Regioselectivity in Metal-Free Indole C-H Borylation: A DFT Investigation

Area of Science:

• Organic Chemistry
• Computational Chemistry

Background:

• Selective C-H borylation of indoles is a key organic transformation.
• Regioselectivity in these reactions is not fully understood experimentally.

Purpose of the Study:

• Investigate the factors governing regioselectivity in indole C-H borylation.
• Provide a theoretical explanation for temperature-dependent regioselectivity.

Main Methods:

• Density Functional Theory (DFT) calculations were employed.
• Two distinct indole borylation reactions were modeled: catalyzed and catalyst-free.

Main Results:

• The B(C6F5)3-catalyzed reaction follows an electrophilic aromatic substitution mechanism, thermodynamically controlled favoring C3 borylation.
• Catalyst-free borylation at high temperature unexpectedly showed C3 isomer stability.
• In situ-generated BH3 coordination to indole nitrogen was identified as the cause for C2 product preference.

Conclusions:

• DFT calculations provide a unified theoretical framework for indole C-H borylation regioselectivity.
• The study elucidates the role of BH3 coordination in reversing thermodynamic control at elevated temperatures.
• This work clarifies the mechanism behind experimentally observed temperature-dependent regioselectivity in metal-free borylation.