Sc(OTf)3 catalysed multicomponent synthesis of chromeno[2,3-d]pyrimidinetriones under solvent-free condition

Article abstract of DOI:10.1080/00397911.2018.1560471

An efficient, simple, and environmentally friendly synthesis of a series of chromeno[2,3-d]pyrimidine-trione derivatives has been accomplished via the three-component reaction of a barbituric acid, dimedone/cyclohexane-1,3-dione, and aromatic aldehydes us

Full text of DOI:10.1080/00397911.2018.1560471

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Sc(OTf)3 catalysed multicomponent synthesis of
chromeno[2,3-d]pyrimidinetriones under solvent-
free condition
Savita Kumari, Dhirendra Kumar, Somaiah Gajaganti, Vandana Srivastava &
Sundaram Singh
To cite this article: Savita Kumari, Dhirendra Kumar, Somaiah Gajaganti, Vandana
Srivastava & Sundaram Singh (2019): Sc(OTf)3 catalysed multicomponent synthesis of
chromeno[2,3-d]pyrimidinetriones under solvent-free condition, Synthetic Communications, DOI:
10.1080/00397911.2018.1560471
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2018.1560471
Sc(OTf)3 catalysed multicomponent synthesis
of chromeno[2,3-d]pyrimidinetriones under
solvent-free condition
Savita Kumari , Dhirendra Kumar , Somaiah Gajaganti, Vandana Srivastava,
and Sundaram Singh
Department of Chemistry, Indian Institute of Technology–BHU, Varanasi, India
ABSTRACT
ARTICLE HISTORY
Received 15 September 2018
An efficient, simple, and environmentally friendly synthesis of a
series of chromeno[2,3-d]pyrimidine-trione derivatives has been
accomplished via the three-component reaction of a barbituric
acid, dimedone/cyclohexane-1,3-dione, and aromatic aldehydes
using Sc(OTf)3 as a recyclable catalyst under solvent-free condition.
This method exploits the use of Sc(OTf)3 as a Lewis acid catalyst in
organic synthesis and offers many rewards such as excellent prod-
uct yield and easy work-up procedure. Harmless reaction condi-
tions, as well as the absence of side-products, are another green
aspects of this protocol.
KEYWORDS
Scandium triflate;
multicomponent reaction;
barbituric acid; solvent-free;
chromeno[2,3-d]pyrimi-
dine-triones
GRAPHICAL ABSTRACT
X
O
O
O
CHO
R
R
(Sc(OTf) ) (5 mol %)
3
HN
HN
R
R
Solvent-free
100 oC, 2h
O
N
H
O
O
N
H
O
O
O
X
1
2a-j
3a-b
4a-s (95-98%)
19 examples
R= H, CH3
Introduction
Green chemistry has become a contemporary research tool to design proficient and
environmentally compatible synthetic methods.[1–3] The main objective of green chemis-
try is to pursue alternative reaction techniques to avoid the use of conventional organic
solvents and with minimum waste generation.
Multi-component reactions (MCRs) are an important tool for gathering three or more
starting material and converting them into a single product of higher molecular weight in a
fast and efficient manner.[4–7] In recent years, MCRs by high merit of their junction, out-
put, high yields, environmental friendliness, and simplicity of implementation have emerged
CONTACT Sundaram Singh
sundaram.apc@itbhu.ac.in
Department of Chemistry, Indian Institute of
Technology–BHU, Varanasi, Uttar Pradesh 221005, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed here.
ß 2019 Taylor & Francis Group, LLC

