"New methods for indoles and [3,4]-fused oxindoles syntheses" and "Copper-catalyzed/mediated difunctionalization of alkenes with alkylnitriles"

Ala Bunescu
EPFL, 2014
EPFL thesis

Abstract

Two main topics were addressed in this manuscript: (1) New methods for indoles and [3,4]-fused oxindoles syntheses; (2) Copper-catalyzed/mediated difunctionalization of alkenes with alkylnitriles. Given the omnipresent character of the indole and oxindole ring systems, their synthesis and functionalization are a research area of main interest. Two different strategies have been developed for the indole motif synthesis. The first method implies a Cucatalyzed heteroannulation of ortho-aminophenylboronic ester and β-ketoester under mild, base free conditions. The second strategy consists in the synthesis of N-arylindoles via a benzannulation reaction with α-N-aryl aminoketone and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate as benzyne precursor. The benzannulation reaction was applied to the synthesis of 5,6-dihydroindolo[1,2-a]quinolone by using cyclic α-N-aryl aminoketone, obtained in one step from commercial compounds via the three-component Povarov reaction. Afterwards, we developed a novel Pd(0)-catalyzed domino reaction, involving carbopalladation/1,4-Pd shift via double C-H bond activation/C-C bond formation for the synthesis of [3,4]-fused oxindoles. In the second part of the manuscript, we addressed the copper-catalyzed difunctionalization of alkenes. The difunctionalization of olefin represents a domain of main interest in organic synthesis due to the availability of the starting material and the possibility to reach high complexity and diversity of products in one single step. We developed a methodology that allows the introduction of a "C(R')(R)CN" group by coppercatalyzed difunctionalization of alkene, using the alkyl nitriles as reaction partner. By applying this methodology, different functionalized classes of compounds were synthesized: phthalides, γ-lactone and isochromanones, epoxides and ketones.

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Ala Bunescu
EPFL, 2014
EPFL thesis

Abstract

Official source

https://infoscience.epfl.ch/record/203264?ln=en

About this result

Related concepts (9)

Related concepts

Related publications (10)

Related publications

Related publications (10)

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

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

Ligand synthesis for homogeneous catalysis

Michael Maurin

Organophosphorus compounds found applications in varied fields of the organic chemistry: they are particularly present in natural compounds such as the deoxyribonucleic acid (DNA) and in the field of catalysis in which their utility is also proven. Thus, this thesis work first focused on the preparation of various phosphorus ligands utilizable in transition metal catalysed reactions. Being given the importance of this type of reaction in organic synthesis, it appears essential to have many ligands at disposal in order to fine-tune and to optimize the reaction conditions as much as possible. Thus, the first objective of this work was to propose a simple and general method for the preparation of monodentate phosphorus ligands. Based on the use of phosphites in substitution for the usual phosphorus trihalides, this method was initially tested during the preparation of different simple triarylphosphines. Thereafter, this method was extended to the synthesis of new ligands having more complex structures. The yields obtained for the latter as well as the variety of the substrates authorized by this method confirmed its value and suggested its application to the synthesis of new heteroaromatic phosphines. The preparation of bidentate phosphorus ligands based on chiral biphenyl motifs was then addressed. For that purpose, the 2,2',6,6' -tetrabromobiphenyl was chosen as a pivot substrate for the development of a modular synthetic approach. Indeed, by means of successive halogen/metal permutational exchanges and after treatment with the suitable electrophile, it was possible to functionalize this substrate, isolate each atropisomer in enantiomerically pure form, and finally convert each one of those into chiral biphenylbisphosphines. In addition, it was also possible, during the synthesis of these ligands, to evaluate the rotational stability of some enantiomerically pure dilithiobiphenyls by means of dynamic nuclear magnetic resonance experiments.

EPFL2007