; [α] 9.75° (c 0.05, CHCl ); H NMR (CDCl ,
D
3
3
4
2
00 MHz) δ: 7.69-7.68 (m, 2H, Ar), 7.46-7.10 (m, 18H, 17 Ar-H+ 1 triazolyl-H), 5.29-5.28 (m,
H, OCH ), 5.22 (s, 1H, OCH ), 5.10 (s, 1H, OCH ), 3.92-3.83 (m, 1H, CH ), 3.74 (t, J = 7.12
2
2
2
2
Hz, 1H, CH ), 3.60-3.34 (m, 1H, CH ), 3.04-2.98 (m, 1H, CH ), 2.83-2.79 (t, J = 7.08 Hz, 2H,
2
2
2
1
3
CH ), 2.47-2.26 (m, 2H, CH ), 1.33 (s, 9H, 3CH ); C NMR (CDCl , 50 MHz) δ: 164.6, 151.6,
2
2
3
3
1
47.7, 143.6, 138.3, 136.4, 135.9, 135.1, 129.0, 128.9, 128.7, 128.7, 128.6, 128.2, 126.7, 125.8,

ACCEPTED MANUSCRIPT
1
25.6, 119.4, 103.9, 74.2, 74.0, 46.1, 40.2, 34.9, 34.8, 31.4; ESI-HRMS calcd for C H N O
4
4
0
43
4
+
[
M + H] 643.3284 found 643.3275.
.1.6 Typical procedure for the synthesis of compounds 34, 35
To a magnetically stirred solution of compound (31, 32) (1.0 mmol) in anhyd.CH Cl as a
4
2
2
solvent, p-toluenesulfonic acid (1.0 mmol) was added at ambient temperature. The resulted
mixture was stirred at same temperature for 30 min to 1 h. After completion, reaction mixture
was neutralized (pH 7.0) with solid NaHCO , filtered and filtrate was concentrated to give a
3
crude mass. The latter was dissolved in ethyl acetate (75 mL), washed with water (2 x 25 mL).
The organic layer was dried (anhydrous Na SO ) and evaporated under reduced pressure to give
2
4
gummy mass, which was chromatographed (SiO , 60-120 mesh) by using hexane: ethylacetate
2
(7: 3) as eluent to give the desired products.
4
.1.6.1 (Z)-3,4-bis(benzyloxy)-1-propyl-5-(2-(4-propyl-1H-1,2,3-triazol-1-yl)ethylidene)-1H-
pyrrol-2(5H)-one (34)
It was obtained by the reaction of compound 31 (0.4 g, 0.81 mmol), p-toluenesulfonic acid (0.14
g, 0.81 mmol) in anhydrous CH Cl (25 mL) in 84% yield (0.32 g) as white solid; mp 144-146
2
2
-1
1
°
C; IR (KBr) νmax cm : 3432, 3021, 2401, 1699, 1215, 928; H NMR (CDCl , 400 MHz) δ: 7.34-
3
7
5
7
.26 (m, 8H, Ar), 7.19-7.15 (m, 2H, Ar), 6.90 (s, 1H, triazolyl), 5.32-5.28 (m, 1H, C=CH), 5.24-
.22 (m, 4H, OCH + CH ), 5.16 (s, 2H, OCH ), 3.40 (t, J = 7.40 Hz, 2H, NCH ), 2.56 (t, J =
2
2
2
2
.60 Hz, 2H, CH ), 1.59-1.53 (m, 2H, CH ), 1.47-1.42 (m, 2H, CH ), 0.87 (t, J = 7.36 Hz, 3H,
2
2
2
1
3
CH of propylamine), 0.80 (t, J = 7.36 Hz, 3H, CH ); C NMR (CDCl , 100 MHz) δ: 164.8,
3
3
3
1
48.4, 143.5, 136.5, 136.0, 134.8, 128.8, 128.8, 128.7, 128.6, 128.1, 120.5, 104.3, 74.1, 73.9,
+
4
5.8, 40.1, 27.9, 22.7, 21.8, 13.9, 11.3; ESI-HRMS calcd for C H N O [M + H] 473.2553
2
8
33
4
3
found 473.2544.

ACCEPTED MANUSCRIPT
4
1
.1.6.2 (Z)-3,4-bis(benzyloxy)-1-octyl-5-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethylidene)-
H-pyrrol-2(5H)-one (35)
It was obtained by the reaction of compound 32 (0.4 g, 0.67 mmol), p-toluenesulfonic acid (0.11
g, 0.67 mmol) in anhydrous CH Cl (25 mL) in 82% yield (0.31 g) as white solid; mp 133-135
2
2
-1
1
°
C; IR (KBr) νmax cm : 3431, 2969, 2401, 1701, 1423, 1215; H NMR (CDCl , 400 MHz) δ:
3
8
7
.52-8.51 (m, 1H, Ar), 8.12-7.71 (m, 1H, Ar), 7.70 (s, 1H, triazolyl), 7.70-7.68 (m, 1H, Ar),
.34-7.16 (m, 11H, Ar), 5.38-5.29 (m, 3H, C=CH+ CH ), 5.23 (s, 2H, OCH ), 5.17 (s, 2H,
2
2
OCH ), 3.42 (t, J = 7.2 Hz, 2H, NCH ), 1.35-1.34 (m, 2H, CH ), 1.21-1.15 (m, 10H, 5CH ), 0.79
2
2
2
2
1
3
(
t, J = 7.2 Hz, 3H, CH ); C NMR (CDCl , 100 MHz) δ: 164.8, 149.5, 143.5, 137.1, 136.5,
3 3
1
4
5
4
36.0, 135.4, 129.0, 128.9, 128.8, 128.8, 128.7, 128.1, 123.0, 122.0, 120.4, 103.4, 74.2, 74.1,
+
6.3, 38.7, 32.0, 31.9, 28.6, 27.0, 22.8, 14.2; ESI-HRMS calcd for C H N O [M + H]
3
5
40
4
3
78.3131 found 578.3125.
.1.7 2D NMR studies.
The 2D NMR Study of compounds 4, 31 and 34 were evaluated on a Bruker Avance- 400 MHz
1
3
(
300K) in CDCl solvent with TMS as an internal standard. C NMR Spectra were recorded
3
with complete proton decoupling. The assignment was carried out with the help of DEPT-135,
DEPT-90, COSY, HSQC and HMBC experiments. All the spectra were recorded in phase
sensitive mode except for COSY which is in magnitude mode. The spectra were acquired with
2
*256 FID for HMBC, 256 Fids for HSQC and 128 Fids for COSY containing 4-16 transients
for all the experiments with a recycle delay of 1.5 sec.
4
4
.2 Biology
.2.1 Cell lines and culture conditions