A novel and efficient synthesis of pyrimido[4,5-d]pyrimidine-2,4,7-trione and pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone derivatives

Article abstract of DOI:10.1016/j.tet.2006.12.043

An efficient and direct procedure for the synthesis of pyrimido[4,5-d]pyrimidine-2,4,7-trione derivatives has been described under?microwave-assisted conditions. Reaction of 6-amino-1,3-dimethyluracil with aromatic aldehydes resulted in the formation of p

Full text of DOI:10.1016/j.tet.2006.12.043

Tetrahedron 63 (2007) 1770–1774
A novel and efficient synthesis of pyrimido[4,5-d]pyrimidine-
2,4,7-trione and pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone
derivatives
*
Minoo Dabiri, Hamid Arvin-Nezhad, Hamid Reza Khavasi and Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, Tehran 1983963113, Iran
Received 30 September 2006; revised 6 December 2006; accepted 14 December 2006
Available online 17 December 2006
Abstract—An efficient and direct procedure for the synthesis of pyrimido[4,5-d]pyrimidine-2,4,7-trione derivatives has been described
under microwave-assisted conditions. Reaction of 6-amino-1,3-dimethyluracil with aromatic aldehydes resulted in the formation of pyrido-
[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone derivatives.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Microwave-assisted organic synthesis is an increasingly
popular field as indicated by numerous publications in the
past few years owing to several advantages, such as en-
hanced reaction rates and increase in yields under milder
conditions.11 The combination of solvent-free reaction con-
ditions and microwave irradiation leads to large reduction in
reaction times, enhancement in conversion and sometimes
in selectivity with several advantages of the eco-friendly
approach, termed green chemistry.12
Pyrimidopyrimidinesare annelateduracilsthat haveattracted
considerable interest in recent years. Their derivatives have
beenknownto displayawiderange ofpharmacologicalactiv-
ities, and their potent inhibitory properties regarding the
tyrosine kinase domain of epidermal growth factor receptor,1
5-phosphoribosyl-1-pyrophosphate synthetase2 and dihydro-
folate reductase3 have been fully demonstrated. Numerous
reports delineate the antitumour,4 antiviral,5 antioxidant,6
antifungal7 and hepatoprotective8 activities of these com-
pounds. Therefore, for the preparation of these complex
molecules large efforts have been directed towards the syn-
thetic manipulation of uracils. As a result, a number of reports
have appeared in the literature that usually describe forcing
conditions, long reaction times and complex synthetic path-
ways.9 Thus new routes for the synthesis of these molecules
have attracted considerable attention allowing for a rapid
entry to these heterocycles.
Considering the above reports in conjunction with our
previous work on microwave-assisted synthesis of hetero-
cyclic compounds,13 and pursuing our studies on multi-
component reactions,14 we wish to report a novel, efficient,
one-pot and three-component method for the preparation
of 5,6-dihydro-1,3-dimethyl-5-aryl pyrimido[4,5-d]pyrim-
idine-2,4,7(1H,3H,8H)-trione derivatives under microwave-
assisted conditions. To the best of our knowledge, this paper
is the first report on the synthesis of some pyrimido[4,5-d]-
pyrimidine-2,4,7-triones with this particular regioisomeric
arrangement. Of course, some related pyrimidopyrimidines
with the mentioned properties have been reported.15
Multi-component reactions (MCRs) are economically and
environmentally very advantageous because multi-step syn-
theses produce considerable amounts of waste mainly due to
complex isolation procedures often involving expensive,
toxic and hazardous solvents after each step. MCRs are per-
fectly suited for combinatorial library synthesis, and thus are
finding increasing use in the discovery process for new drugs
and agrochemicals.10
2. Results and discussion
After some preliminary experimentation, it was found that
a mixture of 6-amino-1,3-dimethyluracil 1, benzaldehyde
2a and urea 3 in the presence of a catalytic amount of acetic
acid (HOAc) afforded 5,6-dihydro-1,3-dimethyl-5-phenyl
pyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-trione 4a in
87% yield under microwave-assisted conditions for 5 min
(Scheme 1).
Keywords: Pyrimido[4,5-d]pyrimidine-trione; Microwave; Pyrido[2,3-d:6,5-d]-
dipyrimidine-2,4,6,8-tetrone; Multi-component.
