Zn[(L)proline]2: An efficient catalyst for the synthesis of biologically active pyrano[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1080/00397910903174390

Biologically active pyrano[2,3-d]pyrimidine derivatives were efficiently synthesized in excellent yields by a three-component, one-pot condensation reaction of malononitrile, benzaldehydes, and barbituric acid using a catalytic amount of Zn[(L)proline]. C

Full text of DOI:10.1080/00397910903174390

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Zn[(L)proline]2: An Efficient Catalyst
for the Synthesis of Biologically Active
Pyrano[2,3-d]pyrimidine Derivatives
Majid M. Heravi a , Azadeh Ghods a , Khadijeh Bakhtiari a & Fatemeh
Derikvand a
a Department of Chemistry, School of Sciences, Alzahra University,
Vanak, Tehran, Iran
Published online: 08 Jun 2010.
To cite this article: Majid M. Heravi , Azadeh Ghods , Khadijeh Bakhtiari & Fatemeh Derikvand (2010)
Zn[(L)proline]2: An Efficient Catalyst for the Synthesis of Biologically Active Pyrano[2,3-d]pyrimidine
Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:13, 1927-1931, DOI: 10.1080/00397910903174390
To link to this article: http://dx.doi.org/10.1080/00397910903174390
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Synthetic Communications1, 40: 1927–1931, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903174390
Zn[(L)PROLINE]2: AN EFFICIENT CATALYST FOR
THE SYNTHESIS OF BIOLOGICALLY ACTIVE
PYRANO[2,3-d]PYRIMIDINE DERIVATIVES
Majid M. Heravi, Azadeh Ghods, Khadijeh Bakhtiari, and
Fatemeh Derikvand
Department of Chemistry, School of Sciences, Alzahra University, Vanak,
Tehran, Iran
Biologically active pyrano[2,3-d]pyrimidine derivatives were efficiently synthesized in
excellent yields by a three-component, one-pot condensation reaction of malononitrile,
benzaldehydes, and barbituric acid using a catalytic amount of Zn[(L)proline].
Keywords: Barbituric acid; pyrano[2,3-d]pyrimidine derivatives; three-component one-pot reaction;
Zn[(L)proline]2
INTRODUCTION
Pyrano[2,3-d]pyrimidine derivatives are annulated uracils that have received
great attention during the past years because of their wide range of biological
activity. Compounds with these ring systems have various pharmacological activities
such as antitumor, cardiotonic, hepatoprotactive, antihypertensive, antibronchitic,
and antifungal activities.[1–4] Therefore, for the preparation of these complex mole-
cules, great efforts have been directed toward the synthetic manipulation of uracils.
A number of methods have been developed for the synthesis of pyrano[2,3-d]pyrim-
idine derivatives from two-component condensation of 2-benzylidene-malononitrile
with barbituric acid.[5–7] However, most of these methods suffer from some dis-
advantages such as long reaction times and complex synthetic pathways. Therefore,
the development of improved methods for the synthesis of these compounds has
relevance in current research.
The role of bis[(L)prolinato-N,O]Zn complex, Zn[(L)proline]2, in organic
chemistry has been documented elsewhere.[8] Recently, we have also reported the
use of this catalyst for the synthesis of quinoxaline derivatives.[9]
Multicomponent reactions (MCRs) have been considered in modern medicinal
chemistry.[10] We have been interested in development of the efficient and environmen-
tally benign synthetic methodologies using economical and ecofriendly catalysts.[11–13]
Herein, we report the synthesis of pyrano[2,3-d]pyrimidine derivatives from a
Received April 13, 2009.
Address correspondence to Majid M. Heravi, Department of Chemistry, School of Sciences,
Alzahra University, Vanak, Tehran 1234, Iran. E-mail: mmh1331@yahoo.com
1927

1928
M. M. HERAVI ET AL.
Scheme 1. Synthesis of pyrano[2,3-d]pyrimidine derivatives in the presence of Zn[(L)proline]2 as catalyst.
three-component, one-pot condensation of benzaldehyde derivatives, malononitrile,
and barbituric acid in the presence of Zn[(L)proline]2 as catalyst (Scheme 1).
RESULTS AND DISCUSSION
The procedure is very simple: 1 equiv of an appropriate aromatic aldehyde was
mixed with 1.2 equiv of malononitrile, 1 equiv of barbituric acid, and Zn[(L)proline]2
(17 mol%) in ethanol (3 mL) and magnetically stirred in a round-bottomed flask
under reflux conditions.
The scope and generality of this method are illustrated with respect to various
aromatic aldehydes. As shown in Table 1, the electron-withdrawing or electron-
donating group on the phenyl rings did not affect the reaction. Unfortunately, the
reaction did not proceed using propionaldehyde and acetaldehyde as aliphatic
aldehydes (Table 1, entries 12 and 13).
Interestingly, in the case of 4-N,N-dimethylamino-benzaldehyde and 3,4-
dimethoxy-benzaldehyde, we did not obtain any product. However, the desired pro-
ducts were obtained in very good yields by 2- or 4-methoxybenzaldehyde. Therefore,
it cannot be due to the complexation–deactivation of the Zn metal by these substitu-
ent groups. It could be due to the strong electron-donating nature of these substitu-
ents, which make the carbonyl ineffective, as shown in Scheme 2.
Table 1. Zn[(L)proline]-catalyzed synthesis of pyrano[2,3-d]pyrimidine derivatives
Mp (ꢀC)
Entry
Aldehyde
PhCHO
Time (min)
Yield (%)a
Found
Reported
1
2
60
70
85
82
80
88
85
90
92
90
88
0
223
225
235
280
230
265
245
245
250
—
224–225[6]
4-Me-PhCHO
2-Me-PhCHO
4-MeO-PhCHO
2-MeO-PhCHO
3-NO2-PhCHO
4-NO2-PhCHO
4-Cl-PhCHO
—
—
3
85
45
4
280–281[7]
—
5
50
30
6
262–263[15]
238–239[7]
242–244[6]
250–251[16]
—
7
30
50
8
9
4-CF3-PhCHO
3,4-(MeO)2-PhCHO
4-N(Me)2-PhCHO
EtCHO
40
10
11
12
13
12 h
12 h
12 h
12 h
0
—
—
—
—
0
MeCHO
0
—
—
aYields refer to isolated pure products.

SYNTHESIS OF PYRANO[2,3-d]PYRIMIDINES
1929
Scheme 2. The strong electron-donating nature of 4-N,N-dimethylamino-benzaldehyde.
Scheme 3. Plausible mechanism.
We have not established an exact mechanism for the formation of
pyrano[2,3-d]pyrimidine derivatives; however, a reasonable possibility is shown in
Scheme 3. The reaction does not afford any enantioselectivity, and it could be due
to the production of a symmetric intermediate as shown in Scheme 3.
In summary, we report here
a high-yielding, one-pot synthesis of
pyrano[2,3-d]pyrimidine derivatives from the condensation of aldehydes, barbituric
acid, and malononitrile under simple and convenient conditions. The conditions
are mild and a wide range of functional groups can be tolerated. Use of Zn[(L)pro-
line] as catalyst offers advantages including simplicity of operation, easy workup,
and excellent yields of products.
EXPERIMENTAL
All the chemicals were purchased from Merck. Melting points were measured
by using the capillary tube method with a Bamstead Electrothermal 9200 apparatus.
1H NMR spectra were recorded on a Bruker AQS Avance 300-MHz spectrometer
using tetramethylsilane (TMS) as an internal standard (CDCl3 solution). Infrared
(IR) spectra were recorded on a Fourier transform (FT)–IR Bruker Tensor 27
(KBr disk). Optical rotation was recorded on an A-Kruss-Optronic (polaremeter
P1000) instrument.

