Access to Isoquinolin-2(1H)-yl-acetamides and Isoindolin-2-yl-acetamides from a Common MCR Precursor

Abstract

We achieved a divergent synthesis of isoquinolin-2­(1H)-yl-acetamides (16 examples, up to 90% yields) and regioselective isoindolin-2-yl-acetamides (14 examples, up to 93% yields) in moderate to good yields by reacting various substituted ethanones or terminal alkynes with Ugi-4CR intermediates via an ammonia-Ugi-4CR/Copper­(I)-catalyzed annulation sequence reaction. The same intermediate thus gives 2D distant but 3D closely related scaffolds, which can be of high interest in exploiting chemistry space on a receptor. The scopes and limitations of these efficient sequence reactions are described, as well as gram-scale synthesis.

Recent Advances in the Synthesis of Peptidomimetics via Ugi Reactions

“…In 2022, Dömling developed a divergent approach to isoquinolin‐2(1 H )‐yl‐acetamides and isoindolin‐2‐yl‐acetamides via copper‐catalyzed annulation of Ugi adducts (Scheme 15). [19] Treating Ugi adducts with ethanones, delivered isoquinolin‐2(1 H )‐yl‐acetamides in moderate to good yields. Different substituted ethanones worked well, leading to the cyclization products in moderate to good yields.…”

Recent Advances in the 3 d‐Transition‐Metal‐Catalyzed Synthesis of Isoquinolines and its Derivatives

“…They extended their protocol to synthesize isoquinolin‐2(1 H )‐yl‐acetamides 156 in two steps in good yields with a slight changes in reaction conditions (Scheme 53). [89] Substituted ethanones 153 were used in place of β ‐ketoesters 152 to produce the final desired products 156 .…”

Diversifying DNA-Tagged Amines by Isocyanide Multicomponent Reactions for DNA-Encoded Library Synthesis

“…Structurally diverse target compounds are accessible through a single reaction step and simple starting materials (Figure B) . In a recent publication, Dömling et al have explored the potential of IMCRs to provide straightforward access to common bioactive scaffolds such as isoquinolines or isoindolines and their application in “scaffold hopping” . Furthermore, in the synthesis of telaprevir, an IMCR is efficiently used to increase overall atom economy by reducing reaction steps .…”

“… 4 In a recent publication, Dömling et al have explored the potential of IMCRs to provide straightforward access to common bioactive scaffolds such as isoquinolines or isoindolines and their application in “scaffold hopping”. 5 Furthermore, in the synthesis of telaprevir, an IMCR is efficiently used to increase overall atom economy by reducing reaction steps. 6 Additionally, they have been used in the synthesis of lactams, a privileged class of heterocycles in medicinal chemistry and drug design.…”