Date: 2 May 2025 | Category: News
Authors: Viktoriia Velichko, Davide Moi, Francesco Soddu, Roberto Scipione, Enrico Podda, Alberto Luridiana, Dario Cambie,* Francesco Secci* and Maria Chiara Cabua
Dario Cambié from the Max Planck Institute of Colloids and Interfaces, Francesco Secci at the University of Cagliari and co-workers have developed a two-step continuous flow synthesis of 1,1-cyclopropane aminoketones using flow chemistry [1]. In this case, photocyclization of 1,2-diketones allows access to 2-hydroxycyclobutanes that then undergo a tandem condensation/ring-contraction process in the presence of aryl- and alkylamines and to furnish 1,1-cyclopropane aminoketones.
Figure 1: Flow-based C1 homologation and alkylation of carboxylic acids
Aminocyclopropanes are present in a number of biologically active molecules [2], with constrained amino-derivatives being proposed as therapeutic agents including MAO inhibitors, opioid antagonists and anticancer agents [1]. However, while there are many routes for preparation of cyclopropylamines such as the Curtius rearrangement [3], Hofmann rearrangement [4], Kulinkovich–Szymoniak reaction [5] and carbene transfer of diazo compounds [6], as well as metal-mediated approaches, the preparation of 1,1-cyclopropane aminoketones in particular is underdeveloped, stymied by challenging synthetic methods and limited options for functionalisation.
However, the use of continuous flow technology has shifted the landscape, with the report of 1,1-cyclopropane aminoketones being prepared from readily available starting materials. In this work, 1,2-diketones were subjected to irradiation at 440 nm in the Vapourtec UV-150 photoreactor to generate the 2-hydroxycyclobutanone intermediate. Upon isolation, subsequent treatment with a thiourea catalyst in the presence of either an aliphatic or aromatic primary amine, provided the target 1,1-cyclopropane-aminoketones in good yields, with a range of functionality tolerated. Telescoping was also possible, where the cyclisation and ring-contraction steps were undertaken in sequence with no purification of the intermediate required allowing rapid access to multigram quantities of materials.
While the use of flow can often expedite a synthetic process and allow more efficient material preparation, the UV-mediated cyclisation step in particular gained significant advantage when using the Vapourtec system. With a custom-made photoreactor the productivity was 18.5 mg/hour, with residence time of 30 minutes. The residence time could be shortened, but overall yield dropped. However, with the Vapourtec UV-150 reactor, productivity could be improved to over 500 mg/hour with a residence time of only 1 minute, a substantial improvement.
References:
[1] Two-step continuous flow-driven synthesis of 1,1-cyclopropane aminoketones. (V. Velichko, D. Moi, F. Soddu, R. Scipione, E. Podda, A. Luridiana, D. Cambie, F. Secci and M. C. Cabua, Chem. Commun., 2025, 61, 1391 – 1394). Https://doi.org/10.1039/d4cc04089a
[2] The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules. (T. T. Talele, J. Med. Chem., 2016, 59, 19, 8712 – 8756). https://doi.org/10.1021/acs.jmedchem.6b00472
[3] trans-Cyclopropyl β-amino acid derivatives via asymmetric cyclopropanation using a (Salen)Ru(II) catalyst. (J. A. Miller, E. J. Hennessy, W. J. Marshall, M. A. Scialdone, S. T. Nguyen, J. Org. Chem., 2003, 68, 7884 – 7886). https://doi.org/10.1021/jo0344079
[4] Efficient Production of Cyclopropylamine by a Continuous-Flow Microreaction System (J. Huang, Y. Geng, Y. Wang, J. Xu, Ind. Eng. Chem. Res., 2019, 58, 36, 16389 – 16394). https://doi.org/10.1021/acs.iecr.9b0243
[5] Titanium-Mediated Synthesis of Primary Cyclopropylamines from Nitriles and Grignard Reagents. (P. Bertus, J. Szymoniak, Synlett, 2007, 9, 1346 – 1356). Https://doi.org/10.1055/s-2007-980342
[6] Catalytic cyclopropanation of alkenes using diazo compounds generated in situ. A novel route to 2-arylcyclopropylamines. (V. K. Aggarwal, J. de Vincente, R. V. Bonnert, Org. Lett., 2001, 3, 17, 2785 – 2788). https://doi.org/10.1021/ol0164177