A simple, one pot synthesis of furo[3,2-c]chromenes and evaluation of antimicrobial activity

Article abstract of DOI:10.1016/j.bmcl.2016.09.022

Synthesis of a number of 2-cyano-4-oxo-3-phenyl-3,4-dihydro-2H-furo[3,2-c]chromene-2-carboxylate compounds (5) have been accomplished by a simple, multicomponent one pot reaction and evaluated for in vitro antimicrobial activity against different Gram-pos

Full text of DOI:10.1016/j.bmcl.2016.09.022

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A simple, one pot synthesis of furo[3,2-c]chromenes and evaluation
of antimicrobial activity
Ashok Kale a, Chiranjeevi Bingi a, Sarada Sripada b, C. Ganesh Kumar b, Krishnaiah Atmakur a,c,
⇑
a Crop Protection Chemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
b Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
c Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a number of 2-cyano-4-oxo-3-phenyl-3,4-dihydro-2H-furo[3,2-c]chromene-2-carboxylate
compounds (5) have been accomplished by a simple, multicomponent one pot reaction and evaluated
for in vitro antimicrobial activity against different Gram-positive and Gram-negative bacterial strains.
The outcome of the screening study showed that compound 5c exhibited promising activity against
Micrococcus luteus MTCC 2470 and Klebsiella planticola MTCC 530. Whereas, compound 5g exhibited
excellent activity against Bacillus subtilis MTCC 121, Micrococcus luteus MTCC 2470, Klebsiella planticola
MTCC 530, Escherichia coli MTCC 739 and displayed a moderate activity against Staphylococcus aureus
MTCC 96 and Candida albicans MTCC 3017 when compared with Ciprofloxacin (standard control).
Ó 2016 Elsevier Ltd. All rights reserved.
Received 1 July 2016
Revised 19 August 2016
Accepted 7 September 2016
Available online xxxx
Keywords:
4-Hydroxy coumarin
Aryl aldehydes
Malanonitrile
N-Chlorosuccinimide
Furo[3,2-c]chromenes
Polycyclic oxygen heterocycles are one of the important fused
heterocycles found in numerous natural products and are known
to possess interesting biological activities.1 Among these scaffolds,
fused coumarin system especially furocoumarines are the sec-
ondary metabolites found in some higher plants such as celery
(Apium graveolens), parsnip (Pastinaca sativa) and carrot (Daucus
carota).2 Naturally occurring furocoumarines prevail in linear as
well as in angular form. For example, Psoralen, Xanthotoxin and
Bergapten are the most abundant linear furocoumarines, whereas
the angular form is represented by angelicin, sphondin, and
pimqinellin.3 These compounds exhibit diverse biological activities
such as fungicidal,4 insecticidal,5 insect antifeedant,6 anti-HIV,7
and anticancer.8 Recently furocoumarines allured the attention
owing to their abilities to arouse drug interactions through inhibi-
tion of cytochrome P450. Grapefruit juice is a well known example
for food drug interaction.9 Further, these compounds have gained a
renewed interest with respect to human health because of their
natural presence in common vegetables.10 Therefore, development
of methodical synthetic routes to prepare these compounds is an
important task in modern organic synthesis.11
N-ylides,3 one pot reaction of 4-hydroxycoumarine and aromatic
aldehyde employing ionic liquid,14 oxidative cyclization of the
Michael adduct of cyclohexane 1,3 dione and chalcones involving
combination of PhI(OAc)2/Bu4NBr/t-BuOK.15 Michael addition/
alkylation of the resultant product of 1,3-dicarbonylcompounds
and 2-nitroacrylates16 in presence of base, and Yb(OTf)3 promoted
propargylation and allylation of 4-hydroxycoumarines.17 However,
all these reports required the use of metal catalysts, ionic liquids,
combination of bases, organic solvents involving multiple syn-
thetic steps and the reported yields were poor in some cases.
