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Greening of Monocyclic N- and O‑Azole Synthesis through

Sonochemistry
Gavin R. Hoffman,* Mustafa M. Saeed, and Allen M. Schoffstall

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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
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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. INTRODUCTION ring-forming reactions. This review highlights significant effects

Sonochemistry is the use of sound, generally in the ultrasonic observed in green ring-forming reactions, such as enhanced
frequency range (20 kHz to 3 MHz) to impart energy for yields, reduced reaction times, milder conditions, and purer
driving a chemical process.1 In this review, “ultrasonic products that facilitate simpler workup procedures, all while
irradiation” will be abbreviated as “USI,” and ultrasound as generating less waste. Notable examples include Cu(I)-
“US.” Sonochemistry is usually performed in liquid media, catalyzed azide−alkyne 1,3-dipolar cycloaddition (CuAAC)
where sound waves induce alternating regions of high reactions and multicomponent reactions (MCR),3 which can
(compression) and low (rarefaction) pressure within the yield distinct results when sonochemistry is used. Some reports
medium.2 Sonochemistry can drive chemical processes through show reaction switching, leading to different product
several modes, including these alternating regions, where US distributions or different products altogether when compared
waves create and collapse tiny bubbles within the medium. with results from conventional heating.3,5
Such processes include homogeneous reactions, in which the Important factors to be considered when performing
extreme conditions within these bubbles generate reactive sonochemistry are the type of probe or bath, the size and
species, and heterogeneous reactions at solid/liquid and type of reaction container, the solvent, amount of solution,
liquid/liquid interfaces. Detailed coverage of the precise temperature, and the frequency and power of the sound waves
mechanisms of sonochemistry has been reported.1 This review applied.1 The energy required to significantly affect chemical
focuses on synthetic applications rather than the physical reactions is roughly 20 MHz at a power of 25−70.1 The energy
mechanisms underlying sonochemistry. Just like photochem- not consumed by the reactants is absorbed by the solvent,
istry, electrochemistry, and microwave irradiation, sonochem-
istry offers many features of green chemistry, including cost-
effectiveness, environmental friendliness, and the potential to Received: March 9, 2025
enhance reaction efficiency.1,3,4 In this way, the increasing use Revised: June 9, 2025
of sonochemistry reflects the broader “greening” of monocyclic Accepted: June 17, 2025
N- and O-azole synthesis. Published: June 26, 2025
Sonochemistry offers several advantages for various reactions
crucial to organic synthesis, including coupling, redox, and
© 2025 The Authors. Published by
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Figure 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.

causing significant warming. A commercial cooling device is coccal penicillin antibiotic used in severe and invasive
often used in addition to containment for the noisy sonication methicillin-susceptible Staphylococcus aureus infections. Oxap-
probe, if used. Water-jacketed glass reaction containers are rozin exemplifies an oxazole-containing compound that also
used to facilitate cooling. Solvents are generally nonvolatile, serves as an NSAID. 1,2,3-Triazoles have received great
polar, and often aqueous6,7 or hydrogen-bonding. In some attention in the literature over the last two decades owing to
cases, phase transfer processes can be replaced by sonochem- their ease of synthesis via CuAAC.13,14 These are present in
istry in a single solvent. Very nonvolatile neoteric solvents, many pharmaceutical compounds, one of which is tazobac-
such as ionic liquids, can be used effectively as solvents with tam,15 a β-lactamase inhibitor added to some penicillin class
biodegradable, nontoxic, and recyclable green features being antibiotics to combat antibiotic resistance from β-lactamases.
important.3,5 Similarly, 1,2,4-triazoles are also a privileged heterocycle found
The N- and O-containing azoles in this review are nonfused in many drugs. These include the prototypical antifungal
and contain two or more heteroatoms: pyrazole, imidazole, fluconazole,16 the antimigraine drug rizatriptan,17 and the
isoxazole, oxazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadia- aromatase inhibitor anastrozole.18 The antihypertensive drug
zole, 1,2,4-oxadiazole, and tetrazole, are important in tiodazosin contains a 1,3,4-oxadiazole and the cystic fibrosis
heterocyclic chemistry and have broad applications across drug ataluren contains a 1,2,4-oxadiazole. Tetrazole is found in
many fields. For example, pyrazoles exhibit a broad spectrum many drugs, of which the widely used antihypertensive
of biological activity for both synthetic and natural derivatives.8 valsartan is one example. Structures of these examples are
Drugs containing pyrazoles include nonsteroidal anti-inflam- shown in Figure 1.
matory drugs (NSAID) such as celecoxib.9 Imidazoles can be Given the broad utility of these azoles in pharmaceuticals
found in drugs such as the widely used antibiotic and organic synthesis, the development of efficient and
metronidazole (common brand name Flagyl). Isoxazoles sustainable methods for their synthesis remains an important
have received attention due to their great synthetic utility area of research. In this regard, sonochemical techniques have
and ease of synthesis. emerged as a powerful tool, offering significant features in
Many methods have been reported for the synthesis of terms of reaction efficiency, selectivity, and environmental
isoxazoles, which also offer unique utility in that their reductive sustainability. Despite being described nearly a century ago by
ring-opened products can further facilitate the synthesis of Wood and Loomis,19 sonochemistry remains an underutilized
other heterocycles.10 Isoxazoles are present in many drugs,11 modality for performing synthetic reactions and received
one notable example of which is oxacillin,12 an antistaphylo- relatively little attention in the literature until recently. When
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performing a SciFinder substructure search of the most cycles are scarce, suggesting that alternative synthetic method-
common azoles outlined in Figure 1 as an example, excluding ologies remain predominant for their formation. Heterocycle
patents, publications containing the terms “ultrasound” or types are presented in the following order: pyrazoles,
“ultrasonication” coupled with the term “synthesis” have imidazoles, isoxazoles, oxazoles, 1,2,3-triazoles, 1,2,4-triazoles,
increased since 2008 (Figure 2). Notably, reports matching 1,3,4-oxadiazoles, 1,2,4-oxadiazoles, and tetrazoles.
these criteria for pyrazoles have risen the most, from 0 reports 2.1. Sonochemical Syntheses of Pyrazoles. The
in 2008 to 187 in late 2024. standard synthesis of pyrazoles typically involves the reaction
of a hydrazine with a β-dicarbonyl compound, such as 1, a
central focus of the subsequent section. Lie Ken Jie and co-
workers28 reported synthesis of pyrazole 2 via USI of
substituted diketones 1 with excess dimethylhydrazine in
water at 60 °C (Scheme 1).

Scheme 1. Synthesis of Pyrazoles 2 via the Aqueous USI of

Diketone 1 with Excess Substituted Dimethylhydrazinea

Figure 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- a
R1 = Me(CH2)5. R2 = MeO2C(CH2)8.
and 1,2,4-triazoles.

A similar synthesis using a diketone such as 1 and hydrazine

The following review outlines sonochemical methods hydrate formed 3,5-dimethylpyrazole from acetylacetone. This
employed in the synthesis of N- and O-azole heterocycles. was reported by Silva and co-workers,29 though hydrazine
Sources were identified through searches conducted in hydrate was used in water for 10 min at 25 °C giving 3,5-
SciFinder, PubMed, Google Scholar, Web of Science, and dimethylpyrazole (99% yield). Phenylhydrazine gave the
Scopus, as well as through the examination of previously corresponding product in 76% yield. Indeed, starting with a
published bibliographies to capture underreported studies. diketone and reacting it with hydrazine is a well-established
Reviews focused on using USI for heterocyclic synthesis have method for synthesizing pyrazoles. Pyrazoles have been
been published20−25 (including for N- and O-containing incorporated into metal complexes,30 thiophenes,31 pyrazo-
heterocycles26); the present work focuses exclusively on N- lones,32 pyrimidin-2-thiones,33 and pyrazolylpyridazine-3-thi-
and O- azoles which have not been covered. Representative one34 derivatives. All involve use of a diketone with hydrazine,
comparative studies evaluating the efficiency of USI relative to and across these reports, yields generally range from 70 to 95%.
conventional synthetic methods are highlighted where Valduga and co-workers35 reported synthesis of pyrazoles 5
applicable. Reported yields are isolated yields unless otherwise and 6 from substituted β-enaminones 3 and hydrazines 4
specified. under the influence of K-10 (a montmorillonite clay powder36)
and USI (Scheme 2). A likely mechanism is the initial
2. SONOCHEMICAL SYNTHESES conjugate addition of the hydrazine to 3, followed by ring
Throughout the following section, reaction times are included closure and loss of NH3 to form 5 and 6. Reaction conditions
along with solvents, catalysts, and other reagents where gave different results for the reaction where R1 = H and R2 =
available. Reports where USI was used but the azole itself CH3. Using the conditions shown in Scheme 2, the only
was not synthesized or remained unchanged while other product formed was 5 (8−65%), whereas the only product
moieties were altered have been omitted (only annulation formed in refluxing ethanol was 5 (30−94%). Substrates
reactions for each respective azole are included). Fused containing other R1 substituents gave mixtures of 5 and 6, and
heterocycles involving the azoles covered in this review, such in different ratios depending on whether K-10 with USI was
as indazole in the case of pyrazole or anthranil in isoxazole, are used or not.35
excluded due to the extensive scope of their reactions, which Roy and co-workers37 synthesized 1,5-disubstituted pyr-
warrant separate reviews. A review of sonochemical methods of azoles 9 via a regioselective hexafluoroisopropanol-promoted
nonazole fused heterocycles has been recently reported.27 cascade cyclization of β-enaminones 7 and aryl hydrazines 8
Sections of this review are organized by heterocycle type, under USI (Scheme 3). The reaction proceeded through
progressing from those containing two identical heteroatoms hexafluoroisopropanol-facilitated condensation, intramolecular
(e.g., pyrazoles and imidazoles) to those incorporating an cyclization, and subsequent aromatization, furnishing N-
additional oxygen or nitrogen heteroatom. Ultrasonic methods arylpyrazoles in yields as high as 87% with excellent functional
for the synthesis of furazans are not included in this review due group tolerance.
to their limited or nonexistent coverage in the current The method is environmentally friendly and sustainable and
sonochemical literature. While sonochemistry has been includes examples of procedures that have been successfully
extensively applied to other azole derivatives, reports scaled up. The proposed mechanism, illustrated in Figure 3,
specifically detailing ultrasonic approaches for these hetero- involves a series of steps: the conjugate addition of the
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Scheme 2. Synthesis of Pyrazoles 5 and 6 via the Reaction of Substituted β-Enaminones 3 with Hydrazines 4a

