New aspects on the selective synthesis of 7-arylpyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1016/S0040-4020(02)00433-7

Pyrido[2,3-d]pyrimidines have been synthesized via a selective cyclocondensation reaction between 6-aminopyrimidines 1 and the Mannich bases, propiophenone hydrochlorides 2. Intermediates for this reaction, such as the Michael addition adduct and the further hydrated pyrido[2,3-d]pyrimidine were isolated to prove the postulated mechanism. NMR analysis of bidimensional experiments allowed to determine unambiguously the process to obtain 7-arylpyrido[2,3-d]pyrimidines.

Full text of DOI:10.1016/S0040-4020(02)00433-7

TETRAHEDRON
Pergamon
Tetrahedron 58 =2002) 4873±4877
New aspects on the selective synthesis of
7-arylpyrido[2,3-d]pyrimidines
a,p
a
a
a
Jairo Quiroga, Henry Insuasty, Braulio Insuasty, Rodrigo Abonõa, Justo Cobo,
b
Â
b
Adolfo Sanchez and Manuel Nogueras
b,p
Â
a
  Â
Grupo de Investigacion de Compuestos Heterocõclicos, Departamento de Quõmica, Universidad del Valle, A.A. 25360 Cali, Colombia
b
  Â
Departamento de Quõmica Inorganica y Organica, Universidad de Jaen, 23071 Jaen, Spain
Â
Â
Received 22 January 2002; revised 8 March 2002; accepted 18 April 2002
AbstractÐPyrido[2,3-d]pyrimidines have been synthesized via a selective cyclocondensation reaction between 6-aminopyrimidines 1 and
the Mannich bases, propiophenone hydrochlorides 2. Intermediates for this reaction, such as the Michael addition adduct and the further
hydrated pyrido[2,3-d]pyrimidine were isolated to prove the postulated mechanism. NMR analysis of bidimensional experiments allowed to
determine unambiguously the process to obtain 7-arylpyrido[2,3-d]pyrimidines. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
nicotinonitriles11 or cyclocondensation of amino-
pyrimidines12 with urea, thiourea in formamide separately
also afforded the title compound. They have also been
prepared by base-catalyzed =KOH) ring transformation
reactions of 6-amino-1,3-dimethyluracil with 6-aryl-3-
cyano-4-methylthio-2H-pyran-2-ones.13
The one-step assemblage of monocyclic as well as poly-
cyclic heterocycles represents a practical approach in
modern organic synthesis. This class of reactions are of
particular interest in combinatorial chemistry1 because it
allows the production of vast arrays of molecules in an
ef®cient mode. Recently, we have reported the selective
preparation of a number of condensed heterocycles as
potential biologically active compounds.2 Amongst these,
pyrido[2,3-d]pyrimidines are of great interest due to the
shown antitumor,3 antifolate,4 antibacterial,5 growth regula-
tor,6 etc. activities. The therapeutic importance of this
nucleus enthused us to developed selective procedures of
synthesis in which substituents could be arranged in a
pharmacophoric pattern to display high order pharmaco-
logical activities.
From early studies14 an empirical rule has emerged which
specify that in annelation reactions involving substituted
6-aminopyrimidines, which have multiple competing sites
for possible ring-annelation, and biselectrophiles such as
b-keto aldehydes, b-keto esters, b-dialdehydes as well as
a-halo ketones, the 5-position of the pyrimidine is the most
nucleophilic and attacks the most electrophilic carbon of the
biselectrophile, followed by ring closure between the
6-amino group and the second electrophilic center =recently
alkynones have also been used as biselectrophiles15). This
experimental observation is supported by computational
studies via AM1 and PM3 calculations, which make
known a direct correlation between charge densities at the
C5-carbon of the 6-aminopyrimidine and their enamine-like
nucleophilicity toward enones.16 However, unexpected
reactions have also been observed in some cases, depending
on the substitution in the pyrimidine, the biselectrophile and
the solvent used.17
Compounds with pyrido[2,3-d]pyrimidine ring system have
earlier been prepared either by base-catalyzed condensation
reaction with benzalacetophenone or benzalpinacolone with
aminouracil7 or by heating methyl vinyl ketone with
6-amino-1,3-dimethyluracil in acetic acid.7 Reaction of
6-aminouracil with active methylene compounds8 or
electron rich enamines9 or benzylidene Meldrum's acid
derivatives10 separately afforded pyrido[2,3-d]pyrimidines
derivatives. Acid-catalyzed intramolecular cyclization of
Our recent studies provided a convenient method for the
preparation of pyrido[2,3-d]pyrimidines by reactions of
6-aminopyrimidines with a,b-unsaturated carbonyl and
carboxylic compounds.18 As part of our continuing interest
in the reaction of aminopyrimidines with a,b-unsaturated
compounds and their precursors, Mannich bases, we have
synthesized 7-arylpyrido[2,3-d]pyrimidines 3 in moderate
to good yields via cyclocondensation reaction between
Keywords: selective cyclocondensation; 6-aminopyrimidine; pyrido[2,3-
d]pyrimidines; Mannich bases.
Corresponding authors. Tel./fax: 157-2-3392440;
e-mail: jaiquir@quimica.univalle.edu.co; Tel.: 134-953-002740; fax:
134-953-012141; e-mail: mmontiel@ujaen.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020=02)00433-7

4874
J. Quiroga et al. / Tetrahedron 58 02002) 4873±4877
Table 2. 13C NMR chemical shifts =d in ppm) of compounds 3a±e
Entry
3a
3b
3c
3d
3e
OCH3
NCH3
C-2
C-4
C-4a
C-5
C-6
C-7
C-8a
Ci
56.0
28.0
55.9
27.9
56.0
28.0
56.0
28.0
56.0
28.1
159.9
161.8
111.6
137.1
116.8
161.3
156.8
137.5
127.3
128.8
130.2
155.8
161.8
110.8
136.8
116.0
161.1
156.8
130.0
128.9
114.2
161.0
156.0
162.0
111.9
137.3
116.7
160.0
157.0
136.3
128.9
129.1
135.1
156.0
161.8
111.9
137.2
116.6
160.0
156.8
136.7
129.3
131.8
124.0
156.4
161.9
112.8
137.7
117.7
159.3
157.1
143.8
123.8
128.7
148.7
Co
Cm
Cp
OCH3 group for 3e 55.3 ppm.
d. On the other hand, initial addition from amino group at
1 in a similar fashion could afford 4. We have found that the
condensation between compounds 1 and 2 was regio-
selective and no other compound was formed =TLC control)
and agrees with that found for others aminopyrimidines and
biselectrophiles.14,15
Scheme 1.
Data from 1H and 13C NMR spectra are displayed in Tables
1 and 2, where the assignment for carbon atoms was based
in DEPT experiments along with bidimensional HMBC and
HSQC =1H±13C) experiments; HMBC and NOESY experi-
ments gave the de®nitive assignment to determine the
regioselectivity in compounds 3a and 3c, hence the hetero-
nuclear correlation observed in the HMBC experiment
between signal assigned to H-5 and C-4, along to the
NOESY correlation found between ortho proton at the
phenyl residue and H-6 were the clue to propose structures
3.
6-aminopyrimidin-4-ones 1 and 3-dimethylaminopropio-
phenone hydrochlorides 2.
In this paper we demonstrate that the reaction of 6-amino-2-
methoxy-3-methylpyrimidin-4=3H)-one 1 with a,b-unsatu-
rated ketones, which are generated in situ by the correspond-
ing precursor Mannich bases 2, as biselectrophiles also
agrees with the above mentioned rule, and lead regio-
selectively to 7-substituted pyrido[2,3-d]pyrimidines and
not to the 5-substituted isomer.
