In vitro antiplasmodial efficacy of synthetic coumarin-triazole analogs

Article abstract of DOI:10.1016/j.ejmech.2018.01.017

Twenty two diverse coumarin-triazole derivatives were synthesized by alkylation of 7-hydroxy-4-methyl-coumarin followed by click chemistry at 7-position. These compounds were evaluated for their in vitro antiplasmodial activity against chloroquine sensitive strain of Plasmodium falciparum (3D7). Compound 9 (7-[1-(2, 4-dimethoxy-phenyl)-1H- [1–3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one) was found most active with IC₅₀ value 0.763 ± 0.0124 μg/mL. Further, the structure of compound 20 was characterized by single crystal X-ray diffraction. In view of impressive results, we considered it worthwhile to validate the results of in vitro antiplasmodial activity by assessing whether these compounds are capable of hampering the catalytic activity of DNA gyrase, thus preventing its supercoiling function.

Full text of DOI:10.1016/j.ejmech.2018.01.017

Accepted Manuscript
In vitro antiplasmodial efficacy of synthetic coumarin-triazole analogs
Neesha Yadav, Drishti Agarwal, Satyanand Kumar, A.K. Dixit, Rinkoo D. Gupta,
Satish K. Awasthi
PII:
S0223-5234(18)30017-5
10.1016/j.ejmech.2018.01.017
EJMECH 10094
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 24 July 2017
Revised Date: 5 January 2018
Accepted Date: 5 January 2018
Please cite this article as: N. Yadav, D. Agarwal, S. Kumar, A.K. Dixit, R.D. Gupta, S.K. Awasthi, In vitro
antiplasmodial efficacy of synthetic coumarin-triazole analogs, European Journal of Medicinal Chemistry
(2018), doi: 10.1016/j.ejmech.2018.01.017.
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ACCEPTED MANUSCRIPT
N
O
O
O
N
N
OCH3
OCH3
COMPOUND 9
Pf 3D7 IC50 = 0.763 + 0.0124 µg/mL
Huh 7 CC50 = >100 µg/mL
DNA gyrase binding
Inhibition
of supercoiling function

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In vitro antiplasmodial efficacy of synthetic coumarin-triazole analogs
Neesha Yadav1, Drishti Agarwal1, Satyanand Kumar1, A. K. Dixit2, Rinkoo D. Gupta3, Satish K.
Awasthi1*
1Chemical Biology Laboratory, Department of Chemistry, University of Delhi, Delhi-110007
2V S S D College, Kanpur University, Kanpur
3Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi- 110021
*Corresponding author:
Prof. Satish K. Awasthi
Chemical Biology Laboratory,
Department of Chemistry,
University of Delhi, Delhi- 110007, India
Tel.: +91- 9582087608
E-mail: satishpna@gmail.com

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Abstract
Twenty two diverse coumarin-triazole derivatives were synthesized by alkylation of 7-hydroxy-4-methyl-
coumarin followed by click chemistry at 7-position. These compounds were evaluated for their in vitro
antiplasmodial activity against chloroquine sensitive strain of Plasmodium falciparum (3D7). Compound 9
(7-[1-(2, 4-dimethoxy-phenyl)-1H-[1, 2, 3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one) was found most
active with IC50 value 0.763 + 0.0124 µg/mL. Further, the structure of compound 20 was characterized by
single crystal X-ray diffraction. In view of impressive results, we considered it worthwhile to validate the
results of in vitro antiplasmodial activity by assessing whether these compounds are capable of hampering
the catalytic activity of DNA gyrase, thus preventing its supercoiling function.
Keywords: Coumarin, Plasmodium falciparum, antiplasmodial, DNA gyrase.

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1. Introduction
Natural products are regarded as rich sources for isolating antiplasmodial compounds such as alkaloids,
flavonoids, glycosides, etc. [1-4]. Coumarin, the most abundant naturally occurring secondary metabolite,
is found in several plant families, essential oils, microorganisms and a few animal species. Coumarins show
certain biochemical properties which exert certain biological effects in the cellular environment. They have
also been proposed for use in clinical medicine. Coumarin derivatives possess a remarkably broad spectrum
of biological activities including antibacterial [5, 6], antifungal [7-9], anticoagulant [10], anti-inflammatory
[11] antitumor [12, 13] and anti-HIV [14]. In addition, these compounds are used as fragrant additives in
food and cosmetics [15]. The commercial application of coumarin includes dispersed fluorescent
brightening agents and as dyes for tuning lasers [16]. Main representatives of this class are the hydroxy
derivatives, viz, 4- and 7-hydroxycoumarins which are biologically active (primarily used as
anticoagulants) and act as precursors for the synthesis of other coumarin derivatives.
Pteryxin and Suksdorfin-A, isolated from Pteryxia terebinthina and L. omatium suksdorfii, respectively, and a
coumarin compound isolated from the roots of Toddalia asiatica, exhibit antiplasmodial activity [17-19].
Further, Tringali and coworkers reported that 5, 6, 7-trimethoxycoumarin and isofraxidin show moderate
activity [20].
The mode of action by which coumarins exert antimalarial activity is, however, not precisely known.
However, they have been established to operate at least in part through DNA gyrase inhibition, leading to
the accumulation of single-stranded DNA breaks [21]. By this means, self-replication of the organelle
where this enzyme is functional in the protozoan parasite, i.e. the apicoplast may also be inhibited, leading
to the death of the parasite in the subsequent replication cycle.

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Azoles are regarded as one of the most important classes of nitrogen containing heterocyclic compounds
that exhibit potent antiplasmodial activity [22]. Among them, the 1, 2, 3-triazole moiety has aroused special
interest due to its excellent pharmacokinetic characteristics, favorable safety profile, as well as the latent ability
for the formation of hydrogen bonds with other active molecules [23]. A number of triazole drugs including
Fluconazole, Voriconazole and Itraconazole have been prevalently used in the anti-infective therapy [24, 25].
Recently, some triazole derivatives have been reported to exhibit good anti-MRSA potency [26], as well as
potent antimalarial, anticancer, antidiabetic, and antiinflammatory activities [27]. A series of chalcone and
dienone hybrid compounds containing aminoquinoline and nucleoside templates has been screened for in
vitro antimalarial activity. Amongst the synthesized compounds, three compounds were found to be highly
potent against D10, Dd2 and W2 strains of Plasmodium falciparum compared with the standard drug
chloroquine [28].
Our recent work showed that incorporation of triazole ring in norfloxacin leads to a substantial increase in
antimalarial activity [29]. This envisioned us to design and synthesize newer coumarin analogs having
altered structural features, with the hypothesis that substituents in the benzopyrone framework would
significantly affect the biological activity and may render them more effective against the malaria parasite.
In the continuation of our ongoing projects on antimalarial lead identification [30-33] we designed an
analog to synthesize different coumarin triazole derivatives involving click chemistry. These derivatives
were evaluated for their in vitro antiplasmodial activity against P. falciparum 3D7 (choroquine-sensitive
strain). Further, we attempted to gain insight into their mechanism of action via inhibition of the enzyme
DNA gyrase.
2. Results and Discussion
2.1 Synthesis of coumarin-triazole analogs

