Radical-polar Crossover Research Articles

Visible-Light-Mediated Vicinal Dihalogenation of Unsaturated C-C Bonds Using Dual-Functional Group Transfer Reagents.

The growing demand for chemical production continues to drive the development of sustainable and efficient methods for introducing molecular complexity. In this context, the exploration of unconventional functional group transfer reagents (FGTRs) has led to significant advancements in practical and atom-efficient synthetic protocols. Aiming to advance the field of valuable organic synthesis, herein we report the successful development of carbon-based, bench-stable, modular, and inexpensive reagents implemented in dual halogen transfer to unsaturated hydrocarbons via photocatalytic activation of reagents based on a radical-polar crossover mechanism. This method beneficially enables vicinal dichlorination, dibromination, and bromo-chlorination reactions of olefins, offering practical alternatives to the use of toxic binary halogens. Detailed mechanistic studies, combining experimental, spectroscopic, and theoretical investigations, revealed a distinctive photocatalytic single-electron transfer reduction of FGTR. This process triggers mesolytic carbon-halogen bond cleavage, followed by a radical 1,2-halide rearrangement, leading to the continuous generation of dihalogen species in the reaction medium. The wide applicability of the developed protocol is demonstrated through an extensive scope of unsaturated molecules, including additional operations on strain-release dihalogenation.

Divergent Synthesis of Trifluoromethyl Ketones via Photoredox Activation of Halotrifluoroacetones

AbstractFluorine's high electronegativity, lipophilicity, and metabolic stability make it a valuable element for drug design and development. Consequently, significant synthetic efforts have focused on introducing fluorine and fluorinated motifs into organic molecules, with the synthesis of trifluoromethyl ketones (TFMKs) recently attracting considerable attention. Building on our ongoing research on radical organofluorine chemistry, we present herein the divergent synthesis of trifluoromethyl ketones directly from olefins using readily available chloro‐ and bromotrifluoroacetone as synthetic precursors of the trifluoroacetonyl radical under photoredox catalysis. Mechanistic studies revealed that the divergence is attained through radical polar crossover (RPC) and hydrogen atom transfer (HAT) mechanisms.

Amine-Ligated Boryl Radical Enabled Hydrofunctionalization of Styrenes via Halogen-Atom Transfer of Alkyl and Aryl Bromides

AbstractHerein, we demonstrate an amine-ligated boryl radical mediated halogen-atom transfer (XAT) strategy with alkyl and aryl bromides to construct C(sp 3)–C(sp 3) and C(sp 3)–C(sp 2) bonds, respectively. The first step involves the photocatalytic and decarboxylative generation of amine-ligated boryl radicals from a carboxylic acid containing amine-ligated borane. The resulting amine-ligated boryl radical undergoes XAT with organobromides to generate carbon-centered radicals, which react with styrenes to afford hydrofunctionalized products. Furthermore, this photocatalytic XAT strategy can be applied to synthesize gem-difluorostyrene and 1,1-disubstituted cyclopropane through a radical-polar crossover mechanism.

Diastereoselective Hydrodifluoromethylation of Alkenyl N-Heterocycles via Photocatalytic Radical-Polar Crossover.

A diastereoselective hydrodifluoromethylation of N-heteroaryl alkenes was successfully established. This method was applicable to an array of N-heteroaryl substrates with both cyclic and acyclic alkenes while displaying tolerance to a variety of functional groups. The conditions were also expanded to obtain hydrotrifluoromethylated products with similar results. Initial mechanistic studies suggest that the final protonation step is accessed through a radical-polar crossover process.

Cu0-Promoted Truce-Smiles Rearrangement for Aryl-Difluoromethylenation of C═C Bonds via a Reductive Radical-Polar Crossover Process.

An efficient Cu0-promoted Truce-Smiles rearrangement for the aryl-difluoromethylenation of C═C bonds by the reaction of N-alkyl-N-(arylsulfonyl)methacrylamide and 2-bromodifluoromethyl-1,3-benzodiazole via a reductive radical-polar crossover process under mild reaction conditions is presented. The protocol enables practical access to a variety of single regioisomer α-aryl-β-difluoromethylene amides in good to excellent yields through consecutive difluoromethylenation, radical-polar crossover, 1,4-aryl migration, SO2 extrusion, and N-H bond formation cascade reaction.

