Electrocatalytic Access to Azetidines via Intramolecular Allylic Hydroamination: Scrutinizing Key Oxidation Steps through Electrochemical Kinetic Analysis

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(28), P. 15360 - 15369

Published: July 10, 2023

Azetidines are prominent structural scaffolds in bioactive molecules, medicinal chemistry, and ligand design for transition metals. However, state-of-the-art methods cannot be applied to intramolecular hydroamination of allylic amine derivatives despite their underlying potential as one the most prevalent synthetic precursors azetidines. Herein, we report an electrocatalytic method sulfonamides access azetidines first time. The merger cobalt catalysis electricity enables regioselective generation key carbocationic intermediates, which could directly undergo C-N bond formation. mechanistic investigations including electrochemical kinetic analysis suggest that either catalyst regeneration by nucleophilic cyclization or second oxidation intermediate is involved rate-determining step (RDS) our protocol highlight ability electrochemistry providing ideal means mediate oxidation.

Language: Английский

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Co-Catalyzed Hydrofluorination of Alkenes: Photocatalytic Method Development and Electroanalytical Mechanistic Investigation

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(7), P. 4380 - 4392

Published: Feb. 1, 2024

The hydrofluorination of alkenes represents an attractive strategy for the synthesis aliphatic fluorides. This approach provides a direct means to form C(sp3)–F bonds selectively from readily available alkenes. Nonetheless, conducting using nucleophilic fluorine sources poses significant challenges due low acidity and high toxicity associated with HF poor nucleophilicity fluoride. In this study, we present new Co(salen)-catalyzed simple utilizing Et3N·3HF as sole source both hydrogen fluorine. process operates via photoredox-mediated polar-radical-polar crossover mechanism. We also demonstrated versatility method by effectively converting diverse array activated varying degrees substitution into hydrofluorinated products. Furthermore, successfully applied methodology 18F-hydrofluorination reactions, enabling introduction 18F potential radiopharmaceuticals. Our mechanistic investigations, conducted rotating disk electrode voltammetry DFT calculations, unveiled involvement carbocation CoIV–alkyl species viable intermediates during fluorination step, contribution each pathway depends on structure starting alkene.

Language: Английский

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Cobalt‐Catalyzed Asymmetric Aza‐Nozaki–Hiyama–Kishi (NHK) Reaction of α‐Imino Esters with Alkenyl Halides

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(7)

Published: Jan. 2, 2024

Chromium-catalyzed enantioselective Nozaki-Hiyama-Kishi (NHK) reaction represents one of the most powerful approaches for formation chiral carbon-heteroatom bond. However, construction sterically encumbered tetrasubstituted stereocenter through NHK still posts a significant challenge. Herein, we disclose cobalt-catalyzed aza-NHK ketimine with alkenyl halide to provide convenient synthetic approach manufacture enantioenriched α-vinylic amino acid. This protocol exhibits excellent functional group tolerance 99 % ee in cases. Additionally, this asymmetric reductive method is also applicable aldimine access trisubstituted stereogenic centers.

Language: Английский

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Mechanism of Alkene Hydrofunctionalization by Oxidative Cobalt(salen) Catalyzed Hydrogen Atom Transfer

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2685 - 2700

Published: Jan. 16, 2024

Oxidative MHAT hydrofunctionalization of alkenes provides a mild cobalt-catalyzed route to forming C–N and C–O bonds. Here, we characterize relevant salen-supported cobalt complexes their reactions with alkenes, silanes, oxidant, solvent. These stoichiometric investigations are complemented by kinetic studies the catalytic reaction catalyst speciation. We describe solution characterization an elusive cobalt(III) fluoride complex, which surprisingly is not species that reacts silane under conditions; rather, aquo complex more active. Accordingly, addition water (0.15 M) speeds reaction, show enables product formation in 2 h at −50 °C acetone. Under these conditions, resting states can be observed UV–vis spectrophotometry, including cobalt(III)-alkyl complex. It comes from transient hydride formed turnover-limiting step cycle. This readily degrades but H2; it releases H+ through bimetallic pathway explains [Co]2 dependence off-cycle reaction. In contrast, rate follows power law kobs[Co]1[silane]1. Because different [Co] degradation lower loading improves yield reducing relative unproductive silane/oxidant consumption. illuminate mechanistic details oxidative lay groundwork for understanding other mediated alkyl complexes.

