scholarly journals A highly site-selective radical sp3 C–H amination of azaheterocycles

2018 ◽  
Vol 9 (30) ◽  
pp. 6440-6445 ◽  
Author(s):  
Keith W. Bentley ◽  
Krysta A. Dummit ◽  
Jeffrey F. Van Humbeck
Keyword(s):  
Hydrogen Atom ◽  
Lewis Acid ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Site Selective

This report describes the development of a novel C–H amination strategy using both a Cu(ii) Lewis acid and an organic hydrogen atom transfer catalyst to activate benzylic C–H bonds adjacent to aromatic N-heterocycles.

scholarly journals Site-Selective A-C-H Functionalization of Trialkylamines via Reversible Hydrogen Atom Transfer Catalysis

2021 ◽  
Author(s):  
Yangyang Shen ◽  
Franziska Schoenebeck ◽  
Ignacio Funes-Ardoiz ◽  
Tomislav Rovis
Keyword(s):  
Drug Discovery ◽  
Hydrogen Atom ◽  
Late Stage ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Bond Functionalization ◽  
Carbon Centers ◽  
Radical Trapping ◽  
Site Selectivity ◽  
Site Selective

Trialkylamines are widely found in naturally-occurring alkaloids, synthetic agrochemicals, biological probes, and especially pharmaceuticals agents and pre-clinical candidates. Despite the recent breakthrough of catalytic alkylation of dialkylamines, the selective a-C(sp3 )–H bond functionalization of widely available trialkylamine scaffolds holds promise to streamline complex trialkylamine synthesis, accelerate drug discovery and execute late-stage pharmaceutical modification with complementary reactivity. However, the canonical methods always result in functionalization at the less-crowded site. Herein, we describe a solution to switch the reaction site through fundamentally overcoming the steric control that dominates such processes. By rapidly establishing an equilibrium between a-amino C(sp3 )-H bonds and a highly electrophilic thiol radical via reversible hydrogen atom transfer, we leverage a slower radical-trapping step with electron-deficient olefins to selectively forge a C(sp3 )-C(sp3 ) bond with the more-crowded a-amino radical, with the overall selectivity guided by Curtin-Hammett principle. This subtle reaction profile has unlocked a new strategic concept in direct C-H functionalization arena for forging C– C bonds from a diverse set of trialkylamines with high levels of site-selectivity and preparative utility. Simple correlation of site-selectivity and 13C NMR shift serves as a qualitative predictive guide. The broad consequences of this dynamic system, together with the ability to forge N-substituted quaternary carbon centers and implement late-stage functionalization techniques, holds tremendous potential to streamline complex trialkylamine synthesis and accelerate drug discovery

scholarly journals Cationic DABCO-based Catalyst for Site-Selective C−H Alkylation via Photoinduced Hydrogen-Atom Transfer

2021 ◽  
Author(s):  
Akira Matsumoto ◽  
Keiji Maruoka
Keyword(s):  
Hydrogen Atom ◽  
Nitrogen Atom ◽  
Crucial Role ◽  
Active Species ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Mechanistic Studies ◽  
Complex Molecules ◽  
Site Selectivity ◽  
Site Selective

A novel class of hydrogen-atom transfer (HAT) catalysts based on the readily available and tunable 1,4-diazabicyclo[2.2.2]octane (DABCO) structure was designed, and their photoinduced HAT catalysis ability was demonstrated. The combination of the optimal HAT catalyst with an acridinium-based organophotoredox catalyst enables highly efficient and site-selective C−H alkylation of substrates ranging from unactivated hydrocarbons to complex molecules. Notably, a HAT catalyst with additional substituents adjacent to a nitrogen atom further improved the site-selectivity. Mechanistic studies suggested that the N-substituent of the catalyst plays a crucial role, assisting in the generation of a dicationic aminium radical as an active species for the HAT process.

Site-selective C(sp3)-H Functionalizations Mediated by Hydrogen Atom Transfer Reactions via α-Amino/α-Amido Radicals

Synthesis ◽  
2021 ◽  
Author(s):  
Jaspreet Kaur ◽  
Joshua Philip Barham
Keyword(s):  
Hydrogen Atom ◽  
Three Dimensional ◽  
Hydrogen Atom Transfer ◽  
Dimensional Structure ◽  
Atom Transfer ◽  
Bond Polarity ◽  
Recent Developments ◽  
A Site ◽  
Site Selective ◽  
And Control

Amines and amides, as N-containing compounds, are ubiquitous in pharmaceutically active scaffolds, natural products, agrochemicals and peptides. Amides in nature bear key responsibility for three-dimensional structure, such as in proteins. Structural modifications to amines and amides, especially at their positions α- to N, bring about profound changes in biological activity oftentimes leading to more desirable pharmacological profiles of small molecule drugs. A number of recent developments in synthetic methodology for the functionalizations of amines and amides omit the need of directing groups or pre-functionalizations, achieving direct activation of the otherwise benign C(sp3)-H bond. Among these, hydrogen atom transfer (HAT) has proven a very powerful platform for the selective activation of amines and amides to their α-amino and α-amido radicals, which can then be employed to furnish C-C and C-X (X=heteroatom) bonds. The ability to both form these radicals and control their reactivity in a site-selective manner is of utmost importance for such chemistries to witness applications in late-stage functionalization. Therefore, this review captures contemporary HAT strategies to realize chemo- and regioselective amine and amide α-C(sp3)-H functionalization, based on bond strength, bond polarity, reversible HAT equilibria, traceless electrostatic directing auxiliaries and steric effects of in situ-generated HAT agents.

scholarly journals Site-Selective A-C-H Functionalization of Trialkylamines via Reversible Hydrogen Atom Transfer Catalysis

2021 ◽  
Author(s):  
Yangyang Shen ◽  
Franziska Schoenebeck ◽  
Ignacio Funes-Ardoiz ◽  
Tomislav Rovis
Keyword(s):  
Drug Discovery ◽  
Hydrogen Atom ◽  
Late Stage ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Bond Functionalization ◽  
Carbon Centers ◽  
Radical Trapping ◽  
Site Selectivity ◽  
Site Selective

Trialkylamines are widely found in naturally-occurring alkaloids, synthetic agrochemicals, biological probes, and especially pharmaceuticals agents and pre-clinical candidates. Despite the recent breakthrough of catalytic alkylation of dialkylamines, the selective a-C(sp3 )–H bond functionalization of widely available trialkylamine scaffolds holds promise to streamline complex trialkylamine synthesis, accelerate drug discovery and execute late-stage pharmaceutical modification with complementary reactivity. However, the canonical methods always result in functionalization at the less-crowded site. Herein, we describe a solution to switch the reaction site through fundamentally overcoming the steric control that dominates such processes. By rapidly establishing an equilibrium between a-amino C(sp3 )-H bonds and a highly electrophilic thiol radical via reversible hydrogen atom transfer, we leverage a slower radical-trapping step with electron-deficient olefins to selectively forge a C(sp3 )-C(sp3 ) bond with the more-crowded a-amino radical, with the overall selectivity guided by Curtin-Hammett principle. This subtle reaction profile has unlocked a new strategic concept in direct C-H functionalization arena for forging C– C bonds from a diverse set of trialkylamines with high levels of site-selectivity and preparative utility. Simple correlation of site-selectivity and 13C NMR shift serves as a qualitative predictive guide. The broad consequences of this dynamic system, together with the ability to forge N-substituted quaternary carbon centers and implement late-stage functionalization techniques, holds tremendous potential to streamline complex trialkylamine synthesis and accelerate drug discovery

Photocatalytic, site-selective oxidations of carbohydrates

2021 ◽  
Author(s):  
Daniel J. Gorelik ◽  
Victoria Dimakos ◽  
Timur Adrianov ◽  
Mark S. Taylor
Keyword(s):  
Hydrogen Atom ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Co Catalyst ◽  
Site Selective

Pyranosides undergo site-selective, aerobic oxidations using a photocatalyst, hydrogen atom transfer mediator and bond-weakening co-catalyst.

scholarly journals Cationic DABCO-based Catalyst for Site-Selective C−H Alkylation via Photoinduced Hydrogen-Atom Transfer

2021 ◽  
Author(s):  
Akira Matsumoto ◽  
Keiji Maruoka
Keyword(s):  
Hydrogen Atom ◽  
Nitrogen Atom ◽  
Crucial Role ◽  
Active Species ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Mechanistic Studies ◽  
Complex Molecules ◽  
Site Selectivity ◽  
Site Selective

A novel class of hydrogen-atom transfer (HAT) catalysts based on the readily available and tunable 1,4-diazabicyclo[2.2.2]octane (DABCO) structure was designed, and their photoinduced HAT catalysis ability was demonstrated. The combination of the optimal HAT catalyst with an acridinium-based organophotoredox catalyst enables highly efficient and site-selective C−H alkylation of substrates ranging from unactivated hydrocarbons to complex molecules. Notably, a HAT catalyst with additional substituents adjacent to a nitrogen atom further improved the site-selectivity. Mechanistic studies suggested that the N-substituent of the catalyst plays a crucial role, assisting in the generation of a dicationic aminium radical as an active species for the HAT process.

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