The Synthesis and Acid-base Properties of α-(Fluoromethyl)- and α-(Difluoromethyl)-substituted Cyclobutane Building Blocks

Authors

DOI:

https://doi.org/10.24959/ophcj.23.274017

Keywords:

cyclobutane, fluorine, acidity/basicity, amine, carboxylic acid

Abstract

Aim. To synthesize cyclobutane-derived amines and carboxylic acids bearing CH2F or CHF2 groups in the α position; to determine the regularities of the effect of fluoroalkyl substituents on the acid-base properties of the title compounds.
Results and discussion. Synthetic approaches to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids have been developed. It has been found that the pKa (pKa(H)) values measured for the title compounds, as well as for their non-substituted and CF3-substituted analogues, are consistent with the electron-withdrawing effect of the corresponding fluoroalkyl substituents.
Experimental part. The synthesis of the title compounds commenced from the known ethyl 1-(hydroxymethyl)cyclobutanecarboxylate or the product of its Swern oxidation (the corresponding aldehyde) and included fluorination, alkaline ester hydrolysis (for carboxylic acids), and modified Curtius rearrangement (for amines). The pKa value was determined from the pre-equivalence point part of the titration curve using the standard acid-base titration.
Conclusions. A newly developed synthetic approach to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids allows to obtain the title compounds in multigram quantities (up to 97 g). With a single exception, the acid-base properties of these products, as well as their parent non-substituted and CF3-substituted analogues, change in a monotonous manner in accordance with inductive electronic effect of the fluorine atom(s).

Supporting Agency

  • The work was supported by Enamine Ltd., Ministry of Education and Science of Ukraine (grants No. 0121U100387 (21BF037-01M) and 0122U001962 (22BF037-02)), and National Academy of Sciences of Ukraine (grant No. 0119U102718).

