tert-Butyl piperazine-1-carboxylate → tert-butyl 4-(2-methyl-3-oxo-1H-isoindol-5-yl)piperazine-1-carboxylate

Temperature

60 °C

In an oven-dried RB flask was added Tris(dibenzylideneacetone)dipalladium(0) (0.046 g, 0.05 mmol) and rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (0.062 g, 0.10 mmol). The flask was evacuated and back-filled with nitrogen. Anhydrous toluene (3 mL) was added and the mixture was stirred at rt for 10 min to give a purple solution. 6-bromo-2-methylisoindolin-1-one (2.261 g, 10 mmol), 1-Boc-piperazine (1.863 g, 10.00 mmol) and Sodium tert-butoxide (1.714 mL, 14.00 mmol) were added in one portion followed by anhydrous toluene (15 mL). The flask was evacuated and back-filled with nitrogen and the resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 days. LCMS shows 10% conversion. Tris(dibenzylideneacetone)dipalladium(0) (0.183 g, 0.20 mmol) and 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.187 g, 0.40 mmol) (RuPhos) were added and the mixture was heated to 80 °C and stirred for 5 h. LCMS shows complete conversion. When cooled to rt the mixture was diluted with EtOAc (25 mL) and stirred for 1 h. The solid was filtered off and washed with EtOAc (50 mL). The filtrate was washed with saturated aqueous Na2CO3 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude producr was purified on a silica gel column eluted with 20-100% EtOAc in Heptane to give a yellow solid; tert-butyl 4-(2-methyl-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (1.890 g, 57.0 %).

ORD record

ord-ce627b9c98e74957a0959e5bb6499f88

Source dataset

750 AstraZeneca ELN dataset

Original link

View source