Photocatalytic Dearomative Intermolecular [2 + 2] Cycloaddition of Heterocycles for Building Molecular Complexity.

Area of Science:

• Organic Chemistry
• Photocatalysis
• Medicinal Chemistry

Background:

• Indole and indoline scaffolds are crucial in pharmaceuticals and agrochemicals.
• The [2 + 2] cycloaddition is a key reaction for synthesizing sp3-rich cyclobutane structures.
• Developing efficient methods for constructing these scaffolds is vital for drug discovery.

Purpose of the Study:

• To establish a general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes.
• To identify suitable indole derivatives for this reaction.
• To explore the scope and mechanism of the developed cycloaddition.

Main Methods:

• Visible-light photocatalysis.
• Substrate-based screening to identify optimal indole motifs (Boc-protected indole-2-carboxyesters).
• Reaction optimization and scope determination with diverse alkenes and indole derivatives, including azaindoles.
• Density Functional Theory (DFT) calculations to elucidate the reaction mechanism.

Main Results:

• A general visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes was achieved.
• Boc-protected indole-2-carboxyesters were identified as effective substrates.
• The reaction showed high yields, excellent regio- and diastereoselectivity with a broad range of alkenes (activated and unactivated) and indoles (including azaindoles).
• DFT studies indicated a triplet-triplet energy transfer initiation mechanism.
• The reaction was successfully scaled to 100 g.

Conclusions:

• A versatile and efficient photocatalytic method for constructing cyclobutane-fused indole scaffolds has been developed.
• The method provides access to diverse, functionalized scaffolds suitable for further derivatization in drug discovery.
• The reaction's broad scope, high selectivity, and scalability make it a valuable tool in synthetic chemistry.