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Design and Development of Chiral Catalysts for Highly Enantioselective Hydrogenation of Amides via Dynamic Kinetic Resolution Under Low Pressure at Room Temperature Open Access


Other title
Dynamic Kinetic Resolution
Chiral Primary Alcohol
Enantioselective Hydrogenation
Type of item
Degree grantor
University of Alberta
Author or creator
Rasu, Loorthuraja
Supervisor and department
Prof. Steven H. Bergens, Department of Chemistry, University of Alberta
Examining committee member and department
Prof. Derrick Clive, Department of Chemistry, University of Alberta
Prof. Rylan Lundgren, Department of Chemistry, University of Alberta
Prof. Frederick West, Department of Chemistry, University of Alberta
Prof. Deryn Fogg, Department of Chemistry, University of Ottawa
Department of Chemistry

Date accepted
Graduation date
2017-11:Fall 2017
Doctor of Philosophy
Degree level
Amide reduction has a long, important history in pharmaceutical and related chemical industries. Traditional stoichiometric reduction methods suffer from numerous drawbacks such as limited functional group tolerance, poor atom economy, and environmental issues. Over the past two decades, significant effort has been dedicated to the development of greener synthetic approaches to amide reduction. Several transition metal (Ru, Fe, Ir, and Mn), bifunctional, and pincer type catalysts were developed for the hydrogenation of amides. These catalysts typically hydrogenate amides under 10–50 atm H2 at 80–150 °C in acidic, neutral, or basic conditions to produce C–O, or C–N cleavage products. This dissertation describes three independent projects on amide hydrogenation. Chapter 2 describes a base-free catalytic system containing [Ru(η3-C3H5)(Ph2P(CH2)2NH2)2]BF4 and NaBH4 for the hydrogenation of amides (0.1–1 mol% Ru, 0.2–2 mol% NaBH4, 50 atm H2, 100 °C in 24 hours) to produce the corresponding alcohol and amine products of C–N cleavage. A variety of functional groups tolerated the hydrogenation. Recent mechanistic studies show that Noyori's hydrogenation catalyst, trans-RuH2((R)-BINAP)((R,R)-dpen), can be deprotonatonated at the N–H position, and the resulting catalysts are extremely active (–80 °C under ~2 atm H2) towards the hydrogenation of imide and amide functional groups. These results motivated the development of an enantioselective catalyst for the hydrogenation of amides reported in this dissertation. A detailed study of high throughput rapid screening, lab-scale screening, and optimization are described in Chapter 3. The moderately air stable, crystalline dichloride precursor trans-RuCl2((S,S)-skewphos)((R,R)-dpen) was utilized with 2-PrONa as base in the presence of 2-PrOH to hydrogenate racemic α-chiral amides to form chiral primary alcohols in high yields and excellent ee (up to 99% yield, 99% ee) via dynamic kinetic resolution at room temperature. An unexpected hydrogenolysis of an sp3–sp2 C–C bond with a phosphine free homogeneous catalysis under mild condition (4 atm H2, room temperature, 4–24 hours, 1 mol% Ru, 15 mol% KOtBu in THF) is also described. For example, the catalysts prepared by reacting cis-[Ru(η3-C3H5)(MeCN)2(COD)]BF4 with diamine ligands transforms the trifluoroacetylamide, 2,2,2-trifluoro-1-(piperidin-1-yl)ethanone into the formylated amine, 1-formylpiperidine, and fluoroform via a catalytic C–C bond hydrogenolysis.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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