Synthesis and cytotoxicity evaluation of novel 1,4-disubstituted 1,2,3-triazoles via CuI catalysed 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.ejmech.2010.08.012

A facile and highly efficient method for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles (β-keto 1,2,3-triazoles) in good to excellent yields from in-situ generated β-ketoazides and terminal alkynes through Cu(I) catalyzed 1,3 dipolar cycloaddition is described. This reaction proceeds smoothly either in water or in a 1:1 mixture of water and acetone at room temperature without use of any additive. The synthesized compounds were screened for their cytotoxicity in A549 (Lung Cancer), HT-29 (Colon Cancer), He La (Cervical Cancer) using MTT assay that exhibited significant cytotoxicity at modest doses.

Full text of DOI:10.1016/j.ejmech.2010.08.012

European Journal of Medicinal Chemistry 45 (2010) 5044e5050
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and cytotoxicity evaluation of novel 1,4-disubstituted 1,2,3-triazoles via
CuI catalysed 1,3-dipolar cycloaddition
,
,
,c,1
Jyothi Vantikommu a 1, Sadanandam Palle b 1, Punganuru Surendra Reddy b
,
Vinodkumar Ramanatham b, Mukkanti Khagga b, Venkateswara Rao Pallapothula a
,
*
a Department of Chemistry, Nizam College, Osmania University, Hyderabad 500006, Andhra Pradesh, India
b Centre for Pharmaceutical. Sciences, I.S.T., J.N.T. University, Hyderabad-500085, Andhra Pradesh, India
c Indian institute of Chemical Technology, Hyderabad-500007, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and highly efficient method for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles (
b-
Received 16 April 2010
Received in revised form
2 August 2010
Accepted 6 August 2010
Available online 12 August 2010
keto 1,2,3-triazoles) in good to excellent yields from in-situ generated -ketoazides and terminal alkynes
b
through Cu(I) catalyzed 1,3 dipolar cycloaddition is described. This reaction proceeds smoothly either in
water or in a 1:1 mixture of water and acetone at room temperature without use of any additive. The
synthesized compounds were screened for their cytotoxicity in A549 (Lung Cancer), HT-29 (Colon
Cancer), He La (Cervical Cancer) using MTT assay that exhibited significant cytotoxicity at modest doses.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
b-Keto 1,2,3-triazoles
1,3-Dipolar cycloaddition
Cytotoxicity
Tosyloxyketones
Copper iodide
Terminal alkynes
1. Introduction
including the need for long reaction times and high temperatures,
as well as the formation of region-isomeric mixtures of products
Cycloaddition reactions involving heteroatoms, such as 1,3-
dipolar cycloaddition, provides rapid access to a wide variety of
interesting five- and six-membered heterocycles, which have found
wide applications in medicinal chemistry and material sciences [1].
Among them, five-membered heterocycles namely, 1,4-disubsti-
tuted 1,2,3-triazoles exhibit a remarkably broad scope of selectivity,
with a wide range of applications across a broad range of thera-
peutic areas [2]. Recently, 1,2,3-triazole fragment has attracted
attention because many compounds possessing 1,2,3-triazole
fragment exhibit useful biological properties [3]. Particularly 1,4-
disubstituted 1,2,3-triazoles showed significant antiproliferative
against a wide variety of human cancer cell lines, including those
that are multidrug resistant [4].
specially when unsymmetrical alkynes are involved. Recently,
Sharpless [6] and Meldal [7] groups, independently re-invigorated
the Huisgen’s 1,3-dipolar cycloaddition by using a sub-stoichio-
metric amount of Cu(I) metal source. The copper-accelerated 1,3-
dipolar cycloaddition reaction of alkynes and azides not only takes
place with high yield under milder conditions, but also leads to
exclusively 1,4-region-isomeric products. Since then, this reaction
has been used for the construction of a variety of multi-valent
structures such as sugar heterodimers, glycoconjugates [8], calix-
sugars [9], dendritic and polymeric materials [10]. Moreover, the
basic triazole ring itself is a potential pharmacophore that has
gained interest over the past few years as several derivatives
exhibited interesting biological activities [11].
The most widely used method for the synthesis of 1,2,3-triazoles
involves the thermally driven 1,3-dipolar cycloaddition of organic
azides with alkynes pioneered by Huisgen [5]. However, there are
major problems commonly associated with this methodology,
2. Results and discussion
2.1. Chemistry
Although, organic azides are stable against most reaction
conditions, compounds of low molecular weight or those contain-
ing several azides (like multi-valent scaffolds) tend to be explosive
* Corresponding author. Tel.: þ91 9491884508; fax: þ91 40-23158666.
