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Mild Divergent Semireductive Transformations of Secondary and Tertiary Amides via Zirconocene Hydride Catalysis

Rebecca A. Kehner, Ge Zhang and Liela Bayeh-Romero*

*Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76706, United States, Email: Liela_RomeroBaylor.edu

R. A. Kehner, G. Zhang, L. Bayeh-Romero, J. Am. Chem. Soc., 2023, 145, 4921-4927.

DOI: 10.1021/jacs.2c11786



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Abstract

Zirconocene hydride catalyzes a mild method for the semireduction of both secondary and tertiary amides to imines. While secondary amides furnish a diverse array of imines in very good yield with excellent chemoselectivity, a reductive transamination of tertiary amides is also achievable in the presence of a primary amine at room temperature.


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proposed mechanism



Glovebox Procedure for the Reduction of Secondary Amides

Solid starting materials (0.5 mmol - 1.0 mmol) were weighed into a flame-dried screw-cap 1 or 2-dram vial equipped with a magnetic stir bar. The vial was transferred to a nitrogen-filled glovebox. Cp2ZrCl2 (7.3 - 14.6 mg, 5.0 mol %) was weighed into the vial. The substrate and catalyst were dissolved in 12 mL of anhydrous PhMe (0.5 M). Diethyl amine (2.6 - 5.2 L, 5.0 mol %) was injected into the reaction mixture using a Hamilton gastight glass microsyringe, followed by the injection of DMMS (245.6 494.0 L, 4.0 equiv) via microsyringe. The vial was capped with an open top screw cap equipped with a silicon septum, sealed with parafilm, and removed from the glovebox. At this point, liquid starting materials were injected under an atmosphere of nitrogen. The vial was sealed with wax and the reaction solution was stirred at 600 rpm at 30 C for 18 - 24 h. The resulting solution was concentrated in vacuo and a 1H NMR yield was obtained using mesitylene (13.8 L, 0.1 mmol) as an internal standard. The crude reaction mixture was filtered through a plug of activated basic alumina (approx. 300 mg) using a solution of 1% NEt3 in hexanes to afford the desired compound.

General Procedure: Glovebox Procedure for the Reductive Transamination of Tertiary Amides

Solid starting materials (0.5 mmol) and solid primary amines (0.525 mmol, 1.05 equiv) were weighed into a flame-dried screw-cap 2-dram vial equipped with a magnetic stir bar. The vial was transferred to a nitrogen-filled glovebox. Cp2ZrCl2 (7.3 mg, 5.0 mol %) was weighed into the vial. The solids were dissolved in 2.5 mL of anhydrous THF (0.2 M). Diethyl amine (2.6 L, 5.0 mol %) was injected into the reaction mixture using a Hamilton gastight glass microsyringe, followed by the injection of DMMS (245.6 L, 4 equiv) via microsyringe. The vial was capped with an open top screw cap equipped with a silicon septum, sealed with parafilm, and removed from the glovebox. Liquid starting materials and liquid primary amines were injected under an atmosphere of nitrogen. The vial was sealed with wax and the reaction solution was stirred at 600 rpm at 23C for 18.5 - 23.5 h. The resulting solution was concentrated in vacuo and a 1H NMR yield was obtained using mesitylene (13.8 L, 0.1 mmol) as an internal standard. The crude reaction mixture was filtered through a plug of activated basic alumina (approx. 300 mg) using a solution of 1% NEt3 in hexanes to afford the desired compound.


Key Words

reduction of amides to imines, imine formation, Schwartz's reagent, DMMS


ID: J48-Y2023