Nickel-Catalyzed Reductive Coupling Research Articles

Stereoconvergent and Enantioselective Synthesis of Z-Homoallylic Alcohols via Nickel-Catalyzed Reductive Coupling of Z/E-1,3-Dienes with Aldehydes.

Stereoconvergent reactions enable the transformation of mixed stereoisomers into well-defined, chiral products─a crucial strategy for handling Z/E-mixed olefins, which are common but challenging substrates in organic synthesis. Herein, we report a stereoconvergent and highly enantioselective method for synthesizing Z-homoallylic alcohols via the nickel-catalyzed reductive coupling of Z/E-mixed 1,3-dienes with aldehydes. This process is enabled by an N-heterocyclic carbene ligand characterized by C2-symmetric backbone chirality and bulky 2,6-diisopropyl N-aryl substituents. Our method achieves excellent stereocontrol over both enantioselectivity and Z-selectivity in a single step, producing chiral Z-homoallylic alcohols that are valuable in natural products and pharmaceuticals.

Nickel-Catalyzed Reductive Decarboxylative Coupling of Diacyl Peroxides with Aryl/Vinyl Halides

Nickel-Catalyzed Reductive Decarboxylative Coupling of Diacyl Peroxides with Aryl/Vinyl Halides

Enantioselective Nickel-Catalyzed Reductive Coupling of Alkenes with Imines for Chiral Amine Synthesis

Enantioselective Nickel-Catalyzed Reductive Coupling of Alkenes with Imines for Chiral Amine Synthesis

Nickel/Photoredox-Catalyzed Carbonylative Cross-Electrophile Coupling of Organohalides and Carboxylic Acid Esters with Phenyl Formate.

A photoinduced nickel-catalyzed reductive carbonylative coupling from organohalides and N-(acyloxy)phthalimide esters with phenyl formate as the carbonyl source has been developed. This reaction could perform smoothly under mild conditions, and a series of aryl-alkyl and alkyl-alkyl unsymmetrical ketones were produced without the need of stoichiometric metal reductants. Mechanistic studies indicate that this reaction was initiated from radical capture by Ni(I)-carbonyl species and subsequent rapid carbonyl insertion.

Aliphatic Hydrosilanes via Nickel-Catalyzed Reductive Csp3-Si Coupling of Primary Alkyl Bromides and Chlorohydrosilanes.

The reductive C-Si coupling of chlorosilanes offers efficient access to organosilanes, but its potential for constructing aliphatic ones remains largely unexplored. This manuscript presents a nickel-catalyzed Csp3-Si coupling reaction of unactivated alkyl-Br and R2Si(H)Cl. This work establishes a new approach for synthesizing highly functionalized aliphatic hydrosilanes from readily available chemical feedstocks. The reaction is easily scalable and can accommodate various functional groups, including carboxylic acids, which are usually incompatible with basic conditions.

Simultaneous Preparation of Sulfides/Selenides and Sulfones via Synergistic Nickel-Catalyzed Reductive Coupling and SN2 Reaction.

Sulfone compounds and thioether compounds are two highly valuable classes of compounds, but it is challenging to prepare sulfone and thioether compounds simultaneously and efficiently. Here we report that sulfides/selenides and sulfones can be obtained simultaneously using allyl bromide/benzyl bromide-activated alkyl bromides and thiosulfonates/selenosulfonates using a nickel-catalyzed reductive coupling and SN2 synergistic strategy, which is characterized by excellent atom and step economy, mild reaction conditions, broad functional group compatibility, and excellent yields.

Nickel-Catalyzed Acid Chlorides with Tetrasulfides for the Synthesis of Thioesters and Acyl Disulfides.

Herein, we report a novel method for the synthesis of thioesters and acyl disulfides via nickel-catalyzed reductive cross-electrophile coupling of acid chlorides with tetrasulfides. This approach for the synthesis of thioesters and acyl disulfides is convenient and practical under mild reaction conditions, relying on easy availability. In addition, a wide range of thioesters and acyl disulfides were obtained in medium to good yields with good functional group tolerance. Moreover, thioesters and acyl disulfides can also be prepared at the gram scale, indicating that they have certain potential for industrial application.

Nickel-Catalyzed Electroreductive Coupling of Alkylpyridinium Salts and Aryl Halides.

An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceutically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts with distinct conditions. Mechanistic insights were critical to enhance the efficiency of coupling using secondary alkylpyridinium salts. Systematic comparisons of the electrochemical and non-electrochemical methods revealed the complementary scope and efficiency of the two approaches.

Nickel-catalyzed reductive coupling reaction of monofluoroalkyl triflates with alkyl carboxylic acids toward the synthesis of α-alkyl-α-fluoro-alkylketones

The synthesis methods of α-fluoro-arylketones were well-established through electrophilic/nucleophilic fluorination and transition metal catalyzed cross-coupling. However, due to the site selectivity and substrate restriction, only a few cases have been developed to afford α-alkyl-α-fluoro-alkylketones. Herein, we report a general and efficient method of preparing diverse α-alkyl-α-fluoro-alkylketones via nickel-catalyzed reductive coupling reaction of monofluoroalkyl triflates with low-cost industrial raw material alkyl carboxylic acids. These transformations demonstrate high efficiency, mild conditions, and excellent functional group compatibility. This strategy provides a general and efficient method for the synthesis of α-alkyl-α-fluoro-alkylketones.

Nickel-Catalyzed Reductive Coupling of Chlorosilanes.

Organosilanes play essential roles in many important research areas. The use of readily available chlorosilanes to catalytically access these compounds is synthetically appealing but remains a long-standing challenge. Nickel-catalyzed reductive cross-coupling reaction has recently emerged as a promising protocol to arrive at this goal. This strategy allows the chlorosilanes to be coupled with various carbon electrophiles under mild conditions. These reactions afford organosilanes with improved molecular diversity, structural complexity, and functional group compatibility. This Concept article summarizes the recent advance on nickel-catalyzed reductive C-Si couplings of chlorosilanes.

