Ionic liquid as an efficient and recyclable reaction medium for the synthesis of pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1002/jhet.1515

Ionic liquid [bmim]BF₄ was found to be an efficient and recyclable reaction medium for the one-pot synthesis of pyrido[2,3-d] pyrimidines. The structures of the products were characterized by IR, ¹H NMR, and HRMS spectra. This method

Full text of DOI:10.1002/jhet.1515

Month 2013
Ionic Liquid as an Efficient and Recyclable Reaction Medium for the
Synthesis of Pyrido[2,3-d]pyrimidines
a
a
a
b
*
Bai-Xiang Du , Yu-Ling Li , Xiang-Shan Wang , and Da-Qing Shi
aSchool of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Xuzhou Normal University, Xuzhou, Jiangsu 221116, China
bCollege of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
*
E-mail: ylli19722@163.com
Received April 14, 2011
DOI 10.1002/jhet.1515
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
OH
N
O
N
Ar
CN
CN
CN
[bmim]BF4
80 oC
N
HN
H2N
ArCHO + H2C
+
H2N
N
H
NH2
NH2
Ionic liquid [bmim]BF4 was found to be an efficient and recyclable reaction medium for the one-pot synthesis of pyrido[2,3-d]
1
pyrimidines. The structures of the products were characterized by IR, H NMR, and HRMS spectra. This method had the advantages
of easier work-up, milder reaction conditions, high yields, and environmentally benign procedure.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
derivatives via a three-component reaction under microwave
irradiation at 120 ꢀC [12]. Shaabani et al. reported on the
synthesis of pyrido[2,3-d]pyrimidines via a one-pot four-
component condensation of amines, diketene, aldehydes,
and 6-amino-1,3-dimethyluracil in the presence of p-toluene-
sulfonic acid as a catalyst in high yields in CH2Cl2 at ambient
temperature [13]. Shi synthesized pyrido[2,3-d]pyrimidine
derivatives via the three-component reaction in water in the
presence of triethylbenzylammonium chloride [14]. These
methods usually require forcing conditions, long reaction
times, and complex synthetic pathways and often react in
organic solvents or catalyzed by catalyst. Thus, the develop-
ment of new and simple synthetic methods for the efficient
preparation of these molecules is therefore an interesting
challenge.
Recently, the use of ionic liquids as environmentally
benign solvents for a broad range of chemical processes
has been advocated [15]. This is due to a number of
intriguing properties of ionic liquids: high thermal and
chemical stability, negligible vapor pressure, nonflamma-
bility, and high capacity. Ionic liquids, especially those
based on the 1,3-dialkylimidazolium cations, have been
shown to be good “solvents” for a wide range of inorganic
and organic reactions. A nice feature of ionic liquid is that
yields can be optimized by changing the anions or proper-
ties of the cation. In addition, several ionic liquids show
enhancement in reaction rates and selectivity, compared
with organic solvents with the added benefit of the ease
of recovery and reuse of these ionic liquids.
Heterocyclic compounds containing nitrogen atoms are
of great value in the design and discovery of new biologi-
cally active compounds. For example, uracil and its deriva-
tives have received considerable attention because of their
wide range of biological activities [1]. Among them,
pyrido[2,3-d]pyrimidines are annulated uracils that have
diverse pharmacological activity such as antitumour, anti-
bacterial, anti-inflammatory antiviral, antihypertensive,
antibronchitic, and antimicrobial activity [2–6].
