A Review on Solvent-free Methods in Organic Synthesis

Abstract

Most of the synthetic chemical transformation reactions involve the use of different organic solvents. Unfortunately, some of these toxic solvents are used in chemical laboratory, industry and have been considered a very serious problem for the health, safety of workers and environmental damage through pollution. The purpose of green chemistry is to provide a path that reduces or eliminates the use of such hazardous toxic solvents. Therefore, the key factor of the green synthetic approach is to utilize renewable materials, nontoxic chemical and to perform the reactions under solvent-free conditions. In this review, we have discussed most recent literature survey on applications of solvent-free techniques in organic synthesis which would offer a new opportunity to a researcher to overcome the problem of using environmental harmful solvents.

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Current Organic Chemistry, 2019, 23, 2295-2318 2295
REVIEW ARTICLE
1385-2728/19 $58.00+.00 © 2019 Bentham Science Publishers
A Review on Solvent-free Methods in Organic Synthesis
Sainath Zangade1,* and Pravinkumar Patil2
1Department of Chemistry Madhavrao Patil ACS College Palam Dist. Parbhani-431720 (M S) India; 2Research Laboratory in
Organic Synthesis, Department of Chemistry, N.E.S. Science College, Nanded-431605(M S), India
A R T I C L E H I S T O R Y
Received: July 17, 2019
Revised: September 29, 2019
Accepted: October 09, 2019
DOI:
10.2174/1385272823666191016165532
Abstract: Most of the synthetic chemical transformation reactions involve the use of dif-
ferent organic solvents. Unfortunately, some of these toxic solvents are used in chemical
laboratory, industry and have been considered a very serious problem for the health, safety
of workers and environmental damage through pollution. The purpose of green chemistry
is to provide a path that reduces or eliminates the use of such hazardous toxic solvents.
Therefore, the key factor of the green synthetic approach is to utilize renewable materials,
nontoxic chemical and to perform the reactions under solvent-free conditions. In this re-
view, we have discussed most recent literature survey on applications of solvent-free
techniques in organic synthesis which would offer a new opportunity to a researcher to
overcome the problem of using environmental harmful solvents.
Keywords: Organic synthesis, solvent-free technique, solid-state reactions, green chemistry, mechanochemistry, microwave irradiation, ul-
trasound irradiation.
1. INTRODUCTION
Many conventional chemical processes make use of large
amounts of toxic and volatile organic solvents (VOs) [1-4]. Re-
placement of such a hazardous reaction solvent is one of the main
goals of green chemistry [5-8]. With growing global environmental
awareness; the design of solvent-free green processes has gained
noticeable attention from the researcher [9-12]. By and large, many
reactions with solvent-free or solid-state conditions have been de-
signed to reduce pollution and cost. These reactions are much easier
for procedural work up and proceed cleanly and efficiently, hence
in short span of time these reactions gained vital importance and
popularity [13-22]. In 1990, the Green chemistry campaign had
been initiated in the USA under pollution prevention legislation by
keeping in view that organic substances could be produced an envi-
ronmentally clean manner. The basic principles aimed at the fol-
lowing goals for guiding a new synthetic strategy.
(1)Production by utilization of atom economical processes
with minimal use of solvents and to reduce the potential
waste.
(2)Production with the use of non-hazardous reagents.
(3)Production with economical energy sources that should not
rely on fossil fuel combustion.
(4)To maximize the yield with the utilization of catalyst when
appropriate.
Multicomponent reactions (MCR) are also of special impor-
tance to the organic ch emists and most of these reactions were car-
ried out under solvent-free conditions in the presen ce of suitable
* Address correspondence to this author at the Department of Chemistry Madhavrao
Patil ACS College Palam Dist. Parbhan i-431720 (M S) India; Tel: +918329323878; E-
mail: drsbz@rediffmail.com
catalyst [23, 24]. This review discusses the application of solvent-
free protocol in organic synthesis over a conventional protocol in-
volving various solvent.
2. ORGANIC TRANSFORMATION UNDER SOLVENT-
FREE CONDITIONS
2.1. Mechanochemistry
2.1.1 Grinding Mode Synthesis
In organic synthesis grinding method has been frequently used
in comparison with the traditional methods [25]. In grinding tech-
nique, reaction proceeds with local heat generated through friction
using mortar and pestle by grinding the crystals of substrate and
reagent in mortar. These reactions offer significant advantages in
terms of simplicity, selectivity and yield [26-30]. Some well-known
solid-state reactions with grinding mode have been reported viz.
Reformatsky and Luche reactions [31], Scheme 1], cyclopropana-
tion reaction [32], Aldol condensations [33], Scheme 2], Dieck-
mann condensations [34, Scheme 3], Knoevenagel condensations
[35, Scheme 4], Reductions [36], Scheme 5], Michael addition [37],
Scheme 6] and phenol coupling reaction [38].
R1R2C=O + BrCH2COOR3R1R2CH(OH)CH2COOR3
Zn
R1R2C=O + BrCH2CH=CH2
Zn R1R2CH(OH)CH2CH=CH2
ArCHO + BrCH2COOEt
Zn ArCH(OH)CH2COOEt
NH4Cl
Scheme 1 . Reformatsky and Luche reaction s in absence of solvent [31].
A class of heterocyclic compounds, 3, 4-dihydropyrimidinone
derivatives (DHPM) exhibit excellent pharmacological properties
such as antib acterial, antitumor, anti-inflammatory activities and
behave as efficient calcium channel blockers [39, 40].
Sainath Zangade

2296 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
CHO
H3C+ H3COC
NaOH
grinding at r.t.
H3CCH
OH
CH2C
O
Scheme 2 . Aldol co ndensation in absence of solvent [33].
n(H2C)
CH2COOEt
CH2COOEt
Base
n(H2C)
COOEt
O
Where n = 2,3
Scheme 3 . Solvent-free deckmann condensation reaction [34].
ArCHO + CH2(CN)2
grinding at r.t. ArCH=C(CN)2
Scheme 4 . Knoevengel reaction under solvent-free grinding method [35].
OH
Me
O
O
Me O
NaBH4
Me
O
O
NaBH4
Me OH
O
(R)-(-) (R,R)-(-)
(R)-(-) (R,R)-(-)
Scheme 5. Reduction of ketones using NaBH4 under solvent-free condition
[36].
Phukanet al. developed novel protocol for Biginelli and related
reaction towards the synthesis of DHPM derivatives using catalyst
hydrated ferric nitrate or clayfen under solvent-free grinding
method. These multicomponent solvent-free reactions compared
with the conventional synthesis in various solvents such as methyl
alcohol, acetone, d ichlo romethane and water and found that the
reaction takes 12 hours to complete [41, Scheme 7]. Therefore the
use of hydrated ferric nitrate or clayfen catalyst has several advan-
tages such as inexpensive catalyst, high yield, avoidance of organic
solvents, and recycling of Fe(NO3)39H2O is possible with clay fen.
COCH3
+H2N
O
NH2+
OHC
Fe(NO3)3 9H2O
grinding at r.t.
NHHN
O
R
R
Where R= 4-OMe, 4-Me, 4-Br, 3-Br, 4-Cl, 2-Cl, 4-OH etc.
Yield: 65-95%
Scheme 7 . Fe(NO
3)3 9H2O Catalysed solvent-free synthesis of dihydro-
pyrimidinone using grinding method [41].
Chalcones and flavonoids constitute one more essential class of
natural compounds with various pharmacological applications.
These compounds have been synthesized by classical methods via
Claisen–Schmidt condensation between respective ketones and
aldehydes in various organic solvents. The equimolar mixture of
substituted acetophenones and aldehydes was ground in open mor-
tar and pestle in th e presen ce of a base (NaOH/KOH) for a period
of 4-15 minutes. On completion of the reaction, as monitored by
TLC, chalcones were formed. The resulting chalcones were further
purified by crystallization from a suitable solvent. These grinding
mode reactions take place efficiently and smoothly in short reaction
time giving high yields of the desired product [42, 43 Schemes 8,
9]. The solven t-free grinding mode of reaction between these car-
bonyl compounds leads to the development of flavonoid chemistry.
Grinding mode synthesis became more interesting due to simplicity,
N
CH3
O
R
OHC
NaOH,
grinding at r.t.
N
O
R
N
O
H3C
NaOH,
grinding at r.t.
R
O
NO
N
Where R= H, CnH2n+1
Yield: >80%.
Scheme 6 . Michael addition reaction under solvent-free condtion [37].

