Dual-Catalysed Intermolecular Reductive Coupling of Dienes and Ketones.

We report a mild, catalytic method for the intermolecular reductive coupling of feedstock dienes and styrenes with ketones. Our conditions allow concomitant formation of a cobalt hydride species and single-electron reduction of ketones. Subsequent selective hydrogen-atom transfer from the cobalt hydride generates an allylic radical which can selectively couple with the persistent radical-anion of the ketone. This radical-radical coupling negates unfavourable steric interactions of ionic pathways and avoids the unstable alkoxy radical of previous radical olefin-carbonyl couplings, which were limited, as a result, to aldehydes. Applications of this novel and straightforward approach include the efficient synthesis of drug molecules, key intermediates in drug synthesis and site-selective late-stage functionalisation.

Dual-Catalytic Structural Isomerisation as a Route to α-Arylated Ketones.

Isomerisation reactions provide streamlined routes to organic compounds which are otherwise hard to directly synthesise. The most common forms are positional, geometrical or stereochemical isomerisations which involve the relocation of a double bond or a change in relative location of groups in space. In contrast, far fewer examples of structural (or constitutional) isomerisation exist where the connectivity between atoms is altered. The development of platforms capable of such rearrangement poses a unique set of challenges because chemical bonds must be selectively cleaved, and new ones formed without overall addition or removal of atoms. Here, we show that a dual catalytic system can enable the structural isomerisation of readily available allylic alcohols into more challenging-to-synthesise α-arylated ketones via a H-atom transfer initiated semi-pinacol rearrangement. Key to our strategy is the combination of a cobalt catalyst and photocatalyst under reductive, protic conditions which allows intermediates to propagate catalytic turnover. By providing an unusual disconnection to structural motifs which are difficult to access through direct arylation, we anticipate inspiring other advanced catalytic isomerisation strategies that will further retrosynthetic logic for complex molecule synthesis.

Photo- and Electrochemical Cobalt Catalysed Hydrogen Atom Transfer for the Hydrofunctionalisation of Alkenes.

Catalytic hydrogen atom transfer from metal-hydrides to alkenes allows feedstock olefins to be used as alkyl radical precursors. The chemoselectivity of this process makes it an attractive synthetic tool and as such it has been regularly used in synthesis of complex molecules. However, onwards reactivity is limited by compatibility with the conditions which form the key metal-hydride species. Now, through the merger with photocatalysis or electrochemistry, milder methods are emerging which can unlock entirely new reactivity and offer perspectives on expanding these methods in unprecedented directions. This review outlines the most recent developments in electro- and photochemical cobalt catalysed methods and offers suggestions on the future outlook.

Photoinduced Cobalt Catalysis for the Reductive Coupling of Pyridines and Dienes Enabled by Paired Single-Electron Transfer.

Selective hydroarylation of dienes has potential to provide swift access to useful building blocks. However, most existing methods rely on dienes stabilised by an aromatic group and transmetallation or nucleophilic attack steps require electron-rich aryl coupling partners. As such, there are few examples which tolerate wide-spread heteroarenes such as pyridine. Whilst allylic C-H functionalisation could be considered an alternative approach, the positional selectivity of unsymmetrical substrates is hard to control. Here, we report a general approach for selective hydropyridylation of dienes under mild conditions using metal catalysed hydrogen-atom transfer. Photoinduced, reductive conditions enable simultaneous formation of a cobalt-hydride catalyst and the persistent radical of easily-synthesised pyridyl phosphonium salts. This facilitates selective coupling of dienes in a traceless manner at the C4-position of a wide-range of pyridine substrates. The mildness of the method is underscored by its functional-group tolerance and demonstrated by applications in late-stage functionalisation. Based on a combination of experimental and computational studies, we propose a mechanistic pathway which proceeds through non-reversible hydrogen-atom transfer (HAT) from a cobalt hydride species which is uniquely selective for dienes in the presence of other olefins due to a much higher relative barrier associated with olefin HAT.

Mild and Chemoselective Carboxylic Acid Reduction Promoted by Borane Catalysis.

Although considerable advances have been made in developing chemoselective transformations of ubiquitous carboxylic acid groups, many challenges still exist. For instance, their selective reduction is problematic if both more nucleophilic and more electrophilic groups are present in the starting material. Here, we address this problem with a simple and mild protocol using bench-stable reagents at ambient temperatures. This platform is able to tolerate a diverse range of functionality, leaving ketones, esters, nitro-groups, olefins, nitriles and amides untouched. A combination of experimental and computational mechanistic experiments demonstrate that this reaction proceeds via hidden borane catalysis with small quantities of in situ generated BH3 playing a key role in the exquisite selectivity that is observed.

Controlling Chemoselectivity of Catalytic Hydroboration with Light.

The ability to selectively react one functional group in the presence of another underpins efficient reaction sequences. Despite many designer catalytic systems being reported for hydroboration reactions, which allow introduction of a functional handle for cross-coupling or act as mild method for reducing polar functionality, these platforms rarely deal with more complex systems where multiple potentially reactive sites exist. Here we demonstrate, for the first time, the ability to use light to distinguish between ketones and carboxylic acids in more complex molecules. By taking advantage of different activation modes, a single catalytic system can be used for hydroboration, with the chemoselectivity dictated only by the presence or absence of visible light.

Using Light to Modify the Selectivity of Transition Metal Catalysed Transformations.

Light has a remarkable and often unique ability to promote chemical reactions. In combination with transition metal catalysis, it offers exciting opportunities to modify catalyst function in a non-invasive manner, most frequently being reported to switch on or accelerate reactions that do not occur in the dark. However, the ability to completely change reactivity or selectivity between two different reaction outcomes is considerably less common. In this Minireview we bring together examples of this concept and highlight their mechanistically distinct approaches. Our overview demonstrates how these non-natural, photo-switchable systems provide key fundamental mechanistic insights, enhancing our understanding and stimulating development of new catalytic activity, and how this might lead to tangible applications, impacting fields such as polymer chemistry.

Visible-Light Controlled Divergent Catalysis Using a Bench-Stable Cobalt(I) Hydride Complex.

While the use of visible light in conjunction with transition metal catalysis offers powerful opportunities to switch between on/-off states of catalytic activity, the next frontier would be the ability to switch the actual function of the catalyst and resulting products. Here we report such an example of multi-dimensional catalysis. Featuring an easily prepared, bench-stable cobalt(I) hydride complex in conjunction with pinacolborane, we can switch the reaction outcome between two widely employed transformations, olefin migration and hydroboration, with visible light as the trigger.

Photocontrolled Cobalt Catalysis for Selective Hydroboration of α,ß-Unsaturated Ketones.

Selectivity between 1,2 and 1,4 addition of a nucleophile to an α,ß-unsaturated carbonyl compound has classically been modified by the addition of stoichiometric additives to the substrate or reagent to increase their "hard" or "soft" character. Here, we demonstrate a conceptually distinct approach that instead relies on controlling the coordination sphere of a catalyst with visible light. In this way, we bias the reaction down two divergent pathways, giving contrasting products in the catalytic hydroboration of α,ß-unsaturated ketones. This includes direct access to previously elusive cyclic enolborates, via 1,4-selective hydroboration, providing a straightforward and stereoselective route to rare syn-aldol products in one-pot. DFT calculations and mechanistic experiments confirm two different mechanisms are operative, underpinning this unusual photocontrolled selectivity switch.

α-Functionalisation of Ketones Through Metal-Free Electrophilic Activation.

Triflic anhydride mediated activation of acetophenones leads to highly electrophilic intermediates that can undergo a variety of transformations when treated with nucleophiles. This electrophilic ketone activation gives access to α-arylated and α-oxyaminated acetophenones under metal-free conditions in moderate to excellent yields and enables extension to the synthesis of arylated morpholines via generation of vinylsulfonium salts. Computational investigations confirmed the transient existence of intermediates derived from vinyl triflates and the role of the oxygen atoms at the para position of aromatic ring in facilitating their stabilisation.

Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles.

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C-X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.

Chemoselective α,ß-Dehydrogenation of Saturated Amides.

We report a method for the selective α,ß-dehydrogenation of amides in the presence of other carbonyl moieties under mild conditions. Our strategy relies on electrophilic activation coupled to in situ selective selenium-mediated dehydrogenation. The α,ß-unsaturated products were obtained in moderate to excellent yields, and their synthetic versatility was demonstrated by a range of transformations. Mechanistic experiments suggest formation of an electrophilic SeIV species.

Chemoselective Intermolecular Cross-Enolate-Type Coupling of Amides.

A new approach for the synthesis of 1,4-dicarbonyl compounds is reported. Chemoselective activation of amide carbonyl functionality and subsequent umpolung via N-oxide addition generates an electrophilic enolonium species that can be coupled with a wide range of nucleophilic enolates. The method conveys broad functional group tolerance on both components, does not suffer from formation of homocoupling byproducts and avoids the use of transition metal catalysts.

Domino N-/C-Arylation via In Situ Generation of a Directing Group: Atom-Efficient Arylation Using Diaryliodonium Salts.

Both aryl components of diaryliodonium salts can be used in a domino one-pot reaction via in situ generation of a directing group. A number of heterocycles undergo N-arylation which is followed by ruthenium-catalyzed C-arylation. Notably the reaction extends well to unsymmetrical diaryliodonium salts with a number of highly selective examples shown.

Cross-Dehydrogenative-Coupling of Alkoxybenzenes with Toluenes: Copper(II) Halide Mediated Tandem Halo/Benzylation of Arenes.

A cross-dehydrogenative-coupling of alkoxybenzenes and toluenes with concomitant halogenation is reported. Conditions employed were the use of stoichiometric copper halide salts and dialkylperoxides to afford a range of bromoalkoxydi- and triarylmethanes. Preliminary mechanistic studies suggest that the in situ production of haloarenes (or dihaloarenes) followed by a copper-mediated coupling of a benzylic radical is operational.

Ruthenium-Catalyzed meta-Selective C-H Bromination.

The first example of a transition-metal-catalyzed, meta-selective C-H bromination procedure is reported. In the presence of catalytic [{Ru(p-cymene)Cl2 }2 ], tetrabutylammonium tribromide can be used to functionalize the meta C-H bond of 2-phenylpyridine derivatives, thus affording difficult to access products which are highly predisposed to further derivatization. We demonstrate this utility with one-pot bromination/arylation and bromination/alkenylation procedures to deliver meta-arylated and meta-alkenylated products, respectively, in a single step.

Highlights from the 56th Bürgenstock Conference on Stereochemistry 2023.

Herein, we share an overview of the scientific highlights from speakers at the latest edition of the longstanding Bürgenstock Conference.

Dual Photoredox/Cobaloxime Catalysis for Cross-Dehydrogenative α-Heteroarylation of Amines.

We report a dual-catalytic platform for the cross-dehydrogenative-coupling between (benzo-)thiazoles and amines which combines low loadings of an iridium photoredox catalyst and a cobaloxime catalyst under blue light irradiation. This transformation occurs without stoichiometric oxidants, giving products in moderate to excellent yields. DFT calculations support the key role of Co(II) for rearomatization of the radical-addition intermediate to generate the product.

α-Fluorination of carbonyls with nucleophilic fluorine.

Given the unique properties of fluorine, and the ability of fluorination to change the properties of organic molecules, there is significant interest from medicinal chemists in innovative methodologies that enable the synthesis of new fluorinated motifs. State-of-the-art syntheses of α-fluorinated carbonyl compounds invariably rely on electrophilic fluorinating agents, which can be strongly oxidizing and difficult to handle. Here we show that reversing the polarity of the enolate partner to that of an enolonium enables nucleophilic fluorinating agents to be used for direct chemoselective α-C-H-fluorination of amides. Reduction of these products enables facile access to ß-fluorinated amines and the value of this methodology is shown by the easy preparation of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed antidepressant drug, is presented as an example of the preserved biological activity after fluorination.

Regioselective synthesis of pyridines by redox alkylation of pyridine N-oxides with malonates.

ABSTRACT: A regioselective synthesis of pyridines by the addition of malonate anions to pyridine N-oxide derivatives, which have been activated by trifluoromethanesulfonic anhydride, is reported. The reaction selectively affords either 2- or 4-substituted pyridines in good yields.