Intermediate Control: Unlocking Hitherto Unknown Reactivity and Selectivity in N-Conjugated Allenes and Alkynes

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: 58(2), P. 281 - 298

Published: Jan. 3, 2025

ConspectusControlling selectivity through manipulation of reaction intermediates remains one the most enduring challenges in organic chemistry, providing novel solutions for selective C-C π-bond functionalization. This approach, guided by activation principles, provides an effective method functional group installation, enabling direct synthesis molecules that are inaccessible conventional pathways. In particular, functionalization N-conjugated allenes and alkynes has emerged as a promising research focus, driven advances controlling reactive strategies. this regard, our group, alongside others, established some new approaches have suitable platform functionalized enamides. Account reviews recent developments field, highlighting modes reactivity selectivity, atom-economical functionalizations, strategies regio- stereocontrol, while mechanistic insights into related transformations.Our study is systematically organized two sections based on substrate type chronological progression. first section, we establish allenamide-derived intermediates, both allenamide-alkyne (AA) cross-coupling few electrophile-promoted hydrofunctionalization reactions. The unprecedented Pd-catalyzed achieved neighboring chelation, with phosphine ligand selection outcome. parallel, functionalizations─including haloalkynylation, hydrooxycarbonylation, hydrodifluoroalkylation, intermolecular hydroamination─are strategic electrophiles or their precursors.Additionally, findings demonstrate how ynamides' toward nucleophiles, controlled activator modulation, expands scope accessible transformations. Key include: (1) chemoselective [2 + 2 2] annulation efficient trapping N-arylated nitrilium ynamides, (2) divergent C-H indole-derived vinylogous ynamides metal via intramolecular hydroarylation, (3) bromoalkynylation-enabled migration 1,3-alkynyl shift.The final section explores N-electron polarization 1,3-enynes enables chemoselectivity metal-free inter- couplings indole substrates. Our modulating conjugation within enyne skeleton─through linear cross conjugation─can pathways control product selectivity.This aims to stimulate broader intermediate-controlled activated π-systems. Future directions include advanced design, strategies, deeper studies enable rational development.

Language: Английский

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Hydro-phosphorothiolation of Styrene and Cyclopropane with S-Hydrogen Phosphorothioates under Ambient Conditions

Organic Letters, Journal Year: 2024, Volume and Issue: 26(24), P. 5141 - 5145

Published: June 7, 2024

A metal-free hexafluoroisopropanol-mediated hydro-phosphorothiolation of styrenes and donor-acceptor cyclopropanes with

Language: Английский

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Allure of HFIP in Unsaturated Carbon−Carbon Bond Functionalization

European Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 27(12)

Published: Feb. 14, 2024

Abstract Hexafluoroisopropanol (HFIP) stands out as a versatile solvent in synthetic chemists’ repertoire, facilitating diverse array of intricate chemical reactions. It demonstrates multifaceted role that extends beyond conventional uses and, many cases, the mechanism appears to be complicated. This feature article elucidates significance HFIP context Lewis and Brønsted acid‐catalyzed reactions with specific emphasis on regio‐ stereoselective functionalization unsaturated carbon‐carbon bonds.

Language: Английский

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H₂O ⋅ B(C₆F₅)₃‐Catalyzed para‐Alkylation of Anilines with Alkenes Applied to Late‐Stage Functionalization of Non‐Steroidal Anti‐Inflammatory Drugs

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(13)

Published: Jan. 15, 2024

Abstract Anilines are core motifs in a variety of important molecules including medicines, materials and agrochemicals. We report straightforward procedure that allows access to new chemical space anilines via their para ‐C−H alkylation. The method utilizes commercially available catalytic H 2 O ⋅ B(C 6 F 5 ) 3 is highly selective for ‐ C ‐alkylation (over N ortho C‐ alkylation) anilines, with wide scope both the aniline substrates alkene coupling partners. Readily alkenes used, include classes first time. mild reaction conditions have allowed be applied late‐stage‐functionalization non‐steroidal anti‐inflammatory drugs (NSAIDs), fenamic acids diclofenac. formed novel NSAID derivatives display improved properties over parent structure.

Language: Английский

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Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 89(9), P. 5927 - 5940

Published: April 23, 2024

A key factor in the development of selective nucleophilic addition to allenamides is controlling reactivity electrophilic intermediates, which generally achieved using an activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general highly chemoselective hydroamination can be accomplished combination 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) NaOAc. Experimental mechanistic studies revealed HFIP mediates proton transfer activate allenamide, while acetate additive significantly contributes N-selective interception. This strategy enables without use metals. We demonstrated various functionalized 1,3-diamines could readily synthesized diversified into value-added structural motifs. Detailed investigations density functional theory role NaOAc formation reactive ultimately governed 1,3-diamine products. Critically, calculations potential energy surface around proton-transfer transition state two different intermediates were formed when was added.

Language: Английский

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Hexafluoroisopropanol (HFIP)-Mediated Intramolecular Cyclization of Allenamides To Access C1-Vinyl Tetrahydro-β-carbolines

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 89(16), P. 11783 - 11788

Published: July 26, 2024

The construction of biologically interesting N-heterocycles under metal-free conditions is a constant goal in industry and academia. Herein, we have developed an hexafluoroisopropanol (HFIP)-mediated intramolecular cyclization allenamides, providing tetrahydro-β-carboline derivatives embedded with C1-vinyl functionality. protocol provided atom-efficiently room temperature broad substrate scope good to excellent yields. potential impact the further highlighted by synthesizing important molecules diversified scaffolds via postsynthetic modifications.

Language: Английский

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para-Selective C-H Functionalization of Anilines: A Review

Journal of Organometallic Chemistry, Journal Year: 2024, Volume and Issue: 1019, P. 123313 - 123313

Published: Aug. 16, 2024

Language: Английский

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HFIP-Mediated Cascade Aminomethylation and Intramolecular Cyclization of Allenamides with N,O-Acetals to Access Tetrahydro-β-carboline Derivatives

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

Published: Jan. 1, 2025

A cascade of two C–C bond forming reactions promoted alone by HFIP is described delivering tetrahydro-β-carboline derivatives embedded with an allylic amine functionality.

Language: Английский

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Catalyst‐ and Additive‐free, Regioselective 1,6‐Hydroarylation of para‐Quinone Methides with Anilines in HFIP

Chemistry - An Asian Journal, Journal Year: 2023, Volume and Issue: 18(23)

Published: Oct. 17, 2023

A simple and efficient method for the synthesis of diarylmethyl-functionalized anilines through hexafluoroisopropanol (HFIP)-mediated regioselective 1,6-hydroarylation reaction para-quinone methides (p-QMs) with under catalyst- additive-free conditions is reported. Various kinds p-QMs amines (e. g. primary, secondary tertiary amines) are well tolerated in this transformation without pre-protection amino group, corresponding products could be generated good to excellent yields satisfactory regioselectivity optimized conditions. In addition adaptable amine compounds, indoles their derivatives also compatible system. This can easily extended a gram scale-synthesis level synthesize target product. Furthermore, it worth noting that some complex small aniline molecules biological activity selectively modified using method. The possible mechanism proposed step-by-step control experiments DFT calculations, showing key process achieving hydrogen bonding effect HFIP substrates.

Language: Английский

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Ortho-allylation of anilines with vinylaziridines in hexafluoroisopropanol

Organic Chemistry Frontiers, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 14, 2024

Reaction of N , -dialkylanilines with 2-vinylaziridines in hexafluoroisopropanol affords 2-monoallylated anilines ( E )-configured C–C double bonds.

Language: Английский

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