Nickel-catalyzed transamidation of aliphatic amide derivatives

Abstract

Transamidation, or the conversion of one amide to another, is a long-standing challenge in organic synthesis. Although notable progress has been made in the transamidation of primary amides, the transamidation of secondary amides has remained underdeveloped, especially when considering aliphatic substrates. Herein, we report a two-step approach to achieve the transamidation of secondary aliphatic amides, which relies on non-precious metal catalysis. The method involves initial Boc-functionalization of secondary amide substrates to weaken the amide C-N bond. Subsequent treatment with a nickel catalyst, in the presence of an appropriate amine coupling partner, then delivers the net transamidated products. The transformation proceeds in synthetically useful yields across a range of substrates. A series of competition experiments delineate selectivity patterns that should influence future synthetic design. Moreover, the transamidation of Boc-activated secondary amide derivatives bearing epimerizable stereocenters underscores the mildness and synthetic utility of this methodology. This study provides the most general solution to the classic problem of secondary amide transamidation reported to date.

Fig. 1. Challenges associated with secondary amide transamidation and the two step-approach to realize this challenging synthetic transformation.

Fig. 2. Variation of the amide substrate. Yields shown reflect the average of two isolation experiments.

Fig. 3. Scope of the amide substrate N-substituent. Yields shown reflect the average of two isolation experiments.

Fig. 4. Scope of the amine nucleophile. Yields shown reflect the average of two isolation experiments. ^aYield determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.

Fig. 5. A series of amine competition experiments. Yields determined by ¹H NMR analysis using hexamethylbenzene as an internal standard.

Fig. 6. Transamidation of enantioenriched amide substrate 38 on gram-scale and transamidation of enantioenriched N-Boc proline substrate 40 using a modified protocol.