Nickel-Catalyzed Ligand-Controlled Selective Reductive Cyclization/Cross-Couplings

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(5), P. 515 - 535

Published: Jan. 23, 2023

ConspectusThe use of quaternary stereocenters during lead candidate optimization continues to grow because improved physiochemical and pharmacokinetic profiles compounds with higher sp3 fraction. Pd-catalyzed redox-neutral alkene difunctionalization involving carbopalladation alkenes followed by nucleophilic-trapping σ-alkyl-palladium intermediates has been developed as an efficient method construct stereocenters. However, the low chemoselectivity air sensitivity organometallic nucleophiles, well their availability accessibility, limit scope application this elegant strategy. Recently, Ni-catalyzed reductive cross-coupling evolved into a privileged strategy easily valuable C(sp3)-C bonds. Despite great progress, enantioselective coupling C(sp3) electrophiles still relies on activated or functionalized alkyl precursors, which are often unstable require multiple steps prepare. Therefore, via selective cyclization/cross-coupling was developed. This not only offers robust practical alternative for traditional but also provides strategic complementarity electrophiles. In Account, we summarize latest results from our laboratory topic. These findings mainly include explorations in modulating enantioselectivity cyclization mode cyclization/cross-couplings.We will first discuss chiral heterocycles focus effects ligands, reductants, additives roles cross-coupling. A wide range have explored, including aryl halides, vinyl alkynyl gem-difluoroalkenes, CO2, trifluoromethyl alkenes, cyano The synthetic potential approach demonstrated synthesis biologically active natural products drug molecules. Second, detail how tune steric nickel catalysts modifying bipyridine ligands regiodivergent cyclization/cross-couplings. Specifically, bidentate favors exo-selective cyclization/cross-coupling, while carboxylic acid-modified ligand permits endo-selective cyclization/cross-coupling. We show activate amide substrate altering electronic properties substituents nitrogen, thereby enabling nucleophilic addition halides carbonyls. Further investigation led tunable cyclization/cross-couplings (addition carbonyl vs 7-endo-cyclization) divergent pharmacologically important 2-benzazepine frameworks. Finally, serendipitously discover that changing oxidation state can control migratory aptitude different groups, thus providing switchable skeletal rearrangement transformation is high value it represents conceptually unprecedented new C-C bond activation. Thus, Account summarizes methods allow formation using variety insight relationship between structure, substrate, selectivity.

Language: Английский

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Switchable 1,2-Rearrangement Enables Expedient Synthesis of Structurally Diverse Fluorine-Containing Scaffolds

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(26), P. 11626 - 11637

Published: May 23, 2022

Skeletal rearrangement that changes the connectivity of molecule via cleavage and reorganization carbon–carbon bonds is a fundamental powerful strategy in complex molecular assembly. Because lack effective methods to control migratory tendency different groups, achieving switchable selectivity skeletal has been long-standing quest. Metal-based dyotropic provides unique opportunity address this challenge. However, remains unexplored. Herein, we show such problem could be solved by modifying ligands on metal catalyst changing oxidation states aptitude thereby providing ligand-controlled, strategy. Experimental density functional theory calculation studies prove rational design. The occurs only when nickel(II) intermediate reduced more nucleophilic nickel(I) species, sterically hindered iPrPDI ligand facilitates 1,2-aryl/Ni rearrangement, while terpyridine promotes 1,2-acyl/Ni rearrangement. This method allows site-selective activation C–C applied for divergent synthesis four medicinally relevant fluorine-containing scaffolds from same starting material.

Language: Английский

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Modular Synthesis of Multifunctionalized CF₃-Allenes through Selective Activation of Saturated Hydrocarbons

ACS Catalysis, Journal Year: 2022, Volume and Issue: 12(16), P. 10207 - 10221

Published: Aug. 5, 2022

Catalytic 1,4-dicarbofunctionalization of 1,3-enynes is a powerful strategy for the synthesis polysubstituted allenes. Despite impressive progress, such still restricted to use alkyl-metallic reagents or pre-activated radical precursors, thus limiting its functional group compatibility and atom economy. Herein, we report that through combination decatungstate photo-hydrogen transfer nickel catalysis, three-component 2-trifluoromethyl-1,3-enynes achieved. This allows modular tetrasubstituted CF3-allenes under exceptionally mild conditions. A variety electrophiles as aryl bromides, alkenyl acyl chlorides, alkynyl bromides were successfully employed traps lead desired products. Another significant advantage most abundant hydrocarbons are used feedstocks, wide range synthetically versatile groups complex drug-like structures can be easily incorporated. Based on experimental density theories, possible catalytic cycle involving 1,3-nickel rearrangement proposed.

Language: Английский

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Nickel‐Catalyzed Defluorinative Asymmetric Cyclization of Fluoroalkyl‐Substituted 1,6‐Enynes for the Synthesis of Seletracetam

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(46)

Published: Sept. 23, 2022

Abstract The introduction of fluorine‐containing groups into organic molecules can significantly affect their physical and chemical properties has long been used as an effective strategy for drug discovery development. Consequently, the development catalytic asymmetric methods synthesis heterocycles is highly desirable sought after. Herein, we describe a nickel‐catalyzed defluorinative cyclization fluoroalkyl‐substituted 1,6‐enynes, providing expedient access to synthetically attractive 4‐fluorovinyl‐substituted 2‐pyrrolidones in good yields with remarkable high levels chemo‐, regio‐, enantioselectivities (90–99 % ee,>35 examples). This protocol features readily available starting materials excellent functional group compatibility, exhibits complementary regioselectivity. utility this was demonstrated enantioselective antiepileptic Seletracetam.

Language: Английский

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Synthesis of Fluorinated Compounds by Nickel-Catalyzed Defluorinative Cross-Coupling Reactions

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(18), P. 12238 - 12268

Published: Sept. 1, 2023

Organofluorine compounds have attracted extensive attention in various industrial fields due to their unique chemical and physical properties. Despite increasing demand a wide range of scientific fields, the synthesis organofluorine still faces several problems, such as difficulties handling fluorinating reagents control chemoselectivity. Compared with formation C–F bonds, activation functionalization carbon–fluorine bonds is very important but challenging topic synthetic chemistry. Due properties nickel, Ni-catalyzed defluorinative cross-couplings been greatly developed past few decades powerful strategies for construction fluorinated organic compounds. This Review summarizes advances cross-coupling aryl fluorides, gem-difluorovinyl trifluoromethyl

Language: Английский

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Ni-catalyzed ligand-controlled divergent and selective synthesis

Science China Chemistry, Journal Year: 2023, Volume and Issue: 66(11), P. 2951 - 2976

Published: May 5, 2023

Language: Английский

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Nickel-catalyzed switchable arylative/endo-cyclization of 1,6-enynes

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 4, 2024

Abstract Carbo- and heterocycles are frequently used as crucial scaffolds in natural products, fine chemicals, biologically pharmaceutically active compounds. Transition-metal-catalyzed cyclization of 1,6-enynes has emerged a powerful strategy for constructing functionalized carbo- heterocycles. Despite significant progress, the regioselectivity alkyne functionalization is entirely substrate-dependent. And only exo -cyclization/cross-coupling products can be obtained, while endo -selective cyclization/cross-coupling remains elusive still poses formidable challenge. In this study, we disclose nickel-catalyzed switchable arylation/cyclization which nature ligand dictates arylation, electrophilic trapping reagents determine selectivity mode. Specifically, using commercially available 1,10-phenanthroline facilitates trans -arylation/cyclization to obtain seven-membered ring 2-naphthyl-substituted bisbox promotes cis access six-membered products. Diastereoselective cyclizations have also been developed synthesis enantioenriched piperidines azepanes, core structural elements pharmaceuticals possessing important biological activities. Furthermore, experimental density functional theory studies reveal that arylation process controlled by steric hindrance ligand; reaction mechanism involves -cyclization followed Dowd-Beckwith-type expansion form

Language: Английский

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Nickel-catalyzed electrophiles-controlled enantioselective reductive arylative cyclization and enantiospecific reductive alkylative cyclization of 1,6-enynes

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 27, 2024

Transition metal-catalyzed asymmetric cyclization of 1,6-enynes is a powerful tool for the construction chiral nitrogen-containing heterocycles. Despite notable achievements, these transformations have been largely limited to use aryl or alkenyl metal reagents, and stereoselective stereospecific alkylative remains unexploited. Herein, we report Ni-catalyzed enantioselective reductive anti-arylative with iodides, providing enantioenriched six-membered carbo- heterocycles in good yields excellent enantioselectivities. Additionally, realized enantiospecific cis-alkylative alkyl bromides, furnishing five-membered high regioselectivity stereochemical fidelity. Mechanistic studies reveal that arylative initiated by oxidative addition Ni(0) halides triggered allylic acetates. The utility this strategy further demonstrated synthesis antiepileptic drug Brivaracetam.

Language: Английский

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Synthesis of gem‐Difluoroalkenes via Ni‐Catalyzed Three‐Component Defluorinative Reductive Cross‐Coupling of Organohalides, Alkenes and Trifluoromethyl Alkenes

Chinese Journal of Chemistry, Journal Year: 2022, Volume and Issue: 40(18), P. 2212 - 2218

Published: June 18, 2022

Comprehensive Summary gem ‐Difluoroalkenes are considered ideal isosteres for metabolically susceptible carbonyl groups in modern drug discovery and medicinal chemistry. In addition, ‐difluoroalkenes used as versatile precursors the synthesis of difluoroalkylated compounds monofluoroalkenes. Therefore, a great deal effort has been devoted to developing efficient methods their preparation. The catalytic defluorinative functionalization trifluoromethyl alkenes represents useful strategy preparation chiral ‐difluoroalkenes. However, most these processes still essentially limited two‐component cross‐couplings form single C—C bonds. Due challenge controlling chemoselectivity carbon‐carbon bond forming events, three‐component cross‐coupling involving multiple formations rarely studied. We report nickel‐catalyzed reductive organohalides, alkenes. A variety electron‐rich electron‐deficient alkenes, well aryl alkyl halides can efficiently participate formation products. This reaction proceeds under mild conditions exhibits excellent functional group compatibility without requiring pendant chelating group, providing functionalized good yields with chemoselectivity.

Language: Английский

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Selective and Controllable Defluorophosphination and Defluorophosphorylation of Trifluoromethylated Enones: An Auxiliary Function of the Carbonyl Group

Organic Letters, Journal Year: 2023, Volume and Issue: 25(20), P. 3745 - 3749

Published: May 11, 2023

The auxiliary function of a carbonyl group in the tunable defluorophosphination and defluorophosphorylation trifluoromethylated enones with P(O)-containing compounds was demonstrated. Controlled replacement one or two fluorine atoms while maintaining high chemo- stereoselectivity achieved under mild conditions, thus enabling diversity-oriented synthesis skeletally diverse organophosphorus libraries─(Z)-difluoro-1,3-dien-1-yl phosphinates, (1Z,3E)-4-phosphoryl-4-fluoro-buta-1,3-dien-1-yl (E)-4-phosphoryl-4-fluoro-1,3-but-3-en-1-ones─in good yields excellent functional tolerance.

Language: Английский

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