Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(13), С. 9045 - 9062

Опубликована: Март 15, 2024

Methods for the synthesis of α-branched alkylamines are important due to their ubiquity in biologically active molecules. Despite development many methods amine preparation, C(sp3)-rich nitrogen-containing compounds continue pose challenges synthesis. While carbonyl reductive amination (CRA) between ketones and is cornerstone method alkylamine synthesis, it sometimes limited by sterically demanding condensation step dialkyl amines more restricted availability compared aldehydes. We recently reported a "higher-order" variant this transformation, alkylative (CAA), which utilized halogen atom transfer (XAT)-mediated radical mechanism, enabling streamlined complex alkylamines. efficacy visible-light-driven approach, displayed scalability issues, competitive was problem certain substrate classes, limiting applicability. Here, we report change reaction regime that expands CAA platform through realization an extremely broad zinc-mediated reaction. This new strategy enabled elimination CRA, simplified purification, improved scope. Furthermore, harnessed carboxylic acid derivatives as alkyl donors facilitated α-trialkyl tertiary amines, cannot be accessed via CRA. Zn-mediated can carried out at variety scales, from 10 μmol setup microtiter plates high-throughput experimentation, gram-scale medicinally-relevant compounds. believe transformation enables robust, efficient, economical access provides viable alternative current benchmark methods.

Язык: Английский

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Continuous Flow Decarboxylative Monofluoroalkylation Enabled by Photoredox Catalysis

JACS Au, Год журнала: 2025, Номер 5(2), С. 684 - 692

Опубликована: Фев. 2, 2025

Herein, we report a scalable and mild strategy for the monofluoroalkylation of wide array Giese acceptors via visible-light-mediated photoredox catalysis in continuous flow. The use flow technology significantly enhances productivity scalability, whereas mildness conditions functional group tolerance are ensured by leveraging 4CzIPN, transition-metal-free organic photocatalyst. Structurally diverse secondary tertiary monofluoroalkyl radicals can thus be accessed from readily available α-monofluorocarboxylic acids. Given reaction conditions, this protocol is also amenable to late-stage functionalization biologically relevant molecules such as menthol, amantadine, bepotastine, estrone derivatives, rendering it suitable application drug discovery programs, which introduction fluorinated fragments highly sought after. This method was extended enable reductive multicomponent radical-polar crossover transformation rapidly increase complexity assembled architectures single synthetic operation.

Язык: Английский

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Photoinduced manganese-catalysed hydrofluorocarbofunctionalization of alkenes

Nature Synthesis, Год журнала: 2022, Номер 1(6), С. 475 - 486

Опубликована: Май 30, 2022

Язык: Английский

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C–H Functionalization of Pyridines via Oxazino Pyridine Intermediates: Switching to para-Selectivity under Acidic Conditions

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(28), С. 15581 - 15588

Опубликована: Июль 10, 2023

para-Selective C-H functionalization of pyridines holds a significant value but remains underdeveloped. Site-switchable under easily tunable conditions expedites drug development. We recently reported redox-neutral dearomatization-rearomatization strategy for meta-C-H via oxazino pyridine intermediates. Here, we demonstrate that these intermediates undergo highly para-selective simply by switching to acidic conditions. A broad scope para-alkylated and arylated is prepared through radical as well ionic pathways. These mild catalyst-free methods are applied the late-stage para-functionalization drugs using limiting reagents. Consecutive meta,para-difunctionalization also achieved with complete regiocontrol relying on pH-dependent reactivity pyridines.

Язык: Английский

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Phenanthroline-Initiated Anti-selective Hydrosulfonylation of Unactivated Alkynes with Sulfonyl Chlorides

ACS Catalysis, Год журнала: 2023, Номер 13(10), С. 6983 - 6993

Опубликована: Май 8, 2023

A simple and general method for anti-selective hydrosulfonylation of unactivated alkynes with sulfonyl chlorides in the presence a catalytic amount phenanthroline-based Lewis base (Me3Si)3SiH as hydrogen atom donor has been developed. The protocol proceeds efficiently under mild metal-free conditions, delivering diverse set (Z)-vinyl sulfones high stereoselectivity. Additionally, displays excellent functional-group compatibility can be applied to late-stage modifications complex drugs their derivatives. Experimental density functional theory studies unveiled that key transformation's success is employment base, which interacts form halogen-bond accelerates cleavage S–Cl bonds irradiation visible light.

Язык: Английский

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Acridine photocatalysis enables tricomponent direct decarboxylative amine construction

Chemical Science, Год журнала: 2024, Номер 15(25), С. 9582 - 9590

Опубликована: Янв. 1, 2024

Diverse amines and amino acids are now readily accessed from carboxylic acids, aldehydes, amine precursors in a direct decarboxylative reaction enabled by homogeneous triple catalytic system based on acridine photocatalysis.

Язык: Английский

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Diversity-oriented synthesis of fluoroalkylated amines via the palladium-catalyzed divergent fluoroalkylamination of 1,3-dienes

Chemical Communications, Год журнала: 2022, Номер 58(37), С. 5614 - 5617

Опубликована: Янв. 1, 2022

Herein, we reported the first versatile and expeditious protocol for diversity-oriented synthesis (DOS) of fluoroalkylated amines via photoinduced palladium-catalyzed cross coupling 1,3-dienes, fluoroalkyl iodides, which features excellent 3,4- 1,4-selectivity controlled by a broad substrate scope as well good function group tolerance, could be extended to late-stage modification bioactive molecules.

Язык: Английский

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Recent Advances in Visible Light‐Mediated Radical Fluoro‐alkylation, ‐alkoxylation, ‐alkylthiolation, ‐alkylselenolation, and ‐alkylamination

The Chemical Record, Год журнала: 2023, Номер 23(9)

Опубликована: Май 22, 2023

Abstract In the last few years, many reagents and protocols have been developed to allow for efficient fluorofunctionalization of a diverse set scaffolds ranging from alkanes, alkenes, alkynes, (hetero)arenes. The concomitant rise organofluorine chemistry visible light‐mediated synthesis synergistically expanded fields mutually benefitted developments in both fields. this context, light driven formations radicals containing fluorine major focus discovery new bioactive compounds. This review details recent advances progress made fluoroalkylation heteroatom centered radical generation.

Язык: Английский

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Merging Copper(I) Photoredox Catalysis and Iodine(III) Chemistry for the Oxy‐monofluoromethylation of Alkenes

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(12)

Опубликована: Янв. 24, 2023

A simple process for the oxy-monofluoromethylation of alkenes is described. In combination with visible-light copper(I) photoredox catalysis, an easily accessible iodine(III) reagent containing monofluoroacetoxy ligands serves as a powerful source monofluoromethyl (CH2 F) radical, enabling step economical synthesis γ-fluoro-acetates from broad range olefinic substrates under mild conditions. Applications to late-stage diversification derived complex molecules, amino acids and fluoromethylated heterocycles are also demonstrated.

Язык: Английский

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C(sp³)–C(sp³) coupling of non-activated alkyl-iodides with electron-deficient alkenes via visible-light/silane-mediated alkyl-radical formation

Chemical Science, Год журнала: 2022, Номер 13(44), С. 13241 - 13247

Опубликована: Янв. 1, 2022

Here, we present a remarkably mild and general initiation protocol for alkyl-radical generation from non-activated alkyl-iodides. An interaction between silane an alkyl iodide is excited by irradiation with visible light to trigger carbon-iodide bond homolysis form the radical. We show how this method can be developed into operationally simple Giese addition reaction that tolerate range of sensitive functionalities not normally explored in established approaches strategically important transformation. The new requires no photocatalyst or other additives uses only commerical tris(trimethylsilyl)silane effectively combine broad halides activated alkenes C(sp3)-C(sp3) bonds embedded within complex frameworks.

Язык: Английский

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