Catalytic Synthesis of ß-(Hetero)arylethylamines: Modern Strategies and Advances.

ß-(Hetero)arylethylamines appear in a myriad of pharmaceuticals due to their broad spectrum of biological properties, making them prime candidates for drug discovery. Conventional methods for their preparation often require engineered substrates that limit the flexibility of the synthetic routes and the diversity of compounds that can be accessed. Consequently, methods that provide rapid and versatile access to those scaffolds remain limited. To overcome these challenges, synthetic chemists have designed innovative and modular strategies to access the ß-(hetero)arylethylamine motif, paving the way for their more extensive use in future pharmaceuticals. This review outlines recent progresses in the synthesis of (hetero)arylethylamines and emphasizes how these innovations have enabled new levels of molecular complexity, selectivity, and practicality.

Synthesis of Unprotected ß-Arylethylamines by Iron(II)-Catalyzed 1,2-Aminoarylation of Alkenes in Hexafluoroisopropanol.

ß-Arylethylamines are prevalent structural motifs in molecules exhibiting biological activity. Here we report a sequential one-pot protocol for the 1,2-aminoarylation of alkenes with hydroxylammonium triflate salts and (hetero)arenes. Unlike existing methods, this reaction provides a direct entry to unprotected ß-arylethylamines with remarkable functional group tolerance, allowing key drug-oriented functional groups to be installed in a two-step process. The use of hexafluoroisopropanol as a solvent in combination with an iron(II) catalyst proved essential to reaching high-value nitrogen-containing molecules.

Exploiting hexafluoroisopropanol (HFIP) in Lewis and Brønsted acid-catalyzed reactions.

Hexafluoroisopropanol (HFIP) is a solvent with unique properties that has recently gained attention for promoting a wide range of challenging chemical reactions. It was initially believed that HFIP was almost exclusively involved in the stabilization of cationic intermediates, owing to its high polarity and low nucleophilicity. However, in many cases, the mechanism of action of HFIP appears to be more complex. Recent findings reveal that many Lewis and Brønsted acid-catalyzed transformations conducted in HFIP additionally involve cooperation between the catalyst and HFIP hydrogen-bond clusters, akin to Lewis- or Brønsted acid-assisted-Brønsted acid catalysis. This feature article showcases the remarkable versatility of HFIP in Lewis and Brønsted acid-catalyzed reactions, with an emphasis on examples yielding mechanistic insight.