Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group

• Published in: Nature chemistry Vol. 9; no. 1; pp. 26 - 32
• Main Authors: Liu, Yongbing, Ge, Haibo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2017; Nature Publishing Group
• Subjects: 140/131; 639/638/403/933; 639/638/549/933; Acids; Aliphatic amines; Alkylamines; Amines; Analytical Chemistry; Biochemistry; Chemistry; Chemistry/Food Science; Glyoxylic acid; Hydrogen bonds; Immunomodulation; Inorganic Chemistry; Ligands; Organic Chemistry; Palladium; Pharmaceutical sciences; Physical Chemistry; Substrates; Transition metals; United States > US; Indianapolis Indiana
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.2606

Transition-metal-catalysed direct C–H bond functionalization of aliphatic amines is of great importance in organic and medicinal chemistry research. Several methods have been developed for the direct
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C–H functionalization of secondary and tertiary aliphatic amines, but site-selective functionalization of primary aliphatic amines in remote positions remains a challenge. Here, we report the direct, highly site-selective γ-arylation of primary alkylamines via a palladium-catalysed C–H bond functionalization process on unactivated
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carbons. Using glyoxylic acid as an inexpensive, catalytic and transient directing group, a wide array of γ-arylated primary alkylamines were prepared without any protection or deprotection steps. This approach provides straightforward access to important structural motifs in organic and medicinal chemistry without the need for pre-functionalized substrates or stoichiometric directing groups and is demonstrated here in the synthesis of analogues of the immunomodulatory drug fingolimod directly from commercially available 2-amino-2-propylpropane-1,3-diol.
Transition-metal-catalysed direct C(
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)−H functionalization of primary aliphatic amines is an attractive– but elusive – process that could provide efficient access to biologically and pharmaceutically important compounds. Now, a palladium-catalysed γ-arylation of primary alkylamines is achieved using an inexpensive, catalytic and transient directing group.