Compared to classic cyclization methods for indole synthesis, direct dehydrogenation methods from indolines are particularly valuable for accessing N-substituted indoles, which in many cases cannot be readily obtained by derivatization of indole N-H due to its low nucleophilicity and competitive C-functionalization. However, the most widely used reagent for indoline dehydrogenation, DDQ, suffers numerous limitations, including relatively high toxicity and cost, the potential for HCN liberation, challenges in removing DDQH2 from the reaction mixtures and undesired side reactions with electron-rich C-H bonds. The high reduction potential of DDQ has also limited opportunities for its regeneration from DDQH2, leading to the formation of stoichiometric waste. These issues have led to a search for for economical, chemoselective and environmentally benign catalytic alternatives to DDQ. Here we report the first example of quinone-catalyzed aerobic dehydrogenation of tertiary amines using a low potential quinone, 1,10-phenanthroline-5,6-dione, which mimics the reactivity of high-potential quinones like DDQ. The catalyst systems can be applied to the dehydrogenation of a variety of N-substituted indolines under mild conditions, while displays broad functional group tolerance. The utility of this method is highlighted in the efficient synthesis of key intermediates en route to the pharmaceutically important molecules.

Highly efficient quinone-catalyzed aerobic dehydrogenation of N-substituted indolines to indoles

256th National Meeting (2018)

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