Click synthesis of some mono/bis 1,2,3-triazoles with ester linkage and their microbicidal activity

Article abstract of DOI:10.14233/ajchem.2017.20671

Synthesis of some new 1,4-disubstituted 1,2,3-triazoles with ester functionality is reported employing Cu(I) catalyzed Huisgen [3+2] cycloaddition reaction of prop-2-yn-1-yl benzoates with 1,4-phenylenebis(methylene) bis(2-azidoacetate) and benzyl 2-azidoacetates. The synthesized compounds were well characterized through FTIR, ¹H NMR, ¹³C NMR and HRMS. Further, the synthesized triazole derivatives were accessed for in vitro antimicrobial activity against one Gram-positive bacterial strain Staphylococcus aureus, three Gram-negative bacterial strains Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes and two fungi Candida albicans and Aspergillus niger. Few of the synthesized disubstituted 1,2,3-triazoles displayed moderate to good inhibitory activity against tested microbial strains.

Full text of DOI:10.14233/ajchem.2017.20671

Asian Journal of Chemistry; Vol. 29, No. 10 (2017), 2171-2176
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20671
Click Synthesis of Some mono/bis 1,2,3-Triazoles with Ester Linkage and their MicrobicidalActivity
*
C.P. KAUSHIK and ASHIMA PAHWA
Department of Chemistry, Guru Jambheshwar University of Science & Technology, Hisar-125 001, India
*Corresponding author: Fax: +91 1662 276240; Tel: +91 1662 263152; E-mail: kaushikcp@gmail.com
Received: 25 March 2017;
Accepted: 31 May 2017;
Published online: 31 August 2017;
AJC-18514
Synthesis of some new 1,4-disubstituted 1,2,3-triazoles with ester functionality is reported employing Cu(I) catalyzed Huisgen [3+2]
cycloaddition reaction of prop-2-yn-1-yl benzoates with 1,4-phenylenebis(methylene) bis(2-azidoacetate) and benzyl 2-azidoacetates.
1
The synthesized compounds were well characterized through FTIR, H NMR, 13C NMR and HRMS. Further, the synthesized triazole
derivatives were accessed for in vitro antimicrobial activity against one Gram-positive bacterial strain Staphylococcus aureus, three
Gram-negative bacterial strains Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes and two fungi Candida albicans and
Aspergillus niger. Few of the synthesized disubstituted 1,2,3-triazoles displayed moderate to good inhibitory activity against tested
microbial strains.
Keywords: Click synthesis, Huisgen [3+2] dipolar cycloaddition, Disubstituted 1,2,3-triazoles, Antibacterial activity, Antifungal activity.
reaction owing to its regioselectivity, efficiency, wide scope,
INTRODUCTION
versatility and functional group compatibility.
Now days, effective treatment for microbial infections has
Therefore, in continuation of our quest of synthesis of
become major concern to medicinal researchers due to increase
in number of drug resistant pathogens. The emerging microbial
resistance stimulated interest of organic researchers into triazole
derivatives to explore as significant antimicrobial agent [1,2].
biologically potent 1,2,3-triazoles [26], we planned to synthe-
size ester linked mono and bis 1,4-disubstituted 1,2,3-triazoles
from prop-2-yn-1-yl benzoates and benzyl 2-azidooacetates/
1,4-phenylenebis(methylene) bis(2-azidoacetate) via Cu(I)
1,2,3-Triazoles, an active class of heterocycles has been reported
catalyzed click reaction. All the synthesized triazole derivatives
were characterized by FTIR, 1H NMR, 13C NMR, HRMS and
to exhibit broad spectrum of biological applications as antiviral
[3], antitubercular [4,5], antimalarial [6], antimicrobial [7-10],
screened against four bacterial strains i.e. Staphylococcus
aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter
aerogenes and two fungal strains i.e. Candida albicans and
antibiotic [11], antioxidant [12], antibiofilm [13], anticancer
[14], anti-HIV [15,16], anticonvulsant [17], antithrombotic
[18], antitumour [19] etc. Despite of this undeniable impor-
Aspergillus niger.
tance in medicinal field, triazoles also displayed paramount
applications in the fields like polymer chemistry [20], material
EXPERIMENTAL
sciences [21] and drug discovery [22]. Strong dipole moment,
stability to acidic/basic hydrolysis assists triazole moieties for
active participation in hydrogen bonding and dipole-dipole
interactions with biological targets.
All the reagents used in present work were procured
in commercially available grade and used without further
purification.Melting points of target compounds were deter-
mined by open capillary tubes on Electrothermal Melting Point
apparatus, LABCO, India and are uncorrected. IR absorption
spectral data were measured on SHIMAZDUIR AFFINITY-I
FT-IR using potassium bromide powder and wave numbers
(ν) were expressed in cm-1. The progress of reaction was moni-
tored by readymade silicagelplates (SIL G/UV254, ALUGRAM)
and visualization was carried out with ultraviolet lamp. The
1H NMR spectra and 13C NMR spectra were recorded on
BRUKER AVANCE II 400 MHz spectrometer at 400 MHz
Earlier, Huisgen 1,3-dipolar cycloaddition [23] between
terminal alkynes and organic azides at thermal conditions were
extensively used for the synthesis of disubstituted 1,2,3-triazole.
This method leads to generation of both 1,4 and 1,5 regioisomers
at elevated temperature. Thereafter, in 2002, Sharpless et al.
[24] and Meldal et al. [25] discovered a new synthetic tool for
the exclusive construction of 1,4-regioisomer by catalyzing
the reaction with Cu(I) salts. This Cu(I) assisted azide-alkyne
cycloaddition reaction has become one of the powerful click

2172 Kaushik et al.
Asian J. Chem.
and 100 MHz respectively in CDCl3/DMSO-d6. Values of
coupling constant (J) were given in Hz. High resolution mass
spectra (HRMS) were acquired on Waters Micromass Q-T of
Micro (ESI) spectrometer.
ester) ppm; HRMS (m/z) calculated for C19H16N3O4F [M+H]+:
370.1158. Found: 370.1128.
1-(2-((4-Methoxybenzyl)oxy)-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methyl 4-fluorobenzoate (3b): White solid;
Yield: 88 %; m.p.: 88-92 °C; FT-IR (KBr, νmax, cm-1): 3148
(C-H str., triazole ring), 3076 (C-H str., aromatic ring), 2986
(C-H str., aliphatic), 1752, 1720 (C=O str., ester), 1604, 1510
(C=C str., aromatic ring), 1282 (C-O asym. str., ester), 1057
(C-O sym. str., ester); 1H NMR (400 MHz, DMSO-d6): 3.80
(s, 3H, OCH3), 5.23 (s, 2H, NCH2), 5.33 (s, 2H, OCH2), 5.57
(s, 2H, OCH2), 6.88 (d, 2H, Ar-H, J = 8.0 Hz), 7.28 (d, 2H, Ar-
H, J = 8.0 Hz), 7.32-7.36 (m, 2H, Ar-H), 8.00-8.04 (m, 2H,
Ar-H), 8.31 (s, 1H, C-H triazole) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 50.7, 55.3, 58.3, 67.9, 114.1, 116.45 (d, 2C,
Ar-C, J = 20.0 Hz), 125.4 (C5 triazole), 125.85 (d, 1C, Ar-C,
J = 3.0 Hz), 126.5, 130.5, 132.25 (d, 2C, Ar-C, J = 10.0 Hz),
143.1 (C4 triazole), 160.1, 165.2 (C=O ester), 165.75 (d, 1C,
Ar-C, J = 250.0 Hz), 166.1 (C=O ester) ppm; HRMS (m/z)
calculated for C20H18N3O5F [M+H]+: 400.1264. Found:
400.1236.
1-(2-((4-Nitrobenzyl)oxy)-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methyl 4-fluorobenzoate (3c): White solid;Yield:
87 %; m.p.: 90-94 °C; FT-IR (KBr, νmax, cm-1): 3137 (C-H
str., triazole ring), 3081 (C-H str., aromatic ring), 2958 (C-H
str., aliphatic), 1748, 1720 (C=O str., ester), 1604, 1459 (C=C
str., aromatic ring),1529 (N-O asym. str., NO2), 1349 (N-O
sym. str., NO2), 1275 (C-O asym. str., ester), 1057 (C-O sym.
str., ester); 1H NMR (400 MHz,DMSO-d6): 5.36(s, 2H, NCH2),
5.43 (s, 2H, OCH2), 5.57 (s, 2H, OCH2), 7.33-7.37 (m, 2H,
Ar-H), 8.00-8.04 (m, 2H, Ar-H), 7.65 (d, 2H, Ar-H, J = 8.4
Hz), 8.23 (d, 2H, Ar-H, J = 8.4 Hz), 8.31 (s, 1H, C-H triazole)
ppm; 13C NMR (100 MHz, DMSO-d6): δ = 50.9, 58.5, 66.0,
116.40 (d, 2C, Ar-C, J = 20.0 Hz), 124.0, 126.45 (d, 1C, Ar-
C, J = 3.0 Hz), 126.9 (C5 triazole), 129.0, 132.25 (d, 2C, Ar-
C, J = 10.0 Hz), 142.4, 143.5 (C4 triazole), 147.7, 165.0 (C=O
ester), 165.75 (d, 1C, Ar-C, J = 250.0 Hz), 167.5 (C=O ester)
ppm HRMS (m/z) calculated for C19H15N4O6F [M+H]+:
415.1009. Found: 415.0965.
General procedure for synthesis of prop-2-yn-1-yl
benzoates (4a-4e): Synthesis of prop-2-yn-1-yl benzoates (4a-
4e) was carried out drop-wise addition of benzoyl chlorides
(1.0 mmol) in the stirred solution of prapargyl alcohol (1.0
mmol) in dichloromethane using N,N-dimethylaminopyridine
(1.2 mmol) as base and resultant mixture was continuously
stirred at 0-10 °C for 2-4 h [27]. On completion of reaction,
dilute solution of hydrochloric acid was added in reaction
mixture and organic product was isolated by extraction with
dichloromethane (3 × 30 mL). Thereafter, solvent was distilled
under vacuum to yield desired terminal alkynes (4a-4e).
General procedure for synthesis of benzyl 2-bromo-
acetates/1,4-phenylene bis(methylene) bis(2-bromoacetate)
(2a-2e)/(5): For synthesis of benzyl 2-bromooacetates/1,4-
phenylene bis(methylene) bis(2-bromoacetate) (2a-2e)/(5),1,4-
phenylenedimethanol/benzyl alcohols (1.0 mmol) were taken
in acetonitrile in round bottom flask. To this, sodium bicarbo-
nate (1.5 mmol/3.0 mmol) was added as base followed by slow
addition of bromoacetylbromide (1.2 mmol/2.4 mmol). The
mixture was stirred with aid of magnetic stirrer at 0-4 °C for
45 min. Upon completion of reaction, product extracted with
dichloromethane (3 × 30 mL) and evaporation of solvent in
vacuum furnished product in good yield.
General procedure for synthesis of 1,4-disubstituted
1,2,3-triazoles (3a-3e)/(6a-6e): For synthesis of target comp-
ounds, to stirred solution of benzyl 2-bromo acetates/1,4-phenylene
bis(methylene) bis(2-bromoacetate) (1.0 mmol) (2a-2e)/(5) in
dimethylsulfoxide, aqueous sodium azide (3.0 mmol/6.0 mmol)
was added at 25-40 °C and continue stirring for 1 h. Thereafter,
prop-2-yn-1-yl benzoates (1.0 mmol/2.0 mmol) (4a-4e), aqueous
copper sulphate pentahydrate (0.1 mmol/0.2 mmol) and sodium
ascorbate (0.4 mmol/0.8 mmol) were added to above resultant
mixture and stirring was continued for 5-10 h at same tempe-
rature. When reaction was completed, ice cold water was added
and precipitated solid residue was filtered and washed with
ammonia solution. Crude product thus obtained purified by
washing with ethyl acetate and dried under vaccum to afford
target product (3a-3e)/(6a-6e) in good yield.
