An Efficient Synthesis and Antibacterial Activity of Some Novel 2-Azetidinone Derivatives of 4H-1,2,4-Triazoles Under Mild Conditions

Article abstract of DOI:10.1002/jhet.3136

We have synthesized the novel 2-azetidinone derivatives by using Schiff bases of 1,2,4-triazoles via a single step protocol. We used DABCO as a good homogenous, ecofriendly, highly reactive, easy to handle, and nontoxic catalyst. In?DABCO catalyzed synthesis of active 2-oxo-azetidine, a highly electrophilic ketene intermediate can react with weakly nucleophilic (N═CH) linkage, which is used as the precursor for the cycloaddition reaction to deliver the desired products in excellent yields with protic solvents. In addition, the DABCO as an economically viable and readily available catalyst is soluble in almost all solvents and their salts easily filtered off from the reaction medium. Moreover, this new synthetic protocol features high conversion in green solvents and a straightforward procedure.

Full text of DOI:10.1002/jhet.3136

Month 2018
An Efficient Synthesis and Antibacterial Activity of Some Novel 2-
Azetidinone Derivatives of 4H-1,2,4-Triazoles Under Mild Conditions
a
Takallum Khan,a
Ritu Yadav,
and Surendra Singh Goundb
*
aDepartment of Chemistry, Dr H. S. Gour University, Sagar, M.P. 470003, India
bDepartment of Microbiology, Dr H. S. Gour University, Sagar, M.P. 470003, India
*
E-mail: yadavritu1971@gmail.com
Received November 1, 2017
DOI 10.1002/jhet.3136
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
We have synthesized the novel 2-azetidinone derivatives by using Schiff bases of 1,2,4-triazoles via a sin-
gle step protocol. We used DABCO as a good homogenous, ecofriendly, highly reactive, easy to handle, and
nontoxic catalyst. In DABCO catalyzed synthesis of active 2-oxo-azetidine, a highly electrophilic ketene in-
termediate can react with weakly nucleophilic (N═CH) linkage, which is used as the precursor for the cyclo-
addition reaction to deliver the desired products in excellent yields with protic solvents. In addition, the
DABCO as an economically viable and readily available catalyst is soluble in almost all solvents and their
salts easily filtered off from the reaction medium. Moreover, this new synthetic protocol features high con-
version in green solvents and a straightforward procedure.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
Among them, Staudinger reaction [2 + 2] ketene-imine
cycloaddition reaction is regarded as one of the most
fundamental and versatile methods for the synthesis of
structurally diverse 2-azetidinone derivatives [25].
β-Lactam antibiotics serve as one of the most important
contributions of science to mankind. The 2-azetidinone
(commonly known as β-lactam) ring system is the basic
structural feature of a number of broad spectrum
This reaction has long been studied experimentally and
theoretically to understand its mechanism and the
rationale for the stereoselectivity. This reaction is carried
out by two ways, one is photochemically and another is
thermally using acid chlorides in the presence of
triethylamine or α-diazoketones as a ketene precursors.
However, in most of the methods, 2-azetidinone
derivatives have been synthesized from the Schiff bases
[26]. By dehydrative cyclo-addition of Schiff bases using
chloroacetyl chloride and Et3N as base catalyst; however,
some problems in recovering the catalyst, solvents
(dioxane), and purification of products have been
encountered, so in place of Et3N, DABCO (Diaza-
bicyclooctane) catalyst has been the choice of our interest
in 2-azetidinones synthesis due to their low cost and
environment-friendly nature [27,28]. In continuation with
our investigations into the synthesis of novel substituted
1,2,4-triazoles derivatives with biological activity, and
due to several advantages of DABCO catalyst, here we
report a new approach for the synthesis of 3-chloro-2-
azetidinonyl-1,2,4-triazole derivatives using DABCO as a
superior basic catalyst. To start with our study, Schiff
antibiotics,
including
penicillins,
cephalosporins,
carbapenems, nocardicins, mono-bactams, clavulanic
acid, and sulbactams (Fig. 1), which have been widely
used as therapeutic agents to treat bacterial infections and
several others [1–4]. 2-Azetidinones exhibit a wide range
of biological activities that includes anti-tubercular [5],
anti-inflammatory [6], antitumor [7], anti-HIV [8],
antimalarial [9], anti-hyperglycemic [10], and analgesic
[11] activities. The biological activity of the β-lactams is
generally believed to be associated with the chemical
reactivity of the four-membered ring and on the
substituents, especially at nitrogen of the 2-oxo-azetidine
ring [12]. 1,2,4-Triazole and its derivatives possess a
great importance in medicinal chemistry and can be used
for the synthesis of numerous heterocyclic compounds
with different biological activities that include anti-
tubercular [13,14], antidepressant [15], anticonvulsant
[16], anticancer [17], antioxidant [18], and antimicrobial
activity [19]. A number of methods for the synthesis of
2-azetidinone derivatives have been reported [20–24].
