New routes to pyridino[2,3-d]pyrimidin-4-one and pyridino-[2,3-d] triazolino[4,5-a]pyrimidin-5-one derivatives

Article abstract of DOI:10.3390/80300333

2-Thioxopyrimidinyl-5-(N,N-dimethylamino)formamidine (5) and 1,3-diphenyltriazolo[3,4-d]pyrimidinyl-N,N-dimethylformamidine (14) were prepared by condensation of 6-amino-2-thioxo-1,3-dihydropyrimidin-4-one (2) and 7-amino-1,3-diphenyl-1,2,4-triazolo[4,3-a]pyrimidin-4-one (13) with dimethylformamide dimethyl-acetal (DMFDMA). Compound 5 reacts with acetophenone and 2-acetylthiophene to give the 2-thioxo-1,3-dihydropyridino[2,3-d]pyrimidin- 4-ones 3a and 3b, respectively. Compounds 3a,b react with hydrazonoyl halides 6,7 to give pyridino[2,3-d]triazolo[4,5-a]pyrimidin-4-ones 11a-d and not the isomeric structures 12a-d. Formamidines of type 14 react with ethyl cyanoacetate, malononitrile and benzoyl acetonitrile to give the 1,3-diphenyl-3a-hydropyridino[2,3-d]1,2,4-triazolo[4,5-a]pyrimidin-4-one derivatives 15a,b and 18, respectively. The structures of the newly synthesized compounds are established on the basis of chemical and spectroscopic evidences as well as their synthesis by alternative methods.

Full text of DOI:10.3390/80300333

Molecules 2003, 8, 333-341
molecules
ISSN 1420-3049
http://www.mdpi.org/
New Routes to Pyridino[2,3-d]pyrimidin-4-one and Pyridino-
[2,3-d]triazolino[4,5-a]pyrimidin-5-one Derivatives
*
Hamdi M. Hassneen and Tayseer A. Abdallah
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt.
* Author to whom correspondence should be addressed; e-mail: Hamdi251@hotmail.com
Received: 2 December 2002; in revised form: 13 January 2003 / Accepted: 9 Jan 2003 / Published 31
March 2003
Abstract: 2-Thioxopyrimidinyl-5-(N,N-dimethylamino)formamidine (5) and 1,3-
diphenyltriazolo[3,4-d]pyrimidinyl-N,N-dimethylformamidine (14) were prepared by
condensation of 6-amino-2-thioxo-1,3-dihydropyrimidin-4-one (2) and 7-amino-1,3-
diphenyl-1,2,4-triazolo[4,3-a]pyrimidin-4-one (13) with dimethylformamide dimethyl-
acetal (DMFDMA). Compound 5 reacts with acetophenone and 2-acetylthiophene to give
the 2-thioxo-1,3-dihydropyridino[2,3-d]pyrimidin-4-ones 3a and 3b, respectively.
Compounds 3a,b react with hydrazonoyl halides 6,7 to give pyridino[2,3-d]triazolo[4,5-
a]pyrimidin-4-ones 11a-d and not the isomeric structures 12a-d. Formamidines of type
14 react with ethyl cyanoacetate, malononitrile and benzoyl acetonitrile to give the 1,3-
diphenyl-3a-hydropyridino[2,3-d]1,2,4-triazolo[4,5-a]pyrimidin-4-one derivatives 15a,b
and 18, respectively. The structures of the newly synthesized compounds are established
on the basis of chemical and spectroscopic evidences as well as their synthesis by
alternative methods.
Keywords: Enaminones, Pyridino[2,3-d]pyrimidin-4-one, Formamidine, Dimethyl-
formamide dimethylacetal, Hydrazonoyl halides.