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We synthesized 7-hydroxy-4-methyl-coumarin by the Pechman condensation from resorcinol by
reacting with ethylacetoacetate in presence of conc. H2SO4 as catalyst. The hydroxyl group of 7-
hydroxy-4-methyl-coumarin was alkylated using propargyl bromide and K2CO3 in acetone. The
compound 7-(prop-2-yn-1-yloxy)-2H-chromen-2-one undergoes cyclo-addition reaction with different
azides in presence of CuSO4.5H2O and sodium ascorbate as reducing agent yielded a series of 1,4-
substituted triazole derivatives 1-22 (figure 1 & table 1). The structures of all synthesized compounds
1
(1-22) were unambiguously established by various spectroscopy techniques viz. FT-IR, ESI-MS, H and
13C- NMR. X-Rays analysis was also carried out on compound 20, which validates the feasibility of the
reaction.
OH
O
O
conc.H2SO4
+
EtO
HO
10°C, 14hr
O
O
OH
Ethylacetoacetate
Resorcinol
K2CO3/Acetone
Br
°
50 C
N
N
O
O
R
N
O
O
O
O
R-N3
1-22
CuSO4/Sodium ascorbate
Figure 1. Scheme showing reagents and conditions used in synthesis of coumarin compounds 1-22

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Table 1. Inhibitory activity of coumarin-triazole compounds against P. falciparum 3D7, and various azides
used for their synthesis
Mean IC50 ± SEa
(µg/mL)
Mean CC50 ±SEa
(µg/mL)
Compound Azide
Product
N3
7.43 + 0.3179
>100
1
N
N
N
O
O
O
Cl
F
Cl
F
N3
6.43 + 0.1453
8.94 + 0.6472
>100
>100
2
3
N
O
O
O
N
N
F
F
N3
Cl
N
O
O
O
N
N
Cl
N3
2.48 + 1.7401
8.43 + 0.3283
>100
>100
4
5
F
N
O
O
O
N
N
F
N3
Cl
N
O
O
O
N
N
Cl
N3
15.40 + 0.8718
>100
6
F
N
O
O
O
N
N
F
F
F

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N3
5.00 + 0.9849
>100
7
N
O
O
O
N
OCF3
N
F3CO
N3
4.16 + 0.6173
0.763 + 0.0124
>100
>100
8
9
N
O
O
O
N
N
NHCOCH3
H3COCHN
N3
OCH3
N
N
O
O
O
N
OCH3
OCH3
OCH3
N3
10
11.06 + 0.333
>100
N
H3CO
OCH3
OCH3
O
O
O
N
N
H3CO
H3CO
OCH3
N3
6.86 + 0.2403
9.46 + 2.5983
>100
>100
11
12
NO2
N
O
O
O
N
N
NO2
N3
N
O
O
O
N
F
N
F
N3
0.893 + 0.0455
>100
13
N
O
O
O
N
N

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N3
4.56 + 0.9261
>100
14
N
O
O
O
N
N
O
O
N3
12.80 + 0.1527
1.496 + 1.0315
>100
>100
15
16
N
O
O
O
N
N
F
F
N3
Cl
N
O
O
O
N
N
Cl
N3
COOMe
3.30 + 0.4041
3.36 + 0.2185
>100
>100
17
18
N
O
O
O
N
N
COOMe
N3
OH
N
O
O
O
N
N
HO
N3H
1.817 + 0.033
6.4 + 0.1732
>100
>100
19
20
N
O
O
O
N
HN
N3
N
O
O
O
N
N

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N3
2.23 + 1.4438
>100
>100
21
22
N
O
O
O
N
N
NO2
O2N
N3
N
10.60 + 0.1732
N
O
O
O
Cl
N
N
Cl
N
a Standard error (n=3).
2.2 The X-ray crystal structure
Single crystals suitable for X-ray diffraction were grown by slow evaporation in ethanol at room
temperature. The data were collected on an Oxford Diffraction Excalibur CCD diffractometer with
graphite monochromated Mo Kα radiation (λ = 0.71073 Å) at 298(2) K. A total of 3144 reflections
were measured, out of which 2607 were found unique. The structure was solved by direct method
using SHELXL-97 and refined by full matrix least-squares method on F2 (SHELXL-97). All
calculations were carried out using the WinGX package of the crystallographic program and
PLATON. For the molecular graphics, program ORTEP-3 and Mercury were used. The final
residual indices are: R 0.0907, for the observed and R 0.2855 for all the reflections using 236
parameters. Packing diagram is given in figure 2, whereas the ortep diagram has been included in
the supplementary information.
Crystallographic data collection, crystal data and the refinement details are summarized in table 2.
The bond distance, bond angles, atomic coordinates and anisotropic displacement parameters are
given in the supporting information table.
X-Ray diffraction study was carried out on compound 20 and data were analyzed. The unit cell
parameters obtained for the single crystal are; a = 5.5405(0.0006) Å, α = 90.14°; b =

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10.5423(0.0016) Å β = 90.01°, c = 14.7610(0.0020) Å, γ = 96.94°and volume =845.09(0.20) Å3,
which clearly indicates that compound 20 is Triclinic crystal with the space group of P-1. Further,
there is intermolecular hydrogen bonding and antiperiplanar structure. The detailed structural data
have been deposited with Cambridge Crystallographic Data Centre No. 846613.
Figure 2. Packing diagram of compound 20
Table 2. Crystal data and structure refinement for compound (20)
Identification code
Empirical formula
Formula weight
Temperature
Shelxl
C20 H17 N3 O3
347.373
293 K
0.71073 Å
Triclinic
Wavelength
Crystal system

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P -1
Space group
Unit cell dimensions
a = 5.5405(0.0006) Å
b = 10.5423(0.0016) Å
c = 14.7610(0.0020) Å
845.09(0.20) Å3
2
α = 90.14°.
β = 90.01°.
γ = 96.94°.
Volume
Z
1.3651 Mg/m3
0.094 mm-1
Density (calculated)
Absorption coefficient
F(000)
364
-6<=h<=6, -10<=k<=12, -17<=l<=16
Index ranges
3144
Reflections collected
Independent reflections
Completeness to theta = 25.50°
Absorption correction
Refinement method
Data / restraints / parameters
Final R indices [I>2sigma(I)]
R indices (all data)
2607
99.80%
Multiscan
Full-matrix least-squares on F2
236
0.0970(2607)
0.2855(3144)
2.3 In vitro efficacies of coumarin-triazole analogs against P. falciparum
It is well documented that coumarin analogs interact with bacterial DNA gyrase, which induces bacterial
death [34]. Since the malaria parasite also harbours gyrase enzyme of the bacterial origin, antiplasmodial

