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Nitrogen-containing heterocycles are important building blocks in many present-day pharmaceuticals. They exert a wide range of biological activities, which is why they are continuing to be of great interest in medicinal chemistry. The aza-Prins cyclization together with N-acyliminium ion chemistry constitute a powerful tool to form such heterocycles. There are previous reports of the formation of a tricyclic piperidine with an acetate-adduct using this approach. When exchanging one of the starting materials to its hydrochloric salt the corresponding chlorine product is formed. This secondary alkyl halide provides a suitable handle for further derivatizations, which enables an extension of the molecule. The aim of this project was to increase the yield of the chlorine product to ≥ 85%, partly by increasing the selectivity of the reaction through minimization of side products.

The reaction is performed as a one-pot synthesis by mixing methyl-(2-formylphenyl)carbamate and 3-buten-1-amine hydrochloride in an acidic solvent, which is subjected to microwave irradiation. Acetic, chloroacetic, dichloroacetic, trifluoroacetic, propionic and methanesulfonic acid were screened as acidic promotors. In the end, two procedures based on chloroacetic acid were optimized. The first procedure was performed in 2.5 equiv. chloroacetic acid in toluene at 140 °C for 20 minutes and resulted in a yield of 99%. These reaction conditions also resulted in the formation of a side product through the competing aza-Cope rearrangement. The second procedure yielded 83% by reacting the starting materials in 10 equiv. chloroacetic acid in toluene at 120 °C for 40 minutes instead. The aza-Cope product did not form in this setting. Exploring a third procedure using 3-buten-1-amine and NaCl as chlorine source under the same reaction conditions as the first procedure yielded only 41% of the product.

In conclusion, chloroacetic acid was shown to be the most selective acidic promotor to use for the specific reaction. There are at least two different methods available, depending on the demands regarding temperature, reaction time, acidity and yield. The aza-Cope product is clearly in need of thermal activation to form, which perhaps could be taken advantage of in other settings. The third procedure presents an alternative route to synthesize analogues by adding the corresponding sodium salt to the reaction mixture, which should be investigated in the future together with biological evaluation.