Electrogenerated base-promoted synthesis of 5-aryl-5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7-triones by multicomponent assembly of barbituric acid, aldehydes and Meldrum's acid at room temperature

Article abstract of DOI:10.1039/c4ra08251f

An electrochemical strategy for the synthesis of pyrano[2,3-d]pyrimidine-2,4,7-triones is described, using an electrogenerated base of the anion of barbituric acid in a one-pot, three component condensation of an aromatic aldehyde, Meldrum's acid and barbituric acid in ethanol in an undivided cell and in the presence of sodium bromide as an electrolyte at room temperature. This protocol has the advantages of high yields, wide application scope and an environmentally benign procedure. This journal is

Full text of DOI:10.1039/c4ra08251f

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Electrogenerated base-promoted synthesis of
5-aryl-5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-
2,4,7-triones by multicomponent assembly of
barbituric acid, aldehydes and Meldrum's acid at
room temperature
Cite this: RSC Adv., 2014, 4, 55313
Received 6th August 2014
Accepted 9th October 2014
DOI: 10.1039/c4ra08251f
*
*
Hojat Veisi, Abbas Maleki, Zahra Omrani and Shahram Lotfi
www.rsc.org/advances
An electrochemical strategy for the synthesis of pyrano[2,3-d]- electrosynthesis one of the most competitive methods of
pyrimidine-2,4,7-triones is described, using an electrogenerated modern organic chemistry.22 Numerous electrochemical
base of the anion of barbituric acid in a one-pot, three component approaches have been developed for bond formations and
condensation of an aromatic aldehyde, Meldrum's acid and barbituric functional group transformations.23
acid in ethanol in an undivided cell and in the presence of sodium
The multi-component reactions (MCRs) have been employed
bromide as an electrolyte at room temperature. This protocol has the for preparing compound libraries by virtue of straightforward
advantages of high yields, wide application scope and an environ- reaction condition, atomic economy, high bond forming effi-
mentally benign procedure.
ciency and great diversity generating potential.24 Methods of
organic transformations based on electrochemically induced
MCRs involving carbonyl compounds have been extensively
developed.25 To date, just one report have been published on the
synthesis of pyrano[2,3-d]pyrimidine-2,4,7-triones via a three-
component reaction of an aromatic aldehyde, Meldrums acid,
and barbituric acid in the presence of K2CO3 that limited due to
hazardous conditions of microwave irradiation.25 To continue
our work on the electrochemical multi-component synthesis of
heterocyclic compound library,27 herein we shall report an
electrogenerated base of the anion of ethanol in a one-pot, three
component condensation of an aromatic aldehyde, Meldrum's
acid and barbituric acid for the fabrication of 5-aryl-5,6-dihydro-
1H-pyrano[2,3-d]pyrimidine-2,4,7-triones in an undivided cell
(Scheme 1).
Initially, to evaluate the synthetic potential of the procedure
proposed and to optimize the electrolysis conditions, the elec-
trochemical multicomponent condensation of 3-nitro-
benzaldehyde, Meldrums acid, and barbituric acid into 5-(3-
nitrophenyl)-5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7-
triones in EtOH in an undivided cell containing an iron elec-
trode as cathode and a graphite electrode as anode at constant
current in the presence of sodium bromide as an electrolyte was
studied at room temperature. As it is indicated in Table 1, the
current density 10 mA cmꢀ2 (I ¼ 50 mA, electrode surface 5 cm2)
in EtOH was found to be the optimum one for the electro-
chemically induced chain process and afforded the highest
yield of product (97%). The current density increase up to 15 mA
cmꢀ2 (I ¼ 75 mA) results in a slight decrease of the reaction
yield, which may be connected with the activation of undesired
direct electrochemical processes possible under these
Pyrimidinone derivatives form a class of important heterocycles
with a wide range of biological1 and pharmaceutical properties.2
They display anti-tumor action; in the treatment of B16 mela-
noma and P388 leukemia3 or antagonize cell proliferation and
induce cell differentiation by inhibiting (a nontelomeric)
endogenous reverse transcriptase.4 Pyrimidine derivatives are of
interest due to their wide range of biological activities.5 The
synthesis of naturally occurring molecules containing a uracil
ring provides signicant synthetic challenges.6 The develop-
ment of clinically useful anticancer (5-uorouracil)7 and anti-
viral drugs (AZT, DDI, BVDU)8–10 has renewed the interest in the
synthetic manipulation of uracils.11 Many substances that have
a uracil moiety in the skeleton of an organic molecule show
antitumor, antibacterial, bronchodilator, antihypertensive,
cardiotonic, hepatoprotective, and antiallergic activities; some
of them also exhibit antimalarial, analgesic, antifungal, and
herbicidal properties.12–19
Electrosynthesis offers chemists many novel and versatile
synthetic protocols. Advantages include high material utiliza-
tion, the use of mild reaction conditions, decreased energy
requirement, ease of control of the reaction, less hazardous
processes as a result of reduced waste production, and the
ability to perform wide range of precisely tunable oxidation and
reduction reactions.20,21 Pronounced growth of investigations in
organic electrochemistry during last three decades has made
Department of Chemistry, Payame Noor University, 19395-4697 Tehran, Islamic
Republic of Iran. E-mail: hojatveisi@yahoo.com; Fax: +98 838 4227463
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Scheme 1 Electrochemical synthesis of 5-aryl-5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7-triones.
Table 1 Electrochemical transformation of 3-nitrobenzaldehyde, Meldrum's acid and barbituric acid into the corresponding 5-(3-nitrophenyl)-
5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7-trionesa
I
Current density
Electricity passed
Entry
(mA)
(mA cmꢀ2
)
Time (min)
(F molꢀ1
)
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
5
10
20
30
40
50
75
—
1
2
4
6
8
10
15
—
360
360
360
360
360
240
240
240
1.11
2.22
4.47
6.71
8.95
7.46
11.19
—
—
—
—
—
—
—
—
Na
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
40
45
75
82
90
97
90
0
a
General procedure: barbituric acid (1 mmol), 3-nitrobenzaldehyde (1 mmol), Meldrum's acid (1 mmol), NaBr (0.1 mmol), ethanol (20 mL), iron
cathode (5 cm2), graphite anode (5 cm2), room temperature. b Yield of isolated product.
conditions and leading to the oligomerization of the starting cell and in the presence of sodium bromide as an electrolyte at
material. In addition, to compare the electrochemical method room temperature. The key advantages of this method are the in
with the chemical one, we used sodium metal as a catalyst situ generation of base, a one-pot reaction in excellent yields
(10 mol%) for the model reaction, but the desired product was under milder conditions, avoidance of polluting or hazardous
not observed.
chemicals or the addition of base or pro-base, and involves an
Under the optimal conditions, the scope and generality of easy work-up procedure.
the reaction was explored. A variety of aryl aldehydes were
investigated to react with Meldrum's acid and barbituric acid,
and the results are summarized in Table 2. It was found that the
Experimental
Typical experimental procedure for electrochemical synthesis
of pyrano[2,3-d]pyrimidine-2,4,7-triones derivatives
aromatic aldehydes with both electron-withdrawing and
donating groups, in reaction with other starting materials, had
excellent isolated yields.
A mixture of aromatic aldehydes (1 mmol), Meldrum's acid
(1 mmol), barbituric acid (1 mmol), and NaBr (0.1 g, 1 mmol) in
EtOH (20 mL) was electrolyzed in an undivided cell equipped
with a magnetic stirrer, a graphite anode, and an Fe cathode at
room temperature under a constant current density of 10 mA
cmꢀ2 (I ¼ 50 mA, electrode surface 5 cm2). The progress of the
reaction was monitored by thin layer chromatography. The
reaction time was in all the cases about 4 h. Aer electrolysis
was nished, the mixture was ltered, then rinsed twice with an
ice-cold ethanol/water solution (9 : 1, 5 mL), and dried under
reduced pressure. All the products were characterized by spec-
troscopy and from physical data.
Taking the above results into consideration, the following
proposed mechanism for the preparation of the related products
is depicted in Scheme 2.28 We presume that the electrogenerated
base in the present case is the anion of barbituric acid, formed
along with dihydrogen by the reduction of barbituric acid at the
cathode.29 Then, Knoevenagel condensation of aldehyde, with
the barbituric acid anion takes place in the solution with the
elimination of water and the formation of the corresponding
intermedate A. The subsequent electrogenerated base-promoted
Michael addition of Meldrum's acid to the electron-decient
Knoevenagel adduct A. Cyclization of B via a translactonization
reaction leads to liberation of an acetone molecule and a
molecule CO2 and also produced the nal product C.
Analytical data for selected compound (Table 2, entry 6)
5-(20,40-dimethoxyphenyl)-5,6-dihydro-2H-pyrano[2,3-d]-
pyrimidine-2,4,7-trione
In conclusion, we have described a novel, efficient, conve-
nient and electrochemical procedure to the synthesis of 5-aryl-
5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7-triones via one-
pot, three component condensation of an aromatic aldehyde,
Meldrum's acid and barbituric acid in ethanol in an undivided
Mp 231–233 C; IR (KBr) (nmax, cmꢀ1): 3410, 3298, 2992, 1722,
ꢁ
1
1691, 1582, 1498, 1443, 1365, 1269, 1171, 1032 cmꢀ1; H NMR
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Table 2 Electrochemical synthesis of 5-aryl-5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7-trionesa
Electricity passed
Entry
Product
(F molꢀ1
)
Yieldb (%)
Mp (ꢁC)
Mp (ꢁC) (ref. 26)
1
7.46
96
290–292
292
2
7.46
95
241–242
240
3
4
5
7.46
7.46
7.46
97
90
95
280–281
219–221
246–248
282
218–220
248–250
6
7.46
94
231–233
235–237
7
7.46
92
276–278
277
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Table 2 (Contd.)
Electricity passed
(F molꢀ1
Entry
Product
)
Yieldb (%)
Mp (ꢁC)
Mp (ꢁC) (ref. 26)
8
7.46
97
271–273
273
a
General procedure: barbituric acid (1 mmol), aldehyde (1 mmol), Meldrum's acid (1 mmol), NaBr (1 mmol), ethanol (20 mL), iron cathode (5 cm2),
graphite anode (5 cm2), current density 10 mA cmꢀ2, 4 hours at room temperature. Yield of isolated product.
b
Scheme 2 Proposed mechanism for the preparation of 5-aryl-5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7-triones.
(DMSO-d6, 200 MHz, d ppm): 3.30 (d, 2H, CH2), 3.85 (s, 3H,
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Acknowledgements
We are thankful to Payame Noor University (PNU) for partial
support of this work.
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