Unravelling Factors Affecting Directed Lithiation of Acylamino-aromatics

Ureas, pivalamides, and carbamates are widely used as directing metalation groups (DMGs) due to their good directing ability, low cost, ease of access, and ease of removal. Lithiation of substituted benzenes having such directing metalation groups using various alkyllithiums in anhydrous solvent at low temperature provides the corresponding lithium intermediates, but lithiation may take place at various sites. Reactions of the lithium reagents obtained in situ with various electrophiles give the corresponding derivatives, typically substituted at the site(s) where initial lithiation occurred, often in high yields. However, it is often difficult to predict what reagents and/or conditions might be needed to give specific products or to draw general conclusions about the factors that influence the reactions, especially when the reagents, temperature, and solvents used in reported reactions are not directly comparable. In this review, therefore, we attempt to unravel the various factors that influence the lithiation of various simple aromatic compounds containing urea, pivalamide, and carbamate groups. 1 Introduction 2 Lithiation with DMG Attached Directly to the Phenyl Ring 2.1 Influence of the DMG 2.2 Influence of Substitution on the Phenyl Ring 3 Lithiation with the DMG Separated by a CH2 Group from the Phenyl Ring 3.1 Effect of the DMG 3.2 Influence of Substitution on the Phenyl Ring 4 Lithiation with the Phenyl Ring and DMG Separated by Two or More CH2 Groups 4.1 Effect of the DMG and Its Distance from the Phenyl Group 4.2 Effect of Substituents on the Phenyl Ring 5 Conclusions