Halogenation effects in intramolecular furan Diels–Alder reactions: broad scope synthetic and computational studies

Abstract

For the first time a comprehensive synthetic and computational study of the effect of halogen substitution on both furan and dienophile for the intramolecular Furan Diels-Alder (IMDAF) reaction has been undertaken. Contrary to our initial expectations, halogen substitution on the dienophile was found to have a significant effect, making the reactions slower and less thermodynamically favourable. However, careful choice of the site of furan halogenation could be used to overcome dienophile halogen substitution, leading to highly functionalised cycloadducts. These reactions are thought to be controlled by the interplay of three factors: positive charge stabilisation in the transition state and product, steric effects and a dipolar interaction term identified by high level calculations. Frontier orbital effects do not appear to make a major contribution in determining the viability of these reactions, which is consistent with our analysis of calculated transition state structural data.

Intramolecular Nitrofuran Diels–Alder Reactions: Extremely Substituent-Tolerant Cycloadditions via Asynchronous Transition States

“…5 We identified a dipolar interaction term (Scheme 1) as an additional factor in halofuran/haloalkene IMDAF reactions. 6 We also discovered a correlation between transition state structure and energy that was consistent with the late transition state indicated in previous reports. 7 We now report the results of our investigations in intramolecular nitrofuran cycloadditions.…”

Unusual Structure-Energy Correlations in Intramolecular Diels–Alder Reaction Transition States

“…Examination of the original scatter plots [19] (reproduced in the Supplementary File) reveals a grouping of both activation energies and Gibbs free energies of the reaction according to the type of substrate present, with those containing halogenated dienophiles tending to have higher barriers and less exergonic free energies than those with halogenated furans. Substrates halogenated on both reaction partners were intermediate in both values, and similar trends were observed experimentally.…”

“…The Diels–Alder reaction of furan has been widely used in the synthesis of complex targets and as a probe for the investigation of substituent effects [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. We recently reported a comprehensive, computational and experimental study of halogenation effects in intramolecular Diels–Alder reactions [19]. The relative rates of many Diels–Alder reactions can be understood in terms of frontier orbital energy differences between the reaction partners [20,21,22,23,24,25].…”

“…Our recent work [19] focused on halogenation effects in both diene and dienophile and resulted in the discovery of a C-X dipole-dipole interaction that contributed to the transition state energy. Calculated FMO energies did not correlate well with the experimentally observed reaction rates.…”

Role of Halogen Substituents on Halogen Bonding in 4,5-DiBromohexahydro-3a,6-Epoxyisoindol-1(4H)-ones

“…The 2-(4-substituted phenyl)-2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-1(6H)-ones (2a−e) were synthesized by the known reaction of acryloyl chloride with the corresponding 4-substituted-N-(furan-2-ylmethyl)anilines (1a−e) in the presence of Et 3 N in toluene (Scheme 1) [31,33,[40][41][42][43]. Compounds 2d and 2e are novel, whereas 2a−c have been reported earlier [31,33,[40][41][42][43], and hence will not be discussed herein. The structures of 2d and 2e were deduced from their IR, 1 H and 13 C NMR spectra (Figures S1 and S2), ESI-MS, and elemental analysis (see experimental section).…”