Activated Alkyl Halides Research Articles

Nickel‐Catalyzed α‐selective Hydroalkylation of Vinylarenes

AbstractC(sp3) centers adjacent to (hetero) aryl groups are widely present in physiologically active molecules. Metal‐hydride‐catalyzed hydroalkylation of alkenes represents an efficient means of forging C(sp3)−C(sp3) bonds, boasting advantages as a wide source of substrates, mild reaction conditions, and facile selectivity manipulation. Nevertheless, the hydroalkylation of vinylarenes encounters constraints in terms of substrate scope, necessitating the employment of activated alkyl halides or alkenes containing chelating groups, remains a challenge. In this context, we report a general nickel‐hydride‐catalyzed hydroalkylation protocol for vinylarenes. Remarkably, this system enables α‐selective hydroalkylation of both aryl and heteroaryl alkenes under an extra ligand‐free condition, demonstrating excellent coupling efficiency and selectivity. Furthermore, through the incorporation of chiral bisoxazoline ligands, we have achieved regio‐ and enantioselective hydroalkylation of vinylpyrroles, thereby facilitating the synthesis of α‐branched alkylated pyrrole derivatives.

Unveiling the Unique Reactivity of Anionic Mn(I) Complexes via Metal-Ligand Cooperation: Nucleophilic Attack on C(sp3)-X Bonds.

Metal-ligand cooperation (MLC) has emerged as a pivotal strategy for the catalytic activation of small molecules within both synthetic and biological arenas. Leveraging this approach, a suite of potent catalytic reactions─encompassing hydrogenation, hydroelementation, and dehydrogenative processes─have been realized, with notable advances in manganese catalysis in recent years. However, the activation of alkyl halides by Mn complexes, which typically requires strong reductants to form Mn(-I) complexes that are incompatible with standard cross-coupling conditions, remains a significant challenge. This limitation underscores the urgent need to investigate alternative methods for activating C(sp3)-X bonds using higher valence state Mn complexes. In response to this challenge, we present the synthesis, characterization, and reactivity of a new anionic Mn(I) complex featuring a redox-active dianionic ligand that induces multiple MLC functionalities. We have discovered an innovative mechanism of MLC, characterized by a single ligand transferring two electrons to the metal center. This novel process facilitates an orbital-symmetry-allowed nucleophilic attack on C(sp3)-X bonds, preserving manganese's oxidative state at +1. To the best of our knowledge, this is the first instance where the MLC strategy via a two-electron transfer process has been utilized to execute an SN2 nucleophilic attack at a C(sp3)-X bond by a relatively electron-deficient metal center like Mn(I). Additionally, the dianionic ligand of the anionic Mn(I) complex exhibits ambident nucleophilicity by reacting with different electrophiles, further highlighting its versatile reactivity.

Redox Activity and Potentials of Bidentate N-Ligands Commonly Applied in Nickel-Catalyzed Cross-Coupling Reactions.

Bidentate N-ligands are paramount to recent advances in nickel-catalyzed cross-coupling reactions. Through comprehensive organometallic, spectroscopic, and computational studies on bi-oxazoline and imidazoline ligands, we reveal that a square planar geometry enables redox activity of these ligands in stabilizing nickel radical species. This finding contrasts with the prior assumption that bi-oxazoline lacks redox activity due to strong mesomeric donation. Moreover, we conducted systematic cyclic voltammetry (CV) analyses of bidentate pyridyl, oxazoline, and imidazoline nitrogen ligands, along with their corresponding nickel complexes. Complexation with nickel shifts the reduction potentials to a more positive region and narrows the differences in redox potentials among the ligands. Additionally, various ligands led to different degrees of bromide dissociation from singly reduced (L)Ni(Ar)(Br) complexes, reflecting varying reactivity in the subsequent activation of alkyl halides, a crucial step in cross-electrophile coupling. These insights highlight the significant electronic effects of ligands on the stability of metalloradical species and their redox potentials, which interplay with coordination geometry. Quantifying the electron-donating, p-accepting properties of these ligands, as well as their effect on catalyst speciation, provides crucial benchmarks for controlling catalytic activity and enhancing catalyst stability.

Nickel-Catalyzed α-selective Hydroalkylation of Vinylarenes.