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2297
efficiency, economy, pollution-free work up and no need of organic
solvent except purification in comparison with conventional synthe-
sis.
RCOCH3 + R'CHO NaOH
grinding at r.t. RCOCH=CHR'
R = 2-furyl, phenyl, 2-naphthyl, p-meC6H4
R' = 2-furyl, 2-thienyl, phenyl, 4-FC6H4, 4-ClC6H4,
p-meC6H4, p-meOC6H4.
Yield: 70-96%, Time: 4-15 min.
Scheme 8. Claisen-Schmidt condensatio n und er solvent-free grinding
method [42].
OH
COCH3
R
+
CHO
R1
R2
R3
KOH
grinding at r.t.
5-7 mins.
OH O
R
R1
R2
R3
Where,
R= H, Br, I
R1,R2,R3= H, OCH3, Cl, F
Yield: > 90%
Scheme 9 . Solvent-free synthesis of chalcones [43].
Coumarins are identified as broadly studied natural products
because of their vital biological activities [44]. Furthermore, these
compounds are useful in food additives, cosmetics, optical bright-
ening agents and dispersed fluorescent and laser dyes [45-47]. In
addition, some coumarins gained much importance because of their
toxicity, carcinogenetic and photodynamic effects [48-50]. These
compounds are versatile intermediates for the synthesi s of furo-
coumarins, chromenes, coumarones, and 2-acyl resorcinols [51].
Coumarins have been synthesized by various methods including the
Perkin [52], Pechmann [53], Knoevenagel [54], Reformatsky [55]
and Wittig [56] reactions. Coumarin derivatives have been synthe-
sized under solvent-free condition by grinding method via one-pot
reaction of aromatic aldehydes, isopropylidene malonate (mel-
drum's acid) and dimedone in the presence of triethylbenzylammo-
nium chloride (TEBA). The different substituted aromatic alde-
hydes, isopropylidenemalonate and dimedone were thoroughly
mixed by grinding in a mortar using pestle to give desired coumarin
derivatives in 5-7 minutes. The obtained coumarin product crystal-
lized from 95% ethanol gave pure product. The yield of the cou-
marin depends on the amount of TEBA used during reaction [57,
Scheme 10, Table 1].
Polyfunctionalized 4H-pyrans structurally similar to the bio-
logically active 1,4-dihydropyridines constitute a structural unit of
many natural products and also act as potential calcium channel
antagonists [58-65]. The 4H-pyrans have a wide range of biological
and pharmacological activities, such as spasmolytic, diuretic, anti-
coagulant and anticancer properties. In the treatment of neurode-
generative disorders, including Alzheimer’s disease, amyotrophic
lateral sclerosis, Huntington’s disease, and Parkinson’s disease
pyrans are very valuable [66]. Recently, the multicomponent syn-
thesis of 4H-pyran was conducted through the reaction of aryl alde-
hyde, malononitrile and ethyl acetoacetate in the presence of mag-
nesium oxide as a basic catalyst under solvent-free environment
using grinding method [64]. The same reactions were conducted
with silica nanoparticles supported catalyst in ethanol solvent [67]
and Cu(II) oxymetasilicate reusable catalyst in methanol solvent
[68]. Smits et al. reported 4H-pyran derivatives by one-pot method
in the presence of ammonium acetate as catalyst under solvent -free
environment at room temperature [69, Sch eme 11]. Initially, Kno-
venagel condensation under solvent-free conditions by grinding of
aryl aldehyde with a malononitrile in the presence of ammoniu m
acetate leads to the formation of benzylidene m alononitrile deriva-
tive. To this derivative ethyl acetoacetate was added in the same
reaction vessel, followed by grinding, workup and recrystallization
in ethanol affording 4H-pyran.
Ar-CHO +
O
O
O
O
CH3
CH3
O
O
CH3
CH3
+
TEBA
grinding at r.t.
O
O Ar
CH3
H3C
O
Where,
Ar = 4-ClC6H4, 4-FC6H4, 4-CH3OC6H4, 4-(CH3)2NC6H4
2,4-Cl2C6H3, 3,4-OCH2OC6H3, 2,4-(CH3O)2C6H3,
4-HO-3-CH3OC6H3.
Yield: > 90%
Time: 5-7 mins.
Scheme 10. Synthesis of coumarin derivatives under solvent-free condition
[57].
Table 1. Optimization the amount of TEBA catalyst on the yield of coumarins.
Entry
Amount of catalyst (mmol)
Yield of Product
(%)
1
2
51
2
3
80
3
4
91
4
5
91
5
7
92

2298 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
Cyclopropane derivatives have a considerable place in organic
chemistry. They can undergo electrophilic, nucleophilic, radical an d
rearrangement reactions and found as key intermediates in a wide
range of natural compounds [70]. Usually, these compounds were
synthesized by Simmons–Smith reaction [71] and metal-catalyzed
decomposition of diazo compounds [72] in the presence of alkene.
These methods often give a mixture of cis and trans products with a
higher yield. Recently, high yield stereoselective synthesis of 1-
carbomethoxy-2-aryl-3,3-dicyanocyclopropane has been reported
through the reaction of arylid ene malononitrile and methoxycar-
bonyl methyltriphenyl arsonium bromide in dimethoxyethane sol-
vent in the presence of K2CO3 [73]. The novel route of high stereo-
selective synthesis of cis-1-carbomethoxy2-aryl-3,3-dicyanocyclo-
propanes i.e. tetrasubstituted cyclopropane was also described with
excellent yield by grinding at room temperature [74, Scheme 12].
The reaction was completed within 20 minutes and the acquired
cyclopropane derivative was purified by silica gel column chroma-
tography with petroleum ether-ethyl acetate.
The improvement in the field of organic photochemistry has
predominantly devoted to fused aromatics such as anthracenes,
dihydroanthracenes, and their derivativ es. Such compounds possess
strong fluorescence emission properties and also used as lum ino-
phores in optically based chemosensors [75-80]. These fused aro-
matics also have useful industrial applications such as photorespon-
sive materials for data storage and optical sw itching, light-emitting
diodes, thin-film transistors, and excellent initiators for anionic an d
cationic polymerizations [81-84]. Alshahateet et al. recently re-
ported the crystal structure analysis and type of interaction present
in the inclusion compound such as 9, 10-diphenyl anthracene. The
equimolar mixtu re of catechol and benzaldehyde was ground to-
gether in the presence of concentrated hydrochloric acid. The resul-
tant reaction mixture was kept at room temperature for 10 days and
crystallized from ethanol to give the desired tetrol derivative of
anthracene [85, Scheme 13].
OH
OH
CHO
+
Conc. HCl
grinding
H
H
OH
OHHO
HO
Yield: 60%
Scheme 1 3. Solvent-free Synthesis of 9,10-dihydro derivative of anthracene
using grinding [85].
Pyrazolines represent a class of N-containing heterocyclic com-
pounds with diverse chemical and pharmacological applications
[86]. Pyrazolin es with a phenyl group at 5th-position have character-
istic film-forming properties, blue photoluminescence and elec-
troluminescence [87]. These compounds exhibit significant biologi-
cal properties like antimicrobial, antitub ercular, antiamoebic, cyto-
toxicity, anti-inflammatory, antican cer, antitumor, anticonvulsant,
anti-infective and antidiabetic [88-97]. Moreover, the presence of
pyrazole ring between two aryl rings facilitates a significant in-
crease in cytotoxic activity against human cancer cell lines [98].
+
solvent-free
grinding at r.t.
S
CN
CN
H3C
O O
OCH3
NH4OAc
O
S
CNH3COOC
H3CNH2
NC
CN
R
H3C
O O
OC2H5
solvent-free
grinding at r.t.
NH4OAc
CN
NH2
H3C
C2H5OOC
R
Where,
R = H, 2-NO2, 3-NO2, 4-NO2, 2-OCH3, 3-CH3.
Yield: 68-81%
Time: 15 mins.
+
Scheme 1 1. Synthesis of 4H-Pyran derivativ es under solvent-free grinding method [69].
Ph3AsCH2CO2CH3Br + ArCH=C(CN)2
grinding
Where,
Ar = Ph, 4-CH3-Ph, 4-Cl-Ph,2-Cl-Ph, 4-NO2-Ph, 4-CH3O-Ph,
2,4-(CH3O)2-Ph, 3,4-OCH2O-Ph, 3,4-(CH3O)2-Ph, 4-Br-Ph
Yield: 71-89%
Time: 30 mins.
K2CO3
H
Ar
CN
CN
H COOCH3
Scheme 1 2. Solvent-free and stereoselective synthesis of substituted cyclopropane derivative by grinding [74].

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2299
Reaction between 1,3-diaryl-2-propene-1-one (chalcone) and
dipolar molecule or 1,2-binucleophile leads to the formation of
pyrazoles. A well-known approach for pyrrole synthesis is the reac-
tion between high polar chalcones with dipolar diazoalkanes and
hydrazine derivatives. The high polarity of the double bond in chal-
cones offers th em to react with various dipolar molecules. The con-
ventional and well-known approach for the synthesis of pyrazoles
was described by the treatment of Chalcones with 1,2-
binucleophilic compounds, such as hydrazines [99]. These one-step
or two-steps transformations are usually carried in acidic conditions
with ethanol or acetic acid as the most common solvents [99-101].
Recently our research group described an efficient, simple and use-
ful solvent-free protocol for the synthesis of 3,5-disubstituted-2-
pyrazolines to overcome the use of hazardous solvent [102, Scheme
14]. The significant advantages of methods are clean and mild reac-
tion conditions, short reaction period, easy workup and higher
yields of the desired product. In an experimental procedure, the
mixture of 2-hydroxychalcones and hydrazines was thoroughly
mixed with a pestle in an open mortar at room temperature. To this
reaction mixture, the catalytic amount of acetic acid was added and
grinding was continued for 5 minutes. The resultant reaction mix-
ture was collected through workup and recrystallized from ethanol
to give the desired product 2-pyrazolines.
Where,
R= H, Br, I
R1, R2, R3 = H, OCH3, Cl, F
AcOH (0.001mmol).
Yield: 78-94%. Time: 8-12 mins.
OH
R
O
R1
R2
R3
AcOH
NH2NH2H2O
grinding at r.t.
8-12 mins.
OH
R
NH
N
R1
R2
R3
Scheme 14. Solvent-free synthesis of 3,5-disustituted-2-pyrazolines [102].
The Michael addition is one of the most important and eco-
nomical reactions which fulfills the condition of converting all the
constituents o f the starting materials into the final product [37].
R1
N
H
R2
Ar
NO2
mixing/ grinding
(1-3 min)
then standing
(5 min)
Ar
NO2
N
R1R2
+
Ar
NO2
mixing/ grinding
(1-2 min)
then standing
(5 min)
Ar
NO2
S
+
R-SH
R
NO2
Michael acceptar Nucleophiles
NO2
NO2
NO2
NO2
NO2
Br
NO2
Cl
NO2
NH2
CH3
H3C
NH2
OCH3
N
H
O
NH2
Cl
NH2
Yield: 100%, Time: 3 mins.
SH
HS
SH
SH
CH3
SH
Br
SH
OCH3
Scheme 1 5. Catalyst-free, solvent-free synthesis of nitro amines / nitro sulfides by Michael addition [103].

2300 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
The electron deficient nitro alkenes, the Michael acceptor un-
derwent conjugate addition by carbon nucleophiles. This conjugate
addition of nucleophiles results in two chiral centers via tetrahedral
intermediate in a single step. A greener and h ighly efficient proto-
col has been reported for the synthesis of nitro amines and nitro
sulfides with approximately 100% yield [103, Scheme 15]. The
mixture of nitro alkenes and amines mixed thoroughly ground with
pestle for only 1-3 minutes and the reaction was monitored on thin-
layer chromatography. After 5 minutes, the corresponding adducts
were obtained. This novel procedure has a number of advantages
such as reduction of costs, waste, energy use, materials consump-
tion, risks and hazards, and non-renew ables [39].
N-Containing 1,4-Dihydropyridines are the important six-
membered heterocyclic compounds. These compounds exhibit a
wide range of pharmaceutical and biological properties such as
inhibition of human cytochrome P450 enzyme [104], angiotensin-
converting enzyme inhibition and blood pressure control on
chronic, nondiab etic nephropathies [105]. Arthur Hantzsch was
discovered and utilized 1,3-dicarbonyl derivatives for the synthesis
of dihydropyridines and pyridines with symmetrical substitution
patterns as potential multi-component substrate [106]. In the classi-
cal Hantzsch reaction, the cyclocondensation of β-keto esters and
aldehyde with ammonia gave 1,4-dihydropyridines. Many modifi-
cations and verifi cations to the Hant zsch synthesis have been mad e
with the use of molecular sieves and pyridine [107], Yb(OTf)3
[108], Me3SiI [109], p-TSA [110], TBAHS [111], ionic liquid [112]
and polymers [113]. One of the research groups described a simple
and efficient method for the synthesis of polyhydroquinoline de-
rivatives via Hantzsch condensation by grinding the three ingredi-
ents at room temperature in solvent-free conditions [114]. A mix-
ture of aldehyde, dimedone and β-ketoester was grinded thoroughly
in the p resence of ammonium acetate for 10-20 minutes till comple-
tion of the reaction and after workup and recrystallization from
ethanol to give respective polyhydroquinoline [114, Scheme 16].
The same reaction was also carried out in ethanol as a reaction sol-
vent and refluxed for 4 hrs to give only 55% yield of polyhydroqui-
noline. Therefore, the key advantages of the grinding method for
the synthesis of polyhydroquinoline are short reaction time, easy
workup and high yields.
R-CHO
O
O
++ NC EWG
girnding at r.t.
solvent-free
N
H
O R
EWG
NH2
EGW = CN or COOR'Where,
R is different substituted aromatics
R' is Et or Me
Yield 80-95%, Time: 10-20 mins.
NH4OAc
Scheme 16. Catalyst- and solvent-free, four-component, and one-pot syn-
thesis of polyhydroquinolines on grinding [114].
Azo dyes are important compounds in many branches of chem-
istry. They are widely used as coloran ts [115, 116], chiral receptors
[117], liquid crystals [118], new glassy materials [119], chiral
switches [120], dyes in drug, food, and cosmetic industries [121]
and for molecular recognition [122]. Therefore, because of wide
applications of the azo dyes, continuous efforts have been made to
achieve simple and eco-friendly methodologies for the synthesis of
these compounds. Recently, various heterogeneous solid acids have
been used for the preparation of azo dyes [123-125]. A series of azo
dyes were efficiently synthesized by mixing aromatic amines and
NaNO2 in the presence of nano-silica supported boron trifluoride
(nano BF3·SiO2). A mixture of aryl diazonium salt and 1-naphthol
was treated under solvent-free condition by grinding technique to
give azodyes. The present methodology has employed and proven
to be simple, rapid, environmentally benign, green, and cost-
effective compared with previous synth etic methods [126, Schemes
17, 18].
NH2
R
NaNO2OBF3 EtOH2
++
Solvent-free,
r.t.
Nano SiO2
NN
OBF3
Nano SiO2
R
Scheme 1 7. Diazotization of aromatic amines in the presence of nano BF3·SiO2 [126].
Solvent-free,
r.t.
NN
OBF3
Nano SiO2
R
1-Naphthol
NaOH
OH
R
Where R = CH3, OCH3, Br, Cl, NO2.
Yield: 80-92%
Scheme 1 8. Diazo coupling of ary l diazonium salts with 1-naphthol under solvent-free grinding conditions [126].

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2301
A survey of the literature reveals that Thiazoles and its deriva-
tives exhibit various biological activities such as antibacterial, anti-
fungal, anti-inflammatory , antiviral, analgesic, antitumor, and cy to-
toxic activities [127-134]. Thiazole compounds containing amino
function ality are the useful structural element in med icinal chemis-
try and have found broad application in drug development for the
treatment of bacterial infection, inflammation, HIV, hypertensio n
and some kind of allergies [135, 136]. Therefore, solvent-free
methods have been extended for the synthesis of 2,4-disubstituted
thiazoles via a condensation reaction of α-halo carbonyl compounds
with thiourea or thioacetamide. In the typical experimental proce-
dure, phenacyl bromide reacts with thioureas in the absence of sol-
vent and catalyst-free environment on just grinding at room tem-
perature for 15-20 minutes to give 2, 4-disubstituted thiazoles.
Moreover, phenacyl bromide with electron-rich functionality as
well as electron-poor functionality efficiently reacts with
thiourea/substituted thiourea equally to afford the corresponding 2-
aminothiazoles in excellent isolated yields [137, Scheme 19].
Ar O
Br
+
H2N
S
Rgrind at r.t. N
S
Ar
R
where,
Ar = C6H5; 4-MeOC6H4;4-ClC6H4
R = NH2, CH3
Yield: > 90%
15-20 min.
Scheme 19. Solvent-free synthesis of 2,4-disubstituted thiazoles under
grinding [137].
Further our review literature extended towards different sol-
vent-free synthesis such as biaryl derivatives. Biaryls are recog-
nized as an important class of compounds in organic synthesis be-
cause of their versatility in both ligand chemistry and materials
chemistry. Biaryls are also found in various types of natural prod-
ucts that show unique biological activity [138-145]. Moreover,
many other methods have been reported to synthesize biaryl deriva-
tives, such as [2 + 2 + 2] cocyclization [146]. There is a need to
develop eco-friendly synthesis of biaryls. Rong et al. reported an
efficient and facile one-pot method for the synthesis of 3-amino-
2,4-dicarbonitrile-5-methylbiphenyl under solvent-free conditions
[147, Scheme 20]. The corresponding aromatic aldehyde, malono-
nitrile and acetone ground thoroughly for just 2-5 minutes in the
presence of sodium hydroxide. The reaction wen t to completion in a
few minutes and obtained the crude product on workup and crystal-
lized from ethanol to give biaryl derivatives.
CHO
R
CN
CN
+
H3C
H3C
O
+
NaOH
grinding
2-5 min.
CN
CN
NH2
H3C
R
Where,
R= H , 4-CH3, 4-OCH3, 4-F, 4-Cl, 4-Br, 3,4-diCl
Yield: 72-81 %, Time: 2-5 mins.
Scheme 20. Solvent-free synthesis of Synthesis of 3-Amino-2,4-
dicarbonitrile-5-methylbiphenyl [147].
The combination of solvent-free and K2O–Al2O3 catalyst was
found to be an efficient route for the synthesis of ethyl α-
cyanocinnamates under grinding [148]. Usually, ethyl α-
cyanocinnamates are prepared via the Knoevenagel condensation
[35] of ethyl cyanoacetate with aromatic aldehydes under homoge-
nous conditions. The catalysts are ammonia, organic amines and
their salts [149], some Lewis acids and bases such as ZnCl2 [150],
CdI2 [151], MgO and ZnO [152] have also been used as catalysts.
Recently, the use of inorganic supported catalysts in organic syn-
thesis has rapidly increased because these reactions often involve
easier work-up procedures than those needed for homogenous
methods [64, 152]. The applications of inorganic catalysts promote
the researcher tow ards the synthesis of ethyl α-cyanocinnamates
using K2O–Al2O3 [148, Scheme 21]. The reaction mixture of alde-
hyde and ethyl cyanoacetate was grinded in the presence of K2O–
Al2O3 for 5 minutes at room temperature to yield corresponding
ethyl α-cyanocinnam ates. The method has a few advantages such as
simple reaction procedure, easy workup and high product yield.
ArCHO +
CN
COOEt
K2O-Al2O3
grinding at r.t.
Ar
H
CN
COOEt
Where,
Ar = C6H5, 4-ClC6H4, 3-ClC6H4, 3-NO2C6H4, 4-NO2C6H4, 4-CH3C6H4,
4-CH3OC6H4, 3,4-(CH2O2)C6H3, 3-OCH3-4-HOC6H3, 4-(CH3)2NC6H4
4-HOC6H5, C6H5CH=CH
Yield: 85-98 %, Time: 5 mins.
Scheme 21. Solvent-free synthesis of cyanocinnamates under grinding
method [148].
2.1.2. High Speed Ball Milling (HSBM) Mode of Solvent-free
Synthesis Ball Milling Reactor
The chemists have been extensively involved in designing new
protocols, based on essential and sustainable appro aches such as
Fig. (1). FRITSC H Planetary Mill PULVERISETTE 5 classic line (Image c ourtesy of FRITSCH GMBH.

2302 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
avoiding toxic and volatile solvents or performing the reaction un-
der solvent-free conditions, load catalytic amounts of catalyst in-
stead of stoichiometric amounts and use nontoxic recyclable cata-
lysts. The work of ‘‘green chemistry’’ inspired our interest to re-
view various research articles on alternative procedure for the syn-
thesis of new molecules. The high speed ball milling (HSBM), a
mechanochemical process under solvent-free conditions, plays an
important role in the acad emic and industrial transformations which
can lead to the reduced amount of catalyst loading, a shorter reac-
tion time, and higher yields [153-159, Fig. 1].
The use of this alternative energy source, for instance, ball mill-
ing, and safer reagents to achieve sub stituted quinolines through N-
deformylation. Initially, substrate 4-chloro-2-phenyl-N-formyl-1,2-
dihydroquinoline 1a was treated with 1.0 equivalent of solid NaOH.
The reaction was conducted in a high-energy vibrational micromill
at 1200 rpm for 15 min and NaCl was u sed as a grinding aid. How-
ever, only 20% o f the product 2a was obtained along with 30% of
4-chloro -N deformylation product 3a. When the same reaction was
performed with 100 mol% of PEG 2000 under the same reaction
condition, the desired product 2a was obtained in 90% yield as a
sole product [160, S cheme 22].
Mechanically activated solid-state reactions are solvent-free re-
actions conducted by grinding or ball milling. High-speed ball mill-
ing (HSBM) is an attractive, mechanically activated method em-
ployed for the synthesis of flavones from β-dicarbonyl compounds
in th e p resence of KHSO4. The reaction went to completion within
5 minutes, giving 95% yield with 50 mol% of KHSO4. The proce-
dure involves the addition of a mixture of β-dicarbonyl, KHSO4 and
silica gel to a reaction vessel. To this, a stainless steel ball was
added and the vessel was closed with lid and gasket. The ball mi lls
were run with a rotational speed of 1290 rpm for only 5 minutes.
After workup with CH2Cl2, the obtained crude product was purified
by column chromatography to give corresponding flavones [161,
Scheme 23, Table 2].
Pyrrole / polysubstituted pyrrole moiety is a core part of many
natural products [162]. Highly substituted pyrrole derivatives
possess significant structural units in many pharmacologically
active compounds viz. porphyrins (e.g. heme and chlorophylls)
[163] and alkaloids (e.g. hygrine, nicotine, tropine and cocaine)
[164]. Several synthetic pyrrole derivatives exhibit biomedical
properties. For example 3-(4-pyridyl)-2-(4-fluorophenyl)-5-(4-
methylsulfinyl-phenyl)-1H pyrrole was reported as orally bioactive
inhibitor of p38 mitogen-activ ated protein (MAP) kinase [165],
-Alzheimer’s disease [166], cancer [167], asthma [168] and cardio-
vascular diseases [169]. 1,2-diaryl-1H-pyrroles [170] and 2,3-
diaryl-1H-pyrroles [171] were identified as cyclooxygenase-2
(COX-2)-selective inhibitors [172], 5-hydroxy-1,5-dihydro-2H
pyrrol-2-ones were found useful in the treatment of patients suffer-
ing from intellectu al or nervous asthenias, memory failures, sense-
cence or mental strain [173]. For the initial pyrrole synthesis by
Paal-Knorr reaction [174], a number of methods have been d evel-
oped for the polysubstituted pyrrole synthesis [175, 176]. Most of
these methods involve costly chemicals, noble heavy metal cata-
lysts, long reaction time and relatively high reaction temperature
N
Cl
CHO NaOH
PEG 2000
(100 mol%)
HSBM
15 mins.
N
2a, 90%
NaOH
NaCl
HSBM, 15 mins.
N
N
Cl
2a, 20% 3a, 30%
1a
Scheme 22. Conversion of 4-chloro-2-phenyl-N-formyl-1,2-dihydroquino-
line under HSBM [160].
O O
R1
OH KHSO4
HSBM
O
O
R2
R1
R1 = H, Cl, Br, CH3, OCH3, NO2, OH
R2= H, Cl, CH3, OCH3, NO2,
R2
Scheme 2 3. Synthesis of flavones by high speed ball milling [161].
Table 2. Optimization of different conditions on the use of KHSO4.
Entry
Amount KHSO4 (mol%)
Time (min)
Yields (%)
1
50
5
95
2
30
5
94
3
20
5
94
4
05
10
88
5
05
25
62

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2303
conditions. Later more economic and environmen tal methods via
Mn (III) acetate promoted radical cyclization under solvent-free
ball milling [177-181] were reported. Zeng et al. developed a sim-
ple and mild synthetic method for 2,5-dimethyl-3,4-dicarboxylate-
pyrroles and N-substituted 3,4-diphenylpyrroles via condensation-
annulation of amines with acetoacetate and 2-phenylacetaldehyde,
respectively. In the typical model reaction of ethyl acetoacetate
with different amines together with stainless ball, reaction vessel is
sealed w ith screw caps and fix ed on the v ibration arms of ball mills.
The reaction mixture was vibrated vigorously at a rate of 1800
rounds per minute (30Hz) for 60 minutes. Th e oxidant Mn(OAc)3
used in this reaction gives excellent results for the formation of
pyrroles [182, Schemes 24, 25].
One of the most useful ways of formations of alkenes is the
Wittig reaction [152] via phosphonium ylide, a dipolar intermedi-
ate. The Horner–Wadsworth–Emmons (HWE) version [183] of the
Wittig reaction focuses on the use of more stabilized phosphonate
ylides. This is a method of choice for the preparation of unsaturated
esters (EWG = COOR). Usually, the phosphonate stabilized carb an-
ion is sufficien tly nucleophilic to react under mild conditions to
yield the olefin. The ball-milling technique was used under solvent-
free conditions to perform a Horner–Wadsworth–Emmons reaction
in the presence of a mild carbonate base [184, Scheme 26]. The
reactions were carried out using different substituted electrophiles.
In general procedure, a mixture of aminophosphoryl acetate and
3,5-dimethoxybenzaldehyde in the presence of carbonate (NaHCO3,
K2CO3, Cs2CO3) base was ground in a planetary ball mill. The best
result was obtained with K2CO3, Cs2CO3 giving 100% conversion
of amino esters. This practical method for the preparation of Boc-
protected amino esters has advantages such as excellent yields and
selectivity.
The high-speed vibration milling (HSVM) technique used for
the effective dimerization of fullerene C60 [185, Scheme 27]. C60
dimer fused with a germacyclopentane ring by the use of the solid-
state reaction of C60 with dichlorodiphenylgermane and lithium
metal. Th e reaction mixture of fullerene C60, dichlorodiphenylger-
mane and lithium powder, in a molar ratio of 1:4:10 was placed in a
vibration-milling capsule together with a mixing ball under argon.
The mixture was vigorously vibrated at the rate of 3500 rpm for 30
min. The separation of the product through cosmosil column gave
dimer of C60.
O O
+R-NH2
H3C OR'
N
H3C
H3C
O
O
OR'
OR'
R
Where R is, C5H5, 4-CH3C6H4, 3-CH3C6H4, 2-CH3C6H4,
4-ClC6H4, 4-BrC6H4, 3,4-di-ClC6H4.
R' is Et, i-pr
Mn(OAc)3
ball milling (30 Hz)
60 min.
Scheme 2 4. Mn(OAc)3-mediated synthesis of 2,5-dimethyl-3,4-dicarboxylate-pyrroles under solvent-free ball milling [182].
Mn(OAc)3
ball milling (30 Hz)
60 min.
R-NH2 +
OHC
N R
Where R is, C5H5, 4-CH3C6H4, 3-CH3C6H4, 2-CH3C6H4,
4-OCH3C6H4, 4-ClC6H4, 4-BrC6H4, 3,4-di-ClC6H4.
R' is -CH2Ph, 4-ClCH2Ph, Cycolhexyl, n-butyl
Yield : 60-92%
Scheme 2 5. Mn(OAc)3-mediated synthesis of N-substituted 3,4-diphenylpyrroles under solvent-free ball milling [182].
P(O)(OMe)2
BocHN
O
OMe
CHO
OMe
MeO
+
Base
Ball-Mill
OMe
MeO
BocHN
O
OMe
OMe
MeO
BocHN
O
OH
+
Scheme 2 6. Solvent-free synthesis of unsaturated amino esters in a ball-mill [184].

2304 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
Aromatic halo compounds can be easily functionalized through
metal-catalyzed cross-coupling reactions [186] in the synthesis of
many interesting natural products [187] and bioactive material
[188]. Iodoaromatic compounds are used in medicine as drug or
diagnostic aids, contractors [189] and bioactive materials [190].
They also have importance in medicinal and pharmaceutical re-
search [191]. The chemistry dealing with the selective introduction
of an iodine atom into organic molecules thus attracted broad inter-
est in the wider specific community.
Our literature survey focused on halogenation, bromination us-
ing NBS (N-bromosuccinimide), NBS–acetonitrile, NBS–H2SO4–
TFA, NBS–BF3–H2O, NBS–Al2O3 (solvent free condition and
Vilsmeier–Haack bromination) [192-197], for chlorination NCS (N-
chlorosu ccinimide)–acetonitrile [198] NCS–CuCl [199] and NCS–
BF3–H2O [195], and for iodination, NIS (N-iodosu ccinimid e)–TFA
[200], NIS–In(OTf)3 [201], NIS–BF3–H2O [195] and NO2–I2 [202].
The chemo and regio-selective aryl bromination and iodination
using respective N-halosuccinimides (NBS/NIS) at room tempera-
ture in the absence of any solvents, catalyst/additives under ball-
milling condition were described [203], however, for chlorination
ceric ammonium nitrate (CAN, NCS-CAN) was used as an addi-
tive. The reactions were found to be environmentally friendly, did
not require aqueous work-up, adopted milder reaction condition and
are economical. Succinimide which is the coupled product pro-
duced from the bromination reaction was also recyclable [203,
Schemes 28, 29, 30].
4 equivalent Ph2GeCl2
Li x 10
HSVM
Under Ar
Ge
Ph
Ph
Scheme 2 7. Dimerization of C60 under HSV M [185].
H
RNBS
Ball milling
Br
R
1 2a-t
Br Br
OCH3BrBr
H3CO
Br
Br
Br
Br
Br
BrBr
Br
Br
OCH3
Br
CHO
Br
Br
OHC
2a, 82% 2b, 85% 2c, 75% 2d, 75%
2e, 80% 2f, 85% 2g, 87% 2h, 86%
OCH3
Br
NO2
OCH3H3CO
Br CHO
OCH3
Br
NH2
Br
NH2
Br
2i, 82% 2j, 85% 2k, 85% 2l, 88%
Br
OCH3
Br
OCH3
OCH3
Br
OCH3
Br
OCH3
H3CO
OCH3
2m, 92% 2n, 90% 2o, 98% 2p, 98%
Br
CN
OCH3
Br
CN
OCH3
Br
NO2
Br
2q, 85% 2r, 90% 2s, 86% 2t, 90%
Scheme 2 8. Catalyst and so lvent-free bromination using N-bromosuccinimide (NBS) [203].

