A Scalable Approach to Primary Amines via the Petasis Reaction

Authors

DOI:

https://doi.org/10.24959/ophcj.25.324183

Keywords:

Petasis reaction, three-component reaction, primary amines, multigram synthesis

Abstract

The efficient and scalable synthesis of homoallylic amines is a subject of significant interest due to the potential applications of these compounds in medicinal and synthetic chemistry. The three-component Petasis reaction is an excellent approach for obtaining these compounds. Based on previous studies, this work explores the α-aminoallylation of ketones and aldehydes using allylboronic acid pinacol ester. Compared to classical methods, the protocol developed reduces the excess of reagents, increasing the environmental friendliness of the process, while maintaining high yields. A wide range of substrates, including various aliphatic, cyclic, and heterocyclic ketones, was studied to identify factors affecting the reactivity. The method was also successfully applied to aldehydes, producing amine-containing building blocks on a large scale. Various work-up procedures were optimized for efficient isolation of the homoallylamines synthesized without the need for chromatographic purification.

Supporting Agency

  • The work was funded by the internal Enamine grant and the Ministry of Education and Science of Ukraine (grant number 0123U102102).

Downloads

Download data is not yet available.

References

  1. Vine, L. E.; Schomaker, J. M. Back to basics. Nature Chemistry 2022, 14 (10), 1093 – 1094. https://doi.org/10.1038/s41557-022-01029-5.
    | |
  2. Afanasyev, O. I.; Kuchuk, E.; Usanov, D. L.; Chusov, D. Reductive Amination in the Synthesis of Pharmaceuticals. Chem. Rev. 2019, 119 (23), 11857-11911. https://doi.org/10.1021/acs.chemrev.9b00383.
    | |
  3. Zawodny, W.; Montgomery, S.L. Evolving New Chemistry: Biocatalysis for the Synthesis of Amine-Containing Pharmaceuticals. Catalysts 2022, 12, 595. https://doi.org/10.3390/catal12060595.
    |
  4. Why pKas Matter in Medicinal Chemistry and a Drug Discovery Amine pKa Table. https://drughunter.com/resource/why-pkas-matter-in-medicinal-chemistry (accessed 1 Nov 2024).
  5. Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54 (10), 3451 – 3479. https://doi.org/10.1021/jm200187y.
    | |
  6. Conn, E. L.; Perry, M. A.; Shi, K.; Wang, G.; Hoy, S.; Sach, N. W.; Qi, W.; Qu, L.; Gao, Y.; Xu, Y.; Schmitt, D. C. Identification of parallel medicinal chemistry protocols to expand branched amine design space. Org. Biomol. Chem. 2022, 20 (18), 3747 – 3754. https://doi.org/10.1039/D2OB00155A.
    | |
  7. Eymery, M.; Tran-Nguyen, V.-K.; Boumendjel, A. Diversity-Oriented Synthesis: Amino Acetophenones as Building Blocks for the Synthesis of Natural Product Analogs. Pharmaceuticals 2021, 14, 1127. https://doi.org/10.3390/ph14111127.
    | |
  8. Hulme, C.; Gore, V. «Multi-component reactions: emerging chemistry in drug discovery “from xylocain to crixivan”. Curr Med Chem 2003, 10 (1), 51 – 80. https://doi.org/10.2174/0929867033368600.
    | |
  9. Petasis, N. A.; Akritopoulou, I. The Boronic Acid Mannich Reaction: A New Method for the Synthesis of Geometrically Pure Allylamines. Tetrahedron Lett. 1993, 34, 583 – 586. https://doi.org/10.1016/S0040-4039(00)61625-8.
    |
  10. Petasis, N. A., Multicomponent Reactions with Organoboron Compounds. In Multicomponent Reactions, 2005; pp 199-223. https://doi.org/10.1002/3527605118.ch7.
    |
  11. Batey, R. A., Nucleophilic Addition Reactions of Aryl and Alkenylboronic Acids and Their Derivatives to Imines and Iminium Ions. In Boronic Acids, 2005; pp 279 – 304. https://doi.org/10.1002/3527606548.ch7.
    |
  12. Guerrera, C. A.; Ryder, T. R., The Petasis Borono-Mannich Multicomponent Reaction. In Boron Reagents in Synthesis, American Chemical Society: 2016; Vol. 1236, pp 275 – 311. https://doi.org/10.1021/bk-2016-1236.ch009.
    |
  13. Saeed, S.; Munawar, S.; Ahmad, S.; Mansha, A.; Zahoor, A.F.; Irfan, A.; Irfan, A.; Kotwica-Mojzych, K.; Soroka, M.; Głowacka, M.; et al. Recent Trends in the Petasis Reaction: A Review of Novel Catalytic Synthetic Approaches with Applications of the Petasis Reaction. Molecules 2023, 28, 8032. https://doi.org/10.3390/molecules28248032.
    | |
  14. Gonzalez, K. J.; Cerione, C.; Stoltz, B. M. Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions. Chem. Eur. J. 2024, 30 (49), e202401936. https://doi.org/10.1002/chem.202401936.
    | |
  15. Pandit, N. T.; Kamble, S. B. The Petasis Reaction: Applications and Organic Synthesis—A Comprehensive Review. Top. Curr. Chem. 2025, 383 (1), 7. https://doi.org/10.1007/s41061-025-00491-2.
    | |
  16. Sugiyama, S.; Imai, S.; Ishii, K. Diastereoselective amidoallylation of glyoxylic acid with chiral tert-butanesulfinamide and allylboronic acid pinacol esters: efficient synthesis of optically active γ,δ-unsaturated α-amino acids. Tetrahedron: Asymmetry 2013, 24 (18), 1069 – 1074. https://doi.org/10.1016/j.tetasy.2013.07.026.
    |
  17. Macé, A.; Tripoteau, F.; Zhao, Q.; Gayon, E.; Vrancken, E.; Campagne, J.-M.; Carboni, B. Tandem Reactions Involving 1-Silyl-3-Boryl-2-Alkenes. New Access to (Z)-1-Fluoro-1-Alkenes, Allyl Fluorides, and Diversely α-Substituted Allylboronates. Org. Lett. 2013, 15 (4), 906 – 909. https://doi.org/10.1021/ol4000263.
    | |
  18. Lawrence, S. A. Amines: Synthesis, Properties and Applications; Cambridge University Press: Cambridge, UK, 2004.
  19. Chiral Amine Synthesis: Methods, Developments and Applications; Nugent, T. C., Ed.; Wiley-VCH: Weinheim, 2010.
  20. Cuprova, L.; Dobbs, A. P., Chapter Five – Cascade aza-Prins reactions. In Adv. Heterocycl. Chem., Scriven, E. F. V.; Ramsden, C. A., Eds. Academic Press: 2020; Vol. 130, pp 251 – 278. https://doi.org/10.1016/bs.aihch.2019.10.006.
    |
  21. Subba Reddy, B. V.; Nair, P. N.; Antony, A.; Lalli, C.; Grée, R. The Aza-Prins Reaction in the Synthesis of Natural Products and Analogues. Eur. J. Org. Chem. 2017, 2017 (14), 1805 – 1819. https://doi.org/10.1002/ejoc.201601411.
    |
  22. Herasymchuk, M.; Melnykov, K.; Druzhenko, T.; Filatov, Y.; Dudenko, D.; Ostapchuk, E.; Volochnyuk, D.; Ryabukhin, S. DOS-like strategy for the spirocyclic MedChem relevant building blocks via Petasis / Grubbs reactions sequence. ChemRxiv 2025; https://doi.org/10.26434/chemrxiv-2025-1l7vt.
    |
  23. Herasymchuk, М.; Fedinchyk, A.; Melnykov, K.; Ostapchuk, E.; Druzhenko, T.; Volochnyuk, D.; Ryabukhin, S. Scalable DOS-like Strategy to the δ-Amino Acids via Petasis/Cross Metathesis Reactions Sequence. ChemRxiv 2025. https://doi.org/10.26434/chemrxiv-2025-fgr52.
  24. Sugiura, M.; Hirano, K.; Kobayashi, S. α-Aminoallylation of Aldehydes with Ammonia: Stereoselective Synthesis of Homoallylic Primary Amines. J. Am. Chem. Soc. 2004, 126 (23), 7182 – 7183. https://doi.org/10.1021/ja049689o.
    | |
  25. Kobayashi, S.; Hirano, K.; Sugiura, M. α-Aminoallylation of aldehydes in aqueous ammonia. Chem. Commun. 2005, 1, 104 – 106. https://doi.org/10.1039/B415264F.
    | |
  26. Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones. Chem. Commun. 2005, 44, 5551 – 5553. https://doi.org/10.1039/B511411J.
    | |
  27. Zhou, Y.; Zhao, Z.-N.; Zhang, Y.-L.; Liu, J.; Yuan, Q.; Schneider, U.; Huang, Y.-Y. Brønsted Acid-Catalyzed General Petasis Allylation and Isoprenylation of Unactivated Ketones. Chem. Eur. J. 2020, 26 (45), 10259 – 10264. https://doi.org/10.1002/chem.202001594.