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activity of coumarin analogs can be attributed to DNA gyrase inhibition, which is suggested to be the new
target for antimalarials in future. Moreover, triazole moiety is a very important pharmacophore unit which
is widely seen in many clinical drugs and critical for wide range of activity, ie. antifungal: clotrimazole,
fluconazole, miconazole; antibacterial: metronidazole, azithromycin. However, their inhibitory role against
the malaria parasites has not yet been explored thoroughly except few known drugs. Keeping all these facts
in mind, we designed an analog and synthesized simple coumarin-triazole derivatives exploiting click
chemistry. Since coumarin and triazole moieties are present in the same molecule, their antiplasmodial
activity would be a result of synergistic interaction. Various substituted coumarin-triazole derivatives were
tested in vitro against chloroquine sensitive 3D7 strain of P. falciparum using artemisinin as a standard
drug. Analysis reveals that some of the compounds show very promising activity. Out of twenty two
compounds, eighteen compounds show IC50 less than 10 µg/mL. Compound 6, 10, 15 and 22 show IC50
more than 10 µg/mL. In compound 22 we inserted 7- chloro quinoline moiety in expecting better result
because quinolones have proven to be successful antimicrobial agents, but we got IC50 10.60 + 0.1732
µg/mL. This may be due to steric hindrance, which might have prevented its binding with DNA gyrase
enzyme. Same steric factor is evident in compound 10 containing 3, 4, 5-trimethoxy phenyl ring.
Compound 6 containing 2, 4-difluoro phenyl ring shows least antimalarial activity with IC50 15.40 + 0.8718
µg/mL and compound 15 having 4-fluoro-2-methyl phenyl ring also shows weak activity with IC50 12.80 +
0.1527 µg/mL. Here, the stereochemical approach may not have been appropriate with DNA gyrase
enzyme. Compound 1, 2, 3, 5, 11 and 12 exhibit moderate activity with IC50 ranging 5-10 µg/mL. Here
activity data of compound 1 (IC50 7.43 + 0.3179 µg/mL) compound 2 (IC50 6.43 + 0.1453 µg/mL) cleared
fluoro substituent in ring gave better result than chloro substituent as compound 3 (IC50 8.94 + 0.6472
µg/mL) and compound 5 (IC50 8.43 + 0.3283 µg/mL). Further, in compound 12 (IC50 9.46 + 2.5983 µg/mL)

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fluoro substituent present at meta position did not give better result. Compound 11 (IC50 6.86 + 0.2403
µg/mL) having nitro group at ortho position exhibited moderate activity.
Further, compounds 7, 8 and 14 containing trifluoromethoxy, acetamide and phenoxy subtituent showed
better results with IC50 ranging 4-5 µg/mL.
Now, if we compare benzyl derivative like compound 20 (IC50 6.4+ 0.1732 µg/mL) and compound 21
(IC50 2.23 + 1.14438 µg/mL), compound 21 (containing 4-Nitro benzyl derivative) shows significant result
may be due to electron withdrawing nature of nitro group. Similarly, increase in activity was observed
when alkyl chain having polar group such as methoxy ethanoate (compound 17; IC50 3.30 + 0.4041µg/mL)
and 2-hydroxyethyl (compound18; IC50 3.36 + 0.2185 µg/mL) were introduced on triazole ring.
Interestingly, compound 21 in which position-1 of triazole ring was left unsubstituted exhibited promising
antimalarial activity with IC50 1.817 + .033 µg/mL, suggesting that the hydrogen of triazole ring might be
forming H- bond with the target site, thus interfering with the normal function of parasite.
In this series, three most active compounds are compound 9 (IC50 0.763 + .0124 µg/mL), compound 13
(IC50 0.893 + 0.0455 µg/mL) and compound 16 (IC50 1.496 + 1.0315 µg/mL). Compound 16 contains 2-
choloro-4-methyl phenyl ring and compound 13 contains 5 –dimethyl phenyl ring. The result suggests that
presence of electron releasing group methyl enhances the antimalarial activity. Compound 9 having 2, 4-
dimethoxy phenyl ring was the most potent compound; presence of two electron releasing methoxy group
at ortho and para position of phenyl ring enhanced the antimalarial activity quite significantly.
Thus, the results presented in table 1 show that most of the new compounds of coumarin-triazole series
exhibited very promising activity ranges, depending on the substitution on position-1 of triazole ring, like
alkyl chain having polar group and phenyl ring having different functional group. The presence of electron
releasing group and electron withdrawing group, their position (ortho, meta and para) in phenyl ring and
their steric hindrance, all the factors might affect the activity, but varying behavior of compounds with

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similar nature of functional groups is still elusive. This study clearly demonstrates that there is need of
systematic SAR study to establish meaningful correlation among various functional groups. Work in this
direction is under progress.
2.4 Effect of coumarin-triazole analogs on the activity of E. coli DNA gyrase
The molecular details of the gyrase-coumarin complex are extensively studied [35]. The coumarins
inhibit the gyrase action by competitive binding to the ATP-binding site of DNA gyrase B (GyrB)
protein. In contrast, the quinolones act in a different manner, by trapping the cleavage complex and
interacting primarily with GyrA and to some extent with GyrB and DNA [36]. Hence, DNA gyrase
has been hypothesized to be a new target for development of newer antimalarial drugs in future.
Substantiating this hypothesis is the fact that the malaria parasite harbours the bacterial type DNA
gyrase enzyme. It requires the apicoplast, a chloroplast-like organelle for survival. Genome of the
apicoplast (plDNA) is a 35 kb circular DNA that is served by gyrase, a prokaryotic type
II topoisomerase [37].
In the present study, we investigated the influence of coumarin-triazole analogs on the supercoiling
activity of DNA gyrase exerted on relaxed plasmid DNA. The results revealed inhibition of the
supercoiling activity, which may be attributed to prevention of ATP hydrolysis required for the
enzymatic cycle and inhibition of the gyrase DNA binding. Figure 3 shows the relative positions of
the relaxed topoisomers (A), linear (B) and supercoiled (C) pHOT1 plasmid DNA, gyrase treated
relaxed DNA (D), and gyrase treated relaxed DNA in the presence of IC50 concentrations of test
compounds 9, 13 and 16, respectively (E-G) and the positive control, ciprofloxacin (H).

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Figure 3. Effect of coumarin-triazole analogs 9, 13 and 16 on E. coli DNA gyrase, using relaxed
pHOT1 plasmid DNA as a substrate. The lower band shows supercoiled DNA. Samples were
analysed by gel electrophoresis.
3. Conclusion
We have synthesized a series of novel coumarin-triazole derivatives (1-22) by exploiting Click Chemistry
on 7-(prop-2yn-1-yloxy)-2H-chromen-2-one. Most of the compounds demonstrated promising in vitro
antiplasmodial activities. However, three compounds with the lowest inhibitory concentration values were
9, 13, 16, with IC50 values of 0.763 + 0.0124, 0.893 + 0.0455 and 1.496 + 1.0315, respectively. Convincing
results were obtained on account of analyzing their inhibitory effect on the supercoiling activity of the
enzyme gyrase, employing E. coli DNA gyrase and relaxed plasmid DNA. Thus, we can conclude that
these compounds can be used as potential leads to synthesize new antimalarial drugs that target the DNA
gyrase enzyme. Furthermore, it would be interesting to study their behavior in Artemisinin-based
Combination Therapy (ACT), as combination partners to the artemisinins.

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4. Experimental procedure
4.1 General methods
Various chemicals and solvents used in this study were purchased from E. Merk (India) and Sigma-Aldrich
Chemicals. Melting points werejhu8iky determined by using open capillary method and are uncorrected. 1H
NMR spectral data were recorded on a BruckerAvance 300MHz and Jeol JNM 400MHz spectrometers
respectively using TMS as an internal standard. The chemical shift values are recorded on δ scale and
coupling constants (J) are in hertz. The following abbreviations were used in reporting spectra: s =singlet, d
= doublet, t = triplet, q = quartet, m = multiple. IR spectra were obtained on a Perkin Elmer Fourier-
transform infrared (FT-IR) spectrophotometer (Spectrum 2000) in potassium bromide disk. ESI-MS spectra
were obtained on Waters Micromass LCT spectrometer. Elemental analysis was done on Elementar GmbH
VarioElanalyzer.
4.2 Preparation of 4-methyl-7-hydroxy coumarin
Concentrated H2SO4 (20mL) was taken into a 250mL round flask and cooled in an ice bath at 0°C.
A solution of resorcinol (2.0g, 18.16 mmol) in ethyacetoacetate (2.4mL, 19mmol) was added
dropwise to the flask with constant stirring while the temperature was carefully kept below at 10°C.
Then the mixture was continued to stir overnight at room temperature. After this period, the
reaction mixture was poured into crushed ice with vigorous stirring. The solid product was filtered
and washed with cold water. Crude product was recrystallized from absolute ethanol to obtain pure
4-methyl-7-hydroxycoumarin with an approximately 60% yield [38].

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4.3 Synthesis of 7-(Prop-2-yn-1-yloxy)-2H-chromen-2-one
To a stirred solution of 4-methyl-7-hydroxy-coumarins (1.76g, 10mmol) in dry acetone, anhydrous
potassium carbonate (1.38g, 10mmol) and propargyl bromide (1.19g, 10mmol) were added. The
resultant mixture was stirred at 50ºC for 18h, then the mixture was cooled and the solvent was
removed under reduced pressure. The residue was redissolved into 15mL of water and extracted
with ethyl acetate. The combined organic phases was washed with water, dried over anhydrous
sodium sulphate and evaporated in vacuum. The crude product was purified by crystallization from
ethyl acetate/hexane mixture to yield light yellow solid product [38].
1
Yield: 90%. mp: 130-132ºC. H NMR (CDCl3, 400MHz) δ ppm: 2.40(s, 3H, 4-CH3), 2.57(s, 1H,
CH of alkyne), 4.76(s, 2H, -O-CH2- methylene proton), 6.16(s, 1H, pyran ring), 6.93(m, 2H, H5 and
H6), 7.5 (s, 1H, H8). 13C NMR (CDCl3, 100MHz) δ ppm: 18.56(CH3), 56.08(-CH2-O), 76.41(C3′
alkyne), 77.31 (C2′ alkyne), 102.04(C3), 112.27(C8), 114.14(C6), 125.55(C5), 152.35(C4 pyran ring),
154.90(C7-O), 160.24 (C=O).
4.4 General procedure for synthesis of alkylazide
Alkyl halide (5.8 mmol) in DMSO (8 mL) was taken in a round bottom flask and sodium azide was
(760mg, 11.69mmol) added and stirred overnight. The reaction mixture was quenched in ice-water
and extracted with diethyl ether, washed successively with 5% bicarbonate solution and dried over
anhydrous sodium sulphate. The solvent was removed by rotary evaporated to give alkyl azide,
yield 70% [39a].

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4.5 General procedure for synthesis of arylazide
Aniline (7.25 mmol) was dissolved in 4.57mL (1:1 ratio HCl:water) and stirred at 0-5˚C. Sodium
azide (468g) was dissolved in 5.67mL of water and added drop wise and then reaction was allowed
to reach at room temperature and stirred further for 30 minutes. The resultant precipitate was
extracted with CHCl3 and washed successively with water. The organic layer was dried over
anhydrous Na2SO4 and the solvent was removed in vacuum to get arylazide in good yield [39a].
4.6 Synthesis of 4-azido-7-chloro-quinoline
To 4,7-dichloroquinoline (1.0gm, 5mmol) solution in anhydrous DMF (4mL) was added sodium
azide (0.650gm, 10mmol) and resulting mixture was stirred at 70˚C for 6h. After completion of
reaction as checked by TLC, the reaction mixture was allowed to cool to room temperature and
diluted with DCM (100mL), washed with water, dried over anhydrous sodium sulphate and
evaporated to dryness. The resulting product residue was crystallized from DCM / hexane mixture
which yielded pure colourless needle like crystals in 80% yield [39b].
4.7 General procedure for synthesis of compounds (1-22)
To a solution of compound 7-(Prop-2-yn-1-yloxy)-2H-chromen-2-one (214 mg, 1.0 mmol) in tert.
BuOH/H2O (1:1), CuSO4.5H2O (37.45mg, 0.15mmol) and sodium ascorbate (59.4mg, 0.30mmol)
were added. The mixture was stirred at room temperature for 15 minute and then azide (1.0 mmol)
was added. The resulting mixture was stirred at room temp. until the starting material was
consumed. After 24h, on completion of the reaction as seen by TLC, the reaction mixture was
extracted with ethylacetate. The combined organic phase washed with water, dried over anhydrous
sodium sulphate and evaporated in vacuum. The crude product was purified by column
chromatography [39a].

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4.7.1. 7-[1-(3-Chloro-4-fluoro-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one
(1)
Yield: 40%. Yellow solid. mp: 182-184°C. MS: m/z = 385.34 (M+), 387 (M+2), 386 (M+1), 210
1
(M-175) . H NMR (DMSO-d6, 300MHz) δppm: 2.36(s, 3H, -CH3), 5.38(s, 2H, -O-CH2-) 6.25(s,
1H, H3 coumarin pyran ring), 7.07(d, 1H, H5, J = 8.1Hz), 7.19(s, 1H, H8 coumarin ring), 7.67(d, 1H,
H6, J = 4.2Hz), 7.87(m, 2H, H6′& H5′ benzene ring), 9.04(s, 1H, H6, benzene ring). 9.05(s, 1H,
triazole ring). 13C NMR ((DMSO-d6, 75MHz) δ ppm: 18.64(CH3), 62.00(-CH2-O), 80.38,
102.12(C3), 111.80(C8), 113.08(C6), 121.60(C5′ benzene ring), 123.04(C6′), 124.03(C2′), 127.06(C5
coumarin ring & C1′ benzene ring) 129.76(CH, ethylene C of triazole ), 139.10(C3′-Cl), 143.84(C,
quaternary carbon of triazole ring), 149.93(C4′), 153.13(C-O Fused in pyran ring), 155.13(C4 pyran
ring), 160.60(C7-O), 161.36(C=O). IR (KBr, cm-1) νmax: 2929.50(C-H stretching), 1718.44( α ,β-
unsaturated ketonic C=O stretching), 1617.95, 1389.05, 1270.58(C-O-C stretching), 1153.71(C-N
stretching in 1,2,3-triazole ring), 1072.62(C-O-C stretching), 845.78. Anal. Calcd for
C19H13ClFN3O3: C, 59.15; H, 3.40; N, 10.89. Found: C, 59.12; H, 5.19; N, 12.49%.
4.7.2. 7-[1-(4-Fluoro-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (2)
Yield: 40%. Yellow solid, mp: 172-174°C. MS: m/z = 351.23 (M+), 352.23 (M+1), 353.22(M+2),
1
176.11(M-175). H NMR ((DMSO-d6, 300MHz) δ ppm: 2.39(s, 3H, -CH3), 5.36(s, 2H, -O-CH2-),
6.22(s, 1H, H3 coumarin pyran ring), 7.04(d, 1H, H5, 7.15(s, 1H, H8 coumarin ring),
J = 7.8Hz), 7.49(m, 2H, H6′ & H2′ benzene ring), 7.67(d, 1H, H6 coumarin ring, J = 8.4Hz), 7.9(br,
s, 2H, H3′ & H5′ benzene ring), 9.02(s, 1H, triazole ring). 13C NMR ((DMSO-d6, 75MHz) δ ppm:
18.12(CH3), 61.85(-CH2-O), 101.57(C3), 111.36(C8), 112.53(C6), 113.45(C3′ & C5′), 116.94(C

