Ultrasound-assisted and trisodium citrate dihydrate-catalyzed green protocol for efficient and one-pot synthesis of substituted chromeno[3′,4′:5,6]pyrano[2,3-d]pyrimidines at ambient conditions

Article abstract of DOI:10.1016/j.tetlet.2019.06.028

A simple, straightforward, and highly efficient multicomponent one-pot synthesis of a series of pharmaceutically interesting functionalized chromeno[3′,4′:5,6]pyrano[2,3-d]pyrimidines has been developed based on a low-cost and environmentally benign trisodium citrate dihydrate catalyst via ultrasound-assisted tandem reactions of 4-hydroxycoumarin, aromatic aldehydes, and barbituric acid/thiobarbituric acid in aqueous ethanol at ambient conditions. Metal-free synthesis, high atom-economy, good to excellent yields, short reaction time, operational simplicity, eco-friendliness, and mild reaction conditions are some of the important features of his protocol.

Full text of DOI:10.1016/j.tetlet.2019.06.028

Accepted Manuscript
Ultrasound-assisted and trisodium citrate dihydrate-catalyzed green protocol for
efficient and one-pot synthesis of substituted chromeno[3',4':5,6]pyrano[3,2-
d]pyrimidines at ambient conditions
Goutam Brahmachari, Khondekar Nurjamal
PII:
S0040-4039(19)30579-9
https://doi.org/10.1016/j.tetlet.2019.06.028
TETL 50869
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 May 2019
10 June 2019
15 June 2019
Please cite this article as: Brahmachari, G., Nurjamal, K., Ultrasound-assisted and trisodium citrate dihydrate-
catalyzed green protocol for efficient and one-pot synthesis of substituted chromeno[3',4':5,6]pyrano[3,2-
d]pyrimidines at ambient conditions, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.06.028
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Ultrasound-assisted and trisodium citrate dihydrate-
catalyzed green protocol for efficient and one-pot
synthesis of substituted chromeno[3',4':5,6]pyrano[3,2-
d]pyrimidines at ambient conditions
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Goutam Brahmachari*, Khondekar Nurjamal
Short Communication
TETL-D-19-00622.R1
Ultrasound-assisted and trisodium citrate dihydrate-catalyzed green protocol for efficient
and one-pot synthesis of substituted chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines at ambient
conditions
1

Goutam Brahmachari*, Khondekar Nurjamal
Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva-Bharati (a Central
University), Santiniketan-731 235, West Bengal, India.
*
Corresponding author. E-mail: brahmg2001@yahoo.co.in; goutam.brahmachari@visva-bharati.ac.in
ORCID
Goutam Brahmachari: http://orcid.org/0000-0001-9925-6281
_
_______________________________________________________________
ABSTRACT
A simple, straightforward, and highly efficient multicomponent one-pot synthesis of a series of
pharmaceutically interesting functionalized chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines has been
developed based on a low-cost and environmentally benign trisodium citrate dihydrate catalyst via
ultrasound-assisted tandem reactions of 4-hydroxycoumarin, aromatic aldehydes, and barbituric
acid/thiobarbituric acid in aqueous ethanol at ambient conditions. Metal-free synthesis, high atom-economy,
good to excellent yields, short reaction time, operational simplicity, eco-friendliness, and mild reaction
conditions are some of the important features of his protocol.
_
_______________________________________________________________
Keywords: Chromenopyranopyrimidines; Ultrasound, Trisodium citrate dihydrate, Green synthesis
The chromeno[3',4':5,6]pyrano[3,2-d]pyrimidine scaffold arises out of a combination of three distinctly
promising heterocycles such as coumarin, pyran, and pyrimidine, all of which, either natural or their
1
synthetic analogs, are well-known for their diverse biological and pharmaceutical potential. Due to the
2
advent of molecular hybridization technique in modern drug discovery program, this kind of molecular
frameworks, anticipating to possess quite extended biological profiles, has also drawn attention of the
synthetic chemists.3 In 2014, Kazemi-Rad et al.4 first-time reported the synthesis of 7-
(
aryl)chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines based on electrolytic strategy using TBAF in CH CN.
3
Still to-date this is the only method available for the target compounds with limited substrate scopes. Hence,
we have been motivated to develop an alternative green protocol for the efficient and convenient synthesis
of this molecular framework of biological interest.
5
As part of our ongoing research in the field of green chemistry-directed synthesis, we herein wish to
report a straightforward and conveniently efficient alternative protocol for the synthesis of diversely
functionalized
7-(aryl)chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines
(4a-4s)
from
the
one-pot
multicomponent reaction between 4-hydroxycoumarin (1), aromatic aldehydes (2), and barbituric acids (3)
in aqueous ethanol using trisodium citrate dihydrate as a commercially available, inexpensive and non-toxic
6
catalyst under the influence of ultrasound at ambient conditions (Scheme 1). The key advantages of this
newly developed protocol are the use of inexpensive and non-toxic food-additive as catalyst and aqueous
ethanol as green solvent, one-pot MCR technique, diversity in products, good to excellent yields, short
reaction time, mild reaction conditions, and reusability of reaction media, thereby satisfying several aspects
of ‘green and sustainable chemistry’.7
2

