C–H Bond Functionalization of Amines: A Graphical Overview of Diverse Methods

Dutta, Subhradeep; Li, Bowen; Rickertsen, Dillon R. L.; Valles, Daniel A.; Seidel, Daniel

doi:10.1055/s-0040-1706051

Cited by 52 publications

(16 citation statements)

References 466 publications

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“…Starting material 2f reacted with bromostyrene 1a , bromomaleate 1d , and bromopyridin-2(1 H )-one 1g , affording the desired alkenylated products 3p , 3q , and 3r in 62, 65, and 50% yields, respectively. With these challenging substituted and heterocyclic substrates, starting materials 2b – f were easily recycled under the standard conditions. However, the mass balances were high, indicating the high chemoselectivity of the reaction.…”

Section: Resultsmentioning

confidence: 99%

Directed Palladium-Catalyzed γ-C(sp³)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Gadde,

Bheemireddy,

Heitkämper

et al. 2024

ACS Catal.

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Directed palladium-catalyzed coupling of remote C(sp3)–H bonds of aliphatic amines with organohalides is a powerful synthetic tool. However, these reactions still possess limitations with respect to cost and resource efficiency, requiring more reactive iodinated reactants and superstoichiometric silver salt reagents. In this work, an efficient regio- and stereospecific silver-free Pd-catalyzed γ-C(sp3)–H alkenylation of cyclohexanamines and heterocyclic analogues with bromoalkenes is reported, which can also be applied on five- and seven-membered rings. DFT methods revealed that the oxidative addition of the organobromide to Pd(II) is not the rate-limiting step but rather γ-C(sp3)–H bond activation in the substrate. The lowest energy complex in the catalytic cycle is a Pd(II)-Br complex coordinated with the reaction product (η2-alkene and a bidentate directing group). The stability of this complex defines the overall energy span of the reaction. Co-catalyst KOPiv plays a pivotal role by exchanging bromide for pivalate in the complex, via precipitation of the KBr coproduct. This removal of bromide from the reaction media decreases the energy span, avoiding the use of superstoichiometric silver salt reagents and allowing decoordination of the reaction product. In addition, pivalate facilitates the C(sp3)–H bond activation in the substrate once another substrate molecule is coordinated. The reaction conditions could be directly applied for (hetero)arylation given the weaker coordination of the reaction product, featuring a (hetero)aryl versus alkenyl and change in resting state. The picolinoyl directing group can be removed via amide esterification.

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Section: Resultsmentioning

confidence: 99%

Directed Palladium-Catalyzed γ-C(sp³)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Gadde,

Bheemireddy,

Heitkämper

et al. 2024

ACS Catal.

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“…Mechanistically, the crux of the alkylamine dehydrogenation revolves around the cleavage of the unreactive α C−H bond. 6,7 As illustrated in Figure 1b, various strategies have been explored to effect this Cα−H bond cleavage, including deprotonation (H + transfer) with vicinal dicarbonyl reagents, 8 hydrogen atom transfer or single electron transfer/deprotonation, 9−11 and metal-catalyzed hydride (H − ) transfer reactions. 12,13 In addition to metalcatalyzed pathways, hydride transfer within alkylamines can also occur without metal assistance, although primarily in intramolecular settings.…”

Section: ■ Introductionmentioning

confidence: 99%

Formaldehyde-Mediated Hydride Liberation of Alkylamines for Intermolecular Reactions in Hexafluoroisopropanol

Cai,

Tang,

et al. 2024

J. Am. Chem. Soc.

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The ability of alkylamines to spontaneously liberate hydride ions is typically restrained, except under specific intramolecular reaction settings. Herein, we demonstrate that this reactivity can be unlocked through simple treatment with formaldehyde in hexafluoroisopropanol (HFIP) solvent, thereby enabling various intermolecular hydride transfer reactions of alkylamines under mild conditions. Besides transformations of small molecules, these reactions enable unique late-stage modification of complex peptides. Mechanistic investigations uncover that the key to these intermolecular hydride transfer processes lies in the accommodating conformation of solvent-mediated macrocyclic transition states, where the aggregates of HFIP molecules act as dexterous proton shuttles. Importantly, negative hyperconjugation between the lone electron pair of nitrogen and the antibonding orbital of amine's α C−H bond plays a critical role in the C−H activation, promoting its hydride liberation.

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“…It has been observed that organic chemists have frequently utilized 1,2,3,4-tetrahydroisoquinolines (THIQs) by activating the α-C(sp 3 )–H position to produce a large variety of biologically important natural and unnatural compounds . Recently, the functionalization of the C–H bond of amines in general and amines having azomethine ylide intermediates has captured the attention of organic chemists due to the wide applicability of such approaches in the synthesis of desired targets. , It is noteworthy to mention that, in most of the cases, α-C(sp 3 )–H activation of THIQs has been realized with protected amines …”

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confidence: 99%

[2 + 3] Annulative Coupling of Tetrahydroisoquinolines with Aryliodonio diazo compounds To Access 1,2,4-Triazolo[3,4-a]isoquinolines

et al. 2022

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Base promoted one-pot annulative coupling of 1,2,3,4tetrahydroisoquinolines (THIQs) with hypervalent iodine(III) species aryliodonio diazo compounds has been devised for the direct construction of 1,2,4-triazolo[3,4-a]isoquinoline derivatives at room temperature in open air for the first time. This approach involves [2 + 3] cascade annulation of nucleophilic THIQ with an electrophilic aryliodonio diazo compound via N−H and α-C1(sp 3 )−H difunctionalization of THIQ.

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C–H Bond Functionalization of Amines: A Graphical Overview of Diverse Methods

Abstract: This Graphical Review provides a concise overview of the manifold and mechanistically diverse methods that enable the functionalization of sp3 C–H bonds in amines and their derivatives.

Cited by 52 publications

References 466 publications

Directed Palladium-Catalyzed γ-C(sp³)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Directed Palladium-Catalyzed γ-C(sp³)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Formaldehyde-Mediated Hydride Liberation of Alkylamines for Intermolecular Reactions in Hexafluoroisopropanol

[2 + 3] Annulative Coupling of Tetrahydroisoquinolines with Aryliodonio diazo compounds To Access 1,2,4-Triazolo[3,4-a]isoquinolines

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C–H Bond Functionalization of Amines: A Graphical Overview of Diverse Methods

Abstract: This Graphical Review provides a concise overview of the manifold and mechanistically diverse methods that enable the functionalization of sp3 C–H bonds in amines and their derivatives.

Cited by 52 publications

References 466 publications

Directed Palladium-Catalyzed γ-C(sp3)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Directed Palladium-Catalyzed γ-C(sp3)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Formaldehyde-Mediated Hydride Liberation of Alkylamines for Intermolecular Reactions in Hexafluoroisopropanol

[2 + 3] Annulative Coupling of Tetrahydroisoquinolines with Aryliodonio diazo compounds To Access 1,2,4-Triazolo[3,4-a]isoquinolines

Contact Info

Product

Resources

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Directed Palladium-Catalyzed γ-C(sp³)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Directed Palladium-Catalyzed γ-C(sp³)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging