Stereoselectivity in Diels−Alder Reactions of Diene-Substituted <i>N</i>-Alkoxycarbonyl-1,2-dihydropyridines

Diene substituent effects on the regiochemical and stereochemical outcomes of uncatalyzed Diels−Alder reactions of <i>N</i>-alkoxycarbonyl-1,2-dihydropyridines with both styrene and methyl vinyl ketone (MVK) were studied. Alkyl substitution on the diene in all cases examined resulted in a kinetic preference for 7-endo isomers (7-phenyl 51−96% exo and 7-acetyl 54−96% exo). For both dienophiles, the highest stereoselectivities (≥89% endo) were observed with 5-methyl or 6-methyl substituents in the dihydropyridine. Theoretical calculations of the energies of gas phase endo and exo transition states at the RHF/3-21G(*) predict that total entropy, Δ<i>S</i><sub>total</sub>, considerations favor endo cycloadducts for both dienophiles with DHP, while total energy considerations, Δ<i>E</i><sup>⧧</sup><sub>o</sub>, favor endo cycloadducts for styrene and exo cycloadducts for MVK. At this level, favored <i>endo-</i>phenyl isomers are correctly predicted for styrene reactions, but the calculation of 7-acetyl exo or endo isomer dominance is diene-substituent-dependent for MVK reactions. The preference for endo addition of MVK to the parent, 5-methyl, and 6-methyl-DHPs was successfully predicted by calculations at the B3LYP/6-31G* theory level.