Bromination of Cycloparaphenylenes: Strain-Induced Site-Selective Bis-Addition and Its Application for Late-Stage Functionalization

2017 ◽  
Vol 129 (35) ◽  
pp. 10564-10568 ◽  
Author(s):  
Eiichi Kayahara ◽  
Rui Qu ◽  
Shigeru Yamago
Keyword(s):  
Late Stage ◽  
Site Selective

Remote C–H Functionalizations by Ruthenium Catalysis

Synthesis ◽  
2021 ◽  
Author(s):  
Korkit Korvorapun ◽  
Ramesh C. Samanta ◽  
Torben Rogge ◽  
Lutz Ackermann
Keyword(s):  
Steric Hindrance ◽  
Late Stage ◽  
Crop Protection ◽  
Full Control ◽  
Site Selectivity ◽  
Important Approach ◽  
Distinct Character ◽  
Ruthenium Catalysis ◽  
Material Sciences ◽  
Site Selective

Synthetic transformations of otherwise inert C–H bonds have emerged as a powerful tool for molecular modifications during the last decades, with broad applications towards pharmaceuticals, material sciences and crop protection. Consistently, a key challenge in C–H activation chemistry is the full control of site-selectivity. In addition to substrate control through steric hindrance or kinetic acidity of C–H bonds, one important approach for the site-selective C–H transformation of arenes is the use of chelation-assistance through directing groups, therefore leading to proximity-induced ortho-C–H metalation. In contrast, more challenging remote C–H activations at the meta- or para-positions continue to be scarce. Within this review, we demonstrate the distinct character of ruthenium catalysis for remote C–H activations until March 2021, highlighting among others late-stage modifications of bio-relevant molecules. Moreover, we highlight important mechanistic insights by experiments and computation, highlighting the key importance of carboxylate-assisted C–H activation with ruthenium(II) complexes.

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 Alkoxylation of Benzylic C–H Bonds via Photoredox Catalysis

2019 ◽  
Author(s):  
Byung Joo Lee ◽  
kimberly deglopper ◽  
Tehshik Yoon
Keyword(s):  
Late Stage ◽  
Functional Group ◽  
Bond Formation ◽  
Bioactive Molecules ◽  
Site Selectivity ◽  
Wide Range ◽  
High Site ◽  
Alkoxy Groups ◽  
Site Selective ◽  
Mediated Oxidation

<div> <div> <div> <p>There are relatively few methods that accom- plish the selective alkoxylation of sp3-hybridized C–H bonds, particularly in comparison to the numerous analogous strate- gies for C–N and C–C bond formation. We report a photo- catalytic protocol for the functionalization of benzylic C–H bonds with a wide range of readily available oxygen nucleo- philes. Our strategy merges the photoredox activation of arenes with copper(II)-mediated oxidation of the resulting benzylic radicals, which enables the introduction of benzylic C–O bonds with high site selectivity, chemoselectivity, and functional group tolerance. This method enables the late- stage introduction of complex alkoxy groups into bioactive molecules, providing a practical new tool with potential appli- cations in synthesis and medicinal chemistry. </p> </div> </div> </div>

scholarly journals Photoredox Catalyzed Site-Selective Generation of Carbanions from C(sp3)-H bonds in Amines

2021 ◽  
Author(s):  
Kathiravan Murugesan ◽  
Karsten Donabauer ◽  
Rok Narobe ◽  
Armin Bauer ◽  
Volker Derdau ◽  
...  
Keyword(s):  
Hydrogen Bonds ◽  
Late Stage ◽  
Carbonyl Compounds ◽  
Chemical Research ◽  
Selective Activation ◽  
Mechanistic Investigation ◽  
Specific Position ◽  
Selective Generation ◽  
Carbon Hydrogen Bonds ◽  
Site Selective

The selective activation of sp3 carbon-hydrogen bonds in presence of multiple C¬-H bonds is challenging and remains of supreme importance in chemical research. Herein, we describe the activation of a C(sp3) H bond in α position to an amine via a carbanion intermediate. In the presence of several α amine sites, only one specific position is selectively activated. Applying this protocol, the proposed carbanion intermediate was effectively trapped with different electrophiles such as deuterium (D+), tritium (T+), or carbonyl compounds compiling over 50 examples. Further, this methodology was used to install deuterium or tritium in different drug derivatives (> 10 drugs) at a selected position in a late-stage functionalization. In addition, the protocol is suitable for a gram-scale synthesis and a detailed mechanistic investigation has been carried out to support our hypothesis.

