Ugi reactions are still a challenge when the concomitant use of ammonia and formaldehyde is required. Herein, we propose a strategy to overcome this challenge using hexamethylenetetramine (HMTA) as a singular key for the employment of these two simple starting materials in the Ugi reaction. Acylaminoacetamide derivatives were prepared in good to excellent yields by this new methodology. The scope and optimization of the reaction conditions were investigated. This novel methodology was successfully applied in the synthesis of two different diketopiperazines (DKPs) using the Ugi/Deprotection + Activation/Cyclization (UDAC) method. A continuous flow approach was also used in this methodology.

The Cover Feature shows a combination that could be called the ugly duckling of the Ugi 4‐component reactions, which involves the concomitant use of the ammonia/formaldehyde pair. There was not a single methodology so far to successfully achieve this goal. The metamorphosis could finally happen with the intermediacy of hexamethylenetetramine (HMTA), which allows the in situ generation of both ammonia and formaldehyde for the Ugi reactions with carboxylic acids and isocyanides, yielding a variety of acylaminoacetamide derivatives in good to excellent yields. More information can be found in the Full Paper by C. K. Z. Andrade et al.