Catalysis through Temporary Intramolecularity: Mechanistic Investigations on Aldehyde-Catalyzed Cope-type Hydroamination Lead to the Discovery of a More Efficient Tethering Catalyst

Abstract

Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.

Synthesis of 1,2-Diamines via Hydroamination Reactions

“…12 They observed increased yields as compared to the system that involved α-benzyloxyacetaldehyde as the catalyst.…”

Enantioselective Carbonyl Catalysis Enabled by Chiral Aldehydes

“…The mechanism of this enantioselective hydroamination (Scheme ) was proposed according to thorough studies of related racemic reactions using α‐benzyloxyacetaldehyde . This reaction starts with condensation of hydroxylamine 10 and chiral aldehyde 8 to afford nitrone 12 , which rapidly undergoes a stereoselective 1,2‐addition with allylic amine 9 to form transient aminal 13 .…”

Temporäre Bildung eines Cyclopropyl‐Oxocarbeniumions ermöglicht eine außerordentlich diastereoselektive Cycloaddition von Donor‐Akzeptor‐Cyclopropanen

“…Bandbreite der Cycloaddition:V ariation der Cyclopropane. Reaktionsbedingungen: 1 (0.1 mmol), 2 (0.2 mmol), TBSOTf (0.01 mmol), Nitromethan (1 mL [10] doch es wird sicherlich zunehmend an Bedeutung in der organischen Synthese gewinnen.…”