Microwave-assisted Synthesis of 5-Deaza-5,8-dihydropterins

Abstract

Three-component cyclocondensation of 2,6-diaminopyrimidin-4-one, 1,3-dicarbonyl compounds or benzoylacetonitrile and aromatic or aliphatic aldehydes in the presence or absence of zinc(II) bromide proceeds under microwave-assisted conditions to give 5-deaza-5,8-dihydropterins in good yield and with total control of regiochemistry.

dihydropyridopyrimidines - three-component cyclocondensations - microwave synthesis - heterocycles - Lewis acids

References

1a Hopkins FG. Nature (London)  1889,  40:  335 

1b Hopkins FG. Nature (London)  1891,  45:  197 

1c Hopkins FG. Nature (London)  1892,  45:  581 

2 Mitchell HK. Snell EE. Williams RJ. J. Am. Chem. Soc.  1941,  63:  2284 

3 Scott JM. Weir DG. Kirke P. In Folate and Neural Tube defects. Folate in Health and Disease   Chap. 12:  Bailey L. B., Marcel Dekker; New York: 1994.  p.329 

4a Taylor EC. Palmer DC. George TJ. Fletcher SR. Tseng CP. Harrington PJ. Beardsley GP. J. Org. Chem.  1983,  48:  4852 

4b DeGraw JI. Christie PH. Colwell WT. Sirotnak FM. J. Med. Chem.  1992,  35:  320 

4c Borrell JI. Teixidó J. Matallana JL. Martínez-Teipel B. Colominas C. Costa M. Balcells M. Schuler E. Castillo MJ. J. Med. Chem.  2001,  44:  2366 

5 Grivsky EM. Lee S. Sigel CW. Duch DS. Nichol CA. J. Med. Chem.  1980,  23:  327 

6a Matsumoto J. Minami S. J. Med. Chem.  1975,  18:  74 

6b Suzuki N. Chem. Pharm. Bull.  1980,  28:  761 

6c Oakes V. Rydon HN. J. Chem. Soc.  1956,  4433 

6d DeGraw JI. Kisliuk RL. Gaumont Y. Baugh CM. J. Med. Chem.  1974,  17:  470 

6e Zakharov AV. Gavrilov MY. Novoselova GN. Vakhrin MI. Konshin ME. Khim-Farm. Zh.  1996,  30:  39 

7 Deyanov AB. Niyazov RK. Nazmetdinov FY. Syropyatov BY. Kolla VE. Konshin ME. Khim-Farm. Zh.  1991,  25:  26 

8 Heckler RE, and Jourdan GP. inventors; Eur. Patent 414  386.  ; Chem. Abstr. 1991, 115, 71630

9 Bagley MC. Hughes DD. Lloyd R. Powers VEC. Tetrahedron Lett.  2001,  42:  6585 

10 Bagley MC. Dale JW. Hughes DD. Ohnesorge M. Phillips NG. Bower J. Synlett  2001,  1523 

11 Bagley MC. Singh N. Chem. Commun.  2001,  2438 

12 Quiroga J. Cisneros C. Insuasty B. Abonía R. Nogueras M. Sánchez A. Tetrahedron Lett.  2001,  42:  5625 

13

In a typical experimental procedure, a mixture of 1,3-diaminopyrimidin-4-one 1 (0.20 g, 1.6 mmol), benzaldehyde (0.34 g, 3.2 mmol), ethyl acetoacetate (0.41 g, 3.2 mmol) and zinc(II) bromide (0.072 g, 0.32 mmol) in DMSO (7 mL) was irradiated for 20 min in a self-tunable CEM microwave synthesizer at 160 °C (initial power 30 W) and then allowed to cool. Water (25 mL) was added and the solution was left to stand for 5-6 h. The precipitated solid was filtered and washed with ethyl acetate to give 5-deaza-5-dihydropterin (3a) (0.38 g, 80%) as a pale yellow solid, mp 179-180 °C (Found: MH⁺, 327.1454. C₁₇H₁₈N₄O₃ requires MH, 327.1457); IR (KBr)/cm^-1: 3317, 3206, 2936, 1660, 1599, 1515, 1455, 1367, 1285, 1224, 1106, 1024; ¹H NMR (DMSO-d ₆; 400 MHz) δ (ppm) 10.34 (1 H, 3, 3-H), 9.06 (1 H, s, 8-H), 7.24-7.00 (5 H, m, PhH), 6.27 (2 H, s, NH₂), 4.82 (1 H, s, 5-H), 3.94 (2 H, q, J = 7.0 Hz, CH₂), 2.31 (3 H, s,
7-Me), 1.10 (3 H, t, J = 7.0 Hz, Me); ¹³C NMR (DMSO-d ₆; 100 MHz) δ (ppm) 167.2 (C), 161.8 (C), 154.4 (C), 154.3 (C), 148.5 (C), 147.5 (C), 128.0 (CH), 127.6 (CH), 125.9 (CH), 101.5 (C), 91.4 (C), 59.2 (CH), 36.8 (CH₂), 18.8 (Me), 14.5 (Me); m/z (APcI) 327 (MH⁺, 100%), 79 (67).