Redox-neutral Reaction Research Articles

Photocatalytic Regioselective Redox-Neutral 1,3-Oxypyridylation of Aryl Cyclopropanes.

Pyridines and cyclopropanes are important structural units in chemistry. Herein, we introduce a photoredox-catalyzed approach for the ring opening and 1,3-oxypyridylation of aryl cyclopropanes using 4-cyanopyridines and carboxylic acids. This sequential process involves single-electron oxidation of the aryl cyclopropane, leading to nucleophilic ring opening and radical pyridylation at the benzylic position. The redox-neutral reaction exhibits high regioselectivity under mild reaction conditions, offering a broad substrate scope and wide applicability.

Intermolecular Regioselective Alkylarylation of Vinylarenes via Photoredox/Nickel Dual Catalysis.

A novel photoredox/nickel dual catalytic intermolecular alkylarylation of vinylarenes with tertiary and secondary alkyltrifluoroborates and aryl bromides is described, which affords 1,1-diarylalkane frameworks that are found in various natural products as well as functionalized molecules in good to excellent yield and regioselectivity through a radical relay process. Notably, this redox-neutral reaction could proceed efficiently with good tolerance of various substrates, including a great diversity of commercially available (hetero)aryl bromides, alkyltrifluoroborates, and vinylarenes.

(Invited) Upconverted Hot Electrons from Semiconductor Nanocrystals for Enhancing Photocatalysis

The exciton-to-hot electron upconversion phenomenon in Mn-doped semiconductor quantum dots (QDs) produces highly energetic hot electrons. These electrons have an average energy just a fraction of 1 eV below the vacuum level, with a subpopulation of hot electrons existing above the vacuum level. This hot electron upconversion process is similar to photon upconversion in lanthanide-doped nanoparticles. However, the final state here is a highly excited hot electron in the conduction band of the host QDs, not a state emitting higher-energy photons. These upconverted hot electrons can be harnessed to carry out thermodynamically and kinetically challenging reduction reactions, benefiting from their high excess kinetic energy and long-range transfer capability. The presentation will discuss recent demonstrations of the benefits of these upconverted hot electrons in various photocatalytic reduction and redox-neutral reactions. Additionally, the development of new materials for more efficient hot electron upconversion and the potential to broaden the application of these energetic hot electrons beyond photocatalysis will be discussed.

Electrocatalytic Radical Cation Diels-Alder Reactions Using Enol Ethers As Dienophiles

Single-electron oxidation enables the conversion of electron-rich alkenes such as styrene derivatives to radical cation species. We have been developing various cycloaddition reactions of radical cations produced by single-electron oxidation using electrochemical and TiO2 photochemical methods. Introducing an electron-rich aryl group which we call a redox tag is a critical part of the process to control the reactivity of the radical cations. During carbon-carbon bonds formation the motif functions as both electron donor and electron acceptor. In addition to styrene derivatives, enol ethers can also be readily oxidized by single electron transfer (SET) electrochemically or photochemically to generate the radical cations. For instance, enol ethers tethered redox tag serves efficient radical cation precursors for [2+2] cycloadditions.[1] The cycloadditions are net redox-neutral reactions and are initiated by the formation of a radical cation by single-electron oxidation and completed by reduction after ring formation.Herein, we present [4+2] cycloadditions using enol ethers as dienophiles by electrochemical oxidation in lithium perchlorate (LiClO4)/nitromethane (MeNO2) system. In the case of disubstituted enol ethers prepared from aldehydes, the approach involving redox tag was successful in obtaining the corresponding cycloadducts, while the desired products were not obtained when the substrates without redox tag were subjected.[2] This result suggests that intramolecular electron transfer from the redox tag is crucial for the formation of the cyclohexene ring systems. In contrast, the trisubstituted enol ethers prepared from ketones allowed the cycloaddition reaction to proceed without the involvement of redox tag. It is expected that the methyl group significantly stabilizes the cyclohexene radical cations to have enough lifetime to be reduced by intermolecular SET. Furthermore, since the cycloaddition reaction of enol ether was completed with a catalytic amount of electricity (0.4 F/mol), a radical cation chain mechanism is proposed in which electron acts as a catalyst.