Therefore, it is not surprising that research on the syn-
thesis of pyrido[2,3-d]pyrimidines has received significant
attention. Stanley synthesized pyrido[2,3-d]pyrimidine-2,
4-diones by the acid-catalyzed and base-catalyzed condensa-
tion of 6-amino-1,3-dimethyluracil with a, b-unsaturated
carbonyl compounds [7]. Quiroga et al. reported the
synthesis of pyrido[2,3-d]pyrimidines by the reaction of
6-amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone and a,
b-unsaturated ketones in boiling DMF [8]. Sharma reported
synthesis of 5,7-disubstituted 3-phenyl- pyrido[2,3-d]
pyrimidine-2,4(1H,3H)-diones starting from chalcone and
malononitrile in a two-step reaction performed in ethanol
or dioxane during 22–24 h [9]. Recently, Wang reported
the synthesis of pyrido[2,3-d]pyrimidines by the reaction of
aldehydes, malononitrile or cyanoacetate, and 4-amino-2,
6-dihydroxylpyrimidine in ethyl alcohol at 80ꢀC using
KF–Al2O3 as catalyst [10]. Agarwal synthesized a library
of pyrido[2,3-d]pyrimidines in high yields on solid support
using microwave irradiation via the resin-bound aldehydes,
6-amino-1,3-dimethyluracil, and compounds having an
active methylene group in acetic acid [11]. Tu reported a
simple and efficient synthesis of pyrido[2,3-d]pyrimidine
In view of the emerging importance of ionic liquids as
reaction media, we report in this paper a novel three-
component one-pot synthesis of well-functionalized pyrido
[2,3-d]pyrimidine in ionic liquid medium (Scheme 1). When
© 2013 HeteroCorporation

B.-X. Du, Y.-L. Li, X.-S. Wang, and D.-Q. Shi
Vol 000
Scheme 1. The reaction of 1, 2, and 3 in ionic liquid [bmim]BF4.
O
Ar
CN
HN
H2N
OH
N
O
N
H
4
NH2
CN
CN
[bmim]BF4
80 oC
N
ArCHO + H2C
+
Ar
H2N
N
NH2
CN
HN
H2N
1
2
3
N
N
NH2
5
three components of aromatic aldehyde 1, malononitrile 2,
and 2,6-diaminopyrimidin-4-one 3 were treated in ionic
liquids [bmim]BF4 at 80 ꢀC for a few hours (Scheme 1),
the unaromatized pyrido[2,3-d]pyrimidine derivatives 4
were obtained in high yields (78–88%) (Table. 1), which is
different from the reaction reported by Shi [14] and Tu
[12]. The desired aromatized product 5 was not obtained
(Scheme 1). To the best of our knowledge, this is the first
report on such a synthesis of unaromatized pyrido[2,3-d]
pyrimidine derivatives.
ranging from 40 to 90 ꢀC. We found that the yield of prod-
uct 4a was improved and the reaction time was shortened
as the temperature increased to 80 ꢀC. The yield plateau
when temperature was further increased to 90 ꢀC (Table 1,
entries 2–5). So, the most suitable reaction temperature is
80 ꢀC. The effect of reaction time on yields of product 4a
was also investigated. The reactions were performed in
ionic liquid [bmim]BF4 for 4, 6, or 8 h at 80 ꢀC (Table 1,
entries 4, 6–7), leading to 4a in 58%, 88%, and 87% yield,
respectively. Thus, the optimal reaction time is 6 h.
Moreover, different ionic liquids were also studied as
shown in Table 1. On the basis of results in Table 1, we
could conclude that [bmim]BF4 was the best ionic liquid
for this reaction.
To explore the scope and limitations of this reaction fur-
ther, we applied this ionic liquid to the reaction of a range
of aromatic aldehydes with 2,6-diaminopyrimidin-4-one
and malononitrile, furnishing the respective 2,7-diamino-5-
aryl-3,4,5,8-tetrahydro-4-oxopyrido[2,3-d]pyrimidine-6-
carbonitrile 4b–p in good to high yields. The results were
summarized in Table 2. All the products were characterized
by melting points, 1H NMR, IR, and HRMS.
