Copper-mediated cross-coupling reactions toward tandem-catalysis

Thomas, Fabian; Herres-Pawlis, Sonja (Thesis advisor); Schwaneberg, Ulrich (Thesis advisor)

Aachen : RWTH Aachen University (2021, 2022)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021

Abstract

Catalytic transformations are key to the development of atom efficient processes. An important functional group in biologically, synthetically and pharmacologically relevant molecules are amines. The central intermediates in atom efficient reactions to introduce an amine function are terminal nitrenes. Terminal nitrene complexes are an elusive species and rational ligand design helps to understand connection between the structure and the reactivity. Therefore, this PhD thesis includes the synthesis of a library of different bis(pyrazolyl)methane ligands. The aim was to investigate the influence of the ligand design on the formation and activity of the generated copper nitrene complexes. This was achieved by variation of the third N donor unit of the ligand, whose electronic as well as the steric properties were varied. By the application of the nitrene generating agent SPhINTs, six novel copper nitrene complexes were synthesized at low temperature in dichloromethane. These nitrene complexes were characterized by ultra-high resolution cryo ESI mass spectrometry, density functional theory, UV/Vis and NMR spectroscopy. It was shown that terminal nitrene complexes are generated as singlet species in high yields. In addition, the thermal stability and catalytic activity was investigated. By variation of the third N donor unit copper nitrene complexes with a high stability as well as a high cata-lytic activity were obtained. At room temperature the C-H amination of different benzylic, alkylic and aromatic substrates and the aziridination of different styrene derivatives is possible. Due to the relevance of enantiomeric pure products, also chiral precursor complexes were used in asymmetric catalytic reactions and enantiomeric enriched products could be obtained. To further increase the atom efficiency of the catalytic amination reaction under avoidance of SPhINTs, also aromatic azides were used as nitrene generating agents. A first success was achieved by the combination of benzoyl azide and electron rich bis(pyrazolyl)methane ligands. Beside copper(I) complexes also iron(II) complexes were investigated as precursor complexes to generate nitrene complexes. Another approach for the development of environmentally sustainable processes are tandem reactions. By the combination of two or more catalysts in one process, a purification of the intermediates is redundant. This leads to savings in energy and solvent consumption as well as in the investment costs. Therefore, in the framework of the SFB 985 in the Subproject A1 the aim was to develop a tandem reaction between a P450 BM3 variant and a copper bis(pyrazolyl)methane complex. Two possible tandem reactions were investigated. In the first tandem reaction a combination of an aromatic hydroxylation of dimethylbenzene to yield dimethylphenol followed by a copper catalyzed C-O cross-coupling to a diphenyl ether was planned. Both reactions could be performed separately, but a combination was not successful. The second approach is the combination of a copper catalyzed benzofuran synthesis from iodophenol and alkyne followed by a hydroxylation of the benzofuran by a P450 BM3 variant. The combination of both reactions could be realized in a stepwise reaction and the addition of EDTA.

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