© 2018 Wiley Periodicals, Inc.

T. Khan, R. Yadav, and S. S. Gound
Vol 000
obtained in a very low percentage along with un-reacted
starting materials after prolonged reaction times. After
that, we carried out the same procedure by using
EtOH/MeOH(20 mL) as a green solvent, with DABCO
used as a homogeneous catalyst for the first time in the
synthesis of 2-azetidinone derivatives at room
temperature stirring for 2–7 h. The corresponding
product was obtained in 83% yield (Table 1). The
coupling of an activated nucleophilic derivatives is a key
step in the addition of the tertiary amine catalyst to the
nucleophilic center to form a stablished nucleophilic
anion as shown in Scheme 2. In situ generated
nucleophile that leads to cyclization and subsequent
elimination of the catalyst and formation of azetidinone
products in excellent yields. All the remaining reactions
were carried out under these conditions. Moreover, the
present protocol was screened with different solvent
systems such as EtOH, MeOH, n-BuOH, CHCl3, DCM,
THF, CH3CN, and dioxane at room temperature as
shown in Table 1. After several experiments,
EtOH/MeOH was proven to be the best choice, because
the other solvents furnished low yields due to less
solubility of Schiff base and stability of ketene
intermediate in these solvents. All the synthesized
Figure 1. Some antibiotics containing 2-azetidinone moiety.
bases of 1,2,4-triazoles reacted with chloroacetyl chloride
at room temp. using DABCO (diaza-bicyclooctane) as the
base catalyst affording 2-azetidinone derivatives of 1,2,4-
triazoles. Systematic study was then carried out using
different solvents like methanol, ethanol, n-BuOH,
acetonitrile, dioxane, benzene, chloroform, and THF; and
at variable temperature and time to optimize the reaction
conditions. These findings have provided justification to
develop an efficient synthesis of 1,2,4-triazolyl-
substituted β-lactams, based on the chemistry shown in
Scheme 1. All the synthesized compounds have been
screened for their antibacterial activity against bacteria;
Bacillus cereus, Escherichia coli, and Staphylcoccus
aureus using Ampicillin as standard drug.
1
compounds were characterized by FT-IR, H NMR, and
13C NMR. The FT-IR absoption band at 1710–
1768 cmÀ1 shows the presence of C═O Stretching in 2-
azetidinone ring.
RESULTS AND DISCUSSION
Antimicrobial screening.
The preliminary biological
activity of the synthesized compounds (3a–3j) were
evaluated against bacterial strains S. aureus, B. cereus
(Gram-positive) and E. coli (Gram-negative). This
We presented DABCO as an efficient and eco-friendly
base catalyst that catalyzes the dehydrative cycloaddition
of chloroacetyl chloride with Schiff base. Herein, the
catalyst is nontoxic, easy to handle, and can be easily
filtered off from the reaction medium because it is
soluble in water and other solvents. In this research, we
aimed to develop a new green and efficient synthesis of
2-azetidinone derivatives at room temperature from
various Schiff bases and chloroacetyl chloride in the
presence of DABCO as a base catalyst with EtOH used
as a green solvent (Scheme 1). Therefore, in order to
optimize the reaction conditions, first, we performed the
reaction between Schiff bases (20 mmol) and
chloroacetyl chloride (20 mmol) under ethanol used as a
solvent in the presence of Et3N as catalyst at room
temperature. The corresponding product yield was
Table 1
Optimization of cyclization reaction conditiona.
