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.

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.

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.

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.

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.

Alkyl Radical Generation from Alkylboronic Pinacol Esters through Substitution with Aminyl Radicals.

Alkylboronic pinacol esters (APEs) are highly versatile reagents in organic synthesis. However, the direct generation of alkyl radicals from commonly used, bench-stable APEs has not been well explored. In this communication, alkyl radical generation from APEs through reaction with aminyl radicals is reported. The aminyl radicals are readily generated by visible-light-induced homolytic cleavage of the N-N bond in N-nitrosamines, and C radical generation occurs through nucleohomolytic substitution at boron. As an application, the highly efficient photochemical radical alkyloximation of alkenes with APEs and N-nitrosamines under mild conditions is presented. A wide range of primary, secondary, and tertiary APEs engage in this transformation that is easily scaled up.

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.

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.

Bis(arylsulfonyl) Peroxide-Mediated Difunctionalization of Cyclic Enol Ethers.

A bis(arylsulfonyl) peroxide-mediated 1,2-difunctionalization of cyclic enol ethers is reported. Bis(nosyl) peroxide selectively sulfonylates the 3-position of enol ethers, generating an oxocarbenium ion that is trapped by a carboxylic acid nucleophile at the 2-position. The reaction proceeds in a good yield and tolerates a variety of cyclic enol ethers, including glycals as well as various carboxylic acids, which act as the oxocarbeium ion trapping reagents.

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.

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.

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.

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.

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.

Aroyl Fluorides as Bifunctional Reagents for Dearomatizing Fluoroaroylation of Benzofurans.

The 2,3-dihydrobenzofuran scaffold is widely found in natural products and biologically active compounds. Herein, dearomatizing 2,3-fluoroaroylation of benzofurans with aroyl fluorides as bifunctional reagents to access 2,3-difunctionalized dihydrobenzofurans is reported. The reaction that occurs by cooperative NHC/photoredox catalysis provides 3-aroyl-2-fluoro-2,3-dihydrobenzofurans with moderate to good yield and high diastereoselectivity. Cascades proceed via radical/radical cross-coupling of a benzofuran radical cation generated in the photoredox catalysis cycle with a neutral ketyl radical formed through the NHC catalysis cycle. The redox-neutral transformation exhibits broad substrate scope and high functional group compatibility. With anhydrides as bifunctional reagents, dearomatizing aroyloxyacylation of benzofurans is achieved and the strategy can also be applied to N-acylated indoles to afford 3-aroyl-2-fluoro-dihydroindoles.

Alternating Terpolymers through Cyclopolymerization and Subsequent Orthogonal Functionalization.

A method for the synthesis of functionalized alternating copolymers by reversible deactivation radical polymerization was developed. Copolymerization by reversible addition-fragmentation chain transfer of hexenyl vinyl ether with a novel fluorinated divinyl monomer yields alternating cyclopolymers that can be chemoselectively modified by three distinct orthogonal functionalization reactions. Along the thiol-ene click reaction and amidation, a third functionalization was achieved via NHC-catalyzed transesterification or acylation resulting in a small library of ABC-type alternating terpolymers.

Formal ß-C-H Arylation of Aldehydes and Ketones by Cooperative Nickel and Photoredox Catalysis.

α-C-H-functionalization of ketones and aldehydes has been intensively explored in organic synthesis. The functionalization of unactivated ß-C-H bonds in such carbonyl compounds is less well investigated and developing a general method for their ß-C-H arylation remains challenging. Herein we report a method that uses cooperative nickel and photoredox catalysis for the formal ß-C-H arylation of aldehydes and ketones with (hetero)aryl bromides. The method features mild conditions, remarkable scope and wide functional group tolerance. Importantly, the introduced synthetic strategy also allows the ß-alkenylation, ß-alkynylation and ß-acylation of aldehydes under similar conditions. Mechanistic studies revealed that this transformation proceeds through a single electron oxidation/Ni-mediated coupling/reductive elimination cascade.

Radical 1-Fluorosulfonyl-2-alkynylation of Unactivated Alkenes.

Sulfonyl fluorides have found widespread use in chemical biology and drug discovery. The development of synthetic methods for the introduction of the sulfonyl fluoride moiety is therefore of importance. Herein, a transition-metal-free radical 1,2-difunctionalization of unactivated alkenes via FSO2 -radical addition with subsequent vicinal alkynylation to access ß-alkynyl-fluorosulfonylalkanes is presented. Alkynyl sulfonyl fluorides are introduced as highly valuable bifunctional radical trapping reagents that also serve as FSO2 -radical precursors. The ß-alkynyl-fluorosulfonylalkanes obtained in these transformations can be readily diversified by using SuFEx click chemistry to obtain sulfonates and sulfonamides.

Oxy-Borylenes as Photoreductants: Synthesis and Application in Dehalogenation and Detosylation Reactions.

While the range of accessible borylenes has significantly broadened over the last decade, applications remain limited. Herein, we present tricoordinate oxy-borylenes as potent photoreductants that can be readily activated by visible light. Facile oxidation of CAAC stabilized oxy-borylenes (CAAC)(IPr2 Me2 )BOR (R=TMS, CH2 CH2 C6 H5 , CH2 CH2 (4-F)C6 H4 ) to their corresponding radical cations is achieved with mildly oxidizing ferrocenium ion. Cyclovoltammetric studies reveal ground-state redox potentials of up to -1.90 V vs. Fc+/0 for such oxy-borylenes placing them among the strongest organic super electron donors. Their ability as photoreductants is further supported by theoretical studies and showcased by the application as stoichiometric reagents for the photochemical hydrodehalogenation of aryl chlorides, aryl bromides and unactivated alkyl bromides as well as the detosylation of anilines.