Use of AlCl3 in Friedel Crafts arylation type reactions and beyond: an overview on the development of unique methodologies leading to N-heteroarenes

Abstract

As a privileged class of heterocyclic compounds N-heteroarenes have found enormous applications in many areas including medicinal/pharmaceutical chemistry and drug discovery. Consequently, a wide variety of methods have been reported for their synthesis. While not free from their own limitations the AlCl₃ mediated methods appeared to have some particular advantages in preparing a number of useful N-heteroarenes. Besides the famous Friedel–Crafts (FC) alkylation/acylation reactions one such example is AlCl₃-induced heteroarylation of arenes and heteroarenes (FC arylation type reactions) that can be used to prepare a certain class of N-heteroarenes in an operationally simple, efficient and cost effective manner. Interestingly, pyridine is not a good substrate in FC alkylation/acylation reactions whereas 2-chloropyridines are indeed effective in heteroarylation reaction. However, no systematic and detailed study regarding the application potential of this method was performed until 2002. Some other examples that emerged in the recent past include AlCl₃ induced heteroarylation–cyclization, hydroarylation–heteroarylation, sulfonyl group migration etc. All these innovative methodologies allowed the direct access to several unique and novel N-heteroarenes some of which showed interesting pharmacological properties including anti-inflammatory, anti-cancer and antibacterial activities when tested in vitro. While unlike FC reactions many of these AlCl₃ mediated methodologies are still in their initial stage of developments, a continuing effort to uncover their further potential in organic synthesis/medicinal chemistry is necessary. The current article provides an overview of these unique methodologies that highlight the use of AlCl₃ beyond FC reactions leading to new N-heteroarenes.