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The Role of the Alcohol and Carboxylic Acid in Directed Ruthenium‐Catalyzed C(sp 3 )H α‐Alkylation of Cyclic Amines
Author(s) -
Bergman Sheba D.,
Storr Thomas E.,
Prokopcová Hana,
Aelvoet Karel,
Diels Gaston,
Meerpoel Lieven,
Maes Bert U. W.
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201201072
Subject(s) - alkylation , catalysis , chemistry , alcohol , carboxylic acid , alkene , ruthenium , selectivity , organic chemistry , medicinal chemistry , combinatorial chemistry
Abstract A general directed Ru‐catalyzed C(sp 3 )H α‐alkylation protocol for piperidines (less‐reactive substrates than the corresponding five‐membered cyclic amines) has been developed. The use of a hindered alcohol (2,4‐dimethyl‐3‐pentanol) as the solvent and catalyst activator, and a catalytic amount of trans ‐1,2‐cyclohexanedicarboxylic acid is necessary to achieve a high conversion to product. This protocol was used to effectively synthesize a number of 2‐hexyl‐ and 2,6‐dihexyl piperidines, as well as the alkaloid (±)‐solenopsin A. Kinetic studies have revealed that the carboxylic acid additive has a significant effect on catalyst initiation, catalyst longevity, and reverses the reaction selectivity compared with the acid‐free reaction (promotes alkylation versus competing alkene reduction).