Synthesis and Antimicrobial Activity of 2-(4-(Hydroxyalkyl)-1H-1,2,3-triazol-1-yl)-N-substituted propanamides

Article abstract of DOI:10.1002/jhet.2988

A series of 21 2-(4-(hydroxyalkyl)-1H-1,2,3-triazol-1-yl)-N-substituted propanamides (1,4-disubstituted 1,2,3-triazoles having amide linkage and hydroxyl group) have been synthesized from click reaction between terminal alkyne and 2-azido-N-substituted propanamide (generated in situ from reaction of 2-bromo-N-substituted propanamide and sodium azide) and characterized by FTIR, ¹H NMR, ¹³C NMR spectroscopy, and HRMS. All the newly synthesized triazoles were tested in vitro for antimicrobial activity against four bacterial cultures – Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Staphylococcus aureus – and two fungal cultures – Candida albicans and Aspergillus niger. The synthesized 1,4-disubstituted 1,2,3-triazoles displayed moderate to good antimicrobial potential against the tested strains.

Full text of DOI:10.1002/jhet.2988

Month 2017
Synthesis and Antimicrobial Activity of 2-(4-(Hydroxyalkyl)-1H-1,2,3-
triazol-1-yl)-N-substituted propanamides
*
C.P. Kaushik
and Raj Luxmi
Department of Chemistry, Guru Jambheshwar University of Science & Technology, Hisar, Haryana 125001, India
*
E-mail: kaushikcp@gmail.com
Received February 14, 2017
DOI 10.1002/jhet.2988
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A series of 21 2-(4-(hydroxyalkyl)-1H-1,2,3-triazol-1-yl)-N-substituted propanamides (1,4-disubstituted
1,2,3-triazoles having amide linkage and hydroxyl group) have been synthesized from click reaction between
terminal alkyne and 2-azido-N-substituted propanamide (generated in situ from reaction of 2-bromo-
N-substituted propanamide and sodium azide) and characterized by FTIR, 1H NMR, 13C NMR spectroscopy,
and HRMS. All the newly synthesized triazoles were tested in vitro for antimicrobial activity against four
bacterial cultures – Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Staphylococcus
aureus – and two fungal cultures – Candida albicans and Aspergillus niger. The synthesized 1,4-
disubstituted 1,2,3-triazoles displayed moderate to good antimicrobial potential against the tested strains.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
prime click reactions, which has been used extensively
for the synthesis of 1,4-disubstituted 1,2,3-triazoles with
high regioselectivity and yield under normal reaction
condition. Click chemistry provides an efficient method
for the construction of the triazole ring with diversified
groups that can be explored as drug entities.
Keeping in view the wide ranging importance of
triazoles, we herein reported the synthesis and
antimicrobial properties of amide linked 1,4-disubstituted
1,2,3-triazoles. The synthesis was carried out from
reaction of terminal alkynes, 2-bromo-N-substituted
In spite of significant progress in treatment of infectious
diseases caused by bacteria and fungi still it remains a
major world health problem owing to increasing
resistance of microbes against the existing drugs. Owing
to this, there is continuous requirement for antimicrobial
having wide spectrum application. This leads to a
challenging task for chemist to synthesize new molecule
with excellent activity. Different heterocyclic compounds
containing nitrogen heteroatom have been explored for
development of microbicidal. In this sequence, five
membered heterocyclic ring systems like triazole gained
appreciable attention due to wide range of biological
activities [1,2]. Triazoles have been reported to exhibit
broad biological spectrum as anticancer [3,4], anti-
HIV [5], antitubercular [6,7], antioxidant [8,9],
antitrypanosomal [10], antimicrobial [11–15], anti-
convulsant [16], antimalarial [17,18], antihistamines [19],
antitumor [20], immune potentiators [21], antiviral
[22,23], anti-inflammatory and [24,25], agents. In addition
to aforementioned medicinal value, several members of
the 1,2,3-triazoles family also show interesting industrial
applications in form of corrosion inhibitions [26], dyes
[27], and optical brightners [28].
propanamide,
and
sodium
azide
in
dimethylformamide/aqueous system in the presence of
Cu(I) catalyst. To the best of our knowledge, all the
synthesized compounds are new. The synthesized
triazoles were characterized by spectroscopic techniques
such as FT-IR, 1H NMR, 13C NMR, HRMS, and
evaluated for antimicrobial potential against Escherichia
coli, Enterobacter aerogenes, Klebsiella pneumoniae,
Staphylococcus aureus, Candida albicans, and
Aspergillus niger.
RESULTS AND DISCUSSION
Several methods have been reported for preparation of
substituted 1,2,3-triazoles [29], but the thermal
cycloaddition reaction of azides with alkynes discovered
by Huisgen [30] has received considerable attention,
which later modified by copper (I)-catalyst [31,32]. The
Cu(I)-catalyzed azide-alkyne cycloaddition is one of the
Chemistry. The starting reactants 2-bromo-N-substituted
propanamide (3a–3g) were synthesized from reaction of
2-bromopropanoyl bromide (2) and aromatic amines
(1a–1g) in dichloromethane using potassium carbonate as
base. 1,4-Disubstituted 1,2,3-triazoles (5a–5u) were
synthesized by reacting 2-azido-N-substituted propanamide
© 2017 Wiley Periodicals, Inc.

C. P. Kaushik and R. Luxmi
Vol 000
with terminal alkyne dimethylformamide : water in the
presence of copper sulfate pentahydrate and sodium
ascorbate with stirring of 6–10 h at 25–40°C. (Scheme 1).
