Building new molecules for medicinal chemistry and organic materials

Indoles are organic compounds that are central structural elements found from drugs to conductive materials. Consequently, synthesis and modification (“functionalization”) of indoles is highly important to organic chemistry and material sciences, but such chemical modifications have been limited in their diversity. Publishing in Angewandte Chemie, EPFL scientists demonstrate a novel “domino” reaction that offers a simple way to install alkynes onto indoles with unprecedented efficiency and selectivity.

Indoles are omnipresent in natural products, bioactive molecules, and organic materials. They consist of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Most chemistry involving indoles focuses on either installing or modifying the pyrrole ring; modifying the benzene ring has proven much more challenging. This creates a significant limitation, as indoles with modified benzene rings can be used in numerous drugs, chemical sensors and organic materials.

“Domino” reaction

Jerome Waser and Yifan Li at EPFL have developed a new method for synthesizing indoles bearing alkyne groups from easily available starting materials. The approach offers a low-energy pathway for introducing an alkyne into the unreactive benzene ring of an indole. Alkynes are a functional group containing two carbon atoms linked by a triple bond, and are currently one of the most versatile starting points to generate chemical diversity in synthetic chemistry, chemical biology and materials science.

The novel reaction is described as “domino”, in that it consists of three steps that virtually trigger each other in a forward direction. Developing such a domino process is a challenging endeavor, as it requires the perfect orchestration of the different steps involved: each intermediate has to display the right reactivity and be generated at the right speed or else the entire reaction chain will be interrupted.

The scientists achieved the perfect domino by designing carefully how catalyst and reagents would be used along the reaction. They replaced the conventional gold catalysts with platinum, and used hypervalent iodine reagents – a highly reactive class of iodine-based compounds developed by Waser’s lab that are now also commercially available.

The breakthrough study paves the way for synthesizing indoles bearing alkyne groups, giving for the first time efficient access to this important class of compounds. Based on the exceptional chemical versatility of alkynes, these alkynylated indoles can be extremely useful building blocks for synthesizing bioactive compounds and organic materials, currently explored by Waser’s group.

However, there is still work to be done. “On an industrial scale, significant improvement in catalyst loading and reagent recycling would be needed to make the process more cost-effective,” says Waser, who is now extending the domino reaction strategy to create other important building blocks for synthetic and medicinal chemistry, as well as materials science.

Reference

Li Y, Waser J. Platinum-Catalyzed Domino Reaction with Benziodoxole Reagents for Accessing Benzene-Alkynylated Indoles. Angewandte Chemie 10 March 2015. DOI: 10.1002/anie.201412321