Design and Synthesis of New Functionalized Boronic Acids for Direct Dehydrative Amidation of Poorly Nucleophilic Amines

• Author / Creator

  Zhou, Jingning

• Amide synthesis has been of great interest to chemists as the amide moiety occrus widely in agrochemicals, pharmaceutical agents, and biologically active molecules. Traditionally, amide bond formation requires the use of activated carboxylic acid derivatives or stochiometric amounts of coupling agents, which are generally toxic, expensive, and result in a large amount of undesired by-products that complicate product purification. To develop more environmentally friendly methodologies and to enhance atom-economy, in the past few decades, chemists have been exploring organoboron-catalyzed dehydrative amidation reactions. A series of bifunctional boronic acid catalysts proposed by Whiting and co-workers exhibited good catalytic activity in direct amide condensation, however they require elevated temperature to afford good yields. Our laboratory reported 5-methoxy-2-iodophenylboronic acid (MIBA) as an efficient catalyst giving high yields at temperatures ranging from ambient to 50 °C. Unfortunately, the substrate scope of MIBA and other catalysts remains limited, especially with aniline derivatives, acyclic secondary amines, and heteroaromatic acids. Attempting to overcome the challenge of amidation of poorly nucleophilic amines, we designed a functionalized boronic acid model aimed at activating the carboxylic acid with the B-O-B motif previously implicated in catalysis, and direct the amine with a proper coordinating group. With balanced structural flexibility and rigidity, boronic acid A7, (2'-(methylthio)-[1,1'-biphenyl]-2-yl)boronic acid, was identified as the most efficient promoter to aid in the formation of anilides. An expanded substrate scope with various aniline derivatives was demonstrated with good reaction efficiency. The scalability of the amidation reaction with A7 along with its reusability exhibited this method’s potential usefulness in large- scale reactions. Although work is required in order to further characterize the putative intermediate and explore the potential interaction between the heteroatom of A7 and the amine, the preliminary NMR experiments support the formation of a diacyloxy B–O–B bridged intermediate. Partial racemization was observed in (R)-2-phenylpropanoic acid synthesis with A7, though it gave a higher ee than MIBA. The loss of enantiomeric purity may be suppressed by lowering the reaction temperature, which would require a more reactive boronic acid.

• Subjects / Keywords

  • Boronic Acids
  • Amidation

• Graduation date

  Fall 2022

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-bq34-qe21

• License

  This thesis is made available by the University of Alberta Library 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.