a
This reaction gave either 5 or 6, depending on if USI or conventional reflux was used. R1 = H, Me, OMe, NO2. R2 = H, Me.

Scheme 3. Synthesis of 1,5-Disubstituted Pyrazoles 9 Using Scheme 4. Synthesis of K-10-Catalyzed Amine-Bearing

USIa Pyrazoles 11 from β-Enaminone O,N-Acetals 10 with
Hydrazinesa

a
Ar = aryl.

arylhydrazine, followed by the elimination of dimethylamine, a

subsequent ring closure, and loss of water. R1 = H, Me, Ph, Bn, allyl, CH(CH3)Ph.
Using β-enaminone O,N-acetals 10 (made from thioates and
the corresponding amine) and K-10, Braibante and co- This report included various aryl substitutions on 13, namely
workers38 synthesized a series of pyrazole secondary amines halogens, nitro, methoxy, and methyl groups. Machado and co-
11 in yields ranging from 45 to 56% (Scheme 4). workers42 reported a highly regioselective synthesis of ethyl-
Mallouk and co-workers39 compared K-10 alone to K-10 1H-pyrazole-3-carboxylates 17 using enones 15 (synthesized
clay-supported copper(II) (commonly called Claycop, which via reaction of the respective acetal with ethyl oxalyl chloride in
has been recently used elsewhere in heterocyclic synthesis40) the presence of pyridine) and 2,4-dichlorophenyl hydrazine
for the oxidation and aromatization of pyrazolines, of which 12 hydrochloride 16 in yields ranging from 71 to 92% (Scheme
was one (Scheme 5). K-10 alone did not act as an oxidant and 6).
resulted in no reaction, whereas Claycop achieved 100% This report compared USI to conventional heating,
conversion and an excellent 96% yield of 14. This report demonstrating that US not only accelerated the reaction but
describes the synthesis of 1,3,5-triphenylpyrazole 14 (when R1 also preserved regioselectivity and purity. This finding is in line
= R2 = H), and p-benzoyl and dihydropyrazoloindole with other reports comparing USI with conventional
derivatives, of which yields ranged from 91 to 96%. Li and heating.43,44 Chate and co-workers45 formed (E)-1-(2-hydrox-
co-workers41 also synthesized several derivatives of 14, albeit yphenyl)-3-(4-(phenylthio)phenyl)-1H-pyrazole-1-carbothioa-
using a substituted chalcone epoxide 13 and excess phenyl- mides 19 via the ring opening of 2-(4-(phenylthio)phenyl)-
hydrazine to form 14 in an excellent 99% yield. 4H-chromen-4-ones 18 with semicarbazide in ethanol and base
The strained nature of the epoxide in 13 likely contributed under USI in yields ranging from 62 to 72% (Scheme 7).
significantly to efficiency of this high-yield reaction, as it is Naphthyridines were combined with hydrazides in yields as
highly susceptible to nucleophilic attack by phenylhydrazine. high as 98% in a similar manner by Ahmed and co-workers.46

Figure 3. Proposed mechanism of 1,5-diarylpyrazole formation in hexafluoroisopropanol by Roy and co-workers.

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Scheme 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 = Ha

a
Various p-benzoyl and dihydropyrazoloindole derivatives underwent similar oxidation under these conditions. Li and co-workers41 synthesized 14
using chalcone epoxides 13 and excess phenylhydrazine in aqueous acid. R1 = Cl, NO2, MeO. R2 = NO2, Me.

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

a
R1 = propyl, substituted phenyl.

Scheme 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 USIa

a
R1 = H, Cl, Me. R2 = H, Me. R3 = H, Cl, F, Me.

