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

• Author / Creator

  Rasu, Loorthuraja

• 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.

• Subjects / Keywords

  • Amides
  • Enantioselective Hydrogenation
  • Chiral Primary Alcohol
  • Dynamic Kinetic Resolution

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3C53FF48

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. 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.