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Methyl‐Selective α‐Oxygenation of Tertiary Amines to Formamides by Employing Copper/Moderately Hindered Nitroxyl Radical (DMN‐AZADO or 1‐Me‐AZADO)
Author(s) -
Nakai Satoru,
Yatabe Takafumi,
Suzuki Kosuke,
Sasano Yusuke,
Iwabuchi Yoshiharu,
Hasegawa Junya,
Mizuno Noritaka,
Yamaguchi Kazuya
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201909005
Subject(s) - formamides , regioselectivity , nitroxyl , chemistry , methylamines , tertiary amine , catalysis , steric effects , amine gas treating , organic chemistry , radical , medicinal chemistry , combinatorial chemistry , photochemistry
Methyl‐selective α‐oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α‐oxygenation at the N ‐methyl positions using molecular oxygen (O 2 ) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl‐selective α‐oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5‐dimethyl‐9‐azanoradamantane N ‐oxyl (DMN‐AZADO) and 1‐methyl‐2‐azaadamanane N ‐oxyl (1‐Me‐AZADO), was very important to promote the oxygenation effectively mainly because these N ‐oxyls have longer life‐times than less hindered N ‐oxyls. Various types of tertiary N ‐methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine‐ N ‐oxyl interactions.