Nitrogen containing heterocycles and their analogues are ubiquitous organic scaffolds found in nature and are known as medicinally important pharmacophores, among which azoles, pyrroles, indoles and quinolines have the most frequent occurrence. Hence, the synthetic exploration and expansion of their applications is critical for realizing their full potential. The inherent reactivity of these heteroarenes has enabled direct bond formation even in unfunctionalized scaffolds through transition-metal catalysis. In this context, the Cu-catalyzed site selective C2-H activation followed by intramolecular cross dehydrogenative coupling (CDC) of 3-substituted pyrroles and indole derivatives was established for direct access to polycyclic heteroarenes in moderate to good yields. Interestingly, the Pd-catalyzed reaction conditions for 3-substituted pyrrole derivatives preferred C5-selective intramolecular CDC over C2-selective products (Scheme 1). Further, as an advancement towards regioselective C-H functionalization of N-heteroaromatics, transition-metal free intermolecular C5-H chalcogenation of 8-aminoquinolines was developed under mild reaction conditions. The successful implementation of this methodology was further established through late-stage derivatization of pamaquine analogue which is known to be an efficient antimalarial.
Scheme 1: Transition metal-catalyzed C2 and C5-selective CDC of N-heteroaromatics