Molecules 2003, 8
334
Introduction
Azoloazine derivatives form a very interesting class of compounds because of their significant
biological and pharmaceutical activities and their chemistry is consequently now receiving
considerable attention [1-4]. As part of our studies aimed at developing simple and efficient syntheses
of polyfunctional heteroaromatics from readily obtained starting materials [5-10]. We now wish to
report the reaction of pyridino[2,3-d]pyrimidines 3 with hydrazonoyl halides 6,7 to give novel
functionalized heterocycles having pyridine rings condensed with other important heterocycles such as
pyrimidines and triazolopyrimidines. In many cases, however, the exact structure of the reaction
products could not be established unequivocally, because several close similar isomeric products could
conceivably be formed. In this paper, we report the synthesis of heterocyclic compounds 3, 5, 11, 14,
15 and 18 and the confirmation of the structures of the resulting products by spectroscopic data as well
as their synthesis by alternative methods. The newly synthesized compounds appear to be promising
substrates for further chemical transformations as well as biological activity evaluations.
Results and Discussion
Enaminones 1a,b were prepared by reaction of dimethylformamide dimethylacetal (DMFDMA)
with acetophenone and 2-acetylthiophene in refluxing dioxane (Scheme 1), as previously described
[11].
Scheme 1
+
DMFDMA
RCOCH3
O
CH3
HN
RCO-CH=CH-N
+
S
NH2
CH3
N
H
1a,b
2
O
R
N
O
HN
HN
S
S
R
N
H
N
N
H
4a,b
3a,b
O
RCO-CH3
H3C
N
CH3
HN
S
DMFDMA
N
2
N
H
5
a, R = Ph; b, R = 2-thienyl

Molecules 2003, 8
335
Enaminones 1a,b condensed readily with 6-amino-2-thioxopyrimidin-4(3H)one (2) [12] in boiling
acetic acid to give either pyridino[2,3-d]pyrimidine derivatives 3a,b or the isomeric structures 4a,b in
1
high yields (Scheme 1). The H-NMR spectra of the resulting products displayed four signals readily
recognizable as arising from two CH (δ 7.91, 8.63) and two NH groups (δ 12.62, 13.17), along with the
multiplet in the aromatic region. Their IR spectra revealed the absence of the bands corresponding to
the amino group. Elemental analysis and mass spectra agreed equally with both structures 3 and 4.
These data alone cannot determine the exact structures of the resulting products therefore conclusive
evidence for the structures was obtained by synthesis of 3a,b via reactions of N,N-
dimethylaminoformamidine 5 with acetophenone and 2-acetylthiophene, respectively (Scheme 1).
Scheme 2
R
N
O
O
Cl
R
N
HN
HN
R'
R-C=N-NHPh
+
N
S
N
H
S
N
H
NHPh
6, R' = Ph
7, R' = COOEt
3
8
R
N
O
R
N
O
SH
N
-H2S
R'
HN
N
HN
S
N
N
H
R'
N
N
Ph
Ph
10
9
R
N
O
R'
R
N
O
N
N
N
or
N
Ph
N
N
N
N
Ph
R'
11
12
RCO-CH3
+ 6
2
O
Ph
O
N
Ph
N
H3C
CH3
N
N
N
DMFDMA
N
N
N
NH2
N
N
Ph
Ph
14
13
11a, R = R' - Ph
11c, R = Ph, R' = COOEt
11b, R = 2-thienyl, R' = Ph
11d, R = 2-thienyl, R' = COOEt

