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

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.

scholarly journals Site-Selective Allylic C-H Amination with Aliphatic Amines

2021 ◽  
Author(s):  
Shengchun Wang ◽  
Yiming Gao ◽  
Demin Ren ◽  
He Sun ◽  
Linbin Niu ◽  
...  
Keyword(s):  
Hydrogen Atom ◽  
Building Blocks ◽  
Hydrogen Atom Transfer ◽  
Allylic Amines ◽  
Allylic Amination ◽  
Alkyl Amines ◽  
Reaction Proceeds ◽  
Bond Options ◽  
A Site ◽  
Site Selective

Abstract The direct coupling of olefins and alkyl amines represents the most efficient and atom-economical approach to prepare aliphatic allylamines which are fundamental building blocks. However, the method that achieves this goal while exhibiting exquisite control over the site at which the amine is introduced remains elusive. Herein, we report that the combination of a photocatalyst and a cobaloxime enables site-selective allylic C–H amination of olefins with secondary alkyl amines to afford allylic amines, eliminating the need for oxidants. This reaction proceeds by a radical-based mechanism distinct from those of existing allylic amination reactions. It affords the product resulting from cleavage of the stronger, primary allylic C–H bonds over other weaker allylic C–H bond options. DFT calculations reveal that this selectivity originates from a cobaloxime-promoted hydrogen atom transfer (HAT) process. Our method is compatible with a broad scope of alkenes, and can be extended to achieve a site- and diastereoselective amination of natural terpenes.

scholarly journals Tris(acetylacetonato) Iron(III): Recent Developments and Synthetic Applications

Synthesis ◽  
2018 ◽  
Vol 51 (01) ◽  
pp. 161-177 ◽  
Author(s):  
Dennis Lübken ◽  
Marius Saxarra ◽  
Markus Kalesse
Keyword(s):  
Hydrogen Atom ◽  
Natural Product ◽  
Cross Coupling ◽  
Short Review ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Coupling Reactions ◽  
Total Syntheses ◽  
Cross Coupling Reactions ◽  
Recent Developments

Tris(acetylacetonato) iron(III) [Fe(acac)3] is an indispensable reagent in synthetic chemistry. Its applications range from hydrogen atom transfer to cross-coupling reactions and to use as a Lewis acid. Consequently, the exceptional utility of Fe(acac)3 has been demonstrated in several total syntheses. This short review summarizes the applications of Fe(acac)3 in methodology and catalysis and highlights its use for the synthesis of medicinally relevant structures and in natural product syntheses.1 Introduction2 Hydrogen Atom Transfer (HAT)3 Oxidations and Radical Transformations4 Synthesis and Use of Alkynes and Allenes5 Cross-Couplings and Cycloisomerizations6 Borylations7 Miscellaneous Reactions8 Conclusions

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 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.

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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