Therefore, there is still a need to emerge with simple methodolo-
gies to prepare these type of compounds.
On the other hand, multicomponent reactions (MCRs) have
become a powerful tool in organic synthesis because of their atom
economy, multiple bond forming efficiency and convergence. Addi-
tionally, MCRs based on ‘bio-solvents’ such as ethanol which is pro-
duced from renewable resources18 is an important parameter as it
is one of the best alternative to hazardous solvents due to the
EHS (Environment, Health and Safety) properties such as increased
biodegradability or reduced ozone depletion potential.19 Consider-
ing these facts and in continuation to our ongoing research work on
the synthesis of furan fused heterocyclic compounds of biological
interest20 herein, report the synthesis of furo[3,2-c]-chromenes in
a one pot, multicomponent reaction in high yields.
Accordingly, a great deal of efforts have been made and a num-
ber of reports have appeared on the synthesis of furocoumarines
which includes manganese(III) acetate promoted reaction of
4-hydroxycoumarine with electron rich alkenes12 and alpha
bromonitroalkenes13 independently. Via in situ generation of
The study was initiated by reacting 4-hydroxy coumarine (1),
benzaldehyde (2) and malanonitrile (3) in ethanol at room
temperature followed by reflux and obtained the compound 4 in
high yields (Scheme 1).
⇑
Corresponding author. Tel.: +91 40 27191436; fax: +91 40 27193382.
E-mail address: krishnu@iict.res.in (K. Atmakur).
http://dx.doi.org/10.1016/j.bmcl.2016.09.022
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kale, A.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.09.022

2
A. Kale et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
OH
OH
O
CN
1) R-OH/Heating, 1hr
2) NCS, rt, 10min
O
O
CN
CN
CN
O
R
O
O
Ethanol
CN
CN
O
O
O
O
Heating, 1hr
O
O
O
O
NH2
2
5
3
1
3
1
2
4
Scheme 1.
R= Ethyl, Methyl, Isopropyl
O
O
O
O
O
O
CN
CN
O
CN
O
O
O
O
O
O
O
O
O
O
CN
O
O
Ethanol
CN
O
O
5a, 96%
5b, 94%
5c, 93%
NCS/ rt,10min
O
O
NH2
4
5a, 96%
O
O
O
Scheme 2.
O
CN
O
CN
O
O
O
CN
O
O
O
In order to synthesize the furochromenes, compound 4 was
treated with N-chlorosuccinimide (NCS) in ethanol at room
temperature. Interestingly, formation of ethyl 2-cyano-4-oxo-3-
O
O
O
O
5d, 92%
5f, 91%
5e, 95%
phenyl-3,4-dihydro-2H-furo[3,2-c]chromene-2-carboxylate
(5)
was obtained in high yields (Scheme 2).
Br
Cl
F
With the formation of a ring contraction product 5, we planned
to prepare the same in a single step. Consequently, 4-hydroxy cou-
marine (1), benzaldehyde (2) and malanonitrile (3) was reacted in
ethanol at reflux temperature followed by sequential addition of
NCS in the same pot (Scheme 3). To our satisfaction, this reaction
gave 5 in high yields. Intrigued by the formation of 5 in a one
pot multicomponent reaction, the same reaction was repeated in
methanol and isopropanol independently and gratifyingly
obtained the corresponding ester compounds 5 in almost equiva-
lent yields.
