A research group including Professor Suguru Yoshida of the Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, and Graduate Students Tomoki Mano, Takahiro Yasuda, and Gaku Orimoto of the Graduate School of Advanced Engineering at Tokyo University of Science, has successfully synthesized useful diazo esters safely from 2-azidoacrylic acid esters without using highly hazardous diazomethane. They confirmed that the synthesis proceeds under mild conditions and can be performed even on a 10-mmol scale. Application as a foundational technology supporting pharmaceutical synthesis is expected. The results were published in Angewandte Chemie International Edition on April 20.
2-Azidoacrylic acid esters are converted into phosphazide intermediates upon treatment with Amphos, followed by nucleophile-driven Michael addition. This transformation proceeds with concurrent nitrogen-nitrogen bond cleavage, affording β-heteroatom-substituted diazo esters efficiently under mild conditions.
Provided by Tokyo University of Science
Diazoacetate derivatives are important compounds for synthesizing a variety of nitrogen-containing compounds and have been widely utilized in organic synthesis, including dipolar cycloadditions and reduction reactions. On the other hand, the synthesis of these compounds has involved steps that use hazardous reagents such as diazomethane, making the development of a more practical and safer production method a long-standing challenge. There has also been a demand for methods to develop new reaction formats by leveraging stable intermediates.
Therefore, based on their unique platform of utilizing azide compounds as stable phosphazides, the research group explored new ways to use the azide group. Specifically, they investigated leveraging the properties of the stable phosphazide intermediate generated from 2-azidoacrylic acid esters.
Azide compounds are compounds possessing an azide group consisting of three nitrogen atoms and are characterized by very high reactivity.
First, using Amphos, a type of phosphine (a group of organic compounds containing a phosphorus atom), they investigated a reaction in which a phosphazide intermediate was formed from a 2-azidoacrylic acid ester, followed by the addition of a thiol. Contrary to expectations, it became clear that the generation of a diazo ester accompanied by the cleavage of the N-N bond proceeded all at once, resulting in a new molecular transformation. This is expected to be a new reaction that can easily synthesize useful diazoacetate derivatives.
In a Michael addition reaction, a nucleophile such as a thiol or an amine adds to a carbon-carbon double bond that easily attracts electrons. They also confirmed that bulky and electron-rich phosphines are suitable for this reaction, with Amphos being the most effective. The reaction can be conducted under mild conditions and succeeded even on a 10-mmol scale.
Regarding the substrate scope, they confirmed that in addition to thiols such as primary and secondary alkyl thiols, aromatic thiols, and protected cysteine derivatives, linear and cyclic secondary amines can also be used. They also demonstrated that the reaction can be extended to the synthesis of fluoxetine derivatives.
On the other hand, they clarified that there are limitations depending on the type of functional group, such as failing to obtain the target product with proline possessing a free carboxylic acid.
When analyzing the reaction mechanism, they confirmed that the formation of the phosphazide intermediate is the crucial step driving the Michael addition and N-N bond cleavage. It was observed by NMR that the phosphazide intermediate remained stable for as long as one hour after Amphos treatment, and its high basicity was considered the source of its reactivity.
The obtained compounds can undergo various transformations, including oxidation, reduction, rhodium-catalyzed reactions, and cycloadditions. The group also demonstrated extensions to nitrogen-containing heterocyclic compounds such as enaminones, indoles, and pyrazoles.
Yoshida stated: "In this study, we were able to find new possibilities for azides. During the research process, there were several occasions where we thought, 'Hmm, a product with a strange structure was obtained,' but each time, we carefully considered the reaction that occurred and cautiously determined the structure, allowing us to clarify the full picture to some extent. Chemistry using stable phosphazides remains unexplored, and by unleashing its potential, we expect to discover a variety of new transformations in the future."
Journal Information
Publication: Angewandte Chemie International Edition
Title: Azide-to-Diazo Transformation Facilitated by Michael Addition via Phosphazide Formation
DOI: 10.1002/anie.4448961
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.