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

Abstract

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.

Pericyclic Cascade Reactions Affording Thienyl- and Benzo[b]thienyl-Fused Architectures: A Synthetic and Density Functional Theory Analysis of Asynchronous Diels–Alder Reactions of Thioarylmaleimides

“…The difference in reactivity between 4a and 4b toward isomerism may be attributed to their differences in aromatic stabilization energies. This observation is consistent with recent experimental findings, 21 although in our case both the rearomatized 2-thienyl and 2-benzo[b]thienyl derivatives could be obtained.…”

“…35,42,45,47 For instance, the origin of the endo preference between 2-(1′-cycloalkenyl)thiophenes and Nphenylmaleimides has been determined to be derived from the presence of secondary orbital interactions (SOIs) and attractive van der Waals (vdW) forces between fragments. 21,47,48 NBO and natural charge analysis provided evidence for similar orbital and electrostatic incentives among TS 1−8 . For example, stabilizing n N′ → π* CC -, n O′ → π* CO -, and π CC → π* C′O -type orbital interactions between the diene and dienophile are present in the endo-TSs but not in the exo-TSs (Figure 9 and Figures S50 and S51).…”

“…This result is consistent with previous reports regarding the spontaneous isomerization of 2-(1′-cycloalkenyl)thiophene-and 2-(1′cycloalkenyl)benzo[b]thiophene-based endo adducts. 21 Unfortunately, the diagnostic nOe correlation was not detected in D−A/rearranged 5a, which left us to investigate further (Figure 5). As NOESY cross-peak signal intensities decrease exponentially as the distance between atoms increases and therefore through-space correlations at distances of 3.5−5 Å are commonly difficult to observe, 32 we wanted to verify whether nOe correlations between H 2 /H 3 and H a /H c should be expected on the basis of the geometry of D−A/rearranged 5a.…”

“…Vinyl furans, indoles, and pyrroles are known to undergo [4+2] cycloaddition with various dienophiles. 14−19 Although fewer examples of vinylthiophene-based cycloadditions exist, presumably due to their aromatic stabilization energy being greater than those of pyrrole and furan, 20,21 the addition of dienophiles such as maleic anhydride, N-phenylmaleimide, and dimethylacetylene-dicarboxylate (DMAD) to 2-vinyl thiophenes and benzo[b]thiophenes is possible. 20−25 Spontaneous isomerization of the ensuing Diels−Alder (D−A) adducts is commonly observed for cycloadditions involving vinylheteroaryls.…”

“…Maleimide 7 can be formed in a few different ways under the S−M conditions. In recent work by Flick and Noland, 21 an ene reaction with an additional 1 equiv of bromo-maleimide 1 is proposed, giving bromo 6 followed by an elimination step to give maleimide 7 (path B, Scheme 1). Other literature precedent shows that C−H activation is possible under these cross-coupling conditions, 27 opening up the possibility that maleimide 7 is formed through rearomatized 5 instead of through D−A adduct 4.…”