Triazenyl Alkynes as Versatile Building Blocks in Multicomponent Reactions: Diastereoselective Synthesis of β‐Amino Amides

Wang, Chaorong; Lai, Zhencheng; Xie, Hujun; Cui, Sunliang

doi:10.1002/ange.202014686

Cited by 6 publications

(2 citation statements)

References 74 publications

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“…As mentioned above, the challenge for unactivated C(sp 3 )−H bonds to involve in Mannich reactions is attributed to their difficult deprotonation and therefore non-nucleophilic properties. In continuation of our interest in multi-component reactions and drug discovery [28][29][30][31] , we hypothesized that the benzylic C(sp 3 )−H bond might possess sufficient reactivity through the electronic effect of (hetero)arenes, thus enabling Mannich type alkylamination. After considerable exploration and optimization of conditions, we realized this hypothesis using electron-rich benzofurans as heteroaryl substrates.…”

Section: Resultsmentioning

confidence: 99%

Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds

Lai

et al. 2022

Nat Commun

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Alkylamines are ubiquitous in pharmaceuticals, materials and agrochemicals. The Mannich reaction is a well-known three-component reaction for preparing alkylamines and has been widely used in academic research and industry. However, the nucleophilic components in this process rely on C(sp2)−H and activated C(sp3)−H bonds while the unactivated C(sp3)−H bonds involved Mannich alkylamination is a long-standing challenge. Here, we report an unprecedented multicomponent double Mannich alkylamination for both C(sp2)−H and unactivated benzylic C(sp3)−H bonds. In this process, various 3-alkylbenzofurans, formaldehyde and alkylamine hydrochlorides assemble efficiently to furnish benzofuran-fused piperidines. Mechanistic studies and density functional theory (DFT) calculations revealed a distinctive pathway that a multiple Mannich reaction and retro-Mannich reaction of benzofuran and dehydrogenation of benzylic C(sp3)−H bonds were key steps to constitute the alkylamination. This protocol furnishes a Mannich alkylamine synthesis from unusual C–H inputs to access benzofuran-fused piperidines with exceptional structural diversity, molecular complexity and drug-likeness. Therefore, this work opens a distinctive vision for the alkylamination of unactivated C(sp3)−H bonds, and provides a powerful tool in diversity-oriented synthesis (DOS) and drug discovery.

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Section: Resultsmentioning

confidence: 99%

Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds

Lai

et al. 2022

Nat Commun

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“…Some other added advantages are improved yields, higher selectivity, facile construction of complex molecules, and no need for isolation of intermediates ( Cioc et al, 2014 ). In recent years, the research endeavors focused on developing new MCRs, and several synthetic protocols have been reported in this direction ( Jethava et al, 2020 ; Wang et al, 2021 ). The amalgamation of MCRs with a naturally occurring catalyst renders a more environmental-friendly chemical methodology.…”

Section: Introductionmentioning

confidence: 99%

Novel Pyran-Linked Phthalazinone-Pyrazole Hybrids: Synthesis, Cytotoxicity Evaluation, Molecular Modeling, and Descriptor Studies

et al. 2021

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A series of novel pyran-linked phthalazinone-pyrazole hybrids were designed and synthesized by a facile one-pot three-component reaction employing substituted phthalazinone, 1H-pyrazole-5-carbaldehyde, and active methylene compounds. Optimization studies led to the identification of L-proline and ethanol as efficient catalyst and solvent, respectively. This was followed by evaluation of anticancer activity against solid tumor cell lines of lung and cervical carcinoma that displayed IC50 values in the range of 9.8–41.6 µM. Molecular modeling studies were performed, and crucial interactions with the target protein were identified. The drug likeliness nature of the compounds and molecular descriptors such as molecular flexibility, complexity, and shape index were also calculated to understand the potential of the synthesized molecules to act as lead-like molecule upon further detailed biological investigations as well as 3D-QSAR studies.

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Metal‐Catalyzed Coupling of N‐Tosylhydrazones with Compounds Containing C−H/Heteroatom‐H Bonds

Akanksha,

Singh,

Asthana

et al. 2024

Asian J Org Chem

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The present review covers various advances in the field of metal‐catalyzed coupling of N‐tosylhydrazones with compounds containing C‐H/heteroatom‐H bonds, including transition metal catalysts i.e., Pd, Rh, Cu, Ag, Ni and Co and resulting alkylated, alkenylated, alkynylated, allenylated, annulated and many other products. A metal carbene migratory insertion process play a key role in carbon‐carbon single bond (C‐C) and carbon‐carbon double bond (C=C) formation and undergoes variety of cascade reactions to synthesize a wide scope of pharmaceutically and medicinally valuable scaffoldings.

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Triazenyl Alkynes as Versatile Building Blocks in Multicomponent Reactions: Diastereoselective Synthesis of β‐Amino Amides

Cited by 6 publications

References 74 publications

Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds

Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds

Novel Pyran-Linked Phthalazinone-Pyrazole Hybrids: Synthesis, Cytotoxicity Evaluation, Molecular Modeling, and Descriptor Studies

Metal‐Catalyzed Coupling of N‐Tosylhydrazones with Compounds Containing C−H/Heteroatom‐H Bonds

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