DIRECTED METALATION OF PI-DEFICIENT AZAAROMATICS - STRATEGIES OF FUNCTIONALIZATION OF PYRIDINES, QUINOLINES, AND DIAZINES

This chapter updates the directed ortho metalation (DoM) reaction of pyridines, quinolines, pyrimidines, pyrazines, and pyridazines. Various directed metalation group (DMGs) (halo, NHCOR and NHC02R, OR and OCONR2, 2-oxazolino, CONHR, CONR2, and masked RCHO and RCOR, SO2NR2) have been described, with major emphasis given to the metalation of halo pyridines, an area in which selectivity and mechanistic aspects have been extensively studied. Reactions of powerful alkyllithiums with halo pyridines, quinolines, and diazines may lead to nucleophilic substitution (by addition-elimination or hetaryne mechanisms), ring opening, halogen-scrambling, and coupling reactions that compete with the desired DoM process. Lithiation chemistry of bare pyridines and pyridine N-oxides is presented, followed by the use of the DoM strategy for the synthesis of natural products and biologically active molecules. The exploration of DoM chemistry in haloheteroaromatics is valuable for two reasons: (a) halo derivatives can be readily prepared from accessible amino, hydroxy, and, at times, unsubstituted systems, and (b) halogens can be subsequently induced to undergo a variety of funcionalizations via addition-elimination, metal-halogen exchange, and cross coupling reactions. Some of these transformations are more facile than in the aromatic series. Thus, DoM tactics may lead to diverse substituted heteroaromatics, which can be difficult to obtain by more classical means. © 1991, Elsevier Inc. All rights reserved.