ACCEPTED MANUSCRIPT
quaternary fused C of coumarin ring), 122.53 (C1′), 123.62 (C5′), 126.52 (CH, ethylene C of triazole
), 132.98(C2′ & C6′), 143.32(C, quaternary carbon of triazole ring), 153.37(C-O Fused in pyran
ring), 154.61(C4 pyran ring), 160.11(C4′-F benzene ring), 160.85 (C7-O), 163.40(C=O). IR (KBr,
cm-1) νmax: 2925.95(C-H stretching), 1717.95 (α, β-unsaturated ketonic C=O stretching), 1609.70,
1516.59, 1388.08(C-O-C stretching), 1158.17 (C-N stretching in 1,2,3-triazole ring), 1071.92(C-O-C
stretching), 845.5. Anal. Calcd for C19H14FN3O3: C, 64.95; H, 4.02; N, 11.96. Found: C, 64.32 ; H,
4.22; N, 11.82%.
4.7.3. 7-[1-(2-Chloro--phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (3)
Yield: 36%. Yellow solid. mp: 118-120°C. MS: m/z = 367.89 (M+), 369.88 (M+2), 368.86 (M+1),
193(M-175) . 1H NMR ((DMSO-d6, 300MHz) δppm: 2.41(s, 3H, -CH3), 5.38 (s, 2H, -O-CH2-), 6.25(s,
1H, H3 coumarin pyran ring), 7.09(d, 1H, H5, J = 8.0Hz), 7.2 (s, 1H, H8 coumarin ring), 7.6-7.8(m, 5H,
4H benzene ring, H6 coumarin ring),8.7(s, 1H, triazole ring). 13C NMR ((DMSO-d6, 75MHz) δ ppm:
18.62(CH3), 61.88(-CH2-O), 102.10(C3), 111.83(C8), 113.13(C6), 113.92 (C quaternary fused C of
coumarin ring), 127.03(C5), 127.70 (C5′), 129.00 (C1′ & C3′), 131.03 (C4′ & C6′), 132.27 (CH, ethylene
C of triazole ), 134.83(C2′-Cl), 142.59(C, quaternary carbon of triazole ring), 153.92(C-O Fused in
pyran ring), 155.14(C4 pyran ring), 160.61(C7-O), 161.45(C=O). IR (KBr, cm-1) νmax : 2922.33(C-H
stretching), 1718.21( α, β-unsaturated ketonic C=O stretching), 1617.78, 1387.97, 1282.08(C-O-C
stretching), 1143.18 (C-N stretching in 1,2,3-triazole ring), 1070.38(C-O-C stretching), 837.28, 761.91.
Anal. Calcd for C19H14ClN3O3: C, 62.05; H, 3.84; N, 11.43. Found: C, 62.01; H, 3.89; N, 11.22%.
4.7.4. 7-[1-(2-Fluoro-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (4)
Yield: 35%. Yellow solid. mp: 128-130°C. MS: m/z = 351.13 (M+), 352.23(M+1), 353.22(M+2),
1
176.11 (M-175). H NMR ((DMSO-d6, 300MHz) δ ppm: 2.38(s, 3H, -CH3), 5.30(s, 2H, -O-CH2-)

ACCEPTED MANUSCRIPT
6.23(s, 1H, H3 coumarin pyran ring), 7.10-8.19(br, 7H, 4H benzene ring & 3H coumarin ring H5,
H6, H8), 8.84(s, 1H, triazole ring). 13C NMR ((DMSO-d6,75MHz) δ ppm: 23.36(CH3), 66.54(-CH2-
O), 106.81 (C3), 116.57 (C8), 117.82 (C6), 118.66 (C, quaternary fused C of coumarin ring),
122.24(C1′), 122.50 (C3′), 129.78(C5), 129.92(C5′), 130.85(C4′), 131.26(C6′), 131.77 (CH, ethylene C
of triazole ), 147.87 (C, quaternary carbon of triazole ring), 157.40 (C-O Fused in pyran ring),
158.64 (C4 pyran ring), 160.72(C7-O), 165.30(C2′-F), 166.16(C=O). IR (KBr, cm-1) νmax: 2924.28
(C-H stretching), 1718.40 (α, β-unsaturated ketonic C=O stretching), 1617.57, 1389.35, 1282.36 (C-
O-C stretching), 1140.09 (C-N stretching in 1,2,3-triazole ring), 1044.25 (C-O-C stretching), 834.21,
765.51. Anal. Calcd for C19H14FN3O3: C, 64.95; H, 4.02; N, 11.96. Found: C, 64.31; H, 4.27; N,
11.83%.
4.7.5. 7-[1-(4-Chloro-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (5)
Yield: 40%. Yellow solid. mp: 200-202°C. MS: m/z = 367.13 (M+),369.07(M+2), 368.07(M+1)
1
193(M-175), 176 . H NMR ((DMSO-d6, 300MHz) δ ppm: 2.40(s, 3H, -CH3), 5.36(s, 2H, -O-CH2-)
6.23(s, 1H, H3 coumarin pyran ring), 7.07(d, 1H, H5, J = 6.3Hz), 7.18(s, 1H, H8, coumarin ring),
7.69( m, 3H, H6 coumarin ring, H2′ and H6′ benzene ring), 7.95(d, 2H, H3′ and H5′ benzene ring),
9.02(s, 1H, triazole ring). 13C NMR ((DMSO-d6, 75MHz) δ ppm: 18.60(CH3), 62.00(-CH2-O),
102.12(C3), 111.94(C8), 113.06(C6), 113.95(C quaternary fused C of coumarin ring), 122.36(C3′
&C5′), 123.73(C2′ & C6′), 127.03(C5), 130.36(CH, ethylene C of triazole ), 133.57(C1′), 135.77(C4′-
Cl), 143.82 (C, quaternary carbon of triazole ring), 153.86(C-O Fused in pyran ring), 155.11(C4
pyran ring), 160.57(C7-O), 161.37(C=O). IR (KBr, cm-1) νmax: 2924.41(C-H stretching), 1718.39 (α,
β-unsaturated ketonic C=O stretching), 1612.28, 1501.14, 1388.50, 1265.51(C-O-C stretching),
1155.15(C-N stretching in 1,2,3-triazole ring), 1070.28(C-O-C stretching), 839.48, 504.28. Anal.
Calcd for C19H14ClN3O3: C, 62.05; H, 3.84; N, 11.43. Found: C, 62.31; H, 3.90; N, 11.20%.

