In-depth insight into structure-reactivity/regioselectivity relationship of Lewis acid catalyzed cascade 4πe-cyclization/dicycloexpansion reaction.

The Lewis acid-catalyzed tittle reaction of 1,3-dicycloalkenlidine ketones is recognized as so far the shortest and most effective 1-step method for construction of angular tricyclic scaffolds, which are extensively found in bioactive terpenoids. Here, a further kinetic study of this reaction with 30 reaction examples is carried out using in situ IR technology and DFT calculation. That enables the creation of well-fitted linear relationships of lnk/(ΔG1‡/T), ΔG1‡/ΔG2, ln(k/kH)/σp, reflecting the structure's effect on reactivity/selectivity, and validating the reaction mechanism. Particularly highlighted is that substituents C1-R1/C3-R2 activate this reaction in the order: alkyl ≈ aryl >> aryl S-, halogen, alkyl O-, and alkyl N-. While electron-withdrawing R1/R2 will inactivate this reaction. When R1 = R2 = Me and m = 4, the reactivity of n-membered substrates follow the order of ring's size: 3 > 4 > 7 > 6 > 5. Then, DFT calculations combined with machine learning algorithms establish a prediction model for first cycloexpansion (i e. regioselectivity). Electron-donating R1/R2 can direct preferentially the first cycloexpansion of its near ring in the order: alkyl > aryl > halogen ≈ alkyl O- > alkyl N- > aryl S-, which can be fitted into the relationship as ΔΔG/(ΔΔG-R1, ΔΔG-R2, ΔΔG-m, ΔΔG-n) or ΔΔG/(m-rse, m-ra, n-rse, n-ra, R1-σp, R2-σp). When R1 and R2 show the similar electronic effect, the first cycloexpansion of m/n takes place in the order of ring's size: 4 > 5 > 6, 7, 8 > 3. Six examples are successfully validated by model prediction and then experiment. In this work, structure-reactivity relationship and regioselectivity predicting model are established.