Intramolecular Radical Amidooxygenation of Alkenes for the Construction of Pyrrolidinones.

An intramolecular 1,2-amidooxygenation of unactivated alkenes for the construction of the pyrrolidinone scaffold containing a masked 5-hydroxymethyl functionality is reported. γ,δ-Unsaturated N-aryloxyamides react with sodium 2,2,6,6-tetramethylpiperidin-1-olate (TEMPONa) to afford alkoxyaminated pyrrolidinones. The cascade proceeds through reductive amidyl radical generation with TEMPONa, 5-exo cyclization, and TEMPO trapping. No transition metal is required to perform these transformations, and complex (fused, bridged) pyrrolidinones are accessible in moderate to good yields. The product alkoxyamines are readily further converted into ketones and alcohols through either oxidation or reduction.

Introduction of the difluoromethyl group at the meta- or para-position of pyridines through regioselectivity switch.

Difluoromethyl pyridines have gained significant attention in medicinal and agricultural chemistry. The direct C-H-difluoromethylation of pyridines represents a highly efficient economic way to access these azines. However, the direct meta-difluoromethylation of pyridines has remained elusive and methods for site-switchable regioselective meta- and para-difluoromethylation are unknown. Here, we demonstrate the meta-C-H-difluoromethylation of pyridines through a radical process by using oxazino pyridine intermediates, which are easily accessed from pyridines. The selectivity can be readily switched to para by in situ transformation of the oxazino pyridines to pyridinium salts upon acid treatment. The preparation of various meta- and para-difluoromethylated pyridines through this approach is presented. The mild conditions used also allow for the late-stage meta- or para-difluoromethylation of pyridine containing drugs. Sequential double functionalization of pyridines is presented, which further underlines the value of this work.

Thermal and Photoinduced Radical Cascade Annulation using Aryl Isonitriles: An Approach to Quinoline-Derived Benzophosphole Oxides.

Herein, we present a radical cascade addition cyclization sequence to access quinoline-based benzophosphole oxides from ortho-alkynylated aromatic phosphine oxides using various aryl isonitriles as radical acceptors and inexpensive tert-butyl-hydroperoxide (TBHP) as a terminal oxidant in the presence of a catalytic amount of silver acetate. Alternatively, the same cascade can be realized through a sustainable photochemical approach utilizing 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as an organic photocatalyst at room temperature. The introduced modular approach shows broad functional group tolerance and offers straightforward access to complex P,N-containing polyheterocyclic arenes. These novel π-extended benzophosphole oxides exhibit interesting photophysical and electrochemical properties such as absorption in the visible region, emission and reversible reduction at low potentials, which makes them promising for potential materials science applications. The photophysical properties can further be tuned by the addition of external Lewis and Brønsted acids.

Meta-Selective Copper-Catalyzed C-H Arylation of Pyridines and Isoquinolines through Dearomatized Intermediates.

C(sp2)-H functionalization offers an efficient strategy for the synthesis of various elaborated N-containing heteroarenes. Along these lines, oxazino pyridines that can be readily prepared from pyridines, have been introduced as powerful substrates in radical- and ionic-mediated meta-C-H functionalization. However, the regioselective meta-C-H arylation of pyridines remains a great challenge. Herein, a copper-catalyzed meta-selective C-H arylation of pyridines and isoquinolines through bench-stable dearomatized intermediates is reported. Electrophilic aryl-Cu(III) species, generated from readily accessible aryl I(III) reagents, enable the efficient meta-arylation of a broad range of pyridines and isoquinolines. The method also allows the meta-selective alkenylation of these heteroarenes using the corresponding alkenyl I(III)-reagents. Late-stage arylation of drug-derived pyridines and larger-scale experiments demonstrate the potential of this synthetic methodology.

Organic Donor-Acceptor Thermally Activated Delayed Fluorescence Photocatalysts in the Photoinduced Dehalogenation of Aryl Halides.

We report a family of donor-acceptor thermally activated delayed fluorescent (TADF) compounds based on derivatives of DMAC-TRZ, that are strongly photoreducing. Both Eox and thus E*ox could be tuned via substitution of the DMAC donor with a Hammett series of p-substituted phenyl moieties while Ered remained effectively constant. These compounds were assessed in the photoinduced dehalogenation of aryl halides, and analogues bearing electron withdrawing groups were found to produce the highest yields. Substrates of up to Ered=-2.72 V could be dehalogenated at low PC loading (1 mol %) and under air, conditions much milder than previously reported for this reaction. Spectroscopic and chemical studies demonstrate that all PCs, including literature reference PCs, photodegrade, and that it is these photodegradation products that are responsible for the reactivity.

Borylative transition metal-free couplings of vinyl iodides with various nucleophiles, alkenes or alkynes.

Alkyl boronic esters are highly valuable compounds in organic chemistry and related fields due to their good stability and highly versatile reactivity. In this edge article, stereoselective borylative couplings of vinyl iodides with various nucleophiles, alkenes or alkynes is reported. These coupling reactions proceed through stereospecific hydroboration and subsequent stereospecific 1,2-metallate rearrangement. The cascades utilize readily available reagents and proceed without the need of a transition metal catalyst.

Skeletal editing of pyridines through atom-pair swap from CN to CC.

Skeletal editing is a straightforward synthetic strategy for precise substitution or rearrangement of atoms in core ring structures of complex molecules; it enables quick diversification of compounds that is not possible by applying peripheral editing strategies. Previously reported skeletal editing of common arenes mainly relies on carbene- or nitrene-type insertion reactions or rearrangements. Although powerful, efficient and applicable to late-stage heteroarene core structure modification, these strategies cannot be used for skeletal editing of pyridines. Here we report the direct skeletal editing of pyridines through atom-pair swap from CN to CC to generate benzenes and naphthalenes in a modular fashion. Specifically, we use sequential dearomatization, cycloaddition and rearomatizing retrocycloaddition reactions in a one-pot sequence to transform the parent pyridines into benzenes and naphthalenes bearing diversified substituents at specific sites, as defined by the cycloaddition reaction components. Applications to late-stage skeletal diversification of pyridine cores in several drugs are demonstrated.

Benzoyldiisopropylchlorosilane: a visible light photocleavable alcohol protecting group.

Silyl chlorides are highly valuable and popular reagents for the protection of alcohols. In this edge article we introduce a photocleavable alcohol protecting group on the basis of acyl silanes. To achieve this, acylchlorosilanes that represent a new class of acylsilanes were developed. They can be easily synthesized in a concise sequence of three steps in high overall yield. Alcohol silyl protection takes place under established mild conditions, akin to those associated with classical silicon-based protecting groups. The removal of the Si-group is achieved at room temperature through exposure to visible light (456 nm) in methanol. We demonstrate a broad spectrum of substrates with remarkable tolerance toward diverse functional groups, highlighting a substantial level of orthogonality with respect to other protecting groups. Furthermore, we showcase the robustness of this approach against various transformations.

Cooperative Photoredox and N-Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α-Trifluoromethyl-Substituted Ketones.

α-Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α-CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem-difluoroalkenes through cooperative photoredox and N-heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre-functionalization, thus enabling an efficient and general synthetic method to access α-CF3 -substituted ketones. A wide variety of gem-difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono- or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.

Access to Polyheterocyclic Compounds through Iron(II)-Mediated Radical Cascade Cyclization Utilizing 2-Ethynylbenzaldehydes and Aryl Isonitriles.

An oxidative radical cascade addition cyclization approach for the synthesis of quinoline-based π-extended polyheterocyclic compounds is reported. Eco-friendly iron catalysis and inexpensive tert-butylhydroperoxide (TBHP) as the oxidant have been utilized in the transformation of various readily available ortho-alkynylated aromatic aldehydes as radical precursors with aryl isonitriles as radical acceptors. Indole and thiophene-based carbaldehydes allow the preparation of quinolines that are π-conjugated with an additional heteroarene moiety in a single sequence by applying the introduced method.

Organic Synthesis Using Nitroxides.

Nitroxides, also known as nitroxyl radicals, are long-lived or stable radicals with the general structure R1R2N-O•. The spin distribution over the nitroxide N and O atoms contributes to the thermodynamic stability of these radicals. The presence of bulky N-substituents R1 and R2 prevents nitroxide radical dimerization, ensuring their kinetic stability. Despite their reactivity toward various transient C radicals, some nitroxides can be easily stored under air at room temperature. Furthermore, nitroxides can be oxidized to oxoammonium salts (R1R2N═O+) or reduced to anions (R1R2N-O-), enabling them to act as valuable oxidants or reductants depending on their oxidation state. Therefore, they exhibit interesting reactivity across all three oxidation states. Due to these fascinating properties, nitroxides find extensive applications in diverse fields such as biochemistry, medicinal chemistry, materials science, and organic synthesis. This review focuses on the versatile applications of nitroxides in organic synthesis. For their use in other important fields, we will refer to several review articles. The introductory part provides a brief overview of the history of nitroxide chemistry. Subsequently, the key methods for preparing nitroxides are discussed, followed by an examination of their structural diversity and physical properties. The main portion of this review is dedicated to oxidation reactions, wherein parent nitroxides or their corresponding oxoammonium salts serve as active species. It will be demonstrated that various functional groups (such as alcohols, amines, enolates, and alkanes among others) can be efficiently oxidized. These oxidations can be carried out using nitroxides as catalysts in combination with various stoichiometric terminal oxidants. By reducing nitroxides to their corresponding anions, they become effective reducing reagents with intriguing applications in organic synthesis. Nitroxides possess the ability to selectively react with transient radicals, making them useful for terminating radical cascade reactions by forming alkoxyamines. Depending on their structure, alkoxyamines exhibit weak C-O bonds, allowing for the thermal generation of C radicals through reversible C-O bond cleavage. Such thermally generated C radicals can participate in various radical transformations, as discussed toward the end of this review. Furthermore, the application of this strategy in natural product synthesis will be presented.

