Nickel‐Catalyzed Umpolung Arylation of Ambiphilic α‐Bromoalkyl Boronic Esters

A nickel‐catalyzed reductive arylation of ambiphilic α‐bromoalkyl boronic esters with aryl halides is described. This platform provides an unrecognized opportunity to promote the catalytic umpolung reactivity of ambiphilic reagents with aryl halides, thus unlocking a new cross‐coupling strategy that complements existing methods for the preparation of densely functionalized alkyl‐substituted organometallic reagents from simple and readily accessible precursors.     

Nickel‐Catalyzed Chain‐Walking Cross‐Electrophile Coupling of Alkyl and Aryl Halides and Olefin Hydroarylation Enabled by Electrochemical Reduction

The first electrochemical approach for nickel‐catalyzed cross‐electrophile coupling was developed. This method provides a novel route to 1,1‐diarylalkane derivatives from simple and readily available alkyl and aryl halides in good yields and excellent regioselectivity under mild conditions. The procedure shows good tolerance for a broad variety of functional groups and both primary and secondary alkyl halides can be used. Furthermore, the reaction was successfully scaled up to the multigram scale, thus indicating potential for industrial application. Mechanistic investigation suggested the formation of a nickel hydride in the electroreductive chain‐walking arylation, which led to the development of a new nickel‐catalyzed hydroarylation of styrenes to provide a series of 1,1‐diaryl alkanes in good yields under mild reaction conditions.     

Preparation of Vinyl Arenes by Nickel‐Catalyzed Reductive Coupling of Aryl Halides with Vinyl Bromides

This work emphasizes the synthesis of substituted vinyl arenes by reductive coupling of aryl halides with vinyl bromides under mild and easy‐to‐operate nickel‐catalyzed reaction conditions. A broad range of aryl halides, including heteroaromatics, and vinyl bromides were employed to yielding products in moderate to excellent yields with high functional‐group tolerance. The nickel‐catalytic system displays good chemoselectivity between the two C(sp²)‐halide coupling partners, thus demonstrating a mechanistic pathway distinct from other stepwise protocols.     

Nickel/Photoredox‐Catalyzed Asymmetric Reductive Cross‐Coupling of Racemic α‐Chloro Esters with Aryl Iodides

A unique nickel/organic photoredox co‐catalyzed asymmetric reductive cross‐coupling between α‐chloro esters and aryl iodides is developed. This cross‐electrophile coupling reaction employs an organic reductant (Hantzsch ester), whereas most reductive cross‐coupling reactions use stoichiometric metals. A diverse array of valuable α‐aryl esters is formed under these conditions with high enantioselectivities (up to 94 %) and good yields (up to 88 %). α‐Aryl esters represent an important family of nonsteroidal anti‐inflammatory drugs. This novel synergistic strategy expands the scope of Ni‐catalyzed reductive asymmetric cross‐coupling reactions.     

Computational Insight into Nickel‐Catalyzed Carbon–Carbon versus Carbon–Boron Coupling Reactions of Primary,Secondary, and Tertiary Alkyl Bromides

The nickel‐catalyzed alkyl–alkyl cross‐coupling (C?C bond formation) and borylation (C?B bond formation) of unactivated alkyl halides reported in the literature show completely opposite reactivity orders in the reactions of primary, secondary, and tertiary alkyl bromides. The proposed Ni^I/Ni^III catalytic cycles for these two types of bond‐formation reactions were studied computationally by means of DFT calculations at the B3LYP level. These calculations indicate that the rate‐determining step for alkyl–alkyl cross‐coupling is the reductive elimination step, whereas for borylation the rate is determined mainly by the atom‐transfer step. In borylation reactions, the boryl ligand involved has an empty p orbital, which strongly facilitates the reductive elimination step. The inability of unactivated tertiary alkyl halides to undergo alkyl–alkyl cross‐coupling is mainly due to the moderately high reductive elimination barrier.     

Nickel‐ and Photoredox‐Catalyzed Cross‐Coupling Reactions of Aryl Halides with 4‐Alkyl‐1,4‐dihydropyridines as Formal Nucleophilic Alkylation Reagents

A combination of nickel and photoredox catalysts promoted novel cross‐coupling reactions of aryl halides with 4‐alkyl‐1,4‐dihydropyridines. 4‐Alkyl‐1,4‐dihydropyridines act as formal nucleophilic alkylation reagents through a photoredox‐catalyzed carbon–carbon (C?C) bond‐cleavage process. The present strategy provides an alternative to classical carbon‐centered nucleophiles, such as organometallic reagents.     

Expedient Synthesis of Chiral α‐Amino Acids through Nickel‐Catalyzed Reductive Cross‐Coupling

A novel method for the synthesis of non‐natural L ‐ and D ‐amino acids by a Ni‐catalyzed reductive cross‐coupling reaction is described. This strategy enables the racemization‐free cross‐coupling of serine/homoserine‐ derived iodides with aryl/acyl/alkyl halides. It provides convenient access to varieties of enantiopure and functionalized amino acids, which are important building blocks in bioactive compounds and pharmaceuticals.     

Visible‐Light‐Promoted Nickel‐ and Organic‐Dye‐Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent

A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel‐ and organic‐dye‐mediated photoredox catalysis is reported. Distinct from widely used palladium‐catalyzed formylation processes, this reaction proceeds by a two‐step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN‐mediated photoredox reaction. The formyl‐radical equivalent then undergoes nickel‐catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products. Significantly, besides aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. Since the mild conditions involved in this reaction tolerate a plethora of functional groups, the process can be applied to the efficient preparation of diverse aromatic aldehydes.     

Metal‐Catalyzed Reductive Coupling Reactions of Organic Halides with Carbonyl‐Type Compounds

Metal‐catalyzed reductive coupling reactions of aryl halides and (pseudo)halides with carbonyl‐type compounds have undergone an impressive development within the last years. These methodologies have shown to be a powerful alternate strategy, practicality aside, to the use of stoichiometric, well‐defined, and, in some cases, air‐sensitive organometallic species. In this Minireview, the recent findings in this field are summarized, with particular emphasis on the mechanistic interpretation of the results and future aspects of this area of expertise.     

Nickel‐Catalyzed Electrochemical Reductive Relay Cross‐Coupling of Alkyl Halides to Aryl Halides

A highly regioselective Ni‐catalyzed electrochemical reductive relay cross‐coupling between an aryl halide and an alkyl halide has been developed in an undivided cell. Various functional groups are tolerated under these mild reaction conditions, which provides an alternative approach for the synthesis of 1,1‐diarylalkanes.     

Highly Chemoselective Iridium Photoredox and Nickel Catalysis for the Cross‐Coupling of Primary Aryl Amines with Aryl Halides

A visible‐light‐promoted iridium photoredox and nickel dual‐catalyzed cross‐coupling procedure for the formation C?N bonds has been developed. With this method, various aryl amines were chemoselectively cross‐coupled with electronically and sterically diverse aryl iodides and bromides to forge the corresponding C?N bonds, which are of high interest to the pharmaceutical industries. Aryl iodides were found to be a more efficient electrophilic coupling partner. The coupling reactions were carried out at room temperature without the rigorous exclusion of molecular oxygen, thus making this newly developed Ir‐photoredox/Ni dual‐catalyzed procedure very mild and operationally simple.     

Nickel‐Catalyzed Carbofluoroalkylation of 1,3‐Enynes to Access Structurally Diverse Fluoroalkylated Allenes

A nickel‐catalyzed 1,4‐carbofluoroalkylation of 1,3‐enynes to access structurally diverse fluoroalkylated allenes has been established. This method has demonstrated high catalytic reactivity, mild reaction conditions, broad substrate scope, and excellent functional‐group tolerance. The key to success is the use of a nickel catalyst to generate different fluoroalkyl radicals from readily available and structurally diverse fluoroalkyl halides to access 1,4‐difunctionalization of 1,3‐enynes by a radical relay. This strategy provides facile synthesis of structurally diverse multisubstituted allenes, and offers a solution for batch production of various fluorinated bioactive molecules for drug discovery by further transformations.     

On the Radical Nature of Iron‐Catalyzed Cross‐Coupling Reactions

The radical nature of iron‐catalyzed cross‐coupling between Grignard reagents and alkyl halides has been studied by using a combination of competitive kinetic experiments and DFT calculations. In contrast to the corresponding coupling with aryl halides, which commences through a classical two‐electron oxidative addition/reductive elimination sequence, the presented data suggest that alkyl halides react through an atom‐transfer‐initiated radical pathway. Furthermore, a general iodine‐based quenching methodology was developed to enable the determination of highly accurate concentrations of Grignard reagents, a capability that facilitates and increases the information output of kinetic investigations based on these substrates.     

Intra‐ and Intermolecular Nickel‐Catalyzed Reductive Cross‐Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides

Nickel‐catalyzed cross‐electrophile coupling reactions of benzylic esters and aryl halides have been developed. Both inter‐ and intramolecular variants proceed under mild reaction conditions. A range of heterocycles and functional groups are tolerated under the reaction conditions. Additionally, the first example of a stereospecific cross‐electrophile coupling of a secondary benzylic ester is described.     

Stereoselective Csp3−Csp2 Cross‐Couplings of Chiral Secondary Alkylzinc Reagents with Alkenyl and Aryl Halides

We report palladium‐catalyzed cross‐coupling reactions of chiral secondary non‐stabilized dialkylzinc reagents, prepared from readily available chiral secondary alkyl iodides, with alkenyl and aryl halides. This method provides α‐chiral alkenes and arenes with very high retention of configuration (dr up to 98:2) and satisfactory overall yields (up to 76 % for 3 reaction steps). The configurational stability of these chiral non‐stabilized dialkylzinc reagents was determined and exceeded several hours at 25 °C. DFT calculations were performed to rationalize the stereoretention during the catalytic cycle. Furthermore, the cross‐coupling reaction was applied in an efficient total synthesis of the sesquiterpenes (S)‐ and (R)‐curcumene with control of the absolute stereochemistry.     

A Metallaphotoredox Strategy for the Cross‐Electrophile Coupling of α‐Chloro Carbonyls with Aryl Halides

Here, we demonstrate that a metallaphotoredox‐catalyzed cross‐electrophile coupling mechanism provides a unified method for the α‐arylation of diverse activated alkyl chlorides, including α‐chloroketones, α‐chloroesters, α‐chloroamides, α‐chlorocarboxylic acids, and benzylic chlorides. This strategy, which is effective for a wide variety of aryl bromide coupling partners, is predicated upon a halogen atom abstraction/nickel radical‐capture mechanism that is generically successful across an extensive range of carbonyl substrates. The construction and use of arylacetic acid products have further enabled two‐step protocols for the delivery of valuable building blocks for medicinal chemistry, such as aryldifluoromethyl and diarylmethane motifs.     

Phosphonium Salts as Pseudohalides: Regioselective Nickel‐Catalyzed Cross‐Coupling of Complex Pyridines and Diazines

Heterobiaryls are important pharmacophores that are challenging to prepare by traditional cross‐coupling methods. An alternative approach is presented where pyridines and diazines are converted into heteroaryl phosphonium salts and coupled with aryl boronic acids. Nickel catalysts are unique for selective heteroaryl transfer, and the reaction has a broad substrate scope that includes complex pharmaceuticals. Phosphonium ions also display orthogonal reactivity in cross‐couplings compared to halides, enabling chemoselective palladium‐ and nickel‐catalyzed coupling sequences.     

Palladium‐Catalyzed Direct Cross‐Coupling of Carboranyllithium with (Hetero)Aryl Halides

A palladium‐catalyzed direct C‐arylation reaction of readily available cage carboranyllithium reagents with aryl halides has been developed for the first time. This method is applicable to a wide range of aryl halide substrates including aryl iodides, aryl bromides, and heteroaromatic halides.     

Ni‐Catalyzed Cross‐Coupling Reaction: The Direct Synthesis of Symmetrical Disulfanes from Aryl and Primary Alkyl Halides

A novel Ni‐catalyzed cross‐coupling reaction is introduced for the direct synthesis of diaryldisulfanes and dialkyldisulfanes from aryl halides and primary alkyl halides at normal atmospheric conditions, respectively. This one‐pot and domino protocol utilizes only 10 mol% of NiCl₂ as a catalyst and morpholin‐4‐ium morpholine‐4‐carbo‐dithioate as a new, stable, solid, and odorless sulfurating reagent in the presence of ethylene glycol as a cosolvent and bidentate ligand in dimethyl formamide (DMF) at 130°C with good to excellent yields and relatively short time reaction.     

Iron‐Catalyzed Cross‐Coupling of Alkenyl Acetates

Stable C O linkages are generally unreactive in cross‐coupling reactions which mostly employ more electrophilic halides or activated esters (triflates, tosylates). Acetates are cheap and easily accessible electrophiles but have not been used in cross‐couplings because the strong C O bond and high propensity to engage in unwanted acetylation and deprotonation. Reported herein is a selective iron‐catalyzed cross‐coupling of diverse alkenyl acetates, and it operates under mild reaction conditions (0 °C, 2 h) with a ligand‐free catalyst (1–2 mol %).