Synthesis of coumarin based Knoevenagel-Ugi adducts by a sequential one pot five-component reaction and their biological evaluation as anti-bacterial agents

Article abstract of DOI:10.1016/j.tetlet.2018.11.030

An efficient multicomponent synthesis of Ugi compounds comprising coumarin backbone has been achieved by employing one pot five component sequential Knoevenagel-Ugi reaction. This method offers the advantages of easy handling procedure, atom economy, mild reaction conditions and good yields of products. A molecular library was synthesized by changing the substituents on two of the independent starting materials. The synthesized compounds were also tested for anti-microbial activities and were found to be moderate to good anti-bacterial agents.

Full text of DOI:10.1016/j.tetlet.2018.11.030

Accepted Manuscript
Synthesis of Coumarin based Knoevenagel-Ugi Adducts by a sequential one pot
Five-Component Reaction and their Biological evaluation as Anti-Bacterial
agents
Sitanshu Kumar, Kapil Mukesh, Kusum Harjai, Vasundhara Singh
PII:
S0040-4039(18)31358-3
https://doi.org/10.1016/j.tetlet.2018.11.030
TETL 50415
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 September 2018
7 November 2018
9 November 2018
Please cite this article as: Kumar, S., Mukesh, K., Harjai, K., Singh, V., Synthesis of Coumarin based Knoevenagel-
Ugi Adducts by a sequential one pot Five-Component Reaction and their Biological evaluation as Anti-Bacterial
agents, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.030
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Synthesis of Coumarin based Knoevenagel-Ugi Adducts by a sequential one pot
Five-Component Reaction and their Biological evaluation as Anti-Bacterial
agents
a
b
b
a *
Sitanshu Kumar , Kapil Mukesh , Kusum Harjai , Vasundhara Singh
a
Department of Applied Sciences, Punjab Engineering College (Deemed to be University), Sector-12, Chandigarh, 160012, India.
Department of Microbiology, Panjab University, Sector-25, Chandigarh, 160014, India..
b
*
Corresponding Author E-mail: vasundhara@pec.ac.in
ABSTRACT:
An efficient multicomponent synthesis of Ugi compounds comprising coumarin backbone has been achieved by
employing one pot five component sequential Knoevenagel-Ugi reaction. This method offers the advantages of easy
handling procedure, atom economy, mild reaction conditions and good yields of products. A molecular library was
synthesized by changing the substituents on two of the independent starting materials. The synthesized compounds
were also tested for anti-microbial activities and were found to be moderate to good anti-bacterial agents.
Multicomponent reactions (MCRs) are useful synthetic tools in
which three or more different starting materials react to form
complex molecules in a one-pot strategy with great efficiency,
1
Anti-viral
atom economy and low synthetic cost . The development of
such processes in which several bonds are formed without
isolation of intermediates receives considerable attention for
the preparation of structurally diverse libraries of drug-like
Anti-tuberculosis
2
-10
compounds.
With regard to four-component processes, the
Antibacterial
Anti-HIV
Anti-influenza
Antibacterial
Antibacterial
Ugi coupling of isocyanides with carbonyl derivatives, amines
and carboxylic acids is known to exhibit high efficiency for a
1
1-19
wide range of starting components.
Most studies have
related to cascades directed towards the preparation of
complex hybrid heterocyclic scaffolds by means of the Ugi
reaction. The Ugi four-component reaction (U-4CR) is one of
the most commonly used MCRs that result in peptide-like
Anti-
inflammatory
2
0-23
products
and has been applied as a powerful approach to
access highly functionalized hybrid heterocyclic structures.
Anti-cancer
2
4-26, 54
Anti-cancer
Anti-cancer
MCR’s have also been reported in literature
to have
applications in the synthesis of hybrid heterocyclic
compounds. Coumarin and its derivatives are important
compounds due to their presence in naturally occurring
Figure 1.
2
7
Coumarin derivatives have been reported to exhibit
aromatic products found in plants and cinnamon flavoured
2
9-30
31
32
33-34
2
8
anticancer,
anti-influenza, anti-HIV, anti-alzheimer,
foods.
Numerous coumarin derivatives have been
3
5
36
37
anti-inflammatory,
antituberculosis,
antiviral,
and
synthesized and reported in literature having diverse
therapeutic relevance as shown in Figure 1.
3
8
antimicrobial activities. The fluorescent properties observed
in some coumarin based Ugi adducts have been used to study

3
9-42
proteins and nucleic acids.
It is important to note that the
existence of the amide groups in coumarin-3-carboxamides
4
3-46
improves the biological activity of these compounds.
In
recent literature, various coumarin based Knoevenagel-Ugi
General Procedure for Synthesis of Ugi adducts (coumarin
based α-acyl amino amides)
4
7-48
adducts have been synthesized
and are found to be
potential agents possessing one or the other biological
An oven-dried round bottomed flask was charged with a
magnetic stir bar, salicylaldehyde (1.0 mmol, 122 mg),
Meldrum’s acid (1.0 mmol; 144 mg) and ethanol (5 mL). The
whole mixture was then stirred vigorously at room temperature
for 10 h to complete the conversion. The completion of the
reaction was confirmed by TLC monitoring, showing the
disappearance of starting material. Thereafter, well stirred
mixture of aldehyde (1 mmol) and amine (1 mmol) in
minimum volume of ethanol were sequentially added to the
flask followed by the addition of isocyanide (1 mmol) and
4
9-51
42
activity
and fluorescent property . In continuation to our
5
2-53
research interest
in MCRs and synthesis of coumarin based
Knoevenagel-Ugi adducts as potential antibacterial agents, we
report the synthesis of coumarin-3-carboxylic acid by a
reaction of salicylaldehyde and meldrum’s acid in ethanol at
5
4
room temperature and the sequential addition of aryl amine,
aromatic aldehyde and isocyanide to yield coumarin based α-
acyl amino amides in a one pot five component Knoevenagel-
Ugi sequential reaction. The general synthetic protocol
followed for coumarin based Knoevenagel-Ugi adducts is
depicted in Scheme 1.
o
continued stirring the mixture at 40 C till completion of the
reaction, confirmed by TLC indicating the disappearance of
starting components. Solvent was removed from crude reaction
mixture under reduced pressure. Crushed ice was added and
the solid product was scratched, filtered, washed thrice with
cold water and dried to obtain the crude product. The crude
product was then recrystallized from a mixture of EtOAc-
Hexane to get the pure product. All the products were
1
13
characterized by using NMR ( H and C) spectroscopy, mass
spectroscopy and elemental analysis. The structures of the
synthesized coumarin based Knoevenagel-Ugi adducts is
shown in Figure 2.
Scheme 1. General procedure for synthesis of coumarin based
Knoevenagel-Ugi adducts.
Experimental
Results & Discussions
All reagents were purchased from Sigma-Aldrich, Fischer and
used without further purification. Melting points were
determined on a Stuart SMP30 melting point apparatus and are
uncorrected. Crude products were recrystallized in mixture of
Amongst the library of the synthesized compounds 6a-6h and
7
a-7h as shown in Figure 2, wherein different substituted
aldehydes were varied while maintaining 2-oxo-2H-chromene-
1
13
3-carboxylic acid (formed in situ by the reaction of
EtOAc and Hexane. H NMR and C NMR spectra were
1
salicylaldehyde and meldrum’s acid) and aniline. The R as o-
recorded in CDCl or DMSO-d6 on a Bruker Avance II 400
3
methoxy and m-hydroxy substituents along with cyclohexyl
spectrometer with TMS as internal standard at room
temperature, the chemical shifts (δ) were expressed in ppm and
J values were given in Hz. The following abbreviations are
used to indicate the multiplicity: s (singlet), d (doublet), t
and tert-butyl isocyanides gave good yields of the products 6b,
6
f, 7b and 7f. Our results also revealed that unsubstituted aryl
aldehyde also gave equivalent yields of the products as in 6a
and 7a. The optimizations of the condensation reaction for
model compound 6b in terms of time of completion of reaction
and reaction solvent were also done and the results are
summarized in Table 1 and Table 2 respectively.
(triplet), q (quartet), m (multiplet). All first order splitting
patterns were assigned on the basis of the appearance of the
multiplet. Splitting patterns that could not be easily interpreted
were designated as multiplet (m).