C(sp3) centers adjacent to (hetero)aryl groups are widely present in physiologically active molecules. Metal-hydride-catalyzed hydroalkylation of alkenes represents an efficient means of forging C(sp3)-C(sp3) bonds, boasting advantages as a wide source of substrates, mild reaction conditions, and facile selectivity manipulation. Nevertheless, the hydroalkylation of vinylarenes encounters constraints in terms of substrate scope, necessitating the employment of activated alkyl halides or alkenes containing chelating groups, remains a challenge. In this context, we report a general nickel-hydride-catalyzed hydroalkylation protocol for vinylarenes. Remarkably, this system enables α-selective hydroalkylation of both aryl and heteroaryl alkenes under an extra ligand-free condition, demonstrating excellent coupling efficiency and selectivity. Furthermore, through the incorporation of chiral bisoxazoline ligands, we have achieved regio- and enantioselective hydroalkylation of vinylpyrroles, thereby facilitating the synthesis of α-branched alkylated pyrrole derivatives.

Tailoring the Degradation of Cyanoarene‐Based Photocatalysts for Enhanced Visible‐Light‐Driven Halogen Atom Transfer

AbstractWe present the strategic design of donor‐acceptor cyanoarene‐based photocatalysts (PCs) aiming to augment beneficial PC degradation for halogen atom transfer (XAT)‐induced dehalogenation reactions. Our investigation reveals a competitive nature between the catalytic cycle and the degradation pathway, with the degradation becoming dominant, particularly for less activated alkyl halides. The degradation behavior of PCs significantly impacts the efficiency of the XAT process, leading to exploration into manipulating the degradation behavior in a desirable direction. Recognizing the variation in the nature and rate of PC degradation, as well as its influence on the reaction across the range of PC structures, we carefully engineered the PCs to develop a pre‐catalyst, named 3DP‐DCDP‐IPN. This pre‐catalyst undergoes rapid degradation into an active form, 3DP‐DCDP‐Me‐BN, exhibited an enhanced reducing ability in its radical anion form to induce better PC regeneration and consequently effectively catalyzes the XAT reaction, even with a challenging substrate.

Tailoring the Degradation of Cyanoarene-Based Photocatalysts for Enhanced Visible-Light-Driven Halogen Atom Transfer.

We present the strategic design of donor-acceptor cyanoarene-based photocatalysts (PCs) aiming to augment beneficial PC degradation for halogen atom transfer (XAT)-induced dehalogenation reactions. Our investigation reveals a competitive nature between the catalytic cycle and the degradation pathway, with the degradation becoming dominant, particularly for less activated alkyl halides. The degradation behavior of PCs significantly impacts the efficiency of the XAT process, leading to exploration into manipulating the degradation behavior in a desirable direction. Recognizing the variation in the nature and rate of PC degradation, as well as its influence on the reaction across the range of PC structures, we carefully engineered the PCs to develop a pre-catalyst, named 3DP-DCDP-IPN. This pre-catalyst undergoes rapid degradation into an active form, 3DP-DCDP-Me-BN, exhibited an enhanced reducing ability in its radical anion form to induce better PC regeneration and consequently effectively catalyzes the XAT reaction, even with a challenging substrate.

Electrochemically Mediated Atom Transfer Radical Polymerization Driven by Alternating Current.

Alternating current (AC) and pulsed electrolysis are gaining traction in electro(organic) synthesis due to their advantageous characteristics. We employed AC electrolysis in electrochemically mediated Atom Transfer Radical Polymerization (eATRP) to facilitate the regeneration of the activator CuI complex on Cu0 electrodes. Additionally, Cu0 served as a slow supplemental activator and reducing agent (SARA ATRP), enabling the activation of alkyl halides and the regeneration of the CuI activator through a comproportionation reaction. We harnessed the distinct properties of Cu0 dual regeneration, both chemical and electrochemical, by employing sinusoidal, triangular, and square-wave AC electrolysis alongside some of the most active ATRP catalysts available. Compared to linear waveform (DC electrolysis) or SARA ATRP (without electrolysis), pulsed and AC electrolysis facilitated slightly faster and more controlled polymerizations of acrylates. The same AC electrolysis conditions could successfully polymerize eleven different monomers across different mediums, from water to bulk. Moreover, it proved effective across a spectrum of catalyst activity, from low-activity Cu/2,2-bipyridine to highly active Cu complexes with substituted tripodal amine ligands. Chain extension experiments confirmed the high chain-end fidelity of the produced polymers, yielding functional and high molecular-weight block copolymers. SEM analysis indicated the robustness of the Cu0 electrodes, sustaining at least 15 consecutive polymerizations.

