Late-stage C–H functionalization : from benzylic C–H oxygenation to aromatic C–H iodination

Tanwar, Lalita; Ritter, Tobias (Thesis advisor); Bolm, Carsten (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


The introduction of heteroatoms into existing bioactive molecules has the potential to alter their physical and biological properties. For instance, nitrogen-based functional groups such as amines, and amides are considered privileged scaffolds in medicinal chemistry and natural products. Furthermore, C–O, and C–F bond forming reactions are of special interest in the synthesis of potential metabolites and in metabolism block strategies, both are important in the drug discovery processes. Although numerous electrophilic oxidants have been developed for C–H Oxygenation, an important remaining challenge is to achieve the transformation with heightened levels of chemo- and site-selectivity. To overcome the challenge, a new strategy for oxidative C–O bond formation for electron-deficient and -rich arenes, heteroarenes, and highly functionalized compounds are made with bis(methanesulfonyl) peroxide as the oxidant. One major advantage over other organic peroxides lies in the convenient preparation of peroxide. The formation of charge-transfer complex between bis(methanesulfonyl) peroxide and arenes is responsible for the chemoselective arene functionalization as compared to peroxide reactivity with other functional groups, such as hydrogen atom transfer (HAT) chemistry. The resulting aryl mesylates are stable phenol precursors, meanwhile, the mesyl group can be readily cleaved under mild conditions to serve as a direct precursor for aryl fluoride formation. Selective monooxidation of methylene C–H bond is challenging because the resulting secondary alcohols are prone to be oxidized further to ketones. Inspired by the high chemoselectivity achieved by bis(methanesulfonyl) peroxide with arenes, led to the development of selective monooxygenation of benzylic C–H bond. By doing so, the problem of chemoselective reduction of phenones to alcohols in the presence of other carbonyl functionality is eliminated, and alkenes as well as alkynes, typically sensitive to oxidative reaction conditions are tolerated, as are basic amines. If tertiary, allylic, and propargylic C–H bonds are present, exclusive functionalization of the benzylic position is observed. Carbamates, esters, imides, and epoxides are tolerated showing the applicability of the method to complex small molecules in the drug discovery process. Proton-coupled electron transfer mechanism (PCET) may account for its distinction from the previous chemoselective C–H oxygenation reaction. Another C–H functionalization which utilizes the use of bis-mesyl peroxide is selective C–H iodination of heteroarenes. Iodoarenes are prevalent building blocks, which have a wide range of applications in the natural products and pharmaceutical industry. We demonstrate the utility of in situ generated iodosulfonates accessed by reaction of iodide with bis-mesyl peroxide by iodinating a large set of heteroarenes in high yield and regioselectivity. Detailed study of the hypothesis that the magnitude of the selectivity can be rationalized by a charge transfer complex between hypoiodite and arene as we observed in the related mesyloxylation reaction was prevented by in situ formation of the reactive intermediate.