The structures of synthesized compounds (5a–5u) were
In case of A. niger, compounds 5d, 5 k, 5r, and 5 t (MIC
0.0384, 0.0353, 0.0340 and 0.0375 μmol/mL respectively)
showed good activity.
As evident from the activity data, all the tested
compounds with Br and NO2 group on phenyl ring
showed good inhibitory activity against both the strains.
The presence of the alkyl group on carbon having free
hydroxyl group improved the antifungal activity against
C. albicans and A. niger.
1
confirmed by FTIR, H NMR, 13C NMR spectroscopy,
and HRMS. In IR spectra compounds, characteristic
absorption band displayed in region 3398–3370 owing to
O–H stretching, 3296–3259 cmÀ1, and 1708–1664 cmÀ1
owing to N–H and C═O stretching of amide
respectively, at 3163–3132 cmÀ1 owing to C–H stretching
of triazole ring.
1H spectra of compounds displayed two characteristic
singlet in the region δ 10.37–11.09 and δ 7.95–8.16
owing to N–H proton and triazolyl proton, respectively.
Aromatic protons appeared in the range of δ 6.89–8.25,
and a single proton attached to N1 of triazoles appeared
as quartet at δ 5.20–5.82. In 13C spectra, a characteristic
signal of C═O appeared in range of δ 167.2–168.8, while
C-4 of triazoles ring resonated in region δ 148.3–156.2.
HRMS results of compounds showed good agreement
with expected values.
EXPERIMENTAL
All chemicals used in the synthesis were purchased from
Alfa-Aesar, Sigma-Aldrich and used without purification.
Thin layer chromatography was used to monitor the
progress of the reactions using n-Hexane, ethyl acetate,
and chloroform in different ratio as mobile phase.
Melting points were determined by open capillary
method and were uncorrected. IR spectra were recorded
on a Shimazdu IR Affinity-I FT-IR spectrophotometer
Antimicrobial activity.
Synthesized triazoles (5a–5u)
were evaluated in vitro antibacterial activity against
Gram-negative bacteria E. coli, E. aerogenes,
using KBr powder, and the values are expressed in cmÀ1
.
The 1H and 13C NMR spectra of the synthesized
compounds were recorded at 400 and 100 MHz,
respectively, using Bruker Avance II 400 MHz NMR
spectrometer in DMSO-d6 solvent, and the chemical
shifts were expressed in δ, while coupling constants (J) in
Hz. Splitting patterns were indicated as s: singlet, brs:
broad singlet, d: doublet, t: triplet, q: quartet, m:
multiplet. HRMS were obtained on Waters Micromass Q-
Tof Micro (ESI) spectrophotometer.
–
K. pneumoniae, and Gram-positive bacteria – S. aureus
by the standard serial dilution method [33]. Results were
compared with the standard drug Norfloxacin in term of
minimum inhibitory concentration (MIC, μmol/mL;
Table 1).
The synthesized compounds showed moderate to good
antibacterial activity. Compounds 5k, 5r, and 5t (MIC,
0.0707, 0.0680, and 0.0375 μmol/mL, respectively)
showed appreciable activity against bacteria E. coli,
E. aerogenes, and K. pneumoniae. In case of S. aureus,
compounds 5d, 5 k, 5r, 5t, and 5u (MIC, 0.0768, 0.0707,
0.0680, 0.0749 and 0.0738 μmol/mL respectively)
displayed potent activity compared to standard.
The aforementioned result revealed that the presence of
electron-withdrawing group Br and NO2 at phenyl ring
improved the antibacterial activity against E. coli,
E. aerogenes, K. pneumoniae, and S. aureus.
Over all, above data of activity revealed that presence of
alkyl group on carbon having free hydroxyl group
increases the antibacterial activity.
All the synthesized triazoles (5a–5u) were also screened
for antifungal activity against C. albicans and A. niger.
Fluconazole was used as reference compound, and the
results were recorded in terms of MIC in μmol/mL.
(Table 2).
General procedure for synthesis of 1,4-disubstituted
1,2,3-triazoles (5a–5u).
For the synthesis of target
compounds, the starting reactants 2-bromo-N-substituted
propanamide (3a–3g) were synthesized by dropwise
addition of 2-bromopropanoyl bromide (1.2 mmol) to
aromatic amines (1a–1g) (1.0 mmol) in the presence of
potassium carbonate (1.5 mmol) using dichloromethane as
solvent at 0–5°C for 15–20 min, and after the completion
of reaction, ice cold water was added to the reaction
mixture and the resulting solid was filtered and dried.
To synthesize the desired triazoles (5a–5u) 2-bromo-N-
substituted propanamide (3a–3g) were stirred with
aqueous sodium azide (3.0 mmol) in dimethylformamide
for 30 min at 25–40°C. In the aforementioned mixture
terminal alkyne (4a–4c), aqueous copper sulfate
pentahydrate (0.1 mmol) and sodium ascorbate
(0.4 mmol) were added, and stirring was continued for 6–
10 h at same temperature. After the completion of
reaction, as indicated by TLC, ice cold water was added
to the reaction mixture, and then filtered the precipitated
solid and washed with aqueous ammonia solution
followed by water. The solid product was recrystallized
with ethyl acetate to get pure product.
