De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis
Abstract Precise control on the product selectivity of a reaction is an important objective in organic synthesis. α-ketoamides are vital intermediates in chemical transformation and privileged motifs in numerous drugs, natural products and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing challenge in catalysis. Herein we disclose an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction of (hetero)aryl halides or pseudohalides for the assembly α-ketoamides in aqueous DMSO under mild conditions. The effectiveness and utility of this protocol are demonstrated by diverse substrate scope (85 examples), late-stage modification of pharmaceuticals, scalability in large-scale synthesis, transformations of functional groups, as well as the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand to modulate the Pd-catalyzed double isocyanide insertion process, thus selectively providing the desired α-ketoamides in a unique manner. In addition, imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, proving them the probable intermediates in the catalytic pathway..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ResearchSquare.com - (2024) vom: 22. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Han, Wen-Yong [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-4272667/v1 |
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| 520 | |a Abstract Precise control on the product selectivity of a reaction is an important objective in organic synthesis. α-ketoamides are vital intermediates in chemical transformation and privileged motifs in numerous drugs, natural products and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing challenge in catalysis. Herein we disclose an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction of (hetero)aryl halides or pseudohalides for the assembly α-ketoamides in aqueous DMSO under mild conditions. The effectiveness and utility of this protocol are demonstrated by diverse substrate scope (85 examples), late-stage modification of pharmaceuticals, scalability in large-scale synthesis, transformations of functional groups, as well as the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand to modulate the Pd-catalyzed double isocyanide insertion process, thus selectively providing the desired α-ketoamides in a unique manner. In addition, imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, proving them the probable intermediates in the catalytic pathway. | ||
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| 700 | 1 | |a Liu, Lu-Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Tu, Li-Ping |e verfasserin |4 aut | |
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