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2305
N
Ar
+
R
H
DDQ / PyBox-1
Ballmilling, 30 Hz N
Ar
R
Where Ar is, 4-MeOC6H4, Ph, 2-MeOC6H4, 4-MeC6H4
R is, Ph, 4-MeC6H4, 4-FC6H4, CO2Me, CO2Et,
2-Py, Pr.
Yield: >70%
Scheme 3 1. Asymmetric coupling reaction of 2-aryl-tetrahydroisoquinolines
with alkynes via ball milling [216].
During the last decade, the d evelopment of cross-
dehydrogenative-coupling (CDC) reaction involved the direct con-
version of C-H bond into C-C bonds. This is due to its special fea-
ture of avoiding the preparation of functional groups and makes
synthetic schemes shorter and more efficient. Therefore, the cross-
dehydrogenative coupling is a promising approach to the minimiza-
tion of byproduct formation and the reduction of the number of
steps of the organic synthesis [204-213]. Using High-Speed Ball-
Milling (HSBM) solvent-free conditions, three types of DDQ-
promoted CDC reactions have been reported [214]. HSBM [215] is
a powerful tool in promoting various solvent-free reactions, to syn-
thesize chiral tetrahydroisoquinoline derivatives through direct sp3
C-H bond activation [216], Scheme 31]. A mixture of tetrahydroi-
soquinoline, oxidant DD Q, PyBox-1 and silica gel was taken in
stainless still and milled with two copper balls. The reaction mix-
ture was vibrated at 30 Hz for 10 minutes with 5 minutes p ause to
give chiral tetrahydroisoquinoline.
2.1.3. Microwave Assisted Solvent-free Synthesis
2.1.3.1. History of Microwave
In 1946, an American engineer Percy le Baron Spencer working
at Raytheon with radar equipment noticed that some candy in his
pocket had melted when he accidentally leaned against an open
waveguide. Spencer conducted more experiments at Raytheon and
began to produce the first microwave oven called Radaranges. Ra-
daranges were large and expensive. In 1967, Amana a subsidiary of
Raytheon developed the first household microwave oven [217]. In
1986, Richard Gedye and coworkers at Laurentain University, Can-
ada and Majetich [218] and Giguere [219] at the University of
H
R
NIS
Ball milling
I
R
3 4a-f
I
I
CHO
I
OCH3
OCH3
OCH3
I
I
NH2
I
OCH3
I
I
OCH3
4a, 70% 4b, 72% 4c, 72%
4d, 75% 4e, 78% 4f, 80%
Scheme 2 9. Iodination of electron rich aromatics using N-iodosuccinimide (NIS) [203].
H
R
NCS-CAN Cl
R
5 6a-d
Ball milling
OCH3
Cl
OCH3
OCH3
Cl
H3CO
OCH3
Cl
OCH3
Cl
6a, 82% 6b, 87% 6c, 90% 6d, 92%
Scheme 3 0. Chlorination with CAN–NCS combinations under ball-milling [203].

2306 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
Georgia, USA, made the microwave transition from kitchen to
chemical laboratory. The researcher reported the number of organic
reactions using commercial m icrowave ovens. Later considering the
safety, reproducible and focused homogenous heating led to the
design of more sophisticated microwave equipment. The new de-
signs were upgrad ed with temperature and pressure detecting de-
vice, enabled to monitor the organic reactions (Fig. 2). Microwave
oven imp arts heating that does not involve in thermal conduction.
Upon exposure to microwave radiations, heat generated in the sam-
ple has been attributed to electric component by dipolar polarization
and ionic conduction mechanisms. Heat radiations get adsorbed on
the surface of material and penetrate several centimeters deep insid e
the core of the m aterial.
The heterocyclic ring system became the principle component
in a number of biological active molecules [220-240]. Pharmaceuti-
cal industries and academic laboratories encouraged a novel and
efficient synthetic methodologies for the development of heterocyc-
lic rings. Five and six-membered heterocyclic compounds like pyr-
roles, indoles, isoxazoles, im idazoles, pyrazoles, indazoles, tria-
zoles, tetrazoles, pyridines and pyrimidines, etc. have been synthe-
sized in sup erior yield under solv ent-free microwave conditions and
dramatic accelerations have been observed in contrast to their clas-
sical procedure. In this review, we discuss synthesis of heterocyclic
compounds under solvent-free microwave irradiation (MWI).
The conversion of 1,4-diketones to pyrroles has been carried
out under microwave irradiation within 2 minutes [241,
Scheme 32].
H3C
CH3
O
O
RNH2
N
H3CCH3
R
where R = CH2C6H5, 4MeOC6H4, 2ClC6H4, etc.
(MW, 100-200 W, 0.5-2.0 min.)
Yield: 75-90%
solvent-free
Scheme 3 2. Synthesis of pyrrole derivatives under solvent-free MWI [241].
The classical Fischer-indole synthesis from aryl hydrazine and a
ketone is speeded-up by several 100-fold using microwave-assisted
syntheses [242, Scheme 33]. The classical Fischer-indole synthesis
from aryl hydrazine and a ketone requires 12 hours to complete
using the conventional method. The reaction was accelerated
through microwavein a very short time of only 2 minutes. A mix-
ture of phenyl hydrazine and cyclohexanone was irradiated success-
fully to get an indole derivative.
N
H
NH2
+
O
H
N
MWI, 30 sec.
Scheme 3 3. Fischer-indole synthesis under solvent-free MWI [242].
The microwave-assisted synthesis imidazole from α-diketone
[243, Scheme 34] is achieved in a short period of time (10 mins)
giving excellent yield (75-85%). The important derivative of imida-
zole was synthesized by the treatment of aryl aldehydes with 1,2-
dikentones under microwave at 130 watts. The reaction was carried
out in the presence of basic alumina-supported and completed in a
short period of time to achieve target molecule. In contrast to this
microwave method the conventional synthesis take 4 hours in acetic
acid as reaction solvent.
R1H
O
+R2
R3
O
O
Al2O3
NH4OAc NNH
R3
R2
R1
R1 = C6H5, 4ClC6H4, 2-thiophenyl etc.
R2 = R3 = C6H5, 4MeC6H4
MW-solvent-free, 130 W, 10 min.
Scheme 3 4. Microwave-assisted synthesis of substituted imidazoles [243].
Landge et al. reported a good example of a one-pot solvent-free
microwave-assisted synthesis of pyrazoles using a bi-functional
noble-metal/solid-acid catalyst, Pd/C/K-10 montmorillonite [244,
Scheme 35].
Ar
O
Ar'
RNHNH2
+
N
N
Ar'
Ar
R
(i)
(i) Pd/C/K-10, MW, 160 °C, 20-30 min
R = Me, Ph, 3-CF3C6H4, 4-NO2C6H4
Ar = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4
Ar' = Ph, 4-FC6H4
Scheme 3 5. Microwave-assisted one-pot synthesis of pyrazoles [244].
The reaction of chalcones with substituted hydrazine’s provided
1,3,5-trisubstituted pyrazoles in excellent yields with high selectiv-
ity (85-100%) [245, Scheme 36]. The improvements in the yields
and reaction time are achieved for the synthesis of trisubstituted
pyridines. The mixture of pyrazole derivative of chalcones and
acetophenones forming an adduct on microwave irradiation for 2-3
minutes in the presen ce of NH4OAc gave pyrazole substituted pyri-
dine derivatives.
The solvent-free N-alkylation reaction of phthalimides has been
reported under microwave irradiation in the presence of tetrabuty-
lammonium bromide (TBAB) and TBAB as a phase transfer cata-
lyst [246]. A mixture of phthalimid e and alkyl halide was treated
under microwave in the presence of K2CO3 and TBAB as a phase
transfer catalyst. The reaction went to comp letion in 4-10 minutes
giving excellent yields of N-alkylated phthalimides (Scheme 37).
Fig. (2). Microwave reactor.

