In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Vladimir Gevorgyan of the Department of Chemistry at the University of Illinois at Chicago will develop transition metal-catalyzed methodologies towards multi-substituted aromatics and heteroaromatics. Although several methods for construction of benzene rings exist, the known catalytic processes suffer from regioselectivity problems. More selective methods require employment of stoichimetric organometallic reagents, thus severely limiting broad application of these methodologies. These limitations will be addressed in the proposed project through the development of highly efficient Pd-catalyzed [4+2] and formal [2+2+2] benzannulation reactions toward regioselective assembly of a multisubstituted benzene ring. Studies toward new pre- and post-benzannulation cascade transformations will dramatically expand the scope of this methodology.

The proposed research, which is at the interface of organometallic and organic chemistry and catalysis, will also provide multidisciplinary training at the undergraduate and graduate level. In addition, Professor Gevorgyan is actively engaged in promoting careers for women in the STEM disciplines. The proposed work is expected to have broader impacts in the health related area by providing new effective routes to biologically important intermediates, and in materials science by allowing easy access to valuable building blocks, which could be utilized in the rapid assembly of complex frameworks and conjugated materials. Moreover, the herein proposed development of "one-pot reactions" may reduce the cost of chemical products and avoid the production of chemical waste, providing both economical and environmental impacts.

Project Report

Multisubstituted polyfunctional aromatic molecules are ubiquitous structural motifs found in biologically important molecules and in synthetic materials. Accordingly, development of highly selective, efficient, and robust methodologies toward assembly of these important cores is highly warranted. The main goals of this NSF-funded project were the development of highly efficient Pd-catalyzed benzannulation reaction and the expansion of its scope toward element-containing aromatics. During this grant period we developed new catalytic conditions, which allowed for a dramatic improvement of the reaction efficacy. Now, this benzannulation reaction can efficiently be accomplished with 0.01 % of palladium catalyst, as opposed to 5.0 % of catalyst used in the previously employed catalytic systems. En route to development of diverse pre-benzannulation cascades, we have developed an efficient set of dimerization methodologies of alkynes toward regiodivergent synthesis of conjugated enynes. It was found that the Pd-catalyzed dimerization reaction of alkynes operates via the hydropalladation route leading to 1,4-enynes, the products of the head-to-head dimerization. In contrast, addition of carboxylate anion switches the mechanism to the carbopalladation path and therefore leads to the formation of 1,3-enynes, the products of the head-to-tail dimerization reaction. Fluoro-containing aromatics, an important class of molecules widely found in pharmaceuticals, agricultural molecules, and in materials, are usually accessed via fluorination of a pre-existing aromatic core. During this grant period, for the first time, we have demonstrated that fluoroarenes can be assembled via an alternative route: through [4+2] cycloaddition of easily available fluoro-containing conjugated enynes. This new method substantially expands an arsenal of polyfunctional fluoroaromatic building blocks for synthetic organic- and medicinal chemistry, as well as for material science. It is believed that the developed methodologies would have a broader impact in the health-related areas and material science by providing effective routes to important building blocks. The developed highly efficient catalytic cycloaddition approach to multisubstituted aromatics is also highly atom-economical and convergent and thus will have an environmental impact. Furthermore, this work, which is at the interface of organometallic and organic chemistry and catalysis, provides multidisciplinary training at the undergraduate (independent research and Summer Research Opportunity Program, regularly engaged in the PI's labs), graduate, and postdoctoral levels. Through direct interaction with laboratory research, undergraduates are directly encouraged to pursue post-bachelor education in scientific research. Furthermore, graduate students benefit from this exchange as it prepares them for future roles as supervisors and mentors.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Tingyu Li
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University of Illinois at Chicago
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