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Synlett 2004(11): 2031-2033  
DOI: 10.1055/s-2004-830866
LETTER
© Georg Thieme Verlag Stuttgart · New York

Concise Synthesis of 1H-Pyrazin-2-ones and 2-Aminopyrazines

Isabelle Adama, David Orainb, Peter Meier*a
a Novartis Institutes for BioMedical Research Basel, Lead Synthesis and Chemogenetics, Global Discovery Chemistry, Lichtstrasse 35, 4056 Basel, Switzerland
b Novartis Institutes for BioMedical Research Basel, Ophthalmics, Global Discovery Chemistry, Klybeckstrasse 141, 4057 Basel, Switzerland
Fax: +41(61)3244236; e-Mail: peter.meier@pharma.novartis.com;
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Publication History

Received 11 May 2004
Publication Date:
04 August 2004 (online)

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Abstract

Convenient syntheses of 1H-pyrazin-2-ones and 2-aminopyrazines are described. By coupling Boc-protected amino acids with α-amino ketones or with amino alcohols and subsequent oxidation, 1H-pyrazin-2-ones were obtained. Transformation into the corresponding pyrazine triflates and substitution with primary or secondary amines led to 2-aminopyrazines. Since these syntheses take advantage of the use of readily available starting materials (e.g., amino acids, aminoalcohols and amines) a variety of the entitled structures can be obtained in few, high yielding steps.

Key words

1H -pyrazin-2-ones - pyrazines - heterocycles - arenes - nucleophilic aromatic substitution

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9

Typical Procedure: Preparation of 3-Ethyl-6-methyl-5-phenyl-1 H -pyrazin-2-one(3e): [1-(1-Methyl-2-oxo-2-phenyl-ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (5a, 150 mg, 0.448 mmol) was dissolved in HCl-MeOH 1.25 N (4.48 mmol HCl) and the resulting solution was stirred 10 h at r.t. The volatiles were evaporated and pyridine (1.5 mL) was added. The resulting reaction mixture was stirred at 80 °C (opened flask!) overnight. After cooling, pyridine was removed under reduced pressure (2-4 mbar). The crude material was dissolved in CH2Cl2 (20 mL) and washed with brine (2 × 15 mL), dried over Na2SO4 and concentrated to give 3e (86 mg, 90%): 1H NMR (400 MHz, DMSO-d 6): δ = 12.2 (s, 1 H), 7.47-7.79 (m, 2 H), 7.38-7.42 (m, 2 H), 7.29-7.33 (m, 1 H), 2.60-2.70 (m, 2 H), 2.23 (s, 3 H), 1.15 (t, J = 7.33 Hz, 3 H). 13C NMR (DMSO-d 6): δ = 155.7, 138.2, 129.2, 128.3, 127.3, 25.6, 17.2, 11.1. HRMS (EI): m/z calcd for C15H17N3O [M + H]+: 256.1444; found: 256.1443.

10

Typical Procedure: Preparation of 4-(3-Methyl-5-phenyl-pyrazin-2-yl)-morpholine(6a): 3,6-Dimethyl-5-phenyl-1H-pyrazin-2-one (3d, 70.7 mg, 0.38 mmol) and DMAP (46.4 mg, 0.38 mmol) were dissolved in pyridine- CH2Cl2 (0.5 mL:3.5 mL). Tf2O (94 µL, 0.57 mmol) was added at 0 °C. The resulting reaction mixture was stirred for 15 min at 0 °C, then for 3 h at r.t. To this mixture CH2Cl2 (50 mL) was added. The organic layer was washed with H2O (3 × 50 mL), sat. NaHCO3 (50 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude pyrazine triflate was dissolved in DMSO (3 mL) and morpholine (3 mmol) was added. The reaction mixture was stirred at 60 °C for 2 h. To this mixture EtOAc (10 mL) was added. The organic layer was washed with H2O (2 × 10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated to give 6a as a white solid (73 mg, 75%): 1H NMR (400 MHz, DMSO-d 6): δ = 8.46 (d, J = 0.49 Hz, 1 H), 7.77-7.80 (m, 2 H), 7.22-7.27 (m, 2 H), 7.17 (tt, J 1 = 1.2 Hz, J 2 = 7.3 Hz, 1 H), 3.54 (t, J = 4.6 Hz, 4 H), 2.96 (t, J = 4.6 Hz, 4 H), 2.32 (d, J = 0.5 Hz, 3 H). 13C NMR (DMSO-d 6): δ = 155.9, 145.5, 143.8, 136.6, 136.1, 129.2, 128.9, 126.1, 66.4, 49.6, 22.2. HRMS (EI): m/z calcd for C8H8NOF [M - H]-: 185.0720; found: 185.0720.

12

The corresponding triflic amide (TfNR2) was detected by LC-MS-analysis of the reaction mixture.