Science 343, 61–65 (2014)

Nitrogen-containing functional groups are prevalent in natural products and biologically active compounds. The incorporation of nitrogen into a molecule during chemical synthesis is not always straightforward, but aziridines offer a potentially attractive route to this end. Their strained three-membered-ring structure and susceptibility to stereo- and regioselective chemistry makes aziridines very useful as intermediates in synthetic strategies. It is this reactivity, however, that also dictates the use of a nitrogen-protecting group during conventional aziridination procedures, which can subsequently lead to unwanted side reactions during deprotection steps.

A direct synthesis of aziridine products without the need for the nitrogen atom to be protected would, therefore, result in shorter and simpler synthetic approaches for nitrogen incorporation. Now, a team of researchers led by László Kürti and John Falck at the University of Texas Southwestern Medical Center and Daniel Ess at Brigham Young University in Utah have developed a simple, chemoselective and stereospecific procedure for the catalytic aziridination of olefins without N-protection. In the key step of the reaction, quantum mechanical calculations have predicted that a rhodium nitrene electrophile is formed from the reaction of a O-(2,4-dinitrophenyl)hydroxylamine aminating agent with a homogeneous rhodium catalyst in trifluoroethanol. Using this intermediate, the stereospecific N–H aziridination of a diverse range of mono, -di- and tri- substituted olefins, and di, -tri- and tetra-substituted styrenes was demonstrated. These transformations were all achieved in good yields under ambient conditions without the need for external oxidants.

Alternatively, by using an N-alkylated nitrogen source, the stereospecific N–Me aziridination of di- and tri- substituted olefins and styrenes could be also be achieved in good yields under mild conditions. As a further demonstration of the utility of this strategy, a selection of the resulting aziridines were subjected to regioselective ring-opening reactions to give pharmaceutically active target amines — such as methoxy- and azido-amines — in excellent yields.