X
HN
NH
O
OH
O
CHO
O
O
Trisodium citrate dihydrate (0.4 equiv.)
NH
EtOH : H O (1:1 v/v; 4 mL), ))))
2
R
+
R
+
US (130 W, 20 kHz, 40% amplitude)
Ambient conditions; 35-60 min
O
N
H
X
O
O
O
4
-Hydroxycoumarin Aromatic aldehyde Barbituric acid
1; 0.25 mmol)
(2; 0.25 mmol)
(3; 0.25 mmol)
Substituted chromeno[3',4':5,6]-
pyrano[3,2-d]pyrimidines 4 (4a-s)
(No Column Chromatography)
(
R = H, 2-NO , 3-NO , 4-NO , 2-F, 4-F, 4-Br, 4-CH ,
19 examples (yield: 74-95%)
2
2
2
3
4
-OCH , 4-CF , 4-CHO
3 3
X = O, S
Scheme 1. Ultrasound-assisted one-pot three-component synthesis of 7-(aryl)chromeno[3',4':5,6]
pyrano[3,2-d]pyrimidines (4)
To optimize the reaction conditions, we first performed a series of trial experiments with our model
reaction between 4-hydroxycoumarin (1; 0.25 mmol), 4-nitrobenzaldehyde (2a; 0.25 mmol), and barbituric
acid (3a; 0.25 mmol) in the presence or absence of trisodium citrate dihydrate in water, ethanol, or aqueous
ethanol (1:1 v/v) at varying conditions (Table 1, entries 1-13). We were delighted to isolate the desired
product, 7-(4-nitrophenyl)chromeno[3',4':5,6]pyrano[2,3-d]pyrimidine-6,8,10(7H,9H,11H)-trione (4a), out
of our model reaction in 87% yield upon ultrasound irradiation (130 W, 20 kHz at 40% amplitude) at
ambient conditions for 35 min in the presence of 0.4 equiv. of trisodium citrate dihydrate as a basic catalyst
in aqueous ethanol (1:1 v/v) (Table 1, entry 9). Compound 4a was characterized by its analytical and
1
13
9
spectral ( H NMR, C NMR and DEPT-135) studies; the physical and spectral data of 4a were found to be
4
comparable with those reported earlier. The overall results are summarized in Table 1.
To check the feasibility and effectiveness of the newly developed protocol, we then carried out a good
number of individual reactions between 4-hydroxycoumarin, a variety of aromatic aldehydes containing
electron-donating or electron-withdrawing substituents in the aromatic ring such as –Me, –OMe, –Br, –F, –
NO , –CF , and –CHO, and either barbituric acid or thiobarbituric acid using the optimized conditions. All
2
3
the reactions underwent smoothly, and the reaction time (35-60 min) and percentage yield (ranging from 74-
5%) for each of the products 4a–4s are shown in Table 2. The substituent groups within aromatic aldehydes
9
used were found to be well-tolerated during the reactions. However, simple aliphatic aldehydes (e.g. n-
butyraldehyde, isobutyraldehyde) did not take part the reaction in an effective manner.
All products were isolated pure just by washing with hot ethanol followed by recrystallization either
9
from ethyl acetate or methanol; no tedious chromatographic purification was needed. The isolated products
were characterized on the basis of analytical data and spectral studies including H-NMR, 13C-NMR, and
1
9
DEPT-135. The known compounds (4a, 4b, 4f and 4h) had physical and spectroscopic data identical to the
literature values.4
Table 1
Screening of solvent system and amount of catalyst-loading in one-pot synthesis of substituted 7-
(
aryl)chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines (4)a
O
HN
NH
O
OH
Catalyst
CHO
NH
experimental conditions
O
O
+
+ O
O N
N
H
O
time (min)
O
O
2
O
O
NO2
1
2a
3a
4
3

Entry Catalyst (equivalency)
Solvent
Conditions
Time %yieldb
(min)
1
2
3
4
5
6
7
8
9
no catalyst
no catalyst
no catalyst
Trisodium citrate dihydrate (0.1 equiv.)
Trisodium citrate dihydrate (0.1 equiv.)
Trisodium citrate dihydrate (0.1 equiv.)
Trisodium citrate dihydrate (0.2 equiv.)
Trisodium citrate dihydrate (0.3 equiv.)
H
EtOH
EtOH-H
H
2
O
ultrasound
ultrasound
ultrasound
ultrasound
ultrasound
ultrasound
ultrasound
ultrasound
60
60
60
35
35
35
60
60
35
35
35
720
nd
nd
nd
36
65
64
70
79
87
57
89
62
2
O (1:1)
2
O
EtOH
EtOH-H
EtOH-H
EtOH-H
2
2
2
O (1:1)
O (1:1)
O (1:1)
Trisodium citrate dihydrate (0.4 equiv.) EtOH-H
2
O (1:1) ultrasound
1
0
1
2
Trisodium citrate dihydrate (0.4 equiv.)
Trisodium citrate dihydrate (1 equiv.)
Trisodium citrate dihydrate (0.4 equiv.)
EtOH-H
EtOH-H
EtOH-H
2
2
2
O (1:2)
O (1:1)
O (1:1)
ultrasound
ultrasound
reflux
1
1
1
3
Trisodium citrate dihydrate (0.4 equiv.)
EtOH-H
2
O (1:1)
rt
720
49
aReaction conditions: 4-Hydroxycoumarin (1; 0.25 mmol), 4-nitrobenzaldehyde (2a; 0.25 mmol), and barbituric acid
3a; 0.25 mmol) in 4 mL of water/ethanol/ethanol-water in the presence or absence of catalyst under ultrasound
(


b
irradiation (US; 130 W, 20 kHz at 40% amplitude)/ reflux (80 C)/room temperature (rt; 28-30 C). Isolated yields. nd:
Not detected
Table 2
Synthesis of substituted 7-(aryl)chromeno[3',4':5,6]pyrano[3,2-d]pyrimidine (4)a,b
X
HN
NH
O
OH
CHO
O
O
Trisodium citrate dihydrate (40 mol%)
NH
EtOH : H O (1:1 v/v; 4 mL), ))))
R
+
2
+
R
O
N
X
O
O
H
US (130 W, 20 kHz, 40% amplitude)
Ambient conditions; 35-60 min
O
O
1
(1 equiv.)
2 (1 equiv.)
3
(1 equiv.)
4a - 4s
O
O
O
O
HN
NH
HN
NH
HN
NH
HN
NH
O
O
O
O
O
O
O
O
O
O
NO2
O
O
O
O
CH3
O
O
OCH3
4
a
4b
4c
4d
8
7% (35 min)
83% (45 min)
O
81% (50 min)
81% (50 min)
O
O
O
HN
NH
O NO2
HN
NH
HN
NH
HN
NH
O
O
O
O
O
O
O
NO2
O
O
O
O
CF3
O
O
Br
O
O
4
e
4g
4h
4
f
8
5% (35 min)
84% (40 min)
S
78% (50 min)
S
8
5% (35 min)
O
O
HN
NH
HN
NH
NH
HN
NH
HN
O
O
O
O
O
O
O
O
O
O
F
O
O
CHO
O
O
O
NO2
O
4
i
4j
74% (40 min)
4l
95% (45 min)
4
k
7
8% (50 min)
9
1% (45 min)
4

S
S
S
S
HN
NH
HN
NH
HN
NH
HN
NH
O
O
O
O
O
O
O
O
O
O
m
CF3
O
O
4n
CH3
S
O
O
4o
OCH3
S
O
O
Br
4
4p
9
0% (45 min)
88% (60 min)
88% (60 min)
8
6% (60 min)
S
HN
NH
NH
HN
NH
O F
HN
O
O
O
O
O
O
CHO
O
O
O
O
F
O
4
q
4r
84% (60 min)
4s
8
2% (45 min)
8
4% (60 min)
aReaction Conditions: 4-hydroxycoumarin (1; 0.25 mmol), aromatic aldehydes (2; 0.25 mmol), and barbituric acids (3;
.25 mmol) in 4 mL of ethanol-water (1:1) under ultrasound irradiation at ambient conditions in the presence of trisodium
0
b
citrate dihydrate (0.4 equiv.; 0.029 g) as a benign catalyst; Isolated yields.
A probable mechanistic pathway for this three-component reaction is outlined in Scheme 2. Initially, the
enolized form 3' of barbituric acid (3) undergoes Knoevenagel reaction with aromatic aldehyde 2 to generate
chalcone intermediate 6 (such a representative chalcone intermediate, 5-(4-methoxybenzylidene)pyrimidine-
2
,4,6-(1H,3H,5H)-trione 6d,8 was successfully isolated and characterized). In the next step, 4-
hydroxycoumarin (1) takes part Michael addition with the in situ formed Knoevenagel adduct 6 to give
intermediate 7, which subsequently undergoes intramolecular ring-closure via energetically favorable 6-exo-
trig process to furnish the desired product 4.
O
O
H
R
H
2
O
OH
O
O
H
Trisodium citrate
aq. EtOH, US
R
O
O
Citrate salt, aq. EtOH
O
NH
R
NH
NH
1
O
NH
H
O
Knoevenagel reaction
(C-C bond formation)
(enolization)
N
H
X
O
N
H
3
X
O
N
H
X
 H O
2
N
H
X
3'
Aldol (-hydroxyketone) 5
Chalcone intermediate 6
6d was isolated and characterized]
[
(
nucleophilic attack of 1
(
C-C bond
through C-3 )
formation)
Michael addition
O
R
O
O
O
R
O
H
O
R
O H
NH
(
intramolecular ring-closure)

H O
O
NH
O
NH
2
O
(
removal of water)
N
H
X
(6-exo-trig process)
(C-O bond formation)
O
N
X
OH
O O
N
X
H
H
4
Cycloadduct 8
Nucleophilic adduct 7
Scheme 2:
A
plausible mechanism for the ultrasound-assisted one-pot synthesis of 7-
(aryl)chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines (4)
It is also worth-noting that we successfully reused the reaction media containing residual starting
materials, catalyst, and solvent obtained upon filtration of the reaction mixture after completion of the
reaction up to the fourth run in the case of our model reaction (Table 2; entry 1). The desired product 4a was
5

isolated in 87-61% yields, and the time-frame was found to be elongated from 45 min (1 run) to 60 min (4th
run). Catalytic efficiency of the catalyst thus substantially decreases with respect to time. The results are
graphically represented in Figure 1. This is also to be mentioned that each filtrate can only be used for a
particular entry due to presence of residual starting materials.
st
Reuse of reaction media for the model reaction (entry 1)
8
7
1
00
8
1
7
2
8
6
4
2
0
0
0
0
0
6
0
60 61
45
45
1
st Run
45
2nd Run
45
3rd Run
60
4th Run
60
Time (min)
Yield
%
87
81
72
61
Time (min)
%Yield
Figure 1. Reusability of reaction media for a representative entry (Table 2, entry 1)
We also examined the feasibility of the present protocol for a scaled-up (on the gram scale; 5 mmol
scale) experiment with the model reaction (Table 2, entry 1). The reaction was found to proceed smoothly
affording the desired product 4a in 78% isolated yield at 60 min; the product yield of this large-scale
reaction is almost similar with that of 0.25 mmol scale entry (Table 2, entry 1) but requires slightly more
time for its completion.
In conclusion, we have developed a straightforward, conveniently efficient and ultrasound-assisted
environmentally benign alternative protocol for easy access to
a
series of diverse 7-
(aryl)chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines from the one-pot three-component reaction between 4-
hydroxycoumarin, aromatic aldehydes, and barbituric acid/2-thiobarbituric acid in aqueous ethanol under the
influence of trisodium citrate dihydrate as a commercially available, inexpensive and non-toxic food-
additive at ambient conditions. Metal-free synthesis, use of eco-friendly catalyst and solvent, mild reaction
conditions, good to excellent yields, short reaction time, operational simplicity and the absence of tedious
separation procedures, clean reaction profiles, gram-scale synthetic applicability, and reusability of reaction
media, are the key advantages of the present one-pot MCRs protocol.
Acknowledgements
Financial support (EMR/2014/001220) from the Science and Engineering Research Board (SERB),
Department of Science and Technology, Government of India, New Delhi is thankfully acknowledged. KN
is grateful to the CSIR, New Delhi for awarding him Senior Research Fellowship.
Conflict of Interest
There are no conflicts of interest to declare.
6