6
b (92%)
6
a (86%)
6
c (88%)
6
f (89%)
6
d (86%)
6e (85%)
6
h (84%)
7a (87%)
6
g (81%)
7
c (88%)
7
d (87%)
7
b (90%)
7
f (90%)
7
g (82%)
7
e (85%)
7
h (85%)
Figure 2. Structure and Isolated yields of products
Reaction Conditions: One-pot reaction; Aldehyde (1.0 mmol), Aniline (1.0 mmol), Coumarin-3-carboxylic acid (1.0 mmol), Isocyanide
o
(
1.0 mmol), EtOH (2 mL), 40 C, 6-8 hours.

Table 1. Optimization of method for Ugi adduct 6b in terms
consistent with the product structure showing peaks at δ
of time of completion of reaction
(ppm) 28.7, 51.8, 55.1, 60.8, 110.0, 116.6, 118.1, 120.3,
1
22.5, 124.6, 126.2, 127.8, 128.0, 128.4, 129.6, 129.8, 131.1,
b
Entry Time (h)
Yield %
20
132.3, 139.0, 141.8, 153.6, 157.4, 158.2, 165.3, 168.7. The
mass spectra of the compound 6b displayed molecular ion
peaks at m/z: 486 [M+1], 508 [M+Na] values. The elemental
analysis showed C: 71.652 %, O: 16.761 %, H: 6.002 % and
N: 5.585 % to be present in Ugi adduct 6b.
1
2
3
4
5
6
7
2
38
3
4
5
57
78
92
6
92
b
Isolated Yield
Anti-microbial activity
All the synthesized compound were evaluated for the in vitro
antimicrobial activity on both gram positive and gram
negative strain bacteria. Two gram negative strains Klebsiella
pneumoniae 43816, Pseudomonas aeruginosa PAO1 and two
gram positive strains Streptococcus aureus MRSA,
Staphylococcus epidermidis were used for screening the
synthesized compounds. All the compounds were soluble in
DMSO, therefore it was used as a control solvent. Cefepime
was used as a standard antibiotic against all the organisms
used in evaluating MIC values. For screening, the diameter of
the microbial inhibition were measured for each compound
Table 2. Optimization of reaction solvent for model
compound 6b
b
Entry
Reaction
Solvent
Ethanol
Methanol
Water
Yield %
1
2
3
92
89
35
b
Isolated Yield
(
100µg/well). All the MICs were performed in triplicates
N=3) for the each test organism and the results are expressed
Using optimized reaction conditions, in the pilot experiment,
salicylaldehyde was reacted with Meldrum’s acid in ethanol at
room temperature for 10 hours to afford coumarin-3-
(
as mean ± standard deviation for each compound. The MIC
values in µM/ml of the compounds against the above
mentioned organisms are presented in Table 3.
5
1
carboxylic acid. Thereafter aniline, o-methoxy benzaldehyde
and tert-butyl isocyanide were added and the mixture stirred
An assessment of the obtained data reveals that some of the
compounds displayed good and the others showed moderate
antibacterial activity when compared with the reference
standard, cefepime. Among the complete library of the
o
at 40 C for 6 hours. After completion of the reaction (6 h), the
desired product was recrystallized in EtOAc:hexane and
isolated in 92% yield. In view of the success of the above
reaction, we explored the scope and limitations of this
reaction by extending the procedure to different aldehydes
and two different isocyanides. The reactions proceeded very
efficiently at mild temperature conditions and led to the
formation of a new class of the coumarin derivatives with α-
acyl amino amide in good yields. Structure of the product was
1
2
compounds synthesized, 7f (R = 3-OH, R = cyclohexyl), 7g
1
2
1
2
(
R = 2-OH, R = cyclohexyl) and 7h (R = 2-NO , R =
2
cyclohexyl) had good potency for gram negative strain
Pseudomonas aeruginosa PAO1, while for the same class of
1
gram negative bacteria Klebsiella pneumoniae 43816, 7e (R
2
1
2
=
4-NO , R = cyclohexyl), 7f (R = 3-OH, R = cyclohexyl)
2
1
13
deduced from its H-NMR, C-NMR, mass spectral data and
1
2
and 7h (R = 2-NO , R = cyclohexyl) showed good potency
2
1
elemental analysis. The H NMR spectrum of compound 6b
with respect to cefepime (0.027 µM/ml). For the gram positive
consisted of a singlet for the methyl protons of the tert-butyl
entity (δ = 1.46 ppm, 9H); a singlet for protons of methoxy
group (δ = 3.26 ppm, 3H); a sharp singlet for CH (δ = 6.46
1
2
1
2
organisms, 6c (R = 4-Me, R = tert-butyl), 6g (R = 2-OH, R
1
2
1
=
tert-butyl), 7e (R = 4-NO , R = cyclohexyl), 7f (R = 3-
2
2
1
2
OH, R = cyclohexyl), 7g (R = 2-OH, R = cyclohexyl), 7h
ppm, 1H); a broad singlet for NH (δ = 6.50 ppm, 1H)
a
1
2
(
R = 2-NO , R = cyclohexyl) showed good potency as
2
multiplet for aromatic protons (6.65−7.50 ppm, 13H); and a
singlet for CH of coumarin ring (δ = 7.76 ppm, 1H). Also, the
antibacterial agents for Staphylococcus epidermidis 3382,
1
2
1
2
while 6b (R = 2-OMe, R = tert-butyl), 6c (R = 4-Me, R =
1
3
proton decoupled C NMR spectrum of 6b is completely
1
2
1
2
tert-butyl), 6g (R = 2-OH, R = tert-butyl), 7a (R = H, R =

1
2
1
cyclohexyl), 7e (R = 4-NO , R = cyclohexyl), 7f (R = 3-OH,
and o-hydroxy substituted phenyl ring with tert-butyl group
and p-nitro, m-hydroxy, o-hydroxy and o-nitro substituted
phenyl ring with cyclohexyl group were found to be
inhibitory for the growth of Staphylococcus epidermidis 3382.
In case of Streptococcus aureus MRSA, compounds
containing o-methoxy, p-methyl, o-hydroxy substituted
phenyl ring with tert-butyl group and o-hydroxy, p-nitro, m-
hydroxy, o-nitro substituted phenyl ring and unsubstituted
phenyl ring with cyclohexyl group showed good inhibitory
results.
2
2
1
2
1
R = cyclohexyl), 7g (R = 2-OH, R = cyclohexyl), 7h (R =
2
2
-NO2,
R
=
cyclohexyl) had good potency for
Streptococcus aureus MRSA in comparison to cefepime
0.008 µM/ml).
(
Table 3. Antimicrobial Evaluation* of synthesized coumarin
based Knoevenagel-Ugi adducts
P.
K.
S.
aeruginosa
PAO1
pneumoniae
43816
epidermidis
3382
S. aureus
MRSA
6
6
6
6
6
6
6
6
7
7
7
7
7
7
7
7
a
b
c
d
e
f
0.458±0.033 0.734±0.044
0.458±0.033
0.334±0.026
0.039±0.004
0.020±0.004
0.649±0.053
0.305±0.024
0.324±0.027
0.041±0.005
0.152±0.020
0.039±0.008
0.108±0.015
0.308±0.024
0.153±0.018
0.018±0.004
0.019±0.004
0.019±0.004
0.036±0.004
0.428±0.031 0.428±0.031 0.107±0.012
Conclusions
0.356±0.030 0.445±0.032
0.221±0.021 0.354±0.025
0.028±0.006
0.885±0.060
In conclusion, we have synthesized bioactive molecules by
incorporating the coumarin nucleus via a one-pot five
component sequential Knoevenagel-Ugi approach, which is
green, efficient in terms of atom economy and avoidance of
multistep synthesis. This protocol has several advantages such
as simple experimental procedure, mild reaction conditions at
almost RT conditions with less side products, simple post -
reaction work up and easy extraction of pure products in good
yields. The functionalized molecules are potential candidates
of medicinal importance as exhibited by their antibacterial
activity. The synthesized compounds showed moderate to
good results in terms of anti-bacterial activity for both gram
positive and gram-negative strains.
0.834±0.056 0.834±0.056 0.417±0.030
0.708±0.043
0.442±0.032
0.417±0.030
0.867±0.058
0.203±0.019
0.842±0.057
0.419±0.030
0.198±0.019
0.104±0.012
0.104±0.012
0.049±0.007
0.708±0.043
0.619±0.042
0.208±0.020
0.346±0.027
0.203±0.019
0.842±0.057
0.419±0.030
0.158±0.021
0.053±0.007
0.209±0.020
0.099±0.011
0.354±0.027
0.055±0.008
0.104±0.012
0.108±0.012
0.101±0.011
0.421±0.030
