Dichloromethane → 4-[1-(3-Hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one

Participants

Reaction Steps

A suspension of 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 289C, 1.825 g, 5.736 mmol), 3-(4-bromo-1H-pyrazol-1-yl)propan-1-ol (1.449 g, 7.066 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (509.5 mg, 0.6239 mmol), and potassium carbonate (2.397 g, 17.34 mmol) in a 4:1 ratio of dioxane (20 mL) to H2O (5 mL) was evacuated and charged with nitrogen several times. The sample was irradiated under microwave conditions [Biotage, 100° C.] for 45 min. The reaction mixture was transferred to a separatory funnel, brine was added, and the reaction was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 25 gram] and purified using the Teledyne/ISCO system [RediSepRf 40 gram silica GOLD], slowly eluting with 0-15% MeOH:CH2Cl2. Fractions containing product were pooled together and concentrated in vacuo, yielding the title material as a yellow solid, 920.0 mg (50%, 2.850 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.99 (d, J=8.34 Hz, 1H), 7.88 (d, J=8.34 Hz, 1H), 4.72 (s, 2H), 4.63 (t, J=5.05 Hz, 1H), 4.25 (t, J=7.07 Hz, 2H), 3.43 (q, J=6.06 Hz, 2H), 3.11 (s, 3H), 1.98 (quin, J=6.63 Hz, 2H). MS (ES+): m/z 317.11 (100) [MH+]. HPLC: tR=0.91 min (TOF, polar—3 min).

Provenance & Evidence