Directed aromatic functionalization

Figure 1: Directed aromatic functionalization methods. The title of this Thematic Series brings to the minds of most organic chemists the beautifully logical aromatic electrophilic substitution (SEAr) [1-5] and, to a lesser extent, nucleophilic aromatic substitution (SNAr) [2,6,7] reactions as taught to many generations of students in their first organic chemistry courses [8] (Figure 1). Being less steeped in history, radical nucleophilic substitution (SRN1) [9] and vicarious nucleophilic substitution (VNS) [10-12], in spite of their considerable synthetic utility, are given sparse mention. By the time students reach the upper years of study, aromatic chemistry receives the label “classical” and is disregarded or relegated to brief coverage. Apart from in English schools [13], heteroaromatic chemistry suffers the same fate. As a consequence, a fresh graduate entering the pharmaceutical industry, who invariably faces a complex aromatic or heteroaromatic as his or her first target molecule, is either lost or must grope around with insufficient background knowledge. Since the late 1970s, over thirty years since the independent discoveries by Gilman and Wittig, the directed ortho metalation (DoM) reaction has trickled into the armamentarium of the synthetic chemist (but not significantly into textbooks [8,14]), as a general and rational strategy for the construction of polysubstituted aromatics and heteroaromatics [15-17]. While comparison with SEAr and SNAr should never be denied, the DoM approach offers incontestable ortho regioselectivity, mild conditions, and perhaps most significantly, broad post-DoM synthetic potential. As a result, it has been called upon, with increasing favor and frequency, by academic and medicinal chemists for small-scale synthesis and by process chemists for multi-kilogram scale routes for clinical candidates and commercial pharmaceuticals and agrochemicals [18-24].