Time
(h)
%Yield
DABCO
%Yield
Et3N
S. No.
Solvents
1
2
3
4
5
6
7
Chloroform
MeOH
Ethanol
Dioxane
DCM
5
3
3
7
4.5
7
6
59.4
89.5
85.8
67.0
68.5
17.2
29.9
30
52
56
28
30
12
18
Acetonitrile
THF
aReaction conditions: 2B (20 mmol), Chloroacetyl chloride (20 mmol),
catalyst (0.5-1 equiv.), solvent (20 mL), 0°C – room temp.
Scheme 1. Synthesis of 2-azetidinone derivatives from 4-amino-1,2,4-triazole.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of 2-Azetidinone Under Mild Conditions
Scheme 2. Plausible mechanism for dehydrative cyclization reaction.
Graph 1. Antibacterial activity of synthesized compounds (3b–3j). [Color figure can be viewed at wileyonlinelibrary.com]
activity was determined by disc diffusion method by
measuring the zone of inhibition in millimeter. The
compounds were dissolved in DMSO at a concentration
of 200 ppm/mL. The antibacterial activity of each
compound was compared with the standard drug
Ampicillin. The results depicted in Graph 1 revealed that
most of the tested compounds displayed variable
inhibitory effects on the growth of tested Gram-positive
and Gram negative bacterial strains. Compound 3b
showed better activity against E. coli (Gram-negative),
while 3d is impotent against B. cereus and S. aureus
(Gram-positive). Compounds 3i and 3b showed an
excellent activity against B. cereus (Gram-positive)
bacterial strain.
CONCLUSIONS
In summary, we have reported an alternative catalyst for
synthetic access to diverse 2-azetidinone derivatives
of 1,2,4-triazoles in excellent yields via DABCO
catalyzed dehydrative cyclization of functionalized Schiff
bases with chloroacetyl chloride and evaluated their
antibacterial activity. We have successfully accomplished
Figure 2. Structure of Synthesized Compounds (3b-3j)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. Khan, R. Yadav, and S. S. Gound
Vol 000
the synthesis of 2-azetidinone moieties (Fig. 2), for the
first time promoted by DABCO as a base catalyst in
EtOH used as green-solvent at low temperature. In
addition, present protocol excludes toxic and hazardous
solvents. This methodology involved shorter reaction
times, good yields, besides being environmentally
benign, inexpensive, and demanding mild reaction
conditions.
1C, CH─N), 153.8(s, 2C, C═N triazole). GC─MS for
C14H15N4O4Cl [M + H]+, 338.04.
Synthesis of 3-chloro-1-(4H-1,2,4-triazolyl)-4-(3-ethoxy-4-
hydroxyphenyl)azetidin-2-one (3b).
Light yellow solid,
m.p.165°C; Yield: 72%, FT─IR (KBr) 1721 cmÀ1
(>C═O stretch. of azetidinone), 3050 cmÀ1 (Ar, CH─
stretch.), 1598 cmÀ1 (C─N Stretch.) 810 cmÀ1 (CH─Cl
stretch. of azetidinone), 1080 cmÀ1 (Ar─OC2H5). 1H
NMR (400 MHz, DMSO, δ ppm): 6.6–6.9 (m, 3H,
Ar─H), 1.5–4.65 (2s, 5H, ─OC2H5), 3.88 (m, 1H,
HC─N), 9.02–9.10 (2 s, 2H, triazole), 4.27 (s, 1H,
─CHCl) ppm; 13C NMR (100 MHz, δ ppm) 115–148 (m,
3Ar─C), 146(s, 1C, C─OEt) 147.8 (s, 1C, C─OH) 13.6,
64.5(2s, 2C, ─C2H5), 168.5 (s, 1C, C═O), 62.2 (s, 1C,
CH─N), 153.5, 157 (2s, 2C, C═N triazole). GC–MS for
C13H13N4O3Cl [M + H]+, 308.06.