In work by Yavari and co-workers,47 hydrazonoyl chlorides Drechslera sorokiniana, while showing weak antibacterial
were reacted with β-nitrostyrenes in ethanol under USI, activity.
forming 1,3,4-trisubstituted pyrazoles in yields 68−98% with In a method by Huang and co-workers,49 they reported use
excellent regioselectivity. of 3-(dimethylamino)-1-arylprop-2-en-1-one 20 with equimo-
Cojocari and co-workers48 synthesized 1,3-disubstituted 2,2- lar hydroxylamine hydrochloride under USI to form 21 in 84−
dimethylcyclopropanes containing pyrazoles from (+)-3- 93% yield (Scheme 8).
carene. The key intermediate, a dibromovinylcyclopropane, Elzupir and co-workers50 reported a synthesis using
was obtained via Wittig olefination and further reacted with substituted chalcones 22 and excess hydrazine sulfate and
hydroxylamine or hydrazines to form heterocyclic derivatives. sodium acetate, furnishing the respective pyrazoles 23 in 23−
Notably, 3,5-dimethylpyrazoles were synthesized on an Al2O3 97% yield (Scheme 9). Yields ranged widely, the lowest being
surface using USI, significantly reducing reaction time while when R1 = NO2. When the aryl group was dimethylaniline, no
maintaining high yields. In keeping with many azoles, the product was obtained. The highest yielding reactions where
synthesized pyrazoles exhibited strong antifungal activity when R1 = H and there was no amine present, suggesting the
against Fusarium avenaceum, Fusarium oxysporum, and aryl amine greatly hindered the reaction. The method used
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Scheme 8. Synthesis of 5-Arylpyrazoles 21 Using 3- borane56 or heterogeneous Pd/Al nanoparticles and sodium
(Dimethylamino)-1-arylprop-2-en-1-ones 20 with borohydride.57
Hydroxylamine Hydrochloride under USIa 2.2. Sonochemical Syntheses of Imidazoles. The use of
USI to assist syntheses of imidazoles has been reviewed
recently58 (including green approaches59). Therefore, only the
very recent articles are covered here. As noted by early
reports,58,60,61 imidazoles can be synthesized from an α-
diketone such as 31 (benzil), an aldehyde like 32, and an
amine such as 33 (Scheme 13). The present report uses these
reagents by an MCR method. The added improvements of USI
a
R1 = Me, H. Ar = aryl, substituted aryl. and a CoCuFe2O4 nanocatalyst enable the reaction to
complete in 10−20 min. Isolated yields of 34 ranged from
83 to 93% using USI at a power of 70 W.62
both USI and microwave (MW) irradiation. In this case, USI The p-TSA-catalyzed synthesis of tri- and tetrasubstituted
primarily facilitated the solvation of enones 22, while MW imidazoles (such as 37 and 38, respectively, in Scheme 14)
irradiation played a more significant role in driving the demonstrates an effective application of USI in higher solvent
reaction. They used various substituted aromatic derivatives of volumes. This method delivers high yields with moderate
22, including a furanyl derivative (33% yield), to form several heating assisted by US (at 24 kHz). Imidazoles 37 were
derivatives of 23. obtained in 80−96% yield, while 38 were obtained in similar
Interestingly, in the case where R1 = NO2 and R2 = yields of 86−93%. In contrast, the use of a benzenesulfonic
dimethylamino in 22, no reaction took place. This work acid catalyst proved less effective.63
highlights an alternative role USI can play in syntheses; the An additional application of the Debus-Radzisewski syn-
primary role of USI in this case was not to facilitate the thesis was reported for the preparation of the 1,2,4,5-
reaction itself but rather to assist in solvating the reagents, tetrasubstituted imidazole 41 via USI (Scheme 15) by Abbas
enabling them to react through other means. and co-workers.64 As in the reports above, ethanol was
Basha and co-workers51 synthesized a series of pyrazoles 25 determined to be the best solvent for this reaction. Reaction
via oxidation of the corresponding aryl dihydropyrazoles 24 times were 25−35 min in 70−80% yield. The reaction time
(Scheme 10) using chloranil in xylene (see Section 2.3, was significantly shorter than the traditional reflux method, and
Scheme 17, for related synthesis of isoxazoles). Yields ranged it produced higher yields compared to the conventional
from 65 to 71%. heating method. Both this reaction and that outlined in
Various other reports have used similar a methodology of Scheme 14 employ ethanol as the solvent and use ammonium
oxidizing the dihydropyrazole using a mild oxidant like acetate as a nitrogen source, along with acid catalysts such as p-
chloranil.52,53 Ghareb and co-workers reported synthesis of TSA or sulfuric acid, under mild heating conditions.
pyrazole 28 from naphthalen-2-yl 2-bromoacetate 26 and Kumar and co-workers65 recently reviewed green methods
acetoacetone 27 in 85−88% yield (Scheme 11).54 In this case, for pyrazole synthesis in general, in part highlighting USI as a
reagents were stirred at room temperature, then underwent sustainable alternative to conventional conditions. They also
USI, then reflux. It is unclear which steps USI had assisted explored solvent-free reactions, eco-friendly catalysts, and
with, or what role USI played in driving the reaction over energy-efficient techniques, and emphasized their potential to
reflux. improve efficiency and reduce environmental impact.
Pise and co-workers55 reported the synthesis of 1,5- 2.3. Sonochemical Syntheses of Isoxazoles. Sono-
disubstituted arylpyrazoles 30 from α,β-cyanoesters 29 chemical techniques have proven highly effective for the
(prepared from ethyl cyanoacetate and aromatic aldehydes) synthesis of isoxazoles, particularly in cycloaddition reactions,
and equimolar phenylhydrazine in the presence of a Cu(I) oxidative transformations, and condensation processes. As
catalyst, the only report using USI to do so (Scheme 12). such, isoxazoles synthesized via cyclization or cycloaddition
Often times, 1,5-disubstitued pyrazoles can be difficult to have seen significant use of USI over the last 15−20 years. A
synthesize using conventional methods. Usually, 1,3-pyrazoles one-pot, three-step process for the regioselective synthesis of
are formed preferentially because of the reaction mechanism, 3,5-disubstituted isoxazoles 45 was reported by Koufaki and
stability of intermediates, and both electronic and steric factors co-workers66,67 using the copper(I)-catalyzed cycloaddition
favor the formation of the 1,3-pyrazole ring over the 1,5- between nitrile oxides generated in situ (43) from aldehydes 42
pyrazole ring. An efficient dehalogenation of aryl halides, and alkynes 44 under USI (Scheme 16). The combination of a
including pyrazole, has recently been reported using ammonia copper(I) catalyst with USI, particularly using both an US bath

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

a
R1 = H, MeO, NO2, N(Me)2, Br. R2 = H, MeO, N(Me)2.

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Scheme 10. Oxidation of Aryl Dihydropyrazoles 24 to Pyrazoles 25a

a
Ar = substituted aryl.

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

Acetoacetone 27a

a
One example (pictured) used ester 26 (85%), while another used the respective ketone with the carbonyl directly attached to the ring (88%).

Scheme 12. Synthesis of 1,5-Disubstituted Pyrazoles 30 via Scheme 14. USI Synthesis of Tri- and Tetrasubstituted
Reaction of α,β-Cyanoesters 29 and Equimolar Imidazoles, 37 and 38, Respectivelya
Phenylhydrazine in the Presence of a Cu(I) Catalysta

a
R1 = Cl, Br, Me, NO2, OMe.

and probe simultaneously, gave the highest yields of up to 75%.

Notably, the dual-frequency USI method exhibited a
synergistic effect, increasing yields compared to conventional
heating or US alone. a
Huang and co-workers49 reported the synthesis of a series of R1 = Ph, Me. R2 = H, alkyl, aryl.
5-arylisoxazoles 46 using 3-(dimethylamino)-1-arylprop-2-en-
1-one 20 (see Section 2.2, Scheme 8, for related synthesis of
pyrazoles) with equimolar hydroxylamine hydrochloride under times (30−45 min). Yields using USI were higher than stirring
USI without using any catalysts (Scheme 17). This method has at room temperature under the same conditions.
advantages of a simple workup (recrystallization), mild One commonly reported method43,68,69 combines propargyl
reaction conditions, high yields (84−96%), and short reaction alcohol with a substituted benzaldoxime 47 under USI

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

a
R1 = H, alkyl, halyl, NO2, OH. R2 = H, alkyl, halyl, NO2, OH.

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

a
Ar = substituted aryl.

Scheme 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 Turningsa

a
R1 = MeO, NO2, F. R2 = propyl, alkylpropargyloxy.

Scheme 17. Synthesis of 5-Arylisoxazoles 46 Using 3- Work by Shen and co-workers43 compared USI to
(Dimethylamino)-1-arylprop-2-en-1-ones 20 with conventional heating using the compounds pictured in Scheme
Hydroxylamine Hydrochloride under USIa 18. Results were compared based on the time required for the
starting material to be fully consumed, as determined by thin
layer chromatography, and the isolated yields of 48. In each
trial, USI consistently showed both higher yields (conven-
tional: 5−73%, USI: 45−87%) and shorter reactions times
(conventional: 3−6 h, USI: 1.5−4.5 h) when compared to
conventional synthesis (Table 1). The degree to which the
a
substituent on 48 was electron-donating directly correlated
R1 = Me, H. Ar = aryl, substituted aryl. with the yield.
Comparison by Shen and co-workers43 of conventional
(Scheme 18), with N-chlorosuccinimide (NCS), an oxidant, to heating and USI for the synthesis of isoxazoles 48 using
generate the respective imidoyl chloride from 47 in situ. propargyl alcohol and a substituted benzaldoxime 47 (reaction
shown in Scheme 18).
Scheme 18. Work by Shen and Co-workers43 Detailing the
Synthesis of Isoxazoles 48 Using Propargyl Alcohol and Table 1. Comparison of Conventional Heating and USI for
Substituted Benzaldoxime 47a Isoxazole Synthesis: Reaction Time and Yield for Various
Substituents

conventional conditions USI

R1 of compound 48 time (h) yield (%) time (h) yield (%)
H 3 27 1.5 70
Cl 5 45 4 74
MeO 4 58 2.5 75
OH 5 20 3 87
tert-butyl 3.2 67 2 74
a
R1 = Cl, OMe, t-Bu, NO2. NCS = N-chlorosuccinimide, DMF = NO2 6 7 4.5 45
N,N-dimethylformamide, Et3N = triethylamine. average 4.37 37.3 2.92 70.8

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These derivatives demonstrated the use of USI in developing workers43 and in agreement with their findings, USI was
and testing bis-isoxazole antifungals. Interestingly, many compared to conventional isoxazole synthesis and showed both
demonstrated efficacy comparable to itraconazole and superior faster reaction times and higher yields. In their comparison and
to fluconazole, two standard antifungal agents widely used in reaction optimization, they examined 61 when R1 = Ph, R2 = p-
clinical practice. Cl-phenyl, and R3 = ethyl. It was determined 1.1 equiv of CAN
Basha and co-workers51 synthesized a series of 5-(2,4- was needed, as yields significantly dropped with 0.5 equiv.
dichlorothiazol-5-yl)-3-aryl-1H-isoxazoles 50 using chloranil, a Ultrasonic bath and probe were compared, with slightly higher
mild oxidant, and USI followed by basic workup to give the yields found using the probe.
corresponding isoxazoles in yields ranging from 65 to 70% Several methods use oxone for oxidation of aldoximes to
(Scheme 19). This method started with the corresponding aryl nitrile oxides.72,73 One is a three-component one-pot synthesis
dihydroisoxazoles 49. Nagarjuna and co-workers reported a using a KI/oxone system converting aldehydes to oximes for in
similar method, with derivates showing antioxidant activity.52 situ nitrile oxide generation followed by cycloaddition alkynes
was reported by Tachallait and co-workers.72 Another is a five-
Scheme 19. Oxidation of Aryl Dihydroisoxazoles 49 to component one-pot synthesis by Mahmoudi and co-workers73
Isoxazoles 50a uses CaCl2 as a chlorine source with oxone via 1,3-dipolar
cycloaddition reaction in water under USI in yields ranging
from 77 to 96% (Scheme 24). USI using an ultrasonic probe
significantly improved reaction times compared to an ultra-
sonic bath and magnetic stirring.
Ultrasonication methods for synthesizing isoxazoles involve
various approaches, often enhancing yields and reducing
reaction times compared to conventional methods.43,44 The
a most cited methods center around using USI in combination
Ar = substituted aryl.
with nitrile oxides generated in situ from aldehydes, which are
Chate and co-workers70 reported using a unique β- then reacted with alkynes to form isoxazoles via 1,3-dipolar
cyclodextrin as supramolecular catalyst and USI for the cycloaddition.43,44,66,68,69
synthesis of isoxazoles. They used substituted 2-arylchromones El Mahmoudi and co-workers74 developed a green, one-pot,
51 with hydroxylamine hydrochloride and thiourea in the three-step synthesis of 3,5-disubstituted isoxazoline/isoxazole-
presence of β-cyclodextrin as a recyclable catalyst in water linked sulfonamides using MgI2/K2CO3/oxone catalysis in
under USI to obtain the desired isoxazoles 52 in excellent water under USI. These compounds were evaluated against
yields (Scheme 20). Pseudomonas aeruginosa for their effects on bacterial growth
and biofilm formation. While the compounds did not inhibit
Scheme 20. Synthesis of Isoxazoles 52 Using USI and a β- bacterial growth, two derivatives significantly destabilized
Cyclodextrin Recyclable Catalyst in Watera mature biofilms by approximately 50%, demonstrating their
potential as biofilm-disrupting agents.
Mokhi and co-workers75 recently reported a unique
synthesis of isoxazole/isoxazoline-linked 1,2,3-triazoles using
a magnetically separable Fe3O4@AgZr2(PO4)3 nanocomposite
catalyst under USI in water. This one-pot, multistep synthesis
provided excellent yields of the target compounds and
highlighted the method’s eco-friendly nature, which also used
oxone in making isoxazoles.
a Nematpour76 developed a convenient, four-component
R1 = MeO, alkyl, halogen.
synthesis of highly functionalized isoxazole-4-carboximida-
mides using trichloroacetonitrile, alkynes, hydroxyimidoyl
Saleh and co-workers71 reported a synthesis of isoxazoles 56 chloride, and amines in the presence of copper(I) iodide
using carbanions 54 generated from 1-phenyl-2- catalyst under USI. This method also gave good yields (71−
(phenylsulfonyl)ethanones 53 with 1-(4-bromophenyl)-2- 93%) under mild conditions of 4-carboxamidine-3,5,N-
bromo-2-hydroximinoethanone 55, in 90−93% yield in under triphenylisoxazole and aryl derivatives regioselectively.
30 min (Scheme 21). 2.4. Sonochemical Syntheses of Oxazoles. Most USI
The authors outline one plausible mechanism, wherein syntheses of oxazoles in the current literature involve benzene-
nucleophilic substitution of the bromide in 55 by carbanion 54 fused oxazoles (i.e., benzoxazole), often synthesized from o-
of β-ketosulphone 53 gives the nonisolable intermediate which hydroxyaniline derivatives. Broadly, green syntheses of
then cyclizes via dehydrative elimination to give 56. Silva and oxazoles, including fused derivatives, have been reviewed
co-workers29 reported a straightforward aqueous synthesis of recently including other modalities.77 Here, we focus on
isoxazole 57 using sonocatalysis of acetylacetone 27 and nonfused oxazole syntheses that have been facilitated by USI.
hydroxylamine hydrochloride (Scheme 22). One of the first reports was that by Burger and co-workers,78
Alaoui and co-workers44 reported a one-pot synthesis of a who used a fluorinated benzamide 65 and obtained oxazole 66
series of novel 3,5-disubstitued isoxazoles 61 using USI of in 89% yield (Scheme 25).
nitrile oxides 59 generated from aldehydes 58, and sulfone In work by Beccalli and co-workers,79 Pd(II) was used to
alkynes 60. These were mediated by the oxidant cerium(IV) induce the cyclization of a propargylamide 67 when traditional
ammonium nitrate (CAN) and gave isoxazoles 61 in 60−95% Pd(II)-catalyzed conditions were ineffective. The reaction did
yields (Scheme 23). In a similar manner to Shen and co- not proceed under standard conditions but was successfully
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Scheme 21. Synthesis of Isoxazoles 56 Using USI with Carbanion 54 and 1-(4-Bromophenyl)-2-bromo-2-
hydroximinoethanone 55a

a
R1 = H, Me, NO2.

Scheme 22. Synthesis of 3,5-Dimethylisoxazole 57 from deep eutectic solvent (i.e., a mixture of two or more
Acetylacetone 27 Using USI compounds that form a liquid with a lower melting point
than that of the individual components) made from choline
chloride and urea (Scheme 27). In comparison with conven-
tional thermal heating, USI improved yields and reduced
reaction times. Interestingly, the authors did energy con-
sumption calculations showing the USI method saved 85%
more energy than conventional heating, further highlighting
the efficiency of USI.80,81 This also exemplifies the reaction of
an otherwise unreactive amide energized to react under USI.
Scheme 23. One-Pot Synthesis of 3,5-Disubstituted Kumar and co-workers82 used chloride-containing ketone 72
Isoxazoles 61 Using Cerium(IV) Ammonium Nitrate under with urea (73) to form oxazole 74, after only 6 min with USI
USI. R1 = Alkyl, Substituted Aryla in 60% yield (Scheme 28). Compounds like 74 (upon further
non-USI modification) were tested for their anti-inflammatory,
analgesic, and free radical scavenging action and compared
with reference drugs in rats. One compound was more active
than the reference drug at a given concentration.
Using USI, Kumar and co-workers,83 made bis(azolyl)-
pyridine-2,6-dicarboxamide derivatives 77 from pyridinedicar-
boxamide 75 and 4-nitrophenacyl bromide 76 (Scheme 29).
Compared with a standard, most synthesized compounds
showed strong antibacterial, antioxidant, and antifungal
activities. The same group later published biological assay
and molecular docking studies of similar compounds, finding
that some showed stronger antimicrobial activity against
Klebsiella pneumoniae than the standard drug.84
2.5. Sonochemical Syntheses of 1,2,3-Triazoles. The
synthesis of 1,2,3-triazoles is most commonly achieved through
the 1,3-dipolar [3 + 2] azide−alkyne cycloaddition, a reaction
a
R2 = alkyl, substituted aryl. R3 = Aryl. CAN = cerium(IV) extensively explored in both conventional and sonochemical
ammonium nitrate, ACN = acetonitrile. methodologies.13,85−87 Namely, they have been made via
CuAAC first introduced by Sharpless and Meldal.85,88 The
copper(I) catalyst not only speeds up the reaction but also
promoted by USI, leading to the formation of the 5- results in the regiospecific synthesis of 1,4-disubstituted
oxazolecarbaldehyde product 68 in 62% yield. This represents isomers. USI further accelerates this reaction. Organic azides
a specific instance where USI enabled product formation in a can be readily prepared by reaction of an organic halide with
case where conventional heating was unsuccessful (Scheme NaN3.13 Cycloaddition between an alkyne and azide can
26). proceed thermally or with the aid of a catalyst. In the absence
Singh and co-workers80 obtained oxazoles 71 from phenacyl of a catalyst, the reaction typically requires elevated temper-
bromides 69 and amides 70 using a combination of USI and a atures and yields a mixture of both 1,4- and 1,5-disubstituted
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Scheme 24. Five-Component One-Pot Synthesis of Isoxazoles 64 Using CaCl2, Aryl Aldehydes 62, and Sulfone 63a

a
R1 = alkyl, aryl.

Scheme 25. One of the First USI Oxazole Syntheses, which examples rather than providing a comprehensive catalog of
Proceeded via the Intramolecular Annulation of 65 to Form such reactions.
Oxazole 66a One of the first syntheses of 1,2,3-triazoles reported using
USI came from Deng and co-workers91 who used USI to
facilitate carbohydrate synthesis via 1,3-dipolar cycloaddition
of azide 78 with alkyne 79 (Scheme 30).
These conditions afforded 1,2,3-triazoles 80 in an impressive
98−99% yield. In the same work, similar syntheses of other
triazole carbohydrates were obtained in yields over 89%.
Reactions such as hydroxyl group acylation, protection/
deprotection, migration, thioglycoside synthesis, and azidogly-
a
R1 = aryl, substituted aryl. coside synthesis were also examined under USI, demonstrating
ultrasonication as an excellent method for accelerating
Scheme 26. Synthesis of 68 via Pd(II) and USI of reactions commonly used in complex carbohydrate synthesis.91
Propargylamine 67a Of all these carbohydrate modifications, glycosylation proved
to be most effective and allowed for the development of a
general protocol.
Similarly using carbohydrates,92 Dondoni and co-workers93
used 1,3-dipolar cycloaddition to position up to four 1,4-
disubstituted 1,2,3-triazole rings bearing carbon-linked glycosyl
fragments on various scaffolds through multiple cycloadditions
in excellent yields. Using 1,3-dipolar cycloaddition under USI
is a common method used to modify carbohydrates,94−96
especially as a linking method97 or to aid in the synthesis of
glycoclusters.98−101
A more generalized noncarbohydrate synthesis was reported
by Sreedhar and co-workers,102 who obtained 1,2,3-triazoles
83 in yields ranging from 52 to 95% using various alkyl and
a allyl halides 81 (which formed the respective azides in situ),
The same reaction under conventional heating gave no product.
terminal alkynes 82, and sodium azide in water at room
temperature (Scheme 31).
products.89 Ruthenium catalysts have been developed to favor USI decreased reaction times in keeping with other reports.
the formation of 1,5-disubstituted products.89 Much like Many other methods have used USI in a similar way, including
conventional methods, these 1,3-dipolar cycloadditions are with propargylamine,103 using DMF,104−106 THF,107 or t-
also extensively employed in sonochemical methods. Though BuOH108 as the solvent.
not USI-focused, updated syntheses of triazoles have been A method using a CuO(II) nanoparticle-catalyzed cyclo-
recently reviewed.90 This section focuses on representative addition has been reported.107 Schätz and co-workers109

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

a
R1 = H, Br, NO2. R2 = NHPh, CH2CN, PhNO2.

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

Scheme 29. Synthesis of Bis-oxazoles 77 via Reaction of 75 Scheme 31. USI Synthesis of 1,2,3-Triazoles 83 Using
with Phenacyl Bromide 76 Copper(I)-Catalyzed 1,3-Dipolar [3 + 2] Cycloadditiona

a
R1 = alkyl, aryl, allyl. R2 = alkyl, aryl. X = Br, Cl, I.

triazoles 86 in yields 84−92% (Scheme 32). The aminonitrile

ligand on the surface of the magnetic core coordinated to the
copper to obtain the final catalyst. This catalyst offers
simplified recovery via magnetic separation.
El-bendary and co-workers114 developed a USI-assisted,
high-throughput parallel synthesis of 1,4-disubstituted 1,2,3-
triazole libraries using a mixed-valence Cu-(I/II) supra-
molecular coordination polymer catalyst. This reduced
reaction times and employed mild conditions.
Jain and co-workers115 developed a USI synthesis of
reported using TEMPO on graphene-coated nanobeads with a fluorescent 1,4-disubstituted triazoles using L-phenylalanine
magnetic cobalt core under USI, giving the desired 1,2,3- as a biocompatible ligand in aqueous media. Unlike previous
triazoles in over 90% yield. Dar and co-workers110 synthesized methods, this approach uniquely utilizes an amino acid ligand
1,4-disubstituted 1,2,3-triazoles through a one-pot reaction (L-phenylalanine), providing improved biocompatibility, water
catalyzed by copper(II)-doped clay under USI, which did not solubility, and eliminating the need for toxic reagents. The
require additional reducing agents and had the benefit of resulting triazoles exhibited fluorescence, demonstrating their
catalyst recyclability. Also Cu-catalyzed, Khorasani and co- potential for applications in bioimaging.
workers111 developed an efficient USI-assisted method for In work by Sherashiya and co-workers,116 they used USI to
synthesizing novel poly(1,2,3-triazolyl)-substituted perhalopyr- aid in the development of 1,2,3-triazoles with antibacterial
idines through click chemistry. They highlighted that activity. They synthesized thiophene-linked pyrazole-1,2,3-
incorporating poly(1,2,3-triazole) and perhalopyridine units triazole hybrids with L-ascorbic acid in ethanol, which showed
provided versatile building blocks with potential in drug strong antimicrobial activity comparable to the clinically used
development, chemical sensing, and the creation of functional antibiotic ciprofloxacin, particularly chloro- and naphthyl-
materials. Mohan and co-workers112 also used Cu, but in the substituted derivatives. Methoxy- and methyl-substituted
setting of cerium-loaded CuO nanoparticles under USI as a compounds showed promising antifungal activity similar to
cost-effective catalyst. Their synthesized 1,2,3-triazoles showed nystatin. Johnpasha and co-workers117 synthesized novel 1,2,3-
notable antibacterial activity against both Gram-positive and triazole intermediates through Cu-catalysis and a PEG-400
Gram-negative bacterial strains. Similarly using a nanoparticle mediated, USI-assisted one-pot reaction. These nonfused
catalyst, Aghajani and co-workers113 reported a method using a triazoles served as key intermediates for preparing fused
recyclable magnetic nanoparticle catalyst, aminonitrile-func- heterocycles, which showed potent anticancer activity against
tionalized Fe3O4, for synthesizing 1,4-disubstituted 1,2,3- two breast cancer cell lines (MCF-7 and MDA-MB-231).

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

a
R1 = hexyl, octyl, (CH2)NHBoc.

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

a
R1 = substituted aryl. R2 = alkyl-substituted phenylacetylenes. X = Cl, Br, I.

Scheme 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

Yadav and co-workers118 synthesized novel 10,11-dihydro-5H- instead of an alkyne to form 1,4-disubstituted 1,2,3-triazoles 92
dibenzo[b,f ]azepine-linked 1,2,3-triazoles via Cu-catalyzed (Scheme 34).
click chemistry using USI, the compounds showed strong
antioxidant properties with one showing notable xanthine Scheme 34. Synthesis of 1,4-Disubstituted-1,2,3-Triazoles
oxidase inhibition, suggesting potential applications in 92 under USI Using Enolizable Aldehyde 91, Aryl Azide 90,
managing oxidative stress-related disorders. and Task-Specific [DBU-Bu]OH under USIa
Mokariya and co-workers119 developed a synthesis of novel
1,2,3-triazole derivatives using a unique, simultaneous micro-
wave and USI method. This combined technique significantly
enhanced yields and reduced reaction times, and some of their
synthesized derivatives showed notable antibacterial activity
against Escherichia coli, Salmonella Typhi, P. aeruginosa,
a
Clostridium tetani, and S. aureus. R1 = aryl, alkyl. Ar = aryl, substituted aryl. DBU = 1,8-
Many reports have demonstrated USI as a helpful modality diazabicyclo(5.4.0)undec-7-ene.
in synthesizing biologically active 1,2,3-triazoles (a review
covering additional biological activities of 1,2,3-triazoles has This method made use of a task-specific ionic liquid made
been recently published120). Generally, copper-catalyzed from the base 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU),
cycloaddition of an azide and alkyne remains the most widely [DBU-Bu]OH, and USI compared with the hydrated ionic
reported method for the conventional synthesis of 1,2,3- liquid tetrabutylammonium hydroxide (Bu4NOH) under
triazoles and is also the most frequently applied technique conventional heating. USI likely enhanced reactivity of the
under USI.102,121−124 enolate intermediate, which forms through base catalysis by
Several sonochemical methods have been reported that do [DBU-Bu]OH. USI provided slightly higher yields compared
not utilize a copper catalyst. One such paper by Kiranmye and to conventional heating and comparable reaction times. In this
co-workers125 describes the synthesis of 4-acyl-1,2,3-triazoles case, work up was similar between the two methods; the
desired product was precipitated, filtered, and recrystallized.
and 1,5-disubstituted-1,2,3-triazoles via eliminative [3 + 2]
This approach addresses limitations in traditional method-
cycloaddition of azides with β-enaminones or nitroolefins
ologies, such as the reliance on toxic Cu(I) which poses
(Scheme 33). Interestingly, they reported USI synthesis of 1,5- challenges for biological applications due to cytotoxicity.
disubstituted 1,2,3-triazoles (88 and 89) from azide 87 without Recent studies have also focused on organocatalytic
the use of a catalyst in yields ranging from 72 to 92%. approaches that employ carbonyl compounds to promote the
Conventionally, and in keeping with other azoles, synthesis of synthesis of highly functionalized 1,2,3-triazoles. In this
1,5-disubstituted derivatives can be challenging due to instance, the generated enamines may act as the dipolarophiles
electronic and steric effects. in 1,3-dipolar cycloadditions with organic azides (enamine-
This method provides excellent regioselectivity and azide [3 + 2] cycloaddition reactions). Singh and co-
incorporates several eco-friendly features, including the use workers128 reported use of DBU and USI in the synthesis of
of USI, water as the solvent, and a catalyst-free process. 1,4,5-trisubstituted-1,2,3-triazoles such as 94 (Scheme 35).
Methods for metal-free126 1,3-dipolar cycloaddition between Various substituted derivatives were synthesized in yields
aryl azides 90 and enolizable aldehydes such as 91 have been ranging from 79 to 95%.
reported. Singh and co-workers127 described one such reaction, They also made a comparison of USI to conventional
a metal-free 1,3-dipolar cycloaddition that utilized aldehyde 91 heating with several derivatives, and in this case, reaction times
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Scheme 35. Synthesis of a 1,4,5-Trisubstituted-1,2,3- Scheme 37. Synthesis of 5-(Substituted Phenyl)-4H-1,2,4

Triazoles 94 from Aryl Azides 93 and Acetylacetone 27 Triazol-3-ols 99 from a Trisubstituted Benzaldehydes 98
Using an Efficient, Recyclable DBU-H2O Catalytic Systema and Semicarbazide Hydrochloride under USIa

a
R1 = substituted phenyl, alkyl, arylalkyl.

and yields were comparable. The average reaction time for

conventional heating was 26.5 min compared to 29 min using a
R1 = H, Cl, Me, OMe, OH, N(Me)2, NO2. R2 = H, NO2. R3 = H,
USI, and average yields were both 86%. Xavier and co- NO2, Cl.
workers129 reported an USI-assisted cycloaddition of many
1,4,5-trisubstituted-1,2,3-triazoles (Scheme 36) in yields of improved yields from 45−65% to 80−95%. Titlin and co-
72−95% with short reaction times (all under 25 min). They workers134 reported a similar synthesis using an aldehyde-
used β-oxo amides 95 and aryl azides 96, but diethylamine substituted diphenylpyrazole 100 using semicarbazide in
instead of DBU. methanol giving 1,2,4-trizole 101 in 92% yield (Scheme 38).
Many 1,2,3-triazoles are 1,4,5-trisubstituted, achievable
through the reaction of an internal alkyne with an organic Scheme 38. Synthesis of 1,2,4-Triazole 101 Using an
azide with or without a catalyst. If the alkyne is symmetric, only Aldehyde-Substituted Diphenylpyrazole 100 and
one regioisomer will be obtained,130,131 such as when dimethyl Semicarbazide under USI
acetylenedicarboxylate is used as the alkyne.130 However, if the
alkyne is asymmetric, a mixture of regioisomers is possible (as
seen in the Huisgen cycloaddition, which forms 1,4- and 1,5-
disubstituted isomers). Venigalla and co-workers132 reported a
catalyst-free, USI-assisted one-pot synthesis of triazole
derivatives from semicarbazide and various aromatic aldehydes
in ethanol. Their approach gave high yields (94−98%) under
mild conditions and short reaction times (<6 min).
2.6. Sonochemical Syntheses of 1,2,4-Triazoles. Of the
sonochemical syntheses discussed thus far, 1,2,4-triazoles have
received the least attention in the literature. This may be due
to the relative complexity of their synthesis compared to other More recently, the same group reported the synthesis of
azoles, and the availability of alternative heterocycles with other derivatives of 101 using the same method in similar
similar functionalities that are easier to synthesize or have been yields. In both studies, molecular modeling was performed on
historically more studied (e.g., 1,2,3-triazoles, imidazoles, or triazole 101.134,135 A USI synthesis of bis-1,2,4-triazoles 105,
pyrazoles). starting with a disemicarbazide-substituted pyridine 102, was
The most commonly reported USI-assisted method for reported by Gunthanakkala and co-workers (Scheme 39) in
synthesizing 1,2,4-triazoles is the reaction of semicarbazides yields as high as 95%.136 This scheme proceeded through the
with aldehydes. One such report by Kumar and co-workers133 respective di-1,3,4-oxadiazoles 104, which upon treatment with
details a one-pot synthesis of 5-(substituted phenyl)-4H-1,2,4 hydrazine hydrate and base, afforded 1,2,4-triazoles 105.
triazol-3-ols 99 from a substituted benzaldehyde 98 and A report by Wang and co-workers137 describes a convenient
semicarbazide hydrochloride under USI (Scheme 37). Yields one-pot synthesis of 108 using α-nitrophenyl hydrazones 106,
ranged from 85 to 90%, and in keeping with prior reports, USI methylene amines 107, and sodium nitrite with benzyl
reduced reaction times and improved yields. Other research triethylammonium chloride (BTEAC) as a phase transfer
detailed the synthesis of 1,2,4-triazol-3-ols such as 99, which catalyst in yields ranging from 39 to 86% (Scheme 40).
exist as tautomers with their 1,2,4-triazolone forms. In addition to alcohol-ketone tautomers, reports have also
This work examined the use of an US probe, US bath, or US detailed the analogous thiol-thione tautomers. A procedure by
probe with bath. In every run, addition of the US probe Al-blewi and co-workers 138 involves the acylation of

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

a
R1 = H, Ph. R2 = 4-Me, 2-Me, 4-OMe, 2-OMe, 4-Cl, 2-Cl, 4-F, 4-NO2. R3 = H, 4-OMe, 2-Me, 4-Me, 2-F, 4-F, 2-NO2, 4-Cl, O-SePh.

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Scheme 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 USIa

a
Ar = Ph, 4-Me-Ph, 4-Cl-Ph.

Scheme 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 USIa

a
R1 = H, NO2, OMe. R2 = phenyl, propyl, ethyl.

thiosemicarbazide with 2,3-dichlorobenzoyl chloride under ably, after formation of the hydrazone with reaction of
USI to form 109, followed by ring closure via dehydrative hydrazine acetate, the terminal amine can engage in
cyclization to afford the target 1,2,4-triazole 110 in an excellent nucleophilic attack of the highly electrophilic central
97% yield (Scheme 41). isothiocyanate carbon. The nitrogen of the isothiocyanate
can then react with the carbonyl and, after addition of NaOH
Scheme 41. Synthesis of Thiol-Substituted 1,2,4-Triazole and tautomerization, the 1,2,4-tiraozle is formed.
110 under USI of 2,3-Dichlorobenzoic Acid 2- Two reports have used USI to assist in the synthesis of 1,2,4-
(Aminothioxomethyl)hydrazide 109 triazoles that had tyrosinase inhibitory activity. Mushtaq and
co-workers141 synthesized novel naphthofuran-linked 1,2,4-
triazoles using a cetyltrimethylammonium bromide-catalyzed
USI-assisted method. These compounds showed strong
tyrosinase inhibitory activity. Saeed and co-workers142
synthesized novel naphthofuran-1,2,4-triazoles using a USI-
assisted, also a BTEAC-catalyzed method such as that from
Wang and co-workers,137 achieving high yields (70−80%).
Two compounds tested exhibited exceptional tyrosinase
Triazole 110 has three tautomers due to mobility of the inhibition, with IC50 values of 0.64 and 3.91 μM, out-
hydrogen between the three triazole nitrogen atoms, and the performing standard reference inhibitors. Molecular docking
1,2,4-triazole ring exists in thiol-thione equilibrium due to studies confirmed strong interactions with the tyrosinase active
mobility of the NH proton between the N-2 and N-4 atoms.138 site.
Also forming a thiol-thione tautomer, Kalyani and co- In sum, the acylation of thiosemicarbazides with USI (97%)
workers139 reported a synthesis of 1,2,4-triazole 112 using and the semicarbazide-aldehyde synthesis (85−92%) are the
trimethylsilyl isothiocyanate and heteroaromatic acid hydra- highest-yielding approaches.
zides under USI (Scheme 42). 2.7. Sonochemical Syntheses of 1,3,4-Oxadiazoles. A
This report aligns with other reports using TMSNCS for the recent review covering the various broader synthetic
synthesis of triazoles, thiadiazoles, and oxadiazoles.140 Presum- approaches to 1,3,4- and 1,2,4-oxadiazoles and their derivatives
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Scheme 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 Isothiocyanatea

a
R1 = H, Me, Br, Cl, NO2.

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

has been reported.143 The 1,3,4-oxadiazoles have been Scheme 44. USI Synthesis of 1,3,4-
prepared by intramolecular ring closures of acylhydrazides Oxadiazolobenzimidazoles 118 from Hydrazide 116
forming a C−O bond. At least a few avenues using this
approach with sonochemistry have been reported. Each
method depends on the formation of an electrophilic carbon
attached to an N−N linkage and cyclization by reaction with a
nucleophilic oxygen. Among methods utilizing diacyl hydra-
zides, the first step is the reaction of an acyl hydrazide with an
activated carboxylic acid derivative, such as an acid halide,
thiocyanate or cyanogen bromide. Recent examples of each are
illustrated. Synthesis of oxadiazoles assisted by US was
reviewed in 2021.144
2,6-Bis(2-(4-methoxyphenylsulfonylmethyl)-1,3,4-oxadiazol- Scheme 45. USI Synthesis of 2-Amino-1,3,4-Oxadiazoles
5-yl)pyridine 115, an excellent antioxidant, was prepared as 121 from Hydrazide 119 and Bromoacetonitrile 120
shown in Scheme 43 by USI at 35 kHz starting from 113 and
114. The corresponding bis-thiadiazole and bis-1-amino-1,2,4-
triazole were also prepared and assisted by USI.145 Similar
ring-closures were reported with POCl3.146
Several 1,3,4-oxadiazolo-tethered 1H-substituted benzimida-
zoles 118 were prepared in a similar fashion using an ultrasonic
bath from hydrazide 116 and carboxylic acid 117 (Scheme
44).147 degradation of type I collagen. Cathepsin K is often
The synthesis of 2-amino-1,3,4-oxadiazoles 121 was overexpressed in human breast cancers and may contribute
accomplished by reacting alkyl and aryl hydrazides such as to tumor invasiveness.149,150
119 with bromoacetonitrile 120 in an ultrasonication bath in Another method involves a one-pot procedure that
yields ranging from 81 to 93% (Scheme 45).148 combines (N-isocyanoamino)triphenylphosphorane 126, an
This USI method for synthesizing 1,3,4-oxadiazoles 121 aryl carboxylic acid 125, and an α-diketone such as 124 to
outperformed both thermal and microwave heating ap- efficiently produce 2,5-disubstituted 1,3,4-oxadiazoles 127
proaches. In similar reports, several of these “dipeptide-like” (Scheme 47).151,152 Yields were 91−95% using USI and 85−
compounds (123) were obtained from 120 and hydrazides 92% using conventional stirring.152
such as 122 in yields ranging from 47 to 76% (Scheme 46), In work by Reddy and co-workers,153 reaction of organic
and many exhibited strong inhibition of cathepsin K, a cysteine hydrazides 128 with phenyl isothiocyanate 129 in ethanol in
protease highly expressed in osteoclasts and implicated in the the presence of a graphene oxide catalyst and DBU afforded
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Scheme 46. USI Preparation of 1,3,4-Oxadiazole-Containing Cathepsin K Inhibitors 123 by Gontijo and Co-workers150

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

a
Ar = substituted aryl.

2,5-disubstituted oxadiazoles 130 when subject to USI under USI aryl hydrazides 133 for 10 h in DMF containing
(Scheme 48). carbon disulfide. Yields ranged from 70 to 93% (Scheme
50).155
Scheme 48. Synthesis of 2-Amino-1,3,4-Oxadiazoles 130
under USI Using a Graphene Oxide Catalyst and DBUa Scheme 50. Synthesis of 5-Aryl-1,3,4-oxadiazole-2-thiols
134 from Aryl Hydrazides 133a

a
R1 = phenyl, substituted phenyl, heteroaryl, and polycyclic aryl
a groups.
R1 = Ph, 4-BrPh, 4-ClPh, 4-FPh, 4-NO2Ph, 4-MePh, 4-OMePh,
pyridyl, Bn, 3,4-Cl2Ph, Ph(CF3)3, 4-SMePh, allyl, cyclohexyl.
Compounds 135 were shown to undergo alkylation at sulfur
A high yield method for the synthesis of 2-pyrazolo- and 2- to give potential pleuromutilin MRSA inhibitors.139,156 The
isoxazolo-1,3,4-oxadiazoles 132 (in yields ranging from 74 to significance of these MRSA inhibitors lies in their potential to
83%) is the oxidative ring closure of substituted acyl combat MRSA, a bacterial strain that poses a major global
hydrazones 131 (Scheme 49). Several of the products formed health threat due to its resistance to multiple antibiotics.
showed appreciable antibacterial activity.154 Recently, a method for preparing 2-amino-1,3,4-oxadiazoles
In a study directed toward the synthesis of possible with USI employed reaction of hydrazine carboxamide-
antimicrobial inhibitors and antioxidant agents, 5-aryl-1,3,4- substituted benzaldehyde diethyl acetals followed by intra-
oxadiazole-2-thiol derivatives 134 were prepared by reacting molecular cyclization.157 Cyclization of diacylhydrazine de-
rivatives using TiO2 nanoparticles in CH2Cl2 at room
temperature has also afforded 2,5-disubstituted 1,3,4-oxadia-
Scheme 49. Synthesis of 2-Isoxazolo- and 2-
zoles in excellent yield.158
Pyrazolooxadiazoles 132 from Substituted Acyl Hydrazones
2.8. Sonochemical Syntheses of 1,2,4-Oxadiazoles.
131a
Cycloaddition reactions using USI improved the conversion of
trichloroacetoamidoxime 136 and an acid halide 135 to 3,5-
disubstituted 1,2,4-oxadiazoles 137 in yields ranging from 84
to 98% in 15 min (Scheme 51),159 compared to the
conventional conditions of a 20-h reflux in toluene, which
resulted in lower yields (60−90%).160
Several 5-acetonyl-1,2,4-oxadiazoles were prepared by
reaction of amidoximes with isobutyl acetoacetate under
ultrasonic irradiation without solvent in 80% yield.161
2.9. Sonochemical Syntheses of Tetrazoles. The
a
Ar = 2-furanyl, 2-bromotriophene, 4-pyridyl. CAN = cerium(IV) synthesis of tetrazoles has garnered minimal attention for the
ammonium nitrate. use of US in enhancing reaction rates and improving product
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Scheme 51. Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles where USI afforded a product while other methods, such as
137 from Trichloroacetoamidoxime 136 and Acid Halides conventional heating did not, are rare.
135a Similarly, the use of four components led to a MCR of 1,5-
disubstituted tetrazoles 143, also an Ugi-azide synthesis. The
method involves no solvent or catalyst and involves use of aryl
aldehyde 140, aryl amine 141, an isonitrile 142, and tosyl azide
(Scheme 53). This MCR works at room temperature and is
complete within 15 min. Yields ranged from 55 to 97%. The
proposed mechanism involves hydrolysis of tosyl azide by a
water molecule formed during imine formation between the
a
starting aldehyde and aniline to form HN3, which protonates
R1 = alkyl, aryl. the imine leaving azide ion, followed by the formation of the
disubstituted tetrazoles 143.165
yields. A recent review summarizing green methods cited just The sonochemical synthesis of 5-substituted 1H-tetrazoles
two contributions using USI among many others.162 A recent 146 catalyzed by ZrP2O7 nanoparticles is illustrated in Scheme
review on green synthetic approaches via multicomponent 54.166 The sonochemical device used was a probe at 20 kHz,
reactions was reported, though USI made up a minimal
portion.163 Notably, US has enabled the formation of products Scheme 54. USI Synthesis of 5-Substituted 1H-Tetrazoles
unattainable through conventional methods. The reaction of 146 Using ZrP2O7 Nanoparticles166
dehydroabietylamine (i.e., leelamine) with butyl isocyanide
failed to yield the expected bis-tetrazole products (139,
Scheme 52) via a pseudo seven-component Ugi reaction
under conventional heating. However, the USI conversion
depicted in Scheme 52 proved successful.

Scheme 52. Preparation of Tetrazolodehydroabietylamine

Derivatives 139 from a Primary Amine (Leelamine, 138)a

which offered faster reactions at room temperature compared

to elevated temperatures. This used aryl aldehydes 144,
malononitrile 145, and sodium azide. Further reaction of 146
with alkyl bromide furnished 1,5-disubstitued tetrazoles, also
facilitated by USI. Both processes resulted in yields 88−94%.
Several reports of green conditions for the preparation of
tetrazoles have appeared. Indeed, it has been clear for two
decades that USI chemistry can bring about superior results
when choosing conditions for the synthesis of tetrazoles.167,168
One example is the USI reaction of ketone 147, alkyl isonitrile
148, and trimethylsilyl azide to produce tetrazoles 149 in pure
form and in high yields without the use of catalysts (Scheme
a
R1 = n-Bu, t-Bu, cyclohexyl, benzyl. 55). The authors preferred the practical features of the US bath
for these experiments.169
A report of a MCR one-pot synthesis of bis-tetrazoles
Four alkyl isocyanides gave satisfactory results. Success is afforded products 153, where individual steps were performed
attributed to the acceleration of the US reaction of the separately using the same reaction vessel starting with
monosubstituted tetrazole due to enhanced reactivity of the dialdehyde 150 and proceeding to 151 through to 153
secondary amine over that of the primary amine starting (Scheme 56). USI permitted reaction completion in twice the
material. Interestingly, the benzyl isocyanide gave the yield and in one-third the time than if no USI was used.
monotetrazole derivative with conventional heating whereas Examples of other aryl groups such as p-diphenyl and 3,5-
the other alkyl isocyanides did not.164 Examples of instances dipyrazyl were also reported.170

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

a
R1 = Cl, OMe, 3,4-OMe, H, NO2, Pyridyl. R2 = H, Br, Cl. R3 = t-Bu, cyclohexyl, 4-MeOPh, 4-ClPh, 2,6-MePh.

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Scheme 55. An Efficient Three-Component USI Passerini Scheme 57. USI Synthesis of 5-Aryltetrazoles 156 and 158
Tetrazole Synthesis of 149169a in an Ionic Liquida

a
R1 = H, alkyl, aryl. R2 = alkyl, aryl. R3 = alkyl, aryl.

A study looking at the efficacy of an ionic liquid (TAIm[I])

for the synthesis of 5-aryltetrazoles 156 determined that MW
heating and USI were each more effective than conventional
heating alone (Scheme 57). 1-Aryltetrazoles 158 have also
been prepared similarly by reacting arylamines with triethy-
lorthoformate.171
a
Several reports of applications of USI syntheses of tetrazoles Ar = Substituted aryl.
for biological testing have been reported recently. For example,
tetrazole agents 160 tested for antihelminthic (i.e., antiparasitic synthetic approaches to the aforementioned azoles, the
worm) activity have been synthesized from 1,2,3-triazole 159 following broad conclusions can be drawn regarding
in the ionic liquid [DBU][OAc] when assisted by USI at 40 sonochemical methods in the present literature:
kHz in 80−90% yield.172 The USI results were superior to a) Pyrazoles: Reaction of a hydrazine with a β-dicarbonyl
conventional conditions by reducing the reaction time by compound30−34,42,175,176 (some forming pyrazolium
about one-third (Scheme 58). Tetrazoles 162 were also salts175,176), oxidation of the dihydropyrazole,39,51−53
synthesized in this report from nitrile 161 in 85−92% yield. synthesis of trisubstituted pyrazoles using β-enami-
Lastly, a green method for synthesis of 1-aryltetrazoles 164 nones,35,49 oxidation,39 or epoxide ring-opening,41 and
is the USI of arylamines 163 with triethyl orthoformate in a Cu(I)-catalyzed method for 1,5-disubstituted pyrazo-
DMF at room temperature in the presence of ZnS nano- les.55
particles and NaN3 (Scheme 59). Yields ranging from 70 to b) Imidazoles: Multicomponent reactions using α-dike-
92% in 15−30 min were obtained for a variety of substituted tones, aldehydes, and amines.62 p-TSA-catalyzed meth-
aryl amines and diamines, a significant improvement over ods improved yields up to 95%,63 while the Debus-
reactions that did not use USI. The US probe used for these Radziszewski reaction under US showed higher
experiments operated at 20 kHz.173 efficiency.58
c) Isoxazoles: Using 1,3-dipolar cycloadditions from in situ
3. SUMMARY nitrile oxides and alkynes,43,44,66,68,69 propenones with
Several comparative studies42−44,49,174 have highlighted the hydroxylamine hydrochloride,49 oxidation using chlor-
advantages of USI compared to conventional methods for the anil,51,52 a β-cyclodextrin catalyst with thiopyrimidines,70
synthesis of azoles, including shorter reaction times, higher a sulfone carbanion approach,71 acetylacetone with
yields, milder conditions, minimized generation of byproducts, hydroxylamine hydrochloride,29 or methods using
and the use of eco-friendly reagents. In reviewing sonochemical oxone as an oxidant.72,73

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

a
R1 = Me, Br, CO2H.

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

a
R1 = H, Me, OH. R2 = H, OMe, Cl, NO2. R3 = H, Me, OH, NO2, Cl.

Scheme 59. USI Synthesis of 1-Aryltetrazoles 164 from ZrP2O7 nanoparticles also improves yields and efficien-
Arylamines 163 in the Presence of ZnS Nanoparticles173 a cy.166

4. FUTURE PERSPECTIVES
The next 5−10 years hold promise for sonochemical azole
synthesis. Reactor design is evolving rapidly. Flow-through and
multitransducer US reactors are emerging that offer more
uniform cavitation and scalability.177 Compared to classic
a
batch setups, continuous flow reactors already demonstrate
Ar = substituted aryl amines. greater efficiency, flexibility, and lower energy use.177 These,
coupled with automation (e.g., high-throughput sonochemical
d) Oxazoles: Methods include intramolecular annulation of workflows178), are expected to help bridge the lab-to-industry
a fluorinated benzamide,78 Pd(II)-catalyzed cyclization gap, making scale-up of sonochemical processes more feasible.
of a propargylamide,79 use of phenacyl bromide with80 Sustainability considerations are also at the forefront. Recent
or without83 a deep eutectic solvent, or using urea.82 reports suggest sonochemical reactors can be more energy
e) 1,2,3-triazoles: Methods include 1,3-dipolar [3 + 2] efficient than conventional stirred reactors179 when optimally
cycloaddition of an azide and alkyne using a copper designed. Techniques like pulsed USI180 further minimize
catalyst102,121−124,131 with several reports involving energy consumption compared to continuous USI.181 Future
carbohydrates,91−93,96,100 eliminative cycloaddition of reactor systems may integrate solvent recycling and energy
azides with β-enaminones or nitroolefins,125 or using a recovery, minimizing waste and improving efficiency in line
task-specific ionic liquid.127 with green chemistry principles.
f) 1,2,4-triazoles: Reaction of a substituted benzaldehyde Several untapped applications await exploration. In medic-
and semicarbazide133−135 is the most common approach. inal chemistry, USI is gaining recognition as a green activation
Other methods include using α-nitrophenyl hydrazones method for constructing bioactive heterocycles.182 This could
with methylene amines using a solid-phase catalyst,137 accelerate the discovery of new N- and O-azole pharmaceut-
using TMSNCS,139 acylation of a thiosemicarbazide icals via rapid, one-pot syntheses. Likewise, materials science
followed by cyclization,138 or reaction from the stands to benefit too. US methods can generate nanomaterials
oxadiazole using hydrazine and base.136 with fine control over particle size and morphology.183
g) 1,3,4-oxadiazoles: Intramolecular ring closures of acylhy- Emerging US microreactors allow efficient, reproducible
drazides, with US improving efficiency.151 Methods nanomaterial synthesis with scalable and eco-friendly oper-
include bis(1,3,4-oxadiazole)-substituted pyridines,148 ation.181 It is conceivable that novel azole-based polymers,
graphene oxide catalysts for 2,5-disubstituted oxadia- catalysts, or nanocomposites will be synthesized sonochemi-
zoles,153 and oxidative ring closures of acyl hydrazones cally, with properties unattainable by conventional means.
with antibacterial activity.154 To realize this future, two practical aspects must improve.
h) 1,2,4-oxadiazoles: USI improved the conversion of First, equipment accessibility remains a challenge. High-power
trichloroacetoamidoxime and an acid halide to 3,5- sonochemical equipment is still relatively scarce and often
disubstituted 1,2,4-oxadiazoles.160 expensive, limiting its use at smaller institutions. Encourag-
i) Tetrazoles: US-assisted multicomponent reactions en- ingly, the marketplace for US reactors is expanding, which
abled the formation of products unattainable through should drive costs down. We anticipate that by 2030,
conventional heating, such as bis-tetrazoles from affordable benchtop and pilot-scale sonicators will be more
dehydroabietylamine and isocyanides.164 Green con- widely available, allowing more laboratories and industries to
ditions include US-assisted ionic liquid synthesis of 5- adopt this technology. Second, the educational gap needs
aryltetrazoles171 and zinc sulfide nanoparticle-catalyzed addressing. At present, sonochemistry rarely features in
methods for tetrazole derivatives.173 US-assisted regio- undergraduate laboratories or curricula. Experts argue that
selective synthesis of 5-substituted 1H-tetrazoles with “teaching and mentorship in sonochemistry are highly needed”
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to build a skilled workforce and ensure safe, effective use of

USI.184 Going forward, integrating sonochemical experiments
■ ACKNOWLEDGMENTS
G.R.H. would like to acknowledge his grandmother, Shirley
and theory into undergraduate chemistry education will Hoffman, for her support and encouragement throughout the
demystify the technique and train the next generation of research and writing process. The authors acknowledge the
chemists in its use. support of the Office of Research and the College of Letters,
The outlook for sonochemical N- and O-azole synthesis is Arts, and Sciences of the University of Colorado Colorado
hopeful. Advancements in reactor design, sustainability, and Springs.
applications, along with improved equipment availability and
training the next generation of chemists in its use, point toward
a future where ultrasonics play a mainstream role in green
organic synthesis. Within the next decade, we expect the
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