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

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.


Directing group strategies for C–H activation.(a) First example of carboxyl-group-assisted β-arylation of an aliphatic acid. (b) General approach for C–H functionalization of aliphatic acids/amino acids. (c) Monodentate directing groups for C–H arylation. (d) Bidentate directing groups for C–H arylation. (e) Our work on ligand-enabled directed C(sp3)-H arylation of carboxylic acids.
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f1: Directing group strategies for C–H activation.(a) First example of carboxyl-group-assisted β-arylation of an aliphatic acid. (b) General approach for C–H functionalization of aliphatic acids/amino acids. (c) Monodentate directing groups for C–H arylation. (d) Bidentate directing groups for C–H arylation. (e) Our work on ligand-enabled directed C(sp3)-H arylation of carboxylic acids.

Mentions: Aliphatic acids are highly important synthetic units, being commonly found in natural products, approved drugs and biologically important molecules12. Direct C–H functionalization of C(sp3)–H bonds in aliphatic acids is highly important and attractive, because it provides a straightforward pathway to afford valuable chemicals with higher atom-economy compared to traditional procedures, for which pre-functionalized substrates are needed345678910. During the last decades, tremendous progress has been made in terms of transition-metal-catalysed functionalization of C–H bonds. Although there have been exciting developments in carboxylate-assisted functionalization of arene C–H bonds1112131415, reports of the direct functionalization of β-C(sp3)–H bonds remain limited. Only the specific structure of a carboxylic acid facilitates direct β-C(sp3)-H functionalization in the presence of a palladium catalyst, as disclosed by Yu et al. in 2007 (Fig. 1a)16. However, the substrate scope was limited to aliphatic acids with a β-quaternary centre, due to the well-known Thorpe–Ingold effect in cyclopalladation17, and ratios of mono- to diarylated products in the range 2.5:1 to 5:1 were observed. Thus, the use of various directing groups to achieve regioselective β-C(sp3)–H bond functionalization of carboxylic acid derivatives18192021222324252627282930313233343536373839404142434445 has been extensively explored in the past decades (Fig. 1).


Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids
Directing group strategies for C–H activation.(a) First example of carboxyl-group-assisted β-arylation of an aliphatic acid. (b) General approach for C–H functionalization of aliphatic acids/amino acids. (c) Monodentate directing groups for C–H arylation. (d) Bidentate directing groups for C–H arylation. (e) Our work on ligand-enabled directed C(sp3)-H arylation of carboxylic acids.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Directing group strategies for C–H activation.(a) First example of carboxyl-group-assisted β-arylation of an aliphatic acid. (b) General approach for C–H functionalization of aliphatic acids/amino acids. (c) Monodentate directing groups for C–H arylation. (d) Bidentate directing groups for C–H arylation. (e) Our work on ligand-enabled directed C(sp3)-H arylation of carboxylic acids.
Mentions: Aliphatic acids are highly important synthetic units, being commonly found in natural products, approved drugs and biologically important molecules12. Direct C–H functionalization of C(sp3)–H bonds in aliphatic acids is highly important and attractive, because it provides a straightforward pathway to afford valuable chemicals with higher atom-economy compared to traditional procedures, for which pre-functionalized substrates are needed345678910. During the last decades, tremendous progress has been made in terms of transition-metal-catalysed functionalization of C–H bonds. Although there have been exciting developments in carboxylate-assisted functionalization of arene C–H bonds1112131415, reports of the direct functionalization of β-C(sp3)–H bonds remain limited. Only the specific structure of a carboxylic acid facilitates direct β-C(sp3)-H functionalization in the presence of a palladium catalyst, as disclosed by Yu et al. in 2007 (Fig. 1a)16. However, the substrate scope was limited to aliphatic acids with a β-quaternary centre, due to the well-known Thorpe–Ingold effect in cyclopalladation17, and ratios of mono- to diarylated products in the range 2.5:1 to 5:1 were observed. Thus, the use of various directing groups to achieve regioselective β-C(sp3)–H bond functionalization of carboxylic acid derivatives18192021222324252627282930313233343536373839404142434445 has been extensively explored in the past decades (Fig. 1).

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.