Three-component synthesis of 5:6 and 6:6 fused pyrimidines using KF-alumina as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2008.06.087

A series of fused pyrimidine derivatives were synthesized by the three-component reaction of an aryl aldehyde, urea, or guanidine in ethyl alcohol/dioxane in presence of 1-methyl-1H-pyrrol-2(3H)-one 1, 1-methylpiperidin-2-one 2, 1-methylindolin-2-one 3, or 1,3-dimethyl-dihydropyrimidine-2,4-dione 9 at 80 °C catalyzed by KF-Al₂O₃. For example, when 1-methyl-1H-pyrrol-2(3H)-one 1, arylaldehyde 4, and urea 5 were treated with KF-Al₂O₃ in ethyl alcohol at 80 °C for 3-5 h, we obtained pyrrolo[2,3-d]pyrimidine derivatives in good yield.

Full text of DOI:10.1016/j.tetlet.2008.06.087

Tetrahedron Letters 49 (2008) 5283–5285
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Tetrahedron Letters
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Three-component synthesis of 5:6 and 6:6 fused pyrimidines
using KF–alumina as a catalyst
*
Pushpak Mizar, Bekington Myrboh
Department of Chemistry, North-Eastern Hill University, Mawlai-Mawkynroh, Shillong, Meghalaya 793 022, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of fused pyrimidine derivatives were synthesized by the three-component reaction of an aryl
aldehyde, urea, or guanidine in ethyl alcohol/dioxane in presence of 1-methyl-1H-pyrrol-2(3H)-one 1,
1-methylpiperidin-2-one 2, 1-methylindolin-2-one 3, or 1,3-dimethyl-dihydropyrimidine-2,4-dione 9
at 80 °C catalyzed by KF–Al2O3. For example, when 1-methyl-1H-pyrrol-2(3H)-one 1, arylaldehyde 4,
and urea 5 were treated with KF–Al2O3 in ethyl alcohol at 80 °C for 3–5 h, we obtained pyrrolo[2,3-d]-
pyrimidine derivatives in good yield.
Received 26 April 2008
Revised 17 June 2008
Accepted 21 June 2008
Available online 25 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Inorganic solid supports as catalysts have been used increas-
ingly in recent years for the synthesis of various biologically active
molecules. Among these inorganic solid supports, potassium fluo-
ride coated with alumina (KF–alumina) has been used as a versatile
reagent for various reactions such as the Knoevenagel condensa-
tion,1 the Henry reaction,2 the Darzens reaction,3 the Wittig reac-
tion,4 the Biginelli reaction,5 and alkylation6 and elimination7
reactions. In this Letter, we report a simple three-component syn-
thesis of 5:6 fused [d] pyrimidines such as pyrazolo[3,4-d]pyrim-
idines,8 pyrrolo[2,3-d]pyrimidines9 as well as 6:6 fused systems
such as pyrido[2,3-d]pyrimidines.10 These heterocycles represent
the aglycons of the more common bicyclic nucleosides, and these
heteroaromatic aglycons have been shown to possess a variety of
biological activities, such as inhibitors of epidermal growth factor
receptor (EGF-R) protein tyrosine kinases and their potential as a
treatment for proliferate diseases involving mitogenic signaling
from the EGF-R has been recognized.11 Derivatives of pyrrolo[2,3-
d]pyrimidines have also been evaluated for their anti-tumor
activities.12
in ethyl alcohol at 80 °C for 3–5 h, we obtained pyrrolo[2,3-d]-
pyrimidine derivatives 6a–e in good yields (Scheme 1). Evidently,
a sequence of reactions involving Biginelli-like condensation took
place during formation of the product. This may be concluded from
the fact that when condensation of 1-methyl-1H-pyrrol-2(3H)-one
1 and benzaldehyde was carried out, 3-benzylidene-1-methyl-1H-
pyrrol-2(3H)-one was isolated as the product13 thereby indicating
that a condensation reaction is the first step in this three-compo-
nent process.
In order to demonstrate the efficiency and the applicability of
the method, the reaction of a series of arylaldehydes with 2 or 3
was carried out to give the corresponding products14–17 7a–e and
8a–e in good yields under identical reaction conditions
(Table 1).
The scope of the reaction was also demonstrated by the synthe-
sis of 7-pyrimido[4,5-d]pyrimidin-2-ones using 1,3-dimethyl-
dihydropyrimidine-2,4-dione 9 as the starting material; the reac-
tion proceeded at 100 °C in the presence of KF/alumina as catalyst
in dioxane to yield the desired products in moderate yield 10a–e
(Scheme 2).
The product was also obtained in good yield when an alkyl or an
electron-donating group was attached to the aromatic ring of 4.
Furthermore, the reaction shown in Scheme 2 proceeded only
when dioxane was used as the solvent. The yield of this reaction
was improved partially when a few drops of acetic acid were
added.
Reports of pyrrolo[2,3-d]pyrimidine derivatives and their syn-
thesis are abundant in the literature.13 However, none of the syn-
thetic procedures provides a general route for the synthesis of
the three types of fused pyrimidines described here. Thus, as part
of our ongoing research on the development of new synthetic
methods, we found that when 1-methyl-1H-pyrrol-2(3H)-one 1,
arylaldehyde 4 and urea/guanidine 5 were treated with KF–Al2O3
In conclusion, we have developed a convenient method for the
synthesis of 5:6 and 6:6 fused pyrimidine derivatives through a
three-component reaction catalyzed by KF/alumina having wide
applicability, thus providing a general method for the synthesis
of potentially biologically active heterocycles.
* Corresponding author. Tel.: +91 364 2722612; fax: +91 364 2228213.
E-mail address: bmyrboh@nehu.ac.in (B. Myrboh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.087

5284
P. Mizar, B. Myrboh / Tetrahedron Letters 49 (2008) 5283–5285
R1
HN
X
N
N
7a-e
R1
N
O
2
O
X
KF/ alumina
ethanol
+
H2N
NH2
+
O
HN
80 oC
N
N
5
X
N
R1
1
6a-e
4
R1
O
N
3
N
N
HX
N
8a-e
Scheme 1. Synthesis of substituted fused pyrimidines.
Acknowledgments
Table 1
Substituted fused pyrimidines
P.M. thanks the CSIR for the award of junior research fellow-
ship; SAIF, NEHU Shillong, and IISc Bangalore for spectral analysis
and the UGC for the Special Assistance Program.
Entry
R1
X
Yield (%)
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
H
O
O
O
86
76
70
81
92
77
81
83
60
66
87
78
76
68
75
50
59
55
54
60
CH3
NH2
NO2
CH3
H
CH3
NH2
NO2
CH3
H
CH3
NH2
NO2
H
OH
CH3
NH2
NO2
NO2
NH
NH
NH
O
NH
O
NH
NH
O
NH
O
O
NH
O
O
NH
O
References and notes
1. Thompson, A. M.; Bridges, A. J.; Fry, D. W.; Kraker, A. J.; Denny, W. A. J. Med.
Chem. 1995, 38, 3780–3788.
2. Bredereck, H.; Gompper, R.; Schuh, H. G.; Theilig, G. Angew. Chem. 1959, 71,
753–760.
3. Monge, A.; Martinez-Merino, V.; Sanmartin, C.; Fernandez, F. J.; Ochoa, M. C.;
Bellver, C.; Artigas, P.; Fernandez-Alvarez, E. Eur. J. Med. Chem. 1989, 24, 209–
216.
4. Matsunaga, T.; Tohda, Y.; Ariga, M. J. Chem. Soc., Perkin Trans. 1 2000, 27–34.
5. (a) Biginelli, P. Ber. 1891, 24, 1317–1345; (b) Biginelli, P. Ber. 1893, 26, 447–
521; (c) Zaugg, H. E.; Martin, W. B. Org. React. 1965, 14, 88–95; (d) Kappe, C. O.
Tetrahedron 1993, 49, 6937–6963; (e) Svetlık, J.; Veizerova, L.; Kettmann, V.
Tetrahedron Lett. 2008, 49, 3520–3523; (f) Suzuki, I.; Iwata, Y.; Takeda, K.
Tetrahedron Lett. 2008, 49, 3238–3241.
8d
8e
10a
10b
10c
10d
10e
6. (a) Trapini, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.; Sanna,
E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42, 3934–3941; (b) Lober, S.; Hubner,
H.; Gmeneir, P. Bioorg. Med. Chem. Lett. 1999, 42, 3934–3940; (c) Rival, Y.;
R1
CHO
X
KF/alumina
N
HN
N
+
+
NH2
O
N
O
dioxane
100 oC
X
N
N
O
H2N
5
R1
10a-e
9
4
Scheme 2. Synthesis fo pyrimido[4,5-d]pyrimidines 10a–e.

