Direct Bis-Alkyl Thiolation for Indoles with Sulfinothioates under Pummerer-Type Conditions

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Heterocyclic Chemistry

Background:

• Indole derivatives are crucial in medicinal chemistry and materials science.
• Efficient methods for functionalizing indoles, particularly with sulfur-containing groups, are highly sought after.
• Existing thiolation methods often require harsh conditions or specific catalysts.

Purpose of the Study:

• To develop a novel, base-free synthetic route for the bis-alkylation of indoles.
• To explore the utility of sulfinothioates as effective thiolation reagents under Pummerer-type conditions.
• To achieve regioselective double C-H thiolation at the C2 and C3 positions of indoles in a one-pot procedure.

Main Methods:

• Employing sulfinothioates activated by 2,2,2-trifluoroacetic anhydride.
• Conducting the reaction under Pummerer-type conditions without the need for a base.
• Utilizing a one-pot strategy for sequential C-H functionalization.

Main Results:

• Demonstrated a base-free bis-alkyl thiolation of indoles.
• Identified sulfinothioates as efficient thiolation reagents for broad applications.
• Achieved regioselective double C-H thiolation at the C2 and C3 positions of indoles.
• Mechanism studies indicated the involvement of a sulfoxonium salt intermediate.

Conclusions:

• The developed method offers a facile and efficient approach for synthesizing bis-alkylated indoles.
• This strategy expands the toolkit for indole functionalization, particularly for introducing sulfur moieties.
• The use of activated sulfinothioates presents a versatile platform for further synthetic explorations.