Nickel-Catalyzed Direct Addition of Diorganozinc Reagents to Phthalimides: Selective Formation of Gamma-Hydroxylactams

Abstract

The nickel-catalyzed addition of diorganozinc reagents to phthalimides proceeds with excellent selectivity to provide 3-substituted-3-hydroxyisoindolin-1-one products. These 3-hydroxy-γ-lactams are produced cleanly in high yield with numerous examples of imide substitution and a broad range of diorganozinc reagents that are prepared and utilized without purification.

Key words

imide - catalysis - lactams - organometallic reagents - nickel

• References and Notes

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• 16 Direct Addition of Et₂Zn to Phthalimides; Typical Procedure: Ph₃P (13.1 mg, 0.055 mmol) and N-phenylphthalimide (111.6 mg, 0.50 mmol) were combined with a stirbar in an oven-dried 25 mL round-bottomed flask. The flask was transferred into an inert atmosphere glove box, where Ni(COD)₂ (14.0 mg, 0.051 mmol) was added. The flask was sealed with a septum and removed from the glove box, whereupon THF (2 mL) was added, followed by Et₂Zn (56.5 μL, 0.55 mmol, 1.1 equiv). The solution was then brought up to temperature in a 55 °C oil bath and stirred for 16 h. Upon completion of the reaction, the mixture was cooled to r.t., the septum was removed and Et₂O (15 mL) was added. The addition of 2 M aq HCl (15 mL) quenched the reaction, which was then extracted with Et₂O (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO₄, and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (hexane–EtOAc, 4:1) to provide 2 (81% yield). Direct Addition with Diorganozinc Reagents Generated In Situ; Typical Method: 1-Bromo-4-tert-butylbenzene (230 μL, 1.33 mmol) was added to an oven-dried 10-mL round-bottomed flask, sealed with a septum, evacuated and refilled with Ar (×3) and dissolved in THF (2 mL). The reaction mixture was cooled to –78 °C, nBuLi (2.5 M in hexanes, 536 μL, 1.34 mmol) was added dropwise and the mixture was stirred at –78 °C for 1 h. In a separate flask, ZnCl₂ (92.1 mg, 0.68 mmol) was dried by heating under vacuum and then dissolved in THF (1 mL). This solution was then added to the solution of ArLi, still at –78 °C. The reaction was removed from the cold bath and allowed to warm to r.t. while stirring for 30 min. In a separate 25 mL round-bottomed flask, N-phenylphthalimide (112 mg, 0.50 mmol) and Ph₃P (14.2 mg, 0.054 mmol) were combined and transferred into an inert atmosphere glove box, where Ni(COD)₂ (14.1 mg, 0.051 mmol) was added. This flask was sealed with a septum and removed from the glove box, whereupon THF (2 mL) was added, followed by the Ar₂Zn solution. The solution was then brought up to 55 °C in an oil bath and stirred for 16 h. Upon completion of the reaction, the mixture was cooled to r.t., the septum was removed and Et₂O (15 mL) was added. The addition of 2 M aq HCl (15 mL) quenched the reaction, which was then extracted with Et₂O (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane–EtOAc, 9:1) to provide 19 as a white solid (80% yield).