The ortho effect in directed C–H activation

Tóth, Balázs L.; Monory, Anna; Egyed, Orsolya; Domján, Attila; Bényei, Attila; Szathury, Bálint; Novàk, Zoltán; Stirling, András

doi:10.1039/d1sc00642h

Cited by 31 publications

(27 citation statements)

References 122 publications

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“…Substituents on the directing group and in the ortho position of the system to be functionalized can negatively affect the reaction outcome by twisting the directing group out of plane. 45 The reaction solvent is chosen based on the desired application. While DCE showed the best overall performance, substitution of EtOAc and CPME is possible if the use of a greener solvent is desired.…”

Section: Resultsmentioning

confidence: 99%

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Merging Directed C–H Activations with High-Throughput Experimentation: Development of Iridium-Catalyzed C–H Aminations Applicable to Late-Stage Functionalization

Weis

Johansson

Korsgren

et al. 2022

JACS Au

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Herein, we report an iridium-catalyzed directed C–H amination methodology developed using a high-throughput experimentation (HTE)-based strategy, applicable for the needs of automated modern drug discovery. The informer library approach for investigating the accessible directing group chemical space, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of reaction application guidelines to aid future users. Applicability to late-stage functionalization of complex drugs and natural products, in combination with multiple deprotection protocols leading to the desirable aniline matched pairs, serve to demonstrate the utility of the method for drug discovery. Finally, reaction miniaturization to a nanomolar range highlights the opportunities for more sustainable screening with decreased material consumption.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Merging Directed C–H Activations with High-Throughput Experimentation: Development of Iridium-Catalyzed C–H Aminations Applicable to Late-Stage Functionalization

Weis

Johansson

Korsgren

et al. 2022

JACS Au

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“…The transformation was extended with the ( Z )‐tri‐fluoropropenylation of 2‐methylacetanilide ( 4 ) using iodonium salt 2 , and the reaction provided the corresponding product 18 in 80% of yield. Since 2 showed decreased reactivity due to the so‐called ortho effect, [19] in order to reach full conversion, the application of forcing conditions (75 °C, 6 h and 1,2‐DCE) was necessary. Similarly, the ( Z )‐heptafluoropentenylation reaction with 3 at elevated temperature produced the product 19 in excellent, 95% of yield.…”

Section: Resultsmentioning

confidence: 99%

Z‐Selective Fluoroalkenylation of (Hetero)Aromatic Systems by Iodonium Reagents in Palladium‐Catalyzed Directed C−H Activation

et al. 2021

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The direct and catalytic incorporation of fluorine containing molecular motifs into organic compounds resulting high-value added chemicals represents a rapidly evolving part of synthetic methodologies, thus this area is in the focus of pharmaceutical and agrochemical research. Herein we report a stereoselective procedure for direct fluorovinylation of aromatic and heteroaromatic scaffolds. This methodology development has been realized by palladium-catalyzed ortho CÀ H activation reaction of aniline derivatives featuring the regioselectivity via directing groups such as secondary of tertiary amides, ureas or ketones. The application of non-symmetrical aryl(fluoroalkenyl)-iodonium salts as fluoroalkenylating agents allowed mild reaction conditions in general for this transformation. The scope and limitations have been thoroughly investigated and the feasibility has been demonstrated by more than 50 examples.

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“…Substituents on the directing group and in the ortho position of the system to be functionalized can negatively affect the reaction outcome by twisting the directing group out of plane. 44 4) Reaction solvent is chosen based on desired application. While DCE showed best overall performance, substitution by EtOAc and CPME is possible if the use of a greener solvent is desired.…”

Section: Application Guidelinesmentioning

confidence: 99%

Merging Directed C−H Activations with High-Throughput Experimentation: Development of Predictable Iridium-Catalyzed C−H Aminations Applicable to Late-Stage Functionalization

Weis

Johansson

Korsgren

et al. 2021

Preprint

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Herein, we report an iridium-catalyzed directed C−H amination methodology developed using a high-throughput experimentation (HTE)-based strategy, applicable for the needs of automated modern drug discovery. The informer library approach for investigating accessible directing group chemical space for the reaction, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of an empirical predictive model to guide future users. Applicability to late-stage functionalization of complex drugs and natural products, in combination with multiple deprotection protocols leading to the desirable aniline matched pairs, serve to demonstrate the utility of the method for drug discovery. Finally reaction miniaturization to a nano molar range highlights the opportunities for more sustainable screening with decreased material consumption.

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The ortho effect in directed C–H activation

Abstract: The term and concept of Ortho Effect (OE) is introduced for the description of steric effects in transition metal catalyzed directed ortho C–H activation reactions to explain and predict reactivities of substrates.

Cited by 31 publications

References 122 publications

Merging Directed C–H Activations with High-Throughput Experimentation: Development of Iridium-Catalyzed C–H Aminations Applicable to Late-Stage Functionalization

Merging Directed C–H Activations with High-Throughput Experimentation: Development of Iridium-Catalyzed C–H Aminations Applicable to Late-Stage Functionalization

Z‐Selective Fluoroalkenylation of (Hetero)Aromatic Systems by Iodonium Reagents in Palladium‐Catalyzed Directed C−H Activation

Merging Directed C−H Activations with High-Throughput Experimentation: Development of Predictable Iridium-Catalyzed C−H Aminations Applicable to Late-Stage Functionalization

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