2
S. KUMARI ET AL.
as a powerful synthetic plan to make “drug-like” diverse structures of heterocyclic
moieties.[8–11]
Transition metal catalyzed carbon-carbon and carbon-heteroatom bond-forming reac-
tions are the vital aspects of organic synthesis to give a biologically active organic
molecular framework. Since catalysts play a central role in organic reactions thus they
are widely applicable to provide energy efficient, selective, atom-economical solutions to
many industrially important problems in organic chemistry synthesis.[12–15] The search
for better and efficient catalysts for various organic reactions is always a challenge for
organic chemists. Triflate salts have been widely used as a Lewis acid catalyst for
organic synthesis since last decades. Among the triflate salts, Sc(OTf)3 has come into
view as a competent, mild, commercially available, economical, reusable water tolerant
Lewis acidic catalyst in organic transformations.[16–18] Usually, most of the traditional
Lewis acids immediately react with water rather than the substrate and are decomposed,
while Sc(OTf)3 is found to be stable in water and worked efficiently in a number of
other organic solvents as a Lewis acid catalyst.[19] The smaller size of scandium (Sc3þ
)
than other ones is another factor which makes it a more efficient catalyst.[20,21] The use
of scandium triflate as a catalyst for organic transformation has been increased
promptly due to the above facts.
Chromenes are one of the important classes of organic compounds which have been
found in several natural products like tocopherols, flavonoids, alkaloids, and anthocya-
nins,[22–26] in addition to biologically active molecules like an antibiotic rhodomyr-
tone[27] and cancer cell apoptosis inducer BENC-511[28] (Figure 1). The syntheses of
chromene and their derivatives have garnered considerable awareness for their precious
biological properties, such as anti-anaphylactic,[29] antitumor,[30] antimicrobial,[31] anti-
coagulant,[32] spasmolytic,[33] and diuretic activities.[34]
Pyrimidine derivatives and pyrimidine annelated heterocycles are also important bio-
logically active compounds.[35,36] The combination of both moiety, i.e. chromene along
with pyrimidine in a single molecular framework may result in the development of bio-
logically and pharmaceutically important compounds. Due to their vital role in pharma-
cology, these compounds are utilized in many fields such as medicinal and
pharmaceutical chemistry viz. in chemotherapy of cancer, against HIV and viral dis-
eases, etc.[37,38]
Currently, a new approach for synthesizing heterocycles containing both pyrimidine
as well as chromene moiety in a single molecule has attracted a great deal of inter-
est.[39–41] Despite the available synthetic methods, there still exists a need for developing
more efficient procedures, which allow the ready synthesis of polycyclic pyrimidine
O
OH
O
Br
NO2
O
HO
O
O
OCH2CH3
Rhodomyrtone
BENC-511
Figure 1. Naturally occurring chromene moieties.

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SYNTHETIC COMMUNICATIONSV
3
systems. However, to best of our knowledge, the synthesis of chromeno[2,3-d]pyrimi-
dine-triones has not previously been reported through such an approach.
The previously reported methods have some limitations, such as the use of substoi-
chiometric amount of catalyst (30% p-TSA, 20% P2O5, 10% InCl3, 15% L-Proline), the
low yield of product and side product.[42–44] Therefore, we are motivated for a better
and greener approach for the synthesis of chromeno[2,3-d]pyrimidine-triones.
Results and discussion
In view of the above and as a part of our contemporary research on the design and
construction of biologically active compounds we report herein the multicomponent
reaction of barbituric acid(1) with substituted aromatic aldehydes (2) and 1,3-dike-
tones(3) in the presence of catalytic amount of Sc(OTf)3 under solvent-free condition at
100 ꢀC to afford chromeno[2,3-d]pyrimidine-triones (4a–s) in excellent yields
(Scheme 1).
Our study initiated by optimizing the reaction conditions by taking the multicompo-
nent reaction of barbituric acid (1), 4-nitrobenzaldehyde (2a) and dimedone (3a) as a
model reaction. The model reaction was examined under a variety of conditions, and
the outcome is given in Table 1. First of all, we screened various catalysts such as,
ꢀ
AlCl3, LiCl, ZnCl2, Ni(OTf)2, Cu(OTf)2, Yb(OTf)3 and Sc(OTf)3 in ethanol at 100 C
ꢀ
because un-catalyzed reaction in ethanol at 100 C proceeded lethargically, and gave
only a trace amount of product 4a after long reaction time (20 h) (Table 1, entry 2)
while at room temperature no desired product was obtained. Out of various catalyst
ZnCl2, LiCl furnished only a trace amount of product while AlCl3 promoted the reac-
tion to some extent (Table 1, entry 3). This result encourages us to take Lewis acid cata-
lyst for this reaction. Literature survey shows that metal triflates are better Lewis acid
catalyst in aqueous as well as organic solvents. Due to this reason, various triflates like
Ni(OTf)2, Cu(OTf)2, Yb(OTf)3 and Sc(OTf)3 were screened. The desired product 4a was
ꢀ
isolated in 60% yield with Sc(OTf)3 (10 mol%) in ethanol at 100 C without any observ-
able side products (Table 1, entry 9). Subsequently, different solvents, such as toluene,
hexane, CHCl3, and water, were also examined. It was found that the polar solvents
provided a better result than non-polar solvents. Surprisingly, 78% yield of product was
obtained in absence of solvent with 10 mol% of Sc(OTf)3 in the only 2 h (Table 1, entry
14). Consequently, the amount of Sc(OTf)3 was also examined (Table 1, entry 14–17).
The result showed that the product was isolated in 98% yield with 5% Sc(OTf)3 at 100
ꢀC (Table 1, entry 15) while only 29% yield of the product was obtained with 3 mol%
Scheme 1. Sc(OTf)3 catalyzed synthesis of substituted chromeno[2,3-d]pyrimidine-triones (4a–s).

4
S. KUMARI ET AL.
Scheme 2. A plausible mechanism for the formation of chromeno[2,3-d]pyrimidine-triones catalyzed
by Sc(OTf)3.
of Sc(OTf)3 (Table 1, entry 16). The effect of temperature (80, 90, 100, 110, and 120
ꢀ
ꢀC) was also studied for this reaction and it was concluded that 100 C was the opti-
mized temperature. The reaction was also carried out without a catalyst under the solv-
ꢀ
ent-free condition at 100 C for 2 h but no product was obtained (Table 1, entry 22).
Even after 12 h, the reaction did not take place (Table 1, entry 23). The molar ratio of
the reactant 1, 2a, and 3a were also optimized and found to be 1:1:1.
To study the Scope and limitation of this multicomponent reaction, various aromatic
aldehydes were allowed to undergo reaction with barbituric acid and cyclic 1,3-diketones
under optimized reaction condition. Usually, this procedure was applicable for ortho-,
meta-, and para-substituted aromatic aldehydes. The reaction proceeds efficiently with
both electron-donating as well as -withdrawing groups and results are included in Table 2.
The structure of product 4l was conclusively confirmed by single crystal X-ray deter-
minations (Figure 2).[45]

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SYNTHETIC COMMUNICATIONSV
5
Table 1. Optimization of reaction conditions for the synthesis of 4a.a
NO2
O
CHO
O
O
O
HN
Reaction Conditions
HN
N
H
O
O
O
N
H
O
O
NO2
1
2a
3a
4a
Entry
Catalyst (mol%)
Solvent
Temperature (ꢀC)
Time(h)
% Yieldb
1
2
3
4
5
6
7
8
–
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Toluene
Hexane
CHCl3
H2O
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Room temp
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
20
20
5
5
5
5
5
5
5
12
12
8
8
2
2
2
2
2
0
Trace
35
Trace
Trace
38
41
45
60
0
AlCl3(10 mol%)
LiCl(10 mol%)
ZnCl2(10 mol%)
Ni(OTf)2(10 mol%)
Cu(OTf)2(10 mol%)
Yb(OTf)3(10 mol%)
Sc(OTf)3(10 mol%)
Sc(OTf)3(10 mol%)
Sc(OTf)3(10 mol%)
Sc(OTf)3(10 mol%)
Sc(OTf)3(10 mol%)
Sc(OTf)3(10 mol%)
Sc(OTf)3(5 mol%)
Sc(OTf)3(3 mol%)
Sc(OTf)3(15 mol%)
Sc(OTf)3(5 mol%)
Sc(OTf)3(5 mol%)
Sc(OTf)3(5 mol%)
Sc(OTf)3(5 mol%)
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
Trace
20
78
98c
29
81
76
80
98
82
0
0
90
2
2
2
2
110
120
100
100
–
12
aBarbituric acid-4-nitrobenzaldehyde-dimedone (1:1:1).
bIsolated yield.
cOptimized reaction condition.
To investigate the reusability of the catalyst, recycling experiments were carried out
on the model reaction of a barbituric acid, 4-nitrobenzaldehyde, and dimedone under
the optimized conditions (Table 3). After completion of the reaction, the catalyst was
recovered by concentrating the aqueous layer (filtrate) under reduced pressure, dried
under vacuum, and reused for the second run. The catalytic activity remains fairly con-
sistent up to fourth consecutive run without any significant decrease in the yield of the
product (Figure 3) .
The reaction was initiated by the activation of carbonyl oxygen of barbituric acid (1)
and aromatic aldehyde (2) through Sc(OTf)3. Activated 1, 3-diketone attacks on A fol-
lowed by the removal of water to give the final product 4 (Scheme 2).
Conclusions
In conclusion, we have developed a new, facile, solvent-free, and efficient one-pot multi-
component synthesis of chromeno[2,3-d]pyrimidine-triones by using resourceful,

6
S. KUMARI ET AL.
Table 2. Screening of substrates for the synthesis of chromeno[2,3-d]pyrimidine-triones.a
Entry
4a
1
2
3
4[a]
Yield[b]
(%)
O
CHO
O
NO2
98
97
HN
N
H
O
O
O
O
O
NO2
HN
3a
2a
O
N
H
O
O
CHO
O
Cl
4b
HN
N
H
O
O
O
O
O
O
Cl
HN
3a
2b
O
N
H
O
O
O
CHO
O
4c
95
96
HN
O
N
H
O
O
O
O
O
HN
2c
3a
O
N
H
O
CHO
O
NO2
O
4d
a
HN
O
N
H
NO2
O
HN
3a
2d
O
N
H
O
O
CHO
O
4e
98
95
HN
O
O
O
O
N
H
O
O
O
HN
3a
2e
O
N
H
O
F
O
CHO
O
4f
HN
N
H
O
O
O
O
F
HN
3a
2f
O
N
H
O
Br
O
CHO
O
4g
96
HN
N
H
O
O
O
O
Br
HN
3a
2g
O
N
H
O

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SYNTHETIC COMMUNICATIONSV
7
Table 2. (Continued)
O
CHO
O
Cl
4h
97
HN
O
O
Cl
N
H
O
O
O
O
O
HN
2h
3a
O
N
H
O
O
O
4i
95
HN
CHO
N
H
O
O
O
HN
3a
2i
O
N
H
O
O
CHO
O
NO2
4j
95
96
HN
N
H
O
O
O
O
O
NO2
HN
3b
2a
O
N
H
O
O
CHO
O
Cl
4k
HN
a
N
H
O
O
O
O
O
O
Cl
HN
3b
2b
O
N
H
O
O
O
CHO
O
4l
98
97
HN
O
N
H
O
O
O
O
O
HN
2c
3b
O
N
H
O
CHO
O
NO2
O
4m
HN
O
N
H
NO2
O
HN
3b
2d
O
N
H
O
O
CHO
O
4n
95
HN
O
O
N
H
O
O
O
HN
3b
2e
O
N
H
O

8
S. KUMARI ET AL.
Table 2. (Continued)
O
CHO
F
O
F
4o
98
HN
N
H
O
O
O
O
O
HN
3b
2f
O
N
H
O
O
CHO
O
Br
4p
96
HN
N
H
O
O
O
O
O
Br
HN
2g
O
N
H
O
3b
O
CHO
O
Cl
O
4q
97
HN
O
Cl
Cl
N
H
O
O
O
HN
a
2h
3b
O
N
H
O
O
CHO
O
Cl
4r
97
HN
Cl
O
N
H
O
O
O
O
Cl
HN
3b
2j
O
N
H
O
O
O
4s
95
HN
CHO
N
H
O
O
O
O
O
HN
3b
2i
O
N
H
O
aProducts were characterized by 1H, 13C NMR, and IR analysis.
bIsolated yield.
Sc(OTf)3 catalyst and readily available starting materials. In this approach, the product
can be isolated very easily without the use of column chromatography. This approach
also offers low catalyst loading, high yield, easy work-up, and broad substrate scope.
Experimental
The barbituric acid, diketones, aromatic aldehydes, and Scandium triflate were pur-
chased from Sigma–Aldrich Chemicals, USA, and E. Merck, Germany and were used as

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SYNTHETIC COMMUNICATIONSV
9
Figure 2. ORTEP image of 4l (CCDC 1831617).
Figure 3. The reusability of the Sc(OTf)3 catalyst for the multicomponent reaction of Barbituric acid,
4-nitrobenzaldehyde, and dimedone.
Table 3. Reusability and recyclability of Sc(OTf)3 catalyst.a
Entry
Run
% Yield
1.
2.
3.
4.
1st
2nd
3rd
4th
98
96b
93b
91b
aReaction condition: Barbituric Acid: 4-nitrobenzaldehyde: dimedone (1.0:1.0:1.0)
and Sc(OTf)3 (5 mol%) were heated at 100 ꢀC for 2 h to produce solid product.
bThe catalyst was recovered by concentrating the aqueous layer.

10
S. KUMARI ET AL.
received. All the reactions were monitored by thin-layer chromatography (TLC) and
visualized using UV light. Infra-Red (IR) spectra were recorded on a Perkin-Elmer
FT–IR spectrometer. The melting points were determined by using Stuart Melting point
apparatus SPM10. Elemental analysis (C, H, and N) were carried out using Perkin
1
Elmer Microanalyser. H and 13C NMR spectra were recorded using Bruker 500 MHz
spectrometer in DMSO-d6 and chemical shift were express as d ppm, using TMS as an
internal reference.
General procedure for the synthesis of Chromeno[2,3-d]pyrimidine-triones (4a–s):
Barbituric acid (2 mmol), dimedone/cyclohexane-1,3-dione (2 mmol), aromatic alde-
ꢀ
hydes (2 mmol) and Scandium triflate (5 mol %) were heated at 100 C for 2 h. After
completion of the reaction (confirmed by TLC), the reaction mixture was diluted with
water and filtered. The solid product was washed with water (3 ꢁ 5 mL). Then, crude
product was recrystallized from ethanol to afford the pure product (4a-s). By evapor-
ation of the filtrate (water), Sc(OTf)3 was recovered quantitatively and reused.
Acknowledgement
The authors acknowledge CIF, IIT (BHU) for instrumentation facilities.
Funding
The authors thank Indian Institute of Technology (BHU) for financial support.
ORCID
Savita Kumari
Dhirendra Kumar
Sundaram Singh
http://orcid.org/0000-0003-1510-6388
http://orcid.org/0000-0001-6537-8168
http://orcid.org/0000-0001-7931-9652
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tains the Supplementary Crystallographic Data for This Paper. These Data can be obtained
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.