EXPERIMENTAL SECTION
Methods and materials.
High quality commercial
reagents and anhydrous solvents were used for synthesis
of all the compounds. The purity of the synthesized
compounds was checked by ascending TLC on precoated
silica-gel plates. Melting points were determined using an
electrothermal melting point apparatus and are
Synthesis
of
3-chloro-1-(4H-1,2,4-triazolyl)-4-(2,4-
dichlorophenyl)-azetidin-2-one (3c).
Off white solid, m.
p.162°C; Yield: 79%, FT─IR (KBr) 1710 cmÀ1 (>C═O
stretch. of azetidinone), 3115 cmÀ1 (Ar, CH─ stretch.),
684 cmÀ1(Ar─Cl Stretch.), 1585 cmÀ1 (C─N Stretch.),
789 cmÀ1 (CH─Cl stretch. of azetidinone). 1H NMR
(400 MHz, DMSO-d6, δ ppm): 7.06–7.98(m, 3H, Ar─H),
3.85 (m, 1H, HC─N), 9.02–9.10 (2s, 2H, triazole), 4.25
(d, 1H,─CHCl) ppm; 13C NMR (100 MHz, δ ppm) 126–
154 (m, 4Ar─C), 133.6 (s, 2C, C─Cl), 168.5 (s, 1C,
C═O), 62.3(s, 1C, CH─N), 68.5 (d, 1C, CH─Cl) 153.8
(s, 2C, C═N triazole). GC─MS for C11H7N4OCl3
[M + H]+ 315.96.
uncorrected. The FTIR spectra were taken on
a
1
SHIMADZU FTIR 8400 spectrophotometer in KBr. H
NMR and 13C NMR spectra (data reported in δ-ppm)
were recorded on Bruker Avance II-400 MHz, with TMS
as internal reference in DMSO-d6. Mass of the
synthesized compounds was identified by GC─MS.
General procedure for synthesis of 3-chloro-1-(4H-1,2,4-
triazolyl)-4-(substituted phenyl) azetidin-2-one (comp.
3a–3j).
A solution of N-arylidene-4H-1,2,4-triazole-4-
amine (0.02 mol) (Schiff bases) 2a–2j in 20 mL
ethanol, DABCO (0.01 mol) was added and stirred for
half an hour at 0–5°C, and then chloroacetyl chloride
(0.02 mol) was added drop-wise stirred the mixture for
about 3-7 h. The completion of the reaction was
monitored by TLC using Chloroform and MeOH (8:2)
as eluent. After completion of the reaction, the solution
were filtered. Filtrate was collected and solvent was
evaporated. The product was washed with water, dried,
and finally recrystallized from ethanol solvent. Residue
Synthesis
of
3-chloro-1-(4H-1,2,4-triazolyl)-4-(4-
nitrophenyl)-azetidin-2-one (3d).
Yellow solid, m.p.
183°C; Yield: 76%, FT─IR (KBr) 1610 cmÀ1 (>C═O
stretch. of azetidinone), 3137 cmÀ1 (Ar, CH─stretch.),
1575 cmÀ1 (C─N Stretch.) 808 cmÀ1 (CH─Cl stretching
of azetidinone), 1397 cmÀ1 (Ar─NO2). 1H NMR
(400 MHz, DMSO-d6, δ ppm): 7.5–8.21 (2d, 4H, Ar─H),
1
3.85 (m, H, HC─N), 9.02–9.10 (2s, 2H, triazole), 4.27(s,
1H, ─CHCl) ppm; 13C NMR (100 MHz, δ ppm) 120–150
(m, Ar─C), 147.95 (s, 1C, C─NO2), 168.5(s, 1C, C═O),
62.2(s, 1C, CH─N), 72.3 (d, 1C, CHCl), 153.8 (s, 2C,
C═N triazole). GC─MS for C11H8N5O3Cl [M + H]+,
contained
DABCO.
