One-pot three-component synthesis of chromeno [2,3-d] pyrimidine derivatives: Novel, simple, and efficient electrochemical approach

Article abstract of DOI:10.1002/jhet.3741

An atom economical, selective, and convenient one-pot protocol for the synthesis of the medicinally privileged novel chromeno [2,3-d] pyrimidine scaffold, viz, multicomponent reaction of barbituric acid derivatives, 1,3 cyclic diketone, and various aldehy

Full text of DOI:10.1002/jhet.3741

Received: 23 July 2019
DOI: 10.1002/jhet.3741
Revised: 28 August 2019
Accepted: 29 August 2019
A R T I C L E
One‐pot three‐component synthesis of chromeno [2,3‐d]
pyrimidine derivatives: Novel, simple, and efficient
electrochemical approach
Jyoti Malviya | Rana Krishna Pal Singh
Electrochemical Laboratory of Green
Abstract
Synthesis, Department of Chemistry,
An atom economical, selective, and convenient one‐pot protocol for the synthe-
University of Allahabad, Allahabad
211002, Uttar Pradesh, India
sis of the medicinally privileged novel chromeno [2,3‐d] pyrimidine scaffold,
viz, multicomponent reaction of barbituric acid derivatives, 1,3 cyclic diketone,
Correspondence
Rana Krishna P Singh, Electrochemical
Laboratory of Green Synthesis,
Department of Chemistry, University of
Allahabad, Allahabad 211002, Uttar
Pradesh, India.
and various aldehydes in the presence of tetra n‐butyl ammonium iodide
(TBAI) as an electrolyte in water media under room temperature, is reported.
This ecologically sound novel concept offers environmentally benign synthetic
route, short reaction times, and easy workup procedure with excellent yield
(88% to 90%) and is also beneficial for diversity‐oriented large‐scale processes.
The synthesized products were characterized by IR, MS, NMR, and CHN
analysis.
Email: singhrkp1@gmail.com; rkp.
singh@rediffmail.com
Funding information
University Grant Commission, Grant/
Award Number: JRF; Council of Scientific
and Industrial Research
1 | INTRODUCTION
intermediates.[5] In this manner, the electrochemically
based multicomponent transformation of organic com-
In modern medicinal and combinational chemistry, mul-
ticomponent methodologies (MCRs) are a versatile tool,
and a central point of its animation to facilitate the prep-
aration of privileged scaffolds consist of a rigid hetero ring
system with well‐defined orientation for target recogni-
tion. It offers indicative advantages over the conventional
linear‐type strategy[1] because of its wide applications
including low waste production, less energy consumption,
proficient enactment, convergence, productivity, flexibil-
ity, and good selectivity excellent yield.[2–4] In recent
years, green chemical processes have become a major
demand in modern synthetic methods. In the combina-
tion of multicomponent reactions (MCRs) and water, a
green solvent has emerged as a new research strategy,
which enables simultaneous growth of both MCRs and
green solvents toward an ideal organic synthesis. The
aim of this powerful approach is the construction of single
complex molecule by the combination of two or more
readily available reactants through a sequential reaction
process in one operation without isolating the reaction
pounds in water media has provided a novel and conve-
nient device with its significant synthetic potential and
ecological advantages. It is rapidly developing highly effi-
cient and environmentally benign synthetic protocols to
deliver lifesaving medicines, accelerating lead optimiza-
tion processes in drug discovery with reduced unneces-
sary environmental impact.
Chromeno pyrimidine derivatives are physiologically
active agents that display interesting therapeutic proper-
ties and are widely present in drugs and natural prod-
ucts[6] and in plants including edible vegetables and
fruits.[7] Chromene heterocyclic scaffolds represent a
“privileged” structural motif well‐distributed in natural
products to prevent diseases[8] with a broad spectrum of
potent biological activities.[9–14] They are used in cos-
metics and pigments industries[15] as biodegradable agro-
chemicals[16] and antibacterial agents.[17]
A research program we have developed an environmen-
tally benign synthetic protocol for synthesis of pharmaco-
logically important heterocyclic skeletons chromeno
J Heterocyclic Chem. 2019;1–11.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
MALVIYA AND SINGH
[2,3‐d] pyrimidins in high yield and purity. In this method,
reaction is preceded by a catalytic amount of an
electrogenerated base, which is produced by the use of a
cheap and environmentally responsible chemical reagent
—electricity in an undivided cell.
3 | CONSTANT POTENTIAL
ELECTROLYSIS
3.1 | Electrochemical synthesis of
chromeno [2,3‐d] pyrimidine derivatives
The electrochemically induced one‐pot three‐component
cyclocondensation of aldehydes, cyclic‐1,3‐diketones, and
barbituric acids has been described in the presence of
water as a reaction medium using tetrabutylammonium
iodide as an electrolyte in undivided cell under constant
potential electrolysis. Reactions in aqueous media are
environmentally safe and have less carcinogenic effects
with a simple workup procedure, which are especially
important in industry (Scheme 1).
A 50‐mL beaker‐type cell consists of a mixture of aro-
matic aldehyde (2 mmol), barbituric acid (2 mmol),
and 1,3 dicarbonyl compounds (2 mmol) (Scheme 1)
stirred in water media with tetrabutylammonium iodide
(1 mmol) as an electrolyte under constant potential elec-
trolysis[18–20] at room temperature for 1‐ to 2‐hour
assembly with platinum plates (1 cm2) as working as
well as counter electrodes and an SCE as reference elec-
trode. The completion of the reaction was confirmed by
thin‐layer chromatography (TLC) plate at regular breaks
of time. After completion of reaction, the mixture was
chilled and the compound was isolated by filtration,
washed with cold water, dried, and then recrystallized
from ethanol to afford the product with excellent yield.
The purity of the product was ascertained by TLC, and
2 | EXPERIMENTAL
2.1 | Apparatus
1
the characterization was done by FTIR, H NMR, 13C
Cyclic voltammetry was performed using ALSCH instru-
ments electrochemical analyzer Model 600A with a tradi-
tional three‐electrode system. All experiments were
carried out in a conventional electrochemical cell—the
electrode system contains platinum as a working elec-
trode and a counter electrode and saturated calomel elec-
trode (SCE) as reference electrode. All melting points
were measured on a Gallenkamp melting point apparatus
in open glass capillaries and are uncorrected. IR spectra
were measured as KBr pellets on a Shimadzu 8201 PC
FT‐IR spectrophotometer. The NMR spectra were
recorded on a DRX 400 (400 MHz) spectrometer in CDCl3
or DMSO. Chemical shifts (δ) are referred in terms of
ppm and J‐coupling constants are given in Hz. Mass spec-
tra were recorded on a Shimadzu GCMS‐QP5050A (EI)
spectrometer. Elemental analysis was carried out on an
Elmer 2400 Elemental Analyzer, CHN mode.
NMR and mass spectral data.
4 | RESULT AND DISCUSSION
In the present study, we report the electrochemically
induced chain procedure for the preparation of products
under mild conditions by the combined electrolysis of
aromatic aldehydes, barbituric acid, and 1,3 cyclic
diketone in an undivided cell in water in the presence
of phase transfer catalyst (TBAI) as an electrolyte
(Scheme 1).
In our present protocol, we have used Barbituric or
thio barbituric acid derivatives as one of the components
for synthesis of chromeno pyrimidine derivatives. They
are an important class of compounds because of their
wide range of pharmaceutical and various biological
activities[21–28] and because they remarkably increase bio-
logical activity when aryl moieties substituted at the 5‐
position of the barbituric[29] and thiobarbituric[30]
nucleus. Cyclic 1,3‐diketones (dimedone) is a second
important component for synthesis of desired products.
It is an adaptable precursor for the synthesis of numerous
hetero, spirocyclic, and xanthene derivatives with their
industrial synthetic and analytical determinations.[31]
2.2 | Chemicals
All chemicals were purchased from Aldrich, Sigma‐
Aldrich, Fluka, etc, and were used without further
purification unless otherwise stated. Water used for the
experiment was double distilled.
SCHEME 1 Electrochemical synthesis
of chromeno pyrimidine derivatives at
constant potential electrolysis [Color
figure can be viewed at wileyonlinelibrary.
com]

MALVIYA AND SINGH
3
TABLE 1 Influence of various electrolytesa
Potential, Time, Yieldb,
Both these compounds are strong acids in aqueous
medium, behave as active methylene groups, and form
electrogenerated bases by passing electricity at constant
potential. They are key steps in the formation of prod-
ucts (4a‐4o).
Entry Electrolyte Solvent
V
h
%
1.
2.
3.
4.
5.
LiClO4
Water
Water
Water
Water
Water
1.85
2.00
1.70
1.65
1.30
5
50
45
68
75
90
NaClO4
5‐6
4‐5
4
n‐Bu4NCl
n‐Bu4NBr
n‐Bu4NI
4.1 | Optimization of electrolytes
1‐2
In a project aiming at the developments of suitable proto-
cols for the preparation of chromeno pyrimidins–based
architectures, we have successfully accomplished the syn-
thesis of 8,9‐dihydro‐8,8‐dimethyl‐1H‐chromeno[2,3‐d]
pyrimidine‐2,4,6(3H,5H,7H)‐trione making use of a holis-
tic approach from environmental and economic points of
view. We have used Bu4NI (TBAI)‐water pair in our pres-
ent protocol to make our procedure more efficient and
appropriate than other reported methods. In Scheme 1,
water acts as a green reaction medium because of its
remarkable benefits such as its nontoxic, noncorrosive,
nonflammable, cheap, and environment‐friendly proper-
ties and high polarity and immiscibility with most
organic compounds. Furthermore, reaction in water has
unique reactivity and selectivity and can be easily sepa-
rated from organic products by simple methods.[32] More-
over, TBAI is an effective tool for synthesis from two
immiscible reactants and provides higher isolated yield
due to higher selectivity achieved by taking advantage
of the great flexibility in designing the microenvironment
of the reaction. Hence, it presents itself as an invaluable
agent for organic synthesis from two or more immiscible
reactants, and all its scope and applications are the sub-
jects of current research (see Schemes 1 and 2). It was
observed that the addition of TBAI to the reaction system
increased the solubility of aromatic aldehyde from
organic phase to aqueous phase and led to dramatically
increased yields (Table 1). Comparison among electro-
lytes revealed that TBAI served its purpose to the best,
consuming just 2 hours and yielding 90% of the product
(Table 1, entry 5).
