A one-pot Biginelli synthesis of 6-unsubstituted 5-aroylpyrimidin-2(1H)- ones and 6-acetyl-1,2,4-triazin-3(2H)-ones

Article abstract of DOI:10.1002/hlca.200900355

The three-component Biginelli-like cyclocondensation reaction of enamines 1, urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6-acetyl-1,2,4-triazin-3(2H)-ones in good yields (Scheme 3).

Full text of DOI:10.1002/hlca.200900355

1204
Helvetica Chimica Acta – Vol. 93 (2010)
A One-Pot Biginelli Synthesis of 6-Unsubstituted 5-Aroylpyrimidin-2(1H)-
ones and 6-Acetyl-1,2,4-triazin-3(2H)-ones
by Elham Sayed Darwisha), Ismail Abdelshafy Abdelhamid*a)b), Miead Adel Nasraa),
Fathy Mohamed Abdel-Gallila), and Daisy Hanna Fleitac)
a) Chemistry Department, Faculty of Science, Cairo University Giza, A. R. Egypt
(ismail_shafy@yahoo.com)
b) Institut fꢀr Organische Chemie der Universitꢁt Hannover, Schneiderberg 1B, DE-30167 Hannover
c) Chemistry Department, American University in Cairo, Egypt
The three-component Biginelli-like cyclocondensation reaction of enamines 1, urea, and aldehydes
in dioxane/acetic acid efficiently afforded the corresponding 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-
ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (¼ hydrazone) 7 with
benzaldehyde and urea afforded 6-acetyl-1,2,4-triazin-3(2H)-ones in good yields (Scheme 3).
Introduction. – The Biginelli reaction is one of the most useful multicomponent
reactions. It offers an efficient way to access multifunctionalized 3,4-dihydropyrimidin-
2(1H)-ones and related heterocyclic compounds. Dihydropyrimidinones (DHPMs)
have attracted considerable interest because of their wide spectrum of pharmacological
and therapeutic activities [1 – 8]. Appropriately functionalized DHPMs have been used
as antihypertensive agents [2 – 5] and potent calcium channel blockers [3][5]. Recently,
DHPMs have also been shown to be useful for the development of anticancer drugs
[6][7]. The established synthesis of DHPMs by the Biginelli reaction [1][9] involves the
one-pot multicomponent condensation of b-keto esters, aldehydes, and urea in
refluxing EtOH containing a catalytic amount of HCl.
Results and Discussion. – As a part of our continued interest in enamine and
azaenamine chemistry [10 – 15], we report here our preliminary investigation dealing
with the use of these compounds as substitutes to b-keto esters utilizing Biginelli
reaction conditions. The utility of enamines gave us the opportunity to prepare
corresponding new 6-unsubstituted 5-aroyl-3,4-dihydropyrimidin-2(1H)-one deriva-
tives in moderate to good yields by means of a simple and efficient protocol for the
Biginelli-like three-component cyclocondensation reactions of aldehydes, enamines,
and urea. In the preliminary study, we found that heating enamine 1a with
benzaldehyde and urea in the presence of dioxane/AcOH resulted in the formation
of condensation product 2a via ammonia and water elimination (Scheme 1). The
chemical structure of compound 2a was established based on spectroscopic data. Thus,
the mass spectra of 2a revealed the molecular-ion peak at m/z 292 (19%). The
1H-NMR spectrum of 2a featured characteristic ds at d(H) 5.43 assigned to HꢀC(4)
and d(H) 7.05 assigned to HꢀC(6). It also showed two broad ss at d(H) 7.87 and 9.34
assigned to HꢀN(1) and HꢀN(3). The Me group and aromatic H-atoms appeared at
ꢂ 2010 Verlag Helvetica Chimica Acta AG, Zꢀrich

Helvetica Chimica Acta – Vol. 93 (2010)
1205
their expected positions. Furthermore, full assignment of the 13C-NMR data confirmed
the structure of 2a, where the key signal at d(C) 53.8 was assigned to C(4) (sp3 C-
atom), that at d(C) 112.9 to C(5), and that at d(C) 191.8 to the CO group. All other C-
atoms appeared as expected. To investigate the scope of this reaction, several other
enamines and aldehydes were studied, as summarized in the Table. In all cases, the
three-component reaction proceeded smoothly and yielded 5-aroyl-3,4-dihydropyr-
imidin-2(1H)-ones 2b – 2f (Table). The structures of the prepared products were
elucidated based on spectroscopic data.
Scheme 1
Table. Yields of Compounds 2a – 2fa)
R
Ar
Yield [%]
R
Ar
Yield [%]
2a
2b
2c
4-MeꢀC6H4
4-MeꢀC6H4
Ph
Ph
66
63
65
2d
2e
2f
thien-2-yl
thien-2-yl
thien-2-yl
Ph
68
70
67
4-MeOꢀC6H4
4-ClꢀC6H4
Ph
4-MeOꢀC6H4
a) Cf. Scheme 1.
Following the recently published literature [16], the mechanism of this reaction
involves the acid-catalyzed formation of an N-acyliminium ion intermediate of type 4
from the aldehyde and urea precursors (via 3). Interception of the iminium ion 4 by
enamine 1 produces an open-chain ureidoenone 5, which subsequently cyclizes to
hexahydropyrimidine 6. Acid-catalyzed elimination of the Me2N group from 6
ultimately leads to the final DHPM product 2 (Scheme 2). The reaction mechanism
can, therefore, be classified as an a-amidoalkylation, or more specifically as an a-
ureidoalkylation.
In an extension of the program to discover versatile routes to the Biginelli-like
reaction, the possible utility of azaenamines was also investigated. It was discovered
that azaenamine (¼ hydrazone) 7 with a sufficiently acidic CH¼N moiety reacted with
benzaldehyde and urea following the reaction conditions described for compounds 2a –
2f, resulting in the formation of 6-acetyl-1,2,4-triazin-3(2H)-ones. The formed products
can be in theory formulated as 8 – 10. The 1H-NMR spectrum indicated the presence of
a 1:2 mixture of 8 and 10, as it showed two signals at d(H) 2.54 and 2.35 for two Me
groups. It also indicated the presence of a ds at d(H) 4.38 and a broad s at d(H) 5.99 for
10. In addition, it featured a d at d(H) 4.90 and a broad s at d(H) 6.15 for 8.

1206
Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2
Scheme 3
Conclusions. – We could establish a new and efficient synthesis of 6-unsubstituted
5-aroylpyrimidin-2(1H)-ones using simple starting materials. We could also extend this
technique to the synthesis of 6-acetyl-1,2,4-triazin-3(2H)-one.
I. A. A. is deeply indebted to the Alexander von Humboldt Foundation, Germany, for granting him a
postdoctoral fellowship. He is also very thankful to Prof. Dr. Holger Butenschçn, Institut fꢀr Organische
Chemie, Leibniz Universitꢁt Hannover, for his kind hospitality.

Helvetica Chimica Acta – Vol. 93 (2010)
1207
Experimental Part
General. M.p.: Stuart melting-point apparatus; uncorrected. IR Spectra: Bruker-Vector-22 FT-IR
spectrophotometer; KBr pellets; in cmꢀ1. 1H- and 13C-NMR Spectra: Varian-Gemini NMR spectrometer;
at 300 or 400 MHz (1H) and 75 or 100 Mz (13C); in (D6)DMSO with Me4Si as internal standard; d in ppm,
coupling constants J in Hz. MS: Shimadzu-GMMS-QP-1000-EX mass spectrometer; at 70 eV; in m/z
(rel. %).
Biginelli-Like Reaction: General Procedure. Urea (1.0 mmol) was added to a soln. of aldehyde
(1.0 mmol) and enamine 1 (a, b, or c) or azaenamine 7 in dioxane (20 ml) and a few drops of AcOH or
HCl, and the mixture was refluxed until the reaction reached completion (TLC monitoring). After
completion of the reaction, the mixture was triturated with H2O, and the crude products were directly
filtrated and purified by recrystallization to afford the products 2a – 2f (see Table) or 8/10 (see below).
3,4-Dihydro-5-(4-methylbenzoyl)-4-phenylpyrimidin-2(1H)-one (2a): White solid. Rf (AcOEt/petro-
leum ether 1:1) 0.5. M.p. 306 – 3088 (EtOH/dioxane). IR: 3240, 3110, 1718, 1641. 1H-NMR (400 MHz):
2.36 (s, Me); 5.43 (d, J ¼ 2.8, HꢀC(4)); 7.05 (d, J ¼ 5.9, HꢀC(6)); 7.26 – 7.87(m, 9 arom. H); 7.87 (br. s, 1
NH); 9.34 (br. s, 1 NH). 13C-NMR (100 MHz): 21.2; 53.8; 112.9; 126.9; 127.8; 128.6; 128.9; 129.4; 136.2;
141.4; 141.7; 144.6; 151.7; 191.8. MS: 292 (19). Anal. calc. for C18H16N2O2 (292.33): C 73.95, H 5.52, N
9.58; found: C 73.93, H 5.49, N 9.46.
3,4-Dihydro-4-(4-methoxyphenyl)-5-(4-methylbenzoyl)pyrimidin-2(1H)-one (2b): White solid. Rf
(AcOEt/petroleum ether 1:1) 0.52. M.p. 242 – 2448 (EtOH/dioxane). IR: 3239, 3109, 1716, 1638.
1H-NMR (300 MHz): 2.34 (s, Me); 3.72 (s, MeO); 5.37 (d, J ¼ 2.4, HꢀC(4)); 6.88 (d, J ¼ 8.1, 2 arom. H);
6.99 (d, J ¼ 5.7, HꢀC(6)); 7.23 – 7.37 (m, 4 arom. H); 7.40 (d, J ¼ 8.1, 2 arom. H); 7.75 (br. s, 1 NH); 9.23
(br. s, 1 NH). MS: 322 (Mþ). Anal. calc. for C19H18N2O3 (322.36): C 70.79, H 5.63, N 8.69; found: C 70.69,
H 5.57, N 8.68.
5-Benzoyl-3,4-dihydro-4-phenylpyrimidin-2(1H)-one (2c): White solid. Rf (AcOEt/petroleum ether
1:1) 0.69. M.p. 298 – 3008 (EtOH/dioxane). IR: 3240, 3110, 1718, 1641. 1H-NMR (300 MHz): 5.43 (d, J ¼
3.3, HꢀC(4)); 7.05 (d, J ¼ 5.4, HꢀC(6)); 7.26 – 7.53 (m, 10 arom. H); 7.85 (br. s, 1 NH); 9.30 (br. s, 1 NH).
MS: 278 (37.4). Anal. calc. for C17H14N2O2 (278.31): C 73.37, H 5.07, N 10.07; found: C 73.24, H 4.98, N
9.79.
3,4-Dihydro-4-phenyl-5-(thien-2-ylcarbonyl)pyrimidin-2(1H)-one (2d): White solid. Rf (AcOEt/
petroleum ether 1:1) 0.6. M.p. 276 – 2788 (EtOH/dioxane). IR: 3249, 3123, 1712, 1646. 1H-NMR
(300 MHz): 5.41 (d, J ¼ 2.4, HꢀC(4)); 7.14 – 7.32 (m, 6 arom. H, 1 NH); 7.47 (d, J ¼ 5.7, HꢀC(6)); 7.65 (d,
J ¼ 3.3, 1 H, thienyl); 7.66 – 7.87 (m, 2 H, thienyl); 9.36 (br. s, 1 NH). 13C-NMR (75 MHz): 21.2; 53.8;
112.9; 126.9; 127.8; 128.9; 129.4; 136.2; 141.4; 141.7; 144.6; 151.7; 191.8. MS: 286 (43.63). Anal. calc. for
C15H12N2O2S (284.33): C 63.36, H 4.25, N 9.85, S 11.28; found: C 63.19, H 4.81, N 9.69, S 11.12.
4-(4-Chlorophenyl)-3,4-dihydro-5-(thien-2-ylcarbonyl)pyrimidin-2(1H)-one (2e): White solid. Rf
(AcOEt/petroleum ether 1:1) 0.56. M.p. 242 – 2448 (EtOH/dioxane). IR: 3256, 3139, 1726, 1661.
1H-NMR (300 MHz): 5.40 (d, J ¼ 3, HꢀC(4)); 6.95 (d, J ¼ 8.7, 2 arom. H); 7.16 (d, J ¼ 8.7, 2 arom. H);
7.26 (d, J ¼ 5.9, HꢀC(6)); 7.48 (br. s, 1 NH); 7.67 (d, J ¼ 4.5, 1 H, thienyl); 7.85 – 7.91 (m, 2 H, thienyl);
9.43 (br. s, 1 NH). MS: 320 (23.8). Anal. calc. for C15H11ClN2O2S (318.78): C 56.52, H 3.48, Cl 11.12, N
8.79, S 10.06; found: C 56.98 H 3.82, Cl 11.38, S 9.91.
3,4-Dihydro-4-(4-methoxyphenyl)-5-(thien-2-ylcarbonyl)pyrimidin-2(1H)-one (2f): White solid. Rf
(AcOEt/petroleum ether 1:1) 0.47. M.p. 276 – 2788 (EtOH/dioxane). IR: 3234, 3109, 1710, 1639.
1H-NMR (300 MHz): 3.71 (s, MeO); 5.35 (d, J ¼ 2.7, HꢀC(4)); 6.86 (d, J ¼ 8.7, 2 arom. H); 7.14 (br. s, 1
NH); 7.17(d, J ¼ 8.7, 2 arom. H); 7.43 (d, J ¼ 6, HꢀC(6)); 7.64 – 7.75 (m, 2 H, thienyl); 7.86 (d, J ¼ 5.1, 1
H, thienyl); 9.32 (br. s, 1 NH). 13C-NMR (75 MHz): 52.9; 55.0; 112.4; 113.7; 120.6; 127.8; 131.3; 132.2;
136.1; 139.4; 142.5; 151.2; 158.5; 182.3. MS: 316 (32.17). Anal. calc. for C16H14N2O3S (314.36): C 61.13, H
4.49, N 8.91, S 10.20; found: C 60.59, H 4.94, N 8.73, S 9.88.
6-Acetyl-4,5- and 1,6-dihydro-2,5-diphenyl-1,2,4-triazin-3(2H)-one (8 and 10; ratio 1:2). White solid.
M.p. 188 – 190 (EtOH/dioxane). IR: 3233, 1690, 1653. 1H-NMR (400 MHz; italic signals for the
predominant isomer 10) 2.35 (s, Me); 2.54 (s, Me); 4.38 (d, J ¼ 4.26, HꢀC(6)); 4.90 (d, J ¼ 3.1, HꢀC(5));
5.99 (br. s, 1 NH); 6.15 (br. s, 1 NH); 6.71 – 7.27 (m, 20 arom. H). 13C-NMR (100 MHz; italic signals for
the predominant isomer 10): 24.2; 24.5; 50.1; 68.2; 115.1; 116.1; 122.7; 125.8; 127.5; 127.6; 127.7;

1208
Helvetica Chimica Acta – Vol. 93 (2010)
127.8; 128.4; 128.5; 128.8; 129.2; 129.5; 129.7; 137.7; 138.3; 141; 141.8; 143.1; 144.8; 194.7; 195.8. MS: 293
(Mþ).
REFERENCES
[1] C. O. Kappe, Tetrahedron 1993, 49, 6937.
[2] C. O. Kappe, W. M. F. Fabian, Tetrahedron 1997, 53, 2803.
[3] G. C. Rovnyak, K. S. Atwal, A. Hedberg, S. D. Kimball, S. Moreland, J. Z. Gougoutas, B. C.
OꢃReilly, J. Schwartz, M. F. Malley, Med. J. Chem. 1992, 35, 3254.
[4] K. S. Atwal, G. C. Rovnyak, B. C. OꢃReilly, J. Schwartz, J. Org. Chem. 1989, 54, 5898.
[5] C. O. Kappe, Eur. J. Med. Chem. 2000, 35, 1043.
[6] T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber, T. J. Mitchison, Science
(Washington, DC, U.S.) 1999, 286, 971.
[7] C. O. Kappe, O. V. Shishkin, G. Uray, P. Verdino, Tetrahedron 2000, 56, 1859.
[8] A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Bean, A. J. Freyer, C. De Brosse, S. Mai, A. Truneh,
D. J. Faulkner, B. Cart, A. L. Breen, R. P. Hertzberg, R. K. Johnson, J. W. Wesley, B. C. M. Potts, J.
Org. Chem. 1995, 60, 1182.
[9] P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360.
[10] S. A. S. Ghozlan, I. A. Abdelhamid, H. Gaber, M. H. Elnagdi, J. Chem. Res. 2004, 12, 789.
[11] S. A. S. Ghozlan, I. A. Abdelhamid, M. H. Elnagdi, H. Gaber, J. Heterocycl. Chem. 2005, 42, 1185.
[12] I. A. Abdelhamid, S. A. S. Ghozlan, H. Kolshorn, H. Meier, M. H. Elnagdi, Heterocycles 2007, 71,
2627.
[13] I. A. Abdelhamid, Synlett 2009, 4, 625.
[14] S. A. S. Ghozlan, I. A. Abdelhamid, H. M. Hassaneen, M. H. Elnagdi, J. Heterocycl. Chem. 2007, 44,
105.
[15] S. A. S. Ghozlan, M. H. Mohamed, A. M. Abdelmoniem, I. A. Abdelhamid, Arkivoc 2009, x, 302.
[16] F. S. Falsone, C. O. Kappe, Arkivoc 2001, ii, 122.
Received October 7, 2009