5-Cyanoacetylpyrimidines as intermediates for 7-aryl-6-cyanopyrido[2,3-d]pyrimidin-5-ones

Article abstract of DOI:10.1016/j.tetlet.2009.08.070

The reactions of N⁴- and 5-cyanoacetyl derivates of 4-aminopyrimidines with aromatic aldehydes have yielded the N-(pyrimidin-4-yl)-3-arylacrylamides and the dihydropyrido[2,3-d]pyrimidines, respectively. The first reaction was a Claisen-Schmidt

Full text of DOI:10.1016/j.tetlet.2009.08.070

Tetrahedron Letters 50 (2009) 6404–6406
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
5-Cyanoacetylpyrimidines as intermediates for
7-aryl-6-cyanopyrido[2,3-d]pyrimidin-5-ones
b
a
a
a
c,
*
Jairo Quiroga a, , Jorge Trilleras , Jaime Gálvez , Braulio Insuasty , Rodrigo Abonía , Manuel Nogueras
,
*
Justo Cobo c
a Grupo de Investigación de Compuestos Heterocíclicos, Department of Chemistry, Universidad del Valle, A. A. 25360 Cali, Colombia
b Grupo de Investigación de Compuestos Heterocíclicos, Programa de Química, Universidad del Atlántico, Km 7 via antigua Puerto Colombia Barranquilla, Colombia
c Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
The reactions of N4- and 5-cyanoacetyl derivates of 4-aminopyrimidines with aromatic aldehydes have
yielded the N-(pyrimidin-4-yl)-3-arylacrylamides and the dihydropyrido[2,3-d]pyrimidines, respectively.
The first reaction was a Claisen–Schmidt reaction catalysed by base, and the second one proceeded via
thermal cyclocondensation.
Article history:
Received 16 April 2009
Revised 20 August 2009
Accepted 20 August 2009
Available online 26 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidin-5-yl-3-oxopropanenitriles
N-(Pyrimidin-4-yl)-2-cyanoacetamides
Pyrido[2,3-d]pyrimidin-2,4,5-triones
Cyclocondensation
Pyrimidine-fused heterocycles are important targets in chemi-
cal biology or medicinal chemistry, and among them, pyrido[2,3-
d]pyrimidine derivatives have attracted much attention because
they are deazapteridines which have shown interesting bio-activi-
ties.1–3 The preparation of this kind of fused pyrimidines has been
extensively investigated and well documented.1,4 They usually
require forcing conditions,5 long reaction times,6 and complex syn-
thetic pathways.7 Thus, the search for new and simple synthetic
routes of these molecules still attracts considerable attention in
order to develop high-throughput methods.2c,8
As a matter of fact, we have already reported the regioselective
synthesis of several 5-aryl-6-cyanopyrido[2,3-d]pyrimidines by
the multicomponent reaction of 6-aminopyrimidines, aryl alde-
hydes, and ethyl cyanacetate8e or 3-oxo-3-phenylpropanenitrile
analogues.8f On the other hand, the cyanoacetyl group has been
used as methylene active residue to prepare diverse and versatile
precursors and heterocyclic products.9
cyanoacetic acid and acetic anhydride (Scheme 1).11 Our synthetic
strategy is based on the nucleophilic character of methylene
carbon in cyanoacetylated compounds.1 These compounds may be
used as intermediates to prepare (via aryl aldehyde through a Clais-
en-Schmidt cyclocondensation) the regioisomers 7-aryl-6-cyano-
pyrido[2,3-d]pyrimidin-5-ones
or
5-aryl-6-cyanopyrido[2,3-
d]pyrimidin-7-ones.12
First, we have used the compound 3-(6-amino-1,2,3,4-tetra-
hydro-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)-3-oxo-propane-
nitrile 1 in the reaction with aromatic aldehydes 2 by heating in
DMF for 15 h to render the desired cyclocondensation products
3–11 in acceptable to good yields. The formation of pyrido[2,3-
d]pyrimidines 3–11 is assumed initially to proceed by the forma-
tion of the corresponding heterocyclic cyanochalcone I as interme-
diate,13 that would suffer an intramolecular Michael addition via
the amino group, followed by an oxidative process which is favored
under reaction conditions (Scheme 2).14 The reactions proceeded
quite well with different substituted aldehydes with electron-
donating/electron-withdrawing groups giving moderate to good
yields. These results are given in Table 1.
Next, the 2-cyano-N-(2,6-dimethoxypyrimidin-4-yl)-acetamide
12 was put to react with aromatic aldehydes 2 in similar conditions
in order to prepare the regioisomeric pyrido[2,3-d]pyrimidines. In
turn, the 2-cyano-N-(2,6-dimethoxipyrimidin-4-yl)-3-arylacryla-
mides 13–24 were isolated in moderate to good yields by a simple
condensation reaction (Scheme 3). Formation of pyridopyrimidines
was not observed.15 After reaction optimization, the compounds
Accordingly, we consider that cyanoacetyl-subtituted 6-amino-
pyrimidines constitute good precursors for the preparation of
versatile functionalized pyrido[2,3-d]pyrimidines. In fact, we have
recently reported the regioselective preparation of 3-pyrimidin-5-
yl-3-oxopropanenitriles and N-(pyrimidin-4-yl)-2-cyanoaceta-
mides10 through the reaction of 6-aminopyrimidines with
* Corresponding authors. Fax: +57 2 33392440 (J.Q.); +34 618907111 (M.N.).
E-mail addresses: jaiquir@univalle.edu.co (J. Quiroga), mmontiel@ujaen.es (M.
Nogueras).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.070

J. Quiroga et al. / Tetrahedron Letters 50 (2009) 6404–6406
6405
R
N
H3C
R
N
O
O
H3C
CN
N
or
X
N
H
N
H3C
CH3
X
N
NH2
H2N
N
O
or
N
CH3
O
R = OCH3, X = O, S
R = Cl, X = S
O
NC
CH3
NCCH2CO2H, Ac2O
50 - 85°C for 5 min.
N
N
O
O
O
H
R
N
O
R'X
N
NH2
R
CN
N
CH3
R'X
N
NH2
CH3
R = H, CH3; R = R' = H, X = S; R = H , R' = CH3, X = S; R = R' = CH3, X = S;
R = H , R' = CH3, X = O; R = R' = H, X = NH
Scheme 1.
O
O
O
O
O
O
O
H3C
O
CN
H
Ar
H3C
O
CN
Ar
CN
H3C
O
N
N
2
N
N
NH2
N
NH2
N
N
H
Ar
DMF, Reflux
CH3
CH3
CH3
1
I
3-11
Scheme 2.
Table 1
Results for the preparation of pyrido[2,3-d]pyrimidines by conventional method
It is important to point out that this method allowed us to obtain
the regioisomeric pyrido[2,3-d]pyrimidin-5-one while the previous
three-component reactions among 6-amino-4-pyrimidinones,
benzaldehydes, and cyanoacetyl derivatives led to the formation of
the pyrido[2,3-d]pyrimidin-7-one.8e
It follows from Tables 1 and 2 that although the yields of all
products ranging from good to excellent, nevertheless no relation-
ship was found between them and the nature of the substituents of
the aldehydes.
Product
Ar
Mp °C
Yield (%)
3
4
5
6
7
8
9
10
11
C6H5
4-ClC6H4
4-BrC6H4
4-FC6H4
4-H3CC6H4
4-H3COC6H4
3-Pyridyl
3,4,5-tri-H3COC6H2
4-F3CC6H4
220–222
229–231
248–250
230–232
255–257
227–229
319–321
260–262
267–269
60
50
90
58
50
42
70
73
95
The structures of all new compounds were determined from
analytical and spectral data, NMR 1D and 2D mainly, MS, and ele-
mental analysis.
In conclusion, we have described the preparation of novel 2-
cyano-N-(2,6-dimethoxypyrimidin-4-yl)-3-arylacrylamides (in
moderate to good yields) as products from the reaction of 2-cy-
ano-N-(2,6-dimethoxipyrimidin-4-yl)-acetamide and aromatic
aldehydes and the preparation of new 7-aryl-6-cyano-1,
could be prepared in 56–95% in ethanol with base catalyst at room
temperature for 2–3 h. Applying this new set of conditions the
cyclocondensation between 1 and 2 did not proceed even under
heating.
O
2
H3C
O
H3C
O
Ar
H
N
O
N
O
Ethanol
NaOH (20 %)
H3C
H3C
CN
O
N
N
H
Ar
O
N
N
H
CN
12
13-24
Scheme 3.

6406
J. Quiroga et al. / Tetrahedron Letters 50 (2009) 6404–6406
8. (a) Mohamed, N. R.; El-Saidi, M. M.; Mahmoud Ali, Y.; Elnagdi, M. H. Sci. Pharm.
Table 2
2007, 75, 9–28; (b) Wang, X.; Zeng, Z.; Shi, D.; Wei, X.; Zong, Z. Synth. Commun.
2004, 34, 4331–4338; (c) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R.; Nogueras,
M.; Cobo, J. Tetrahedron Lett. 2006, 47, 27–30; (d) Quiroga, J.; Cisneros, C.;
Insuasty, B.; Abonía, R.; Cruz, S.; Nogueras, M.; de la Torre, J. M.; Sortino, M.;
Zacchino, S. J. Heterocycl. Chem. 2006, 43, 299–306; (e) Quiroga, J.; Alvarado, M.;
Insuasty, B.; Nogueras, M.; Sánchez, A.; López, M. D. J. Heterocycl. Chem. 1999,
36, 113–115; (f) Quiroga, J.; Cisneros, C.; Insuasty, B.; Abonía, R.; Nogueras, M.;
Sánchez, A. Tetrahedron Lett. 2001, 42, 5625–5627.
Synthesis of 2-cyano-N-(2,6-dimethoxypyrimidin-4-yl)-3-arylacrylamides deriva-
tives by condensation reaction between 2-cyano-N-(2,6-dimethoxypyrimidin-4-yl)-
acetamide 12 and aldehydes using NaOH as catalyst
Product
Ar
Mp °C
Yield (%)
13
14
15
16
17
18
19
20
21
22
23
24
C6H5
4-ClC6H4
4-BrC6H4
2-FC6H4
148–150
229–231
238–240
165–167
218–220
221–223
211–213
227–229
252–254
211–213
253–255
174–176
60
60
56
61
73
82
56
72
80
95
76
93
9. (a) Gálvez, J.; Quiroga, J.; Cobo, J.; Low, J.; Glidewell, C. Acta Crystallogr., Sect. C
2008, 64, 385–387; (b) Sánchez, A.; Trilleras, J.; Cobo, J.; Low, J.; Glidewell, C.
Acta Crystallogr., Sect. C 2007, 63, 287–291; (c) Elmaati, T. Acta Chim. Slov. 2002,
49, 721–732; (d) Jachak, M.; Tantak, C.; Toche, R.; Badgujar, N. Monatsh. Chem.
2004, 135, 1529–1538; (e) Radwan, M.; El-Sherbiny, M. Bioorg. Med. Chem.
2007, 15, 1206–1211; (f) Sun, C.; Ji, S.; Liu, Y. Tetrahedron Lett. 2007, 48, 8987–
8989; (g) Radwan, M. A. A.; Ragab, E. A.; Sabry, N. M.; El-Shenawy, S. M. Bioorg.
Med. Chem. 2007, 15, 3832–3841; (h) Zhu, S.; Ji, S.; Su, X.; Sun, C.; Liu, Y.
Tetrahedron Lett. 2008, 49, 1777–1781; (i) Ibrahim, H. M.; Makhseed, S.; Abdel-
Motaleb, R. M.; Makhlouf, A-M. A-S.; Elnagdi, M. H. Heterocycles 2007, 71,
1951–1966.
4-FC6H4
4-H3CC6H4
4-H3COC6H4
3,4-OCH2O-C6H3
4-O2NC6H4
2-HOC6H4
4-(H3C)2NC6H4
3-Pyridyl
10. (a) Quiroga, J.; Trilleras, J.; Gálvez, J.; Insuasty, B.; Abonía, R.; Nogueras, M.;
Cobo, J. Tetrahedron Lett. 2008, 49, 5672–5675; (b) Trilleras, J.; Low, J.; Cobo, J.;
Marchal, A.; Glidewell, C. Acta Crystallogr., Sect. C 2008, 64, 149–154.
11. (a) Slätt, J.; Janosik, T.; Wahlström, N.; Bermang, J. J. Heterocycl. Chem. 2005, 42,
141–145; (b) Slätt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760–2765; (c)
Kappe, T.; Stelze, H. P.; Ziegler, E. Monatsh. Chem. 1983, 114, 953–963.
12. (a) Berghot, M. A.; Moawad, E. B. Eur. J. Pharm. Sci. 2003, 20, 173–179; (b)
Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W. J.; Troth, J. R.; Coffen, D. L.
Tetrahedron 1998, 54, 4085–4096.
13. (a) Kolosov, M. A.; Orlov, V. D.; Kolos, N. N.; Shishkin, O. V.; Zubatyuk, R. I.
ARKIVOC 2007, xvi, 187–194; (b) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R.;
Nogueras, M.; Sánchez, A.; Cobo, J.; Low, J. N. J. Heterocycl. Chem. 2001, 38, 53–
60; (c) Quiroga, J.; Cobo, D.; Insuasty, B.; Abonía, R.; Nogueras, M.; Cobo, J.;
Vázquez, Y.; Gupta, M.; Derita, M.; Zacchino, S. Arch. Pharm. 2007, 340, 603–
606.
3-dimethyl-1,2,3,4,5,8-hexahydro-pyrido[2,3-d]-pyrimidin-2,4,5-
triones. This is an efficient, simple, and regioselective alternative
via cyclocondensation reactions from the isomeric precursor 3-
(6-amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidin-
5-yl)-3-oxopropanenitrile.
The chemical and biological properties of the new compounds
obtained in these experiments are under investigation.
Acknowledgments
14. 7-Aryl-6-cyano-1,3-dimethyl-l-2,4,5-trioxo-1,2,3,4,5,8-hexahydropyrido[2,3-
d]pyrimidines 3–11. A solution of 3-(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-
The authors thank Universidad del Valle, COLCIENCIAS, the Uni-
versidad de Jaén (project reference UJA-07-16-33), ‘Servicios Técn-
icos de Investigación of Universidad de Jaén’ and the staff for data
collection, the Consejería de Innovación, Ciencia y Empresa (Junta
de Andalucía, Spain) and Ministerio de Ciencia e Innovación (pro-
ject reference SAF2008-04685-C02-02) for financial support, and
Walter Torres for reviewing this manuscript.
tetrahydro-pyrimidin-5-yl)-3-oxopropanenitrile
aldehydes 2 (1.0 mmol) in DMF (1.0 mL) was heated during 15 h. The resulting
precipitate was filtered, washed with ethanol, and recrystallized from
1 (1.0 mmol) and aromatic
a
mixture of EtOH–DMF (7:3). Data for 6-cyano-1,3-dimethyl-7-phenyl-
1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidin-2,4,5-trione 3: Yellow solid mp
220–222 °C. Yield 60%. IR (KBr, cmÀ1): 3250 (NH), 2218 (C„N), 1708, 1646
(C@O), 1600 (C@N). 1H NMR (DMSO-d6, 400 MHz, rt) d (ppm): 3.24 (s, 3H, 3-
NCH3), 3.52 (s, 3H, 1-NCH3), 7.53 (t, 1H, Hp), 7.60 (d, 2H, Hm, J = 8.42 Hz), 7.91
(d, 2H, Ho, J = 8.42 Hz,), 8.65 (s, 1H, NH). 13C NMR (DMSO-d6 100 MHz, rt) d
(ppm): 27.4 (3-NCH3), 29.5 (1-NCH3), 94.5 (C„N), 95.8 (C9), 117.0 (C6), 128.3
(Cm), 130.4 (Co), 135.2 (Ci), 136.3 (Cp), 150.7 (C2), 153.3 (C10), 162.0 (C7), 162.5
(C4), 172.8 (C5). The mass spectrum shows the following peaks: MS (30 eV) m/
z (%): 308 (M+). Anal. Calcd for C16H12N4O3: C, 62.34; H, 3.92; N, 18.17. Found C,
62.26; H, 3.86; N, 18.09.
References and notes
1. Lunt, E.; Newton, C. C.. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Boulton, A. J., Mc Killop, A., Eds.; Pergamon Press: Oxford, 1984;
Vol. 3, pp 199–232. and pp 260–261.
2. (a) Tu, S.; Li, C.; Shi, F.; Zhou, D.; Shao, Q.; Cao, L.; Jiang, B. Synthesis 2008, 369–
376; (b) Bagley, M. C.; Hughes, D. D.; Lloyd, R.; Powers, V. E. C. Tetrahedron Lett.
2001, 42, 6585–6588; (c) Devi, I.; Kumar, B. S. D.; Bhuyan, P. J. Tetrahedron Lett.
2003, 44, 8307–8310; (d) Devi, I.; Borah, H. N.; Bhuyan, P. J. Tetrahedron Lett.
2004, 45, 2405–2408.
15. 3-Aryl-2-cyano-N-(2,6-dimethoxypyrimidin-4-yl)-acrylamides 13–24. A solution
of 2-cyano-N-(2,6-dimethoxypyrimidin-4-yl)acetamide 12 (1.0 mmol) and
aromatic aldehyde 2 (1.0 mmol) in ethanol with a catalytic amount of NaOH
(20%, 5 drops) was stirred during 2–3 h at room temperature. The resulting
precipitate was filtered, washed with ethanol, and recrystallized from
a
mixture of DMF–ethanol. Data for 2-cyano-N-(2,6-dimethoxy-pyrimidin-4-yl)-
3-phenylacrylamide 13: Yellow solid, mp 148–150 °C. Yield 60 %. IR (KBr,
cmÀ1): 3335 (NH), 2219 (C„N), 1697 (C@O). 1H NMR (DMSO-d6, 400 MHz, rt) d
(ppm): 3.91 (s, 6H, OCH3), 7.10 (s, 1H, H-5), 7.60 (m, 3H, Hm and Hp), 7.98 (d,
2H, Ho, J = 8.00 Hz), 8.39 (s, 1H, Hb), 11.08 (s, 1H, NH). 13C NMR (DMSO-d6,
100 Hz, rt) d (ppm): 53.9 (OCH3), 54.1 (OCH3), 88.5 (C5), 107.0 (C„N), 129.2
(Cm), 130.2 (Co), 131.8 (Ci), 132.6 (Cp), 151.8 (Cb), 164.4 (C6), 172.4 (C2). The
mass spectrum shows the following peaks: MS (30 eV) m/z (%): 310 (M+, 100),
309 (23), 281 (32), 233 (25), 205 (55), 156 (30), 128 (65), 101 (36), 77 (58).
Anal. Calcd for C16H14N4O3: C, 61.93; H, 4.55; N, 18.05. Found C, 61.82; H, 4.60;
N, 18.11.
3. (a) Kanth, S. R.; Reddy, G. V.; Kishore, K. H.; Rao, P. S.; Narsaiah, B.; Murthy, U. S.
N. Eur. J. Med. Chem. 2006, 41, 1011–1016; (b) Bulicz, J.; Bertarelli, D. C. G.;
Baumert, D.; Fülle, F.; Müller, C. E.; Heber, D. Bioorg. Med. Chem. 2006, 14, 2837–
2849; (c) Tu, S.; Zhang, J.; Zhu, X.; Xu, J.; Zhang, Y.; Wang, O.; Jia, R.; Jiang, B.;
Zhang, J. Bioorg. Med. Chem. Lett. 2006, 16, 3578–3581.
4. Tamura, G.; Sakaguchi, T.; Klawasaki, T.; Kita, Y. Heterocycles 1975, 3, 183–186.
5. Hirota, K.; Kuki, H.; Maki, Y. Heterocycles 1994, 37, 563–570.
6. (a) Srivastava, P.; Saxena, A. S.; Ram, V. J. Synthesis 2000, 541–544; (b) Broom,
A. D.; Shim, J. L.; Anderson, G. L. J. Org. Chem. 1976, 41, 1095–1099.
7. Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.; Nichol, C. A. J. Med. Chem. 1980,
23, 327–329.