Presently, green chemistry is a movement that proactively seeks to create alternative and earth-friendly processes. It is a growing field open for innovation and cost-effective measures to enrich the scientific community while catering to an increasing world population. A technique available to green chemistry is photochemistry. The use of light as a means of chemical change can offer energy saving solutions to chemical reactions performed in organic chemistry.
1,2-diazine N-oxides are bench top stable starting materials rendering them useful building blocks for complex molecules. The photochemistry of pyridazine N-oxides has not been rigorously exploited because of the lack of efficient regioselective access and inability to control competitive reactions. They possess the potential for development of many reaction pathways, including ring-opening and photoreduction. During our investigations of the photochemical ring-opening, we observed an intermediate that is formed after exposure to UV light. To the best of our knowledge, this transient compound has not been isolated or heavily exploited for new reactions. Herein, I will describe our efforts to exploit this (Z)-diazoenone intermediate for applications in heterocycle synthesis using heat and transition metal catalysis
The first strategic use of pyridazine N-oxide to nitrogen heterocycles is disclosed. Our synthesis began with readily available 3,6-dichloropyridazine N-oxide and a regioselective Suzuki-Miyaura cross-coupling with PdCl2dppf which selectively couples at C3. Furthermore, aromatic substitution (SNAr) reactions were amenable toward these electron deficient heterocycles to furnish a library of non-symmetric photosubstrates. Upon photolysis with UV light (hv= 350 nm) and elevated temperatures, photochemical ring opening was observed to provide elaborate pyrazole motifs. We varied the electronics of pyridazine N-oxides at C3 with electron withdrawing and electron donating aryl groups. C6 was functionalized with various nucleophiles including nitrogen, oxygen and sulfur. Additionally, we were able to demonstrate this method as a tool in synthesis in our first application to a target molecule.
We found reaction conditions to distinguish between competitive ring opening reaction pathways (1) thermal cyclization to afford pyrazole and (2) formation of a π-excessive building block, 2-aminofuran. However, 2-aminofurans are labile and readily oxidize in air, rendering them buildings with obvious limitations.
We report a method to synthesize 2-aminofurans using a combination of UV light and rhodium catalysis. These reactive intermediates are used in Diels-Alder cycloaddition reactions with alkenes to give entry to heterocyclic scaffolds found within natural products such as carbazoles and dibenzofurans. Our scope highlighted N-oxides with nucleophilic nitrogen and oxygen as an extension of the library of N-oxides used for pyrazole formation. Moreover, we harnessed the functionality of these scaffolds from synthetically accessible pyridazine N-oxides using our established regioselective approach to non-symmetric N-oxides. We were able to find dienophiles compatible with our system extending the groups incorporated into the carbazole skeletons. In our system, we found limitations and describe our efforts to rationalize our observations.
In our quest of finding the synthetic utility of 2-aminofurans in Diels-Alder chemistry, we found 2-aminofurans harboring a nitrogen nucleophile in the ortho position of the aryl ring at C3, as introduceing new reactivity producing 1H-indole-2-acetamide. Indole scaffolds have a wide array of value in organic synthesis. Our strategy is to explore the acid-catalyzed isomerization of 2-aminofuran to functionalized indoles that would be difficult to make. Ring opening of heterocyclic N-oxides can be a powerful tool in organic synthesis. Key to our success was access to pyridazine N-oxides with functionality around the pyridazine nucleus that allowed for control of the competitive pathways.
|Advisor:||Frederich, James H.|
|Commitee:||Fajer, Peter, Miller, Brian, Saltiel, Jack|
|School:||The Florida State University|
|Department:||Chemistry and Biochemistry|
|School Location:||United States -- Florida|
|Source:||DAI-B 81/3(E), Dissertation Abstracts International|
|Subjects:||Chemistry, Organic chemistry|
|Keywords:||Methodology, Photochemistry, Pyridazine, Synthesis|
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