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Synlett 2007(20): 3117-3122  
DOI: 10.1055/s-2007-992358
LETTER
© Georg Thieme Verlag Stuttgart · New York

Ag+-Mediated Synthesis of Substituted Furo[2,3-b]pyrazines

Denis S. Ermolat’ev, Vaibhav Pravinchandra Mehta, Erik V. Van der Eycken*
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax: +32(16)327990; e-Mail: erik.vandereycken@chem.kuleuven.be;
Further Information

Publication History

Received 2 September 2007
Publication Date:
08 November 2007 (online)

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Abstract

A highly efficient method for the preparation of trisubstituted furo[2,3-b]pyrazines has been developed. Sonogashira coupling reaction with the readily available 1-(4-methoxybenzyl)-3,5-dichloropyrazin-2(1H)-ones was followed by silver-catalyzed heteroannulation to provide the corresponding 2-chlorofuro[2,3-b]pyrazines in excellent yields. The latter were subjected to Suzuki or Buchwald-Hartwig coupling reaction for further decoration.

Key words

annulations - pyrazin-2(1H)-ones - catalysis - furo[2,3-b]pyrazines - cross-coupling

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Sonogashira Coupling Reaction on 1-(4-Methoxy-benzyl)-3,5-dichloropyrazin-2(1 H )-ones 1a-d; Typical Procedure
In a 50 mL microwave vial were successively dissolved, in DMF-Et3N (1:1, 20 mL), pyrazinone 1 (5 mmol), acetylene 2 (6.25-7.5 mmol), Pd(PPh3)Cl2 (35 mg, 1 mol%), and CuI (28 mg, 3 mol%). The reaction tube was sealed, and irradiated in the cavity of a Milestone-MYCROSYNTH multimode reactor at a ceiling temperature of 80 °C at 80 W maximum power for 10 min. After the reaction mixture was cooled with an airflow for 15 min, then it was extracted with CH2Cl2 (2 × 150 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography (from 10% to 30% EtOAc in PE) to afford compounds 3a-m.
5-Chloro-1-(4-methoxybenzyl)-3-(phenylethynyl)pyr-azin-2(1 H )-one (3a)
Yield 86%; mp 119-120 °C. 1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.33 (m, 5 H), 7.17 (s, 1 H), 6.93 (d, J = 8.2 Hz, 2 H), 5.04 (s, 2 H), 3.82 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 160.6, 155.2, 141.2, 133.1, 130.9, 130.4, 128.9, 127.1, 126.5, 126.2, 121.8, 115.2, 99.1, 85.9, 55.8, 53.0. HRMS (EI): m/z calcd for C20H15ClN2O2: 350.0822; found: 350.0831.

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Typical Procedure for the Preparation of Furopyrazines 4a-m
In a 25 mL flask pyrazinone 3 (2 mmol) was dissolved in anhyd CH2Cl2 (12 mL). Then, AgOTf (11 mg, 2 mol%) and TFA (0.8 mL, 10 mmol, 5 equiv) were added and the reaction mixture was stirred at r.t. for 5-20 min. After reaction completion the solvent was evaporated and the residue was subjected to silica gel column chromatography (from 20% to 50% CH2Cl2 in PE) to afford compounds 4a-m. 2-Chloro-6-phenylfuro[2,3- b ]pyrazine (4a)
Yield 91% yield; mp 174-176 °C. 1H NMR (300 MHz, CDCl3): δ = 8.21 (s, 1 H), 7.95 (d, J = 8.3 Hz, 2 H), 7.53 (m, 3 H), 7.17 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 162.3, 154.6, 146.0, 142.1, 136.6, 131.3, 129.6, 128.8, 126.2, 101.2. HRMS (EI): m/z calcd C12H7ClN2O: 230.0247; found: 230.0246.

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Typical Procedure for the Preparation of Furopyrazines 5a-g In a 15 mL microwave vial were successively dissolved, in DMF-H2O (1:1, 6 mL), furopyrazine 4 (0.7 mmol), boronic acid 6 (0.86 mmol, 1.25 equiv), Pd(PPh3)4 (8 mg, 1 mol%), and Na2CO3 (150 mg, 2 equiv). The reaction tube was sealed and irradiated in the cavity of a Milestone-MYCROSYNTH multimode reactor at a ceiling temperature of 100 °C at 100 W maximum power for 10 min. After the reaction mixture was cooled with an airflow for 15 min, then it was extracted with CH2Cl2 (2 × 50 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was subjected to silica gel flash chromatography (from 10% to 50% CH2Cl2 in PE) to afford compounds 5a-g.
2-(4-Chlorophenyl)-6-propylfuro[2,3- b ]pyrazine (5a)
Yield 81%; mp 143-144 °C. 1H NMR (300 MHz, CDCl3): δ = 8.55 (s, 1 H), 8.94 (d, J = 8.3 Hz, 2 H), 7.48 (d, J = 8.3 Hz, 2 H), 6.65 (s, 1 H), 2.87 (d, J = 7.5 Hz, 2 H), 1.86 (m, 2 H), 1.06 (d, J = 7.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 166.2, 154.7, 148.6, 141.9, 135.7, 135.3, 134.1, 129.4, 129.1 (2×), 128.3 (2×), 103.8, 31.2, 20.6, 13.7. HRMS (EI): m/z calcd for C15H13ClN2O: 272.0716; found: 272.0708.

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Typical Procedure for the Preparation of Furopyrazines 5h-l In a 15 mL microwave vial were successively dissolved, in 1,4-dioxane (4 mL), furopyrazine 4 (0.5 mmol), amine 6 (0.63 mmol, 1.25 equiv), Pd(OAc)2 (3.5 mg, 3 mol%), and (±)-BINAP (11 mg, 3.3 mol%), tetrabutylammonium bromide (1.0-1.2 equiv), and NaOt-Bu (1.5-1.7 equiv). The reaction tube was sealed and irradiated in the cavity of a Milestone-MYCROSYNTH multimode reactor at a ceiling temperature of 120 °C at 300 W maximum power for 15 min. After the reaction mixture was cooled with an airflow for 15 min, then it was extracted with CH2Cl2 (2 × 50 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was subjected to silica gel flash chromatography (from 10% to 30% EtOAc in PE) to afford compounds 5h-l. 2-Morpholin-4-yl-6-phenylfuro[2,3- b ]pyrazine (5h)
Yield 91%; mp 95-97 °C. 1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 8.3 Hz, 2 H), 7.76 (s, 1 H), 7.46 (m, 3 H), 7.03 (s, 1 H), 3.89 (t, J = 4.6 Hz, 4 H), 3.57 (t, J = 4.6 Hz, 4 H). 13C NMR (75 MHz, CDCl3): δ = 159.9, 155.2, 151.1, 130.3, 129.9, 129.4 (2×), 125.8 (2×), 124.4, 101.3, 67.1, 46.7. HRMS (EI): m/z calcd for C16H15N3O2: 281.1164; found: 281.1174.