Related Experiment Video
Updated: Nov 5, 2025

Achieving Moderate Pressures in Sealed Vessels Using Dry Ice As a Solid CO2 Source
Published on: August 17, 2018
Transient Directing Group Enabled Pd-catalyzed γ-C(sp3)-H Oxygenation of Alkyl Amines
Yan-Qiao Chen1, Yongwei Wu1, Zhen Wang1
1Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037.
Abstract:
We report a general protocol for γ-C(sp3)-H acyloxylation and alkoxylation of free amines using 2-hydroxynicotinaldehyde as the transient directing group. In the presence of an electrophilic fluorinating bystanding oxidant and acetic acid, a wide range of aliphatic amines could be oxygenated selectively at the γ-methyl positions. A vast variety of aryl, heteroaryl, and aliphatic acids could also be successfully coupled under this C-O bond formation reaction to afford amine containing esters. Switching the nucleophile from acids to alcohols enables alkoxylation of free amines. Importantly, natural products and drug molecules such as ibuprofen, isozepac, fenbufen, and lithocholic acid are all compatible coupling partners. Notably, synthesis of these mono-protected amino alcohols from free amino alcohols using conventional selective protection are not always feasible.
Related Concept Videos
ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3
Diazonium Group Substitution: –OH and –H
Acid-Catalyzed α-Halogenation of Aldehydes and Ketones
In the first step of the mechanism, the acid protonates the carbonyl oxygen resulting in a resonance-stabilized cation, which subsequently loses an α-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the –OH group. Consequently, the double bond attacks an electrophilic halogen to form a...
Preparation of 1° Amines: Gabriel Synthesis
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an...
meta-Directing Deactivators: –NO2, –CN, –CHO, –⁠CO2R, –COR, –CO2H
Directing Effect of Substituents: ortho–para-Directing Groups

