Byproduct‐Catalyzed Four‐Component Reactions of Aldehydes with Hexamethyldisilazane, Chloroformates, and Nucleophiles in Acetonitrile Leading to Protected Primary Amines, β‐Amino Esters, and β‐Amino Ketones

Abstract

Multicomponent reactions are a very powerful tool for the construction of complex organic molecules by using readily available starting materials. While most of the multicomponent reactions discovered so far consist of three components, the reactions with four or more components remain sparse. We have successfully developed several four-component reactions using a catalytic amount of water as a hydrolyzing agent to decompose byproduct chlorotrimethylsilane (TMSCl) to yield secondary byproduct HCl that serves as a catalyst. In the presence of 40 mol % of water, the four-component reaction of aldehydes with hexamethyldisilazane (HMDS), chloroformates, and silylated nucleophiles proceeds smoothly at room temperature to give a range of protected primary amines in moderate to excellent yields. Importantly, a wide variety of protic carbon nucleophiles, such as beta-keto esters, beta-diketones, and ketones, have further been explored as suitable substrates for the synthesis of protected beta-amino esters and beta-amino ketones that are useful building blocks for various pharmaceuticals and natural products. These four-component reactions proceed through a pathway of tandem nitrogen protection/imine formation/imine addition, and the decomposition of byproduct TMSCl, generated in the first step of nitrogen protection, with water results in the formation of secondary byproduct HCl, a strong Brønsted acid that catalyzes the following imine formation/imine addition. Taking advantage of the fact that alcohols or phenols are also able to decompose byproduct TMSCl to yield secondary byproduct HCl, no catalyst is needed at all for the four-component reactions with aldehydes bearing hydroxy groups.