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References

  1. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315–8359. https://doi.org/10.1021/acs.jmedchem.5b00258.
  2. Mei, H.; Remete, A. M.; Zou, Y.; Moriwaki, H.; Fustero, S.; Kiss, L.; Soloshonok, V. A.; Han, J. Fluorine-Containing Drugs Approved by the FDA in 2019. Chinese Chem. Lett. 2020, 31, 2401–2413. https://doi.org/10.1016/j.cclet.2020.03.050.
  3. Yerien, D. E.; Bonesi, S.; Postigo, A. Fluorination Methods in Drug Discovery. Org. Biomol. Chem. 2016, 14, 8398–8427. https://doi.org/10.1039/C6OB00764C.
    |
  4. Inoue, M.; Sumii, Y.; Shibata, N. Contribution of Organofluorine Compounds to Pharmaceuticals. ACS Omega 2020, 5, 10633–10640. https://doi.org/10.1021/acsomega.0c00830.
  5. Han, J.; Remete, A. M.; Dobson, L. S.; Kiss, L.; Izawa, K.; Moriwaki, H.; Soloshonok, V. A.; O’Hagan, D. Next Generation Organofluorine Containing Blockbuster Drugs. J. Fluor. Chem. 2020, 239, 109639. https://doi.org/10.1016/j.jfluchem.2020.109639.
  6. Kolk, M. R. van der; Janssen, M. A. C. H.; Rutjes, F. P. J. T.; Blanco-Ania, D. Cyclobutanes in Small-Molecule Drug Candidates. ChemMedChem 2022, 17 (9), e202200020. https://doi.org/10.1002/cmdc.202200020.
  7. Li, J.; Gao, K.; Bian, M.; Ding, H. Recent Advances in the Total Synthesis of Cyclobutane-Containing Natural Products. Org. Chem. Front. 2019, 7, 136–154. https://doi.org/10.1039/C9QO01178A.
  8. Grygorenko, O. O.; Volochnyuk, D. M.; Ryabukhin, S. V.; Judd, D. B. The Symbiotic Relationship Between Drug Discovery and Organic Chemistry. Chem. Eur. J. 2020, 26, 1196–1237. https://doi.org/10.1002/chem.201903232.
  9. Abdel-Magid, A. F. Cannabinoid Receptor Agonists for the Potential Treatment of Pain, Neurological Disorders, Fibrotic Diseases, Obesity, and Many More. ACS Med. Chem. Lett. 2021, 12, 1188–1190. https://doi.org/10.1021/acsmedchemlett.1c00331.
  10. Liu, G.; Abraham, S.; Liu, X.; Xu, S.; Rooks, A. M.; Nepomuceno, R.; Dao, A.; Brigham, D.; Gitnick, D.; Insko, D. E.; Gardner, M. F.; Zarrinkar, P. P.; Christopher, R.; Belli, B.; Armstrong, R. C.; Holladay, M. W. Discovery and Optimization of a Highly Efficacious Class of 5-Aryl-2-Aminopyridines as FMS-like Tyrosine Kinase 3 (FLT3) Inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 3436–3441. https://doi.org/10.1016/j.bmcl.2015.07.023.
  11. Peterson, E. A.; Evans, R.; Gao, F.; Bolduc, P.; Pfaffenbach, M.; Xin, Z. 2H-Indazole Derivatives and Their Use in the Treatment of Disease. WO2020263967A1, Jun 24, 2020.
  12. Han, S.; Thoresen, L.; Jung, J. K.; Zhu, X.; Thatte, J.; Solomon, M.; Gaidarov, I.; Unett, D. J.; Yoon, W. H.; Barden, J.; Sadeque, A.; Usmani, A.; Chen, C.; Semple, G.; Grottick, A. J.; Al-Shamma, H.; Christopher, R.; Jones, R. M. Discovery of APD371: Identification of a Highly Potent and Selective CB2 Agonist for the Treatment of Chronic Pain. ACS Med. Chem. Lett. 2017, 8, 1309–1313. https://doi.org/10.1021/acsmedchemlett.7b00396.
  13. Dolbier, W. R.; Gray, T. A.; Keaffaber, J. J.; Celewicz, L.; Koroniak, H. Kinetic and Thermodynamic Effects in the Thermal Electrocyclic Ring-Openings of 3-Fluorocyclobutene, 3,3-Difluorocyclobutene, and 3-(Trifluoromethyl)Cyclobutene. J. Am. Chem. Soc. 1990, 112, 363–367. https://doi.org/10.1021/ja00157a055.
  14. Song, Z. J.; Qi, J.; Emmert, M. H.; Wang, J.; Yang, X.; Xiao, D. Two Scalable Syntheses of 3-(Trifluoromethyl)Cyclobutane-1-Carboxylic Acid. Org. Process Res. Dev. 2021, 25, 82–88. https://doi.org/10.1021/acs.oprd.0c00422.
  15. Sarver, P. J.; Bacauanu, V.; Schultz, D. M.; DiRocco, D. A.; Lam, Y.-hong; Sherer, E. C.; MacMillan, D. W. C. The Merger of Decatungstate and Copper Catalysis to Enable Aliphatic C(sp3)–H Trifluoromethylation. Nat. Chem. 2020, 12, 459–467. https://doi.org/10.1038/s41557-020-0436-1.
  16. Demchuk, O. P.; Hryshchuk, O. V.; Vashchenko, B. V.; Trofymchuk, S. A.; Melnykov, K. P.; Skreminskiy, A.; Volochnyuk, D. M.; Grygorenko, O. O. Fluoroalkyl-Containing 1,2-Disubstituted Cyclobutanes: Advanced Building Blocks for Medicinal Chemistry. Eur. J. Org. Chem. 2021, 87–95. https://doi.org/10.1002/ejoc.202001345.
  17. Dmowski, W.; Wolniewicz, A. Selective Reactions of 1,1-Cycloalkanedicarboxylic Acids with SF4. A Route to 1,1-Bis(Trifluoromethyl)Cycloalkanes, 1-Fluoroformyl-1-(Trifluoromethyl)Cycloalkanes and 1-(Trifluoromethyl)-1-Cycloalkane­carboxylic Acids. J. Fluor. Chem. 2000, 102, 141–146. https://doi.org/10.1016/S0022-1139(99)00233-X.
  18. Iwasaki, M.; Yorimitsu, H.; Oshima, K. Synthesis of (2-Arylethylidene)Cyclobutanes by Palladium-Catalyzed Reactions of Aryl Halides with Homoallyl Alcohols Bearing a Trimethylene Group at the Allylic Position. Synlett 2009, 2009, 2177–2179. https://doi.org/10.1055/s-0029-1217703.
  19. Holovach, S.; Melnykov, K. P.; Skreminskiy, A.; Herasymchuk, M.; Tavlui, O.; Aloshyn, D.; Borysko, P.; Rozhenko, A. B.; Ryabukhin, S. V.; Volochnyuk, D. M.; Grygorenko, O. O. Effect of gem-Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes. Chem. Eur. J. 2022, 28 (19), e202200331. https://doi.org/10.1002/chem.202200331.
  20. Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities. ChemMedChem 2007, 2, 1100–1115. https://doi.org/10.1002/cmdc.200700059.
  21. Armarego, W. L. F.; Chai, C. Purification of Laboratory Chemicals, 5th ed.; Elsevier: Oxford, 2003, 632 pp. https://doi.org/10.1016/B978-0-7506-7571-0.X5000-5.

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Published

2023-08-30

How to Cite

(1)
Demchuk, O. P.; Grygorenko, O. O. The Synthesis and Acid-Base Properties of α-(Fluoromethyl)- and α-(Difluoromethyl)-Substituted Cyclobutane Building Blocks. J. Org. Pharm. Chem. 2023, 21, 3-9.

Issue

Vol. 21 No. 2 (2023)

Section

Original Researches

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