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Iron-Mediated Direct Arylation of N-Heteroarenes with (Hetero)aryl Boronic Acids and Esters

Enright, Mollie C
http://orcid.org/0000-0002-2829-953X
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1683201347885241

Abstract Details

2023, Doctor of Philosophy, University of Toledo, Chemistry.
Transition metal chemistry has revolutionized the modern world. However, some of the most important catalytic transformations rely on scarce and expensive precious metals with high toxicity. Iron is an attractive alternative to most precious metals as it is the most abundant transition metal on Earth, and also in biological systems, making it both inexpensive and minimally toxic. Though its development lags severely behind those of metals in Groups 9 and 10, homogeneous iron catalysis provides ample opportunity to develop new methods for achieving the same chemical scaffolds. Specifically, we are interested in iron-mediated methods for coupling of N-heteroarenes with aryl- and heteroarylboronic acids and esters for generating pharmaceutical building blocks and ligand precursors. The current state-of-the-art synthetic routes for bi(hetero)aryl compounds rely on the palladium-catalyzed Suzuki-Miyaura reaction. The direct Suzuki-Miyaura-type C2-arylation of pyrrole with heteroarylboronic acids and esters catalyzed by an iron-tetraazamacrocycle is reported in chapter 2. An abbreviated optimization of reaction conditions is reported alongside the development of an improved work-up, relative to previous reports. The reaction of pyrrole with 22 heteroarylboronic acids and 14 heteroarylboronic esters is presented, including the synthesis of 17 novel 2-heteroarylpyrrole compounds. Products were characterized by NMR spectroscopy and high-resolution mass spectrometry. Testing the use of tert-butylhydroperoxide as an oxidant instead of molecular oxygen lead to oxidation of boronic acids. Additionally included in this chapter is discussion of major by-products of the cross-coupling reactions and various control experiments. In chapter 3, we expanded our studies to the regioselectivity of arylation of mono- and disubstituted pyridines with phenylboronic acid. Most methods for the direct arylation of pyridine suffer from poor regioselectivity. In contrast to the original reports using the iron-tetraazamacrocycle, which had demonstrated significant C2-selectivity, we found that breaking the symmetry of the pyridine decreased regioselectivity for the cross-coupling reaction. Additionally, we found that 2-bromopyridine undergoes oxidation rather than arylation while 3-bromopyridine demonstrates suppressed reactivity when compared to methyl- and dimethylpyridines. Finally, we provide proof-of-concept that pyrazine and quinoxaline can undergo iron-macrocycle-mediated cross-coupling with aryl- and heteroarylboronic acids. Appendix 1 includes a study on the temperature-dependent formation of an iron-catalyzed oxidation by-product of pyrrole.
Mark Mason (Committee Chair)
429 p.
Chemistry; Organic Chemistry
iron catalysis; pyrrole; pyridine; cross-coupling; direct arylation; heteroarylboronic acids

Recommended Citations

Citations

  • Enright, M. C. (2023). Iron-Mediated Direct Arylation of N-Heteroarenes with (Hetero)aryl Boronic Acids and Esters [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1683201347885241

    APA Style (7th edition)

  • Enright, Mollie. Iron-Mediated Direct Arylation of N-Heteroarenes with (Hetero)aryl Boronic Acids and Esters. 2023. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1683201347885241.

    MLA Style (8th edition)

  • Enright, Mollie. "Iron-Mediated Direct Arylation of N-Heteroarenes with (Hetero)aryl Boronic Acids and Esters." Doctoral dissertation, University of Toledo, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1683201347885241

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Toledo and OhioLINK.
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