Halogen Atom Transfer Research Articles

Data for Catalytic Defluorinative Ketyl-Olefin Coupling by Halogen-Atom Transfer

Data for Catalytic Defluorinative Ketyl-Olefin Coupling by Halogen-Atom Transfer

Data for Catalytic Defluorinative Ketyl-Olefin Coupling by Halogen-Atom Transfer

Data for Catalytic Defluorinative Ketyl-Olefin Coupling by Halogen-Atom Transfer

Merging Hydrogen Atom Transfer and Halogen Atom Transfer for Iodide-Catalyzed Radical Reductive Cyclization of 1,6-Enynes.

Described herein is the development of a metal-free iodide-catalyzed radical reductive cyclization of 1,6-enynes. A strategy involving in situ iodination/radical cyclization/silyl radical-mediated halogen atom transfer/hydrogen atom transfer for the synthesis of functionalized pyrrolidines has been proposed. Using this halogen-atom abstraction protocol, 1,6-enynes with various vinyl halides including inert fluorides, chlorides, and reactive bromides could be transformed into substituted pyrroles via a multistep radical isomerization process.

Photoinduced α‐C−H Amination of Cyclic Amine Scaffolds Enabled by Polar‐Radical Relay

AbstractHerein, we report a polar‐radical relay strategy for α‐C−H amination of cyclic amines with N‐chloro‐N‐sodio‐carbamates. The relay is initiated by in situ generation of cyclic iminium intermediate using N‐iodosuccinimide (NIS) oxidant as an initiator, which then operates through a series of polar (addition and elimination) and radical (homolysis, hydrogen‐ and halogen atom transfer) reactions to enable the challenging C−N bond formation in a controlled manner. A broad range of α‐amino cyclic amines were readily accessed with excellent regioselectivity, and the superb applicability was further demonstrated by functionalization of biologically relevant compounds.

Photoinduced α-C-H Amination of Cyclic Amine Scaffolds Enabled by Polar-Radical Relay.

Herein, we report a polar-radical relay strategy for α-C-H amination of cyclic amines with N-chloro-N-sodio-carbamates. The relay is initiated by in situ generation of cyclic iminium intermediate using N-iodosuccinimide (NIS) oxidant as an initiator, which then operates through a series of polar (addition and elimination) and radical (homolysis, hydrogen- and halogen atom transfer) reactions to enable the challenging C-N bond formation in a controlled manner. A broad range of α-amino cyclic amines were readily accessed with excellent regioselectivity, and the superb applicability was further demonstrated by functionalization of biologically relevant compounds.

Visible-Light Enabled C(sp3)-C(sp2) Cross-Electrophile Coupling via Synergistic Halogen-Atom Transfer (XAT) and Nickel Catalysis.

We herein report the first visible-light-mediated cross-coupling of unactivated alkyl iodides with aryl bromides through synergistic halogen atom transfer (XAT) and nickel catalysis. This simple protocol operates under mild reaction conditions and tolerates a variety of functional groups affording C(sp3)-C(sp2) cross-coupling products in good to moderate yields.

Direct SN2 or SN2X Manifold─Mechanistic Study of Ion-Pair-Catalyzed Carbon(sp3)-Carbon(sp3) Bond Formation.

Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp3)-carbon(sp3) bonds in a pentanidium-catalyzed substitution reaction. Computational mechanistic studies were carried out to investigate the proposed SN2X manifold, which consists of two primary elementary steps: halogen atom transfer (XAT) and subsequent SN2. For the first calculated model on original experimental substrates, XAT reaction barriers were more kinetically competitive than an SN2 pathway and connect to thermodynamically stable intermediates. Extensive computational screening modeling was then done on various substrate combinations designed to study the steric influence and to understand the mechanistic rationale, and calculations reveal that sterically congested substrates prefer the SN2X manifold over SN2. Different halides as leaving groups were also screened, and it was found that the reactivity increases in the order of I > Br > Cl > F, in agreement with the strength of C-X bonds. However, DFT modeling suggests that chlorides can be a viable substrate for the SN2X process, which should be further explored experimentally. ONIOM calculations on the full catalyst model predicted the correct stereochemical outcome, and further catalyst screening with cationic Me4N+ and K+ predicted that pentanidium is still the choice for SN2X C-C bond formation.