0.104±0.012
0.025±0.006
0.041±0.014
0.052±0.007
0.049±0.007
g
h
a
b
c
d
e
f
g
h
Cefe-
pime
0.027±0.008
0.027±0.008
0.008±0.0003
0.008±0.0003
Acknowledgements
*DMSO was used as control solvent and Cefepime as standard
The authors are thankful to Punjab Engineering College
antibiotic, MIC values are represented in µM/ml.
(Deemed to be University), Chandigarh for necessary
facilities and RSIC-CIL, Panjab University, Chandigarh for
spectroscopic analysis.
The study of structure-activity relationship (SAR studies) of
the potencies indicate that the compounds containing
cyclohexyl ring showed overall better antibacterial activity
compared to the compounds containing tert-butyl group.
Synthesized Ugi adducts containing p-methyl, m-hydroxy, o-
nitro, o-hydroxy and p-nitro groups on phenyl ring along with
unsubstituted phenyl ring were found to possess good
antimicrobial activity in comparison to other coumarin based
Ugi adducts. In case of Pseudomonas aeruginosa PAO1, the
compounds containing o-nitro, o-hydroxy and m-hydroxy
groups on phenyl ring showed comparable results in
inhibiting bacterial growth. For Klebsiella pneumoniae
Supplementary Data
Supplementary data (supplementary data including relevant
preparation procedures for all compounds, characterization
1
13
data of all compounds, H/ C NMR and MS spectra for
model compounds) associated with this article can be found.
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HIGHLIGHTS

Synthesized coumarin based adducts via sequential Knoevenagel-Ugi approach.


The compounds were tested for their anti-bacterial activity and showed moderate to
good anti-bacterial properties.


Compounds are active against both gram positive and gram negative bacterial strains.
Methodology adopted offers easy handling procedure, atom economy and mild
reaction conditions.

A simple one-pot sequential multi component, uncatalyzed strategy gave products in
high yield and purity.

Synthesis of Coumarin based Knoevenagel-Ugi Adducts by a sequential one pot
Five-Component Reaction and their Biological evaluation as Anti-Bacterial
agents
a
b
b
a *
Sitanshu Kumar , Kapil Mukesh , Kusum Harjai , Vasundhara Singh
a
Department of Applied Sciences, Punjab Engineering College (Deemed to be University), Sector-12, Chandigarh, 160012, India.
Department of Microbiology, Panjab University, Sector-25, Chandigarh, 160014, India..
b
*
Corresponding Author E-mail: vasundhara@pec.ac.in
GRAPHICAL ABSTRACT