A novel approach to the synthesis of 1,2,3-triazoles and their SAR studies

Article abstract of DOI:10.1007/s00044-009-9215-7

A series of biologically active 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3- dihydro- 1H-1,2,3-triazole derivatives has been synthesized. The compounds were synthesized in excellent yields (80-85%) and the structures were established on the basis of corresponding IR, 1H NMR, and elemental analysis data. The purity has been ascertained on the basis of chromatographic resolution using acetic acid-toluene (4:6 v/v) as binary eluent. All the compounds (4a-l) have been tested for their antifungal activity against a representative panel of fungal microbes. These synthesized compounds exhibited significant activities against A. niger, C. albicans, C. azyma, and A. flavus. For all the tests conducted, voriconazole was used as the control drug. The hydrophobic parameter (log P) also has been quantized for correlation of structure with biological activity, and a critical evaluation of structure-activity relationship (SAR) has been performed. Birkhaeuser Boston 2009.

Full text of DOI:10.1007/s00044-009-9215-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:589–602
DOI 10.1007/s00044-009-9215-7
ORIGINAL RESEARCH
A novel approach to the synthesis of 1,2,3-triazoles
and their SAR studies
Pratibha Sharma Æ Ashok Kumar Æ Siya Upadhyay Æ
Jitendra Singh Æ Vinita Sahu
Received: 4 February 2009 / Accepted: 15 April 2009 / Published online: 15 May 2009
¨
Ó Birkhauser Boston 2009
Abstract A series of biologically active 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihy-
dro-1H-1,2,3-triazole derivatives has been synthesized. The compounds were synthe-
sized in excellent yields (80–85%) and the structures were established on the basis of
corresponding IR, 1H NMR, and elemental analysis data. The purity has been ascertained
on the basis of chromatographic resolution using acetic acid-toluene (4:6 v/v) as binary
eluent. All the compounds (4a–l) have been tested for their antifungal activity against a
representative panel of fungal microbes. These synthesized compounds exhibited
significant activities against A. niger, C. albicans, C. azyma, and A. flavus. For all the
tests conducted, voriconazole was used as the control drug. The hydrophobic parameter
(log P) also has been quantized for correlation of structure with biological activity, and a
critical evaluation of structure-activity relationship (SAR) has been performed.
Keywords 4-Acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole ꢀ
Antifungal activity ꢀ SAR ꢀ log P
Introduction
1,2,3-triazoles are attractive constructs due to their unique chemical properties and
structure, which find many applications in medicinal, pharmacological, and agricul-
tural fields. Members of this family have been widely used due to their profound
antibacterial, fungicidal, anti-inflammatory, antiviral, and plant growth regulatory
activities (Kupchinsky et al., 1998; Moreno-Manas et al., 1992; Czollner et al., 1990;
Orbai and Moneim, 2001; Er-Rhaimini and Mornet, 1992; Silvester, 1994). Also, such
P. Sharma (&) ꢀ A. Kumar ꢀ S. Upadhyay ꢀ J. Singh ꢀ V. Sahu
School of Chemical Sciences, Devi Ahilya University, Takshashila Campus, Indore,
MP 452 001, India
e-mail: drpratibhasharma@yahoo.com

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Med Chem Res (2010) 19:589–602
triazoles derivatives have been found to elicit their role, as peptide nanotubes (Horne
et al., 2003, 2004; Van Maarseveen et al., 2005), protease inhibitors (Whiting et al.,
2006), cyclopeptide analogues (Roice et al., 2004; Punna et al., 2005; Angell and
Burgess, 2005; Bock et al., 2006), and as peptide chain analogues (Angelo and Arora,
2005; Aucagne and Leigh, 2006; Montagnat et al., 2006; Paul et al., 2006; Zhang and
Fan, 2006). However, due to the lack of convenient direct methods for their synthesis,
these aromatic heterocycles have not received as much attention as they deserve.
Now, various combinations of several classes of triazole-based antifungal agents
(e.g., fluconazole, itraconazole, voriconazole, and posaconazole) are available
commercially with their significant drug resistance capability. A systematic perusal
of literature revealed that recently a variety of methods have been developed for the
synthesis of triazole derivatives, including metal catalyzed synthesis and solvent-
free synthesis (Amantini et al., 2005; Barral et al., 2007; Barluenga et al., 2006;
Chuprakov et al., 2007; Kamijo et al., 2003; Lipshutz and Taft, 2006; Rodionov
et al., 2007).
Buoyed from aforementioned information and in continuation of our previous
work on versatile synthesis of biologically active heterocyclic compounds (Sharma
et al., 2005, 2006a, b, c), this study was designed to compose an elegant synthetic
route for a series of 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole
(4a–l) using accessible starting materials. Furthermore, in the present study, we
have evaluated the in vitro antifungal activity against a number of fungal microbes:
A. niger, C. albicans, C. azyma, A. flavus. The resultant SAR screening parameters
revealed that the representative compounds possess profound antifungal activities.
Furthermore, of a number of various physiochemical parameters, Log P (log of
n-octanol water partition coefficient) has been chosen as the most promising
parameter, which influences the biological activity to a greater extent.
Chemistry
A series of biologically active 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro 1H-1,2,
3-triazole derivatives (4a–l) were synthesized by initial diazotization of various
substituted anilines (1a–l) under temperature-controlled conditions (0–5°C). It was
followed by treatment with active methylene compound in the presence of mild base
to form 3-arylazo-pentane 2,4-dione (2a–l). In a subsequent step, 3-arylazo-pentane
2,4-dione (2a–l) was refluxed with 2-ethanolamine in presence of potassium acetate
to afford 5-membered cyclized product, i.e., 4-acetyl-2-aryl-5-methyl-N-hydroxy
ethyl-2,3-dihydro-1H-1,2,3-triazole (3a–l). It was refluxed under acidic condition
for 5 h to afford the requisite 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro-1H-1,
2,3-triazole (4a–l) in 80–85% yield. The precipitate so obtained were washed with
water and recrystallized with ethyl alcohol. The reaction sequence for the title
compounds is outlined in Scheme 1.
All synthesized compounds were found in good agreement with the elemental
analysis. The structural assignments are in accordance with IR and 1H NMR spectral
data. Furthermore, the calculated heat of formations (DH) at PM3 semiempirical