scholarly journals A general arene C–H functionalization strategy via electron donor-acceptor complex photoactivation

2021 ◽  
Author(s):  
Abhishek Dewanji ◽  
Leendert van Dalsen ◽  
James Rossi-Ashton ◽  
Eloise Gasson ◽  
Giacomo Crisenza ◽  
...  
Keyword(s):  
Electronic Properties ◽  
Electron Donor ◽  
Late Stage ◽  
Aryl Halide ◽  
Aryl Radical ◽  
Sulfonium Salt ◽  
Radical Species ◽  
Metal Free ◽  
Donor Acceptor ◽  
Site Selective

The photoactivation of electron donor-acceptor (EDA) complexes has emerged as a sustainable, selective and versa-tile strategy for the generation of radical species. However, when it comes to aryl radical formation, this strategy remains hamstrung by the electronic properties of the aromatic radical precursors and electron-deficient aryl halide acceptors are required. This has prevented the implementation of a general synthetic platform for aryl radical for-mation. Our study introduces triarylsulfonium salts as acceptors in photoactive EDA-complexes, used in combina-tion with catalytic amounts of newly-designed amine donors. The sulfonium salt label renders inconsequential the electronic features of the aryl radical precursor and, more importantly, it is installed regioselectively in native aro-matic compounds by C–H sulfenylation. Using this general, site-selective aromatic C–H functionalization approach, we have developed metal-free protocols for the alkylation and cyanation of arenes, and showcased their application in both the synthesis and the late-stage modification of pharmaceuticals and agrochemicals.

scholarly journals Site-Selective C-H Halogenation using Flavin-Dependent Halogenases Identified via Family-Wide Activity Profiling

2019 ◽  
Author(s):  
Brian F. Fisher ◽  
Harrison M. Snodgrass ◽  
Krysten A. Jones ◽  
Mary C. Andorfer ◽  
Jared C. Lewis
Keyword(s):  
Mass Spectrometry ◽  
Directed Evolution ◽  
High Throughput ◽  
Sequence Space ◽  
Late Stage ◽  
Narrow Range ◽  
Function Analysis ◽  
Complex Compounds ◽  
Time Savings ◽  
Site Selective

<p>Herein, we describe the use of a high-throughput mass spectrometry-based screen to evaluate a broad set of over one hundred putative FDH sequences drawn from throughout the FDH family. Halogenases with novel substrate scope and complementary regioselectivity on large, three-dimensionally complex compounds were identified. This effort involved far more extensive sequence-function analysis than has been accomplished using the relatively narrow range of FDHs characterized to date, providing a clearer picture of the regions in FDH sequence space that are most likely to contain enzymes suitable for halogenating small molecule substrates. The representative enzyme panel constructed in this study also provides a rapid means to identify FDHs for lead diversification via late-stage C-H functionalization. In many cases, these enzymes provide activities that required several rounds of directed evolution to accomplish in previous efforts, highlighting that this approach can achieve significant time savings for biocatalyst identification and provide advanced starting points for further evolution.</p>

scholarly journals Aryl Sulfonium Salts for Site‐Selective Late‐Stage Trifluoromethylation

2019 ◽  
Vol 58 (41) ◽  
pp. 14615-14619 ◽  
Author(s):  
Fei Ye ◽  
Florian Berger ◽  
Hao Jia ◽  
Joseph Ford ◽  
Alan Wortman ◽  
...  
Keyword(s):  
Late Stage ◽  
Sulfonium Salts ◽  
Site Selective

Late‐Stage Peptide Macrocyclization by Palladium‐Catalyzed Site‐Selective C−H Olefination of Tryptophan

2020 ◽  
Vol 132 (34) ◽  
pp. 14794-14800
Author(s):  
Zengbing Bai ◽  
Chuangxu Cai ◽  
Wangjian Sheng ◽  
Yuxiang Ren ◽  
Huan Wang
Keyword(s):  
Late Stage ◽  
Palladium Catalyzed ◽  
Site Selective
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