Platinum-Catalyzed Domino Reactionwith Benziodoxole Reagents for Accessing Benzene-Alkynylated Indoles

Indoles are omnipresent in natural products, bioactive molecules, and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene-ringfunctionalized indoles with an unsubstituted pyrrole ring remains more challenging. Reported herein is a platinumcatalyzed cyclization/alkynylation domino process to selectively obtain C5-or C6-functionalized indoles starting from easily available pyrroles. The work combines, for the first time, a platinum catalyst with ethynylbenziodoxole hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.

Synthesis of Alkynylated Heterocycles by Direct C-H Alkynylation or Domino Alkynylation Reactions

Yifan Li

Heterocycles are important compounds in organic chemistry. To introduce functional groups on heterocycles or synthesize functionalized heterocycles stays a hot topic of research. Among all the functional groups, alkynes attracted a lot of attention not only because of their occurrence in organic compounds, like synthetic pharmaceuticals, natural products and organic materials, but also because of their versatile chemistry, such as metal catalyzed cyclization and [3+2] annulation reactions. Therefore, it is of great importance to introduce alkynes on heterocycles or synthesize alkynylated heterocycles in an efficient and regioselective manner. The Sonogashira reaction has dominated the introduction of alkynes on heterocycles. Even though the method is well established, there are several shortcomings such as stoichiometric waste production and poor stability or accessibility of the starting materials. To introduce alkynes on heterocycles in an efficient fashion, direct C-H alkynylation has been intensiely investigated as an alternative in the last decades. Based on the previous work in our group, direct C-H alkynylation was extended to access C2- alkynylated furans using a gold catalyst and triisopropylsilyl ethynyl benziodoxolone (TIPS-EBX). For less nucleophilic substrates like benzofurans, the use of Zn(OTf)2 was necessary to activate the EBX reagent. Although direct C-H alkynylation provides a straightforward way to access alkynylated heterocycles, it is limited to the inherently more reactive positions such as the C2 position of five-membered heterocycles or the heterocyclic ring of benzofused heterocycles. It is therefore challenging to find pathways to obtain heterocycles functionalized at other positions. Domino reactions could provide a solution to this challenge, as the metal-carbon bond could be installed on positions different from the ones obtained via a direct metallation approach. Based on this concept, unprecedented cyclization-alkynylation domino reactions were developed to access alkynylated heterocycles. Starting from easily prepared allenic ketones or ortho- ethynylated phenols or thioanisoles, C3 alkynylated furans, benzofurans and benzothiophenes can be rapidly accessed. This is a breakthrough as it allows for the introduction of alkynes on less nucleophilic positions. These products are difficult to obtain via direct C-H alkynylation as it occurred exclusively on C2 position of furans, benzofurans and benzothiophenes. Nevertheless, this approach was still limited to more reactive heterocycles. We then turned our efforts to develop domino reactions to functionalize the less reactive benzene ring. We found that with C2 or C3-substituted pyrroles as starting materials, C5 or C6 alkynylated indoles can be easily formed when combining a platinum catalyst with a bistrifluoromethyl benziodoxole reagent. In summary, a series of alkynylated heterocycles were obtained via direct alkynylation or domino reactions combining hypervalent iodine reagents and metal catalysts. This discovery is expected to find broad application to access diverse alkynylated heterocycles. It also set the bases for the development of new domino processes with different metal catalysts and electrophilic reagents in the future.

EPFL2016

Development of New Strategies of Umpolung with Cyclic Hypervalent Iodine Reagents

Paola Caramenti

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 Î±-cyano Î±-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. Î±-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 Î²-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 Î±-cyano Î±-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 CâH 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.

EPFL2019

Catalytic Formal Homo-Nazarov Reaction and Other Cyclizations of Cyclopropanes

Filippo De Simone

The increasing progress in medicinal chemistry and chemical biology requires more versatile synthetic strategies for the generation of libraries of active compounds and theirs analogues. A wide range of biologically active natural and synthetic compounds contain a complex polycyclic heterocyclic scaffold as core structure. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. The goal of my PhD thesis was the development of a new catalytic cyclization reaction – the formal homo-Nazarov reaction. Starting from cyclopropanes as the smallest carbocycles, we were able to build-up complex carbocyclic and heterocyclic molecules, including alkaloid natural products. This thesis is divided in three main chapters, introduction, formal homo-Nazarov reaction and cyclization reactions of aminocyclopropanes. In the introductory part, the electronic properties and synthetic approaches to generate cyclopropanes are first described. Next, important examples of annulation and cyclization reactions involving cyclopropanes are discussed, pointing out the importance of activating and/or polarizing substituents on the three member ring. The second chapter of this thesis is dedicated to the development of a new catalytic method for the cyclization of vinyl cyclopropyl ketones –the formal homo-Nazarov cyclization. Optimization of the catalytic conditions is described, as well as extension of the substrate scope to a wide range of heterocycles and carbocycles. The reaction mechanism is then investigated using kinetic, labeling and trapping experiments. The results of these investigations indicate a stepwise mechanism through carbocationic intermediates. Moreover, the influence of an additional polarizing ester substituent on the cyclopropane is discussed, as well as the resulting scope extension. Finally, a first example of asymmetric induction for the catalytic formal homo-Nazarov cyclization using chiral Lewis acid catalysts is presented. The third chapter reports the extension of the catalytic homo-Nazarov cyclization to aminocyclopropanes. The reaction occurs under mild conditions and highly diastereoselective cyclizations are obtained via an acyliminium intermediate generated through opening of the cyclopropane. The presented methodology allowed an excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners. The utility of the developed methodology is demonstrated by the generation of two different polycyclic scaffolds of natural products starting from a common intermediate. Based on this method, a formal total synthesis of the Aspidosperma alkaloid aspidospermidine is presented. The scope and limitations of our methodology are presented on an extended range of aryl- and vinyl- cyclopropyl ketones bearing indole, pyrrole, pyran, benzofuran or thiophene groups as electron-rich aryl or alkene substituents, and cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane. Finally, the versatility of our cyclization method is demonstrated by its successful application in the total synthesis of the natural alkaloid goniomitine, accomplished in 13 linear steps with an overall yield of 11%. The availability of goniomitine and several of its analogues in significant amount allowed the first studies of the bioactivity of this class of alkaloids, which displayed only low cytotoxicity (IC50: 15-123 µM).

EPFL2012