A two-step approach to achieve secondary amide transamidation enabled by nickel catalysis

Abstract

A long-standing challenge in synthetic chemistry is the development of the transamidation reaction. This process, which involves the conversion of one amide to another, is typically plagued by unfavourable kinetic and thermodynamic factors. Although some advances have been made with regard to the transamidation of primary amide substrates, secondary amide transamidation has remained elusive. Here we present a simple two-step approach that allows for the elusive overall transformation to take place using non-precious metal catalysis. The methodology proceeds under exceptionally mild reaction conditions and is tolerant of amino-acid-derived nucleophiles. In addition to overcoming the classic problem of secondary amide transamidation, our studies expand the growing repertoire of new transformations mediated by base metal catalysis.

Figure 1. Development of Ni-catalysed secondary amide transamidation.

(a) An illustration of the challenges currently faced with secondary amide transamidation. (b) The two-step approach to achieve net transamidation of secondary amides via N-functionalization and C–N bond activation.

Figure 2. Key experiments and reaction discovery.

Failed reaction using substrate 8a in the absence of catalyst/ligands or activating group (entries 1 and 2), initial promising result (entry 3) and optimized reaction conditions (entry 4). For entries 1–3, yields shown were determined by ¹H NMR analysis with an internal standard. For entry 4, the yield shown reflects the average of two isolation experiments.

Figure 3. Scope of methodology.

The scope of the transamidation methodology was evaluated with respect to the Boc-activated amide substrate (entries 1–10), and with respect to the amine nucleophile using 8b (entries 11–18). Reactions were carried out using Ni(cod)₂ (5–10 mol%), SIPr (10–20 mol%), substrate (1.00 equiv), amine (1.5–2.5 equiv) and toluene (1.0 M) at 35–60 °C for 14 h. Yields shown reflect the average of two isolation experiments.

Figure 4. The two-step approach for transamidation with amino-acid derivatives.

The scope of the transamidation was evaluated with various amino-acid derivatives to give products 32–37. Amide 29 was first Boc-activated with Boc₂O (3.0 equiv), 4-(dimethylamino)pyridine (30 mol%) and CH₃CN (0.20 M) at 50 °C for 19 h. The transamidation reactions were then carried out using Ni(cod)₂ (5–10 mol%), SIPr (10–20 mol%), substrate (1.00 equiv), amine (1.2 equiv) and toluene (1.0 M) at 35 °C for 14 h. Yields shown reflect the average of two isolation experiments.