Synthesis of silacycles via metal hydrogen atom transfer and radical-polar crossover mechanism

In this study, we have developed an efficient method for silacycle synthesis using metal hydride hydrogen atom transfer (MHAT) and radical-polar crossover (RPC) mechanism. Allylic silanols were synthesized via one-step condensation and then cyclized under mild conditions using N-fluoropyridinium tetrafluoroborate (Me3NFPY·BF4) as the oxidant under cobalt catalysis. This approach yielded five-, six-, and seven-membered silacycles with high selectivity, with the six-membered rings being the favored products. Density functional theory (DFT) calculations provided valuable insights into the reaction mechanisms and highlighted the role of ring strain in determining product selectivity. This study demonstrated the effectiveness of combining MHAT/RPC methodologies with silicon tethering, thus offering a robust platform for expanding the use of silicon-based strategies in synthetic chemistry.

Enantioselective Synthesis of α‐Aryl Ketones by a Cobalt‐Catalyzed Semipinacol Rearrangement

A highly enantioselective cobalt‐catalyzed semipinacol rearrangement of symmetric α,α‐diarylallylic alcohols is disclosed. A chiral cobalt‐salen catalyst generates a highly electrophilic carbocation surrogate following hydrogen atom transfer and radical–polar crossover steps. This methodology provides access to enantioenriched α‐aryl ketones through invertive displacement of a cobalt(IV) complex during 1,2‐aryl migration. A combination of readily available reagents, silane and N‐fluoropyridinium oxidant, are used to confer this type of reactivity. An exploration into the effect of aryl substitution revealed the reaction tolerates para‐ and meta‐halogenated, mildly electron‐rich and electron‐poor aromatic rings with excellent enantioselectivities and yields. The yield of the rearrangement diminished with highly electron‐rich aryl rings whereas very electron‐deficient and ortho‐substituted arenes led to poor enantiocontrol. A Hammett analysis demonstrated the migratory preference for electron‐rich aromatic rings, which is consistent with the intermediacy of a phenonium cation.

Enantioselective Synthesis of α-Aryl Ketones by a Cobalt-Catalyzed Semipinacol Rearrangement.

A highly enantioselective cobalt-catalyzed semipinacol rearrangement of symmetric α,α-diarylallylic alcohols is disclosed. A chiral cobalt-salen catalyst generates a highly electrophilic carbocation surrogate following hydrogen atom transfer and radical-polar crossover steps. This methodology provides access to enantioenriched α-aryl ketones through invertive displacement of a cobalt(IV) complex during 1,2-aryl migration. A combination of readily available reagents, silane and N-fluoropyridinium oxidant, are used to confer this type of reactivity. An exploration into the effect of aryl substitution revealed the reaction tolerates para- and meta-halogenated, mildly electron-rich and electron-poor aromatic rings with excellent enantioselectivities and yields. The yield of the rearrangement diminished with highly electron-rich aryl rings whereas very electron-deficient and ortho-substituted arenes led to poor enantiocontrol. A Hammett analysis demonstrated the migratory preference for electron-rich aromatic rings, which is consistent with the intermediacy of a phenonium cation.

Merging New and Old Concepts: Tandem Oxidative Radical‐Polar Crossover Ritter Amidation via Multicomponent Photo‐ and Electrochemical Processes

Nitrogen‐containing drug molecules and pharmaceuticals are ubiquitous, rendering the construction of C–N bonds a crucial target in methodology development. The Ritter reaction is a well‐established method for accessing C–N bonds by generating amide functionality through the reaction of carbocations and nitriles. Since its discovery back in 1948, the Ritter reaction has progressively advanced towards milder and more sustainable conditions for carbocation generation. In this regard, notable contributions have been made by means of single electron transfer (SET) chemistry. Nowadays, photo‐ and electrochemistry are established methods of choice for the generation of reactive radical intermediates and their subsequent oxidation via radical‐polar crossover (RPC) mechanism. We review recent examples of tandem RPC and Ritter‐type protocols, demonstrating how photo‐ and electrochemical energies have been effectively harvested to expand the precursor pool for the Ritter reaction and also reimagine the process with novel mechanisms and additives.

Radical-Based Enantioconvergent Reductive Couplings of Racemic Allenes and Aldehydes.

Transition metal-catalyzed radical-based enantioconvergent reactions have become a powerful strategy to synthesize enantiopure compounds from racemic starting materials. However, existing methods primarily address precursors with central chirality, neglecting those with axial chirality. Herein, we describe the enantioconvergent reductive coupling of racemic allenes with aldehydes, facilitated by a photoredox, chromium, and cobalt triple catalysis system. This method selectively affords one product from sixteen possible regio- and stereoisomers. The protocol leverages CoIII-H mediated hydrogen atom transfer (MHAT) and Cr-catalyzed radical-polar crossover for efficient stereoablation of axial chirality and asymmetric addition, respectively. Supported by mechanistic insights from control experiments, deuterium labeling, and DFT calculations, our approach offers synthetic chemists a valuable tool for creating enantioenriched chiral homoallylic alcohols, promising to advance radical-based strategies for synthesizing complex chiral molecules.

Paired Electrolysis Enables Reductive Heck Coupling of Unactivated (Hetero)Aryl Halides and Alkenes.

The formation of carbon-carbon (C-C) bonds is a cornerstone of organic synthesis. Among various methods to construct Csp2-Csp3 bonds, the reductive Heck reaction between (hetero)aryl halides and alkenes stands out due to its potential efficiency and broad substrate availability. However, traditional reductive Heck reactions are limited by the use of precious metal catalysts and/or limited aryl halide and alkene compatibility. Here, we present an electrochemically mediated, metal- and catalyst-free reductive Heck reaction that tolerates both unactivated (hetero)aryl halides and diverse alkenes such as vinyl boronates and silanes. Detailed electrochemical and deuterium-labeling studies support that this transformation likely proceeds through a paired electrolysis pathway, in which acid generated by the oxidation of N,N-diisopropylethylamine (DIPEA) at the anode intercepts an alkyl carbanion formed after radical-polar crossover at the cathode. As such, this approach offers a sustainable method for the construction of Csp2-Csp3 bonds from (hetero)aryl halides and alkenes, paving the way for the development of other electrochemically mediated olefin difunctionalization reactions.

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.

Photo-/Electrocatalytic Difunctionalization of Alkenes Enabled by C-H Radical Functionalization.

The difunctionalization of alkenes represents a powerful tool to incorporate two functional groups into the alkene bones for increasing molecular complexity and has been widely utilizations in chemical synthesis. Upon the catalysis of the green, sustainable, mild photo-/electrochemistry technologies, much attentions have been attracted to the development of new tactics for the transformations of the important alkene and alkane feedstocks driven by C-H radical functionalization. Herein, we summarize recent advances in the photo-/electrocatalytic difunctionalization of alkenes enabled by C-H radical functionalization. We detailedly discuss the substrate scope and the mechanisms of the photo-/electrocatalytic alkene difunctionalization reactions by selecting impressive synthetic examples, which are divided into four sections based on the final terminated step, including oxidative radical-polar crossover coupling, reductive radical-polar crossover coupling, radical-radical coupling, and transition-metal-catalyzed coupling.

Et3Al/Light-Promoted Radical-Polar Crossover Reactions of α-Alkoxyacyl Tellurides.

Here, we report new radical-polar crossover reactions of α-alkoxy carbon radicals for constructing highly oxygenated molecules with contiguous stereocenters. The method employs a 370 nm UV light-emitting diode (LED) for the photoexcitation of α-alkoxyacyl telluride, and Et3Al as the radical initiator and terminator. First, Et3Al and UV LED promoted radical coupling between the α-alkoxyacyl telluride and cyclopentenone via C-Te bond homolysis, CO expulsion, and C-C bond formation. Second, Et3Al converted the radical species to the corresponding aluminum enolate. Third, the second C-C bond formation occurred via a polar mechanism: intermolecularly with aldehydes/ketones and intramolecularly with epoxide, producing aldol and SN2 adducts, respectively. The present coupling reactions increase the molecular complexity in a single step by stereoselective formation of the two hindered C-C bonds. The devised method is expected to be useful for the expeditious assembly of densely oxygenated natural products.

Photoredox-Catalyzed Alkylamination of Alkenes via Oxidative Radical-Polar Crossover and Site-Selective 1,5-Hydrogen Atom Transfer.

We reported the visible-light-mediated photoredox-catalyzed oxidative radical-polar crossover and 1,5-hydrogen atom transfer combined site-selective remote C(sp3)-N cross-coupling alkylamination of alkenes. Various anilines and hydroxamides (1,5-hydrogen atom transfer reagents) could be tolerated. The mechanistic studies indicated the radical nature of the reaction and the indispensability of light and photocatalyst. Stern-Volmer fluorescence quenching and cyclic voltammetry experiments have been used to outline the proposed reaction pathway.

