Synthesis of quinolone substituted 2-azetidinone derivatives

Article abstract of DOI:10.2298/JSC120617081M

Acetanilide was converted into 2-chloro-3-formylquinoline by reaction with DMF-POCl₃ at 80-90 °C and then condensed with aromatic primary amines to give Schiff bases 3a-c. These Schiff bases were then reacted with acid chlorides in toluene in the presence of a base to give 1,3,4-trisubstituted-2- azetidinones. Copyright (C)2013 SCS.

Full text of DOI:10.2298/JSC120617081M

J. Serb. Chem. Soc. 78 (5) 621–625 (2013)
UDC 547.551.42+547.831+547.554+542.913
JSCS–4443
Short communication
SHORT COMMUNICATION
Synthesis of quinolone substituted 2-azetidinone derivatives
*
UDAY C. MASHELKAR , MUKESH S. JHA** and BEENA U. MASHELKAR
Organic Research Laboratory, S. S. and L. S. Patkar College, Goregaon (West),
Mumbai 400 062, India
(Received 17 June, revised 30 July 2012)
Abstract: Acetanilide was converted into 2-chloro-3-formylquinoline by reac-
tion with DMF–POCl3 at 80–90 °C and then condensed with aromatic primary
amines to give Schiff bases 3a–c. These Schiff bases were then reacted with
acid chlorides in toluene in the presence of a base to give 1,3,4-trisubstituted-2-
azetidinones.
Keywords: acetanilide; 2-chloro-3-formylquinoline; aromatic amine; acid chlo-
ride; tributylamine; 2-azetidinone.
INTRODUCTION
Malaria is one of the most widespread diseases in the world besides tuber-
culosis and AIDS. The World Health Organization estimates that about 40 % of
the world’s population presently lives under malarial threat and approximately
300–500 million cases of malaria occur annually, leading to 1–3 million deaths.
Mortality is particularly high in children under the age of five, accounting for
1,2
about 25 % of childhood deaths in Africa. Malaria is caused by different spe-
cies of Plasmodium, of which Plasmodium falciparum is the most virulent human
malarial parasite and the others include P. vivax, P. malariae and P. ovale. A
major reason for the continued severity of the worldwide malarial problem is the
increasing resistance of malarial parasites to the available antimalarial drugs,
such as chloroquine. Although continued attempts to develop a vaccine for mala-
ria are ongoing, drugs remain the only available treatment option.
Quinoline-containing compounds have long been used for the treatment of
malaria, beginning with quinine. The systematic modification of quinine led to
the potent and inexpensive 4-aminoquinoline drug, chloroquine, and other related
drugs. After worldwide development of drug resistance to chloroquine, the ratio-
*,** Corresponding authors. E-mails: (*)ucmashelkar@rediffmail.com;
(**)Jhamukesh1@rediffmail.com
doi: 10.2298/JSC120617081M
621
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MASHELKAR, JHA and MASHELKAR
nal approach in chemistry and screening efforts produced mefloquine, another
quinoline-containing compound that was highly active against the chloroquine
resistant strains of P. falciparum.
Since the development of mefloquine, there have been several reports of new
potent quinoline compounds. Most of these contain the 7-chloroquinoline nucleus
of chloroquine and vary in the length and nature of their basic amine side chain.
Currently, compounds such as amodiaquine are promising leads for the develop-
ment of new drugs.
The β-lactam class of compounds has served an important and highly suc-
cessful role in the pharmaceutical industry. Miracle drugs such as penicillins and
cephalosporins have significantly improved human health and life expectancy.
Although most penicillin- and cephalosporin-like compounds have been obtained
by biosynthesis, chemical modification of intermediates for bioassay of
antibacterial activity has become important because of the growing resistance of
bacteria to penicillin and cephalosporin-like compounds and the need for medi-
3,4
cines with more specific antibacterial activity. Developments in the field of
5–8
β-lactams
during the last decades indicate that the only essential feature for
the antibacterial activity in these compounds is the presence of the β-lactam
(2-azetidinone) ring. Azetidinone derivatives have also been recognized as TNF-
9
alpha converting enzyme (TACE) inhibitors and agents with new biological
10
11
12
13
activities, such as anticancer, anticoccidial, cardiovascular, antiviral,
14
15,16
mutagenic, anticonvulsant and anti-inflammatory.
Bearing this in mind, it was decided to synthesize 2-azetidinones that have
the quinoline moiety at position 3.
RESULTS AND DISCUSSION
2-Chloro-3-formylquinoline (2) was prepared according to a procedure re-
17
ported in literature by reacting acetanilide (1) with DMF–POCl at 80–90 °C
3
and characterized by its physical and spectral data, which were in accordance
with the literature. The IR spectrum of compound 2 showed a band for one car-
–1
1
bonyl group at 1726 cm and the H-NMR spectrum indicated the presence of
an aldehyde proton at δ 10.60 ppm. 2-Chloro-3-formylquinoline (2) was con-
densed with various aromatic amines to yield Schiff bases 3a–c. The reactions
were monitored by TLC. After completion of the reactions, the products were fil-
tered and dried to afford the Schiff bases 3a–c, which were characterized by their
physical and spectral data. In general their IR spectra showed the absence of a
–1
carbonyl band and the appearance of a band for –CH=N– at 1612 cm . Other
–1
1
bands were present at 1501 & 1593 cm . The H-NMR spectra showed the ab-
sence of an aldehyde proton and presence of a –CH=N– (azomethine) proton at δ
9.0 ppm.
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SYNTHESIS OF QUINOLINE SUBSTITUTED 2-AZETIDINONES
623
These Schiff bases 3a–c were then reacted with acid chlorides in the pre-
sence of a base to yield the 1,3,4-trisubstituted-2-azetidinones 4a–h. The IR
1
spectra of compounds 4a–h showed the absorption for one carbonyl. In the H-
NMR spectra, two doublets for C -H and C -H were present. The envisaged
3
4
reaction sequence is depicted in Scheme 1.
Scheme 1. The reaction sequence.
The structures of compounds 4a–h were established based on their IR and
1
H-NMR spectra. As reported in the literature, cis-isomer shows higher values of
18
the coupling constant than the trans-isomer. The majority of the isolated com-
pounds showed lower values of the coupling constant, confirming the trans-aze-
tidinone. However, a few of them showed a mixture of both, in which the trans-
azetidinones contained small amounts of cis-azetidinone (Table I).
EXPERIMENTAL
All the compounds were identified by examination of their spectral data and physical
properties. The reported yields refer to the isolated yields of the desired products. Melting
points were determined on Buchi-545 melting point apparatus and are uncorrected. The
progress of the reaction was monitored by TLC. The IR spectra were recorded on a Perkin
Available online at www.shd.org.rs/JSCS/
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Copyright (C)2013 SCS

624
MASHELKAR, JHA and MASHELKAR
1
Elmer Spectrum-1 (FTIR) instrument using KBr discs, The H- and 13C-NMR spectra were
recorded in CDCl3 using an Avance 400 MHz Bruker spectrometer with TMS as the internal
standard. The mass spectra were recorded on a Thermo Finigan Ion Trap GCMS Polaris Q
instrument. The dry reactions were performed under nitrogen with magnetic/mechanical
stirring. The analytical and spectral data of the synthesized compounds are given in the
Supplementary material to this paper.
TABLE I. Stereochemistry of compounds 4a–h
Compound
R1
R2
Isolated isomer
4a
4b
4c
4d
4e
4f
4-F
4-Cl
3-NO2
4-F
4-Cl
3-NO2
4-F
H
H
H
Trans
Trans:cis (86:14)
Trans
Trans:cis (78: 22)
Trans
4-OCH3
4-OCH3
4-OCH3
4-Cl
Trans
Trans
Trans
4g
4h
4-Cl
4-Cl
Synthesis of 2-chloro-3-formylquinoline (2)
To a stirred solution of acetanilide (6.75 g, 50.0 mmol) in dry DMF (10.95 g, 150.0
mmol) at 0–5 °C, POCl3 (92.1 g, 600 mmol) was added dropwise and the mixture was stirred
at 80–90 °C for a time ranging between 4–16 h. The mixture was then poured onto crushed
ice, stirred for 5 min and the resulting solid was filtered, washed well with water and dried.
The compounds were purified by recrystallisation from either ethyl acetate or acetonitrile.
General procedure for the synthesis of N-[(2-chloroquinolin-3-yl)methylene]benzenamine
derivatives (3a–c)
An intimate mixture of 2-chloro-3-formylquinoline (2) (10 mmol) and the corresponding
aromatic primary amine (11 mmol) was refluxed in 2-propanol (25 mL) for 6–7 h. The
progress of the reaction was monitored by TLC. After completion of the reaction, the reaction
mass was cooled to 10 °C and the product was filtered and washed with cold 2-propanol to
obtain the solid products.
General procedure for the synthesis of 1,3,4-trisubstituted-2-azetidinones (4a–h)
A mixture of an N-((2-chloroquinolin-3-yl)methylene)benzenamine derivative (10 mmol)
(3a–c), acid chlorides (20 mmol) and tri-n-butylamine (30 mmol) in toluene (50 mL) was
refluxed for 3–4 h. The progress of the reaction was monitored by TLC. After completion of
the reaction, the reaction mixture was then cooled to room temperature and 1:1 HCl (40–50
mL) was added. The organic layer was separated and washed with water, followed by
NaHCO3 solution and finally with water and dried over anhydrous sodium sulfate before the
solvent was removed under reduced pressure. The required compound was isolated using
column chromatography (n-hexane:ethyl acetate = 90:10) and thereafter it was crystallized
from ethanol.
CONCLUSION
In conclusion, novel 4-(2-chloroquinolin-3-yl)-1,3-diphenylazetidin-2-ones
were synthesized under mild condition starting from acetanilide.
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SYNTHESIS OF QUINOLINE SUBSTITUTED 2-AZETIDINONES
625
SUPPLEMENTARY MATERIAL
Analytical and spectral data for the synthesized compounds are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgements. The authors are thankful to management of the Ipca Laboratories,
Dr. Ashok Kumar, Dr. Suneel Dike, Dr. S.R. Soudagar, Dr Gaurav Sahal and Mr. Brajesh
Sharma for providing the necessary support for the work.
И З В О Д
СИНТЕЗА ХИНОЛИЛ-СУПСТИТУИСАНИХ 2-АЗЕТИДИНОНА
UDAY C. MASHELKAR, MUKESH S. JHA и BEENA U. MASHELKAR
Organic Research Laboratory, S. S. and L. S. Patkar College, Goregaon (West), Mumbai 400 062, India
Ацетанилид је преведен у 2-хлор-3-формилхинолин помоћу DMF–POCl3 загре-
вањем на 80–90 °C, a кондензацијом са примарним аминима производ је преведен у
Шифове базе 3а–c. Шифове базе реакцијом са хлоридима карбоксилних киселина у
присуству базе, у толуену, као производ дају 1,3,4-трисупституисане 2-азетидине.
(Примљено 17. јуна, ревидирано 30. јула 2012)
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