Synthesis and cytotoxicity of novel (E)-2-phenylchroman-4-one-O-((1-substituted-1H-1,2,3-triazol-4-yl)methyl) oxime derivatives

Article abstract of DOI:10.1080/00397911.2020.1759645

A series of new flavanone-triazole hybrids (7a–m) were synthesized from flavanone oximes (6a–c) via multistep synthetic strategy, involving Cu (I) catalyzed azide, alkyne 1,3-dipolar cycloaddition by Click reaction. All the synthesized compounds were tested for their cytotoxicity against HCT-15, HeLa, NCI-H522, and HEK-293 (normal cell line) cell lines. Compounds 6a, 7a, 7b, 7d, 7e, 7j, and 7m showed the significant cytotoxicity, wherein compound 7b showed potential cytotoxicity against NCI-H522 cell line and compounds 6a and 7a were offensive with HEK-293 in their toxicity profile.

Full text of DOI:10.1080/00397911.2020.1759645

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Synthesis and cytotoxicity of novel (E)-2-
phenylchroman-4-one-O-((1-substituted-1H-1,2,3-
triazol-4-yl)methyl) oxime derivatives
Madhu Gutam, Sudhakar Mokenapelli, Jayaprakash Rao Yerrabelli, Somesh
Banerjee, Partha Roy & Prasad Rao Chitneni
To cite this article: Madhu Gutam, Sudhakar Mokenapelli, Jayaprakash Rao Yerrabelli, Somesh
Banerjee, Partha Roy & Prasad Rao Chitneni (2020): Synthesis and cytotoxicity of novel (E)-2-
phenylchroman-4-one-O-((1-substituted-1H-1,2,3-triazol-4-yl)methyl) oxime derivatives, Synthetic
Communications, DOI: 10.1080/00397911.2020.1759645
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1759645
Synthesis and cytotoxicity of novel (E)-2-phenylchroman-4-
one-O-((1-substituted-1H-1,2,3-triazol-4-yl)methyl) oxime
derivatives
Madhu Gutama , Sudhakar Mokenapellia , Jayaprakash Rao Yerrabellia
Somesh Banerjeeb, Partha Royb, and Prasad Rao Chitnenia
,
aDepartment of Chemistry, Natural Products Laboratory, Osmania University, Hyderabad, Telangana,
b
India; Department of Biotechnology, Molecular Endocrinology Laboratory, Indian Institute of
Technology, Roorkee, Uttarakhand, India
ABSTRACT
ARTICLE HISTORY
Received 10 January 2020
A series of new flavanone-triazole hybrids (7a–m) were synthesized
from flavanone oximes (6a–c) via multistep synthetic strategy, involv-
ing Cu (I) catalyzed azide, alkyne 1,3-dipolar cycloaddition by Click
reaction. All the synthesized compounds were tested for their cyto-
toxicity against HCT-15, HeLa, NCI-H522, and HEK-293 (normal cell
line) cell lines. Compounds 6a, 7a, 7b, 7d, 7e, 7j, and 7m showed
the significant cytotoxicity, wherein compound 7b showed potential
cytotoxicity against NCI-H522 cell line and compounds 6a and 7a
were offensive with HEK-293 in their toxicity profile.
KEYWORDS
Cytotoxicity; 13-dipolar
cycloaddition; flavanone;
123-triazoles
GRAPHICAL ABSTRACT
Introduction
New-fangled medicinal chemistry faces various tasks from numerous directions, as well
as the need for both potency and specificity of any therapeutic agent. Flavanone is an
important natural secondary metabolite with significance to cure and prevent tumor,
senescence and cardiovascular diseases.[1,2] Flavanone is a member of the flavonoids,
which are polyphenols found in plant kingdom. On an average, people intake of flavo-
noids is about 50–150 mg per day from vegetables, fruits, and other food sources.[3]
Flavanones are potential source for the discovery of biologically active lead compounds
and therefore have been focused in research and development in the last three deca-
des.[4] The flavanone scaffold is an important intermediate and building block in
CONTACT Prasad Rao Chitneni
prasadraoou@yahoo.com
Department of Chemistry, Natural Products Laboratory,
Osmania University, Hyderabad, Telangana, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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M. GUTAM ET AL.
organic synthesis in the design of new lead compounds.[5] The 1,2,3-triazole moiety
does not occur in nature, even though triazole derivatives are known to exhibit various
pharmacological properties such as anticancer,[6,7] antimicrobial,[8,9] anticonvulsant,[10]
antitubercular,[11] analgesic,[12] and antiviral activities.[13] The major problem commonly
associated with 1,2,3-triazole synthetic methodology,[14] including the need for long
reaction time and high temperature, as well as the formation of regioisomeric mixture
of products when unsymmetrical alkynes are involved.[15] To avoid the regioisomeric
mixture, Sharpless pioneered Cu (I) catalyzed Click reaction between organic azides and
alkynes resulted regioselective-1,4-disubstituted-1,2,3-triazoles with good yields.[16] In
view of several applications of flavanones and triazoles, we planned to synthesize novel
1,2,3-triazoles on flavanone skeleton adopting Click chemistry.
Results and discussion
Chemistry
The synthetic outline for the synthesis of novel flavanone-triazole hybrids (7a–m) is shown
in Scheme 1. The key intermediates, (E)-2-phenylchroman-4-one O-prop-2-yn-1-yl oxime
derivatives (6a–c) were prepared by four steps methodology. Initially, aldehydes (2a,b) con-
densed with 2-hydroxy acetophenones (1a,b) in basic medium to afforded corresponding
chalcones (3a–c). Subsequently, cyclization of intermediates 3a–c in the presence of hydro-
chloric acid in ethanol under reflux condition gave respective flavanone derivatives
(4a–c).[17] Furthermore, compounds 4a–c were treated with hydroxylamine hydrochloride
in the presence of sodium acetate in THF, methanol, and water in 1:1:1 ratio under reflux to
give exclusively (E)-2-phenylchroman-4-one oxime derivatives (5a–c) respectively.[18] The
propargylation of compounds 5a–c with propagyl bromide and potassium carbonate in acet-
one under reflux condition gave the desired precursors (E)-2-phenylchroman-4-one O-
prop-2-yn-1-yl oxime derivatives (6a–c).
Finally, compounds 6a–c undergo regioselective 1,3-dipolar cycloaddition with eagerly
prepared substituted phenyl/benzyl azides in the presence sodium ascorbate and
CuSO4ꢀ5H2O under Click reaction condition to give selectively 1,4-isomer of corre-
sponding
(E)-2-phenylchroman-4-one-O-((1-substituted-1H-1,2,3-triazol-4-yl)methyl)
oximes (7a–m) with good yields. These results were shown in (Table 1). All the synthe-
1
sized compounds were characterized by H NMR, 13C NMR, and ESI-MS.
Cytotoxic evaluation
Initially, all 16 compounds were tested for their cytotoxicity against three cancerous cell
lines such as HCT-15, HeLa, NCI-H522 and one normal cell line HEK-29 IC50 values
were shown in Table 2. The synthesized compounds showed diverse effect on the three
cell lines tested. Descriptively 7k compound have moderate cytotoxic effect on only
HCT-15 cell line, 6b and 7l have mild cytotoxic effect on only Hela cell line while 6a,
7j, and 7m showed moderate cytotoxic effect on NCI-H522 cell line only. The com-
pounds 7d, 7f, and 7g showed moderate cytotoxicity against HCT-15 and HeLa cell
lines both while 7i showed moderate cytotoxicity against HeLa and NCI-H522 cell line
and 7b against HCT-15 and NCI-H522 cell lines. 7a, 7e, and 7h are three synthesized

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Scheme 1. Reagents and conditions: (i) KOH, EtOH, rt, 12 h, 60%; (ii) EtOH, HCl, reflux, 24 h, 70%; (iii)
NH2OHꢀHCl, CH3COONa,THF:CH3OH:H2O (1:1:1), 80 ꢁC, 3 h, 80–82%; (iv) Propargyl bromide, acetone,
K2CO3, 70 ꢁC, 3 h, 80–85%; (v) R3–N3, sodium ascorbate, CuSO4ꢀ5H2O, DMF, H2O, rt, 4 h, 80–85%.
compounds among all which have mild to moderate cytotoxicity against all three cell
lines tested. Specific among all, the compound 7b has found to have high cytotoxicity
against NCI-H522 cell line. Interestingly, all the compounds showing anti-cancer activ-
ity did not affect HEK-293 cell line, except 6a and 7a.
Evaluation of apoptosis by using acridine orange/ethidium bromide (AO/
EB) staining
HCT-15, HeLa and NCI-H522 cells were again treated for 24 hours with synthesized
compounds at IC50 value. The double staining was executed using equimolar mixture of
AO/EB. The stained cells were analyzed by fluorescent microscopy. The captured images