E-mail address: pallapothulav@gmail.com (V.R. Pallapothula).
These authors contributed equally to the work.
1
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.012

J. Vantikommu et al. / European Journal of Medicinal Chemistry 45 (2010) 5044e5050
5045
the product (entries 3e5). However, the reaction in acetone:water
(1:1) mixture gave 76% of the corresponding triazoles in 12h. As can
be seen from the Table 1,
a
-bromo acetophenone showed higher
reactivity compared to
reaction conditions.
a-tosyloxy acetophenone under similar
Having optimized the reaction conditions, different
a-bromo
Scheme 1. Regioselective synthesis of functionalized 1,4-disubstituted-1,2,3-triazoles.
and -tosyloxyketones were reacted with sodium azide, followed
a
by cycloaddition with phenylacetylene and the results are pre-
sented in Table 2. It is worth mentioning here that electron
donating substituents like methyl, methoxy and electron with-
drawing substituents such as chloro, bromo groups at para posi-
tions of both a-bromo and a-tosyloxyketones were equally effective
towards the nucleophilic substitution of azide followed by 1,3-
dipolar cycloaddition.
To extend the general applicability of this reaction, a wide variety
of terminal alkynes were reacted with in-situ generated organic
azide from a-bromo or a-tosyloxy acetophenone and sodium azide
and the results are given in Table 3. p-Methyl-, 2, 4, 5-trimethyl- and
p-pentyl-substituted phenylacetylenes were found to be more
reactive when compared to the m-methoxy-substituted phenyl-
acetylene and p- methoxynaphyl acetylene (Table 3, entries 1e5).
The reaction with propargyl alcohol and octyne afforded the prod-
ucts in moderate yield (Table 3, entries 6 and 7). Among the
heterocyclic terminal alkynes, 2-ethynyl pyridine was more reactive
when compared with 3-ethynyl thiophene (Table 3, entries 8 and 9).
and are difficult to handle [12] and hence recently few procedures
that involve the generation the azides in-situ followed by azide-
alkyne cycloaddition have been reported [13]. Despite these
advances, there is a need to broaden the scope of one-pot multi-
step reaction in combination with “click chemistry” [14]. As part of
our ongoing research program directed towards the synthesis of
triazoles under various reaction conditions [15], we have studied
the reactivity of
Herein, we report an efficient approach for the one-pot synthesis of
-keto triazoles from -bromo or tosyloxyketones, sodium azide,
a-bromo and tosyloxyketones in such reactions.
b
a
and alkynes in the presence of a catalytic amount of CuI (Scheme 1)
and evaluation of their cytotoxicity. This three-component reaction,
proceeds via the formation of b-keto azide from a-bromo or tosy-
loxyketones and sodium azide followed by 1,3-dipolar cycloaddi-
tion with terminal alkynes to give 1,4-disubstituted 1,2,3-triazoles
in good to excellent yields.
Initially, the effect of solvents on the formation of triazoles using
phenacyl bromide and tosyloxy acetophenone with sodium azide
and phenylacetylene in the presence of CuI (5 mol%) as the catalyst
at ambient temperature was investigated and the results are
illustrated in Table 1. Further, solvent effects for the formation of
triazoles with phenacyl bromide have also been screened, and
among the solvents tested DCM and THF required longer reaction
times with 45% and 55% yields respectively. Other polar solvents
like MeOH, DMF and acetonitrile gave the desired product in 59%,
62% and 65% yields, respectively, with a significant decrease in the
reaction times. However, the reaction in water exhibited high
catalytic activity with 81% yield of the desired product whereas
a mixture of water: acetone (1:1) also gave the product in good
yield (72%). Under similar conditions, when the reaction was
carried out in acetone the product was obtained in moderate yield.
