Development of direct C-H amidation at the C-8 position of quinoline N-oxides

Abstract

8-Aminoquinoline is an important structural motif found in numerous natural and synthetic compounds with broad applications in medicinal and coordination chemistry. For efficient synthetic protocol, we have developed an iridium-catalyzed regioselective C-H amidation of quinoline N-oxides at the 8-position by using N-oxide as directing group and azides as amidation source. This high selectivity was found to be achieved through the smooth formation of an intermediate of N-oxide-chelated iridacycle. Mechanistic studies revealed a key role of acid additives. The amidation proceeded efficiently over a wide range of heterocyclic substrates under mild conditions with high functional group tolerance. Using our protocol, Zinquin ethyl ester (a fluorescent zinc indicator) was synthesized in a straightforward manner. A practical synthetic route to 8-aminoquinolines has been developed by using readily installable and easily deprotectable carbamate amidating reagents. This reaction was facile to afford directly 8-aminoquinoline N-oxides protected by practical protecting group such as Cbz, Boc and Fmoc, resulting in high synthetic efficiency. Two scalable procedures were optimized under the Rh(III)-catalyzed conditions using either pre-generated chlorocarbamates or carbamates in a two-step one-pot process. Both approaches are highly convenient to perform under mild conditions enabling scalable processes. Facile deprotection of the synthetically versatile amidating groups was achieved under mild Pd-catalyzed transfer hydrogenation conditions with the simultaneous deoxygenation of quinoline N-oxides in excellent overall efficiency.