1930
M. M. HERAVI ET AL.
Synthesis of Bis[(L)prolinato-N,O]Zn Complex
The catalyst was prepared according to the reported procedure in the
literature.[14]
Synthesis of Pyrano[2,3-d]pyrimidine Derivatives:
General Procedure
A mixture of an appropriate aromatic aldehyde (1 mmol), malononitrile
(1.2 mmol), barbituric acid (1 mmol), and Zn[(L)proline] (17 mol%) in ethanol
(3 mL) was magnetically stirred in a round-bottomed flask under reflux conditions.
The progress of the reaction was monitored by thin-layer chromatography (TLC)
using chloroform=ethyl acetate as the eluent. Upon completion of the reaction, the
mixture was cooled to room temperature. The precipitated solid was collected by fil-
tration. For further purification, the product was washed with water and recrystal-
lized from ethanol. Pure products were obtained in excellent yields as summarized
in Table 1.
Spectroscopic Data for New Products
7-Amino-6-cyano-5-(4-methylphenyl)-5H-pyrano[2,3-d]pyrimidine-2,4(1-
1
H,3H)-diones (entry 2). H NMR (DMSO-d6, 300 MHz): d ¼ 2.25 (s, 3H, CH3),
4.17 (s, 1H, CH), 7.07 (s, 6H, ArH & NH2), 11.046 (s, 1H, NH), 12.043 (s, 1H,
NH) ppm; 13C NMR (DMSO-d6, 75 MHz): d ¼ 36.55, 59.83, 89.38, 120.03, 127.58,
128.15, 129.15, 130.02, 145, 150.37, 153.15, 158.51, 163 ppm. Anal. calcd. (%): C,
60.81; H, 4.05; N, 18.92. C15H12N4O3 found: C, 60.65; H, 4.22; N, 18.93.
7-Amino-6-cyano-5-(2-methylphenyl)-5H-pyrano[2,3-d]pyrimidine-
2,4(1H,3H)-diones (entry 3). IR (KBr): tmax ¼ 3431, 3345, 3262, 3170, 3061, 2201,
1
1719, 1680, 1673, 1587 cmꢁ1; H NMR (CDCl3, 300 MHz): d ¼ 2.48 (s, 3H, CH3),
4.54 (s, 1H, CH), 7.01–7.1 (m, 6H, ArH & NH2), 11.03 (s, 1H, NH), 12.05 (s, 1H,
NH) ppm. Anal. calcd. (%): C, 60.81; H, 4.05; N, 18.92. C15H12N4O3 found: C,
60.15; H, 4.31; N, 18.61.
7-Amino-6-cyano-5-(2-methoxy-phenyl)-5H-pyrano[2,3-d]pyrimidine-
2,4(1H,3H)-diones (entry 5). IR (KBr): tmax ¼ 3388, 3306, 3258, 3187, 3076, 3008,
2196, 1717, 1676, 1638, 1604 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz): d ¼ 3.75 (s, 3H,
CH3), 4.5 (s, 1H, CH), 6.8–7.2 (m, 6H, ArH & NH2), 10.99 (s, 1H, NH), 11.98 (s, 1H,
NH) ppm. Anal. calcd. (%): C, 57.69; H, 3.85; N, 17.95. C15H12N4O4 found: C,
58.01; H, 3.96; N, 18.11.
7-Amino-6-cyano-5-(3-nitrophenyl)-5H-pyrano[2,3-d]pyrimidine-2,4(1H,
3H)-diones (entry 6). 1H NMR (DMSO-d6, 300 MHz): d ¼ 4.48 (s, 1H, CH), 7.27
(s, 2H, NH2), 7.59–7.64 (m, 1H, ArH), 7.74–7.76 (m, 1H, ArH), 8.07–8.12 (m, 2H,
ArH), 11.09 (s, 1H, NH), 12.15 (s, 1H, NH) ppm.

SYNTHESIS OF PYRANO[2,3-d]PYRIMIDINES
1931
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