A new method produces amines that are impractical or even impossible to make via conventional approaches and that hold particular promise for pharmaceuticals, claim its developers at The Scripps Research Institute, La Jolla, Calif. The technique, which involves chemoselective cross-coupling of olefins and nitroamines, provides a practical way that is without precedent to directly convert a nitroarene to a hindered secondary amine, the researchers contend. It can synthesize a wide variety of such amines, including ones that resist breakdown by enzymes in the body.
Figure 1. Team at The Scripps Research Institute developed novel hydroamination process. Source: The Scripps Research Institute.
The technique uses simple olefins as the radical source, an inexpensive silane and zinc metal as reductants, and an abundant iron salt as a catalyst — and works smoothly under mild conditions, the researchers explain.
“This is interesting science because a transformation like this has never been seen before,” notes Phil Baran, a professor in the chemistry department at Scripps. “Part of what’s unique about this scientific advance is that it’s also being immediately applied by industry — it’s pretty darn useful.” The method was used to make more than 100 different amines — with much of the work taking place at Bristol-Myers Squibb, New Brunswick, N.J., and Kemxtree, a contract research firm in Somerset, N.J. More details appear in a recent article in the journal Science.
“While testing this new methodology, we were able to rapidly access targeted intermediate compounds for which other standard methods of preparation had failed,” says Bill Pitts of Bristol-Myers Squibb.
“This reaction is conceptually novel, yet simple and practical to carry out — just in the past two months we’ve used it for dozens of decagram-scale reactions in our lab,” adds Swaminathan Natarajan of Kemxtree.
“Some of the compounds we made contain sensitive functional groups that can’t survive conventional amine synthesis reactions,” notes Jimghan Gui, lead author of the article. Functional groups tolerated include alcohols, amines and even boronic acids.
“We are going to extend the utility of the method to other amine types, explore enantioselective variants, improve efficiency/yield, and extend the scope even further,” says Baran.
This development follows the Scripps researchers’ previous success in developing a method for olefin cross-coupling (“Simple Method Forms Unique C-C Bonds”).