An efficient synthesis of pyrido[2,3-d][6,5-d]dipyrimidine and 5,5′-arylmethylenebis(2,6-diaminopyrimidinone) derivatives under microwave irradiation

Article abstract of DOI:10.1002/jhet.1647

A series of pyrido[2,3-d][6,5-d]dipyrimidine and 5,5′- arylmethylenebis(2,6-diaminopyrimidinone) derivatives have been synthesized through a rapid reaction of aromatic aldehydes with aminopyrimidines in acetic acid under microwave irradiation. This method

Full text of DOI:10.1002/jhet.1647

January 2014
An Efficient Synthesis of Pyrido[2,3-d][6,5-d]dipyrimidine and
5,50-Arylmethylenebis(2,6-diaminopyrimidinone) Derivatives under
Microwave Irradiation
277
*
Zhilan Lin, Huiling Hu, Xinkui You, Xueli Zhang, and Yuan Gao
College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen, Guangdong, 518060 China
*
E-mail: szgaoy@tom.com
Received November 17, 2011
DOI 10.1002/jhet.1647
Published online 22 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
R
R
O
HN
O
O
HN
H2N
CHO
O
N
O
N
NH2
HN
NH
N
NH2
HN
H2N
NH
NH2
CH3
R
O
N
N
N
O
HOAc
MWI
HOAc
MWI
N
NH2
NH2
CH3
CH3
A series of pyrido[2,3-d][6,5-d]dipyrimidine and 5,50-arylmethylenebis(2,6-diaminopyrimidinone)
derivatives have been synthesized through a rapid reaction of aromatic aldehydes with aminopyrimidines
in acetic acid under microwave irradiation. This method has the advantages of simple operation, high
yields, short reaction time, and easy work-up.
J. Heterocyclic Chem, 51, 277 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
The importance of pyrimidine and their derivatives is well
recognized by synthetic [1] and biological [2] chemists;
much attention has been paid to the synthetic manipulations
of pyrimidines [3]. Of these heterocycles, pyrido[2,3-d]
pyrimidines present particularly valuable biological activities
such as antitumor [4], antimicrobial [5], diuretic [6], inhibit-
ing dihydrofolate reductases, and tyrosine kinases [7].
Therefore, it is very important and necessary to synthesize
or structurally modify pyrido[2,3-d]pyrimidine derivatives
bearing potential bioactivities. Most of the literature focused
on other heterocyclic ring fused with pyrimidines, but there
were few reports on the synthesis of dipyrimidines. Recently,
Shaker et al. [8] reported three-component one-pot synthesis
of pyrido[2,3-d][6,5-d]dipyrimidines using conventional
heating. This method involved long reaction time and large
amounts of organic solvents with only low yield products.
Thus, the development of more rapid and efficient entry to
these heterocycles has attracted our attention.
Microwave irradiation (MWI) has rapidly gained popularity
in organic synthesis because it could lead to higher yields of
pure products, easier operation, higher degree of atom
economy and shorter reaction time as compared with the
traditional heating methods [9–12]. We have already
reported the synthesis of several heterocyclic compounds
under MWI [13–15]. As a continuation of our efforts on the
construction of heterocyclic scaffolds, we have developed a
facile, rapid method for the synthesis of pyrido[2,3-d][6,5-d]
dipyrimidine derivatives by two-component reaction in acetic
acid under MWI (Scheme 1).
To explore the scope applicability and versatility of this
method, various reaction conditions were investigated,
including solvent and temperature variations. Initially, to
search for the optimal solvent, the reaction of 4-chlorophenyl
aldehyde 1a (1 mmol) with 6-amino-1-methyluracil 2
(2 mmol) was examined using solvents (2 mL) of DMF,
DMSO, ethylene glycol, acetic acid, and ethanol, respec-
tively. All the reactions were irradiated under MWI at
100ꢀC and 250 W for a given time, and then the crude
products were purified by recrystallization from 95%
EtOH and DMF, and the results were summarized in
Table 1.
The results revealed that the reaction in acetic acid gave
the highest yield (Table 1, entry 4). Acetic acid was thus
chosen as the solvent for all further reactions.
To further optimize the reaction temperature, the same
reaction was carried out in acetic acid at temperatures ranging
from 90 to 140ꢀC, with an increment of 10ꢀC each time. The
yield of product 3a was increased, and the reaction time was
shortened as the temperature was increased from 90 to 130ꢀC
(Table 2, entries 6–8). However, the yield decreased when
the temperatures were further increased to 140ꢀC (Table 2,
entry 6). Therefore, 130ꢀC was considered to be the most
suitable temperature for the reaction.
Under these optimized reaction conditions (130ꢀC, acetic
acid as solvent), a series of 5-aryl-1,9-dimethyl-pyrido[2,3-d]
[6,5-d]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone 3 was
synthesized with this simple reaction procedure. The results
(Table 3) showed that aromatic aldehydes bearing either
© 2013 HeteroCorporation

278
Z. Lin, H. Hu, X. You, X. Zhang, and Y. Gao
Vol 51
Table 3
Scheme 1
Synthesis of 3 under MWI in acetic acid.
Time
(min)
Yieldsa
(%)
Entry
Compound
Ar
4-ClC6H4
4-CH3C6H4
3-NO2C6H4
4-OH-3-NO2C6H3
3,4-(OCH3)2C6H3
4-OCH3C6H4
3,4-(OCH2O)
C6H3
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
10
12
15
14
12
12
13
82
71
78
81
74
75
76
3g
Table 1
Optimization of solvent of compound 3a.
MWI, microwave irradiation.
aIsolated yields.
Entry
Solvent
Time (min)
Yieldsa (%)
1
2
3
4
5
DMF
DMSO
Ethylene glycol
HOAc
EtOH
16
8
10
7
65
43
76
82
73
Scheme 2
R
O
12
O
N
CHO
O
N
aIsolated yields.
HOAc
HN
H2N
HN
H2N
NH
+
2
R
MWI
NH2
N
NH2
NH2
NH2
Table 2
Optimization of temperature of compound 3a.
1
4
5
Entry
T(ꢀC)
Time (min)
Yieldsa (%)
was further confirmed by single crystal X-ray diffraction
analysis. Figures 1 and 2 showed the molecular structures
of 3f (a molecular of ethanol is elided) and 5a, respectively.
Although the detailed mechanism of the aforementioned
reaction remains to be fully clarified, the formation of
5-aryl-1,9-dimethyl-pyrido[2,3-d][6,5-d]dipyrimidine-2,4,6,8
(1H,3H,7H,9H)-tetraone 3 could be explained by a reaction
sequence presented in Scheme 3. We proposed that the
reaction proceeded via a reaction sequence of Knoevenagel
condensation, Michael addition, cyclization, deamination,
and aromatization.
1
2
3
4
5
6
90
100
110
120
130
140
15
13
12
10
7
53
62
70
79
82
80
7
aIsolated yields.
electron-donating (such as alkoxyl groups) or electron-
withdrawing (such as nitro or halide groups) functional groups
were all suitable for the synthesis of compounds 3. Moreover,
a heterocyclic aldehyde, piperonal (Table 3, entry 7), also
showed a high yield.
In conclusion, the series of pyrido[2,3-d][6,5-d]dipyrimi-
dine and 5,50-arylmethylenebis(2,6-diaminopyrimidinone)
derivatives were synthesized via two-component reaction
After optimization of the experimental variables, the
versatility of the microwave-assisted reaction was tested
using 2,4-diamino-6-hydroxypyrimidine 4 as the starting
material to react with aromatic aldehydes 1, and the
results showed that the expected products were not
obtained, but an uncyclized product 5,50-(arylmethylene)bis
[2,6-diaminopyrimidin-4(3H)-one] 5 was produced (Scheme 2
and Table 4). An explanation for the formation of the aroma-
tization compound 3 but the open-chain compound 5 may
come from the presence of the electron withdrawing carbonyl
group in position 2 of compound 2. The carbonyl group
activates the amino group in position 6 by lowering the degree
of conjugation of the pyrimidine ring and promotes the
cyclization contrary to the case of amino in compound 4.
