Highly Enantioselective Organocatalytic aza-Henry Reaction of Nitroalkanes to N-Boc Isatin Ketimines

We report a highly enantioselective aza-Henry reaction of nitroalkanes with N-Boc isatin ketimines 1. A cinchona alkaloid derived bifunctional catalyst C5, featuring a C6 hydroxy group, is identified as a powerful catalyst for this reaction. Accordingly, under an atmosphere of nitrogen, to a 10 mL Schlenk tube are added C5 (0.03 mmol, 14.6 mg), MS5 angstrom (120 mg), nitromethane (4.5 mmol, 244 mu L) and 3.0 mL of toluene successively, followed by the addition of N-Boc isatin ketimine 1 (0.3 mmol). The resulting mixture is stirred at 20 degrees C till the full consumption of the ketimine, monitored by TLC analysis. After the solvent is removed under reduced pressure, the residue is directly subjected to column chromatography, using an eluent of dichloromethane and acetone (10 : 1, V/V), to afford the desired product 3. Under this condition, a variety of differently substituted N-Boc isatin ketimines work well with MeNO2 to provide the Mannich adduct in up to 91% ee. A 1.0 mmol scale reaction of 1a and MeNO2 is examined, giving adduct 3a in 87% yield and 90% ee. Unfortunately, unprotected isatin derived N-Boc isatin ketimine 1j provides the corresponding product in only 66% ee, suggesting the importance of the N-protecting group of isatin in securing high enantioselectivity. Nitroethane and nitropropane are also viable for this reaction, affording the corresponding products in high yield and excellent ee value, albeit with moderate diastereoselectivity.