Synthesis of 2-azetidinones substituted coumarin derivatives

Article abstract of DOI:10.2298/JSC111024045M

α-Naphthol was converted into 4-methyl-2H-benzo[h]chromen-2-one by reacting with ethyl acetoacetate in the presence of bismuth trichloride. The product was oxidized to 2-oxo-2H-benzo[h]chromene-4-carbaldehyde and then condensed with aromatic primary amines to give Schiff bases 3a-d. These Schiff bases were then reacted with acid chlorides in the presence of a base in toluene to give 1,3,4-substituted 2-azetidinones.

Full text of DOI:10.2298/JSC111024045M

J. Serb. Chem. Soc. 77 (10) 1339–1344 (2012)
JSCS–4355
UDC 542.913+547.85+547.587.51+
547.23–31
Original scientific paper
Synthesis of 2-azetidinones substituted coumarin 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 24 October 2011, revised 5 April 2012)
Abstract: α-Naphthol was converted into 4-methyl-2H-benzo[h]chromen-2-one
by reacting with ethyl acetoacetate in the presence of bismuth trichloride. The
product was oxidized to 2-oxo-2H-benzo[h]chromene-4-carbaldehyde and then
condensed with aromatic primary amines to give Schiff bases 3a–d. These
Schiff bases were then reacted with acid chlorides in the presence of a base in
toluene to give 1,3,4-substituted 2-azetidinones.
Keywords: α-naphthol; selenium dioxide; aromatic amine; acid chloride; ethyl
acetoacetate; tri-n-butylamine; 2-azetidinone.
INTRODUCTION
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.
1–4
Developments in the field of β-lactams
during the last decades indicate
that the only essential feature for antibacterial activity in these compounds is the
presence of the β-lactam (2-azetidinone) ring. It was reported that the presence of
an aliphatic substituent on the nitrogen and a carbonyl group on the imine carbon
5
does not give any β-lactam via the di-anion–imine cycloaddition reaction. How-
ever, van der Veen reported the formation of cis-β-lactams via [2+2] cycloaddi-
tion reaction involving an in situ prepared ketene and an imine derived from phe-
6
nyl glyoxal and 2-phenylethylamine. Azetidinone derivatives are also reco-
7
gnized as transcatheter arterial chemoembolization (TACE) inhibitors and agents
8
9
with new biological activities, such as anticancer, anticoccidial, cardiovas-
10
11
12
13,14
cular, antiviral, mutagenic, anticonvulsant and anti-inflammatory agents.
A number of publications and patents have appeared in recent years discus-
sing the synthesis of different types of coumarin derivatives and their antibacte-
Corresponding authors. E-mail: (*)ucmashelkar@rediffmail.com;
(**)Jhamukesh1@rediffmail.com
doi: 10.2298/JSC111024045M
1339
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MASHELKAR, JHA and MASHELKAR
15
16
17
rial, antifungal and other biological properties. The coumarin skeleton is
18
also present in novobiocin and other recently discovered antibiotics, such as
19
20
coumermycin and chartreusin. Coumarins substituted with different hetero-
cycles at the position 4 have been shown to possess promising antibacterial ac-
21
tivity. Bearing this in mind, it was decided to synthesize 2-azetidinones that
have a coumarin moiety substituent at position 4.
RESULTS AND DISCUSSION
22
The 4-methyl coumarin derivative was obtained in excellent yield (92 %)
by reacting α-naphthol with ethyl acetoacetate in the presence of bismuth trichlo-
–1
ride (5 mol %). The IR spectrum of compound 1 showed a band at 1711 cm for
1
C=O stretching along with other bands. The H-NMR spectrum of compound 1
in CDCl showed a doublet at δ 2.56 ppm for methyl protons and a quartet at δ
3
6.41 ppm for C –H. It was then oxidized to the corresponding formyl derivative
3
2 with selenium dioxide. The IR spectrum of compound 2 in KBr showed peaks
–1
1
at 1727 and 1706 cm for the two carbonyl groups and the H-NMR spectrum of
2 showed the presence of signal at δ 10.23 ppm for the aldehydic proton. The
formyl compound 2 was condensed with various aromatic amines to yield the
23
Schiff bases 3a–d. The IR spectra of the compounds 3a–d showed an absorp-
–1
1
tion for only one carbonyl group and band for C=N at 1634 cm . The H-NMR
spectra showed the absence of an aldehydic proton and presence of the –CH=N–
proton at δ 8.8 ppm. These Schiff bases were then reacted with acid chlorides in
the presence of base to give the 1,3,4-substituted 2-azetidinones 4a–l. The IR
1
spectra of compounds 4a–l showed absorptions for two carbonyls. In the H-NMR
spectra there were two doublets for C –H and C –H. The envisaged reaction
3
4
sequence is depicted in Scheme 1.
1
Structures of the compounds 4a–l were established by their IR and H-NMR
spectra. Their cis/trans stereochemistry depends mainly on the substituent pre-
sent on the ketene part, as usually the imine is presumed to exist in the more
stable E-configuration. The results can be better explained through a zwitter ion
intermediate formed by the attack of the nitrogen lone pair of the imine on the
24,25
ketene, occurring through the less hindered side of the latter.
The origin of
the diastereoselectivity and influence of reaction conditions on the diastereose-
26
lectivity in the Staudinger syntyhesis have been carefully investigated recently.
The results indicated that:
1) The diastereoselectivity is controlled by the competition between the di-
