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Synthesis

Reaction aminates C–H bonds selectively

Manganese phthalocyanine catalyst shows preference for least-hindered benzylic C–H bonds

by Stu Borman
May 7, 2018 | APPEARED IN VOLUME 96, ISSUE 19

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The White group’s reaction favors amination at the least sterically hindered benzylic site (green) among several possible selective-amination sites (red).

Many approved drugs contain benzylic nitrogens, which can influence bioactivity substantially. A new catalytic reaction that adds amine groups to benzylic C–H bonds more selectively than was previously possible could be useful to derivatize molecules for drug discovery. M. Christina White of the University of Illinois, Urbana-Champaign, and coworkers employed manganese(III) perchloro­phthalocyanine to catalyze amination of one benzylic C–H bond selectively in substrates with other benzylic sites (Nat. Chem. 2018, DOI: 10.1038/s41557-018-0020-0). Removing a sulfur-containing protecting group from the initial products generates the free-amine final products. In substrates with multiple benzylic sites, amination occurs preferably at the least sterically encumbered and most electron-rich benzylic C–H bond. In the presence of a Brønsted or Lewis acid, the reaction also works on substrates already containing basic nitrogens. Existing C–H amination methods either do not work for such compounds or they aminate C–H bonds adjacent to the nitrogen. White and coworkers used the approach to aminate a series of drugs and druglike molecules such as citalopram, estrone and dextromethorphan analogs, and biflavonoids, some of which could not be aminated in the same ways before. The university has licensed the catalyst to MilliporeSigma.

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