Series of Functionalized 5-(2-Arylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1 H,3 H)-diones: A Water-Mediated Three-Component Catalyst-Free Protocol Revisited

Article abstract of DOI:10.1021/acs.joc.0c00732

A water-mediated and catalyst-free practical method for the synthesis of a new series of pharmaceutically interesting functionalized 5-(2-arylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-diones has been accomplished based on a one-pot multicomponent reaction between arylglyoxal monohydrates, 2-aminopyridines/2-aminopyrimidine, and barbituric/N,N-dimethylbarbituric acids under reflux conditions. The salient features of this protocol are avoidance of any additive/catalyst and toxic organic solvents, use of water as reaction medium, clean reaction profiles, operational simplicity, ease of product isolation/purification without the aid of tedious column chromatography, good to excellent yields, and high atom-economy and low E-factor.

Full text of DOI:10.1021/acs.joc.0c00732

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Article
A Series of Functionalized 5-(2-Arylimidazo[1,2-a]pyridin-3-
yl)pyrimidine-2,4(1H,3H)-diones: A Water-Mediated
Three-Component Catalyst-Free Protocol Revisited
Goutam Brahmachari, Nayana Nayek, Indrajit Karmakar,
Khondekar Nurjamal, Swapan K Chandra, and Anindita Bhowmick
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 May 2020
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A Series of Functionalized 5-(2-Arylimidazo[1,2-a]pyridin-3-yl)pyrimi-
dine-2,4(1H,3H)-diones: A Water-Mediated Three-Component Cata-
lyst-Free Protocol Revisited
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Goutam Brahmachari*, Nayana Nayek, Indrajit Karmakar, Khondekar Nurjamal, Swapan K Chandra,
and Anindita Bhowmick
Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), San-
tiniketan-731 235, West Bengal, India
Supporting Information
_________________________________________________________________________________________________________
ABSTRACT: A water-mediated and catalyst-free practical method for the synthesis of a new series of pharmaceutically interesting
functionalized 5-(2-arylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-diones has been accomplished based on a one-pot multi-
component reaction between arylglyoxal monohydrates, 2-aminopyridines/2-aminopyrimidine and barbituric/N,N-dimethylbarbituric
acids under reflux conditions. The salient features of this protocol are avoidance of any additive/catalyst and toxic organic solvents,
use of water as reaction medium, clean reaction profiles, operational simplicity, ease of product isolation/purification without the aid
of tedious column chromatography, good to excellent yields, and high atom-economy and low E-factor.
_________________________________________________________________________________________________________
1. INTRODUCTION
of their own, still they suffer from many shortcomings such as
use of metal and costly catalysts, toxic organic solvents, and
harsh reaction conditions. Hence, as part of our ongoing en-
deavors in developing green synthetic methods for biologically
important molecular scaffolds,20 we have been motivated to
search out for an operationally facile alternative route for this
very interesting template having functionalized at C-3 with bar-
bituric acid, an important class of biologically promising py-
rimidine derivatives,21 with a view to access a new series of
substituted 5-(2-arylimidazo[1,2-a]pyridin-3-yl)pyrimidine-
2,4-diones (4). Based on retrosynthetic analysis, we envisioned
that the targeted scaffold could be synthesized from its starting
ingredients, i.e. phenylglyoxals, 2-aminopyridines and bari-
buturic acids. Upon optimization of best-suited reaction condi-
tions with our model reaction with simple phenylglyoxal mon-
ohydrate, 2-aminopyridine and barbituric acid, we were finally
successful in our endeavor to prepare our desired product 4a in
excellent yield within reasonable time-frame, just on refluxing
the starting components in water medium. After then, we sud-
denly came across with the literature report of generation of
furo[2,3-d]pyrimidines (4′) out the same reaction under almost
Imidazo[1,2-a]pyridine represents a key structural scaffold for
a plethora of bioactive molecules1 exhibiting a wide range of
pharmaceutical activities that include antioxidant,2 anti-inflam-
matory,3 anticancer,4 antiviral,5 antibacterial,6 antifungal,7 an-
tiprotozonal,8 antituberculosis,9 antileishmanial,10 antiulcer,11
anticonvulsant12 and antiosteoporotic.13 Figure 1 offers a
glimpse of such bioactive molecules. A number of potential
drugs (Figure 2) available in the market, namely alpidem (an-
xiolytic),14 zolpidem (treating insomnia and brain disorder),15
saripidem (sedative),16 nicopidem (anxiolytic),16 zolimidine
(antiulcer),17 and olprinone (treating acute heart failure),18 bear
this 5,6-fused nitrogen heterocyclic unit in their molecular
framework. As results, the recent past has seen a tremendous
interest and devoted endeavors in constructing the imidazo[1,2-
a]pyridine nucleus with its functionalized derivatives based on
varying synthetic techniques19 that include the use of both ho-
mogeneous and heterogeneous catalysts, oxidants, organic sol-
vents, high temperature, microwave, and electrolysis; Scheme
1 represents few examples of these recently reported methods.
Although the previously reported protocols bear certain merits
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identical reaction conditions.22 For conclusive verification for
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this marked difference, we repeated our model reaction for a
number of times and in all cases, we isolated our proposed
product 4a instead of 4′a. Besides conventional spectroscopic
studies, the single crystal X-ray structural analysis (Figure 3)
of compound 4a confirmed the presence of an imidazo[1,2-
a]pyridine nucleus substituted with a phenyl group at C-2 and
a hydroxy pyrimidinedionyl ring at C-3, which is in absolute
contrary to compound 4′a as reported previously.22 This pre-
sent communication, thus, reports on a water-mediated, con-
venient, and catalyst-free practical method for the synthesis of
a new series of functionalized 5-(2-arylimidazo[1,2-a]pyridin-
3-yl)pyrimidine-2,4(1H,3H)-diones (4) from the one-pot mul-
ticomponent reaction between arylglyoxal monohydrates (1),
2-aminopyridines/2-aminopyrimidine (2) and barbituric/N,N-
dimethylbarbituric acids (3) in water at reflux (110 °C); the
overall results are summarized in Scheme 1. The key ad-
vantages of this newly developed protocol are the clean reac-
tion profile, use of no added catalyst, water as reaction medium,
no need of column chromatographic purification, good to ex-
cellent yields, and high atom-economy and low E-factor. In
recent times, performing organic transformations in aqueous
medium due to the safe and green nature of water,23 and also
developing catalyst-/additive-free synthetic protocols24 have
drawn much attention.
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Figure 1. Representative examples of few bioactive imid-
azo[1,2-a]pyridine analogs
2. RESULTS AND DISCUSSION
To optimize the reaction conditions, we commenced our stud-
ies with the model reaction involving a mixture of phenylgly-
oxal monohydrate (1a; 0.25 mmol), 2-aminopyridine (2a; 0.25
mmol) and barbituric acid (3a; 0.25 mmol), and performed a
series of trial reactions using different acid/base catalysts or no
catalyst in the absence or presence of varying solvents (viz. wa-
ter, acetonitrile, ethanol and dimethyl sulfoxide) either at am-
bient conditions or heating/reflux (Table 1, entries 1-11). As
results, water came out as the best solvent for this conversion
at reflux condition in the absence of any additive, in terms of
yield and time. We thus achieved the best result for our model
reaction in synthesizing the desired product, 6-hydroxy-5-(2-
phenylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-di-
one (4a), in 93% yield at 2 h (Table 1, entry 3) upon refluxing
the reactants dissolved in 3 mL of water at 110 C) without any
additive and/or catalyst. We also checked these optimized re-
action conditions in case of somewhat larger scales (viz. 0.5 and
1.0 mmol) for this model reaction and found satisfactory (see
Experimental). Compound 4a was characterized on the basis of
detailed spectral (1H NMR, 13C NMR, DEPT-135, HRMS and
X-ray single crystal) studies. The overall results are summa-
rized in Table 1.
Figure 2. Marketed drug molecules bearing imidazo[1,2-
a]pyridine scaffold
Scheme 1. Catalyst-free one-pot synthesis of substituted 5-
(2-arylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4-diones
(4) in water
Table 1. Optimization of Reaction Conditions
Entry Catalyst
(mol%)
Solvent
(3 mL)
Conditions
Time Yield
(h)
(%)a,b
−
H2O
H2O
EtOH
heating (80 C)
−
1
no catalyst
3
rt (28-30 C)
−
93
2
3
4
no catalyst
no catalyst
no catalyst
20
2
reflux (110 C)
reflux (110 C)
5
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reflux (110 C)
5
no catalyst
EtOH-
H2O (1:1)
CH3CN
DMSO
H2O
5
21
1
2
3
4
reflux (110 C)
heating (110 C)
reflux (110 C)
reflux (110 C)
reflux (110 C)
−
−
84
66
09
6
7
8
9
no catalyst
no catalyst
citric acid (20)
acetic acid (20)
triethylamine (20) H2O
5
5
2.5
5
5
H2O
10
5
6
7
8
reflux (110 C)
11
K2CO3 (20) H2O
5
14
aReaction conditions: A mixture of phenylglyoxal monohydrate (1a; 0.25
mmol), 2-aminopyridine (2a; 0.25 mmol) and barbituric acid (3a; 0.25
mmol) was stirred in the absence or presence of solvent(s) with the use of

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varying catalysts or no catalyst either at room temperature (28-30 C) or
heating/reflux (110 C). bIsolated yields.
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To check the viability of this newly developed protocol,
we then carried out a set of five reactions between 4-bromo-
phenylglyoxal (1b)/4-chlorophenylglyoxal (1c)/4-fluoro-
phenylglyoxal (1d)/4-methoxyphenylglyoxal (1e)/4-nitro-
phenylglyoxal (1e) monohydrate, 2-aminopyridine (2) and bar-
bituric acid (3) in water (3 mL) under the optimized reaction
conditions; all the reactions took place efficiently furnishing
the expected products 4b, 4c, 4d, 4e, and 4f, in 82%, 97%, 86%,
82% and 74% yield, respectively, within 2-8 h. The model re-
action was found to proceed efficiently when we used N,N-di-
methylbarbituric acid in place of unsubstituted barbituric acid
to give the desired product, 6-hydroxy-1,3-dimethyl-5-(2-phe-
nylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione
(4g) in 77% yield at 2.5 h. Encouraged with these satisfactory
results, we then carried out a set of twelve different reactions
between substituted arylglyoxals, barbituric acid/N,N-dime-
thylbarbituric acid and 2-aminopyridine derivatives (viz. 2-
amino-4-methylpyridine, 2-amino-5-methylpyridine, 2-amino-
5-chloropyridine) under the optimized reaction conditions. All
these reactions underwent smoothly, thereby affording the de-
sired 6-hydroxy-5-(2-arylimidazo[1,2-a]pyridin-3-yl)pyrimi-
dine-2,4-dione derivatives 4h–4t with good to excellent yields
ranging from 64-96% within 1-8 h (Table 2). To our delight, 2-
aminopyrimidine, when used in place of 2-aminopyridine, also
took part in the reaction resulting the expected products, 5-(2-
phenylimidazo[1,2-a]pyrimidin-3-yl)pyrimidine-2,4(1H,3H)-
diones 4u-4x with excellent yields (81-90%) within reasonable
time frame (2-8 h; Table 2). Table 2 summarizes the overall
results.
aReaction conditions: A mixture of substituted arylglyoxal monohydrates (1;
0.25 mmol), 2-aminopyridines/2-aminopyrimidine (2; 0.25 mmol) and barbi-
turic acids (3; 0.25 mmol) in 3 mL of water was refluxed at 110 C in the
absence of any catalyst. bIsolated yields. E-factor expressed in g/g.
All of the products 4a–4x were isolated as pure upon sim-
ple filtration, followed by washing with hot distilled water (2
mL; in some cases, washed with 2 mL of hot distilled water
containing 2-3 drops of ethanol). All are new compounds and
were fully characterized on the basis of their detailed spectral
1
studies including H NMR, 13C NMR, DEPT-135, 2D-NMR
(for two representative entries, 4e and 4l) and HRMS (see ex-
perimental).
To our delight, we were successful in developing suitable
crystals for 6-hydroxy-5-(2-phenylimidazo[1,2-a]pyridin-3-
yl)pyrimidine-2,4(1H,3H)-dione (4a), and its single crystal X-
ray structural analysis (CCDC 1990483; unit cell parameters: a
= 8.5683(10) Å, b = 10.3368(12) Å, c = 11.1001(13) Å, P-1)
documented in this present communication (see Supporting In-
formation) is in full structural agreement. Figure 3 shows the
ORTEP and Packing diagram of the molecule. The overall mo-
lecular geometry of the compound, including bond distances
has a normal range.25 The bond lengths C3-O3 is little bit
longer {1.254(2) Å} compared to C1-O1 {1.230(2) Å} and C2-
O2 {1.236(2) Å}. These closeness in C-O bond distances is a
signature of dynamic keto-enol tautomerism present in this par-
ticular ring of the structure. The crystal lattice of compound 4a
contains three water molecules in the asymmetric unit, which
are connected by numerous short contacts and hydrogen bonds
propagated along a-, b- and c-axis to form three-dimensional
supramolecular network. The single crystal X-ray analysis of
compound 4a, thus, confirmed the presence of an imidazo[1,2-
a]pyridine framework within the molecule bearing an aryl sub-
stituent at C-2 and a 6-hydroxypyrimidine-2,4(1H,3H)-dionyl
moiety at C-3, which is in contrary to the previously reported
furo[2,3-d]pyrimidines (4′).22
Table 2. Synthesis of substituted 5-(2-arylimidazo[1,2-
a]pyridin-3-yl)pyrimidine-2,4-diones (4)
Figure 3. a) The ORTEP view of the molecule 4a, showing
the atom-labelling scheme (displacement ellipsoids are
drawn at the 30% probability level); b) The packing ar-
rangement of 4a viewed along a-axis
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greenness of a process; calculated RME in a range of
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56.48−84.62% thus ascertains a quite greenness for the whole
process. Similarly, PMI evaluation (84.19−50.37 g/g) is also
supportive with this view. The calculated E-factors (g/g) in the
range of 0.77−0.18 are encouraging; the respective E-factor for
each entry is shown in Tables 2. All other parameters have also
been found to be in order. Respective data and their calcula-
tions for all the entries are given in the Supporting Information.
Fig. 3a
Fig. 3b
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We herein propose a possible mechanism (Scheme 2) for
the catalyst-free one-pot synthesis of substituted 5-(2-arylimid-
azo[1,2-a]pyridin-3-yl)pyrimidine-2,4-diones (4) via a three-
component reaction between arylglyoxal monohydrates (1), 2-
aminopyridines/2-aminopyrimidine (2) and barbituric acids (3)
in water under reflux condition. In the first step, a chalcone in-
termediate 6 is generated out of Knoevenagel-type reaction be-
tween arylglyoxal 1′ and enolic form 3′ of barbutiric acid (3)
in refluxing water medium. In the next step, this chalcone in-
termediate 6 takes part in aza-Michael reaction with 2-amino-
pyridines/2-aminopyrimidine (2) to form adduct 7, which rap-
idly undergoes intramolecular ring-closure via energetically-
favored 5-exo-trig process, thereby resulting the cycloadduct 8
that furnishes the desired product 4 upon removal of water. The
whole process involves the removal of three molecules of water
as green waste (Scheme 2). An alternative route via the for-
mation of an imine intermediate arising out of the reaction be-
tween 1 and 2, was excluded because the predicted imine, in
that case, would result differently substituted imidazo[1,2-
a]pyridine scaffold, i.e. 6-hydroxy-5-(3-arylimidazo[1,2-
a]pyridin-2-yl)pyrimidine-2,4-diones, upon follow-up reaction
with 3, which was not detected in the course of the reaction.
3. CONCLUSIONS
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In conclusion, we developed a facile, straightforward and effi-
cient synthetic protocol for new series of pharmaceutically in-
teresting functionalized 5-(2-arylimidazo[1,2-a]pyridin-3-
yl)pyrimidine-2,4(1H,3H)-diones (4) from the one-pot multi-
component reaction between arylglyoxal monohydrates (1), 2-
aminopyridines/2-aminopyrimidine (2) and barbituric/N,N-di-
methylbarbituric acids (3) in water at reflux in the absence of
any added catalyst. The notable features of this present protocol
include avoidance of additive/catalyst, use of water as reaction
medium, operational simplicity and clean reaction profiles,
ease of product isolation/purification without the aid of tedious
column chromatography, good to excellent yields, and high
atom-economy and low E-factor, thereby satisfying the triple
bottom line philosophy of green and sustainable chemistry.27
4. EXPERIMENTAL SECTION
4.1 General. All chemicals (analytical grade) other than
arylglyoxal monohydrates were purchased from reputed com-
panies and used without further purification. Arylglyoxal mon-
ohydrates (1a-1f) used in this present study were prepared by
oxidizing the corresponding acetophenones with selenium di-
oxide as per previously reported procedure.28 NMR (1H, 13C,
DEPT-135, COSY-45, HMQC, HMBC) spectra were collected
on a Bruker DRX (400 MHz) spectrometer using DMSO-d6
containing 1-2 drops of saturated NaOH solution in D2O, as
solvent. Chemical shifts were reported in δ (ppm), relative to
the internal standard, TMS. The signals observed are described
as s (singlet), d (doublet), t (triplet), and m (multiplet). Cou-
pling constants are reported as J value in Hz. Mass spectrome-
try was obtained using a Waters QT of Premier Micromass
(ESI) as well as Bruker maXis Impact (Q-TOF) high resolution
mass spectrometer. Melting point was recorded on a Chemiline
CL-725 melting point apparatus and is uncorrected. X-ray sin-
gle crystallographic data were collected on Bruker-AXS
SMART APEX/CCD diffractometer using MoKradiation (
= 0.71073 Å) in an -2 scan mode. Thin Layer Chromatog-
raphy (TLC) was performed using silica gel 60 F254 (Merck)
plates.
Scheme 2. Proposed mechanism for synthesis of 6-hydroxy-
5-(2-arylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4-diones
(4)
4.2 General experimental procedure for the prepara-
tion of substituted 5-(2-arylimidazo[1,2-a]pyridin-3-yl)py-
rimidine-2,4-diones (4): A magnetic stir bar, substituted aryl-
glyoxal monohydrates (1; 0.25 mmol), 2-aminopyridines/2-
aminopyrimidine (2; 0.25 mmol), barbituric acid/N,N-dime-
thylbarbituric acid (3, 0.25 mmol) and 3 mL of water were
transferred to an oven-dried reaction vessel in a sequential
manner, and then the reaction mixture was stirred under reflux
condition (110 °C) on an oil-bath for stipulated time-frame (1-
8 h). The progress of the reaction was monitored by TLC. On
completion of the reaction, a solid mass precipitated out which
was filtered off, followed by purification of the crude product
just by washing with 2 mL of hot distilled water (in some cases,
To evaluate green credentials of the present protocol, we
calculated a series of green metrics26 such as effective mass
yield (EMY), atom economy (AE), atom efficiency (AEf), car-
bon efficiency (CE), reaction mass efficiency (RME), optimum
efficiency (OE), mass productivity (MP), mass intensity (MI)
and process mass intensity (PMI), E-factor, and water intensity
(WI) for all the synthesized compounds 4 (4a-4x) (see the Sup-
porting Information). The calculated effective mass yield, atom
economy, and atom efficiency for the method amounts to up to
84.62%, 88.43%, and 84.89%, respectively. The calculated car-
bon efficiency (64.0−96.0%) for this process is also quite good.
RME, involving masses of all reactants, yield, and atom econ-
omy, is regarded as the most useful metric to determine the
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washed with 2 mL of hot distilled water containing 2-3 drops
D2O):  = 169.5 (C=C(ONa)), 159.4 (2 × −N=C(ONa)),
142.9, 139.4, 135.5, 130.3, 128.7 (2C), 127.5 (2C), 125.6,
123.0, 115.8, 109.9, 107.4, 76.8 ppm. HRMS (ESI-TOF): m/z
[M+H]+ calcd for C17H12ClN4O3; 355.0598; found, 355.0593.
1
2
3
4
5
6
7
8
of ethanol). The structure of each compound was confirmed by
spectral studies including 1H-NMR, 13C-NMR, DEPT-135 and
HRMS. The structure of each purified compound was con-
1
firmed by detailed spectral studies H, 13C NMR, DEPT-135,
4.4.4 5-(2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-6-hy-
droxypyrimidine-2,4(1H,3H)-dione (4d). Yellow solid, 73 mg,
2D-NMR and HRMS (2D-NMR for two representative entries,
4e and 4l). Further structural confirmation for a representative
entry, 6-hydroxy-5-(2-phenylimidazo[1,2-a]pyridin-3-yl)py-
rimidine-2,4(1H,3H)-dione (4a; CCDC 1990483), based on
single X-ray crystallographic studies was also supplemented
(see SI).
1
yield 86%, mp>300C. H NMR (400 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 8.09-8.06 (m,
2H, Ar-H), 7.72-7.70 (m, 1H, Ar-H), 7.44 (d, J = 8.4 Hz, 1H,
Ar-H), 7.10-7.07 (m, 3H, Ar-H), 6.68-6.65 (m, 1H, Ar-H)
ppm.13C{1H} NMR (100 MHz, DMSO-d6 + one drop of satu-
rated solution of NaOH in D2O):  = 171.3 (C=C(ONa)),
161.9 (2 × −N=C(ONa)), 160.7 (JCF = 232 Hz), 142.9, 139.5,
133.1, 128.9 (2C, JCF = 7.0 Hz), 125.7, 122.8, 121.8, 115.6,
114.2 (2C, JCF = 20 Hz), 109.7, 77.4 ppm. HRMS (ESI-TOF):
m/z [M+H]+ calcd for C17H12FN4O3; 339.0893; found,
339.0896.
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4.3 Larger (millimolar) scale synthesis of model com-
pound 4a: A magnetic stir bar, phenylglyoxal monohydrate
(1a; 1.0 mmol), 2-aminopyridine (2a; 1.0 mmol), barbituric
acid (3a, 1.0 mmol) and 10 mL of water were transferred to an
oven-dried reaction vessel in a sequential manner, and then the
reaction mixture was stirred under reflux condition (110 °C) on
an oil-bath for 2 h (monitored by TLC). On completion of the
reaction, a solid creamy-white mass precipitated out which was
filtered off, followed by purification of the crude product by
washing with 5 mL of hot distilled water containing 5 drops of
ethanol. Upon drying, pure 4a was isolated in 91% yield (290
mg), the physical and spectral properties (see SI) of which were
found identical with those obtained in 0.25 mmol scale reaction
(Table 2; entry 1).
4.4.5 6-Hydroxy-5-(2-(4-methoxyphenyl)imidazo[1,2-a]pyri-
din-3-yl)pyrimidine-2,4(1H,3H)-dione (4e). Grey solid, 72 mg,
1
yield 82%, mp>300C. HNMR (400 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 7.89 (d, J =
8.4 Hz, 2H, Ar-H), 7.74 (d, J = 6.8 Hz, 1H, Ar-H), 7.48 (d, J =
8.8 Hz, 1H, Ar-H), 7.17-7.14 (m,1H, Ar-H), 6.90 (d, J = 8.8
Hz, 2H, Ar-H), 6.78-6.75 (m,1H, Ar-H), 3.75 (s, 3H, Ar-OCH3)
ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + one drop of satu-
rated solution of NaOH in D2O):  = 165.7 (C=C(ONa)),
158.5 (2C, −N=C(ONa) & CAr−OCH3), 154.3 (−N=C(ONa)),
143.8, 141.9, 129.0, 128.7 (2C), 125.4, 123.9, 118.1, 116.1,
113.8 (2C), 111.0, 76.5, 55.5 (Ar-OCH3) ppm; 2D-NMR:
COSY-45, HMQC and HMBC interactions are shown in the
Supplementary Information. HRMS (ESI-TOF): m/z [M-
H]− calcd for C18H13N4O4; 349.0937; found, 349.0938.
4.4 The spectral data of all the compounds 4 (4a – 4x) are given
below:
4.4.1 6-Hydroxy-5-(2-phenylimidazo[1,2-a]pyridin-3-yl)py-
rimidine-2,4(1H,3H)-dione (4a). White solid, 74 mg, yield

