Journal of Molecular Liquids 315 (2020) 113766

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Journal of Molecular Liquids

journal homepage: www.elsevier.com/locate/molliq

Review

Polyethylene glycol: A promising approach for sustainable

organic synthesis
Jay Soni, Nusrat Sahiba, Ayushi Sethiya, Shikha Agarwal ⁎
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Mohanlal Sukhadia University, Udaipur 313001, Rajasthan, India

a r t i c l e i n f o a b s t r a c t

Article history: Over the last decade, polyethylene glycol (PEG) has emerged as a green and inexpensive catalyst as well as a sol-
Received 27 February 2020 vent in a number of chemical transformations. It serves as a stable, recyclable and biodegradable polymeric cat-
Received in revised form 1 July 2020 alyst in the organic synthesis, as it could be reused several times without significant loss in its catalytic activity. Its
Accepted 6 July 2020
properties are environmentally benign as compared to other organic solvents. This article presents an overview
Available online 11 July 2020
on the use of PEG as a catalyst and a solvent with main emphasis on its role in organic reactions and its usefulness
Keywords:
in green synthesis. Moreover, the article focuses on the recent progress made in the PEG catalyzed synthesis of
PEG several heterocyclic compounds.
Green solvent © 2020 Elsevier B.V. All rights reserved.
Sustainable catalyst
Green chemistry
Michael addition
Knoevenagel condensation

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Structure of PEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Neoteric synthetic applications of polyethylene glycol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3.1. PEG as catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3.2. PEG as reaction medium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4. Challenges and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
List of abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

1. Introduction
In current scenario, sustainable chemistry is the urgent demand for
the synthesis of new compounds and drugs. Catalysts and solvents
play an important role in the organic synthesis. Green chemistry, also
called sustainable chemistry, basically focusses on the process design
in order to minimize the use and generation of harmful substances. As
a matter of fact, it is considered that synthetic methods should prevent
pollution and reduce consumption of non-renewable resources, in order
⁎ Corresponding author.
E-mail address: shikhaagarwal@mlsu.ac.in (S. Agarwal).
to minimize the amount of venomous waste and by-products. The rou-
tine solvents used in current era have several flaws viz. they are harmful,
combustible, toxic, accumulating, non biodegradable, etc. Thus, there is
an urgent need to replace the conventional organic solvents by green
solvents having characteristics like safe, non-toxic, cost-effective, sus-
tainable, harmless and recyclable, etc. Solvent-free or use of green or-
ganic solvents has become the emerging trend of current synthetic
protocols. Great efforts have been done on developing reactions that in-
cludes either solvent-free conditions or H2O, PEG (Poly ethylene glycol),
ionic liquids, super critical carbon dioxide, etc. mediated transforma-
tions. In the context of green solvents, (PEG) [1–9] is a potential solvent
system due to its high structure flexibility, biocompatibility,

https://doi.org/10.1016/j.molliq.2020.113766
0167-7322/© 2020 Elsevier B.V. All rights reserved.
2 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766
Fig. 1. Green aspects of PEG.
amphiphilicity, devoid of any steric hindrances, and high hydration ca-
pacity [10]. In addition, it possesses certain unique properties like
non-volatility, low cost, reduced toxicity, recyclability, low inflammabil-
ity, easy degradability, high miscibility with organic compounds, and
stability even at high temperatures. It not only serves as a novel mild
and efficient reaction medium but also as a phase transfer catalyst that
is frequently replacing expensive and environmentally harmful cata-
lysts, used in chemical synthesis (Fig. 1). Due to the above-stated prop-
erties, PEG composites find applications in organic synthesis such as
nitration of phenols [11], excellent oxidizing agents [12] solvents
[13,14], etc. Moreover, it has been used as an emulsifier in manufactur-
ing of cosmetics and pharmaceuticals [15], industrial applications
[16–17], hard tissue engineering [18], biodiesel production [19], sham-
poo [20], ulcer productivity activity [21], etc. They have also served as
promising nano modules in biomaterials and green chemistry [22] as
well as carriers of anticancer drugs [23]. In past decades, several re-
searchers have propounded different strategies of PEG to explore its sol-
vent and catalytic behavior. Tang et al. reviewed PEG based solid-solid
PCM (phase change materials) that worked as solar energy harvesters
[24]. Kong et al. [25] and Belsey's group [26] summarized the use of
PEG-composites in various diseases. Vafaeezadeh and Hashemi [27]
reviewed the applications of PEG as reaction media in coupling reac-
tions. Furthermore, Pires et al. [28] reviewed the role of PEG on Pd-
and Cu- catalyzed cross-coupling reactions. Literature studies showed
that there is no review available in the recent years which gives ample
information regarding the role of PEG as reaction media and catalyst.
Keeping in mind the huge potential of PEG, the role of PEG as solvent
as well as catalyst in several organic reactions along with the role of
PEG-400 and other PEGs in organic synthesis has been explored for
the last 5 years in this article. We hope that this work will demonstrate
a helpful map for the vast readers and may act as a good source of liter-
ature for the researchers who are working to design green protocols for
organic transformations. This review article has been divided into vari-
ous sub-sections viz. structure of PEG, role of PEG as reaction media and
catalyst along with its synthetic applications for the better understand-
ing of the readers.
2. Structure of PEG
Polyethylene glycol is the polymeric form of ethylene glycol which
acts as an important organic complex and chemical intermediate used
in the synthesis of organic compounds and industrial processes e.g.
anti-freezing agent, energy, plastics, automobiles, and chemicals.
Ethylene glycol is the simplest diol and possesses numerous unique
properties owing to its characteristic structure (i.e., two hydroxyl (OH)
groups at adjacent positions along a hydrocarbon chain). It is an
odorless, colorless, relatively non-volatile and hygroscopic liquid with
low viscosity. It is completely miscible with many polar solvents such
as water, alcohols, glycol ethers, and acetone and only slightly soluble
in non-polar solvents such as benzene, toluene, dichloroethane, and
chloroform. It is difficult to crystallize [29–30].
Furthermore, it is used as a precursor for the synthesis of crown
ethers. Crown ether consists of rings containing several ether linkage.
They act as phase transfer catalysts due to the binding ability of oxygen
with the metal ion and the exterior part being hydrophobic, form com-
plex. Due to the presence of chelate effect and macrocyclic effect, crown
ethers display strong attraction for different cations than their divided
or acyclic analogs. The binding of the cation within the cavity of crown
ether depends on its size and charge density. Thus, the crown ether is
imported to carry out the reactions in non polar solvents that are cata-
lyzed by inorganic salts. [31].
PEG is a polyether composed of repeated ethylene glycol units
[(CH2CH2O)n]. It is formed by the interlinkage of ethylene oxide with
H2O, ethylene glycol and its oligomers. They have been classified into
various grades on the basis of increasing molecular weight. PEGs having.
Weight 100 to 700, are liquids at room temperature, those between
1000 and 2000 are soft solids, and PEGs with molecular weight N2000
are hard crystalline solids with melting points of around 63 °C [32]. The
chain length of PEG depends on the reactant ratio and various types of
catalysts. PEG also known as PEO (polyethylene oxide), based on their
molecular weight. Low molecular weighted (Mw b 40,000) polymers
termed as PEG and high molecular weighted (Mw N 1,00,000) polymers
named PEO. Their chemical properties are same due to the presence of
same functional groups, but physical properties like viscosity, colour
etc. are different because of different chain length of ethylene glycol.
This difference also affects their utility in different areas of industries.
The commercial PEG bears diverse degree of polymerization and acti-
vates functional groups. The chemical structure of main PEG derivatives
has been shown in Fig. 2. The miscellaneous applications of PEG have
been illustrated in Fig. 3.
3. Neoteric synthetic applications of polyethylene glycol
3.1. PEG as catalyst
The designing of a protocol with catalyst is focused on achieving
high activity with low amount of catalyst loading, using “greener” reac-
tion conditions, and ensuring good recyclability. The unique features of
PEG like presence of –OH group, low molecular weight, coordinating
ability, variation in associated groups, and stability at high temperature,
acidic, and basic conditions make it an efficient, recyclable and econom-
ical catalyst. Additionally, PEG easily modifies the surface of nanoparti-
cles which enhances their catalytic activity, hydrophilicity and
decreases agglomeration. In various reactions, it works as PTC, due to
the bonding of metal ions with polyethylene oxide chain of PEG. Re-
cently, magnetic nanoparticles (MNPs) have received considerable in-
terest in the field of green sustainable catalysis [33–36]. The
properties of PEO polymer is easily controllable via using different addi-
tives and conjugates, which enhance the reactivity of varied nanoparti-
cles in several reactions [37]. A great emphasis has been done on the
reactions providing valuable heterocycles incorporating the advances
in PEG-catalyst systems done over the past decades in terms of
stereoselectivity, productivity and chemoselectivity. Numerous proper-
ties of PEG make it a ecofriendly catalyst like simple workup, recyclable,
use in couple of reactions which reduce the synthetic steps and cost too
[38–51] (Fig. 4). The presence of H atom of OH group makes it a strong
Lewis acid and this helps PEG to initiate several transformations and fac-
ile synthesis of several heterocyclic scaffolds [52–53].
Mirfakhraei et al. [54] reported Fe3O4/PEG-SO3H as a heterogeneous
magnetic nanocatalyst for the selective oxidation of a number of sulfides
into their respective sulfoxides and sulfones with H2O2 as the terminal
oxidant (Scheme 1). This acidic magnetic catalyst has several
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 3

(C2H4O)n+1H2O HO O OH
n
Chemical Formula Chemical Structure

* *
O
O O OH

N O O

Zwitterionic polymers
Poly(hydroxyfunctional acrylates)
Eg. Ploy(carboxybetaine methacrylate)
(pCBMA) Eg. Poly(2-hydroxyethyl methacrylate)
(pHEMA)

N O
O O
* H *

Poly(vinylpyrrolidone) Poly(glycerol)

Fig. 2. Chemical structure of PEG and PEG alternatives designed.

advantages over the conventional acid catalyst viz. high chemo-
selectivity, control over the degree of oxidation (which offers access to
sulfoxides or sulfones), high catalytic behavior under mild reaction con-
ditions, good to excellent yields, convenient removal of the catalyst via
external magnet and recyclability of the catalyst for multiple runs
without noticeable decrease in the reaction yields, etc. Fe3O4/PEG
were sulfonated by chloro sulfonic acid to make Fe3O4/PEG-SO3H
nanocomposites.
Ponduri and coworkers [55] developed a highly improved method
for the synthesis of isoxazolyl pyrrole derivatives from a one-pot

Fig. 3. Miscellaneous applications of PEG.

