Thermodynamic Insight into Donor–Acceptor Cyclopropane Reactions with 1-Methylindole

Computational and experimental approaches were used to study the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 1-methylindole. In these reactions, the cyclopropane ring is activated for heterolytic cleavage by the electron-withdrawing properties of the methyl esters at C1 and the electron-donating behavior of the phenyl group at C2. The reaction with 1-methylindole produces a diastereomeric zwitterionic intermediate that can either abstract hydrogen from the indole C4 to form a Friedel–Crafts addition product or proceed via electrophilic addition and intramolecular cycloaddition to form a cyclopenta-fused indole. Density functional theory calculations with the B3LYP functional and the 6-31G** basis set were used, in a variety of solvent environments, to determine the energies and conformations of the zwitterionic intermediate as well as the Friedel–Crafts and annulated products. Three stable conformations were identified for each diastereomeric zwitterionic intermediate. The lowest energy conformer contained a geometry pre-optimized for hydrogen abstraction from C4 leading to the Friedel–Crafts product. The second most stable zwitterionic conformer placed the C1 enolate within 3.7 Å of C5, facilitating the formation of the annulation product. Barriers between all species were determined. The Friedel–Crafts product was 5–11 kcal/mol more stable than the annulation product, depending on the solvent environment. To verify these findings, we monitored the disappearance of reactant and formation of products using NMR. Initially, annulation proceeded faster than Friedel–Crafts product formation; however, as the reaction proceeded, a full conversion of cyclopropyl reactant to Friedel–Crafts product was observed, in agreement with the computational results suggesting that the Friedel–Crafts product was enthalpically favored.