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2307
Ar'
O
N
N
Cl Ph
Me
+Ar Me
O(i)
NN
Ph
Cl Me
N
NN
Ar Ar
Ph
Cl Me
O
O
Ar
Ar
(ii)
(i) EtOH, NaOH, reflux 2.5 hrs (ii) NH4OAc, MWI 2-3 min, Yield 60-90%
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 3,4,5-
triMeOC6H2, 2-thiophenyl
Scheme 36. Microwave assisted synthesis of trisubtituted pyridines using
NH4OAc [245].
NH + RX
O
O
K2CO3, TBAB
MWI, 4-10 min.
NR
O
O
Scheme 37. Solvent-free N-alkylation of phthalimide in presence of TBAB
under MWI [246].
Upon exposure to microwave irradiation, the diacetate deriva-
tives of aromatic aldehydes rapidly cleaved on the solid support of
neutral alumina surface. In these deprotection reactions, selectivity
is achievable by adjusting the duration of microwave exposure. A
typical example of molecule bearing acetoxy functionality (R-
OCOCH3), the aldehydes diacetate is selectively removed in 30
seconds, and further extended period of 2 minutes is required to
cleave both the diacetate and ester groups. The obtained yields are
better than those obtained by conventional methods. The same is
applicable for compounds having olefinic moieties such as cin-
namaldehyde diacetate [247, Scheme 38].
R
H3COCO
OCOCH3
neutral, Al2O3
MWI, 40 sec R
CHO
R= H, Me, CN, NO2, OCOCH3
Scheme 38. Cleavage of diacetate derivatives of aromatic aldehydes over
Al2O3 under MW [2 47].
The different selective and solvent-free oxidation reactions
have been reported using microwave irradiation [248-250]. The
oxidation of secondary alcohol to ketone was successfully done
under microwave irradiation and solvent-free conditions using
montmorillonite K-10 clay-supported [Iron(III) nitrate] (clayfen).
The reaction mixture was irradiated for 15-60 seconds to give ke-
tone. The method is inexpensive and selective and avoids the use of
organic solvents (Scheme 39).
R2
R1
OH Clayfen
MWI, 60 sec.
R1
R2
O
R1 = Ph, 4MeC6H4, 4MeOC6H4; R2 = H
Yield 87-96 %
clayfen- [Iron(III) nitrate]
Scheme 39. Oxidation of alcohol using montmorillonite K-10 clay-
supported [Iron(III) nitrate] [248].
Similar oxidation of alcohols to ketones was reported using
MnO2-silica supported under solvent-free microwave irradiation.
The method is extensively useful in terms of improvement in yields
and reducing the tim e of reaction compared to conventional oxida-
tion using different organic solvents (S cheme 40).
R2
R1
OH
MnO2-Silica
MWI, 20-60 sec.
R1
R2
O
R1 = Ph, 4MeC6H4, 4MeOC6H4, Ph-CH=CH; R2 = H
Yield 67-96 %
Scheme 4 0. Oxidation of alcohol using MnO2-Silica under solvent-free
condition [249].
Microwave synthesis was utilized for the selective oxidation of
the active methylene group of arenes. The reaction was conducted
in the presence of KMnO4-alumina supported under solvent-free
microwave irradiation. The mixture of KMnO4-alumina supported
9H-fluorene on irradiation for 10-30 minutes to afford 9H-fluoren-
9-one in excellent yield (Scheme 41).
KMnO4-Alumina
MWI, 10-30 min.
O
Scheme 4 1. Oxidation of arenes with permanganate KMnO4–alumina under
solvent-free condition [2 50].
The microwave-induced organ ic reaction enhancement
(MORE) chemistry has been extensively studied for rearrangem ent
reactions such as pinacol–pinacolone, beckmann rearrangement,
fries- rearrangement, etc. under solvent-free conditions [251-257].
A solvent-free pinacol–pinacolone rearrangement under microwave
irradiation in combin ation with Al3+-montmorillonite K-10 clay.
1,2-diol in support with Al3+-montmorillonite irradiated for 15 min-
utes afforded the rearrangement product in excellent yields. These
results of microwave were compared to conventional heating in an
oil bath where the reaction times are too long of 15 hours (Scheme
42).
HO
OH Al+3
Montmorillonite
MWI, 15 min. O
Scheme 42. Solventless pinacol–pinacolone rearrangement using micro-
wave irradiation [251].

2308 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
The Beckmann rearrangement montmorillonite K-10 clay/
AlCl3, ZnCl2-SiO2 was performed using dry media under micro-
wave irradiation. The notable advantages of the method are high
yield and short reaction time (7-12 minutes) (Schemes 43, 44).
Montmorillonite
K-10 Clay
MWI, 7-10 mins.
R1
O
NHR2
R1= C6H5, CH3
R2= C6H5, 4-OCH3C6H4, 4-ClC6H4, 4-NO2C6H4
Yield: > 80%
N
OHR1
R2
Scheme 4 3. Beckmann rearrangement of ketoximes using MWI [252].
R1
R2
N
OH
MWI, 7-12 min.
R1C
O
NHR2
R1= C6H5, CH3
R2= C6H5, 4-OMeC6H4, 4-OEtC6H4, 4-OHC6H4, 4-MeC6H4 4-ClC6H4
4-BrC6H4, C6H5-C6H4.
Yield: > 75%
AlCl3, ZnCl2-SiO2
Scheme 44. Soli-supported Beckmann rearrangement of ketoximes using
MWI [253].
The mixture of phenolic ester, dry distilled chlorobenzene and
anhydrous AlCl3 was stirred and irradiated under domestic micro-
wave for 3-12 minutes. The reaction mixtures were cooled down to
room temperature and workup by using conc. HC l to giv e hy-
droxyacetophenone. The method is useful in terms of a simple pro-
cedure, short reaction time and higher yields and purity of the prod-
uct (Scheme 45).
OCOR
R'
AlCl3, PhCl, MW,
Stirring
1 atm.
OH
R'
COR
OH
R'
COR
+
R= CH3, CH2CH3, Ph
R' = H, CH3, NO2.
Scheme 4 5. Fries rearrangement under MWI [257].
While flavonoid compounds are a group of natural products
found in fruits, vegetables, nuts and flowers, the most abundant
being the flavones. Members of this class display a wide variety of
biological activities and have been useful in the treatment of vari-
ous diseases. Flavones have been prepared by a variety of methods
such as Allan–Robinson synthesis and from chalcones via an in-
tramolecular Wittig strategy. The most popular method for the syn-
thesis of flavones is Baker–Venkataraman rearrangement in which
o-hydroxyacetophenone is benzoylated to form the benzoyl ester
followed by treatment with base (pyridine/KOH) to effect an acyl
group migration, forming a 1,3-diketone. The solvent-free synthesis
of flavones was conducted under microwave irradiation of o-
hydroxydibenzoylmethanes adsorbed on montmorillonite K-10 clay
for 1–2 minutes. Rapid and exclusive formation of cyclized fla-
vones was obtained in good yields [258, Scheme 46]. Verma et al.
reported microwave-accelerated solvent-free reactions on mineral
solid supports, which describe the utility of microwave irradiation
towards organic chemistry [259-277].
Among many classes of organic photochromic compounds, spi-
rooxazines have been proven to be one of the most useful due to
possible practical applications [278, 279]. The reported method for
the synthesis of spirooxazines is a reaction between methylenic
base and 1-nitroso-2-naphthol [280]. This reaction generally leads
to a low yield of spirooxazines, ev en if optimization of experimen-
tal conditions allowed improving them in some cases [281].
Rickwood et al. developed a method for the synthesis of 6’-
morpholino spirooxazines by the reaction between 1-oximino-
naphthoquinone (tautomeric form of 1-nitroso-2-naphthol) with
morpholine [282]. A method needs to be developed for the synthe-
sis of substituted spiroindolinonaphth[2,1-b][1,4]oxazines using
microwave irradiation. In typical reaction condition, the equimolar
mixture of 1-nitrosonaphthol with indoline derivatives was irradi-
ated in a microwave oven Synthewave 402 for 15 minutes to pro-
duce respective spirooxazines. The same reaction was carried out in
the presence of morpholine using microwave irradiation [283,
Scheme 47].
There are only a few research papers on the application of MW
assisted enzymatic reactions, focusing p redominantly on organic
small molecule transformations [284-289]. However, Leadbeater
and coworkers studied the effect of MW irradiation on lipase cata-
lyzed trans esterification of methyl acetoacetate in toluene [290].
They found no differences between conventional and MW heating.
Other researchers investigated the influence of MW heating on the
stability of Candida antarctica lipase B (CALB) and the kinetic
study of butyl butyrate synthesis. They reported an increase in en-
zymatic stability under the MW field in organic med ium which
revealed a possible explanation for an increase in conversion rates
observed for some enzymatic syntheses carried out under MW heat-
ing [291]. The microwave-assisted enzymatic polymerization of
PLGA copolymers [292] was reported by Atsushi and coworkers in
2009.
Microwave accelerated enzymatic polymerization reaction re-
mains largely unexplored and offers unique advantages such as
selectivity, no need fo r toxic m etal catalyst and use of mild reaction
conditions [293, 294]. Poly-ε-caprolactone (PCL) is the most exten-
OH
O O
R1
R2
K-10 clay
MW,
1-2 min.
O
R1
O
R2
R1= H, OCH3
R2 = H, OCH3, CH3, NO2; Yield: 75-80 %
Scheme 4 6. Synthesis of flavones on Montmorillonite K 10 Clay with Microwaves [258].

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2309
sively studied polymerization reaction and useful for the enzymatic
ring-opening reaction [293]. PCL synthesis has also been studied
extensively using chem ical catalysis in various conditions including
bulk (solvent less) conditions [295, 296]. The microwave-assisted
ring-opening polymerization of ε-caprolactone catalyzed by CALB
[297, Scheme 48] w as systematically represented by Matos et al.
OO
Lipase, MW O (CH2)5C
O
n
Scheme 4 8. Microwave assisted ring opening polymerization [297].
2.1.4. Ultrasound/ultrasonic Irradiated Solvent-free synthesis
Ultrasound reactor
Fig. (3). Ultrasound reactor (Image courtesy of Toption lab).
Under ultrasonic irradiation, organic transformations occur in
high yield, short reaction times, or milder reaction conditions. Ul-
trasound irradiation can also be used and presents similar advan-
tages to microwave irradiation. Good yields, shorter reaction times
and mild conditions are some of its advantages wh en compared
with classical methods [298-302, Fig. 3].
The joint application of ultrasound irradiation and solid-phase
catalysts in the reactions under solvent-free conditions gives special
attributes such as enhanced reaction rate and improved yields in
chemical processes. The use of ZrOCl2.8H2O in combination with
ultrasound irradiation is found to be an efficient protocol for one-
pot reaction of amines, aromatic aldehydes, and Meldrum’s acid to
form 8-aryl-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6-(5H)-one
and 4-aryl-3,4-dihydroquinolin-2-(1H)-one [303, Scheme 49]. The
reactions w ere performed under so lvent-free conditions with excel-
lent yield (95%) of the desired p roduct.
An efficient method of solvent-free synthesis of tri-
arylmethanes, catalyzed by ZrOCl2
.8H2O was reported. This is a
green synthetic procedure of 3-carboxycoumarins in which conden-
sation of substituted benzaldehydes and Meldrum’s acid was done
in water using catalytic amounts of zirconium oxide chloride under
ultrasound irradiation [304, Scheme 50]. Initially, the feasibility of
this method was verified under different conditions by the conden-
sation of salicylaldehyde with Meldrum’s acid. Under harsh reac-
tion conditions such as long reaction time and high temperature, the
desired product was obtained in good yields.
The highly efficient and one-pot solvent-free method has been
reported for the synthesis of 4-methyl-2H-chromen-2-one using 1-
chlorom ethyl-4-fluoro-1, 4-diazoniabicyclo[2.2.2]octane bistetra-
fluoroborate is (Selectfluor TMF-TEDA-BF4) catalyst [305,
Scheme 51]. The reaction times were reduced and yields were im-
proved under ultrasonic irradiation. The Selectfluor catalyst is fea-
sible due to its commercial value, stability, easy recovery, easy
handling, and good activity.
N
R1
CH2
Me Me
R
NO
N
R1
Me Me
N
O
A
B
R
N
R1
Me Me
R
O
N
Where,
A is
O
H
N
NO
HO MWI
,
B is
NO
HO
MWI
,
R = Me, C16H13; R1 = H, Cl, NO2, OMe.
Scheme 4 7. Microwave-Assisted Solvent-Free Synthesis of th e Substituted Spiroindolino naphth[2,1-b][1,4]oxazines [283].

2310 Current Organic Chem istry, 2019, Vol. 23, No. 21 Zangade and Patil
Kaur and coworkers reported an efficient protocol for the syn-
thesis of aryl-14-H-dibenzo[a,j] xanthenes and 4-substituted 2H-
chromen -2-ones. The use of manganese perchlorate catalyst in
combination with ultrasonic irradiation has various applications
such as clean, simple and green process [306, Schemes 52, 53].
CONCLUSION
Nowadays the Solvent-free and solid-state reactions or proto-
cols are widely used for the synthesis of biologically active com-
pounds. The reaction in the absence of toxic and volatile organic
solvents has several advantages such as reduction in reaction time,
simple workup procedure, improvement in yields of products and
no need of organic solvent during the reaction. The combination of
solvent-free reactions with various supported catalysts further leads
to the development of environmentally green process. Therefore,
this review article is significant for researchers to utilize methods
such as grinding, high-speed ball mills, and microwave/ultrasound
irradiation.
NH2
O
O
+ ArCHO +
O
O
O
O
O
ON
HO
Ar
or
NH2
or
N
HO
Ar
10 mol %
ZrOCl28H2O
)))), 30-40 0C
Where Ar; C6H5, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4,
2-ClC6H4, 4-ClC6H4, 2,4-Cl2C6H3, 2-NO2C6H4,
3-BrC6H4.
Scheme 49 . Ultrasound-accelerated, one-pot, solvent-free synthesis of 8-aryl-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6-(5H)-one and 4 -aryl-3,4-dihydro-
quinolin-2(1 H)-one derivatives [303].
OH
CHO O
O
O
O
ZrOCl2.8H2O
)))), 6 min.
+
O O
OH
O
Scheme 5 0. Solvent-free Synthesis of 3-carboxycoumarins under ultrasound irradiation [304].
OH
Me
O
OMe
O
+
Selectfluor
)))), Solvent-free
O
Me
O
Scheme 5 1. Synthesis of 4-methyl-2Hchromen-2-one under ultrasound radiations [305].
OH
+ PhCHO
Manganese
Perchlorate
))))
O
Ph
Scheme 5 2. Synthesis of aryl-14-H-dibenzo[a,j] xanthenes under ultrasonic irradiation [306].
Me
OH
Me
Me
Me
Me
O
OC2H5
O
+
Manganese
Perchlorate
))))
O
Me
O
Me
Me
Me
Me
Scheme 5 3. Synthesis of 4-substituted 2H-chromen-2-ones under ultrasonic irradiation [306].

A Review o n Solvent -free Methods in Organic Synthesis Curren t Organic Chemistry , 2019, Vol. 23 , No. 21 2311
LIST OF ABBREVIATIONS
MCR = Multicomponent reactions
MW = Microwave
VOs = Volatile organic solvents
AcOH = Acetic acid
Me = Methyl
Et = Ethyl
OMe = Methoxy
i-pr = Isopropyl
Ph = Phenyl
MAP = Mitogen-activated protein
r.t = Room temperature
DHPM = 3, 4- Dihydropyrimidinone
TEBA = Triethyl benzyl ammonium chloride
DHP = 1, 4- Dihydropyridine
p-TSA = Para toluene sulphonic acid
TBAHS = Tetra butyl ammonium hydrogen
sulfate
HSBM = High speed ball milling
PEG = Polyethylene glycol
COX = Cyclo oxygenase
HWC = Horner- Wadesworth-Emmons
EWG = Electron withdrawing group
HSVM = High speed vibration milling
NBS = N-bromo succininmide
NCS = N- chloro succininmide
NIS = N- Iodo succininmide
CAN = Ceric ammonium sulfate
CDC = Cross dehydrogenative coupling
DDQ = 2, 3-dichloro-5,6-dicyano-1,4-benz-
oquinone
MWI = Microwave irradiation
TBAB = Tetra butyl ammonium bromide
MORE = Microwave induced organic reac-
tions enhancement
CALB = Candida antartica lipase B
PCL = Poly ε caprolactone
PEET = Phenethylthiazolethiourea
SelectfluorTM F-TEDA-BF4
= (1-ch loromethyl-4-fluoro-1,4-
diazoniabicyclo [2.2.2]octane
bis(tetrafluoroborate)
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The au th ors declare no conflict of interest, financial or oth-
erwis e.
ACKNOWLEDGEMENTS
Authors are thankful to N.E.S Science college, research institu-
tion for providing UGC network service for the reference of re-
search p aper.
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