Med Chem Res (2010) 19:589–602
591
NaNO2/HCl
0ꢀ5 oC
(i)
O
O
NH2
N
CH3
CH3
R
(ii)
N
R
O
CH
CH
3
3
1 a-l
2 a-l
O
R
NH2CH2CH2OH
ꢀH2O
a
b
c
d
e
f
H
3-Cl
3-OH
4-OH
4-COOH
3-CH3
CH3
O
3-NO2
4-NO2
g
h
i
N
N
H3C
OH
NH
4-CH3
4-Cl
j
3 a-l
k
l
3-OCH3
R
4-OCH
3
H3PO4
1,2 elimination
ꢀH2O
CH3
O
N
N
H3C
CH2
NH
R
4 a-l
Scheme 1 Overview of synthetic pathway of 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-
triazole (4a–l)
method using MOPAC 2007 program for the representative compound 4a was
-62.70 kcal/mol, which is in accordance with the stability of 4-acetyl-2-aryl-5-
methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole derivatives. PM3 optimized geometry
of a representative compound (4a) is depicted in Fig. 1.

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Med Chem Res (2010) 19:589–602
Fig. 1 PM3 optimized ORTEP view of 4-acetyl-2-phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-
triazole (4a)
Results and discussion
All the newly synthesized compounds have been successfully screened in vitro for
their antifungal activities against an assortment of fungi, i.e., Aspergillus niger 281,
Candida albicans 227, Aspergillus flavus 871, and Candida azyma1452 using paper
disc method. The saboured dextrose agar media was used for fungal growth. Inocula
containing approximately 107 colony forming units (CFU) per milliliter of fungi
were prepared from broth culture in log phase. The fungi plate was incubated at
30°C for 28 hours. Voriconazole was screened under similar conditions as reference
antifungal drug. All of the synthesized compounds delineate significant antimicro-
bial potency against tested fungal microbes compared with the reference drug,
which is further supported by biological investigations shown in Table 1. All tests
were conducted in the three replications. The biological activities were reported
(Table 1) in terms of percent of inhibition, i.e., % Inhibition = {(a - b)/a} 9 100,
where a and b stands for the zone of inhibition of reference drug and synthesized
compounds, respectively.
To find out log P (Skagerbeg et al., 1989), the calculations were performed at
SCF (self consistent field theory) level using PM3 (Hamiltonian Inc.) in MOPAC
6.0 package (Stewart, 1989, 1990). Geometry optimization of all synthesized
compound was performed by using Chem 3D software. An overview of the
antifungal data shows that the synthesized 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-
dihydro-1H-1,2,3-triazole derivatives (4a–l) gave promising results when tested in
vitro against various fungi.
It is revealed from the data presented in Table 1 that the compounds bearing
chloro, methyl, and methoxy substituent are more active. Hence, alkylation of
hydroxyl group tends to enhance the antifungal activity. Also, meta substituted
derivatives are more active compared with para substituted. Thus, 4-acetyl-2-
(3’-chloro) phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4b) is highly
active. In general, it has been observed that antifungal results follow the pattern:

Med Chem Res (2010) 19:589–602
593
Table 1 Antifungal screening studies of 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole
(4a-l)
R
Log P
Percent inhibition (a - b/a 9 100)
C. albicans
A. niger
C. azyma
A. flavus
4a
4b
4c
4d
4e
4f
H
3.33
4.04
2.66
2.66
3.07
3.82
3.31
3.31
3.82
4.04
3.36
3.36
-31.25
-93.75
18.75
-33.33
-100.00
11.11
-26.67
-86.67
26.67
-13.33
-73.33
40.00
3–Cl
3–OH
4–OH
4–COOH
3–CH3
3–NO2
4–NO2
4–CH3
4–Cl
25.00
16.67
33.33
46.67
6.25
-11.11
-72.22
-33.33
-27.78
-66.67
-94.44
-50.00
-44.44
6.67
33.33
-62.50
-6.25
0.00
-60.00
0.00
-46.67
13.33
4g
4h
4i
6.67
20.00
-56.25
-87.50
-43.75
-37.50
-53.33
-80.00
-40.00
-33.33
-40.00
-66.67
-26.67
-20.00
4j
4k
4l
3–OCH3
4–OCH3
Values of a for control drug (voriconazole) are 16, 18, 15, and 15 mm against C. albicans, A. niger, C.
azyma, and A. flavus, respectively
3-Cl [ 4-Cl [ 3-CH3 [ 4-CH3 [ 3-OCH3[ 4-OCH3 [ H [ 3-NO2 [ 4-NO2 [
4-COOH [ 3-OH [ 4-OH.
The screening results revealed that the synthesized compounds are highly active
against A. niger and least against A. flavus (Fig. 2). In general activity follows the
pattern: A. niger [ C. albicans [ C. azyma, [ A. flavus.
Furthermore, hydrophobic properties have been quantized for correlation of
structure with biological activity. The data exhibited in Table 1 reveal that the
chloro derivative has high value of log P, i.e., 4.04 and the hydroxyl group
containing compound has low value of log P, i.e., 2.66. Thus, it is inferred that
triazole derivative having chloro group exhibit more antifungal activity than
compounds possessing hydroxyl group. A perusal of data reveals a significant
correlation (r2 = 0.9–0.97) between biological activity and log P against all
microbes. Also, the standard deviation does not exceed 1.396 (Fig. 3).
Conclusively, we have synthesized a new series of active 4-acetyl-2-aryl-5-methyl-
1-vinyl-2,3-dihydro-1H-1,2,3-triazole derivatives (4a–l) in a highly efficient manner.
Furthermore, antifungal studies performed on these compounds revealed that they
gave promising results when tested in vitro against various fungi. Hydrophobic
properties also justify the correlation of structure with elicited biological activity. The
value of log P exhibited a good correlation (r2 [ 0.9) with biological activity.
Experimental procedure
All the chemicals used were of AR grade purity. IR spectra were recorded on Perkin
Elmer model 377 spectrophotometer in KBr pellets. IR frequencies were measured

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Med Chem Res (2010) 19:589–602
Fig. 2 Graphical representation of biological activity of substituted 4-acetyl-2-aryl-5-methyl-1-vinyl-
2,3-dihydro 1H-1,2,3-triazole (4a–l)
(a)
(b)
0.6
0.4
0.4
0.2
Y=2.452-0.812X
SD=0.130
r=0.950, r =0.902
Y=2.253-0.787X
SD=0.064
4-OH
2
4-OH
r=0.986, r2=0.97
0.2
4-COOH
4-NO2
3-NO2
0.0
3-OH
4-COOH
3-OH
0.0
4-NO2
-0.2
-0.4
-0.6
-0.8
-1.0
-0.2
-0.4
-0.6
-0.8
-1.0
H
H
4-OCH3
3-OCH3
3-NO2
4-OCH3
3-OCH3
4-CH3
3-CH3
4-CH3
3-CH3
4-Cl
3-Cl
C. albicans
4-Cl
3-Cl
A. niger
2.8 3.0
2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4
2.4
2.6
3.2
3.4
3.6
3.8
4.0
4.2
log P
log P
(c)
(d)
4-OH
0.4
0.2
Y=2.536-0.821X
0.6
0.4
Y=2.742-0.840X
SD=0.1396
4-OH
SD=0.129
r=0.952, r2=0.906
r=0.947, r2=0.90
4-COOH
3-OH
4-COOH
4-NO
4-NO2
3-NO2
3-OH
0.2
0.0
3-NO22
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
H
H
4-OCH3
3-OCH3
4-OCH3
3-OCH3
-0.2
-0.4
-0.6
-0.8
4-CH3
3-CH3
4-CH3
3-CH3
4-Cl
4-Cl
3-Cl
A. flavus
C. azyma
3-Cl
2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4
2.4
2.6
2.8 3.0
3.2
3.4
3.6
3.8
4.0
4.2
log P
log P
Fig. 3 Plot of biological activity verses log P screened against a C. albicans, b A. niger, c C. azyma d A.
flavus
in cm-1. 1H NMR spectra were recorded in CDCl3 solution in 5-mm tubes at 25°C
on a Bruker DRX-300 instrument (300 MHz FT NMR with low and high
temperature facility -90°C to ?80°C) with deuterium signal as the lock and TMS

Med Chem Res (2010) 19:589–602
595
as internal standard. Chemical shifts were measured in d ppm units. The melting
points were determined on an electric melting point apparatus (Biotech Bombay,
India) in open capillaries and are uncorrected. The purity of all the synthesized
compounds was ascertained by TLC resolution on silica gel-G (E Merck) using
acetic acid-toluene (4:6, v/v) as binary eluent. Elemental analyses were performed
on Elemental analyzer (Elemental Vario, EL III Carlo Erba 1108) at Central Drug
Research Institute, Lucknow, India.
General procedure for the synthesis of 3-arylazo-pentane 2,4-dione
(Jain and Pandey, 1987) (2a–l)
Pertinent aniline derivatives (1a–l) (0.01 M) were dissolved in 4.0 ml of HCl and
4.0 ml of distilled water and kept at freezing temperature in the refrigerator. To this,
an aqueous solution of sodium nitrite (2 g, 0.01 M) in 4 ml of distilled water was
added drop wise with continuous stirring keeping the temperature in the vicinity of
0–5°C. Meanwhile, in another beaker acetyl acetone (2 g, 0.01 M), sodium acetate
(7 g, 0.01 M) and 20 ml of ethyl alcohol were taken and cooled in an ice bath. The
diazotized solution was added to this solution drop wise with thorough stirring
under temperature-controlled conditions. The reaction mixture was kept for
overnight period, filtered through suction, washed with water, and dried in vacuum.
Fine, yellow crystals of the 3-arylazo-pentane 2,4-dione (2a–l) were obtained,
which were recrystallized from a mixture of DMF and ethyl alcohol.
Synthesis of 4-acetyl-2-aryl-5-methyl-N-hydroxy ethyl-2,
3-dihydro-1H-1,2,3-triazole (3a–l)
In a 250-ml, round-bottom flask, 3-phenylazo-pentane 2,4-dione (2a–l) (0.15 M)
and 2-hydroxy ethanolamine (13.7 g, 2.25 M) in alcoholic solution of potassium
acetate (4.6 g, 2.25 M) in 25 ml of ethyl alcohol as a solvent were taken and stirred
at room temperature. After stirring for 30 min, precipitate that was generated was
filtered and washed with 10 ml of ethyl alcohol. The fine crystals of 4-acetyl-2-aryl-
5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-triazole (3a–l) were obtained in
good yield.
Synthesis of 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole
(4a–l)
In a 250-ml, round-bottom flask, 4-acetyl-2-aryl-5-methyl-N-hydroxy ethyl-2,3-
dihydro-1H-1,2,3-triazole (3a–l) (0.67 M) and 25 ml of 85% ortho-phosphoric acid
were taken and refluxed for 30 minutes in the presence of porous porcelain in ethyl
alcohol. After cooling to room temperature, precipitate that was obtained was
filtered, thoroughly washed with water, and recrystallized from ethyl alcohol. Fine,
yellow crystals of 4-acetyl-2-aryl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole
(4a–l) were obtained in 80–85% yield.

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Med Chem Res (2010) 19:589–602
4-Acetyl-2-phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-triazole (3a)
IR (m, cm-1); 3585 (O–H), 3410 (–NH, five membered), 2850, 2940 (C–H, sp3), 3055
(C–H, sp2), 2955 (C–H, sp2), 1711 (C=O), 1610 (C=C), 1475, 1455 (C C, ring str.),
1336 (C–N), 1050 (C–O), 948, 892, 825 (sub. phenyl). 1HNMR (d ppm); 2.34 (s, 3H,
CH3), 2.58 (s, 3H, COCH3), 3.72 (s, 1H, OH), 3.91 (t, 2H, CH2), 4.03 (t, 2H, CH2),
7.52 (s, 5H, Ar–H), 12.32 (s, 1H, NH); FAB-MS (M??H) 248; mp (°C) 150–151;
Yield (%) 78; Found (calcd) % C, 63.10 (63.14); H, 6.91 (6.93); N, 16.95 (16.99).
4-Acetyl-2-(30-chloro)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3b)
IR (m, cm-1); 3580 (O–H), 3442 (NH, five membered), 3086 (C–H, sp2), 2878, 2935
(C–H, sp3), 1698 (C=O), 1618 (C=C), 1586, 1553, 1405 (C C, ring str.), 1343
(C–N), 1052 (C–O), 812, 801 (sub phenyl), 582 (C–Cl). 1HNMR (d ppm); 2.37 (s, 3H,
CH3), 2.54 (s, 3H, COCH3), 3.75 (s, 1H, OH),3.89 (t, 2H, CH2), 4.10 (t, 2H, CH2),
7.31–7.62 (m, 4H, Ar–H), 12.21 (s, 1H, NH); FAB-MS (M??H) 283; mp (°C) 142–
143; Yield (%) 82; Found (calcd) % C, 55.38 (55.42); H, 5.69 (5.72); N, 14.89 (14.91).
4-Acetyl-2-(30-hydroxy)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3c)
IR (m, cm-1); 3685 (OH, Free), 3425 (NH, five membered), 3091 (C–H, sp2), 2855,
2942 (C–H, sp3), 1708 (C=O), 1659 (C=C), 1597, 1553, 1508 (C C, ring str.),
1339 (C–N), 1048 (C–O), 903, 812, 752 (sub phenyl). 1HNMR (d ppm); 2.34 (s, 3H,
CH3), 2.55 (s, 3H, COCH3), 3.64 (s, 1H, OH), 3.89 (t, 2H, CH2), 4.08 (t, 2H, CH2),
6.81–7.21 (m, 4H, Ar–H), 8.14 (s, 1H, OH), 12.5 (s, 1H, NH); FAB-MS (M??H)
264; mp (°C) 141–142; Yield (%)75; Found (calcd) % C, 59.25 (59.30); H, 6.48
(6.51); N, 15.90 (15.96).
4-Acetyl-2-(40-hydroxy)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3d)
IR (m, cm-1); 3665 (OH, Free), 3430 (NH, five membered), 2860, 2952 (C–H, sp3),
3095 (C–H, sp2), 1712 (C=O), 1655 (C=C), 1595, 1557, 1505 (C C, ring str.),
1341 (C–N), 1049 (C–O), 906, 815, 754 (sub phenyl). 1HNMR (d ppm); 2.34 (s, 3H,
CH3), 2.58 (s, 3H, COCH3), 3.82 (s, 1H, OH), 3.86 (t, 2H, CH2), 4.13 (t, 2H, CH2),
6.9–7.3 (m, 4H, Ar–H), 8.36 (s, 1H, OH), 12.42 (s, 1H, NH); FAB-MS (M??H)
264; mp (°C) 137–138; Yield (%)78; Found (calcd) % C, 59.25 (59.30); H, 6.48
(6.51); N, 15.90 (15.96).
4-acetyl-2-(40-carboxy)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3e)
IR (m, cm-1); 3300–2617 (OH, br), 3436 (NH, five membered), 2862, 2948 (C–H,
sp3), 3100 (C–H, sp2), 1705 (C=O), 1652 (C=C), 1593, 1554, 1507 (C C, ring

Med Chem Res (2010) 19:589–602
597
1
str.), 1340 (C–N), 1053 (C–O), 902, 815, 752 (sub phenyl). HNMR (d ppm); 2.34
(s, 3H, CH3), 2.57 (s, 3H, COCH3), 3.82 (s, 1H, OH), 3.85 (t, 2H, CH2), 4.15 (t, 2H,
CH2), 7.62–8.11 (m, 4H, Ar–H) 11.12 (s, H, OH), 12.33 (s, 1H, NH); FAB-MS
(M??H) 292; mp (°C) 147–148; Yield (%)74; Found (calcd) % C, 57.68 (57.72); H,
5.82 (5.88); N, 14.37(14.42).
4-acetyl-2-(30-methyl)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3f)
IR (m, cm-1); 3658 (OH, Free), 3430 (NH, five membered), 2862, 2956 (C–H, sp3),
3108 (C–H, sp2), 1715 (C=O), 1658 (C=C), 1597, 1553, 1512 (C C, ring str.),
1333 (C–N), 1052 (C–O), 912, 805, 754 (sub phenyl). 1HNMR (d ppm); 2.11 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 2.55 (s, 3H, COCH3), 3.83 (t, 2H, CH2), 3.89 (s, 1H, OH),
4.10 (t, 2H, CH2), 6.91–7.32 (m, 4H, Ar–H), 12.52 (s, 1H, NH); FAB-MS (M??H)
262; mp (°C) 130–131; Yield (%)70; Found (calcd) % C, 64.31 (64.35); H, 7.31
(7.33); N, 16.04 (16.08).
4-acetyl-2-(30-nitro)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-triazole
(3g)
IR (m, cm-1); 3651 (OH, Free), 3315 (–NH), 3005 (C–H, sp2), 2868, 2958 (C–H,
sp3), 3009 (C–H, sp2), 1715 (C=O), 1621 (C=C), 1471, 1452 (C C, ring str.),
1555, 1372 (–NO2), 1342 (C–N), 1052 (C–O), 946, 894, 822 (sub. phenyl). 1HNMR
(d ppm); 2.29 (s, 3H, CH3), 2.58 (s, 3H, COCH3), 3.82 (t, 2H, CH2), 3.88 (s, 1H,
OH), 4.05 (t, 2H, CH2), 7.51–8.21 (m, 4H, Ar–H), 12.28 (s, 1H, NH); FAB-MS
(M??H) 293; mp (°C) 135–136; Yield (%) 73; Found (calcd) % C, 53.39 (53.42);
H, 5.50 (5.52); N, 19.14 (19.17).
4-acetyl-2-(40-nitro)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-triazole
(3h)
IR (m, cm-1); 3650 (OH, Free), 3315 (–NH), 3006 (C–H, sp2), 2862, 2953 (C–H,
sp3), 1712 (C=O), 1627 (C=C), 1471, 1453 (C C, ring str.), 1552, 1376 (–NO2),
1
1334 (C–N), 1053 (C–O), 952, 895, 820 (sub. phenyl). HNMR (d ppm); 2.32 (s,
3H, CH3), 2.54 (s, 3H, COCH3), 3.72 (s, 1H, OH), 3.88 (t, 2H, CH2), 4.15 (t, 2H,
CH2), 7.45–8.33 (m, 4H, Ar–H), 12.5 (s, 1H, NH); FAB-MS (M??H) 293; mp (°C)
130–131; Yield (%)78; Found (calcd) % C, 53.39 (53.42); H, 5.50 (5.52); N, 19.14
(19.17).
4-acetyl-2-(40-methyl)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3i)
IR (m, cm-1); 3655 (OH, Free), 3432 (NH, five membered), 2862, 2954 (C–H, sp3),
3105 (C–H, sp2), 1714 (C=O), 1658 (C=C), 1597, 1551, 1510 (C C, ring str.),
1332 (C–N), 1048 (C–O), 912, 805, 752 (sub phenyl). 1HNMR (d ppm); 2.35 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 2.55 (s, 3H, COCH3), 3.71 (s, 1H, OH), 3.83 (t, 2H, CH2),

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4.10 (t, 2H, CH2), 7.33 (m, 4H, Ar–H), 12.6 (s, 1H, NH); FAB-MS (M??H) 262;
mp (°C) 132–133; Yield (%)71; Found (calcd) % C, 64.31 (64.35); H, 7.31 (7.33);
N, 16.04 (16.08).
4-acetyl-2-(40-chloro)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3j)
IR (m, cm-1); 3634 (OH, Free), 3445 (NH, five membered), 3063 (C–H, sp2), 2868,
2958 (C–H, sp3), 1680 (C=O), 1643 (C=C), 1580, 1551, 1401 (C C, ring str.),
1342 (C–N), 1046 (C–O), 811, 807 (sub phenyl), 583 (C–Cl). 1HNMR (d ppm); 2.34
(s, 3H, CH3), 2.56 (s, 3H, COCH3), 3.79 (s, 1H, OH), 3.82 (t, 2H, CH2), 4.05 (t, 2H,
CH2), 7.32–7.66 (m, 4H, Ar–H), 12.1 (s, 1H, NH); FAB-MS (M??H) 283; mp (°C)
140–141; Yield (%) 78; Found (calcd) % C, 55.38 (55.42); H, 5.69 (5.72); N, 14.88
(14.91).
4-acetyl-2-(30-methoxy)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3k)
IR (m, cm-1); 3660 (OH, Free), 3442 (NH, five membered), 3046 (C–H, sp2), 2862,
2949 (C–H, sp3), 1713 (C=O), 1652 (C=C), 1587, 1551, 1516 (C C, ring str.),
1335 (C–N), 1046 (C–O), 913, 814, 756 (sub phenyl). 1HNMR (d ppm); 2.39 (s, 3H,
CH3), 2.56 (s, 3H, COCH3), 3.71 (s, 3H, OCH3), 3.82 (t, 2H, CH2), 3.86 (s, 1H,
OH), 4.13 (t, 2H, CH2), 6.80–7.32 (m, 4H, Ar–H), 12.62 (s, 1H, NH); FAB-MS
(M??H) 278; mp (°C) 130–131; Yield (%)70; Found (calcd) C, 60.60 (60.63); H,
6.88 (6.91); N, 17.28 (17.31).
4-acetyl-2-(40-methoxy)phenyl-5-methyl-N-hydroxy ethyl-2,3-dihydro-1H-1,2,3-
triazole (3l)
IR (m, cm-1); 3585 (OH, Free), 3442 (NH, five membered), 3056(C–H, sp2), 2868,
2958 (C–H, sp3), 1718 (C=O), 1650 (C=C), 1586, 1551, 1515 (C C, ring str.),
1332 (C–N), 1048 (C–O), 912, 815, 758 (sub phenyl). 1HNMR (d ppm); 2.35 (s, 3H,
CH3), 2.52 (s, 3H, COCH3), 3.77 (s, 3H, OCH3), 3.85 (t, 2H, CH2), 3.96 (s, 1H,
OH), 4.10 (t, 2H, CH2), 6.71–7.42 (m, 4H, Ar–H), 12.2 (s, 1H, NH); FAB-MS
(M??H) 278; mp (°C) 134–135; Yield (%)73; Found (calcd) C, 60.60 (60.63); H,
6.88 (6.91); N, 17.28 (17.31).
4-Acetyl-2-phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4a)
IR (m, cm-1); 3408 (–NH, five membered), 3030 (C–H, sp2), 2926 (C–H, sp2), 1707
(C=O), 1625(C=C), 1473, 1451 (C C, ring str.), 1242(C–N), 949, 894, 826 (sub.
1
phenyl). HNMR (d ppm); 2.36 (s, 3H, CH3), 2.57 (s, 3H, COCH3), 5.10 (d, 2H,
CH2), 5.49 (t, 1H, CH), 7.5 (s, 5H, Ar–H), 12.3 (s, 1H, NH); FAB MS (M??H) 230;
mp (°C) 143–144; Yield (%)79; Found (calcd) % C, 68.01 (68.10); H, 6.51 (6.59);
N, 18.24 (18.33).

Med Chem Res (2010) 19:589–602
599
4-Acetyl-2-(30-chloro)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4b)
IR (m, cm-1); 3448 (NH, Five membered), 3086 (C–H, sp2), 2878 (C–H, sp3), 1698
(C=O), 1643 (C=C), 1641(C=C), 1589, 1552,1403 (C C, ring str.), 1441 (C–N),
812, 800 (sub phenyl), 586 (C–Cl). 1HNMR (d ppm); 2.35 (s, 3H, CH3), 2.58 (s, 3H,
COCH3), 5.09 (d, 2H, CH2), 5.45 (t, 1H, CH), 7.0–7.4 (m, 4H, Ar–H), 12.4 (s, 1H,
NH); FAB MS (M??H) 265; mp (°C) 140–141; Yield (%) 80; Found (calcd) % C,
59.14 (59.21); H, 5.29 (5.35); N, 15.93 (15.86).
4-Acetyl-2-(30-hydroxy)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4c)
IR (m, cm-1); 3755 (OH, Free), 3436 (NH, five membered), 3091(C–H, sp2), 2836
(C–H, sp3), 1708 (C=O), 1659(C=C), 1599, 1555, 1508 (C C, ring str.), 1444 (C–
1
N), 905, 815, 753 (sub phenyl). HNMR (d ppm); 2.36 (s, 3H, CH3), 2.59 (s, 3H,
COCH3), 5.0 (s, 3H, OH), 5.12 (d, 2H, CH2), 5.47 (t, 1H, CH2), 6.8–7.1 (m, 4H, Ar–
H), 12.6 (s, 1H, NH); FAB MS (M??H) 246; mp (°C) 136–137; Yield (%)72;
Found (calcd) % C, 63.59 (63.66); H, 6.08 (6.16); N, 17.06 (17.13).
4-Acetyl-2-(40-hydroxy)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4d)
IR (m, cm-1); 3758 (OH, Free), 3438 (NH, five membered), 3092 (C–H, sp2), 2837
(C–H, sp3), 1710 (C=O), 1660 (C=C), 1600, 1556, 1506 (C C, ring str.), 1446 (C–
1
N), 907, 813, 751 (sub phenyl). HNMR (d ppm); 2.37 (s, 3H, CH3), 2.61 (s, 3H,
COCH3), 5.3 (s, 3H, OH), 5.11 (d, 2H, CH2), 5.49 (t, 1H, CH), 6.9–7.3 (m, 4H, Ar–
H), 12.4 (s, 1H, NH); FAB MS (M??H) 246; mp (°C) 132–133; Yield (%)74;
Found (calcd) % C, 63.55 (63.66); H, 6.02 (6.16); N, 17.02 (17.13).
4-Acetyl-2-(40-carboxy)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4e)
IR (m, cm-1); 3756 (OH, Free), 3434 (NH, five membered), 3100 (C–H, sp2), 2841
(C–H, sp3), 1700 (C=O), 1657 (C=C), 1597, 1553, 1509 (C C, ring str.), 1442 (C–
1
N), 904, 814, 751 (sub phenyl). HNMR (d ppm); 2.36 (s, 3H, CH3), 2.59 (s, 3H,
COCH3), 5.15 (d, 2H, CH2), 5.48 (t, 1H, CH), 7.6–8.1 (dd, 4H, Ar–H) 11.1 (s, 3H,
OH), 12.3 (s, 1H, NH); FAB MS (M??H) 274; mp (°C) 137–138; Yield (%)68;
Found (calcd) % C, 61.42 (61.53); H, 5.42 (5.53); N, 15.27(15.38).
4-Acetyl-2-(30-methyl)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4f)
IR (m, cm-1); 3434 (NH, five membered), 3108 (C–H, sp2), 2892 (C–H, sp3), 1717
(C=O), 1661 (C=C), 1598, 1555, 1510 (C C, ring str.), 1435 (C–N), 910, 806, 753
1
(sub phenyl). HNMR (d ppm); 2.31 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.52 (s, 3H,
COCH3), 5.12 (d, 2H, CH2), 5.41 (s, 1H, CH), 7.2 (s, 4H, Ar–H), 12.6 (s, 1H, NH);
FAB MS (M??H) 244; mp (°C) 130–131; Yield (%)70; Found (calcd) % C, 69.01
(69.11); H, 6.89 (7.04); N, 17.21 (17.27).

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4-Acetyl-2-(30-nitro)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4g)
IR (m, cm-1); 3309 (–NH), 3005 (C–H, sp2), 2930 (C–H, sp2), 1710 (C=O), 1623
(C=C), 1475, 1455 (C C, ring str.), 1581, 1376 (–NO2), 1240 (C–N), 949, 893,
1
821 (sub. phenyl). HNMR (d ppm); 2.30 (s, 3H, CH3), 2.50 (s, 3H, COCH3), 5.08
(d, 2H, CH2), 5.46 (s, CH), 7.5–8.2 (m, 4H, Ar–H), 12.3 (s, 1H, NH); FAB MS
(M??H) 275; mp (°C) 143–144; Yield (%) 79; Found (calcd) % C, 56.82 (56.93);
H, 5.01 (5.14); N, 20.35 (20.43).
4-Acetyl-2-(40-nitro)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4h)
IR (m, cm-1); 3308 (–NH), 3006 (C–H, sp2), 2929 (C–H, sp2), 1708 (C=O), 1624
(C=C), 1474, 1455 (C C, ring str.), 15821, 1378 (–NO2), 1240 (C–N), 951, 894,
821 (sub. phenyl).1HNMR (d ppm); 2.31(s, 3H, CH3), 2.55 (s, 3H, COCH3), 5.09 (d,
2H, CH2), 5.48 (s, CH), 7.4–8.3 (dd, 4H, Ar–H), 12.5 (s, 1H, NH); FAB MS
(M??H) 275; mp (°C) 140–141; Yield (%)76; Found (calcd) % C, 56.86 (56.93); H,
5.05 (5.14); N, 20.32 (20.43).
4-Acetyl-2-(40-methyl)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4i)
IR (m, cm-1); 3432 (NH, five membered), 3111(C–H, sp2), 2896 (C–H, sp3), 1720
(C=O), 1675 (C=C), 1600, 1557, 1512 (C C, ring str.), 1431 (C–N), 911, 808, 751
1
(sub phenyl). HNMR (d ppm); 2.32 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.51 (s, 3H,
COCH3), 5.12 (d, 2H, CH2), 5.42 (s, 1H, CH), 7.6 (s, 4H, Ar–H), 12.6 (s, 1H, NH);
FAB MS (M??H) 244; mp (°C) 132–133; Yield (%)69; Found (calcd) % C, 69.02
(69.11); H, 6.96 (7.04); N, 17.18 (17.27).
4-Acetyl-2-(40-chloro)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4j)
IR (m, cm-1); 3450 (NH, five membered), 3083 (C–H, sp2), 2871 (C–H, sp3), 1686
(C=O), 1644 (C=C), 1643(C=C), 1587, 1553, 1404 (C C, ring str.), 1443 (C–N),
810, 809 (sub phenyl), 584 (C–Cl). 1HNMR (d ppm); 2.34 (s, 3H, CH3), 2.56 (s, 3H,
COCH3), 5.12 (d, 2H, CH2), 5.42 (s, CH), 7.2–7.3 (dd, 4H, Ar–H), 12.1 (s, 1H, NH);
FAB MS (M??H) 265; mp (°C) 143–144; Yield (%) 82; Found (calcd) % C, 59.15
(59.21); H, 5.26 (5.35); N, 15.93 (15.86).
4-Acetyl-2-(30-methoxy)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4k)
IR (m, cm-1); 3433 (NH, five membered), 3053 (C–H, sp2), 2833 (C–H, sp3), 1710
(C=O), 1655 (C=C), 1590, 1554, 1510 (C C, ring str.), 1429 (C–N), 910, 820, 755
(sub phenyl). 1HNMR (d ppm); 2.39 (s, 3H, CH3), 2.57 (s, 3H, COCH3), 3.73 (s, 3H,
OCH3), 5.13 (d, 2H, CH2), 5.44 (s, 1H, CH), 6.8–7.3 (m, 4H, Ar–H), 12.6 (s, 1H,
NH); FAB MS (M??H) 260; mp (°C) 142–143; Yield (%) 76; Found (calcd) C,
64.72 (64.85); H, 6.50 (6.61); N, 16.12 (16.20).

Med Chem Res (2010) 19:589–602
601
4-Acetyl-2-(40-methoxy)phenyl-5-methyl-1-vinyl-2,3-dihydro-1H-1,2,3-triazole (4l)
IR (m, cm-1); 3434 (NH, five membered), 3056 (C–H, sp2), 2835 (C–H, sp3), 1712
(C=O), 1656 (C=C), 1589, 1553, 1512 (C C, ring str.), 1433 (C–N), 911, 818, 753
(sub phenyl). 1HNMR (d ppm); 2.37 (s, 3H, CH3), 2.55 (s, 3H, COCH3), 3.78 (s, 3H,
OCH3), 5.15 (d, 2H, CH2), 5.46 (s, 1H, CH), 6.7–7.2 (dd, 4H, Ar–H), 12.2 (s, 1H,
NH); FAB MS (M??H) 260; mp (°C) 140–141; Yield (%)75; Found (calcd) C,
64.70 (64.85); H, 6.52 (6.61); N, 16.13 (16.20).
Acknowledgements The authors thank Central Drug Research Institute, Lucknow, India, for providing
spectroanalytical facilities and to the Council of Scientific and Industrial Research (CSIR), New Delhi,
for providing research fellowship to one of the authors (VS).
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