To corroborate the above proposed steps sequence in the
formation of compounds 3, we carried out the reaction
2. Results and discussion
between
1 and 3-dimethylamino-p-nitropropiophenone
hydrochloride 2d under similar conditions, either shorter
reaction time or lower temperature =see Section 4). In
those situations, the Michael adduct 5, the hydrated cyclic
product 6 or well the desired product 3d were isolated
depending on the reaction time. So as logic in time order
compound 5 was obtained ®rst, then 6 and the last one was
3d. Hence the formation of 3d is assumed to proceed as
indicated above, that is by an initial Michael type addition
Aminopyrimidinone 1 reacts with equimolecular amounts
of 3-dimethylaminopropiophenone hydrochloride 2 in
absolute ethanol under re¯ux to afford 7-arylpyrido[2,3-
d]pyrimidines 3a±d as unique product =see Scheme 1).
3-Dimethylaminopropiophenones are relatively unstable
and easily lose the amino group forming aryl vinyl
ketones.19
Michael type nucleophilic addition of carbon atom C-5 at
the pyrimidine ring to the formed aryl vinyl ketone and
subsequent cyclization with water elimination yields 3a±
Table 1. 1H NMR data of 3a±e
Entry
3a
3b
3c
3d
3e
2-OCH3, s
3-NCH3, s
5-H, da
4.10
3.36
8.44
7.97
8.22
7.56
4.10
3.39
8.38
7.90
8.18
7.09
4.10
3.36
8.45
7.98
8.23
7.60
4.10
3.40
8.43
7.94
8.14
7.72
4.15
3.43
8.51
8.01
8.42
8.32
6-H, da
Ar, Ho, m
Ar, Hm, m
OCH3 group for 3e at 3.85 ppm.
Jˆ8.3 Hz.
a
Scheme 2.

J. Quiroga et al. / Tetrahedron 58 02002) 4873±4877
4875
Figure 1.
Figure 2.
of the most nucleophilic carbon atom in aminopyrimidine to
the activated double bond of aryl vinyl ketone18b,e,f,20 yield-
ing Michael adduct 5 which by an intramolecular cycliza-
tion between amino and carbonyl group gives compound 6.
Finally, one molecule of water is eliminated from 6 giving
6,7-dihydropyrido[2,3-d]pyrimidinones, which further
oxidation yields the aromatic compound 3d =Scheme 2).
Elemental analysis and mass spectral data suggest that the
adduct resulted from the condensation of one molecule of
aminopyrimidine 1 with two of compound 2e accompanied
by loss of water molecule. Such product was fully charac-
terized by analytical and spectroscopic methods as
compound 7 =1H and 13C NMR spectroscopic data
shown in Fig. 2). The assumption that initially pyrido[2,3-
d]pyrimidine ring system 3e is formed, and then reacts with
a second molecule of a,b-unsaturated ketone through C-6 at
pyrido[2,3-d]pyrimidine to yield compound 7 is discarded
because 7 is not formed when 3e is reacted directly with the
Mannich base 2e =Scheme 3). We consider that the reaction
should proceed through a second alkylation of the initial
Michael adduct =5e) on the active methylene, then the
new intermediate 8 would proceed in the same manner as
above, through cyclocondensation to compound 7 =Scheme
3). This type of alkylation was observed in the case of
methoxy derivatives of chalcones,21 and it is also well-
known that alkylation of CH groups activated by carbonyl
groups have mainly been carried out using ketonic Mannich
bases.22
The structures of intermediates 5 and 6 were also com-
pletely characterized by spectroscopic and analytical
1
methods. H and 13C NMR data are displayed in Fig. 1.
According to the mentioned results, the rest of compounds
3a±c should be formed by a like way to 3d.
The reaction of 1 with 2e led to 3e =Ar0ˆp-CH3O0Ph) in
60% yield when the molar relation was 2:1 =see Scheme 3).
Surprisingly when the ratio was 1:1, a different and yellow
crystalline product was separated.
3. Conclusions
We have demonstrated that the cyclocondensation of
6-aminopyrimidine 1 with 3-dimethylaminopropiophenone
hydrochlorides 2 affords selectively the 7-arylpyrido[2,3-
d]pyrimidines 3 under mild conditions, in moderate to
good yields. That supports and agrees with the previously
formulated empirical rule about cyclocondensation between
6-aminopyrimidines and biselectrophiles. Intermediates
type 5 and 6 in the pathway to pyrido[2,3-d]pyrimidines 3
have been isolated and characterized for ®rst time, what
provides de®nitive evidence about the mechanism.
4. Experimental
4.1. General methods
Melting points were determined in a Buchi Melting Point
Apparatus and are uncorrected. The 1H and 13C NMR spec-
tra were run on a Bruker DPX 300 spectrometer operating at
300 and 75 MHz, respectively, using dimethyl sulfoxide-d6
as solvent and tetramethylsilane as internal standard. The
Scheme 3.

4876
J. Quiroga et al. / Tetrahedron 58 02002) 4873±4877
mass spectra were scanned on a Hewlett Packard HP
Engine-5989 spectrometer =equipped with a direct inlet
probe) and operating at 70 eV. The elemental analysis has
been obtained using a LECO CHNS-900 equipment. Reac-
tion progress and purity of the products were monitored by
thin layer chromatography =TLC) on Merck Silica Gel
60GF254 =0.2 mm) aluminium precoated sheets with
¯uorescent indicator, the spots were visualized by ultra-
violet irradiation, and using chloroform as eluent.
peaks: MS =70 eV) m/z =%)ˆ298 =32), 297 =M1, 100), 282
=13), 268 =31), 267 =11), 253 =20), 197 =14), 72 =10), 64 =10),
56 =10). Anal. Calcd for C16H15N3O3: C, 64.64; H, 5.09; N,
14.13. Found: C, 64.56; H, 5.16; N, 14.08.
4.2.6. Synthesis of 6-amino-2-methoxy-3-methyl-5-[3-/4-
nitrophenyl)-3-oxopropyl]pyrimidin-4/3H)-one 5.
A
solution of 6-aminopyrimidine 1 =2.0 mmol) and an equi-
molar amount of the 3-dimethylamino-p-nitropropio-
phenone hydrochloride 2d =2.0 mmol) in ethanol =25 ml)
was stirred overnight at room temperature, then, part of
solvent was removed under reduced pressure and the reac-
tion mixture was cooled overnight. The resulting orange
precipitate was ®ltered, washed with ethanol and recrystal-
lized from ethanol. Mp 2208C, yield 65%. The mass spec-
trum shows the following peaks: MS =70 eV) m/z =%)ˆ332
=M1, 25), 312 =52), 283 =18), 268 =13), 182 =100), 167 =81),
155 =26), 72 =16), 57 =24). Anal. Calcd for C15H16N4O5: C,
54.22; H, 4.85; N, 16.86. Found: C, 54.27; H, 4.81; N, 16.96.
4.2. General procedure for the preparation of the 7-aryl-
2-methoxy-3-methylpyrido[2,3-d]pyrimidin-4-ones 3
A solution of 6-aminopyrimidine 1 =2.0; 4.0 mmol for reac-
tion between 1 and 2e) and an equimolar amount of the
3-dimethylaminopropiophenone hydrochloride
2
=2.0
mmol) in ethanol =10 ml) was heated at re¯ux for 1±2 h.
Then the reaction mixture was cooled overnight. The result-
ing precipitated was ®ltered, washed with ethanol and
recrystallized from ethanol to afford the desired products 3.
4.2.7. Synthesis of 7-hydroxy-2-methoxy-3-methyl-7-/4-
nitrophenyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-
4/3H)-one 6. Method A: A solution of compound 5
=2.0 mmol) in ethanol =10 ml) was heated at re¯ux for
10 min, then the resulting white precipitate was ®ltered,
washed with ethanol and recrystallized from ethanol.
Yield 68%.
4.2.1. 2-Methoxy-3-methyl-7-phenylpyrido[2,3-d]pyri-
midin-4/3H)-one 3a. This compound was obtained accord-
ing to general procedure as white crystals. Mp 1788C, yield
60%. The mass spectrum shows the following peaks: MS
=70 eV) m/z =%)ˆ267 =M1, 100), 252 =12), 238 =31), 223
=20), 167 =11), 140 =16). Anal. Calcd for C15H13N3O2: C,
67.41; H, 4.90; N, 15.72. Found: C, 67.55; H, 4.83; N, 15.63.
Method B: A solution of 6-aminopyrimidine 1 =2.0 mmol)
and an equimolar amount of the 3-dimethylamino-p-nitro-
propiophenone hydrochloride 2d =2.0 mmol) in ethanol
=15 ml) was heated at re¯ux during 10 min, then the result-
ing white precipitate was ®ltered, washed with ethanol and
recrystallized from ethanol. Mp 2098C, yield 72%. The
mass spectrum shows the following peaks: MS =70 eV)
m/z =%)ˆ332 =M1, 36), 315 =30), 314 =33), 313 =27), 282
=12), 182 =100), 167 =85), 155 =29), 111 =26), 72 =22), 57
=22). Anal. Calcd for C15H16N4O5: C, 54.22; H, 4.85; N,
16.86. Found: C, 54.31; H, 4.74; N, 16.73.
4.2.2. 7-/p-Chlorophenyl)-2-methoxy-3-methylpyrido-
[2,3-d]pyrimidin-4/3H)-one 3b. This compound was
obtained according to general procedure as white crystals.
Mp 2188C, yield 62%. The mass spectrum shows the follow-
ing peaks: MS =70 eV) m/z =%)ˆ303/301 =M1, 36/100), 286
=14), 272 =38), 257 =23). Anal. Calcd for C15H12ClN3O2: C,
59.71; H, 4.01; N, 13.93. Found: C, 59.57; H, 4.14; N, 13.79.
4.2.3. 7-/p-Bromophenyl)-2-methoxy-3-methyl-7-phenyl-
pyrido [2,3-d]pyrimidin-4/3H)-one 3c. This compound
was obtained according to general procedure as white crys-
tals. Mp 2188C, yield 60%. The mass spectrum shows the
following peaks: MS =70 eV) m/z =%)ˆ347/345 =100/98,
M1), 332 =12), 316 =37), 303 =24), 288 =12), 247 =10), 166
=21), 140 =13), 72 =15), 56 =12), 42 =10). Anal. Calcd for
C15H12BrN3O2: C, 52.04; H, 3.49; N, 12.14. Found: C,
52.15; H, 3.35; N, 12.26.
4.2.8. Synthesis of 2-methoxy-6-/p-methoxyphenetyl)-7-
/p-methoxyphenyl)-3-methylpyrido[2,3-d]pyrimidin-
4/3H)-one 7. This compound was obtained according to
general procedure =3a±e) as white crystals. Mp 1778C,
yield 45%. The mass spectrum shows the following peaks:
MS =70 eV) m/z =%)ˆ459 =M1, 43), 324 =100), 310 =95),
135 =64), 77 =20). Anal. Calcd for C26H25N3O5: C, 67.96; H,
5.48; N, 9.14. Found: C, 67.88; H, 5.53; N, 9.22.
4.2.4. 2-Methoxy-3-methyl-7-/p-nitrophenyl)pyrido[2,3-
d]pyrimidin-4/3H)-one 3d. This compound was obtained
according to general procedure as pale yellow crystals. Mp
2758C, yield 70%. This compound also was obtained by
heating at re¯ux in ethanol of compound 6 for 1 h, yield
70%. The mass spectrum shows the following peaks: MS
=70 eV) m/z =%)ˆ312 =100, M1), 297 =11), 283 =32), 268
=23), 254 =12), 194 =10), 166 =10), 72 =10). Anal. Calcd for
C15H12N4O4: C, 57.69; H, 3.87; N, 17.94. Found: C, 57.61;
H, 3.74; N, 17.79.
Acknowledgements
We are grateful to COLCIENCIAS and Universidad del
Â
Valle and to the `Ministerio de Educacion, Cultura y
Â
Â
Deportes =Programa de Cooperacion con Iberoamerica,
AECI)' of Spain for ®nancial support to part of this work.
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according to general procedure, using two moles of amine
and one mole of propiophenone 2e, as white crystals. Mp
1738C, yield 60%. The mass spectrum shows the following
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