First catalytic synthesis of 7-ferrocenyl-2,4-dioxopyrido [2,3-d]pyrimidines derivatives in water

Article abstract of DOI:10.1016/j.molcata.2006.09.018

The reaction of 6-amino-1,3-dimethyluracil with substituted ferrocenyl-ketoalkynes using nickel cyanide as homogeneous catalyst precursor in aqueous alkaline medium, affords 5-substituted-7-ferrocenyl-dioxopyrido[2,3-d]pyrimidines derivatives, in moderate

Full text of DOI:10.1016/j.molcata.2006.09.018

Journal of Molecular Catalysis A: Chemical 266 (2007) 294–299
Short communication
First catalytic synthesis of 7-ferrocenyl-2,4-dioxopyrido [2,3-d]
pyrimidines derivatives in water
a
a
b
´
Ivonne Arellano , Pankaj Sharma , Jose Luis Arias ,
a
a
a,∗
´
Alfredo Toscano , Armando Cabrera , Noe Rosas
a Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Ciudad Universitaria, Circuito Exterior, Coyoaca´n,
04510 Me´xico, Mexico
b Facultad de Estudios Superiores Cuautitla´n, Universidad Nacional Auto´noma de Me´xico, Cuautitla´n Izcalli,
C.P. 54700, Estado de Me´xico, Mexico
Received 2 June 2006; received in revised form 8 September 2006; accepted 11 September 2006
Available online 16 September 2006
Abstract
The reaction of 6-amino-1,3-dimethyluracil with substituted ferrocenyl-ketoalkynes using nickel cyanide as homogeneous catalyst precursor in
aqueous alkaline medium, affords 5-substituted-7-ferrocenyl-dioxopyrido[2,3-d]pyrimidines derivatives, in moderate yields under mild conditions.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Ferrocenylpyrimidines; Nickel; Catalysis; Cyclocarbonylation
1. Introduction
moiety has been readily applied for the drugs design, a syn-
ergistic effect between ferrocene and pyrimidines could be
of interest. Here we wish to report the novel and facile syn-
thesis of some 7-ferrocenyl-2,4-dioxopyrido[2,3-d]pyrimidines
in water, by coupling and heterocyclization of ferrocenyl-␣-
ketoalkynes with 6-amino-1,3-dimethyluracil, in water as a
reaction medium, under exceptionally mild conditions (room
temperature and atmospheric pressure) using a nickel catalytic
system viz. Ni(CN)2/CO/KCN/NaOH.
The substituted pyrimidines present very important poten-
tial pharmacological and biological activities [1–5], and there
exist some reports on the synthesis of 2,4-dioxopyrido[2,3-
d]pyrimidines derivatives in moderates yields in organic
medium. These traditional syntheses of named compounds
involve multi-step reaction sequences, stringent reaction con-
ditions such as: high temperature, high pressures, the use of
toxic solvents and long reaction times commonly resulting in
low yields [6].
Recently, our group developed anionic catalytic species of
Ni(0) [7] in water which induce the cyclocarbonylation reaction
of alkynes, alkynyl-ketones and alkynyl-enones [8], afford-
ing lactones, lactams, pyrones, pyrimidines, naphthyridines and
quinolinones in good yields [9–13]. These reactions are per-
formed in a basic medium containing nickel cyanide, potassium
cyanide under carbon monoxide.
2. Experimental
2.1. Materials and methods
Syntheses of 7-ferrocenyl-2,4-dioxopyrido[2,3-d]pyrimi-
dines obtained by the reaction of ferrocenyl-␣-ketoalkynes with
6-amino-1,3-dimethyluracil. The pyrimidine derivatives being
characterized by the usual analytical spectroscopy, e.g. 1H and
13C NMR, IR, and mass spectrometry (FAB+ and electronic
impact), the structures of compounds 1-phenyl-3-ferrocenyl-
propynone (1a), 7-ferrocenyl-5-phenyl-2,4-dioxopyrido[2,3-d]
pyrimidine (2a) and 7-ferrocenyl-5-(3,5-dimethoxy-phenyl)-
dioxopyrido[2,3-d]pyrimidine (2b) were unambiguously estab-
lished by X-ray crystallography (Figs. 1, 2a and b and Table 1).
Though many 5-substituted-2,4-dioxopyrido[2,3-d]pyrimi-
dines derivatives are known, pyrimidines substituted by ferro-
cenyl group are still unknown. Considering that the ferrocene
∗
Corresponding author. Tel.: +52 56224556; fax: +52 56162203.
E-mail address: noe@servidor.unam.mx (N. Rosas).
1381-1169/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2006.09.018

I. Arellano et al. / Journal of Molecular Catalysis A: Chemical 266 (2007) 294–299
295
Fig. 1. 1-Phenyl-3-ferrocenyl-propynone.
2.2. Synthesis of ferrocenyl-α-ketoalkynes: general
procedure
At the end of the reaction (3 h), aq. 2.5 M HCl (40 mL) was
added to neutralize the Et3N and the mixture was diluted with
an aqueous solution of NaHCO3. Ethyl acetate was used to
extract the product. After the usual workup, the organic solvent
was removed at reduced pressure in arotatory evaporatorresult-
ing ing the crude product which was crystallized from ethyl
acetate/hexane mixture.
Ferrocenyl-␣-ketoalkynes were synthesized by coupling fer-
rocenylethyne with acyl chlorides in dry argon atmosphere at
room temperature according to the method reported in Ref. [14].
As shown in Scheme 1.
A
mixture of ferrocenylethyne (420 mg, 2 mmol),
PdCl2(PPh3)2 (140 mg, 0.2 mmol), and CuI (38 mg, 0.2 mmol)
in anhydrous Et3N (100 mL), was stirred under argon for
30 min.
The appropriate acyl chloride (3 mmol) was added. The
progress of the reaction was followed by GC in a Hewlett
Packard 5890, with HP 225 (10 m × 053 mm) packed column.
2.3. Synthesis of ferrocenyl-pyrimidines: general procedure
The 7-ferrocenyl-2,4-dioxopyrido[2,3-d]pyrimidines were
synthesized by coupling of ferrocenyl-␣-ketoalkynes with 6-
amino-1,3-dimethyluracil. The general reaction is shown in
Scheme 2.
Table 1
Crystal data and structure refinementor ferrocenyl-␣-ketoalkyne (1a) and derivatives of 7-ferrocenyl-2,4-dioxopyrido[2,3-d]pyrimidines (2a and 2b)
Compounds
1a
2a
2b
Empirical formula
Formula weight
Crystal system
Space group
C
19H14FeO
C25H21FeN3O2
451.30
Triclinic
P-1
C27H25FeN3O4
511.35
Monoclinic
P21/c
314.15
Orthorhombic
Pbca
Crystal size (mm)
0.298 × 0.182 × 0.022
10.449(1)
13.322(1)
20.852(2)
90
90
90
2902.6(4)
8
1.438
0.316 × 0.124 × 0.026
9.8676(8)
10.2006(9)
11.481(1)
98.003(2)
112.788(2)
101.350(2)
1014.4(8)
2
0.286 × 0.282 × 0.056
12.833(1)
11.797(1)
15.580(1)
90
104.89(1)
90
2279.5(3)
4
˚
a (A)
˚
b (A)
˚
c (A)
α (◦)
β (◦)
γ (◦)
3
˚
Volume (A )
Z
Density (calc.) (Mg/cm3)
1.477
0.772
1.490
0.703
μ (mm−1
)
1.033
Reflections collected
19865
8622
18810
Independent reflections
3328
3720
4179
R
0.1492
0.0669
0.0518
GOF
Δ/σ (einsteen A
0.941
1.357/−0.455
1.040
0.435/−0.267
1.037
0.375/−0.175
−3
˚
)

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I. Arellano et al. / Journal of Molecular Catalysis A: Chemical 266 (2007) 294–299
Fig. 2. (a) 7-Ferrocenyl-1,3-dimethyl-5-phenyl-pyrido-[2,3-d]pyrimidine-2,4-dione. (b) 7-Ferrocenyl-5-(3,5-dimethoxyphenyl)-1,3-pyrido-[2,3-d]pyrimidine-2,4-
dione.
A typical experiment was performed as follows. A 5N NaOH
solution (50 mL) was degassed and saturated with CO under
atmospheric pressure for 30 min, 2 mmol of Ni(CN)2·4H2O
(366 mg, 2 mmol) was added to the solution, the mixture
was kept at room temperature overnight, with stirring and
slow bubbling of CO (2–3 mL/min), until a pale yellow solu-
tion was obtained. Addition of 15 mmol of KCN (975 mg)
resulted in a color change to orange. After stirring for
0.5 h the corresponding ferrocenyl-␣-ketoalkynes and the 6-
amino-1,3-dimethyluracil compounds were added (10 mmol).
The evolution of the reaction was following by TLC. The
products (ferrocenyl-␣-ketoalkynes and ferrocenyl-pirido[2,3-
d]pyrimidin-2,4-diones) were quantified by GC in a Hewlett
Packard 5890 analyzer with a HP 225 (10 m × 0.53 mm) col-
umn packed. At the end of the reaction, ethyl acetate was used
to extract the product. After evaporation of the solvent fol-

I. Arellano et al. / Journal of Molecular Catalysis A: Chemical 266 (2007) 294–299
297
Scheme 1.
Scheme 2.
(C C), 1548 (C N); 1H NMR (300 MHz, CDCl3, δ in ppm) 3.36
(s, 3H, CH3N), 3.81 (s, 3H, CH3N), 4.11 (s, 5H, cp-ring), 4.56 (s,
2H, cp-ring), 5.04 (s, 2H, cp-ring), 7.02 (s, 1H, C CH), 7.34 (m,
2H, 3,5-phenyl), 7.46 (d, 3H, 2,4,6-phenyl); 13C NMR (75 MHz,
CDCl3, δ in ppm) 28.4 (NCH3), 30.06 (NCH3), 68.6 (C, cp-
ring), 70.3 (C, cp-ring), 71.6 (C, cp-ring), 118.1 (C9), 120.2
(C6), 127.6 (C, phenyl), 127.9 (C, phenyl), 128.1 (C, phenyl),
129.2 (C5), 130.6 (C7), 137.6 [N(C O)N], 152.1 [N(C O)C],
160.9 (C CN).
lowed by drying over MgSO4, the pure crystalline products were
obtained.
2.4. Product characterization
2.4.1. 1-Phenyl-3-ferrocenyl-propynone (1a)
The product was obtained as described in the general proce-
dure in a 62% yield as a yellow solid (mp 70 ◦C); mass spectrum
EI: m/z (%) = 314 (100), 105 (24), 77 (19); IR (selected, cm−1
)
1
2179 (C C), 1624 (C O); H NMR (300 MHz, CDCl3, δ in
ppm) 4.27 (s, 5H cp-ring), 4.41 (s, 2H, cp-ring), 4.67 (s, 2H ring-
cp), 7.50 (dd, 2H, 3,5-phenyl), 7.60 (d, 1H, 2,6-phenyl), 8.20 (d,
2H, 4-phenyl); 13C NMR (75 MHz, CDCl3, δ in ppm) 60.4 (C,
cp-ring), 70.6 (C, cp-ring), 70.9 (C, cp-ring), 73.2 (C, cp-ring),
85.6 (Fc–C C), 96.7 (C C–CO), 128.6 (2C, 3,5-phenyl), 129.5
(2C, 2,6-phenyl), 133.8 (1C, 4-phenyl), 137.3 (1C, 1-phenyl),
177.7 (C O).
2.4.4. 7-Ferrocenyl-5-(3,5-dimethoxyphenyl)-1,3-dimethyl-
pyrido[2,3-d]pyrimidine-2,4-dione (2b)
The product was obtained as described in the general proce-
dure in a 56% yield as dark red crystals (mp 208 ◦C); IE: m/z
(%) = 511 (100), 446 (85); IR (cm−1) 1705, 1659 (C O), 1589
(C C), 1548 (C N); 1H NMR (300 MHz, CDCl3, δ in ppm) 3.39
(s, 3H, CH3N), 3.82 (s, 3H, CH3N), 3.91 (s, 6H, OCH3), 4.21 (s,
5H, cp-ring), 4.51 (s, 2H, cp-ring), 4.75 (s, 2H, cp-ring), 6.62 (s,
2.4.2. 1-(3,5-Dimethoxyphenyl)-3-ferrocenyl-
propynone (1b)
1H, 4-phenyl), 7.30 (s, 2H, 2,6-phenyl), 8.10 (s, 1H, C CH); 13
C
NMR (75 MHz, CDCl3, δ in ppm) 28.6 (NCH3), 30.3 (NCH3),
55.6 (OCH3), 69.2 (C, cp-ring), 70.5 (C, cp-ring), 72.6 (C, cp-
ring), 84.5 (1C, 4-phenyl), 102.3 (2C, 2,6-phenyl), 105.5 (C9),
120.6(C6), 139.7(1C, 1-phenyl), 151.6(C5), 151.82(C7), 154.5
[N–(C O)N], 157.4 (2C, 3,5-phenyl), 161.4 [N(C O)].
The product was obtained in a 60% yield as orange-reddish
crystals (mp. 93 ◦C); mass spectrum FAB+: m/z (%) = 374 (77),
375 (44), 136 and 154 (100); IR (cm−1) 2195 (C C), 1634
1
(C O); H NMR (300 MHz, CDCl3, δ in ppm) 3.87 (s, 6H,
OCH3), 4.28 (s, 5H, cp-ring), 4.41 (s, 2H, cp-ring), 4.67 (s,
2H, cp-ring), 6.70 (s, 1H, 4-phenyl), 7.34 (s, 1H, 2,6-phenyl);
13C NMR (75 MHz, CDCl3, δ in ppm) 55.7 (OCH3), 60.3 (C,
cp-ring), 70.5 (C, cp-ring), 70.9 (C, cp-ring), 73.2 (C, cp-ring),
85.6 (C C), 96.5 (C C), 106.3 (1C, 4-phenyl), 107.2 (2C, 2,6-
phenyl), 139.3 (1C, 1-phenyl), 160.9 (2C, 3,5-phenyl), 177.2
(C O).
3. Results and discussion
It should be mentioned here that previously our group has
reported [13,15] the synthesis of 5-substituted-2,4-dioxo[2,3-
d]pyrimidines for which nucleophilic Michael’s type attack of
Ni(0) anion (NiCN4−4), (1) onto the conjugated triple bond of
the ␣-ketoalkyne yielding the species (2) as is shown in the
Scheme 3.
Thespecies(1)isobtainedwhenanexcessofKCNisaddedto
an alkaline solution of Ni(CN)2 in CO atmosphere. It is known
that the presence of carbon monoxide in the media attains an
equilibria which involves different carbonylic species in the
2.4.3. 7-Ferrocenyl-1,3-dimethyl-5-phenyl-pyrido[2,3-d]
pyrimidine-2,4-dione (2a)
The product was obtained in a 50% yield as described in the
general procedure as red crystals (mp 210 ◦C); mass spectrum
IE: m/z (%) = 451 (100); IR (cm−1) 1702, 1658 (C O), 1589

298
I. Arellano et al. / Journal of Molecular Catalysis A: Chemical 266 (2007) 294–299
Scheme 3.
solution [7].
we evaluate the influence of the ferrocenyl group as R in the
same reaction and we obtained the 5-substituted-7-ferrocenyl-
dioxopyrido[2,3-d]pyrimidines shown in Table 2.
HO/CN−/CO
NiII(CN)2
ꢀ
[NiII(CN)2(CO)2]CꢀO[NiI(CN)(CO)3]
In this case, the preference for nucleophilic attack is in the
carbonylic part of the ketoalkyne. It seems that the triple bond
conjugates with the ferrocenyl group because the know electron
donor effect of this moiety [16,17]. However the very impor-
tant steric effect generated by the bulky (Fc) group determines
the addition to the keto side (species 3). The possible reaction
pathway involved in this process is shown in Scheme 4.
CO
CN−
ꢀ[Ni0(CN)(CO)3]−1 ꢀ [Ni0(CN)4]−4
In addition, the presence of carbon monoxide in the sys-
tem results in a reductive atmosphere, which promotes low
oxidation states of nickel in the reaction. In the present work
Table 2
Synthesis of 7-ferrocenyl-1,3-dimethyl-5-phenyl-pyrido-[2,3-d]pyrimidine-2,4-dione (2a), and 7-ferrocenyl-5-(3,5-dimethoxyphenyl)-1,3-pyrido-[2,3-d]pyrimidine-
2,4-dione (2b)a, by a reaction of cyclocarbonylation of ferrocenyl-␣-ketoalkynes with 6-amino-1,3-dimethyluracil
Ferrocenyl-␣-ketoalkynes
7-Ferrocenyl pyrimidines
Yield (%)
Reaction time (h)
62
10
60
12
a
Reactions conditions: ferrocenil-␣-ketoalkynes (3.14 g, 10 mmol), 6-amino-1,3-dimethyluracil (1.57 g, 10 mmol), 5N NaOH solution (50 mL), Ni(CN)2·4H2O
(366 mg, 2 mmol), KCN (975 mg, 15 mmol), CO atmospheric pressure and room temperature.

I. Arellano et al. / Journal of Molecular Catalysis A: Chemical 266 (2007) 294–299
299
Scheme 4.
Additionally, no products of this reaction were obtained in the
absence of CO atmosphere or in the absence of Ni(CN)2/HO−
system.
[4] M. Sielecki, J.F. Boylan, P.A. Benfield, G.L. Trainor, J. Med. Chem. 43
(2000) 1.
[5] Patent WO 2005/090344. Novel dichloro-phenyl-pyrido[2,3-d]pyrimidine
derivates, their manufacture and use as pharmaceutical agents.
[6] I. Devi, B.S.D. Kumar, P.J. Bhuyan, Tetrahedron Lett. 44 (2003) 8307.
[7] N. Rosas, A. Cabrera, P. Sharma, H. Arzoumanian, J. Mol. Catal. 156
(2000) 1038.
4. Conclusion
[8] N. Rosas, J.L. Arias, A. Cabrera, RecentResearchTrendsinOrganometallic
Chemistry, Publishers Research Editors India, 2005, pp. 65–86.
[9] N. Rosas, P. Sharma, I. Arellano, M. Ram´ırez, D. Pe´rez, S. Herna´ndez, A.
Cabrera, Organometallics 24 (2005) 4893.
[10] A. Cabrera, J.L. Arias, P. Sharma, N. Rosas, Recent Research Trends in
Organometallic Chemistry, Publishers Research Editors India, 2005, pp.
33–64.
[11] H. Arzoumanian, M. Jean, D. Nuel, A. Cabrera, J.L. Garc´ıa, N. Rosas,
Organometallics 14 (1995) 5438.
[12] H. Arzoumanian, M. Jean, D. Nuel, N. Rosas, Organometallics 16 (1997)
2726.
[13] N. Rosas, P. Sharma, A. Cabrera, G. Pe´nieres, J.L. Garc´ıa, L.A. Maldonado,
Heterocycles 60 (2003) 2631.
[14] Y. Juxing, W. Xiaojun, L. Yongmin, W. Xiaoli, C. Baohua, M. Yongxiang,
Synthesis 3 (2004) 331.
[15] N. Rosas, P. Sharma, C. Alvarez, A. Cabrera, R. Ram´ırez, H. Arzoumanian,
J. Chem. Soc., Perkin Trans. 1 (2001) 2341.
It was found that the reaction between 6-amino-1,3-
dimethyluracil and substituted ketoalkynes (in the presence of
catalytic promoter) depends on the nature of the alkynyl sub-
stituent. With weak electronic donor groups (as n-butyl and
Ph) yields 5-substituted pyrimidines via the 1,4 Michael’s type
condensation [15], however with strong donor groups (as fer-
rocenyl moiety), the nucleophilic attack (by the Ni(0) anion
formed in situ) seems to be at the carbonylic group of ynone,
resulting finally in 7-substituted pyrimidine derivatives. System-
atic work on this reaction, different subtituents groups are in
progress.
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