Scaffolds of thiophene and benzothiophene are the important class of bioactive compounds found abundant in nature. The Diels-Alder reactions of 2-(1′-cycloalkenyl)thiophenes and 2-(1′-cycloalkenyl)benzo[b]thiophenes having the alkene groups present in five-, six-, seven-, eight-, and twelve-membered rings with substituted N-phenylmaleimides are characterized. The size of the cycloalkene rings plays a critical role in dictating the product distributions of expected and isomerized Diels-Alder adducts. 2D NMR studies indicate that the isolated isomers for 2-(1′-cycloalkenyl)thiophenes having five-, six-, and seven-membered rings are aromatized benzothiophene products, whereas eight- and twelve-membered rings are un-rearranged adducts. In addition, the product of subsequent ene-reaction with the N-phenylmaleimide is isolated for the five- and six-membered ring cases. Interestingly, in the 2-(1′-cycloalkenyl)benzo[b]thiophene having five-, six-, seven-, eight-, and twelve-membered rings, the un-rearranged dibenzothiophene Diels-Alder adduct is isolated in every instance. Molecular mechanics and density functional theory (M06-2X and PBE0-D3) calculations are performed to understand the differential reactivity of the various dienes for both the initial Diels-Alder reaction and a possible, subsequent ene reaction.
Bibliographical noteFunding Information:
The authors thank Victor G. Young Jr., Ph.D. (X-ray Crystallographic Laboratory, University of Minnesota) for assistance with the crystal structure and the Wayland E. Noland Research Fellowship Fund at the University of Minnesota Foundation for generous financial support of this project. We thank Venkata Narina, Çağatay Dengiz, Mathew A. Helppi, Jeanette L. Tensfeldt, and Derek Aschbacher for their initial inputs on this project. We thank the Minnesota Supercomputing Institute (MSI) for providing key computational resources.
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