Development of New Strategies of Umpolung with Cyclic Hypervalent Iodine Reagents

Organic chemistry is essential for the development of a modern society and technical progress requires the continuous development of synthetic methodologies Novel, efficient, selective and flexible protocols are employed to access complex frameworks from simple starting materials. However, classical synthetic methods often relies on the intrinsic reactivity of functional groups, reducing the portfolio of available reactions for synthetic chemists. The reversal of classical reactivity of functional groups allows alternative disconnection pathways and can improve synthetic efficiency. The research presented in this thesis was aimed at the development of new strategies of Umpolung with hypervalent iodine reagents. Three new Umpolung methods have been investigated. First a strategy for the synthesis of enantioenriched α-cyano α-allyl ketones has been developed. Second, novel indole- and pyrrole-based hypervalent iodine reagents have been synthesized and applied in the context of metal-catalysis ad metal-free transformations. Third, a new class of umpoled enamides and enol ethers have been prepared from simple starting materials. α-Cyano carbonyls are important structural motifs of bioactive compounds and natural products. Nitriles are also versatile building blocks that undergo a plethora of transformations, which are usually accessed by transfer of the nucleophilic cyanide anion to electrophiles. The reactivity of cyanide can be reversed by the use of hypervalent iodine reagents. Part I focus on the application of umpoled nitriles for the functionalization of carbonyls. With these reagents, a variety of β-keto esters were successfully cyanated in racemic fashion. Inspired by previous results obtained in our group, a decarboxylative asymmetric allylic alkylation strategy was applied for the synthesis of enantioenriched quaternary α-cyano α-allyl ketones embedded in an indanone framework. Cyclic indanone derivatives were accessed in good yields and enantioselectivities. Indole and pyrrole heterocycles are often embedded in relevant drugs, natural products and materials. Their ubiquity inspired decades of intensive research for both their synthesis and functionalizations. Especially functionalization methods mainly focused on their intrinsic nucleophilic properties. The field exploiting their electrophilic derivatization was severely underdeveloped. An alternative strategy to access electrophilic indole and pyrrole synthons takes advantage of the unique properties of hypervalent iodine. In Part II of this thesis, indole- and pyrrole-based benziodoxoles were prepared and used for the metal-catalyzed direct indole transfer on aromatic C–H bonds. A large variety of indole-aryl frameworks, previously elusive or accessed via multi-step syntheses, were accessed in a straightforward manner, starting from simple commercially available building blocks. A direct oxidative metal-free cross-coupling for the synthesis of mixed bi-(hetero)aryl-indoles was then developed. The reaction worked well with our previously synthesized reagents, and a new class of electrophilic indoles (activated at the C2 carbon) was specifically developed for this transformation, further expanding the pool of available benziodoxoles.