Efficient one-pot synthesis of substituted pyrido[2,3-d]pyrimidines from vinamidinium and chloropropeniminium salts

Article abstract of DOI:10.1080/00397911.2010.545163

A novel and efficient one-pot preparation of 6-substituted pyrido-[2,3-d]pyrimidines by cyclocondensation of 6-amino-1,3-dimethyluracil with symmetrical vinamidinium salts under basic conditions has been developed. Regioselectivity was observed with an unsymmetrical chloropropeniminium salt. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.545163

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Efficient One-Pot Synthesis
of Substituted Pyrido[2,3-
d]pyrimidines from Vinamidinium and
Chloropropeniminium Salts
Mohamed Adnen Hadj Ayed a , Thouraya Gmiza a , Jamel Eddine
Khiari b & Béchir Ben Hassine a
a University of Monastir, Laboratoire de Synthèse Organique
Asymétrique et Catalyse Homogène (01UR1201), Faculté des
Sciences de Monastir, Tunisia
b University of Carthage, Laboratoire de Chimie Organique et
Analytique, Institut Supérieur de l'Education et de la Formation
Continue, Bardo, Tunisia
Accepted author version posted online: 17 Nov 2011.Published
online: 27 Feb 2012.
To cite this article: Mohamed Adnen Hadj Ayed , Thouraya Gmiza , Jamel Eddine Khiari & Bchir
Ben Hassine (2012) Efficient One-Pot Synthesis of Substituted Pyrido[2,3-d]pyrimidines from
Vinamidinium and Chloropropeniminium Salts, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:12, 1824-1831, DOI:
10.1080/00397911.2010.545163
To link to this article: http://dx.doi.org/10.1080/00397911.2010.545163
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Synthetic Communications1, 42: 1824–1831, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.545163
EFFICIENT ONE-POT SYNTHESIS OF SUBSTITUTED
PYRIDO[2,3-d]PYRIMIDINES FROM VINAMIDINIUM
AND CHLOROPROPENIMINIUM SALTS
Mohamed Adnen Hadj Ayed,1 Thouraya Gmiza,1
2
Jamel Eddine Khiari, and Bechir Ben Hassine
1
´
University of Monastir, Laboratoire de Synthese Organique Asymetrique et
1
`
Catalyse Homogene (01UR1201), Faculte des Sciences de Monastir, Tunisia
´
`
´
2University of Carthage, Laboratoire de Chimie Organique et Analytique,
´
Institut Superieur de l’Education et de la Formation Continue, Bardo, Tunisia
GRAPHICAL ABSTRACT
Abstract A novel and efficient one-pot preparation of 6-substituted pyrido-[2,3-d]pyrimi-
dines by cyclocondensation of 6-amino-1,3-dimethyluracil with symmetrical vinamidinium
salts under basic conditions has been developed. Regioselectivity was observed with an
unsymmetrical chloropropeniminium salt.
Keywords 6-Amino-uracil; chloropropeniminium salts; cyclocondensation; trisubstituted
pyrido[2,3-d]pyrimidines; vinamidinium salts
Received September 25, 2010.
´
Address correspondence to Bechir Ben Hassine, University of Monastir, Laboratoire de Synthese
Organique Asymetrique et Catalyse Homogene (01UR1201), Faculte des Sciences de Monastir 5019,
`
´
`
´
Tunisia. E-mail: bechirbenhassine@yahoo.fr
1824

TRISUBSTITUTED PYRIDO[2,3-d]PYRIMIDINES
1825
INTRODUCTION
The importance of uracil and its annulated derivatives is well recognized by
synthetic[1] and biological[2] chemists. 6-Amino-uracil derivatives represent a very
important class of functionalized uracils. Moreover, 6-amino-uracils have wide
applications as starting materials for the synthesis of a number of fused uracils of bio-
logical significance, such as pyrano-, pyrido-, pyrazolo-, pyrimido-, and pyridazino-
pyrimidines.[3,4]
Pyrido[2,3-d]pyrimidines constitute a broad class of annelated uracils that
received considerable attention in past years because of their wide range of biological
activities as antibacterial,[5] antitumor,[6] cardiotonic,[7] hepatoprotective, [8] and vaso-
dilator activities.[9] Additionally, some compounds of this class exhibit antialergic,[10]
antimalarial,[11] and anticonvulsive[12] activities. Therefore, much effort has been
directed toward the synthetic manipulation of uracil to prepare these complex mole-
cules. However, there still remain many challenges in the synthesis of these naturally
occurring complex molecules.[13–16]
In this article, we present an unprecedented synthetic approach for the prep-
aration of pyrido[2,3-d]pyrimidines using vinamidinium salts. In the past years, one
of the primary interests of our research group has been to investigate the preparation
and the application of vinamidinium salts[17–20] in organic synthetic chemistry. These
substances are very important synthons that have the potential to serve as three car-
bon building blocks for the synthesis of carbocyclic and heterocyclic compounds.[21]
Some fused heterocyclic systems such as carbazoles, benzodiazepines, and triazo-
lo[1,5-a]pyrimidines were also successfully obtained via cyclocondensation of vinami-
dinium salts with appropriate nucleophiles.[22–24] However, this methodology was not
yet investigated in pyrido-pyrimidines synthesis.
RESULTS AND DISCUSSION
Herein, we report the one-pot, two-component condensation of 6-amino-1,3-
dimethyluracil 1 and vinamidinium salts 2, leading to the desired 6-substituted
pyrido[2,3-d]pyrimidines 3 with good yields (Scheme 1).
The cyclocondensation of 6-amino-uracil 1 with symmetrical vinamidinium
perchlorates 2a–f has provided the desired 6-substituted pyrido[2,3-d]pyrimidines
Scheme 1. Synthesis of 6-substituted pyrido[2,3-d]pyrimidines 3a–f.