rect ring-closure and the isomerization of the imine moiety in the zwitter ionic
intermediates generated from imines and ketenes;
2) electron donating ketene substituents and electron withdrawing imine sub-
stituents accelerate the direct ring closure, leading to a preference for a cis-β-lac-
tam formation, while electron withdrawing ketene substituents and electron do-
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SYNTHESIS OF 2-AZETIDINONES SUBSTITUTED COUMARIN DERIVATIVES
1341
nating imine substituents slow the direct ring closure, leading to a preference for
trans-β-lactam formation;
3) the electronic effect of the substituents on the isomerization is a minor
factor in influencing the diastereoselectivity;
4) different ketene-generation pathways, solvent, additives usually existing
in the reaction system, and photo- and microwave-irradiations do not affect the
diastereoselectivity;
5) the reaction temperature really influences the diastereoselectivity for some
reactions and can be used to tune the same. The stereoselectivity was determined
1
by H-NMR. The cis isomer shows a higher value of coupling constant than the
27
trans isomer (Table I).
Scheme 1. Synthesis route of 4-methylcoumarin derivative.
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 a Buchi-545 melting point apparatus and are uncorrected. The
progress of the reaction was monitored by TLC. The IR spectra were recorded by Perkin
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MASHELKAR, JHA and MASHELKAR
Elmer Spectrum-1 (FTIR) using the KBr disc technique, The 1H-NMR and 13C-NMR spectra
were recorded in CDCl3 using a Bruker Avance 400 MHz spectrometer (chemical shifts, δ, are
in ppm) 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 nit-
rogen with magnetic/mechanical stirring.
TABLE I. Stereochemistry of compounds 4a–l
Compound
R1
R2
Isolated isomer
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-F
4-Cl
4-OCH3
3-NO2
4-F
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
4-OCH3
4-OCH3
4-OCH3
4-OCH3
Trans
Trans
Cis
Trans
Trans
Trans
Cis
Trans
Cis
Cis
4-Cl
4-OCH3
3-NO2
4-F
4-Cl
4-OCH3
3-NO2
4j
4k
4l
Cis
Trans
4-Methyl-2H-benzo[h]chromen-2-one (1)
A mixture of α-naphthol (5 mmol) and ethyl acetoacetate (5 mmol) and BiCl3 (5 mol %)
was heated at 110 °C for 2 h. The completion of the reaction was monitored by TLC. The
reaction mixture was cooled to room temperature and poured into 10 g of crushed ice. The
crystalline product was collected by filtration under vacuum suction and washed with cold
water. The pure product was obtained by recrystallization from hot ethanol.
2-Oxo-2H-benzo[h]chromene-4-carbaldehyde (2)
Compound 1 (0.10 mmol) was dissolved in xylene (50 ml) at 60–70 °C, and then SeO2
(0.13 mmol) was added to the solution, which was refluxed for 6–7 h. The hot reaction mix-
ture was filtered to remove the insoluble selenium. The filtrate gave fine crystalline product
on cooling to 10 °C.
General procedure for the synthesis of 4-[(phenylimino)methyl]benzo[h]chromen-2-ones (3a–d)
An intimate mixture of the 4-formyl derivative compound (2) (10 mmol) and corres-
ponding aromatic primary amine (11 mmol) was refluxed in toluene for 6–7 h with azeotropic
removal of the water formed during the reaction. The reaction was monitored by TLC. After
completion of the reaction, the reaction mass was cooled to 10 °C and the product was washed
with cold toluene to obtain the solid products.
General procedure for synthesis of 4-(2-oxo-2H-benzo[h]chromen-4-yl)-1,3-diphenylazetidin-
-2-ones (4a–l)
An intimate mixture of the 4-imino coumarin derivatives (10 mmol) (3a–d), the required
acid chloride (20 mmol) and tri-n-butylamine (30 mmol) in toluene was refluxed for 3–4 h.
The reaction was monitored by TLC until the absence of 4-imino coumarins. Reaction mass
was then cooled to room temperature and 40–50 ml 1:1 HCl:H2O added. The organic layer
that separated was washed with water followed by NaHCO3 solution and finally with water.
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SYNTHESIS OF 2-AZETIDINONES SUBSTITUTED COUMARIN DERIVATIVES
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After drying over anhydrous Na2SO4, the solvent was removed under reduced pressure.
Compound was isolated using flash chromatography and thereafter crystallized using ethanol.
CONCLUSION
In conclusion, novel 4-(2-oxo-2H-benzo[h]chromen-4-yl)-1,3-diphenylazeti-
din-2-ones were synthesized under mild conditions starting from α-naphthol.
SUPPLEMENTARY MATERIAL
Analytic and spectral data of 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 the management of Ipca Laboratories,
Dr. Suneel Dike, Dr. S. R. Soudagar, Dr Gaurav Sahal and Mr. Brajesh Sharma, for providing
the necessary support for this study.
И З В О Д
СИНТЕЗА 2-AЗЕТИДИНОН-СУПСТИТУИСАНИХ ДЕРИВАТА КУМАРИНА
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
У реакцији α-нафтола и етил-ацетоацетата, у присуству бизмут-трихлорида, добијен
је 4-метилбензо[h]хромен-2-он. Оксидацијом производа добијен је 2-оксо-2H-бензо[h]-
хромен-4-карбалдехид који кондензацијом са ароматичним примарним аминима даје
Шифове базе 3a–d. Шифове базе у реакцији са хлоридима киселина, у присуству базе, у
толуену као производ дају супституисане 2-азетидиноне.
(Примљенo 24. октобра 2011, ревидирано 5. априла 2012)
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