Chemists at the Tokyo University of Science (TUS) in Japan have developed a new method to produce a class of highly versatile chemical building blocks used in drug development, replacing a hazardous process with a safer, milder alternative.
The research, published in the journal Angewandte Chemie International Edition on April 20, 2026, centres on diazo compounds, molecules used extensively in the synthesis of drug candidates, dyes, agrochemicals, and functional materials. These compounds are reactive and valuable precisely because they can be transformed into many different products, but they are traditionally made using diazomethane, a substance that is both highly toxic and difficult to handle safely, particularly at larger laboratory scales.
The team, led by Professor Suguru Yoshida of the TUS Department of Biological Science and Technology, found a way to produce diazo compounds starting from azides, a different class of nitrogen-containing molecules, using a reaction pathway that sidesteps diazomethane entirely.
The approach works by first treating a compound called 2-azidoacrylic acid ester with a phosphine reagent known as Amphos. This generates a reactive intermediate called a phosphazide, which is more chemically active than the original azide. When a nucleophile, a molecule that forms chemical bonds by donating electrons, is added, a reaction called Michael addition occurs. This breaks a bond between two nitrogen atoms and produces the desired diazo ester under mild conditions.
The discovery was initially unexpected. The team was studying how azides behave when temporarily stabilised by phosphines and noticed that adding a thiol, a sulfur-containing compound, produced a diazo compound rather than the anticipated azide product.
By varying the nucleophiles used in the reaction, the researchers were able to produce a wide range of diazo compounds with different chemical groups attached, including those containing sulfur and nitrogen atoms. These products can then be converted into structures commonly found in pharmaceutical molecules, including indoles and pyrazoles.
“Diazo compounds are important intermediates widely used in the synthesis of drug candidates, functional molecules, and heterocyclic compounds. We expect that this will contribute to the development of a wide range of research fields as a fundamental technology that enables the more practical and flexible synthesis of diverse diazo compounds,” Prof. Yoshida said.
The team now plans to extend the method to a broader range of starting materials, including azidoacrylamides, which could expand the variety of nitrogen-containing compounds accessible through this approach.
The study was co-authored by Master’s student Tomoki Mano, doctoral student Takahiro Yasuda, and former student Gaku Orimoto, and was funded by the Japan Society for the Promotion of Science (JSPS) and the Asahi Glass Foundation.
