Smiles Rearrangements

Smiles rearrangements are intramolecular nucleophilic aromatic substitutions (SN Ar) involving skeletal rearrangements of the type ArX(CR1R2)nYH→ArY(C)nXH with X and Y holding for heteroatoms. Six-membered heterocycles such as pyridines or pyrimidines participate in Smiles rearrangements without requiring a further activating group. As a consequence, these reactions have been widely used in medicinal chemistry, giving access to biologically relevant aminopyridine and aminopyrimidine derivatives. This chapter begins with a discussion of the general principles controlling Smiles rearrangements, illustrating the general mechanistic pathway of the Julia-Kocienski olefination. It focuses on the Smiles rearrangements reported during the last 10 years, highlighting recent integration of Smiles rearrangements in complex synthetic cascades. The chapter also emphasizes relevant experimental details for implementation of Smiles-based strategies. Cascades toward fused heterocyclic systems represent early and rather simple examples of this approach. Their use in more elegant and complex synthetic schemes really began with the Julia-Kocienski olefination.