Mechanochemical solvent-free and catalyst-free one-pot synthesis of pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones with quantitative yields

Article abstract of DOI:10.3390/molecules14010474

Solvent-free synthesis of pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones by ball-milling and without any catalyst is described. This method provides several advantages such as being environmentally friendly, using a simple workup procedure, and affording high

Full text of DOI:10.3390/molecules14010474

Molecules 2009, 14, 474-479; doi:10.3390/molecules14010474
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Mechanochemical Solvent-Free and Catalyst-Free One-Pot
Synthesis of Pyrano[2,3-d]Pyrimidine-2,4(1H,3H)-Diones with
Quantitative Yields
Sara Mashkouri and M. Reza Naimi-Jamal *
Organic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and
Technology, 16846 Tehran, Iran
*
Author to whom correspondence should be addressed; E-mail: naimi@iust.ac.ir.
Received: 26 November 2008; in revised form: 13 January 2009 / Accepted: 14 January 2009 /
Published: 19 January 2009
Abstract: Solvent-free synthesis of pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones by ball-
milling and without any catalyst is described. This method provides several advantages such
as being environmentally friendly, using a simple workup procedure, and affording high
yields.
Keywords: Solvent-free reaction; Barbituric acid; Pyrimidinediones; Heterocyclic
compounds; Ball-milling.
Introduction
Recently, much attention has been paid to the development of new methods for the synthesis of
heterocyclic compounds, due to their potential importance in the pharmaceutical and agricultural fields.
Among the others, pyrimidine derivatives are of high interest, because they generally show diverse
biological properties such as antitumor, analgesic, antibacterial, and fungicidal activities [1-4].
Solvent-free reactions lead to new environmentally benign procedures that save resources and
energy. These kind of reactions promise to be an essential facet of ‘Green Chemistry” and are of high
interest from both the economical and synthetic point of view. Solvent-free reactions possess some
advantages over traditional reactions in organic solvents, for example they not only reduce the burden of
organic solvent disposal, but also enhance the rate of many organic reactions.

Molecules 2009, 14
475
Multicomponent reactions (MCRs) are generally one-pot reactions, in which three or more starting
materials react together to form a product, where basically all or most of the atoms contribute to the
newly formed product [5]. In an MCR, a product is assembled according to a cascade of elementary
chemical reactions. These kind of reactions profit from avoiding unnecessary separation and purification
procedures.
Ball-milling is referred generally to be a mechanical technique which is widely applied for the
grinding of minerals into fine particles, and the preparation or modification of inorganic solids [6-9]. Its
applications in the organic synthesis are relatively scarce, but have attained more importance during the
past decade. Kaupp et al. have discovered the usefulness of ball-milling in organic synthesis which has
been the subject of some papers and reviews [10-14]. Some recent examples of using a ball-mill in
organic synthesis include solvent-free Knoevenagel condensation [15], protection of diols and diamines
[
16], functionalization of fullerenes [17], reductive benzylation of malononitrile [18], preparation of
phosphorus ylides [19], Heck-type cross-coupling reactions [20], and enantioselective organocatalytic
aldol reaction [21]. Numerous typical examples of scaling up of the use of ball-mills have been given
for organic and some inorganic syntheses. These include solvent-free salt formations, complexations,
condensations of amines, heterocyclic syntheses, Knoevenagel condensations, cascade reactions,
halogen additions, stereo- and regiospecific protective reactions, and redox reactions [10, and references
therein].
The general procedures for the preparation of pyrano[2,3-d] pyrimidine-2,4(1H,3H)-diones include
the reaction of arylidenemalononitriles with barbituric acid under traditional hot reaction conditions [22,
2
3] or under microwave irradiation [24]. In these methods the requisite arylidenemalononitriles are
previously prepared from malononitrile and aldehydes. Recently, direct condensation of aldehydes,
malononitrile and barbituric acid in aqueous media has been reported under ultrasound irradiation [25],
or catalyzed by diammonium hydrogen phosphate [26].
We now wish to report one-pot synthesis of pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones in high to
excellent yields by simply ball-milling a stoichiometric mixture of an aldehyde, malononitrile, and
barbituric acid without any catalyst or solvent and (Scheme 1).
Scheme 1. Quantitative preparation of pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones.
O
Ar
O
O
O
CN
CN
CN
no solvent
no catalyst
HN
+
+
HN
NH
Ar
H
O
N
H
NH2
O
O
1
2
3
4
Results and Discussion
6 4
-Chlorobenzaldehyde (1, Ar=4-ClC H ), malononitrile (2) and barbituric acid (3) (1.0 mmol each)
4
were placed in a clean 10 mL temperature controlled ball-mill vessel equipped with 2 stainless steel
balls, the vessel was closed and the milling started at room temperature at a speed of 20-25 Hz. After
every 10 min milling cycles, the progress of the reaction was monitored by TLC. The milling was

Molecules 2009, 14
476
continued for 90 minutes overall, after that TLC of the reaction mixture showed no significant reaction.
Higher temperature millings were achieved by circulating hot water inside the double walled stainless
steel ball mill beaker. Different temperatures were examined and it was found that using boiling water
as circulant, the reaction was complete after 55 minutes. The produced water of the condensation
reaction was simply removed from the crude product by heating at 80 °C under reduced pressure.
Spectral data and the melting point of the product corresponded well with literature values. Other
aldehydes were also examined and it was found that in all cases the boiling water temperature was
enough high to complete the reaction. Because no excess of reagents was used, the products were
generally obtained with no waste and no further tremendous purification processes were needed. In most
cases the products were obtained in enough pure form, or a simple crystallization was enough, if it was
necessary. The results are summarized in Table 1. The products were characterized by comparison of
their spectral data and melting points with those reported in literature. It is specially noteworthy that all
1
the products show a characteristic single peak in the H-NMR spectra at about 4.2-4.8 ppm, which
1
3
corresponds to the benzylic proton of the ArCH group. The more interesting signal in the C-NMR
spectra is the signal of about 58-60 ppm, which belongs to the α-C to the CN group. These results have
been previously reported for the same and for similar structures [15, 26].
Table 1. Synthesis of pyrano [2,3-d] pyrimidine-2,4(1H,3H)-diones under solvent-free and
catalyst-free conditions.
Entry
Ar
Product
4a
Time
Yield
M.P. (°C) [ref]
a
1
2
3
4
5
6
7
8
6
C H
70
90
55
60
15
25
60
30
>99
206-209 (208-210) [24]
213-215 (213-215) [24]
234-237 (239-240) [25]
257-258 (262-263) [22]
255-257 (262-263) [25]
227-229 (237-238) [25]
229-230 (230-231) [26]
287-288 (280-281) [24]
5
a
2-ClC
6
6
H
4
4
4b
>99
a
4-ClC
H
4c
>99
a
2-NO
2
C
6
H
4
4
4
4d
>99
a
3-NO
2
C
6
H
4e
>99
a
4-NO C H
4f
>99
2
6
b
4-BrC
4-CH OC H
4
6
H
4
4g
94
a
4h
>99
3
6
a
b
Yields refer to conversion yields. isolated yield
A possible mechanism is outlined in Scheme 2. The reaction may proceed at first via a Knoevenagel
condensation of aldehyde 1 with malononitrile 2 to afford the Michael acceptor 5. This was confirmed
by the fact that at 50 °C, the reaction of 4-chlorobenzaldehzde, malononitrile, and barbituric acid
6 4
produced 4-chlorobenzylidene malononitrile (5, Ar=4-ClC H ), while barbituric acid was remained
unchanged. Such solvent-free Knoevenagel reactions have been previously reported [15]. The active
methylene of barbituric acid 3 reacted then via its enol form with 5 in a Michael addition reaction to
give the intermediate 6, which is then tautomerized to 7. Intramolecular cyclizative condensation of 7
gave 8. Finally the tautomerization of 8 afforded the expected products 4.

Molecules 2009, 14
477
Scheme 2. Possible mechanism for the preparation of 4.
O
O
O
HO
HN
O
Ar
O
NH
HN
NH
CN
CN
CN
CN
HN
3
O
O
ArCH
2
ArCHO + CH (CN)2
O
N
H
1
2
5
6
O
Ar
O
O
Ar
O
O
Ar
CN
CN
NH
CN
N
HN
HN
HN
O
N
H
NH2
O
N
O
N
H
OH
H
4
8
7
In summary, we have reported herein a quantitative synthesis of various pyrano[2,3-d]pyrimidine-
2
,4(1H,3H)-diones from stoichiometric mixtures of pure reactants in a simple mechanochemical method
without the necessity for use of solvents, addition or removal of catalysts, or solvent-consuming
workups. The fact of no catalyst of any kind may seem remarkable at first glance, but it has been proven
in recent years that many of the reactions studied, can indeed be performed done without any auxiliary
[11, 12, 14-15, 27-28].
Experimental
General
Melting points were determined with a Kofler hot stage melting point apparatus and are uncorrected.
Ball mill apparatus was a Retch MM2000. Infrared (IR) spectra were recorded with a Shimadzu 8400s
1
13
FT-IR spectrometer using potassium bromide pellets. H-NMR and C-NMR spectra were recorded on
a 500MHz DRX-500 Avance Bruker spectrometer in DMSO-(d ). Reagents were obtained from
6
commercial resources and were used without further purification. All products are known compounds
and were identified by comparing of their physical and spectra data with those reported in the literature.
General synthetic procedure
Aldehyde (1), barbituric acid (2) and malononitrile (3) (1.0 mmol each) were poured in a 10 mL
stainless steel double-walled ball mill beaker equipped with fittings for circulating water. Two stainless
steel balls of 12 mm in diameter were used. Ball milling was performed at 20–25 Hz frequency at 96°C
temperature (using boiling water as circulant) for the time given in Table 1. The solid powder was dried
at 80 °C in vacuum to give the product 4, which was purified by recrystallization from DMF-ethanol, if
necessary.

Molecules 2009, 14
478
Acknowledgements
We acknowledge Iran University of Science and Technology (IUST) for partial financial support of
this work and Prof. Gerd Kaupp for his kind donation of ball mill apparatus and chemicals.
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Sample Availability: Samples of the compounds 4a, 4c, 4f, and 4h are available from the authors.
2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
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