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Research Article Open access CC BY 4.0

Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates

Rowan I. L. Meador, Nilamber A. Mate, John D. Chisholm

Organics · pp. 111–121 · Published 24 May 2022

10.3390/org3020009

Abstract

N-Alkyl pyrazoles are important heterocycles in organic and medicinal chemistry, demonstrating a wide range of biological activity. A new method for the N-alkylation of pyrazoles has been developed using trichloroacetimidate electrophiles and a Brønsted acid catalyst. These reactions provide ready access to N-alkyl pyrazoles which are present in a variety of medicinally relevant lead structures. Benzylic, phenethyl and benzhydryl trichloroacetimidates provide good yields of the N-alkyl pyrazole products. Unsymmetrical pyrazoles provide a mixture of the two possible regioisomers, with the major product being controlled by sterics. This methodology provides an alternative to other alkylation methods that require strong base or high temperature.

Alkylation Pyrazole Alkyl Chemistry Electrophile Catalysis Organic chemistry Combinatorial chemistry

References (54)

  1. 1 Gulia, 2017, Palladium-Catalyzed Pyrazole-Directed sp3 C-H Bond Arylation for the Synthesis of β-Phenethylamines [DOI]
  2. 2 Li, 2019, Rhodium(III)-catalyzed unreactive C(sp3)-H alkenylation of N-alkyl-1H-pyrazoles with alkynes [DOI]
  3. 3 Du, 2021, Iridium-catalyzed regio- and enantioselective borylation of unbiased methylene C(sp3)-H bonds at the position β to a nitrogen center [DOI]
  4. 4 Papageorgiou, 1998, Pyrazole Bioisosteres of Leflunomide as B-Cell Immunosuppressants for Xenotransplantation and Chronic Rejection: Scope and Limitations [DOI]
  5. 5 Kumari, 2020, Amide Bond Bioisosteres: Strategies, Synthesis, and Successes [DOI]
  6. 6 Graham, 2014, Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitors [DOI]
  7. 7 Wilkening, 2006, Estrogen receptor β-subtype selective tetrahydrofluorenones: Use of a fused pyrazole as a phenol bioisostere [DOI]
  8. 8 Rout, 2021, Selective functionalization of the 1H-imidazo[1,2-b]pyrazole scaffold. A new potential non-classical isostere of indole and a precursor of push-pull dyes [DOI]
  9. 9 Kucukguzel, 2015, Recent advances in bioactive pyrazoles [DOI]
  10. 10 Faria, 2017, Recently reported biological activities of pyrazole compounds [DOI]
  11. 11 Li, X., Yu, Y., and Tu, Z. (2021). Pyrazole scaffold synthesis, functionalization, and applications in Alzheimer’s disease and Parkinson’s disease treatment (2011–2020). Molecules, 26. [DOI]
  12. 12 Mykhailiuk, 2021, Fluorinated Pyrazoles: From Synthesis to Applications [DOI]
  13. 13 Santos, N.E., Carreira, A.R.F., Silva, V.L.M., and Braga, S.S. (2020). Natural and biomimetic antitumor pyrazoles, a perspective. Molecules, 25. [DOI]
  14. 14 Yin, 2017, Nitrogen-rich azoles as high density energy materials: Reviewing the energetic footprints of heterocycles [DOI]
  15. 15 Zhang, S., Gao, Z., Lan, D., Jia, Q., Liu, N., Zhang, J., and Kou, K. (2020). Recent advances in synthesis and properties of nitrated-pyrazoles based energetic compounds. Molecules, 25. [DOI]
  16. 16 Kashyap, 2020, Inorganic and organic anion sensing by azole family members [DOI]
  17. 17 Tigreros, 2020, Recent progress in chemosensors based on pyrazole derivatives [DOI]
  18. 18 Taleb, 2020, Metal-organic frameworks based on pyrazole subunit for batteries applications: A systematic review [DOI]
  19. 19 Matos, 2010, Experimental and theoretical study of pyrazole N-alkylation catalyzed by basic modified molecular sieves [DOI]
  20. 20 Almena, 1998, Alkylation and arylation of pyrazoles under solvent-free conditions: Conventional heating versus microwave irradiation [DOI]
  21. 21 Tejeda, 1990, Synthesis of N-alkylpyrazoles by phase transfer catalysis without solvent [DOI]
  22. 22 Wang, 2019, Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents [DOI]
  23. 23 Mosallanejad, 2018, Application of Tsunoda reagent to the convenient synthesis of drug-like pyrazoles [DOI]
  24. 24 Gill, 2015, N-vinylation and N-allylation of 3,5-disubstituted pyrazoles by N-H insertion of vinylcarbenoids [DOI]
  25. 25 Beattie, 2010, Synthesis and evaluation of two series of 4′-aza-carbocyclic nucleosides as adenosine A2A receptor agonists [DOI]
  26. 26 Haydl, 2015, Regio- and Enantioselective Synthesis of N-Substituted Pyrazoles by Rhodium-Catalyzed Asymmetric Addition to Allenes [DOI]
  27. 27 Arredondo, 2017, Enantioselective Palladium-Catalyzed Carbene Insertion into the N-H Bonds of Aromatic Heterocycles [DOI]
  28. 28 Wang, 2019, Enantioselective γ-Addition of Pyrazole and Imidazole Heterocycles to Allenoates Catalyzed by Chiral Phosphine [DOI]
  29. 29 Bengel, 2021, Engineered Enzymes Enable Selective N-Alkylation of Pyrazoles With Simple Haloalkanes [DOI]
  30. 30 Arachchi, 2021, Iridium-Catalyzed Enantioselective Allylic Substitutions of Racemic, Branched Trichloroacetimidates with Heteroatom Nucleophiles: Formation of Allylic C-O, C-N, and C-S Bonds [DOI]
  31. 31 Arnold, 2013, Rhodium-catalyzed asymmetric amination of allylic trichloroacetimidates [DOI]
  32. 32 Wong, 2013, Silver-catalysed intramolecular hydroamination of alkynes with trichloroacetimidates [DOI]
  33. 33 Maleckis, 2010, Catalytic Enantioselective Synthesis of 4-Vinyl-2-trichloromethyloxazoline: An Access to Enantioenriched Vinylglycinol Surrogate [DOI]
  34. 34 Anderson, 2005, Catalytic Asymmetric Synthesis of Chiral Allylic Amines. Evaluation of Ferrocenyloxazoline Palladacycle Catalysts and Imidate Motifs [DOI]
  35. 35 Wallach, 2015, Brønsted Acid Catalyzed Monoalkylation of Anilines with Trichloroacetimidates [DOI]
  36. 36 Wallach, 2016, Alkylation of Sulfonamides with Trichloroacetimidates under Thermal Conditions [DOI]
  37. 37 Mate, 2022, Alkylation of isatins with trichloroacetimidates [DOI]
  38. 38 McHardy, S.F., and Vetelino, M.G. (2005). Preparation of 1-diphenylmethylpyrazoles as Opioid Receptor Ligands. (6960609B2), U.S. Patent.
  39. 39 Overman, 2005, The allylic trihaloacetimidate rearrangement
  40. 40 Cran, 2014, Copper-Catalyzed N-tert-Butylation of Aromatic Amines under Mild Conditions Using tert-Butyl 2,2,2-Trichloroacetimidate [DOI]
  41. 41 Iversen, T., and Bundle, D.R. (1981). Benzyl trichloroacetimidate, a versatile reagent for acid-catalyzed benzylation of hydroxy-groups. J. Chem. Soc. Chem. Commun., 1240–1241. [DOI]
  42. 42 Nakajima, 1988, MPM (4-methoxybenzyl)-protection of hydroxy functions under mild acidic conditions [DOI]
  43. 43 Ali, 2003, Protection of Hydroxy Groups with Diphenylmethyl and 9-Fluorenyl Trichloroacetimidates—Effect on Anomeric Stereocontrol [DOI]
  44. 44 Howard, 2016, Formation of DPM ethers using O-diphenylmethyl trichloroacetimidate under thermal conditions [DOI]
  45. 45 Pangborn, 1996, Safe and Convenient Procedure for Solvent Purification [DOI]
  46. 46 Zhao, 2014, Nucleophilic Substitution Catalyzed by a Supramolecular Cavity Proceeds with Retention of Absolute Stereochemistry [DOI]
  47. 47 Adhikari, 2017, Rearrangement of Benzylic Trichloroacetimidates to Benzylic Trichloroacetamides [DOI]
  48. 48 Zhang, 2015, Rhodium-catalyzed benzylic fluorination of trichloroacetimidates [DOI]
  49. 49 Mahajani, 2018, Synthesis of 1,1′-Diarylethanes and Related Systems by Displacement of Trichloroacetimidates with Trimethylaluminum [DOI]
  50. 50 Li, 2009, Gold(I)-catalyzed arylmethylation of terminal alkynes [DOI]
  51. 51 Ali, 2004, Imidomethylation of C-nucleophiles using O-phthalimidomethyl trichloroacetimidate and catalytic amounts of TMSOTf [DOI]
  52. 52 Song, 2018, DDQ-Catalyzed Direct C(sp3)-H Amination of Alkylheteroarenes: Synthesis of Biheteroarenes under Aerobic and Metal-Free Conditions [DOI]
  53. 53 Olsen, 2017, A mild halogenation of pyrazoles using sodium halide salts and Oxone [DOI]
  54. 54 Shi, 2021, Boron carbonitride photocatalysts for direct decarboxylation: The construction of C(sp3)-N or C(sp3)-C(sp2) bonds with visible light [DOI]

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