Catalytic Reductive Functionalization of Tertiary Amides using Vaska’s Complex: Synthesis of Complex Tertiary Amine Building Blocks and Natural Products

Abstract

The tertiary amide is a ubiquitous functional group and plays an irreplaceable role in medicinal chemistry. Its robust nature has meantin the pastthat selective manipulation of this motif remained elusive. The reductive activation through hydrosilylation of tertiary amidesusing Vaska’s complex (IrCl­(CO)­(PPh3)2)has emerged as a powerful strategy for the chemoselective transformation of amides into reactive enamines and iminium ions. Furthermore, these synthetically valuable species can be accessed in the presence of traditionally more reactive functional groups. This approach to amide reductive activation via hydrosilylation has been exploited in a range of downstream C–C bond forming processes and has seen significant applications in total synthesis, enabling streamlined routes for the synthesis of complex natural product architectures. This perspective covers the development of this synthetic strategy, from initial hydrosilylation studies to its flourishing use in the reductive functionalization of amide-containing molecules, both simple and complex.

Reductive Functionalization of Amides in Synthesis and for Modification of Bioactive Compounds

“…An excellent review covering nucleophilic addition to amides, including the reduction/addition approach, was published some time ago by Chida and Sato, who presented selected recent advances in this field (Sato et al, 2018 ). In addition, very recently, Dixon and coworkers summarized the application of iridium-catalyzed reactions of tertiary amides for the synthesis of complex amine building blocks and natural products (Matheau-Raven et al, 2020 ). In contrast, this section is dedicated to all types of amides and only to the application of reductive functionalization of amides in natural products synthesis and is focused on examples omitted from or published after the appearance of the mentioned reviews.…”

Ativação de Amidas – Um Instrumento Elegante para a Quimiosseletividade

“…Este procedimento foi facilmente adaptável a amidas, lactamas, alcaloides e péptidos. Desde então, outros métodos da redução da amida a grupo nitrilo emergiram, assim como estratégias de conversão de amidas terciárias a enaminas e iões imínio usando o complexo de Vaska [21].…”

Reduction of Secondary Amides to Imines Catalysed by Schwartz’s Reagent

“…9 Several groups have since expanded on these seminal reports to develop methods for the reductive functionalization of secondary and tertiary amides by addition of a variety of nucleophiles to the transiently formed imine derivatives. [10][11][12][13][14] Scheme 1. The challenge of chemoselectivity in the catalytic reduction of amides to amines or imines.…”