Green synthesis of pyrano[2,3-d]-pyrimidine derivatives in ionic liquids

Article abstract of DOI:10.1080/00397910500282661

Pyrano[2,3-d]pyrimidine derivatives were synthesized in high yields by a condensation reaction between arylmethylidenemalononitrile and barbituric acid using room-temperature ionic liquids such as 1-n-butyl-3-methylimidazolium tetrafluoroborate ([BMIm]BF<

Full text of DOI:10.1080/00397910500282661

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Green Synthesis of Pyrano[2,3‐d]‐pyrimidine
Derivatives in Ionic Liquids
Jing Yu a b c & Hanqing Wang a
a Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, China
b Cardiology Department, the Second Hospital of Lanzhou University,
Lanzhou, China
c Graduate School of Chinese Academy of Sciences, Beijing, China
Version of record first published: 20 Aug 2006.
To cite this article: Jing Yu & Hanqing Wang (2005): Green Synthesis of Pyrano[2,3‐d]‐pyrimidine Derivatives
in Ionic Liquids, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:24, 3133-3140
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Synthetic Communicationsw, 35: 3133–3140, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500282661
Green Synthesis of Pyrano[2,3-d]-
pyrimidine Derivatives in Ionic Liquids
Jing Yu
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, China, Cardiology Department, the Second Hospital of
Lanzhou University, Lanzhou, China, and Graduate School of Chinese
Academy of Sciences, Beijing, China
Hanqing Wang
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, China
Abstract: Pyrano[2,3-d]pyrimidine derivatives were synthesized in high yields by a
condensation reaction between arylmethylidenemalononitrile and barbituric acid
using room-temperature ionic liquids such as 1-n-butyl-3-methylimidazolium tetra-
fluoroborate ([BMIm]BF4) or 1-butylpyridinium tetrafluoroborate ([BPy]BF4) as
solvents under neutral conditions.
Keywords: Barbituric acid, green synthesis, ionic liquid, pyrano[2,3-d]pyrimidine
INTRODUCTION
Pyrano[2,3-d]pyrimidine derivatives are annelated uracils that have received
considerable attention during the past years because of their wide range of
biological activity. Compounds with these ring systems have diverse pharma-
cological activity such as antitumor, cardiotonic, hepatoprotactive, anti-
hypertensive, antibronchitic, and antifungal activity.[1–4] Therefore, for the
preparation of these complex molecules, large efforts have been directed
Received in Japan March 22, 2005
Address correspondence to Jing Yu, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, China. Fax: þ86-931-8277088;
E-mail: yujing2304@sina.com
3133

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J. Yu and H. Wang
toward the synthetic manipulation of uracils. As a result, a number of reports
have appeared in literature,[5] which usually require forcing conditions, long
reaction times, and complex synthetic pathways. Thus, new routes for the
synthesis of these molecules have attracted considerable attention in the
search for a rapid entry to these heterocycles.
Room-temperature ionic liquids, especially those based on the 1-alkyl-3-
methylimidazolium, have promise as attractive alternatives to conventional
solvents. Besides their special characteristics,[6] they can even not only
promote some organic reactions,[7] but also provide the chemoselectivity to
some reaction processes[8] and simple and convenient isolation of product
in catalytic reactions.[9] Especially in the condensation reactions with some
nitrogen-containing compounds, the reaction rate could be greatly accelerated
in ionic liquids as evidenced by many recent published works.[10–12] Our new
approach reported herein involves the use of room-temperature ionic liquids
as solvents for the synthesis of pyrano[2,3-d]pyrimidine derivatives by con-
densation reaction between arylmethylidenemalononitrile and barbituric
acid reaction under solvent-free conditions.
EXPERIMENTAL
A Representative Procedure
Phenylmethylidenemalononitrile (5 mmol) and barbituric acid (5 mmol) were
dissolved into 1.5 g of ionic liquid in a 50-mL round-bottom flask equipped
with a magnetic stirrer, and the mixture was heated at 908C for 3 h with
vigorous stirring. After the reaction, the resulting solid product with pale
yellow color was crushed, washed with water, filtered, and dried in vacuum
to afford the primary product. A pure product was obtained by further recrys-
tallization of the primary product with a mixture solvent containing water
and DMF (yield: 84%) (Scheme 1). The characterization of the products is
well known, therefore, only the basic identifications including FT-IR (IFS
1
120HR, Bruker), H NMR (FT-80A, using TMS as internal standard), and
melting-points measurements were conducted.
Scheme 1.

Pyranol[2,3-d]pyrimidine Derivatives
3135
Table 1. Condensation reaction between phenylmethylidenemalononitrile and
barbituric acid in different solvents
Entry
Solvents
Time (h)
Temp. (8C)
Yield (%)
1
[BMIm]BF4
[EMIm]BF4
[BPy]BF4
3
3
90
90
90
90
90
90
60
84
72
65
0
2
3
3
4
Toluene
10
10
1
5a
6
ClCH2CH2Cl
[BMIm]BF4
[BMIm]BF4
0
57
46
7
3
aThe reaction was performed at reflux temperature.
RESULTS AND DISCUSSION
We have performed condensation reaction between arylmethylidenemalono-
nitrile and barbituric acid in ionic liquids as well as in organic solvents to
compare the efficiency of ionic liquids, and the results are presented in
Table 1. The choice of ionic liquids was motivated by their wide use, and
they are therefore the most widely available (see Scheme 2).
Initial experimentation was undertaken in [BMIm]BF4 using phenyl-
methylidenemalononitrile and barbituric acid as substrates under an air atmos-
phere, the mixture was heated at 908C for 3 h (Table 1, entry 1). After reaction,
the reaction vessel was cooled to room temperature, and the solid compound
obtained was recrystallized from a water/DMF mixture solvent to give a
(1.19 g, 84%) mp 210–2128C. The structure was confirmed as a from the
spectroscopic data and elemental analysis. The IR spectra exhibited sharp
bands at 3268 cm21 (NH2) and 2179 cm21 (CN). The NMR spectra showed
Scheme 2. Ionic liquids used in the present work.

3136
J. Yu and H. Wang
the absence of the methylene proton of the barbituric acid and the presence of
a proton at 7.14 (s, 2H, NH2). The other signals appeared at d 7.55–7.78
(m, 5H, ArH), 11.19 (s, 1H, NH), and 12.21 (s, 1H, NH). Some other ionic
liquids,
such
as
1-ethyl-3-methylimidazolium
tetrafluoroborate
([EMIm]BF4) and 1-butylpyridinium tetrafluoroborate ([BPy]BF4), also
worked well, but the yields of a were slightly inferior as compared with
that of [BMIm]BF4 (Table 1, entries 2 and 3). No reaction could be
observed at 908C in organic solvents, such as toluene and 1, 2-dichloroethane
(entries 4 and 5). These results clearly show the determining role of ionic
liquid in these reactions as compared to organic solvents. The subsequent
condition-optimization experiments revealed that both the 3 h time and
908C temperature were necessary to complete the reaction. When 1 h or
608C was used, the pyrano[2,3-d]pyrimidine yield only reached 57% and
46%, respectively (entries 6 and 7).
In subsequent studies, we used [BMIm]BF4 to promote the condensation
reaction of various aromatic aldehydes with barbituric acid, and the results are
summarized in Table 2. Analogous with procedure of a, compounds b–f could
be synthesized by utilizing corresponding aromatic aldehydes and barbituric
acid, and the structures were confirmed from the spectroscopic data and
elemental analysis (Table 2).
According the structure of product, the mechanism of the condensation
reaction most likely involves a Michael addition of arylmethylidenemalono-
nitrile to barbituric acid; the resulting product (1) readily undergoes an
interconvertible isomerization to form an enol (2); an intramolecular
cycloaddition between hydoxy (–OH) and CN then occurred to afford an
imine (3), which could be isomerized to give the desired product (4)
(Figure 1).
One of the main aims of using ionic liquids as solvents was to study the
possibility of its recyclability and reusability. Because [BMIm]BF4 is an air-
and moisture-stable ionic liquid, it could be recovered from the resulting
aqueous solution by means of removal of volatile components under
vacuum conditions (at 808C in 12-mm Hg for 2 h). It was reused for the con-
densation reaction between phenylmethylidenemalononitrile and barbituric
acid. The reaction was carried out three times in consecutive runs with only
a slight decrease in isolated yields (Table 2, entry 7).
Analytical Data for Our Products
1
a: Yield: 84%, mp 224–2258C (lit.[13] 2258C); H NMR (DMSO-d6) d: 4.25
(s, 1H, CH), 7.14 (s, 2H, NH2), 7.55–7.78 (m, 5H, ArH), 11.19 (1H, NH),
12.21 (s, 1H, NH); IR (KBr) n: 3380, 3300, 3268, 3085, 2179, 1710, 1671,
1633 cm21. Anal. calcd. for C14H10N4O3 (M: 282.258): C, 59.57; H, 3.57;
N, 19.85; found C, 59.76; H, 3.44; N, 20.01.

Pyranol[2,3-d]pyrimidine Derivatives
3137
Table 2. Synthesis of pyrano[2,3-d]pyrimidine derivatives in [BMIm]BF4
Time Yield
Entry
Aldehydes
Products
Number (h)
(%) Mp. (8C)
1
a
b
c
d
3
3
3
3
84
92
94
90
224–225
242–244
215–216
225–226
2
3
4
5
e
5
88
201–203
6
f
5
95
210–212
(continued)

3138
J. Yu and H. Wang
Table 2. Continued
Time Yield
Number (h) (%) Mp. (8C)
Entry
Aldehydes
Products
7a
a
3
82
210–212
aReused a third time.
b: Yield: 92%, mp 242–2448C; 1H NMR (DMSO-d6) d: 4.55 (s, 1H, CH), 7.17
(s, 2H, NH2), 7.30–7.78 (m, 4H, ArH), 11.09 (1H, NH), 12.18 (s, 1H, NH);
IR (KBr) n: 3381, 3301, 3188, 2979, 2205, 1722, 1679, 1641, 1600 cm21
.
Anal. calcd. for C14H9ClN4O5 (M: 316.703): C, 53.09; H, 2.86; N, 17.69;
found C, 53.20; H, 2.73; N, 17.93.
c: Yield: 94%, mp 215–2168C; 1H NMR (DMSO-d6) d: 4.74 (s, 1H, CH), 7.08
(s, 2H, NH2), 7.28–7.49 (m, 4H, ArH), 11.17 (1H, NH), 12.26 (s, 1H, NH);
IR (KBr) n: 3469, 3423, 3375, 3312, 2831, 2202, 1715, 1667 cm21. Anal.
calcd. for C14H9ClN4O5 (M: 316.703): C, 53.09; H, 2.86; N, 17.69; found
C, 53.31; H, 2.78; N, 17.49.
d: Yield: 90%, mp 225–2268C; 1H NMR (DMSO-d6) d: 4.26 (s, 1H, CH), 7.11
(s, 2H, NH2), 7.47–7.59 (m, 4H, ArH), 11.09 (1H, NH), 12.14 (s, 1H, NH);
IR (KBr) n: 3389, 3307, 3260, 3181, 2200, 1722, 1677, 1644 cm21. Anal.
Figure 1. Possible mechanism for the present synthesis of pyrano[2,3-d]pyrimidine.

Pyranol[2,3-d]pyrimidine Derivatives
3139
calcd. for C14H9FN4O3 (300.249): C, 56.00; H, 3.02; N, 18.66; found C, 56.17;
H, 2.83; N, 18.89.
e: Yield: 88%, mp 201–2038C; 1H NMR (DMSO-d6) d: 4.73 (s, 1H, CH), 7.20
(s, 2H, NH2), 7.54–7.75 (m, 3H, ArH), 11.16 (1H, NH), 12.20 (s, 1H, NH);
IR (KBr) n: 3387, 3301, 3253, 3181, 3074, 2190, 1718, 1671, 1640 cm21
.
Anal. calcd. for C14H8Cl2N4O3 (M: 351.148): C, 47.89; H, 2.30; N, 15.96;
found C, 48.16; H, 2.19; N, 16.11.
f: Yield: 95%, mp 210–2128C; 1H NMR (DMSO-d6) d: 3.86 (s, 3H, CH3O),
3.94 (s, 3H, CH3O), 4.20 (s, 1H, CH), 7.10 (s, 2H, NH2), 7.60–7.89 (m, 3H,
ArH), 11.43 (1H, NH), 12.22 (s, 1H, NH); IR (KBr) n: 3384, 3228, 3150,
3079, 2228, 1743, 1699, 1660 cm21. Anal. calcd. for C16H14N4O5
(M: 342.310): C, 56.14; H, 4.12; N, 16.37; found C, 56.39; H, 3.98; N, 16.19.
CONCLUSION
In summary, ionic liquids proved to be excellent media and catalysts for the
synthesis of pyrano[2,3-d]pyrimidine derivatives from arylmethylidenemalo-
nonitrile and barbituric acid. Many pyrano[2,3-d]pyrimidines could be
obtained in good to excellent yields. The ionic liquid [BMIm]BF4 can be
recovered conveniently and reused three times, although with a slight loss of
activity. Moreover, this methodology offers significant improvements with
regard to yield of products, simplicity in operation, and green aspects
(avoiding toxic catalysts and solvents). These advantages of this novel
catalytic system are expected to contribute to the development of more
benign synthesis of pyrano[2,3-d]pyrimidine derivative.
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