Results of antifungal data revealed that triazoles
exhibited moderate to good activity. Compounds 5k, 5r,
and 5t (MIC 0.0707, 0.0340 and 0.0375 μmol/mL
respectively) displayed potent fungicidal activity against
C. albicans.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
1,4-disubstituted 1,2,3-triazoles
Scheme 1. Synthesis of amide linked 1,4-disubstituted 1,2,3-triazoles (5a–5u).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

C. P. Kaushik and R. Luxmi
Vol 000
Table 1
Antibacterial activity of 1,4-disubstituted 1,2,3-triazoles (5a–5u) (MIC in μmol/mL).
Escherichia coli
Enterobacter aerogenes
Klebsiella pneumoniae
Staphylococcus aureus
Compound
(MTCC 443)
(NCDC 106)
(NCDC 138)
(MTCC 3160)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
0.2030
0.0946
0.0890
0.0768
0.0904
0.0858
0.0843
0.0911
0.0855
0.0809
0.0707
0.0821
0.0782
0.0770
0.0867
0.0816
0.0774
0.0680
0.0785
0.0375
0.0738
0.0391
0.1015
0.1892
0.0890
0.0768
0.0904
0.0858
0.0843
0.0911
0.0855
0.0809
0.0707
0.1642
0.0782
0.0770
0.0867
0.0816
0.0774
0.0680
0.0785
0.0375
0.0738
0.0391
0.1015
0.0946
0.1781
0.0768
0.1809
0.0858
0.0843
0.0911
0.0855
0.1619
0.0707
0.1642
0.0782
0.1541
0.0867
0.0816
0.1548
0.0680
0.1570
0.0375
0.0738
0.0391
0.2030
0.1892
0.1781
0.0768
0.1809
0.1716
0.0843
0.0911
0.0855
0.1619
0.0707
0.1642
0.1564
0.1541
0.0867
0.0816
0.1548
0.0680
0.1570
0.0749
0.0738
0.0783
5q
5r
5s
5t
5u
Norfloxacin
3084 (C–H str. aromatic ring), 2968 (C–H str., aliphatic),
1695 (C═O str. amide), 1548, 1448 (C═C str., aromatic
ring). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.78 d
(3H, J = 8 Hz), 4.55 d (2H, OCH2, J = 8 Hz), 5.22 t (1H,
OH, J = 8 Hz), 5.55 q (1H, J = 8 Hz), 7.10 t (1H, Ar–H,
J = 8 Hz), 7.34 t (2H, Ar–H, J = 8 Hz), 7.60 d (2H, Ar–
H, J = 8 Hz), 8.12 s (1H, C–H triazole), 10.50 s (1H,
N–H amide). 13C NMR spectrum (DMSO-d6), δ, ppm:
18.3, 55.5, 59.2, 119.9, 122.4 (C5 triazole), 124.4, 129.3,
138.8, 148.3 (C4 triazole), 167.7 (C = O). Found, m/z:
247.1189 [M + H]+ C12H14N4O2 Calculated, m/z:
Table 2
Antifungal activity of 1,4-disubstituted 1,2,3-triazoles (5a–5u) (MIC in
μmol/mL).
Candida albicans
(MTCC 227)
Aspergillus niger
(MTCC 282)
Compound
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
0.1015
0.0946
0.0890
0.0768
0.0904
0.0858
0.0843
0.0911
0.0855
0.0809
0.0707
0.0821
0.0782
0.0770
0.0867
0.0816
0.0774
0.0340
0.0785
0.0375
0.0738
0.0408
0.1015
0.0946
0.0890
0.0384
0.0904
0.0858
0.0843
0.0911
0.0427
0.0809
0.0353
0.0821
0.0782
0.0770
0.0433
0.0408
0.0774
0.0340
0.0785
0.0375
0.0738
0.0102
247.1117.
N-(4-Fluorophenyl)-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-
1-yl)propanamide (5b). Appearance: white solid; yield:
92%; mp 118–120°C. IR spectrum, ν, cmÀ1: 3378 (O–H
str.), 3271 (N–H str.), 3143 (C–H str. triazole), 3069
(C–H str. aromatic ring), 2968 (C–H str., aliphatic),
1674 (C = O str. amide), 1554, 1458 (C = C str.,
1
aromatic ring). H NMR spectrum (DMSO-d6), δ, ppm:
5q
5r
5s
5t
1.78 d (3H, J = 8 Hz), 4.55 s (2H, OCH2), 5.22 s (1H,
OH), 5.53 q (1H, J = 8 Hz), 7.18 t (2H, Ar–H,
J = 8 Hz), 7.62 t (2H, Ar–H, J = 8 Hz), 8.12 s (1H, C–
H triazole), 10.57 s (1H, N–H amide). 13C NMR
spectrum (DMSO-d6), δ, ppm: 18.3, 55.5, 59.1, 115.9 d
(J = 30 Hz), 121.7 d (J = 10 Hz), 122.4 (C5 triazole),
135.2 d (J = 10 Hz), 148.3 (C4 triazole), 158.8 d
5u
Fluconazole
Characterization
of
synthesized
1,4-disubstituted
1,2,3-triazoles. 2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-
(J
= 240), 167.7 (C═O). Found, m/z: 265.1095
[M + H]+. C12H13FN4O2. Calculated, m/z: 265.1023.
N-(4-Chlorophenyl)-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-
1-yl)propanamide (5c). Appearance: white solid; yield:
N-phenylpropanamide (5a).
Appearance: white solid;
yield: 89%; mp 128–130°C. IR spectrum, ν, cmÀ1: 3381
(O–H str.), 3259 (N–H str.), 3142 (C–H str. triazole),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
1,4-disubstituted 1,2,3-triazoles
88%; mp 136–138°C. IR spectrum, ν, cmÀ1: 3378 (O–H
str.), 3261 (N–H str.), 3132 (C–H str. triazole), 3094 (C–
H str. aromatic ring), 2968 (C–H str., aliphatic), 1664
(C═O str. amide), 1548, 1456 (C═C str., aromatic ring).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.78 d (3H,
J = 8 Hz), 4.55 s (2H), 5.21 s (1H, OH), 5.54 q (1H,
J = 8 Hz), 7.40 d (2H, Ar–H, J = 8 Hz), 7.62 d (2H,
Ar–H, J = 8 Hz), 8.12 s (1H, C–H triazole), 10.64 s
(1H, N–H amide). 13C NMR spectrum (DMSO-d6), δ,
ppm: 18.2, 55.5, 59.2, 121.5, 122.4 (C5 triazole), 128.0,
129.3, 137.8, 148.3 (C4 triazole), 167.9 (C═O). Found,
m/z: 281.0800 (35Cl), 283.0770 (37Cl) [M + H]+.
C12H13ClN4O2. Calculated, m/z: 281.0727 (35Cl),
283.0731 (37Cl).
(3H, J = 8 Hz), 4.55 d (2H, OCH2, J = 8 Hz), 5.23 t
(1H, OH, J = 8 Hz), 5.59 q (1H, J = 8 Hz), 7.85 d (2H,
Ar–H), 8.15 s (1H, C–H triazole), 8.25 d (2H, Ar–H),
11.08
s
(1H, N–H amide). 13C NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 18.1, 55.5, 59.3, 119.8,
122.6 (C5 triazole), 125.5, 143.2, 144.9, 148.4 (C4
triazole), 168.7 (C═O). Found, m/z: 292.1039 [M + H]+.
C12H13N5O4. Calculated, m/z: 292.0968.
2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-(naphthalen-1-
yl)propanamide (5g).
Appearance: white solid; yield:
93%; mp 140–142°C. IR spectrum, ν, cmÀ1: 3381 (O–H
str.), 3270 (N–H str.), 3142 (C–H str. triazole), 3051
(C–H str. aromatic ring), 2951 (C–H str., aliphatic),
1681 (C═O str. amide), 1554, 1454 (C═C str., aromatic
ring). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.89 d
(3H, J = 8 Hz), 4.56 s (2H, OCH2), 5.22 s (1H, OH),
5.82 q (1H, J = 8 Hz), 7.67–7.51 m (4H, Ar–H), 7.82 d
(2H, Ar–H, J = 8 Hz), 7.97 d (2H, Ar–H, J = 8 Hz),
8.04 d (1H, Ar–H, J = 8 Hz), 8.16 s (1H, C–H triazole),
10.47 s (1H, N–H amide). 13C NMR spectrum (DMSO-
d6), δ, ppm: 18.6, 55.5, 58.9, 122.5 (C5 triazole), 122.9,
126.0, 126.5, 126.6, 126.7, 128.3, 128.7, 133.1, 134.2,
148.3 (C4 triazole), 168.7 (C═O). Found, m/z: 297.1347
[M + H]+. C16H16N4O2. Calculated, m/z: 297.1273.
N-(4-Bromophenyl)-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-
1-yl)propanamide (5d). Appearance: white solid; yield:
96%; mp 154–156°C. IR spectrum, ν, cmÀ1: 3377 (O–H
str.), 3275 (N–H str.), 3142 (C–H str. triazole), 3053
(C–H str. aromatic ring), 2951 (C–H str., aliphatic),
1666 (C = O str. amide), 1541, 1448 (C═C str., aromatic
ring). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.79 d
(3H, J = 8 Hz), 4.57 s (2H, OCH2), 5.24 s (1H, OH),
5.55 q (1H, J = 8 Hz), 7.59–7.50 m (4H, Ar–H), 8.13 s
(1H, C–H triazole), 10.64 s (1H, N–H amide). 13C NMR
spectrum (DMSO-d6), δ, ppm: 18.2, 55.5, 59.2, 116.1,
121.9, 122.4 (C5 triazole), 132.2, 138.2, 148.3 (C4
triazole), 167.9 (C═O). Found, m/z: 325.0298 (79Br),
327.0274 (81Br) [M + H]+. C12H13BrN4O2. Calculated,
m/z: 325.0222 (79Br), 327.0201 (81Br).
2-(4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
phenylpropanamide (5h).
Appearance: white solid;
yield: 89%; mp 158–160°C. IR spectrum, ν, cmÀ1: 3396
(O–H str.), 3286 (N–H str.), 3145 (C–H str. triazole),
3051 (C–H str. aromatic ring), 2960 (C–H str.,
aliphatic), 1678 (C═O str. amide), 1554, 1500, 1446
2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)
1
propanamide (5e). Appearance: white solid; yield: 94%; mp
(C═C str., aromatic ring). H NMR spectrum (DMSO-
134–136°C. IR spectrum, ν, cmÀ1: 3383 (O–H str.), 3275
(N–H str.), 3142 (C–H str. triazole), 3031 (C–H str.
aromatic ring), 2954 (C–H str., aliphatic), 1662 (C═O
str. amide), 1550, 1450 (C═C str., aromatic ring) 1243
d6), δ, ppm: 1.48 s (6H), 1.77 d (3H, J = 8 Hz), 5.13 s
(1H, OH), 5.53 q (1H, J = 8 Hz), 7.10 t (1H, Ar–H,
J = 8 Hz), 7.34 t (2H, Ar–H, J = 8 Hz), 7.60 d (2H, Ar–
H, J = 8 Hz), 8.00 s (1H, C–H triazole), 10.51 s (1H,
N–H amide). 13C NMR spectrum (DMSO-d6), δ, ppm:
18.3, 31.2, 59.1, 67.5, 119.9 (C5 triazole), 124.4, 129.3,
138.8, 156.1 (C4 triazole), 167.8 (C═O). Found, m/z:
275.1502 [M + H]+. C14H18N4O2. Calculated, m/z:
275.1430.
1
(C–O asym. Str., ether), 1032 (C–O sym. Str., ether). H
NMR spectrum (DMSO-d6), δ, ppm: 1.77 d (3H,
J = 8 Hz), 3.72 s (3H, OCH3), 4.54 d (2H, OCH2,
J = 8 Hz), 5.21 t (1H, OH, J = 8 Hz), 5.51 q (1H,
J = 8 Hz), 6.90 d (2H, Ar–H, J = 8 Hz), 7.51 d (2H,
Ar–H, J = 8 Hz), 8.10 s (1H, C–H triazole), 10.37 s
(1H, N–H amide). 13C NMR spectrum (DMSO-d6), δ,
ppm: 18.4, 55.5, 59.1, 114.4, 121.5, 122.3 (C5 triazole),
131.9, 148.3 (C4 triazole), 156.1, 167.2 (C═O). Found,
m/z: 277.1293. [M + H]+. C13H16N4O3. Calculated, m/z:
277.1222.
N-(4-Fluorophenyl)-2-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-
triazol-1-yl)propanamide (5i).
Appearance: white solid;
yield: 88%; mp 198–200°C. IR spectrum, ν, cmÀ1: 3396
(O–H str.), 3296 (N–H str.), 3163 (C–H str. triazole),
3078 (C–H str. aromatic ring), 2978 (C–H str., aliphatic),
1678 (C═O str. amide), 1558, 1454 (C═C str., aromatic
ring). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.48 s
(6H), 1.77 d (3H, J = 8 Hz), 5.13 s (1H, OH), 5.50 q (1H,
J = 8 Hz), 7.18 t (2H, Ar–H, J = 8 Hz), 7.63 d (2H, Ar–
H, J = 8 Hz), 8.00 s (1H, C–H triazole), 10.57 s (1H, N–
H amide). 13C NMR spectrum (DMSO-d6), δ, ppm: 18.3,
31.1, 59.1, 67.5, 115.9 d (J = 30 Hz), 119.9 (C5 triazole),
121.8 d (J = 10 Hz), 135.2 d (J = 10 Hz), 156.1 (C4
triazole), 158.8 d (J = 240 Hz), 167.7 (C═O). Found, m/
2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-(4-nitrophenyl)
propanamide (5f). Appearance: yellow solid; yield: 89%;
mp 178–180°C. IR spectrum, ν, cmÀ1: 3378 (O–H str.),
3274 (N–H str.), 3159 (C–H str. triazole), 3088 (C–H
str. aromatic ring), 2966 (C–H str., aliphatic), 1708
(C═O str. amide), 1554, 1458 (C═C str., aromatic ring),
1502 (N-O str., asym., NO2), 1340 (N-O str., sym.,
1
NO2). H NMR spectrum (DMSO-d6), δ, ppm: 1.82 d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

C. P. Kaushik and R. Luxmi
Vol 000
z: 293.1405 [M + H]+. C14H17FN4O2. Calculated, m/z:
293.1336.
triazole), 3056 (C–H str. aromatic ring), 2970 (C–H str.,
aliphatic), 1699 (C═O str. amide), 1564, 1456 (C═C str.,
aromatic ring), 1516 (N–O str., asym., NO2), 1342 (N–O
str., sym., NO2). 1H NMR spectrum (DMSO-d6), δ, ppm:
1.48 s (6H), 1.81 d (3H, J = 8 Hz), 5.14 s (1H, OH), 5.57
q (1H, J = 8 Hz), 7.86 d (2H, Ar–H, J = 8 Hz), 8.03 s
(1H, C–H triazole), 8.25 d (2H, Ar–H, J = 8 Hz), 11.09 s
(1H, N–H amide). 13C NMR spectrum (DMSO-d6), δ,
ppm: 18.1, 31.1, 59.2, 67.5, 119.8 (C5 triazole), 120.2,
125.5, 143.2, 144.9, 156.2 (C4 triazole), 168.8 (C═O).
N-(4-Chlorophenyl)-2-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-
triazol-1-yl)propanamide (5j).
Appearance: white solid;
yield: 85%; mp 198–200°C. IR spectrum, ν, cmÀ1: 3387
(O–H str.), 3280 (N–H str.), 3145 (C–H str. triazole),
3051 (C–H str. aromatic ring), 2975 (C–H str.,
aliphatic), 1676 (C═O str. amide), 1548, 1454 (C═C
1
str., aromatic ring). H NMR spectrum (DMSO-d6), δ,
ppm: 1.48 s (6H), 1.77 d (3H, J = 8 Hz), 5.13 s (1H,
OH), 5.50 q (1H, J = 8 Hz), 7.40 d (2H, Ar–H,
J = 12 Hz), 7.63 d (2H, Ar–H, J = 12 Hz), 8.00 s (1H,
C–H triazole), 10.65 s (1H, N–H amide). 13C NMR
spectrum (DMSO-d6), δ, ppm: 18.2, 31.1, 59.1, 67.5,
120.0 (C5 triazole), 121.5, 128.0, 129.3, 137.8, 156.1
(C4 triazole), 167.9 (C═O). Found, m/z: 309.1111 (35Cl),
311.1084 (37Cl). [M + H]+. C14H17ClN4O2. Calculated,
m/z: 309.1040 (35Cl), 311.1044 (37Cl).
Found, m/z: 320.1352 [M
Calculated, m/z: 320.1281.
+
H]+. C14H17N5O4.
2-(4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
(naphthalen-1-yl)propanamide (5n).
Appearance:
white solid; yield: 87%; mp 90–92°C. IR spectrum, ν,
cmÀ1: 3381 (O–H str.), 3278 (N–H str.), 3142 (C–H str.
triazole), 3057 (C–H str. aromatic ring), 2980 (C–H str.,
aliphatic), 1672 (C═O str. amide), 1541, 1456 (C═C
1
str., aromatic ring). H NMR spectrum (DMSO-d6), δ,
N-(4-Bromophenyl)-2-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-
ppm: 1.50 s (6H), 1.89 d (3H, J = 8 Hz), 5.16 s (1H,
OH), 5.82 q (1H, J = 8 Hz), 7.69–7.51 m (4H, Ar–H),
7.82 d (1H, Ar–H, J = 8 Hz), 8.07–7.96 m (3H, 2Ar–H,
C–H triazole), 10.47 s (1H, N–H amide). 13C NMR
spectrum (DMSO-d6), δ, ppm: 18.6, 31.2, 58.9, 67.6,
120.1 (C5 triazole), 122.5, 122.9, 126.0, 126.5, 126.6,
126.7, 128.3, 128.7, 133.0, 134.2, 156.1 (C4 triazole),
triazol-1-yl)propanamide (5k). Appearance: white solid;
yield: 94%; mp 202–204°C. IR spectrum, ν, cmÀ1
:
3381, 3282 (N–H str.), 3145 (C–H str. triazole), 3069
(C–H str. aromatic ring), 2978 (C–H str., aliphatic),
1676 (C═O str. amide), 1546, 1446 (C═C str., aromatic
ring). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.47 s
(6H), 1.77 d (3H, J = 8 Hz), 5.12 s (1H, OH), 5.50 q
(1H, J = 8 Hz), 7.59–7.51 m (4H, Ar–H), 8.00 s (1H,
C–H triazole), 10.64 s (1H, N–H amide). 13C NMR
spectrum (DMSO-d6), δ, ppm: 18.2, 31.1, 59.1, 67.5,
116.1, 120.0 (C5 triazole), 121.9, 132.2, 138.2, 156.1
(C4 triazole), 167.9 (C═O). Found, m/z: 353.0611
(79Br), 355.0583 (81Br) [M + H]+. C14H17BrN4O2.
Calculated, m/z: 353.0535 (79Br), 355.0514 (81Br).
168.8 (C═O). Found, m/z: 325.1657 [M
C18H20N4O2. Calculated, m/z: 325.1586.
+
H]+.
2-(4-(2-Hydroxybutan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
phenylpropanamide (5o).
Appearance: white solid;
yield: 86%; mp 118–120°C. IR spectrum, ν, cmÀ1: 3393
(O–H str.), 3286 (N–H str.), 3163 (C–H str. triazole),
3055 (C–H str. aromatic ring), 2978 (C–H str.,
aliphatic), 1680 (C═O str. amide), 1546, 1450 (C═C
2-(4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
1
str., aromatic ring). H NMR spectrum (DMSO-d6), δ,
(4-methoxyphenyl)propanamide (5l).
Appearance:
ppm: 0.76 t (3H, J = 8 Hz), 1.44 s (3H), 1.78–1.72 m
(5H), 4.98 s (1H, OH), 5.53 q (1H, J = 8 Hz), 7.10 t
(1H, Ar–H, J = 8 Hz), 7.34 t (2H, Ar–H, J = 8 Hz),
7.60 d (2H, Ar–H, J = 8 Hz), 7.97 s (1H, C–H triazole),
10.50 s (1H, N–H amide). 13C NMR spectrum (DMSO-
d6), δ, ppm: 8.8, 18.3, 28.6, 35.9, 59.1, 70.2, 119.9,
120.7 (C5 triazole), 124.4, 129.3, 138.8, 155.1 (C4
triazole), 167.8 (C═O). Found, m/z: 289.1657 [M + H]+.
C15H20N4O2. Calculated, m/z: 289.1586.
white solid; yield: 84%; mp 136–138°C. IR spectrum, ν,
cmÀ1: 3375 (O–H str.), 3296 (N–H str.), 3143 (C–H str.
triazole), 3060 (C–H str. aromatic ring), 2981 (C–H str.,
aliphatic), 1666 (C═O str. amide), 1548, 1462 (C═C
str., aromatic ring) 1243 (C–O asym. str., ether), 1032
1
(C–O sym. str., ether). H NMR spectrum (DMSO-d6),
δ, ppm: 1.48 s (6H), 1.76 d (3H, J = 8 Hz), 3.73 s (3H,
OCH3), 5.12 s (1H, OH), 5.50 q (1H, J = 8 Hz), 6.91 d
(2H, Ar–H, J = 8 Hz), 7.52 d (2H, Ar–H, J = 8 Hz),
7.99 s (1H, C–H triazole), 10.37 s (1H, N–H amide).
13C NMR spectrum (DMSO-d6), δ, ppm: 18.4, 31.2,
55.6, 59.1, 67.5, 114.4, 119.9 (C5 triazole), 121.4,
131.9, 156.1, 156.1 (C4 triazole), 167.2 (C═O). Found,
m/z: 305.1607 [M + H]+. C15H20N4O3. Calculated, m/z:
305.1535.
N-(4-Fluorophenyl)-2-(4-(2-hydroxybutan-2-yl)-1H-1,2,3-triazol-1-
yl)propanamide (5p). Appearance: white solid; yield: 93%;
mp 140–142°C. IR spectrum, ν, cmÀ1: 3391 (O–H str.),
3283 (N–H str.), 3157 (C–H str. triazole), 3062 (C–H
str. aromatic ring), 2974 (C–H str., aliphatic), 1680
(C═O str. amide), 1552, 1454 (C═C str., aromatic ring).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.75 t (3H,
J = 8 Hz). 1.44 s (3H), 1.78–1.72 m (5H), 4.98 s (1H,
OH), 5.51 q (1H, J = 8 Hz), 7.18 t (2H, Ar–H,
J = 8 Hz), 7.63 t (2H, Ar–H, J = 8 Hz), 7.96 s (1H, C–H
2-(4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
(4-nitrophenyl)propanamide (5m). Appearance: yellow
solid; yield: 90%; mp 156–158°C. IR spectrum, ν, cmÀ1
:
3398 (O–H str.), 3273 (N–H str.), 3157 (C–H str.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
1,4-disubstituted 1,2,3-triazoles
triazole), 10.57 s (1H, N–H amide). 13C NMR spectrum
(DMSO-d6), δ, ppm: 8.8, 18.3, 28.6, 35.9, 59.1, 70.3,
115.9 d (J = 30 Hz), 120.7 (C5 triazole), 121.8 d
(J = 10 Hz), 135.2 d (J = 10 Hz), 155.1 (C4 triazole),
158.8 d (J = 240), 167.7 (C═O). Found, m/z: 307.1562
[M + H]+. C15H19FN4O2. Calculated, m/z: 307.1492.
156.1, 167.3 (C═O). Found, m/z: 319.1762 [M + H]+.
C16H22N4O3. Calculated, m/z: 319.1692.
2-(4-(2-Hydroxybutan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
(4-nitrophenyl)propanamide (5t). Appearance: yellow
solid; yield: 90%; mp 128–130°C. IR spectrum, ν, cmÀ1
:
3390 (O–H str.), 3276 (N–H str.), 3151 (C–H str.
triazole), 3086 (C–H str. aromatic ring), 2970 (C–H str.,
aliphatic), 1697 (C═O str. amide), 1586, 1458 (C═C
str., aromatic ring), 1502 (N–O str., asym., NO2), 1338
N-(4-Chlorophenyl)-2-(4-(2-hydroxybutan-2-yl)-1H-1,2,3-triazol-1-
yl)propanamide (5q). Appearance: white solid; yield: 90%;
mp 162–164°C. IR spectrum, ν, cmÀ1: 3378 (O–H str.),
3286 (N–H str.), 3140 (C–H str. triazole), 3062 (C–H
str. aromatic ring), 2978 (C–H str., aliphatic), 1680
(C═O str. amide), 1546, 1450 (C═C str., aromatic ring).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.75 t
(3H, J = 8 Hz), 1.44 s (3H), 1.79–1.72 m (5H), 4.98 s
(1H, OH), 5.51 q (1H, J = 8 Hz), 7.40 d (2H, Ar–H,
J = 12 Hz), 7.63 d (2H, Ar–H, J = 12 Hz), 7.97 s (1H,
C–H triazole), 10.64 s (1H, N–H amide). 13C NMR
spectrum (DMSO-d6), δ, ppm: 8.8, 18.2, 28.6, 35.9,
59.1, 70.2, 120.7 (C5 triazole), 121.5, 128.0, 129.3,
137.8, 155.1 (C4 triazole), 167.9 (C═O). Found, m/z:
1
(N–O str., sym., NO2). H NMR spectrum (DMSO-d6),
δ, ppm: 0.75 t (3H, J = 8 Hz), 1.44 s (3H), 1.82–1.72 m
(5H), 4.98 s (1H, OH), 5.57 q (1H, J = 8 Hz), 7.86 d
(2H, Ar–H, J = 8 Hz), 8.00 s (1H, C–H triazole), 8.25 d
(2H, Ar–H, J = 8 Hz), 11.09 s (1H, N–H amide). 13C
NMR spectrum (DMSO-d6), δ, ppm: 8.8, 18.1, 28.6,
35.9, 59.2, 70.2, 119.8, 120.9 (C5 triazole), 125.5,
143.2, 144.9, 155.2 (C4 triazole), 168.8 (C═O). Found,
m/z: 334.1505 [M + H]+. C15H19N5O4. Calculated, m/z:
334.1437.
2-(4-(2-Hydroxybutan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
323.1267 (35Cl), 325.1237 (37Cl) [M
+
H]+.
(naphthalen-1-yl)propanamide (5u).
Appearance:
C15H19ClN4O2. Calculated, m/z: 323.1197 (35Cl),
325.1201 (37Cl).>
white solid; yield: 94%; mp 106–108°C. IR spectrum, ν,
cmÀ1: 3378 (O–H str.), 3269 (N–H str.), 3152 (C–H str.
triazole), 3055 (C–H str. aromatic ring), 2970 (C–H str.,
aliphatic), 1674 (C═O str. amide), 1541, 1456 (C═C
N-(4-Bromophenyl)-2-(4-(2-hydroxybutan-2-yl)-1H-1,2,3-triazol-1-
yl)propanamide (5r). Appearance: white solid; yield: 89%;
1
mp 172–174°C. IR spectrum, ν, cmÀ1: 3370 (O–H str.),
3282 (N–H str.), 3152 (C–H str. triazole), 3082 (C–H
str. aromatic ring), 2976 (C–H str., aliphatic), 1672
(C═O str. amide), 1546, 1450 (C═C str., aromatic ring).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.75 t (3H,
J = 8 Hz), 1.44 s (3H), 1.78–1.72 m (5H), 4.98 s (1H,
OH), 5.51 q (1H, J = 8 Hz), 7.59–7.51 m (4H, Ar–H),
7.97 s (1H, C–H triazole), 10.63 s (1H, N–H amide).
13C NMR spectrum (DMSO-d6), δ, ppm: 8.8, 18.2, 28.6,
35.9, 59.1, 70.2, 116.1, 120.7 (C5 triazole), 121.9,
132.2, 138.2, 155.1 (C4 triazole), 168.0 (C═O). Found,
m/z: 367.0770 (79Br), 369.0738 (81Br). [M + H]+.
C15H19BrN4O2. Calculated, m/z: 367.0691 (79Br),
369.0671 (81Br).
str., aromatic ring). H NMR spectrum (DMSO-d6), δ,
ppm: 0.75 t (3H, J = 8 Hz). 1.46 s (3H), 1.90–1.74 m
(5H), 4.98 s (1H, OH), 5.82 q (1H, J = 8 Hz), 8.02 m
(8H, 7Ar–H, C–H triazole), 10.45 s (1H, N–H amide),
13C NMR spectrum (DMSO-d6), δ, ppm: 8.8, 18.5, 28.7,
36.0, 58.9, 70.3, 120.9 (C5 triazole), 122.5, 122.9,
126.0, 126.5, 126.6, 126.7, 128.3, 128.7, 133.1, 134.2,
155.1 (C4 triazole), 168.7 (C═O). Found, m/z: 339.1813
[M + H]+. C19H22N4O2. Calculated, m/z: 339.1743.
Antimicrobial activity.
The antimicrobial testing of
newly synthesized compounds was assessed in vitro
against Gram-negative bacteria – E. coli (MTCC 443),
E. aerogenes (NCDC 106), K. pneumoniae (NCDC 138),
Gram-positive bacteria – S. aureus (MTCC 3160) and two
fungal strains – C. albicans (MTCC 227), A. niger (MTCC
282) through standard serial dilution method [33] using a
stock solution of 100 μg/mL concentration. Nutrient broth
and sabouraud dextrose were employed as culture media
for bacteria and fungus, respectively. Norfloxacin and
Fluconazole were used as standard drug for bacterial and
fungal activity assay, respectively. A stock solution of test
compounds and control drug were serially diluted to get
concentration of 50, 25, 12.5, 6.25, and 3.12 μg/mL. All
these dilutions were inoculated with respective bacterial
and fungal strain in saline solution and incubated at 37°C
for 24 h in case of all bacteria, at 25°C in case of
C. albicans for 48 h and at 25°C for 120 h in case of
A. niger and then compared with control drug. The
antimicrobial activity of compounds was represented in
2-(4-(2-Hydroxybutan-2-yl)-1H-1,2,3-triazol-1-yl)-N-
(4-methoxyphenyl)propanamide (5s).
Appearance:
white solid; yield: 86%; mp 110–112°C. IR spectrum, ν,
cmÀ1: 3370 (O–H str.), 3286 (N–H str.), 3140 (C–H str.
triazole), 3062 (C–H str. aromatic ring), 2972 (C–H str.,
aliphatic), 1676 (C═O str. amide), 1546, 1458 (C═C
str., aromatic ring) 1243 (C–O asym. str., ether), 1034
1
(C–O sym. str., ether). H NMR spectrum (DMSO-d6),
δ, ppm: 0.75 t (3H, J = 8 Hz), 1.44 s (3H), 1.77–1.72 m
(5H), 3.72 s (3H, OCH3), 4.97 s (1H, OH), 5.49 q (1H,
J = 8 Hz), 6.90 d (2H, Ar–H, J = 8 Hz), 7.51 d (2H,
Ar–H, J = 8 Hz), 7.95 s (1H, C–H triazole), 10.37 s
(1H, N–H amide). 13C NMR spectrum (DMSO-d6), δ,
ppm: 8.8, 18.4, 28.6, 35.9, 55.6, 59.1, 70.2, 114.4,
120.6 (C5 triazole), 121.4, 131.9, 155.1 (C4 triazole),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

C. P. Kaushik and R. Luxmi
Vol 000
[15] Kaushik, C. P.; Luxmi, R.; Singh, D.; Kumar, A. Mol Divers
2017, 21, 137.
terms of minimum inhibitory concentration (MIC,
μmol/mL) which reflects as the lowest concentration of
compound that completely inhibits the growth of each strain.
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CONCLUSION
A small library of 2-(4-(hydroxyalkyl)-1H-1,2,3-triazol-
1-yl)-N-substituted propanamides (5a–5u) have been
synthesized via Cu(I) catalyzed reaction of terminal
alkynes and 2-azido-N-substituted propanamide. Further,
these triazoles were tested in vitro antimicrobial activity
against Gram-negative bacteria – E. coli, E. aerogenes,
K. pneumoniae, and Gram-positive bacteria – S. aureus
and two fungal strains – C. albicans and A. niger by a
standard serial dilution method. Compounds 5r and 5t
showed potent activity against all the microbial strains.
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SUPPORTING INFORMATION
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Additional Supporting Information may be found online
in the supporting information tab for this article.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet