Water Mediated Domino Knoevenagel-Michael-cyclocondensation Reaction of Malononitrile, Various Aldehydes and Barbituric Acid Derivatives Using Boric Acid Aqueous Solution System Compared with Nano-titania Sulfuric Acid

Article abstract of DOI:10.1002/jccs.201500115

Nano-titania sulfuric acid (TSA) and boric acid [B(OH)₃] were efficiently utilized for domino Knoevenagel-Michael-cyclocondensation reaction of malononitrile, various aldehydes and barbituric acid derivatives to synthesis of pyrano[2,3-d]pyrimi

Full text of DOI:10.1002/jccs.201500115

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Water Mediated Domino Knoevenagel-Michael-cyclocondensation Reaction of
Malononitrile, Various Aldehydes and Barbituric Acid Derivatives Using Boric Acid
Aqueous Solution System Compared with Nano-titania Sulfuric Acid
Ardeshir Khazaei,a* Heidar Ali Alavi Nika and Ahmad Reza Moosavi-Zareb*
aFaculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683, Iran
bDepartment of Chemistry, University of Sayyed Jamaleddin Asadabadi, Asadabad, 6541835583, Iran
(Received: Mar. 23, 2015; Accepted: Jul. 1, 2015; Published Online: Aug. 14, 2015; DOI: 10.1002/jccs.201500115)
Nano-titania sulfuric acid (TSA) and boric acid [B(OH)3] were efficiently utilized for domino
Knoevenagel-Michael-cyclocondensation reaction of malononitrile, various aldehydes and barbituric
acid derivatives to synthesis of pyrano[2,3-d]pyrimidine diones. It is interesting that in boric acid aqueous
solution system, H+ which abstracted from water by the interaction with B(OH)3, efficiently catalyzed the
reaction.
Keywords: Pyrano[2,3-d]pyrimidine dione; Nano-titania sulfuric acid; Boric acid; Barbituric acid;
Malononitrile; Aldehyde.
INTRODUCTION
The condensation of barbituric acid deriva-
tives, various aldehydes and malonitrile us-
ing TSA or B(OH)3.
Scheme 1
Multi-component reactions (MCRs) achieve signifi-
cant task in combinatorial chemistry due to the ability to
prepare target compounds with more efficiency and atomic
economy by the reaction of three or more compounds to-
gether in a single step. Moreover, MCRs increase simplic-
ity and synthetic efficiency on the conventional organic
transformations.1–5
The synthesis of pyrano[2,3-d]pyrimidine dione de-
rivatives is important because of their significant anti-
tumor,6 antibacterial,7 antihypertensive,8 hepatoprotec-
tive,8 cardiotonic,8 vasodilator,9 bronchiodilators9 and
antiallergic properties.10 Moreover, some of them can be
widely applied as antimalarial,11 antifungal,12 analgesics13
and herbicidal14 materials. Several methods have been used
for the preparation of pyrano[2,3-d]pyrimidine dione de-
rivatives.15-27 However, some of them suffer from the draw-
backs such as the use of toxic metals, the use of volatile
organic solvents, high cost and low yields.
reaction, the condensation of barbituric acid, benzaldehyde
and malonitrile was selected as model reaction. Then this
reaction was studied under two different conditions. In the
first condition, the model reaction was examined in the
presence of different amounts of nano-titania sulfuric acid
(Nano-TSA) at range of 25 °C to reflux temperature of eth-
anol and in another condition, the model reaction was
tested using different amounts of boric acid [B(OH3)] at
range of 25 °C to reflux condition in tetrahydrofuran. The
best results were obtained using 20 mg of TSAunder reflux
condition of aqueous ethanol and 10 mol% of B(OH)3 un-
der reflux condition of aqueous tetrahydrofuran. Increas-
ing the reaction time did not improve the results (Table 1).
In the next step, the model reaction was examined us-
ing 20 mg of TSAand 10 mol% of B(OH)3 with various sol-
vents. The results are summarized in Table 2. As can be
seen in Table 2, EtOH/H2O (19:1) and THF/H2O (8:2) in
the presence of TSA and B(OH)3 were the best solvents in
this reaction.
Having the above facts in mind, we have recently suc-
cessfully synthesized pyrano[2,3-d]pyrimidine dione de-
rivatives via the domino Knoevenagel-Michael-cyclocon-
densation reaction of malononitrile, various aldehydes and
barbituric acid derivatives using nano-titania sulfuric acid
and boric acid (Scheme 1).
RESULTS AND DISCUSSION
At first, to optimize the reaction conditions, as model
To study the generality and scope of the catalysts, we
* Corresponding author. Email: moosavizare@yahoo.com
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201500115
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Article
Khazaei et al.
