Carbon-SO3H: An efficient catalyst for the synthesis of biscoumarin under ambient reaction conditions and their in silico studies

Article abstract of DOI:10.1080/00397911.2020.1780613

In this article, we have established a highly promising approach for the synthesis of biscoumarins via domino Knoevenagel–Michael condensation of 4-hydroxycoumarin and aromatic aldehydes in 2:1 ratio using carbon-SO₃H as a solid acid catalyst i

Full text of DOI:10.1080/00397911.2020.1780613

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Carbon-SO H: An efficient catalyst for the
3
synthesis of biscoumarin under ambient reaction
conditions and their in silico studies
Ayushi Sethiya, Pankaj Teli, Anu Manhas, Dinesh Agarwal, Jay Soni, Nusrat
Sahiba, Prakash Jha & Shikha Agarwal
To cite this article: Ayushi Sethiya, Pankaj Teli, Anu Manhas, Dinesh Agarwal, Jay Soni, Nusrat
Sahiba, Prakash Jha & Shikha Agarwal (2020): Carbon-SO H: An efficient catalyst for the
3
synthesis of biscoumarin under ambient reaction conditions and their in silico studies, Synthetic
Communications, DOI: 10.1080/00397911.2020.1780613
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https://doi.org/10.1080/00397911.2020.1780613
Carbon-SO H: An efficient catalyst for the synthesis of
3
biscoumarin under ambient reaction conditions and their
in silico studies
a
a
b
c
a
Ayushi Sethiya , Pankaj Teli , Anu Manhas , Dinesh Agarwal , Jay Soni ,
a
d
a
Nusrat Sahiba , Prakash Jha , and Shikha Agarwal
a
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Mohan Lal Sukhadia University,
b
Udaipur, India; School of Chemical Sciences, Central University of Gujarat, Gandhinagar, India;
c
d
Department of Pharmacy, Bhupal Nobel University, Udaipur, India; School of Applied Materials
Science, Central University of Gujarat, Gandhinagar, India
ABSTRACT
ARTICLE HISTORY
In this article, we have established a highly promising approach for
the synthesis of biscoumarins via domino Knoevenagel–Michael con-
densation of 4-hydroxycoumarin and aromatic aldehydes in 2:1 ratio
Received 20 March 2020
KEYWORDS
Aldehdyes; biscoumarins;
carbon-SO H catalyst; click
3
chemistry; 4-hydroxy
coumarin; molecular
docking
using carbon-SO
new protocol produced a, aꢀ -benzylidene bis(4-hydroxycoumarin)
derivatives in high to excellent yields. For this, carbon-SO H solid
3 2
H as a solid acid catalyst in H O: EtOH (1:1). This
3
acid catalyst has been prepared from glycerol and sulfuric acid and
characterized by FT-IR, SEM, TGA, and X-ray diffraction methods. This
approach has several advantages such as high atom-economy
(96.05%), excellent yields (88-100%), no need of further purification
techniques, that is, column chromatography, easy workup, less reac-
tion time, cost-effective, avoid the use of hazardous solvents, recyc-
lability of catalyst, etc. Moreover, molecular docking studies have
been performed on selected proteins methylenetetrahydrohyrofolate
reductase (MTHFR) and cytochrome P450 3A4 (CYP3A4) to identify
the potency of the synthesized compounds (3a–j). Among the syn-
thesized compounds 3i, 3e, and 3b showed the highest docking
score against both the proteins.
GRAPHICAL ABSTRACT
CONTACT Shikha Agarwal
shikhaagarwal@mlsu.ac.in
Synthetic Organic Chemistry Laboratory, Department of
Chemistry, Mohan Lal Sukhadia University, Durga Nursery Road, Udaipur 313001, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
A. SETHIYA ET AL.
Introduction
The designing of biologically active scaffolds and lead compounds using green protocols
[
1]
by minimizing the pollution and adverse impact on the environment is inevitable. For
this, alternative pathways that avoid the use of conventional toxic metal catalysts, sol-
vents, and utilize sustainable and cost-effective sources are indeed required. Therefore,
the designing of drugs and its precursors using eco-friendly solvents and catalysts has
become one of the most captivating areas in the research field.
Coumarin derivatives are highly valuable scaffolds in the field of synthetic and
pharmaceutical chemistry (Fig. 1). It is present in various plants viz. tonka bean
[
2]
(Dipteryx odorata), sweet woodruff (Galium odoratum), etc.
Among coumarin derivatives, biscoumarins are the well-known class of these com-
[
3]
pounds. These have immense therapeutic applications like anti-coagulant,
urease
[
4]
[5]
[6]
[7]
inhibitory, anti-leishmanial, a-glucosidase inhibitor, anti-microbial, enzymatic
[
8]
[9]
[10–12]
inhibition activity,
HIV integrase,
anticancer,
etc. Instead of numerous
pharmacological activities, it showed other applications in the field of organic lumines-
[
13]
[14]
[15]
cence material,
tors.
polymer synthesis,
WLED display,
and organic semiconduc-
[
16]
Several synthetic pathways have been employed for their synthesis including
Knoevenagel, Pechmann, Perkin, Reformatsky, and Wittig reactions. The
Figure 1. Available drugs possessing biscoumarin scaffold.

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3
Knoevenagel–Michael reaction is also involved in the synthesis of various biologically
[
17–19]
active scaffolds.
prepare biscoumarin derivatives.
marin derivatives using methyl iodide and heating the complex with HCl.
several researchers have developed various synthetic methodologies for the synthesis of
In the past reports, several methodologies have been designed to
[
20,21]
Abramovitch et al. synthesized a series of biscou-
[
22]
Thereafter,
[
23]
biscoumarins using heterogeneous catalysts like W-doped ZnO nanocomposites,
methyl pyrrolidonium zinc chloride,
N-
[
24]
[25]
ionic liquid [Dabco-H][AcO],
ethylene gly-
[
26]
[27]
[28]
col,
zwitterionic liquid (ZIL) coated CuO,
o-benzenedisulfonimide,
ceric ammonium nitrate,
FeNi -ILs
3
[
29]
[30]
[31]
[32]
nanoparticles,
Fe O @SiO @VB1-Ni(II),
3
[34]
taurine,
4
2
[
33]
[35]
HY-Zeolite,
VB1,
choline hydroxide,
etc. Several acid catalysts like glacial acetic
[
36]
[37]
[38]
acid,
acid,
phosphotungstic acid,
succinimide-N-sulfonic acid
pentafluropropanoic acid,
phosphor-sulfonic
[
39]
[40]
[41]
[42]
other lewis acids like RuCl3,
ZnCl2,
etc.
were also used to improve the selectivity, yield and atom economy. These synthetic
pathways have their own merits but include harsh reaction conditions. To overcome
these restrictive causes, solid acid catalysts have gained enormous attention due to their
surface properties and good acidic characters. In lieu of this, different solid acid cata-
[
43]
lysts have also been used for biscoumarin synthesis such as sulfonated rice husk,
[
44]
[45]
starch–sulfuric acid,
silica-bonded n-propyldiethylenetriamine sulfamic acid,
melamine trisulphonic acid,
cellu-
Pistachio peels based sulfonic
However, the literature-reported pathways have provided efficient access to bis-
[
46]
[47]
lose sulfonic acid,
[
48]
acid.
coumarins but include harsh reaction conditions, tedious workup, long reaction time,
expensive catalyst, high catalyst loading, limited substrate scope, and use of hazardous
solvents. To beat such circumstances and to find a more beneficial protocol, a new eco-
friendly method needs to be developed to combat several environmental issues. An
[
49]
exhaustive literature study has been done by our research group
and it was found
that no work has been done using glycerol-based carbon-SO H for the synthesis of bis-
3
coumarins to date. Keeping all these points into consideration; we have developed a
robust carbon-SO H catalyst for the synthesis of biscoumarin derivatives. Carbon-SO H
3
3
[
50–52]
has been used earlier to catalyze diverse organic transformations
and also fruitful
for the multi-component reactions to synthesize 4-thiazolidinones, thiazepinones,
[
53,54]
etc.
Taking all the points into mind, we have designed a novel approach for the
generation of biologically potent biscoumarin derivatives (3a–j) using carbon-SO H as a
3
robust catalyst. (Scheme 1).
For the molecular docking studies of synthesized compounds (3a–j), we have selected
cytochrome P450 3A4 (CYP3A4) and methylenetetrahydrohyrofolate reductase
(
1
MTHFR) enzyme predicted by PASS online program (PASS online-Way2Drug) (Table
[
55]
[56]
) and literature studies.
PDB IDs pertaining to CYP3A4 and MTHFR are 4D75
[
57]
and 6FCX,
respectively. The PASS computer program allows estimating the probable
profile of the biological activity of a drug-like organic compound. CYP3A4 catalyzes
various oxidative reactions and is recognized as a xenobiotic-metabolizing enzyme in
[
56]
humans.
HIV infection.
reduction of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate which is indir-
The inhibition of this enzyme is considered beneficial in the treatment of
[
58]
Again, in humans, MTHFR is involved in catalyzing the irreversible
[
57]
ectly involved in the biosynthesis of purines and monophosphates.
sidered essential for the exploration of anti-cancer drugs.
This target is con-
[
59]

