New practical routes to furnish 8-aminoquinoline derivatives have been developed by employing readily installable and easily deprotectable carbamate reagents via the C-H functionalization strategy. More specifically, we employ N-chlorocarbamates as the working reagent, whose versatility has been severely overlooked thus far. Although synthetic approaches to allow for this type of C-N bond formation have been developed previously, the removal of the N-protecting group suffered from multi-step procedures and harsh reaction conditions. Furthermore, while the 8-aminoquinoline derivatives have a myriad of utilities in materials and medicinal chemistry, the synthetic challenges from the conventional methods greatly restricted their greater implementation. In this regard, we have developed a mild Rh-catalyzed C-H amidation of quinoline N-oxide compounds using carbamates as the nitrogen source. This catalytic system has been successfully applied to the C-H amidation of quinoline N-oxides with various substitutions, proving the compatibility of this method over a diverse scope. In addition, deoxygenation to yield quinoline derivatives was also achieved by mild Pd-catalyzed transfer hydrogenation conditions with simultaneous N-deprotection, to complete the successful installation of amines to the C-8 position of quinoline. Notable features of the presently developed chemistry can be summarized as follows: (1) The present study exhibits the facile access to 8-aminoquinolines compared to the conventional methods, via practical amidating groups and a subsequent controllable deprotection strategy. (2) N-Chlorobenzyloxy carbamate reagent is scalable, stable, and easily isolable both as a starting material and in reaction with the catalytic system to produce 8-(Cbz-amino)quinoline N-oxide in excellent yield. (3) A one-pot two-step process with generation of the amidating reagent from economic chlorinating sources, followed by catalytic reaction with our proposed method has been developed and eliminates a work-up step.

Synthesis of 8-aminoquinolines by using carbamate reagents: Facile installation and deprotection of practical amidating groups

252nd National Meeting (2016)

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