Electronic substrate variations for improved intramolecular styryl Diels-Alder reactions to access analogs of deoxypodophyllotoxin

3-Phenylallyl arylpropynoic ester variations were produced and reacted under thermal conditions to generate racemic analogs of the anticancer agent deoxypodophyllotoxin. The intramolecular styryl Diels-Alder reaction (ISDA) with a [4 + 2]-cycloaddition followed by a 1,3-H shift gave the lactone products, obtained using 70% isopropyl alcohol/o-dichlorobenzene as solvent under sealed-tube conditions, 110–160 °C. Yields ranged from 36 to 84% isolated yield, demonstrating a significant substituent electronic effect. Electron-donating and electron-withdrawing aryl substituents, R, R′ included trimethoxy and nitro groups served to probe matched/miss-matched reactivity. Moderate 70% yields were achieved with 4-nitro-trimethoxyphenyl variations reacted at lower temperature, 110 °C, for 5 h. The findings show that moderate thermal conditions can be developed to uncover further refinements of this useful process.