4
A. SETHIYA ET AL.
Scheme 1. General reaction for the synthesis of Biscoumarin.
Table 1. Prediction of biological activity by PASS online program for biscoumarin deriva-
tives (Selective).
P
a
P
i
Activity
0.914
0.907
0.900
0.896
0.893
0.806
0.783
0.799
0.526
0.426
0.005
0.009
0.004
0.004
0.002
0.001
0.003
0.033
0.046
0.045
Methylenetetrahydrofolate reductase (NADPH) inhibitor
Membrane integrity agonist
Aldehyde oxidase inhibitor
Monodehydroascorbate reductase (NADH) inhibitor
Aryl-alcohol dehydrogenase (NADPþ) inhibitor
HIV-2 reverse transcriptase inhibitor
Antiviral (HIV)
Ubiquinol-cytochrome-c reductase inhibitor
Platelet adhesion inhibitor
Cytochrome P450 stimulant
Note: These types of activities may be revealed by the compound, where P
a i
> P and so they are put into the biological
activity spectrum. If P > 0.5, the compound is likely to reveal its activity in the experiment.
a
Results and discussion
Chemistry
As a part of our continued interest in catalysis, carbon-SO H was found to be an effi-
3
cient catalyst due to its good catalytic activity, easy recoverability, and reusability up to
several runs without loss in the activity. These characteristics have inspired us to estab-
lish its viability in the synthesis of biscoumarin derivatives and for further exploration;
[
60,61]
we prepared carbon-SO H catalysts as reported in the literature
for the synthesis
3
of biscoumarin derivatives. The schematic mechanism for its synthesis and structure has
[
62,63]
been proposed (Fig. 2).
The synthesized catalyst was well characterized by FT-IR, XRD, SEM, and TGA and
the results were in accordance with the previously reported papers. As per FT-IR spec-
ꢀ
1
tra of the carbon-SO H catalyst, the two absorption bands at 1146 and 1025 cm due
3
to the sulfuric acid group assured the formation of catalysts. The absorption bands
ꢀ
1
appeared at range 3000–3500 cm
can be endorsed to O–H stretching vibrations
ꢀ1
(
including SO H, COOH, and adsorbed water). The peak at 3737 cm
is due to
3

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SYNTHETIC COMMUNICATIONS
5
Figure 2. Proposed Schematic mechanism for the carbonization of glycerol by conc. sulfuric acid.
Figure 3. IR spectrum of synthesized carbon-SO H.
3
ꢀ
1
ꢀ1
adsorbed water and at 3603 cm is due to OH group of COOH group, 3016 cm is
ꢀ
1
related to bonded OH of SO H group. The absorption band at 1742 cm is related to
3
the carbonyl functional group (Fig. 3). All these absorption peaks were in good agree-
[
60]
ment with the previously synthesized C-SO H catalyst as per Devi et al.
In X-ray dif-
3
ꢁ
ꢁ
fraction (XRD) diffraction peaks at 2h ¼ 15–30 and 2h ¼ 40–50 recognized amorphous
[
60]
structure of carbon (Fig. 4).
The morphology of the sample was investigated with the
scanning electron microscopy (SEM), which showed the agglomerate structure of par-
ticles (Fig. 5). The thermal stability of the catalyst was evaluated using the thermogravi-
[
60]
metric analysis and the results are shown in (Fig. 6).
Thermal degradation patterns
depend on the dehydration temperature, which affects both the number of carbon

6
A. SETHIYA ET AL.
Figure 4. XRD pattern of synthesized carbon-SO H.
3
Figure 5. SEM images of synthesized carbon-SO H catalyst.
3
functional groups present and the degree of carbonization. The catalyst showed an ini-
ꢁ
tial mass loss due to adsorbed water. A second mass loss was seen at 150–200 C, most
[
64,65]
likely due to the loss of SO H groups
TGA analysis showed that the catalyst was
3
ꢁ
[62]
stable to 300 C.
To examine the catalytic efficiency of carbon-SO H catalyst, the reaction of 4-OH
3
Coumarin 1 (5 mmol) and 4-Cl benzaldehyde (2.5 mmol) 2a was taken as the model
reaction. For this, the reactants were taken in 50 mL round-bottomed flask with 10 mg
of catalyst in solvent-free conditions and stirred at room temperature for an appropriate
time (Table 2, Entry 2). The progression of the reaction was monitored by TLC and it
took 60 min for the completion of the reaction and a 75% yield was obtained. Parallel

