A novel and expedient synthesis of 7-pyrimidinylpyrimido[4,5-d] pyrimidinones

Article abstract of DOI:10.1002/hlca.200900183

A novel and efficient procedure for the synthesis of new 7-pyrimidinylpyrimido[4,5-d]pyrimidinone derivatives was elaborated via the base-promoted cyclodimerization reaction of 5-[(dimethylamino)-methylidene]-6- iminopyrimidine-2,4(1H,3H)-dione hydrochlorides. In an analogous manner, a 2-thioxo analog was prepared starting with the corresponding 2-thioxopyrimidin-4-one.

Full text of DOI:10.1002/hlca.200900183

Helvetica Chimica Acta – Vol. 93 (2010)
153
A Novel and Expedient Synthesis of 7-Pyrimidinylpyrimido[4,5-
d]pyrimidinones
by Mohammad R. Mohammadizadeh*a), Mojtaba Bahramzadeha), Ali A. Mohammadib), and
Ali R. Karimic)
a) Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
(phone/fax: þ 98(771)4541494; e-mail: mrmohamadizadeh@pgu.ac.ir)
b) Chemistry Department, Faculty of Science, Islamic Azad University-Sabzevar Branch,
P. O. Box 9618814711, Sabzevar, Iran
c) Department of Chemistry, Arak University, Arak 38156, Iran
A novel and efficient procedure for the synthesis of new 7-pyrimidinylpyrimido[4,5-d]pyrimidinone
derivatives was elaborated via the base-promoted cyclodimerization reaction of 5-[(dimethylamino)-
methylidene]-6-iminopyrimidine-2,4(1H,3H)-dione hydrochlorides. In an analogous manner, a 2-thioxo
analog was prepared starting with the corresponding 2-thioxopyrimidin-4-one.
Introduction. – N-containing heterocycles have attracted considerable attention as
they are integral components of many natural products, dyes, agrochemicals, and
pharmaceuticals. Among the condensed N-heterocycles, pyrimido[4,5-d]pyrimidines
represent an attractive target due to their interesting pharmacological activities
regarding the modulation of antitumor drug acitivity [1], antioxidant (lipid perox-
idation inhibitors) [2], and antiviral activities [3], and potent inhibitory action on the
tyrosine kinase domain of epidermal growth factor receptor [4], 5-phosphoribosyl-1-
pyrophosphate synthetase [5], and dihydrofolate reductase [6]. Some of them are used
clinically as effective cardiovascular [7] and antineoplastic agents [8]. The most
promising methods up to now for the synthesis of pyrimido[4,5-d]pyrimidines are
derived from multistep cyclocondensation reactions of pyrimidine and uracil deriva-
tives [9][10] and usually required drastic conditions, long reaction times, and complex
synthetic pathways.
Results and Discussion. – 5-[(Dimethylamino)methylidene]-6-imino-1,3-dimethyl-
pyrimidine-2,4(1H,3H)-dione hydrochloride (1a) was previously synthesized from the
reaction of 6-amino-1,3-dimethyluracil and SOCl2 in DMF and used frequently as
precursor for efficient syntheses of various pyrimidine fused heterocycles [9a][11]. In
continuation of our studies and the development of highly expedient methods for the
synthesis of annulated uracils of potentially biological importance [12], we report
herein a novel and simple method for the efficient synthesis of some new 7-
pyrimidinylpyrimido[4,5-d]pyrimidinone derivatives in excellent yields within a few
minutes (Table).
The experimental procedure for this reaction is remarkably simple and does not
require the use of vigorous conditions or inert atmospheres. When a solution of the salt
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Table. Synthesis of New Derivatives of 7-Pyrimidinylpyrimido[4,5-d]pyrimidinones 2a – 2e
2a)
R1
R2
X
Yieldb)
a
b
c
d
e
Me
Me
Ph
PhCH2
Me
Me
H
H
H
Me
O
O
O
O
S
95
90
80
88
95
a) The structures of the products 2a – 2e were fully characterized by NMR and mass spectroscopy.
b) Refers to isolated pure products.
1 in DMF was treated with Et3N, 7-pyrimidinylpyrimido[4,5-d]pyrimidinone deriva-
tives 2 were produced and simply isolated by addition of H2O to the mixture and
filtration of the product. The reactions proceeded rapidly under mild conditions and the
results were excellent in terms of yields and product purity. However, in the absence of
Et3N, the products were obtained in low yields after long reaction times. This indicates
that a basic catalyst is required for this reaction. The results are summarized in the
Table.
Except for 2a, which has also been synthesized independently via condensation
reaction of 6-amino-1,3-dimethyl-5-thioformyluracil derivatives with enamines [13], all
other products 2 are new and were characterized on the basis of their elemental
analyses and IR, 1H-NMR, 13C-NMR, and MS data. For example, the 1H-NMR
spectrum of 2d exhibited two sharp singlets at d(H) 4.38 and 5.21, readily recognized as
arising from two PhCH2 groups along with singlets at d(H) 8.05 and 8.79 for the uracil
and pyrimidopyrimidine ¼CH groups, respectively. Additional signals for ten aromatic
H-atoms are located as mutiplets in the range of d(H) 7.25 – 7.33, and two NH groups
1
resonated at d(H) 10.78 and 11.66. The H-decoupled 13C-NMR spectrum of 2d
showed 20 distinct resonances in agreement with the proposed structure. The signals at
d(C) 43.0 and 44.0 ppm correspond to the benzylic CH2 groups. The mass spectrum of
2d revealed a strong molecular ion peak at m/z 454, which confirmed the proposed
molecular formula for this compound.
A reasonable mechanism for the formation of the product 2 is outlined in the
Scheme. The reaction occurs via an initial formation of the spiro[pyrimidine-4,2’-
pyrimido[4,5-d]pyrimidine] derivative 3, via cyclocondensation of 1 as shown in the
Scheme. The intermediate 3 can take a H-atom to form 3’, which suffers a
rearrangement together with elimination of dimethylammonium chloride to give the
5,6-dihydro-7-pyrimidinylpyrimido[4,5-d]pyrimidine 4. The latter then undergoes
subsequent Me2NH elimination to afford the fully aromatized product 2. Probably,
the most important role of Et3N is the deprotonation of 1 to form the relatively

