Aliphatic C-H Oxidations for Late-Stage Functionalization

The atomistic change of C(sp(3))-H to C(sp(3))-O can have a profound impact on the physical and biological properties of small molecules. Traditionally, chemical synthesis has relied on pre-existing functionality to install new functionality, and directed approaches to C-H oxidation are an extension of this logic. The impact of developing undirected C-H oxidation reactions with controlled site-selectivity is that scientists gain the ability to diversify complex structures at sites remote from existing functionality, without having to carry out individual de novo syntheses. This Perspective offers a historical view of why, as recently as 2007, it was thought that the differences between aliphatic C-H bonds of the same bond type (for example, 2 degrees aliphatic) were not large enough to distinguish them preparatively with small molecule catalysis in the absence of directing groups or molecular recognition elements. We give an account of the discovery of Fe(PDP)-catalyzed non-directed aliphatic C-H hydroxylations and how the electronic, steric, and stereoelectronic rules for predicting site-selectivity that emerged have affected a shift in how the chemical community views the reactivity among these bonds. The discovery that site-selectivity could be altered by tuning the catalyst [i.e., Fe(CF3-PDP)] with no changes to the substrate or reaction now gives scientists the ability to exert control on the site of oxidation on a range of functionally and topologically diverse compounds. Collectively, these findings have made possible the emerging area of late-stage C-H functionalizations for streamlining synthesis and derivatizing complex molecules.