Cobalt-Catalyzed Intramolecular Markovnikov Hydrocarbonylation of Unactivated Alkenes via Hydrogen Atom Transfer.

A cobalt-catalyzed intramolecular Markovnikov hydroalkoxycarbonylation and hydroaminocarbonylation of unactivated alkenes has been developed, enabling highly chemo- and regioselective synthesis of α-alkylated γ-lactones and α-alkylated γ-lactams in good yields. The mild reaction conditions allow use of mono-, di- and trisubstituted alkenes bearing a variety of functional groups. Preliminary mechanistic studies suggest the reaction proceeds through a CO-mediated hydrogen atom transfer (HAT) and radical-polar crossover (RPC) process, in which a cationic acylcobalt(IV) complex is proposed as the key intermediate.

Cobalt‐Catalyzed Intramolecular Markovnikov Hydrocarbonylation of Unactivated Alkenes via Hydrogen Atom Transfer

A cobalt‐catalyzed intramolecular Markovnikov hydroalkoxycarbonylation and hydroaminocarbonylation of unactivated alkenes has been developed, enabling highly chemo‐ and regioselective synthesis of α‐alkylated γ‐lactones and α‐alkylated γ‐lactams in good yields. The mild reaction conditions allow use of mono‐, di‐ and trisubstituted alkenes bearing a variety of functional groups. Preliminary mechanistic studies suggest the reaction proceeds through a CO‐mediated hydrogen atom transfer (HAT) and radical‐polar crossover (RPC) process, in which a cationic acylcobalt(IV) complex is proposed as the key intermediate.

Radical Fluorosulfonamidation: A Facile Access to Sulfamoyl Fluorides.

Recently, the introduction of fluorosulfonyl (-SO2F) groups have attracted considerable research interests, as this moiety could often afford enhanced activities and new functions in the context of chemical biology and drug discovery. Herein, we report the design and synthesis of 1-fluorosulfamoyl-pyridinium (FSAP) salts, which could serve as an effective photoredox-active precursor to fluorosulfamoyl radicals and enable the direct radical C-H fluorosulfonamidation of a variety of (hetero)arenes. This method features mild conditions, visible light, broad substrate scope, good group tolerance, etc., and a metal-free protocol is also viable by using organic photocatalysts. Further, FSAP can also be applied to the radical functionalization of alkenes via 1,2-difunctionalization, radical distal migration, tandem radical-polar crossover reactions, etc. In addition, a formal C-H methylamination of (hetero)arenes by combining this radical C-H fluorosulfonamidation with subsequent hydrolysis as well as product derivatization are also demonstrated.

Chromium Catalyzed Asymmetric Reformatsky Reaction.

This study describes an unprecedented chromium-catalyzed asymmetric Reformatsky reaction, enabling the synthesis of chiral β-hydroxy carbonyl compounds from α-chlorinated or α-brominated esters and amides. By employing a chiral chromium/diarylamine bis(oxazoline) catalyst, we achieved relatively broad functional group tolerance. Distinct from known reports, the protocol operates under both classical and photoredox conditions, facilitated by the in situ formation of a nucleophilic chiral chromium intermediate through a radical-polar crossover mechanism. Preliminary mechanistic insights, supported by DFT calculations, identify the nucleophilic aldehyde addition as the key stereo-determining step. This approach not only overcomes the limitations of existing Reformatsky reactions but also provides a versatile strategy for accessing complex chiral molecules.

Polarity-Matched Initiation of Radical-Polar Crossover Reactions for the Synthesis of C-Allyl Glycosides with gem-Difluoroalkene Groups.

Herein, we disclose a general method for the assembly of C-allyl glycosides containing gem-difluoroalkene groups via a radical-polar crossover strategy. Central to the success of this process is the polarity matching between the benzenesulfinate radical and the glycosyl donor, which facilitates the initiation of the glycosyl radical and the subsequent formation of gem-difluoroalkene sugar derivatives. This method demonstrated good compatibility with various glycosyl donors and functional groups. Furthermore, we showcase the utility of this method in modifying amino acids, potentially paving the way for analogous modifications to peptides.