Palladium-Catalyzed Oxidation of β-C(sp³)–H Bonds of Primary Alkylamines through a Rare Four-Membered Palladacycle Intermediate

Abstract

Site-selective functionalizations of C-H bonds are often achieved with a directing group that leads to five-or sixmembered metallacyclic intermediates. Analogous reactions that occur through four-membered metallacycles are rare. We report a challenging palladium-catalyzed oxidation of primary C-H bonds β to nitrogen in an imine of an aliphatic amine, a process that occurs through a four-membered palladacyclc intermediate. The success of the reaction relies on the identification, by a study on H/D exchange, of a simple directing group (salicylaldehyde) capable of inducing the formation of this small ring. To gain insight into the mechanism of this unusual oxidation reaction, a series of mechanistic experiments and DFT calculations were conducted. The experimental studies showed that cleavage of the C-H bond is rate-limiting, and formation of the strained four-membered palladacycle is thermodynamically uphill. DFT calculations corroborated these conclusions and suggested that the presence of an intramolecular hydrogen bond between the oxygen of the directing group and hydroxyl group of the ligating acetic acid that is crucial for stabilization of the palladacyclic intermediate.

Palladium-Catalyzed Regioselective Arylation of Unprotected Allylamines

“…Having ruled out that CO 2 was serving as a transient directing group, the directing effect must come from the amine. For an insertion mechanism using a mononuclear Pd catalyst, however, that would suggest that a relatively rare four-membered palladacycle would be forming, which we considered unlikely given the lack of either a strongly chelating directing group 64 or bulky substrate. 65 , 66 As previously mentioned, while trying to probe the role of CO 2 , we realized that we could not generate meaningful kinetics data using our cinnamylamine substrates: the initial rates were irreproducible.…”

Transient Directing Groups in Metal−Organic Cooperative Catalysis

“…(1)]. [140] While two key substrate coordinated palladium complexes could be isolated, DFT calculations suggested that the reaction would be likely to involve a rare 4,6-palladacbiycle, unfortunately not isolable.…”

Transient imine directing groups for the C–H functionalisation of aldehydes, ketones and amines: an update 2018–2020

“…Hartwig published a mechanistically intriguing method to achieve β-acetoxylation of imines via a strained 4-membered palladacyclic intermediate (Scheme 24). 73 While the reaction required a preformed imine to be effective, hence not transient, it was impressive that such a strained intermediate can be accessed. Salicylaldehyde was found to be an effective directing group along with N-Boc-alanine as a ligand.…”