Diels-Alder/Ene Reactivities of 2-(1'-Cycloalkenyl)thiophenes and 2-(1'-Cycloalkenyl)benzo[b]thiophenes with N-Phenylmaleimides: Role of Cycloalkene Ring Size on Benzothiophene and Dibenzothiophene Product Distributions

Noland, W. E.; Kumar, H. V.; Reddi, Y.; Cramer, C. J.; Novikov, A. V.; Kim, H.; Zhu, Y.; Chin, Y. C.; Zhou, Y.; Radakovic, P.; Uprety, A.; Xie, J.; Flick, G. C.
J. Org. Chem. 2020, 85, 5265 (doi:10.1021/acs.joc.9b03363).

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 Dielsā-lder reaction and a possible, subsequent ene reaction.