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.