4 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

Solvent free
Synthesis

Green Synthesis One pot

Synthesis
Reusable
Organic
Synthesis
Catalyst
Water mediated
Multi-component
Synthesis
Synthesis
Polymer biodegradable catalyst
Eco-friendly
Synthesis

Fig. 4. Various synthetic aspects of PEG.

scope. The recyclability of the catalyst was also investigated and it was
Fe3O4 / PEG-SO3H O
S O R2 found that PEG-400/H2O could be easily recovered and efficiently
R2 R1 S or S reused up to four cycles. In this protocol, PEG-400 played a significant
H2O2, RT R1 R2 R1 O catalytic role as compared to other catalysts. Here, PEG-400 water
pairing served as best catalyst reaction medium for this multi compo-
nent reaction. The study revealed that no reaction took place in the ab-
R1 and R2= Aryl , alkyl sence of the catalyst. In this reaction, PEG acted as Lewis acid and
facilitated the Michael addition to furnish the desired product.
Scheme 1. Fe3O4/PEG-SO3H catalyzed oxidation of sulfides to sulfonides and sulfones Initially, the PEG-400 activated the nitroolefins, then conjugate addi-
using H2O2. tion of isoxazolyl enamino esters took place to form (I) via Michael ad-
dition. Then, intermediate (I) was attacked by the nitrogen atom to
reaction of isoxazolyl enamino esters and nitroolefins by using PEG- form the intermediate (II). Finally, water and nitroxyl molecules were
400/H2O under metal-free conditions (Scheme 2a). The advantages of eliminated to afford oxazolyl pyrrole derivatives (Scheme 2b).
this method are metal-free, base-free, fast reaction procedure, opera- Another similar, rapid and facile one-pot three-component reaction
tional simplicity, better yield, purification without chromatography, for the direct arylation of heteroarenes via C\\H bond activation with
avoiding the use of toxic catalysts or solvents and broad substrate PEG-400 as an environmental benign reaction medium was reported

a O
CO2Et
EtO H3C
Ph
+ NO2
H3C HN CH3 Ph H3C N

N H2O, 25o C N
O O

Ph Ph
= PEG-400

b R1 H
O H O H EtO2C R1
EtO2C
EtO2C R1
OH R2
EtO O R
R2 N N -H2O
N R H3C N OH R
HN R N R O N R2
H3C O 2 -HNO
+ H3C OH H3C
R1 N
N N O N
St O St O St
O St

II
I

St= CH= CH-Ph = PEG-400

Scheme 2. a. Formation of isoxazolyl pyrroles using PEG-400 as reusable catalyst. b. Plausible mechanism for the preparation of isoxazolyl pyrroles using PEG-400 as catalyst.
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 5

by Jian and colleagues [56] in the presence of functionalized RuCl3.H2O
as a catalyst at 120 °C (Scheme 3a). It was observed that excellent func-
tional group compatibility was obtained with easily regulated ratio of
mono- to di-arylated product by varying the reaction conditions. Upon
completion of the reaction, the catalyst was recycled and could be
reused six times with no loss of catalytic performance. In this reaction,
PEG-400 act as superior solvent as compared to other solvents i.e. the
coordination of PEG with Ru promoted its performance.
Firstly, Ru(III) species was reduced to Ru(II) by hydroxyl group in
PEG-400. The reaction started with the cyclometalation of
phenylpyridine to form intermediate (III) from acetate-assisted dehy-
drogenation process. After that, intermediate (III) reacted with

a F

F
F
RuCl3.xH2O N DCCP
+ + +
(A, B, C)
N 3 equiv base N
Cl Dehydrogena
120oC
toin cross
under air coupling
F
product

N N N
N
F F
F

N N N

F
A B C

= PEG-400

b
N
a
H O
O O

Ru (II) Ru (II)
RuCl3 O CH3COOK
+ CH3COOK N
Cl Cl

I II CH3COOH, KCl

N
OOCH2CH3
ab OOCCH3 Ru (II)
Ru (IV) N
N
Cl
III
IV b
Cl

= PEG-400

Scheme 3. a. Arylation of 2-phenylpyridine with 1-chloro-3-fluorobenzene in the presence of PEG-400. b. Putative mechanism for ruthenium-catalyzed direct arylation of 2-
phenylpyridine using PEG-400.
6 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

chlorobenzene involving an oxidative-addition process to change into
intermediate (IV), which on progress by reductive elimination gave
the desired monoarylated product and active ruthenium species (I).
When most of the b was used up, intermediate (III) easily reacted
with ab or a to afford DCCP (Scheme 3b).
Safaei-Ghomi and Eshteghal [57] reported the synthesis of highly ef-
ficient and green catalyst Fe3O4/ PEG/succinic anhydride nanocatalyst
for the synthesis of benzoxanthenes via one pot 3-component conden-
sation reaction of aldehydes, 2-hydroxynaphthalene-1, 4-dione and 2-
naphthol or dimedone under ultrasonic irradiations (Scheme 4a). The
probable mechanism for the reaction using Fe3O4/PEG/succinic anhy-
dride nanoparticle has been presented in (Scheme 4b). The synthesis
of dibenzo xanthene-dione and benzoxanthene-trione derivatives in-
volved Michael addition, cyclization and isomerization. The Michael ad-
dition reaction between α, β-unsaturated carbonyl compound (I) and
2-hydroxynaphthalene-1, 4-dione gave intermediate (II), followed by
cyclodehydration that led to benzoxanthene derivatives in the presence
of nano-Fe3O4/PEG/succinic anhydride.
This protocol offers various advantages viz. easy work-up, excellent
yields, short reaction times, use of ultrasonic irradiation as a green
method, powerful technology, recoverability of the catalyst and modest
catalyst loading. The catalyst was recycled for 4 runs without loss in
activity.
Zahra and coworkers [58] have described a clean and highly-
efficient synthetic route for the one-pot synthesis of pyrimidinone/
thione derivatives in the presence of PEG-SANM nano-catalyst under
solvent-free conditions (Scheme 5a). Avoiding the use of toxic solvents,
short reaction times, less catalyst loading, and high yields are the advan-
tages of the synthetic route. In addition, the recyclability of this catalyst
is attractive and useful. PEG played an important role in this reaction as
with increase in amount of PEG in the nanocomposites, the interlayer
spaces of nanocomposites increased which has been confirmed by

a
O
O

+ Ar H OH
HO
O
O O

O Ar O O Ar

O O
O O

= PEG

b a
R
OH
O
O H OH O O
O H
-H2O
R I O

R
= PEG

R R
R O
H O
O

-H2O O
OH O
O O OH O II
O

Scheme 4. a. Synthesis of dibenzo xanthene-diones and benzo xanthene-triones by nano-Fe3O4/PEG/succinic anhydride. b. The proposed pathway for the synthesis of dibenzo xanthene-
diones.
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 7

a X

ArCHO + H2N NH2

Solvent-Free, 80oC
X= O, S

O O O

O
Ar
Ar
O Ar
NH NH
NH
N X N X
H H
N X
H

= PEG-SANM nanocatalyst

b O NH2
O R1 O R1 O
O O
R1 O NH2 R2 N NH2
R2 R2 R2 H
H -H2O O
O OH O

O R1 O R1
H
R2 NH R2 NH
= PEG-SANM nanocomposite
N O N O
H

Scheme 5. a. Synthesis of pyrimidinone/thione derivatives in the presence of PEG-SANM nanocatalyst. b. Putative mechanism of Biginelli reaction catalyzed using PEG-SANM nanocatalyst.

