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Synthesis

Photoredox Catalysis Activates Aryl C–H Bonds In Amination Reaction

Organic Synthesis: Site-selective reaction provides a general path to wide range of aryl amines

by Bethany Halford
September 18, 2015 | APPEARED IN VOLUME 93, ISSUE 37

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Nicewicz and coworkers were able to site-selectively tack a pyrazole group onto the complex arene O-acetylcapsaicin.
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Nicewicz and coworkers were able to site-selectively tack a pyrazole group onto the complex arene O-acetylcapsaicin.

By combining two red-hot areas of organic chemistry—photoredox catalysis and C–H activation—chemists have discovered a method for transforming aryl C–H bonds into C–N bonds.

The site-selective amination, which links arenes to aromatic nitrogen heterocycles or ammonia, offers chemists an easy way to make derivatives of aromatic compounds. Such a transformation could be a boon for medicinal chemists and agrochemical makers.

Aromatic nitrogen heterocycles turn up in many biologically active compounds, explains David A. Nicewicz, a chemistry professor at the University of North Carolina, Chapel Hill, who spearheaded the research. The new reaction lets chemists make many different kinds of such molecules using one easy procedure that tolerates numerous functional groups (Science 2015, DOI: 10.1126/science.aac9895). “We think that this will be very valuable to medicinal chemists who are looking to make different derivatives of a lead compound,” Nicewicz says.

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Credit: Lars Sahl
Nicholas E. Tay (from left), Kaila A. Margrey, Nicewicz, and Romero stand before the blue light used in their photoredox catalysis reaction.
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Credit: Lars Sahl
Nicholas E. Tay (from left), Kaila A. Margrey, Nicewicz, and Romero stand before the blue light used in their photoredox catalysis reaction.

This isn’t the only way to transform aryl C–H bonds into C–N bonds, but the reaction offers several advantages over previously reported methods. Unlike in metal-catalyzed aminations, there’s no need to add or remove templating groups to the arene. Also, the arene, which can often be time-consuming to prepare, doesn’t need to be used in excess, as it does in arene aminations that use hypervalent iodine reagents.

The new amination reaction also has the advantage of being site-specific, selectively tacking the nitrogen onto the position para to electron-donating groups on the arene in most cases. The transformation also can be performed late in a synthetic sequence, allowing researchers to add amines onto complex arenes.

To run the reaction, chemists simply mix an arene with either an aromatic nitrogen heterocycle, such as imidazole or pyrazole, or an ammonia equivalent, such as ammonium carbamate, in the presence of an acridinium catalyst and the cocatalyst 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Then the chemists simply irradiate the system with blue light in the presence of oxygen.

The addition of the TEMPO cocatalyst—an idea of coauthor Nathan A. Romero—turned out to be key to getting the reaction to work well, Nicewicz tells C&EN. The chemists think the TEMPO is abstracting a hydrogen atom at a critical stage to form the aromatized product. “TEMPO is an oxygen-centered stable radical,” Nicewicz explains. “Oftentimes, it absolutely stops radical reactions dead in their tracks. But here it turns out to be the catalyst.” Although it’s not the first example of TEMPO behaving this way, he says, “it’s not the first thing you’d grab off the shelf as a cocatalyst for a radical-type reaction.”

Tehshik Yoon, an expert in photoredox catalysis at the University of Wisconsin, Madison, says, “This is a really great result, both from a synthetic perspective and a fundamental photocatalytic perspective.”

He is particularly interested in how the reagents combine so productively, noting that there are many reasons why this reaction shouldn’t work. The methodology “offers an elegant, nonobvious design for a really powerful catalyst system,” he says. “It makes you reimagine what might be possible in a photocatalytic system.”

JUST RIGHT
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Although there are eight aromatic C–H bonds in this arene substrate, the reaction transforms just one of them.

This article has been translated into Spanish by Divulgame.org and can be found here.

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