Advancing the Catalytic Frontier: New Horizons in Allylic Amine Synthesis Unveiled in 2022

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By Valentinos Mouarrawis and Sander Kluwer

Did you know that amine-containing pharmaceuticals are an essential functional component of numerous vital medications? These molecules can be found in a wide range of drugs, including antibiotics, breast cancer treatments, painkillers, and more. In fact, amine moieties are present in approximately 80% of the top 200 small-molecule pharmaceuticals. While aliphatic amines make up approximately 43% of amine-containing substances used in active pharmaceutical ingredients (APIs), their efficient synthesis can be a challenge. Particularly when traditional methods like nucleophilic substitution reactions and reductive amination are not working well with more complex pharmaceutical structures. As a result, finding efficient ways to synthesize amine-containing compounds is a vital area of research that can improve downstream processes and open up more synthetic pathways to access complex structures. The importance of this research area is highlighted by three high-profile papers that appeared over the course of 2022.

One approach to synthesize amination products efficiently is through metal-catalyzed allylic C-H amination reactions. However, aliphatic and aromatic amines with free N-H groups have a tendency to coordinate with palladium salts more strongly than olefins, resulting in the formation of a bis(amine)-palladium complex. This significantly decreases the electrophilicity of palladium and the reactivity of the catalyst, and to avoid deactivation of the palladium catalyst, the nitrogen must thus be protected, although protection also reduces the nucleophilicity (creating a new challenge). Additionally, extra steps are needed for protection and deprotection. These challenges sparked an active research field, and as a result several important breakthroughs in the field of catalytic amination of alkenes to form allylic amines were reported in 2022. These developments addressed various challenges that previously hindered the synthesis of allylic amines, and added new tools to the synthetic chemist’s toolkit.  

One of these pioneering contributions to this field was presented by Professor Christina White and her colleagues, which was published in Science (DOI: 10.1126/science.abn8382). They were able to synthesize complex tertiary allylic amines using a novel strategy that involved converting the starting amine into an BF₃ ammonium salt. This prevented the undesired coordination of the amine to the catalyst in the electrophilic metal-catalyzed reaction. The slow release of the free amine under the reaction conditions from the BF₃-protected amine leads to low concentrations of the nucleophile and enables a productive allylic amination catalytic pathway. One of the outstanding features of this novel approach is its straightforward synthetic procedure. As 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 broad applicability of this synthetic methodology by synthesizing a total of 81 different tertiary amines, including 12 actual drugs and 10 complex derivatives. Additionally, they were able to streamline the synthesis of an anti-obesity drug using this approach, reducing the number of steps from 12 to 5 and increasing the yield from 5.0% to 8.5%.

In the same year, Huanfeng Jiang and his colleagues made a groundbreaking contribution to the field of catalysis. They developed a novel method for synthesizing a wide range of tertiary allylic amines in a single step. This new approach utilizes [Pd(dppp)] catalysts and, unlike previous methods, does not require the use of a nucleophilicity masking agent such as BF3. The authors propose that this is made possible by the use of a specific oxidant (2,6-dimethylbenzoquinone, 2,6-DMBQ) that serves a dual purpose in the catalytic process. The authors hypothesized that the oxidant acts as:

• An electron transfer agent for Pd(0)/Pd(II) reoxidation
• Prevents coordination of the amine to the metal catalyst through intermolecular hydrogen bonding between the quinone and the amine

The stabilization of the Pd(II)/Pd(0)/Pd(II) catalytic cycle, as a result of this, allows for high catalytic activity in the allylic amination of alkenes, making it a highly effective method. The existence of alkylamines in various drugs indicates that efficient methods for the synthesis of such compounds using catalytic oxidative amination could be valuable. Under standard conditions, several pharmaceutical compounds (figure 3) including naftifine, cinnarizine, AC1 inhibitor, and abamine were synthesized with good yields (75-92%) and high regio- and stereoselectivity by the oxidative amination of the corresponding alkene.

Yet another recent publication from 2022 titled,”Asymmetric intermolecular allylic C–H amination of alkenes with aliphatic amines” in Science, the group of Vladimir Gevorgyan introduces a new method for the production of allylic amines. The proposed method is based on a homolytic mode of allylic C–H bond cleavage, which serves as an alternative to the commonly used heterolytic counterpart that operates through Pd(II)–alkene coordination. Interestingly, this strategy uses an uncommon Pd(0/I/II) cycle, which is fundamentally distinct from the common Pd(II/0) paradigm. This synthetic methodology enables the use of alkenes with different substitutions in combination with primary and secondary aliphatic amines to obtain branched allylic amine products. Furthermore, this method can even be utilized to selectively produce chiral allylic amines with good enantio- and diastereoselectivities. Additionally, when applied to compounds with multiple allylation sites, it demonstrates good regioselectivity. This novel approach opens up new avenues for the synthesis of a wide range of amine derivatives and provides the process chemist with a powerful tool for the synthesis of these compounds. 

When comparing the three recently published methods of allylic amination highlighted in this blog, it is clear that they have distinct differences as well as shared similarities. For instance, the method developed by Christina White’s team involves an extra step to form the BF₃-amine complex and utilizes a non-commercially available ligand. However, the benefit of this method is its simplicity, as it can be performed under ambient air (as no phosphine ligand is involved) without the need for specialized equipment or precautions to exclude moisture. On the other hand, the method developed by Huanfeng Jiang’s group utilizes an inexpensive commercially available ligand and has the lowest catalyst loading among the three methods. The last method, developed by Vladimir Gevorgyan, requires the highest catalyst loading and the use of blue LED to oxidize Pd(0) to Pd(I), which could be a limitation in the absence of such infrastructure. However, this method allows for the synthesis of secondary amines and open the pathway toward asymmetric synthesis using a commercially available chiral ligand such as BINAP, resulting in enantio- and diastereoenriched allylic amines.

These contributions have significantly advanced the field of accessing allylic amines catalytically and opened up new pathways for the production of allylic amines, thus showcasing the importance of catalysis and high throughput screening of reaction components and conditions in the field of chemical synthesis.

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.

References:

• Article 1: 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)
• Article 2: Palladium-catalysed selective oxidative amination of olefins with Lewis basic amines by Yangbin Jin, Yaru Jing, Chunsheng Li, Meng Li, Wanqing Wu, Zhuofeng Ke and Huanfeng Jiang. (DOI: 10.1038/s41557-022-01023-x)
• Article 3: Asymmetric intermolecular allylic C–H amination of alkenes with aliphatic amines by Kelvin Pak Shing Cheung, Jian Fang, Kallol Mukherjee, Andranik Mihranyan, Vladimir Gevorgyan. (DOI: 10.1126/science.abq1274)