Nickel-Catalyzed Enantioselective Negishi Cross-Couplings of Racemic Secondary alpha-Bromo Amides with Alkylzinc Reagents: (S)-N-Benzyl-7-cyano-2-ethyl-N-phenylheptanamide
Author(s)Lou, Sha; Fu, Gregory C.
Nickel-Catalyzed Enantioselective Negishi Cross-Couplings of Racemic Secondary α-Bromo Amides with Alkylzinc Reagents: (S)-N-Benzyl-7-cyano-2-ethyl-N-phenylheptanamide
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Procedure: A. (5-Cyanopentyl)zinc(II) bromide (1). An oven-dried, 200-mL pear-shaped Schlenk flask equipped with a magnetic stirbar (egg shaped, 25.4 × 12.7 mm) and an argon line connected to the standard taper outer joint is purged with argon for 5 min. Zinc powder (9.80 g, 150 mmol, 1.50 equiv) (Note 1) is added through the open neck, and then the flask is capped with a rubber septum and heated in an oil bath under high vacuum (0.5 mmHg) at 70 °C for 30 min. Then, the flask is refilled with argon, and anhydrous 1,3-dimethyl-2-imidazolidinone (DMI; 100 mL) (Note 2) is added via syringe. Iodine (I2) (634 mg, 2.50 mmol, 0.0250 equiv) (Note 3) is added in one portion through the neck. The neck is re-capped with a rubber septum, and the reaction mixture is stirred at 70 °C in an oil bath until the red color fades (~5 min). 6-Bromohexanenitrile (13.2 mL, 100 mmol, 1.00 equiv) (Note 4) is added via syringe over 4 min, and the reaction mixture is stirred at 70 °C for 12 h. Then, the oil bath is removed, and the mixture is allowed to cool at rt for 1 h without stirring. During this time, the unreacted zinc powder settles at the bottom of the flask. The flask is equipped with a fritted filter tube of medium porosity capped with an oven-dried, 2-necked 250-mL round-bottom flask, and the supernatant solution is filtered under argon by inverting the set-up (Note 5). The resulting clear yellow solution is employed in the next step without further purification. 1H NMR spectroscopy is used to determine that the concentration of the alkylzinc solution is 0.72 M (Note 6). This organozinc solution can be stored under argon at 0-4 °C for up to 3 weeks without deterioration.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
John Wiley & Sons, Inc.
Lou, Sha and Gregory C. Fu. "Nickel-Catalyzed Enantioselective Negishi Cross-Couplings of Racemic Secondary alpha-Bromo Amides with Alkylzinc Reagents: (S)-N-Benzyl-7-cyano-2-ethyl-N-phenylheptanamide." Organic Syntheses, Vol. 87, p.330 (2010).
Author's final manuscript