1,2-Aminoxyalkylation of alkenes with alkyl iodides and TEMPONa through SET- and XAT-processes.

1,2-Aminoxyalkylation of alkenes with alkyl iodides and TEMPONa in combination with an aryldiazonium salt as an XAT mediator is reported. Various primary, secondary and tertiary alkyl iodides engage as C-radical precursors in the 1,2-aminoxyalkylation with electrophilic alkenes as radical acceptors. The product alkoxyamines are readily transformed to the corresponding alcohols or ketones upon reduction or oxidation, respectively. Mechanistic investigations reveal that aryl radicals, generated through SET-reduction of the aryl diazonium salt with TEMPONa, engage in XAT from unactivated alkyl halides to give alkyl radicals that can add to alkenes. Trapping of the adduct radicals with TEMPO provides the 1,2-aminoxyalkylation products. Transition metals are not required for these transformations that are conducted under mild conditions. Perfluoroalkyl halides directly react with TEMPONa and an aryldiazonium salt as XAT-mediator is not required for alkene 1,2-aminoxyperfluoroalkylation.

C-H Functionalization of Pyridines via Oxazino Pyridine Intermediates: Switching to para-Selectivity under Acidic Conditions.

para-Selective C-H functionalization of pyridines holds a significant value but remains underdeveloped. Site-switchable C-H functionalization of pyridines under easily tunable conditions expedites drug development. We recently reported a redox-neutral dearomatization-rearomatization strategy for meta-C-H functionalization of pyridines via oxazino pyridine intermediates. Here, we demonstrate that these oxazino pyridine intermediates undergo highly para-selective functionalization simply by switching to acidic conditions. A broad scope of para-alkylated and arylated pyridines is prepared through radical as well as ionic pathways. These mild and catalyst-free methods are applied to the late-stage para-functionalization of drugs using pyridines as the limiting reagents. Consecutive meta,para-difunctionalization of pyridines is also achieved with complete regiocontrol relying on the pH-dependent reactivity of oxazino pyridines.

Photocatalytic phosphine-mediated water activation for radical hydrogenation.

The chemical activation of water would allow this earth-abundant resource to be transferred into value-added compounds, and is a topic of keen interest in energy research1,2. Here, we demonstrate water activation with a photocatalytic phosphine-mediated radical process under mild conditions. This reaction generates a metal-free PR3-H2O radical cation intermediate, in which both hydrogen atoms are used in the subsequent chemical transformation through sequential heterolytic (H+) and homolytic (H•) cleavage of the two O-H bonds. The PR3-OH radical intermediate provides an ideal platform that mimics the reactivity of a 'free' hydrogen atom, and which can be directly transferred to closed-shell π systems, such as activated alkenes, unactivated alkenes, naphthalenes and quinoline derivatives. The resulting H adduct C radicals are eventually reduced by a thiol co-catalyst, leading to overall transfer hydrogenation of the π system, with the two H atoms of water ending up in the product. The thermodynamic driving force is the strong P=O bond formed in the phosphine oxide by-product. Experimental mechanistic studies and density functional theory calculations support the hydrogen atom transfer of the PR3-OH intermediate as a key step in the radical hydrogenation process.

Lewis Acid Catalyzed Formal (3+2)-Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes.

Design, synthesis and application of benzene bioisosteres have attracted a lot of attention in the past 20 years. Recently, bicyclo[2.1.1]hexanes have emerged as highly attractive bioisosteres for ortho- and meta-substituted benzenes. Herein we report a mild, scalable and transition-metal-free protocol for the construction of highly substituted bicyclo[2.1.1]hexan-2-ones through Lewis acid catalyzed (3+2)-cycloaddition of bicyclo[1.1.0]-butane ketones with disubstituted ketenes. The reaction shows high functional group tolerance as documented by the successful preparation of various 3-alkyl-3-aryl as well as 3,3-bisalkyl bicyclo[2.1.1]hexan-2-ones (26 examples, up to 89 % yield). Postfunctionalization of the exocyclic ketone moiety is also demonstrated.

