Heterocycles via ortho-Lithiated Benzamides

Ortho-lithiated N,N-diethyl benzamides, readily generated by treatment of the corresponding amides with c -B u L i or t-BuLi in THF or Et20/TMEDA at -78", are important new synrhons (dl-reagents) for the regiospecific construction of highly substituted aromatic derivatives which are difficult to obtain by classical (usually electrophilic substitution) chemistry ( s .This paper will demonstrate the utility of elithiated benzamides f o r the synthesis of contiguously substituted aromatics, phthalide and isochroman-1,3-dime heterocycles, phthalideisoquinoline alkaloids, anthraquinone natural products, polycyclic anrhraquinones and corresponding P A H ' s , heterocyclic beneoquinones, and ellipticine alkaloids. 2The term directed metalation is defined as the depratanation of an sp -carbon a to a heteroatom-containing suhstituent on an aromatic or olefinic substrate.In this context, ortho metalation refers specifically to aromatic substrates (Fig. 1). -The ortho directing group Z 1) anchors the strong b a s e anvariably an a l k y llithium reagent) b y coordination, 2) provides an inductive electron-withdrawing effect in the deprotonation step, and 3) stnhilizes the ortha metalated inter-.Systems in which the Z group bears acidic hydrogen require