Synthesis and antimicrobial activity of azetidin-2-one fused 2-chloro-3-formyl quinoline derivatives

Article abstract of DOI:10.13005/ojc/320423

Azetidin-2-one fused 2-chloro-3-formyl quinolines derivatives, 3-chloro-4-(2-chloro-8/7/6-methoxyquinolin-3-yl)-1-(2,4-dinitro/4-nitro phenylamino)azetidin-2-one,3-chloro-4-(2-chloro-8/7/6-chloroquinolin-3-yl)-1-(2,4-dinitro/4-nitro phenylamino)azetidin-2-one, 3-chloro-4-(2-chloro-8/7/6-methylquinolin-3-yl)-1-(2,4-dinitro/4-nitrophenylamino) azetidin-2-one were synthesized by four steps, respectively from N-arylacetamides, 2-chloro-3-formyl quinolines, 2,4-dinitro/4-nitro phenyl hydrazine reflux with chloroacetyl chloride and triethyl amine. However yields of quinolines having electron donating groups in all cases. The structures of the synthesized compounds have been established on the basis of physical and spectral data. The antibacterial and antifungal activity of these compounds was tested by filter paper disc method against Staphylococcus aureus (MTCC96), Escherichia coli (MTCC722) and Candida albicans (MTCC183). The results showed that azetidin-2-one fused 2-chloro-3-formyl quinolines derivatives are better in inhibiting the growth of both types of organisms. Compounds AZT b2, AZT b3 to AZT g2, AZT g3 were found to be more potent compared to standard drug.

Full text of DOI:10.13005/ojc/320423

ISSN: 0970-020 X
CODEN: OJCHEG
016, Vol. 32, No. (4):
Pg. 1977-1982
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
2
www.orientjchem.org
Synthesis and Antimicrobial Activity of Azetidin-2-one
Fused 2-Chloro-3-formyl Quinoline Derivatives
1
1
2
GOVIND NAYAK *, BIRENDRA SHRIVASTAVA and AKHLESH KUMAR SINGHAI
1
School of Pharmaceutical Sciences, Jaipur National University, Jaipur- 302 025, India.
2
Lakshmi Narain College of Pharmacy, Bhopal- 462 021, India.
Corresponding author E-mail : nayak.govind@rediffmail.com
http://dx.doi.org/10.13005/ojc/320423
(Received: June 13, 2016; Accepted: July 28, 2016)
ABSTRACT
Azetidin-2-one fused 2-chloro-3-formyl quinolines derivatives, 3-chloro-4-(2-chloro-8/7/6-
methoxyquinolin-3-yl)-1-(2,4-dinitro/4-nitro phenylamino)azetidin-2-one,3-chloro-4-(2-chloro-8/7/6-
chloroquinolin-3-yl)-1-(2,4-dinitro/4-nitro phenylamino)azetidin-2-one, 3-chloro-4-(2-chloro-8/7/6-
methylquinolin-3-yl)-1-(2,4-dinitro/4-nitrophenylamino) azetidin-2-one were synthesized by four
steps, respectively from N-arylacetamides, 2-chloro-3-formyl quinolines, 2,4-dinitro/4-nitro phenyl
hydrazine reflux with chloroacetyl chloride and triethyl amine. However yields of quinolines having
electron donating groups in all cases. The structures of the synthesized compounds have been
established on the basis of physical and spectral data. The antibacterial and antifungal activity of
these compounds was tested by filter paper disc method against Staphylococcus aureus (MTCC96),
Escherichia coli (MTCC722) and Candida albicans (MTCC183).The results showed that azetidin-2-
one fused 2-chloro-3-formyl quinolines derivatives are better in inhibiting the growth of both types of
organisms.Compounds AZT b2, AZT b3 to AZT g2, AZT g3 were found to be more potent compared
to standard drug.
Keywords: 2-chloro-3-formyl-quinoline, Vilsmeier-Haack reagent, 2, 4-dinitro/4-nitro
phenyl hydrazine, triethyl amine, chloroacetyl chloride, antimicrobial activity.
INTRODUCTION
are used for a convenient starting material of various
further substituted quinoline.
Substituted quinolines are very simply,
efficiently and conveniently synthesized in less time
and high yield with less amount of raw material under
mild condition with the help of Vilsmeier-Haack
1
Formylation of heterocyclic compounds ,
may be achieved by heating heterocyclic compound
withVilsmeier reagent i.e (DMF+POCl )phosphorous
3
reagent (DMF+POCl ) and substituted acetanilide.
Quinoline has been posssess a wide spectrum of
biological activities.Now a days quinoline derivatives
oxychlorideanddimethylformamide, theintermediate
is hydrolysed in the presence of mild base give
2-(ortho)-substituted heterocyclic compound . This
3
2

1978
NAYAK et al., Orient. J. Chem., Vol. 32(4), 1977-1982 (2016)
reaction is known as Vilsmeier-Haack reaction.
The treatment of infectious diseases still remains
an important and challenging problem. The search
METHODS AND MATERIALS
All chemicals were used of analytical grade
of novel antimicrobial agents is a field of current from Chemdyes Corporation (Chemco) limited. All
and growing interest. Many compounds have been melting points were taken in open capillaries tube
synthesized with this aim;their clinical use has been and are an correct. The progress of all reaction of
limited by their relatively high risk of toxicity, bacterial the synthesized compound was monitored by TLC
3
-4
resistance and/or pharmacokinetic deficiencies
.
i.e (Thin layer chromatography). TLC was run using
According to the literature, pyrazoloquinoline and silica gel PF254, 366 as an adsorbent and ethyl acetate
triazolo-thiadiazole quinoline derivatives are reported - n-hexane in different ratio as eluent. Spot were
to possess various biological activities such as visualized using solid fumes, by keeping ofTLC plate
5
6
7
antibacterial , antifungal anti-inflammatory . As a in iodine chamber.
part of our continuing interest, we have investigated
for the first time cyclic azetidin-2-one fused 2-chloro-
3-formyl quinoline derivatives with an aryl hydrazine
group.
REACTION
Step I
Conc.HCl
Step I
R
R
(CH CO) 0
3 2
+
2
NH
NHCOCH3
1
2
Structure 1& 2 R= 2-OCH , 3-OCH , 4-OCH , 2-Cl, 3-Cl, 4-Cl
3
3
3
Step II
DMF-POCl3
CHO
0
R
R
8
0-90 CStep II
NHCOCH3
N
Cl
2
3
Structure 3 R= 8-OCH , 7-OCH , 6-OCH3, 8-Cl, 7-Cl, 6-Cl
3
3
Step III
CHO
CH=N-NH-Ar
Cl
R
H NNH-Ar
2
+
R
Step III
N
Cl
N
3
4 b2, 4 c2, 4 d2, 4 e2, 4 f2, 4 g2
b3, 4 c3, 4 d3, 4 e3, 4 f3, 4 g3
4

NAYAK et al., Orient. J. Chem., Vol. 32(4), 1977-1982 (2016)
1979
Step III
Ar
NO2
4
4
b2, 4 c2, 4 d2, 4 e2, 4 f2, 4 g2
NO2
NO2
b3, 4 c3, 4 d3, 4 e3, 4 f3, 4 g3
Step IV
CH
NH Ar
Cl
H
(
C H ) N
Step IV
ClCH COCl
2 5 3
R
+
2
C
O
R
Cl
Cl
N
CH
N-NH
N
Ar
4
4
b2, 4 c2, 4 d2, 4 e2, 4 f2, 4 g2
b3, 4 c3, 4 d3, 4 e3, 4 f3, 4 g3
AZT b2-AZT g2
AZT b3-AZT g3
Table 1: Physical data of synthesized compounds
S.
No.
Code
Molecular
formula
Molecular
Weight (gm)
Melting
point
Percentage R value(Ethylacetate
f
yield
: n-hexane)
o
1
2
3
4
5
6
7
8
9
1
1
1
1
.
.
.
.
.
.
.
CFQ
C H NOCl
191.616
478.690
434.231
478.690
434.231
478.690
434.231
482.321
436.542
482.321
436.542
482.321
436.542
144-146 C
79
74
55
68
61
81
74
80
89
84
64
56
92
0.67
0.76
0.65
0.69
0.89
0.58
0.68
0.89
0.75
0.72
0.61
0.97
0.79
10
6
o
AZT b2
AZT b3
AZT c2
AZT c3
AZT d2
AZT d3
AZT e2
AZT e3
AZT f2
AZT f3
AZT g2
AZT g3
C H Cl N O
264-267 C
19
13
2
5
6
4
6
4
6
4
5
3
5
3
5
3
o
C H Cl N O
210-214 C
19
14
2
4
o
C H Cl N O
228-235 C
19
13
2
5
o
C H Cl N O
186-189 C
19
14
2
4
o
C H Cl N O
219-225 C
19
13
2
5
o
C H Cl N O
164-167 C
19
14
2
4
o
C H Cl N O
211-214 C
18
10
3
5
o
C H Cl N O
189-192 C
18
11
3
4
o
0
1
2
3
C H Cl N O
196-198 C
18
10
3
5
o
C H Cl N O
167-169 C
18
11
3
4
o
C H Cl N O
187-192 C
18
10
3
5
o
C H Cl N O
156-162 C
18
11
3
4
Experimental Procedure for
s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet,
dd-doublet of doublet ( HNMR).
IR spectra were recorded on a FT-IR
1
1
(
Bruker) spectrophotometer, HNMR Bruker Avance
II 400 MHz instrument using DMSO as solvent
and TMS as internal reference (Chemical shift in
ä, ppm). The following abbreviations were used to
indicate the position of functional groups in term
of stretching and bending (FT-IR), peak multiplicity
Step I Preparation of ortho substituted
acetanilide
Aniline (5 ml) is dissolved in hydrochloric
acid (4.6 ml concentrated hydrochloric acid and
8, 9
12.5ml water) in a beaker. To the clear solution are

1980
NAYAK et al., Orient. J. Chem., Vol. 32(4), 1977-1982 (2016)
added acetic anhydride (6.5 ml).The mixture is stirred
until acetic anhydride has completely reacted. The
mixture are immediately poured in to a solution of
sodium acetate (8.3 gm) in water (25 ml).The solution
is stirred and cooled in ice.The separated acetanilide
is filtered. It is recrystallized from boiling water
fumes of hydrogen chloride. It is manufactured
industrially on a large scale from phosphorus
trichloride and oxygen or phosphorus pentoxide. It
is mainly used to make phospha (Table 1).
Step III Preparation of 2-chloro-8-methoxy-3-
((2, 4-dinitro/4-nitro phenylhydrazono) methyl)
quinoline (4b2-4g2 and 4 b3-4 g3)
(
(
100-125 ml) to which ethyl alcohol has been added
Table 1).
To a DMF solution of 2-chloro-8-
Step II Preparation of 2-chloro-3-formyl-
quinoline CFQ 8
methoxyquinoline-3-carbaldehyde 6 mmoles were
added aryl hydrazine (phenyl hydrazine 11 mmoles)
and refluxed for three hours, and then left to cool to
room temperature or the solvent was removed and
the separated solid was poured in to the water. The
precipitated product was filtered, washed well with
water and dried (Table 1).
, 9
To
a
s o l u t i o n o f a c e t a n i l i d e
(
N-phenylacetamide) (5 mmoles) in dry DMF (15
o
mmoles) at 0-5 C POCl (60 mmoles) was added
3
dropwise with stirring and the mixture was then
o
stirred at 80 – 100 C for time ranging between 4-16
hr. The mixture was poured on to crush ice, stirred
for 5 minutes and the resulting solid filtered, washed
well with water and dried. The compounds were
recrystallized from ethyl acetate.Phosphoryl chloride
Step IV Preparation of 3-chloro–4-(2-chloro–8-
methoxyquinolin–3-yl) – 1- (2, 4-dinitro/4-nitro
phenylamino)–azetidin–2-one (AZT b2-AZTg2
and AZT b3-AZT g3)
(
commonly called phosphorus oxychloride) is a
colorless liquid with the formula POCl .It hydrolyses
in moist air to phosphoric acid to release choking
The compound 2-chloro-8-methoxy-3-((2,
4-dinitro/4-nitro phenylhydrazono) methyl) quinoline
3
Table 2: Antimicrobial activities of Compounds
AZT b2-AZT g3 (Diameter of the zone of inhibition in mm)
Compound
Antibacterial activity
Antifungal activity
Staphylococcus
Escherichia coli
Candida albicans
aureus(MTCC96)
(MTCC722)
(MTCC183)
AZT b2
AZT b3
AZT c2
AZT c3
AZT d2
AZT d3
AZT e2
AZT e3
AZT f2
AZT f3
AZT g2
AZT g3
Standard
11
14
13
15
11
14
13
15
11
14
13
15
18
0
9
10
8
11
9
13
14
13
8
14
13
12
6
13
14
12
18
0
9
12
10
9
7
11
8
10
13
0
*Control
*
The solvent (control) is Dimethy formamide
1
2
3
. Staphylococcus aureus reference compound Amikacin
. Escherichia coli reference compound Amikacin
. Candida albicans reference compound Ketoconazole

NAYAK et al., Orient. J. Chem., Vol. 32(4), 1977-1982 (2016)
1981
step-III b1 (0.01 mol) was dissolved in DMF (40ml)
and triethylamine (0.02 mol) was added to it.
Chloroacetyl chloride (0.02 mol) was added dropwise
a period of 30 minutes. The reaction mixture was
refluxed for 5 hr, and filtered to separate the solid
formed. The filtrate was poured on to crushed ice,
the product was filtered and recrystallized from
ethylacetate (Table 1).
1H, H-4) 8.34 (m, 1H, H-8) 7.28 (C=O group d, 1H)
3.17 (m, CH-N aromatic)
3-chloro-4-(2, 8/7/6-dichloroquinolin-3-yl)-
1-(4-nitro phenylamino) azetidin-2-one (AZT e3,
-
1
AZT f3, AZT g3): FT-IR cm 3362.55 (C – H Str, Ar)
1681.83 (C=O Str) 1531.60 (C = N Str) 1418.67 (C
1
– N Str, Ar) 776.88 (C – Cl, Bending). HNMR (400
MHz, DMSO), d; 7.40 – 8.01 (m,Ar-H) 10.24 (s, 1H,
CH Heteroaromatic proton) 8.03 (s, 1H, H-4) 7.50
(m, 1H, H-7) 6.58 (C=O, d, 1H).
Characterization data of the synthesized
compound1
0-11
-
1
Acetanilide: FT-IR cm 3295 (N-H), 1664
1
Antimicrobial activity12-18
(
CO), 1584 (C=C), HNMR (400 MHz, DMSO),
d; 8.72 (s, 1H, NH), 2.1 (s, 3H, CH ), 7.2 (d, 1H,
Ar-H).2-Chloro-3-formyl quinoline (CFQ):FT-IR cm
The compounds AZT b2 - AZT g3 were
3
-1
tested for their antibacterial activity and antifungal
activity by filter paper disc method using nutrient broth
medium (contained g/L: beef extract 30gm; Casein
hydrolysate 17.5 gm; soluble starch 1.5gm; pH 7.4).
The Gram-positive and Gram-negative bacteria
utilized in this study consisted of Staphylococcus
aureus, Escherichia coli and fungi Candida albicans.
In the filter paper disc method, sterile paper discs
(05mm) impregnated with compound dissolved
in DMF (Dimethyl formamide) at concentration
200µg/mL were used. Then, the paper disc
impregnated with the solution of the compound
tested was placed on the surface of the media
inoculated with the microorganism.The plates were
2896.53 (C – H Str,Ar) 1684.39 (C=O Str) 1574.14
(
7
C=N Str) 1455.03 (C = C Str) 1367.35 (C – N Str,Ar)
49.25 (C – Cl Bending) HNMR (400 MHz, DMSO),
1
d; 10.5 (s, 1H, CHO), 8.8 (s, 1H, H-4), 8.1 (m, 1H,
H-6), 7.7 (m, 1H, H-7)
3
- c h l o r o – 4 - ( 2 - c h l o r o – 8 / 7 / 6 -
methoxyquinolin–3-yl)-1-(2, 4-dinitro phenylamino)
azetidin - 2 –one (AZT b2, AZT c2, AZT d2):FT-IR
–
-
1
cm 2998.1(C-H Ar), 3449.10 (N-H Str), 1682.51
(
C=O Str), 1139.46 C – N (Str Ar), 758.25 (C – Cl
1
Bending). HNMR (400 MHz, DMSO), d; 12.10 (s,
NH) 9.21 (s, 1H, CHO) 7.98 (s, 1H, C4- H) 7.67
o
(
m,CH-5) 3.83 (s, CH ).
incubated at 37 C for sufficient period of time. After
3
incubation were noted and the results are given in
Table 2.
3
- c h l o r o – 4 - ( 2 - c h l o r o – 8 / 7 / 6 -
methoxyquinolin–3-yl)-1-(4-nitro phenylamino)
azetidin - 2 – one (AZT b3, AZT c3, AZT d3):
–
RESULTS AND DISCUSSION
-
1
FT-IR cm 3262.86 (N– H Str, Ar) 1696.94 (C=O
Str) 1566.45 (C=N Str) 1592.64 (N-H bending in
All the synthesized compounds were
confirmed by their spectral data (Table 1) and the
screened for anti-bacterial against Staphylococcus
aureus, Escherichia coli and ant-fungal activity
against Candida albicans, compounds (AZT b2-
AZT g2) showed moderate to good antibacterial
and antfungal activity (Table 2) when compared
to that of reference Amikacin and Ketoconazole
respectively. The structures of all compounds
1
amide) 1052.68 (CH O Str). HNMR (400 MHz,
DMSO), d; 7.82 – 8.01 (m, Ar-H) 10.37 (s, 1H, CH
heteroaromatic proton) 8.43 (s, 1H, H-4) 7.79 (d,
C=O) 4.1 (d, 1H CH-Cl ) 3.35 (s, 3H, OCH ) 7.32
3
3
(
d, 1H, H-5).
3
-chloro-4-(2,8/7/6-dichloroquinolin-3-yl)-
1
-(2, 4-dinitro phenylamino) azetidin-2-one (AZT
e2, AZT f2, AZT g2): FT-IR cm 3487.00 (C – H Str,
Ar) 3306.34 (N-H Str) 1748.36 (C=O Str) 1519.21
C = N Str) 1335.03 (C – N Str, Ar) 1060.31 (CH O,
Str) 794.11 (C – Cl, Str) 722.06 (C – Cl Bending).
-
1
1
were confirmed by FT-IR and H NMR spectra
(2.3 sections). The FT-IR spectra of the azetidine
fused 2-chloro-3-formyl quinoline derivatives AZT
b2 –AZT g2 showed absorption bands at about
(
3
1
-1
HNMR (400 MHz, DMSO), d; 7.31 – 8.17 (m,Ar-H)
0.16 (s, 1H, CH Heteroaromatic proton) 8.78 (s,
1748-1708 cm characteristic for C=O stretching
-
1
1
vibration, 1528-1519 cm for C=N Stretching

NAYAK et al., Orient. J. Chem., Vol. 32(4), 1977-1982 (2016)
1982
-
1
associated with quinoline 2927 cm for C-H aromatic
quinolines the possible transformations of these
functionalities could afford the new quinolines (AZT
b2-AZT g2), which are equally important synthon for
the synthesis of fused quinoline systems.
-
1
stretching, 759 cm absorption for C-Cl stretching,
absorption band at 3306.34 cm for N-N=C vibration
provided confirmatory evidence for ring closure.
-1
1
Further support was obtained from the HNMR
spectra, resonance assigned 10.6 d (s, 1H, CHO),
8
.5 d (s,1H, H-4), 2.6 d (s, 3H, CH ) for 6-methyl/7-
ACKNOWLEDGEMENTS
3
methyl/8-methyl (2.8 d, s,3H), 4.0 d (s, 3H, OCH3)
for 6-methoxy/7-methoxy/8-methoxy, 10.7 (s, 1H,
CHO), 8.5 (s, 1H, H-4), 7.7 (m, 1H, H-5), 7.5 (s,
The authors are grateful to the LNCP,
Bhopal for providing the necessary facilities to carry
out this research work, and also thankful to the SAIF
Lab, Panjab university, Chandigarh for recording the
spectral data of the compounds.
1H, H-8), 7.2( m, 1H, H-6), 10.8 (s, 1H, CHO), 8.6
(
(
s, 1H, H-4), 8.1 (m, 1H, H-8), 7.7 (m, 1H, H-7), 7.6
s, 1H, H-5) for the confirmation of the compounds.
Having obtained chloro and formyl group substituted
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