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 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 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 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

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 Hydrogen atom transfer in the photochemical isomerization of hydrazones of 1,2,4-oxadiazole derivatives

2021 ◽  
Author(s):  
Maurizio D’Auria
Keyword(s):  
Hydrogen Atom ◽  
Nitrogen Atom ◽  
Ring Opening ◽  
Singlet State ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Excited Singlet ◽  
Photochemical Isomerization ◽  
Oxadiazole Derivatives ◽  
Concerted Reaction

AbstractDFT calculations on the photoisomerization of hydrazones of 1,2,4-oxadiazole derivatives to 1,2,5-triazoles have been performed showing that the reaction occurred through the first excited singlet state. The Z isomer gave the reaction through a hydrogen atom transfer of the hydrazonic nitrogen atom to the nitrogen atom in four position on the oxadiazole ring. In this case, the isomerization was a concerted reaction. The E isomer could undergo the same reaction. However, it could not be a concerted reaction but required the presence of a ring opening intermediate.

scholarly journals On the Mechanism of Electrochemical Generation and Decomposition of Phthalimide N-oxyl (PINO)

2021 ◽  
Author(s):  
Cheng Yang ◽  
Luke Farmer ◽  
Derek Pratt ◽  
Stephen Maldonado ◽  
Corey Stephenson
Keyword(s):  
Electron Transfer ◽  
Hydrogen Atom ◽  
Catalytic Efficiency ◽  
Hydrogen Atom Transfer ◽  
Second Order ◽  
Atom Transfer ◽  
Multiple Site ◽  
Mechanistic Studies ◽  
Electrochemical Generation ◽  
Bulk Electrolysis

Phthalimide <i>N</i>-oxyl (PINO) is a potent hydrogen atom transfer (HAT) catalyst that can be generated electrochemically from <i>N</i>-hydroxyphthalimide (NHPI). However, catalyst decomposition has limited its application. This paper details mechanistic studies of the generation and decomposition of PINO under electrochemical conditions. Voltammetric data, observations from bulk electrolysis, and <a>computational</a> studies suggest two primary aspects. First, base-promoted formation of PINO from NHPI occurs via multiple-site concerted proton-electron transfer (MS-CPET). Second, PINO decomposition occurs by at least two second-order paths, one of which is greatly enhanced by base. Optimal catalytic efficiency in PINO-catalyzed oxidations occurs in the presence of bases whose corresponding conjugate acids have <a>p<i>K</i><sub>a</sub></a>s in the range of 12-15, which strike a balance between promoting PINO formation and minimizing its decay.

scholarly journals A general strategy for C(sp3)–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Isabelle Nathalie-Marie Leibler ◽  
Makeda A. Tekle-Smith ◽  
Abigail G. Doyle
Keyword(s):  
Hydrogen Atom ◽  
Hydrogen Atom Transfer ◽  
General Strategy ◽  
Photoredox Catalysis ◽  
Mechanistic Studies ◽  
Methyl Radical ◽  
Site Selectivity ◽  
Carbon Centered Radical ◽  
Electrophilic Reagents ◽  
Nucleophilic Reagents

AbstractPhotoredox catalysis has provided many approaches to C(sp3)–H functionalization that enable selective oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp3)–H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical—a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis—enabling new site-selectivity for late-stage C(sp3)–H functionalization.

Enhancing Reactivity and Site-Selectivity in Hydrogen Atom Transfer from Amino Acid C–H Bonds via Deprotonation

2018 ◽  
Vol 20 (3) ◽  
pp. 808-811 ◽  
Author(s):  
Luca Maria Pipitone ◽  
Giulia Carboni ◽  
Daniela Sorrentino ◽  
Marco Galeotti ◽  
Michela Salamone ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hydrogen Atom ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Site Selectivity

scholarly journals Modifying Positional Selectivity in C–H Functionalization Reactions with Nitrogen-Centered Radicals: Generalizable Approaches to 1,6-Hydrogen-Atom Transfer Processes

Synlett ◽  
2019 ◽  
Vol 31 (02) ◽  
pp. 102-116 ◽  
Author(s):  
Melanie A. Short ◽  
J. Miles Blackburn ◽  
Jennifer L. Roizen
Keyword(s):  
Hydrogen Atom ◽  
Functional Groups ◽  
Reactive Species ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Structural Constraints ◽  
Reaction Intermediates ◽  
Transfer Processes ◽  
Selective Functionalization ◽  
Site Selectivity

Nitrogen-centered radicals are powerful reaction intermediates owing in part to their ability to guide position-selective C(sp3)–H functionalization reactions. Typically, these reactive species dictate the site of functionalization by preferentially engaging in 1,5-hydrogen-atom transfer (1,5-HAT) processes. Broadly relevant approaches to alter the site-selectivity of HAT pathways would be valuable because they could be paired with a variety of tactics to install diverse functional groups. Yet, until recently, there have been no generalizable strategies to modify the position-selectivity observed in these HAT processes. This Synpacts article reviews transformations in which nitrogen-centered radicals preferentially react through 1,6-HAT pathways. Specific attention will be focused on strategies that employ alcohol- and amine-anchored sulfamate esters and sulfamides as templates to achieve otherwise rare γ-selective functionalization reactions.1 Introduction2 Transformations that Rely on Structural Constraints or Weakened C–H Bonds to Favor 1,6-HAT Processes3 Sulfamate Esters Engage Selective 1,6-HAT Processes4 Expansion to 1,6-HAT Processes with Masked Amine Substrates5 Conclusions and Outlook

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