XRD data. It was found that PEG-SANM nanocomposites with high ratio
of PEG to SANM showed higher acidity due to spatial exclusion orienta-
tion of SO3H group outside the modified clay and also speeded up the
activity of catalyst. This was evidenced by the comparison of reaction
process using PEG SANM and SANM only under similar reaction condi-
tions and it was found that the desired products were obtained in high
yields (90–95%) in 5 min using PEG-SANM while (85–90%) yields were
obtained in 10 min using SANM only. Thus, pH (acidity) may be the rea-
son for the activity.
A green and rapid protocol for the synthesis of diverse 3,5-disubsti-
tuted hydantoins in the presence of PEG solvents as grinding agents was
investigated by Mascitti et al. [59]. The hydantoins were prepared from
α-amino methyl esters via in situ intramolecular cyclization reaction of
the ureido derivative (B), which was obtained from N-
carbamoylimidazole activated amino ester derivative (A) by reaction
with various amines (Scheme 6). The effect of solvent on the reaction
rate and the product yield was probed by the researchers. The reaction
scheme was studied in the presence of various PEG additives via adding
different amount of PEG i.e. different molecular weight (MW
600–5000 Da) or chain end group and it was found that the yields in-
creased on using variable amount of PEGs. The base activity was also in-
creased due to presence of H2O in PEG and PEG crown ether like effect.
Thus PEG polymers have been proved as ecofriendly and safe alterna-
tives with respect to classic solvents in LAG procedure due to their
low M.P. (45–60 °C), low toxicity and low vapour pressure. Grinding
in the presence of PEGs was cleaner, greener and fast as compared to
dry grinding.
A novel method for the synthesis of bis-3,4-dihydropyrimidin-2
(1H)-one derivatives using substituted aldehyde, acyclic/cyclic methy-
lene compounds and urea (Scheme 7a) in the presence of solid acid cat-
alyst, i.e. perchloric acid-modified PEG-6000 (PEG-HClO4) was
developed by Siddiqui et al. [60]. The PEG-6000 (PEG-HClO4) catalyst
revealed high yields. This observation explained that the catalytic effi-
ciency not only depends on acidic catalytic sites but also on the ease
of access of the active sites. The catalyst was recyclable without any
loss of activity up to four cycles. The catalyst PEG-HClO4 was cheap,
8 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766
N N N
N Dry-grinding or PEG-assisted grinding
R1
O O
OMe
N N
H2N.ClH
450 rpm, 40 min
O 50 balls
N-carbamoylimidazole
activated amino ester
A
= Hanusa's formation for reaction
activated by mechanochemistry
Scheme 6. PEG-assisted grinding method for the synthesis of 3,5–disubstituted hydantoins.
easy to prepare, biodegradable, recyclable, non-volatile, eco-friendly
polymer-based solid acid catalyst which work under thermal solvent-
free conditions. Eco benign, easy to handle, quick, avoidance of organic
solvents, good to excellent yields and reusability of PEG-6000 (PEG-
HClO4) made the synthesis of pyrimidin derivatives facile.
The best yields were obtained within 3 min on using 0.06 g of PEG-
HClO4 under solvent free conditions at 70 °C. Further increase in amount
of catalyst and temperature did not significantly improve the yield. Ad-
ditionally, it was analyzed that solvent free condition was more favor-
able for the better yields as compared to other solvent system
(Scheme 7b).
In this reaction, PEG acted as Lewis acid catalyst that fascinated the
lone pair of oxygen of carbonyl group and increased nucleophilicity of
carbon that was attacked by the NH2 group of urea to form imine as
an intermediate that was further attacked by the dimedone to furnish
the desired compound.
Hiebel et al. [61] demonstrated a green synthetic method for the
preparation of 2-arylimidazo[1,2-a]pyridines from the reaction of 2-
amino pyridines with various phenacyl bromides in the presence of
NaHCO3 with PEG-400 using MWI for 10 min at 120 °C, while 2,3-
diarylimidazo[1,2-a]pyridines were synthesized by the reaction of 2-
amino pyridines with different phenacyl bromides in the presence of
NaHCO3 with PEG-400 at 120 °C under MWI followed by addition of var-
ious aryl bromides, KOAc, and Pd(OAc)2 under irradiation for 1–2 h at
220 °C (Scheme 8). PEG-400 acts as an excellent solvent for MWI due
to its permanent dipole and high boiling point (BP). A decrease in yield
in water was observed perhaps, due to poor solubility of reagent in H2O.
A simple and highly efficient S-and N-arylation of 2-
mercaptobenzothiazole was investigated by Li et al. [48] in the presence
of copper/PEG-400 (Scheme 9). Copper source and reaction tempera-
ture played a significant role in this reaction, as initially S-arylation of
2-mercaptobenzothiazole was achieved by using CuI/PEG-400 at 50 °C
and for N-arylation, CuO/PEG-400 at 140 °C catalyst system was used.
Both were compatible with a variety of aryl halides and selectively
gave the desired S-or N-arylation products in good to excellent yields.
Maleki et al. [63] reported the synthesis of novel, highly efficient, re-
cyclable and green Fe3O4@PEG-SO3H nanocatalyst for the synthesis of
DHPMs via one-pot multicomponent condensation reaction of β-
ketoester, various aldehydes, and urea or thiourea by using H2O:EtOH
as solvent system in the presence of Fe3O4@PEG-SO3H at room temper-
ature (Scheme 10). The authors carried out a comparative study of the
catalytic efficiency of Fe3O4@PEG-SO3H with other catalysts. The com-
parative study showed that the use of Fe3O4@PEG-SO3H resulted in
R1 R1
OMe R2 OMe
N HN N
H R2-NH2, K2CO3
H
O 450 rpm, 2h O
B
cyclization
PEG grinding additive
O
R1
N R2
HN
O
reactions with shorter times and higher yield of the products. The recy-
clability of the catalyst was also investigated by the authors and it was
found that catalyst could be reused up to six cycles with slight changes
in catalytic efficiency. The catalyst showed a good TON and TOF in the
range of 57.142–67.857 and 0.816–3.392 h−1 respectively.
Similarly, Maleki et al. [64] reported the synthesis of β-amino car-
bonyl derivatives via one-pot multicomponent condensation reaction
of aniline, aldehyde and ketone with ethanol in the presence of
Fe3O4@PEG-SO3H as a superparamagnetic heterogeneous nanocatalyst
at room temperature (Scheme 11). The optimum catalyst loading was
also evaluated and it was found that 0.005 g of catalyst with EtOH pro-
duced 68% of product in 150 min, 0.010 g produced 94% yield in 25 min
and 0.015 g generated 82% product yield in 95 min. Thus, 0.010 g of cat-
alyst was chosen as the optimum amount of catalyst. The recyclability of
the catalyst was also examined and it was found that Fe3O4@PEG-SO3H
could be reused up to 5 runs. The efficiency of the present methodology
was revealed from the recyclability of catalyst, high TON (35.29–67.14)
and TOF (47.09–163.76) values.
There are many reactions that are catalyzed by the PEG due to its
ubiquitous properties and are summarized in Table 1.
3.2. PEG as reaction medium
PEG has been emerged as an ideal solvent system in synthetic chem-
istry due to its flexibility of degradation, less possibility of formation of
side products, stability in acidic and basic conditions and many more
[69]. Additionally, it can coordinate with metal and form a stable com-
plex with them although at the cost of selectivity.
One pot process of reduction of alkenes is one of the most successful
chemical procedure. Reduction of alkenes by using NaBH4–NiCl2.6H2O
in EtOH/PEG-400 as solvent under mild conditions has been introduced
by Li et al. [70] (Scheme 12). Ni (0) NPs formed in an ethanol/PEG-400
solution displayed uniform distribution. The authors used EtOH/ PEG-
400 for the reduction of alkenes. The catalytic system exhibited good ac-
tivity, recyclability and general applicability. In addition, the method
was cheap, convenient, and also applicable at industrial level for the re-
duction of alkenes.
Ding et al. [71] elucidated highly efficient and a green AGET ATRP
(activators generated by electron transfer for atom transfer radical poly-
merization) system, which was formed without using any additional li-
gands, using FeCl3·6H2O as a catalyst, and MMA (methyl methacrylate)
as a monomer for PEG-400. The authors also studied the effect of various
factors, such as the type of ATRP initiator, the molecular weight of PEG,
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 9

a
H O O
O
+
O H H
or H NH2
H2N
X O
O
Thermal solvent free
H
70oC
or
H

O
O
O
H
X
O O
O R O O

HN NH NH
O
R1
N O
HN O H
NH O
O R1 R HN NH

R1
HN
NH R
O

= PEG---HClO4

b
H2N O

O O
O O N
O O HC CH HC CH
HC CH
HC CH N
NH2 H2N
O O O NH2
= PEG---HClO4 H2N
NH2

H2N O
O O O O
NH NH
O
HN NH CH CH
HN -2 NH
O O O
O NH2

Scheme 7. a. Synthesis of bis-dihydrophrimidin-2(1H)-one and dihyropyrimidin-2(1H)-one derivatives using PEG-HClO4 as a catalyst. b. Plausible mechanism for synthesis of bis 3,4-
dihydropyrimidin-2(1H)-one.

polymerization temperature, reducing agent and solvent. Here PEG-400
was used both as solvent and ligand, as shown in (Scheme 13). The re-
ducing agent AsAc-Na was used for the reduction of Fe(III) from higher
to lower oxidation state Fe(II), after that the process was progressed as
normal ATRP catalyzed by FeCl2.
One-pot tandem Knoevenagel condensation of isatin chalcones with
aromatic/heteroaromatic ketone for the synthesis of a large variety of
bioactive spirooxindoles using PEG 400 as biosolvent and phase transfer
catalyst was reported by Gupta and co-workers [72]. PEG acted as novel
mild and efficient reaction medium as well as PTC to replace expensive
10 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

O 1. NaHCO3 Ar
120oC, MWI,10 min N
N + R2
R2 R1 N
Br R1
NH2 2.ArBr
Pd(OAc)2 +
KOAc, 220oC, MWI, 1h

R2= Me, Cl, OBn, CF3, CMeO2

R1 = OMe, Cl, F, CF3, CMeO2, NO2 = PEG-400

Scheme 8. Preparation of 2-arylimidazo[1,2-a]pyridines using PEG-400.

X
S
SH +
N
Cul, NaOH X = I, Br CuO, KOH
50-80oC 140oC
24 h 24 h

S S
S S
N N
= PEG-400

Scheme 9. S- and N-arylation of 2-mercaptobenzothiazole using PEG-400 as catalyst system.

and harmful catalysts for the synthesis (Scheme 14). The catalytic activ-
ity of PEG 400 might be due to its aprotic ethereal site that might behave
as a general base and facilitates the formation of carbanion/enolate from
isatin moiety in order to increase the rate of condensation. PEG was re-
covered and reused for five runs without considerable loss in its activity.
The benefits of this protocol are high atom economy, easy handling,
catalyst free, less reaction time, use of eco-friendly solvent and high
yields.
Li et al. [73] discovered a novel and efficient catalytic system for the
reduction of α-pinene to cis-pinane by NaBH4 using NiCl2.6H2O catalyst
in PEG-800/ethanol at room temperature. Ni nanoparticles generated in
situ behaved as reservoir for active catalyst. The conversion of α-pinene
and the selectivity of cis-pinane reached 97% and 98%, respectively
under optimal reaction conditions. The chain length of PEGs played an
important role in the reduction of α-pinene and it was found that reac-
tion did not occur in the absence of PEGs (Scheme 15).
The conversion rate increased as the chain length of PEG increased.
i.e. 90%, 93%, 94%, 97% for PEG-200, PEG-400, PEG-600 and PEG-800 re-
spectively but in contrast, the yield decreased on using high molecular
weight PEG (1000, 1500, 2000 & 4000) which might be due to the
higher viscosity of reaction medium.
Hasaninejad and Beyrati [74] used PEG-400 as a green and biode-
gradable polymeric solvent for one-pot, two-step, multicomponent syn-
thesis of novel asymmetrical bis-spirooxindole derivatives by the

R2
O H
C
X
O H O O
2 C
H3C C C C O R1 + + H2N NH2 R1 O NH
R2 EtOH, RT
N X
H
R1 = Et, Me R2 = OMe, OH, Cl, Br, H X = O, S

= Fe3O4@PEG-SO3H

Scheme 10. Synthesis of DHPMs in the presence of Fe3O4@PEG-SO3H as a catalyst.