aReaction conditions: benzaldehyde 1 (1 mmol), barbituric acid 2 (1 mmol),
1,3 cyclic diketone 3 (1 mmol).
bIsolated yields after purification.
derivatives under electrochemical condition. Initially, we
tested the reaction of barbituric acid 2a (1 mmol), benzal-
dehyde 1a (1 mmol), and dimedone 3a (1 mmol) using
different solvents including water, ACN, DMF, THF, eth-
anol, methanol, and 1,4 dioxane in tetrabutylammonium
iodide as an electrolyte under constant potential as
shown in Table 2. All the reactions of this model
proceeded efficiently at room temperature. The progress
of the reaction was monitored by TLC. The yield obtained
with the number of solvents is shown in Table 2. We
found the best result with water‐tetrabutylammonium
iodide in comparison with the other solvents. Inspired
by this result, aqua. TBAI (entry 7, Table 2) was then
selected as solvent‐electrolyte pair for all further electro-
chemically assisted synthesis to afford the required prod-
ucts (Schemes 1 and 2, Table 2).
TABLE 2 Solvent optimization for the synthesis of compound
(4a) under constant potential electrolysis
Potential, Current, Time, Yield,
Entry Solvent
V
mA
h
%
1.
2.
3.
4.
5.
6.
7.
Ethanol
1.70
1.75
18
16
12
09
06
04
24
3‐4
3‐4
4‐5
4‐5
4‐6
4‐6
1‐2
72
67
56
40
28
15
85
Methanol
Acetonitrile 1.90
DMF 2.00
1,4 dioxane 2.10
4.2 | Optimization of solvents
THF
2.30
1.40
In our next study, we searched for an appropriate
medium for the synthesis of chromeno [2,3‐d] pyrimidine
Water
SCHEME 2 Electrochemical synthesis
of spiro chromeno [2,3‐d] pyrimidine
under CPE [Color figure can be viewed at
wileyonlinelibrary.com]

4
MALVIYA AND SINGH
the electrogenerated base going to the corresponding rad-
ical, whereas reductive peaks at 0.60 V represent formation
of electrogenerated bases from barbituric acid and
dicarbonyl compound (active methylene compounds) by
the removal of single electron, which involves as a key step
in the formation of product 4a (Figure 1).
4.3 | Optimization of substrates
Here we have reported an efficient procedure to afford
the chromeno [2,3‐d] pyrimidine derivatives (4a‐4o) in
high yields (Schemes 1 and 2). As electrochemical reac-
tion proceeds, the color of reaction mixture changes from
colorless to yellow, and then brownish indicates forma-
tion of final product. The procedure was simple and easy
to operate; generally, the reaction was completed after 1
to 2hours and precipitate, corresponding to the formation
of the product in almost all the cases and separated by
simple filtration. As we can see in Table 3, the method
probed into work with wide variety of substrates. In these
entire reactions, wonderful yields were obtained. The
present protocol was especially favored because it offers
advantages of high yields, short reaction times, simple
clean reactions, and easy workup. Furthermore, this
method is of interest in the perspective of environmen-
tally greener and safer method.
The conversion of the starting compounds into a series
of products (Table 1) with excellent yields were obtained
by passing 0.48 to 0.71 F/mol range of electricity under
16 to 21 mA/cm2 current densities at constant potential
electrolysis. Each reaction has been proceeding with con-
stant potential and definite value of current density.
When potential is increases, current is also increases but
reaction yield is decrease slightly due to starting off an
activation of the undesired oligomerization of the
starting materials.
4.5 | Mechanism
The mechanism shown in Scheme 3 is based on the con-
cept of a stabilized interaction between the cation and the
face of the aromatic ring[33] that plays an important role
in nature, particularly in synthetic systems.
The transfer of benzaldehyde from aqueous phase to
organic phase is facilitated by the binding between the aro-
matic p system and quaternary nitrogenous cation through
van der Waals contact. This promotes the reaction between
reagents with opposite solubility preferences. On the basis
of all our experimental results, we have proposed a plausi-
ble mechanism for the formation of products (Scheme 3).