* Corresponding author. Tel.: +98 21 22401765; fax: +98 21 22431663;
e-mail: a_bazgir@sbu.ac.ir
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.043

M. Dabiri et al. / Tetrahedron 63 (2007) 1770–1774
1771
O
Ar
Ph
O
Ph
O
O
O
Me
O
Me
O
Me
O
Me
O
Me
O
N
NH
O
HOAc
5 min
N
N
NH
N
N
+ ArCHO +
H2N
HOAc
5 min
+
+
1
NH2
N
Me
N
H
O
H2N
H2N
NH2
NH2
N
Me
NH2
N
Me
N
Me
O
N
Me
N
H
O
1
2a-f
3
4a-f
5
3
4a
Scheme 1.
Scheme 2.
In order to find a catalyst effective for the synthesis of
the pyrimido[4,5-d]pyrimidine-2,4,7-trione derivatives under
microwave-assisted conditions, we examined this condensa-
tion reaction in the absence and the presence of several cat-
alysts. The best results were obtained when HOAc was
used (Table 1).
situ by reaction of the aldehyde with 6-amino-1,3-dimethyl-
uracil.16 Then, the intermediate 5 was converted to iminium
cation 6 and the subsequent addition of urea to the iminium
cation, followed by cyclization afforded the corresponding
5,6-dihydro-1,3-dimethyl-5-aryl pyrimido[4,5-d]pyrimidine-
2,4,7(1H,3H,8H)-trione and ammonia (Scheme 3). The elim-
ination of ammonia from urea has been reconfirmed by
replacement of urea by N-methyl urea resulting in the same
product.
Table 1. Catalyst effect on the reactiona
Entry
Catalyst
Yieldsb (%)
1
2
3
4
5
6
CH3COOH
CF3COOH
4-Me–C6H4SO3H
LiCl
ZnCl2
CuCl2
87
37
41
<20
<20
<20
O
O
Ar
O
Me
2
O
Me
O
Me
N
N
N
+
ArCHO
N
Me
NH2
NH2H2N
N
Me
N
O
Me
Ar
1
5
a
A mixture of benzaldehyde (1 mmol), urea (1.5 mmol), 6-amino-1,3-
dimethyluracil (1 mmol) and catalyst (0.5 mmol) were exposure for
5 min under MW irradiation.
Ar
O
O
O
Me
O
HN
Me
O
N
H2N
NH2
-NH3 O
N
1
b
+
4
Isolated yields.
NH2
H2N
N
Me
N
Me
H2N
Encouraged by this success, we extended this reaction of
6-amino-1,3-dimethyluracil with a range of other aromatic
aldehydes 2b–f and urea under similar conditions (using
HOAc), furnishing the respective pyrimido[4,5-d]pyrim-
idine-2,4,7-triones 4b–f in high yields. The optimized results
are summarized in Table 2. High yields were obtained using
aromatic aldehydes carrying electron-donating or electron-
withdrawing substituents.
6
Scheme 3.
During our investigation on the synthesis of pyrimido[4,5-
d]pyrimidine-2,4,7-triones, we found that in the absence of
urea, 6-amino-1,3-dimethyluracil and aromatic aldehyde
using similar conditions (MW/HOAc) gave 5-aryl-1,3,7,9-
tetramethylpyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone
7 in 20–30% yields (Scheme 4).
Table 2. Reaction of 6-amino-1,3-dimethyluracil, aldehydes and urea under
MW irradiationa
Product 4
Ar
Yieldb (%)
O
O
Ar
O
Me
2
O
Me
O
Me
+ 5
O
a
b
c
d
e
f
C6H5
87
86
75
80
76
80
HOAc
5 min
N
N
N
+
ArCHO
4-Me–C6H4
4-OMe–C6H4
4-Cl–C6H4
4-F–C6H4
4-Br–C6H4
N
Me
N
N
N
Me
1
NH2
Me
7
20-30%
a
With power of 900 W.
Isolated yields.
Scheme 4.
b
To the best of our knowledge, there are no reports in the
literature for the formation of pyrido[2,3-d:6,5-d] dipyr-
imidine-2,4,6,8-tetrone derivatives via direct condensation
of aldehydes with 6-amino-1,3-dimethyluracil. Very few
methods are reported in the literature for the preparation of
pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrones.17 These
methods suffer from one or more disadvantages such as
low yield, long reaction time, use of toxic solvent, harsh
reaction conditions and lack of easy availability/preparation
of the starting materials.
For the investigation of the reaction mechanism, it is notable
that when 6-amino-1,3-dimethyluracil, benzaldehyde and
ureawereirradiatedfor1 min, theintermediate 5was formed,
which was isolated and characterized by spectroscopic
methods. When intermediate 5 was isolated and reacted
with urea in the presence of HOAc under microwave irradia-
tion, the mixture of 4a and 6-amino-1,3-dimethyluracil 1 was
obtained. After purification of the reaction mixture product
4a was obtained in good yields (Scheme 2). Replacement
of urea with N-methyl urea afforded product 4a in 89% yield.
Therefore, due to the biological importance of pyridine
derivatives and in order to improve the yields of pyrido-
[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone derivatives, we
According to the results, the reaction can mechanistically be
considered to proceed through the intermediate 5 formed in

1772
M. Dabiri et al. / Tetrahedron 63 (2007) 1770–1774
H3
C3
examined the reaction in different conditions. The best
results were obtained in ionic liquid 1-butyl-3-methylimid-
azolium bromide ([bmim]Br) as solvent at 100 ꢀC catalyzed
by p-TSA for 4 h. Several aromatic aldehydes carrying ei-
ther electron-donating or electron-withdrawing substituents
reacted and gave the products 7a–e in good yields (Table 3).
H2
C2
C1
O4
C4
H4
H5
S1
H15a
C15
H14b
H16b
C16
H16a
H15b
H1
C5
C6
C7
H16c
C14
O3
C11
H15c
H14c
Table 3. Synthesis of pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone
derivatives
H7
H1d
H14a
N4
C12
C9
O
O
Ar
O
C10
N1
Me
2
O
Me
O
Me
[bmim]Br/p-TSA
100 °C/4 h
N
O2
N
N
C8
+ 5
ArCHO
+
N3
N2
O1
N
N
N
O
N
NH2
H13b
H13c
H2d
Me
Me
Me
1
C13
7a-e
H13a
50-54%
Figure 1. X-ray crystal structure of 4a.
Product 7
Ar
Yielda (%)
a
b
c
d
e
C6H5
54
50
52
53
51
Br1
C1
4-Me–C6H4
4-Cl–C6H4
4-Br–C6H4
4-F–C6H4
a
C2
Isolated yields.
C3
C4
O4
C16
O1
C7
The reaction can be mechanistically considered to proceed
via the initial formation of the intermediate 5, followed by
the loss of a molecule of ammonia from 5 through cyclo-
condensation to yield intermediate 8. The product 7 is then
formed by facile air oxidation of intermediate 8 (Scheme 5).
C15
C5
C17
C6
C8
O2
N5
C14
O3
C12
N1
C9
C11
N4
N3
N2
C10
Figure 2. X-ray crystal structure of 7d.
O
O
Ar
O
Me
2
O
C13
Me
O
Me
N
N
N
ArCHO
+
N
Me
NH2
NH
N
Me
2H2N
N
O
Me
1
5
-NH3
The novelty and synthetic usefulness of these methodologies
were demonstrated by the efficient synthesis of uracil
derivatives.
O
Ar
O
N
O
Ar
O
N
Me
O
Me
Me
O
Me
N
N
N
N
[O]
N
N
H
O
N
N
O
4. Experimental
Me
Me
Me
Me
7
8
Scheme 5.
4.1. General procedure for the preparation of 5,6-dihy-
dro-1,3-dimethyl-5-phenyl pyrimido[4,5-d]pyrimidine-
2,4,7(1H,3H,8H)-trione 4a under microwave irradiation
The structures of the products 4a–f and 7a–e were character-
ized by IR, 1H NMR, 13C NMR and MS spectra. The struc-
tures of 4a and 7d were confirmed by a single-crystal X-ray
analysis18 (Figs. 1 and 2). The structure of 7d consists of
alternating stacks, linked together by some short contacts.
A mixture of 6-amino-1,3-dimethyluracil (1 mmol), benz-
aldehyde (1 mmol), urea (1.5 mmol) and acetic acid
(0.5 mmol) in a Pyrex test tube was irradiated for 5 min at
atmospheric pressure with a power of 900 W (the microwave
oven was a domestic National model NN-6653 with select
power levels). After cooling, the reaction mixture was
washed with water (15 mL) and then recrystallized from
EtOH/H2O to afford the pure product 4a as a white powder
(87%). Mp 324 ꢀC (dec); IR (KBr) (nmax/cmꢁ1) 3321, 3112,
1687, 1654, 1636; 1H NMR (300 MHz, DMSO-d6) dH 3.09
(3H, s, CH3), 3.35 (3H, s, CH3), 5.23 (1H, s, CH), 7.31
(5H, m, arom), 8.09 (1H, s, NH), 9.82 (1H, s, NH);
13C NMR (75 MHz, DMSO-d6) dC 27.4, 29.9, 51.6, 85.9,
126.3, 127.4, 128.3, 143.9, 145.3, 150.7, 151.8, 159.4;
MS, m/z (%): 286 (M+, 25), 242 (23), 209 (100), 152 (74),
3. Conclusion
We have described a novel, efficient and one-pot synthesis
of pyrimido[4,5-d]pyrimidine-2,4,7-trione derivatives via
a three-component cyclocondensation reaction of 6-amino-
1,3-dimethyluracil, aromatic aldehydes and urea under
microwave irradiation. In addition, a novel synthesis of
pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone derivatives
by the condensation reaction of 6-amino-1,3-dimethyluracil
and aromatic aldehydes in ionic liquid were introduced.

M. Dabiri et al. / Tetrahedron 63 (2007) 1770–1774
1773
82 (57), 51 (49). Anal. Calcd (%) for C14H14N4O3: C, 58.73;
H, 4.93; N, 19.57. Found C, 58.66; H, 4.91; N, 19.61.
1639; 1H NMR (300 MHz, DMSO-d6) dH 3.09 (3H, s,
CH3), 3.36 (3H, s, CH3), 5.25 (1H, s, CH), 7.11–7.37 (4H,
m, arom), 8.10 (1H, s, NH), 9.85 (1H, s, NH); 13C NMR
(75 MHz, DMSO-d6) dC 27.9, 30.4, 51.5, 86.2, 115.5 (d,
J¼21 Hz), 128.8 (d, J¼8.3 Hz), 145.8, 151.2, 152.1,
159.9, 161.9 (d, J¼241 Hz); MS, m/z (%) 304 (M+, 15),
260 (27), 209 (100), 152 (26), 82 (28). Anal. Calcd (%) for
C14H13FN4O3: C, 55.26; H, 4.31; N, 18.41. Found C,
55.37; H, 4.41; N, 18.50.
4.2. General procedure for the preparation of 5-phenyl-
1,3,7,9-tetramethylpyrido[2,3-d:6,5-d] dipyrimidine-
2,4,6,8-tetrone 7a in ionic liquid
A mixture of 6-amino-1,3-dimethyluracil (2 mmol), benz-
aldehyde (1 mmol), p-TSA (0.5 mmol) and ionic liquid
[bmim]Br (0.3 g) was stirred at 100 ꢀC in a pre-heated oil
bath for 4 h. After cooling, the reaction mixture was washed
with water (15 mL) and the solid product was filtered off.
Column chromatography on silica gel using EtOAc/hexane
(1:3) gave the product 7a as a white powder (54%). Mp
4.2.5. 5,6-Dihydro-1,3-dimethyl-5-(4-bromophenyl) pyr-
imido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-trione (4f). Mp
307 ꢀC (dec); IR (KBr) (nmax/cmꢁ1) 3323, 1709, 1688,
1
1661, 1636; H NMR (300 MHz, DMSO-d6) dH 3.07 (3H,
254–256 ꢀC; Rf (1:3 EtOAc/hexane) 0.74; IR (KBr) (nmax
/
s, CH3), 3.34 (3H, s, CH3), 5.21 (1H, s, CH), 7.27–7.49
(4H, m, arom), 8.11 (1H, s, NH), 9.87 (1H, s, NH);
13C NMR (75 MHz, DMSO-d6) dC 27.9, 30.4, 51.7, 85.8,
120.9, 129.1, 131.7, 143.8, 145.9, 151.1, 152.0, 159.9;
MS, m/z (%) 365 (M+, 9), 285 (14), 209 (100), 152 (30),
82 (21). Anal. Calcd (%) for C14H13BrN4O3: C, 46.05; H,
3.59; N, 15.34. Found C, 45.98; H, 3.49; N, 15.44.