1-(2-((4-Chlorobenzyl)oxy)-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methyl 4-fluorobenzoate (3d): White solid;
Yield: 92 %; m.p.: 89-93 °C; FT-IR (KBr, νmax, cm-1): 3143
(C-H str., triazole ring), 3081 (C-H str., aromatic ring), 2935
(C-H str., aliphatic), 1719, 1706 (C=O str., ester), 1603, 1462
(C=C str., aromatic ring), 1283 (C-O asym. str., ester), 1057
Characterization of synthesized compounds
1
1-[2-(Benzyloxy)-2-oxoethyl]-1H-1,2,3-triazol-4-
yl)methyl-4-fluorobenzoate (3a): White solid; Yield: 85 %;
m.p.: 86-90 °C; FT-IR (KBr, νmax, cm-1): 3152 (C-H str., triazole
ring), 3076 (C-H str., aromatic ring), 2958 (C-H str., aliphatic),
1752, 1720 (C=O str., ester), 1603, 1508 (C=C str., aromatic
ring), 1274 (C-O asym. str., ester), 1054 (C-O sym. str., ester);
1H NMR (400 MHz, CDCl3): 5.23(s, 2H, NCH2), 5.25 (s, 2H,
OCH2), 5.46 (s, 2H, OCH2), 7.06-7.11 (m, 2H, Ar-H), 7.31-
7.34 (m, 5H, Ar-H), 7.89 (s, 1H, C-H triazole), 8.02-8.05 (m,
2H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3): δ = 50.7, 58.0,
67.9, 115.45 (d, 2C, Ar-C, J = 20.0 Hz), 125.5 (C5 triazole),
125.95 (d, 1C, Ar-C, J = 3.0 Hz), 128.4, 128.6, 128.7, 132.25
(d, 2C, Ar-C, J = 10.0 Hz), 134.4, 143.0 (C4 triazole), 165.2
(C=O ester), 165.75 (d, 1C, Ar-C, J = 250.0 Hz), 166.0 (C=O
(C-O sym. str., ester); H NMR (400 MHz,DMSO-d6): 5.35
(s, 2H, NCH2), 5.43 (s, 2H, OCH2), 5.57 (s, 2H, OCH2), 7.32-
7.36 (m, 2H, Ar-H), 7.41-7.45 (m, 4H, Ar-H), 8.00-8.03 (m,
2H, Ar-H),8.58 (s, 1H, C-H triazole) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 50.7, 58.3, 67.9, 116.40 (d, 2C, Ar-C, J =
20.0 Hz), 125.4 (C5 triazole), 126.2 (d, 1C, Ar-C, J = 3.0 Hz),
129.0, 129.9, 132.65 (d, 2C, Ar-C, J = 10.0 Hz), 132.9, 134.8,
143.1 (C4 triazole), 165.0 (C=O ester), 165.65 (d, 1C, Ar-C, J
= 250.0 Hz), 166.0 (C=O ester) ppm; HRMS (m/z) calculated
for C19H15N3O4ClF [M+H]+: 404.0813 (35Cl), 406.0784 (37Cl).
Found: 404.0735 (35Cl), 406.0706 (37Cl).
1-(2-((4-Methylbenzyl)oxy)-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methyl 4-fluorobenzoate (3e): White solid;Yield:
85 %; m.p.: 84-88 °C; FT-IR (KBr, νmax, cm-1): 3148 (C-H

Vol. 29, No. 10 (2017)
Click Synthesis of Some mono/bis 1,2,3-Triazoles with Ester Linkage and their Microbicidal Activity 2173
str., triazole ring), 3076 (C-H str., aromatic ring), 2935 (C-H
str., aliphatic), 1742, 1720 (C=O str., ester), 1603, 1440 (C=C
str., aromatic ring), 1291 (C-O asym. str., ester), 1053 (C-O
(C=O ester) ppm; HRMS (m/z) calculated for C32H26N8O12
[M+H]+: 715.1704. Found: 715.1611.
(1,1'-(((1,4-Phenylenebis(methylene))bis(oxy))bis(2-
oxoethane-2,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis-
(methylene) bis(4-fluorobenzoate) (6d): White solid;Yield:
85 %; m.p.: 136-140 °C; FT-IR (KBr, νmax, cm-1): 3137 (C-H
str., triazole ring), 3087 (C-H str., aromatic ring), 2958 (C-H
str., aliphatic), 1740, 1721 (C=O str., ester), 1606, 1509 (C=C
str., aromatic ring), 1275 (C-O asym. str., ester), 1054 (C-O
sym. str., ester); 1H NMR (400 MHz,DMSO-d6): 5.21(s, 4H,
NCH2), 5.43 (s, 4H, OCH2), 5.51 (s, 4H, OCH2), 7.35 (d, 4H,
Ar-H, J = 8.8 Hz), 7.38 (s, 4H, Ar-H), 8.01-8.05 (m, 4H, Ar-
H), 8.29 (s, 2H, C-H triazole) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 50.9, 58.5, 66.6, 116.46 (d, 2C, Ar-C, J =
20.0 Hz), 126.9 (C5 triazole), 126.41 (d, 1C, Ar-C, J = 3.0
Hz), 128.7, 132.65 (d, 2C, Ar-C, J = 10.0 Hz), 135.9, 142.3
(C4 triazole), 165.0 (C=O ester), 165.65 (d, 1C, Ar-C, J = 250.0
Hz), 167.6 (C=O ester) ppm; HRMS (m/z) calculated for
C32H26N6O8F2 [M+H]+: 661.1814. Found: 661.1730.
(1,1'-(((1,4-Phenylenebis(methylene))bis(oxy))bis(2-
oxoethane-2,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis-
(methylene) bis(4-methylbenzoate) (6e): White solid;Yield:
85 %; m.p.: 162-166 °C; FT-IR (KBr, νmax, cm-1): 3154 (C-H
str., triazole ring), 3031 (C-H str., aromatic ring), 2963 (C-H
str., aliphatic), 1750, 1721 (C=O str., ester), 1611, 1446 (C=C
str., aromatic ring), 1270 (C-O asym. str., ester), 1049 (C-O
sym. str., ester); 1H NMR (400 MHz,DMSO-d6): 2.38(s, 6H,
CH3), 5.20 (s, 4H, NCH2), 5.41 (s, 4H, OCH2), 5.51 (s, 4H,
OCH2), 7.34 (d, 4H, Ar-H, J = 8.0 Hz), 7.37 (s, 4H, Ar-H),
7.86 (d, 4H, Ar-H, J = 8.0 Hz), 8.29 (s, 2H, C-H triazole)
ppm; 13C NMR (100 MHz, DMSO-d6): δ = 21.6, 50.8, 57.8,
66.6, 126.9 (C5 triazole), 127.1, 128.6, 129.7, 129.9, 135.8,
142.5 (C4 triazole), 144.3, 165.9 (C=O ester), 167.6 (C=O
ester) ppm; HRMS (m/z) calculated for C34H32N6O8 [M+H]+:
653.2315. Found: 653.2232.
1
sym. str., ester); H NMR (400 MHz, CDCl3): 2.23 (s, 3H,
CH3), 5.10(s, 2H, NCH2), 5.15 (s, 2H, OCH2), 5.38 (s, 2H,
OCH2), 6.96-7.12 (m, 6H, Ar-H), 7.81 (s, 1H, C-H triazole),
7.92-7.95 (m, 2H, Ar-H)ppm; 13C NMR (100 MHz, CDCl3): δ
= 21.1, 50.8, 58.0, 67.9, 115.50 (d, 2C, Ar-C, J = 20.0 Hz),
125.6 (C5 triazole), 125.9 (d, 1C, Ar-C, J = 3.0 Hz), 128.6,
129.3, 131.5, 132.25 (d, 2C, Ar-C, J = 10.0 Hz), 138.6, 142.9
(C4 triazole), 165.2 (C=O ester), 165.75 (d, 1C, Ar-C, J = 250.0
Hz), 166.1 (C=O ester) ppm; HRMS (m/z) calculated for
C20H18N3O4F [M+H]+: 384.1315. Found: 384.1290.
(1,1'-(((1,4-Phenylenebis(methylene))bis(oxy))bis(2-
oxoethane-2,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis-
(methylene) dibenzoate (6a): White solid;Yield: 85 %; m.p.:
148-152 °C; FT-IR (KBr, νmax, cm-1): 3148 (C-H str., triazole
ring), 3085 (C-H str., aromatic ring), 2958 (C-H str., aliphatic),
1729, 1702 (C=O str., ester), 1611, 1460 (C=C str., aromatic
ring), 1270 (C-O asym. str., ester), 1054 (C-O sym. str., ester);
1H NMR (400 MHz,DMSO-d6): 5.22 (s, 4H, NCH2), 5.42 (s,
4H, OCH2), 5.52 (s, 4H, OCH2), 7.32-7.36 (m, 4H, Ar-H),
7.57 (t, 2H, Ar-H, J = 8.0 Hz), 8.05 (d, 4H, Ar-H, J = 8.0 Hz),
8.30 (s, 1H, C-H triazole) ppm; 13C NMR (100 MHz, DMSO-
d6): δ = 50.8, 59.1, 66.6, 126.9 (C5 triazole), 128.3, 128.6,
129.6, 129.8, 133.2, 135.9, 142.5 (C4 triazole), 164.5 (C=O
ester), 167.5 (C=O ester) ppm; HRMS (m/z) calculated for
C32H28N6O8[M+H]+: 625.2002. Found: 625.1913.
(1,1'-(((1,4-Phenylenebis(methylene))bis(oxy))bis(2-
oxoethane-2,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis-
(methylene) bis(4-methoxybenzoate)(6b):White solid;Yield:
85 %; m.p.: 166-170 °C; FT-IR (KBr, νmax, cm-1): 3137 (C-H
str., triazole ring), 3084 (C-H str., aromatic ring), 2958 (C-H
str., aliphatic), 1758, 1712 (C=O str., ester), 1606, 1509, 1460
(C=C str., aromatic ring), 1257 (C-O asym. str., ester), 1054
1
(C-O sym. str., ester); H NMR (400 MHz,DMSO-d6): 3.83
General procedure for in vitro antimicrobial evalua-
tion:All the newly synthesized mono and bis ester linked 1,4-
disubstituted 1,2,3-triazoles(3a-3e)/(6a-6e) were accessed for
in vitro antimicrobial activity against one Gram-positive bacterial
strain viz. Staphylococcus aureus (MTCC 3160), three Gram-
negative bacterial strains viz. Escherichia coli (MTCC 443),
Klebsiella pneumonia (NCDC 138) and Enterobacter aerogenes
(NCDC 106) and two fungi viz. Candida albicans (MTCC
227) and Aspergillus niger (MTCC 282)] using standard serial
dilution technique.
(s, 6H, OCH3), 5.21(s, 4H, NCH2), 5.39 (s, 4H, OCH2), 5.51
(s, 4H, OCH2), 7.05 (d, 4H, Ar-H, J = 8.8 Hz), 7.37 (s, 4H, Ar-
H), 7.92 (d, 4H, Ar-H, J = 8.8 Hz), 8.27 (s, 2H, C-H triazole)
ppm; 13C NMR (100 MHz, DMSO-d6): δ = 50.9, 55.9, 57.8,
67.0, 114.6, 122.0, 126.8 (C5 triazole), 128.6, 131.8, 135.9,
142.6 (C4 triazole), 163.8, 165.6 (C=O ester), 167.5 (C=O
ester) ppm; HRMS (m/z) calculated for C34H32N6O10 [M+H]+:
685.2213. Found: 685.2112.
(1,1'-(((1,4-Phenylenebis(methylene))bis(oxy))bis(2-
oxoethane-2,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis-
(methylene) bis(4-nitrobenzoate) (6c): White solid; Yield:
85 %; m.p.: 142-146 °C; FT-IR (KBr, νmax, cm-1): 3154 (C-H
str., triazole ring), 3081 (C-H str., aromatic ring), 2958 (C-H
str., aliphatic), 1749, 1718 (C=O str., ester), 1609, 1449 (C=C
str., aromatic ring),1544 (N-O asym. str., NO2), 1352 (N-O
sym. str., NO2), 1268 (C-O asym. str., ester), 1051 (C-O sym.
str., ester); 1H NMR (400 MHz,DMSO-d6): 5.22(s, 4H, NCH2),
5.50 (s, 4H, OCH2), 5.52 (s, 4H, OCH2), 7.39 (s, 4H, Ar-H),
8.19 (d, 4H, Ar-H, J = 8.8 Hz), 8.33 (d, 4H, Ar-H, J = 8.8 Hz),
8.36 (s, 2H, C-H triazole) ppm; 13C NMR (100 MHz, DMSO-
d6): δ = 50.8, 59.1, 66.9, 124.4, 127.0 (C5triazole), 128.7, 131.2,
135.9, 141.9, 142.5 (C4triazole), 150.8, 164.5 (C=O ester), 167.6
RESULTS AND DISCUSSION
Synthetic route of desired target compounds (3a-3e)/(6a-
6e) with ester functionality were outlined in Scheme-I and II.
Prop-2-yn-1-yl benzoates (4a-4e) were synthesized by drop-
wise addition of benzoyl chlorides in stirred solution of
propargyl alcohol in dry dichloromethane taking N,N-
dimethylamino-pyridine as base. Synthesis of benzyl 2-
bromooacetates/1,4-phenylenebis(methylene) bis(2-
bromoacetate) (2a-2e)/(5) were carried out by taking 1,4-
phenylenedimethanol/benzyl alcohols, sodium bicarbonate in
acetonitrile and adding slowly bromoacetyl bromide in it.
Finally, the ester linked desired 1,4-disubstituted 1,2,3-triazoles

2174 Kaushik et al.
Asian J. Chem.
O
O
R1
O
F
(1)
N
NaN3, CuSO4.5H2O
Sodium ascorbate
O
N
N
O
F
+
DMSO/ H2O (7:3)
25-40 ºC, 7-14 h
O
O
(3a
-
3e
)
2a: R1 = H
2d: R1 = Cl
Br
O
2b: R1 = OCH3 2e: R1 = CH3
R1
H
OCH3
NO2
Cl
Compound
3a
3b
3c
3d
3e
2c: R1 = NO
2
R1
(2a-2e)
CH3
Scheme-I
O
O
N
O
N
N
O
O
R
NaN3, CuSO4.5H2O
4a 4e
( - )
O
Sodium ascorbate
O
R
+
DMSO/ H2O (7:3)
25-40 ºC, 7-14 h
R
O
O
O
Br
O
N
N
N
O
4a
4d 1
/ : R = F
: R = H
O
4b
4e
: R = CH3
(6a-6e)
: R = OCH3
R1
Compound
Br
4c: R = NO2
O
6a
6b
6c
6d
6e
H
OCH3
NO2
F
5
( )
CH3
Scheme-II
(3a-3e)/(6a-6e) were synthesized via click reaction between
prop-2-yn-1-yl benzoates (4a-4e) and 2-azidoacetates/1,4-
phenylenebis(methylene) bis(2-azido-acetate)which were
prepared by in situ reaction of respective bromides (2a-2e)/
(5) with sodium azide.
in vitro Microbicidal activity: Synthesized 1,4-disubsti-
tuted 1,2,3-triazole derivatives with ester functionality (3a-
3e)/(6a-6e)were accessed for in vitro microbicidal activity
against one Gram-positive bacterial strain i.e. Staphylococcus
aureus (MTCC 3160), three Gram-negative bacterial strains
i.e. Escherichia coli (MTCC 443), Klebsiella pneumonia (NCDC
138) and Enterobacter aerogenes (NCDC 106) and two fungi
i.e. Candida albicans (MTCC 227) and Aspergillus niger (MTCC
282)] by standard serial dilution technique [28]. Results were
represented in minimum inhibitory concentrations (MIC) in
terms of µmol/mL. Norfloxacin and fluconazole were used as
standard drug for antibacterial and antifungal strains respec-
tively.
It can be analyzed from Table-1 that the synthesized comp-
ounds exhibited average to good antibacterial activity against
tested bacterial strains. Some of the synthesized triazoles 3d
(MIC, 0.0310), 6c (MIC, 0.0350), 6d (MIC, 0.0378) against
S. aureus; 3c (MIC, 0.0302), 6c (MIC, 0.0350), 6d (MIC,
0.0378) against E. coli; 3b (MIC, 0.0313), 3c (MIC, 0.0302),
6c (MIC, 0.0350), 6d (MIC, 0.0378), against Klebsiella
pneumoniae; 3c (MIC, 0.0603), 3d (MIC, 0.0619), 6c (MIC,
0.0700), 6d (MIC, 0.0757) against Enterobacter aerogenes
revealed apppreciable bactericidal efficacy. Compound 6c and
Afterwards, synthesized target compounds were charac-
1
terized by various spectral techniques like FTIR, H NMR,
13C NMR spectroscopy and HRMS. In FTIR spectra, C-H stret-
ching of triazole ring absorbed in the region at 3154-3137
cm-1. Absorption bands in the region at 1758-1719 cm-1 and
1721-1702 cm-1 owing to >C=O stretching of esters confirm
the formation of triazole derivatives. Absorption bands due to
C-H stretching of aromatic rings were observed in the range
at 3087-3031 cm-1. Likewise, in 1H NMR spectra, characteristic
singlet due to triazolyl proton exhibited in the region at δ 7.81-
8.58. Signals due to other aromatic protons were exhibited in
their expected range. Moreover, appearance of two signals in
region at δ 125.4-127.0 and 142.3-143.5 due to C5 and C4 of
triazole moiety respectively is significant feature of 13C NMR
spectra of ester linked triazole derivatives. Signals in 13C NMR
at δ 164.5-165.9 and δ 166.0-167.6 assigned to carbonyl carbon.
Values obtained from high resolution mass spectra were in
accordance with calculated values.

Vol. 29, No. 10 (2017)
Click Synthesis of Some mono/bis 1,2,3-Triazoles with Ester Linkage and their Microbicidal Activity 2175
TABLE-1
in vitro ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES OF 1,4-DISUBSTITUTED 1,2,3-TRIAZOLES
Minimum inhibitory concentration (MIC, µmol/mL)
Compound
Antibacterial activity
Gram-positive bacteria Gram-negative bacteria
S. aureus E. coli K. pneumoniae
Antifungal activity
C. albicans
A. niger
E. aerogenes
0.1354
0.1252
0.0603
0.0619
0.1304
0.0801
0.1461
0.0700
0.0757
0.1532
0.0783
–
0.1354
0.0626
0.0603
0.0310
0.1304
0.0400
0.0730
0.0350
0.0378
0.0766
0.0391
–
0.1354
0.0626
0.0302
0.0619
0.0652
0.0400
0.0730
0.0350
0.0378
0.0766
0.0391
–
0.1354
0.0313
0.0302
0.1238
0.0652
0.0801
0.0730
0.0350
0.0378
0.0766
0.0391
–
0.0677
0.0626
0.0302
0.0310
0.1304
0.0801
0.0730
0.0350
0.0189
0.0766
–
0.1354
0.0626
0.0151
0.0155
0.0652
0.0400
0.0365
0.0175
0.0189
0.0766
–
3a
3b
3c
3d
3e
6a
6b
6c
6d
6e
Norfloxacin
Fluconazole
0.0408
0.0102
4. B.K. Singh,A.K.Yadav, B. Kumar,A. Gaikwad, S.K. Sinha,V. Chaturvedi
and R.P. Tripathi, Carbohydr. Res., 343, 1153 (2008);
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and V. Kumar, Organometallics, 32, 7386 (2013);
6d found to possess broad spectrum antibacterial efficiency
against all tested bacterial strains in comparison to standard.
Antibacterial screening data revealed that in case of com-
pounds 3a-3e, triazoles having 4-substituted benzyl moiety
displayed better antibacterial activity in comparison to
unsubstituted benzyl moiety. Compounds possessing electron
withdrawing nitro group on benzyl moiety/benzoate moiety
are more prolific than compounds substituted with electron
releasing groups.
As listed in Table-1, compound 3c (MIC, 0.0302), 3d
(MIC, 0.0310), 6c (MIC, 0.0350), showed comparable anti-
fungal activity to standard drug against C. albicans. Compound
6d (MIC, 0.0189) showed two fold antifungal efficacy to
standard drug against C. albicans. Compound 3c (MIC, 0.0151),
3d (MIC, 0.0155), 6c (MIC, 0.0175), 6d (MIC, 0.0189) found
to possess better antifungal efficacy against A. niger.
https://doi.org/10.1021/om4009229.
6.
J. de O. Santos, G.R. Pereira, G.C. Brandao, T.F. Borgati, L.M.Arantes,
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https://doi.org/10.1007/s00706-015-1544-2.
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Synth. Commun., 45, 1977 (2015);
https://doi.org/10.1080/00397911.2015.1056796.
9. C.P. Kaushik, K. Kumar, K. Lal and S.K. Singh, Chem. Biol. Interface,
4, 341 (2014).
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Conclusion
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In summary, a convenient and straightforward click synthesis
of some mono and bis 1,4-disubstituted 1,2,3-triazoles was
carried out via Cu(I) catalyzed reaction of prop-2-yn-1-yl ben-
zoates with 1,4-phenylenebis(methylene) bis(2-azidoacetate)
and benzyl 2-azidoacetates. All synthesized triazole derivatives
were characterized by IR, NMR and mass spectrometry and
also evaluated for in vitro microbicidal activity. Compound
6c and 6d were found to display good antibacterial efficiency
while, compound 6d was found to possess excellent efficiency
against fungus C. albicans.
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ACKNOWLEDGEMENTS
The authors are highly grateful to University Grants
Commission, New Delhi, India for financial assistance.
16. X. Ren, X. Pan, Z. Zhang, D. Wang, X. Lu, Y. Li, D. Wen, H. Long, J.
Luo,Y. Feng, X. Zhuang, F. Zhang, J. Liu, F. Leng, X. Lang,Y. Bai, M.
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