Unactivated Alkyl Halides Research Articles

Enantioselective C(sp3)–C(sp3) Reductive Cross-Electrophile Coupling of Unactivated Alkyl Halides with α-Chloroboronates via Dual Nickel/Photoredox Catalysis

Substantial advances in enantioconvergent C(sp3)-C(sp3) bond formations have been made with nickel-catalyzed cross-coupling of racemic alkyl electrophiles with organometallic reagents or nickel-hydride-catalyzed hydrocarbonation of alkenes. Herein, we report an unprecedented enantioselective C(sp3)-C(sp3) reductive cross-coupling by the direct utilization of two different alkyl halides with dual nickel/photoredox catalysis system. This highly selective coupling of racemic α-chloroboronates and unactivated alkyl iodides furnishes chiral secondary alkyl boronic esters, which serve as useful and important intermediates in the realm of organic synthesis and enable a desirable protocol to fast construction of enantioenriched complex molecules.

Electrochemical nickel-catalysed defluoroalkylation ofgem-difluoroalkenes with alkyl halides

Herein, a direct and efficient electrochemical method for the synthesis of monofluoroalkene products was promoted usinggem-difluoroalkenes and unactivated alkyl halides as starting materials with a nickel catalyst.

1,2-Aminoxyalkylation of alkenes with alkyl iodides and TEMPONa through SET- and XAT-processes.

1,2-Aminoxyalkylation of alkenes with alkyl iodides and TEMPONa in combination with an aryldiazonium salt as an XAT mediator is reported. Various primary, secondary and tertiary alkyl iodides engage as C-radical precursors in the 1,2-aminoxyalkylation with electrophilic alkenes as radical acceptors. The product alkoxyamines are readily transformed to the corresponding alcohols or ketones upon reduction or oxidation, respectively. Mechanistic investigations reveal that aryl radicals, generated through SET-reduction of the aryl diazonium salt with TEMPONa, engage in XAT from unactivated alkyl halides to give alkyl radicals that can add to alkenes. Trapping of the adduct radicals with TEMPO provides the 1,2-aminoxyalkylation products. Transition metals are not required for these transformations that are conducted under mild conditions. Perfluoroalkyl halides directly react with TEMPONa and an aryldiazonium salt as XAT-mediator is not required for alkene 1,2-aminoxyperfluoroalkylation.

Cathodic Carbonyl Alkylation of Aryl Ketones or Aldehydes with Unactivated Alkyl Halides.

An efficient cathodic carbonyl alkylation of aryl ketones or aldehydes with unactivated alkyl halides has been realized through the electrochemical activation of iron. The protocol is believed to include a radical-radical coupling or nucleophilic addition process, and the formation of ketyl radicals and alkyl radicals has been demonstrated. The protocol provides various tertiary or secondary alcohols by the formation of intermolecular C-C bonds under safe and mild conditions, is scalable, consumes little energy, and exhibits a broad substrate scope.

Photoredox cooperative N-heterocyclic carbene/palladium-catalysed alkylacylation of alkenes

Three-component carboacylation of simple alkenes with readily available reagents is challenging. Transition metal-catalysed intermolecular carboacylation works for alkenes with strained ring or directing groups. Herein, we develop a photoredox cooperative N-heterocyclic carbene/Pd-catalysed alkylacylation of simple alkenes with aldehydes and unactivated alkyl halides to provide ketones in good yields. This multicomponent coupling reaction features a wide scope of alkenes, broad functional group compatibility and free of exogenous photosensitizer or external reductant. In addition, a series of chlorinated cyclopropanes with one or two vicinal quaternary carbons is obtained when chloroform or carbon tetrachloride is used as the alkyl halide. The reaction involves the alkyl radicals from halides and the ketyl radicals from aldehydes under photoredox cooperative N-heterocyclic carbene/Pd catalysis.

Green and efficient synthesis of chiral amines and hydroxylamines by indium (zinc)-copper-mediated alkylation reaction in aqueous media

A simple and environmentally friendly method for the alkylation of various chiral nitrones in water using unactivated alkyl halides has been developed. Both the chiral amines and hydroxylamines could be obtained with superior yields and high diastereoselectivity, with a wise choice of different metal complexes. The novelly developed reaction has the characteristics of environmental protection, simple operating, high efficiency, and regioselectivity superbly.

Nickel-Catalyzed, Manganese-Assisted Denitrogenative Cross-Electrophile-Coupling of Benzotriazinones with Alkyl Halides for ortho-Alkylated Benzamides.

A nickel-catalyzed denitrogenative cross-electrophile-coupling of benzotriazinones with unactivated alkyl halides (X = Cl, Br, I) in the presence of manganese powder as a reductant has been developed. The reaction furnishes ortho-alkylated secondary benzamides in modest to good yields under mild conditions. The scope of the reaction is demonstrated with 25 examples, showing good tolerance of steric hindrance and common functional groups, thus providing an efficient protocol to ortho-alkylated benzamide derivatives without the use of preprepared organometallic reagents.

Ligand-Controlled Cobalt-Catalyzed Regiodivergent Alkyne Hydroalkylation.

Regiodivergent alkyne hydroalkylation to generate different isomers of an alkene from the same alkyne starting material would be beneficial; however, it remains a challenge. Herein, we report a ligand-controlled cobalt-catalyzed regiodivergent alkyne hydroalkylation. The sensible selection of bisoxazoline (L1) and pyridine-oxazoline (L8) ligands led to reliable and predictable protocols that provided (E)-1,2-disubstituted and 1,1-disubstituted alkenes with high E/Z stereoselectivity and regioisomeric ratio starting from identical terminal alkyne and alkyl halide substrates and produced trisubstituted alkenes in the case of internal alkynes. This method exhibits a broad scope for terminal and internal alkynes with a wide range of activated and unactivated alkyl halides and shows excellent functional group compatibility.

Facile and general electrochemical deuteration of unactivated alkyl halides

Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using D2O as the economical deuterium source was reported. In addition to primary and secondary alkyl halides, sterically hindered tertiary chlorides also work very well, affording the target deuterodehalogenated products with excellent efficiency and deuterium incorporation. More than 60 examples are provided, including late-stage dehalogenative deuteration of natural products, pharmaceuticals, and their derivatives, all with excellent deuterium incorporation (up to 99% D), demonstrating the potential utility of the developed method in organic synthesis. Furthermore, the method does not require external catalysts and tolerates high current, showing possible use in industrial applications.

Nickel‐Catalyzed Reductive Acylation of Carboxylic Acids with Alkyl Halides and N‐Hydroxyphthalimide Esters Enabled by Electrochemical Process

AbstractA sustainable Ni‐catalyzed reductive acylation reaction of carboxylic acids via an electrochemical pathway is presented, affording a variety of ketones as major products. The reaction proceeds at ambient temperature using unactivated alkyl halides and N‐hydroxyphthalimide (NHP) esters as coupling partners, which exhibits several synthetic advantages, including mild conditions and convenience of amplification (58% yield for 6 mmol scale reaction).magnified image

Access to 3-alkylselenindoles by multicomponent reaction of indoles, selenium powder and unactivated alkyl halides under transition-metal-free conditions

Herein, we reported a convenient and efficient multicomponent reaction of indoles, selenium powder and unactivated alkyl halides. This protocol provides a practical, and facile approach for the synthesis of 3-alkylselenindole derivatives. The advantages of this strategy include mild and transition-metal-free conditions, broad functional group tolerance, the use of simple and easily accessible seleniium powder and alkyl halides as coupling partners. More importantly, the reaction proceeded smoothly with a large scale (>10 g, >90% yield), which further highlighted the potential application of this selenation strategy.

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.