The detailed mechanism of this one‐pot three‐component
reaction rationalizes the formation of product 4a, which
could be explained via a plausible pathway (Scheme 3).
The reaction may be initiated by the deprotonation of
dimedone and formed electrogenerated base of dimedone
(EGB). This anion undergoes knovenagel condensation
with aldehyde (1a‐1o) and formed benzylidene dimedone
intermediate (ii) with the elimination of water molecule.
Then, EGB of barbituric acid 3b promoted Michael addi-
tion with electron deficient adduct intermediate (ii)
followed by dehydration and cyclization, which lead to
corresponding products (4a‐4o).
The scope of this reaction was explored by using isatin
derivatives instead of aldehydes, and spiro chromeno
[2,3‐d] pyrimidines were obtained with good yield
(Scheme 2).
We conducted the model reaction through three‐
component condensation of isatins, dimedone, and
barbituric acid in the same solvent‐electrolyte condition
(Scheme 2, Table 3, entries 13 to 15).
4.6 | Spectral analysis
The identification of compounds was done on the basis of
the spectral interpretation. The structures were established
1
13
by IR, H NMR,
C NMR, and mass and elemental
4.4 | Cyclic voltammetry
analysis.
Cyclic voltammetry of substrates were recorded using
water as solvent and Bu4NBr as supporting electrolyte at
ambient temperature. The experiments were carried out
using three electrodes in a compartment cell. Both work-
ing and counter electrodes were platinum wire. The poten-
tial of the working electrode was measured versus
4.6.1 | 8,9‐Dihydro‐8,8‐dimethyl‐5‐phenyl‐
1H‐chromeno[2,3‐d]pyrimidine‐2,4,6(3H,5H,
7H)‐trione 4(a)
Offwhite solid, mp 185°C‐187°C; IR (KBr) μ: 3325, 2915,
1
Ag/AgCl reference electrode at scan rate of 0.01 V s−1
.
2196, 1725, 1687, 1672, 1510, 1383, 1035 cm−1; H NMR
Cyclic voltammogram of 1 mmol of mixture of substrates
(aryl aldehyde, barbituric acid, and dicarbonyl com-
pounds) (scan rate: 0.01 V s−1; t = 25 1°C) exhibits two
anodic peaks with potential 0.70 and 1.4 V, where anodic
peaks correspond to transformation of iodide to iodine or
(400 MHz, CDCl3): d = 1.11,1.15 (2s, 6H, 2CH3), 2.18
(q, 2H, CH2), 2.86 (s, 2H, CH2), 4.80 (s, 1H, CH) 5.45,
10.40 (s, 2H, 2NH), 6.95‐7.00 (m, 2H, ArH), 7.35‐7.42 (m,
2H, ArH); 13C NMR (100 MHz, CDCl3) d = 27.5, 28.1,
29.6, 39.3, 42.3, 50.6, 80.5, 114.9, 125.8, 127.6, 128.7,

MALVIYA AND SINGH
5
TABLE 3 CPE of various aldehyde, barbituric acid, and 1,3 dicarbonyl compounds at platinum electrode
Barbituric
Acid
(2a or 2b)
1,3 Cyclic
Diketone
(3a or 3b)
Current
Density,
mA/cm2
Amount of
Electricity
Passed, F/mol
Entry
Aldehyde (Ar)
Product (4a‐4o)
Potential, V
Yield, %
1.
C6H5
2a
3a
1.30
24
0.55
90
2.
p‐NO2C6H5
2a
3a
1.34
26
0.57
86
3.
4.
m‐NO2C6H5
2a
2a
3a
3a
1.37
1.45
23
21
0.52
0.54
86
82
p‐OMe C6H5
5.
6.
p‐MeC6H5
2a
2a
3a
3a
1.42
1.35
21
25
0.56
0.50
80
84
p‐ClC6H5
7.
8.
m‐OHC6H5
2a
2a
3a
3b
1.45
1.42
20
22
0.54
0.52
80
83
C6H5
9.
p‐NO2C6H5
2a
3b
1.28
24
0.60
85
(Continues)

6
MALVIYA AND SINGH
TABLE 3 (Continued)
Barbituric
Acid
(2a or 2b)
1,3 Cyclic
Diketone
(3a or 3b)
Current
Density,
mA/cm2
Amount of
Electricity
Passed, F/mol
Entry
Aldehyde (Ar)
Product (4a‐4o)
Potential, V
Yield, %
10.
p‐OMeC6H5
2a
3b
1.44
23
0.60
82
11.
12.
C6H5
2b
2b
3a
3a
1.45
1.32
19
20
0.53
0.54
80
80
p‐ClC6H5
13.
14.
15.
Isatin
Isatin
Isatin
2a
2b
2a
3a
3a
3b
1.50
1.55
1.52
19
18
18
0.62
0.63
0.62
82
80
81
129.6,130.1, 140.2,149.5, 155.2,160.3,162.8, 197.5; MS
(m/z): 339 [M + 1]+; Anal. Calcd for C19H18N2O4 (338.1);
C, 67.44; H, 5.36; N, 8.28. Found: C, 67.50; H, 5.35; N, 8.32.
(d, J = 8.7 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3):
d = 27.3, 28.4, 38.3, 43.3, 51.4, 79.5, 113.9, 121.8, 123.2,
129.6, 130.1, 131.6, 147.2,149.5, 155.1, 160.5, 163.8,
198.8; MS (m/z): 384 [M + 1]+; Anal. Calcd for
C19H17N3O6 (383.1); C, 59.54; H, 4.47; N, 10.96. Found:
C, 59.50; H, 4.45; N, 10.92.
4.6.2 | 8,9‐Dihydro‐8,8‐dimethyl‐5‐(4‐nitro-
phenyl)‐1H‐chromeno[2,3‐d]pyrimidine2,4,
6(3H,5H,7H)‐trione 4(c)
4.6.3 | 8,9‐Dihydro‐8,8‐dimethyl‐5‐(4‐me-
thoxyphenyl)‐1H‐chromeno[2,3‐d]pyrimi-
dine2,4,6(3H,5H,7H)‐trione 4(d)
Yellow solid, mp 160°C‐162°C; IR (KBr): μ = 3342, 2955,
1
2196, 1712, 1689, 1660, 1530, 1377, 1040 cm−1; H NMR
(400 MHz, CDCl3): d = 1.15,1.20 (2 s, 6H, 2CH3) 2.19
(m, 2H, CH2), 2.85 (s, 2H, CH2), 4.87(s, 1H, CH), 5.60,
10.80 (2 s, 2H, 2NH), 7.37(d, J = 6.6 Hz, 2H, ArH), 8.17
White solid, mp 207°C‐209°C; IR (KBr): μ = 2924, 1695,
1
1630, 1626, 1569, 1508, 1480 cm−1; H NMR (400 MHz,

MALVIYA AND SINGH
7
CDCl3): d = 0.96, 1.05 (2 s, 6H, 2CH3), 2.14 (q, J = 6.9 Hz,
2H, CH2), 2.40 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 4.69 (s,
1H, CH), 5.43, 10.48 (2 s, 2H, 2NH), 6.77 (d, J = 8.4 Hz,
2H, ArH), 7.10 (d, J = 7.5 Hz, 2H, ArH), 8.25 (d,
J = 8.7 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3):
d = 27.4, 28.5, 29.1, 29.5, 32.6, 33.8, 40.8, 50.9, 56.4,
90.3, 115.1, 121.8, 122.1, 128.6, 135.9, 145.4, 147.4, 150.7,
152.8, 161.5, 161.9, 197.5; MS (m/z): 369 [M + 1]+; Anal.
Calcd for C20H20N2O5 (368.1); C, 65.21; H, 5.47; N, 7.60.
Found: C, 65.20; H, 5.45; N, 7.62.
4.6.4 | 8,9‐Dihydro‐8,8‐dimethyl‐5‐p tolyl‐1
H‐chromeno[2,3‐d] pyrimidine 2,4,6 (3H,5H,
7H)‐trione 4(e)
Brown solid, mp 215°C‐217°C; IR (KBr): μ = 3133, 3091,
1
2931, 1689, 1649, 1542, 1487 cm−1; H NMR (400 MHz,
CDCl3): d = 1.02, 1.10 (2 s, 6H, 2CH3), 2.19 (q,
J = 6.9 Hz, 2H, CH2), 2.26 (s, 2H, CH2), 2.35 (s, 3H,
ArCH3), 4.77 (s, 1H, CH), 5.94, 10.37 (2 s, 2H, 2NH),
6.90 (d, J = 7.8 Hz, 2H, ArH), 7.20 (d, J = 7.5 Hz,
FIGURE 1 Cyclic voltammogram of the solution of aldehyde and
active methylene compounds on a platinum electrode (area
2.5 mm2) at scan rate 0.01 V s−1 [Color figure can be viewed at
wileyonlinelibrary.com]
SCHEME 3 Proposed mechanism for the synthesis (4a‐4o) at constant potential electrolysis [Color figure can be viewed at
wileyonlinelibrary.com]

8
MALVIYA AND SINGH
2H, ArH), 7.34 (d, 1H, ArH); 13C NMR (100 MHz,
CDCl3): d = 24.3, 27.2, 28.9, 30.2, 31.9, 34.1, 41.3, 50.8,
57.1, 92.2, 116.9, 128.5, 128.8, 129.7, 130.6, 139.2, 147.6,
150.3, 161.7, 197.4; MS (m/z): 353 [M + 1]+; Anal. Calcd
for C20H20N2O4 (352.1); C, 68.17; H, 5.72; N, 7.95.
Found: C, 68.20; H, 5.75; N, 7.92.