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7
4
3
3
2
2
1
1
00.0
50.0
00.0
50.0
00.0
50.0
00.0
2
2
5.00
0.00
5
4
4
3
.000
.500
.000
.500
15.00
1
0.00
5
0
.00
.00
5
0.0
3.000
50.0
100.0
150.0
Temp Cel
200.0
250.0
Figure 6. TGA and DTA curve of synthesized carbon-SO H catalyst.
3
Table 2. Typical optimization of the solvent for the preparation of bis(4-hydroxycoumarin)
derivatives.
Entry
Catalyst (mg)
Solvent
Temperature
Time (min)
Yield
1
2
3
4
5
6
Solvent-free
Solvent-free
Solvent -free
RT
RT
RT
RT
RT
RT
240
60
60
60
60
60
No reaction (%)
b
10
20
20
20
20
75
80
75
72
b
a
2
H O
a
EtOH
b
2
H O:EtOH (1:1)
85
Reaction conditions: 4-Cl benzaldehyde (2.5 mmol), 4-OH coumarin (5 mmol).
a
The reaction was not completed.
The yields are related to the isolated products.
b
Table 3. Optimization of catalyst concentration and temperature.
Entry
Catalyst (mg)
Solvent
Temperature
Time (min)
Yield (%)
a
1
2
3
4
5
6
7
25
30
35
20
25
30
35
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O:EtOH (1:1)
O:EtOH (1:1)
O:EtOH (1:1)
O:EtOH (1:1)
O:EtOH (1:1)
O:EtOH (1:1)
O:EtOH (1:1)
RT
RT
RT
80 C
80 C
35
30
30
20
20
20
20
88
90
90
90
a
a
ꢁ
a
ꢁ
a
94
ꢁ
ꢁ
a
80 C
100
a
80 C
100
Reaction conditions: 4-Cl benzaldehyde (2.5 mmol), 4-OH coumarin (5 mmol).
a
The yields are related to the isolated products.
to this, the same reaction was performed with 20 mg of catalyst and gave an 80% yield
Table 2, Entry 3). Then, we optimized the reaction conditions by varying solvents and
(
performed the reaction in the water at room temp. (Table 2, Entry 4) and 75% yield
was obtained. Simultaneously, the reaction was carried out in ethanol and H O:EtOH
2
(1:1) with 20 mg of catalyst (Table 2, Entry 5, 6). It was noteworthy that the high yields
were obtained in H O:EtOH (1:1).
2

8
A. SETHIYA ET AL.
Table 4 Synthesis of bis(4-hydroxycoumarin) derivatives in the presence of carbon-SO H as
3
the catalyst.
Entry
Aldehyde
Symbol for product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
4-ClꢂC
6
H
4
3a
3b
3c
3d
3e
3f
3g
3h
3i
20 min
22 min
25 min
20 min
20 min
10 min
15 min
15 min
25 min
20 min
100
95
91
92
94
95
88
96
89
95
4-OHꢂC
6
H
H
4
4-CNꢂC
6
4
4-FꢂC
6
H
4
4-NO
2
ꢂC
6
ꢂC
H
4
3-OCH
3
6
H
4
2-Thiophene
4-NMe
ꢂC
1-Naphthyl
4-OC
ꢂC
2
6 4
H
1
0
2
H
5
6
H
4
3j
Table 5. Comparative study on the present method with the reported methods.
Catalyst
S no.
Catalyst
Catalyst-free
loading
Solvent
Condition
Time
Yield (%) Ref.
[66]
1
.
H
2
O
Microwave irradiation at
8–10 min
76–94
65–78
90–98
ꢁ
1
50 W and 150 C
[
36]
2
.
Glacial acetic acid
or Ethanol
Phospho tungstic acid
Pentafluropropanoic acid 40 mol%
Phospho sulfonic acid
Reflux
6 h
ꢁ
[37]
38]
3
4
5
6
7
8
9
1
.
.
.
.
.
.
.
15 mol%
H
H
2
O
O
Heat 80 C
Reflux
14–25 min
60–100 min 86–92
15–90 min
25–35 min
35 min
10–70 min
100–150 min 80–90
3–20 min 85–95
[
2
ꢁ
[39]
[41]
[42]
[43]
50 mg
5 mol%
15 mol% Solvent-free
40 mg
20 mg
Solvent-free
Heat 100 C
63–93
75–95
85–90
87–95
ꢁ
RuCl
ZnCl
3
H
2
O
Heat 80 C
ꢁ
2
110 C
ꢁ
Sulfonated rice husk
Cellulose sulfonic acid
H
H
2
O
O
Heated at 80 C
Reflux
[46]
2
ꢁ
[48]
0. Carbon-based solid acid 50 mg
from pistachio peel
Stirred at 80 C
[31]
[32]
[33]
1
1
1
1
1
1. Ceric Ammonium Nitrate 10 mol %
2. Taurine
3. Zeolite-HY
4. Fe
H
2
O
O
RT, Stirring
Reflux
360–480 min 75–98
35–85 min 84–96
60–180 min 80–96
30–50 min
180 min
0.20 mmol H
2
EtOH
Reflux
II
ꢁ
[30]
3
O
4
@SiO
2
@VB1-Ni
10 mg
0.5 mol% Solvent-free
Solvent-free
110 C
78–98
90–95
[27]
5. ZIL@CuO
Mechanical ball mining
with speed
of 600 rpm
Reflux with stirring
[24]
1
6. N-methyl pyrrolidonium 20 mg
zinc chloride
7.
Solvent-free
30–50 min
78–97
ꢁ
[26]
1
1
Ethylene glycol 90 C
1.5–3 h
25–30 min
82–92
74–91
[28]
8. o-Benzenedi
sulfonimide
50 mol%
H
2
O
Reflux
[
34]
1
2
9. VB
0. Carbon-SO
1
1 mol%
30 mg
H
H
2
O/solvent free RT
O:EtOH (1:1) Stirring at 80 C
180–600 min 82–94
ꢁ
3
H
2
10–25 min 88–100 Present
work
To expedite the reaction, the amount of catalyst was successively increased (Table 3).
With an increase in the amount of catalyst, the product yield increased and reaction
time decreased. The reaction temperature was also optimized (Table 3, Entry 4-6). The
ꢁ
best results were obtained in H O:EtOH (1:1) by stirring at 80 C with 30 mg of catalyst
2
and 100% yield was obtained. (Table 3, Entry 6). Further increase in the catalyst con-
centration did not affect the reaction time.
In order to investigate the synthetic utility and the scope of the reaction, a series of
aryl aldehydes having electron-withdrawing and electron-donating groups as well as het-
eroaryl derivatives were scrutinized. All aldehydes gave high yields irrespective of the
nature of the substituents as summarized in (Table 4).

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9
Scheme 2. Putative mechanism for carbon-SO H catalyzed synthesis of biscoumarin derivatives.
3
The appropriateness of this process was determined by comparing the model reaction
with the previously reported protocols (Table 5).
Although some of the previously reported methods took less time as compared to
Carbon-SO H catalyst they suffer from low yields and involve toxic and costly reagents
3
for the synthesis of catalyst, tedious work-up, and harsh reaction conditions. Whereas
the present work has several benefits like reusability and recyclability of catalyst, cost-
efficient pathway, avoids the use of hazardous solvents with excellent yields, high atom
economy, and high E-factor in a short period of time. The structures of all the synthe-
1
13
sized compounds (3a-j) were corroborated by FT-IR, H NMR, C NMR, Mass spec-
trometry, and elemental analysis. The FT-IR spectrum showed a broad absorption at
ꢀ
1
3
058 cm due to OH stretching frequency. The vibrational modes of C¼O and C–O
ꢀ1
groups appeared at 1695–1440 and 1350 cm , respectively. In addition, the resonating
signal at d 8–11 ppm was attributed to the OH proton in H NMR spectra. But OH res-
1
onating signals of some compounds were broadened or disappeared due to the inter-
action with the aqueous DMSO-d as a polar and hydrogen bond acceptor solvent. The
6
methine proton became visible as a singlet near to d 6.7–5.5 ppm. Additionally, in the
1
3
C NMR spectra, the signals at d 166.26–162.21 and d 35.72–31.44 ppm corresponded
to carbonyl and methine carbon atoms.
The putative mechanism for the formation of biscoumarin derivatives was elaborated
in Scheme 2. The carbon-SO H enhanced the electrophilic character of carbonyl carbon
3
of aldehyde. It underwent Knoevenagel condensation with one molecule of 4-

1
0
A. SETHIYA ET AL.
Table 6. Docking scores of the selected hits with the 6FCX protein.
a
a
a
a
a
a
b
Molecules
Docking score
Match score
Lipo score
Ambig. score
Clash score
Rot score
Match
3
3
3
3
3
3
3
3
3
3
a
i
e
f
b
g
j
h
a
c
d
ꢀ26.37
ꢀ25.41
ꢀ24.01
ꢀ23.93
ꢀ22.11
ꢀ21.72
ꢀ21.15
ꢀ20.76
ꢀ20.70
ꢀ20.69
ꢀ24.30
ꢀ24.39
ꢀ23.48
ꢀ23.74
ꢀ22.11
ꢀ25.14
ꢀ21.64
ꢀ21.34
ꢀ21.07
ꢀ18.77
ꢀ11.04
ꢀ09.68
ꢀ13.45
ꢀ11.28
ꢀ18.07
ꢀ12.02
ꢀ11.19
ꢀ10.25
ꢀ14.13
ꢀ12.97
ꢀ07.79
ꢀ10.48
ꢀ11.22
ꢀ06.29
ꢀ12.39
ꢀ08.31
ꢀ09.42
ꢀ08.74
ꢀ09.80
ꢀ09.44
4.36
6.73
10.33
3.58
7.00
7.00
8.40
8.40
7.00
9.80
7.00
7.00
7.00
7.00
35
25
24
28
21
24
25
24
20
25
ꢀ9.90
8.55
8.71
7.18
11.91
8.10
kJ/mol.
b
number of matches.
Match score: contribution of interacting groups; Lipo score: lipophilic-contact area contribution; Ambig score: lipophilic-
hydrophilic ambiguous contact area; Clash score: clash penalty contribution; Rot score: entropy contribution of ligand
conformation.
Figure 7. Graphical representation of the docked molecules (3a–j) within the binding pocket of
6FCX protein.
hydroxycoumarin to furnish intermediate I, followed by the Michael addition with the
second molecule of 4-hydroxycoumarin and formed the desired product.
Docking assessment
Protein 6FCX
From the docking result of 6FCX, it was observed that all the synthesized compounds
(
3a-j) showed binding with the 6FCX protein (Table 6). From Table 6, it was concluded
that 3i showed the highest docking score of ꢀ26.37 kJ/mol followed by 3e, 3f, 3b, and
g (Fig. 7). Further, on considering the 3D orientation of the docked molecules, All
3
molecules were docked within the same pocket of the protein (Fig. 7; Docked structures
of other compounds are provided in SI).
On analyzing the 2D and 3D interaction plots (Fig. 8) of the docked compounds, it
was observed that almost in all molecules, greater than 3 H-bonding interactions were
reported with the interaction with amino acid Tyr197 and His201 being the common
one. Moreover, the number of other H-bonding and hydrophobic interactions were also
witnessed as shown in Figure 7. Therefore, based on the docking score and population

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Figure 8. Pictorial representation of all the ligands docked within the same active site of
FCX protein.
6
Figure 9. The 2D/3D interaction of highest docked molecules 3i, 3e, 3b.

1
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A. SETHIYA ET AL.
Table 7. Docking scores of the selected hits with 4D75 protein.
a
a
a
a
a
a
b
Molecules
Docking score
Match score
Lipo score
Ambig. score
Clash score
Rot score
Match
3
3
3
3
3
3
3
a
i
ꢀ13.85
ꢀ11.56
ꢀ09.53
ꢀ08.00
ꢀ05.02
ꢀ01.32
06.86
ꢀ10.42
ꢀ13.03
ꢀ16.33
ꢀ09.65
ꢀ07.90
ꢀ07.84
ꢀ06.81
ꢀ16.05
ꢀ11.49
ꢀ08.47
ꢀ11.50
ꢀ102.56
ꢀ11.76
ꢀ12.07
ꢀ5.83
ꢀ6.77
ꢀ5.81
ꢀ4.65
ꢀ4.23
ꢀ4.01
ꢀ6.68
06.06
07.34
07.29
05.40
07.27
09.89
17.22
7.00
7.00
8.40
7.00
7.00
7.00
9.80
29
18
22
25
22
24
17
e
b
h
d
a
j
kJ/mol.
b
number of matches.
Match score: contribution of interacting groups; Lipo score: lipophilic-contact area contribution; Ambig score: lipophilic-
hydrophilic ambiguous contact area; Clash score: clash penalty contribution; Rot score: entropy contribution of ligand
conformation.
Figure 10. Graphical representation of the seven active docked molecules within the binding pocket
of 4D75 protein.
of the docked compounds, compounds 3i, 3e, 3f, 3b, 3g, and 3j can be considered as
potent molecules for inhibiting the activity of the enzyme (Fig. 9).
Protein 4D75
After conducting docking on 4D75, it was observed that out of 10 molecules, only 7
were able to bind in the active site of the respective protein (Table 7). It is clearly evi-
dent from Table 7, that 3i showed the highest docking score of ꢀ13.85 kJ/mol followed
by 3e, 3b, 3h, 3d, and 3a (Fig. 10). On observing the 3D orientation of the docked mol-
ecules, it was obvious that all the molecules bound well within the same pocket
(Fig. 10).
From the generated 2D and 3D interaction plots, it was observed that among the syn-
thesized molecules 3i, 3e, and 3j showed H-bonding interaction with the amino acid
[
56]
Arg 212, which is considered important for the inhibition of the enzyme
(Fig. 11).
Besides, in 3d and 3a, the interaction with Arg212 was seen in the hydrophobic form.
Moreover, among all the molecules, a common hydrophobic interaction was observed
[
56]
with Arg105 and Hem 601, which was also documented as the crucial interaction.
Thus, we can conclude that based on the docking score and presence of crucial interac-
tions, 3e, 3i, and 3b can be considered as the potent inhibitors of CYP3A4 protein (Fig.
12; The docked structure of the other compounds in SI).

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Figure 11. Pictorial representation of all the ligands docked within the same active site of
D75 protein.
4
Figure 12. 2D and 3D interaction plots of the docked 3i, 3e, and 3b ligands within the binding
pocket of 4D75 protein.
Green chemistry matrices for a reaction
[
67,68]
When green chemistry matrix
was calculated, it was found that the reaction has
low environment-factor (E-factor ¼ 0.0421), high atom economy (AE ¼ 96.05%),

1
4
A. SETHIYA ET AL.
process mass intensity (PMI ¼ 1.74) and reaction mass efficiency (RME ¼ 95.9%), with
excellent eco-score (90) as shown in SI. These values clearly specified the eco-friendly
nature of the present technique.
Conclusions
In this study, carbon-SO H being a heterogeneous and recyclable robust catalyst was
3
found to be very efficient for the production of biscoumarin derivatives by a click
chemistry approach. The protocol is facile and environmentally benign as it doesn’t
involve any solvent, high atom economy, and no by-products are generated. The excel-
lent yields (88–100%) under mild reaction conditions in just 10–25 min made this
protocol a user-friendly approach for the synthesis of biscoumarins. The synthesis of
the catalyst was very simple and easily recovered and reused for successive cycles. The
docking studies were also performed in order to enhance its biological profile. In the
future, this carbon-SO H shall be used for many multi-component reactions and for the
3
high throughput screening in medicinal chemistry. From the docking outcome of both
calculations, it can be concluded that commonly 3e and 3b form stable binding interac-
tions with CYP3A4 and MTHFR enzymes. In the case of both enzymes, the docked
compounds are able to form crucial H-bonding and other hydrophobic interactions.
Thus, we may consider these compounds (3i, 3e, 3b) may show inhibitory activity
against the selected proteins.
Experimental
All chemicals were procured from Sigma-Aldrich, Spectrochem, Loba-Chemie and used
without further purification. Melting points were determined in open capillary tubes and
were uncorrected. The IR spectra were recorded in KBr pellets on a Bruker FT-IR spectrom-
1
13
eter. The H NMR (500MHz) and C NMR (500 MHz) spectra of synthesized derivatives
were scanned on a Bruker Avance NEO 500 MHz spectrometer using tetramethylsilane
(
TMS) as an internal standard and DMSO as a solvent. The mass spectra were recorded on a
Waters Xevo G2-S QT spectrometer. XRD analysis was done by X-Ray diffractometer
Rikagu Miniflex) and SEM was performed on Nova nano SEM 450. The TG/DTA analysis
(
was done by TG/DTA7300 of EXSTAR. The purity of derivatives was examined by thin-
layer chromatography (TLC) eluting with hexane:ethylacetate in (1:1) ratio.
General procedure for the synthesis of glycerol-based carbon sulfonic
acid catalyst
The glycerol-based carbon sulfonic acid catalyst was synthesized by taking a mixture of gly-
cerol (20 g) and concentrated sulfuric acid (80g) and was gently heated on a sand bath in a
ꢁ
temperature range of 180–200 C for 20–30min, to assist in situ partial carbonization and
sulfonation. The mixture was kept at that temperature for about 40min (until foaming
ceased) to get the polycyclic aromatic carbon compound. The crude product was allowed to
kept at normal temperature and treated with hot distilled water under agitation till the
decant water neutralized and pH became 7. The partially crystalline black color product was

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ꢁ
filtered and dried in an oven at 120 C for 2–3 h until it was free from moisture. The weight
[
60,61]
of the dried catalyst was found to be 9.22gm.
General procedure for the synthesis of biscoumarin derivatives
To synthesize biscoumarin, a mixture of 4-OH coumarin (5 mmol) and aromatic alde-
hyde (2.5 mmol) with 30 mg of catalyst in H O: EtOH were taken in a round bottom
2
ꢁ
flask equipped with a magnetic stirrer. The mixture was stirred at 80 C for an adequate
time. The progress of the reaction was monitored by TLC. Dichloromethane was added
to recover the catalyst. The acquired solid was dried and washed with ethanol to remove
impurities. The desired products (3a–j) were obtained in high to excellent yields in a
short period of time (10–25 min). The recovered catalyst was dried in an oven and again
used for the next reaction.
Methodology of molecular docking
[
69,70]
Molecular docking calculations were performed by using FlexX module
of LeadIT
[
71]
[69]
2.1.8 program.
This module utilizes an incremental construction based algorithm
to assemble the ligand incrementally within the active site of the protein chain. Thus, it
provides flexibility to the molecules selected for conducting docking. Moreover, this
module calculates free binding energy (DG) of the docked ligand-protein complexes by
[
72]
employing the modified B o€ hm’s scoring function.
In order to perform the molecular
docking studies, 10 synthesized biscoumarin compounds (3a–j) were selected (Fig. 13).
[
73]
These molecules were generated in the form of the SYBYL mol2 file format
and
were compiled as a hit library. The constructed hit library was prepared in the Accelrys
[
74]
discovery studio version 4.0
hydrogen atoms, assign formal charges, and uses CHARMm force field
the energy of the ligands. The selected protein files of 4D75 and 6FCX were prepared in
which involved correction of the atoms, bond types, add
[
75]
to minimize
[
69,70]
[71]
the Receptor Preparation Wizard of the FlexX
module of LeadIT 2.1.8 program.
The preparation involved the addition of the polar hydrogen atoms, assigning of the
atom-type, and removal of the crystallographic water. The active site in the case of
4
D75 was selected based on the known experimental inhibitor (PK9) with a defined
[
69,70]
radius of 6.5 Å around the inhibitor. However, in the case of 6FCX, the FlexX
modules of LeadIT
[
71]
automatically detect the binding site present in the protein.
Therefore, all the binding sites were docked separately in order to analyze the inter-
action pattern. The chemical uncertainties were resolved by employing ProToss mod-
[
76]
ule
of the LeadIT 2.1.8 program which optimized the ligands, cofactors, residues,
and assigned the appropriate protonation and tautomers state within the binding site of
the protein chain. In addition, to handle the steric clashes, default docking and chemical
parameters were used. To perform the calculations, a hybrid entropy and enthalpy-
based docking scheme were executed to locate the fragments. To find rational docking
poses, the maximum number of solutions per interaction was set to 50. After docking,
the docked interactions were reported in the form of protein-ligand 2D interaction plots
[
77]
[71]
via PoseView widget
of LeadIT 2.1.8 program.

1
6
A. SETHIYA ET AL.
Figure 13. Library of synthesized Biscoumarin derivatives.
Table 8. Recyclability of Carbon-SO H catalyst for the synthesis of 4-Cl benzaldehdye.
3
Catalyst cycle
Fresh
I
II
III
IV
V
VI
Time (min)
Isolated yield (%)
20
100
20
100
20
99
20
96
25
90
25
86
25
80
Screening and reusability of the catalyst
The catalyst was insoluble in the reaction mixture and was recovered using dichlorome-
thane (DCM). The recovered catalyst was washed with ethanol and dried in an oven for
further use. The catalyst was recovered and reused up to the 5th run. For the first three
runs, there is no loss in catalytic activity but for the next fourth run, there was slight
decrease in the yield of the product. IR spectra showed that there is no change in the
structure of recycled catalyst up to 3 runs. After the 5th run, the reaction time increased
and the yield decreased (Table 8 and Fig. 14). The catalytic activity of recycled catalyst
(Run 1, 2, and 3) can also be deduced by comparing its IR with a fresh catalyst (Fig. 15).

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SYNTHETIC COMMUNICATIONS
17
1
1
20
00
80
60
40
20
0
Fresh I Run II Run III Run IV V Run VI
Run
Run
Catalytic efficiency
Figure 14. The catalytic efficiency of recovered catalyst.
Figure 15. The IR spectrum of recovered catalyst with the fresh catalyst.
Spectral Characterization of synthesized biscoumarin derivatives
3
,3’-((4-Chlorophenyl)methylene)-bis-(4-hydroxy-2H-chromen-2-one) (3a)
ꢁ
ꢁ
[26]
ꢀ1
White solid; 100% Yield; mp 252–254 C. (Lit. mp 258–260 C)
IR max/cm
3
3
225–3058 (OH), 2919 (sp C-H), 1671(C¼O), 1600, 1511, 1493 (C¼C aromatic), 1330
2 1
and 1091 (C–O), 746–935 (sp C–H), 811–832 (Cl); H NMR (500 MHz, DMSO-d ) d
6
6
.31 (s, 1H, CH), 7.18 (dd, 2H, J ¼ 8.5 Hz, 1 Hz, Ar–H), 7.27 (m, 2H, Ar–H), 7.30–7.33
(m, 2H Ar–H), 7.57–7.60 (m, 2H Ar–H), 7.89 (dd, J ¼ 8 Hz, 1.5 Hz, 2H), 10.55 (broad,

1
8
A. SETHIYA ET AL.
1
3
2
1
4
H, OH); C NMR (100 MHz, DMSO-d ) d 165.13, 164.39, 155.39, 153.05, 133.08,
6
29.8, 128.66, 125.89, 124.75, 116.34, 114.99, 113.97, 103.58, 54.63, 34.22. ESI-MS (m/z):
46.5 (Mþ)
1
Full experimental details and copies of FT-IR, HNMR spectra of all the synthesized
compounds associated with this article have been provided in supporting information.
The 2D and 3D docked structures of all the other derivatives with 6FCX and 4D75 pro-
tein, green chemistry matrix calculation, and eco-score are shown in the supplementary
file. This material can be found via the “Supplementary Content” section of this
article’s webpage.
The experimental section of this work has been given in the supporting information.
1
The H NMR and IR spectrum of synthesized model compounds (3a–j) are provided.
The 2D and 3D molecular docked structure of synthesized compounds is also provided
in supporting information.
Acknowledgments
The authors are thankful to the Head of Department of Chemistry for providing necessary
laboratory facilities. The Department of Physics, University College of science, MLSU, Udaipur is
duly acknowledged for TGA, DTA, and XRD analysis. The authors would also like to acknow-
ledge the Sophisticated Analytical Instrumentation Facility, Chandigarh, India, and Material
Research Center Malviya National Institute of Technology Jaipur (MNIT, Jaipur) for carrying out
the spectral analysis. A. Sethiya is thankful to UGC-MANF (MANF-2018-19-RAJ-91971) and P.
Teli and N. Sahiba are thankful to CSIR for providing Junior Research Fellowship to carry out
this work.
Funding
This work was supported by the UGC-MANF [MANF-2018-19-RAJ-91971] and CSIR.
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