Language: Английский

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Cobalt-catalyzed HAT reaction for asymmetric hydrofunctionalization of alkenes and nucleophiles

Chem Catalysis, Journal Year: 2023, Volume and Issue: 3(3), P. 100526 - 100526

Published: Feb. 13, 2023

Language: Английский

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Constructing Four-Membered Heterocycles by Cycloisomerization

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(7), P. 4101 - 4110

Published: March 10, 2023

Four-membered heterocycles are highly sought after in modern drug discovery as they provide beneficial properties to the target molecules. Despite tremendous efforts by synthetic research community, there is a need for simple and new method incorporate these motifs into design Herein, we reveal cycloisomerization strategy construction of oxetane azetidine rings via metal hydride hydrogen atom transfer/radical polar crossover, which challenging both enthalpically entropically. This suitable synthesizing polysubstituted four-membered heterocycles. mild functional-group tolerant reaction has broad substrate scope, including spiro structure, an important motif research. Various heterocyclic building blocks can be synthesized product derivatization. We also discuss mechanism, focusing on ring formation, deuterium experiments DFT studies.

Language: Английский

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Cobalt‐Catalyzed Enantioselective Reductive α‐Chloro‐Carbonyl Addition of Ketimine to Construct the β‐Tertiary Amino Acid Analogues

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(25)

Published: Jan. 22, 2024

β-Tertiary amino acid derivatives constitute one of the most frequently occurring units in natural products and bioactive molecules. However, efficient asymmetric synthesis this motif still remains a significant challenge. Herein, we disclose cobalt-catalyzed enantioselective reductive addition reaction ketimine using α-chloro carbonyl compound as radical precursor, providing expedient access to diverse array enantioenriched β-quaternary analogues. This protocol exhibits outstanding enantioselectivity broad substrate scope with excellent functional group tolerance. Preliminary mechanism studies rule out possibility Reformatsky-type confirm involvement species stereoselective process. The synthetic utility has been demonstrated through rapid assembly iterative oligopeptide, showcasing its versatile platform for late-stage modification drug candidates.

Language: Английский

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Thiyl Radical Trapped by Cobalt Catalysis: An Approach to Markovnikov Thiol–Ene Reaction

Organic Letters, Journal Year: 2024, Volume and Issue: 26(3), P. 591 - 596

Published: Jan. 12, 2024

In the presence of a thiyl radical species, catalytic Markovnikov thiol–ene reaction is challenging because it prefers to proceed via pathway, thereby leading anti-Markovnikov selectivity. this work, rare example engaged in enabled by cobalt catalysis reported. This protocol features avoidance unique oxidants, exclusive regioselectivity, and broad substrate scope. Scalable synthesis late-stage modification complex molecules demonstrate practicability protocol.

Language: Английский

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Cobalt-Catalyzed Carbon–Heteroatom Transfer Enables Regioselective Tricomponent 1,4-Carboamination

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(12), P. 8508 - 8519

Published: Feb. 21, 2024

Tricomponent cobalt(salen)-catalyzed carbofunctionalization of unsaturated substrates by radical-polar crossover has the potential to streamline access broad classes heteroatom-functionalized synthetic targets, yet reaction platform remained elusive, despite well-developed analogous hydrofunctionalizations mediated high-valent alkylcobalt intermediates. We report herein development a cobalt(salen) catalytic system that enables carbofunctionalization. The entails tricomponent decarboxylative 1,4-carboamination dienes and provides direct route aromatic allylic amines obviating preformed allylation reagents protection oxidation-sensitive amines. merges acridine photocatalysis with regioselective 1,4-carbofunctionalization facilitates radical polar phases coupling process, revealing critical roles reactants, as well ligand effects nature formal species on chemo- regioselectivity.

Language: Английский

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Fe/Thiol Cooperative Hydrogen Atom Transfer Olefin Hydrogenation: Mechanistic Insights That Inform Enantioselective Catalysis

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(25), P. 17296 - 17310

Published: June 14, 2024

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis complex molecules, but traditional catalysts have difficulty with enantioselective reduction electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling mild challenging selectivity that complementary hydrogenations H2. Further, mHAT presents asymmetric induction through cooperative (cHAT) chiral thiols. Here, we report insights from mechanistic study iron-catalyzed achiral cHAT reaction leverage deliver stereocontrol Kinetic analysis variation silane structure point hydride iron as likely rate-limiting step. The data indicate selectivity-determining step quenching alkyl radical by thiol, which becomes more potent H donor when coordinated iron(II). resulting iron(III)–thiolate in equilibrium other species, including FeII(acac)2, shown be predominant off-cycle species. enantiodetermining nature thiol trapping enables net commercially available glucose-derived catalyst up 80:20 enantiomeric ratio. To best our knowledge, this first demonstration via mHAT. These findings advance understanding act proof principle development reactions.

Language: Английский

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