tert-Butyl as a Functional Group: Non-Directed Catalytic Hydroxylation of Sterically Congested Primary C-H Bonds.

The tert-butyl group is a common aliphatic motif extensively employed to implement steric congestion and conformational rigidity in organic and organometallic molecules. Because of the combination of a high bond dissociation energy (~100 kcal mol-1) and limited accessibility, in the absence of directing groups, neither radical nor organometallic approaches are effective for the chemical modification of tert-butyl C-H bonds. Herein we overcome these limits by employing a highly electrophilic manganese catalyst, [Mn(CF3bpeb)(OTf)2], that operates in the strong hydrogen bond donor solvent nonafluoro-tert-butyl alcohol (NFTBA) and catalytically activates hydrogen peroxide to generate a powerful manganese-oxo species that effectively oxidizes tert-butyl C-H bonds. Leveraging on the interplay of steric, electronic, medium and torsional effects, site-selective and product chemoselective hydroxylation of the tert-butyl group is accomplished with broad reaction scope, delivering primary alcohols as largely dominant products in preparative yields. Late-stage hydroxylation at tert-butyl sites is demonstrated on 6 densely functionalized molecules of pharmaceutical interest. This work uncovers a novel disconnection approach, harnessing tert-butyl as a potential functional group in strategic synthetic planning for complex molecular architectures.

Catalyst and Medium Control over Rebound Pathways in Manganese-Catalyzed Methylenic C-H Bond Oxidation.

The C(sp3)-H bond oxygenation of a variety of cyclopropane containing hydrocarbons with hydrogen peroxide catalyzed by manganese complexes containing aminopyridine tetradentate ligands was carried out. Oxidations were performed in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and 2,2,2-trifluoroethanol (TFE) using different manganese catalysts and carboxylic acid co-ligands, where steric and electronic properties were systematically modified. Functionalization selectively occurs at the most activated C-H bonds that are α- to cyclopropane, providing access to carboxylate or 2,2,2-trifluoroethanolate transfer products, with no competition, in favorable cases, from the generally dominant hydroxylation reaction. The formation of mixtures of unrearranged and rearranged esters (oxidation in HFIP in the presence of a carboxylic acid) and ethers (oxidation in TFE) with full control over diastereoselectivity was observed, confirming the involvement of delocalized cationic intermediates in these transformations. Despite such a complex mechanistic scenario, by fine-tuning of catalyst and carboxylic acid sterics and electronics and leveraging on the relative contribution of cationic pathways to the reaction mechanism, control over product chemoselectivity could be systematically achieved. Taken together, the results reported herein provide powerful catalytic tools to rationally manipulate ligand transfer pathways in C-H oxidations of cyclopropane containing hydrocarbons, delivering novel products in good yields and, in some cases, outstanding selectivities, expanding the available toolbox for the development of synthetically useful C-H functionalization procedures.