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electron-rich species 1’, which undergoes a faster cyclodimerization reaction with 1,
compared with the same dimerization reaction which slowly takes place in the absence
of Et3N.
Scheme. Proposed Mechanism for the Base-Promoted Synthesis of 7-Pyrimidinylpyrimido[4,5-d]pyr-
imidinones 2
In conclusion, our results demonstrate a novel, simple, and efficient synthesis of
new 7-pyrimidinylpyrimido[4,5-d]pyrimidinone derivatives of potential biological
significance in excellent yields.
Experimental Part
General. M.p.: Electrothermal 9100 apparatus; uncorrected. IR Spectra: Shimadzu IR-470
1
spectrophotometer. H- and 13C-NMR spectra: Bruker 500 DRX AVANCE at 500 and 125 MHz, resp.;
d in ppm. EI-MS: Shimadzu QP 1100EX mass spectrometer operating at an ionization potential of 14 eV.
Elemental analyses (CHN) were performed using a Heraeus CHN-O-Rapid analyzer.
Compounds 1a – 1e were synthesized based on a published procedure [9a][11] and characterized by
their 1H-NMR spectra. Other chemicals were of commercial grade and used without further purification.
7-Pyrimidinylpyrimido[4,5-d]pyrimidinones. General Procedure. A mixture of 5-[(dimethylamino)-
methylidene]-6-imino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione hydrochloride (1a, 0.247 g, 1 mmol) and
Et3N (0.140 ml, 1 mmol) in DMF (5 ml) was stirred at r.t. for 30 min. Then, H2O (20 ml) was added, the
mixture was filtered, and the obtained precipitate was washed with hot H2O (3 ꢀ 10 ml) to give the pure
1,3-dimethyl-7-(1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)pyrimido[4,5-d]pyrimidine-
2,4(1H,3H)-dione (2a) in 95% yield. All products were sufficiently pure for IR, NMR, and MS analysis.
In the cases that more pure product was necessary (i.e., CHN analysis) it could be recrystallized from a
DMSO/H2O (70 :30) mixture.

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1,3-Dimethyl-7-(1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)pyrimido[4,5-d]pyrimidine-
2,4(1H,3H)-dione (2a). Yield: 314 mg (95%). White powder. M.p. 3108 [13]. IR (KBr): 1726, 1656.
1H-NMR ((D6)DMSO): 3.29 (s, Me); 3.34 (s, Me); 3.52 (s, Me); 3.63 (s, Me); 8.50 (s, ¼CH); 8.75 (s,
¼CH). 13C-NMR ((D6)DMSO): 28.7; 28.8; 29.7; 38.4; 106.0; 110.5; 149.1; 151.5; 156.7; 158.6; 160.2;
160.5; 165.0; 168.1.
1-Methyl-7-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxopyrimidin-5-yl)pyrimido[4,5-d]pyrimidine-
2,4(1H,3H)-dione (2b). Yield: 272 mg (90%). White powder. M.p. > 3158 (dec.). IR (KBr): 3309, 1705,
1
1651, 1581. H-NMR ((D6)DMSO): 3.30 (s, Me); 3.34 (s, Me); 8.20 (s, ¼CH); 8.75 (s, ¼CH); 10.79 (s,
NH); 11.51 (br. s, NH). Because of low solubility in suitable NMR solvents, the 13C-NMR spectra were
not recorded. MS: 302 (50, Mþ), 287 (40), 247 (100). Anal. calc. for C12H10N6O4 (302.25): C 47.69, H 3.33,
N 27.81; found: C 47.77, H 3.20, N 27.75.
1-Phenyl-7-(1,2,3,4-tetrahydro-2,4-dioxo-1-phenylpyrimidin-5-yl)pyrimido[4,5-d]pyrimidine-
2,4(1H,3H)-dione (2c). Yield: 341 mg (80%). White powder. M.p. > 3158. IR (KBr): 3100, 3066, 1701,
1
1651, 1581. H-NMR ((D6)DMSO): 7.29 – 7.44 (m, 10 arom. H); 7.99 (s, ¼CH); 8.85 (s, ¼CH); 9.04 (s,
NH); 10.79 (s, NH). 13C-NMR ((D6)DMSO): 107.7; 111.9; 120.1; 127.2; 128.8; 129.4; 129.8; 130.0; 130.1;
138.9; 139.5; 150.5; 151.9; 157.6; 158.8; 160.8; 161.0; 164.0. MS: 426 (25, Mþ), 336 (60), 309 (100). Anal.
calc. for C22H14N6O4 (426.39): C 61.97, H 3.31, N 19.71; found: C 61.92, H 3.39, N 19.50.
1-Benzyl-7-(1-benzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)pyrimido[4,5-d]pyrimidine-
2,4(1H,3H)-dione (2d). Yield: 400 mg (88%).White powder. M.p. 227 – 2288. IR (KBr): 3400, 3250, 1710,
1
1650, 1580. H-NMR ((D6)DMSO): 4.38 (s, CH2); 5.21 (s, CH2); 7.25 – 7.33 (m, 10 arom. C); 8.05 (s,
¼CH); 8.79 (s, ¼CH); 10.78 (s, NH); 11.66 (s, NH). 13C-NMR (CDCl3): 43.0; 44.0; 101.1; 102.8; 127.3;
127.6; 128.01; 128.8; 137.4; 137.5; 139.8; 151.4; 151.5; 154.2; 155.1; 156.9; 156.7; 160.8; 168.3; 168.8. MS:
454 (85, Mþ), 91 (100). Anal. calc. for C24H18N6O4 (454.44): C 63.43, H 3.99, N 18.49; found: C 63.40, H
3.80, N 18.56.
2,3-Dihydro-1,3-dimethyl-7-(1,2,3,4-tetrahydro-1,3-dimethyl-4-oxo-2-thioxopyrimidin-5-yl)-2-thioxo-
pyrimido[4,5-d]pyrimidin-4(1H)-one (2e). Yield: 318 mg (95%). White powder. M.p. 3128. IR (KBr):
1705, 1651, 1581, 1554. 1H-NMR (CDCl3): 3.65 (s, Me); 3.66 (s, Me); 3.82 (s, Me); 4.01 (s, Me), 9.01 (s,
¼CH), 9.02 (s, ¼CH). Because of low solubility in suitable NMR solvents, the 13C-NMR spectra were
not recorded. MS: 362 (100, Mþ), 347 (65), 318 (85), 288 (75). Anal. calc. for: C14H14N6O2S2 (362.43): C
46.40, H 3.89, N 23.19; found: C 46.54, H 3.95, N 23.03.
The authors thank the Research Council of Persian Gulf University of Bushehr for financial support
of this work. We would like also to thank the referee and Dr. H. Eslami for their helpful comments.
REFERENCES
[1] N. J. Curtin, H. C. Barlow, K. J. Bowman, A. H. Calvert, R. Davison, B. T. Golding, B. Huang, P. J.
Loughlin, D. R. Newell, P. G. Smith, R. J. Griffin, J. Med. Chem. 2004, 47, 4905; T. J. Delia, M.
Baumann, A. Bunker, Heterocycles 1993, 35, 1397.
[2] J. P. de la Cruz, T. Carrasco, G. Ortega, F. Sanchez de la Cuesta, Lipids 1992, 27, 192.
[3] Y. S. Sanghvi, S. B. Larson, S. S. Matsumoto, L. D. Nord, D. F. Smee, R. C. Willis, T. L. Avery, R. K.
Robins, G. R. Revankar, J. Med. Chem. 1989, 32, 629.
[4] G. W. Rewcastle, A. J. Bridges, D. W. Fry, J. R. Rubin, W. A. Denny, J. Med. Chem. 1997, 40, 1820.
[5] D. W. Fry, M. A. Becker, R. L. Switzer, Mol. Pharmacol. 1995, 47, 810.
[6] M. G. Gebauer, C. McKinlay, J. E. Gready, Eur. J. Med. Chem. 2003, 38, 719.
[7] ꢂMartindale: The Extra Pharmacopoeiaꢃ, 28th edn., Ed. J. E. F. Reynolds, Pharmaceutical Press,
London, 1982, p. 1618.
[8] ꢂMartindale: The Extra Pharmacopoeiaꢃ, 28th edn., Ed. J. E. F. Reynolds, Pharmaceutical Press,
London, 1982, p. 1730.
[9] a) K. Hirota, Y. Kitade, H. Sajiki, Y. Maki, Synthesis 1984, 589; b) K. Hirota, Y. Kitade, H. Sajiki,
Y. Kitade, Y. Maki, J. Chem. Soc., Perkin Trans. 1 1990, 123.
[10] S. K. Srivastava, W. Haq, P. M. S. Chauhan, Bioorg. Med. Chem. Lett. 1999, 9, 965.
[11] K. Hirota, Y. Kitade, S. Senda, J. Heterocycl. Chem. 1985, 22, 345.

Helvetica Chimica Acta – Vol. 93 (2010)
157
[12] J. Azizian, M. R. Mohammadizadeh, A. A. Mohammadi, A. R. Karimi, F. Teimouri, Heteroatom
Chem. 2007, 18, 16; J. Azizian, M. R. Mohammadizadeh, F. Teimouri, A. A. Mohammadi, A. R.
Karimi, Synth. Commun. 2006, 36, 3631.
[13] K. Hirota, K. Kubo, H. Sajiki, Y. Kitade, M. Sako, Y. Maki, J. Org. Chem. 1997, 62, 2999.
Received May 17, 2009