Tertiary amines, made of a nitrogen bound to three carbons, occur frequently in drug structures but are complicated to make. Synthesis often requires multiple steps under different reaction conditions dictated by what functional groups are on the molecule. To cut through this synthetic red tape, M. Christina White and coworkers at the University of Illinois Urbana-Champaign have developed a fast approach to making tertiary amines that works on many types of molecules.
The team combined readily available terminal olefins, secondary amines, an oxidant, and a palladium sulfoxide catalyst to make over 80 tertiary amines, including drugs and drug derivatives (Science 2022, DOI: 10.1126/science.abn8382). The group doesn’t have to tailor the reaction conditions according to starting materials but can use the same reagents and metal catalyst to synthesize tertiary amines containing a wide variety of functional groups. The reaction is also highly selective, producing only the linear version of the allylic tertiary amine and exclusively forming a single configuration of the double bond.
Besides being applicable to many different functional groups, White says, the reaction is straightforward to run: “Open to air, open to moisture, just applying a little heat.” These uncomplicated conditions could allow chemists to automate the reaction, she says. In total, the team combined 48 secondary amines and 34 terminal olefins to form compounds that include several drugs currently on the market, such as the antipsychotics Abilify and Semap and the antihistamines flunarizine and cinnarizine. In addition, many existing drugs are complex secondary amines, White says. The group converted several examples of these compounds, including Paxil and Prozac, into tertiary amines. This opens up an easy route to making new drugs out of old ones, she says.
The simplicity of the approach could speed up the drug discovery process by allowing drug discovery chemists to quickly make a variety of molecules, White says.
A key part of the research was finding an answer to an old problem. Many N-containing compounds can’t be combined with the metal catalysts that chemists often use to break C–H bonds. Amines with a lot of electron density on the N, called basic amines, tend to bind to the metal and kill the catalyst. White and coworkers had developed a work-around for this problem when using primary amines as reagents, but the approach did not work with secondary amines. In the new research, the group sought a way to slowly release the amine into the reaction to minimize reaction with the catalyst. “With very small amounts of the secondary amine, the Pd would still be able to effectively interact with the C–H bond,” White says.
To achieve this slow amine trickle, the researchers needed to stop the lone pair of electrons on the amine N from binding to the catalyst. Converting the starting amine to an ammonium salt blocks the lone pair, so it can no longer attack the catalyst, White says. The Pd is then free to insert into the olefin’s C–H bond, while the ammonium salt reacts very slowly to re-form the secondary amine. As it appears in the reaction mixture, the secondary amine couples with the olefin, ultimately forming the tertiary amine (example shown).
Combining electron-hungry metals such as Pd with basic groups like secondary amines has always been challenging, says Tobias Ritter, an organic chemist at the Max Planck Institute for Kohlenforschung. Finding a way to deliver just the right amount of the reactive amine without poisoning the catalyst is a practical way to make valuable molecules directly with olefins, he says.