Merging Halogen-Atom Transfer (XAT) and Copper Catalysis for the Modular Suzuki-Miyaura-Type Cross-Coupling of Alkyl Iodides and Organoborons.

We report here a mechanistically distinct approach to achieve Suzuki–Miyaura-type cross-couplings between alkyl iodides and aryl organoborons. This process requires a copper catalyst but, in contrast with previous approaches based on palladium and nickel systems, does not utilizes the metal for the activation of the alkyl electrophile. Instead, this strategy exploits the halogen-atom-transfer ability of α-aminoalkyl radicals to convert secondary alkyl iodides into the corresponding alkyl radicals that then are coupled with aryl, vinyl, alkynyl, benzyl, and allyl boronate species. These novel coupling reactions feature a simple setup and conditions (1 h at room temperature) and facilitate access to privileged motifs targeted by the pharmaceutical sector.

Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis.

The formation of carbon-carbon bonds lies at the heart of synthetic organic chemistry and is widely applied to construct complex drugs, polymers, and materials. Despite its importance, catalytic carbonyl arylation remains comparatively underdeveloped, due to limited scope and functional group tolerance. Herein we disclose an umpolung strategy to achieve radical carbonyl arylation via dual catalysis. This redox-neutral approach provides a complementary method to construct Grignard-type products from (hetero)aryl bromides and aliphatic aldehydes, without the need for pre-functionalization. A sequential activation, hydrogen-atom transfer, and halogen atom transfer process could directly convert aldehydes to the corresponding ketyl-type radicals, which further react with aryl-nickel intermediates in an overall polarity-reversal process. This radical strategy tolerates─among others─acidic functional groups, heteroaryl motifs, and sterically hindered substrates and has been applied in the late-stage modification of drugs and natural products.

Photoredox Polyfluoroarylation of Alkyl Halides via Halogen Atom Transfer.

Polyfluoroarene moieties are of interest in medicinal chemistry, agrochemicals, and material sciences. Herein, we present the first polyfluoroarylation of unactivated alkyl halides via a halogen atom transfer process. This method converts primary, secondary, and tertiary alkyl halides into the respective polyfluoroaryl compounds in good yields in the presence of amide, carbamate, ester, aromatic, and sulfonamide moieties, including derivatives of complex bioactive molecules. Mechanistic work revealed that this transformation proceeds through an alkyl radical generated after the halogen atom transfer.

Catalytic defluorinative ketyl-olefin coupling by halogen-atom transfer.

Ketyl–olefin coupling reactions stand as one of the fundamental chemical transformations in synthetic chemistry and have been widely employed in the generation of complex molecular architectures and natural product synthesis. However, catalytic ketyl–olefin coupling, until the recent development of photoredox chemistry and electrosynthesis through single-electron transfer mechanisms, has remained largely undeveloped. Herein, we describe a new approach to achieve catalytic ketyl–olefin coupling reactions by a halogen-atom transfer mechanism, which provides innovative and efficient access to various gem-difluorohomoallylic alcohols under mild conditions with broad substrate scope. Preliminary mechanistic experimental and computational studies demonstrate that this radical-to-polar crossover transformation could be achieved by sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and β-fluoro elimination.

Silyl-mediated photoredox-catalyzed radical–radical cross-coupling reaction of alkyl bromides and ketoesters

A strategy for cross-coupling between organic bromides and carbonyl compounds is developed by combining photocatalysis and halogen atom transfer using a photocatalyst and tris(trimethylsilyl)silane.

Access to gem-Difluoroalkenes via Organic Photoredox-Catalyzed gem-Difluoroallylation of Alkyl Iodides.

An organic photoredox-catalyzed gem-difluoroallylation of α-trifluoromethyl alkenes with alkyl iodides via C-F bond cleavage for the synthesis of gem-difluoroalkene derivatives is reported. This transition-metal-free transformation utilized a readily available organic dye 4CzIPN as the sole photocatalyst and employed a common chemical N,N,N',N'-tetramethylethylenediamine as the radical activator of alkyl iodides via halogen-atom transfer. In addition, a variety of iodides, including primary, secondary, and tertiary alkyl iodides, were tolerated and provided good to high yields.

