Direct arene amination

27 Sep 2011

A new gold-catalyzed reaction for the synthesis of aromatic amines could lead to greener production of pharmaceuticals and other fine chemicals

A gold catalyst brings together an arene (blue) and an azodicarboxylate (red) to produce an aromatic hydrazide (top). Also shown is the structure of the antihypertensive drug Hydralazine (apresoline).

A gold catalyst brings together an arene (blue) and an azodicarboxylate (red) to produce an aromatic hydrazide (top). Also shown is the structure of the antihypertensive drug Hydralazine (apresoline).

Pharmaceuticals and agrochemicals frequently contain aromatic amines. Even in cases where an aromatic amine is not present in the final product, it can often serve as an important intermediate in the synthesis of heterocyclic compounds, which form the basis of many pharmaceutical products. As such, synthetic organic methodology to produce aromatic amines is arguably one of the most important reactions for the fine chemicals industry.

Yugen Zhang and co-workers from the A*STAR Institute of Bioengineering and Nanotechnology have now developed a new gold-catalyzed method for the formation of aromatic hydrazides by direct reaction of an azodicarboxylate with an arene carbon–hydrogen bond. Aromatic hydrazides are close relatives of aromatic amines. They can be converted to aromatic amines easily or, as in the case of the antihypertensive drug hydralazine (apresoline), can be found in the drug molecule itself. “Previous research into these reactions focused on acid-catalyzed activation of the azodicarboxylate partner,” explains Zhang. “We believe our method was successful because the gold catalyst could activate both reacting partners.”

In recent years, metal-catalyzed reactions to form a carbon–nitrogen bond by reaction of aromatic halides have become increasingly widespread. Such reactions, however, require an additional step to form the initial carbon–halogen bond. The methodology reported by Zhang and co-workers does not require this first step and is an example of a rapidly emerging area of chemistry known as C–H activation.

Chemical reactions are rarely perfectly efficient, so simply eliminating a step, as in the aforementioned halogenation, can result in a higher overall yield of product. More importantly, the application of chemical reactions on an industrial scale may lead to the production of vast quantities of waste solvents and byproducts. Consequently, eliminating a step in the process can benefit the environment as well as providing a more efficient process.

There are several reasons why other groups have never developed such processes before. The first reason is that C–H bonds are typically not very reactive. The second reason is that there are often many C–H bonds in organic molecules, so selecting one to react can be difficult.

So far, Zhang and his team have shown their reaction is successful for the amination of a range of simple arenes. “We are particularly excited about the successful reaction with electron-deficient arenes, which nobody has made before,” says Zhang. “We are now trying to expand the scope of possible substrates for these reactions. We hope that the approach might ultimately be applied in the industry.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Bioengineering and Nanotechnology.

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Gu, L., Neo, B.S. & Zhang Y. Gold-catalyzed direct amination of arenes with azodicarboxylates. Organic Letters 13, 1872–1874 (2011). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature