反应详情

温度

80 °C

A mixture of 2-(dicyclohexylphosphino)-2′,4′,6%-tri-isopropyl1,1′-biphenyl(Strem Chemicals, Newburyport, Mass., 110 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, Newburyport, Mass., 105 mg, 0.115 mmol), potassium phosphate tribasic (1.83 g, 8.63 mmol), (R)-6-(2-(benzyloxy)ethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (503a, 1.10 g, 2.88 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (830 mg, 2.32 mmol) in 1,4-dioxane (12 mL), water (3.60 mL) in a sealed glass tube was heated in a heating block at 80° C. for 2 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude reaction mixture was chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 20-100% EtOAc in hexanes then 0-10% MeOH in DCM) affording (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (503b, 555 mg, 1.14 mmol, 40% yield) as a dark brown oil. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.01 (1H, dd, J=7.9, 1.5 Hz), 7.89 (1H, dd, J=7.5, 1.5 Hz), 7.19-7.28 (3H, m), 7.08-7.17 (3H, m), 6.69 (1H, s), 4.75 (1H, dd, J=6.7, 5.1 Hz), 4.45 (2H, q, J=11.3 Hz), 3.70-3.77 (1H, m), 3.62-3.70 (1H, m), 3.55 (3H, s), 2.19-2.31 (1H, m), 1.98-2.09 (1H, m), 1.54 (9H, s). m/z (ESI, +ve) 486.0 (M+1)′.

1. extractionextracted with EtOAc (2×50 mL)
2. washwashed with brine
3. dry with materialdried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated
6. customThe crude reaction mixture
7. customwas chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column