Application of α-Aminoalkyl Radicals as Reaction Activators

Abstractα-Aminoalkyl radicals are easily accessible through multiple pathways from various precursors. Apart from their utilization as nitrogen-containing building blocks, they have recently been used as halogen atom abstraction reagents or single-electron reductants to transform organic halides or sulfonium salts into their corresponding highly reactive radical species. Benefiting from the richness of various halides and the diverse reactivity of radical intermediates, new transformations of halides and sulfonium salts have been developed. This short review summarizes this emerging chemistry that uses α-aminoalkyl radicals as the reaction activators.1 Introduction2 Activation of Halides as Halogen-Atom Transfer Agents2.1 Addition to Unsaturated Bonds2.1.1 Addition to C=C Bonds2.1.2 Addition to C=O Bonds2.2 Substitution Reactions2.2.1 Deuteration2.2.2 Olefination2.2.3 Allylation2.2.4 Aromatic Substitution2.2.5 Amination3 Activation of Sulfonium Salts as Single-Electron Reductants4 Conclusion and Outlook

Applications of Halogen-Atom Transfer (XAT) for the Generation of Carbon Radicals in Synthetic Photochemistry and Photocatalysis.

The halogen-atom transfer (XAT) is one of the most important and applied processes for the generation of carbon radicals in synthetic chemistry. In this review, we summarize and highlight the most important aspects associated with XAT and the impact it has had on photochemistry and photocatalysis. The organization of the material starts with the analysis of the most important mechanistic aspects and then follows a subdivision based on the nature of the reagents used in the halogen abstraction. This review aims to provide a general overview of the fundamental concepts and main agents involved in XAT processes with the objective of offering a tool to understand and facilitate the development of new synthetic radical strategies.

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

Merging Halogen-Atom Transfer (XAT) and Cobalt Catalysis to Override E2-Selectivity in the Elimination of Alkyl Halides: A Mild Route toward contra-Thermodynamic Olefins.

We report here a mechanistically distinct tactic to carry E2-type eliminations on alkyl halides. This strategy exploits the interplay of α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with desaturative cobalt catalysis. The methodology is high-yielding, tolerates many functionalities, and was used to access industrially relevant materials. In contrast to thermal E2 eliminations where unsymmetrical substrates give regioisomeric mixtures, this approach enables, by fine-tuning of the electronic and steric properties of the cobalt catalyst, to obtain high olefin positional selectivity. This unprecedented mechanistic feature has allowed access to contra-thermodynamic olefins, elusive by E2 eliminations.

Precise Introduction of the -CHnX3-n (X = F, Cl, Br, I) Moiety to Target Molecules by a Radical Strategy: A Theoretical and Experimental Study.

Addition of halomethyl radicals to form bioactive molecules has recently become an efficient strategy. The reaction has a bottleneck, however, which is the effective and selective generation of the proper halomethyl •CHnX3-n radical by combining CHnX4-n with a carbon radical. Understanding the reactivity and selectivity of carbon radicals in the hydrogen atom transfer (HAT) and halogen atom transfer (XAT) reactions of CHnX4-n is key to the development of such an attractive method. With the help of the emerging data-driven strategy, DFT calculations were used to explore various correlations. For selectivity, the relative energy barriers between HAT and XAT reactions (ΔG⧧H - ΔG⧧X) correlate reasonably well with the three parameters ΔGH, ΔGX, and IP, and the correlation studies reveal that the calculated IPinver and the experimental ΔBDE can be used to conveniently predict the selectivity. Predicted selectivities are consistent with experimental determinations. This work not only provides a possibility for selecting carbon radicals with the known or easily obtained physicochemical data but also demonstrates that the informatic workflow such as generating data and identifying correlations has potential applications in mining reaction rules.

Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer

Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature. The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues. The SN2 reaction is essential in organic chemistry, but its substrate scope is limited. Now, a strategy based on halogen-atom transfer using α-aminoalkyl radicals and copper catalysis enables coupling of secondary alkyl iodides with N-nucleophiles with SN2-like programmability.

Late-Stage Heteroarylation of Hetero(aryl)sulfonium Salts Activated by α-Amino Alkyl Radicals.

We report a late‐stage heteroarylation of aryl sulfonium salts through activation with α‐amino alkyl radicals in a mechanistically distinct approach from previously reported halogen‐atom transfer (XAT). The new mode of activation of aryl sulfonium salts proceeds in the absence of light and photoredox catalysts, engaging a wide range of hetarenes. Furthermore, we demonstrate the applicability of this methodology in synthetically useful cross‐coupling transformations.