2.2. Cytotoxicity evaluation
Cytotoxicity of compounds 3aep in A549, HT-29 and HeLa cells
was evaluated by MTT assay based on mitochondrial reduction of
the yellow MTT tetrazolium dye to a highly colored blue formazan
product [16]. This assay usually shows high correlation with
number of living cells, cell proliferation and release of mitochon-
drial matrix enzymes [14]. The values of MTT test in A549, HT-29
and Hela cells incubated for 48 h in DMEM media with b-keto 1,2,3-
triazoles are presented in Table 4. Among the compounds (1,4-
disubstituted 1,2,3-triazoles, 3a-p) tested, compound 3c with
1-phenyl-butan-1-one at 1st position and phenyl group at 4th
position exhibited the highest activity against A549, HT-29 and
Similarly, different solvents were tested for the synthesis of
b-keto
HeLa cells with IC50 values of 26 mM, 116 mM, 1550 mM, respectively
triazoles from -tosyloxy acetophenone. The reaction in DCM, THF
a
[16]. Compound 3h and 3i with p-tolyl and 2,4,5-trimethyl phenyl
gave the corresponding triazoles in low yield and also required
prolonged reaction times (entries 1 and 2), whereas the reaction in
MeOH, DMF, acetonitrile has resulted in slightly improved yields of
substituents at 4th position also showed potency against A549 and
HT-29 cells with IC50 values of 292
mM, 238 mM (3h) and 91 mM,
190 M (3i), respectively. Compounds 3k and 3o with phenyl
m
Table 1
Effect of solvent on the synthesis of -keto1,2,3-triazoles.a
Entry
Solvent
Br
OTs
Time (h)
Yield (%)
Time (h)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
CH2Cl2
THF
MeOH
DMF
CH3CN
H2O
24
24
8
8
8
8
8
8
45
55
59
62
65
81
72
30
24
24
8
12
16
24
12
12
45
30
60
65
62
57
76
46
Acetone:H2O(1:1)
Acetone
a
Reaction conditions: phenacyl bromide or -tosyloxyketone (1 mmol), sodium azide (1.5 mmol), phenylacetylene (1.2 mmol), CuI (5 mol %), solvent (6 ml).

5046
J. Vantikommu et al. / European Journal of Medicinal Chemistry 45 (2010) 5044e5050
Table 2
Synthesis of
b-keto 1,2,3-triazoles using different
a-tosyloxy ketones and a
-bromo ketones with phenylacetylene and sodium azide.a
Entry
Ketone 1
Product 3c
X
Time (h)
Yield (%)b
Br
OTs
8
12
81
76
1
Br
OTs
8
12
80
71
2
3
Br
OTs
8
12
85
76
Br
OTs
8
12
78
65
4
5
6
Br
OTs
8
12
80
73
Br
OTs
8
12
80
71
Br
OTs
8
12
76
68
7
a
Reaction conditions as exemplified in the typical experimental procedure.
b
c
Isolated yields.
All products were characterized by IR, 1H &13C NMR, Mass spectroscopy and elemental analysis.
ethanone substituent at 1st position and m-methoxy phenyl and
thiophene at position e four showed potency against only A549
cells. The remaining compounds were less potent with IC50 values
demonstrated an inhibition of tubulin assembly at 53% and 59%
respectively (Table 5).
greater than 300
mM against all cell lines tested.
2.3. Conclusion
Cell viability assay revealed that compounds 3c, 3e, 3h and 3i
exhibited cytotoxic activity against cell lines of various origins. To
investigate whether the antiprolifirative activities of these
compounds derived from the interaction of tubulin, they were
In conclusion, 1,4-disubstituted 1,2,3-triazoles (
azoles) have been synthesized directly from a variety of
b
-keto1,2,3-tri-
-bromo or
a
tosyloxyketones, terminal alkynes and sodium azide using CuI as
catalyst at room temperature via a sequence of nucleophilic
displacement and 1,3-dipolar cycloadditions either in water or in
a 1:1 mixture of water and acetone at room temperature. The
advantage of the present method described here is very simple and
facile and can be applicable to a wide range of substrates with high
functional group tolerance. The synthesized triazoles exhibited
significant cytotoxicity against A549, HT-29 and HeLa cells at
evaluated for their inhibition of tubulinpolymerization at 30 mM. For
comparison, colchicine and Podophyllotoxin were examined in
contemporaneous experiments. Interestingly, compounds 3c, 3e, 3h
and 3i showed inhibition of tubulin polymerization. Interestingly
compounds 3c and 3e showed inhibition of tubulin polymerization.
However compounds 3h and 3i less effective as tubulin polymeri-
zation inhibitors. In contrast, Podophyllotoxin and colchicine

J. Vantikommu et al. / European Journal of Medicinal Chemistry 45 (2010) 5044e5050
5047
Table 3
Synthesis of
b
-keto 1,2,3-triazoles using different
Terminal alkyne 2
a-tosyloxyketones and a
-bromo ketones with substituted phenylacetylenes and sodium azide.a
Entry
Product 3c
Time (h)
Yield (%)b
Br
OTs
8
12
86
80
1
2
3
4
Br
OTs
8
12
80
74
Br
OTs
8
12
85
81
Br
OTs
8
12
74
68
Br
OTs
24
24
61
45
5
Br
OTs
12
16
75
62
6
7
8
Br
OTs
12
16
79
63
Br
OTs
12
16
77
58
Br
OTs
12
16
86
78
9
a
Reaction conditions as exemplified in the typical experimental procedure.
