Light-Dependent Amide or Thioamide Formation of Acylsilanes with Amines using Elemental Sulfur

Abstract

Due to the diverse chemical and physical properties of functional groups, mild and controllable ligation methods are often required to construct complex drugs and functional materials. To make diverse sets of products with tunable physicochemical properties, it is also useful to employ complimentary ligation methods that adopt the same starting materials. Here, we disclose the efficient and modular synthesis of amides or thioamides through the chemical ligation of acylsilanes with amines, simply by turning a light on or off. This method is fast, mild, high-yielding and displays excellent functional-group tolerance. The versatility of these reactions is highlighted by their ability to perform post-synthetic modifications on a variety of marketed medications, peptides, natural substances, and compounds with biological activity. In-depth computational and experimental studies clarified the photo-dependent umpolung of reactivity of acylsilanes, namely: photoexcitation leads to nucleophilic O-silyl carbenes that react with S₈ to form O-silyl thionoesters and eventually amides. In contrast, acylsilanes react as electrophiles with amines thermally in the dark, with C→O silyl transfer, prior to reacting with S₈ to form thioamides. These mechanistic details are expected to guide the development of similar coupling reactions.