Radical Precursors Research Articles

Synthesis and Suzuki-Miyaura Cross-Coupling of Alkyl Amine-Boranes. A Boryl Radical-Enabled Strategy.

Alkyl organoborons are powerful materials for the construction of C(sp3)-C(sp2) bonds, predominantly via Suzuki-Miyaura cross-coupling. These species are generally assembled using 2-electron processes that harness the ability of boron reagents to act as both electrophiles and nucleophiles. Herein, we demonstrate an alternative borylation strategy based on the reactivity of amine-ligated boryl radicals. This process features the use of a carboxylic acid containing amine-ligated borane that acts as boryl radical precursor for photoredox oxidation and decarboxylation. The resulting amine-ligated boryl radical undergoes facile addition to styrenes and imines through radical-polar crossover manifolds. This delivers a new class of sp3-organoborons that are stable solids and do not undergo protodeboronation. These novel materials include unprotected α-amino derivatives that are generally unstable. Crucially, these aliphatic organoboron species can be directly engaged in Suzuki-Miyaura cross-couplings with structurally complex aryl halides. Preliminary studies suggest that they enable slow-release of the corresponding and often difficult to handle alkyl boronic acids.

Harnessing the potential of acyl triazoles in bifunctional cobalt-catalyzed radical cross-coupling reactions

Persistent radicals facilitate numerous selective radical coupling reactions. Here, we have identified acyl triazole as a new and versatile moiety for generating persistent radical intermediates through single-electron transfer processes. The efficient generation of these persistent radicals is facilitated by the formation of substrate-coordinated cobalt complexes, which subsequently engage in radical cross-coupling reactions. Remarkably, triazole-coordinated cobalt complexes exhibit metal-hydride hydrogen atom transfer (MHAT) capabilities with alkenes, enabling the efficient synthesis of diverse ketone products without the need for external ligands. By leveraging the persistent radical effect, this catalytic approach also allows for the development of other radical cross-coupling reactions with two representative radical precursors. The discovery of acyl triazoles as effective substrates for generating persistent radicals and as ligands for cobalt catalysis, combined with the bifunctional nature of the cobalt catalytic system, opens up new avenues for the design and development of efficient and sustainable organic transformations.

Aerobic Oxysulfonylation of Olefins Using N-Sulfonylaminophthalimides as Sulfonyl Radical Precursors.

Readily accessible N-sulfonylaminophthalimides were developed to be efficient sulfonyl radical precursors upon being treated with a base/oxidant under mild conditions. The method was applied to the oxysulfonylation of olefins, providing β-ketosulfones and isobenzofurans stereoselectively. On the basis of control experiments, density functional theory calculations, and the literature, a plausible radical mechanism was proposed. The findings offered a chance to develop novel radical precursors based on diversely substituted N-aminophthalimides, which might establish a universal mild approach for the generation of various radicals.

Photocatalyzed 1,3-Bromodifluoroallylation of [1.1.1]Propellane with α-Trifluoromethylalkenes and KBr Salts.

Herein we unveil a visible-light-driven transition-metal-free 1,3-bromodifluoroallylation of [1.1.1]propellane. This reactivity is harnessed through organophotocatalysis, providing practical synthetic pathways to 1-brominated-3-gem-difluoroallylic bicyclo[1.1.1]pentane derivatives, particularly derived from readily available α-trifluoromethylalkenes and inexpensive KBr salts utilized as precursors for bromine radicals. Mechanistic investigations reveal that bromide anions quench the excited state of the photocatalyst, leading to the formation of bromine radicals, which react in a strain-release radical addition process rather than hydrogen atom abstraction with [1.1.1]propellane.

Copper‐Catalyzed Radical‐Induced Annulation‐Halo(bi)cyanomethylation of Indole‐Tethered 1,6‐Enynes toward Pyrrolo[1,2‐a]indoles

AbstractA copper‐catalyzed radical‐induced annulation‐halocyanomethylation of indole‐linked 1,6‐enynes has been established using haloacetonitrile as radical precursors, enabling the synthesis of 21 cyanomethylated pyrrolo[1,2‐a]indoles with yields ranging from 42% to 81% and a Z/E ratio up to 19:1. Moreover, by adjusting the reaction temperature, a variation of the annulation‐bromobicyanomethylation process was achieved, resulting in the production of 12 bicyanomethylated pyrrolo[1,2‐a]indole isomers in yields of 41–68%. The stereoisomeric mixture of bicyanomethylated products could be purified to their pure configurations through recrystallization. The proposed reaction mechanism was formulated through a series of control experiments.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation.

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and β-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

Oxidative Difunctionalization of N-Aryl Bicyclobutyl Amides with Aldehydes: Divergent Synthesis of Acylated and Alkylated 3-Spirocyclobutyl Oxindoles.

An efficient and operationally simple oxidative radical difunctionalization of N-aryl bicyclobutyl (BCB) amides with aldehydes is described. It was found that acylated 3-spirocyclobutyl oxindoles were generated from the coupling of BCB-amides and aromatic aldehydes, while reactions gave exclusively decarbonylative alkylarylation products using alkyl aldehydes as radical precursors.

Photoredox-Catalyzed Amino-Radical-Transfer-Mediated Three-Component Alkylarylation of Alkenes.

We herein reported a novel photoredox-catalyzed three-component alkylarylation of vinyl arenes with alkylboronic pinacol esters (APEs) and cyanoarenes via radical addition/cross-coupling to construct 1,1-diarylalkanes. In this transformation, alkyl radicals were easily available by visible-light-induced oxidative N-H cleavage of morpholine, which used APEs as a radical precursor. Furthermore, this protocol exhibited a broad substrate scope, enabling various styrenes, APEs, and cyanoarenes, as well as bioactive molecule derivatives.

N-Heterocyclic carbene catalytic 1,2-boron migrative acylation accelerated by photocatalysis.

The transformation of organoboron compounds plays an important role in synthetic chemistry, and recent advancements in boron-migration reactions have garnered considerable attention. Here, we report an unprecedented 1,2-boron migrative acylation upon photocatalysis-facilitated N-heterocyclic carbene catalysis. The design of a redox-active boronic ester substrate, serving as an excellent β-boron radical precursor, is the linchpin to the success of this chemistry. With the established protocol, a wide spectrum of β-boryl ketones has been rapidly synthesized, which could further undergo various C─B bond transformations to give multifunctionalized products. The robustness of this catalytic strategy is underscored by its successful application in late-stage modification of drug-derived molecules and natural products. Preliminary mechanistic investigations, including several control experiments, photochemistry measurements, and computational studies, shed light on the catalytic radical reaction mechanism.

Direct Excitation Strategy for Deacylative Couplings of Ketones.

The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical-generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon-centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C-C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible-light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni-metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non-catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst-free approaches in cutting-edge research.

Direct excitation strategy for deacylative couplings of ketones

The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical‐generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon‐centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C–C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible‐light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni‐metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non‐catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst‐free approaches in cutting‐edge research.

Introduction of Difluoromethyl Through Radical Pathways

AbstractDuring the past decade, radical difluoromethylation has emerged as a powerful and versatile tool for the incorporation of difluoromethyl into various organic compounds. These reactions feature mild reaction conditions, very good functional group compatibilities, and quite broad substrate scopes, thus having drawn much attention and got rapid developments. A diverse range of difluoromethyl radical precursors have been developed for a series of radical difluoromethylation reactions. This review summarizes and discusses the advance in the radical difluoromethylation reactions, which are organized according to the protocols of generating difluoromethyl radical.

Organophotocatalyzed C‐Si Bond Fragmentation Using Silyl Ethers as Radical Precursors

In this work, silyl ethers of phenols and alcohols have been successfully prepared and tested as neutral carbon (silicon) centered radical precursors. The organocophotocatalyzed oxidation (by the Fukuzumi catalyst) of these ethers caused the cleavage of a C‐Si (or a Si‐Si) bond for the release of the desired radical to be used for the forging of C(sp3)‐C(sp3) (or C(sp3)‐Si) bonds via a Giese reaction.

