Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
J Org Chem. 2020 Apr 17;85(8):5265-5287. doi: 10.1021/acs.joc.9b03363. Epub 2020 Mar 31.
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[]thiophenes having the alkene groups present in five-, six-, seven-, eight-, and twelve-membered rings with substituted -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 -phenylmaleimide is isolated for the five- and six-membered ring cases. Interestingly, in the 2-(1'-cycloalkenyl)benzo[]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.
噻吩和苯并噻吩的骨架是在自然界中大量存在的具有生物活性的重要化合物类别。本文对具有五元、六元、七元、八元和十二元环的烯基取代的 - 苯基马来酰亚胺的 2-（1'-环烯基）噻吩和 2-（1'-环烯基）苯并[]噻吩的 Diels-Alder 反应进行了研究。环烯烃环的大小在决定预期和异构化 Diels-Alder 加合物的产物分布方面起着关键作用。2D NMR 研究表明，具有五元、六元和七元环的 2-（1'-环烯基）噻吩的分离异构体是芳构化的苯并噻吩产物，而八元和十二元环是未重排的加合物。此外，对于五元环和六元环的情况，还分离出了与 - 苯基马来酰亚胺随后进行的ene 反应的产物。有趣的是，在具有五元、六元、七元、八元和十二元环的 2-（1'-环烯基）苯并[]噻吩中，未重排的二苯并噻吩 Diels-Alder 加合物在每种情况下都被分离出来。本文还进行了分子力学和密度泛函理论（M06-2X 和 PBE0-D3）计算，以了解各种二烯在初始 Diels-Alder 反应和可能随后的 ene 反应中的不同反应性。
