CuH‐Catalyzed Asymmetric Hydroamidation of Vinylarenes

Zhou, Yujing; Engl, Oliver D.; Bandar, Jeffrey S.; Chant, Emma D.; Buchwald, Stephen L.

doi:10.1002/ange.201802797

Cited by 17 publications

(4 citation statements)

References 38 publications

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“…As a second and conceptually distinct approach, intermolecular hydroamidation via transition metal-mediated π-bond activation has been pursued. However, for years limited success has been achieved with the Markovnikov-selective functionalization of unactivated olefins, and examples of α-tertiary amide synthesis are particularly rare 29 – 33 .…”

Section: Introductionmentioning

confidence: 99%

Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation

et al. 2021

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Abstractα-Tertiary amides are of great importance for medicinal chemistry. However, they are often challenging to access through conventional methods due to reactivity and chemoselectivity issues. Here, we report a single-step approach towards such amides via cobalt-catalyzed intermolecular oxidative hydroamidation of unactivated alkenes, using nitriles of either solvent- or reagent-quantities. This protocol is selective for terminal alkenes over groups that rapidly react under known carbocation amidation conditions such as tertiary alcohols, electron-rich alkenes, ketals, weak C−H bonds, and carboxylic acids. Straightforward access to a diverse array of hindered amides is demonstrated, including a rapid synthesis of an aminoadamantane-derived pharmaceutical intermediate.

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Section: Introductionmentioning

confidence: 99%

Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation

et al. 2021

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“…Specifically, copper(I) hydride complexes have been shown to catalyze hydroamination reactions between alkenes and hydroxylamine esters. 14 Despite the number of electrophilic aminating reagents that have been developed for the synthesis of chiral secondary 15 and tertiary amines 16–25 as well as amides 26 , there have not been any reports of enantioselective transformations that allow for the direct synthesis of primary amines from olefins, in part due to the lack of a suitable electrophilic amine source.…”

Section: Introductionmentioning

confidence: 99%

A Practical Electrophilic Nitrogen Source for the Synthesis of Chiral Primary Amines by Copper-Catalyzed Hydroamination

2018

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A mild and practical method for the catalytic installation of the amino group across alkenes and alkynes has long been recognized as a significant challenge in synthetic chemistry. As the direct hydroamination of olefins using ammonia requires harsh conditions, the development of suitable electrophilic aminating reagents for formal hydroamination methods is of importance. Herein, we describe the use of 1,2-benzisoxazole as a practical electrophilic primary amine source. Using this heterocycle as a new amino group delivery agent, a mild and general protocol for the copper-hydride-catalyzed hydroamination of alkenes and alkynes to form primary amines was developed. This method provides access to a broad range of chiral α-branched primary amines and linear primary amines, as demonstrated by the efficient synthesis of the antiretroviral drug Maraviroc and the formal synthesis of several other pharmaceutical agents.

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“…Given the recent advances in asymmetric C–H bond functionalization with chiral Rh(III) catalysis 30 – 33 , we also investigated a number of chiral catalysts for the asymmetric synthesis of α-methyl branched amines (see Supplementary Table 3 ). The Rh-complex 59 employing Cramer’s elegantly designed chiral ligand 34 , gave the most promising initial results with 86:14 to 92:8 enantiomer ratios obtained for α-methyl branched amines 60 - 63 incorporating different directing groups and both electron-poor and electron rich aromatic amides 7 ( Fig 4d ).…”

Section: Resultsmentioning

confidence: 99%

“…α-Branched amines displaying an exceedingly broad range of functionality have been incorporated into many approved pharmaceuticals and clinical candidates ( Fig. 1a ) 1 – 7 . The synthesis of α-branched amines by formation of a C–C bond at the sp 3 carbon branch site is strategic because it enables a convergent preparation from smaller precursors with simultaneous introduction of a stereogenic centre 8 .…”

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confidence: 99%

α-Branched amines by catalytic 1,1-addition of C–H bonds and aminating agents to terminal alkenes

2019

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α-Branched amines are present in hundreds of pharmaceutical agents and clinical candidates and are important targets for synthesis. Here we show the convergent synthesis of α-branched amines from three readily accessible starting materials: aromatic C–H bond substrates, terminal alkenes, and aminating agents. This reaction proceeds by an intermolecular formation of C–C and C–N bonds at the sp 3 carbon branch site through an uncommon 1,1-alkene addition pathway. The reaction is carried out under mild conditions and has high functional group compatibility. Ethylene and propylene feedstock chemicals are effective alkene inputs with ethylene in particular providing for the one step synthesis of α-methyl branched amines, a motif prevalent in drug structures. The reaction is scalable, and 1% loading of an air stable dimeric rhodium precatalyst is effective for several different types of products. The use of chiral catalysts also enables the asymmetric synthesis of α-branched amines.

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CuH‐Catalyzed Asymmetric Hydroamidation of Vinylarenes

Cited by 17 publications

References 38 publications

Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation

Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation

A Practical Electrophilic Nitrogen Source for the Synthesis of Chiral Primary Amines by Copper-Catalyzed Hydroamination

α-Branched amines by catalytic 1,1-addition of C–H bonds and aminating agents to terminal alkenes

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