A one-step photochemical method that converts nitrogen and carbon to convert pyrazole to imidazole research

Scientists have developed a photochemical reaction that converts pyrazole into imidazole by swapping a nitrogen atom and a carbon atom in a single step.¹ This method leaves the rest of the molecule untouched, opening a direct path to compounds that are otherwise expensive or require custom manufacturing.

Pyrazoles and imidazoles are very important compounds in medicinal chemistry, and rank among the most common heterocycles in pharmaceutical compounds. Because of their close structural relationship, chemists often prepare imidazole analogues of pyrazole-based drugs, and vice versa. But imidazoles tend to be expensive or not commercially available, which means chemists need to make them from scratch.

now, Daniele Leonori From RWTH Aachen University in Germany and his team reviewed research conducted 30 years ago by James Pavlik and colleagues at Worcester Polytechnic Institute in Massachusetts, US, which showed that UV light can catalyze the rearrangement of the pyrazole ring.

These early reactions often resulted in complex mixtures, low yields, and decomposition. “What we really did was take this very preliminary data that was available, and realize that we could build a very powerful synthetic method,” Leonori says. Building on these foundations, his team developed a reaction that works with a wide range of functional groups, including relatively inactive substituents such as methyl groups and other less innocent substituents, such as alcohols or amides.

It is crucial that this method be effective when applied to molecules of interest in medicinal chemistry. Among the examples they provided, the researchers prepared an imidazole analogue of stanozolol, a drug used to treat hereditary angioedema.

Richmond SarpongAn expert in natural product synthesis at the University of California, Berkeley in the US, says the reactions will help medicinal chemists “easily study the properties of these two structural forms by preparing one from the other.” This would avoid tedious synthesis of both compounds. This kind of late-stage diversification has been the subject of many medicinal chemistry dreams.

Another interesting aspect of the research is the reaction mechanism. It begins with photoexcitation of the pyrazole, followed by homolytic degradation of the N-N bond. This results in a two-radical intermediate, which is then transformed into the final product. Leonori points out that Pavlik suggested something similar in his early observations of the reaction. In the new study, the team used computational analysis and deuterium labeling experiments to validate “the very preliminary evidence of what Pavlik pushed forward in the 1990s.”

Huying Zeng, an organic chemistry expert from Lazhou University in China, highlights that Leonori’s group reported a very relevant shift last year.³ Some products have already shown interaction of pyrazole with imidazole. He says the current study is important “because it turns those previous examples onto a broader synthetic platform and gives a clearer mechanistic picture.”

The key to the success of this reaction is the choice of solvent, as this plays an important role in stabilizing the reaction intermediate leading to the selective formation of the imidazole product. While optimizing the reaction, Leonori’s team found that a solvent that conferred hydrogen bonding such as hexafluoroisopropanol was necessary to run this reaction and avoid the formation of multiple products.

Transformation has some limitations. “Ideally, one prefers to use longer wavelength light (such as a blue LED).” However, given the strength of the transformation achieved here, it is still likely to find benefit, Sarpong says. While Zeng says the shift is not universal: “simple.” n-Alkyl, n– Benzoyl, and n-Tosyl pyrazoles were problematic in some cases, with no interaction or removal of protection observed. The reaction is also sensitive to where the substituents are placed on the pyrazole. Leonori echoed these concerns and also explained that the main limitation is that the molecule can only be rearranged in one way.

Scalability is another disadvantage of React. To explore this aspect, the researchers tested the reaction in a flow chemistry setup, which allowed them to obtain imidazole products in multi-gram quantities. However, access to this type of device can limit its wider use. Despite these limitations, Zeng considers “this a valuable method for editing scaffolds at a late stage.”

Leonori’s team is now exploring how to extend this concept to other periodic systems.