Nickel-catalyzed electrochemical carboxylation of unactivated aryl and alkyl halides with CO2

Electrochemical catalytic reductive cross couplings are powerful and sustainable methods to construct C−C bonds by using electron as the clean reductant. However, activated substrates are used in most cases. Herein, we report a general and practical electro-reductive Ni-catalytic system, realizing the electrocatalytic carboxylation of unactivated aryl chlorides and alkyl bromides with CO2. A variety of unactivated aryl bromides, iodides and sulfonates can also undergo such a reaction smoothly. Notably, we also realize the catalytic electrochemical carboxylation of aryl (pseudo)halides with CO2 avoiding the use of sacrificial electrodes. Moreover, this sustainable and economic strategy with electron as the clean reductant features mild conditions, inexpensive catalyst, safe and cheap electrodes, good functional group tolerance and broad substrate scope. Mechanistic investigations indicate that the reaction might proceed via oxidative addition of aryl halides to Ni(0) complex, the reduction of aryl-Ni(II) adduct to the Ni(I) species and following carboxylation with CO2.

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

AbstractThe engagement of unactivated alkyl halides in copper‐catalyzed cross‐coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper‐catalyzed Negishi‐type cross‐coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi‐type difluoromethylation approach has been applied to the late‐stage modification of densely functionalized pharmaceutical agents and natural products.

Copper-Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon-Iodine Bonds.

The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper-catalyzed Negishi-type cross-coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon-iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi-type difluoromethylation approach has been applied to the late-stage modification of densely functionalized pharmaceutical agents and natural products.

Dynamic multiligand catalysis: A polar to radical crossover strategy expands alkyne carboboration to unactivated secondary alkyl halides

<h2>Summary</h2> We describe a dual strategy in Cu catalysis based on an unprecedented dynamic multiligand coordination pool that triggers cooperative polar/radical pathways in a single catalytic cycle. This strategy has been applied to address a restricting limitation inherent to Cu-catalyzed B₂pin₂-carboboration of alkynes—the very low reactivity of the intermediate vinyl-Cu(I) species, which renders conventional methods ineffective with alkyl electrophiles other than simple primary halides. The crossover strategy enabled by ligand exchange in an organometallic intermediate overcomes this reactivity issue, expanding the scope of carboboration to unactivated secondary alkyl halides, and opens new avenues to access stereodefined tetrasubstituted vinylboronates. The method is regio- and stereoselective, shows excellent functional group tolerance, and allows the incorporation of complex carbo- and heterocyclic fragments at either reaction partner.

Diversity‐Oriented Synthesis of Aliphatic Fluorides via Reductive C(sp3)−C(sp3) Cross‐Coupling Fluoroalkylation

AbstractMonofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel‐catalyzed monofluoromethylation of unactivated alkyl halides using a low‐cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross‐coupling of two alkyl halides. Results with 1‐bromo‐1‐fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp3)‐C(sp3) cross‐coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional‐group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first‐order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate‐determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.

Diversity-Oriented Synthesis of Aliphatic Fluorides via Reductive C(sp3 )-C(sp3 ) Cross-Coupling Fluoroalkylation.

Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel-catalyzed monofluoromethylation of unactivated alkyl halides using a low-cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross-coupling of two alkyl halides. Results with 1-bromo-1-fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp3 )-C(sp3 ) cross-coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional-group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first-order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate-determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.

Unactivated Alkyl Halides in Transition-Metal-Catalyzed C–H Bond Alkylation

Alkylation represents an important organic transformation in molecular science to develop privileged alkylated arenes and heteroarenes. Especially, the direct C–H bond alkylation using unactivated ...

Dynamic Multiligand Catalysis: A Closed/Open Shell Crossover Strategy Expands Alkyne Carboboration to Unactivated Secondary Alkyl Halides

We describe a dual strategy in Cu catalysis based on an unprecedented dynamic multiligand coordination pool that enables cooperative closed/open shell pathways. This strategy has been applied to address a restricting limitation inherent to Cu-catalyzed B2(pin)2-carboboration of alkynes: conventional methods usually fail with alkyl electrophiles other than simple primary halides due to the very low reactivity of the intermediate vinyl-Cu(I) species. The crossover strategy enabled by ligand exchange in an organometallic intermediate overcomes this reactivity issue, thus expanding the scope of carboboration to unactivated secondary alkyl halides and opening new avenues to access of stereodefined tetrasubstituted vinylboronates. The method is regio- and stereoselective, shows excellent functional group tolerance, and allows the incorporation of complex carbo- and heterocyclic fragments at either reaction partner.