Isolated yields.
b
c
All products were characterized by IR, 1H &13C NMR.

5048
J. Vantikommu et al. / European Journal of Medicinal Chemistry 45 (2010) 5044e5050
Table 4
GTP to all the wells. Since polymerization of tubulin is light sensi-
tive entire reaction was carried out in the absence of light. Poly-
merization reaction was monitored by the increase in fluoroscence
at 360/420 nm excitation/emission wavelength using VARIOSCAN
multimode plate reader at 37 ꢀC. fluoroscence was recorded at
every 60 s intervals for up to 1 h. TLC analyses was performed on
Merck precoated silica gel 60-F254 plates. Melting points were
measured in open capillary and are uncorrected. IR spectra were
recorded on a Perkin-Elmer, SpectrumGX FT-IR spectrometer as KBr
pellets. The 1H & 13C NMR spectra were recorded on a Varian-
Gemini 200 MHz and Bruker-Avance 300 MHz Spectrometers.
In vitro cytotoxic activities of compounds 3aep against human cancer cell lines e
A549, HT-29 and HeLa.
Entry
Compound
IC50 m
Ma
A549
HT-29
HeLa
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
Colchicine
>300
>300
26
>300
>300
>300
>300
292
91
>300
187
>300
>300
>300
260
>300
<1.0
>300
>300
116
>300
49
>300
>300
238
>300
>300
155
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
<1.0
Chemical shifts (
d
) are reported in ppm, using TMS (
d
¼ 0) as an
9
190
internal standard in CDCl3. ESI mass spectra were recorded on
a Finnigan Finnigan LCQ Advantagemax spectrometer and EI mass
spectra were recorded on a GC-MS QP2010 Plus (Shimadzu).
10
11
12
13
14
15
16
>300
>300
>300
>300
>300
>300
>300
<1.0
3.2. General procedure for the synthesis of 1,2,3-triazoles(3aep)
A mixture of a-bromo or tosyloxy ketone 1 (1 mmol) sodium
azide 2 (1.5 mmol), phenylacetylene 3 (1.2 mmol), and CuI (5 mol %)
in water (6 mL) or water/acetone (1:1) was stirred at ambient
temperature for 8e12 h. After completion of the reaction (as
monitored by TLC), the catalyst was filtered through Celite and the
product was extracted with ether (3 ꢁ10 mL). After removing the
solvent under vacuum, the crude product was purified by column
chromatography on silica gel using hexane-ethyl acetate mixture
(7:3) as eluent.
a
IC50, compound concentration required to inhibit tumor cell proliferation by
50%.
modest doses mechanestic studies indicate that these compounds
inhibits tubulin polymerixation in vitro.
3. Experimental section
3.2.1. 1-Phenyl-2-(4-phenyl-[1,2,3]triazol-1-yl)-ethanone (3a)
White solid; mp 172e175 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.34; IR
3.1. Materials and methods
(KBr): 3087, 2929, 1700, 1586, 1443, 1223, 982, 761, 688 cmꢂ1 1H
.
All chemicals were purchased from Aldrich and S.D Fine
Chemicals Pvt. Ltd. India and were used as received. All the solvents
used were of LR grade from Merck India Pvt. Ltd.
NMR (300 MHz, CDCl3): 5.85 (s, 2H), 7.29e7.42 (m, 3H), 7.52e7.69
(m, 3H), 7.84 (d, 2H, J ¼ 7.6 Hz), 7.91 (s, 1H), 8.04 (d, 2H, J ¼ 8.3 Hz).
a-bromo and
13C NMR (75 MHz, CDCl3):
d 55.48, 121.37, 125.85, 127.31, 128.24,
a
-tosyloxyketones were prepared according to reported literature
128.87, 129.17, 132.18,133.97, 194.71. ESI MS (m/z): 264 (M þ H)þ.
Anal. Calcd for C16H13N3O: C, 72.99; H, 4.98; N, 15.96. Found: C,
72.58; H, 4.84; N, 15.92.
methods [17]. HT-29 (Colon cancer), A549 (Lung cancer), HeLa
(Cervical cancer) cell line was obtained from National Center for
Cell Science (NCCS), Pune, India. DMEM (Dulbeccos Modified Eagles
Medium), MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetra-
zolium bromide], Trypsin, EDTA were purchased from Sigma
Chemicals Co (St.Louis, MO, USA), Fetal bovine serum were
purchased from Gibco. Tubulin polymerization is temperature and
light sensitive, pure un-polymerized tubulin was obtained from
Cytoskeliton, USA. In the presence of GTP it polymerizes and
polymerized tubulin gives fluorescence in a linear fashion. Fluo-
rescence can be used for estimation of tubulin polymerization. Set
of compounds are tested for their tubulin polymerization inhibition
activity. The assay was carried out in a 384 well plate in PEM buffer
[80 mM PIPES (pH-6.9), 1 mM MgCl2, 1 mM EGTA, 10% glycerol].
3.2.2. 1-Phenyl-2-(4-phenyl-[1,2,3]triazol-1-yl)-propan-1-one (3b)
White solid; mp 122e125 ꢀC; Rf (40% EtOAc/Hexane) ¼ 0.42; IR
(KBr): 3137, 2924, 1694, 1588, 1463, 1218, 1090, 971, 963 cmꢂ1 1H
.
NMR (300 MHz, CDCl3):
d
1.83 (d, 3H, J ¼ 7.3 Hz), 6.47 (q, 1H,
J ¼ 7.3 Hz), 7.26e7.49 (m, 6H), 7.80 (d, 2H, J ¼ 7.8 Hz), 7.88 (s, 1H),
8.01 (d, 2H, J ¼ 8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 18.39, 59.29,
118.59, 125.9, 128.30, 128.85, 129.49, 129.55, 130.22, 132.14, 192.94.
ESI MS (m/z): 279 (M)2þ. Anal. Calcd for C17H15N3O: C, 73.63; H,
5.45; N, 15.15. Found: C, 73.84; H, 5.60; N, 14.97.
3.2.3. 1-Phenyl-2-(4-phenyl-[1,2,3]triazol-1-yl)-butan-1-one (3c)
White solid; mp 114e116 ꢀC; Rf (40% EtOAc/Hexane) ¼ 0.5; IR
(KBr): 3119, 2963, 1697, 1596, 1383, 1223, 1077, 765 cmꢂ1. 1H NMR
Briefly, the reaction mixture in a total volume of 10
PEM buffer, GTP (1 mM) in the presence or absence of test
compound (30 mM). The reaction was initiated by the addition of
ml contained
(300 MHz, CDCl3):
d
0.99 (t, 3H, J ¼ 7.6 Hz), 2.07e2.19 (m, 1H),
2.23e2.35 (m, 1H), 6.31 (dd, 1H, J ¼ 6.0, 9.8 Hz), 7.28e7.64 (m, 6H),
7.82 (d, 2H, J ¼ 7.0 Hz), 7.99 (s, 1H), 8.07 (d, 2H, J ¼ 8.3 Hz). 13C NMR
Table 5
Effect of b
-keto 1,2,3-triazoles on in vitro tubulin polymerization.a
(75 MHz, CDCl3):
d 10.39, 26.80, 65.08, 118.85, 125.74, 128.21,
128.80, 129.14, 130.57, 134.44, 194.22. ESI MS (m/z): 292 (M þ H)þ.
Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C,
74.24; H, 5.69; N, 14.57.
Compounds
Fluoroscence
% Polymerization
% Inhibition
Control
Podophyllotoxin
Colchicine
3c
3e
3h
3i
9.7
4.5
4.1
7.8
8.6
9.4
9.1
100
0.0
53.8
58.1
19.3
14.1
2.8
46.2
41.9
80.7
85.9
97.2
93.4
3.2.4. 2-(4-Phenyl-[1,2,3]triazol-1-yl)-1-p-tolyl-ethanone (3d)
White solid; mp 158e160 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.27; IR
(KBr): 2832, 1700, 1598, 1385, 1223, 1074, 814 cmꢂ1 1H NMR
.
6.6
(300 MHz, CDCl3):
d
2.40 (s, 3H), 5.81 (s, 2H), 7.12 (d, 2H, J ¼ 8.0 Hz),
a
All compounds were tested at concentration of 30
m
M, colchicine and Podo-
7.41e7.69 (m, 5H), 7.81 (s, 1H), 7.92 (d, 2H, J ¼ 8.0 Hz). 13C NMR
phyllotoxin were tested at 3 mM and assay is performed in 384 well plate at
360e420 nm.
(75 MHz, CDCl3): d 21.20, 55.32, 120.18, 125.59, 126.36, 127.91,

J. Vantikommu et al. / European Journal of Medicinal Chemistry 45 (2010) 5044e5050
5049
128.53, 129.09, 131.43, 134.76, 140.02, 146.91, 190.85. EI MS (m/z):
277 (M)þ. Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15.
Found: C, 73.51; H, 5.34; N, 15.22.
8.03 (d, 2H, J ¼ 7.6 Hz). 13C NMR (75 MHz, CDCl3):
d
14.02, 22.52,
31.04, 31.48, 35.70, 55.45, 121.05, 125.74, 127.89, 128.18, 128.85,
129.14, 134.03, 134.55, 143.13, 148.34, 190.29. EI MS (m/z): 333 (M)þ.
Anal. Calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C,
74.92; H, 7.11; N, 12.69.
3.2.5. 2-[4-(4-Methoxy-phenyl)-[1,2,3]triazol-1-yl]-1-phenyl-
ethanone (3e)
White solid; mp 106e109 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.33; IR
3.2.11. 2-[4-(3-Methoxy-phenyl)-[1,2,3]triazol-1-yl]-1-phenyl-
ethanone (3k)
(KBr): 3093, 1703, 2840, 1498, 1450, 1247, 1220, 1026, 823 cmꢂ1. 1H
NMR (300 MHz, CDCl3):
d
3.84 (s, 3H), 5.85 (s, 2H), 6.92 (d, 2H,
White solid; mp 167e170 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.31; IR
J ¼ 8.7 Hz), 7.44e7.66 (m, 3H), 7.74 (s,1H), 7.80 (d, 2H, J ¼ 8.0 Hz), 8.04
(KBr): 3438, 2956, 2361, 1701, 1496, 1249, 1223, 1030, 824 cmꢂ1. 1H
(d, 2H, J ¼ 7.3 Hz). 13C NMR (75 MHz, CDCl3):
d
33.30, 55.45, 114.19,
NMR (300 MHz, CDCl3): d 3.84 (s, 3H), 5.86 (s, 2H), 7.28e7.42 (m,
120.50, 127.10, 127.31, 127.95, 128.21, 129.20, 131.99, 134.61, 140.43,
161.58, 188.14. EI MS (m/z): 293 (Mþ). Anal. Calcd for C17H15N3O2: C,
69.61; H, 5.15; N, 14.33. Found: C, 69.42; H, 5.09; N, 14.51.
8H), 7.74 (s, 1H), 8.01 (d, 2H, J ¼ 8.1 Hz). 13C NMR (75 MHz, CDCl3):
d
55.32, 55.38, 112.05, 121.35, 126.95, 127.12, 127.56, 127.98, 128.31,
128.93, 130.05, 134.01, 137.89, 160.20, 190.21. ESI MS (m/z): 294
(MþH)þ. Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33.
Found: C, 69.42; H, 5.09; N, 14.51.
3.2.6. 1-(4-Bromo-phenyl)-2-(4-phenyl-[1,2,3]triazol-1-yl)-
ethanone (3f)
Pale yellow colour solid; mp 115e118 ꢀC; Rf (30% EtOAc/
Hexane) ¼ 0.37; IR (KBr): 3083, 2925, 1696, 1484, 1231, 1078, 762,
3.2.12. 2-[4-(6-Methoxy-naphthalen-2-yl)-[1,2,3]triazol-1-yl]-1-
phenyl-ethanone (3l)
691 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
5.81 (s, 2H), 7.29e7.44 (m,
White solid; mp 160e163 ꢀC; Rf (40% EtOAc/Hexane) ¼ 0.32; IR
3H), 7.52e7.63 (m, 2H), 7.71 (s, 1H), 7.83 (d, 2H, J ¼ 7.3 Hz), 7.99 (d,
(KBr): 3446, 2923, 2852, 2362, 1702, 1456, 1218, 1026, 760 cmꢂ1. 1H
2H, J ¼ 7.8 Hz). 13C NMR (75 MHz, CDCl3):
d
55.30, 121.31, 125.79,
NMR (300 MHz, CDCl3): d 3.93 (s, 3H), 5.86 (s, 2H), 7.43e7.64 (m,
128.27, 128.24, 128.88, 129.60, 129.75, 132.54, 134.75, 136.18, 189.51.
ESI MS (m/z): 343 (M þ H)þ. Anal. Calcd for C16H12BrN3O: C, 56.16;
H, 3.53; N, 12.28. Found: C, 56.05; H, 3.62; N, 12.35.
9H), 7.99 (s, 1H), 8.08 (d, 2H, J ¼ 8.3 Hz). 13C NMR (75 MHz, CDCl3):
d
55.29, 59.92, 105.82, 118.18, 124.16, 124.43, 126.51, 127.24, 128.49,
129.03, 129.60, 134.28, 139.92, 148.19, 156.79, 190.56. ESI MS (m/z):
344 (M þ H)þ. Anal. Calcd for C21H17N3O2: C, 73.45; H, 4.99; N,
12.24. Found: C, 73.21; H, 4.81; N, 12.32.
3.2.7. 1-(4-Chloro-phenyl)-2-(4-phenyl-[1,2,3]triazol-1-yl)-
ethanone (3g)
White solid; mp 106e109 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.35; IR
3.2.13. 2-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-1-phenyl-ethanone
(3m)
(KBr): 3122, 2987, 1706, 1456, 1352, 1223, 1076, 765 cmꢂ1. 1H NMR
(300 MHz, CDCl3):
d
5.83 (s, 2H), 7.23e7.59 (m, 7H), 7.75 (s,1H), 7.98
White solid; mp 115e118 ꢀC; Rf (10% CH3OH/CH2Cl2) ¼ 0.29; IR
(d, 2H, J ¼ 7.8 Hz). 13C NMR (75 MHz, CDCl3):
d
55.34, 125.92,128.32,
(KBr): 3306, 1690, 1443, 1225, 933, 755 cmꢂ1 1H NMR (200 MHz,
.
129.13, 129.72, 130.61, 134.43, 135.54, 139.44, 190.11. ESI MS (m/z):
265 (M þ 1)þ. Anal. Calcd for C16H12N3O: C, 64.54; H, 4.06; N, 14.11.
Found: C, 64.42; H, 4.12; N, 41.14.
DMSO d6):
d
4.67 (d, 2H, J ¼ 5.9 Hz), 4.85 (t, 1H, J ¼ 5.9 Hz), 5.96 (s,
2H), 7.50e7.66 (m, 3H), 7.77 (s, 1H), 8.04 (d, 2H, J ¼ 8.1 Hz). 13C NMR
(50 MHz, CDCl3):
d 55.36, 56.70, 123.50, 128.12, 128.24, 129.17,
134.67, 148.02, 190.02. ESI MS (m/z): 218 (M þ 1)þ. Anal. Calcd for
C11H11N3O2: C, 60.82; H, 5.10; N, 19.34. Found: C, 60.30; H, 4.96; N,
19.42.
3.2.8. 1-Phenyl-2-(4-p-tolyl-[1,2,3]triazol-1-yl)-ethanone (3h)
White solid; mp 158e160 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.28; IR
(KBr): 2930, 1700, 1448, 1347, 1223, 976, 817 cmꢂ1 1H NMR
.
(300 MHz, CDCl3):
d
2.39 (s, 3H), 5.83 (s, 2H), 7.19 (d, 2H, J ¼ 8.1 Hz),
3.2.14. 2-(4-Hexyl-[1,2,3]triazol-1-yl)-1-phenyl ethanone (3n)
White solid; mp 106e108 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.26; IR
(KBr): 3396, 3062, 2926, 2852, 1594, 1706, 1447, 1220, 1057, 985,
7.38e7.73 (m, 5H), 7.86 (s, 1H), 8.03 (d, 2H, J ¼ 8.0 Hz). 13C NMR
(75 MHz, CDCl3):
d 21.24, 55.36, 125.71, 128.18, 128.79, 129.14,
129.40,129.84,134.49,137.95,139.06,190.36. EI MS (m/z): 277 (M)þ.
Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.45; H, 5.31; N, 14.95.
756 cmꢂ1
.
1H NMR (200 MHz, CDCl3):
d
0.89 (t, 3H, J ¼ 6.6 Hz),
1.27e1.41 (m, 6H), 1.63e1.77 (m, 2H), 2.75 (t, 2H, J ¼ 7.3 Hz), 5.76 (s,
2H), 7.40 (s, 1H), 7.48e7.65 (m, 3H), 8.01 (d, 2H, J ¼ 8.03 Hz).13C
NMR (75 MHz, CDCl3):
d 14.02, 22.52, 25.66, 28.92, 29.24, 31.58,
3.2.9. 1-Phenyl-2-[4-(2,4,5-trimethyl-phenyl)-[1,2,3]triazol-1-yl]-
ethanone (3i)
55.36, 125.08, 128.15, 134.03, 134.46, 190.61. ESI MS (m/z): 272
(M þ 1)þ. Anal. Calcd for C16H21N3O: C, 70.82; H, 7.80; N, 15.49.
Found: C, 69.98; H, 7.61; N, 15.69.
White solid; mp 165e167 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.32; IR
(KBr): 2951, 1712, 1447, 1221, 1601, 994, 753 cmꢂ1 1H NMR
.
(300 MHz, CDCl3):
d
2.27 (s, 3H), 2.28 (s, 2H), 2.43 (s, 3H), 5.87 (s,
3.2.15. 1-Phenyl-2-(4-thiophen-3-yl-[1,2,3]triazol-1-yl)-ethanone
(3o)
2H), 7.00 (s, 1H), 7.44e7.67 (m, 3H), 7.76 (s, 1H), 8.04 (d, 2H,
J ¼ 7.5 Hz). 13C NMR (75 MHz, CDCl3):
d
19.06, 19.38, 20.68, 55.36,
White solid; mp 167e170 ꢀC; Rf (40% EtOAc/Hexane) ¼ 0.31; IR
123.20, 127.16, 128.15, 129.14, 130.01, 132.17, 132.66, 134.09, 134.20,
134.55, 136.59, 190.35. EI MS (m/z): 305 (Mþ). Anal. Calcd for
C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C, 74.15; H, 5.87; N,
13.82.
(KBr): 2988, 1703, 1595, 1448, 1321, 1222, 943 cmꢂ1 1H NMR
.
(300 MHz, CDCl3):
d
5.84 (s, 2H), 7.21 (d, 1H, J ¼ 6.2 Hz), 7.32e7.43
(m, 5H), 7.81 (s, 1H), 8.03 (d, 2H, J ¼ 7.6 Hz). 13C NMR (75 MHz,
CDCl3):
d 53.99, 121.26, 122.91, 125.47, 125.88, 126.93, 128.06,
128.88, 129.23, 134.55, 147.41,189.88. EI MS (m/z): 269 (M)þ. Anal.
Calcd for C14H11N3OS: C, 62.43; H, 4.12; N, 15.60; S, 11.91. Found: C,
62.62; H, 3.98; N, 15.74; S, 11.87.
3.2.10. 2-[4-(4-Pentyl-phenyl)-[1,2,3]triazol-1-yl]-1-phenyl-
ethanone (3j)
White solid; mp 172e175 ꢀC; Rf (30% EtOAc/Hexane) ¼ 0.39; IR
(KBr): 3086, 2925, 2854, 1704, 1451, 1346, 1221, 981, 756 cmꢂ1. 1H
3.2.16. 1-Phenyl-2-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-ethanone
(3p)
NMR (300 MHz, CDCl3):
d
0.90 (t, 3H, J ¼ 6.8 Hz), 1.30e1.39 (m, 4H),
1.58e1.69 (m, 2H), 2.62 (t, 2H, J ¼ 7.5 Hz), 5.83 (s, 2H), 7.19 (d, 2H,
Yellowish green solid; mp 173e175 ꢀC; Rf (50% EtOAc/
Hexane) ¼ 0.35; IR (KBr): 3065, 2936, 1705, 1593, 1561, 1443, 1350,
J ¼ 7.6 Hz), 7.50e7.68 (m, 3H), 7.73 (d, 2H, J ¼ 8.3 Hz), 7.86 (s, 1H),

5050
J. Vantikommu et al. / European Journal of Medicinal Chemistry 45 (2010) 5044e5050
1225, 1049, 993, 755 cmꢂ1 1H NMR (300 MHz, CDCl3):
. d 5.88 (s,
[5] (a) G. L’Abbe, Chem. Rev. 69 (1969) 345e363;
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2H), 7.17e7.23 (m, 1H), 7.51e7.81 (m, 3H), 8.05 (d, 2H, J ¼ 7.5 Hz),
8.27 (s, 2H), 8.54 (d, 1H J ¼ 6.0 Hz). 13C NMR (75 MHz, CDCl3):
(c) C.-K. Sha, A.K. Mohanakrishnan, in: A. Padwa, W.H. Pearson (Eds.),
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
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[6] H.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, Angew. Chem., Int. Ed.
Engl. 41 (2002) 2596e2599.
d
55.57, 120.32, 122.86,123.93,128.18,129.14, 134.58, 136.82, 149.42,
189.85. ESI MS (m/z): 265 (M þ H)þ. Anal. Calcd for C15H12N4O: C,
68.17; H, 4.58; N, 21.20. Found: C, 68.02; H, 4.32; N, 21.44.
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Acknowledgement
Jyothi V, thanks the AP Council of Science & Technology
(APCOST) for awarding the Young Scientist Fellowship (YSF) and the
Nizam College, Osmania University, Hyderabad, India for the facil-
ities to carryout the research work. P.S.R. thanks the Council of
Scientific and Industrial Research, New Delhi, for the award of
Senior Research Fellowship.
(b) A.J. Scheel, H. Komber, B.I. Voit, Macromol. Rapid Commun. 25 (2004)
1175e1180;
(c) D.J.V.C. Von Steenis, O.R.P. David, G.P.F. Van Srrijdonck, J.H. Van Maar-
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