1,8-Addition/[3,3]-Rearrangement in the Functionalization of Unactivated Indole C(sp³)-H Bonds

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Indole derivatives are crucial scaffolds in medicinal chemistry.
• Direct functionalization of C-H bonds in indoles remains a synthetic challenge.
• Efficient synthesis of all-carbon quaternary centers is highly desirable.

Purpose of the Study:

• To develop a novel catalytic method for indole C(sp3)-H bond functionalization.
• To synthesize indole derivatives with all-carbon quaternary centers.
• To explore the synthetic utility of the resulting products.

Main Methods:

• Brønsted acid-catalyzed 1,8-conjugate addition/[3,3]-rearrangement reaction.
• Utilized propargylic p-quinomethanes (p-QMs) and 2,3-disubstituted indoles.
• Gold-catalyzed transformation of indole products.

Main Results:

• Achieved direct functionalization of unactivated C(sp3)-H bonds of indoles.
• Synthesized various indole derivatives featuring an all-carbon quaternary center.
• Demonstrated efficient conversion of alkynyl indoles to indole-fused pyridine tricycles.

Conclusions:

• The developed methodology offers an efficient route to complex indole structures.
• The reaction proceeds via a proposed mechanism elucidated by control experiments.
• The synthetic utility is highlighted by the subsequent gold-catalyzed transformation.