RESULTS AND DISCUSSION
We began our study on the reaction showed in Scheme 1
by optimizing the reaction conditions for the preparation of
4a. A summary of the optimization experiments was
provided in Table 1. It was found that no conversion to
product occurred even after 24 h at room temperature
(Table 1, entry 1). To optimize the reaction temperature,
we carried out the reactions at different temperatures
The electronic effect of aryl group on this reaction was
also investigated. Under the optimized reaction conditions,
the aldehydes bearing both electron-withdrawing and
electron-donating substituents readily provided pyrido
[2,3-d]pyrimidine derivatives in high yields (Table 2).
Therefore, the electronic nature of the substrate had no
significant effect on this reaction.
On the basis of the experimental results, we proposed a
plausible mechanism for the formation of derivatives 4 as
shown in Scheme 2. Initially, Knoevenagel condensation
of aromatic aldehyde 1 with malononitrile 2 could lead to
the formation of intermediate 6. Then, Michael addition
between 6 and 3 would give intermediate 7, which would
undergo a rapid imine–enamine tautomerization to give 8.
Finally, the product would be produced by an intramolecu-
lar cyclization of the amino group attacking carbon atom of
the CN of the intermediate 8 and tautomerization between
imine–enamine.
Table 1
Optimization of the reaction conditions for synthesis of 4a.
Entry
T (ꢀC)
Medium
Time (h)
Yielda (%)
1
2
3
4
5
6
7
9
rt
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[emim]Br
[pmim]Br
[bmim]Br
[emim]BF4
[pmim]BF4
[bmim]PF6
24
9
7
4
6
6
8
6
6
6
6
6
6
0
30
35
58
85
88
87
35
40
30
60
62
65
40
60
80
90
80
80
80
80
80
80
80
80
9
10
11
12
13
Reaction condition: 5 mL of ionic liquid, 1 mmol aromatic aldehyde,
1 mmol malononitrile, 1 mmol 2,6-diaminopyrimidin-4-one.
aIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Ionic Liquid as an Efficient and Recyclable Reaction Medium for the
Synthesis of Pyrido[2,3-d]pyrimidines
100
Table 2
88
88
Synthesis of 4 in ionic liquid [bmim]BF4.
87
85
85
83
80
60
40
20
0
Entry
Ar
Time (h)
Products
Yields (%)a
1
2
3
4
5
6
4-ClC6H4
4-CH3C6H4
4-NO2C6H4
2,4-Cl2C6H3
3-NO2C6H4
3,4-(CH3)
2C6H3
6
7
4
5
5
8
4a
4b
4c
4d
4e
4f
88
81
79
83
82
84
7
8
4-FC6H4
4
8
4g
4h
85
80
3,4-
OCH2OC6H3
2-NO2C6H4
2-ClC6H4
3-CH3OC6H4
3,4-Cl2C6H3
3-HOC6H4
3-ClC6H4
4-BrC6H4
3-FC6H4
9
7
6
4
8
6
5
6
5
4i
4j
81
78
80
83
85
84
86
88
10
11
12
13
14
15
16
1
2
3
4
5
6
4k
4l
4m
4n
4o
4p
Reaction cycle number
Figure 1. Reusability of ionic liquid [bmim]BF4.
Finally, the recovery and reuse of the ionic liquid
[bmim]BF4 were studied by using the preparation of 4a
as a model. As the poor solubility of products in ionic
liquids, they were easily separated by simple filtration
and the filtrate could be recovered easily by drying at
80 ꢀC in vacuum for several hours. As shown in Figure 1,
the reaction medium could be recycled at least six times
without significant decrease of the yields, which ranged
from 88% to 83%.
Reaction condition: 5 mL ionic liquid, 1 mmol aromatic aldehyde, 1 mmol
malononitrile, 1 mmol 2,6-diaminopyrimidin-4-one, 80 ꢀC.
aIsolated yields.
These products were unaromatized pyrido[2,3-d]pyrimidine
derivatives, almost insoluble in ionic liquid and rapidly
precipitated from the reaction system once formed. Shi and
Tu synthesized aromatized pyrido[2,3-d]pyrimidines under
different conditions we had mentioned in the Introduction,
and under these reaction conditions, unaromatized pyrido
[2,3-d]pyrimidines were just intermediates, and they would
experience a dehydrogenation process to obtain aromatized
pyrido[2,3-d]pyrimidine derivatives.
The electronic absorption spectra of 5 Â 10À5 M solutions
of 4a–p in DMSO was measured (Table 3). The longest
wavelength maximum absorption (lmax) of all the com-
pounds was located between 268 and 301 nm. Studies on
the fluorescent properties of these compounds were also
carried out in DMSO (Table 3).
Scheme 2. Reaction mechanism of 1, 2, and 3 in ionic liquid [bmim]BF4.
CN
CN
CN
Knovenagel
ArCH
C
+
H2C
ArCHO
Condensation
CN
1
2
6
O
N
Ar
OH
O
Ar
CN
CN
CN
CN
HN
H2N
Michael
addition
N
HN
ArCH
+
C
C
CN
NH2
H2N
N
N
H2N
NH2
NH
N
3
6
7
8
O
Ar
O
N
Ar
CN
NH
CN
HN
HN
H2N
H2N
N
N
N
H
NH2
H
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B.-X. Du, Y.-L. Li, X.-S. Wang, and D.-Q. Shi
Vol 000
(s, 1H, CH). HRMS Calcd for C14H12N7O3 (M+ H+): requires
326.1002, found: 326.1011.
Table 3
UV/visible data and fluorescence properties for compounds 4 in DMSO.
2,7-Diamino-5-(2,4-dichlorophenyl)-3,4,5,8-tetrahydro-4-
oxopyrido[2,3-d]pyrimidine-6-carbonitrile 4d. mp >300 ꢀC. IR
(KBr, n, cmÀ1): 3465, 3362, 3167, 2189, 1666, 1555, 1462, 1398,
1302, 1207, 1136, 1049, 794. 1H NMR (DMSO-d6, d, ppm): 7.55
(s, 1H, ArH), 7.40–7.45 (m, 2H, ArH), 7.03 (s, 2H, 2Â NH), 6.18
(s, 2H, NH2), 5.81 (s, br, 2H, NH2), 4.78 (s, 1H, CH). HRMS
Calcd for C14H11Cl2N6O (M + H+): requires 349.0371, found:
349.0378.
2,7-Diamino-5-(3-nitrophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4e. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3469, 3390, 3167, 2188, 1668, 1553, 1533, 1465, 1395,
1349, 1300, 1203, 1139, 1067, 786. 1H NMR (DMSO- d6, d,
ppm): 8.06–8.14 (m, 2H, ArH), 7.62–7.65 (m, 2H, ArH), 7.09
(s, 2H, 2Â NH), 6.32 (s, br, 2H, NH2), 6.19 (s, 2H, NH2), 4.63
(s, 1H, CH). HRMS Calcd for C14H12N7O3 (M+ H+): requires
326.1002, found: 326.1016.
2,7-Diamino-5-(3,4-dimethylphenyl)-3,4,5,8-tetrahydro-4-
oxopyrido[2,3-d]pyrimidine-6-carbonitrile 4f. mp >300 ꢀC. IR
(KBr, n, cmÀ1): 3480, 3438, 3370, 3153, 2190, 1672, 1555, 1453,
1389, 1298, 1207, 1147, 1093,797. 1H NMR (DMSO-d6, d,
ppm): 7.04 (d, 2H, J = 7.6 Hz, ArH), 6.94 (s, 1H, ArH), 6.93
(d, 1H, J = 8.4 Hz, ArH), 6.68 (s, 2H, 2Â NH), 6.13 (s, br, 4H,
2Â NH2), 2.17 (s, 6H, 2Â CH3). HRMS Calcd for C16H17N6O
(M+ H+): requires 309.1464, found: 309.1467.
lmax
(nm)
e
lem
(nm)
Entry Compound
(104/L molÀ1 cmÀ1
)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
270
270
274
270
268
269
271
271
268
269
269
274
301
269
269
270
1.32
1.82
2.50
1.60
2.36
2.50
1.58
2.36
1.64
1.50
1.75
1.60
0.79
1.20
1.26
1.55
360
360
360
360
360
359
353
367
355
354
371
360
361
365
370
363
7
8
9
4g
4h
4i
10
11
12
13
14
15
16
4j
4k
4l
4m
4n
4o
4p
EXPERIMENTAL
Melting points were determined in open capillaries without
further correction. IR spectra were recorded on a Tensor 27 spec-
trometer (Bruker, Ettlingen, Germany) in KBr. We obtained H
NMR spectra from a solution in DMSO-d6 with Me4Si as an in-
ternal standard by using a Bruker-400 spectrometer (Bruker, Zur-
ich, Switzerland). Using a MicroTOF-QII instrument (Bruker,
Bremen, Germany), we obtained HRMS data.
1
2,7-Diamino-5-(4-fluorophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4g.
mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3326, 3159, 2189, 1669, 1556, 1463, 1431, 1302, 1203,
1138, 1062, 797. 1H NMR (DMSO-d6, d, ppm): 7.20–7.24
(m, 2H, ArH), 7.10–7.15 (m, 2H, ArH), 6.95 (s, 2H, 2Â NH), 6.20
(s, br, 2H, NH2), 6.12 (s, 2H, NH2), 4.44 (s, 1H, CH). HRMS
Calcd for C14H12FN6O (M+ H+): requires 299.1057, found:
299.1076.
General procedure for preparation of 4.
flask was charged with aromatic aldehyde
A dry 50-mL
(1 mmol),
1
malononitrile
2
(1 mmol), 2,6-diaminopyrimidin-4-one
3
(1 mmol), and ionic liquid [bmim]BF4 (5 mL). The mixture
was stirred at 80 ꢀC for 4–8 h to complete the reaction
(monitored by TLC), then cooled to room temperature. The
solid was filtered off and washed with water. The filtrate of
ionic liquid [bmim]BF4 was then recovered for reuse by drying
at 80 ꢀC several hours in vacuo. The crude product was purified
by recrystallization from DMF to give 4.
2,7-Diamino-5-(3,4-methylelnedioxyphenyl)-3,4,5,8-tetrahydro-
4-oxopyrido[2,3-d]pyrimidine-6-carbonitrile 4h. mp >300 ꢀC.
IR (KBr, n, cmÀ1): 3470, 3395, 3315, 2194, 2146, 1654, 1557,
1457, 1393, 1248, 1137, 1036, 923, 797. 1H NMR (DMSO-d6, d,
ppm): 6.92 (s, 2H, 2Â NH), 6.83 (d, 2H, J = 8.0 Hz, ArH), 6.68
(d, 1H, J = 7.2 Hz, ArH), 6.11 (s, br, 4H, 2Â NH2), 5.98 (s, 2H,
CH2), 4.33 (s, 1H, CH). HRMS Calcd for C15H13N6O3 (M+ H+):
requires 325.1049, found: 325.1058.
2,7-Diamino-5-(4-chlorophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4a.
mp >300 ꢀC. IR (KBr, n,
2,7-Diamino-5-(2-nitrophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4i. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3476, 3395, 3154, 2191, 1667, 1631, 1556, 1520, 1461,
cmÀ1): 3465, 3428, 3327, 3195, 2180, 1671, 1553, 1460, 1383,
1
1306, 1208, 1047, 855, 799. H NMR (DMSO-d6, d, ppm): 7.49
1
(d, 2H, J= 8.4 Hz, ArH), 7.15 (d, 2H, J= 8.4 Hz, ArH), 6.97 (s, 2H,
2Â NH), 6.21 (s, br, 2H, NH2), 6.13 (s, 2H, NH2), 4.42 (s, 1H,
CH). HRMS Calcd for C14H12ClN6O (M+H+): requires 315.0761,
found: 315.0770.
1395, 1338, 1302, 1209, 1139, 1035, 812, 786, 741. H NMR
(DMSO-d6, d, ppm): 7.87 (d, 1H, J = 8.4 Hz, ArH), 7.68 (t, 1H,
J = 7.6Hz, ArH), 7.5 (t, 1H, J = 7.6 Hz, ArH), 7.31 (d, 1H,
J = 8.0Hz, ArH), 7.06 (s, 2H, 2Â NH), 6.26 (s, 2H, NH2), 6.01
(s, 2H, NH2), 4.94 (s, 1H, CH). HRMS Calcd for C14H12N7O3
(M+ H+): requires 326.1002, found: 326.1011.
2,7-Diamino-5-(4-methylphenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4b.
mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3487, 3437, 3369, 3146, 2190, 1674, 1553, 1454, 1389,
1294, 1145, 1095, 1041, 793. 1H NMR (DMSO-d6, d, ppm):
7.06–7.11 (m, 4H, ArH), 6.88 (s, 2H, 2Â NH), 6.13 (s, br, 4H,
2Â NH2), 4.36 (s, 1H, CH), 2.25 (s, 3H, CH3). HRMS Calcd for
C15H15N6O (M + H+): requires 295.1307, found: 295.1327.
2,7-Diamino-5-(2-chlorophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4j.
mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3463, 3387, 3819, 3169, 2189, 1661, 1556, 1457, 1394,
1
1301, 1206, 1137, 1036, 788, 756, 684. H NMR (DMSO-d6, d,
ppm): 7.40–7.52 (m, 4H, ArH), 6.98 (s, 2H, 2Â NH), 6.14 (s, 2H,
NH2), 5.74 (s, br, 2H, NH2), 4.76 (s, 1H, CH). HRMS Calcd for
C14H12ClN6O (M+H+): requires 315.0761, found: 315.0776.
2,7-Diamino-5-(3-methoxyphenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4k. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3486, 3426, 3369, 3163, 2191, 1682, 1636, 1551, 1457,
1387, 1279, 1144, 1100, 1045, 919, 880, 794, 712, 662. 1H NMR
2,7-Diamino-5-(4-nitrophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4c. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3356, 3160, 2192, 1667, 1626, 1557, 1521, 1462, 1397,
1347,1304, 1205, 1140, 1043. 1H NMR (DMSO-d6, d, ppm):
8.20 (d, 2H, J = 8.8 Hz, ArH), 7.46 (d, 2H, J = 8.4 Hz, ArH), 7.09
(s, 2H, 2Â NH), 6.29 (s, br, 2H, NH2), 6.19 (s, 2H, NH2), 4.62
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Ionic Liquid as an Efficient and Recyclable Reaction Medium for the
Synthesis of Pyrido[2,3-d]pyrimidines
(DMSO-d6, d, ppm): 7.20–7.24 (m, 1H, ArH), 6.90 (s, 2H, 2Â NH),
6.71–6.80 (m, 3H, ArH), 6.15 (s, 2H, NH2), 6.08 (s, 2H, NH2), 4.37
(s, 1H, CH), 3.72 (s, 3H, OCH3). HRMS Calcd for C15H15N6O2
(M+ H+): requires 311.1256, found: 311.1270.
2,7-Diamino-5-(3,4-dichlorophenyl)-3,4,5,8-tetrahydro-4-
oxopyrido[2,3-d]pyrimidine-6-carbonitrile 4l. mp >300 ꢀC. IR
(KBr, n, cmÀ1): 3480, 3389, 3168, 2190, 1666, 1623, 1555, 1468,
1398, 1205, 1064, 702. 1H NMR (DMSO-d6, d, ppm): 7.55
(d, 1H, ArH), 7.40–7.46 (m, 2H, ArH), 7.04 (s, 2H, 2Â NH), 6.20
(s, 2H, NH2), 5.83 (s, br, 2H, NH2), 4.77 (s, 1H, CH). HRMS
Calcd for C14H11Cl2N6O (M + H+): requires 349.0371, found:
349.0368.
simplicity, green reaction media, and good to high yields
make this procedure an interesting approach. Meanwhile,
ionic liquid [bmim]BF4 could be reused for several rounds
without apparent loss of activity. More significantly, this work
clearly demonstrates the potential of a room temperature ionic
liquid to act as an efficient and recyclable reaction medium
and shows much promise for further applications.
Acknowledgments. We are grateful to the National Natural
Science Foundation of China (nos. 21104064, 21172188), the
Natural Science Foundation of XuZhou Normal University
(10XLR03), and Priority Academic Program Development of
Jiangsu Higher Education Institutions for the financial support.
2,7-Diamino-5-(3-hydroxyphenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4m. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3463, 3372, 3277, 3168, 2167, 1669, 1525, 1474, 1387,
1
1304, 1212, 1137, 1036, 788, 756, 684. H NMR (DMSO-d6, d,
ppm): 10.42 (s, 1H, OH), 9.25 (s, 1H, NH), 8.68 (s, 1H, NH),
7.00–7.03 (m, 1H, ArH), 6.52–6.60 (m, 3H, ArH), 6.43 (s, br, 2H,
NH2), 5.72 (s, 2H, NH2), 4.24 (s, 1H, CH). HRMS Calcd for
C14H13N6O2 (M + H+): requires 297.1100, found: 297.1105.
2,7-Diamino-5-(3-chlorophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4n. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3475, 3396, 3176, 1658, 1556, 1463, 1393, 1301, 1296,
1130, 1080, 790. 1H NMR (DMSO-d6, d, ppm): 7.23–7.36
(m, 3H, ArH), 7.10–7.13 (m, 1H, ArH), 6.99 (s, 2H, 2Â NH),
6.23 (s, br, 2H, NH2), 6.13 (s, 2H, NH2), 4.44 (s, 1H, CH).
HRMS Calcd for C14H12ClN6O (M+ H+): requires 315.0761,
found: 315.0770.
2,7-Diamino-5-(4-bromophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4o. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3380, 3162, 2193, 1669, 1557, 1464, 1396, 1304, 1205,
1141, 1040, 825, 793. 1H NMR (DMSO-d6, d, ppm): 7.49 (d, 2H,
J = 8.8 Hz, ArH), 7.14 (d, 2H, J = 8.4 Hz, ArH), 6.94 (s, 2H,
2Â NH), 6.17 (s, br, 2H, NH2), 6.09 (s, 2H, NH2), 4.41 (s, 1H,
CH). HRMS Calcd for C14H12BrN6O (M + H+): requires
359.0256, found: 359.0278.
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2,7-Diamino-5-(3-fluorophenyl)-3,4,5,8-tetrahydro-4-oxopyrido
[2,3-d]pyrimidine-6-carbonitrile 4p. mp >300 ꢀC. IR (KBr, n,
cmÀ1): 3524, 3481, 3399, 3158, 2189, 1661, 1557, 1459, 1394,
1298, 1201, 1135, 1042, 798. 1H NMR (DMSO-d6, d, ppm):
7.32–7.38 (m, 1H, ArH), 6.96–7.06 (m, 5H, ArH+ 2Â NH), 6.21
(s, br, 2H, NH2), 6.11 (s, 2H, NH2), 4.45 (s, 1H, CH). HRMS
Calcd for C14H12FN6O (M + H+): requires 299.1057, found:
299.1073.
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CONCLUSION
In conclusion, we have developed a simple and clean
method for the preparation of 2,7-diamino-5-aryl-3,4,5,
8-tetrahydro-4-oxopyrido[2,3-d]pyrimidine-6-carbonitrile
derivatives in ionic liquid [bmim]BF4. The operational
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet