Synthesis and biological activity of new 2,6-diphenyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridines

Article abstract of DOI:10.1134/S1070363216120483

An efficient one-pot synthesis of new 2,6-diphenyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridines is presented. This involves the three-component reaction of aldehydes with ketones and ammonium acetate in the presence of catalytic amount of iodine/AcOH. The

Full text of DOI:10.1134/S1070363216120483

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 12, pp. 2845–2848. © Pleiades Publishing, Ltd., 2016.
Synthesis and Biological Activity
of New 2,6-Diphenyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridines1
N. J. P. Subhashini*, Ch. B. Reddy, P. A. Kumar, and B. Lingaiah
Department of Chemistry, University College of Technology, Osmania University, Hyderabad, 500007 India
*e-mail: njsubhashini@yahoo.co.in
Received July 1, 2016
Abstract—An efficient one-pot synthesis of new 2,6-diphenyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridines is
presented. This involves the three-component reaction of aldehydes with ketones and ammonium acetate in the
presence of catalytic amount of iodine/AcOH. The newly synthesized compounds were characterized by IR, 1H,
13C NMR spectra, and MS data. The products were screened for antibacterial and antifungal activity. Some of
the tested compounds exhibited high activity.
Keywords: triazole, aldehydes, 2,6-diphenyl-triazolyl-pyridine, ammonium acetate, iodine, and antimicrobial activity
DOI: 10.1134/S1070363216120483
INTRODUCTION
carbaldehyde (4a‒4c) [14–16] with substituted ace-
tophenones (5a‒5c) and iodine/acetic acid by mi-
crowave irradiation with high yields. The newly
synthesized compounds were characterized by IR,
NMR and Mass spectral data.
Pyridine ring system, particularly 2,4,6-triarylpyri-
dine [1, 2] are important synthons in supra molecular
chemistry due to their P-stacking ability and specific H-
bonding capacity [3]. High thermal stability of the com-
pounds indicates their certain potential as monomeric
building blocks in thin films and organometallic poly-
mers [4]. Most of such pyridines demonstrate pro-
nounced activity as antimalarial, vasodilator, anaesthetic,
anticovulsant, antiepileptic, antitumor agents and some
other biology and medicine related activities [5–7].
Antibacterial activity. All synthesized compounds
were screened in vitro for antibacterial activity against
gram +ve bacterial strains Staphylococcus aureus
(ATCC-9144), Bacillus cereus (ATCC-11778) and
gram –ve bacterial strains Escherichia coli (ATCC-
8739), Proteus vulgaris (ATCC-29213) by the cup-plate
agar diffusion method at 25, 50 and 100 µg/mL concen-
trations. The zone of inhibition (in mm) was compared
with the standard drug Ampicillin (Table 1). All syn-
thesized compounds were active against the tested
strains. The compounds 6e, 6f, 6i demonstrated the
highest potency.
2,4,6-Triaryl substituted pyridines (Krohnke pyri-
dines) [8] have been synthesized traditionally via the
reaction of N-phenacyl pyridinium salts with α,β-
unsaturated ketones in the presence of ammonium ace-
tate [9]. Synthesis of poly substituted pyridines usually is
carried out by multi component reactions that involve
condensation of acetophenones and benzaldehydes with
ammonia under high temperature and microwave irradia-
tion [10]. Some recently developed methods involved
microwave irradiation, ionic liquids, TMSI, I2, NaOH
in PEG-400 [11], PEG-300 along with NaOH [12], and
catalytic amount of acetic acid [13].
Antifungal activity. All synthesized compounds
were screened in vitro for antifungal activity against
Aspergillus Niger (ATCC-9029), Candida albicans
(ATCC-2091), Aspergillus foetidus
(NCIM-0505),
and Candida rogosa (ATCC-9849). The zone of inhi-
bition (in mm) was compared with standard drug Am-
photericin-B (Table 2). The products demonstrated
moderate to high activity against the tested fungal strains.
RESULTS AND DISCUSSION
EXPERIMENTAL
In the present study new 2,6-diphenyl-4-(1-phenyl-
1H-1,2,3-triazol-4-yl)pyridines (6a‒6i) were synthe-
sized by the reaction of 1-Aryl-1H-[1,2,3]triazole-4-
Melting points were determined in open capillary
tubes on a Gallen-Kamp MFB-595 apparatus. Ele-
mental analysis was performed on a Perkin Elmer
CHN-2400 analyzer. IR spectrum were recorded on a
1 The text was submitted by the authors in English.
2845

2846
SUBHASHINI et al.
Scheme 1. Synthesis of 1-aryl-1H-[1,2,3]triazole-4-carbaldehydes (4a-4c).
R1
R1
NH2
N3
1
3
2
N
N
O
N
OH
N
R1
R1
N
N
H
1a−1c
2a−2c
3a−3c
4a−4c
R1 = H, 2-OMe, 2-Cl. (1) NaNO2, HCl 10%, 2–4 h, room temperature; (2) propargyl alcohol, CuSO4·5H2O, sodium
ascorbate, H2O : DMF (1 : 2), 3 h, room temperature; (3) IBX/DMSO, 3 h, room temperature.
Scheme 2. Synthesis of 2,6-diphenyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine (6a-6i).
R1
N N
R1
N
NH4OAc
R2
I2/AcOH, MWI
+
N
5−8 min
O
N
O
N
N
R2
H
R2
4a−4c
5a−5c
6a−6i
R1 = H, R2 = H (6a); R1 = H, R2 = 4-Me (6b); R1 = H, R2 = 4-Cl (6c); R1 = 2-Cl, R2 = H (6d); R1 = 2-Cl, R2 = 4-Me (6e);
R1 = 2-Cl, R2 = 4-Cl (6f); R1 = 2-OMe, R2 = H (6g); R1 = 2-OMe, R2 = 4-Me (6h); R1 = 2-OMe, R2 = 4-Cl (6i).
1
Perkin-Elmer FT-IR 8400s for KBr disks. H and 13C
NMR spectra were recorded on a Bruker Avance II
400 spectrometer in CDCl3 using TMS as the internal
standard. Mass spectra were recorded on a SHIMA-
DZU LCMS 2020 mass spectrometers. Progress of
reactions was monitored by TLC (Silica gel, alumin-
ium sheets 60 F254, Merck).
Synthesis of substituted 1-aryl-1H-[1,2,3]triazole-4-
carbaldehydes 4a‒4c. Mixture of a substituted 1-aryl-
1H-[1,2,3]triazole-4-carbaldehyde (1 mmol), substi-
tuted acetophenone 5a‒5c (2 mmol), ammonium
acetate (1.3 mmol) and I2 (0.1 mmol) in acetic acid
was treated by microwave irradiation. Progress of
the reaction was monitored by TLC extracted with
Table 1. Antibacterial activity of compounds 6a–6i
Zone of inhibition, mm
S. aureus
B. cereus
E. coli
P. vulgaris
Product
(ATCC-9144)
(ATCC-11778)
(ATCC-8739)
(ATCC- 29213)
25
7
6
05
06
09
10
5
50
8
7
8
7
11
12
7
7
11
100
9
9
10
10
13
13
8
25
10
8
7
8
10
12
6
7
11
50
11
9
100
13
12
10
12
16
18
11
11
15
25
9
9
8
9
15
15
8
10
13
50
11
11
9
11
16
17
10
11
15
100
13
13
12
12
18
19
11
12
16
25
7
8
6
7
9
12
7
7
10
50
9
10
8
100
6a
6b
6с
6d
6e
6f
6g
6h
6i
11
12
10
11
15
18
10
11
14
9
10
13
15
9
9
13
9
12
14
8
8
11
6
8
9
12
Ampicillin
8
10
11
10
13
16
13
15
17
10
12
15
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SYNTHESIS AND BIOLOGICAL ACTIVITY
Table 2. Antifungal activity of compounds 6a-6i
2847
Zone of inhibition, mm
A.niger
A.foetidus
C.albicans
C.rogosa
Product
(ATCC-9021)
(NCIM-0505)
(ATCC-2091)
(ATCC- 9849)
25
6
7
5
7
11
12
5
50
8
8
8
9
12
13
7
100
25
6
5
7
7
10
9
6
50
7
7
9
8
11
12
6
100
9
8
10
9
12
14
8
25
5
7
6
7
9
10
7
50
7
8
7
8
11
12
8
100
9
9
8
9
12
14
9
25
5
6
6
5
9
10
6
50
6
7
7
6
10
11
7
100
7
8
7
7
12
13
8
6a
6b
6с
6d
6e
6f
9
10
9
10
14
15
7
6g
6h
6i
6
9
7
11
9
12
4
8
6
10
8
12
8
9
8
10
9
11
6
7
8
8
9
11
Amphotericin B
10
12
13
9
11
13
10
11
12
8
9
11
ethyl acetate. The solvent was evaporated under
reduced pressure. The crude product was purified by
silica-gel column chromatography using ethyl acetate–
hexane (1 : 4) as an eluent to afford pure products.
4-[1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl]-2,6-
diphenylpyridine (6d). Yield 92%, mp 200–202°C.
1
IR spectrum, ν, cm–1: 1569, 1516. H NMR spectrum,
δ, ppm: 7.98 s (1H, triazole H), 7.79–7.83 m (3H, Ar-
H), 7.65–7.69 m (3H, Ar-H), 7.32–7.38 m (10H, Ar-
H). 13C NMR spectrum, δ, ppm: 149.5, 147.9, 134.9,
131.4, 130.6, 130.3, 129.1, 128.6, 127.7, 127.0, 124.9,
123.4, 123.2, 117.4, 115.3, 111.7. M 409 [M + H]+.
Found, %: C 73.40; H 4.11; N 13.66. C25H17ClN4. Cal-
culated, %: C 73.44; H 4.19; N 13.70.
2,6-Diphenyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)-
pyridine (6a). Yield 86%, mp 178–180°C. IR spec-
trum, ν, cm–1: 1572, 1512. 1H NMR spectrum, δ, ppm:
7.92 s (1H, triazole H), 7.62–7.74 m (7H, Ar-H), 7.58–
7.64 m (10H, Ar-H). 13C NMR spectrum, δ, ppm:
150.1, 147.0, 131.2, 130.8, 130.5, 129.0, 128.6, 128.5,
127.2, 125.0, 123.1, 121.4, 120.0, 117.2, 115.9, 115.6,
110.7. M 375 [M + H]+. Found, %: C 80.05; H 4.79; N
14.89. C25H18N4. Calculated, %: C 80.19; H 4.85; N
14.96.
4-[1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl]-2,6-
di-p-tolylpyridine (6e). Yield 88%, mp 168–170°C.
1
spectra, ν, cm–1: 1581, 1516. H NMR spectrum, δ,
ppm: 7.95–7.98 m (3H, triazole H, Ar-H), 7.61–7.65 m
(3H, Ar-H), 7.42–7.46 m (6H, Ar-H), 7.09–7.12 m
(3H, Ar-H), 2.41 s (6H, Ar-CH3). 13C NMR spectrum,
δ, ppm: 149.6, 147.8, 134.9, 130.6, 130.3, 129.2,
128.6, 127.7, 127.0 124.9, 123.6, 123.2, 117.3, 115.2,
112.8, 20.4. M 437 [M + H]+. Found, %: C 74.14; H
4.78; N 12.75. C27H21ClN4. Calculated, %: C 74.22; H
4.84; N 12.82.
4-(1-Phenyl-1H-1,2,3-triazol-4-yl)-2,6-di-p-tolyl-
pyridine (6b). Yield 85%, mp 190–192°C. IR spec-
trum, ν, cm–1: 1576, 1520. 1H NMR spectrum, δ, ppm:
8.01 s (1H, triazole H), 7.65–7.70 m (6H, Ar-H), 7.38–
7.45 m (6H, Ar-H), 7.28–7.31 m (3H, Ar-H), 2.21 s
(6H, Ar-CH3). 13C NMR spectrum, δ, ppm: 151.4,
147.8, 137.6, 131.3, 130.7, 129.3, 128.6, 127.1, 125.7,
125.0, 122.9, 122.7, 119.5, 117.2, 114.9, 114.8, 112.6,
20.3. M 403 [M + H]+. Found, %: C, 80.48; H, 5.47; N,
13.87. C27H22N4. Calculated, %: C, 80.57; H, 5.51; N,
13.92.
2,6-Bis(4-chlorophenyl)-4-[1-(2-chlorophenyl)-
1H-1,2,3-triazol-4-yl]pyridine (6f). Yield 90%, mp
1
160–162°C. IR spectrum, ν, cm–1: 1575, 1518. H
NMR spectrum, δ, ppm: 8.01 s (1H, triazole H), 7.97–
8.00 m (1H, Ar-H), 7.81–7.85 m (3H, Ar-H), 7.59–7.62
m (3H, Ar-H), 7.25–7.43 m (7H, Ar-H). 13C NMR
spectrum, δ, ppm: 150.9, 147.9, 134.0, 131.4, 131.2,
129.7, 129.2, 128.6, 127.0, 124.9, 123.0, 121.4, 119.2,
117.3, 115.0, 112.8. M 477 [M + H]+. Found, %: C
62.80; H 3.09; N 11.62. C25H15Cl3N4. Calculated, %: C
62.85; H 3.16; N 11.73.
2,6-Bis(4-chlorophenyl)-4-(1-phenyl-1H-1,2,3-
triazol-4-yl)pyridine (6c). Yield 90%, mp 196–198°C.
1
IR spectrum, ν, cm–1: 1579, 1523. H NMR spectrum,
δ, ppm: 7.9 m (3H, triazole H, Ar-H), 7.5 m (8H,
Ar-H), 7.1 m (1H, Ar-H), 6.9 m (4H, Ar-H). 13C NMR
spectrum, δ, ppm: 150.6, 147.6, 137.6, 131.1, 130.8,
129.3, 128.7, 127.1, 125.5, 125.0, 122.9, 122.2, 119.5,
117.5, 114.9, 114.6, 112.9. M 443 [M + H]+. Found, %:
C 67.65; H 3.62; N 12.58. C25H16Cl2N4. Calculated, %:
C 67.73; H 3.64; N 12.64.
4-[1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl]-
2,6-diphenylpyridine (6g). Yield 90%, mp 195–197°C.
1
IR spectrum, ν, cm–1: 1577, 1515. H NMR spectrum,
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SUBHASHINI et al.
δ, ppm: 8.18 s (1H, triazole H), 7.94–7.98 m (2H,
Ar-H), 7.42–7.55 m (8H, Ar-H), 7.20–7.26 m (6H, Ar-
H), 3.81 s (3H, O-CH3). 13C NMR spectrum, δ, ppm:
150.9, 149.1, 147.0, 130.8, 130.5, 130.3, 129.0, 128.4,
127.1, 125.5, 123.8, 123.3, 120.8, 117.2, 115.8, 112.9,
110.8, 56.0. M 405 [M + H]+. Found, %: C 77.12; H
4.82; N 13.78. C26H20N4O. Calculated, %: C 77.21; H
4.98; N 13.85.
authors BR is grateful to UGC, New Delhi for award
of SRF. Another author (NJPS) is also thankful to UGC
(MRP-F no. 39-772/2010(SR) and OU-DST-PURSE
Programme (no. A-37/PURSE/coord/2012 for financial
support.
REFERENCES
1. Balasubramanian, M. and Keay, J.G., in Comprehensive
Heterocyclic Chemistry II, Katritzky, A.R., Rees, C.W.,
and Scriven, E.V.F., Eds., London: Pergamon Press,
1996, vol. 5, p. 245.
2. Klimesova, V., Svoboda, M., Waisser, K., Pour, M., and
Kaustova, J., IL Farmaco, 1999, vol. 54, p. 666. doi
10.1016/S0014-827X(99)00078-6
3. Newkome, G.R., Patri, A.K., Holder, E., and
Schubert, U.S., Eur. J. Org. Chem., 2004, p. 235. doi
10.1002/ejoc.200300399
4. Kelch, S. and Rehahn, M., Macromolecules, 1999,
vol. 32, p. 5818. doi 10.1021/ma990266u
4-[1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl]-
2,6-di-p-tolylpyridine (6h). Yield 86%, mp 188–190°C.
1
IR spectrum, ν, cm–1: 1580, 1518. H NMR spectrum,
δ, ppm: 8.52 s (1H, triazole H), 8.10–8.15 m (6H,
Ar-H), 7.91–7.92 m (1H, Ar-H), 7.42–7.44 m (1H,
Ar-H), 7.34–7.36 m (4H, Ar-H), 7.12–7.15 m (2H,
Ar-H), 3.98 s (3H, O-CH3), 2.23 s (3H, Ar-CH3). 13C
NMR spectrum, δ, 157.5, 151.5, 145.5, 139.4, 139.0,
136.7, 130.4, 129.3, 127.0, 126.1, 125.5, 123.2, 121.3,
114.6, 112.3, 56.1, 21.3; M 433 [M + H]+. Found, %: C
77.62; H 5.45; N 12.90. C28H24N4O. Calculated, %: C
77.75; H 5.59; N 12.95.
5. Lowe, G., Droz, A.S., Vilaivan, T., Weaver, G.W.,
Tweedale, L., Pratt, J.M., Rock, P., Yardley, V., and
Croft, S.L., J. Med. Chem., 1999, vol. 42, p. 999. doi
10.1021/jm981074c
2,6-Bis(4-chlorophenyl)-4-(1-(2-methoxyphenyl)-
1H-1,2,3-triazol-4-yl)pyridine (6i). Yield 92%,
6. Han, H. and Hurley, L.H., Trends Pharmacol. Sci.,
2000, vol. 21, p. 136. doi 10.1016/S0165-6147(00)01457-7
7. Li, J.L., Harrison, R.J., Reszka, A.P., Brosh, R.M.,
Bohr, V.A., Neidle, S., and Hickson, I.D., Biochemistry.,
2001, vol. 40, p. 15194. doi 10.1021/bi011067h
8. Jones, G., in Comprehensive Heterocyclic Chemistry II,
Katritzky, A.R., Rees, C.W., and Scriven, E.V.F.,
Eds., London: Pergamon Press, 1996, vol. 5, p. 168.
9. Krohnke, F. and Zecher, W., Angew. Chem. Int. Ed.,
1962, vol. 1, p. 626. doi 10.1002/anie.196206261
10. Brauch, S., Berkel, S.S., and van Westermann, B.,
Chem. Soc. Rev., 2013, vol. 42, p. 4948. doi 10.1039/
C3CS35505E
11. Smith, C.B., Raston, C.L., and Sobolev, A.N., Green
Chem., 2005, vol. 7, p. 650. doi 10.1039/B507581
12. Winter, A., van den Berg, A.M.J., Hoogenboom, R.,
Kickelbick, G., and Schubert, U.S., Synthesis, 2006,
p. 2873. doi 10.1055/s-2006-942525
13. Adib, M., Tahermansouri, H., Koloogani, S.A., Moham-
madi, B., and Bijanzadeh, H.R., Tetrahedron Lett.,
2006, vol. 47, p. 5957. doi 10.1016/j.tetlet.2006.01.162
14. Richardson, S.K., Jeganathan, A., Mani, R.S.,
Haley.B.E., Watt, D.S., Trusal, L.R., Tetrahedron,
1987, vol. 43, p. 2925. doi 10.1016/S0040-4020(01)
86831-9
1
mp 164–167°C. IR spectrum, ν, cm–1: 1578, 1522. H
NMR spectrum, δ, ppm: 8.39 s (1H, triazole H), 7.96–
8.02 m (4H, Ar-H), 7.95–7.98 m (3H, Ar-H), 7.62–
7.66 d (3H, J =15.1 Hz, Ar-H), 7.41–7.45 m (1H,
Ar-H), 7.18–7.20 m (3H, Ar-H), 3.95 s (3H, O-CH3).
13C NMR spectrum, δ, ppm: 150.9, 147.0, 130.8,
130.6, 130.3, 129.0, 128.5, 127.1, 125.4, 124.9, 123.7,
123.0, 120.8, 117.2, 116.2, 112.9, 112.8, 110.8, 56.3.
M 473 [M + H]+. Found, %: C 65.91; H 3.76; N 11.78.
C26H18Cl2N4O. Calculated, %: C 65.97; H 3.83; N 11.84.
CONCLUSIONS
In the present study a number of new 2,6-diphenyl-
4-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridines (6a-6i) has
been synthesized via the three-component one-pot re-
action of substituted 1-phenyl-1H-[1,2,3]triazole-4-car-
baldehydes with substituted acetophenones and am-
monium acetate. All synthesized compounds have
been characterised by spectral data and elemental analy-
sis. All compounds demonstrated high antimicrobial
activity against bacteria and fungi.
ACKNOWLEDGMENTS
15. Rostovtsev, V.V., Green, L.G., Fokin, V.V., and
Sharpless, K.B., Angew. Chem. Int. Ed., 2002, vol. 41,
p. 2596. doi 10.1002/15213773(20020715)41::14<2596::
AIDANIE2596>3.0.CO;2-4
16. Karabulut, H.R.F. and Kac-an, M., Turk. J. Chem., 2003,
vol. 27, p. 713.
Authors are grateful to the Head, Department of
Chemistry, Osmania University for providing labora-
tory facilities, and Director, Central Facilities for Re-
search and Development (CFRD), Osmania Univer-
sity, Hyderabad for providing spectral data. One of the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016