Medicinal chemistry applications of the Dimroth Rearrangement to the synthesis of biologically active compounds

Abstract

The Dimroth Rearrangement (DR) is an isomerization process involving the translocation of exo- and endocyclic nitrogen atoms in heterocyclic systems via a ring opening, rotation, and ring closure mechanism. Originally discovered over 120 years ago, the mechanistic occurrence of the DR on multiple heterocycles has been widely studied, and its application to the synthesis of biologically active compounds is well documented, albeit on some occasions not directly referenced. A surprisingly high number of drug discovery programs take advantage of the DR for the synthesis of heterocycle-containing compounds, including 4-aminopyrimidines and 4-anilinoquinazolines. Evidence of the flexibility and valuable potential of the DR can be found in the use of this reaction in the manufacture processes of several active pharmaceutical ingredients (APIs) on a commercial scale, allowing a reduction in the manufacturing costs and the environmental burden of the synthetic routes. The aim of this review is to outline the generality and broad applicability of the DR to the synthesis of biologically active compounds and highlight the opportunities to utilize this tool more widely within the medicinal chemistry toolbox.