Predicting success in Cu-catalyzed C–N coupling reactions using data science

Science Advances, Journal Year: 2024, Volume and Issue: 10(3)

Published: Jan. 17, 2024

Data science is assuming a pivotal role in guiding reaction optimization and streamlining experimental workloads the evolving landscape of synthetic chemistry. A discipline-wide goal development workflows that integrate computational chemistry data tools with high-throughput experimentation as it provides experimentalists ability to maximize success expensive campaigns. Here, we report an end-to-end data-driven process effectively predict how structural features coupling partners ligands affect Cu-catalyzed C–N reactions. The established workflow underscores limitations posed by substrates while also providing systematic ligand prediction tool uses probability assess when will be successful. This platform strategically designed confront intrinsic unpredictability frequently encountered deployment.

Language: Английский

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Catalytically Relevant Organocopper(III) Complexes Formed through Aryl-Radical-Enabled Oxidative Addition

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(22), P. 15176 - 15185

Published: May 21, 2024

Stepwise oxidative addition of copper(I) complexes to form copper(III) species via single electron transfer (SET) events has been widely proposed in copper catalysis. However, direct observation and detailed investigation these fundamental steps remain elusive owing largely the typically slow rate instability species. We report herein a novel aryl-radical-enabled stepwise pathway that allows for formation well-defined alkyl–CuIII from CuI complexes. The process is enabled by SET an aryl diazonium salt CuII radical. Subsequent iodine abstraction alkyl iodide radical affords radical, which then reacts with complex. structure resultant [(bpy)CuIII(CF3)2(alkyl)] characterized NMR spectroscopy X-ray crystallography. Competition experiments have revealed at different iodides undergo consistent carbon-centered radicals. intermediate formed during identified as four-coordinate complex, [CuII(CH3CN)2(CF3)2], through electronic paramagnetic resonance (EPR) studies. catalytic relevance high-valent organo-CuIII demonstrated C–C bond-forming reductive elimination reactivity. Finally, localized orbital bonding analysis formal CuIII indicates inverted ligand fields σ(Cu–CH2) bonds. These results demonstrate catalysis provide general strategy investigate

Language: Английский

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Site‐Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines**

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(8)

Published: Jan. 5, 2024

Abstract The introduction of trifluoromethyl groups into organic molecules is paramount importance in modern synthetic chemistry and medicinal chemistry. While methods for constructing C(sp 2 )−CF 3 bonds have been well established, the advancement practical comprehensive approaches forming remains considerably restricted. In this work, we describe an efficient site‐specific deaminative trifluoromethylation reaction aliphatic primary amines to afford corresponding alkyl compounds. proceeds at room temperature with readily accessible N ‐anomeric amide (Levin's reagent) bench‐stable bpyCu(CF ) (Grushin's reagent, bpy=2,2′‐bipyridine) under blue light. protocol features mild conditions, good functional group tolerance, moderate yields. Remarkably, method can be applied direct, late‐stage natural products bioactive molecules. Experimental mechanistic studies were conducted, a radical mechanism proposed, wherein dual roles Grushin's reagent elucidated.

Language: Английский

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Copper‐Catalyzed Enantioselective C(sp³)−SCF₃ Coupling of Carbon‐Centered Benzyl Radicals with (Me₄N)SCF₃

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(11)

Published: Jan. 26, 2024

Abstract In contrast with the well‐established C(sp 2 )−SCF 3 cross‐coupling to forge Ar−SCF bond, corresponding enantioselective coupling of readily available alkyl electrophiles chiral bond has remained largely unexplored. We herein disclose a copper‐catalyzed radical range secondary/tertiary benzyl radicals easily (Me 4 N)SCF reagent. The key success lies in utilization phosphino‐oxazoline‐derived anionic N,N,P‐ligands through tuning electronic and steric effects for simultaneous control reaction initiation enantioselectivity. This strategy can successfully realize two types asymmetric reactions, including enantioconvergent racemic halides three‐component 1,2‐carbotrifluoromethylthiolation arylated alkenes under mild conditions. It therefore provides highly flexible platform rapid assembly an array enantioenriched SCF ‐containing molecules interest organic synthesis medicinal chemistry.

