Nickel-Catalyzed Direct Addition of Diorganozinc Reagents to Phthalimides: Selective Formation of Gamma-Hydroxylactams
Received: 26 June 2013
Accepted after revision: 04 September 2013
16 October 2013 (online)
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.
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).