Recent synthetic strategies for the functionalization of fused bicyclic heteroaromatics using organo-Li, -Mg and -Zn reagents†

Abstract

This review highlights the use of functionalized organo-Li, -Mg and -Zn reagents for the construction and selective functionalization of 5- and 6-membered fused bicyclic heteroaromatics. Special attention is given to the discussion of advanced syntheses for the preparation of highly functionalized heteroaromatic scaffolds, including quinolines, naphthyridines, indoles, benzofurans, benzothiophenes, benzoxazoles, benzothiazoles, benzopyrimidines, anthranils, thienothiophenes, purine coumarins, chromones, quinolones and phthalazines and their fused heterocyclic derivatives. The organometallic reagents used for the desired functionalizations of these scaffolds are generally prepared in situ using the following methods: (i) through directed selective metalation reactions (DoM), (ii) by means of halogen/metal exchange reactions, (iii) through oxidative metal insertions (Li, Mg, Zn), and (iv) by transmetalation reactions (organo-Li and Mg transmetalations with ZnCl₂ or ZnO(Piv)₂). The resulting reactive organometallic reagents allow a wide range of C–C, C–N and C–X cross-coupling reactions with different electrophiles, employing in particular Kumada or Negishi protocols among other transition metal (Pd, Ni, Co, Cu, Cr, Fe, etc.)-catalyzed processes. In addition, key developments concerning selective metalation techniques will be presented, which rely on the use of RLi, LDA and TMP metal bases. These methods are now widely employed in organic synthetic chemistry and have proven to be particularly valuable for drug development programs in the pharmaceutical industry. New and improved protocols have resulted in many Li, Mg and Zn organyls now being compatible with functionalized aryl, heteroaryl, alkenyl, alkynyl and alkyl compounds even in the presence of labile functional groups, making these reagents well-suited for C(sp²)–C(sp²), C(sp²)–C(sp) and C(sp²)–C(sp³) cross-coupling reactions with fused heteroaryl halides. In addition, the use of some transition metal-catalyzed processes occasionally allows a reversed role of the reactants in cross-coupling reactions, providing alternative synthetic routes for the preparation of fused heteroaromatic-based bioactive drugs and natural products. In line with this, this article points to novel methods for the functionalization of bicyclic heteroaromatic scaffolds by organometallic reagents that have been published in the period 2010–2023.