155.2, 160.3, 162.8, 197.5; MS (m/z): 295 [M + 1]+;
Anal. Calcd for C17H14N2O3 (294.3); C, 69.38; H, 4.79;
N, 9.52. Found: C, 69.50; H, 4.75; N, 9.53.
4.6.8 | 8,9‐Dihydro‐5‐(4‐nitrophenyl‐1H‐
chromeno[2,3‐d]pyrimidine2,4,6(3H,5H,7H)
‐trione 4(i)
4.6.5 | 8,9‐Dihydro‐8,8‐dimethyl‐5‐(4‐chlo-
rophenyl)‐1H‐chromeno[2,3‐d] pyrimidine
2,4,6(3H,5H,7H)‐trione 4(f)
Yellow solid, mp 172°C‐174°C; IR (KBr): μ = 3042, 2958,
1
2194, 1715, 1685, 1670, 1535,1370, 1050 cm−1; H NMR
(400 MHz, CDCl3): d = 2.19 (m, 2H, CH2), 2.60 (m, 2H,
CH2), 2.85 (m, 2H, CH2), 4.83 (s, 1H,CH), 7.28 (d,
J = 6.6 Hz, 2H, ArH), 8.10 (d, J = 8.7 Hz, 2H, ArH),
10.66, 11.70 (2 s, 2H, 2NH); 13C NMR (100 MHz, CDCl3):
d = 18.6, 37.3, 43.6, 51.2, 79.4, 113.8, 121.3, 123.5, 129.4,
130.1, 131.2, 147.5,149.2, 155.1, 160.3, 163.7, 198.2; MS
(m/z): 356 [M + 1]+; Anal. Calcd for C17H13N3O6
(355.1); C, 57.47; H, 3.69; N, 11.83. Found: C, 57.50; H,
3.75; N, 11.88.
White solid, mp 187°C‐188°C; IR (KBr): μ = 2944, 1729,
1685, 1680, 1528 cm−1 1H NMR (400 MHz, CDCl3):
;
d = 1.13, 1.16, 2.25 (q, J = 4.5 Hz, 2H, CH2), 2.68 (s,
2H, CH2), 5.36, 10.46 (2 s, 2H, 2NH), 4.97 (s, 1H, CH),
6.91‐6.98 (m, 2H, ArH), 7.38‐7.40 (m, 2H, ArH); 13C
NMR (100 MHz, CDCl3): d = 27.4, 28.1, 29.2, 29.6, 32.7,
40.4, 50.2, 92.3, 114.6, 115.8, 115.9, 129.5, 129.9, 138.8,
150.7, 151.2, 161.3, 161.6, 195.9; MS (m/z): 373
[M + 1]+, 375 [M + 3]+; Anal. Calcd for C19H17ClN2O4
(372.0); C, 61.21; H, 4.60; N, 7.51. Found: C, 61.20; H,
4.75; N, 7.52.
4.6.9 | 8,9‐Dihydro‐5‐(4‐methoxyphenyl‐1H
‐chromeno[2,3‐d] pyrimidine 2,4,6(3H,5H,
7H)‐trione 4(j)
4.6.6 | 8,9‐Dihydro‐8,8‐dimethyl‐5‐(3‐hyd-
roxyphenyl)‐1H‐chromeno[2,3‐d] pyrimi-
dine 2,4,6(3H,5H,7H)‐trione 4(g)
White solid, mp 215°C‐217°C; IR (KBr): μ = 2920, 1685,
1
1635, 1630, 1564, 1501, 1484 cm−1; H NMR (400 MHz,
CDCl3): d = 2.14 (q, J = 6.9 Hz, 2H, CH2), 2.40 (m, 2H,
CH2), 2.82 (m, 2H, CH2), 3.75 (s, 3H, OCH3), 4.62 (s,
1H, CH), 6.80 (d, J = 8.4 Hz, 2H, ArH), 7.15 (d,
J = 7.5 Hz, 2H, ArH), 8.22 (d, J = 8.7 Hz, 1H, ArH),
10.40, 11.90 (2 s, 2H, 2NH); 13C NMR (100 MHz, CDCl3):
d = 18.1, 28.7, 29.1, 32.2, 33.2, 40.5, 50.9, 56.3, 90.2, 115.2,
121.7, 122.2, 128.1, 135.2, 145.2, 147.1, 150.2, 152.4, 161.7,
161.7, 197.2; MS (m/z): 341 [M + 1]+; Anal. Calcd for
C18H16N2O5 (340.1); C, 63.52; H, 4.74; N, 8.23. Found:
C, 63.50; H, 4.75; N, 8.22.
White solid, mp 234°C‐236°C; IR (KBr): μ = 3483, 2933,
1715, 1682, 1665, 1524 cm−1; 1H NMR (400 MHz, CDCl3):
d = 1.07, 1.13 (2 s, 6H, 2CH3), 2.26 (s, 2H, CH2), 2.57 (q,
J = 6.3 Hz, 2H,CH2), 5.26, 10.48 (2 s, 2H, 2NH), 4.84 (s,
1H, CH), 6.62 (d, J = 7.8 Hz, 2H, ArH), 6.85 (s, 1H,
ArH), 7.08‐7.13 (m, 2H, ArH), 8.28 (s, 1H, OH); 13C
NMR (100 MHz, CDCl3): d = 27.6, 28.2, 28.9, 29.2, 32.3,
32.9, 40.5, 50.6, 92.1, 114.0, 115.8, 116.1, 119.8, 129.3,
144.5, 150.4, 151.3, 155.8, 161.0, 161.2, 197.0; MS (m/z):
355 [M + 1]+; Anal. Calcd for C19H18N2O5 (354.1); C,
64.40; H, 5.12; N, 7.91. Found: C, 64.42; H, 5.19; N, 7.94.
4.6.10 | 2,3,8,9‐Tetrahydro‐8,8‐methyl‐5‐
phenyl‐2thioxo‐1H‐chromeno[2,3‐d]pyrimi-
dine‐4,6(5H,7H)‐dione 4(k)
4.6.7 | 8,9‐Dihydro‐5‐phenyl‐1H‐chromeno
[2,3‐d]pyrimidine‐2,4,6(3H,5H,7H)‐trione 4
(h)
White crystal, mp 230°C‐232°C: IR (KBr): μ = 3042,
1
White solid, mp 198°C‐200°C: IR (KBr) μ : 3330, 2905,
2950, 2191, 1712, 1689, 1670, 1530,1377, 1040 cm−1; H
2190, 1732, 1681, 1670, 1518, 1389, 1037 cm−1
;
1H
NMR (400 MHz, CDCl3): d = 1.13, 1.18 (2 s, 6H,
2CH3) 2.15 (m, 2H, CH2), 2.75 (s, 2H, CH2), 4.85 (s,
1H,CH), 7.17 (d, J = 6.6 Hz, 2H, ArH), 8.07 (d,
J = 8.7 Hz, 2H, ArH), 10.67, 11.95 (2 s, 2H, 2NH); 13C
NMR (100 MHz, CDCl3): d = 27.3, 28.4, 38.3, 43.3,
51.4, 79.5, 113.9, 121.8, 123.2, 129.6, 130.1, 131.6, 147.2,
149.5, 155.1, 163.8, 178.4, 198.8; MS (m/z): 355
NMR (400 MHz, CDCl3): d = 2.28 (q, J = 4.4 Hz, 2H,
CH2), 2.54 (m, 2H, CH2), 2.80 (t, 2H, CH2), 4.90 (s,
1H, CH), 6.85‐7.10 (m, 2H, ArH), 7.35‐7.42 (m, 2H,
ArH), 10.65 (s, H, NH), 12.00 (s, H, NH); 13C NMR
(100 MHz, CDCl3) d = 18.7, 29.6, 39.3, 41.3, 50.6, 80.5,
113.9, 125.8, 127.6, 128.7, 129.6, 130.1, 140.2, 149.5,

MALVIYA AND SINGH
9
[M + 1]+; Anal. Calcd for C19H18N2O3S (354.1); C,
64.39; H, 5.12; N, 7.90. Found: C, 64.50; H, 5.15; N, 7.92.
4.6.14 | 8,9‐Dihydrospirochromeno[2,3‐d]
pyrimidine‐5,3′‐indolin‐2,2′,4,6(1H,3H,7H)‐
tetraone 4(o)
White solid, mp > 300°C; IR (KBr): μ = 3320, 2963, 1685,
1629, 1545, 1522, 1480, 1430, 1365, 1333, 1156, 1026 cm−1
4.6.11 | 2,3,8,9‐Tetrahydro‐8,8‐methyl‐5‐(4‐
chlorophenyl)‐2thioxo‐1H‐chromeno[2,3‐d]
pyrimidine‐4,6(5H,7H)‐dione 4(l)
;
1H NMR (400 MHz, CDCl3): d = 2.04 (q, 2H, CH2), 2.39
(q, J = 4.5 Hz, H, CH2), 2.68 (s, 2H, CH2), 6.69‐6.78 (m,
3H, ArH), 10.11, 10.90, 11.85 (3 s, 3H, 3NH); 13C NMR
(100 MHz, DMSO) d = 18.4, 31.4, 46.3, 50.8, 89.7, 109.1,
110.5, 112.7, 113.6, 135.5, 137.9, 149.6, 153.6, 155.1,
161.6, 163.7, 178.3, 195.4; MS (m/z): 352 [M + 1]+; Anal.
Calcd for C18H13N3O5 (351.1); C, 61.54; H, 3.73; N, 11.96.
Found: C, 631.55; H, 3.75; N, 11.90.
White solid, mp 205°C‐207°C; IR (KBr): μ = 2945, 1730,
1680, 1670, 1528 cm−1 1H NMR (400 MHz, CDCl3):
;
d = 1.12, 1.18, (2 s, 6H, 2CH3) 2.35 (q, J = 4.5 Hz, 2H,
CH2), 2.60 (s, 2H, CH2), 4.99 (s, 1H, CH), 6.92‐6.99 (m,
2H, ArH), 7.30‐7.40 (m, 2H, ArH), 10.46, 11.90 (2 s, 2H,
2NH); 13C NMR (100 MHz, CDCl3): d = 27.4, 28.1, 29.2,
29.6, 32.7, 40.4, 50.2, 92.3, 114.6, 115.8, 115.9, 129.5,
129.9, 138.8, 150.7, 151.2, 161.6, 178.2, 195.9; MS (m/z):
389 [M + 1]+, 391 [M + 3]+; Anal. Calcd for
C19H17ClN2O3S (388.1); C, 58.68; H, 4.41; N, 7.20. Found:
C, 58.70; H, 4.45; N, 7.22.
5 | CONCLUSION
Conclusively, we have developed a novel, efficient, green,
and sustainable protocol for synthesis of a series of bio-
logically and pharmacologically active chromeno [2,3‐d]
pyrimidine derivatives via one‐pot three‐component con-
densation of an aldehyde, barbituric acid, and dimedone
in aqueous TBAI medium without use of hazardous
organic solvents and corrosive acids or bases media. The
reactions proceeded at a reasonable time, and pure prod-
uct was obtained. This work will not only lead to practical
synthetic methods but also assure the expansion of the
versatility of clean organic reactions in water. The main
advantage of the present methodology is a simple workup
procedure, milder reaction conditions, and excellent
yields of the products with high selectivity and cheap
reagent electricity, which represent an important plat-
form for the design and discovery of various drugs and
drug‐related molecules.[34]
4.6.12 | 8‐8Dimethyl‐8,9‐dihydrospirochro-
meno[2,3‐d]pyrimidine‐5,3′‐indolin‐2,2′,4,6
(1H,3H,7H)‐tetraone 4(m)
White solid, mp > 300°C; IR (KBr): μ = 3340, 2960, 1680,
1625, 1540, 1520, 1485, 1435, 1360, 1330, 1155, 1025 cm−1
;
1H NMR (400 MHz, CDCl3): d = 0.98, 1.04 (2 s, 6H,
2CH3), 2.18 2.35 (q, J = 4.5 Hz, 2H, CH2), 2.63 (s, 2H,
CH2), 6.60‐6.65 (m, 3H, ArH), 10.18, 10.98, 11.90 (3 s,
3H, 3NH); 13C NMR (100 MHz, DMSO) d = 27.3, 28.3,
31.4, 46.3, 50.8, 89.7, 109.1, 110.5, 112.7, 113.6, 135.5,
137.9, 149.6, 153.6, 155.1, 161.6, 163.7, 178.3, 195.4; MS
(m/z): 380 [M + 1]+; Anal. Calcd for C20H17N3O5
(379.1); C, 63.32; H, 4.52; N, 11.08. Found: C, 63.40; H,
4.45; N, 11.10.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the
Council of Scientific and Industrial Research and Univer-
sity Grant Commission. Authors gratefully acknowledge
the SAIF, Punjab University, Chandigarh, for providing
all the spectroscopic data.
4.6.13 | 8,8Dimethyl‐2‐thioxo‐2,3,8,9‐tetra-
hydrospirochromeno[2,3‐d]pyrimidine‐5,3′‐
indoline‐2′4,6(1H,7H) trione 4(n)
White crystals, mp > 300°C; IR (KBr): μ = 3365, 2962,
1
1625, 1490, 1455, 1395, 1365, 1135, 1095, 1045 cm−1; H
ORCID
NMR (400 MHz, CDCl3): d = 0.96, 1.05 (2 s, 6H, 2CH3),
2.08 (q, J = 4.5 Hz, 2H, CH2), 2.65 (s, 2H, CH2), 6.80 (s,
1H, ArH), 7.10‐7.18 (d, 2H, 2ArH), 10.40, 10.63, 11.98
(3 s, 3H, 3NH); 13C NMR (100 MHz, DMSO) d = 26.3,
28.3, 32.4, 45.3, 50.8, 92.7, 109.3, 112.9, 117.6, 121.6,
135.3, 143.1, 143.9, 153.6, 159.1, 164.7, 174.3, 177.4,
199.4; MS (m/z): 396 [M + 1]+; Anal. Calcd for
C20H17N3O4S (395.1); C, 60.75; H, 4.33; N, 10.63. Found:
C, 60.78; H, 4.35; N, 10.70.
Rana Krishna Pal Singh
2924-4485
https://orcid.org/0000-0002-
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
How to cite this article: Malviya J, Singh RKP.
One‐pot three‐component synthesis of chromeno
[2,3‐d] pyrimidine derivatives: Novel, simple, and
efficient electrochemical approach. J Heterocyclic
Chem. 2019;1–11. https://doi.org/10.1002/jhet.3741
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