Accepted Manuscript

Recent developments on ultrasound assisted catalyst-free organic synthesis

Bubun Banerjee

PII: S1350-4177(16)30335-2
DOI: http://dx.doi.org/10.1016/j.ultsonch.2016.09.023
Reference: ULTSON 3380

To appear in: Ultrasonics Sonochemistry

Received Date: 9 August 2016

Revised Date: 23 September 2016
Accepted Date: 27 September 2016

Please cite this article as: B. Banerjee, Recent developments on ultrasound assisted catalyst-free organic synthesis,
Ultrasonics Sonochemistry (2016), doi: http://dx.doi.org/10.1016/j.ultsonch.2016.09.023

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 Review_Ultrasonics Sonochemistry

Recent developments on ultrasound assisted catalyst-free organic synthesis

Bubun Banerjee*

Department of Chemistry, Indus International University, V.P.O. Bathu, Distt. Una, Himachal
Pradesh-174301, India, Email: banerjeebubun@gmail.com

In the memory of my heavenly grandmother, Bani Banerjee

____________________________________________________
ABSTRACT

.
Mother Nature needs to be protected from ever increasing chemical pollutions associated
with synthetic organic processes. The fundamental challenge for today’s methodologists is to
make their protocols more environmentally benign and sustainable by avoiding the extensive use
of hazardous reagents and solvents, harsh reaction conditions, and toxic metal catalysts.
However, the people of the twenty-first century are well aware about the side effects of those
hazardous substances used and generated by the chemical processes. As a result, the last decade
has seen a tremendous outburst in modifying chemical processes to make them ‘sustainable’ for
the betterment of our environment. Catalysts play a crucial role in organic synthesis and thus
they find huge applications and uses. Scientists’ continuously trying to modify the catalysts to
reduce their toxicity level, but the most benign way is to design an organic reaction without
catalyst(s), if possible. It is worthy to mention that the involvement of ultrasound in organic
synthesis is sometimes fulfilling this goal. In many occasions the applications of ultrasound can
avoid the use of catalysts in organic reactions. Such beneficial features as a whole have
motivated the organic chemists to apply ultrasonic irradiation in more heights and as a results, in
recent past, there were immense applications of ultrasound in organic reactions for the synthesis
of diverse organic scaffolds under catalyst-free condition. The present review summarizes the
latest developments on ultrasound assisted catalyst-free organic synthesis reported so far.

KEYWORDS

Ultrasonic irradiation, Sonochemistry, Catalyst-free synthesis, Organic synthesis, Sustainable

chemistry

1
1. Introduction

Synthetic organic processes have tremendous applications in chemical industry to

produce various organic compounds in the form of fine chemicals, medicinal and pharmaceutical
agents, agrochemicals, and many others [1-4]. But sometimes chemical industries release toxic
and hazardous waste materials which pollutes the environment. However, the people of the
twenty-first century are well aware about the side effects of those hazardous substances used and
generated by the chemical processes. Mother Nature needs to be protected from ever increasing
chemical pollutions associated with synthetic organic processes. The fundamental challenge for
today’s methodologists is to make their protocols more environmentally benign and sustainable
by avoiding the extensive use of hazardous reagents and solvents, harsh reaction conditions, and
toxic metal catalysts [5-8]. As a result, the last decade has seen a tremendous outburst in
modifying chemical processes to make them ‘sustainable’ for the betterment of our environment.

It is well-established that catalysts play a crucial role in organic synthesis and thus they
find huge applications and uses. Scientists are always trying to modify the catalysts to reduce
their toxicity level, but the most benign way is to design an organic reaction protocol without
using any catalyst(s), if feasible! The involvement of ultrasound in organic synthesis is
sometimes fulfilling this goal. Ultrasound irradiated reactions are much more advantageous over
the traditional thermal methods in terms of reaction rates, yields, purity of the products, product
selectivity, etc [9-13]. Ultrasonic irradiation on reaction mixture generates a huge number of
cavitation bubbles which grows up rapidly and subsequently undergoes vigorous collapses which
results the formation of micro-jets that can produce fine emulsion between the reactants [14].
Furthermore, these violent collapses of cavitation bubbles also increase the local temperature
within the reaction mixture which eventually leads to cross the activation energy barrier [15].
Thus, in many occasions the applications of ultrasound can avoid the use of catalysts in organic
reactions. Such beneficial features as a whole have motivated the organic chemists to explore the
application of ultrasound in more heights and as a results, in recent past, there were immense
applications of ultrasound in organic reactions for the synthesis of diverse organic scaffolds
under catalyst-free condition. The present review summarizes the latest developments on
ultrasound assisted catalyst-free organic synthesis reported so far.

2. Applications of ultrasound in the catalyst-free organic synthesis

This section describes the up to date developments on the ultrasound assisted catalyst-free
organic synthesis under greener conditions.

2.1. Ultrasound assisted catalyst free organic synthesis under solvent free conditions

In the last decade, organic synthesis protocol under solvent-free conditions are becoming so
popular that it is often claimed that the ‘best solvent is no solvent’ [16].

2
2.1.1. N-formylation of amines

The formylation of amines is one of the important tools for the synthesis of various
pharmaceutically promising compounds [17,18]. In recent past, a number of synthetic methods
have been reported in the literature for the N-formylation using various homogeneous as well as
heterogeneous catalysts such as I2 [19], ZnCl2 [20], ZnO [21], KF-Al2O3 [22], TiO2-SiO42− [23],
HCOONa [24] etc. In some methods harsh reaction conditions [25,26] was employed. Toxic
solvent was also used in some occasions [27,28]. In this context, Habibi et al. (Scheme 1) [29]
developed a new, straightforward, environmentally benign, convenient protocol for the synthesis
of N-formylated (3) products from the reactions of various amines (1) and formic acid (2) under
catalyst-free neat conditions using ultrasound irradiation at room temperature.

Entry R R1 % Yield Entry R R1 % Yield

1 C6H5 H 97 12 4-OCH3-C6H4 H 95
2 2-Cl-C6H4 H 96 13 4-COCH3-C6H4 H 93
3 4-NO2-C6H4 H 95 14 3-CF3-C6H4 H 92
4 2-OH-C6H4 H 93 15 C6H5 CH3 93
5 4-OH-C6H4 H 95 16 1-phenylpiperazine - 92
6 4-Cl-C6H4 H 96 17 C6H5CH2 H 94
7 4-Br-C6H4 H 97 18 C6H5CH2 C6H5CH2 92
8 2,5-(Cl)2- C6H3 H 95 19 C6H5 C6H5 92
9 2-CH3-C6H4 H 94 20 1-naphthyl H 94
10 2-CH3-C6H4 H 95 21 morpholine - 87
11 2,4-(CH3)2-C6H3 H 94

Scheme 1: Ultrasound promoted catalyst-free N-formylation of amines under neat conditions

2.1.2. Protection of alcohols

Mojtahedi et al. (Scheme 2) [30] reported a facile and efficient method for the protection of
alcohols as well as phenols (4) by hexamethyldisilazane (5) to form the corresponding silyl
ethers (6) with the influence of ultrasonic irradiation at room temperature without using any
catalyst under solvent-free conditions.

3
Scheme 2: Ultrasound mediated catalyst-free protection of alcohols under solvent-free condition

2.1.3. N-Boc protection of amines

Protection of amino group is very common in the total synthesis and in this purpose tert-
butoxycarbonyl (Boc) group is widely used for the protection of amine among various other
protecting groups. Many methods are available in the literature for this reaction using various
catalysts such as ZrCl4 [31], LiClO4 [32], HClO4/SiO2 [33], Cu(BF4)2.9H2O [34],
Zn(ClO4)2.6H2O [35], La(NO3)3.6H2O [36], montmorillonite K-10 [37], amberlyst-15 [38],
H3PW12O40 [39], sulfamic acid [40] etc. in the presence or absence of various solvents.
Chankeshwara et al. (Scheme 3) [41] reported an aqueous mediated catalyst-free protocol for this
reaction. Jia and his group (Scheme 3) [42] developed a facile method for this N-Boc protection
of amine under solvent-free condition. Recently Amira et al. (Scheme 3) [43] employed
ultrasound for the Boc protection of the various amines (1) using di-tert-butyl dicarbonate (7)
under catalyst-free, solvent-free conditions and observed that the reaction completed within just
few minutes.

2.1.4. Synthesis of 8-aryl-7,8-dihydro-[1,3]-dioxolo[4,5-g]quinolin-6(5H)-one

Quinolines are important class of bioactive heterocycles possesses various pharmacological

efficacies especially anti-malarial activity [44-45]. After noticing this Azarifar et al. (Scheme 4)
[46] developed a simple, efficient, ultrasound assisted one-pot convenient method for the
synthesis of novel 8-aryl-7,8-dihydro-[1,3]-dioxolo[4,5-g]quinolin-6-(5H)-one derivatives (12)
via the three-component reactions of various aromatic aldehydes (9), isopropylidene malonate
(10) and 3,4-methylendioxyaniline (11) under catalyst-free and solvent-free conditions at
ambient temperature.

4
Scheme 3: Ultrasound mediated catalyst-free N-Boc protection of under solvent-free conditions.

Entry R % Yield Entry R %

Yield
1 C6H5 83 6 4-OCH3-C6H4 76
2 4-CH3-C6H4 77 7 2-OCH3-C6H4 77
3 4-Cl-C6H4 85 8 2-Cl-C6H4 85
4 2,4-(Cl)2-C6H4 88 9 2-NO2-C6H4 82
5 3-Br-C6H4 86

Scheme 4: Ultrasound promoted catalyst-free synthesis of 8-aryl-7,8-dihydro-[1,3]-dioxolo[4,5-

g]quinolin-6(5H)-ones

2.1.5. Synthesis of α-aminophosphonates

α-Aminophosphonate derivatives possess antimalarials [47], antifungal [48], and antibiotic [49]
activities. α-Aminophosphonates are mainly synthesized by the Kabachnik-Fields (phospha-
Mannich) reaction via the condensation of various amines, carbonyl compounds (aldehydes and
ketones) and dialkyl phosphites [50]. There are number of methods reported in the literature for
the synthesis of α-aminophosphonates from the reactions of carbonyl compounds (13), primary
amines (1a), and triethylphosphite (14) or diethyl phosphonate (15) employing various catalytic
system such as Zr(IV) salts [51], InCl3 [52], MgBr2 [53], NbCl5 [54], Silica sulfuric acid [55],
Al(H2PO4)3 [56], Ce(OTf)4 [57], CeCl3.7H2O [58], BF3-SiO2 [59], MoO2Cl2 [60], nano Fe3O4

5
[61], in presence or absence of solvents. Chandrasekhar et al. (Scheme 5) [62] reported a
catalyst-free protocol for the synthesis of α-aminophosphonates at room temperature under
solvent free conditions within 15 mins to 12 hrs timeframe. Xia et al. (Scheme 5) [63]
demonstrated an ultrasound irradiated catalyst-free method for the synthesis of the same
scaffolds using diethyl phosphonate (15) with comparatively short reaction time. Later on, Dar et
al. (Scheme 5) [64] described an ultrasound promoted, efficient, catalyst-free protocol for the
synthesis of α-aminophosphonates within few seconds under neat conditions at room
temperature using triethylphosphite (14) as phosphonate source.

Scheme 5: Ultrasound mediated catalyst-free synthesis of α-aminophosphonates under solvent-

free conditions

2.1.6. Synthesis of N,N-diarylsubstituted formamidines

A simple, efficient, catalyst-free, ultrasound assisted protocol was developed by Dar et al.
(Scheme 6) [65] for the synthesis of N,N′-diarylsubstituted formamidines (18) from the reactions
of various primary amines (1a) and triethylorthofornate (17) under solvent-free conditions at
room temperature.

Entry R % Yield Entry R % Yield

1 C6H5 98 8 4-CF3-C6H4 86
2 4-CH3-C6H4 98 9 2-CN-C6H4 78
3 4-F-C6H4 81 10 4-OCH3-C6H4 98
4 4-I-C6H4 78 11 2-CH3-C6H4 96
5 4-Br-C6H4 69 12 2-Cl-C6H4 67
6 4-Cl-C6H4 72 13 4-NO2-C6H4 64
7 2-F-C6H4 84 14 2-OCH3-C6H4 95

Scheme 6: Ultrasound mediated catalyst-free synthesis of N,N′-diarylsubstituted formamidines

under solvent-free conditions
6
2.2. Ultrasound assisted catalyst free organic synthesis in aqueous medium

Last decades has shown tremendous outburst of chemical reactions performed ‘‘in- or on-water’’
conditions [66] to make them ‘sustainable’ for the betterment of our environment. Scientists’ are
choosing water as a solvent not only because of its environmental friendliness but also it is
cheap, non-flammable, and abundantly available.

2.2.1. Synthesis of rhodanines

Rhodanines (21), in particular, have significant pharmacological efficacies including the

inhibition of targets such as HCV NS3 protease [67] and β-lactamase [68]. Rostamnia et al.
(Scheme 7) [69] demonstrated a facile, straightforward, environmentally benign, efficient, rapid,
high-yielding, catalyst-free protocol for the synthesis of rhodanines from the reactions of various
primary amines (1a), carbon disulfide (19) and dialkyl but-2-ynedioate (20) in water using
ultrasonic irradiation.

2.2.2. Synthesis of dihydroquinolines

1,4-Dihydroquinoline derivatives have also attracted attention because those comprise a large
family of medicinally significant compounds and are used in production of antihypertension,
antidiabetic, and many other drugs [70-72]. Pagadala et al. (Scheme 8) [73] developed a simple,
efficient, catalyst-free one-pot four-component protocol for the synthesis of a series of
dihydroquinoline derivatives (26, 27) from the condensation of various aldehydes (9),
malononitrile (22), ammonium acetate (23) and 2-naphthol (24)/resorcinol (25) in aqueous
medium under ultrasound irradiation at 60 OC.

Entry R1 R2 % Yield Entry R1 R2 % Yield

1 C6H5CH2 CH3 94 5 C6H5CH(CH3) CH3 92
i
2 4-Cl-C6H4CH2 CH3 93 6 Bu CH3 88
3 2-Cl-C6H4CH2 CH3 91 7 Allyl CH3 90
i
4 2-Cl-C6H4CH2 C2H5 92 8 Pr CH3 86

Scheme 7: Ultrasound mediated catalyst-free synthesis of Rhodanines in aqueous media

7
 Entry R % Yield of 27 Entry R % Yield of 26
1 C6H5 96 1 C6H5 97
2 4-Br-C6H4 94 2 4-Br-C6H4 95
3 4-OH-C6H4 90 3 2-Cl-C6H4 90
4 4-Cl-C6H4 92 4 4-Cl-C6H4 94
5 4-OH-C6H4 90

Scheme 8: Ultrasound promoted catalyst-free synthesis of dihydroquinolines

2.2.3. Synthesis of biscoumarins

Biscoumarins (29), the bridge-substituted dimers of 4-hydroxycoumarin, are found to exhibit

significant phytochemicals efficacies such as antimicrobial [74], cytotoxic [75] and potent HIV-1
integrase inhibitor [76,77] activities. Such handful of diverse applications of biscoumarins have
drawn considerable interest during the last several years among the synthetic chemists to develop
useful synthetic routes to this scaffolds of potential interest; as a result a good number of
methods are already reported [78-87]. Although these available methodologies possess notable
merits, still they suffer from drawbacks such as use of metal catalysts, toxic organic solvents,
harsh reaction condition, longer reaction time etc. Al-Kadasi et al. (Scheme 9) [88] developed a
simple, efficient, rapid, ultrasound assisted catalyst-free one pot three-component protocol for
the synthesis of biscoumarins (29) by condensing 4-hydroxycoumarin (28) with various aromatic
aldehydes (9) in water at ambient temperature.

2.2.4. Ultrasound assisted catalyst-free aza-Michael addition reaction

A simple, facile, catalyst-free Michael addition of ferrocenylenones with aliphatic amines was
described by Yang et al. (Scheme 10) [89] to afford 1-ferrocenyl-3-amino carbonyl compounds
(31) with high yields using ultrasonic irradiation under neat condition at room temperature. Later
on, Banik and his group (Scheme 10) [90] developed another simple, straightforward, rapid,
aqueous mediated catalyst-free protocol for the aza-Michael addition reaction of several amines
(1) to α, β-unsaturated carbonyl compounds (30) employing ultrasonic irradiation.

8
 Entry R % Yield Entry R % Yield
1 C6H5 98 5 2-OCH3-C6H4 92
2 4-Cl-C6H4 98 6 4-NO2-C6H4 83
3 2-Cl-C6H4 90 7 4-OH-C6H4 95
4 4-OCH3-C6H4 85 8 3,4,5-(OCH3)3-C6H2 85

Scheme 9: Ultrasound promoted catalyst-free synthesis of biscoumarins in aqueous media

Scheme 10: Ultrasound assisted catalyst-free synthesis of synthesis of β-aminocarbonyl

compounds

2.2.5. Synthesis of pyrroles and pyridazines

Pyrroles and pyridazines skeleton are very common in natural products, pharmaceuticals, and
various bioactive molecules [91-92]. To realize the importance, a facile, straightforward,
efficient, aqueous mediated ultrasound assisted method was developed by Eftekhari-Sis et al.
(Scheme 11) [93] for the synthesis of 6-aryl-3-methylpyridazine-4-carboxylic acid esters (35)
and 5-aryl-4-hydroxy-2-methyl-1H-pyrrole-3-carboxylic acid esters (36) via three component
reactions of arylglyoxal hydrates (32), β-dicarbonyl compounds (12) and hydrazine hydrate (34)
or ammonium acetate respectively (23) respectively at room temperature.

9
 Entry R R1 % Yield Entry R R1 % Yield
of 35 of 36
1 H CH3 90 1 H OCH3 90
2 H OCH3 91 2 H OC2H5 90
3 H OC2H5 85 3 H OC(CH3)3 93
4 4-Cl CH3 95 4 4-Cl OCH3 75
5 4-Cl OC2H5 90 5 4-Cl OC2H5 88
6 4-Br CH3 50 6 4-Cl OC(CH3)3 80
7 4-Br OC2H5 90 7 4-Br OCH3 85
8 4-NO2 CH3 95 8 4-Br OC2H5 75
9 4-NO2 OCH3 95 9 4-NO2 OC(CH3)3 75
10 4-NO2 OC2H5 90
11 4-NO2 OC(CH3)3 70

Scheme 11: Ultrasound promoted catalyst-free synthesis of pyrroles and pyridazines in water

2.2.6. Synthesis of dithiocarbamates

Organic dithiocarbamates are important synthetic intermediates of various biologically active

compounds [94]. Azizi et al. (Scheme 12) [95] reported a simple, straightforward, ultrasound
assisted, catalyst-free one-pot three-component condensation of primary or secondary amines
(1), carbon disulfide (19) and unsaturated carbonyl compounds (30) or alkyl halides (37) for the
rapid synthesis of dithiocarbamates (38, 39) in water at room temperature.

Scheme 12: Ultrasound promoted catalyst-free synthesis of dithiocarbamates in water

2.2.7. Synthesis of β-aminoalcohols

β-Aminoalcohols (41) are useful building blocks of various biologically active natural products
[96], unnatural amino acids [97], and chiral auxiliaries [98]. As a result a number of methods are
available in the literature for the synthesis of β-aminoalcohols using various Lewis acids as
catalysts [99-102], solid phase synthesis [103,104], ionic liquids [105-107], heteropolyacids
[108], fluorinated solvents [109] etc. Azizi et al. (Scheme 13) [110] developed a catalyst free
protocol for the synthesis of β-aminoalcohols (41) in aqueous media at room temperature within
5-24 hours. Later on, Abaee et al. (Scheme 13) [111] reported a simple, straightforward,

10
ultrasound assisted catalyst-free protocol for the synthesis of β-aminoalcohols (41) in water
within just 30 minutes from the reactions of epoxides (40) with various primary or secondary
animes (1) at room temperature.

Scheme 13: Ultrasound mediated catalyst-free synthesis of β-aminoalcohols at room

temperature.

2.2.8. Synthesis of substituted thiourea

A simple, catalyst-free, one-pot three-component condensation of primary (1a) or secondary

amines (1) with carbon disulfide (19) was developed by Azizi et al. (Scheme 14) [112] for the
rapid high-yielding synthesis of thiourea derivatives (42, 43) using ultrasonic irradiation in water
at room temperature.

Scheme 14: Ultrasound mediated catalyst-free synthesis of substituted thiourea in water.

2.2.9. Synthesis of spiro[indole-3,4′-pyrazolo[3,4-e][1,4]thiazepines]

Dandia et al. (Scheme 15) [113] demonstrated a simple, straightforward, efficient, ultrasound
assisted, catalyst-free one-pot three-component domino reactions of isatins (44), 3-amino-5-
methylpyrazoles (45) and 2-mercaptoacetic acid derivatives (46) to afford corresponding
biologically relevant spiro[indole-3,4′-pyrazolo[3,4-e][1,4]thiazepines] (47) with excellent yields
in water at room temperature.

11
 Entry R R1 R2 % Yield
1 H H H 91
2 H H CH3 92
3 5-CH3 H H 90
4 5-CH3 H CH3 89
5 5-Cl H H 90
6 5-Br H H 88
7 5,7-diCH3 H H 90
8 H CH2-C6H5 H 91
9 H CH2-C6H5 CH3 90

Scheme 15: Ultrasound promoted catalyst-free synthesis of spiro[indole-3,4′-pyrazolo[3,4-

e][1,4]thiazepines]

2.3. Ultrasound assisted catalyst-free organic synthesis in other solvents

2.3.1. Synthesis of 4,4-(arylmethylene)bis (3-methyl-1-phenyl-1H-pyrazol-5-ols)

A green and convenient approach was developed by Hasaninejed et al. (Scheme 16) [114] for the
rapid synthesis of 4,4-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) (48) with
excellent yields from the reactions of aromatic aldehydes (9), alkyl acetoacetate (33) and
phenylhydrazines derivatives (34a) using ultrasonic irradiation in aqueous ethanol (1:1) at room
temperature.

Entry R R1 R2 % Yield Entry R R1 R2 % Yield

1 C6H5 CH3 H 98 11 2-furyl CH3 H 97
2 4-Cl-C6H4 CH3 H 92 12 2-naphthyl CH3 H 96
3 3-Cl-C6H4 CH3 H 95 13 1-naphthyl CH3 Br 94
4 2-Cl-C6H4 CH3 H 93 14 3-Cl-C6H4 CH3 Br 83
5 4-Br-C6H4 CH3 H 98 15 4-Cl-C6H4 CH3 Br 90

12
6 2-Br-C6H4 CH3 H 97 16 4-Br-C6H4 CH3 Br 87
7 4-NO2-C6H4 CH3 H 96 17 4-CF3-C6H4 CH3 Br 98
8 3-OH-C6H4 CH3 H 98 18 4-CN-C6H4 CH3 CH3 85
9 4-OH-C6H4 CH3 H 98 19 4-Cl-C6H4 C6H5 H 97
10 2-thienyl CH3 H 98 20 3-NO2-C6H4 C6H5 H 98

Scheme 16: Ultrasound promoted catalyst-free pseudo five component synthesis of 4,4-
(arylmethylene)bis (3-methyl-1-phenyl-1H-pyrazol-5-ols)

2.3.2. Synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones

A simple, facile, ultrasound assisted, one-pot three component catalyst free synthesis of 6H-1-
benzopyrano[4,3-b]quinolin-6-ones (50) was demonstrated by Mulakayala et al. (Scheme 17)
[115] via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde (49) with various
aromatic primary amines (1a) in methanol at room temperature.

2.3.3. Synthesis of ketene imines

Emtiazi et al. (Scheme 18) [116] reported a simple, convenient, catalyst-free, efficient protocol
for the synthesis of ketene imines (54) with excellent yields via a one-pot three-component
condensation of cyclohexyl isocyanide (51), diethyl acetylenedicarboxylate (52), and 1,4-
dihydropyridines (53) using ultrasonic irradiation in hexane as solvent at room temperature
within just 20 minutes.

Entry R % Yield Entry R % Yield

1 H 95 6 3-F 94
2 2-OCH3 92 7 4-F 93
3 3,4-diF 90 8 4-OCH3 91
4 2,3diF 92 9 4-CH3 89
5 3-Br 89 10 4-Cl 93

Scheme 17: Ultrasound promoted catalyst-free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-

ones

13
 Entry R % Yield Entry R % Yield
1 C6H5 90 6 4-Cl-C6H4 82
2 3-NO2-C6H4 82 7 4-OCH3-C6H4 80
3 2-F-C6H4 82 8 4-CH3-C6H4 80
4 3-F-C6H4 85 9 2-furyl 85
5 4-F-C6H4 83

Scheme 18: Ultrasound promoted catalyst-free synthesis of ketene imines at room temperature

2.3.4. Synthesis of 2,2’-(1,4-phenylene)bis[1-acetyl-1,2-dihydro-4H-3,1-benzoxazin-4-one]

derivatives

A simple, efficient, rapid, catalyst-free, convenient protocol for the synthesis of 2,2’-(1,4-
phenylene)bis[1-acetyl-1,2-dihydro-4H-3,1-benzoxazin-4-one] derivatives (57) was developed
by Azarifar et al. (Scheme 19) [117] via the reaction between anthranilic acids (55) and
terephthalaldehyde (56) using ultrasonic irradiation in acetic anhydride as a solvent at 55 OC.

Entry R R1 % Yield
1 H H 85
2 OCH3 OCH3 75
3 H COOH 70
4 Br H 78
5 Cl H 74
Scheme 19: Ultrasound promoted catalyst-free synthesis of 2,2’-(1,4-phenylene)bis[1-acetyl-1,2-
dihydro-4H-3,1-benzoxazin-4-one] derivatives

2.3.5. Synthesis of quinoxaline derivatives

Quinoxaline derivatives possess a wide spectrum of biological efficacies including

antimycobacterial, cardiotonic, antidepressant, antitumor etc. [118-121] activities. As a result, a
number of methods are already been reported in the literature for the synthesis of this important
class of bioactive scaffolds using various catalyst such as MnO2 [122], POCl3 [123], I2 [124,125],

14
CAN [126], CuSO4·5H2O [127], Zn[(L)proline]2 [128], Ni-nanoparticles [129], silica sulfuric
acid [130], NH4Cl [131] etc. In 2009, Guo et al. (Scheme 20) [132] developed a simple,
convenient, catalyst-free, high yielding method for the synthesis of quinoxaline derivatives (60)
via the condensation of various 1,2-diketones (58) with 1,2-diamines (59) under ultrasonic
irradiation in ethanol at room temperature.

2.3.6. Synthesis of dispiropyrrolizidines

Ge et al. (Scheme 21) [133] reported a straightforward, efficient catalyst-free ultrasound

irradiated protocol for the rapid synthesis of biologically relevant dispiropyrrolizidine containing
tetracyclic frameworks (63) from the one-pot three-component reactions between dipolarophile
(61), isatin (44) and L-proline (62) via the formation of azomethine ylides in methanol at ambient
temperature.

Entry R R1 % Yield Entry R R1 % Yield

1 C6H5 H 98 7 4-OCH3-C6H4 H 90
2 C6H5 CH3 99 8 4-OCH3-C6H4 CH3 91
3 C6H5 NO2 37 9 2-furyl H 96
4 4-CH3-C6H4 H 93 10 2-furyl CH3 96
5 4-CH3-C6H4 CH3 95 11 C2H5 H 81
6 4-CH3-C6H4 NO2 36 12 C2H5 CH3 80
Scheme 20: Ultrasound promoted catalyst-free synthesis of quinoxaline derivatives

Entry R1 R2 % Yield Entry R1 R2 % Yield

1 H H 74 9 4-Cl 6-CH3 74
2 H 6-CH3 77 10 2-Cl H 59
3 H 6-OCH3 80 11 4-F H 82
4 H 6-Cl 67 12 4-CF3 H 86
5 H 8-CH3 71 13 4-Br 6-OCH3 75
6 H 5,8-(CH3)2 78 14 2,4-diCl 6-CH3 53
7 4-Cl H 80 15 4-CH3 6-OCH3 42
8 4-Cl 6-OH 84

15
Scheme 21: Ultrasound mediated catalyst-free synthesis of dispiropyrrolizidines

2.3.7. Synthesis of functionalised spiropyrrolidine and spiropyrrolizidine

Spiro oxindole skeleton is very common in the core units of many naturally occurring molecules
that possess significant biological activities such as anti-leukemic, anti-convulsant [134],
antiviral activities [135]. To realize the importance of this scaffolds, a series of novel dicyano
functionalized spiropyrrolizidines (66, 67) and spiropyrrolidines (69, 70) were synthesized by
Rezaei et al. (Scheme 22) [136] via one-pot three-component reactions of various
arylidenemalononitriles (64), isatin (44)/acenaphthenequinone (65) and proline (62) or N-
methyl/phenylglycine (68) respectively via the formation of azomethine ylides intermediate
under catalyst-free condition in methanol using microwave irradiation at room temperature.

Entry R1 R2 % Yield of 70 Entry R1 R2 % Yield of 70

1 4-Cl CH3 83 6 3,4-(OCH3)2 CH3 79
2 4-Br CH3 85 7 H CH3 82
3 3-Br CH3 82 8 4-Cl CH3 85
4 4-F CH3 90 9 4-F C6H5 92
5 4-CH3 CH3 85 10 4-CH3 C6H5 80

Scheme 22: Ultrasound promoted catalyst-free synthesis of spiropyrrolidines and

spiropyrrolizidines

16
2.3.8. Synthesis of 4-amino-5-carboxamido-1,2,3-triazoles

Gladkov et al. (Scheme 23) [137] described a simple, convenient, catalyst-free ultrasound
assisted one-pot three-component reactions of aromatic aldehydes (9), 1,3-cyclohexadione
derivatives (71) and polyfunctional 4-amino-5-carboxamido-1,2,3-triazole (72) in methanol to
afford the corresponding biologically promising 8-oxo-4,5,6,7,8,9-hexahydro-[1,2,3]triazolo[5,1-
b]quinazoline-3-carboxamide derivatives (73) with moderate to good yields at room temperature.

Entry R X % Yield Entry R X % Yield

1 C6H5 CH2 61 6 C6H5 CH3 78
2 4-OCH3C6H4 CH2 43 7 4-OCH3C6H4 CH3 86
3 2-OCH3C6H4 CH2 51 8 2-OCH3C6H4 CH3 88
4 4-Br-C6H4 CH2 75 9 4-Br-C6H4 CH3 91
5 4-Cl-C6H4 CH2 69 10 4-Cl-C6H4 CH3 77

Scheme 23: Ultrasound promoted catalyst-free synthesis of 4-amino-5-carboxamido-1,2,3-

triazoles

2.3.9. Synthesis of pyrido[2,3-d]pyrimidines

Recently, pyrido[2,3-d]pyrimidines are in focus because of their significant biological efficacies

such as antitumor, antibacterial, anti-inflammatory, anti-fungal, and anti-leishma activity [138].
A series of pyrido[2,3-d]pyrimidine derivatives (77, 78) was synthesized by Tu et al. (Scheme
24) [139] under the influence of ultrasonic irradiation via the three-component condensation
reactions of various aldehydes (9), 2,6-diaminopyrimidine-4(3H)-one (74) and either tetronic
acid (75) or 1,3-indanedione (76) respectively in ethylene glycol as solvent without using any
catalyst at 65 OC.

17
 Entry R % Yield of 77 Entry R % Yield of 78
1 4-Cl-C6H4 94 1 4-Cl-C6H4 92
2 4-BrC6H4 95 2 4-Br-C6H4 94
3 4-OCH3C6H4 93 3 4-F-C6H4 93
4 3-OCH3-4-OH-C6H3 91 4 3NO2-C6H4 92
5 C6H5 92 5 C6H5 91
6 4-NO2-C6H4 94 6 2,3-(CH2O)2C6H3 90

Scheme 24: Ultrasound promoted catalyst-free synthesis of pyrido[2,3-d]pyrimidines

2.3.10. Synthesis of pyrrolidine-2-spiro-3′-oxindoles

Chen et al. (Scheme 25) [140] demonstrated a simple, efficient, catalyst-free ultrasound assisted
one-pot three component 1,3-dipolar cycloadditions of isatins (44), L-proline (62) and 1,4-
naphthoquinone (79) to afford the corresponding biologically promising pyrrolidine-2-spiro-3′-
oxindoles (80) with good to excellent yields via the formation of azomethine ylide in methanol at
ambient temperature.

Entry R % Yield Entry R % Yield

1 H 98 5 CH2(CH2)3CH3 81
2 6-Br 72 6 CH2CH2CH2Br 70
3 1-CH3 85 7 1-CH2C6H5 90
4 1-CH2-CH=CH2 76

Scheme 25: Ultrasound promoted catalyst-free synthesis of pyrrolidine-2-spiro-3′-oxindoles

2.3.11. Synthesis of 1,3,4-oxadiazoles

Ramazani et al. (Scheme 26) [141] synthesized a series of biologically promising 1,3,4-
oxadiazole derivatives (83) with good to excellent yields within just 27 minutes via a facile and
one-pot three-component reactions between biacetyl (58), (E)-cinnamic acids (81) and N-
isocyanimino-triphenylphosphorane (82) in dichloromethane under catalyst-free condition using
ultrasound irradiation at room temperature.

Entry R R1 % Yield Entry R R1 % Yield

18
 1 4-CH3 H 97 5 H CH3 92
2 4-F H 96 6 3-Cl H 94
3 4-Cl H 94 7 3-OCH3 H 93
4 H H 91

Scheme 26: Ultrasound promoted catalyst-free synthesis of 1,3,4-oxadiazoles

2.3.12. Synthesis of dispiropyrrolidines

Liu et al. (Scheme 27) [142] synthesized a series of biologically attractive dispiropyrrolidine
derivatives (85) via a one-pot catalyst-free three-component domino cycloaddition reactions
between isatins (44), sarcosine (68) and 5-arylidene-1,3-thiazolidine-2,4-dione (84a) or 5-
arylidene-4-thioxo-1,3-thiazolidine-2-one (84b) in ethanol under ultrasonic irradiation at room
temperature.

Entry R X % Yield Entry R X % Yield

1 CH3 O 75 7 CH3 S 82
2 H O 72 8 H S 80
3 NO2 O 83 9 NO2 S 85
4 F O 71 10 F S 81
5 Cl O 75 11 Br S 84
6 Br O 78

Scheme 27: Ultrasound promoted catalyst-free synthesis of dispiropyrrolidines

2.3.13. Synthesis of both 5-arylisoxazole and 5-aryl-1H-pyrazole derivatives

The isoxazoles and pyrazoles are widely distributed among the naturally occurring
pharmaceuticals active natural products possesses significant and wide spectrum of biological
efficacies that includes anti-HIV, antimicrobial, antiviral, antitumor, anti-inflammatory,
antifungal, antidepressant, potent and selective antagonism of N-methyl-D-aspartate (NMDA)
receptor,etc. [143-148]. Releasing the importance of these classes of heterocycles Huang et al.
(Scheme 28) [149] developed a simple, efficient, straightforward catalyst-free protocol for the
synthesis of a series of both 5-arylisoxazoles (88) as well as 5-aryl-1H-pyrazoles (89) from the
reactions of 3-(dimethylamino)-1-aryl-prop-2-en-1-one (86) with hydroxylamine hydrochloride
(87) or hydrazine hydrate (34) respectively under ultrasound irradiation in ethanol at room
temperature within just 45 minutes.

19
Entry R R1 % Yield Entry R R1 % Yield
of 89 of 88
1 4-Cl CH3 90 1 4-Cl-C6H4 CH3 93
2 4-Br CH3 92 2 4-Br-C6H4 CH3 95
3 2,4-diCl CH3 86 3 2,4-diCl-C6H3 CH3 91
4 4-OCH3 CH3 93 4 4-OCH3-C6H4 CH3 87
5 4-COOCH3 CH3 87 5 4-COOCH3 CH3 96
6 4-BocNH CH3 89 6 4-BocNH CH3 84
7 4-Cl H 84 7 4-Cl-C6H4 H 89
8 4-OCH3 H 86 8 4-OCH3-C6H4 H 87
9 4-Br H 89 9 1-Naphthyl H 85
10 H CH3 87 10 4-CH3C6H4 CH3 90
11 C6H5 CH3 89
12 4-Br-C6H4 H 86

Scheme 28: Ultrasound promoted catalyst-free synthesis of dispiropyrrolidines

3. Conclusions

The present review summarizes the latest developments on ultrasound assisted catalyst-free
organic synthesis reported so far. Now-a-days, it is the fundamental challenge to make organic
synthetic protocols more environmentally benign and sustainable by avoiding the extensive use
of hazardous reagents and solvents, harsh reaction conditions, and toxic metal catalysts. It is
meaningless to mention that catalysts play a crucial role in organic synthesis and thus they find
huge applications and uses. Scientists are always involved to modify the catalysts to reduce their
toxicity level, but the most benign way is to design an organic reaction protocol without using
any catalyst(s), if feasible! The implementation of ultrasound in organic synthesis was very much
helpful to achieve this goal. Ultrasound irradiated reactions are not only advantageous over the
traditional thermal methods in terms of reaction rates, yields, purity of the products, product
selectivity, etc but also in many occasions the applications of ultrasound can avoid the use of
catalysts in organic reactions. As a result, in recent past, there were immense applications of
ultrasound in organic reactions for the synthesis of diverse organic scaffolds under catalyst-free
condition. Therefore the present review will surely make some impacts on the on-going
developments in this direction as it is one of the thrusting areas for today’s organic
methodologists worldwide.

20
Acknowledgements

The author is thankful to the Indus International University, Una, Himachal Pradesh, India for
the support and the Kartha Education Society, Mumbai, India for the financial help. The author is
grateful to Mrs. Piyasi Brahmachari for her support throughout.

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__________

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 Graphical Abstract

Recent developments on ultrasound assisted catalyst-free organic synthesis

Bubun Banerjee*

Department of Chemistry, Indus International University, V.P.O. Bathu, Distt. Una, Himachal
Pradesh-174301, India, Email: banerjeebubun@gmail.com

______________________________________________________________________________

30
Highlights

• Ultrasound assisted heterocycles synthesis

• Ultrasound assisted catalyst-free synthesis
• Ultrasound assisted catalyst-free synthesis under solvent-free condition
• Ultrasound assisted catalyst-free synthesis in water

31