Mechanistic Investigation\nof the Pseudo-Halogen Effect\nin Enantioselective Aminocatalyzed [6 + 4] and [10 + 6] Cycloadditions:\nEnabling Unique Favorskii-Like Rearrangements

A mechanistic investigation into the novel combination\nof the <i>pseudo</i>-halogen effect with enantioselective\naminocatalysis\nunravels the mechanistic intricacies of [6 + 4] and [10 + 6] higher-order\ncycloadditions and the succeeding new Favorskii-like rearrangements.\nBy introducing the OTf-group into the tropone framework, it can serve\nboth as an activator for the cycloaddition and as a proficient leaving\ngroup within the corresponding cycloadduct, thus enabling unprecedented\nring-contracting Favorskii-like rearrangements. Integrating the -OTf\ngroup creates an electron-deficient 6π-component leveraging\nthe <i>pseudo</i>-halogen effect by enhancing the polarization\nand introducing new strategic interaction points. This modification\ncomplements electron-rich 4π- and 10π-components from\namino-activated 2,4-dienals or indene-carbaldehydes. A comprehensive\nDFT investigation supported by experimental results demonstrates that\nthe [6 + 4] system proceeds through a rate-limiting stepwise <i>exo</i>-cycloaddition leading to a cycloadduct initially in\na boat-conformation, subsequently transitioning to the more stable\nchair-conformation. The change in conformation ensures an S<sub>N</sub>1-like expulsion of the -OTf group, generating a stable carbocation\nbridgehead primed for a novel Favorskii-like seven-to-six ring-contracting\nrearrangement, resulting in the experimentally observed product. As\nproof-of-concept for the cycloaddition/Favorskii-like rearrangement,\nit is demonstrated that this approach can be extended to an unprecedented\n[10 + 6] cycloaddition. In contrast to the [6 + 4] system, the [10\n+ 6] system distinguishes itself with a concerted S<sub>N</sub>1-like/Favorskii-like\nsix-to-five ring-contracting rearrangement, representing the rate-limiting\nstep. This novel concept results in the experimental isolation of\nstructurally complex products in high <i>peri</i>-, <i>diastereo</i>-, and <i>enantioselectivity</i> with\nmoderate yield. These findings demonstrate the <i>pseudo</i>-halogen effect’s multifaceted role in promoting and enabling\nnovel reactivity.