New Method Allows Easy Synthesis of Valuable Amine-Containing Pharmaceuticals
Scientists from X-Chem, in collaboration with researchers at AstraZeneca, RWTH Aachen University, University of Manchester and Instituto de Estudios Ambientales y Recursos Naturales, have developed a powerful new approach for making amine-containing heterocyclic compounds that are important ingredients in many pharmaceuticals and other high-value chemicals. The traditional methods for adding amine groups to heterocyclic rings like pyridines, pyrroles and furans have major limitations — they often require multiple steps, use harsh conditions, give poor yields and struggle with incorporating complex amine components.
The new strategy is published in Nature Catalysis. In the publication, the team circumvents these issues by taking a fundamentally different approach. Rather than modifying an existing heterocyclic aromatic ring, they start with readily available saturated heterocyclic ketones as building blocks. These ketones can easily be derivatized using standard carbonyl chemistry methods.
The key step is condensing the ketone with an amine component to form an “enamine” intermediate. This enamine then undergoes a remarkable sequence of mild photochemical oxidation and desaturation reactions, mediated by iridium and cobalt catalysts, to strip out hydrogens and form the desired amine-substituted heterocycle.
“Our method allows us to stitch in amine groups at positions that are very difficult to target using standard aromatic functionalization reactions,” said coauthor Augusto Hernandez-Perez, associate principal scientist at X-Chem. “And we can do it in just a single operation from simple precursors under mild conditions.”
Notably, the same mild reaction conditions could be applied to make a wide variety of valuable heterocyclic products, including pyridines, pyrroles, furans, thiophenes and pyrazoles substituted with primary and secondary amines. Even complex amine components like constrained piperidines and piperazines were well tolerated.
A Project Sprouting From a Hard Challenge and an Industry-Academia Discussion
The project serendipitously started in 2022 when Hernandez and his team struggled with late-stage functionalization of a pyrrolidine moiety.
“The challenge was to put an aryl group on the nitrogen of the pyrrolidine. Most C-N couplings such as Buchwald-Hartwig, Ullman, Chan-Lam-Evans and others failed,” said Hernandez.
The team found procedures published by Professor Daniele Leonori from the University of Manchester — A photochemical dehydrogenative strategy for aniline synthesis — and decided to give them a try, but the protocols, when used to arylate pyrrolidine moieties, provided low yields.
Hernandez reached out to Leonori and had several discussions. At the same time, the X-Chem team further investigated the scope of the photochemical strategy. Instead of generating aryl rings, they pivoted to generating pyridine rings. They quickly succeeded in discovering novel reaction conditions.
“The Leonori group had previously attempted synthesizing pyridine rings using the photochemical dehydrogenative strategy but failed. We shared our data, and they tried again in their lab. Within a week, they were able to obtain similar yields as ours, and we initiated the collaboration with Leonori’s group that resulted in this publication,” said Hernandez.
Allowing Easier Late-Stage Functionalization for Drug Discovery Programs
The collaborative team demonstrated the method on pharmaceuticals like the ADHD drug atomoxetine, the antidepressant paroxetine and the smoking cessation aid cytisine. They were able to efficiently add amine groups at key positions that would be very difficult to target otherwise.
“This desaturative coupling approach really opens up fundamentally new retrosynthetic disconnections for these invaluable heterocyclic substructures,” said Hernandez. “The strategy could streamline synthesis routes and allow easier late-stage functionalization for drug discovery programs.”
The work also provides fundamental new mechanistic insights into cooperativity between photoredox and cobalt catalysis pathways. Detailed studies suggest the cobalt catalyst plays two distinct roles — first activating the substrates via hydrogen atom transfer, and then facilitating key oxidation steps.
With its broad scope, mild conditions, simple starting materials and unique mode of amine installation, Leonori’s new method promises to significantly expand the tool kit for synthesizing high-value amine-containing heterocycles across pharmaceutical, agrichemical and materials applications. The study demonstrated how X-Chem supports drug discovery programs by collaborating with innovators to incorporate new synthetic methods to access compounds that are difficult to generate otherwise.
Synthetic Innovation Broadens Drug Discovery Project Success
Building upon our expertise and a commitment to quality and success, X-Chem has a strong track record (17 compounds reading IND-enabling toxicology studies and seven compounds progressing to Phase I or beyond) in developing and expanding hits derived from different hit identification methods, such as phenotypic screens, high-throughput screens, fragment screens, structure-based designs, chemo-proteomics, AI/ML generative models, structure-based designs and DNA-encoded chemical library screens.
If you are interested in learning more, please contact us and follow us on LinkedIn. No matter your indication of interest, we get hits to exponentially accelerate your drug discovery program.