N-Alkoxyphthalimides as Nitrogen Electrophiles to Construct C-N Bonds via Reductive Cross-Coupling.

N-Alkoxyphthalimides, one kind of phthalimide derivative, have great importance in synthesis, mainly used as free radical precursors. While the phthalimide unit, for a long time, was treated as part of the waste stream. Construction of C-N bonds has always been a hot spot, especially in reductive cross-coupling. Herein, a nickel-catalyzed reductive cross-coupling reaction of N-methoxyphthalimides with alkyl halides is described, where N-methoxyphthalimides serve as nitrogen electrophiles. This tactic provides a new approach to construct C-N bonds under mild neutral conditions. Alkyl chlorides, bromides, iodides, and sulfonates are all fit to this transformation. Moreover, the reaction could tolerate a broad substrate scope, especially base-sensitive functional groups (boron or silicon groups), as well as competitive nucleophilic groups (phenols and amides), which are incompatible with traditional Gabriel synthesis under basic conditions, demonstrating a complementary role of this work to Gabriel synthesis.

The Strategies Towards Electrochemical Generation of Aryl Radicals.

The advancement in electrochemical techniques has unlocked a new path for achieving unprecedented oxidations and reductions of aryl radical precursors in a controlled and selective manner. This approach facilitates the construction of aromatic carbon-carbon and carbon-heteroatom bonds. In light of the green merits and the growing importance of this technique in aryl radical chemistry, this review aims to provide an overview of the recent advance in the electrochemical generation of aryl radicals organized by the aryl radical precursor type, with a focus on the substrate scope, limitation, and underlying mechanism, thereby inspiring future work on electrochemical aryl radical generation.

Insights into the pH-dependent mechanism of peracetic acid activation by biochar-supported zero-valent iron/cobalt bimetallic nanoparticles: The shift of reactive sites and the dual role of hydrogen peroxide

The peracetic acid (PAA)-based water purification process is often controlled by the solution pH. Herein, we explored the usage of biochar (BC) supported zero-valent iron/cobalt nanoparticles (Fe/Co@BC) for triggering PAA oxidation of sulfamethazine (SMT), and discovered the PAA activation mechanisms at different pHs. Fe/Co@BC exhibited extraordinary PAA activation efficiency over the pH range of 3.0–8.2, effectively broadening the working pH of the zero-valent iron nanoparticles (NZVI)-PAA process. Specifically, the SMT removal efficiency increased by 8.3 times in Fe/Co@BC-PAA system compared to the NZVI-PAA system at pH 8.2. Besides, the leaching and recycling experiments indicated the improved stability and reusability of the materials. For the mechanism study, the main reactive species was •OH under acidic conditions and R-O•/Fe(IV) under neutral/alkaline conditions. More interestingly, the reactive sites on Fe/Co@BC shifted from Fe species to Co species as pH increased, and the role of H2O2 in this reaction system also shifted from a radical precursor to a radical scavenger with increasing pH. This study highlights the distinct mechanism of PAA activation by bimetallic composites under different pH conditions and provides a new efficient approach for PAA activation to degrade organic contaminants.

Accurately Predicting Spatiotemporal Variations of Near-Surface Nitrous Acid (HONO) Based on a Deep Learning Approach.

Gaseous nitrous acid (HONO) is identified as a critical precursor of hydroxyl radicals (OH), influencing atmospheric oxidation capacity and the formation of secondary pollutants. However, large uncertainties persist regarding its formation and elimination mechanisms, impeding accurate simulation of HONO levels using chemical models. In this study, a deep neural network (DNN) model was established based on routine air quality data (O3, NO2, CO, and PM2.5) and meteorological parameters (temperature, relative humidity, solar zenith angle, and season) collected from four typical megacity clusters in China. The model exhibited robust performance on both the train sets [slope = 1.0, r2 = 0.94, root mean squared error (RMSE) = 0.29 ppbv] and two independent test sets (slope = 1.0, r2 = 0.79, and RMSE = 0.39 ppbv), demonstrated excellent capability in reproducing the spatiotemporal variations of HONO, and outperformed an observation-constrained box model incorporated with newly proposed HONO formation mechanisms. Nitrogen dioxide (NO2) was identified as the most impactful features for HONO prediction using the SHapely Additive exPlanation (SHAP) approach, highlighting the importance of NO2 conversion in HONO formation. The DNN model was further employed to predict the future change of HONO levels in different NOx abatement scenarios, which is expected to decrease 27-44% in summer as the result of 30-50% NOx reduction. These results suggest a dual effect brought by abatement of NOx emissions, leading to not only reduction of O3 and nitrate precursors but also decrease in HONO levels and hence primary radical production rates (PROx). In summary, this study demonstrates the feasibility of using deep learning approach to predict HONO concentrations, offering a promising supplement to traditional chemical models. Additionally, stringent NOx abatement would be beneficial for collaborative alleviation of O3 and secondary PM2.5.

Nickel‐Catalyzed Highly Selective Radical C−C Coupling from Carboxylic Acids with Photoredox Catalysis

AbstractControlling the cross‐coupling reaction between two different radicals is a long‐standing challenge due to the process occurring statistically, which would lead to three products, including two homocoupling products and one cross‐coupling product. Generally, the cross‐coupling selectivity is achieved by the persistent radical effect (PRE) that requires the presence of a persistent radical and a transient radical, thus resulting in limited radical precursors. In this paper, a highly selective cross‐coupling of alkyl radicals with acyl radicals to construct C(sp2)−C(sp3) bonds, or with alkyl radicals to construct C(sp3)−C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (2,2′ : 6′,2′′‐terpyridine) to enable radical cross‐coupling process to Ni‐mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90 % yield), and also a new solution for the challenging double decarboxylative C(sp3)−C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late‐stage functionalization of natural‐occurring carboxylic acids and drugs.

Nickel-Catalyzed Highly Selective Radical C-C Coupling from Carboxylic Acids with Photoredox Catalysis.

Controlling the cross-coupling reaction between two different radicals is a long-standing challenge due to the process occurring statistically, which would lead to three products, including two homocoupling products and one cross-coupling product. Generally, the cross-coupling selectivity is achieved by the persistent radical effect (PRE) that requires the presence of a persistent radical and a transient radical, thus resulting in limited radical precursors. In this paper, a highly selective cross-coupling of alkyl radicals with acyl radicals to construct C(sp2)-C(sp3) bonds, or with alkyl radicals to construct C(sp3)-C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (2,2' : 6',2''-terpyridine) to enable radical cross-coupling process to Ni-mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90 % yield), and also a new solution for the challenging double decarboxylative C(sp3)-C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late-stage functionalization of natural-occurring carboxylic acids and drugs.

Modular assembly of arenes, ethylene and heteroarenes for the synthesis of 1,2-arylheteroaryl ethanes.

The 1,2-arylheteroaryl ethane motif stands as a privileged scaffold with promising implications in drug discovery. Conventional de novo syntheses of these molecules have relied heavily on pre-functionalized synthons, entailing harsh conditions and multi-step processes. Here, to address these limitations, we present a modular approach for the direct synthesis of 1,2-arylheteroaryl ethanes using feedstock chemicals, including ethylene, arenes and heteroarenes. We disclosed a photo triplet-energy-transfer-initiated radical cascade process, leveraging homolytic cleavage of C-S bonds in aryl sulfonium salts as the key step to access aryl radicals with excellent regioselectivity. This method allows for rapid structural diversification of bioactive molecules, showcasing excellent functional group tolerance and streamlining the synthesis of bioactive compounds and their derivatives. Furthermore, our approach can be extended to propylene, non-gaseous terminal alkenes and various other electrophilic radical precursors, including heteroaryl radicals, hydroxyl radicals, trifluoromethyl radicals and α-carbonyl alkyl radicals. This study highlights the significance of radical polarity matching in designing selective multi-component couplings.