Simplified synthesis

Kürti, a synthetic organic chemist, and his team have created a nitrogen umpolung reagent—a reagent reverses the polarity of nitrogen atoms, which in turn enables them to react differently with other atoms—for synthesizing aminating agents.

“This novel approach represents an operationally simple, scalable and environmentally friendly alternative to transition metal-catalyzed, carbon-nitrogen cross-coupling methods that are currently used to access structurally diverse amines,” Kürti said in a press release.

“The synthetic and mechanistic results presented here constitute a breakthrough in the field of carbon-nitrogen bond-formation and will be of considerable interest not only to synthetic and medicinal chemists but also to the theoretical, structural and organometallic communities,” he added.

The method was covered in a paper in the Journal of the American Chemical Society titled “Practical Singly and Doubly Electrophilic Aminating Agents: A New, More Sustainable Platform for Carbon–Nitrogen Bond Formation.”

Amines, compounds derived from ammonia molecules, have one nitrogen and three hydrogen atoms. In primary amines, one of those hydrogen atoms is replaced by a substituent, such as an aryl or an alkyl group. Secondary amines, however, have only one hydrogen directly attached to the nitrogen besides the two substituents. Aminating agents form new carbon-nitrogen bonds in an unusual manner since their nitrogen atoms are electron-poor, meaning they carry a partially positive charge and react readily with electron-rich carbon nucleophiles.

The Rice team, led by postdoctoral researcher Padmanabha Kattamuri, used ketomalonate hydrate, an umpolung reagent, that reverses a nitrogen atom’s normal polarity.

Kürti says his lab has been studying this type of chemistry since they moved to Rice University in June 2015. “Dr. Kattamuri synthesized nearly two dozen electrophilic aminating agents, and with careful screening of the reagents, we determined the optimal reagent structure and reaction conditions,” he says. “We have over 80 examples of carbon-nitrogen bond-formation in our JACS full paper.”

Kürti noted that currently, amine synthesis can entail transition metals, high temperatures/pressures or strong oxidants. By comparison, the lab can synthesize hundreds of grams of the new reagent in a large reactor in about two-and-a-half days, and an open container of the reagent was used for nearly two years with no drop in function.

“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 temperature,” Kürti tells DDNews. “The N-umpolung reagent is inexpensive; the aryl as well as alkyl Grignard reagents are commercially available or can be readily prepared. There are many currently unknown transformations in which N-electrophilic imines can be used; these discoveries will be made in due course in my laboratory as well as in academic as well as industrial laboratories worldwide.”

There are several types of molecules this approach can help with, he says, such as “Those molecules that have a di-substituted N atom(s) in them—in other words, we can make secondary amines with this approach quickly and very efficiently under mild conditions. Eighty percent of approved drugs as well as agrochemicals contain at least one N atom. Over one-third (~37 percent) of drug candidates contain aromatic amines (i.e., arylamines) as substructures. Our method is especially well suited for the synthesis of symmetrical as well as unsymmetrical diarylamines.”

The team hopes to improve on the efficiency of this method, with Kürti noting that “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. One great challenge that we would like to address is the possibility to use only a catalytic amount of N-umpolung reagent along with a given primary amine.”

This work received support from Rice University, the National Institutes of Health, the National Science Foundation, the Robert A. Welch Foundation, Amgen and Biotage.