Exploring the peri- and stereo- selectivities of the cycloaddition reaction of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one with N-phenylmaleimide (NPM) and dimethylacetylenedicarboxylate (DMAD) - A DFT study.

The [4 + 2] cycloaddition reactions of 2-styrylchromones have been predominantly described as one of the efficient methods for the synthesis of xanthones-a prominent class of tricyclic molecules that occur widely in nature. These xanthones are well known for their pharmacological activities especially their role as anti-cancer agents in the medicinal world. In this study, the mechanistic insight into the unusual (peri- and stereo-) selectivities of the reaction of 2-(2-dimethylaminovinyl)-1-benzopyran-4-one (A1) with N-phenylmaleimide (NPM) and dimethylacetylenedicarboxylate (DMAD) has been studied using density functional theory (DFT) at the M06-2X/6-311G (d, p) level of theory. The reaction of A1 and NPM in dimethylformamide (DMF) is periselective towards the initial formation of a [4 + 2] cycloadduct and stereoselectively in an exo fashion with an activation energy of 6.8kcalmol and a rate constant of 6.43×10s which occurs about 878 million times faster than the closest competing pathway for the initial [2 + 2] cycloaddition fashion with an activation energy of 19.0kcalmol and a rate constant of 7.32×10s. For the substituent effect on the reaction, the reaction selectivity is still maintained where the exo intermediate remains the most kinetically favored cycloadduct. However, the magnitude of the barriers increases slightly with a margin of about 0.1-4.8kcalmol for the electron-donating groups (EDGs) in the order; strong EDGs (OH < NH < OCH) < weak EDGs (<Ph) and 5.3-6.4kcalmol for electron-withdrawing groups in the order; strong EWGs (CF) < weak EWGs (Cl < Br). On the other hand, DMAD periselectively adds across the amino substituted olefinic bond of A1 via an initial [2 + 2] stepwise cycloaddition fashion followed by an intramolecular rearrangement to form the xanthone product. The rate constant of the rate-determining step in the pathway for the formation of the kinetically favored [4 + 2] cycloadduct with an activation barrier of 17.3kcalmol is 1.29s which occurs about 373,000 times slower than the most preferred pathway affording a [2 + 2] cycloadduct with an activation barrier of 9.7kcalmol and a rate constant of 4.81×10s. Both reactions are normal electron-demand cycloaddition reactions and are kinetically controlled.