The Amine-Carbonyl Reaction and their Role in Catalysis

Kuan, Suzie Hui Chin (2021) The Amine-Carbonyl Reaction and their Role in Catalysis. Masters thesis, University Malaysia Sarawak.

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Abstract

The metal catalyzed carbon-carbon bond formation reactions are among the most important and useful methods for organic synthesis. During the past century, significant progress has been made in this field to develop an ideal catalyst for cross-coupling chemistry. This can be achieved by changing the types of ligands coordinated to the metal center due to the catalytic properties of the metal complexes is usually a combination of the steric environment that the ligands impart, in addition to their electronic influence on the metal center. In this project, two series of diimine compounds bearing electron donating and electron withdrawing substituent (R-DAB) were synthesized by condensation reaction and then reacted with the dichlorobis(acetonitrile)palladium(II) precursor, [PdCl2(MeCN)2], to form palladium(II) diimine, [PdCl2(R-DAB)], complex. The catalytic efficiency of [PdCl2(R-DAB)] complexes in Sonogashira cross-coupling reaction was examined by reacting methyl-4-bromobenzoate and 2-methylbut-3-yn-2-ol for 5 hours under nitrogen condition at 70 °C. The initial hypothesis of this work was the strong trans-effect from diimine ligand in [PdCl2(R-DAB)], which can enhance the rate of reductive elimination and subsequently promote the formation of cross-coupling product. Unfortunately, the results showed that the [PdCl2(R-DAB)] complexes were incapable to induce the cross-coupling reaction. In order to increase the electron density on the palladium metal center and consequently accelerate the reactivity rate of cross-coupling reaction, palladium(II) diamine complex were synthesized based on structural modification of [PdCl2(R-DAB)]. However, these complexes were also unable to perform the catalytic reaction by forming palladium black within 10 minutes of the reaction. The reasons for failure of all of the palladium complexes to catalyze Sonogashira cross-coupling reactions is due to the energy level of LUMO is much higher than the 3d-orbitals of phosphorus which restrict the effectiveness of back-bonding and prevent the oxidative addition from happening as well as resulting the formation of palladium black particle after terminal alkyne was added into the reaction. In addition, a direct C-H/N-H oxidative coupling of primary and secondary amine with glyoxal was developed. This reaction can be achieved by using 4 equivalents of CuCl2•2H2O as the oxidant, Cs2CO3 (1.3 equiv) and CF3COOH (1.0 equiv) as the additives in MeTHF at 70 °C for 5 hours under N2 atmosphere. The yield was increased from 20% in the beginning to 70% under the aforementioned conditions. This transformation is also well tolerated for a series of aniline substrates with a wide variety of substitution patterns and functionalities. This protocol can be easily scaled up which demonstrate the practicality of this transformation and this can be applicable in the field of organic synthesis and medicinal chemistry.

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