HCl
salt
was
separated
from the reaction mixture by simple filtration. Different
4-(4-aryl-2-azetidinonyl)-1,2,4-triazoles have synthesized
using same procedure, and purified by column
chromatography using chloroform: MeOH: ethylacetate
(8:2:1) as eluent.
Synthesis of 3-chloro-1-(4H-1,2,4-triazolyl)-4-(3,4,5-trimetho
xyphenyl)azetidin-2-one (3a). Brownish solid, m.p. 172°C;
293.06.
Synthesis of 3-chloro-1-(4H-1,2,4-triazolyl)-4-(4-hydroxy
phenyl)azetidin-2-one (3e). Off white solid, m.p. 190°C;
Yield: 78%, FT─IR (KBr) 1729 cm-1 (>C═O stretch. of
azetidinone), 3105 cmÀ1 (Ar, CH─stretch.), 1589 cmÀ1
(C─N Stretch.) 824 cmÀ1 (CH─Cl stretching of
Yield: 81%, FT─IR (KBr) 1730 cmÀ1 (>C═O stretch. of
azetidinone), 3115 cmÀ1 (Ar, CH─ stretch.), 1590 cmÀ1
(C─N Stretch.) 791 cmÀ1 (CH─Cl stretch. of
azetidinone), 1130 cmÀ1 (Ar─OCH3). 1H NMR
(400 MHz, DMSO-d6, δ ppm): 7.16(s, 2H, Ar─H), 3.75–
3.85 (2s, 9H, ─OCH3), 2.50 (t, 1H, HC─N), 9.02–9.10
(2s, 2H, triazole), 4.27 (d, 1H, ─CHCl) ppm; 13C NMR
(100 MHz, DMSO-d6, δ ppm) 127–158 (m, Ar─C),
55.9–60.2 (2s, 3C, ─OCH3), 168.5(s,1C,C═O), 60.2 (s,
1
azetidinone), 1323 cmÀ1 (Ar─OH). H NMR (400 MHz,
DMSO-d6, δ ppm): 7.1–7.9(2d, 4H, Ar─H), 5.26(Broard
peak, 1H,-OH), 3.85 (m, 1H, HC─N), 9.02–9310 (2s,
2H, triazole), 4.27(d, 1H, ─CHCl) ppm; 13C NMR
(100 MHz, δ ppm) 115–153.8 (m, 5C, Ar─C), 158.9 (s,
1C, ─C─OH), 162.3(s, 1C, C═O), 62.2 (s, 1C, CH─N),
69.21 (s, 1C, CHCl), 152.9 (s, 2C, C═N triazole).
GC─MS for C11H9N4O2Cl [M + H]+, 264.04.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of 2-Azetidinone Under Mild Conditions
Synthesis of 3-chloro-1-(4H-1,2,4-triazolyl)-4-(4-chlorophenyl)-
3.81(s, 3H, ─OCH3), 3.85 (m, 1H, HC─N), 9.02–9.10
(2s, 2H, triazole), 4.27(d, 1H, ─CHCl) ppm; 13C NMR
(100 MHz, δ ppm) 117–158 (m, 6C, Ar─C), 53.27 (s, 3C,
─OCH3), 168.8 (s, 1C, C═O), 65.7 (d, 1C, CHCl), 153.8
(s, 2C, C═N triazole). GC─MS for C12H11N4O2Cl
[M + H]+, 278.08.
azetidin-2-one (3f). Yellow solid, m.p. 175°C; Yield: 80%,
FT─IR (KBr) 1768 cmÀ1 (>C═O stretch. of azetidinone),
3080 cmÀ1 (Ar, CH─ stretch.), 1520 cmÀ1 (C─N Stretch.)
