Synthesis
General procedure for the synthesis of 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one from 6-bromo-2,3-dihydro-isoindol-1-one and pinacol bis(boronic acid) ester: to a solution of 6-bromo-2,3-dihydro-isoindol-1-one (1 eq.) in anhydrous dioxane (0.1 M) was added bis (pinacol) diboron (1.1 eq.), potassium acetate (3.5 eq.) and 1,1'-bis(diphenylphosphino)ferrocene (dppf, 0.05 eq.). The reaction mixture was degassed with nitrogen for 20 minutes. Subsequently, dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (PdCl2(dppf), 0.05 eq.) was added and the mixture was degassed again for 5 minutes. Under nitrogen protection, the reaction mixture was heated to 70 °C for 2 hours and then warmed to 120 °C to continue the reaction for 16 hours. After completion of the reaction, the mixture was partitioned between ethyl acetate (EtOAc) and water. The aqueous phase was further extracted with ethyl acetate, the organic phases were combined, dried with magnesium sulfate (MgSO4), filtered and concentrated in vacuum. The residue was sonicated with ethyl acetate and the suspension was filtered through a sintered funnel, the collected gray solid was dried and used directly in the next reaction without further purification. The yield of the product 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one was 82% with a purity of 29%, and the main impurity was boric acid.LC-MS (ESP) analysis showed m/z: 519.5 [2M + H]+ with a retention time (R/T) of 3.38 minutes.
References
[1] Patent: WO2008/23161, 2008, A1. Location in patent: Page/Page column 117
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
[3] Patent: WO2017/107089, 2017, A1. Location in patent: Page/Page column 37; 38
[4] Patent: WO2017/68412, 2017, A1. Location in patent: Page/Page column 208; 209
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 11, p. 4978 - 4992