Table 4
Synthesis of 5 under MWI in acetic acid.
Time
(min)
Yieldsa
(%)
Entry
Compound
Ar
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
4-NO2C6H4
4-ClC6H4
4-BrC6H4
3-CH3C6H4
3-NO2C6H4
4-OH-3-NO2C6H3
2-NO2C6H4
8
7
9
11
10
7
82
78
78
81
74
67
76
5g
10
1
All the products 3 and 5 were characterized by IR, H
NMR, and elemental analysis. The structure of 3f and 4a
MWI, microwave irradiation.
aIsolated yields.
Journal of Heterocyclic Chemistry
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January 2014
An Efficient Synthesis of Dipyrimidine Derivatives under Microwave Irradiation
279
Scheme 3
CH3
N
CH3
N
CH3
N
NH2
O
O
H2N
+
O
H2N
+
O
-H2O
HN
NH
NH
CHAr
H
Ar
O
O
O
O
Ar
O
N
Ar
O
O
N
HN
NH
HN
NH
O
O
N
H3C
N
H
NH2
O
O
N
CH3
H2N
NH
CH3
CH3
O
Ar
N
O
O
Ar
O
HN
NH
HN
NH
-NH3
-2H
O
N
N
O
O
N
N
N
O
H
CH3
CH3
CH3
CH3
Figure 1. X-ray structure of 3f.
Version B (Japan) spectrometer with KBr pellets. 1H NMR
spectrum was obtained on a Varian INOVA-400 MHz spec-
trometer (USA) with TMS as internal standard and DMSO-
d6 as solvent. Elemental analysis was determined by using
an Elementar-vario EL cube (Germany)elemental analysis in-
strument. The reflection data of 3f were collected on a Bruker
FRAMBO (Germany) multiwire proportional diffractometer with
an area detector at 293(2)K. The reflection data of 5a were col-
lected on a Rigaku Saturn724+ CCD diffractometer (Japan)with
an area detector at 173(2)K.
General procedure for the syntheses of compounds 3 and 5
with MWI. The mixture of aromatic aldehyde (1 mmol) and 6-
amino-1-methyluracil (2 mmol) or 2,4-diamino-6-hydroxypyrimidine
(2 mmol) in acetic acid (2 mL) was irradiated at 250 W and at
130ꢀC for a given time. The reaction mixture was cooled to
room temperature and poured into water (50 mL), filtered to
give the crude product, which was further purified by
recrystallization from 95% EtOH and DMF.
5-(4-Chlorophenyl)-1,9-dimethyl-pyrido[2,3-d][6,5-d]
dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (3a).
This
compound was obtained according to the aforementioned general
procedure; mp 285–286ꢀC; IR (KBr): n 3420, 3055, 1708, 1500,
1577, 1620, 1384 cmꢁ1; H NMR(400MHz, DMSO-d6, d, ppm):
1
Figure 2. X-ray structure of 5a.
3.24 (s, 6H, N-CH3), 7.09 (d, 2H, J = 9.0Hz, ArH), 7.22 (d, 2H,
J = 9.0Hz, ArH), 10.29 (s, 2H, NH). Anal. Calcd for
C17H12ClN5O4: C, 52.93; H, 3.14; N, 18.15; found C,
52.63; H, 3.10; N, 18.35.
of aromatic aldehydes with aminopyrimidines in acetic
acid under MWI. Compared with other methods, this
new method has the advantages of better performance,
shorter reaction time, more environmental friendliness,
and easier work-up.
5-(4-Methylphenyl)-1,9-dimethyl-pyrido[2,3-d][6,5-d]
dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (3b).
This
compound was obtained according to the aforementioned general
procedure; mp >300ꢀC; IR (KBr): n 3417, 3055, 1720, 1458,
1
1512, 1550, 1612, 1388 cmꢁ1; H NMR(400 MHz, DMSO-d6, d,
ppm): 2.49 (s, 3H, CH3), 3.53 (s, 6H, N-CH3), 6.89 (d, 2H,
J = 9.0Hz, ArH), 7.07 (d, 2H, J = 9.0 Hz, ArH), 11.35 (s, 2H,
NH). Anal. Calcd for C18H15N5O4: C, 59.18; H, 4.14; N, 19.17;
found C, 59.02; H, 4.23; N, 19.39.
EXPERIMENTAL
Microwave irradiation was carried out in a monomodal
Emrys Creator from Personal Chemistry (Shanghai Sineo
Mas-II) under atmospheric pressure. Melting points were de-
termined with an X-4 apparatus (China) and were uncorrected.
IR spectra were recorded on a Perkin Elmer Spectrum One
5-(4-Nitrolphenyl)-1,9-dimethyl-pyrido[2,3-d][6,5-d]
dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (3c).
This
compound was obtained according to the aforementioned general
procedure; mp >300ꢀC; IR (KBr): n 3417, 3058, 1712, 1458,
Journal of Heterocyclic Chemistry
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Z. Lin, H. Hu, X. You, X. Zhang, and Y. Gao
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1
1527, 1562, 1615, 1388 cmꢁ1; H NMR(400 MHz, DMSO-d6, d,
ppm): 3.56 (s, 6H, N-CH3), 7.51–8.21 (m, 4H, ArH) , 11.50 (s,
2H, NH). Anal. Calcd for C17H12N6O6: C, 51.52; H, 3.05; N,
21.21; found C, 51.75; H, 3.26; N, 21.18.
5,50-[(3-Methylphenyl)methylene]bis[2,6-diaminopyrimidin-4
(3H)-one] (5d). This compound was obtained according to the
aforementioned general procedure; mp >300ꢀC; IR (KBr): n
3469, 3413, 3134, 2473, 2068, 1638, 1531, 1400, 1157; 1H NMR
(400 MHz, DMSO-d6, d, ppm): 2.21 (s, 3H, CH3), 4.78 (s, 1H,
CH), 6.44 (s, 6H, 3NH2), 6.85–6.87 (m, 2H, ArH), 6.98–7.05 (m,
2H, ArH), 9.17 (s, 1H, ArH), 10.41 (s, 4H, 2NH, 1NH2). Anal.
Calcd for C16H18N8O2: C, 54.23; H, 5.12; N, 31.62; found C,
54.58; H, 5.32; N, 31.87.
5-(4-Hydroxy-3-nitrophenyl)-1,9-dimethyl-pyrido[2,3-d][6,5-d]
dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (3d).
This
compound was obtained according to the aforementioned general
procedure; mp >300ꢀC; IR (KBr): n 3460, 3058, 1710, 1519,
1578, 1612, 1388 cmꢁ1; H NMR(400MHz, DMSO-d6, d, ppm):
1
3.24 (s, 6H, N-CH3), 6.95–7.49 (m, 3H, ArH) , 7.93 (s, 1H, OH),
11.35 (s, 2H, NH). Anal. Calcd for C17H12N6O7: C, 49.52; H,
2.93; N, 20.38; found C, 49.28; H, 3.04; N, 20.45.
5,50-[(3-Nitrophenyl)methylene]bis[2,6-diaminopyrimidin-4
(3H)-one] (5e). This compound was obtained according to the
aforementioned general procedure; mp >300ꢀC; IR (KBr): n
1
5-(3,4-Dimethoxyphenyl)-1,9-dimethyl-pyrido[2,3-d][6,5-d]
3460, 3145, 2480, 2009, 1638, 1400, 1159; H NMR(400MHz,
dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (3e).
This
DMSO-d6, d, ppm): 5.45 (s, 1H, CH), 6.20 (s, 6H, 3NH2), 7.47–
7.48 (m, 2H, ArH), 7.82 (s, 1H, ArH), 7.85 (s, 1H, ArH), 10.00
(s, 4H, 2NH, 1NH2). Anal. Calcd for C15H15N9O4: C, 46.75; H,
3.92; N, 32.71; found C, 46.93; H, 3.71; N, 32.83.
compound was obtained according to the aforementioned
general procedure; mp >300ꢀC; IR (KBr): n 3417, 3051, 1708,
1
1461, 1515, 1550, 1365 cmꢁ1; H NMR(400 MHz, DMSO-d6,
d, ppm): 3.53 (s, 6H, N-CH3), 3.62 (s, 3H, CH3), 3.77 (s, 3H,
CH3), 6.51–6.86 (m, 3H, ArH), 11.37 (s, 2H, NH). Anal.
Calcd for C19H17N5O6: C, 55.47; H, 4.17; N, 17.02; found C,
55.36; H, 4.26; N, 17.01.
5,50-[(4-Hydroxy-3-nitrophenyl)methylene]bis[2,6-diaminopy
rimidin-4(3H)-one] (5f).
This compound was obtained
according to the aforementioned general procedure; mp >300ꢀC;
IR (KBr): n 3477, 3426, 3023, 2486, 2066, 1625, 1527, 1478,
1
5-(4-Methoxyphenyl)-1,9-dimethyl-pyrido[2,3-d][6,5-d]
1163; H NMR(400 MHz, DMSO-d6, d, ppm): 5.31 (s, 1H, CH),
dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (3f).
This
6.14 (s, 6H, 3NH2), 6.96 (d, 1H, J = 8.8 Hz, ArH), 7.21 (d, 1H,
J = 8.6Hz, ArH), 7.46 (s, 1H, ArH), 9.98 (s, 4H, 2NH, 1NH2),
10.49 (s, 1H, OH). Anal. Calcd for C15H15N9O5: C, 44.89; H,
3.77; N, 31.41; found C, 44.51; H, 3.67; N, 31.67.
compound was obtained according to the aforementioned general
procedure; mp 292–293ꢀC; IR (KBr): n 3421, 3055, 1708, 1458,
1
1512, 1550, 1612, 1365 cmꢁ1; H NMR(400 MHz, DMSO-d6, d,
ppm): 3.53 (s, 6H, N-CH3), 3.78 (s, 3H, CH3), 6.83 (d, 2H,
J = 9.0 Hz, ArH), 6.94 (d, 2H, J = 9.0 Hz, ArH), 11.36 (s, 2H,
NH). Anal. Calcd for C18H15N5O5: C, 56.69; H, 3.96; N, 18.37;
found C, 56.46; H, 4.03; N, 18.42.
5,50-[(2-Nitrophenyl)methylene]bis[2,6-diaminopyrimidin-4
(3H)-one] (5g). This compound was obtained according to the
aforementioned general procedure; mp >300ꢀC; IR (KBr): n
3363, 3125, 3076, 2477, 2070, 1630, 1592, 1400, 1158; 1H NMR
(400MHz, DMSO-d6, d, ppm): 5.90 (s, 1H, CH), 6.15 (s, 6H,
3NH2), 7.24–7.31 (m, 2H, ArH), 7.44–7.52 (m, 2H, ArH), 9.67 (s,
2H, 1NH2), 10.12 (s, 2H, 2NH). Anal. Calcd for C15H15N9O4: C,
46.75; H, 3.92; N, 32.71; found C, 46.52; H, 3.91; N, 29.89.
5-(3,4-Methylenedioxyphenyl)-1,9-dimethyl-pyrido[2,3-d][6,5-d]
dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (3g).
This
compound was obtained according to the aforementioned general
procedure; mp >300ꢀC; IR (KBr): n 3421, 3058, 1708, 1433,
1
1504, 1558, 1369 cmꢁ1; H NMR(400MHz, DMSO-d6, d, ppm):
Determination of X-ray crystal structures. 3f. Growth of
a single crystal was carried out in ethanol and DMF at room
3.53 (s, 6H, N-CH3), 6.02 (s, 2H, CH2), 6.43–6.82 (m, 3H, ArH),
11.39 (s, 2H, NH). Anal. Calcd for C18H13N5O6: C, 54.69; H,
3.31; N, 17.72; found C, 54.73; H, 3.07; N, 17.56.
temperature. Crystal data for C19H17.50N5O5.50
,
M = 403.88,
5,50-[(4-Nitrophenyl)methylene]bis[2,6-diaminopyrimidin-4
(3H)-one] (5a). This compound was obtained according to the
aforementioned general procedure; mp >300ꢀC; IR (KBr): n 3492,
3132, 2475, 2071, 1639, 1401, 1159; 1H NMR(400 MHz, DMSO-
d6, d, ppm): 5.45 (s, 1H, CH), 6.16 (s, 6H, 3NH2), 7.27 (d, 2H,
J = 9.0 Hz, ArH), 8.05 (d, 2H, J = 9.0 Hz, ArH), 10.00 (s, 4H,
2NH, 1NH2). Anal. Calcd for C15H15N9O4: C, 46.75; H, 3.92; N,
32.71; found C, 46.90; H, 3.74; N, 33.09.
monoclinic, space group C2/c, a = 20.7085(3)
Å, b = 7.5830
(10)Å, c = 24.8406(3)Å, V = 3898.72(9)Å3, Z = 8, T = 293(2) K,
m = 0.873mmꢁ1
, 15764 reflections measured, 3574 unique
reflections, R =0.0185, Rw = 0.2576. Cambridge Crystallographic
Data Centre (CCDC) number is 852433.
5a. Growth of a single crystal was carried out in ethanol and
DMF at room temperature. Crystal data for C15H15N9O4,
M= 385.36, triclinic, space group P21/c, a= 18.324(5) Å, b= 8.544
(2) Å, c= 17.092(5) Å, V= 2407.3(11) Å3, Z=4, T= 173(2) K,
5,50-[(4-Chlorophenyl)methylene]bis[2,6-diaminopyrimidin-4
(3H)-one] (5b). This compound was obtained according to the
aforementioned general procedure; mp 298–300ꢀC; IR (KBr): n
3340, 3198, 2920, 2361, 1633, 1593, 1456, 1159; 1H NMR
(400 MHz, DMSO-d6, d, ppm): 5.34 (s, 1H, CH), 6.11 (s, 6H,
3NH2), 7.02 (d, 2H, J = 8.8 Hz, ArH), 7.19 (d, 2H, J = 8.8 Hz,
ArH), 9.92 (s, 4H, 2NH, 1NH2). Anal. Calcd for C15H15ClN8O2:
C, 48.07; H, 4.03; N, 29.90; found C, 48.17; H, 3.98; N, 29.06.
5,50-[(4-Bromophenyl)methylene]bis[2,6-diaminopyrimidin-4
(3H)-one] (5c). This compound was obtained according to the
aforementioned general procedure; mp >300ꢀC; IR (KBr): n
3332, 3167, 2922, 2361, 1645, 1455, 1398, 1159; 1H NMR
(400 MHz, DMSO-d6, d, ppm): 5.31 (s, 1H, CH), 6.14 (s, 6H,
3NH2), 6.97 (d, 2H, J = 8.6 Hz, ArH), 7.32 (d, 2H, J = 8.6 Hz,
ArH), 9.95 (s, 4H, 2NH, 1NH2). Anal. Calcd for C15H15BrN8O2:
C, 42.97; H, 3.61; N, 26.73; found C, 42.89; H, 3.97; N, 26.41.
m =0.081mmꢁ1
,
11213 reflections measured, 5472 unique
reflections, R= 0.0439, Rw = 0.2312. CCDC number is 852434.
Acknowledgments. We are grateful to the financial support from
the National Natural Science Foundation of China (No. 81071144)
and Natural Science Foundation of the Guangdong Province
(No. 9451806001002961).
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DOI 10.1002/jhet

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An Efficient Synthesis of Dipyrimidine Derivatives under Microwave Irradiation
281
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet