Chemoselective Transamidation of Thioamides by Transition‐Metal‐Free N−C(S) Transacylation

Abstract

Thioamides represent highly valuable isosteric in the strictest sense “single‐atom substitution” analogues of amides that have found broad applications in chemistry and biology. A long‐standing challenge is the direct transamidation of thioamides, a process which would convert one thioamide bond (R−C(S)−NR1R2) into another (R−C(S)−NR3N4). Herein, we report the first general method for the direct transamidation of thioamides by highly chemoselective N−C(S) transacylation. The method relies on site‐selective N‐tert‐butoxycarbonyl activation of 2° and 1° thioamides, resulting in ground‐state‐destabilization of thioamides, thus enabling to rationally manipulate nucleophilic addition to the thioamide bond. This method showcases a remarkably broad scope including late‐stage functionalization (>100 examples). We further present extensive DFT studies that provide insight into the chemoselectivity and provide guidelines for the development of transamidation methods of the thioamide bond.

Copper-Catalyzed Transamidation of Unactivated Secondary Amides via C–H and C–N Bond Simultaneous Activations

“…Stahl, Gellman, and their colleagues developed various Lewis acid-mediated or -catalyzed transamidation reactions, but these reactions tend to produce an equilibrium mixture of reactants and product amides, especially in the transamidation reaction between secondary amides and primary amines (see Scheme a). − In recent years, the Ni catalysts developed by Garg − and the Pd catalysts disclosed by Szostak − effectively realized the general method of transamidation of amides through the oxidative addition of transition metals to the C–N bond of amides and the following action of acyl metal species with appropriate nucleophiles (see Scheme b). Whereas most of the efficient methods have been developed using tertiary amides, the focus on omnipresent secondary amides is limited. − …”

Construction of hybrid ionic liquid‐catalysts for the highly effective conversion of H2S by nitriles into thioamides

“…As an important class of sulfurcontaining chemicals, thioamides are widely applied in metal extraction, heterocyclic preparation, pharmaceutical synthesis, and material manufacturing. [15][16][17][18][19] For example, thioamides play an important role as intermediates in the production of disease treatment drugs, such as the production of carbimazole for hyperthyroidism, ethionamide for tuberculosis. 20,21 However, for homogeneous catalytic systems, the process of separating thioamides is challenging because thioamides may be classified as hydrogen bond donors (HBDs), which can easily interact with homogeneous ILs to form a new deep eutectic mixture, further limiting product separation.…”

Nucleophilic Addition/Electrocyclization Strategy toward Polyheterocyclic-Fused Quinoline-2-thiones in Green Solvent

“…Sulfur-containing compounds are widely present in numerous natural products, agrochemicals, pharmaceuticals, and materials . Among them, isothiocyanates (ITCs) are well-known as a key reagent in the Edman peptide sequencing, whose molecular structures constitute the heteroallene functionality of −NCS, which impart unique reactivities to themselves as versatile thiocarbonylation platforms for diversely accessing thioamide-typed allylic and cyclic scaffolds .…”