In the world of organic chemistry, nitrogen-containing organic compounds are ubiquitous, forming the backbone of pharmaceuticals, agrochemicals, dyes, and functional materials. To build these important molecules, chemists often rely on highly reactive intermediates that can be transformed into many different products. One such important class is diazoacetic acid ester derivatives, which are widely used to construct a diverse range of organonitrogen compounds. Diazo compounds are molecules that contain a pair of connected nitrogen atoms, known as a diazo group, which makes them highly reactive and useful in many chemical transformations. However, they are typically prepared using hazardous reagents, such as diazomethane, a highly toxic and difficult-to-handle compound. Avoiding this reagent represents a significant safety advantage, particularly for routine and larger-scale synthesis.
Researchers from the Tokyo University of Science in Japan have now developed a novel method to generate diazo compounds that avoids the need for these toxic precursors. Their approach, based on a unique Michael addition reaction mediated by the azide-to-diazo conversion, enables the synthesis of β-heteroatom-substituted 2-diazopropionic acid esters from readily accessible starting materials under mild conditions.
The team was led by Professor Suguru Yoshida of the Department of Biological Science and Technology and included Tomoki Mano, a second-year Master’s student, Takahiro Yasuda, a first-year doctoral student, and Gaku Orimoto, who completed his Master’s degree in 2023. The study was published in the journal Angewandte Chemie International Edition on April 20, 2026.
“We discovered a novel form of transformation from 2-azidoacrylate esters to diazo compounds via the formation of a phosphazide intermediate and subsequent Michael addition,” says Prof. Yoshida.
The Michael addition is a classic organic reaction in which a nucleophile, a molecule that donates electrons to form a chemical bond, adds to an electron-deficient alkene, which is a molecule containing a carbon–carbon double bond that lacks electrons. Common nucleophiles include thiols, which are sulfur-containing compounds, and amines, which are nitrogen-containing compounds. The researchers adapted this well-known transformation to convert an azide group into a diazo group by forming a reactive phosphazide intermediate.
They pretreated 2-azidoacrylic acid esters with a bulky, electron-rich phosphine called Amphos, also known as di( tert -butyl)(4-(dimethylamino)phenyl)phosphine, which generated a relatively stable phosphazide intermediate. Upon subsequent Michael addition of nucleophiles, this intermediate undergoes nitrogen–nitrogen bond cleavage, which is a process where a bond between two nitrogen atoms breaks, to produce the desired diazo ester.
The discovery was made while the researchers were studying how azides, which are molecules containing a chain of three nitrogen atoms, behave when they are temporarily stabilized, or protected, by phosphines (phosphorus-containing compounds). They observed that pretreatment of an azide with Amphos, followed by the addition of a thiol, unexpectedly yielded a diazo compound instead of the anticipated azide product.
This occurs because the phosphazide intermediate formed by Amphos is more reactive than the original azide compound. When a nucleophile is added, it reacts through a Michael addition pathway that leads to the formation of diazo esters, accompanied by nitrogen–nitrogen bond cleavage.
Within this reaction, heteroatoms, which are atoms other than carbon and hydrogen, such as sulfur or nitrogen, can also be introduced at the β-position, which is a specific location on the molecule next to the reactive site of the diazo ester, creating highly functionalized products. By changing the nucleophiles used in the reaction, the researchers were able to create a wide variety of β-heteroatom-substituted diazo esters. These compounds can then be further transformed into many useful products, including sulfones, hydrazones, and nitrogen-containing heterocycles such as indoles and pyrazoles—structures commonly found in pharmaceuticals and bioactive molecules. This highlights the method’s potential utility in medicinal chemistry and synthetic chemistry applications where flexible access to diazo intermediates is valuable.
The reaction proceeds under mild conditions and avoids the use of hazardous diazomethane, offering a safer and operationally simple approach. While demonstrated at the laboratory scale, the method shows promising potential for broader synthetic applications.
“Diazo compounds are important intermediates widely used in the synthesis of drug candidates, functional molecules, and heterocyclic compounds. Therefore, 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,” says Prof. Yoshida.
Having established this method, the researchers are now working to expand the range of starting materials, including extending it to azidoacrylamides, which could enable the creation of a wider variety of nitrogen-containing compounds with potential applications in pharmaceuticals and functional materials.
***
Reference
DOI: 10.1002/anie.4448961
About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society," TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
Website: https://www.tus.ac.jp/en/medi
About Professor Suguru Yoshida from Tokyo University of Science
Dr. Suguru Yoshida is a Professor at Tokyo University of Science (TUS), Faculty of Advanced Engineering, Department of Biological Science and Technology. He earned his doctorate in engineering from Kyoto University. After postdoctoral fellowships at Kyushu University and the University of Hawaii at Manoa, and faculty positions at Tokyo Medical and Dental University, he joined TUS. He leads the Yoshida Group, focusing on organic chemistry for life science, including click chemistry, cationic and strained intermediates, and synthesis of organosulfur and organophosphorus compounds. He has received the BCSJ Awards, Commendation for Science and Technology by MEXT, and Thieme Chemistry Journals Award.
Funding information
This work was supported by JSPS KAKENHI (Grant Number: JP23K17920) and Asahi Glass Foundation.
Angewandte Chemie International Edition
Experimental study
Not applicable
Azide-to-Diazo Transformation Facilitated by Michael Addition via Phosphazide Formation
20-Apr-2026
The authors declare no conflicts of interest.