A Photochemical Organocatalytic Strategy for the α-Alkylation of Ketones by using Radicals

Reported herein is a visible-light-mediated radical approach to the α-alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon SN2-based activation of alkyl halides and blue light irradiation. The resulting open-shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two-electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox-neutral nature of this process makes it compatible with a cinchona-based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α-alkylation of ketones

Synergistic Effect of Ketone and Hydroperoxide in Brønsted Acid Catalyzed Oxidative Coupling Reactions

Waste not wasted: A mechanistic study of the autoxidative coupling of xanthene with cyclopentanone uncovered an autoinductive effect of the waste product hydrogen peroxide. It generates radicals in the presence of acid and ketones, which accelerate the reaction by providing an additional pathway to the reactive hydroperoxide intermediate. This discovery could be applied to achieve other Brønsted acid-catalyzed oxidative coupling reactions

Interplay of Method Development and Mechanistic Studies – From Aerobic Oxidative Coupling to Radical Reactions via Alkenyl Peroxides

This account summarizes how scientific advances were made in the authors’ research group by combining method development in organic synthesis with detailed mechanistic studies. The discovery of an unexpected autoxidative coupling reaction led, by virtue of an ever increased understanding of its mechanism, to a strategy for green C–H functionalization reactions, novel modes of radical generation, addition reactions of ketones to alkenes and new insights into an old reaction, the Baeyer–Villiger oxidation

Brønsted acid-catalyzed C-H Functionalisation of N-Protected Tetrahydroisoquinolines via Intermediate Peroxides

An organocatalytic oxidative synthesis of N-protected tetrahydroisoquinolines is described by C–H functionalization via intermediate peroxides. The peroxides were synthesized from tert-butylhydroperoxide under metal-free thermal conditions and were converted into the final products by Brønsted acid catalyzed substitution. The nucleophile scope was investigated in detail and proved to be broad; N-deprotection of the coupling products could also be achieved

Oxidative coupling reactions for the functionalisation of C–H bonds using oxygen

Oxidative coupling reactions enable the direct formation of a new bond from two C–H or heteroatom–H bonds without the need for special activating or leaving groups, and are thus interesting in the context of green chemistry. In order to attain high atom economy and sustainability, it is desirable to conduct these reactions catalytically with oxygen or air as terminal oxidant. Here, a representative overview of such reactions is given, illustrating the substrate scope and the variety of catalyst systems. Additionally, mechanisms and general strategies to utilise oxygen in such reactions are discussed

Acid-Mediated Formation of Radicals or Baeyer-Villiger Oxidation from Criegee Adducts

The acid-mediated reaction of ketones with generates radicals, a process with reaction conditions similar to those of the Baeyer-Villiger oxidation but with an outcome resembling the formation of hydroxyl radicals via ozonolysis in the atmosphere. The Baeyer-Villiger oxidation forms esters from ketones, with the preferred use of peracids. In contrast, alkyl hydroperoxides and hydrogen peroxide react with ketones by condensation to form alkenyl peroxides, which rapidly undergo homolytic O-O bond cleavage to form radicals. Both reactions are believed to proceed via Criegee adducts, but the electronic nature of the peroxide residue determines the subsequent reaction pathways. DFT calculations and experimental results support the idea that, unlike previously assumed, the Baeyer-Villiger reaction is not intrinsically difficult with alkyl hydroperoxides and hydrogen peroxide but rather that the alternative radical formation is increasingly favored

Acid-Catalyzed Oxidative Radical Addition of Ketones to Olefins

Based on a mechanistic study, we have discovered a Brønsted acid catalyzed formation of ketone radicals. This is believed to proceed via thermally labile alkenyl peroxides formed in situ from ketones and hydroperoxides. The discovery could be utilized to develop a multicomponent radical addition of unactivated ketones and tert-butyl hydroperoxide to olefins. The resulting γ-peroxyketones are synthetically useful intermediates that can be further transformed into 1,4-diketones, homoaldol products, and alkyl ketones. A one-pot reaction yielding a pharmaceutically active pyrrole is also described

Photochemical Organocatalytic Borylation of Alkyl Chlorides, Bromides, and Sulfonates

Reported herein is a photochemical strategy for the borylation of alkyl halides using bis(catecholato)diboron as the boron source. This method exploits the ability of a nucleophilic dithiocarbonyl anion organocatalyst to generate radicals via an SN2-based photochemical catalytic mechanism, which is not reliant on the redox properties of the substrates. Therefore, it grants access to alkyl boronic esters from readily available but difficult-to-reduce electrophiles, including benzylic and allylic chlorides, bromides, and mesylates, which were inert to or unsuitable for previously reported metal-free borylation protocols

Synthesis of Oxindoles by Brønsted Acid Catalyzed Radical Cascade Addition of Ketones

Oxindoles bearing ketone side chains in the 3-position can be synthesized by BrOnsted acid catalysis from N-aryl methacrylamides, ketones, and hydroperoxides. The cyclized products are presumably formed in a radical cascade reaction, initiated by decay of intermediate alkenyl peroxides. In the case of acrylic substrates that do not undergo cyclization, -peroxyketones were isolated instead, indicating that the final cyclization step of the cascade does not take place in these cases