Marion H. Emmert
Amy M. Peterson
John C. MacDonald
Shawn C. Burdette
Presented herein is the development, optimization and mechanistic investigation of an Fe-catalyzed reaction for the Cα-H oxidation of tertiary aliphatic amines to form amides, and related synthetic reactions. Traditional amide synthesis typically involves nucleophilic substitution, and thus produces stoichiometric waste. The need to develop safer, more efficient methodologies for amide synthesis is well documented. The field of transition metal catalysis has made progress toward meeting this synthetic need by developing a variety of transition metal-catalyzed reactions for the oxidation of primary, secondary and benzylic amines. However, tertiary aliphatic Cα-H amine oxidation had not been developed. Guided by literature precedent, and inspired by cytochrome P450, initial investigations involved the evaluation of Fe-based transition metal catalysts with a variety of mono- and bidentate ligands, oxidants and solvents. Ultimately, the ligands picolinic acid and pyridine, the oxidant tert-butyl peroxybenzoate, and water as additive were identified as key players in this catalytic reaction. Through the systematic evaluation of reaction conditions, the Cα-H oxidation of tripropylamine to form N,N-dipropylpropanamide was optimized to afford 63% yield. The Cα-H oxidation of a variety of other amine substrates, including the complex pharmaceutical amines Lidocaine and Donepezil, were optimized to afford amide product in synthetically useful yields. Preliminary mechanistic investigations revealed water to be the source of the O atom in amide formation. Furthermore, these studies suggested that the amine substrate forms an iminium ion after C-H activation, which then undergoes nucleophilic attack by water to form a hemiaminal intermediate. These results allowed us to hypothesize that other nucleophiles, such as CN-, may be used to attack the iminium ion intermediate and thus afford other products. Using slightly modified reaction conditions, this catalytic system was optimized to perform Cα -H cyanation of dimethylaniline. This finding expanded the utility of the reaction as well as supported the mechanistic hypothesis of the presence of an iminium intermediate. Once the Fe/picolinic acid-catalyzed reaction for the Cα-H oxidation of tertiary aliphatic amines was firmly established, detailed mechanistic investigations were conducted using tripropylamine as substrate. Using in-situ IR spectroscopy, the structure of the resting state of the catalyst was probed. These studies revealed that picolinic acid binds to the Fe center in a 1:1 ratio to produce the catalytically active species. Amine substrate as well as water and pyridine were also found to be coordinated to the Fe center. Furthermore, initial rate kinetics were used to establish the dependence of the reaction rate on the concentration of each reaction component. Through these investigations, the kinetic order in each reagent was established and a rate law determined. Additionally, a primary kinetic isotope effect was observed using deuterated substrate, which implicated C-H bond cleavage as the turnover-limiting step in the catalytic cycle. Finally, Eyring studies and oxidant radical probe reactions were conducted, and implicated a concerted 2e- turnover- limiting step. This finding is in contrast to many mechanisms of Fe-catalyzed oxidation reactions found in the literature and allowed us to propose the unprecedented, detailed mechanistic hypothesis described herein. The research presented here establishes an unprecedented amide synthesis methodology through the use of both simple and complex amines. Because this catalytic reaction selectively oxidizes the Cα-H bonds of amines, a high percentage of atoms in the starting material are incorporated into the amide product, and it thus affords a significant increase in atom economy. The mechanistic work offers unique insight into 2e- Fe-oxidation catalysis, and may serve as a foundation for additional optimization, including industrial scale-up.
Worcester Polytechnic Institute
Chemistry & Biochemistry
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Legacy, C. J. (2018). Fe-Catalyzed Ca-H Oxidation of Tertiary Amines: Synthetic and Mechanistic Studies. Retrieved from https://digitalcommons.wpi.edu/etd-dissertations/40
catalysis, synthesis, oxidation, mechanism, chemistry