 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 11

HN
NH2 O O

H R
+ R +
EtOH, RT O

= Fe3O4@PEG-SO3H R = Cl, Br, NO2, OMe, OH, Me, H

Scheme 11. Synthesis of β-amino carbonyl derivatives in the presence of Fe3O4@PEG-SO3H.

reaction of N-alkyl isatin, isatin derivatives, alkylmalonates and C\\H
activated carbonyl compounds in the presence of K2CO3 at room tem-
perature (Scheme 16). The synthetic pathway for the synthesis of titled
compounds consisted of two steps. Firstly, asymmetrical bis-isatin de-
rivatives were obtained from the condensation of N-alkyl isatin and
isatin derivatives. Then, the resulting products were treated with alkyl
malonates and carbonyl compounds to afford the related asymmetrical
bisspirooxindole derivatives.
The reaction was done in different solvents using different amount
of reagent, K2CO3 and it was found that 1.5 mmol K2CO3 in PEG-400
showed highest yield (94%) in 7 h at room temperature as compared
to other solvents which gave low yields.
Another interesting aspects of PEG as a solvent in reaction was re-
ported by Borges and co-workers [75] for the preparation of β-
arylthio-α,β-unsaturated esters, aldehydes and ketones via
hydrothiolation of electron-deficient alkynes with arylthiols. Here,
(E)-β-arylthio unsaturated carbonyl compounds were selectively ob-
tained from aldehydes and the (Z) stereoisomer was obtained from
ester and ketone. The reaction was performed using different solvents
and it was found that low yields were obtained in glycerol, ethanol
and THF and even without solvent (Scheme 17).
When PEG-400 was used at room temperature, low yield (47%) was
obtained but as the temperature was raised (60-80 °C), the yield was in-
creased to (84–87%). This study indicated that PEG-400 might be acti-
vating the Michael acceptor and facilitating the attack by thiol. It was
also found that PEG-400 worked efficiently even after five successive
reactions.
Multistep synthesis of isoquinolinone, isocoumarin and olefination
of Weinreb amides by activation of C\\H bond using Ru(II)/PEG-400
as green and ecological media was reported by Yedage and Bhanage
[76] (Scheme 18). Regioselective and stereoselective formation of new
C\\N, C\\O and C\\C bonds via one step fission of O\\H, C\\H, N\\O
and N\\H bonds were observed. The method is sustainable due to its
peculiar characteristics such as atom economy, reuse of overpriced ru-
thenium based homogeneous catalyst, mild reaction conditions with
simple extraction process, multitasking catalyst for C\\H activation,
scalable up to gram level and simple workup process. PEG worked as
facile reaction media for this cross coupling reaction along with its

Table 1
Different multi-component reactions that are catalyzed by PEG as a catalyst.

S.no. Reactants Reaction Product structure Comments Ref.

conditions

PEG-SO3H
Substituted 2-amino phenols and substituted PEG acts as support for sulphonic acid catalyst as well as
1. 60–65 °C [65]
benzoic acids solvent medium.
(5–6 h)

PEG-SO3H
2. Substituted phenol and dicarbonyl compounds Excellent yield, recycled at least three times. [47]
80 °C (10 min.)

Aldehyde, ethyl acetoacetate, and PEG-SO3H PEG-SO3H as catalyst in which the functionalized PEG
3. [39]
urea/thiourea MW acts simultaneously as catalyst and as solvent

PS–PEG (Polystyrene-PEG) bound sulfonic acid exhibited

PS-PEG-SO3H good catalytic
4. Aldehyde, ethyl acetoacetate, urea/thiouera Dioxane: activity in the Biginelli-type reaction with good yield and [68]
2-propanol good recyclability
upto six times without any loss in catalytic activity.
12 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

NaBH4 recyclability. The versatility of PEG was studied and it was found that
EtOH PEG-400 worked well as compared to other PEGs (200, 600, 2000,
5mol% NiCl2.6H2O 4000), since PEG is cheap, easy to handle, stable, non toxic and recycla-
ble. Thus, its use in the synthesis of triarylmethane derivatives was
found to be an efficient protocol.
Hydrogen Donation Revaprasadu et al. [77] derived an eco-friendly Friedel-Crafts alkyl-
R1 ation for the preparation of triarylmethane derivatives, which were syn-
R1 Stable Ni (0)
thesized via one-pot condensation of various electron-rich arenes with
R2 30oC R2 a broad variety of aldehydes using polyethylene glycol (PEG-400) as a
green solvent at 50–60 °C in high yields (Scheme 19). The study inves-
------EtOH tigated that some compounds exhibited high anti-viral activity against
tobacco mosaic virus. Environmental acceptability, excellent yields,
simple work-up procedure, cleaner reaction profile, eco-friendly sol-
vent, shorter reaction times, inexpensive and recyclable non-ionic sol-
vent are notable features of this protocol to synthesize potentially
= PEG-400 useful anti-viral products.
Reddy and coworkers [78] presented a green, rapid, and eco-friendly
Scheme 12. Reduction process of alkenes using NaBH4 - NiCl2·6H2O in EtOH/PEG-400 as process for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5d]
solvent system. pyrimidin-4(1H)-one derivatives via one-pot mechanism by coupling

m
ka kp
Pn - X + Fe(II)Cl2/ Fe(III)Cl3/ + Pn. Pn-Pm
kda kt

Reducing agent AsAc-Na

= PEG-400

Scheme 13. Mechanism for AGET ATRP in PEG-400.

O
X
O C
R H3C stirring at 70oC HO
C X
O +
O X O
N
H N
H

Solvent free
stirring at 120oC stirring at 100oC

O X
C

X
O
N
H

Isatins
R- H, F, Cl, Br, CH3 = PEG-400
X - H or N

Scheme 14. Synthesis of 3-hydroxy-2-oxindoles and 3-methylene-2-oxindoles using PEG-400 as solvent system.
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 13

NiCl2.6H2O +
+ NaBH4

Cis-pinane Trans-pinane
α -pinene
= PEG-800/ Ethanol

Scheme 15. Reduction of α-pinene using PEG-800.

O CN O NH2
O +
+ HN R
O Y
O K2CO3 O Y
N
N O O
O RT N

N R

X O N R
O
O
Y
= PEG-400
O
H2N

Scheme 16. Preparation of novel asymmetrical bis-spirooxindoles in the presence of K2CO3 in PEG-400 at room temperature.

of 1-H-benzo[d]imidazol-2-amine, various aldehydes and 2-
cyanoacetamide with PEG-400 as a reaction media (Scheme 20a, b).
The reaction was studied under different parameters viz temperature,
solvents and catalyst in order to enhance the yield of the product. Use
of different catalysts did not give satisfactory results. Different solvent
system resulted in less yields even at elevated temperature. But, as the
reaction was performed using PEG-400 even without catalyst at room
temperature, high yield were obtained in short reaction time. On further
increasing temperature, no change in yield was found.
Nagaraju et al. [79] reported an eco-friendly one-pot four-
component cascade reaction utilizing α-enolic dithioesters, aldehydes,
cyclic 1,3-diketones and cysteamine in water–PEG-400 via stirring for
20 min at 100 °C over a preheated oil bath for direct synthesis of highly
diversified thiazoloquinoline scaffolds (Scheme 21a). A plausible mech-
anistic pathway for the formation of thiazoloquinoline scaffolds has
been shown in (Scheme 21b). Initially, the formation of cyclic N,S-acetal
(I) by the reaction of α-enolic dithioester with cysteamine took place
which was isolated and characterized. After that, aldehyde with cyclic
1,3-diketone gave Knoevenagel product (II), a highly reactive ortho-
quinonemethide intermediate (that could not be isolated (I))
underwent addition with ortho-quinonemethide intermediate (II) via
an aza–ene fashion to create acyclic intermediate (III) and gave
imine–enamine and keto–enol tautomerization to form intermediate
(IV), which rapidly underwent intramolecular dehydrative N-
cyclization to prepare the desired triheterocyclic products.
The adaptable design shows various tendencies such as numerous
bond formation efficiency, functional tolerances, etc. PEG-400 increased
solubility of reactants that led to high interfacial area and lower mass
transfer resistance. The optimization studies for solvent concluded
that PEG-400 alone gave 75% yields in 6 h while PEG:H2O mix (1:9)
gave 92% yields within 2 h.
Convergent and eco-compatible protocol for the synthesis of 5-aryl-
1,2,4-triazolidine-3-thiones using PEG-400 as solvent was reported by
Rathinam and Appaswami [80]. The study elucidated that the reaction
of 4-chlorobenzaldehyde and thiosemicarbazide in the presence of sol-
vent PEG-400 reaction was strongly influenced by the temperature
(Scheme 22). The yield was quite good (97%) at 80 °C for 6 min with
PEG-400 as the solvent. High yields, simple method, high atom

SR1 G R G
N2, 60oC
R G + R1SH +
R SR1
Z E

R= R1= Ph,
= PEG-400
G= CHO, COOEt, COC6H5

Scheme 17. Synthesis of β-arylthio-α, β-unsaturated compound using PEG-400 as recyclable solvent system.
14 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

Ar R

Ru (II)

PEG-400

R = NMeOMe R = NMeOMe R= NHOMe R= OH

Ph
Ph Ph
Ph
Ph Ph
Ph

O O
O O
Me
N Me NH
H N O
Ph Ph
Ph
Ph Ph
Ph Ph

Scheme 18. Ru(II)-PEG-400 catalyzed annulations via C-H bond activation.

