Metal-Free Transamidation of Secondary Amides via Selective N-C Cleavage under Mild Conditions

Yongmei Liu, Shicheng Shi, Marcel Achtenhagen, Ruzhang Liu and Michal Szostak*

*Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States, Email: michal.szostakrutgers.edu

Y. Liu, S. Shi, M. Achtenhagen, R. Liu, M. Szostak, Org. Lett., 2017, 19, 1614-1617.

DOI: 10.1021/acs.orglett.7b00429

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Abstract

Nonplanar, electronically destabilized amides are powerful intermediates in organic synthesis. A highly selective method for transamidation of common secondary amides under mild, metal-free conditions relies on transient N-selective functionalization to weaken amidic resonance. This procedure accomplishes challenging transamidation of secondary amides under mild conditions.

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General Procedure for Metal-Free Transamidation

An oven-dried vial equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles. Dichloromethane (typically, 1.0 M), triethylamine (typically, 3.0 equiv) and amine (typically, 3.0 equiv) were sequentially added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature for an indicated time. After the indicated time, the reaction mixture was diluted with CH₂Cl₂ (5 mL) and filtered. The organic layer was washed with HCl (1.0 N, 10 mL), brine (10 mL), dried, and concentrated. A sample was analyzed by ¹H NMR (CDCl₃, 500 MHz) and GCMS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. Unless stated otherwise, the crude product was purified by flash chromatography (EtOAc/hexanes) to give analytically pure product.

Metal-Free Transamidation of Secondary Amides by N-C Cleavage

Md. M. Rahman, G. Li, M. Szostak, J. Org. Chem., 2019, 84, 12091-12100.

Thioesterification and Selenoesterification of Amides via Selective N-C Cleavage at Room Temperature: N-C(O) to S/Se-C(O) Interconversion

Md. M. Rahman, G. Li, M. Szostak, Synthesis, 2020, 52, 1060-1066.

Key Words

amides, transamidation

ID: J54-Y2017