Regioselective Formal ß-Allylation of Carbonyl Compounds Enabled by Cooperative Nickel and Photoredox Catalysis.

The Tsuji-Trost reaction between carbonyl compounds and allylic precursors has been widely used in the synthesis of natural products and pharmaceutical compounds. As the α-C-H bond is far more acidic than the ß-C-H bond, carbonyl compounds undergo highly regioselective allylation at the α-position and their ß-allylation is therefore highly challenging. This innate α-reactivity conversely hampers diversity, especially if the corresponding ß-allylation product is targeted. Herein, we present a formal intermolecular ß-C-C bond formation reaction of a broad range of aldehydes and ketones with different allyl electrophiles through cooperative nickel and photoredox catalysis. ß-Selectivity is achieved via initial transformation of the aldehydes and ketones to their corresponding silyl enol ethers. The overall transformation features mild conditions, excellent regioselectivity, wide functional group tolerance and high reaction efficiency. The introduced facile and regioselective ß-allylation of carbonyl compounds proceeding through cooperative catalysis allows the preparation of valuable building blocks that are difficult to access from aldehydes and ketones using existing methodology.

Regiodivergent C-H Acylation of Arenes by Switching from Ionic- to Radical-Type Chemistry Using NHC Catalysis.

The Friedel-Crafts acylation reaction, which belongs to the class of electrophilic aromatic substitutions is a highly valuable and versatile reaction in synthesis. Regioselectivity is predictable and determined by electronic as well as steric factors of the (hetero)arene substrate. Herein, a radical approach for the acylation of arenes and heteroarenes is presented. C-H acylation is achieved through mild cooperative photoredox/NHC radical catalysis with the cross-coupling of an arene radical cation with an NHC-bound ketyl radical as a key step. As compared to the classical Friedel-Crafts acylation, a regiodivergent outcome is observed upon switching from the ionic to the radical mode. In these divergent reactions, aroyl fluorides act as the acylation reagents in both the ionic as well as the radical process.

Rhodium-Catalyzed Hydrosilylation of Alkenes with Acylhydrosilanes.

Acylsilanes are an important class of organosilicon compounds that have gained increased attention recently. Their various reaction modes in particularly their ability to generate carbenes under thermal or photochemical conditions render them valuable reagents in organic synthesis. In this communication, an unprecedented route towards acylsilanes is reported by introducing the acylsilane moiety directly in a single step through alkene hydrosilylation. In this context, acylhydrosilanes representing a novel class of acylsilanes are introduced and applied as silylation reagents in rhodium catalyzed alkene hydrosilylations to access a great variety of acylsilanes. These reactions occur in good to excellent yields under mild conditions and show high functional group tolerance and atom economy.

Enantioselective Copper-Catalyzed Fukuyama Indole Synthesis from 2-Vinylphenyl Isocyanides.

Enantioenriched chiral indoles are of high interest for the pharmaceutical and agrochemical industries. Herein, we present an asymmetric Fukuyama indole synthesis through a mild and efficient radical cascade reaction to access 2-fluoroalkylated 3-(α-cyanobenzylated) indoles by stereochemical control with a chiral copper-bisoxazoline complex using 2-vinylphenyl arylisocyanides as radical acceptors and fluoroalkyl iodides as C-radical precursors. Radical addition to the isonitrile moiety, 5-exo-trig cyclization, and Cu-catalyzed stereoselective cyanation provide the targeted indoles with excellent enantioselectivity and good yields. Due to the similar electronic and steric properties of the two aryl substituents to be differentiated, the enantioselective construction of the cyano diaryl methane stereocenter is highly challenging. Mechanistic studies reveal a negative nonlinear effect which allows proposing a model to explain the stereochemical outcome. Scalability and potential utility of the enantioenriched 3-(α-cyanobenzylated) indoles as hubs for chiral tryptamines, indole-3-acetic acid derivatives, and triarylmethanes are demonstrated, and a formal synthesis of a natural product analogue is disclosed.

meta-Selective C-H Functionalization of Pyridines.

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization of C-H bonds in pyridines is a straightforward approach to access valuable substituted pyridines. Compared to the direct ortho- and para-functionalization, meta-selective pyridine C-H functionalization is far more challenging due to the inherent electronic properties of the pyridine entity. This review summarizes currently available methods for pyridine meta-C-H functionalization using a directing group, non-directed metalation, and temporary dearomatization strategies. Recent advances in ligand control and temporary dearomatization are highlighted. We analyze the advantages as well as limitations of current techniques and hope to inspire further developments in this important area.