Molecules 2003, 8
336
The required intermediate 5 was obtained by condensation of 2 with DMFDMA in boiling dioxane
1
(Scheme 1). The H-NMR spectrum of 5 displayed six singlets recognizable as arising from the two
methyls (δ 2.99, 3.11), the CH=N- (δ 5.24), the CH of the pyrimidine ring at δ 8.14 and two NH
groups at δ 11.61 and 11.79 ppm. Structure 5 was further confirmed by its mass spectrum, which gave
an intense molecular ion peak at m/z 198.
Treatment of 3a,b with hydrazonoyl chlorides 6 and 7 in boiling chloroform in the presence of
triethylamine led to the formation of either 11a-d or the isomeric structures 12a-d (Scheme 2).
Structures 11a-d could be established for these products based on their alternate syntheses. For
example, formamidine 14 reacts with acetophenone in boiling glacial acetic acid to give a product
which was found to be identical in all respects (mp, mixed mp, IR, 1H-NMR) with structure 11a. The
1
structure assignments of 11a-d were also supported by spectroscopic data. For example, the H-NMR
spectra revealed the absence of the signals corresponding to the N,N-dimethylaminoformamidine
group, instead it showed two doublets at 7.91, 8.63 corresponding to protons at positions 7,8 in the
pyridine ring. Compound 14 was obtained by condensation of 7-amino-1,3-diphenyl-1,2,4-triazolo[4,3-
a]pyrimidin-5-one (13), prepared via dipolar cycloaddition of 2 with hydrazonoyl halide 6 in
chloroform in the presence of triethylamine, with DMFDMA (Scheme 2).
1
The structure of 14 was confirmed by elemental analysis and spectroscopic data (IR, H-NMR,
13C-NMR, mass spectra). For example, the mass spectrum gave an intense molecular peak at m/z 358.
The 1H-NMR spectrum showed the characteristic signals of N,N-dimethylformamidine group at δ 3.14
(s, 3H), 3.15 (s, 3H), 5.66 (s, 1H) in addition to a multiplet in the aromatic region. The 13C-NMR
spectra of 14 revealed two sp3 carbons, which can be assigned to the two methyl groups at δ 35.61, and
41.80 and a signal at δ 91.80 assigned to the N=CH, in addition to the carbon atoms in the aromatic
system. The versatile compound 14 can also allow the synthesis of condensed pyridino[2,3-
d]triazolo[4,5-a]pyrimidin-4-ones. To demonstrate its potential, 14 was reacted with ethyl cyanoacetate
and malononitrile in boiling glacial acetic acid to yield products of condensation 15a,b by elimination
of dimethylamine and then cyclization (Scheme 3).
Scheme 3
Ph
Y
N
O
N
X
X
Y
N
N(CH3)2
13
N
N
Ph
+
17a,b
15a,b
CNCH2X
14
+
X;
COOEt; NH2
CN; NH2
Y
a
b

Molecules 2003, 8
337
The mass spectra of the products showed intense peaks at m/z 426 and 379 assignable to the
1
molecular ion peaks of the compounds 15a and 15b, respectively. The H-NMR spectrum of 15a
indicated the disappearance of the protons from the N,N-dimethylformamidine group, and instead
showed a triplet at δ 1.29 (3H) and a quartet at 4.20 ppm (2H), assigned to ethoxycarbonyl group. The
structures of the products were also confirmed by their alternative synthesis via reaction of 13 with
enaminones 17a and 17b, respectively. Despite the fact that heterocyclic amines are well known to
exist preferentially in the amino rather than the imine form, compounds 15a and 15b exist mainly, at
least in DMSO solution, in the imine form (Scheme 4). This was confirmed by their 1H-NMR spectra
which revealed two signals for two NH groups at about δ 5.68 and 11.73 ppm (1H each) which
disappeared on shaking with deuterium oxide.
Scheme 4
O
N
NH2
N
O
N
NH
Ph
N
Ph
N
R
R
N
N
N
N
N
H
Ph
Ph
R = CN; COOET
Compound 14 also reacts under similar conditions with benzoylacetonitrile to give the
condensation product 18 by elimination of dimethylamine and water (Scheme 5). The mass spectrum
of the product gave an intense peak at m/z 440 corresponding to the expected molecular ion peak of
18. The structure was also confirmed by its alternative synthesis from 19 and 13 (Scheme 5).
Scheme 5
Ph
N
O
Ph
CN
NC
N
N(CH3)2
13
N
+
PhCO
N
N
19
Ph
18
CNCH2COPh
14
+
.
In conclusion, the have reported the preparation of readily obtainable formamidines that are
valuable precursors for the synthesis of a variety of heteroaromatics of potential interest for biological
evaluation.