Electrochemically Mediated Atom Transfer Radical Polymerization Driven by Alternating Current

AbstractAlternating current (AC) and pulsed electrolysis are gaining traction in electro(organic) synthesis due to their advantageous characteristics. We employed AC electrolysis in electrochemically mediated Atom Transfer Radical Polymerization (eATRP) to facilitate the regeneration of the activator CuI complex on Cu0 electrodes. Additionally, Cu0 served as a slow supplemental activator and reducing agent (SARA ATRP), enabling the activation of alkyl halides and the regeneration of the CuI activator through a comproportionation reaction. We harnessed the distinct properties of Cu0 dual regeneration, both chemical and electrochemical, by employing sinusoidal, triangular, and square‐wave AC electrolysis alongside some of the most active ATRP catalysts available. Compared to linear waveform (DC electrolysis) or SARA ATRP (without electrolysis), pulsed and AC electrolysis facilitated slightly faster and more controlled polymerizations of acrylates. The same AC electrolysis conditions could successfully polymerize eleven different monomers across different mediums, from water to bulk. Moreover, it proved effective across a spectrum of catalyst activity, from low‐activity Cu/2,2‐bipyridine to highly active Cu complexes with substituted tripodal amine ligands. Chain extension experiments confirmed the high chain‐end fidelity of the produced polymers, yielding functional and high molecular‐weight block copolymers. SEM analysis indicated the robustness of the Cu0 electrodes, sustaining at least 15 consecutive polymerizations.

Anti‐Selective Carbosilylation: Nickel‐Catalyzed Multicomponent Reaction of Solid Me3SiZnI

AbstractThe stereodefined and highly substituted vinylsilanes are essential building blocks for constructing complex organic molecules. Transition metal‐mediated silylmetalation of alkynes was developed to overcome the limitations of conventional hydrosilylations; however, a very limited study was carried out to utilize transient vinylmetal species in cross‐coupling reactions. Moreover, they produce syn‐adduct, and the anti‐selective cross‐coupling is still unknown and highly desired. Silylzinc reagents are highly functional group tolerant, however, their synthesis from pyrophoric silyllithium and dissolved lithium salts hampers cross‐coupling reactions. Our novel solid silylzinc reagents circumvent these constraints are employed in the anti‐selective synthesis of vinylsilanes via a multi‐component reaction involving Me3SiZnI, terminal alkynes, and activated alkyl halides. An intensive computational and experimental investigation of the mechanism reveals an equilibrium between the intermediate syn‐ and anti‐adducts; the greater barrier at the single electron reduction of alkyl halides and the thermodynamic stability of the Ni(III) adduct determine the anti‐selectivity.

Electrochemically Driven para-Selective C(sp2)-H Alkylation Enabled by Activation of Alkyl Halides without Sacrificial Anodes.

With alkyl halides (I, Br, Cl) as a coupling partner, an electrochemically driven strategy for para-selective C(sp2)-H alkylation of electron-deficient arenes (aryl esters, aldehydes, nitriles, and ketones) has been achieved to access diverse alkylated arenes in one step. The reaction enables the activation of alkyl halides in the absence of sacrificial anodes, achieving the formation of C(sp2)-C(sp3) bonds under mild electrolytic conditions. The utility of this protocol is reflected in high site selectivity, broad substrate scope, and scalable.

Visible-light-induced alkyl-arylation of olefins via a halogen-atom transfer process.

Visible-light-induced three-component 1,2-alkyl-arylation of alkenes and alkyl radical addition/cyclization of acrylamides have been realized via a photocatalytic halogen-atom transfer (XAT) process. This metal-free protocol utilizes readily available tertiary alkylamine as both an electron donor and an XAT reagent for the activation of alkyl halides using naphthalimide (NI)-based organic photocatalysts. This process features broad substrate scope and good functional group tolerance under mild conditions, and could be effectively applied to a variety of medicinally relevant substrates.

Mechanochemical reduction of alkyl and aryl halides using mesoporous zinc oxide.

In this study, we propose a mechanochemical approach that combines mesoporous ZnO (m-ZnO) as a mechanoredox catalyst and silane-mediated atom transfer chemistry to achieve efficient hydrodehalogenation of organic halides. The reaction can be conducted under mild conditions without the use of a large amount of organic solvent. Substrates ranging from activated alkyl halides to unactivated aryl halides were converted to the corresponding debrominated hydrogenation products in moderate to excellent isolated yields (50-95%). In addition, m-ZnO can be recycled and reused without appreciable loss of catalytic activity.

Palladium-catalyzed carbonylation of activated alkyl halides via radical intermediates

In this review, we summarize and discuss recent achievements in palladium-catalyzed carbonylative reactions of activated alkyl halides. Aliphatic carboxylic acid derivates were prepared effectively with various nucleophiles.

Photocatalyzed Amination of Alkyl Halides to Access Primary Amines.

