Greening of Monocyclic N- and O‑Azole Synthesis through Sonochemistry

Abstract

Sonochemistry is a fascinating branch of chemistry that applies sound waves in the ultrasonic frequency range to facilitate chemical processes. Although this technique is powerful, it remains underutilized in synthetic chemistry. By leveraging mechanisms of acoustic cavitation, sonochemistry initiates and enhances reactions, offering advantages such as cost-effectiveness, environmental sustainability, and improved reaction efficiency. Significantly, product yields in ring-closing reactions can be enhanced through sonochemistry. In certain cases, sonochemistry may also lead to altered product distributions. In this narrative review, we delve into the realm of N- and O-azoles, noting that the existing literature on sonochemistry as a synthetic method constitutes only about a tenth of all reports in this area. However, it is noteworthy that nearly all studies indicate improved outcomes when employing sonochemistry relative to traditional methods. As a green and sustainable synthetic approach, sonochemistry plays a crucial role in the synthesis of important heterocycles, many of which have significant pharmaceutical applications. This review covers synthetic reports including reaction conditions, solvents, catalysts, and reagents, spanning the past three decades, with an emphasis on contributions from 2020 through early 2025.

1

Common drugs containing N- and O-azoles: celecoxib, a pyrazole-containing COX-2 selective nonsteroidal anti-inflammatory drug (NSAID); metronidazole, an imidazole-containing antibiotic; oxacillin, an isoxazole-containing β-lactam antibiotic of the penicillin class; oxaprozin, an oxazole-containing NSAID; tazobactam, a 1,2,3-triazole-containing β-lactamase inhibitor; anastrozole, a 1,2,4-triazole-containing aromatase inhibitor; tiodazosin, a 1,3,4-oxadiazole-containing antihypertensive agent; ataluren, a 1,2,4-oxadiazole-containing cystic fibrosis drug; and valsartan, a tetrazole-containing antihypertensive agent.

2

Growth in frequency of publications containing the terms “ultrasound” or “ultrasonication” and “synthesis” in a SciFinder substructure search from 2008 to 2024 for isoxazoles, pyrazoles, 1,2,3- and 1,2,4-triazoles.

1. Synthesis of Pyrazoles 2 via the Aqueous USI of Diketone 1 with Excess Substituted Dimethylhydrazine

2. Synthesis of Pyrazoles 5 and 6 via the Reaction of Substituted β-Enaminones 3 with Hydrazines 4

3. Synthesis of 1,5-Disubstituted Pyrazoles 9 Using USI

3

Proposed mechanism of 1,5-diarylpyrazole formation in hexafluoroisopropanol by Roy and co-workers.

4. Synthesis of K-10-Catalyzed Amine-Bearing Pyrazoles 11 from β-Enaminone O,N-Acetals 10 with Hydrazines

5. Synthesis of 1,3,5-Triphenylpyrazole 14 via Oxidation and Aromatization of the Corresponding Pyrazoline 12 Using K-10 Clay-Supported Copper­(II) Nitrate (Claycop), when R₁ = R₂ = H

6. Synthesis of Ethyl 1H-pyrazole-3-carboxylates 17 from Enones 15 and Hydrazine 16

7. Synthesis of (E)-1-(2-Hydroxyphenyl)-3-(4-(phenylthio)­phenyl)-1H-pyrazole-1-carbothioamides 19 via the Ring Opening of 2-(4-(Phenylthio)­phenyl)-4H-chromen-4-ones 18 with Semicarbazide under USI

8. Synthesis of 5-Arylpyrazoles 21 Using 3-(Dimethylamino)-1-arylprop-2-en-1-ones 20 with Hydroxylamine Hydrochloride under USI

9. Synthesis of Pyrazoles 23 Using Substituted Chalcones 22 and Consecutive USI/MW Irradiation

10. Oxidation of Aryl Dihydropyrazoles 24 to Pyrazoles 25

11. Synthesis of 2-Naphthalenyl 3,5-Dimethyl-1H-pyrazole-1-acetate 28 from Naphthalen-2-yl 2-Bromoacetate 26 and Acetoacetone 27

12. Synthesis of 1,5-Disubstituted Pyrazoles 30 via Reaction of α,β-Cyanoesters 29 and Equimolar Phenylhydrazine in the Presence of a Cu­(I) Catalyst

13. Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles 34 Assisted via USI, Starting with α-Diketone 31, Aryl Aldehyde 32, and Arylamine 33

14. USI Synthesis of Tri- and Tetrasubstituted Imidazoles, 37 and 38, Respectively

15. Preparation of 1,2,4,5-Tetrasubstituted Imidazoles 41 via USI

16. Three-Component Cu­(I)-Catalyzed One-Pot Synthesis of 3,5-Disubstituted Isoxazoles 45 Combining Use of 40 kHz US Bath and 20 kHz Probe in the Presence of Copper Turnings

17. Synthesis of 5-Arylisoxazoles 46 Using 3-(Dimethylamino)-1-arylprop-2-en-1-ones 20 with Hydroxylamine Hydrochloride under USI

18. Work by Shen and Co-workers Detailing the Synthesis of Isoxazoles 48 Using Propargyl Alcohol and Substituted Benzaldoxime 47

19. Oxidation of Aryl Dihydroisoxazoles 49 to Isoxazoles 50

20. Synthesis of Isoxazoles 52 Using USI and a β-Cyclodextrin Recyclable Catalyst in Water

21. Synthesis of Isoxazoles 56 Using USI with Carbanion 54 and 1-(4-Bromophenyl)-2-bromo-2-hydroximinoethanone 55

22. Synthesis of 3,5-Dimethylisoxazole 57 from Acetylacetone 27 Using USI

23. One-Pot Synthesis of 3,5-Disubstituted Isoxazoles 61 Using Cerium­(IV) Ammonium Nitrate under USI. R₁ = Alkyl, Substituted Aryl

24. Five-Component One-Pot Synthesis of Isoxazoles 64 Using CaCl₂, Aryl Aldehydes 62, and Sulfone 63

25. One of the First USI Oxazole Syntheses, which Proceeded via the Intramolecular Annulation of 65 to Form Oxazole 66

26. Synthesis of 68 via Pd­(II) and USI of Propargylamine 67

27. Synthesis of Oxazoles 71 via Reaction of 69 with Amide 70 Using USI and a Deep Eutectic Solvent

28. Synthesis of Oxazoles 74 via Reaction of 72 with Urea, 73, under USI

29. Synthesis of Bis-oxazoles 77 via Reaction of 75 with Phenacyl Bromide 76

30. Synthesis of Carbohydrate-Containing 1,2,3-Triazoles 80 from Azide 78 and Alkyne 79 under USI

31. USI Synthesis of 1,2,3-Triazoles 83 Using Copper­(I)-Catalyzed 1,3-Dipolar [3 + 2] Cycloaddition

32. Synthesis of 1,4-Disubstituted 1,2,3-Triazoles 86 Using a Recyclable Magnetic Aminonitrile-Functionalized Fe₃O₄ Nanoparticle Catalyst

33. Synthesis of 1,5-Disubstituted 1,2,3-Triazoles 88 and 1,4-Disubstituted-1,2,3-Triazoles 89 under USI from Eliminative [3 + 2] Cycloaddition of Azides 87

34. Synthesis of 1,4-Disubstituted-1,2,3-Triazoles 92 under USI Using Enolizable Aldehyde 91, Aryl Azide 90, and Task-Specific [DBU-Bu]­OH under USI

35. Synthesis of a 1,4,5-Trisubstituted-1,2,3-Triazoles 94 from Aryl Azides 93 and Acetylacetone 27 Using an Efficient, Recyclable DBU-H₂O Catalytic System

36. Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles 97 Using β-oxo Amides 95 and Aryl Azides 96

37. Synthesis of 5-(Substituted Phenyl)-4H-1,2,4 Triazol-3-ols 99 from a Trisubstituted Benzaldehydes 98 and Semicarbazide Hydrochloride under USI

38. Synthesis of 1,2,4-Triazole 101 Using an Aldehyde-Substituted Diphenylpyrazole 100 and Semicarbazide under USI

39. Synthesis of bis-1,2,4-Triazoles 105 from Their Respective 1,3,4-Oxadiazoles 104 upon the Addition of Hydrazine Hydrate and Base under USI

40. Synthesis of 1,2,4-Triazoles 108 Using α-Nitrophenyl Hydrazones 106, Methylene Amines 107, and Sodium Nitrite with Benzyl Triethylammonium Chloride (BTEAC) as Phase Transfer Catalysis under USI

41. Synthesis of Thiol-Substituted 1,2,4-Triazole 110 under USI of 2,3-Dichlorobenzoic Acid 2-(Aminothioxomethyl)­hydrazide 109

42. Synthesis of Thiol-Containing 1,2,4-Triazoles 112 via Trimethylsilyl Isothiocyanate and Ester 111, Which after Reaction with Hydrazine Acetate, Forms the Hydrazone That Undergoes Cyclization with Isothiocyanate

43. 1,3,4-Oxadiazole 115 Formation Assisted by USI from 113 and 114

44. USI Synthesis of 1,3,4-Oxadiazolobenzimidazoles 118 from Hydrazide 116

45. USI Synthesis of 2-Amino-1,3,4-Oxadiazoles 121 from Hydrazide 119 and Bromoacetonitrile 120

46. USI Preparation of 1,3,4-Oxadiazole-Containing Cathepsin K Inhibitors 123 by Gontijo and Co-workers

47. A One-Pot Method for the Synthesis of Oxadiazoles 127 Using (N-Isocyanoamino)­triphenylphosphorane 126, Aryl Carboxylic Acid 125, and α-Diketone 124

48. Synthesis of 2-Amino-1,3,4-Oxadiazoles 130 under USI Using a Graphene Oxide Catalyst and DBU

49. Synthesis of 2-Isoxazolo- and 2-Pyrazolooxadiazoles 132 from Substituted Acyl Hydrazones 131

50. Synthesis of 5-Aryl-1,3,4-oxadiazole-2-thiols 134 from Aryl Hydrazides 133

51. Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles 137 from Trichloroacetoamidoxime 136 and Acid Halides 135

52. Preparation of Tetrazolodehydroabietylamine Derivatives 139 from a Primary Amine (Leelamine, 138)­

53. A MCR (Ugi-azide Synthesis) of 1,5-Disubstituted Tetrazoles 143 Using No Solvent or Catalyst

54. USI Synthesis of 5-Substituted 1H-Tetrazoles 146 Using ZrP₂O₇ Nanoparticles

55. An Efficient Three-Component USI Passerini Tetrazole Synthesis of 149

56. A One-Pot, Multi-Step Syntheses of Bis-tetrazoles 153

57. USI Synthesis of 5-Aryltetrazoles 156 and 158 in an Ionic Liquid

58. USI Synthesis of Anthelmintic Tetrazoles 160 from Starting Nitrile Substitute 1,2,3-Triazoles 159

59. USI Synthesis of 1-Aryltetrazoles 164 from Arylamines 163 in the Presence of ZnS Nanoparticles