Amine Organocatalysis of Remote, Chemoselective C(sp3)-H Hydroxylation.

We introduce an organocatalytic approach for oxaziridinium-mediated C-H hydroxylation that employs secondary amines as catalysts. We also demonstrate the advantages of this operationally simple catalytic strategy for achieving high yielding and highly selective remote hydroxylation of compounds bearing oxidation-sensitive functional groups such as alcohols, ethers, carbamates, and amides. By employing hexafluoroisopropanol as the solvent in the absence of water, a proposed hydrogen bonding effect leads to, among other advantages, as high as ≥99:1 chemoselectivity for remote aliphatic hydroxylation of 2° alcohols, an otherwise unsolved synthetic challenge normally complicated by substantial amounts of alcohol oxidation. Initial studies of the reaction mechanism indicate the formation of an oxaziridinium salt as the active oxidant, and a C-H oxidation step that proceeds in a stereospecific manner via concerted insertion or hydrogen atom transfer/radical rebound. Furthermore, preliminary results indicate that site selectivity can be affected by amine catalyst structure. In the long term, we anticipate that this will enable new strategies for catalyst control of selectivity based on the abundance of catalytic scaffolds that have proliferated over the last twenty years as a result of Nobel Prize-winning discoveries.

Selective Heteroaryl N-Oxidation of Amine-Containing Molecules.

The first examples of nonenzymatic N-oxidation of heteroarenes in the presence of amines are reported. Pyridine, quinoline, and isoquinoline N-oxides are selectively formed in the presence of more reactive aliphatic and alicyclic amines by use of an in situ protonation strategy and an iminium salt organocatalyst. Application to late-stage functionalization that mimics phase 1 metabolism of small-molecule drugs is also demonstrated.