The research group headed by Prof. He Lin of the State Key Laboratory of Low Carbon Catalysis and Carbon Dioxide Utilization of the Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, (LICP, CAS) in collaboration with Prof Lei Aiwen's research group at Wuhan University, has achieved the one-step carbonylative synthesis of unsymmetrical ureas by a non-phosgene route.
Unsymmetrical ureas can form multiple stable hydrogen bonds with proteins, and drugs containing urea functional groups interact with their targets with unique biological activities, which play an important role in drug development and medicinal chemistry.
At present, the synthesis of urea compounds in industry mainly uses the phosgene method. Due to the different nitrogen-containing fragments attached to the same carbonyl site, a stepwise assembly of amines onto the carbonyl group using the phosgene method is required. The first step involves the reaction of CO with chlorine to generate a highly toxic phosgene, followed immediately by the reaction of an amine with the phosgene to generate the desired isocyanate intermediate/acyl chloride, after which the isocyanate/acyl chloride is subsequently reacted with another amine to generate an unsymmetrical urea in a three-step process, in which a large amount of corrosive hydrochloric acid is generated.
The catalytic oxidative carbonylation of amines is the most direct route to produce urea, but when two different amines are used as substrates, it is difficult to distinguish them from each other in terms of reactivity, and both symmetric and unsymmetrical ureas are generated simultaneously, making it difficult to regulate the selectivity.
Based on the subtle differences in the physicochemical properties of different amines, a synchronous recognition strategy was adopted to integrate a novel reaction mechanism of nucleophilic carbonylation half-reaction (recognition of primary amines) and radical carbonylation half-reaction (recognition of secondary amines) in a catalytic reaction of amine oxidative carbonylation, and a unique reaction window for the one-step synthesis of unsymmetrical ureas by a non-phosgene route was obtained.
Fig. 1. Strategies for synthesizing unsymmetrical ureas.
The new carbonylation mode is not only applicable to alkyl amines, but also to various aromatic and halogenated amines. In addition, NH3 can be activated by catalytic carbonylation to react with secondary amines to prepare the corresponding unsymmetrical ureas. Intramolecular recognition of primary and secondary amines can also occur. Nearly one hundred examples of combinations have yielded absolutely dominant asymmetric products, further confirming the unique reaction mechanism. In terms of the carbonyl source, CO can be used or we can start from CO2 to achieve process re-engineering for the synthesis of nitrogen-containing carbonyl compounds by the phosgene method.
The results were published in Science with title of ‘Synchronous recognition of amines in oxidative carbonylation toward unsymmetric ureas’. The first author of the paper is Wang Jinhui from Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, while Wang Shengchun, a postdoctoral fellow from Institute for Advanced Studies, Wuhan University, and Wei Zhihong, a lecturer from Institute of Molecular Science, Shanxi University, are the co-first authors, and He Lin, a researcher from Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, and Lei Aiwen, a professor from Wuhan University, are the co-corresponding authors. Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences is the first completion unit of this work.
Contact:
He Lin
Email: helin@licp.cas.cn
Lanzhou Institute of Chemical Physics