3-Iodooxetane → 6,7-Dimethoxy-2-(oxetan-3-yl)-4-phenoxyquinazoline

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

H2O2 (30% in H2O; 110 μL, 1.1 mmol) was added dropwise over 1-2 min to a stirred solution of 6,7-dimethoxy-4-phenoxyquinazoline 1k (100 mg, 0.35 mmol), concentrated H2SO4 (38 μL, 0.71 mmol), 3-iodooxetane (130 mg, 0.71 mmol) and iron(II) sulfate heptahydrate (30 mg, 0.11 mmol) in DMSO (3.5 mL) at 60 °C. After 1-2 min a further portion of iron(II) sulfate heptahydrate (30 mg, 0.11 mmol) was added and the mixture was stirred at 60 °C for 30 min. Further H2O2 (110 μL, 1.1 mmol) and iron(II) sulfate heptahydrate (30 mg, 0.11 mmol) was added, and the mixture was stirred at 60 °C for 20 min. After allowing to cool, the mixture was poured into a 0.2 M solution of NaOH (50 mL) and Et2O (30 mL). The aqueous and organic layers were partitioned and the organic layer was dried (MgSO4), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by column chromatography on silica gel using EtOAc as eluent to give the desired product 2k (11 mg, 9%) as a solid. Also isolated from the column was a mixture of starting 6,7-dimethoxy-4-phenoxyquinazoline 1k and desired product 2k (17 mg). The mixture of 1k and 2k (17 mg) was purified further by preparative high-performance liquid chromatography (column: Gemini C18; size: 150 x 21.2 mm; eluent: 20-90% CH3CN in 10 mM aqueous Et2NH; run time: 20 min; detection: UV at 254 nM) to give recovered 6,7-dimethoxy-4-phenoxyquinazoline 1k (7 mg, 7%) and the desired product 2k (6 mg, 5%). The aqueous layer from the workup above was saturated with solid NaCl and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed under vacuum to leave a crude solid (ca. 110 mg). The solid was purified by high-performance liquid chromatography to give 6,7-dimethoxy-2-(oxetan-3-yl)quinazolin-4(3H)-one 2j (13 mg, 14%). Also recovered from the high-performance liquid chromatography column was 6,7-dimethoxy-quinazolin-4(3H)-one. Total yield of desired product 2k = 17 mg (14%); Total yield of 6,7-dimethoxy-2-(oxetan-3-yl)quinazolin-4(3H)-one 2j = 13 mg (14%).

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