770 cmÀ1 (CH─Cl stretching of azetidinone), 680 cmÀ1
1
(Ar─Cl). H NMR (400 MHz, DMSO-d6, δ ppm): 7.06–7.8
(2d, 4H, Ar─H), 3.85 (m, 1H, HC─N), 9.02–9.10 (2s, 2H,
triazole), 4.27(d, 1H, ─CHCl) ppm; 13C NMR (100 MHz, δ
ppm) 127–158.(m, Ar─C), 132.3 (s, 1C, ─C─Cl), 166.5 (s,
1C, C═O), 62.2(d, 1C, CH─N), 68.4 (d, 1C, CHCl), 158.4 (s,
2C, C═N triazole). GC─MS for C11H8N4OCl2 [M + H]+,
Acknowledgments. One of the author (T. K.) is very much
grateful to UGC New Delhi for the award of Moulana Azad
National Fellowship. We are thankful to the Head, Department
of Chemistry, SIC of Dr H. S. Gour University, for providing
laboratory and other facility. Authors are also thankful the SAIF,
Chandigarh for carrying out 1H NMR and 13C NMR spectra.
282.05.
Synthesis of 3-chloro-1-(4H-1,2,4-triazolyl)-4-(4-bromophenyl)
azetidin-2-one (3g). Off white solid, m.p. 210°C; Yield: 76%,
FT─IR (KBr) 1720 cmÀ1 (>C═O stretch. of azetidinone),
3115 cmÀ1 (Ar, CH─stretch.), 1590 cmÀ1 (C─N Stretch.),
791 cmÀ1 (CH─Cl stretching of azetidinone), 610 cm-1
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(Ar─Br). H NMR (400 MHz, DMSO-d6, δ ppm): 7.3–
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methylphenyl) azetidin-2-one (3h).
Off white solid, m.
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stretch. of azetidinone), 3129 cmÀ1 (Ar, CH─stretch.),
1596 cmÀ1 (C─N Stretch.) 805 cmÀ1 (CH─Cl stretching
of azetidinone), 2937 cmÀ1 (Ar─CH3). 1H NMR
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1C, CHCl) 144.2 (d, 2C, C═N triazole). GC─MS for
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Synthesis of 3-chloro-1-(4H-1,2,4-triazolyl)-4-(4-methoxyphenyl)
azetidin-2-one (3i).
Brown solid, m.p.165°C; Yield: 72%,
FT─IR (KBr) 1712 cmÀ1 (>C═O stretch. of azetidinone),
3115 cmÀ1 (Ar, CH─ stretch.), 1590 cm-1 (C─N Stretch.)
791 cmÀ1 (CH─Cl stretching of azetidinone), 1130 cmÀ1
1
(Ar─OCH3). H NMR (400 MHz, DMSO-d6, δ ppm): 7.0–
7.6 (2d, 4H, Ar─H), 3.83 (s, 3H, ─OCH3), 3.85 (m, 1H,
HC─N), 9.02–9.10 (2s, 2H, triazole), 4.27 (d, 1H, ─CHCl)
ppm; 13C NMR (100 MHz, δ ppm) 127–160 (m, 6C, Ar─C),
55.84 (s, 3C, ─OCH3), 161.8 (s, 1C, C═O), 153.0 (s, 2C,
C═N triazole). GC─MS for C12H11N4O2Cl [M + H]+ 278.08.
Synthesis of 3-chloro-1-(4H-1,2,4-triazol-4-yl)-4-(3-metho
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xyphenyl) azetidin-2-one (3j).
White solid, m.p.122°C;
Yield: 75% FT─IR (KBr) 1680 cmÀ1 (>C═O stretch. of
azetidinone), 3125 cmÀ1 (Ar, CH─ stretch.), 1596 cmÀ1
(C─N Stretch.) 793 cmÀ1 (CH─Cl stretching of
azetidinone), 1133 cmÀ1 (Ar─OCH3). 1H NMR
(400 MHz, DMSO-d6, δ ppm): 7.0–7.6(m, 4H, Ar─H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. Khan, R. Yadav, and S. S. Gound
Vol 000
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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