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Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

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ABSTRACT

α-amino acids bearing aromatic side chains are important synthetic units in the synthesis of peptides and natural products. Although various β-C-H arylation methodologies for amino acid derivatives involving the assistance of directing groups have been extensively developed, syntheses that directly employ N-protected amino acids as starting materials remain rare. Herein, we report an N-acetylglycine-enabled Pd-catalysed carboxylate-directed β-C(sp3)-H arylation of aliphatic acids. In this way, various non-natural amino acids can be directly prepared from phthaloylalanine in one step in good to excellent yields. Furthermore, a series of aliphatic acids have been shown to be amenable to this transformation, affording β-arylated propionic acid derivatives in moderate to good yields. More importantly, this ligand-enabled direct β-C(sp3)-H arylation could be easily scaled-up to 10 g under reflux conditions, highlighting the potential utility of this synthetic method.

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Substrate scope of aryl iodides.Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (5 mol%), Ag2CO3 (0.2 mmol), K2CO3 (0.1 mmol), Ac-Gly-OH (0.06 mmol), HFIP (2 ml), 100 °C, 24 h. Isolated yields. aPd(OAc)2 (10 mol%). b110 °C.
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f2: Substrate scope of aryl iodides.Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (5 mol%), Ag2CO3 (0.2 mmol), K2CO3 (0.1 mmol), Ac-Gly-OH (0.06 mmol), HFIP (2 ml), 100 °C, 24 h. Isolated yields. aPd(OAc)2 (10 mol%). b110 °C.


Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids
Substrate scope of aryl iodides.Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (5 mol%), Ag2CO3 (0.2 mmol), K2CO3 (0.1 mmol), Ac-Gly-OH (0.06 mmol), HFIP (2 ml), 100 °C, 24 h. Isolated yields. aPd(OAc)2 (10 mol%). b110 °C.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384235&req=5

f2: Substrate scope of aryl iodides.Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (5 mol%), Ag2CO3 (0.2 mmol), K2CO3 (0.1 mmol), Ac-Gly-OH (0.06 mmol), HFIP (2 ml), 100 °C, 24 h. Isolated yields. aPd(OAc)2 (10 mol%). b110 °C.

View Article: PubMed Central - PubMed

ABSTRACT

α-amino acids bearing aromatic side chains are important synthetic units in the synthesis of peptides and natural products. Although various β-C-H arylation methodologies for amino acid derivatives involving the assistance of directing groups have been extensively developed, syntheses that directly employ N-protected amino acids as starting materials remain rare. Herein, we report an N-acetylglycine-enabled Pd-catalysed carboxylate-directed β-C(sp3)-H arylation of aliphatic acids. In this way, various non-natural amino acids can be directly prepared from phthaloylalanine in one step in good to excellent yields. Furthermore, a series of aliphatic acids have been shown to be amenable to this transformation, affording β-arylated propionic acid derivatives in moderate to good yields. More importantly, this ligand-enabled direct β-C(sp3)-H arylation could be easily scaled-up to 10 g under reflux conditions, highlighting the potential utility of this synthetic method.

No MeSH data available.


Related in: MedlinePlus