Language: Английский

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Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(13), P. 9444 - 9454

Published: March 21, 2024

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, bond formation relies on interaction between nucleophile-sequestered metal complexes and radicals, limiting nucleophile scope to sterically uncongested ones. coupling of congested nucleophiles poses significant challenge due difficulties in transmetalation, restricting reaction generality. Here, we describe probable outer-sphere nucleophilic attack mechanism that circumvents challenging transmetalation associated with nucleophiles. This strategy enables general copper-catalyzed N-alkylation aromatic amines secondary/tertiary alkyl halides exhibits catalyst-controlled stereoselectivity. It accommodates diverse amines, especially bulky secondary primary ones deliver value-added (>110 examples). is expected inspire more nucleophiles, particularly ones, accelerate

Language: Английский

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Oxidative Substitution of Organocopper(II) by a Carbon-Centered Radical

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(33), P. 23555 - 23565

Published: Aug. 8, 2024

Copper-catalyzed coupling reactions of alkyl halides are believed to prominently involve copper(II) species and radicals as pivotal intermediates, with their exact interaction mechanism being the subject considerable debate. In this study, a visible light-responsive fluoroalkylcopper(III) complex, [(terpy)Cu(CF3)2(CH2CO2tBu)] Trans-1, was designed explore mechanism. Upon exposure blue LED irradiation, Trans-1 undergoes copper–carbon bond homolysis, generating Cu(II) carbon-centered radicals, where radical then recombines intermediate, resulting in formation Cis-1, Cis isomer Trans-1. Beyond this, well-defined fluoroalkylcopper(II) intermediate ligated sterically hindered ligand isolated underwent full characterization electronic structure studies. The collective experimental, computational, spectroscopic findings work strongly suggest that organocopper(II) engages via an "oxidative substitution" mechanism, which is likely operational pathway for copper-catalyzed C–H trifluoromethylation reactions.

Language: Английский

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Multiligand Enabled, Copper-Catalyzed Hiyama Coupling of Arylsilanes with Unactivated Secondary Alkyl Halides: Reaction Development and Mechanistic Insights

Chemical Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A multiligand-involved Cu catalysis offers an efficient Hiyama coupling of arylsilanes with unactivated alkyl halides, where copper NHC and phenanthroline ligands were account for C(sp 2 )–Si activation )–C(sp 3 ) formation, respectively.

Language: Английский

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Copper–Carbon Homolysis Competes with Reductive Elimination in Well-Defined Copper(III) Complexes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(48), P. 26152 - 26159

Published: Nov. 22, 2023

Despite the recent advancements of Cu catalysis for cross-coupling alkyl electrophiles and frequently proposed involvement alkyl-Cu(III) complexes in such reactions, little is known about reactivity these high-valent complexes. Specifically, although reversible interconversion between an alkyl-CuIII complex radical/CuII pair has been catalysis, direct observation steps well-defined CuIII remains elusive. In this study, we report synthesis investigation complexes, which exclusively undergo a Cu-C homolysis pathway to generate radicals CuII species. Kinetic studies suggest bond dissociation energy 28.6 kcal/mol CuIII-C bonds. Moreover, four-coordinate could be converted solvated alkyl-CuIII-(CF3)2, undergoes highly efficient C-CF3 bond-forming reductive elimination even at low temperatures (-4 °C). These results provide strong support recombination with form species, elusive step that Cu-catalyzed mechanisms. Furthermore, our work demonstrated significantly influenced by subtle changes coordination environment. Lastly, reactive neutral alkyl-CuIII-(CF3)2 species (or weakly bound solvent molecules) suggests they might true intermediates many trifluoromethylation reactions.

Language: Английский

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Implementation of micelle-enabled C(sp²)–C(sp³) cross-electrophile coupling in pharmaceutical synthesis

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(17), P. 2349 - 2352

Published: Jan. 1, 2024

A sustainable C(sp 2 )–C(sp 3 ) cross-electrophile coupling was developed between readily available 5-bromophthalide and 1-benzyl-4-iodopiperidine under micellar conditions, leading to a key intermediate of one our development compounds.

Language: Английский

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Recent Advances in Theoretical Studies on Cu-Mediated Bond Formation Mechanisms Involving Radicals

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(4), P. 2429 - 2454

Published: Feb. 1, 2024

Copper-catalyzed radical transformations establish a powerful toolkit to construct versatile complex organic compounds. The copper-mediated bond formation step of radicals plays critical role in controlling chemo- and stereoselectivity copper-catalyzed transformation reactions. This involves three possible pathways: ion-type formation, substitution, reductive elimination. review highlights the recent advances theoretical studies on mechanisms models selectivity Cu-mediated radical-involved providing general mechanistic comprehension this key elementary copper catalysis.

Language: Английский

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