Synthesis of 4H-Pyrazino[1,2-a]pyrimidine-4,9(8H)-diones and Imidazo[1,2-a]pyrazin-8(7H)-ones

Abstract

A facile method of synthesis of 4H-pyrazino[1,2-a]-­pyrimidine-4,9(8H)-diones and imidazo[1,2-a]pyrazin-8(7H)-ones from the corresponding 3-amino-2(1H)-pyrazinones is described.

Key words

heterocyclic compounds - bicyclic compounds - ­Conrad–Limpach condensation - parallel synthesis

• References

• 1 Pitt WR, Perry DM, Groom CR. J. Med. Chem. 2009; 52: 2952
• 2 Matsutani S, Mizushima Y. EU Patent 0329126, 1989
• 3 Larsen RD In Science of Synthesis . Vol. 15. Georg Thieme Verlag; Stuttgart: 2005: 551
• 4 Pawar VG, De Borggraeve WM. Synthesis 2006; 2799 ; and references cited therein
• 5 Guo T, Hunter RC, Zhang R, Greenlee WJ. Tetrahedron Lett. 2007; 48: 613
• 6 Representative Procedure for the Preparation of 4H-Pyrazino[1,2-a]pyrimidine-4,9(8H)-diones 12a–n; 2-Methyl-8-phenyl-4H-pyrimido[1,2-a]pyrazine-4,9(8H)-dione (12a): 3-Amino-1-phenylpyrazin-2(1H)-one (11a; 100 mg, 0.53 mmol), methyl 3-oxobutanoate (3a; 0.576 mL, 5.34 mmol) and methanesulfonic acid (0.035 mL, 0.53 mmol) were dissolved in anhyd MeCN (1.2 mL) and sealed into a microwave tube. The reaction was heated at 180 °C over a period of 30 min within the microwave reactor (see ref. 12). The crude product was purified by flash silica chromatography (elution gradient 0–100% EtOAc in isohexane) to afford 2-methyl-8-phenyl-4H-pyrimido[1,2-a]pyrazine-4,9(8H)-dione (12a) as a white solid (124 mg, 89%); mp 238.5–239.2 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.53 (s, 3 H), 6.55 (s, 1 H), 6.90 (d, J = 6.4 Hz, 1 H), 7.35–7.60 (m, 5 H), 7.76 (d, J = 6.4 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 24.49, 103.58, 111.92, 120.18, 125.78, 129.08, 129.71, 139.20, 144.66, 154.61, 157.54, 164.56. HRMS (ESI+): m/z [M + H⁺] calcd for C₁₄H₁₁N₃O₂: 254.0924; found: 254.0938.
• 7 3-Amino-1,5-diphenylpyrazin-2(1H)-one (14; R = Ph) was obtained in a Suzuki cross-coupling reaction between 3-amino-5-bromo-1-phenylpyrazin-2(1H)-one (10a) and phenylboronic acid in 42% yield.
• 8 A Representative Procedure for the Preparation of Imidazo[1,2-a]pyrazin-8(7H)-ones 16a–k; 2,7-Diphenylimidazo[1,2-a]pyrazin-8(7H)-one (16b): 3-Amino-1-phenylpyrazin-2(1H)-one (11a; 100 mg, 0.53 mmol), 2-bromo-1-phenylethanone (4b; 133 mg, 0.67 mmol) and Et₃N (0.093 mL, 0.67 mmol) were dissolved in anhyd MeCN (1.2 mL) and sealed into a microwave tube. The reaction was heated to 170 °C over a period of 45 min in the microwave reactor (see ref. 12). The solid was filtered off, washed with Et₃N and recrystallised from MeCN to afford 2,7-diphenylimidazo[1,2-a]pyrazin-8(7H)-one (16b) as white crystals (85 mg, 55%); mp 304.9–306.9 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.20 (d, J = 5.9 Hz, 1 H), 7.35 (t, J = 7.3 Hz, 1 H), 7.43–7.59 (m, 7 H), 7.65 (d, J = 5.9 Hz, 1 H), 7.94 (dd, J = 8.2, 1.0 Hz, 2 H), 8.33 (s, 1 H). HRMS (ESI+): m/z [M + H⁺] calcd for C₁₈H₁₃N₃O: 288.1131; found: 288.1134.
• 9 For example, in a NOE experiment irradiation of the proton at the 5-position of imidazo[1,2-a]pyrazin-8(7H)-one ring in 16a and 16j resulted in enhancement of R² proton signal in compound 16a (R² = H) and in the case of 16j (R² = Me) the protons of the methyl group.
• 10a Goodacre SC, Hallett DJ, Carling RW, Castro JL, Reynolds DS, Pike A, Wafford KA, Newman R, Atack JR, Street LJ. Bioorg. Med. Chem. Lett. 2006; 16: 1582
• 10b Dwyer MP, Paruch K, Alvarez C, Doll RJ, Keertikar K, Duca J, Fischmann TO, Hruza A, Madison V, Lees E, Parry D, Seghezzi W, Sgambellone N, Shanahan F, Wiswell D, Guzi TJ. Bioorg. Med. Chem. Lett. 2007; 17: 6216
• 10c MacLeod A, Mitchell DR, Palmer N, Parsy CC, Goldsmith MD, Harris CJ. World Patent 2009024585, 2009
• 11 Davey DD. J. Org. Chem. 1987; 52: 4379
• 12 Single-mode CEM Explorer and Biotage Initiator automated microwave reactors were used.