We demonstrate that oxime ester derivatives can be used as both a halogen atom transfer (XAT) agent and an imine source under photocatalytic conditions, allowing the radical amination of alkyl halides, resulting in the formation of a broad scope of imines. Hydrolysis of the latter gives direct access to the corresponding primary amines. Mechanistically, the reaction is believed to proceed through the formation of aryl radical intermediates, which are responsible for the activation of alkyl halides via XAT.

Trinuclear Gold-Catalyzed 1,2-Difunctionalization of Alkenes.

Activated alkyl halides have been extensively explored to generate alkyl radicals with Ru- and Ir- photocatalysts for 1,2-difunctionalization of alkenes, but unactivated alkyl bromides remain challenging substrates due to their strong reduction potential. Here we report a three-component 1,2-difunctionalization reaction of alkenes, unactivated alkyl bromides and nucleophiles (e.g., amines and indoles) using a trinuclear gold catalyst [Au3 (tppm)2 ](OTf)3 . It can achieve the 1,2-aminoalkylation and 1,2-alkylarylation readily. This protocol has a broad reaction scope and excellent functional group compatibility (>100 examples with up to 96 % yield). It also affords a robust formal [2+2+1] cyclization strategy for the concise construction of pyrrolidine skeletons under mild reaction conditions. Mechanistic studies support an inner-sphere single electron transfer pathway for the successful cleavage of inert C-Br bonds.

Bifunctional Fluorescent Probes for the Detection of Mustard Gas and Phosgene

Mustard gas [sulfur mustard (SM)] and phosgene are the most frequently used chemical warfare agents (CWAs), which pose a serious threat to human health and national security, and their rapid and accurate detection is essential to respond to terrorist attacks and industrial accidents. Herein, we developed a fluorescent probe with o-hydroxythioketone as two sensing sites, AQso, which can detect and distinguish mustard gas and phosgene. The dual-sensing-site probe AQso reacts with mustard gas to form a cyclic product with high sensitivity [limit of detection (LOD) = 70 nM] and is highly selective to SM over phosgene, SM analogues, active alkylhalides, acylhalides, and nerve agent mimics, in ethanol solutions. When encountering phosgene, AQso rapidly converts to cyclic carbonate, which is sensitive (LOD = 14 nM) and highly selective. Their sensing mechanisms of AQso to mustard gas and phosgene were well demonstrated by separation and characterization of the sensing products. Furthermore, a facile test strip with the probe was prepared to distinguish 2-chloroethyl ethyl sulfide (CEES) and phosgene in the gas phase by different fluorescence colors and response rates. Not using the complicated instrument, the qualitative and quantitative detection of CEES or phosgene can be achieved only by measuring the red-green-blue (RGB) channel intensity of the test strip after being exposed to CEES or phosgene gas by the smartphone with an RGB color application.

Photomediated Tandem Sulfonyl Addition-Chemoselective N-Cyclization of o-Alkenyl Aryl Ureas: Direct Assembly of Functionalized Dihydroquinazolinones.

Photoredox-mediated tandem addition-chemoselective cyclization of o-alkenyl aryl ureas is reported for the synthesis of sulfonyl and activated alkyl-decorated dihydroquinazolinones. By a careful choice of o-alkenyl aryl urea starting materials, we achieved chemoselective N-cyclization in the presence of more reactive amidic oxygen. We have demonstrated the scope of the methodology with a variety of sulfonyl chlorides and activated alkyl halides. Finally, large-scale synthesis of sulfonyl-substituted dihydroquinazolinone showcases the synthetic utility of the methodology.

Electrochemical Trifluoromethylselenolation of Activated Alkyl Halides

AbstractA practical electrochemical method for the generation of CF3Se− anion from a shelf‐stable reagent (TsSeCF3) is reported allowing the metal‐free trifluoromethylselenolation of activated alkyl halides. Trifluoromethylselenolated compounds have been obtained in modest to excellent yields under the optimized reaction conditions. Finally, cyclic voltammetric and 19F NMR studies are presented and allowed to gain insight into the reaction mechanism.

Electrochemically driven cross-electrophile coupling of alkyl halides.

Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp3 carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of carbon(sp3)-carbon(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective3-5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp3)-carbon(sp3) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst,and shows improved chemoselectivity compared with existing methods.

Synthesis of 4-O-Alkylated N-Acetylneuraminic Acid Derivatives.

The synthesis of 4-O-alkyl analogues of N-acetylneuraminic acid (Neu5Ac) and the scope of the reaction are described. Activated alkyl halides and sulfonates and primary alkyl iodides give products in useful yields. The utility of the methodology is exemplified using a thiophenyl Neu5Ac building block to synthesize a 4-O-alkyl DANA analogue. These results expand the toolbox of Neu5Ac chemistry with value in drug discovery and for the design of novel tools to study the biology of Neu5Ac lectins.