Nickel-catalyzed reductive coupling of arylcarboxylic acid 2-pyridyl esters with alkyl methanesulfonates: access to alkyl aryl ketones.

Alkyl aryl ketones were synthesized via a nickel-catalyzed reductive coupling reaction of arylcarboxylic acid (2-pyridyl)esters with primary and secondary alkyl methanesulfonates under mild reaction conditions. This method suits a wide range of substrates and shows good compatibility with functional groups.

Photoinduced nickel-catalyzed reductive acyl cross-coupling: facile access to all carbon quaternary aliphatic ketones

A photochemical nickel-catalyzed reductive acyl coupling of unstrained tertiary acyl electrophiles with 1°, 2°, and 3°-alkyl radical precursors to synthesize sterically hindered α-tertiary dialkyl ketones is developed.

Nickel-catalyzed reductive coupling of nitroarenes and phosphine oxides to access phosphinic amides

We report a nickel-catalyzed reductive cross-coupling between readily available nitroarenes and phosphine oxides to access phosphinic amides.

Benchtop nickel-catalyzed reductive coupling of aldehydes with alkynes and ynamides.

We demonstrate the potential of Ni(COD)(DQ), a bench-stable Ni0 complex, as a catalyst for the reductive coupling of aldehydes with alkynes and ynamides, providing silylated allyl alcohols with excellent yields and regioselectivities. Mass spectrometric identification of the intermediates and DFT studies supported the proposed mechanism.

Ni-Catalyzed Reductive Coupling of Heteroaryl Bromides with Tertiary Alkyl Halides.

We disclose here a nickel-catalyzed reductive coupling of bromopyridines with tertiary alkyl bromides for the synthesis of alkylated pyridines bearing an all-carbon quaternary center. This strategy features mild conditions, broad substrate scope, and high functional group tolerance. The method reported here offers an alternative solution to the challenging task of forging sterically congested alkylpyridines, which we believe will significantly benefit the synthetic community and pharmaceutical industry.

Diastereoselective and Enantioselective Nickel-Catalyzed Reductive Coupling of Imines and Unactivated Alkenes

Diastereoselective and Enantioselective Nickel-Catalyzed Reductive Coupling of Imines and Unactivated Alkenes

Direct Synthesis of α-Aryl-α-Trifluoromethyl Alcohols via Nickel Catalyzed Cross-Electrophile Coupling.

A nickel-catalyzed reductive cross-electrophile coupling between the redox-active N-trifluoroethoxyphthalimide and iodoarenes is documented. The protocol reproduces a formal arylation of trifluoroacetaldehyde under mild conditions in high yields (up to 88 %) and with large functional group tolerance (30 examples). A combined computational and experimental investigation revealed a pivotal solvent assisted 1,2-Hydrogen Atom Transfer (HAT) process to generate a nucleophilic α-hydroxy-α-trifluoromethyl C-centered radical for the Csp2 -Csp3 bond forming process.

Zinc-Free, Scalable Reductive Cross-Electrophile Coupling Driven by Electrochemistry in an Undivided Cell.

Nickel-catalyzed reductive cross-electrophile coupling reactions are becoming increasingly important in organic synthesis, but application at scale is limited by three interconnected challenges: a reliance on amide solvents (complicated workup, regulated), the generation of stoichiometric Zn salts (complicated isolation, waste disposal issue), and mixing/activation challenges of zinc powder. We show here an electrochemical approach that addresses these three issues: the reaction works in acetonitrile with diisopropylethylamine as the terminal reductant in a simple undivided cell (graphite(+)/nickel foam(-)). The reaction utilizes a combination of two ligands, 4,4'-di-tert-butyl-2,2'-bipyridine and 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine. Studies show that, alone, the bipyridine nickel catalyst predominantly forms protodehalogenated aryl and aryl dimer, whereas the terpyridine nickel catalyst predominantly forms bialkyl and product. By combining these two unselective catalysts, a tunable, general system results because excess radical formed by the terpyridine catalyst can be converted to product by the bipyridine catalyst. As the aryl bromide becomes more electron rich, the optimal ratio shifts to have more of the bipyridine nickel catalyst. Lastly, examination of a variety of flow-cell configurations establishes that batch recirculation can achieve higher productivity (mmol product/time/electrode area) than single-pass, that high flow rates are essential to maximizing current, and that two flow cells in parallel can nearly halve the reaction time. The resulting reaction is demonstrated on gram scale and should be scalable to kilogram scale.

Nickel-Catalyzed Reductive Coupling of γ-Metalated Ketones with Unactivated Alkyl Bromides.

A nickel-catalyzed reductive cross-coupling reaction of aryl cyclopropyl ketones with easily accessible unactivated alkyl bromides to access aryl alkyl ketones has been developed. This strategy facilitates access to various of γ-alkyl-substituted ketones via ring opening of cyclopropyl ketones (26 examples, 50-90% yield). Initial mechanistic studies revealed that the reaction proceeds via radical cleavage of the alkyl bromide.

Total Synthesis of Sarpagine Alkaloid (-)-Normacusine B.

An asymmetric total synthesis of the sarpagine alkaloid (-)-normacusine B is presented. Salient features of this synthesis include a photocatalytic nitrogen-centered radical cascade reaction to assemble the tetrahydrocarbolinone skeleton, a titanium-mediated intramolecular amide-alkene coupling to construct the bridged azabicyclo[3.3.1]nonane moiety, and a nickel-catalyzed reductive Heck coupling to assemble the azabicyclo[2.2.2]octane ring system.