Brønsted Acid-Catalyzed Intramolecular Hydroalkoxylation/Claisen Rearrangement of Ynamides^★

Abstract

A Brønsted acid-catalyzed intramolecular hydroalkoxylation/Claisen rearrangement of ynamides for the synthesis of eight-membered lactams is presented. Firstly, the keteniminium intermediate was generated from the activation of ynamide by Brønsted acid, which could interact with intramolecular hydroxy group through hydrogen bonding and ion pairing effects. Then, the tandem hydroalkoxylation/Claisen rearrangement took place and produced eight-membered lactams. Meanwhile, preliminary studies were conducted into the chiral Brønsted acid-catalyzed kinetic resolution, and several chiral eight-membered lactams were successfully synthesized. Other notable features of this metal-free method include the simple procedure, mild reaction conditions and good functional group compatibility. This research provides a practical method for the synthesis of biologically important eight-membered lactam skeletons. Accordingly, MsOH (5 mol%, 0.005 mmol, 0.32 μL) was added to the solution of ynamide (1 equiv., 0.1 mmol) in dry PhCl (4 mL) at room temperature. The reaction mixture was then stirred at 60 ℃ and the progress of the reaction was monitored by thin layer chromatography (TLC). Upon completion, the reaction was quenched with Et3N (0.005 mmol, 0.7 μL), concentrated and purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, V∶V＝5∶1), to afford the desired eight-membered lactam. Under this condition, a series of ynamides with different substituents worked smoothly to provide the corresponding eight-membered lactams efficiently. Furthermore, chiral Brønsted acid (10 mol%, 0.005 mmol, 3.5 mg) and H2O (0.05 mmol, 0.9 μL) were added to the solution of ynamide (1 equiv., 0.05 mmol) in PhCl (2 mL) at -20 ℃ and the progress of the reaction was monitored by TLC. Upon completion, the reaction was quenched with Et3N (0.005 mmol, 0.75 μL), concentrated and purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, V∶V＝5∶1), to afford the chiral eight-membered lactam and chiral substrate. Also, a plausible mechanism involving the hydrogen bonding and ion pairing effects is proposed based on experimental results.