Synthesis of branched and linear aryl allylic alcohols: C[sbnd]H bond allylation of 2-aryl-3H-indoles with vinyl cyclic carbonates

Presented herein is an effective synthesis of branched and linear allyl arenes based on the reactions of 2-aryl-3H-indoles with 5-methylene-1,3-dioxan-2-one or 4-vinyl-1,3-dioxolan-2-one. Mechanistically, the reactions are initiated by Rh(III)-catalyzed aryl C(sp2)–H bond activation/cyclometallation followed by vinyl coordination/migratory insertion and β–O elimination through release of CO2 as the only by-product. By using this newly developed protocol, a group of 2-aryl-3H-indole derivatives bearing the substructure of either branched or linear allylic alcohol were obtained in good efficiency. Notably, the linear allylic alcohols were obtained with excellent E/Z selectivity when unsubstituted vinyl-1,3-dioxolan-2-one was used as the allyl surrogate. With advantages such as easily available starting materials, mild and redox-neutral reaction conditions, good compatibility with a broad range of functional groups, benign solvent and divergent products, this protocol is expected to be used in the synthesis of indole-based functional molecules.

Switchable Regioselective C-H Activation/Annulation of Acrylamides with Alkynes for the Synthesis of 2-Pyridones.

A catalyst-based switchable regioselective C-H activation/annulation of acrylamides with propargyl carbonates has been developed, delivering C5 or C6 alkenyl substituted 2-pyridones. This robust protocol proceeds with a broad substrate scope and good functional group tolerance under redox-neutral reaction conditions. More significantly, this reaction is highly effective with previously challenging unsymmetrical alkynes, including unbiased alkyl-alkyl substituted alkynes, with perfect and switchable regioselectivity. Additionally, mechanistic studies and DFT calculations were performed to shed light on the switchable regioselectivity.

Electrochemical stereoselective borylation of Morita-Baylis-Hillman adducts to functionalized allylic boronates.

Herein, we disclose a highly efficient and facile electrochemical borylation of Morita-Baylis-Hillman adducts without using any metal catalyst. This methodology demonstrates excellent regio- and stereo-selectivity, leading to a wide range of functionalized E-allylic boronates, including derivatives of ibuprofen and menthol. Under mild and straightforward conditions, this redox-neutral reaction, combined with the scalability and synthetic applications of the allylic boronate esters, underscores its potential for a wide range of applications in organic synthesis.

Metal-free photoinduced generation and alkynylation of carbamoyl radicals: a facile synthesis of alkynyl amides.

A metal-free photoinduced alkynylation of carbamoyl radicals with hypervalent iodine(III) reagents for a facile synthesis of alkynyl amides is described. This protocol features good functional group tolerance and a broad substrate scope for direct synthesis of alkynyl amide derivatives in good to excellent yields under mild and redox-neutral reaction conditions. The synthetic application is demonstrated by the late-stage installation of alkynyl amides into natural products and active pharmaceutical relevant molecules. The mechanistic studies indicated the simultaneous existence of photoredox catalytic and direct photoexcited processes, and the quantum yields confirmed the occurrence of the radical chain propagation process.

Metal-free visible light-induced cross-dehydrogenative coupling of benzocyclic imines with water/P(O)H compounds: efficient access to functionalized benzazepines/ones

A metal-free visible light-induced cross-dehydrogenative coupling of aldimines with nucleophiles in a one-pot fashion is first reported, which features high efficiency,the absence of external oxidants, and mild and redox-neutral reaction conditions.

Metal-free, photoredox-catalyzed aromatization-driven deconstructive functionalization of spiro-dihydroquinazolinones with α-CF3 alkenes.

Metal-free, photoredox-catalyzed aromatization-driven deconstructive functionalization of spiro-dihydroquinazolinones with α-CF3 alkenes is presented. The readily available spiro-dihydroquinazolinones reacted efficiently with α-CF3 alkenes during photocatalysis to give the gem-difluoroallylated and the CF3-containing quinazolin-4(3H)-ones in good yields with excellent chemoselectivity. The selectivity depends on the electron effect of substituents in α-CF3 alkenes. A wide range of four-, five-, six-, seven-, eight- and twelve-membered spiro-dihydroquinazolinones were compatible with this transformation. The protocol is also characterized by the mild and redox-neutral reaction conditions, good functional group compatibility and excellent atom economy. Mechanistic studies revealed that the reaction proceeds via a radical pathway.

Aromatic C(sp2 )-H Functionalization by Consecutive Paired Electrolysis: Dibromination of Aryl Amines with Dibromoethane at Room Temperature.

Herein, we disclose a facile and efficient electrochemical method for the dibromination of aryl amines by double functionalization of aromatic C(sp2 )-H (both para and ortho) under metal- and external oxidant-free conditions at room temperature for the first time. The reaction is demonstrated using 1,2-dibromoethane to dibrominate a wide range of N-substituted aryl amines in a simple setup with C(+)/Pt(-) electrodes under mild reaction conditions. This transformation proceeds smoothly with a broad substrate scope affording the valuable and versatile N-substituted 2,4-dibromoanilines in moderate to excellent yields with high regioselectivity. In this paired electrolysis, cathodic reduction of 1,2-DBE followed by anodic oxidation generates bromonium intermediates, which then couple with anilines to furnish the dibrominated products. It represents a distinctive approach to challenging redox-neutral reactions. The versatility of the electrochemical ortho-, para-dibromination was reflected by unique regioselectivities for challenging aryl amines and gram-scale electrosynthesis without the use of a stoichiometric oxidant or an activating agent.

Convergent Deboronative and Decarboxylative Phosphonylation Enabled by the Phosphite Radical Trap "BecaP".

Carbon-phosphorus bond formation is significant in synthetic chemistry because phosphorus-containing compounds offer numerous indispensable biochemical roles. While there is a plethora of methods to access organophosphorus compounds, phosphonylations of readily accessible alkyl radicals to form aliphatic phosphonates are rare and not commonly used in synthesis. Herein, we introduce a novel phosphorus radical trap "BecaP" that enables facile and efficient phosphonylation of alkyl radicals under visible light photocatalytic conditions. Importantly, the ambiphilic nature of BecaP allows redox neutral reactions with both nucleophilic (activated by single-electron oxidation) and electrophilic (activated by single-electron reduction) alkyl radical precursors. Thus, a broad scope of feedstock alkyl potassium trifluoroborate salts and redox active carboxylate esters could be employed, with each class of substrate proceeding through a distinct mechanistic pathway. The mild conditions are applicable to the late-stage installation of phosphonate motifs into medicinal agents and natural products, which is showcased by the straightforward conversion of baclofen (muscle relaxant) to phaclofen (GABAB antagonist).

Visible-Light-Promoted Click [3+2] Cycloaddition of Aziridine with Alkyne: An Efficient Synthesis of Dihydropyrrolidine

AbstractA photocatalytic [3+2] cycloaddition of aziridines with activated alkynes is reported under visible-light irradiation in the presence of ruthenium catalyst. This chemical transformation provides polysubstituted pyrrolidines in good yields based on the click chemistry philosophy. The reaction successfully represents a primary trial of cyclocarboamination through photocascade catalysis combining energy transfer and redox neutral reactions.

Rhodium-Catalyzed Intramolecular Acylation of 2-(Indol-1-yl)-benzoic Acids under Redox-Neutral Conditions

AbstractWe developed a novel access to indoloindolone by a rhodium-catalyzed intramolecular acylation of 2-(indol-1-yl)benzoic acids. This reaction proceeds via the in situ formation of a mixed anhydride under redox-neutral reaction conditions. Preliminary mechanistic investigations revealed that the in situ formed mixed anhydride participates in the C–H activation step, which is facilitated by a RhI catalyst. The utility of this reaction was demonstrated by a large-scale reaction.

Radical-Based Convergent Paired Electrolysis.

Electrochemistry offers a sustainable platform for discovering reactions involving single-electron transfer (SET) that generates highly reactive and synthetically versatile radical species. Compared with photochemistry similarly specializing in SET which requires expensive photocatalysts, electrochemistry employs low-cost electricity to drive the electron flow. Paired electrolysis makes use of both half-reactions, thus obviating the need for sacrificial reactions and maximizing the atom and energy economy. In convergent paired electrolysis, anodic oxidation and cathodic reduction occur simultaneously to generate two intermediates, which are then coupled to furnish the product. It represents a distinctive approach to challenging redox-neutral reactions. However, the gap between the two electrodes makes it hard for a reactive intermediate to come across the other coupling partner. This concept article summarizes recent state-of-the-art advances on radical-based convergent paired electrolysis, which adopted different strategies to overcome the difficulty.

Carbohydrate-DNA Conjugation Enabled by Glycosyl Radicals Generated from Glycosyl Sulfinates.

Herein, we report a method that enables the synthesis of carbohydrate-DNA conjugates by radical addition. Key to the success is the use of readily available, bench-stable, and unprotected glycosyl sulfinates as precursors to glycosyl radicals. The redox neutral reaction proceeds under mild and simple conditions and tolerates a broad substrate scope. A small library of carbohydrate-DNA conjugates was prepared.

Photoredox-Catalyzed Redox-Neutral Decarboxylative C–H Acylations of Coumarins with α-Keto Acid

A novel and green photocatalytic strategy for the synthesis of C-4-acylated coumarins with α-keto acids and 3-nitrocoumarin has been developed. This operationally simple protocol works under mild reaction conditions, providing convenient access to 4-acyl coumarin derivatives. The control experimental results showed that the nitro radical produced by the cleavage of the C-N bond acts as an electron acceptor to complete the photocatalytic cycle, achieving a redox-neutral reaction.

Deuterodehalogenation Under Net Reductive or Redox-Neutral Conditions Enabled by Paired Electrolysis.

Interest in deuterated active pharmaceutical ingredients (APIs) is increasing as deuteration holds promise for kinetic isotope effect (KIE) regulated fine-tuning of API performance. Moreover, deuterium isotope labeling is frequently carried out to study organic and bioorganic reaction mechanisms and to facilitate complex target synthesis. As such, methods for highly selective deuteration of organic molecules are highly desirable. Herein, we present an electrochemical method for the selective deuterodehalogenation of benzylic halides via a radical-polar crossover mechanism, using inexpensive deuterium oxide (D2 O) as the deuterium source. We demonstrate broad functional group compatibility across a range of aryl and heteroaryl benzylic halides. Furthermore, we uncover a sequential paired electrolysis regime, which permits switching between net reductive and overall redox-neutral reactions of sulfur-containing substrates simply by changing the identity of the sacrificial reductant employed.

The triplet state of deprotonated mesoionic carbene Breslow intermediates is thermally accessible: Distal difunctionalization of aldehydes

N-Heterocyclic carbene (NHC)-catalyzed transformations through electron-pair-transfer processes have witnessed remarkable developments in the past decades, especially the umpolung of aldehydes via the Breslow intermediates (BIs). The role of BIs in single-electron transfer (SET) pathways has long been established in biosynthesis, and in the last decade, it was extended to NHC organocatalysis. Here, we report that deprotonated mesoionic carbene BIs (BI - s) have an astonishing small singlet/triplet (S/T) gap of only 4.0 kcal/mol, resulting in a thermally accessible triplet state. This low-lying excited state allows for a series of distal difunctionalizations of aryl aldehydes via biradical processes. At the formyl side, an oxidative esterification reaction takes place concomitantly with a reduction of the aryl side. Here, three types of chemical transformation are demonstrated: hydro(deutero)defunctionalization, hydrogenation, and reductive alkylation. • The triplet state of deprotonated MIC-Breslow intermediates is thermally accessible • Catalytic distal difunctionalization of aryl aldehydes via biradical pathways • Redox-neutral reactions with simultaneous oxidative esterification and reduction Over the past decades, N-heterocyclic carbene (NHC)-based organocatalysis, which involves the umpolung of aldehydes via Breslow intermediates (BIs), has been developed as an important approach in organic synthesis. Among them, NHC-catalyzed electron-pair reactions and radical reactions have been established via BIs and BI − s, respectively. In this article, we disclose that the triplet state of deprotonated mesoionic carbene BIs is thermally accessible. Taking advantage of this property, we describe a mesoionic-carbene-catalyzed distal difunctionalization reaction of aryl aldehydes via biradical pathways. These reactions feature redox neutrality with simultaneous oxidative esterification and reduction. Yan and co-workers report that deprotonated mesoionic carbene Breslow intermediates (BIs) have an astonishing small singlet/triplet (S/T) gap of only 4.0 kcal/mol, resulting in a thermally accessible triplet state. This low-lying excited state allows for a series of distal difunctionalizations of aryl aldehydes via biradical processes. At the formyl side, an oxidative esterification reaction takes place concomitantly with a reduction of the aryl side.

A Catharanthus roseus Fe(II)/α-ketoglutarate-dependent dioxygenase catalyzes a redox-neutral reaction responsible for vindolinine biosynthesis

The Madagascar’s periwinkle is the model plant for studies of plant specialized metabolism and monoterpenoid indole alkaloids (MIAs), and an important source for the anticancer medicine vinblastine. The elucidation of entire 28-step biosynthesis of vinblastine allowed further investigations for the formation of other remarkably complex bioactive MIAs. In this study, we describe the discovery and characterization of vindolinine synthase, a Fe(II)/α-ketoglutarate-dependent (Fe/2OG) dioxygenase, that diverts assembly of tabersonine to vinblastine toward the formation of three alternatively cyclized MIAs: 19S-vindolinine, 19R-vindolinine, and venalstonine. Vindolinine synthase catalyzes a highly unusual, redox-neutral reaction to form a radical from dehydrosecodine, which is further cyclized by hydrolase 2 to form the three MIA isomers. We further show the biosynthesis of vindolinine epimers from tabersonine using hydrolase 2 catalyzed reverse cycloaddition. While the occurrence of vindolinines is rare in nature, the more widely found venalstonine derivatives are likely formed from similar redox-neutral reactions by homologous Fe/2OG dioxygenases.