Why Does an Inert C4–H Bond in Indolyl Aldehyde Get Activated Unexpectedly by a Rh(III) Catalyst over a More Reactive C2–H Bond while the Opposite Is True for Acetophenone? Guidelines for Inverting Regioselectivity

Rh­(III)-catalyzed regioselective C–H activation/alkyne insertion/cyclization of indolyl aldehyde and acetophenone with alkynes was investigated using density functional theoretical models. Previously, it was observed that acetophenone demonstrates activation of the more reactive C2–H bond, but indolyl aldehyde showed an unexpected reactivity of the inert C4–H bond under comparable conditions. To understand this substrate-dependent outcome and provide a set of much-awaited guiding principles to invert the regioselectivity as desired, the reaction mechanisms for C2–H and C4–H pathways were elucidated in detail and compared. Our study indicates that the five-membered rhodacycle intermediate, formed in the C2–H pathway, becomes a thermodynamic sink in the case of indolyl aldehyde, and, as a result, the subsequent alkyne insertion step becomes energetically too costly. This finding is in striking contrast to the C4–H mechanism of indolyl aldehyde and the C2–H pathway of acetophenone where no such thermodynamic sink was found, and, consequently, the barriers of the alkyne insertion transition states are significantly reduced to provide highly regioselective outcomes. We discover the key structural features that control formation of the thermodynamic sink intermediate, and we further report an in-silico design of optimal systems to successfully resolve the problems arising from the thermodynamic trap in the C2–H pathway. A set of general guidelines has been proposed that can be adopted in an experimental laboratory to switch the selectivity toward the exclusive formation of the C2–H activated product, cyclopenta­[b]­indol-1-ol, without extensive experimentation, thus saving manpower, energy, and chemical waste. To date, there has been no report of formation of this product from indolyl aldehyde.