O
O
O
O
O
O
CN
CN
CN
O
O
O
O
O
O
O
O
O
5h, 96%
5i, 93%
5g, 96%
CN
OH
NO2
O
O
O
Having obtained the compound 5 in high yields, experiments
were carried out with varying NCS quantity. However, best yields
were obtained with 1 equiv. Similar results were also obtained with
NBS and NIS. Whereas, I2, KI, CuBr, CuI and NaClO2 failed to give the
product 5 (see Table 1). Structure of 5 was characterized based on
the spectral data and was also comparable with the previous
report.21 With the set of reaction conditions in hand, this protocol
was generalized by reacting compound 1 with various aromatic
aldehydes, malanonitrile and obtained the corresponding products
5a–5r. A wide range of functional groups such as electron donating
and electron withdrawing groups on 2 were well tolerated. How-
ever, yields are varied. Electron releasing groups gave better yields
than electron withdrawing groups. Fused aromatic aldehydes such
as naphthaldehyde produced the corresponding furo chromene
product (5r) However, 2-methoxy naphthaldehyde could not pro-
duce the pyran compound and olefin (Knoevenagel product) is
recovered. Further, hetero aromatic aldehydes are ended up with
only pyran compounds and not leading to the desired products
even in ethanol, methanol, isopropyl alcohol and water. Further-
more, aliphatic aldehydes also failed to produce the pyran com-
pound (4) and only the Knoevenagel product recovered.
Based on the previous reports, a plausible mechanism is pro-
posed. It is very well known that compound 4 can be obtained
by the reaction of 4-hydroxy coumarine, benzaldehyde and
malanonitrile by Knoevenagel condensation followed by Michael
addition. Thus obtained compound 4 upon treatment with NCS
gives imine ‘A’. Then the alkoxy group from the solvent interacts
with the imine resulting in CAO bond dissociation followed by
elimination of HCl leading to five membered ring. Further, hydrol-
ysis of imine leads to the desired product 5.
O
O
O
CN
CN
CN
O
O
O
O
O
O
O
O
O
5k, 89%
5l, 92%
5j, 90%
Cl
CF3
CF3
O
O
O
Cl
CN
O
O
CN
O
CN
O
O
O
O
O
O
O
O
O
5n, 94%
5o, 95%
5m, 93%
NO2
O
O
O
O
O
O
O
O
O
CN
CN
CN
O
O
O
O
O
O
O
O
O
5q, 92%
5p, 96%
5r, 97%
Scheme 3. Reaction conditions: 4-hydroxy coumarine (1, 2.8 mmol), benzaldehyde
(2, 2.8 mmol) and malononitrile (3, 2.8 mmol) in 5 mL ethanol at 80 °C temperature
about 1 h and then added NCS (4, 2.8 mmol) rt 15 min. Yields refers to pure
products.
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A. Kale et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 1
Optimization of reaction conditions for the synthesis of furochromene compounds (5)
S. no
Solvent
Reagent
Temperature
Yields of 5 (%)
1
2
3
4
5
6
7
8
Ethanol
Methanol
Isopropanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
NCS (1 equiv)
NCS (1 equiv)
NCS (1 equiv)
NCS (0.1 equiv)
NCS (0.2 equiv)
NCS (0.5 equiv)
NIS (1 equiv)
NBS (1 equiv)
I2
KI
CuBr
CuI
NaClO2
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
96
94
95
32
47
68
95
95
NR
NR
NR
NR
NR
9
10
11
12
13
Reflux = Reflux to room temperature, NR = No Reaction.
Bold indication for high yields that are obtained with these parameters.
Table 2
Antimicrobial activity of furochromene compounds (5a–5r)
Entry Test
compounds
Minimum inhibitory concentration (
l
g/mL)
Escherichia
planticola MTCC coli MTCC
Staphylococcus
aureus MTCC 96 subtilis MTCC MLS16 MTCC
Bacillus
S. aureus
Micrococcus
luteus MTCC
2470
Klebsiella
Pseudomonas
aeruginosa MTCC
2453
Candida
albicans MTCC
3017
121
2940
530
739
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
>250
>250
125
>250
>250
>250
62.5
>250
>250
>250
>250
>250
>250
>250
>250
62.5
>250
>250
62.5
250
>250
>250
7.8
>250
>250
>250
>250
>250
250
>250
>250
>250
>250
>250
—
>250
>250
125
>250
>250
15.6
>250
125
>250
>250
15.6
250
>250
>250
7.8
>250
>250
>250
>250
>250
250
>250
>250
>250
>250
>250
—
>250
>250
>250
>250
>250
>250
15.6
62.5
125
>250
>250
>250
>250
>250
>250
>250
>250
>250
—
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
—
>250
>250
>250
>250
>250
>250
62.5
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
>250
>250
>250
62.5
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
—
>250
7.8
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
—
9
10
11
12
13
14
15
16
17
18
>250
>250
a
Miconazole
(Standard
control)
Ciprofloxacin
(Standard
control)
—
7.8
a
0.9
0.9
0.9
0.9
0.9
0.9
0.9
—
The highlighted values are the indication for best results.