Molecules 2003, 8
Experimental
General
338
All melting points are uncorrected. IR spectra (KBr pellets) were recorded with a Pye Unicam SP-
3000 IR spectrophotometer. NMR spectra were determined on a Varian Gemini 200 spectrometer
using DMSO-d6 as solvent and TMS as internal standard; chemical shifts are reported in δ units (ppm).
Mass spectra were measured at 70eV using a Shimadzu GCMS-QP 1000 EX instrument.
Microanalyses were performed on a Perkin-Elemer 2400 CHN Elemental Analyzer at the University of
Cairo Microanalytical Center. Compounds 6 [13], 7 [14], 13 [15] were prepared following published
procedures. Unless stated otherwise standard workups consisted of allowing the reaction mixtures to
cool, collecting the precipitates formed and recrystallizing them from dimethylformamide (DMF). The
analytical and spectral data of compounds prepared is summarized in Tables 1 and 2.
General Procedures for the Synthesis of 2-Thioxo-1,3-dihydropyridino[2,3-d]pyrimidin-4-ones (3a,b).
Method A. Enaminones 1a,b (0.001 mol) were refluxed with 2 (1.43 g, 0.001 mol) in glacial acetic acid
(20 mL) for 2h to give compounds 3a,b after the standard workup.
Method B. Formamidine 5 (1.98 g, 0.001 mol) was refluxed with 2-acetylthiophene (1.26 g, 0.001 mol)
or acetophenone (1.20 g, 0.001 mol) in glacial acetic acid (10 mL) for 2h. The products were identical
in all respects (mp, mixed mp, IR) to those prepared by method A.
Synthesis of 2-thioxopyrimidinyl-5-(N,N-dimethylamino)formamidine (5)
A mixture of 2 (1.47 g, 0.001 mol) and DMFDMA (1.19 g, 0.012 mol) was refluxed in dioxane (25
mL) for 3h. The reaction mixture was then cooled to room temperature and the product was collected
and crystallized from DMSO.
General Procedure for the Synthesis of Pyridino[2,3-d]1,2,4-triazolo[4,3-a]pyrimidin-4-ones (11a-d)
Method A: To a mixture of compound 3 (0.005 mol) and hydrazonoyl halides 6,7 (0.005 mol) in
chloroform (40 mL) triethylamine (0.7 mL, 0.005 mol) was added. The reaction mixture was refluxed
until the hydrazonoyl halides disappeared (4-6 h) as indicated by TLC analysis. The solvent was
evaporated under reduced pressure and the residue was treated with methanol (10 mL).
Method B: A mixture of formamidine 14 (1.79 g, 0.005 mol) and 2-acetylthiophene (1.26 g, 0.005 mol)
or acetophenone (1.2 g, 0.005 mol) was refluxed in acetic acid for 3 h to give 11a,b, identical in all
respects (mp, mixed mp, IR) to that prepared by Method A.

Molecules 2003, 8
339
Synthesis of 1,3-diphenyltriazolo[3,4-d]pyrimidinyl-N,N-dimethylformamidine (14)
7-Amino-1,3-diphenyl-1,2,4-triazolo[4,3-a]pyrimidine-5-one (13, 1.51 g, 0.005 mol) was refluxed
in DMFDMA (10 mL) for 3h.
General Procedure for the Synthesis of Pyridino[2,3-d]triazolo[4,5-a]pyrimidin-5-ones (15,18).
A solution of 14 (1.79 g, 0.005 mol) and a nitrile compound (0.005 mol) was refluxed in acetic acid
(10 mL) for 2h.
Table 1. Analytical data of the synthesized compounds
Compd.
no.
Yield m.p. oC
Mol. formula
(Mol. Wt)
C13H9N3OS
255.10
C11H7N3OS2
261.08
C7H10N4OS
198.11
C26H17N5O
415.19
C24H15N5OS
421.17
C23H17N5O3
411.19
C21H15N5O3S
417.17
C20H18N6O
358.20
Analysis Calcd (Found)
Color
(%)
75
solvent
260-261
DMF
C
H
N
S
3a
yellowish
white
yellow
61.15 3.55 16.47
61.40 3.71 16.53
50.56 2.70 16.09
50.54 2.52 16.37
42.40 5.08 28.28
42.49 5.15 28.36
75.15 4.12 16.86
75.25 4.23 17.06
68.38 3.58 16.62
61.31 3.74 16.52
67.12 4.16 17.03
67.25 4.08 17.29
60.41 3.62 16.78
60.26 3.40 16.63
67.00 5.06 23.46
67.24 5.35 23.58
64.76 4.25 19.71
64.73 4.21 19.86
66.46 3.45 25.85
66.78 3.62 25.70
73.61 3.66 19.09
73.79 3.51 19.24
12.54
12.59
24.51
24.45
16.15
16.33
3b
5
80
85
78
80
76
75
90
75
80
82
254-255
DMF
339-341
DMSO
281-282
DMF
287-289
DMF
286-288
DMF
216-218
DMF
208-209
DMF
350-352
DMF
335-337
DMF
yellow
11A
11B
11C
11D
14
colorless
yellowish
white
yellow
7.59
7.36
yellow
colorless
yellow
7.67
7.82
15a
15b
18
C23H18N6O3
426.20
C21H13N7O
379.17
C27H16N6O
440.19
colorless
yellowish
white
327-328
DMF

Molecules 2003, 8
340
Table 2. Spectroscopic data of synthesized compounds
Compd.
no.
IR (ν/cm-1)
M+
1H-NMR (δ/ppm)
3a
1686 (CO), 3255
(NH)
255 7.56-7.59 (m, 3H, aromatic-H), 7.91 (d, 1H, pyridine),
8.18-8.22 (m, 2H, aromatic-H), 8.63 (d, 1H, pyridine),
12.62 (s, 1H, NH), 13.17 (s, 1H, NH).
3b
5
1680 (CO), 3343
(NH)
261 7.25-9.22 (m, 5H, aromatic-H), 12.86 (s, 1H, NH), 13.32
(s, 1H, NH).
1648 (CO), 3256
(NH)
198 2.99 (s, 3H, CH3); 3.11 (s, 3H, CH3), 5.24 (s, 1H,
N=CH), 8.14 (s, 1H, pyrimidine), 11.61 (s, 1H, NH),
11.79 (s, 1H, NH).
11a
11b
11c
1710 (CO)
1702 (CO)
415 7.88 (d, 1H, pyridine); 7.56-8.00 (m, 15H, aromatic-H);
8.63 (d, 1H, pyridine).
421 7.23-8.49 (m, 13H, aromatic-H); 7.91 (d, 1H, pyridine);
8.73 (d, 1H, pyridine).
1715 (CO) 1720 411 1.42 (t, J = 7Hz, 3H, CH3); 4.25 (q, J = 7Hz, 2H, CH2);
(ester CO)
7.21-8.24 (m, 10H, aromatic-H); 7.72 (d, 1H, pyridine),
8.50 (d, 1H, pyridine).
11d
14
1700(CO), 1715 417 1.41 (t, J = 7 Hz, 3H, CH3), 4.28 (q, J = 7 Hz, 2H, CH2),
(ester CO)
7.73 (d, 1H, pyridine-H), 5.45-8.11 (m, 8H, aromatic-H),
8.55 (d, 1H, pyridine-H).
1702 (CO)
358 3.14 (s, 3H, CH3), 3.15 (s, 3H, CH3), 5.66 (s, 1H, N=CH),
7.21-8.40 (m, 10H, aromatic H), 8.59 (s, 1H, pyrimidine
H-6).
15a
15b
1690 (CO), 1715
(ester CO)
426 1.29 (t, J=7Hz, 3H, CH3), 4.20 (q, J= 7Hz, 2H, CH2),
5.85 (s, 1H, NH), 7.46-8.10 (m, 10H, aromatic-H), 8.92
(s, 1H, pyridine), 11.78 (s, 1H, NH).
1720 (CO), 2229 337 5.68 (s, 1H, NH), 7.47-8.17 (m, 10H, aromatic-H), 8.66
(CN), 3193, 3400
(2 NH)
(s, 1H, pyridine), 11.73 (s, 1H, NH).
18
1728 (CO), 2221 440 7.48-8.29 (m, 15H, aromatic-H); 9.15 (s, 1H, pyridine)
(CN)