cmꢁ1) 2923, 1718, 1678, 1552; 1H NMR (300 MHz,
CDCl3) dH 3.32 (6H, s, CH3), 3.81 (6H, s, CH3), 7.11–7.53
(5H, m, arom); 13C NMR (75 MHz, CDCl3) dC 28.6, 30.4,
105.0, 125.5, 127.8, 128.0, 137.6, 151.0, 153.4, 159.1,
160.0; MS, m/z (%): 379 (M+, 98), 364 (100), 321 (85),
293 (74), 265 (87), 127 (63), 43 (71). Anal. Calcd (%) for
C19H17N5O4: C, 60.15; H, 4.52; N, 18.46. Found C, 60.24;
H, 4.59; N, 18.34.
4.2.6. 6-Amino-5-((6-amino-1,2,3,4-tetrahydro-1,3-di-
methyl-2,4-dioxopyrimidin-5-yl)(phenyl)methyl)-1,3-di-
methyl pyrimidine-2,4(1H,3H)-dione (5). Yield 78%. Mp
305–307 ꢀC. IR (KBr) (nmax/cmꢁ1) 3457, 3389, 3199,
4.2.1. 5,6-Dihydro-1,3-dimethyl-5-(4-methylphenyl) pyr-
imido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-trione (4b).
Mp 315 ꢀC (dec); IR (KBr) (nmax/cmꢁ1) 3307, 3112, 1687,
1658; 1H NMR (300 MHz, DMSO-d6) dH 2.25 (3H, s,
CH3), 3.09 (3H, s, NCH3), 3.35 (3H, s, NCH3), 5.19 (1H, s,
CH), 7.12–7.18 (4H, m, arom), 8.04 (1H, s, NH), 9.80 (1H,
s, NH); 13C NMR (75 MHz, DMSO-d6) dC 21.1, 27.9, 30.4,
51.9, 86.6, 126.7, 129.3, 137.0, 141.5, 145.7, 151.2, 152.3,
159.9; MS, m/z (%) 300 (M+, 21), 209 (100), 152 (36), 109
(24), 82 (49), 55 (41). Anal. Calcd (%) for C15H16N4O3: C,
59.99; H, 5.37; N, 18.66. Found C, 60.12; H, 5.46; N, 18.52.
1
2998, 1697, 1648, 1581; H NMR (300 MHz, DMSO-d6)
dH 3.14 (6H, s, CH3), 3.32 (6H, s, CH3), 5.58 (1H, s, CH),
7.08–7.21 (5H, m, arom), 7.44 (4H, br s, NH2); 13C NMR
(75 MHz, DMSO-d6) dC 28.4, 30.4, 35.8, 86.6, 125.3,
127.0, 128.1, 140.1, 151.0, 154.7, 163.4; MS, m/z (%) 398
(M+, 92), 242 (100), 185 (14), 57 (23). Anal. Calcd (%)
for C19H22N6O4: C, 57.28; H, 5.57; N, 21.09. Found C,
57.36; H, 5.64; N, 20.54.
4.2.7. 5-Methylphenyl-1,3,7,9-tetramethylpyrido[2,3-d:
6,5-d] dipyrimidine-2,4,6,8-tetrone (7b). Mp 331–
333 ꢀC. IR (KBr) (nmax/cmꢁ1) 2954, 1715, 1672, 1557;
1H NMR (300 MHz, CDCl3) dH 2.48 (3H, s, CH3), 3.33
(6H, s, CH3), 3.79 (6H, s, CH3), 7.02 (2H, d, J¼8.6 Hz,
arom), 7.33 (2H, d, J¼8.1 Hz, arom); 13C NMR (75 MHz,
CDCl3) dC 21.7, 28.6, 30.5, 105.1, 125.4, 128.9, 134.6,
137.3, 151.0, 153.3, 159.1, 160.5; MS, m/z (%) 393 (M+,
100), 352 (18), 335 (18), 279 (14), 115 (78), 77 (65). Anal.
Calcd (%) for C20H19N5O4: C, 61.06; H, 4.87; N, 17.80.
Found C, 60.98; H, 4.79; N, 17.87.
4.2.2. 5,6-Dihydro-1,3-dimethyl-5-(4-methoxyphenyl)
pyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-trione (4c).
Mp 307 ꢀC (dec); IR (KBr) (nmax/cmꢁ1) 3350, 1684, 1666;
1H NMR (300 MHz, DMSO-d6) dH 3.09 (3H, s, CH3), 3.36
(3H, s, CH3), 3.71 (3H, s, OCH3), 5.18 (1H, s, CH), 6.87–
7.42 (4H, m, arom), 8.03 (1H, s, NH), 9.79 (1H, s, NH);
13C NMR (75 MHz, DMSO-d6) dC 27.9, 30.4, 51.5, 55.5,
86.7, 114.1, 127.9, 136.7, 145.6, 151.2, 152.2, 159.0, 159.9;
MS, m/z (%) 315 (M+ꢁ1, 23), 285 (69), 209 (100), 152
(52), 82 (100). Anal. Calcd (%) for C15H16N4O4: C, 56.96;
H, 5.10; N, 17.71. Found C, 57.07; H, 5.19; N, 17.81.
4.2.8. 5-Chlorophenyl-1,3,7,9-tetramethylpyrido[2,3-
d:6,5-d] dipyrimidine-2,4,6,8-tetrone (7c). Mp 300–
302 ꢀC. IR (KBr) (nmax/cmꢁ1) 1716, 1690, 1666, 1552;
1H NMR (300 MHz, CDCl3) dH 3.33 (6H, s, CH3), 3.79
(6H, s, CH3), 7.06 (2H, d, J¼8.4 Hz, arom), 7.33 (2H, d,
J¼8.4 Hz, arom); 13C NMR (75 MHz, CDCl3) dC 28.6,
30.5, 104.9, 127.0, 128.4, 133.7, 136.0, 150.8, 153.4, 158.7,
159.1; MS, m/z (%) 413 (M+, 100), 355 (16), 299 (30), 243
(14), 69 (20), 43 (65). Anal. Calcd (%) for C19H16ClN5O4:
C, 55.15; H, 3.90; N, 16.92. Found C, 55.07; H, 3.99;
N, 16.81.
4.2.3. 5,6-Dihydro-1,3-dimethyl-5-(4-chlorophenyl) pyr-
imido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-trione (4d).
Mp 312 ꢀC (dec); IR (KBr) (nmax/cmꢁ1) 3324, 1689, 1660,
1636; 1H NMR (300 MHz, DMSO-d6) dH 3.08 (3H, s,
CH3), 3.35 (3H, s, CH3), 5.21 (1H, s, CH), 7.34–7.36 (4H,
m, arom), 8.10 (1H, s, NH), 9.86 (1H, s, NH); 13C NMR
(75 MHz, DMSO-d6) dC 27.2, 29.7, 50.9, 85.2, 128.0,
128.1, 131.7, 142.6, 145.2, 150.5, 151.3, 159.2; MS, m/z
(%) 321 (M+, 14), 276 (26), 209 (100), 152 (30), 82 (43),
57 (28). Anal. Calcd (%) for C14H13ClN4O3: C, 52.43; H,
4.09; N, 17.47. Found C, 52.31; H, 4.17; N, 17.58.
4.2.9. 5-Bromophenyl-1,3,7,9-tetramethylpyrido[2,3-d:
6,5-d] dipyrimidine-2,4,6,8-tetrone (7d). Mp 321–
323 ꢀC. IR (KBr) (nmax/cmꢁ1) 2954, 1709, 1671, 1557;
1H NMR (300 MHz, CDCl3) dH 3.33 (6H, s, CH3), 3.79
4.2.4. 5,6-Dihydro-1,3-dimethyl-5-(4-fluorophenyl) pyr-
imido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-trione (4e).
Mp 308 ꢀC (dec); IR (KBr) (nmax/cmꢁ1) 3309, 1691, 1663,

1774
M. Dabiri et al. / Tetrahedron 63 (2007) 1770–1774
12. Varma, R. S. Green Chem. 1999, 1, 43.
(6H, s, CH3), 7.00 (2H, d, J¼8.4 Hz, arom), 7.62 (2H, d,
J¼8.4 Hz, arom); 13C NMR (75 MHz, CDCl3) dC 28.6,
30.5, 104.9, 121.9, 127.3, 131.3, 136.5, 150.8, 153.4,
158.7, 159.1; MS, m/z (%) 458 (M+, 100), 352 (18), 335
(18), 279 (14), 115 (78), 77 (65). Anal. Calcd (%) for
C19H16BrN5O4: C, 49.80; H, 3.52; N, 15.28. Found C,
49.89; H, 3.56; N, 15.37.
13. (a) Shaabani, A.; Bazgir, A. Tetrahedron Lett. 2004, 45,
2575; (b) Shaabani, A.; Dabiri, M.; Bazgir, A. Dyes
Pigments 2006, 71, 68; (c) Bazgir, A. J. Chem. Res.,
Synop. 2006, 1.
14. (a) Shaabani, A.; Bazgir, A. Mol. Divers. 2004, 8, 141; (b)
Shaabani, A.; Teimouri, M. B.; Bazgir, A.; Bijanzadeh, H. R.
Mol. Divers. 2003, 6, 199.
15. Sakai, T.; Kawasaki, H.; Abe, H.; Hayakawa, K.; Iida, T.;
Kikuchi, S.; Yamaguchi, T.; Nanayama, T.; Kurachi, H.;
Tamaru, M.; Hori, Y.; Takahashi, M.; Yoshida, T. PCT Int.
Appl. WO 2005121142, 2005.
16. Yoneda, F.; Takayama, F.; Koshiro, A. Chem. Pharm. Bull.
1979, 27, 2507.
17. (a) Hirota, K.; Kitade, Y.; Senda, S. J. Heterocycl. Chem. 1985,
22, 345; (b) Elderfield, R. C.; Wharmby, M. J. Org. Chem.
1967, 32, 1638; (c) Vanden Berghe, D. A.; Vlietinck, A.
J. Heterocycl. Chem. 1988, 25, 217; (d) Singh, K.; Singh, J.;
Singh, H. Tetrahedron 1998, 54, 935; (e) Nagamatsu, T.;
Sakuma, Y.; Yoneda, F. Synthesis 1983, 923.
4.2.10. 5-Fluorophenyl-1,3,7,9-tetramethylpyrido[2,3-d:
6,5-d] dipyrimidine-2,4,6,8-tetrone (7e). Mp 270–272 ꢀC.
1
IR (KBr) (nmax/cmꢁ1) 2941, 1718, 1682, 1552; H NMR
(300 MHz, CDCl3) dH 3.33 (6H, s, CH3), 3.80 (6H, s, CH3),
7.06–7.27 (4H, m, arom); 13C NMR (75 MHz, CDCl3)
dC 28.6, 30.5, 105.1, 115.3 (d, J¼21.7 Hz), 127.3 (d,
J¼8.0 Hz), 133.2, 133.3, 150.9, 153.4, 159.1, 162.3 (d,
J¼245 Hz); MS, m/z (%) 397 (M+, 100), 378 (26), 283 (24),
168 (97), 77 (65). Anal. Calcd (%) for C19H16FN5O4: C,
57.43; H, 4.06; N, 17.62. Found C, 57.50; H, 4.13; N, 17.71.
Acknowledgements
18. X-ray data for 4a: (C14H14N4O3) (CH3SOCH3),
M¼364.43 g/mol, monoclinic system, space group P21/c,
We gratefully acknowledge financial support from the
Research Council of Shahid Beheshti University.