    | |
  28. Saejong, P.; Zhong, J.; Rojas, J. J.; White, A. J. P.; Choi, C.; Bull, J. A. Synthesis of 3,3-Disubstituted Thietane Dioxides. J. Org. Chem. 2024, 89 (21), 15718 – 15732. https://doi.org/10.1021/acs.joc.4c01843.
    | |
  29. Francisco, K. R.; Varricchio, C.; Paniak, T. J.; Kozlowski, M. C.; Brancale, A.; Ballatore, C. Structure property relationships of N-acylsulfonamides and related bioisosteres. Eur. J. Med. Chem. 2021, 218, 113399. https://doi.org/10.1016/j.ejmech.2021.113399.
    | |
  30. Zhao, L.; Meng, X.; Zou, Y.; Zhao, J.; Wang, L.; Zhang, L.; Wang, C. Directed Nickel-Catalyzed Diastereoselective Reductive Difunctionalization of Alkenyl Amines. Org. Lett. 2021, 23 (21), 8516 – 8521. https://doi.org/10.1021/acs.orglett.1c03210.
    | |
  31. Randl, S.; Blechert, S. Concise Enantioselective Synthesis of 3,5-Dialkyl-Substituted Indolizidine Alkaloids via Sequential Cross-Metathesis−Double-Reductive Cyclization. J. Org. Chem. 2003, 68 (23), 8879 – 8882. https://doi.org/10.1021/jo0346095.
    | |
  32. Dilek, I.; Madrid, M.; Singh, R.; Urrea, C. P.; Armitage, B. A. Effect of PNA Backbone Modifications on Cyanine Dye Binding to PNA−DNA Duplexes Investigated by Optical Spectroscopy and Molecular Dynamics Simulations. J. Am. Chem. Soc. 2005, 127 (10), 3339 – 3345. https://doi.org/10.1021/ja045145a.
    | |
  33. Melnykov, K. P.; Artemenko, A. N.; Ivanenko, B. O.; Sokolenko, Y. M.; Nosik, P. S.; Ostapchuk, E. N.; Grygorenko, O. O.; Volochnyuk, D. M.; Ryabukhin, S. V. Scalable Synthesis of Biologically Relevant Spirocyclic Pyrrolidines. ACS Omega 2019, 4 (4), 7498 – 7515. https://doi.org/10.1021/acsomega.9b00896.
    | |
  34. Melamed, J. Y.; Zartman, A. E.; Kett, N. R.; Gotter, A. L.; Uebele, V. N.; Reiss, D. R.; Condra, C. L.; Fandozzi, C.; Lubbers, L. S.; Rowe, B. A.; McGaughey, G. B.; Henault, M.; Stocco, R.; Renger, J. J.; Hartman, G. D.; Bilodeau, M. T.; Trotter, B. W. Synthesis and evaluation of a new series of Neuropeptide S receptor antagonists. Bioorg. Med. Chem. Lett. 2010, 20 (15), 4700 – 4703. https://doi.org/10.1016/j.bmcl.2010.04.143.
    | |
  35. Qin, L.; Liu, Z.; Zard, S. Z. Carbon Radical Attack on a Pyrimidine Nitrogen. An Unusual Entry into Polycyclic Aminopyrimidones. Org. Lett. 2014, 16 (11), 2966 – 2969. https://doi.org/10.1021/ol501104h.
    | |
  36. Vasu, D.; Fuentes de Arriba, A. L.; Leitch, J. A.; de Gombert, A.; Dixon, D. J. Primary α-tertiary amine synthesis via α-C–H functionalization. Chemical Science 2019, 10 (11), 3401 – 3407. https://doi.org/10.1039/C8SC05164J.
    | |
  37. Watanabe, K.; Kuroda, S.; Yokoi, A.; Ito, K.; Itsuno, S. Enantioselective synthesis of optically active homoallylamines by allylboration of N-diisobutylaluminum imines. J. Organomet. Chem. 1999, 581 (1), 103 – 107. https://doi.org/10.1016/S0022-328X(99)00048-0.
    |
  38. Peggion, C.; Flammengo, R.; Mossel, E.; Broxterman, Q. B.; Kaptein, B.; Kamphuis, J.; Formaggio, F.; Crisma, M.; Toniolo, C. Mag: a Cα-Methylated, Side-chain Unsaturated α-Amino Acid. Introduction into Model Peptides and Conformational Preference. Tetrahedron 2000, 56 (22), 3589 – 3601. https://doi.org/10.1016/S0040-4020(00)00274-X.
    |

Downloads

Published

2025-05-05

How to Cite

(1)
Ryabukhin, S. V.; Herasymchuk, M. V. A Scalable Approach to Primary Amines via the Petasis Reaction. J. Org. Pharm. Chem. 2025, 23, 11-21.

Issue

Vol. 23 No. 1 (2025)

Section

Advanced Researches

License

Copyright (c) 2025 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).