Azide Radical Initiated Ring Opening of Cyclopropenes Leading to Alkenyl Nitriles and Polycyclic Aromatic Compounds

We report herein a radical‐mediated amination of cyclopropenes. The transformation proceeds through a cleavage of the three‐membered ring after the addition of an azide radical on the strained double bond and leads to tetrasubstituted alkenyl nitrile derivatives upon loss of N2. With 1,2‐diaryl substituted cyclopropenes, this methodology could be extended to a one‐pot synthesis of highly functionalized polycyclic aromatic compounds (PACs). This transformation allows the synthesis of nitrile‐substituted alkenes and aromatic compounds from rapidly accessed cyclopropenes using only commercially available reagents.

New Strategies for the Functionalization of Alkenes Exploiting Tethering Chemistry and Ring Strain

Bastian Antoine Rodolphe Claude Muriel

Amino alcohols, cyclopropanes and nitriles are privileged structural motifs found in the scaffold of natural products and bioactive compounds. In addition, they are versatile building blocks in organic chemistry. The development of new and increasingly efficient synthetic methods to access these chemical motifs from readily available feedstocks is therefore highly desirable. In this context, alkenes have been substrates of choice to rapidly access complex molecules, as two new functionalities can be installed across their double bond. To achieve such transformations, palladium catalysis and radical chemistry stand as two of the most efficient strategies. In this thesis, a new palladium-catalyzed carboamination of allylic alcohols using a trifluoroacetaldehyde-based tether was first investigated. The tether could be easily installed on diverse allylic alcohol substrates, the formed hemiaminals underwent in high yield and diastereoselectivities the desired transformation under optimized conditions. Both alkynyl- and aryl-bromides could be used as electrophilic partners in the reaction. For the latter, in order to supress a competitive Heck-pathway, a new phosphine-based ligand âFuXPhosâ had to be developped and was key to reach high yields for the aminoarylation in combination with CsOTf as additive. The tether in the obtained products could be cleaved under acidic conditions delivering valuable amino alcohol derivatives. This difunctionalization strategy mediated by palladium was then applied to the strained alkene of cyclopropenes. While preliminary results for the intramolecular carbo-amination and carbo-etherification of cyclopropenes could be obtained, the difficulty to access the starting materials for these transformations led to consider a more convergent approach to access functionalized cyclopropanes. Using radical chemistry, a novel synthesis of bicyclo[3.1.0]hexanes could be developed, by a (3+2) annulation of cyclopropylanilines with cyclopropenes mediated by photoredox. The scope of the transformation was broad for both reaction partners, but the products were obtained with low diastereoselectivities. It was found that by combining difluorocyclopropenes with a bulky aromatic N-substituent on the cyclopropylamine, the corresponding fluorinated bicyclo[3.1.0]hexanes could be accessed in good yields and diastereoselectivities under slightly re-optimized conditions. Finally, the possibility to achieve an amination reaction of cyclopropenes using N-centered radicals was investigated. It was discovered that the addition of azidyl radicals to the double bond of cyclopropenes under photoredox conditions led to the formation of two new products coming from an unexpected ring cleavage: an alkenyl nitrile and a quinoline. While the formation of the quinoline product could not be optimized above 47% yield, conditions could be found for the selective formation of the alkenyl nitrile in high yields using cheap and commercial reagents. Through the scope investigations it was discovered that an aryl-substituent on the double bond of the cyclopropene substrates was necessary for the transformation to proceed. Despite this limitation various substrates could be engaged in the transformation and delivered the corresponding alkenyl nitriles in high yields. With 1,2-diaryl substituted cyclopropenes a synthesis of valuable polycyclic aromatic compounds could be developed, through a one pot radical amination / oxidative cyclization.

EPFL2021

Access to Chiral Cyclopentane Scaffolds by Enantioselective Nickel-Catalyzed Annulations

Joachim Sven Ernst Ahlin

The cyclopentane scaffold has attracted much attention due to its ubiquity in numerous bioactive natural products such as prostaglandins and polyquinanes. However, despite a plethora of available procedures to access this motif, a lack of methods that rival the generality of the Diels-Alder reaction for the synthesis of six-membered rings represents an important gap. Thus, the development of protocols providing efficient access to functionalized chiral cyclopentanes from simple and readily accessible starting materials is highly desirable. In this respect, the tremendous advances in the development of nickel-catalyzed carbon-carbon bond-forming reactions, combined with the unique properties of N-heterocyclic carbenes have led to the development of new approaches to five-membered carbocyclic rings. These include nickel-catalyzed reductive couplings and reductive [3+2] cycloadditions. These strategies are attractive, as functionalized five-membered carbocyclic rings can be accessed from two simple pi-components without any changes in atom connectivity. Despite the recent development of numerous chiral N-heterocyclic carbenes and their successful application in various transition metal-catalyzed reactions, applications in asymmetric nickel catalysis remain scarce. This thesis describes the development of efficient enantioselective nickel-catalyzed methodologies for the formation of five-membered carbocycles from readily accessible and inexpensive starting materials, enabled by two novel chiral N-heterocyclic carbene ligands. First, the development of an intermolecular enantioselective nickel-catalyzed reductive [3+2] cycloaddition of unsaturated aromatic esters and internal alkynes for the synthesis of cyclopentenones is described. For this scalable methodology, a bulky chiral C1-symmetric N-heterocyclic carbene ligand was shown to facilitate the efficient asymmetric synthesis of cyclopentenones from a wide range of mesityl enoates and internal alkynes under mild conditions. Unsymmetrically substituted alkynes were incorporated in a regioselective fashion and the cyclopentenones were synthesized in high yields and enantioselectivity. As a second methodology for the construction of chiral cyclopentane scaffolds, an intermolecular diastereoselective and enantioselective nickel-catalyzed reductive three-component coupling of various aryl aldehydes, norbornene derivatives and silanes is described, which gives access to synthetically valuable silyl-protected indan-1-ols via an aromatic C(sp2)-H functionalization. A bulky chiral C2-symmetric N-heterocyclic carbene ligand possessing a 1,2-(dinaphthalen-1-yl)ethylene diamine scaffold provided the silylated indan-1-ols under mild and scalable conditions, as a single diastereoisomer, in high enantioselectivity and good regioselectivity in the case of meta-substituted aryl aldehydes.

EPFL2016

Nickel-catalyzed Hydrosilylation of Alkenes and Transition-Metal-Free Intermolecular α-C-H Amination of Ethers

Ivan Buslov

Transition-metal-catalyzed hydrosilylation of olefins is one of the most important methods for the preparation of organosilicon compounds, which have broad applications in both synthetic and material chemistry. For decades, precious metals, principally platinum-based complexes, have been utilized as catalysts for olefin hydrosilylation. However, due to the high and volatile cost and low abundance of Pt, the development of active and selective catalysts based on Earth-abundant metals is highly desirable. In the first chapter, a short overview of state-of-the-art Pt catalysts and recent advances in development of Fe, Co and Ni-catalysts for olefin hydrosilylation is given. The applications, mechanisms and remaining challenges of transition-metal-catalyzed hydrosilylation are discussed. In the chapter 2, chemoselective anti-Markovnikov hydrosilylation of functionalized alkenes using well-defined bis(amino)amide nickel pincer complexes is described. The catalysts exhibit both high turnover frequencies and turnover numbers. Alkenes containing amino, ester, amido, ketone, and formyl groups are selectively hydrosilylated with Ph2SiH2. Chemoselective hydrosilylation of carbon-carbon double bond in the presence of formyl group using a base metal catalyst is reported for the first time. A modification of reaction conditions allows tandem isomerization-hydrosilylation reactions of internal alkenes to give terminal alkyl silanes. Hydrosilylation of alkenes with tertiary silanes is more attractive from practical point of view. The screening of various nickel alkoxide complexes with reduced steric bulk led us to discovery of an efficient heterogeneous catalyst for alkene hydrosilylation with commercially relevant tertiary silanes (chapter 3). The catalyst exhibits high activity in anti-Markovnikov hydrosilylation of unactivated terminal alkenes and isomerizing hydrosilylation of internal alkenes. The catalyst can be applied to synthesize a single terminal alkyl silane from a mixture of internal and terminal alkene isomers. Furthermore, the same catalyst can be used to remotely functionalize an internal alkene derived from a fatty acid. Chapter 4 describes a catalytic system composed of a nickel amido(bisoxazoline) complex and NaOtBu for an unexpected synthetic transformation, leading to the synthesis of functionalized alkyl hydrosilanes from readily available alkenes and alkoxysilanes. This method provides a convenient and safe alternative to hydrosilylation using flammmable and potentially dangerous Me2SiH2, MeSiH3 and SiH4. The reaction mechanism was also described. Efficient and atom-economical creation of C-N bond is one of the major tasks in synthetic organic chemistry. Direct C-H amination has emerged as an attractive method for the construction of new C-N bonds. In the chapter 5 a new transition-metal free method for the intermolecular amination of the alpha-C-H bonds of ethers is described. Using a hypervalent iodine reagent as oxidant the amination of cyclic and acyclic alkyl ethers with a wide range of amides, imides, and amines was achieved. The utility of this method was demonstrated in the synthesis of Tegafur and its analogues. This transition-metal-free method provides a rapid access to a large number of nitrogen-containing organic molecules that may serve as useful synthetic intermediates or biologically active agents.

EPFL2016

New Strategies for the Functionalization of Alkenes Exploiting Tethering Chemistry and Ring Strain

Bastian Antoine Rodolphe Claude Muriel

EPFL2021

Nickel-catalyzed Hydrosilylation of Alkenes and Transition-Metal-Free Intermolecular α-C-H Amination of Ethers

Ivan Buslov

EPFL2016

Access to Chiral Cyclopentane Scaffolds by Enantioselective Nickel-Catalyzed Annulations

Joachim Sven Ernst Ahlin

EPFL2016