1
93%, mp ˃290 C. HNMR (400 MHz, DMSO-d6 + one drop
of saturated solution of NaOH in D2O):  = 8.05 (d, J = 7.6 Hz,
2H, Ar-H), 7.70 (d, J = 6.8 Hz, 1H, Ar-H), 7.42 (d, J = 8.8 Hz,
1H, Ar-H), 7.25 (t, J = 7.2 Hz, 2H, Ar-H), 7.14-7.11 (m, 1H,
Ar-H), 7.08-7.05 (m, 1H, Ar-H), 6.65 (t, J = 6.4 Hz, 1H, Ar-H)
ppm.13C{1H} NMR (100 MHz, DMSO-d6 + one drop of satu-
rated solution of NaOH in D2O):  = 171.1 (C=C(ONa)),
161.3 (2 × −N=C(ONa)), 142.8, 140.3, 136.7, 127.4 (2C),
127.1 (2C), 125.5 (2C), 122.5, 122.1, 115.6, 109.5, 77.2 ppm.
HRMS (ESI-TOF): m/z [M+H]+ calcd for C17H13N4O3;
321.0988; found, 321.0989.
4.4.6 6-Hydroxy-5-(2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidine-2,4(1H,3H)-dione (4f). Dark brown solid, 68
1
mg, yield 74%, mp>300C. H NMR (400 MHz, DMSO-d6 +
one drop of saturated solution of NaOH in D2O):  = 8.24-8.14
(m, 4H, Ar-H), 7.73 (brs, 1H, Ar-H), 7.48 (brs, 1H, Ar-H),7.16
(brs, 1H, Ar-H), 6.73 (brs, 1H, Ar-H) ppm. 13C{1H} NMR (100
MHz, DMSO-d6 + one drop of saturated solution of NaOH in
D2O):  = 170.9 (C=C(ONa)), 161.6 (2 × −N=C(ONa)),
144.9, 143.4, 137.9, 127.4, 126.3, 125.2, 124.1, 122.9, 120.7,
116.0, 110.3 (2C), 107.9, 77.5 ppm. HRMS (ESI-TOF): m/z
[M+H]+ calcd for C17H12N5O5; 366.0838; found, 366.0839.
4.4.2 5-(2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)-6-hy-
droxypyrimidine-2,4(1H,3H)-dione (4b). Pale yellow solid, 82
1
mg, yield 82%, mp>300C. H NMR (400 MHz, DMSO-d6 +
4.4.7 6-Hydroxy-1,3-dimethyl-5-(2-phenylimidazo[1,2-a]pyri-
din-3-yl)pyrimidine-2,4(1H,3H)-dione (4g). Yellowish white
one drop of saturated solution of NaOH in D2O):  = 7.93 (d,
J = 8.4 Hz, 2H, Ar-H), 7.67 (d, J = 7.2 Hz, 1H, Ar-H), 7.44 (d,
J = 8.8 Hz, 3H, Ar-H), 7.14-7.11 (m,1H, Ar-H), 6.71 (t, J = 6.8
Hz, 1H, Ar-H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 +
one drop of saturated solution of NaOH in D2O):  = 170.9
(C=C(ONa)), 160.9 (2 × −N=C(ONa)), 143.2, 139.2, 135.8,
130.6 (2C), 129.3 (2C), 125.8, 123.5, 122.4, 119.2, 115.8,
110.3, 77.4 ppm. HRMS (ESI-TOF): m/z [M+H]+ calcd for
C17H12BrN4O3; 399.0093; found, 399.0099.
1
solid, 54 mg, yield 77%, mp>300C. H NMR (400 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in D2O):
 = 7.94 (d, J = 7.2 Hz, 2H, Ar-H), 7.74 (d, J = 6.8 Hz, 1H, Ar-
H), 7.52 (d, J = 8.8 Hz, 1H, Ar-H), 7.34-7.30 (m, 2H, Ar-H),
7.21-7.16 (m, 2H, Ar-H), 6.78-6.74 (m, 1H, Ar-H), 3.15 (s,
6H, −NCH3) ppm.13C{1H} NMR (100 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 161.8 (2 ×
H3CN=C(ONa)), 153.3 (C=C(ONa)), 143.2, 141.3, 136.1,
127.8 (2C), 126.9 (2C), 126.2, 125.2, 123.4, 119.2, 115.9,
110.5, 75.8, 27.2 (2 × NCH3) ppm. HRMS (ESI-TOF): m/z
[M+H]+ calcd for C19H17N4O3; 349.1301; found, 349.1304.
4.4.3 5-(2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-6-hy-
droxypyrimidine-2,4(1H,3H)-dione (4c). Yellow solid, 86 mg,
1
yield 97%, mp>300C. H NMR (400 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 8.05 (d,J =
8.4 Hz, 2H, Ar-H), 7.73 (d, J = 6.8 Hz, 1H, Ar-H), 7.46 (d, J =
8.8 Hz, 1H, Ar-H), 7.33 (d, J = 8.0 Hz, 2H, Ar-H), 7.13-7.10
(m, 1H, Ar-H), 6.70 (brs, 1H, Ar-H) ppm. 13C{1H} NMR (100
MHz, DMSO-d6 + one drop of saturated solution of NaOH in
4.4.8 6-Hydroxy-5-(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-
yl)pyrimidine-2,4(1H,3H)-dione (4h). Pale yellow solid, 59 mg,