ACCEPTED MANUSCRIPT
4.7.6. 7-[1-(2,4-Difluoro-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (6)
Yield: 35%. Yellow solid. mp: 170-172°C. MS: m/z = 369.17 (M+), 370.16(M+1), 371.18(M+2),
177.1(7-hydroxy coumarin cation). 1H NMR ((DMSO-d6, 300MHz) δ ppm: 2.36(s, 3H, -CH3),
5.39(s, 2H, -O-CH2-) 6.24(s, 1H, H3 coumarin pyran rings), 7.09-7.20(br, 2H, H5 and H6), 7.37(s,
1H, H3′, benzene ring), 7.71(s, br, 2H, H5′ and H6′, benzene ring), 7.93(s, 1H, H8), 8.80(s, 1H,
triazole). IR (KBr, cm-1) νmax: 3069.46, 2925.08(C-H stretching), 1710.86(α, β-unsaturated ketonic
C=O stretching), 1612.87, 1517.46, 1388.02, 1279.07(C-O-C stretching), 1198.58, 1142.00(C-N
stretching in 1,2,3-triazole ring), 1067.42(C-O-C stretching), 1013.82, 836.90, 609.44. Anal. Calcd
for C19H13F2N3O3: C, 61.79; H, 3.55; N, 11.38. Found: C, 61.61; H, 3.89, N, 11.22%.
4.7.7. 7-[1-(4-Trifluoromethoxy-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one
(7)
Yield: 35%. Yellow solid. mp: 154-156°C. MS: m/z = 417.17 (M+), 332(M-OCF3), 177 (7-hydroxy
1
coumarin cation). H NMR ((DMSO-d6, 300MHz) δ ppm: 2.40(s, 3H, -CH3), 5.38(s, 2H, -O-CH2-)
6.24(s, 1H, H3 coumarin pyran rings), 7.08(d, 2H, H5 and H6, J = 8.7Hz), 7.62-772(m, 3H, H2′ and
H6′ benzene ring and H8), 8.06(d, 2H, H3′ and H5′ benzene ring , J = 8.7Hz), 9.05(s, 1H, triazole).
13C NMR ((DMSO-d6, 75MHz) δ ppm: 18.62(CH3), 61.96(-CH2-O), 102.07(C3), 111.87(C8),
113.08(C6), 113.94(C quaternary fused C of coumarin ring), 122.68(CF3), 123.16(C3′ &C5′),
123.97(C1′), 127.05(C5), 135.83(C2′ &C6′), 143.83(C, quaternary carbon of triazole ring),
148.41(C4′-O), 153.92(C-O Fused in pyran ring), 155.10(C4 pyran ring), 160.62(C7-O),
161.32(C=O). IR (KBr, cm-1) νmax: 2925.22(C-H stretching), 1743.20 (α, β-unsaturated ketonic C=O
stretching), 1612.50, 1517.53, 1389.32, 1261.94 (C-O-C stretching), 1156.10 (C-N stretching in

ACCEPTED MANUSCRIPT
1,2,3-triazole ring), 1027.39(C-O-C stretching), 839.99, 502.60. Anal. Calcd for C20H14F3N3O4: C,
57.56; H, 3.38; N, 10.07. Found: C, 57.53; H, 3.86; N, 10.22%.
4.7.8.
N-{4-[4-(4-Methyl-2-oxo-2H-chromen-7-yloxylmethyl)-[1,2,3]
triazol-1-yl]-phenyl}-
acetamide (8)
1
Yield: 38%. Yellow solid. mp: 150-152°C. MS: m/z = 390.16(M+), 391.16(M+1), 392(M+2). H
NMR ((DMSO-d6, 300MHz) δ ppm: 2.04(s, 3H, -CO-CH3), 2.4(s, 3H, -CH3), 4.94(s, 2H, -O-CH2-),
6.26(s, 1H, H3 coumarin pyran ring), 7.03(d, 2H, H5 and H6, J = 12.0Hz), 7.46(d, 2H, H2′ and H6′, J
13
= 8.7Hz), 7.56(d, 2H, H3′ and H5′, J = 8.7Hz), 9.01(s, 1H, triazole), 10.095(s, 1H, NH). C NMR
((DMSO-d6,75MHz) δ ppm: 18.20(CH3,coumarin ring methyl C), 24.08(CH3 amide methyl C),
56.11(-CH2-O), 78.98, 78.59, 101.87(C3), 111.58(C8), 112.63(C6), 113.73(C1′&C quaternary fused
C of coumarin ring), 114.55(C3′ &C5′), 120.89(C2′ &C6′), 126.63(C5), 131.54 (CH, ethylene C of
triazole), 138.71(C4′-N & quaternary carbon of triazole ring), 153.47(C-O Fused in pyran ring),
154.53(C4 pyran ring), 160.15(C=O), 168.57(C=O of amide). IR (KBr, cm-1) νmax: 3305.17(N-H
Stretching in amide), 2926.13(C-H stretching), 1718.81(α, β-unsaturated ketonic C=O stretching),
1390.01, 1364.04, 1282.09, 1262.03(C-O-C stretching), 1155.58(C-N stretching in 1,2,3-triazole
ring), 1070.35(C-O-C stretching), 1017.94, 822.01, 504.20. Anal. Calcd for C21H18N4O4: C, 64.61;
H, 4.65; N, 14.35. Found: C, 64.59; H, 4.97; N, 14.32%.
4.7.9. 7-[1-(2,4-Dimethoxy-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (9)
Yield: 30%. Yellow solid. mp:170-172°C. MS: m/z = 393.12(M+), 394.13(M+1), 395.11 (M+2),
1
218 (M-175). H NMR ((DMSO-d6, 300MHz) δ ppm: 2.41(s, 3H, 4-CH3 coumarin ring), 3.78 (s,
6H, 2′ and 4′-OCH3), 5.36(s, 2H, -OCH2-), 6.24(s, 1H, H3 pyran ring), 7.13(m, 2H, aromatic),
7.43(m, 3H, aromatic), 7.80(s, 1H, H3′), 8.68(s, 1H, triazole ring). 13C NMR ((DMSO-d6,75MHz) δ

ACCEPTED MANUSCRIPT
ppm: 18.60(CH3), 56.28(2′-OCH3), 57.01(4′-OCH3), 61.91(-CH2-O), 102.11(C3), 111.58(C8),
111.80(C6), 113.13(C quaternary fused C of coumarin ring), 113.88(C3′), 114.74(C1′), 116.36(C5′),
126.27(C6′), 127.00(C5), 127.44(CH, ethylene C of triazole ), 142.28(C, quaternary carbon of
triazole ring), 145.96(C2′-O), 153.61(C4′-O), 153.88(C-O Fused in pyran ring), 155.15(C4 pyran
ring), 160.60(C7-O), 161.48(C=O). IR (KBr, cm-1) νmax: 2926.01(C-H stretching), 1728.48(α, β-
unsaturated ketonic C=O stretching), 1615.75, 1511.97, 1511.97, 1389.79, 1292.63, 1281.18(C-O-C
stretching), 1146.77(C-N stretching in 1,2,3-triazole ring), 1071.82, 1042.84(C-O-C stretching),
862.58, 810.45, 705.16. Anal. Calcd for C21H19N3O5; C, 64.12; H, 4.87; N, 10.60. Found: C, 64.01;
H, 4.89; N, 10.22%.
4.7.10. 7-[1-(3,4,5-Trimethoxy-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one
(10)
Yield: 28%. Yellow solid, mp: 142-144°C. MS: m/z = 423.16 (M+), 248(M-175), 177(hydroxy
1
coumarin). H NMR ((DMSO-d6, 300MHz) δ ppm: 2.39(s, 3H, -CH3), 3.71(s, 3H, 4-OCH3), 3.87(s,
6H, 3-OCH3 and 4-OCH3), 5.3(s, 2H, -CH2-O-), 6.23(s, 1H, H3 coumarin pyran ring), 7.07(d, 1H,
H5, J = 8.4Hz), 7.08-7.17(m, 3H, H8 coumarin ring, H2′ and H6′ benzene ring), 7.09(d, 1H, H6 J =
8.7Hz), 9.03(s, 1H, triazole ring), 13C NMR ((DMSO-d6,75MHz) δ ppm: 18.18(CH3), 56.31(3′-
OCH3 &5′-OCH3), 60.23(4′-OCH3), 61.72(-CH2-O), 98.13, 101.65, 102.20(C3), 110.27(C8),
111.41(C6), 112.64(C2′), 112.90(C4′), 113.51(C quaternary fused C of coumarin ring), 123.47(C1′),
126.59(C5), 132.43(CH, ethylene C of triazole ), 137.39(C4′), 143.09(C, quaternary carbon of
triazole ring), 153.45(C3′&C5′), 153.56(C-O Fused in pyran ring), 154.68(C4 pyran ring), 160.18(C7-
O), 160.97(C=O). IR (KBr, cm-1) νmax: 2930.68(C-H stretching), 1717.53(α, β-unsaturated ketonic
C=O stretching), 1610.74, 1510.30, 1389.06, 1277.49, 1265.72(C-O-C stretching), 1126.41(C-N

ACCEPTED MANUSCRIPT
stretching in 1,2,3-triazole ring), 1073.56(C-O-C stretching), 861.26, 820.30. Anal. Calcd for
C22H21N3O6: C, 62.41; H, 5.00; N, 9.92. Found: C, 62.21; H, 5.64; N, 10.13%.
4.7.11. 7-[1-(2-Nitro-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (11)
Yield: 35%. Yellow solid. mp: 146-148°C. MS: m/z = 378.10 (M+), 173(M-175). 1H NMR
((DMSO-d6, 300MHz) δ ppm: 2.41(s, 3H, -CH3), 5.39(s, 2H, -O-CH2-), 6.29(s, 1H, H3 coumarin
pyran ring), 8.91(s, 1H, triazole ring), 7.20(s, 1H, H8 coumarin ring), 7.09(d, 1H, H5, J = 6.0Hz),
7.72(d, 1H, H6, J = 6.9Hz) , 7.86-7.95(m, 3H, H4′, H5′ & H6′ benzene ring), 8.24(d, 1H, H3′ benzene
ring, J = 6.6Hz). 13C NMR ((DMSO-d6, 75MHz) δ ppm: 18.63(CH3), 61.83(-CH2-O), 102.05(C3),
111.84(C8), 113.10(C6), 115.90(C quaternary fused C of coumarin ring), 119.62(C1′), 126.08(C3′),
127.04(C5), 128.16(C4′), 129.47(C6′), 131.81(CH, ethylene C of triazole ), 134.97(C5′), 136.21,
143.26(C, quaternary carbon of triazole ring), 144.50(C2′-NO2), 153.92(C-O Fused in pyran ring) ,
155.13(C4 pyran ring), 160.62, 161.40(C=O). IR (KBr, cm-1) νmax: 2920.02(C-H stretching),
1735.98( α ,β-unsaturated ketonic C=O stretching), 1617.96, 1524.91, 1345.94(-NO2 sym stretching),
1278.65(C-O-C stretching), 1154.55(C-N stretching in 1,2,3-triazole ring), 1017.41(C-O-C
stretching), 839.57, 740.83. Anal. Calcd for C19H14N4O5: C, 60.32; H, 3.73; N, 14.81. Found: C,
60.17; H, 3.89; N,14.65%.
4.7.12. 7-[1-(3-Fluoro-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (12)
Yield: 40%. Yellow solid. mp: 178-180°C. MS: m/z = 351.10 (M+) 352.23(M+1), 353.22(M+2),
1
176.11 (M-175). H NMR ((DMSO-d6, 300MHz) δ ppm: 2.41(s, 3H, -CH3), 5.39(s, 2H, -CH2-O-),
6.24(s, 1H, H3), 7.08(d, 1H, J = 9.0Hz), 7.18(s, 1H, H8), 7.39(d, 1H, H6, J = 6.9Hz), 7.66-7.72(m,
2H, H4′ and H5′), 7.81-7.88(m, 2H, H2′ and H6′). 13C NMR ((DMSO-d6,75MHz) δ ppm: 18.51(CH3),
62.00(-CH2-O), 102.09(C3), 107.95, 108.30, 111.83(C8), 113.03(C6), 113.94(C4′&C2′), 115.87(C

ACCEPTED MANUSCRIPT
quaternary fused C of coumarin ring), 116.51(C5′), 123.76(C6′), 126.90(C5), 132.27(CH, ethylene C
of triazole ), 138.20(C1′), 143.84(C, quaternary carbon of triazole ring), 153.82(C-O Fused in pyran
ring), 155.09(C4 pyran ring), 160.58(C7-O), 161.30(C3′-F), 164.48(C=O). IR (KBr, cm-1) νmax
:
3161.20(C-H stretching), 1700.21(α, β-unsaturated ketonic C=O stretching), 1612.81, 1384.34,
1296.92(C-O-C stretching), 1146.58(C-N stretching in 1,2,3-triazole ring), 1072.17(C-O-C
stretching), 1037.88, 868.38, 853.48, 801.18, 529.35. Anal. Calcd for C19H14FN3O3: C, 64.95; H,
4.02; N, 11.96. Found: C, 64.30 ; H, 4.29; N, 11.72%.
4.7.13. 7-[1-(3,5-Dimethyl-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one (13)
1
Yield: 30%. Yellow solid. mp :202-204°C. MS: m/z = 361.14 (M+). H NMR ((DMSO-d6,
300MHz) δ ppm: 2.41(s, 9H, 3-CH3), 5.36(s, 2H, -CH2-O,), 6.24(s, 1H, pyran ring), 7.10(m, 3H,
aromatic proton), 7.53(s, 2H, H2′ and H5′), 7.72(d, 1H, aromatic proton, J = 8.1Hz), 8.93(s, 1H,
triazole ring). IR (KBr, cm-1) νmax: 2919.65 (C-H stretching), 1717.61(α, β-unsaturated ketonic C=O
stretching), 1612.81, 1390.28, 1370.28, 1265.88(C-O-C stretching), 1199.40, 1138.71( C-N
stretching in 1,2,3-triazole ring), 1070.91(C-O-C stretching), 1017.93, 841.30, 808.35, 681.12,
439.12. Anal. Calcd for C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.65; H, 5.98, N,
11.61%.
4.7.14. 4-Methyl-7-[1-(4-phenoxy-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-chromen-2-one (14)
Yield: 30%. Yellow solid. mp: 144-146°C. MS: m/z = 425.67(M+), 332 (M- Ph+), 93 (Ph-O),77
1
(Ph+). H NMR ((DMSO-d6, 300MHz) δ ppm: 2.41(s, 3H, 4-CH3 aromatic ring) 5.37(s, 2H, -CH2-
O-), 6.24(s, 1H, H3 coumarin pyarn ring), 7.10(m, 3H, aromatic proton), 7.21 (m, 4H aromatic
proton), 7.45(t, 2H, aromatic ring, J = 15.6Hz, J′=7.8Hz, J”=7.8Hz), 7.2 (d, 2H, aromatic ring, J =
8.7Hz), 7.90 (d, 2H, J = 8.7Hz), 8.96 (s, 1H, triazole ring). 13C NMR ((DMSO-d6,75MHz) δ ppm:

ACCEPTED MANUSCRIPT
18.08(CH3), 61.56(-CH2-O), 101.61 (C3), 111.32 (C8), 112.55(C6), 113.42 (C quaternary fused C of
coumarin ring), 119.15(2C aromatic), 119.18(2C aromatic), 122.21(2C aromatic), 123.20(2C
aromatic), 124.12(1C aromatic), 126.49(C5), 130.20(C1′), 131.87(CH, ethylene C of triazole ),
143.09 (C, quaternary carbon of triazole ring), 153.32 (C-O Fused in pyran ring), 154.61 (C4 pyran
ring), 155.89 (C4′-O), 157.00 (C-O phenoxy), 160.05(C7-O), 160.89(C=O). IR (KBr, cm-1) νmax
:
2935.57 (C-H stretching), 1733.94 (α, β-unsaturated ketonic C=O stretching), 1612.08, 1513.81,
1388.29, 1241.30(C-O-C stretching), 1155.12 (C-N stretching in 1,2,3-triazole ring), 1071.14(C-O-C
stretching), 1024.15, 833.68, 699.06. Anal. Calcd for C25H19N3O4: C, 70.58; H, 4.50; N, 9.88.
Found: C, 70.12; H, 4.84; N, 9.78%.
4.7.15. 7-[1-(4-Fluoro-2-methyl-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one
(15)
Yield: 30%. Yellow solid. mp: 140-142°C. MS m/z = 365.12 (M+),190(M-175), 177(hydroxy
coumarin cation). 1H NMR ((DMSO-d6, 300MHz) δ ppm: 1.23(s, 3H, 2′-CH3 of azide ring), 2.08(s,
3H, 4-CH3 of coumarin ring), 5.37(s, 2H, -CH2-O-), 6.07(s, 1H, H3 pyran ring), 6.80(d, 2H,
aromatic proton J = 6.6Hz), 7.21(s, 1H), 7.41(s, 1H), 7.80(m, 3H, aromatic), 9.53(s, 1H, triazole
ring). IR (KBr, cm-1) νmax
:
2923.48(C-H stretching), 1715.21(α, β-unsaturated ketonic C=O
stretching), 1611.91, 1509.45, 1379.85, 1266.27(C-O-C stretching), 1203.52, 1139.56(C-N
stretching in 1,2,3-triazole ring), 1021.98(C-O-C stretching), 827.87, 683.55, 456.47. Anal. Calcd for
C20H16FN3O5: C, 65.75; H, 4.41; N, 11.50. Found: C, 65.18; H, 4.74; N,11.48%.
4.7.16. 7-[1-(2-Chloro-4-methyl-phenyl)-1H-[1,2,3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one
(16)

ACCEPTED MANUSCRIPT
Yield: 40%. Yellow solid. mp :148-150°C. MS: m/z = 381.10 (M+), 383.11(M+2), 382(M+1),
206.05(M-175). 1H NMR ((DMSO-d6, 300MHz) δ ppm: 2.41(s, 3H, 4-CH3 pyran ring), 2.50(s, 3H,-
CH3 aromatic ring attached with triazole) 5.37(s, 2H, -CH2-O-), 6.24(s, 1H, H3 coumarin pyran
ring), 7.08(d, 1H, H6 coumarin ring , J = 8.7Hz), 7.2(s, 1H, H8 coumarin ring), 7.39(d, 1H, H5′, J =
7.8Hz), 7.5-7.6(m, 2H, H3′ and H6′), 7.71(d, 1H, H5, J = 8.7Hz) , 8.71(s, 1H, triazole ring). 13C NMR
((DMSO-d6,75MHz) δ ppm: 18.61(CH3 coumarin ring), 20.91(CH3 benzene ring), 61.93(-CH2-O),
102.12(C3), 111.83(C8), 113.13(C6), 113.92(C quaternary fused C of coumarin ring), 127.02(C5),
127.67(C1′), 128.50(C5′), 128.60(C6′), 129.42(C3′), 131.10(CH, ethylene C of triazole ), 132.38(C2′),
142.53(C, quaternary carbon of triazole ring), 142.65(C4′), 153.89(C-O Fused in pyran ring),
155.15(C4 pyran ring), 160.59(C7-O), 161.47(C=O). IR (KBr, cm-1) νmax: 3144.15, 2923.48(C-H
stretching), 1715.21(α, β-unsaturated ketonic C=O stretching), 1611.91, 1509.45, 1379.85,
1266.27(C-O-C stretching), 1203.52, 1139.56(C-N stretching in 1,2,3-triazole ring), 1021.98(C-O-C
stretching), 827.87, 456.47. Anal. Calcd for C20H16 Cl N3O3: C, 62.91; H, 4.22; N, 11.50. Found: C,
62.12; H, 4.52; N,14.38%.
4.7.17. [4-(4-Methyl-2-oxo-2H-chromen-7-yloxymethyl)-[1,2,3] triazol-1-yl]-acetic acid methyl
ester (17)
Yield: 42%. Yellow solid. mp: 138-140°C. MS: m/z = 329.16 (M+), 315(M-CH3), 271 (M-
COOMe). 1H NMR ((DMSO-d6, 300MHz) δ ppm: 2.39(s, 3H, -CH3), 3.7(s, 3H, -OCH3), 5.30(s,
2H, -CH2-N-), 5.44(s, 2H, CH2-O-), 7.04(d, 1H, H5, J = 9.0Hz), 7.15(s, 1H, H8), 7.67(d, 1H, H6, J =
8.7Hz), 8.30(s, 1H, triazole ring). 13C NMR ((DMSO-d6,75MHz) δ ppm: 18.59(CH3), 50.79(-
OCH3), 53.02, 56.52(CH2-N), 61.97(-CH2-O), 101.92, 102. 26(C3), 111.75(C8), 113.00(C6),
114.00(C quaternary fused C of coumarin ring), 126.95(C5 &CH, ethylene C of triazole ), 142.60(C,
quaternary carbon of triazole ring), 153.82(C-O, Fused in pyran ring), 154.00(C4, pyran ring),