economic, fast, direct as well as low-cost and eco-friendly nature are the
best properties of PEG.
Mekala and colleagues [81] investigated a well-organized and one-
pot synthesis of 1,2 disubstituted benzimidazoles by the reaction of
two mole of aldehydes with one mole of substituted benzene 1,2- di-
amines using effective and non-toxic PEG-400 as a reaction medium
without use of catalyst at 60 °C (Scheme 23a). The mechanism involved
nucleophilic attack of phenylenediamine on the carbonyl carbon. Here,
the electrophilicity of the carbonyl carbon has been enhanced in PEG-
400 medium rather than the other solvents and the reaction by remov-
ing the liberated water, which is soluble in PEG-400 and enabled its con-
version to the corresponding benzimidazole (Scheme 23b). The rate of
reaction was compared in different solvents and it was observed that re-
action in PEG-400 was highly facile and gave high yields (86%) under
stirring at 60 °C for 4 h. PEG can be used upto three times without loss
in its activity. Benefits of this reaction are mild condition, recyclable re-
action medium, operational simplicity and high product yields.
Carbonylative Sonogashira coupling reaction is a very important
transformation in organic chemistry for the preparation of alkynyl ke-
tone derivatives. Recently, Cai and co-workers [82] envisioned that
PdCl2 (PPh3)2 in a mixture of water and PEG-2000 (1:1) is a highly
active catalyst for the carbonylative Sonogashira coupling reaction of
aryliodides with terminal alkynes. The reaction proceeded at mild ther-
mal conditions and at the atmospheric pressure of carbon monoxide in
equal weights of PEG-2000 and H2O mixture (Scheme 24a). The effect of
PEG was initially investigated on carbonylative Sonogashira coupling
reaction of aryl iodides with terminal alkynes in water. In the absence
of PEG-2000, low yields were obtained while on addition of PEG-2000,
excellent yields were obtained but on further increase in amount of
PEG-2000, decrease in yield was found. The mixture of PEG-2000 with
other solvents was also analyzed and the products obtained were
found in low yields. On proceeding mixture of PEG-2000 with H2O, ex-
cellent yields were obtained as shown in (Fig. 5). In addition, various
chain length of PEGs were also examined and PEG-2000 was found su-
perior to PEG-600, PEG-1000 and PEG-400.
The putative pathway for the synthesis of alkynylketones was
shown in (Scheme 24b). It involved reduction of PdCl2(PPh3)2 to Pd
(0)(PPh3)2 by CO and H2O followed by oxidative addition of an aryl io-
dide to Pd(0)(PPh3)2 giving arylpalladium(II) complex (I), which
underwent migratory addition of carbon monoxide to form
acylpalladium(II) complex (II). Subsequent transmetalation between
(II) and terminal alkyne in the presence of a base and reductive

R Ar Ar
2 Ar-H + CHO
50-60o C

= PEG-400 R

R = H, p-CN, m-NO2, p-OH, m-Cl, o-OCH3, p-OCH3

Scheme 19. Synthesis of novel triarylmethanes using PEG-400.

 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 15

a O
R NH
R
N O N NH
+ 2R-CHO + N NH
NH2
C
N H2N RT N
H

= PEG-400

b
H O O
H O O
N b H N
O N OH OH N NH2
n C R H2N N
C NH2
H2N -H2O R NH2
HO R N
H O H O
H
OH OH
n n

O O
NH O O NH2
R NH2 R
R R NH2 R
NH
N NH
N R N NH2
NH N NH
NH NH N
N H
N N

Scheme 20. a. Synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5d]pyrimidin-4(1H)-one under catalyst free conditions using PEG-400. b. Mechanism of synthesis of benzo[4,5]imidazo
[1,2-a]-pyrimido[4,5-d]pyrimidin-4(1H)-ones with PEG-400.

elimination of alkynyl ketone (IV) form the intermediate (III) and re-
formed Pd(0)(PPh3)2. The possibility of catalyst recycling has been ex-
plored, and it could be reused six times with excellent yields.
An eco-friendly asymmetric Michael addition of aldehydes to trans-
β-nitrostyrenes using PEG-400 as recyclable solvent was reported by
Paixão and co-workers [83] (Scheme 25). The nitrostyrene substrates
bearing the β-aryl substituent with withdrawing –NO2 group, gave the
corresponding Michael derivatives in quantitative yield with good dia-
stereomeric ratios and excellent ee values upto 99%. After the comple-
tion of reaction, the PEG could be completely recovered and hence
reused for five consequent reactions with good yields and selectivity.
The authors proposed that the improved reactivity and selectivity of
their catalytic system has been attributed to the host–guest complexa-
tion between PEG and nitrostyrene which stimulated the nucleophilic
addition of resulted enamine generated from the reaction between al-
dehyde and organo-catalyst.
Srivastava [84] reported use of PEG-400 as a solvent system for the
synthesis of Wieland Miescher ketone using L-proline as a catalyst.
PEG-400 mediated L-proline (1 mol%) was found adequate for the syn-
thesis of this ketone via non selective conjugated addition reaction
followed by enantio- selective intermolecular aldol condensation of
triketone. The triketone was synthesized by the reaction of
methylcyclohexane-1, 3-dione, methyl vinyl ketone followed by
enantioselective intermolecular aldol condensation reaction of
triketone. PEG 400 mediated L-proline was found to be sufficient for
the synthesis of Wieland-Miescher ketone. Short reaction time, use of
catalyst upto eight times, high yield and high selectivity were the
major benefits of this reaction (Scheme 26).
Nickel-catalyzed Sonogashira coupling of aryl halides with terminal
alkynes in PEG-400/H2O was reported by Wei and coworkers [85]. One-
pot two-component cross-coupling reactions of different types of aryl
iodides with various alkynes progressed smoothly at 100 °C in PEG-
400:H2O with K2CO3 for the formation of corresponding aryl acetylenes
in high yields under the optimized reaction conditions (Scheme 27).
The effect of solvent was also studied on the reaction. It was found
that a combination of PEG-400 and H2O is more effective than PEG-
400 unaided as solvent. The reaction in PEG-400/H2O (3:2) was respon-
sible for high yields. PEG-400: H2O system was reusable up to six times
with no considerable loss in action. Thus, this protocol presented advan-
tages such as good-to-excellent yields, easy work-up, flexible reaction
conditions, and economic practicability.
Goodajdar et al. [86] presented a green, rapid, and eco-friendly pro-
cess for the synthesis of aryl azides and thiocyanates catalyzed by PEG-
DIL-MnCl4. Aryl azides and thiocyanates were prepared via a one-pot,
two-component reaction of benzyl halide and NaN3/NH4SCN under
H2O as a solvent at 100 °C in the presence of PEG-DIL-MnCl4 catalyst
(Scheme 28a). The advantages of this protocol are easy workup, high ef-
ficiency, eliminating toxic solvents and reducing environmental im-
pacts. PEG-DIL-MnCl4 represented its activity as a Lewis acid reagent
and considerably accelerated the reaction. Mn2+ acted like a Lewis
acid with an empty orbital which increased the speed of reaction by
connecting to the leaving group (Scheme 28b).
A green, direct and well-organized protocol for the synthesis of a se-
ries of isoxazolylchromeno[2,3-b]pyridine-3carboxylate derivatives has
been reported by Ponduri et al. [87]. One-pot reaction of
isoxazolylenamino esters and 3-formylchromones by employing water
16 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

a O
O R2 O
H2N
CHO R3 R1
+ + R3
OH S + O
R2 R3 -H2O S N
R1 SMe R3
HS

R1 - aryl, hetaryl, alkyl

= PEG-400
R2 - arylcyclohexyl
R3- Me,H

O H R2 O
b S
H2N O NH
N,S acetal R1 R3
OH S +
formation I S N III
R1
R1 SMe R3
HS OH
R2
tautomerization
O O O O imine-enamine
Knovenagel and keto-enol
CHO
+
condensation R3 R3
R2 R3 R3 II O R2 O

R1 R3
S O IV
NH R3

N-cyclization
-H2O

O R2 O

R1 R3
S N
R3

Scheme 21. a. Synthesis of thiazoloquinolines using PEG-400 as solvent system. b. Possible mechanism for the synthesis of thiazoloquinoline derivatives in presence of PEG-H2O.

as a reaction medium and polyethylene glycol-400 (PEG-400) as the
green promoter was employed (Scheme 29a). PEG-400 and H2O (1:9)
at 100 °C gave excellent results (88% yield). The optimization of an
amount of PEG-400 was studied and it was found that when the amount
was increased (20 and 50 mol%) or decreased (5 mol%) in the ratio of
PEG-400: H2O, no considerable increase in yield was observed. Simi-
larly, PEG-400/H2O (1:9 at 100 °C) was the most effective solvent
media for this one-pot protocol. The recyclability of the solvent system
was also investigated and it was found that PEG-400/H2O could be
reused up to five cycles.
A plausible pathway for the formation of isoxazolylchromeno[2,3-b]
pyridine was proposed in (Scheme 29b). Firstly, the reaction between
compound isoxazolylenamino esters and 3-formylchromones by using
PEG-400 took place to form intermediate, followed by elimination to
produce another intermediate to afford the desired product.
Dehydrogenative C\\H arylation of 1,2,3-triazoles was reported by
Ferlin and coworkers [88]. The intramolecular C\\H arylation of triazole
was accomplished with the help of a reusable palladium catalyst in PEG
(Scheme 30). The effect of PEG's molecular weight and the palladium
source was examined and high molecular weight PEG-20000 and Pd
(OAc)2 emerged as the best solvent and catalyst, along with pivalic
acid providing optimal performance. The authors also examined the re-
cyclability of PEG mixture. It was found that the efficiency of PEG de-
creased a little less after some consecutive runs.
A similar solvent system has been used for the synthesis of
dihydropyridines by Bathula and co-workers [89] (Scheme 31). Green,
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 17

S
HN
O H
H H 5-12 min HN N R
+ N N 1
H2N R1
R
S
R

R1 - H, CH3 , C6H5
R - H, 4-Cl, 4-Br, 4-F, 4-OH, 4-CH3 ,3-NO2, 2-Cl, 2-OH = PEG-400

Scheme 22. Synthesis of 2-aryl-1,2,4-triazolidine-3-thiones under catalyst free condition using PEG-400 as solvent system.

systematic, eco-friendly and versatile method has been developed for the
facile and one-pot synthesis of dihydropyridines by Indion 860 catalyzed
reaction of aniline, aldehydes and ethyl-3,3-diethoxypropionate in the
presence of PEG-400. The study revealed that the authors have used
other solvents like ethanol, 1,4-dioxane and water and these were
found to be less effective in comparison to PEG-400 and PEG-400 was
found highly effective solvent for the reaction resulting in high yields.
Ghom et al. [90] described an efficient and sustainable method for
the one-pot direct iodination and dehydrogenation of dihydrobenzo[a]
carbazoles using periodic acid in PEG-400 under mild conditions in
high to excellent yields (Scheme 32a). The advantages of the reaction
are metal-free cheap catalyst, easy work-up, benign reaction conditions
and elevated regio-selectivity. PEG-400 played an imperative role as a
green solvent system in the reaction. The optimum amount of PEG as
a solvent for this reaction was also evaluated. The viscosity increased
with the increase in molecular weight of PEGs. However, on further in-
crease in the temperature, the yield remained same. Thus, PEG-400 was
established as a best reaction solvent for this reaction.
The mechanism of reaction has been shown in (Scheme 32b). The
dihydrobenzo[a]carbazole was found susceptible to reduce the oxida-
tion state of periodic acid, which has been converted to iodic acid via de-
hydrogenation process. High amount of periodic acid helped in

a CHO
60oC N
NH2 R1 R2
+ 2 R2 N
R1
NH2

R2
R1 - H, CH3, Cl, NO2
R2 - H, Cl, Me, OH, OMe, OEt = PEG-400

b
O H
H NH2 N H
NH2 O R -H2O N H
+ N R
-H2O N R N
R H a R -OPEG
NH2 + HO
R H-O R

O
H

H
N
N
R
R
= PEG-400 N
N
R
R

Scheme 23. a. Preparation of 1,2-disubstituted benzimidazoles using PEG-400 as a solvent system. b. Mechanism for the PEG-mediated synthesis of benzimidazoles in the presence of PEG-400.
18 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

a
I O
PdCl2(PPh3)2
+ CO + R C R
Et3N, 25oC, 24 h G
G

G - electron withdrawing group or electron donating group = PEG-2000/ H2O

R- aliphatic and aromatic group

b PdCl2(PPh3)2
CO H2O PPh3
PPh3
CO O
Arl
Pd(0)(PPh3)2 Ar Pd I Ar C Pd I
II
PPh3 I PPh3

PPh3
O Et3N
Ar C Pd R H R
PPh3 III
O
Ar C R
IV

Scheme 24. a. Pd-catalyzed carbonylative coupling of various alkynes and aryl iodides in PEG-2000/H2O mixture. b. Possible mechanism for carbonylative coupling reaction.

protonation. The formed iodic acid could strongly be chelated with PEG-
400 to afford the iodinated product.
The PEG-400 was studied as an efficient, eco-friendly and reusable
solvent cum activator for the synthesis of aza-arene derivatives through
a one-pot multi-component coupling of 2,6-dimethyl-pyridine or 2-
methylquinoline, malononitrile and aldehydes through a sp3 bond
functionalization by Mallepalli et al. [91] (Scheme 33a). The mild reac-
tion conditions, inexpensive reaction medium, operational simplicity
and high yields are the main advantages of this protocol. It was reported
that the reaction doesn't require any additive or acid catalyst.
A proposed mechanistic pathway for the formation of aza-arene de-
rivatives has been presented in (Scheme 33b). 2,6-Dimethyl pyridine
100
Isolated yield (%)
existed in an equilibrium with the corresponding enamine in the pres-
ence of PEG-400 solvent because of protonation of ring nitrogen. PEG-
400 initiated Knoevenagel condensation of benzaldehyde and
malononitrile offered 2-benzylidene malononitrile via intermediate.
Michael addition of enamine on α,β unsaturated compound facilitated
the formation of aza-arene intermediate, which further converted into
desired product, 2(1-phenyl-2-(pyridin-2-yl)ethyl)malononitrile.
A similar green, eco-friendly, facile and easy synthesis of thiadiazolo
[3,2-a]pyrimidine-6-carboxylate derivatives was reported by Kasaboina
et al. [92] (Scheme 34). The reaction involved multicomponent conden-
sation reaction of benzosuberone with 1,3,4-thiadiazol-2-amine,
ethylacetoacetate and substituted benzaldehyde in the presence of
PEG-400 as a solvent system. The use of PEG-400 reaction medium
was highly beneficial as the system remained neutral, which helped to
maintain numerous acid and base functional groups as unchanged.

80 Ganapathi et al. [93] used PEG-600 as a new and efficient solvent

system for the synthesis of diphenyl substituted pyrazoles via conven-
60 tional and microwave assisted efficient synthesis. The reaction involved
40 one-pot multicomponent reaction of acetophenone, 4-hydroxy benzal-
20 dehyde and NaOH in PEG-600 as solvent via Claisen–Schmidt condensa-
tion. PEG-600 is inexpensive, non-toxic, eco-friendly, water soluble and
0 potentially recyclable, eco-friendly, short reaction time, high yields are
0 1 2 3 4 5 attractive point of this protocol.
An eco-compatible protocol for the synthesis of (benzo[d]imidazo
Amount of PEG-2000 in water (g) [2,1-b]thiazol-3-yl)-2H-chromen-2-one using ethanol-PEG-600 as a
recyclable solvent was reported by Balwe et al.[94] (Scheme 35a).
Fig. 5. Effect of mixture of PEG-2000 and water on the carbonylative coupling reaction. One-pot multi-component cascade coupling reaction of 2-
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 19

SC6H13

N SC6H13
O R2
H OTMS
NO2 O
H + R2 H NO2
R1 PhCO2H, 4oC R1

Cl Br OMe
F NO2
R2 =
OMe Br

= PEG-400

Scheme 25. Asymmetric Michel addition using organocatalyst in PEG-400 reaction.

O O
O
L-proline
AcOH, hydroxyquinone
+ RT
O O O O
O H2O, 72-75oC

= PEG-400

Scheme 26. Organocatalysts/PEG (400) catalytic system for the synthesis of Wieland-Miescher ketone.

aminobenzothiazole, arylglyoxal monohydrate and 4-hydroxycoumarin
in ethanol-PEG-600 under catalyst-free condition gave high yields. The
benefits of this method include green technology, mild reaction condi-
tions, short reaction time and excellent yields.
The effect of type of solvent and solvent dosage were also studied by
the researchers to optimize the reaction parameters i.e. the mild acidic
nature of PEG-600, which enhanced the rate of reaction to complete
the conversion of reactants in short reaction time to afford excellent
yields. However, in PEG-H2O, most organic scaffolds have an extremely
low solubility, which resulted in lower yield of products. Straightly, the
advantage of the combination of ethanol-PEG-600 was that it afforded
products that could be rendered very pure by simply washing the
solid crude products with cold ethanol without chromatographic
purification.
The mechanism of reaction involved Knoevenagel condensation be-
tween arylglyoxals and 4-hydroxycoumarin to form an adduct which
acted as a strong Michael acceptor that further reacted with the nitro-
gen of 2-aminobenzothiazole ring giving intermediate. Then, an

NiCl2(PPh3)2
CuI
I + R2 R2
R1 K2CO3 , 100 °C R1

-----H2O

R1= 4-Me, 4-MeO, 4-Cl, 4-CF3, 3-Iodopyridine , 2-Iodothiophene, 4-NC

R2= Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, n-C6H13

=PEG-400

Scheme 27. Nickel-catalyzed Sonogashira coupling in PEG-400/H2O.

20 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766
a
----DIL-MnCl4
CH2X + NH4SCN
R1
X= Cl R1= H
X= Br R1= H a
X= Br R1= 2,4-diCl
b
O N +N
O A
Na+
O
O N +N
Scheme 28. a. Synthesis of benzyl thiocyanate from benzyl halide catalysed by PEG-DIL-MnCl4. b. Possible mechanism for promotion of reaction by PEG-DIL-MnCl4.
intramolecular cyclic condensation between the amino and the car-
bonyl groups of the Michael adduct took place to provide new interme-
diate, which then underwent subsequent elimination of water to afford
the desired product (Scheme 35b).
Highly efficient, inexpensive, environmentally benign and recyclable
Pd/PEG-400 system for the synthesis of aromatic esters was reported by
Gaikwad and Bhanage [95] (Scheme 36a). Iodobenzene and phenol
were used for the reaction using PEG-400 as a solvent with base
(Na2CO3) under CO (balloon) atmosphere at room temperature giving
moderate to good yields (97%). This protocol displayed high turn over
number (TON) 142.64 and turn over frequency (TOF) 5.94 h−1 .
The plausible reaction mechanism of oxime palladacycle catalyzed
phenoxycarbonylation for ester synthesis was shown in (Scheme
36b). Initially, Pd(0) got inserted between aryl iodide via breaking of
C\\I bond to form species (II). Then CO (g) coordinated with aryl palla-
dium species (II) to form (III). After that, phenol reacted with species
(III) to form (IV) and reductive elimination of palladium from (IV)
took place to offer phenyl benzoate product.
The researchers compared the solvent efficiency of PEG and PEG-400
with water. Thus, PEG-400 served as an efficient solvent giving 75%
yield of products. It was observed that the PEG-400 was recyclable at
least five times with very little loss in product yield.
Azide−alkyne cycloaddition was carried out using a variety of Cu
catalysts to produce triazoles from lipophilic and hydrophilic substrates
in PEG-2000 (Scheme 37) and was reported by Billault et al. [96]. Chela-
tion of the catalytic copper by PEG was investigated by electron para-
magnetic resonance spectroscopy. PEG protected Cu from atmospheric
oxidation, allowing the reaction to proceed without an inert atmo-
sphere. Cu was retained in PEG once the solvent was recycled, reducing
the concentration of metal in the product. The PEG−Cu solvent could be
recycled six times without loss in activity, although Cu was gradually ac-
cumulated in the PEG phase. Ultrafiltration could be used to remove
water-soluble cycloadduct, the lipophilic products were removed with
dichloromethane, and diethyl ether was used to precipitate PEG.
CH2SCN
R1
H2O
X= Br R1= 4-Me
X= Br R1= 4-OMe
= PEG
MnCl42-
B
R1
B= N3-, SCN-
A green and novel tandem oxidative alkenylation/oxa-Michael addi-
tion reaction of benzoic acids with alkenes to form phthalides has been
demonstrated by Zhao et al. [97] (Scheme 38) using RuCl2(p-cymene)]
2/Cu[OAc]2 as a catalyst in the presence of PEG-400/H2O system. Here
PEG phase was easily recovered and reused six times without any con-
siderable loss of activity.
An efficient transition metal and catalyst-free synthesis of 1,3,5-tri-
azines from benzylamines and N-substituted benzylamines amidine
by aerobic oxidation has been carried out in PEG-600 without the
need of Ru phosphine catalyst was reported by Tiwari and Bhanage
[98] (Scheme 39).The reaction did not proceed in water, ethanol or glyc-
erol at 100 °C. However, use of PEG-600 as a solvent achieved 70% yields.
Greener, ecofriendly, gram-scale, phosphine ligand free synthesis,
simple-workup, use of easily recoverable catalyst, cheap oxidant and
short reaction procedures are other advantages of this protocol.
A novel one pot multi-component stereo and a regioselective syn-
thesis of dispirooxindole pyrrolidine linked 1,2,3-triazole from isatin,
sarcosine, malononitrile and aryl azide using Cu(I) catalyst in PEG-400
was demonstrated by Kumari and Khurana [99] (Scheme 40). High
yields (92%) in short reaction time (2 h) was achieved in 10% v/v PEG-
400/ H2O, whereas a range of both protic and aprotic polar solvents
gave very low yields. Increased solubility of reagents and the hydrogen
bonding properties of water were supposed to play a significant role in
the reaction.
Catalyst-free multi component synthesis of selenopyridines in PEG-
400 using ultrasound irradiation was proposed by Khan and group [100]
(Scheme 41). Selenopyridines were synthesized from aldehydes,
malononitrile, and benzene selenol which involved the creation of
four new bonds. The effect of temperature was also studied and it was
found that increase in temperature from 25 °C to 50 °C were responsible
for reduction in the reaction time but the yield of the desired product
was also reduced. It was suggested that PEG activated the aldehyde
and malononitrile to form an intermediate and played an active role in
the catalytic cycle.
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 21

a
O
O O
EtO
O EtO
H3C HN CH3 CHO
+ H3C N O
O H2O, 100°C H3C
N
O N
Ph O
Ph
= PEG-400

b
H O
O O
O O O O HO H O
H O OEt
EtO
H H + H
H2O N R
H3C H3C N O
O O
H R

O O O O

EtO 6 -electro-cyclization EtO

= PEG-400
H3C N O H3C N O
H3C
R R
R= N
O
Ph

Scheme 29. a. Synthesis of isoxazolyl chromeno[2,3-b]pyridine-3carboxylate derivatives with PEG-400 as solvent system. b. Possible mechanism for preparation of isoxazolyl chromeno
[2,3-b]pyridine-3carboxylate derivatives using PEG-400.

An environmentally benign one pot multi-component synthesis of
biologically active pyrrolo[1,2-a]quinoxaline, synthesized from
benzylamine and 1-(2-aminoaryl)pyrrole using K2S2O8 as an oxidant
and PEG-400 as a green and reusable solvent in moderate to excellent
yield was reported by Patil et al. [101] (Scheme 42). Here, PEG-400 be-
haved as a green recyclable solvent, neither loss in its activity nor signif-
icant decrease in yield of product was observed.
Disale et al. [102] explicated simple, mild and ecofriendly synthesis
of benzyl phosphonates from benzyl chloride and diethyl phosphate
as model substrates using PEG/KI as a catalytic system. In this protocol,
PEG not only acted as a reaction medium but also worked as a PTC
(Scheme 43). The reaction was found to be solvent dependent giving
the best results in PEG-400. PEG enhanced the reactivity of the inorganic
base by chelation of the counter ions and helped to improve the

O N O
H [Pd] N
N N
N Oxidant, Acid
n-Pent
N H 140oC

n-Pent
= PEG-2000

Scheme 30. Dehydrogenative C-H arylation of triazole in the presence of PEG-2000.

22 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

R
EtO2C CO2Et
O OEt O Indion 860
Ar NH2 + R + N
H OEt OEt 95°C
Ar

Ar = 4-MeC6H4, 2-MeOC6H4
= PEG-400
R = 4-BrC6H4, C6H5, 3-BrC6H4, 4-ClC6H4, 4-CNC6H4

Scheme 31. Indion 860 as catalyst in the synthesis of 1,4-dihydropyridines under PEG-400.

efficiency of green synthetic approach. Various hydroxides and carbon-
ates of other alkali and alkaline earth metals were applied as bases to
promote this transformation in PEG.
Reddy et al. [103] demonstrated a new approach for the synthesis of
2-amino pyridine in good yields (82–90%) by a MCR reaction using FeF3
as a catalyst under sonication in PEG-400 as a solvent. The protocol is
compatible with both aliphatic and aromatic aldehydes either having
electron withdrawing or donating groups. No reaction took place in
the absence of catalyst (Scheme 44).
A green method for the synthesis of isoxazoles and isoxazolines by 1,
3 dipolar cycloaddition of benzoylnitromethane/ethyl 2-nitroacetate
with dipolarophiles using PEG-400 and H2O in 1:1 ratio has been re-
ported by Chary and coauthors [104] (Scheme 45a). A variety of
solvents like 1,4-dioxane, DMF, DMSO, acetonitrile etc. were used but
no product was formed even after prolonged heating. To scrutinize the
diversity of this methodology, different alkynes as well as alkenes
were employed as dipolarophiles. The pathway progressed finely with
both aromatic alkynes affording isoxazoles in good yields.
A plausible mechanism of the reaction showed that PEG/H2O played
a key role in the reaction. Initially nitro group was activated by PEG/H2O
as shown in (Scheme 45b). A chelate type of complex (A) was formed
due to H-bonding and got tautomerized to B that further underwent
1,3-dipolar cycloaddition with dipolarophiles to form C. Finally, C on
exclusion of water and PEG afforded the desired product.
Reddy et al. [105] devised an eco-benign pathway for the synthesis
of 3-arylmethyl/diarylmethyl indoles using PMA-SiO2. It is a three

a
I
H5IO6

N RT N
H H

= PEG-400

b
H5IO6

N
N H
N H
H
HIO3
+
HIO3
H2O
+
O
O O
I
= PEG-400
I
O O
O
N
H

Scheme 32. a. Iodination of dihydrobenzocarbazole under PEG-400 as solvent at room temperature. b. Mechanism of one pot iodination using H5IO6 in presence of PEG-400.
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 23

a
CHO

+ + NC CN CN
RT N
N CN

= PEG-400

b
H
+ ----OH
N CH2 N

H O H

H H H CN
-H2O
H O H
O O CN
O
H
H H NC CN

NC CN

= PEG-400 N
C
N

C
N

Scheme 33. a. Synthesis of 2-substituted aza-arenes by PEG mediated Knoevenagel condensation through sp3 C-H reaction. b. Mechanism of formation of aza-arene derivatives with PEG-400.

component reaction (indoles, aldehydes, and N,N-disubstituted A environmental friendly pathway for the synthesis of 5-substituted
anilines) that involved aza-Friedel–Crafts reaction in PEG-400 thieno[2,3-c]pyran-7-ones has been developed by Rao et al. [106] via Cu
(Scheme 46). catalyzed coupling-cyclization of 3-iodothiophene-2-carboxylic acid

CH3

O O
N NH2
H O CH3
N R
S O O
Cl
+ H3C N N
H3C + O CH3
N
Cl S
R
H3C H3C

H3C

R= 4-Cl, 2,4-di-Cl, 2-Me, 4-Me, 2-Br, 4-Br, H, 4-F,2-OMe, 3-OMe = PEG-400

Scheme 34. Synthesis of thiadiazolo[3,2-a]pyrimidine-6carboxylate derivatives using PEG-400.

24 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

a
OH O
O OH
N OH R1
+ EtOH O
R NH2 + R1
S OH O O N
R N
S
= PEG-600-EtOH

R1 = C6H5, 3-OMeC6H4, 4-FC6H4, 4-NO2C6H4, 3,4-OCH2O-C6H3

R = 6-CH3, H, 6-OCH3, 6-Cl, 6-F

b S
H2N
N
O O
OH O O
O -H2O - H2O O
R1 OH
OH +
R1 O OH
O O O O N NH O
OH
I R1
S N
II N
S

Scheme 35. a. Synthesis of (benzo[d]imidazo[2,1-b]thiazol-3-yl)-2H-chromen-2-one derivatives by using ethanol-PEG-600. b. Mechanistic proposal for the synthesis of (benzo[d]imidazo
[2,1-b]thiazol-3-yl)-2H-chromen-2-one derivatives.

with terminal alkynes in the presence of K2CO3 in PEG 400 under soni-
cation. High yields were obtained in the presence of PEG-400 as com-
pared to other solvents like ethanol and n-butanol. A series of
compounds was formed in acceptable yields by varying terminal al-
kynes (Scheme 47a).
The mechanism of reaction showed that PEG played the role of li-
gand and formed Cu(I) complex by the interaction of cuprous iodide
with PEG under sonication. This underwent oxidative addition with
the carboxylate anion of reactant to form the arene-Cu species (II). Al-
kyne react with (II) in the presence of base to form arene-Cu(III)-alkyne
species (III), that on reductive elimination of ‘Cu’ gave the 3-
alkynylthiophene-2-carboxylate with the regeneration of catalyst (I)
(Scheme 47b).
Similar catalyst, solvent and reaction conditions has been used for
the synthesis of isocoumarin by Chary et al. [107]. The reaction did not
occur in the presence of other solvents like water, H2O: PEG (1:1)
[Scheme 48]. The 20 mol% of catalyst was just sufficient for the good
yield of product and no yield increased upon further increase in catalyst
loading. The PEG-400 was recovered and recycled. The mechanism of
the reaction is similar to the previously mentioned mechanism.
Synthesis of some of the heterocyclic scaffolds in the presence of PEG
as a solvent has been summarized in Table 2.
4. Challenges and future perspectives
Previously, researchers have faced and addressed number of grand
challenges for PEG synthesis, modification and their applications. At
the present time, a modified mature technology is basal need for PEG
production for utilizing their tremendous potential. Regarding catalytic
role of PEG, there are some flaws like lack of knowledge of its nature and
active sites, poor thermal stability, and its key role in the reaction mech-
anism. Researchers also introduced sulfuric acid-modified PEG 6000
(PEG-OSO3H) as a biodegradable and recyclable catalyst in green or-
ganic synthesis, but it also includes some disadvantages viz. handling is-
sues, corrosiveness, tedious work-up and toxic waste generation [117].
To overcome all these issues, we need to design a rational catalytic pro-
cess which shall abolish the use of toxic substrate and diminish cost,
water and energy consumption. According to the green chemistry, the
proper selection of solvent for a synthesis can significantly increase
the sustainability of a chemical production procedure. PEG as a solvent
works more efficiently than other neoteric solvent system due to
knowledge of their well-defined toxicology profiles. PEG is less polar
as compared to ionic liquids and deep eutectic solvents and plays signif-
icant role in specific synthetic procedures. Regenerating PEG is another
epochal concern because as a solvent we can no longer distil PEG and
chemical regeneration is also a challenging process [118]. In the conse-
quence of above discussion, it is worth mentioning that there is ample
scope in the sphere of PEG, therefore the existing conventional technol-
ogies as well as alternative processes should be explored, particularly
those that are environmentally friendly and renewable and reveal
high impact in the near future.
5. Conclusion
In the present scenario, where the prime focus is on PEG, we have
given an overview of the applications of polyethylene glycol as a biode-
gradable catalyst and solvent system, showing excellent activity in var-
ious organic reactions. It is important to note that most of the syntheses
catalyzed by PEG were under solvent free conditions. In addition, the
use of H2O as a medium for some organic reactions catalyzed by PEG
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 25

a
Pd O
R2
I OH
O
R1 + R2 CO R1
Na2CO3,
RT

R1 = CH3, OCH3, NC, NO2, C6H5 = PEG-400

R2 = CH3, OCH3, Cl, F, C6H5

b I

I
Pd * I
Pd (0)
II

O O
OPh
Pd Pd * I
HI
OH
IV III

Scheme 36. a. Synthesis of aromatic esters with Pd/PEG-400. b. The possible mechanism of oxime palladacycle catalyzed phenoxycarbonylation reaction.

make these protocols green, clean and ecological. Excellent accessibility, biodegradability represent important environmentally benign charac-
inexpensive, biodegradable and many reactive sites are major proper- teristics. It has been proved as a green, recyclable and highly effective
ties of this catalyst. Their low-toxicity, low volatility, and catalyst and reaction medium in a broad range of organic synthesis.

Cu
RO N3 + RO N
N N

= PEG-2000
R= H/ Ac
Scheme 37. Azide-alkyne cycloaddition carried out in PEG-2000 to produce a variety of triazol compounds.

O O
[RuCl2(P-cymene)]2
OH R1 O
R1 + R2 Cu(OAc)2.H2O 80oC
H R2

= PEG-400/H2O

Scheme 38. Optimization of ruthenium-catalyzed oxidative alkenylation of 2-methylbenzoic acid with butyl acrylate using PEG-400 solvent system.
26 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

Ar N Ar
NH-HCl O2 , 130oC
Base N N
Ar NH2 + 2 NH2 Ar
Ar
= PEG-600

Scheme 39. Catalyst-free synthesis of 1,3,5-triazines in PEG-600 using O2.

NC NC
N
O CN NC
R H
N COOH + Ar-N3 NH
+
O + O CuSo4.5H2O
N N O O
N 100oC
H
Ar N
N N

R = H, NO2, Br = PEG-400

Scheme 40. Synthesis of novel dispirooxindole pyrrolidine linked 1,2,3-triazole conjugates using Cu(I) as a catalyst in PEG-400.

R
SeH
NC CN
O CN +
+ 2
R H CN US, RT H2N N Se

=PEG-400

R= C6H5, 4-OMeC6H4, 3-OPh-C6H4, 4-Br-C6H4, 4-CN-C6H4, 4-Me-C6H4, 3,4-OMe-C6H3, 3,4-Cl-C6H3

Scheme 41. Synthesis of seleno-tethered pyridines using PEG-400.

N N
NH2 +
K2S2O8 , RT N
NH2

= PEG-400

Scheme 42. Synthesis of Pyrrolo[1,2-a]quinoxalines using PEG-400 as solvent at room temperature.

O OC H
O OC H 2 5
Cl 2 5 P
+ H P OC2H5
OC2H5 KI/K2CO3, RT

= PEG-400

Scheme 43. Synthesis of benzyl phosphonates using PEG-400/KI.K2CO3 system.

 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 27

R
Ar-COMe Ar'NH2 FeF3 (10 Mol%) CN
+
Air Ar N NHAr'
RCHO CH2(CN)2
3h, 60 °C

= PEG-400

Scheme 44. Ultrasound assisted synthesis of N-substituted 2-aminopyridines using FeF3.

a O
R
N
Z O ( isoxazole derivative)
O
R
NO2
Z
O
R N
Z= Ar or OEt
Z O ( isoxazoline derivative)

= PEG :H2O ( 1:1)

H
b R R1
H O H N O H
O H O N R O
O H O Path a H
N R1 O H H C
NO2 R1
Z O H O n H B
H O -H2O
A H -H2O
Path b
R1 = COPh
R1
= PEG R1 R1
R N
R1 N O O
N N O
O

Scheme 45. a. Synthesis of isoxazole and isoxazoline derivatives. b. Proposed reaction mechanism for the synthesis isoxazoles and isoxazolines.

R3
R
R3 N
PMA-SiO2(15 mol%)
R1 + RCHO + N R3
N R1
R3 90-95°C N
R2
R2
10-14 h
=PEG-400

Scheme 46. Synthesis of 3-arylmethyl/diarylmethyl indoles using PMA-SiO2 in PEG-400.

28 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

a I R
+ R
S CuI, K2CO3 S O
COOH
RT, 2-3 hr O

=PEG-400

R= CMe2OH, –CH2CH2OH, –CH2CH2CH2OH, CHMeOH, –CH2CH2CH2Me, –CH2(CH2)4Me, –CH2OH, –

CH2CHMeOH, –CH2OPh, –CH2OC6H4NO2-p, –CH2NHPh

b
S CuI
OH
PEG + K2CO3 O
HOOC I Cu R

R
K2CO3 KI + KHCO3
IV
A
O Cu OH
(I) OK
S
S
I S OK O
KOOC I O
Reductive elimination
Oxidative addition O K

HO
O
(III) Cu
Cu O (III)
OK R V
Cu
HO I OK
S O
S O HO
II S O O

III KHCO3
K2CO3 I
R
H R KI + KHCO3 K2CO3

Cyclization
Coupling

Scheme 47. a. Cu-mediated synthesis of 5 substituted thieno[2,3-c]pyran-7-ones in PEG-400. b. Putative mechanism for the Cu-mediated coupling-cyclization in PEG under ultrasound.

CuI, K2CO3 O
+ RT, 2-3 h
O
CO2Me R R

20-50 mol% CuI OMe

K2CO3, 24-72 h
O
= PEG-400
Scheme 48. Cu-mediated synthesis of isocoumarin in PEG-400.
 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766 29

Table 2
The role of PEG as solvent to catalyze diverse organic transformations:

S.n o. Reactants Reaction conditions Product structure Comments Ref.

Aldehyde, malononitrile, PEG-400:H2O (Solvent)

The PEG-400 was recovered and reused for four
1. acetophenone and Δ for 6 h [108]
cycles without loss of significant activity.
ammonium acetate 80 °C

PEG-400
Aryl hydrazine and
[Ru(p-cymene)Cl2]2, Cu
2. substituted phenyl Excellent yield, recycled at least three times. [109]
(OAc)2, AgSbF6,Δ at 110 °C,
acetylene
RT 10–12 h

4-Iodoanisoles and phenyl PEG-3400 acts as phase transfer catalyst in

3. PEG-3400, CuI, K2CO3, MW [110]
acetylene reaction.

β-Dicarbonyl compound, PEG-400

4. Inexpensive and non toxic solvent system. [111]
various aldehydes and urea Δ at 100 °C

PEG-400 Pd(OAc)2/K2CO3 This protocol provides excellent selectivity to

Hypervalent iodine reagents
5. catalytic system. E-product, and the catalytic system could be [112]
and olefins
Δ at 40 °C for 18 h. reused for five times.

PEG-400 (Solvent)
Indole, aldehydes and KH2PO4
6. PEG-400 could be recycled up to five times. [113]
methylene group Cu(OAc)2
Δ at 70 °C

PEG-1000
o-Aminophenol and PEG-400 gave better yield as compared to other
7. PTSA [114]
S-ethylated-N-acylthioureas aprotic solvents.
Δ at 120 °C

4-Bromoacetophenone and PEG-6000 (Solvent), It showed high catalytic reusability potential for
8. [115–116]
phenylacetylene PEG-PdL catalyst ten times.
30 J. Soni et al. / Journal of Molecular Liquids 315 (2020) 113766

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