Modular Synthesis of Benzocyclobutenes via Pd(II)-Catalyzed Oxidative [2+2] Annulation of Arylboronic Acids with Alkenes

Benzocyclobutenes (BCBs) are highly valuable compounds in organic synthesis, medicinal chemistry, and materials science. However, catalytic modular synthesis of functionalized BCBs from easily accessible starting materials remains limited. We report herein an efficient synthesis of diversely functionalized BCBs by a Pd(II)-catalyzed formal [2+2] annulation between arylboronic acids and alkenes in the presence of N-fluorobenzenesulfonimide (NFSI). An intermolecular carbopalladation followed by palladium oxidation, intramolecular C(sp2)−H activation by a transient C(sp3)−Pd(IV) species, and selective carbon−carbon (C−C) bond-forming reductive elimination from a high-valent five-membered palladacycle is proposed to account for the reaction outcome. Kinetically competent oxidation of alkylPd(II) to alkylPd(IV) species is important to avoid the formation of a Heck adduct. The reaction forges two C−C bonds of the cyclobutene core and is compatible with a wide range of functional groups. No chelating bidentate directing group in the alkene part is needed for this transformation.

Photochemical Alkynylations with Hypervalent Iodine Reagents

Stephanie Grace Elizabeth Amos

Over the past twenty years, photochemical transformations have gained in importance in organic chemistry. Indeed, the development of photocatalysts has allowed the use of visible light as an energy source for chemical transformations. More specifically, photoredox chemistry has emerged as a valuable tool for the generation of free radical intermediates, enabling the organic chemist to envisage new bond disconnections and bond formations.For the organic chemist, the triple CïºC bond, or alkyne, is a versatile functional group. Alkynes are valuable building blocks for accessing more complex scaffolds. They also have multiple applications in medicinal chemistry, materials science, and chemical biology. Hence, the development of strategies that give access to alkynes is highly relevant. Due to the innate electronics of the alkyne, its transfer was initially limited to the alkynylation of electron-poor positions (electrophiles), however the development of alkyne transfer reagents have allowed the alkynylation of electron-rich positions (nucleophiles), and, more recently, the alkynylation of radicals. Specifically, ethynylbenziodoxolones (EBXs), hypervalent iodine (III) reagents bearing an alkyne, have frequently been used for the alkynylation of radicals. In combination with photochemical conditions they have enabled the activation of multiple functional groups (for example: carboxylates, potassium alkyl trifluoroborates salts, or Î±-oxo C-H bonds) for the introduction of an alkyne.The first objective of this research was to enable the photochemical difunctionalisation of double bonds to allow the introduction of an alkyne and a second functional group using EBXs. Indeed, difunctionalisation strategies are highly valuable as they can allow a rapid increase in molecular complexity in a single step. We found that enamides and enol ethers could undergo an alkynylative difunctionalisation with EBXs in presence of a photocatalyst and a hypervalent iodine additive. This method gave access to 1-alkynyl-1,2-aminoalcohols and diols scaffolds, which can be selectively deprotected to deliver the free alcohol or free amine.The second objective of this thesis was to develop a deoxyalkynylation strategy to allow the conversion of alcohols into alkynes. Starting from cesium oxalates, in presence of a photocatalyst and the EBX reagent, we could access a broad scope of aliphatic arylalkynes. Interestingly, the key to success for this project was found in the choice of light source: to ensure high yields, two high intensity blue LED lamps (440 nm, ca. 80 W) were required. During our mechanistic studies we discovered that this light source could also generate an excited state EBX species. We then decided to explore this discovery: we were delighted to find that the EBX alone under irradiation could promote the photomediated alkynylation of carboxylates, trifluoroborates, enamides, imines and Î±-oxo C-H bonds. Although the understanding of this process is still in the preliminary stages, we believe that the discovery of the direct photoexcitation of EBXs will enable facile reaction discovery and complement photocatalysed strategies.

EPFL2022

Cyclopropanes and Hypervalent Iodine Reagents: High Energy Compounds for Applications in Synthesis and Catalysis

Jonathan Brand, Filippo De Simone, Stefano Nicolai, Jérôme Waser

One of the major challenges faced by organic chemistry is the efficient synthesis of increasingly complex molecules. Since October 2007, the Laboratory of Catalysis and Organic Synthesis (LCSO) at EPFL has been working on the development of catalytic reactions based on the Umpolung of the innate reactivity of functional groups. Electrophilic acetylene synthons have been developed using the exceptional properties of ethynyl benziodoxolone (EBX) hypervalent iodine reagents for the alkynylation of heterocycles and olefins. The obtained acetylenes are important building blocks for organic chemistry, material sciences and chemical biology. The ring-strain energy of donor-acceptor cyclopropanes was then used in the first catalytic formal honno-Nazarov cyclization. In the case of aminocyclopropanes, the method could be applied in the synthesis of the alkaloids aspidospermidine and goniomitine. The developed methods are expected to have a broad potential for the synthesis and functionalization of complex organic molecules, including carbocycles and heterocycles.

2011

Copper-Catalyzed Oxy-Alkynylation of Diazo Compounds with Hypervalent Iodine Reagents

Durga Prasada Rao Hari, Jérôme Waser

Alkynes have found widespread applications in synthetic chemistry, biology, and materials sciences. In recent years, methods based on electrophilic alkynylation with hypervalent iodine reagents have made acetylene synthesis more flexible and efficient, but they lead to the formation of one equivalent of an iodoarene as side-product. Herein, a more efficient strategy involving a copper-catalyzed oxy-alkynylation of diazo compounds with ethynylbenziodoxol(on)e (EBX) reagents is described, which proceeds with generation of nitrogen gas as the only waste. This reaction is remarkable for its broad scope in both EBX reagents and diazo compounds. In addition, vinyl diazo compounds gave enynes selectively as single geometric isomers. The functional groups introduced during the transformation served as easy handles to access useful building blocks for synthetic and medicinal chemistry.

American Chemical Society2016

Photochemical Alkynylations with Hypervalent Iodine Reagents

Stephanie Grace Elizabeth Amos

EPFL2022