Researchers at Rice University, Houston, have devised a noncatalytic approach to the formation of carbon-nitrogen bonds. Their method, which relies on an umpolung (polarity-reversal) reagent, promises an operationally simple, scalable and environmental friendly alternative to current transition-metal-catalyzed cross-coupling routes for producing amines, they believe. Such amines play an important role in a variety of active pharmaceutical ingredients, agrochemicals and functional materials, they note.
The method can directly produce symmetrical and unsymmetrical diaryl-, arylalkyl- and dialkylamines. Sterically and electronically tunable ketomalonate-derived imines and oximes can serve as the umpolung reagent.
The development of a practical single and double umpolung of nitrogen provides unprecedented flexibility for coming up with efficient synthesis routes, the researchers believe. Moreover, it can be combined with a wide variety of existing metal-catalyzed transformations, they say.
“Overall, this new N-umpolung approach opens up chemical routes that were previously only available by the use of expensive transition metals and ligands. One huge advantage here is that no lengthy optimization is required when a particular C–N bond is to be made. Even aryl-nitrogen bonds can be prepared at or below ambient temperatures. The N-umpolung reagent is inexpensive, the aryl- as well as alkyl Grignards are commercially available or can be readily prepared,” notes László Kürti, an associate professor of chemistry at Rice and coauthor of a recent paper about the process in the Journal of the American Chemical Society (JACS).
“Before our JACS paper was published, there was a dearth of synthetically useful N-electrophilic aminating agents. Now, with the use of the N-umpolung agent (i.e., di-isopropyl keto malonate hydrate) virtually any primary amine (R–NH2) can be converted to the corresponding N-electrophilic imine. This approach opens up a vast N-electrophilic chemical space and many different nucleophiles can attack the electrophilic N atom, forging new carbon-nitrogen bonds.” Kürti explains.
“We believe that the degree of N-electrophilicity can be further modulated by changing the structure of the N-umpolung reagent. Therefore, we are actively making new and more powerful N-umpolung reagents and evaluating these in a variety of carbon-nitrogen bond-forming transformations.”
“We have already demonstrated that the nitrogen umpolung reagent (i.e., di-isopropyl keto malonate hydrate) can be made on the multi-hundred-gram scale… I anticipate that the reagents can be produced readily on the multi-kilogram scales.
“In summary, our N-electrophilic imines indeed will likely be very useful substrates and valuable N-sources in many mechanistically different transformations,” says Kürti.