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M. GUTAM ET AL.
Table 1. Synthesis of title compounds.
Entry
R3
Yield(%)
mp(°C)
7a
80
165
7b
7c
7d
82
85
80
168
170
155
7e
7f
7g
7h
7i
84
80
82
80
84
170
173
155
156
164
CN
CN
CN
7j
83
80
152
155
O
7k
O
shows early apoptosis (yellow arrow), late apoptosis (blue arrow) and necrosis condition
(green arrows) in cells treated with compounds found effective in MTT assay.
Unaffected cells are represented with red arrow in the images. In brief AO is absorbed
by live cells and dead cells both, whereas EB is absorbed by dead cells only when the
cytoplasmic membrane integrity is lost as in case of apoptosis or necrosis. The staining
images of HCT-15, HeLa and NCI-H522 cell lines are shown in Figures 1–3,
respectively.

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Table 2. IC50 values of synthesized compounds in mMb.
a
Entry
Compound
HCT-15
HeLa
NCI-H522
HEK-293
81.9 4.9
118.7 0.7
369.2 0.5
61.4 3.7
n.s
1.
2.
3.
4.
5.
6.
7.
8.
6a
6b
6c
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
>100
>100
>100
34.5 4.9
32.9 4.6
>100
>100
31.0 17.7
>100
11.4 1.5
>100
14.2 2.1
>100
>100
28.2 16.7
5.4 2.7
>100
>100
16.1 1.6
>100
>100
>100
426.1 2.9
n.s
19.4
8
18.9 5.6
15.6 2.4
36.0 14.4
46.6 15.6
38.1 13.7
23.1 11.2
>100
>100
25.4 6.8
>100
17.4 5.9
36.5 18.8
25.4 4.2
34.3 16.6
>100
>100
30.1 7.6
>100
662.1 11.9
189.0 1.3
127.4 1.4
967.2 15.8
145.3 1.5
619.6 4.6
n.s
n.s
n.s
>100
>100
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
42.5 9.7
31.6 12.8
20.8 1.3
>100
>100
>100
11.18 0.22
22.86 1.2
16.8 2.1
13.47 0.87
26.54 3.2
Cyclophosphamide
5-Fluorouracil
3.63 0.19
5.18 0.51
a50% growth inhibition as determined by MTT assay (24 hour drug exposure).
bCompounds tested in triplicate, data expressed as mean value SEM of three independent experiment.
n.s.: describes non-significant value; drug whose IC50 values found non-convergent for HEK-293 cells only.
Figure 1. Fluorescent micrographs of AO/EB stained HCT-15 cells incubated for 24 hours. (a–c) Vehicle
treated cells, (d–f) cells treated with compound 7a, (g–i) with compound 7b, (j–l) with compound 7d,
(m–o) with compound 7e, (p–r) with compound 7f, (s–u) with compound 7g, (v–x) with compound
7h and (y–aa) with compound 7k.
Conclusion
In summary, we developed an efficient and facile protocol for the synthesis of regiose-
lective novel flavanone-triazole derivatives via Cu(I) catalyzed 1,3-dipolar cycloaddition
of (E)-2-phenylchroman-4-one O-prop-2-yn-1-yl oxime derivatives (6a–c) and phenyl/

6
M. GUTAM ET AL.
Figure 2. Fluorescent micrographs of AO/EB stained HeLa cells incubated for 24 hours. (a–c) Vehicle
treated cells, (d–f) cells treated with compound 7a, (g–i) with compound 7d, (j–l) with compound 7e,
(m–o) with compound 7f, (p–r) with compound 7g, (s–u) with compound 7h, (v–x) with compound
7i, (y–aa) with compound 7l, and (ab–ad) with compound 6b.
Figure 3. Fluorescent micrographs of AO/EB stained NCI-H522 cells incubated for 24 hours. (a–c)
Vehicle treated cells, (d–f) cells treated with compound 7a, (g–i) with compound 7b, (j–l) with com-
pound 7e, (m–o) with compound 7h, (p–r) with compound 7i, (s–u) with compound 7j, (v–x) with
compound 7m, and (y–aa) with compound 6a.

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aryl azides. The entire synthesized compounds showed cell line subjective but diverse
cytotoxic effect against the HCT-15, HeLa and NCI-H522 cell line. Compound 7b is
most vivid cytotoxicity against NCI-H522, in addition to better safety profile; these
results are fortified to further research on these flavanone based triazole derivatives.
Experimental
Instrumentation and chemicals
All chemicals were purchased from Sigma-Aldrich and solvents from SD Fine
Chemicals Pvt. Ltd. Solvents were purified as per the procedures given in the “Text
book of practical organic chemistry” by Vogel (6th Edition). Silica gel pre-coated alumi-
num sheets (60F254, Merck) were used for monitoring the progress of reaction and
purity of final products. The spots on TLC plates were visualized by exposure to ultra-
violet light (UV) at 254 nm. Column chromatography was performed using Merck silica
1
gel 60–120 mesh. H NMR spectra were recorded on Bruker spectrometer at 400 MHz
spectrometer, 13C NMR spectra were acquired on 100 MHz with tetramethylsilane as an
internal standard, chemical shift (d) are reported in ppm. (d) Shift (multiplicity, cou-
pling constant, proton count). Mass spectral analysis was accomplished using electro
spray ionization (ESI) techniques.
General method for the synthesis of substituted oximes (5a–c)
Hydroxylamine hydrochloride (1.11 g, 16 mmol) was added to flavanone (2.0 g, 9 mmol)
(4a) which is dissolved in THF (15 mL) solvent in presence of sodium acetate (1.28 g,
16 mmol), methanol and water (1:1:1) and the mixture was stirred at reflux temperature
for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was
poured into water and extracted with ethylacetate (150 mL). The organic layer was
washed with water (3 ꢂ 150 mL) and dried over anhydrous Na2SO4, filtered and concen-
trated under reduced pressure. The crude product was purified by column chromatog-
raphy using hexane: ethylacetate (7:3) to obtain the pure product (5a).
Synthesis of (E)-2-phenylchroman-4-one oxime (5a)
1
Yield: 80%, White solid, mp: 165 ꢁC. H-NMR (400 MHz, CDCl3) d 8.21 (s), 7.86 (dd,
J ¼ 8.2, 1.5 Hz, 1H), 7.51 (m, 2H), 7.44 (m, 2H), 7.38 (m, 1H), 7.36–7.28 (m, 1H), 7.00
(m, 2H), 5.13 (dd, J ¼ 12.5, 3.2 Hz, 1H), 3.61 (dd, J ¼ 17.3, 3.0 Hz, 1H), 2.80 (dd,
J ¼ 17.3, 12.5 Hz, 1H).13C-NMR (100 MHz, CDCl3) d 156.7, 150.2, 139.7, 131.3, 128.7,
128.4, 126.2, 123.8, 121.7, 118.1, 117.9, 77.1, 30.4. MS (ESI): m/z 240 [M þ H]þ. Anal.
Calcd for C15H13NO2: C, 75.30; H, 5.48. Found: C, 75.16, H, 5.55%.
General method for the synthesis of (E)-2-arylchroman-4-one O-prop-2-yn-1-yl
oximes (6a-c)
Propargyl bromide (0.89 g, 7.53 mmol) was added slowly to a stirring mixture of the
Oxime (5a) (1.5 g, 6.27 mmol) and anhydrous K2CO3 (1.040 g, 7.53 mmol) in Acetone

8
M. GUTAM ET AL.
(15 mL), and the stirring continued at reflux temperature for 3 h. After completion of
the reaction (monitored by TLC), solvent was removed under reduced pressure and
water was added (50 mL) into the reaction mixture. The reaction mixture was extracted
with ethylacetate (150 mL). The combined organic layer was washed with water
(3 ꢂ 150 mL) and dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by column chromatography using
hexane: ethylacetate (9:1) to obtain the pure product (6a).
Synthesis of (E)-2-phenylchroman-4-one O-prop-2-yn-1-yl oxime (6a)
1
Yield: 85%, Yellow solid, mp: 155 ꢁC. H-NMR (400 MHz, CDCl3) d 7.96 (d, J ¼ 7.5 Hz,
1H), 7.45–7.25 (m, 6H), 6.97 (m, 2H), 5.06 (brd, J ¼ 12.5 Hz, 1H), 4.76 (brs, 2H), 3.49
(brd, J ¼ 17.6 Hz, 1H), 2.75 (m, 1H), 2.47 (brs, ꢃCH, 1H). 13C-NMR (100 MHz, CDCl3)
d 156.8, 150.1, 139.8, 131.4, 128.7, 128.5, 126.2, 124.4, 121.6, 118.0, 117.9, 79.8, 77.1,
74.6, 61.8, 31.3. MS (ESI): m/z 278 [M þ H]þ. Anal. Calcd for C18H15NO2: C, 77.96; H,
5.45. Found: C, 77.66, H, 5.27%.
General methods for the synthesis of (E)-2-arylchroman-4-one O-((1-aryl-1H-1,2,3-
trizol-5yl)methyl) oximes (7a–m)
(E)-2-phenylchroman-4-one O-prop-2-yn-1-yl oxime (6a) (0.1 g, 0.36 mmol) and various
phenyl/benzyl azides (0.04 g, 0.43 mmol) were dissolved in DMF (5 mL) then sodium
ascorbate (0.3 mmol, 300 mL of freshly prepared 1 M solution in water) and copper (II)
sulfate pentahydrate (7.5 mg, 0.03 mmol, in 100 mL of water) was added. The homoge-
neous mixture was stirred vigorously for 4 h, until to become clear solution and TLC
analysis indicated complete consumption of the reactants. The reaction mixture was
diluted with water (50 mL), cooled in ice, and the precipitate was collected by filtration.
After washing the precipitate with cold water (2 ꢂ 25 mL), the crude product was puri-
fied by column chromatography using hexane: ethylacetate (8:2) to obtain the pure
product (7a).
(E)-2-phenylchroman-4-one O-((1-phenyl-1H-1,2,3-trizol-5yl)methyl) oxime (7a)
1
Yield: 80%, White solid, mp: 165 ꢁC. H-NMR (400 MHz, CDCl3) d 8.01 (s, 1H), 7.96
(dd, J ¼ 8.5, 1.6 Hz, 1H), 7.74 (dd, J ¼ 8.6, 1.3 Hz, 2H), 7.53 (m, 2H), 7.45 (m, 3H), 7.40
(m, 2H), 7.35 (m, 1H), 7.29 (m, 1H), 7.00 (m, 2H), 5.41 (s, 2H), 5.08 (dd, J¼ 2.3,
3.0 Hz, 1H), 3.52 (dd, J ¼ 17.3, 3.0 Hz, 1H), 2.77 (dd, J ¼ 17.3, 12.3 Hz, 1H). 13C-NMR
(100 MHz, CDCl3) d 156.7, 149.7, 145.3, 139.7, 137.0, 131.3, 129.7, 128.8, 128.4, 126.2,
124.1, 121.5, 121.3, 120.6, 118.7, 118.0, 76.9, 67.6, 31.2. MS (ESI): m/z 397 [M þ H]þ.
Anal. Calcd for C24H20N4O2: C, 72.21; H, 5.09. Found: C, 72.09, H, 5.19%.
Acknowledgments
GM thanks to the UGC-New Delhi, India, for providing Senior Research fellowship, Head
Department of Chemistry and CFRD, Osmania University, Hyderabad, India for providing
laboratory facilities and spectral data.

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ORCID
Madhu Gutam
http://orcid.org/0000-0003-2963-566X
Sudhakar Mokenapelli
Jayaprakash Rao Yerrabelli
http://orcid.org/0000-0001-9575-4830
http://orcid.org/0000-0003-4387-8334
Prasad Rao Chitneni
http://orcid.org/0000-0003-0062-9856
References
[1] Zhang, J.; Brodbelt, J. S. J. Am. Chem. Soc. 2004, 126, 5906–5919. DOI: 10.1021/
ja031655d.
[2] Guharay, J.; Sengupta, B.; Sengupta, P. K. Proteins. 2001, 43, 75–81. DOI: 10.1002/1097-
0134(20010501)43:2<75::AID-PROT1019>3.0.CO;2-7.
[3] Linseisen, J.; Radtke, J.; Wolfram, G. Flavonoidzufuhr Erwachsener in Einem Bayerischen
€
Teilkollektiv Der Nationalen Verzehrsstudie. Z Ernahrungswiss. 1997, 36, 403–412. DOI:
10.1007/BF01617836.
[4] Havsteen, B. Flavonoids, a Class of Natural Products of High Pharmacological Potency.
Biochem. Pharmacol. 1983, 32, 1141–1148. DOI: 10.1016/0006-2952(83)90262-9.
[5] Silberberg, M.; Gil-Izquierdo, A.; Combaret, L.; Remesy, C.; Scalbert, A.; Morand, C.
Biomed. Pharmacother. 2006, 60, 529–535. DOI: 10.1016/j.biopha.2006.07.083.
[6] Holla, B. S.; Poojary, K. N.; Rao, B. S.; Shivananda, M. K. Eur. J. Med. Chem. 2002, 37,
511–517. DOI: 10.1016/S0223-5234(02)01358-2.
[7] Holla, B. S.; Veerendra, B.; Shivananda, M. K.; Poojary, B. Eur. J. Med. Chem. 2003, 38,
759–767. DOI: 10.1016/S0223-5234(03)00128-4.
[8] Prasad, D. J.; Ashok, M.; Karegoudar, P.; Poojary, B.; Holla, B. S.; Kumari, N. S. Eur. J.
Med. Chem. 2009, 44, 551–557. DOI: 10.1016/j.ejmech.2008.03.025.
[9] Turan, Z. G.; Kaplancikli, Z. A.; Yildiz, M. T.; Chevallet, P.; Kaya, D. Eur. J. Med. Chem
2005, 40, 607–613. DOI: 10.1016/j.ejmech.2005.01.007.
[10] Amir, M.; Shikha, K. Eur. J. Med. Chem. 2004, 39, 535–545. DOI: 10.1016/j.ejmech.2004.
02.008.
ꢀ
[11] Walczak, K.; Gondela, A.; Suwinski, J. Eur. J. Med. Chem. 2004, 39, 849–853. DOI: 10.
1016/j.ejmech.2004.06.014.
[12] Almasirad, A.; Tabatabai, S. A.; Faizi, M.; Kebriaeezadeh, A.; Mehrabi, N.; Dalvandi, A.;
Shafiee, A. Bioorg. Med. Chem. Lett. 2004, 14, 6057–6059. DOI: 10.1016/j.bmcl.2004.09.
072.
[13] Sandra, F.; Andrea, C. K.; Diogo, K.; Guilherme, F. S.; Waldiceu, A. V. J.; Claudia,
N. D. S.; Juliano, B. Sci. Rep. 2017, 7, 41864. DOI: 10.1038/srep41864.
[14] Labbe, G. Chem. Rev. 1969, 69, 345–363. DOI: 10.1021/cr60259a004.
[15] Tornøe, C. W.; Christensen, C.; Meldal, M. Org. Chem. 2002, 67, 3057–3064. DOI: 10.
1021/jo011148j.
[16] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed.
2002, 41, 2596–2599. DOI: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.
CO;2-4.
[17] Madhu, G.; Sudhakar, M.; Santosh Kumar, K.; Rajashekher Reddy, G.; Sravani, A.;
Ramakrishna, K.; Prasad Rao, C. Russ. J. Gen. Chem. 2017, 87, 2421–2428. DOI: 10.1134/
S1070363217100243.
[18] (a) Emami, S.; Shafiee, A. Heterocycles. 2001, 55, 2059–2074. (b) Emami, S.;
Ghanbarimasir, Z. Eur. J. Med. Chem. 2015, 93, 539–563. DOI: 10.1016/j.ejmech.2015.02.
048.