Instant Macrocyclizations via Multicomponent Reactions
Michael Fragkiadakis, Paraskevi-Kleio Anastasiou, Marios Zingiridis, Marios E. Triantafyllou‐Rundell, Atilio Reyes Romero, Constantinos C. Stoumpos, Constantinos G. Neochoritis
Abstract
Macrocycles fascinate chemists due to both their structure and their applications. However, we still lack efficient and sustainable synthetic methods, giving us straightforward access to them. Herein, a rapid macrocyclization utilizing a two-step, one-pot approach based on orthogonal multicomponent reaction (MCR) tactics is introduced. This synthetic protocol, which is based on Ugi and Groebke-Blackburn-Bienaymé reactions with isocyanides tethered to alkyl tosylates, yields medium sized macrocycles that are otherwise difficult to achieve. Single crystal structures reveal conformational reorganization via intramolecular hydrogen bonding, and modeling studies profile the synthesized libraries.