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Amine-BF3 salts do the trick. How to introduce tertiary amine in late-stage functionalization?
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By Valentinos Mouarrawis and Sander Kluwer
Amine-containing pharmaceuticals are estimated to be 43% of all the drug candidates’, making their synthetic accessibility critical for the production of medicines. Tertiary amines are found in some of the most impactful pharmaceuticals such as antibiotics, breast cancer drugs, opioid pain medications, antihistamines, blood thinners, HIV treatments, antimigraine medications, and many more. Although tertiary amines make up 60 % of the amine-containing APIs, their efficient synthesis remains challenging. Classic synthetic methods include nucleophilic substitution reactions of alkyl halides (1), reductive amination of the corresponding aldehydes or ketones (2), and Tsuji-Trost allylic aminations of (E)-allylic alcohols, acetates, or carbonates (3). However, the applied reaction conditions using strong electrophiles or reducing conditions might be incompatible with the complex API structure.
Scheme 1. Classic methods for the synthesis of tertiary amines.
Among the current methods, an approach to efficiently synthesize more complex amination products is the metal-catalyzed allylic C-H amination reaction. However, current technologies require the protection of the nitrogen to circumvent the coordination and thereby deactivating of palladium catalyst, which in turn leads to several limitations:
- Only protected 1o amines can be used as the protection of 2o amines leads to deactivation.
- At high concentrations, reduction or inhibition of the catalyst may take place.
- Extra synthetic steps are required (protection, deprotection, cyclization).
To solve this synthetic bottleneck and access complex tertiary allylic amines, Prof. Christina White and coworkers came up with a creative strategy (DOI: 10.1126/science.abn8382) by converting the starting amine to the ammonium salt. This synthetic tweak occupies the lone pair of the nitrogen, so it can no longer bind to the catalyst during the electrophilic metal-catalyzed reaction. The slow liberation of the free amine ensures low concentrations of the nucleophile and provide the solution for a productive allylic amination catalytic pathway.
Figure 2. The challenge for the direct palladium-catalyzed C–H activation catalysis (left) and the solution (right).
What is remarkable about this novel approach is its easy synthetic procedure. White explains “You don’t need to handle it with a lot of precautions, you can run it open to air and you don’t have to exclude water. You just need your starting materials, the palladium/SOX catalyst, and a little heat.’’ The researchers demonstrated the wide applicability of this synthetic methodology, by making a total of 81 different tertiary amines, including 12 actual drugs and 10 complex derivatives. In addition, by implementing this approach in the synthesis of an anti-obesity drug they were able to reduce the number of synthetic steps of a previous route from 12 to 5 and increase the yield from 5.0 to 8.5%. We feel that this new procedure for accessing tertiary amine moieties will lead to more efficient synthetic pathways and it will be taken up by the synthetic community.
Scheme 2. The synthetic strategy of an anti-obesity drug involving the methodology reported in this study (DOI: 10.1126/science.abn8382).
About InCatT (www.incatt.nl): InCatT B.V. is a company specialized in catalyst screening and catalyst development from initial catalyst-lead finding to process optimization. Over the years we have worked with different industries ranging from Flavor & Fragrance, Bio-based industry, Pharmaceutical, and bulk chemical industry to solve their most challenging projects.
Article: “Allylic C–H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis”
By Siraj Z. Ali, Brenna G. Budaitis, Devon F. A. Fontaine, Andria L. Pace, Jacob A. Garwin, M. Christina White
DOI: 10.1126/science.abn8382