Supplementary data
1
13
Supplementary data (these data include experimental details, analytical data, H and C NMR spectra of all
the synthesized compounds 4 (4a-4s), along with those for isolated intermediate 6d) associated with this
article can be found, in the online version, at http://...
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General experimental procedure for the synthesis of 7-(aryl)chromeno[3',4':5,6]pyrano[3,2-d] pyrimidines (4):
9
4
-Hydroxycoumarin (1; 0.25 mmol), aromatic aldehydes (2; 0.25 mmol), barbituric acids (3; 0.25 mmol),
trisodium citrate dihydrate (0.4 equiv.; 0.029 g) and 4 mL of aqueous ethanol (1 : 1 v/v) were transferred to an
oven-dried glass-vessel in a sequential manner at ambient conditions, and the reaction mixture was then
irradiated with ultrasound (130 W, 20 kHz at 40% amplitude) for stipulated time-frame (35-60 min). The
progress of the reaction was monitored by TLC. On completion of the reaction, 10 mL of water was added to the
resulting reaction mixture when a solid mass precipitated out which was filtered off to get the crude products 4
and purified just by washing with hot ethanol (5 mL) followed by recrystallization either from ethyl acetate or
methanol. The structure of each compound was confirmed by analytical as well as conventional spectral studies.
Representative compounds: 7-(4-Nitrophenyl)chromeno[3',4':5,6]pyrano[2,3-d]pyrimidine-6,8,10(7H,9H,11H)-

1
trione (4a): Off-white solid; yield: 87% (88 mg; 0.25 mmol scale), mp: >300 C. H NMR (400 MHz, DMSO-
d
1
1
1
6
):  = 10.02 (br s, 2H, 2 × -NH), 8.06 (d, J = 8.8 Hz, 2H, Ar-H), 7.80 (d, J = 7.2 Hz, 1H, Ar-H), 7.57-7.51 (m,
1
3
H, Ar-H), 7.33-7.25 (m, 4H, Ar-H), 6.21 (s, 1H, -CH) ppm. C NMR (100 MHz, DMSO-d ):  = 165.72 (CO),
6
64.24 (2 × CONH), 152.75, 152.22, 151.00, 145.12, 131.35, 127.84 (2C), 123.95, 123.29, 122.96 (2C), 118.79,
15.58 (2C), 104.53, 89.06, 34.24 (CH) ppm. Elemental analysis: calcd (%) for C H N O : C, 59.27; H, 2.74;
2
0
11
3
7
N, 10.37; found: C, 59.09; H, 2.72; N, 10.40. 7-Phenyl-10-thioxo-10,11-dihydrochromeno[3',4':5,6]pyrano[2,3-

d]pyrimidine-6,8(7H, 9H)-dione (4k): White solid; yield: 91% (86 mg; 0.25 mmol scale), mp: 196-198 C.
1H NMR (400 MHz, DMSO-d
dt, J = 7.8 & 1.2 Hz, 1H, Ar-H), 7.33-7.26 (m, 2H, Ar-H), 7.17 (t, J = 7.6 Hz, 2H, Ar-H), 7.09-7.05 (m, 3H, Ar-
H), 6.12 (s, 1H, -CH) ppm. 13C NMR (100 MHz, DMSO-d
):  = 173.53 (C=S), 164.97 (CO), 164.81 (CONH),
64.42, 152.68, 142.57, 132.04, 128.34 (2C), 127.20 (2C), 125.59, 124.40, 124.05, 118.90, 116.22, 105.98,
04.40, 94.94, 34.24 (CH) ppm. Elemental analysis: calcd (%) for C20 S: C, 63.82; H, 3.21; N, 7.44;
):  = 11.45 (s, 2H, 2 × -NH), 7.79 (dd, J = 7.8, 1.2 & 0.8 Hz, 1H, Ar-H), 7.56
6
(
6
1
1
12 2 4
H N O
found: C, 63.52; H, 3.18; N, 7.40.
8

Highlights





Ultrasound-assisted and trisodium citrate dihydrate-catalyzed one-pot MCR
Green synthesis of substituted chromeno[3',4':5,6]pyrano[3,2-d]pyrimidines
Use of ambient conditions, and low-cost and eco-friendly catalyst and solvent
Large-scale application, no column chromatography and operationally simple
Practically no waste (water is a green waste) and reusability of the reaction media
9