Discovery and Mechanistic Study of Al^III-Catalyzed Transamidation of Tertiary Amides

Abstract

Cleavage of the C-N bond of carboxamides generally requires harsh conditions. This study reveals that tris(amido)Al(III) catalysts, such as Al2(NMe2)6, promote facile equilibrium-controlled transamidation of tertiary carboxamides with secondary amines. The mechanism of these reactions was investigated by kinetic, spectroscopic, and density functional theory (DFT) computational methods. The catalyst resting state consists of an equilibrium mixture of a tris(amido)Al(III) dimer and a monomeric tris(amido)Al(III)-carboxamide adduct, and the turnover-limiting step involves intramolecular nucleophilic attack of an amido ligand on the coordinated carboxamide or subsequent rearrangement (intramolecular ligand substitution) of the tetrahedral intermediate. Fundamental mechanistic differences between these tertiary transamidation reactions and previously characterized transamidations involving secondary amides and primary amines suggest that tertiary amide/secondary amine systems are particularly promising for future development of metal-catalyzed amide metathesis reactions that proceed via transamidation.

Synthesis, Characterization, and Catalytic Activity of a Series of Aluminium–Amidate Complexes

“…Stahl demonstrated that a tris(amidate) aluminium species was the resting state of the catalyst in his transamidation chemistry and that catalytically viable species were generated through facile ligand substitution reactions under the reaction conditions. [35,36] We suggest similar fluxionality here, where one of the amidate ligands is protonated off of the aluminium ion by an equivalent of 2-propoanol to generate a catalytically viable Al-alkoxide under the reaction conditions. [52] We also investigated the competency of the Al-amidate complexes to serve as catalysts for the Oppenauer oxidation [53] of alcohols to the corresponding carbonyl compounds.…”

“…[33] Despite these chemistries, the application of aluminium amidate complexes as catalysts has not been investigated. The Stahl group has reported the Al 2 (NMe 2 ) 6 -catalyzed transamidation of carboxamides, [34] and has shown that aluminium amidate functional groups are important moieties under the reaction conditions, [35,36] suggesting that Al-amidate complexes may be viable catalytic species. Herein, we report the synthesis of a series of Al-amidate complexes that vary in ligand : metal stoichiometry.…”

6.11 N-Acylation Reactions of Amines

“…101 This method allowed stoichiometric amounts of AlCl 3 to be used to N-acylate primary and secondary amines using activated N-tosyl, N-benzoyl, and Npivaloylamides as acyl donors. Gellman and coworkers have described a series of metal-catalyzed equilibrium-controlled transamidation reactions of primary and secondary amines using secondary and tertiary amides as acyl donors, [102][103][104] with Zr(NMe 2 ) 4 found to be a particularly efficient catalyst for the transamidation of secondary amines using tertiary amides ( Figure 18). 104 Impressively, this catalytic system also promoted tertiary amide metathesis at room temperature, affording transamidation protocols with significant potential for dynamic combinatorial chemistry applications.…”

Development of Synthetic Receptors using Dynamic Combinatorial Chemistry

“…The thermodynamically controlled amide exchange may be catalyzed by amidoaluminum complexes in organic solvents; however, the relatively high temperatures required (90 -120 ° C) represent a limitation for its use in DCLs of receptors [42,43] . Alternatively, enzyme -catalyzed transimination has been reported.…”