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Synlett 2012; 23(20): 2935-2938
DOI: 10.1055/s-0032-1317686
DOI: 10.1055/s-0032-1317686
letter
Synthesis of 4H-Pyrazino[1,2-a]pyrimidine-4,9(8H)-diones and Imidazo[1,2-a]pyrazin-8(7H)-ones
Further Information
Publication History
Received: 06 September 2012
Accepted after revision: 02 November 2012
Publication Date:
28 November 2012 (online)
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.
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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.
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- 12 Single-mode CEM Explorer and Biotage Initiator automated microwave reactors were used.