Arenes Hook Up

MAKING CERTAIN pharmaceuticals and electronic chemicals could get much simpler, thanks to a new catalytic reaction for coupling two different arenes together.

Coupling one aromatic molecule to another usually requires elaborate functionalization of one or both aromatics beforehand to ensure the compounds react efficiently and selectively with one another. Now, the University of Ottawa's Keith Fagnou and David R. Stuart have devised a way to stick benzene and an N-acetylindole together without functionalizing them first. The reaction proceeds in high yields with high regioselectivity and, most important, produces no self-coupled by-products (Science 2007, 316, 1131).

"The way biaryls are made commercially today, you have to preactivate everything. You can't just couple two carbon atoms together at their C-H bonds," Fagnou explains. The problem is that until now, coupling reactions haven't been selective enough to avoid the stew of homocoupled biaryls that are produced along with the desired cross-coupled biaryl. "How do you get two things to react only with the other coupling partner and not with itself?" Fagnou says. "That was the trick that needed to be solved."

Fagnou and Stuart realized that by selecting aromatic compounds based on nucleophilicity and C-H acidity, they could get one arene to react selectively with the catalyst. The catalyst/arene complex then reacts exclusively with the other arene.

It took a lot of optimization to get the cross-coupling to work, Fagnou and Stuart acknowledge. They had to employ a palladium trifluoroacetate catalyst, along with copper(II) acetate for catalyst regeneration. Critical to the reaction's success were two additives, 3-nitropyridine and cesium pivalate, and the pivalic acid solvent.

The new process "could have immense practical importance for the synthesis of materials, electronic devices, and drugs," writes Jonathan A. Ellman of the University of California, Berkeley, in a Science commentary. "However, further advances will be required to enhance reaction efficiency, for example, by reducing catalyst and terminal oxidant loading levels."