P. Mizar, B. Myrboh / Tetrahedron Letters 49 (2008) 5283–5285
5285
Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992, 40, 1170–1178; (d) Lyon, M.;
Kercker, T. Org. Lett. 2004, 26, 4989–4994; (e) Jaramillo, C.; Carretero, C.; de
Diego, E.; Hamoduchi, C.; del Prado, M.; Roldan, J. L.; Sanchez-Martinez, C.
Tetrahedron Lett. 2002, 43, 9051–9056; (f) Kaminski, J. J.; Wallmark, B.; Briving,
C.; Andersson, B. M. J. Med. Chem. 1991, 34, 533–542; (g) Georges, G.;
Vercauteren, D. P.; Vanderveken, D. J.; Horion, R.; Evrard, G. H.; Durant, F. V.;
George, P.; Wick, A. Eur. J.Med. Chem. 1993, 28, 323–332.
crude product was purified by silica gel column chromatography using CH2Cl2
and methanol (9:1) as eluent to obtain an off-white solid 6a. Mp = 254–256 °C.
IR (KBr) 1785 cmÀ1 1H NMR (DMSO-d6, 400 MHz) d ppm 2.01 (t, J = 7.4 Hz, 2H),
.
2.52 (s, 3H, CH3), 2.61 (t, J = 7.4 Hz, 2H), 7.23–7.31 (m, 5H, aromatic), 11.26 (br
s, 1H, NH); 13C NMR (CDCl3, 100 MHz) d ppm 30.5, 36.4, 57.5, 107.1, 126.5,
127.7, 129.1, 134.2, 135.1, 156.5, 160.3. MS (CI) m/z = 228.12 (M+1). Anal. Calcd
for C13H13N3O: C, 69.18; H, 5.77; N, 18.49. Found: C, 69.21; H, 5.71; N, 18.52.
14. Compound 7b: IR (KBr) 1778 cmÀ1. Mp >300 °C. 1H NMR (DMSO-d6, 400 MHz)
d ppm 1.42 (m, 2H), 1.91 (t, J = 7.1 Hz, 2H), 2.37 (s, 3H, CH3), 2.45 (s, 3H, CH3),
2.56 (t, J = 7.1 Hz, 2H), 7.02–7.21 (m, 4H, aromatic), 11.15 (s, 1H, NH); 13C NMR
(CDCl3, 100 MHz) d ppm 21.7, 24.3, 25.1, 35.1, 45.7, 105.6, 126.1, 128.7, 130.9,
133.2, 137.7, 156.2, 159.6. MS (CI) m/z = 256.14 (M+1). Anal. Calcd for
7. (a) Bristow, N. W.; Charlton, P. T.; Peak, D. A.; Short, W. F. J. Chem. Soc. 1954,
616–629; (b) Tadeka, K.; Shudo, K.; Okamoto, T.; Kousuge, T. Chem. Pharm. Bull.
1978, 26, 2924; (c) Knott, E. B. J. Chem. Soc. 1956, 1360–1365; (d) Sugiura, S.;
Akoi, H. K.; Inouf, S.; Goto, T. Yakukagaku Zasshi 1970, 90, 436–442; (e) Saint-
Ruf, G.; Loukakou, B.; Zousi, C. J. Heterocycl. Chem. 1981, 18, 1565–1570; (f)
Ohta, M.; Masaki, M. Bull. Chem. Soc. Jpn. 1960, 37, 1392–1399.
8. Brown, D. J. The Pyrimidines, 1st ed.; Wiley: NY, 1962; pp 19–105.
9. Bystryakova, I. D.; Burova, I. A.; Chelysheva, G. M.; Zhilinkova, S. V.; Smirnova,
N. M.; Safonova, T. S. Khim-Farm. Zh. 1991, 25, 31–37.
C
15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.65; H, 6.68; N, 16.56.
15. Compound 8e: IR (KBr) 3451 cmÀ1. Mp >300 °C. 1H NMR (DMSO-d6, 400 MHz)
d ppm 3.65 (s, 3H, CH3), 6.15 (s, 2H, NH2) 7.21–7.23 (m, 1H, aromatic), 7.24–
7.30 (m, 4H, aromatic), 7.32–7.35 (m, 2H, aromatic), 7.44 (d, J = 7.1 Hz, 2H); 13
C
10. Deyanov, A. B.; Niyazov, R. K.; Nazmetdinov, F. Y.; Syropyatov, B. Y.; Kolla, V. E.;
Konshin, M. E. Khim-Farm. Zh. 1991, 25, 26–32.
NMR (CDCl3, 100 MHz) d ppm 44.6, 102.4, 111.3, 119.1, 120.5, 122.5, 127.6,
127.9, 128.5, 129.1, 131.8, 133.5, 136.7, 162.7, 163.7. MS (CI) m/z = 275.13.
Anal. Calcd for C17H14N4: C, 74.43; H, 5.14; N, 20.42. Found: C, 74.53; H, 5.184;
N, 20.62.
11. (a) Jourdan, F.; Laduree, D.; Robba, M. J. Heterocycl. Chem. 1994, 31, 305–312;
(b) Anderson, E. L.; Casey, J. E.; Greene, L. C.; Lafferty, J. J.; Reiff, H. E. J. Med.
Chem. 1964, 7, 259–268; (c) Russell, P. B.; Hitchings, J. H. J. Am.Chem. Soc. 1951,
73, 3763–3770; (d) Bruni, F.; Selleri, S.; Costanzo, A.; Guerrini, G.; Casilli, M. L.;
Giusti, L. J. Heterocycl. Chem. 1995, 32, 291–298; (e) Barlin, G. B.; Kotecka, B.;
Rieckmann, K. H. Aust. J. Chem. 1996, 49, 647–650; (f) Selleri, S.; Bruni, F.;
Costanzo, A.; Guerrini, G.; Casilli, M. L. Farmaco 1995, 50, 679–688.
16. Compound 10d: IR (KBr) 1675 cmÀ1. Mp = 252–253 °C. 1H NMR (DMSO-d6,
400 MHz) d ppm 2.41 (s, 3H, CH3) 2.68 (s, 6H, CH3), 3.92 (s, 2H, CH2), 7.01 (d,
J = 7.0 Hz, 2H, aromatic), 7.15 (d, J = 7.2 Hz, 2H, aromatic), 11.36 (s, 1H, NH);
13C NMR (CDCl3, 100 MHz) d ppm 24.6, 29.7, 38.0, 46.5, 103.6, 126.2, 128.5,
131.6, 134.1, 138.2, 154.9, 156.4, 158.6. MS(CI) m/z = 283.13 (MÀ1). Anal. Calcd
for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C, 63.47; H, 5.77; N, 19.61.
17. Compound 10e: IR (KBr) 1680, 3385 cmÀ1. Mp = 257–258 °C 1H NMR (DMSO-
d6, 400 MHz) d ppm 2.67 (s, 6H, CH3), 3.95 (s, 2H, CH2), 7.56 (d, J = 7.2 Hz, 2H,
aromatic), 8.18 (d, J = 7.2 Hz, 2H, aromatic), 11.57 (s, 1H, NH); 13C NMR (CDCl3,
100 MHz) d ppm 29.8, 36.9, 46.5, 102.6, 120.9, 126.9, 134.2, 140.3, 147.5, 155.7,
156.2, 159.1. MS (CI) m/z = 316.10 (M+1). Anal. Calcd for C14H13N5O4: C, 53.33;
H, 4.16; N, 22.21. Found: C, 53.43; H, 4.26; N, 22.11.
12. Girgis, N. S.; Michael, M. A.; Smee, D. F.; Alaghamandan, H. A.; Robins, R. K.;
Cottam, H. B. J. Med. Chem. 1990, 33, 2750–2755.
13. General reaction procedure: Synthesis of 6a: A dry 100 mL flask was charged
with benzaldehyde 4 (8 mmol), urea 5 (8 mmol), 1-methylpyrrolidin-2-one 1
(8 mmol), KF/Al2O3 (1 g), and EtOH (30 mL). The mixture was stirred at 80 °C
for 5–8 h. The reaction mixture, after completion (monitored by TLC), was
cooled to room temperature, the solvent was evaporated in vacuum, and the