The Smiles rearrangement in the syntheses of azaphenothiazines. Part I

The Smiles rearrangement, an intramolecular nucleophilic aromatic substitution proving to be a synthetically useful tool to obtain various types compounds of diverse applications, has undergone a potent revival in recent years. Phenothiazines and azaphenothiazines, one of the most bioactive heterocyclic scaffolds in medicinal chemistry providing recognized drugs and recently drug candidates, have been synthesized in multistep processes through the Smiles rearrangement of S-N type. The Smiles rearrangement during the syntheses of azaphenothiazines occurs more frequently than one can expect and observe. This review discusses cascades of C-S coupling/S-N Smiles rearrangement/C-S cyclization and S-N Smiles rearrangement/C-S cyclization steps, competition of the rearrangement with the Ullmann type cyclization (C-N cyclization), an influence of the azine nature, steric hindrance and reaction conditions (neutral, basic, weakly acidic, strongly acidic and thermal) on the reaction pathways and efficiency, occurrence of a very rare double Smiles rearrangement, importance of proper structural analysis and confusing chemical literature on azaphenothiazines. (C) 2019 Elsevier B.V. All rights reserved.