Table 1. Effect of different amounts of catalyst and temperature
on the reaction between barbituric acid (2 mmol),
benzaldehyde (2 mmol), malonitrile (2.2 mmol)
Temp.
Time Yielda
Catalyst
Amount of catalyst
(°C)
(min)
(%)
TSA
10 mg
15 mg
reflux
reflux
reflux
reflux
25
90
90
90
90
90
90
90
40
40
40
40
40
40
40
67
72
88
88
45
56
88
60
79
87
87
53
74
87
TSA
TSA
20 mg
TSA
30 mg
TSA
20 mg
TSA
20 mg
45
TSA
20 mg
reflux
reflux
reflux
reflux
reflux
25
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
7 mol % (8.5 mg)
10 mol % (12 mg)
12 mol % (14.5 mg)
15 mol % (18 mg)
10 mol % (14.5 mg)
10 mol % (14.5 mg)
10 mol % (14.5 mg)
45
reflux
a Isolated yield.
Table 2. Reaction of barbituric acid (2 mmol), benzaldehyde (2
mmol), malonitrile (2.2 mmol) using TSA (20 mg) or
B(OH)3 (10 mol%) in different solvents under reflux
condition
Entry Catalyst
Solvent
Time (min) Yielda (%)
1
TSA
TSA
H2O
126
90
34
88
76
58
49
82
25
81
71
52
28
48
32
55
87
2
EtOH/H2O (19:1)
EtOH/H2O (7:3)
EtOH/H2O (5:5)
EtOH/H2O (2:8)
CH3CN
3
TSA
98
4
TSA
113
125
85
5
TSA
6
TSA
7
B(OH)3
H2O
190
125
156
160
160
112
40
8
B(OH)3 EtOH/H2O (19:1)
9
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
EtOH/H2O (7:3)
EtOH/H2O (5:5)
EtOH/H2O (2:8)
CH3CN
10
11
12
13
14
15
THF/H2O (2:8)
THF/H2O (5:5)
THF/H2O (8:2)
40
40
a Isolated yield.
extended our study using [Nano-TSA] (20 mg) and 10
mol% of B(OH)3 in EtOH/H2O (19:1) and THF/H2O (8:2)
with various aromatic aldehydes to give a series of
pyrano[2,3-d]pyrimidine dione derivatives under reflux
conditions (Table 3). Various aromatic aldehydes contain-
ing electron-with drawing substituents, electron-releasing
substituents and halogens on their aromatic rings were uti-
lized successfully in the reaction, and gave the corre-
sponded products in high yields and in short reaction times.
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Synthesis of Pyrano[2,3-d]pyrimidine Diones
enole form after tautomerisation and attacks to cyanoolefin
compound (I) as Michael acceptor to give II. Finally,
cyclocondensation of II gives III which is converted to de-
sired product. It is interesting that produced H+ from water
could be successfully catalyzed the reaction. For this pur-
pose, we tested the model reaction in the presence of
B(OH)3 and in the absence of solvent. In this condition the
yield of product was very low. This observation clearly
showed that B(OH)3 could not be catalyzed the reaction
lonely. Also, by increasing the water in the reaction media,
the yield of the reaction was reduced due to the dissolution
of starting materials in water (Table 2). In another method,
nano-TSA as a Brønsted acid, by releasing H+, was effi-
ciently utilized for the synthesis of pyrano[2,3-d]pyrimi-
dine diones with a similar mechanism.
The proposed mechanism for the synthesis
of Pyrano[2,3-d]pyrimidine diones cata-
lyzed by B(OH)3.
Scheme 2
The acidity of aqueous boric acid solution is exclu-
sively due to the interaction of B(OH)3 with water and the
attraction of OH– by boric acid to give B(OH)4– and release
of H+ in the aqueous solution.28 Therefore in a proposed
mechanism that is shown in Scheme 2, at first, malo-
nonitrile is reacted to carbonyl group of aldehyde which is
activated by produced H+ and affords to intermediate I after
removing one molecule of H2O. Barbituric acid converts to
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Article
Khazaei et al.
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EXPERIMENTAL
General: All chemicals were purchased from Merck or
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General procedure for the synthesis of pyrano[2,3-d]py-
rimidine diones using nano-titania sulfuric acid (TSA) and
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In summary, we have introduced nano-titania sulfuric
acid (TSA) and boric acid solution as efficient catalytic
systems for the synthesis of pyrano[2,3-d]pyrimidine
diones by the domino Knoevenagel-Michael-cyclocon-
densation reaction of malononitrile, various aldehydes and
barbituric acid derivatives. Easy purification, high yields,
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ACKNOWLEDGEMENTS
The authors gratefully acknowledge partial support
of this work by the Research Affairs Office of Bu-Ali Sina
University (Grant number 32-1716 entitled development of
chemical methods, reagents and molecules), University of
Sayyed Jamaleddin Asadabadi and Center of Excellence in
Development of Chemical Method (CEDCM), Hamedan,
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