a
No activity.
Plausible mechanism
O
O
O
O
Cl
Cl
CN
NH
O
CN
CN
R-OH
NCS
O
O
OH
O
O
NH2
NH
R
R
O
H
'A'
4
O
O
Hydrolysis
O
O
CN
CN
O
O
-HCl
R
R
O
O
O
HN
5
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4
A. Kale et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 3
evaluated for in vitro antimicrobial activity against different
Gram-positive and Gram-negative bacterial strains and emerged
with two prominent compounds (5c, 5g) with excellent antimicro-
bial activity and a moderate MBC activity as presented in Tables 2
and 3.
Minimum bactericidal concentration (MBC) of furochromene compounds (5c and 5g)
Test
compounds
Minimum bactericidal concentration (
l
g/mL)
Bacillus
subtilis
Micrococcus
luteus MTCC
2470
Klebsiella
planticola
MTCC 530
Escherichia
coli MTCC
739
MTCC 121
Acknowledgements
5c
5g
—
62.5
62.5
62.5
1.17
62.5
62.5
1.17
—
62.5
1.17
Ciprofloxacin 1.17
We are grateful to SERB-DST, New Delhi, India for financial sup-
port (grant no. SB/EMEQ-075/2013). Ashok is thankful to UGC for
the award of JRF.
Next, compounds 5a–5r were screened for in vitro antimicro-
bial activity against different Gram-positive strains such as
Staphylococcus aureus MTCC 96, Bacillus subtilis MTCC 121
Staphylococcus aureus MLS16 MTCC 2940 and Micrococcus luteus
MTCC 2470, and Gram-negative bacterial strains such as Klebsiella
planticola MTCC 530, Escherichia coli MTCC 739, Pseudomonas
aeruginosa MTCC 2453 and Candida albicans MTCC 3017. The out-
come of the screening study showed that compound 5c (Table 2,
entry 3) exhibited promising activity against Micrococcus luteus
MTCC 2470 and Klebsiella planticola MTCC 530. Whereas, moderate
activity was observed against Bacillus subtilis MTCC 121. Further,
compound 5g (Table 2, entry 7) showed excellent antimicrobial
Supplementary data
Supplementary data (1H, and 13C spectra of representative com-
pounds (5a–5r) and general information) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/10.
1016/j.bmcl.2016.09.022.
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of 5c probably isopropyl group might have contributed to the
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any activity. Presence of other electron withdrawing and electron
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mum tested concentration of 250
are tabulated in Table 2.
lg/mL. The results to this regard
Based on the promising antimicrobial activity of compounds 5c
and 5g, they were further screened for minimum bactericidal con-
centration (MBC) activity. Outcome of the study showed that, com-
pound 5c exhibited moderate MBC activity 62.5
Micrococcus luteus MTCC 2470 and Klebsiella planticola MTCC 530,
while 5g exhibited moderate MBC activity 62.5 g/mL against
lg/mL against
l
Bacillus subtilis MTCC 121, Micrococcus luteus MTCC 2470, Klebsiella
planticola MTCC 530 and Escherichia coli MTCC 739.
In conclusion, we have synthesized a number of new furo[3,2-c]
chromene compounds in a multicomponent one pot reaction,
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Please cite this article in press as: Kale, A.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.09.022