Synfacts 2021; 17(01): 0023
DOI: 10.1055/s-0040-1719283
Synthesis of Heterocycles

N-Alkylation of Hetarenes through Electrochemical Oxidation of Carboxylic Acids

(Pfizer) Contributor(s):
Victor Snieckus
,
Dominik K. Kölmel
Sheng T, Zhang H.-J, Shang M, He C, Vantourout JC, Baran PS. * Scripps Research, La Jolla, USA
Electrochemical Decarboxylative N-Alkylation of Heterocycles.

Org. Lett. 2020;
22: 7594-7598
DOI: 10.1021/acs.orglett.0c02799.
 

Significance

The alkylation of N-heterocycles is among the most widely employed reactions in medicinal chemistry. The current report details a new approach to this versatile reaction. Through the electrochemical anodic oxidation of abundant feedstock carboxylic acids 1, carbocations were generated and subsequently intercepted by hetarenes 2. The corresponding N-alkylated hetarenes 3 were obtained in moderate to high yields from a diverse range of substrate combinations.


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Comment

The presented transformation is thought to proceed through the anodic oxidation of the carboxylic acid substrates 1. Upon decarboxylation, the corresponding carbocations are generated, which readily react with various hetarenes 2. Therefore, the scope of this reaction is limited to carboxylic acids 1 that can be converted into reasonably long-lived carbocations (i.e., secondary and tertiary carboxylic acids). In line with this mechanistic hypothesis, certain substrates 1 were shown to undergo cationic rearrangement to form more stable carbocations prior to the formation of the new C–N bond.


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Publication History

Publication Date:
16 December 2020 (online)

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