ꢀ
˚
a¼12.258(2), b¼18.520(3), c¼16.362(3) A, b¼109.554(14) ,
V¼3500.3(10) A , Z¼8, Dc¼1.38 g cmꢁ3
,
m(Mo Ka)¼
3
˚
0.214 mmꢁ1, crystal dimension of 0.3ꢂ0.2ꢂ0.1 mm. The
structure was solved by using SHELXS. The structure refine-
ment and data reduction were carried out with SHELXL of
the X-Step32 suite of programs.19 The non-hydrogen atoms
were refined anisotropically by full matrix least-squares on
F2 values to final R1¼0.0998, wR2¼0.2461 and S¼1.080
with 475 parameters using 6642 independent reflections (q
range¼1.72–25.69ꢀ). Hydrogen atoms were located from ex-
pected geometry and were not refined. Crystallographic data
for 4a have been deposited with the Cambridge Crystallo-
graphic Data Centre. Copies of the data can be obtained, free
of charge, on application to The Director, CCDC 615113,
Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk. X-ray data
for 7d: (C19H16BrN5O4), M¼458.27 g/mol, monoclinic
References and notes
1. Rewcastle, G. W.; Bridges, A. J.; Fry, D. W.; Rubin, J. R.;
Denny, W. A. J. Med. Chem. 1997, 40, 1820.
2. Fry, D. W.; Becker, M. A.; Switzer, R. L. Mol. Pharmacol.
1995, 47, 810.
3. Gready, J. E.; McKinlay, C.; Gebauer, M. G. Eur. J. Med. Chem.
2003, 38, 719.
4. Sanghhvi, Y. S.; Larson, S. B.; Matsumoto, S. S.; Nord, L. D.;
Smee, D. F.; Willis, R. C.; Avery, T. H.; Robins, R. K.;
Revankar, G. R. J. Med. Chem. 1989, 32, 629.
5. Tenser, R. B.; Gaydos, A.; Hay, K. A. Antimicrob. Agents
Chemother. 2001, 45, 3657.
6. De la Cruz, J. P.; Carrasco, T.; Ortega, G.; Sanchez De la
Cuesta, F. Lipids 1992, 27, 192.
7. Nizamuddin; Mishra, M.; Srivastava, M. K.; Khan, M. H.
Indian J. Chem. 2001, 40, 49.
8. Ram, V. J.; Goel, A.; Sarkhel, S.; Maulik, P. R. Bioorg. Med.
Chem. 2002, 10, 1275.
9. (a) Hirota, K.; Huang, J.; Sajiki, H.; Maki, Y. Heterocycles
1986, 24, 2293; (b) Niess, R.; Robins, R. K. J. Heterocycl.
Chem. 1970, 7, 243; (c) Hirota, K.; Kitade, H.; Sajiki, H.;
Maki, Y. Synthesis 1984, 589; (d) Gohain, M.; Prajapati, D.;
Gogoi, B. J.; Sandhu, J. S. Synlett 2004, 1179; (e) Bernier,
J. L.; Lefebvre, A.; Lespognol, C.; Navarro, J.; Perio, A. Eur.
J. Med. Chem. 1977, 12, 341; (f) Prajapati, D.; Thakur, A. J.
Tetrahedron Lett. 2005, 46, 1433.
system, space group P21/m, a¼13.032(3), b¼7.0814(15),
3
c¼13.413(3) A, b¼115.889(17)ꢀ, V¼1113.6(5) A , Z¼2,
Dc¼1.36 g cmꢁ3, m(Mo Ka)¼1.88 mmꢁ1, crystal dimension
of 0.35ꢂ0.32ꢂ0.20 mm. The structure was solved by using
SHELXS. The structure refinement and data reduction were
carried out with SHELXL of the X-Step32 suite of programs.19
The non-hydrogen atoms were refined anisotropically by full
matrix least-squares on F2 values to final R1¼0.0712,
wR2¼0.2116 and S¼1.078 with 173 parameters using 2567 in-
dependent reflections (q range¼1.69–26.78ꢀ). Hydrogen atoms
were located from expected geometry and were not refined.
Crystallographic data for 7d have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data
can be obtained, free of charge, on application to The Director,
CCDC 629593, Union Road, Cambridge CB2 1EZ, UK. Fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
˚
˚
10. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168;
(b) Ugi, I.; Domling, A. Endeavour 1994, 18, 115; (c) Heck, S.;
Domling, A. Synlett 2000, 424.
19. X-STEP32 Version 1.07b, X-ray Structure Evaluation Package;
Stoe & Cie: Darmstadt, Germany, 2000.
11. (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199; (b)
Caddick, S. Tetrahedron 1995, 51, 10403.