High-temperature water unlocks urea as nitrogen-source towards imidazoles

Abstract

Urea is a non-toxic, harmless, and abundant bulk organic chemical featuring high nitrogen content. Therefore, urea could be a prime green candidate for introducing nitrogen atoms into organic molecules. In this regard, urea in organic synthesis has been mainly employed as building block, component of solvent systems, catalyst, or for pH adjustment, while uses of urea as NH₃-source towards the construction of small organic compounds are scarce. Here, nothing but high-temperature water (HTW) is employed to conduct the aquathermolysis of urea, generating NH₃ to propel the Debus–Radzsisweski multicomponent reaction (MCR) towards imidazoles. The approach does neither require additional catalysts nor reaction auxiliaries or volatile organic compounds as solvent. Urea was used as N-source in combination with different 1,2-diketones and aldehydes featuring a variety of functional groups towards 23 lophine analogues (190 °C, 1–3 hours). Moreover, the presented synthesis performs equally or better than classical syntheses when acid-sensitive substrates are employed. The greenness of the synthesis using urea in HTW was assessed through green metrics and compared with syntheses reported in the literature in a large-scale fashion. Overall, the reported syntheses feature E-factor and process mass intensity values in ranges comparable to those of syntheses reported in literature.