Synthesis of Substituted 1,4-Benzodiazepines by Palladium-Catalyzed Cyclization of <i>N</i>-Tosyl-Disubstituted 2-Aminobenzylamines with Propargylic Carbonates
A synthesis of substituted 1,4-benzodiazepines has been developed via palladium-catalyzed cyclization of <i>N</i>-tosyl-disubstituted 2-aminobenzylamines with propargylic carbonates. The reaction proceeds through the formation of π-allylpalladium intermediates, which undergo intramolecul...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/14/3004 |
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| Summary: | A synthesis of substituted 1,4-benzodiazepines has been developed via palladium-catalyzed cyclization of <i>N</i>-tosyl-disubstituted 2-aminobenzylamines with propargylic carbonates. The reaction proceeds through the formation of π-allylpalladium intermediates, which undergo intramolecular nucleophilic attack by the amide nitrogen to afford seven-membered benzodiazepine cores. In reactions involving unsymmetrical diaryl-substituted carbonates, regioselectivity was observed to favor nucleophilic attack at the alkyne terminus substituted with the more electron-rich aryl group, suggesting that electronic effects play a key role in determining product distribution. The versatility of this reaction was further demonstrated by constructing a benzodiazepine framework found in bioactive molecules, indicating its potential utility in medicinal chemistry. Mechanistic insights supported by stereochemical outcomes and X-ray crystallographic analysis of key intermediates reinforce the proposed reaction pathway. This palladium-catalyzed protocol thus offers an efficient and practical approach to access structurally diverse benzodiazepine derivatives. |
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| ISSN: | 1420-3049 |