1
yield 70%, mp ˃290 C. H NMR (400 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 7.99 (d, J = 7.6
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Hz, 2H, Ar-H), 7.60 (d, J = 6.8 Hz, 1H, Ar-H), 7.27 (d, J = 7.6
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128.3 (2C), 124.8, 120.4, 113.7, 112.9 (2C), 111.9, 77.5, 54.9
(Ar-OCH3), 20.8 (Ar−CH3) ppm; 2D-NMR: COSY-45, HMQC
and HMBC interactions are shown in the Supplementary Infor-
mation. HRMS (ESI-TOF): m/z [M−H]− calcd for C19H15N4O4;
363.1093; found, 363.1099.
1
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3
4
5
6
7
8
Hz, 2H, Ar-H), 7.23 (brs, J = 8.4 Hz, 1H, Ar-H), 7.15-7.11 (m,
1H, Ar-H), 6.55 (d, J = 6.8 Hz, 1H, Ar-H), 2.33 (s, 3H, Ar-CH3)
ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + one drop of satu-
rated solution of NaOH in D2O):  = 168.2 (C=C(ONa)), 157.6
(2 ×−N=C(ONa)), 143.5, 140.4, 136.8, 133.2, 127.6 (2C), 127.1
(2C), 125.8, 124.9, 120.4, 114.2, 112.5, 76.6, 20.9 (Ar-CH3)
ppm. HRMS (ESI-TOF): m/z [M−H]− calcd for C18H13N4O3;
333.0988; found, 333.0980.
4.4.13 6-Hydroxy-5-(7-methyl-2-(4-nitrophenyl)imidazo[1,2-
a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4m). Brown

1
solid, 61 mg, yield 64%, mp >300 C. H NMR (400 MHz,
DMSO-d6+ one drop of saturated solution of NaOH in D2O):
 = 8.22−8.16 (m, 4H, Ar-H), 7.67 (d, J = 7.2 Hz, 1H, Ar-H),
7.30 (br s, 1H, Ar-H), 6.65 (d, J = 7.2 Hz, 1H, Ar-H), 2.35 (s,
3H, Ar−CH3) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 165.9
(C=C(ONa)), 155.1 (2 × −N=C(ONa)), 145.2, 144.2, 143.6,
138.4, 134.9, 127.4 (2C), 125.4, 123.3 (2C), 122.2, 114.7,
113.6, 76.3, 20.9 (Ar−CH3) ppm. HRMS (ESI-TOF): m/z
[M−H]− calcd for C18H12N5O5; 378.0838; found, 378.0830.
4.4.9 5-(2-(4-Bromophenyl)-7-methylimidazo[1,2-a]pyridin-3-
yl)-6-hydroxypyrimidine2,4(1H,3H)-dione (4i). Yellowish
white solid, 99 mg, yield 96%, mp>300C. 1H NMR (400 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in D2O):
 = 7.93 (d, J = 8.4 Hz, 2H, Ar-H), 7.62 (d, J = 6.8 Hz, 1H, Ar-
H), 7.46 (d, J = 8.4 Hz, 2H, Ar-H), 7.24 (brs, 1H, Ar-H), 6.57
(d, J = 6.8 Hz, 1H, Ar-H), 2.34 (s, 3H, Ar-CH3) ppm.
13C{1H} NMR (100 MHz, DMSO-d6 + one drop of saturated
solution of NaOH in D2O):  = 167.1 (C=C(ONa)), 156.5 (2
×−N=C(ONa)), 143.6, 139.4, 136.1, 133.6, 130.6 (2C), 129.0
(2C), 125.0, 120.2, 118.9, 114.4, 112.8, 76.4, 20.9 (Ar−CH3)
ppm. HRMS (ESI-TOF): m/z [M−H]− calcd for C18H12BrN4O3;
411.0093; found, 411.0095.
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16
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18
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27
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34
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36
37
38
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46
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60
4.4.14
6-Hydroxy-1,3-dimethyl-5-(7-methyl-2-phenylimid-
azo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione
(4n).

1
Pale yellow solid, 78 mg, yield 86%, mp >300 C. H NMR
(400 MHz, DMSO-d6 + one drop of saturated solution of
NaOH in D2O):  = 7.89-7.87 (m, 2H, Ar-H), 7.60 (d, J = 6.8
Hz, 1H, Ar-H), 7.30-7.26 (m, 3H, Ar-H), 7.18-7.14 (m, 1H, Ar-
H), 6.61-6.59 (m, 1H, Ar-H), 3.12 (s, 6H, 2 × −NCH3), 2.34 (s,
3H, Ar−CH3) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 161.9 (2 ×
H3CN=C(ONa)), 153.4 (C=C(ONa)), 143.6, 140.8, 136.1,
133.9, 127.8 (2C), 126.8 (2C), 126.1, 124.5, 118.7, 114.2,
113.0, 75.9, 27.2 (2 × NCH), 20.8 (Ar−CH3) ppm. HRMS
(ESI-TOF): m/z [M−H]− calcd for C20H17N4O3; 361.1301;
found, 361.1300.
4.4.10 5-(2-(4-Chlorophenyl)-7-methylimidazo[1,2-a]pyridin-
3-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4j). Creamy
white solid, 76 mg, yield 83%, mp>300C. 1H NMR (400 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in D2O):
 = 8.03 (d, J = 8.4 Hz, 2H, Ar-H), 7.60 (d, J = 6.8 Hz, 1H, Ar-
H), 7.28 (d, J = 8.4 Hz, 2H, Ar-H), 7.20 (brs, 1H , Ar-H), 6.50
(d, J = 6.8 Hz, 1H, Ar-H), 2.31 (s, 3H, Ar−CH3) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6 + one drop of saturated solution of
NaOH in D2O):  = 171.3 (C=C(ONa)), 161.9 (2
×
−N=C(ONa)), 147.5, 143.4, 138.8, 135.9, 133.3, 130.1, 128.8
(2C), 127.5, 125.4, 122.2, 114.2, 112.4, 77.7, 20.9 (Ar−CH3)
ppm. HRMS (ESI-TOF): m/z [M−H]− calcdfor C18H12ClN4O3;
367.0598; found, 367.0590.
4.4.15 6-Hydroxy-5-(8-methyl-2-phenylimidazo[1,2-a]pyri-
din-3-yl)pyrimidine-2,4(1H,3H)-dione (4o). Creamy white

1
solid, 60 mg, yield 71%, mp ˃290 C. H NMR (400 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in D2O):
 = 7.98 (d, J = 7.6 Hz, 2H, Ar-H), 7.48 (br s, 1H, Ar-H), 7.36
(d, J = 8.8 Hz, 1H, Ar-H), 7.25 (t, J = 7.6 Hz, 2H, Ar-H), 7.13
(t, J = 7.2 Hz, 1H, Ar-H), 6.97 (dd, J = 9.2 and 1.6 Hz, 1H, Ar-
H), 2.22 (s, 3H, Ar-CH3) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in
D2O):  = 171.0 (C=C(ONa)), 161.1 (2 × −N=C(ONa)),
142.2, 140.5, 136.6, 127.7 (2C), 127.2 (2C), 126.0, 125.8,
122.9, 121.7, 118.9, 115.2, 77.6, 17.9 (Ar−CH3) ppm. HRMS
(ESI-TOF): m/z [M−H]− calcd for C18H13N4O3; 333.0988;
found, 333.0983.
4.4.11 5-(2-(4-Fluorophenyl)-7-methylimidazo[1,2-a]pyridin-
3-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4k). Pale yellow
1
solid, 72 mg, yield 82%, mp>300C. H NMR (400 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in D2O):
 = 7.85-7.82 (m, 2H, Ar-H), 7.61 (d, J = 6.8 Hz, 1H, Ar-H),
7.25 (brs, 1H, Ar-H), 7.10 (t, J = 8.8 Hz, 2H, Ar-H), 6.66 (dd,
J = 6.8, 1.2 Hz, 1H, Ar-H), 2.31 (s, 3H, Ar−CH3) ppm.
13C{1H} NMR (100 MHz, DMSO-d6 + one drop of saturated
solution of NaOH in D2O):  = 167.0 (2C, C=C(ONa) and
−N=C(ONa)), 161.8 (JCF = 242 Hz), 155.7 (−N=C(ONa)),
144.6, 140.4, 136.1, 132.4, 129.3 (2C, JCF= 7 Hz), 124.8,
117.8, 115.4 (2C, JCF = 21 Hz), 114.5 (2C), 77.7, 21.3
(Ar−CH3) ppm. HRMS (ESI-TOF): m/z [M−H]− calcdfor
C18H12FN4O3; 351.0893; found, 351.0896.
4.4.16 5-(2-(4-Bromophenyl)-8-methylimidazo[1,2-a]pyridin-
3-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4p). Pale yellow

1
solid, 86 mg, yield 83%, mp >300 C. H NMR (400 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in D2O):
 = 7.97 (d, J = 8.0 Hz, 2H, Ar-H), 7.50 (br s, 1H, Ar-H), 7.43
(d, J = 8.4 Hz, 2H, Ar-H), 7.36 (d, J = 9.2 Hz, 1H, Ar-H), 6.97
(d, J = 9.2 Hz, 1H, Ar-H), 2.21 (s, 3H, Ar−CH3) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6 + one drop of saturated solution of
NaOH in D2O):  = 171.2 (C=C(ONa)), 161.7
(2 × −N=C(ONa)), 142.0, 139.2, 136.1, 130.3 (2C), 129.0 (2C),
125.9, 123.1, 122.3, 118.6 (2C), 115.2, 77.4, 17.9 (Ar−CH3)
ppm. HRMS (ESI-TOF): m/z [M−H]− calcd for C18H12BrN4O3;
411.0093; found, 411.0095.
4.4.12
6-Hydroxy-5-(2-(4-methoxyphenyl)-7-methylimid-
azo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4l). Pale
1
yellow solid, 79 mg, yield 87%, mp>300C. HNMR (400
MHz, DMSO-d6 + one drop of saturated solution of NaOH in
D2O):  = 7.94 (d, J = 8.8 Hz, 2H, Ar-H), 7.56 (d, J = 6.8 Hz,
1H, Ar-H), 7.18 (brs,1H, Ar-H), 6.83 (d, J = 8.8 Hz, 2H, Ar-
H), 6.49 (dd,J = 6.8, 1.2 Hz, 1H, Ar-H), 3.73 (s, 3H,
Ar−CH3), 2.32 (s, 3H, Ar−CH3) ppm. 13C{1H} NMR (100
MHz, DMSO-d6 + one drop of saturated solution of NaOH in
D2O):  = 171.1 (C=C(ONa), 161.3 (−N=C(ONa)), 157.4
(2C, −N=C(ONa) & CAr−OCH3), 143.1, 139.9, 132.5, 129.5,
4.4.17 5-(2-(4-Chlorophenyl)-8-methylimidazo[1,2-a]pyridin-
3-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4q). Pale yellow
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
1
solid, 84 mg, yield 91%, mp >300 C. H NMR (400 MHz,
DMSO-d6 + one drop of saturated solution of NaOH in D2O):
 = 8.04 (br s, 2H, Ar-H), 7.51 (br s, 1H, Ar-H), 7.37−7.31 (m,
3H, Ar-H), 6.98 (br s, 1H, Ar-H), 2.21 (s, 3H, Ar−CH3) ppm.
13C{1H} NMR (100 MHz, DMSO-d6 + one drop of saturated
solution of NaOH in D2O):  = 171.4 (C=C(ONa)), 162.0 (2
×−N=C(ONa)), 142.3, 139.4, 135.9, 130.3, 128.8 (2C), 127.6,
127.0, 126.1, 123.3, 122.4, 118.9, 115.4, 77.7, 18.1 (Ar−CH3)
ppm. HRMS (ESI-TOF): m/z [M−H]− calcd for C18H12ClN4O3;
367.0598; found, 367.0593.
TOF): m/z [M+Na]+ calcd for C16H10N5O3Na; 344.0760; found,
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2
3
4
5
6
7
8
344.0752.
4.4.22 5-(2-(4-Bromophenyl)imidazo[1,2-b]pyridazin-3-yl)-6-
hydroxypyrimidine-2,4(1H,3H)-dione (4v). Pale yellow solid,
90 mg, yield 90%, mp >300 C. 1H NMR (400 MHz, DMSO-

d6 + one drop of saturated solution of NaOH in D2O):  = 8.35-
8.33 (m, 1H, Ar-H), 8.03− 8.01 (m, 3H, Ar-H), 7.47 (d, J = 8.4
Hz, 2H, Ar-H), 6.83-6.80 (m,1H, Ar-H) ppm. 13C{1H} NMR
(100 MHz, DMSO-d6 + one drop of saturated solution of NaOH
in D2O):  = 161.9 (3C; (C=C(ONa) and (2 × −N=C(ONa)−)),
148.4, 147.1, 140.6, 136.2, 134.3, 131.1 (2C), 130.1 (2C),
121.8, 120.0, 107.4, 77.3 ppm. HRMS (ESI-TOF): m/z
[M+Na]+ calcd for C16H9BrN5O3Na; 421.9865; found,
421.9846.
9
4.4.18 5-(2-(4-Fluorophenyl)-8-methylimidazo[1,2-a]pyridin-
3-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4r). Yellowish
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
1
white solid, 75 mg, yield 85%, mp >300 C. H NMR (400
MHz, DMSO-d6 + one drop of saturated solution of NaOH in
D2O):  = 8.05- 8.01 (m, 2H, Ar-H), 7.48 (br s, 1H, Ar-H), 7.34
(d, J = 8.8 Hz, 1H, Ar-H), 7.08−7.04 (m, 2H, Ar-H), 6.95 (d, J
= 9.2 Hz, 1H, Ar-H), 2.22 (s, 3H, Ar−CH3) ppm. 13C{1H} NMR
(100 MHz, DMSO-d6 + one drop of saturated solution of NaOH
in D2O):  = 170.9 (C=C(ONa)), 161.9 (2× −N=C(ONa)),
160.3 (JCF = 162 Hz), 141.9, 139.5, 133.3, 128.7 (2C, JCF= 7.0
Hz), 125.6, 123.0, 121.7, 118.4, 115.1, 114.0 (2C, JCF = 20.0
Hz), 77.0, 17.8 (Ar−CH3) ppm. HRMS (ESI-TOF): m/z
[M+Na]+ calcd for C18H12FN4O3Na; 375.0869; found,
375.0874.
4.4.23 5-(2-(4-Chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)-6-
hydroxypyrimidine-2,4(1H,3H)-dione (4w). Pale yellow solid,
72 mg, yield 81%, mp >300 C. 1H NMR (400 MHz, DMSO-

d6+ one drop of saturated solution of NaOH in D2O):  = 8.34
(br s, 1H, Ar-H), 8.07-8.01 (m, 3H, Ar-H), 7.33 (br s, 2H, Ar-
H), 6.82 (br s, 1H, Ar-H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6+ one drop of saturated solution of NaOH in
D2O):  = 165.7 (3C; (C=C(ONa) and (2 × −N=C(ONa)−)),
153.9, 151.2, 148.1, 142.8, 134.6, 134.4 (2C), 133.5, 129.9,
129.4, 117.0, 109.7, 77.2 ppm. HRMS (ESI-TOF): m/z
[M+Na]+ calcd for C16H9ClN5O3Na; 378.0370; found,
378.0353.
4.4.19
6-Hydroxy-5-(2-(4-methoxyphenyl)-8-methylimid-
(4s).
azo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione
Yellowish white solid, 66 mg, yield 73%, mp >300 C.
1H NMR (400 MHz, DMSO-d6 + one drop of saturated solution
of NaOH in D2O):  = 7.82 (d, J = 8.4 Hz, 2H, Ar-H), 7.43 (br
s, 1H, Ar-H), 7.35 (d, J = 8.8 Hz, 1H, Ar-H), 7.00 (d, J = 9.2
Hz, 1H, Ar-H), 6.84 (d, J = 8.4 Hz, 2H, Ar-H), 3.71 (s, 3H,
Ar−CH3), 2.20 (s, 3H, Ar−CH) ppm. 13C{1H} NMR (100
MHz, DMSO-d6 + one drop of saturated solution of NaOH in
D2O):  = 171.5 (C=C(ONa)), 161.3 (−N=C(ONa)), 158.3
(2C, −N=C(ONa) & CAr−OCH3), 142.9, 140.9, 129.2, 128.9
(2C), 127.1, 123.1, 120.2, 120.0, 115.4, 113.9 (2C), 78.9, 55.6
(Ar-OCH3), 18.3 (Ar−CH3) ppm. HRMS (ESI-TOF): m/z
[M+Na]+ calcd for CH15N4O4Na; 387.1069; found, 387.1072.
4.4.24 5-(2-(4-Fluorophenyl)imidazo[1,2-c]pyrimidin-3-yl)-6-
hydroxypyrimidine-2,4(1H,3H)-dione (4x). Pale yellow solid,
70 mg, yield 82%, mp >300 C. 1H NMR (400 MHz, DMSO-
d6+ one drop of saturated solution of NaOH in D2O):  = 8.40
(br s, 1H, Ar-H), 8.06 (br s, 3H, Ar-H), 7.15 (br s, 2H, Ar-H),
6.89 (br s, 1H, Ar-H) ppm. 13C{1H} NMR (100 MHz, DMSO-
d6+ one drop of saturated solution of NaOH in D2O):  = 165.2
(2C; (C=C(ONa) and (−N=C(ONa)−)), 161.9 (JCF = 243 Hz),

153.7 (−N=C(ONa)−), 149.4, 147.4, 142.1, 133.8, 132.3 (JCF
=
2.0 Hz), 129.6 (2C, JCF = 8.0 Hz), 117.2, 115.3 (2C, JCF = 20
Hz), 108.2, 75.8 ppm. HRMS (ESI-TOF): m/z [M+Na]+ calcd
for C16H9FN5O3Na; 362.0665; found, 362.0644.
4.4.20 5-(8-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)-6-hy-
droxypyrimidine-2,4(1H,3H)-dione (4t). white solid, 78 mg,
yield 88%, mp >300 C. 1H NMR (400 MHz, DMSO-d6 + one
drop of saturated solution of NaOH in D2O):  = 7.85-7.80 (m,
3H, Ar-H), 7.52 (br s, 1H, Ar-H), 7.33-7.26 (m, 4H, Ar-H)
ppm. C{1H} NMR (100 MHz, DMSO-d6 + one drop of satu-
rated solution of NaOH in D2O):  = 165.8 (C=C(ONa)),
154.0 (2 × −N=C(ONa)), 144.1, 143.5, 135.5, 129.6 (2C),
128.8, 128.1 (2C), 126.9, 123.6, 120.4, 118.7, 117.7, 77.8 ppm.
HRMS (ESI-TOF): m/z [M+Na]+ calcd for C17H10ClN4O3Na;
377.0417; found, 377.0412.
ASSOCIATED CONTENT
Supporting Information
Scanned copies of respective H NMR, 13C NMR, 2D-NMR
1
(for 4e and 4l) and HRMS spectra for all the synthesized com-
pounds 4a-4x, along with X-ray single crystallographic analysis
for a representative entry, 6-hydroxy-5-(2-phenylimidazo[1,2-
a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4a), are
docu-
mented in the Supporting Information. CCDC 1990483 contains
the supplementary crystallographic data for 4a that can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif. Working formulas for
calculations of green metrics and respective calculated data for all
the synthesized compounds are also supplemented.
4.4.21
6-Hydroxy-5-(2-phenylimidazo[1,2-b]pyridazin-3-
yl)pyrimidine-2,4(1H,3H)-dione (4u). Yellowish white solid,

68 mg, yield 85%, mp >300 C. 1H NMR (400 MHz, DMSO-
d6 + one drop of saturated solution of NaOH in D2O):  = 8.36-
8.34 (m, 1H, Ar-H), 8.06 (d, J = 7.2 Hz, 2H, Ar-H), 8.01 (dd,
J = 6.6, 2.0, 1.6 Hz, 1H, Ar-H), 7.30 (t, J = 7.6 Hz, 2H, Ar-H),
7.19− (m, 1H, Ar-H), 6.87-6.84 (m, 1H, Ar-H) ppm.
13C{1H} NMR (100 MHz, DMSO-d6 + one drop of saturated
solution of NaOH in D2O):  = 161.1 (3C; (C=C(ONa) and (2
× −N=C(ONa)−)), 147.7, 146.6, 141.5, 136.2, 133.4, 127.7
(2C), 127.5 (2C), 126.4, 120.7, 106.8, 76.8 ppm. HRMS (ESI-
FAIR Data is available as Supporting Information for Publi-
cation and includes the primary NMR FID files for compounds 4a-
4x. The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 9
varicella-zoster virus (VZV): part II. Bioorg. Med. Chem. 2008,
16, 9536-9545.
*Goutam Brahmachari: E-mail: brahmg2001@yahoo.co.in;
goutam.brahmachari@visva-bharati.ac.in
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5
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6. (a) Shukla, N. M.; Salunke, D. B; Yoo, E.; Mutz, C. A.; Balakrishna,
R.; David, S. A. Antibacterial activities of Groebke-Blackburn-
Bienaymé-derived imidazo[1,2-a]pyridin-3-amines. Bioorg. Med.
Chem. Lett. 2012, 20, 5850-5863. (b) Bode, M. L.; Gravestock, D.;
Moleele, S. S.; van der Westhuyzen, C. W.; Pelly, S. C.;
Steenkamp, P. A.; Hoppe, H. C.; Khan, T.; Nkabinde, L. A. Imid-
azo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside re-
verse transcriptase inhibitors. Bioorg. Med. Chem. 2011, 19, 4227-
4237. (c) Bae, J. S.; Lee, D. W.; Lee, D. H.; Jeong, D. S. PCT Int.
Appl WO2007011163A1, 2007.
ORCID: http://orcid.org/0000-0001-9925-6281
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
NN is grateful to the DST, New Delhi for providing her Senior
Research Fellowship under DST-INSPIRE Research Program.
Both of IK and AB are also thankful to the UGC, New Delhi for
sponsoring them Senior Research Fellowship and Junior Research
Fellowship, respectively. The authors are also thankful to IIT,
Kanpur and IISER, Kolkata for extending HRMS measurement fa-
cility, and to the Department of Chemistry, Visva-Bharati for in-
frastructural facilities.
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7. Chernyak, N.; Gevorgyan, V. General and efficient copper-cata-
lyzed three-component coupling reaction towards imidazohetero-
cycles: one-pot synthesis of alpidem and zolpidem. Angew. Chem.
Int. Ed. 2010, 49, 2743-2746.
8. (a) Ismail, M. A.; Arafa, R. K.; Wenzler, T.; Brun, R.; Tanious, F.
A.; Wilson W. D.; Boykin, D. W. Synthesis and antiprotozoal ac-
tivity of novel bis-benzamidino imidazo[1,2-a]pyridines and
5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines. Bioorg. Med. Chem.
2008, 16, 683-691. (b) Scribner, A.; Dennis, R.; Lee, S.; Ouvry,
G.; Perrey, D.; Fisher, M.; Wyvratt, M.; Leavitt, P.; Liberator, P.;
Gurnett, A.; Brown, C.; Mathew, J.; Thompson, D.; Schmatz, D.;
Biftuu, T. Synthesis and biological activity of imidazopyridine an-
ticoccidial agents: Part II. Eur. J. Med. Chem. 2008, 43, 1123-
1151. (c) Biftu, T.; Feng, D.; Fisher, M.; Liang, G. B.; Qian, X.;
Scribner, A.; Dennis, R.; Lee, S.; Liberator, P. A.; Brown, C.; Gur-
nett, A.; Leavitt, P. S.; Thompson, D.; Mathew, J.; Misura, A.; Sa-
maras, S.; Tamas, T.; Sina, J. F.; McNulty, K. A.; McKnight, C.
G.; Schmatz, D. M.; Wyvratt, M. Synthesis and SAR studies of
very potent imidazopyridine antiprotozoal agents. Bioorg. Med.
Chem. Lett. 2006, 16, 2479-2483.
REFERENCES
1. (a) Hsu, N.; Jha, S. K.; Coleman, T.; Frank, M. G. Paradoxical ef-
fects of the hypnotic Zolpidem in the neonatal ferret. Behav. Brain
Res. 2009, 201, 233-236. (b) Hanson, S. M.; Morlock, E. V.; Sat-
yshur, K. A.; Czajkowski, C. Structural requirements for Eszopi-
clone and Zolpidem binding to the γ-aminobutyric acid type-A
(GABAA) receptor are different. J. Med. Chem. 2008, 51, 7243-
7252, and references cited therein. (c) Gueiffier, E. C.; Gueiffier,
A. Recent progress in the pharmacology of imidazo[1,2-a]pyri-
dines. Mini-Rev. Med. Chem. 2007, 7, 888-899. (d) Harrison, T.
S.; Keating, G. M. Zolpidem: a review of its use in the manage-
ment of insomnia. CNS Drugs, 2005, 19, 65-89.
2. Xi, G. L.; Liu, Z. Q. Introducing ferrocene into imidazo[1,2-a]pyri-
dine by Groebke three-component-reaction for scavenging radi-
cals and inhibiting DNA oxidation. Tetrahedron, 2015, 71, 9602-
9610.
9. (a) Moraski, G. C.; Oliver, A. G.; Markley, L. D.; Cho, S.;
Franzblau, S. G.; Miller, M. J. Scaffold-switching: An exploration
of 5,6-fused bicyclic heteroaromatics systems to afford antituber-
culosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates.
Bioorg. Med. Chem. Lett. 2014, 24, 3493-3498. (b) Ramachan-
dran, S.; Panda, M.; Mukherjee, K.; Choudhury, N. R.; Tantry, S.
J.; Kedari, C. K.; Ramachandran, V.; Sharma, S.; Ramya, V, K.;
Guptha, S.; Sambandamurthy, V. K. Synthesis and structure activ-
ity relationship of imidazo[1,2-a]pyridine-8-carboxamides as a
novel antimycobacterial lead series. Bioorg. Med. Chem. Lett.
2013, 23, 4996-5001.
3. (a) Lacerda, R. B.; De Lima, C. K. F.; Da Silva, L.;Romeiro, N. C.;
Miranda, A. L.P.; Barreiro, E. J.; Fraga, C. A. M. Discovery of
novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-
a]pyridine symbiotic prototypes. Bioorg. Med. Chem. 2009, 17,
74-84. (b) Zhou, J, P.; Ding, Y. W.; Zhang, H. B.; Xu, L.; Dai, Y.
Synthesis and anti-inflammatory activity of imidazo[1,2-a]pyrim-
idine derivatives. Chin. Chem. Lett. 2008, 19, 669-672.
4. (a) Yu, Y.; Han, Y.; Zhang, F.; Gao, Z.; Zhu, T.; Dong, S.; Ma, M.
Design, synthesis, and biological evaluation of imidazo[1,2-a]pyr-
idine derivatives as novel PI3K/mTOR dual inhibitors. J. Med.
Chem. 2020, 63, 3028-3046. (b) Baviskar, A. T.; Madaan, C.;
Preet, R.; Mohapatra, P.; Jain, V.; Agarwal, A.; Guchhait, S. K.;
Kundu, C. N.; Banerjee, U. C.; Bharatam, P. V. N-Fused imidaz-
oles as novel anticancer agents that inhibit catalytic activity of
topoisomerase IIα and induce Apoptosis in G1/S Phase. J. Med.
Chem. 2011, 54, 5013-5030. (c) Kim, O.; Jeong, Y.; Lee, H.;
Hong, S.-S.; Hong, S. Design and synthesis of imidazopyridine an-
alogues as inhibitors of phosphoinositide 3-kinase signaling and
angiogenesis. J. Med. Chem. 2011, 54, 2455-2466.
10. Marchand, P.; Bazin, M. A.; Pagniez. F.; Riviere, G.; Bodero, L.;
Marhadour, S.; Nourrisson, M. R.; Picot, C.; Ruchaud, S.; Bach,
S.; Baratte, B.; Sauvain, M.; Pareja, D. C.; Vaisberg, A. J.; Le
Pape, P. Synthesis, antileishmanial activity and cytotoxicity of 2,3-
diaryl- and 2,3,8-trisubstituted imidazo[1,2-a]pyrazines. Eur. J.
Med. Chem. 2015, 103, 381-395.
11. Katsura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Takasugi, H. Stud-
ies on antiulcer drugs. II. synthesis and antiulcer activities of im-
idazo[1, 2-a]pyridinyl-2-alkylaminobenzoxazoles and 5, 6, 7, 8-
tetrahydroimidazo[1,2-a]pyridinyl derivatives. Chem. Pharm.
Bull. 1992, 40, 371-380.
12. (a) Ulloora, S.; Shabaraya, R.; Aamir, S.; Adhikari, A. V. New
imidazo[1,2-a]pyridines carrying active pharmacophores: synthe-
sis and anticonvulsant studies. Bioorg. Med. Chem. Lett. 2013, 23,
1502-1506. (b) Fradley, R. L.; Guscott, M. R.; Bull, S.; Hallett, D.
J.; Goodacre, S. C.; Wafford, K. A.; Garrett, E. M.; Newman, R.
J.; O’Meara, G. F.; Whiting, P. J.; Rosahl, T. W.; Dawson, G. R.;
Reynolds, D. S.; Atack, J. R. Differential contribution of
GABA(A) receptor subtypes to the anticonvulsant efficacy of ben-
zodiazepine site ligands. J. Psychopharmacol. 2007, 21, 384-391.
5. (a) Manvar, P.; Shaikh. F.; Kakadiya, R.; Mehariya, K.; Khunt, R.;
Pandey, B.; Shah, A. Synthesis of novel imidazo[1,2-a]pyridine-
4-hydroxy-2H-coumarins by Groebke–Blackburn–Bienaymé
multicomponent reaction as potential NS5B inhibitors. Tetrahe-
dron 2016, 72, 1293-1300. (b) Enguehard-Gueiffier, C.; Musiu, S.;
Henry, N.; Véron, J. B.; Mavel, S.; Neyts, J.; Leyssen, P.;
Paeshuyse, J.; Gueiffier, A. 3-Biphenylimidazo[1,2-a]pyridines or
[1,2-b]pyridazines and analogues, novel Flaviviridae inhibitors.
Eur. J. Med. Chem. 2013, 64, 448-463, and references cited
therein. (c) Veron, J. B.; Allouchi, H.; Enguehard -Gueiffier, C.;
Snoeck, R.; De Clercq G. A. E.; Gueiffier, A. Influence of 6- or 8-
substitution on the antiviral activity of 3-arylalkylthiomethylimid-
azo[1,2-a]pyridine against human cytomegalovirus (CMV) and
13. Sorbera, L.A., Castaner, J.; Leeson, P. A. Minodronic acid. Drugs
Fut. 2002, 27, 935-941.
14. Langer, S. Z.; Arbilla, S.; Benavides, J.; B. Scatton. Zolpidem and
alpidem: two imidazopyridines with selectivity for omega 1- and
ACS Paragon Plus Environment

Page 9 of 9
The Journal of Organic Chemistry
omega 3-receptor subtypes. Adv. Biochem. Psychopharmacol.
1990, 46, 61-72.
transformations at ambient conditions: our sincere efforts to the
cause of green chemistry practice. Chem. Rec. 2016, 16, 98-123,
and references cited therein.
1
2
3
4
5
6
7
15. Katritzky, A. R.; Xu, Y. J.; Tu, H. Regiospecific synthesis of 3-
substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines,
and imidazo[1,2-c]pyrimidine. J. Org. Chem. 2003, 68, 4935-
4937.
21. (a) Brahmachari, G.; Nayek, N. Catalyst-free one-pot three-com-
ponent synthesis of diversely substituted 5-aryl-2-oxo-/thioxo-2,3-
dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-
triones under ambient conditions. ACS Omega, 2017, 2, 5025-
5035, and references cited therein. (b) Sharma, P.; Rane, N.; Gur-
ram, V. K. Synthesis and QSAR studies of pyrimido[4,5-d]pyrim-
idine-2,5-dione derivatives as potential antimicrobial agents.
Bioorg. Med. Chem. Lett. 2004, 14, 4185-4190.
16. Sanger, D.J. Behavioural effects of novel benzodiazepine (omega)
receptor agonists and partial agonists: increases in punished re-
sponding and antagonism of the pentylenetetrazole cue. Behav.
Pharmacol. 1995, 6, 116-126.
8
9
17. (a) Du, B.; Shan, A.; Zhang, Y.; Zhong, X.; Chen, D.; Cai, K.
Zolpidem arouses patients in vegetative state after brain injury:
quantitative evaluation and indications. Am. J. Med. Sci. 2014, 3,
178-182. (b) Hsua, N.; Jha, S. K.; Coleman, T.; Frank, M. G. Par-
adoxical effects of the hypnotic Zolpidem in the neonatal ferret.
Behav. Brain Res. 2009, 201, 233-236. (c) Hanson, S. M.; Mor-
lock, E. V.; Satyshur, K. A.; Czajkowski, C. Structural require-
ments for Eszopiclone and Zolpidem binding to the γ-aminobu-
tyric acid type-A (GABAA) receptor are different. J. Med. Chem.
2008, 51, 7243-7252. (d) Harrison, T. S.; Keating, G. M.
Zolpidem: a review of its use in the management of insomnia. CNS
Drugs 2005, 19, 65-89.
22. Khoeiniha, R.; Olyaei, A.; Saraei, M. Catalyst-free synthesis of
novel 4H-indeno[1,2-b]furan-4-ones and furo[2,3-d]pyrimidines
in water. Syn. Commun. 2018, 48, 155-160.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
23. (a) Brahmachari, G. Synthesis of biologically relevant heterocycles
in aqueous media. Asian J. Org. Chem. 2018, 7, 1982-2004, and
references cited therein. (b) Gawande, M. B.; Bonifacio, V. D. B.;
Luque, R.; Branco, P. S.; Varma, R. S. Benign by design: catalyst-
free in-water, on-water green chemical methodologies in organic
synthesis. Chem. Soc. Rev. 2013, 42, 5522-5551. (c) Chanda, A.;
Fokin, V. V. Organic synthesis “on water”. Chem. Rev. 2009,
109, 725-748.
18. Gueiffier, E. C. and Gueiffier, A. Recent progress in the pharma-
cology of imidazo[1,2-a]pyridines. Mini-Rev. Med. Chem. 2007,
7, 888-899.
24. Brahmachari, G. Catalyst-free organic synthesis. Royal Society of
Chemistry: Cambridge, U.K., 2018.
25. (a) Dhanalakshmi, G.; Ramanjaneyulu, M.; Thennarasu, S.; Ara-
vindhan, S. Crystal structure and Hirshfeld surface analysis of two
imidazo[1,2-a]pyridine derivatives: N-tert-butyl-2-(4-methoxy-
phenyl)-5-methylimidazo[1,2-a]pyridin-3-amine and N-tert-bu-
tyl-2-[4-(dimethylamino)phenyl]imidazo[1,2-a]pyridin-3-amine.
Acta Cryst. 2019, E74, 1913-1918. (b) Brahmachari, G.; Das, S.;
Biswas (Sinha), M. B.; Kumar, A.; Srivastava, A. K.; Misra, N.,
3,5,7-Trimethoxyphenanthrene-1,4-dione: a new biologically rel-
evant natural phenanthrenequinone derivative from Dioscorea
prazeri and studies on its single X-ray crystallographic behavior,
molecular docking and other physico-chemical properties. RSC
Adv. 2016, 6, 7317-7329.
19. (a) Feng, M. L.; Li, S. Q.; He, H. Z.; Xi, L.Y.; Chen, S. Y.; Yu. X.
Q. Electrochemically initiated intermolecular C–N formation/cy-
clization of ketones with 2-aminopyridines: an efficient method for
the synthesis of imidazo[1,2-a]pyridines. Green Chem. 2019, 21,
1619-1624, and references cited therein. (b) Kusy, D.; Maniukie-
wicz, W.; Katarzyna, B. M. Microwave-assisted synthesis of 3-
formyl substituted imidazo[1,2-a]pyridines. Tetrahedron Lett.
2019, 60, 151244. (c) Karamthulla, S.; Khan, M. N.; Choudhury,
L. H. Microwave-assisted synthesis of novel 2,3-disubstituted im-
idazo[1,2-a]pyridines via one-pot three component reactions. RSC
Adv. 2015, 5, 19724-19733. (d) Yu, C.; Chen, X.; Wu, R.; Yang,
G.; Shi, J.; Pan, L. One-pot synthesis of N-(imidazo[1,2-a]pyridin-
3-yl)-substituted sulfonamides using catalytic zinc chloride. Eur.
J. Org. Chem. 2014, 2037-2043. (e) Talbot, E. P. A.; Richardson,
M.; McKenna, J. M.; Toste, F. D. Gold catalysed redox synthesis
of imidazo[1,2-a]pyridine usingpyridine N-oxide and alkynes.
Adv. Synth. Catal. 2014, 356, 687-691. (f) Xu, X.; Hu, P.; Yu, W.;
Hong, G.; Tang, Y.; Fang, M.; Li, X. Bu4NI-catalyzed synthesis of
imidazo[1,2-a]pyridines via oxidative coupling of aminopyridines
with nitroolefins. Synlett 2014, 25, 718-720. (g) Santra, S.; Bagdi,
A. K.; Majee, A.; Hajra, A. Iron(III)-catalyzed cascade reaction
between nitroolefins and 2-aminopyridines: synthesis of imid-
azo[1,2-a]pyridines and easy access towards zolimidin. Adv.
Synth. Catal. 2013, 355, 1065-1070, and references cited therein.
26. (a) Sheldon, R. A. Metrics of green chemistry and sustainability:
past, present and future. ACS Sustainable Chem. Eng. 2018, 6, 32-
48. (b) Abou-Shehada, S.; Mampuys, P.; Maes, B. U. W.; Clark, J.
H.; Summerton, L. An evaluation of credentials of a multicompo-
nent reaction for the synthesis of isothioureas through the use of a
holistic CHEM21 green metrics toolkit. Green Chem. 2017, 19,
249-258. (c) Roschangar, F.; Sheldon, R. A.; Senanayake, C. H.
Overcoming barriers to green chemistry in the pharmaceutical in-
dustry – the green aspiration levelTM concept. Green Chem. 2015,
17, 752-768. (d) Jiménez-González, C.; Constable, D. J. C.; Pon-
der, C. S. Evaluating the “Greenness” of chemical processes and
products in the pharmaceutical industry – a green metrics primer.
Chem. Soc. Rev. 2012, 41, 1485-1498. (e) Constable, D. J. C.; Cur-
zons, A. D.; Cunningham, V. L. Metrics to ‘green’ chemistry—
which are the best? Green Chem. 2002, 4, 521-527.
20. (a) Brahmachari, G.; Mandal, M. One-pot multicomponent synthe-
sis of a new series of curcumin-derived 4H-pyrans under ambient
conditions. J. Heterocycl. Chem. 2020, 57, 744-750. (b) Brah-
machari, G.; Nurjamal, K. Ultrasound-assisted and trisodium cit-
rate dihydrate-catalyzed green protocol for efficient and one-pot
synthesis of substituted chromeno[3′,4′:5,6]pyrano[2,3-d]pyrim-
idines at ambient conditions. Tetrahedron Lett. 2019, 60, 1904-
1908. (c) Brahmachari, G.; Nurjamal, K.; Karmakar, I.; Begam, S.;
Nayek, N.; Mandal, B. Development of a water-mediated and cat-
alyst-free green protocol for easy access to a huge array of diverse
and densely functionalized pyrido[2,3-d:6,5-d′]dipyrimidines via
one-pot multicomponent reaction under ambient conditions. ACS
Sustainable Chem. Eng. 2017, 5, 9494-9505. (d) Brahmachari, G.;
Banerjee, B. Facile and chemically sustainable one-pot synthesis
of a wide array of fused O- and N-heterocycles catalyzed by triso-
dium citrate dihydrate under ambient conditions. Asian J. Org.
Chem. 2016, 5, 271-286. (e) Brahmachari, G. Design of organic
27. Anastas, P. T.; Warner, J. C. Green chemistry: theory and practice;
Oxford University Press: Oxford, 2000.
28. (a) Marjani, A. P.; Khalafy, J.; Farajollahi, A. Synthesis of ethyl 2-
Amino-4-benzoyl-5-oxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-
3-carboxylates by a one-pot, three-component reaction in the pres-
ence of TPAB. J. Heterocycl. Chem. 2019, 56, 268-274. (b) Mar-
jani, A. P.; Abdollahi, S.; Ezzati, M.; Nemati-Kandeb, E. A facile
synthesis of xanthene-1,8(2H)-dione derivatives by using
tetrapropylammonium bromide as catalyst. J. Heterocycl. Chem.
2018, 55, 1324-1330. (c) Riley, H. A.; Gray, A. R. Phenylglyoxal.
Organic Syntheses; Wiley & Sons: New York, NY, Collect. II,
1943, p. 509.
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