Theoretical Investigation on the Mechanistic Pathways of Cp*Cobalt(III)-
Catalyzed Transformation of N-Substituted Carbamoyl Indoles to
Pyrroloindolone Derivatives
Authors: Das Gourab Kanti , Saha Rohini , Saha Saptarshi 
Published: August 2022

Aim:
A theoretical study on the Cp*cobalt(III) catalyzed C-H functionalization transformation of N-substituted carbamoyl indoles with alkyne derivatives to pyrroloindolone derivatives has been performed using DFT method.

Background:
Indole skeleton is an important part for developing regioselective C-H bond functionalisation reactions. Pyrrolo[1,2-a]indole bearing a 6-5-5 tricyclic skeleton (Scheme-1) is an important structural component found in many biologically active natural products and pharmaceuticals, (such as antitumor mitomycin C, antimalarial flinderole B etc.).Thus C−H activation process has great demand methods for efficiently synthesizing a pyrrolo[1,2-a]indole unit from readily available starting materials. One such attractive report was published by Matsunaga & Kanai et.al., Which shows pyrroloindolone derivatives can be synthesized (Scheme-2) through Cp*Co(III) catalysed C-H alkenylation and annulations from N-substituted carbamoyl indoles.

Objective:
Our current project deals with the determination of the rate determining step of the reaction, to determine the energetically favourable pathway. Investigation of the actual reason behind the regioselectivity of the products whether it is steric or electronic effects of the substituents.

Method:
The geometry optimization and energy calculations of all the systems were carried out with the Gaussian 09 software. Construction of trial geometries, monitoring the progress of calculations and visualization of the final output were done by several graphical user interface softwares like Gauss View, Molden etc. Geometry optimization of all species is performed using M06-2X functional in DFT method as a method for performing optimization of structures. 6-31G (d, p) basis set was employed for all non-metal atoms and the LANL2DZ basis set was employed for cobalt. To find out the geometries of several transition structures on the potential energy surface (PES) of the reaction pathway, relaxed scan method was used.

Result:
DFT study on a reaction of carbamoyl indoles with alkyne derivatives by activate Co(III)Cp* catalytic condition is done here. The target scheme followed the energetics of two possible pathways. The initial step of the reaction is the alkyne insertion step which needs 21.27 kcal mol-1 amount of energy. In the first case the final annulated product has been generated through a carbon-carbon bond formation, proton transfer and demetallation processes in path-a. The global activation barrier has been found to be quite high (30.17 kcal mol-1). However the study of the second pathway, which generated the simple alkenylated product through the proto-demetalation process in path-b, reveals a more reliable activation barrier (21.27 kcal mol-1).

Conclusion:
Comparison of the energy requirement clearly reveals that the formation of the final product should go through favourable simple alkenylation process that is path-b for dimethyl amine. Due to lower energy barrier the simple alkenylation pathway (i.e Path-b) is more favourable one. Initial alkyne addition step is the rate determining step. The regioselectivity of the alkyne addition is purely governed by the steric crowding around the substrate. Thus the favourable mode of alkyne addition has lower energy barrier due to lesser steric interactions. This theoretical investigation may guide the future researchers for developing some other economical route for generating similar derivatives.