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

<A NAME="RD16402ST-1A">1a</A> Hopkins FG. Nature (London)  1889,  40:  335 

<A NAME="RD16402ST-1B">1b</A> Hopkins FG. Nature (London)  1891,  45:  197 

<A NAME="RD16402ST-1C">1c</A> Hopkins FG. Nature (London)  1892,  45:  581 

<A NAME="RD16402ST-2">2</A> Mitchell HK. Snell EE. Williams RJ. J. Am. Chem. Soc.  1941,  63:  2284 

<A NAME="RD16402ST-3">3</A> 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 

<A NAME="RD16402ST-4A">4a</A> Taylor EC. Palmer DC. George TJ. Fletcher SR. Tseng CP. Harrington PJ. Beardsley GP. J. Org. Chem.  1983,  48:  4852 

<A NAME="RD16402ST-4B">4b</A> DeGraw JI. Christie PH. Colwell WT. Sirotnak FM. J. Med. Chem.  1992,  35:  320 

<A NAME="RD16402ST-4C">4c</A> 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 

<A NAME="RD16402ST-5">5</A> Grivsky EM. Lee S. Sigel CW. Duch DS. Nichol CA. J. Med. Chem.  1980,  23:  327 

<A NAME="RD16402ST-6A">6a</A> Matsumoto J. Minami S. J. Med. Chem.  1975,  18:  74 

<A NAME="RD16402ST-6B">6b</A> Suzuki N. Chem. Pharm. Bull.  1980,  28:  761 

<A NAME="RD16402ST-6C">6c</A> Oakes V. Rydon HN. J. Chem. Soc.  1956,  4433 

<A NAME="RD16402ST-6D">6d</A> DeGraw JI. Kisliuk RL. Gaumont Y. Baugh CM. J. Med. Chem.  1974,  17:  470 

<A NAME="RD16402ST-6E">6e</A> Zakharov AV. Gavrilov MY. Novoselova GN. Vakhrin MI. Konshin ME. Khim-Farm. Zh.  1996,  30:  39 

<A NAME="RD16402ST-7">7</A> Deyanov AB. Niyazov RK. Nazmetdinov FY. Syropyatov BY. Kolla VE. Konshin ME. Khim-Farm. Zh.  1991,  25:  26 

<A NAME="RD16402ST-8">8</A> Heckler RE, and Jourdan GP. inventors; Eur. Patent 414  386.  ; Chem. Abstr. 1991, 115, 71630

<A NAME="RD16402ST-9">9</A> Bagley MC. Hughes DD. Lloyd R. Powers VEC. Tetrahedron Lett.  2001,  42:  6585 

<A NAME="RD16402ST-10">10</A> Bagley MC. Dale JW. Hughes DD. Ohnesorge M. Phillips NG. Bower J. Synlett  2001,  1523 

<A NAME="RD16402ST-11">11</A> Bagley MC. Singh N. Chem. Commun.  2001,  2438 

<A NAME="RD16402ST-12">12</A> Quiroga J. Cisneros C. Insuasty B. Abonía R. Nogueras M. Sánchez A. Tetrahedron Lett.  2001,  42:  5625 

<A NAME="RD16402ST-13">13</A>

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).