4-Methylmorpholine → N-hydroxy-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]isoindoline-5-carboxamide

Participants

Reaction Steps

To a mixture of N-methylpyrrole-2-carboxylic acid (25.7 mg, 0.21 mmol) and methyl 2,3-dihydro-1H-isoindole-5-carboxylate hydrochloride (40 mg, 0.19 mmol) in DCM was added HATU (78.2 mg, 0.21 mmol) and N-methylmorpholine (0.1 mL, 0.91 mmol). The heterogenous mixture was stirred overnight at room temperature during which time the mixture became a homogenous solution. The reaction solution was washed with saturated aqueous NaHCO3 (2 mL) and the layers separated. The aqueous layer was washed with additional methylene chloride (3 mL) and the combined organic layers were concentrated. The residue obtained was dissolved in methanol (3 mL), and to the solution was added hydroxylamine hydrochloride (39 mg, 0.56 mmol) and potassium hydroxide (0.1 g, 1.8 mmol). The resulting mixture was heated to 80° C. for 30 minutes. Upon cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in DMSO (1 mL), the insolubles removed via filtration and purified by reverse phase prep-HPLC to afford the title compound as a white solid (27.1 mg, 50%). LCMS: (FA) ES+ 286; 1H NMR (d6-DMSO, 400 MHz) δ 7.80-7.71 (m, 1H), 7.84 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.43 (br d, J=10.2 Hz, 1H), 6.95 (t, J=2.1 Hz, 1H), 6.76 (dd, J=3.8, 1.6 Hz, 1H), 6.10 (dd, J=3.8, 2.5 Hz, 1H), 5.05 (br s, 2H), 4.87 (br s, 2H), 3.77 (s, 3H).

Provenance & Evidence