Molecules 2003, 8
341
13C-NMR data (δ, DMSO-d6): (5): 167.27 (CO), 160.94 (CS), 163.35, 158.31, 96.48 (N=CH), 36.17
(CH3), 14.48 (CH3); (14): 168.37 (CO), 158.82, 157.44, 148.89, 145.72, 137.78, 131.17, 129.89,
129.65, 128.23, 127.40, 127.00, 121.44, 91.80 (N=CH), 41.80 (CH3), 35.61 (CH3); (15a): 165.44 (CO),
158.33(CO), 158.58, 151.60, 149.89, 146.59, 137.91, 133.32, 131.03, 129.44, 129.33, 127.74, 122.89,
116.62, 87.69, 80.78, 77.22, 62.79 (CH2), 15.95(CH3)
References
1.
Elnagdi, M. H.; Al-Awdi, N.; Erian, A.W. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V. eds, Pergamon Press: London, 1996; Vol 4, p. 431
Desenko, S. V.; Komykhov, S. A.; Orlov, V. D.; Meier, H. J Hetrocyclic Chem. 1998, 35, 989.
Quiroga, J.; Insuasty, B.; Graz S.; Hernandez, P.; Bolafios, A.; Moreno, R.; Hormoza, A.; de
Almeidas, H. J Heterocyclic Chem, 1998, 35, 1333.
2.
3.
4.
5.
Greenhill, J. V. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W. eds.
Pergamon Press: London, 1984; Vol 5, p. 305.
Abdelhadi, H. A.; Elwan, N. M.; Abdallah, T. A.; Hassaneen, H. M. Tetrahedron, 1996, 52,
3451.
6.
7.
8.
9.
Hassaneen, H. M.; Abdelhadi, H. A.; Abdallah, T. A. Tetrahedron, 2001, 57, 10133.
Abdelhadi, H. A.; Abdallah, T. A.; Hassaneen, H. M. Heterocycles 1995, 41, 1999.
Abdallah, T. A.; Abdelhadi, H. A.; Ibrahim, A. A.; Hassaneen, H. M. Synth Comm 2002, 32, 581.
Awad, E. M.; Elwan, N. M.; Hassaneen, H. M.; Linden, A.; Heimgartner, H. Helv Chim Acta
2002, 85, 320.
10. Awad, E. M.; Elwan, N. M.; Hassaneen, H. M.; Linden, A.; Heimgartner, H. Helv Chim Acta
2001, 84, 1172.
11. Al–Omran, F.; Abdelkhalik, M. M.; Elnagdi, M. H. Heteroatom Chem 1995, 6, 545.
12. Hübsch, W.; Pfleiderer, W. Helv Chim Acta 1988, 71, 1379.
13. Wolkof, P. Can. J.Chem. 1975, 53, 1333.
14. Eweiss, N. F.; Abdelhamid, A. O. J.Heterocycl Chem. 1980, 17, 1713.
15. Mosselhi, A. N. Monatsh Chem. 2002, 133, 1297
Sample availability: Samples not available.
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