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Synfacts 2015; 11(11): 1121
DOI: 10.1055/s-0035-1560694
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Boron-Catalyzed N-Alkylation of Amines Using Carboxylic Acids

Contributor(s):
Philip Kocienski
Fu M.-C, Shang R, * Cheng W.-M, Fu Y. * University of Science and Technology of China, Hefei, P. R. of China
Boron-Catalyzed N-Alkylation of Amines Using Carboxylic Acids.

Angew. Chem. Int. Ed. 2015;
54: 9042-9046
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Further Information

Publication History

Publication Date:
19 October 2015 (online)

 
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Key words

Cinacalcet - Butenafine - Piribedil - N-alkylation - carboxylic acids - boron catalysis - frustrated Lewis pairs

Significance

The boron-based catalyst B(C6F5)3, which can form a frustrated Lewis pair (FLP), catalyzes the N-alkylation of amines using carboxylic acids in the presence of a silane reducing agent. The boron catalyst enables reductive carbon–nitrogen bond formation in preference to the reduction of the carboxylic acid. Only 1.0 mol% of the boron catalyst is required. Twenty-four examples of the N-methylation of various primary and secondary amines using formic acid and eighteen examples of the N-alkylation of aniline with various carboxylic acids illustrate the scope of the reaction.


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Comment

The utility of the N-alkylation reaction is illustrated by the small-scale synthesis of three pharmaceutical agents. Cinacalcet (Sensipar®, Mimpara®) is a calcimimetic that is useful for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease and hypercalcaemia in patients with parathyroid carcinoma. Piribedil (Pronoran®) is a D2 and D3 receptor agonist that is used to treat Parkinson's disease. Butenafine (Mentax®) is a squalene epoxidase inhibitor that blocks the synthesis of ergosterol. It is used as a topical antifungal agent.


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