1826
M. A. H. AYED ET AL.
Table 1. Synthesis of 6-substituted pyrido[2,3-d]pyrimidines 3a–f
Compound
R
Yielda (%)
3a
3b
3c
3d
3e
3f
Ph
92
96
90
73
78
89
4-MeOPh
4-MePh
PhSO2
4-MePhSO2
CHO
aIsolated yield.
3a–f in good to excellent yields (Table 1). The reactions were conducted by heating
the reagents in dimethylformamide (DMF) at 100 ꢀC for 12 h in the presence of
sodium hydride.
Additionally, as shown in Table 1, the phenylsulfonyl and 4-methylphenylsulfo-
nyl at the C6-substituent (3d and 3e) affected the cyclocondensation reaction. This
may be the result of the ‘‘push–pull’’ relationship between the strong electron-
withdrawing sulfonyl group at the C2 position and the enamine group, in the corre-
sponding vinamidinium salts (2d and 2e), allowing the imino group to behave like
an isolated moiety. This behavior has been also observed in a previous work.[20]
It has already been mentioned that chloropropeniminium salts, which are
precursors to unsymmetrical vinamidinium salts, function also as useful three-carbon
synthons for the preparation of heterocyclic compounds.[25] Because there could be
two possible substituted pyrido[2,3-d]pyrimidine products, the question of regiochem-
istry needed to be addressed. The reaction of uracil 1 and chloropropeniminium salt 4
was performed under similar conditions to those reported previously. Both regioi-
somers were obtained in good yield, but the 5-substituted pyrido[2,3-d]pyrimidine
isomer 5 was preferred in a ratio of 5:2 (Scheme 2).
The structure of each isomer was determined by comparison of their proton–
proton coupling constants with pyridine system and known samples. As an example,
the 7-substituted isomer 6 is known[26] and has a coupling constant of 8 Hz, which is
consistent with the minor isomer having a coupling constant of 8.1 Hz. This is also in
accordance with the coupling constant for pyridine hydrogens at the 3 and 4 positions
ranging from 7.2 to 8.5 Hz. Moreover, the coupling constant of the major isomer 5 is
4.8 Hz, which is consistent with pyridine hydrogens at 2 and 3 positions. The proton–
proton coupling constants of compounds 3a–f, 5 and 6 are listed in Table 2.
Scheme 2. Regioselective condensation of 6-amino-1,3-dimethyluracil with chloropropeniminium salt 4.

TRISUBSTITUTED PYRIDO[2,3-d]PYRIMIDINES
1827
Table 2. Proton–proton coupling constants of products 3a–f, 5, and 6
Compound
X
Y
Z
Solvent
Jab (Hz)
Jbc (Hz)
Jac (Hz)
3a
3b
3c
3d
3e
3f
5
Ha
Ha
Ha
Ha
Ha
Ha
Ha
Ph
Ph
Hc
Hc
Hc
Hc
Hc
Hc
Ph
Hc
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
—
—
—
—
—
—
4.8
—
—
—
—
—
—
—
—
8.1
2.3
2.4
2.0
2.2
2.3
2.4
—
4-MeOPh
4-MePh
PhSO2
4-MePhSO2
CHO
Hb
Hb
6
—
CONCLUSION
In conclusion, we have described a novel, efficient, simple, and regioselective
method for the preparation of pyrido[2,3-d]pyrimidine derivatives in reasonably
good yield, via cyclocondensation reaction of 6-amino-1,3-dimethyluracil with sym-
metrical vinamidinium salts and an unsymmetrical chloropropeniminium salt.
EXPERIMENTAL
Pyrido[2,3-d]pyrimidines 3a–e
General procedure. A mixture of 6-amino-1,3-dimethyluracil (1 mmol),
vinamidinum salt (1 mmol), and sodium hydride (2.2 mmol) in DMF (5 mL) was
stirred at 100 ꢀC for 12 h (the progress of reaction was monitored by thin-layer
chromatography, TLC). After cooling to room temperature, the reaction mixture
was quenched by saturated NH4Cl solution and extracted three times with CHCl3.
The combined organic layers were washed two times with water, dried over Na2SO4,
filtered, and concentrated to give the crude product, which was purified by column
chromatography on silica gel (hexane=EtOAc 8:2).
1,3-Dimethyl-6-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-2,4-
dione 3a. White solid: mp 135–137 ꢀC; 1H NMR (300 MHz, CDCl3) d: 3.56 (s, 3H),
3.75 (s, 3H), 6.90 (m, 3H), 7.43 (d, 2H, J ¼ 8.4 Hz), 8.50 (d, 1H, J ¼ 2.3 Hz), 8.81 (d, 1H,
J ¼ 2.3 Hz); 13C NMR (75 MHz, CDCl3) d: 28.4, 29.2, 118.4, 127.1, 128.6, 129.8, 131.3,
135.7, 142.3, 151.0, 152.5, 154.8, 162.6. Anal. calcd for C15H13N3O2: C, 67.41; H, 4.90;
N, 15.72%. Found: C, 67.36; H, 4.87; N, 15.68%. Mass m=z (EI, 30 eV): Mþ267.
1,3-Dimethyl-6-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyri-
1
midine-2,4-dione 3b. White solid: mp 163–165 ꢀC; H NMR (300 MHz, CDCl3)

1828
M. A. H. AYED ET AL.
d: 3.45 (s, 3H), 3.69 (s, 3H), 3.80 (s, 3H), 6.96 (d, 2H, J ¼ 8.7 Hz), 7.49 (d, 2H,
J ¼ 8.7 Hz), 8.53 (d, 1H, J ¼ 2.4 Hz), 8.79 (d, 1H, J ¼ 2.4 Hz); 13C NMR (75 MHz,
CDCl3) d: 28.9, 30.1, 55.8, 110.9, 115.2, 128.4, 128.9, 132.4, 135.1, 152.0, 152.4,
154.3, 160.4, 162.0. Anal. calcd for C16H15N3O3: C, 64.64; H, 5.09; N, 14.13%.
Found: C, 64.59; H, 5.06; N, 14.10%. Mass m=z (EI, 30 eV): Mþ297.
1,3-Dimethyl-6-(p-tolyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-2,4-
dione 3c. White solid: mp 148–150 ꢀC; 1H NMR (300 MHz, CDCl3) d: 2.32 (s, 3H),
3.71 (s, 3H), 3.78 (s, 3H), 7.11 (d, 2H, J ¼ 8.6 Hz), 7.56 (d, 2H, J ¼ 8.6 Hz), 8.44 (d,
1H, J ¼ 2.0 Hz), 8.75 (d, 1H, J ¼ 2.0 Hz); 13C NMR (75 MHz, CDCl3) d: 21.1, 27.8,
28.6, 120.5, 128.4, 129.2, 133.7, 135.4, 137.6, 140.9, 148.5, 153.3, 154.0, 164.6. Anal.
calcd. for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94%. Found: C, 68.26; H, 5.35; N,
14.90%. Mass m=z (EI, 30 eV): Mþ281.
1,3-Dimethyl-6-(phenylsulfonyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimid-
ine-2,4-dione 3d. White solid: mp 216–218 ꢀC; 1H NMR (300 MHz, CDCl3) d: 3.65
(s, 3H), 3.72 (s, 3H), 7.48 (m, 1H), 7.75 (m, 4H), 8.54 (d, 1H, J ¼ 2.2 Hz), 9.01 (d, 1H,
J ¼ 2.2 Hz); 13C NMR (75 MHz, CDCl3) d: 26.6, 28.3, 127.5, 129.8, 131.3, 132.4,
134.1, 142.7, 145.0, 147.2, 150.9, 154.8, 166.5. Anal. calcd. for C15H13N3O4S: C,
54.37; H, 3.95; N, 12.68%. Found: C, 54.34; H, 3.91; N, 12.62%. Mass m=z (EI,
30 eV): Mþ331.
1,3-Dimethyl-6-(p-tolylsulfonyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimid-
ine-2,4-dione 3e. White solid: mp 242–244 ꢀC; 1H NMR (300 MHz, CDCl3) d: 2.38
(s, 3H), 3.49 (s, 3H), 3.68 (s, 3H), 7.43 (d, 2H, J ¼ 8.2 Hz), 7.82 (d, 2H, J ¼ 8.2 Hz),
8.51 (d, 1H, J ¼ 2.3 Hz), 8.97 (d, 1H, J ¼ 2.3 Hz); 13C NMR (75 MHz, CDCl3) d:
20.7, 28.2, 30.5, 126.2, 129.6, 131.1, 133.5, 142.8, 144.0, 145.3, 148.8, 151.7, 155.3,
165.9. Anal. calcd. for C16H15N3O4S: C, 55.64; H, 4.38; N, 12.17%. Found: C,
55.60; H, 4.36; N, 12.13%. Mass m=z (EI, 30 eV): Mþ345.
1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-
carbaldehyde 3f
General procedure. A mixture of 6-amino-1,3-dimethyluracil (1 mmol),
vinamidinum salt 2f (1 mmol), and sodium hydride (2.2 mmol) in DMF (5 mL)
was stirred at 100 ꢀC for 12 h. After cooling to room temperature, H2O (20 mL)
and 1 N HCl (2 mL) were added, and the mixture was allowed to stir at room
temperature for 2 h, then neutralized with saturated aqueous NaHCO3 solution.
The aqueous mixture was extracted with four portions of ethyl acetate. The com-
bined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography on silica gel (hexane=EtOAc 8:2) to
give a white solid (mp 168–170 ꢀC).
Spectroscopic data. 1H NMR (300 MHz, CDCl3) d: 3.48 (s, 3H), 3.76 (s, 3H),
8.86 (d, 1H, J ¼ 2.4 Hz), 9.11 (d, 1H, J ¼ 2.4 Hz), 10.09 (s, 1H); 13C NMR (75 MHz,
CDCl3) d: 28.8, 30.2, 110.6, 127.3, 139.2, 151.1, 153.9, 155.5, 160.5, 188.7. Anal. calcd.
for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17%. Found: C, 54.74; H, 4.10; N, 19.15%.
Mass m=z (EI, 30 eV): Mþ219.

TRISUBSTITUTED PYRIDO[2,3-d]PYRIMIDINES
1829
6-Amino-1,3-dimethyluracil with Chloropropeniminium Salt 4
General procedure. Were added to a solution of 6-amino-1,3-dimethyluracil
(1 mmol) in DMF (5 mL), sodium hydride (2.2 mmol) and chloropropeniminium
salt 4 (1 mmol). The mixture was stirred at 100 ꢀC for 16 h. After cooling to room
temperature, the reaction mixture was quenched by saturated NH4Cl solution and
extracted several times with CHCl3. The combined organic layers were washed
two times with water, dried over Na2SO4, filtered, and concentrated to give the crude
mixture of 5 and 6 in a yield of 97%. The products were isolated by column chroma-
tography on silica gel (CH2Cl2).
1,3-Dimethyl-5-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-2,4-
1
dione 5. White solid: mp 168–170 ꢀC; H NMR (300 MHz, CDCl3) d: 3.38 (s, 3H),
3.78 (s, 3H), 7.02 (d, 1H, J ¼ 4.8 Hz), 7.27–7.32 (m, 2H), 7.43–7.46 (m, 3H), 8.61 (d,
1H, J ¼ 4.8 Hz); 13C NMR (75 MHz, CDCl3) d: 28.9, 30.6, 108.4, 122.4, 128.1,
128.3, 128.6, 139.5, 151.7, 152.3, 152.6, 154.9, 161.0. Anal. calcd. for C15H13N3O2:
C, 67.41; H, 4.90; N, 15.72%. Found: C, 67.38; H, 4.85; N, 15.70%. Mass m=z (EI,
30 eV): Mþ267.
1,3-Dimethyl-7-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-2,4-
1
dione 6. White solid: mp 184–186ꢀC; H NMR (300 MHz, CDCl3) d: 3.51 (s, 3H),
3.83 (s, 3H), 7.51–7.54 (m, 3H), 7.67 (d, 1H, J ¼ 8.1 Hz), 8.11-8.15 (m, 2H), 8.50 (d,
1H, J ¼ 8.1 Hz); 13C NMR (75MHz, CDCl3) d: 28.5, 29.5, 109.1, 115.2, 127.6, 129.0,
130.7, 137.6, 138.4, 150.8, 151.7, 161.3, 161.4. Anal. calcd. for C15H13N3O2: C, 67.41;
H, 4.90; N, 15.72%. Found: C, 67.36; H, 4.87; N, 15.68%. Mass m=z (EI, 30eV): Mþ267.
ACKNOWLEDGMENT
´ ´
The authors thank the DGRS (Direction Generale de la Recherche Scientifique)
from the Tunisian Ministry of Higher Education and Research for the financial
support of this research.
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