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Late-stage C-H Functionalization: From Benzylic C-H Oxygenation to Aromatic C-H Iodination

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Tanwar,  Lalita
Research Department Ritter, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Tanwar, L. (2021). Late-stage C-H Functionalization: From Benzylic C-H Oxygenation to Aromatic C-H Iodination. PhD Thesis, Rheinisch-Westfälische Technische Universität, Aachen.


Cite as: https://hdl.handle.net/21.11116/0000-0009-BB6F-9
Abstract
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.