Tetrahedron

Tetrahedron 112 (2022) 132753
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tetrahedron report 1261
Grindstone chemistry: A “green” approach for the synthesis and

derivatization of heterocycles
Mainak Banerjee a, *, Padmini C. Panjikar a, b, Dharmendra Das a, Shruti Iyer a,
Akhil A. Bhosle a, Amrita Chatterjee a, **
a
Department of Chemistry, BITS Pilani, K. K. Birla Goa Campus, Goa, 403 726, India
b
Parvatibai Chowgule College of Arts & Science (Autonomous), Margao, Goa, India
a r t i c l e i n f o a b s t r a c t
Article history: The famous quote by ancient great philosopher Aristotle, “No Coopora nisi Fluida” means “No reaction
Received 7 December 2021 occurs in the absence of solvent.” Chemistry till the last century was developed based on this philosophy.
Received in revised form In the current century, with the growing environmental concerns and global warming, it has become
17 March 2022
imperative to minimize the usage of hazardous chemicals and solvents. Over a few decades, the appli-
Accepted 23 March 2022
cation of mechanical energy for reactions, called “mechanochemistry,” has emerged as a solvent-less and
Available online 2 April 2022
alternative technique for chemical transformations. The simple and ancient tool for “mechanochemistry,”
a pair of mortar and pestle, also called “grindstone chemistry,” is revitalized in recent years for a myriad
Keywords:
Grindstone
of reactions from simple two-component condensation reactions to multicomponent reactions even to
Mechanochemistry the synthesis of materials. Many of these reactions by grinding in a mortar-pestle led to the construction
Liquid assisted grinding of various heterocycles. The method has benevolent characteristics such as clean and safe reaction
Neat grinding profile, high atom economy, time-efficiency and over a period of time, it proved as a viable alternative to
Mortar-pestle traditional solution-phase reactions. While the main focus of this review article is to cover the literature
Heterocycles available on the use of mortar-pestle for the construction and derivatization of heterocycles, a brief
overview of “grindstone chemistry” is included to give readers an out-and-out idea on its potential as a
sustainable technology for the future.
© 2022 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1. Simple instrumentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2. Features of grindstone chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.3. Grinding vs. ball-milling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.4. The scope of grindstone chemistry: Other than organic transformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. Grindstone derived organic transformations: A brief account . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1. Traditional CeC bond formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2. Formation of Schiff base and related derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.3. Aromatic substitution reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.4. Miscellaneous other reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.5. Multicomponent reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3. Heterocycle synthesis by grindstone chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.1. Five-membered heterocycles with a single heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.1.1. Pyrroles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
* Corresponding author.
** Corresponding author.
E-mail addresses: [email protected] (M. Banerjee), [email protected]
pilani.ac.in (A. Chatterjee).
https://doi.org/10.1016/j.tet.2022.132753
0040-4020/© 2022 Elsevier Ltd. All rights reserved.
M. Banerjee, P.C. Panjikar, D. Das et al. Tetrahedron 112 (2022) 132753
3.1.2. Furans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.1.3. Thiophenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.2. Six-membered heterocycles with a single heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2.1. Pyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2.2. Pyrans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.3. Five-membered with two heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3.1. Pyrazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3.2. Imidazolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.3.3. Thiazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
3.3.4. 1,3-Benzazoles: Benzimidazoles, benzoxazoles, benzothiazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.3.5. Indoloindoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.4. Six-membered with two heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.4.1. Pyrimidines and pyrimidones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.4.2. Quinazolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
3.4.3. Quinoxalines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.4.4. Phthalazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.4.5. Perimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.4.6. Naphthyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.5. Heterocycles with three or more heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.5.1. Oxadiazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.5.2. Chromano[4,3-c]isoxazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.5.3. Dihydropyrano[2,3-c]pyrazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.6. Fused heterocycles with N-atom at the ring junction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.6.1. Imidazo[1,2-a]pyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.6.2. Benzo[d]imidazo[2,1-b]thiazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.6.3. Triazolopyridazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.6.4. Azolopyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.7. Spirocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.8. Diversity oriented heterocycle synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4. Derivatization of heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
5. Summary and future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
1. Introduction grindstone chemistry, was introduced by Toda et al. in the last

century [24,25]. The technique offers solvent-free or solvent-less
“Sustainability” is no longer a fancy term but a deliberation for reactions, often works in the absence of a catalyst, avoids an
chemical transformations in the current scenario. Sustainable extensive work-up step in addition to faster reaction kinetics and
chemistry must meet the present needs without compromising better regio- or stereo-selectivity [26]. Gradually, it became an
future generations and the ecosystem [1]. A chemical trans- effective tool for a variety of organic reactions including Michael
formation under solvent-less or neat conditions minimizes toxicity, addition [27] aldol condensation [28], Claisen-Schmidt condensa-
reduces pollution and energy demands, and lowers the overall cost tion [29], Wittig reaction [30], Horner-Wadsworth-Emmons reac-
of the process [2e4]. This has inspired a large group of researchers tion [31], organocatalysis [32], peptide synthesis [33] etc. More
to adopt green and contemporary technologies such as sono- importantly, this method is found to be equally effective for the
chemical synthesis [5e7], microwave irradiation [8,9], flow- construction of heterocyclic compounds of biological interest in the
chemistry [10], mechanochemistry [11,12] as potential alterna- last few years [34e37]. The early developments of grindstone
tives to conventional “organic media'' based chemical trans- chemistry have been pioneered and reviewed by Tanaka and Toda
formations [13,14]. Notably, mechanochemistry, in which the [22]. Later, this segment of mechanochemistry was only partly
activation energy of a chemical reaction is provided by sheer fric- covered by Wang in 2013 [17], Menendez in 2018 [23], Fris ci
c in
tional force, has been recognized by IUPAC as one of the ten leading 2020 [21], Su in 2020 [38].
world-changing technologies [15]. Although known for years, Heterocycles are the most privileged class of compounds for
mechanochemical reactions were mostly ignored by chemists of their wide spectrum bioactivities [39e41]. Heterocycles feature in a
the 20th century, but it has brought in a revolutionary change in the large number of pharmaceutical products (APIs) and are often the
21st century towards achieving sustainability [16]. In a typical targets for new drug design and discovery [42e44]. The synthesis
mechanochemical process, the reactions are induced by the input of heterocycles is one of the most commonly explored chemical
of mechanical energy, most commonly by grinding in a mortar- transformations [45]. Simple heterocycles can be classified in terms
pestle or by milling in a planetary ball-mill/mixer-mill/shaker- of ring size and the number of hetero-atoms in them. Especially,
mill. Although mechanical milling with higher energy input is a nitrogen-containing heterocycles are vastly abundant among nat-
superior and versatile technique for organic transformations ural products. The porphyrin rings constitute chlorophyll, heme,
[17e21], the grinding in a mortar-pestle with features like simple and vitamin B12; drugs of natural origin like reserpine, morphine,
instrumentation and easy operation is an equally useful method in penicillin are N-containing. The heterocycles present in RNA and
the paradigm of synthetic organic chemistry [17,22,23]. The use of a DNA play important roles in the biochemical processes of living
mortar-pestle for organic transformation, more popularly known as organisms [41]. These electron-rich compounds with high
2
coordinating abilities also feature in broad areas of applications in (e.g. Retsch mortar-grinder, RM200), wherein, reactants in a mortar
various agrochemicals [46], fragrance industry [47], polymers are ground by an electrically operated pestle. Again, mortar/pestle
[48,49], dyes [50], material synthesis [51e53], and several other is made of various hard materials like porcelain, Agate, zirconia,
spheres [41]. An enormous number of methodologies have been stainless steel, etc. A monitor can measure the grinding speed and a
developed targeting common heterocycles like five-members pyr- timer can be set for a reaction. A large automated grindstone
roles, indoles, pyrazoles, oxazole, benzimidazole, or six-membered apparatus can be envisaged for industrial-scale synthesis.
pyridines, pyrans, quinolones, quinazolines, quinoxalines, couma-
rins, etc. [54e58]. Again, complex heterocycles including fused 1.2. Features of grindstone chemistry
heterocycles (e.g. imidazopyridine) or spirocycles (e.g. indolo-
pyrroles), are of medicinal interest or marketed drugs and thus, are Apart from the fact that grindstone chemistry is sustainable as
common synthetic targets [59e64]. Grindstone chemistry has been most of the reactions are carried out under neat or solventless
widely employed in the synthesis of several of these heterocycles conditions, it displays numerous features that establish it as a
and often in solvent-free and catalyst-free approaches in much promising alternative technique for chemical transformations.
economical and eco-friendly ways than conventional methods. Often frictional force provided by “grinding” is good enough to
Although grindstone chemistry is a part of “mechanochemistry” complete the reactions in a time- and energy-efficient manner. The
and is growing at an appreciable pace, not much emphasis has been reactions are set in “open-air” making aerial oxidation a common
given in any of the recently published excellent review articles. In feature of several transformations [34,66]. However, exposure to
this review article, we attempt to comprehensively cover the moisture may be detrimental to moisture-sensitive reactions.
literature available on the construction and derivatization of het- Additionally, the use of volatile reactants is avoided unless the re-
erocycles using a simple “mortar-pestle.” Meanwhile, we felt it action is very fast. The “open-system” also offers easy and effortless
would be legitimate to provide a brief update on the entire spec- ways for monitoring the progress of a reaction. For instance, the
trum of “grindstone chemistry” to give readers a wholesome idea of synthesis of cis-fused chromano[4,3-c]isoxazoles in a mortar-pestle
the potential of this “green” technology as a viable alternative to by Bhutia et al. was monitored by recording IR spectra at regular
conventional methods to achieve “sustainability” in the future. intervals to check the conversion of the intermediate nitrones and
the cyclized products [65].
1.1. Simple instrumentation Interestingly, grindstone chemistry is often assisted by additives
and in many cases, it results in faster reaction kinetics and better
The grindstone chemistry developed using “mortar-pestle” as yields. For example, Banerjee and coworkers reported sluggish
the grinding tool, which are usually made of Agate, granite or reaction for benzimidazole formation as unreacted starting mate-
porcelain and are available in variable sizes. Agate is the commonly rials were trapped inside the solid mass of intermediate imine and
used material because of its hardness and low porosity (Fig. 1). product under neat condition, which was boosted by the addition
However, manual grinding, carried out by a person, is a labor- of a little amount of EtOH [66]. This technique is commonly known
intensive process, which often raises some concerns like, does the as liquid assisted grinding (LAG) or solvent-drop grinding, evolved
reaction kinetics depend on the physical power or the grinding from kneading, in which a small volume of a liquid is added to the
speed? Other pertinent questions are how long the hand-grinding reaction mixture, measured by the ratio ofliquid volume to reactant
can be continued or what is the scalability? For manual grinding, weight (h) [67]. This provides a liquid-solid dual-phase for free
steady and gentle grinding is usually enough for a reaction to interaction of the reactants facilitating product formation. Based on
proceed in the forward direction and hardly affects the reaction the parameter, h a method can be termed as neat grinding (h ¼ 0),
kinetics, however, exceptions are also seen. Bhutia et al. observed LAG (up to 2 mL/mg of substrate), slurrying (ca. 2e12 mL/mg of
that the rate of reaction is dependent on the force applied for substrate) or solution-phase reactions (>12 mL/mg of substrate). For
grinding the reaction mixture, wherein, fast and steady grinding LAG, it is considered that the reactant solubility does not affect the
yields product in a substantially reduced time compared to gentle reaction outcome. There are examples where common solvents are
grinding [65]. These problems can be largely addressed by auto- replaced by polymer, ionic liquid, etc. as the grinding auxiliary and
mation in the grinding process. The electrical grinders are available the corresponding methods are termed as POLAG (polymer assisted
Fig. 1. Different types of grinding tools.
3
grinding) [68], IL-AG (ionic liquid assisted grinding) [69], ILAG (ion chemistry [73]. However, simple grinding is occasionally more
and liquid assisted grinding) [70], etc. A common component of efficient and economical than a similar method using milling
POLAG is the use of polyethylene glycol (e.g. PEG-400), which technique, for example, quinazoline synthesis reported by Kunti-
offered excellent outcomes where other grinding auxiliary failed to kana et al. [80] took only a few min for completion under a solvent-
deliver [68]. Besides, a variety of solid matrices were used as the free condition while a similar reaction in a ball-mill took several
grinding auxiliaries to facilitate a reaction such as Su and coworkers hours for completion [81].
used silica for the synthesis of propargyl amines [71], alumina was
used by Wu and coworkers for the synthesis of quinoxalines [72], 1.4. The scope of grindstone chemistry: Other than organic
KCl was used by Bhutia et al. for the synthesis of 7-oxa-4-thia-1- transformations
aza-bicyclo[3.2.1]-octane 4,4-dioxides [73].
Among other features, it aids in easy separation and purification There are growing numbers of successful use of grindstone
of products; often the work-up step is avoided and sufficiently pure chemistry in the synthesis or formation of valuable materials and
solid product is directly collected [74]. In several cases, easy re- intricate structures including co-crystals, composites, dyes, metal
covery of heterogeneous catalysts by simple extraction of products organic frameworks (MOFs), covalent organic frameworks (COFs),
by organic solvent and recycling is a common feature of grindstone etc. [17,21,23]. For instance, Das et al. constructed a new crystalline
chemistry. Patel et al. employed ionic liquid [DBU][Ac] as the hydrazone-linked COF [TpTh (LAG)], COFs containing the porphyrin
catalyst for the synthesis of 3,4-dihydropyrano[c]chromenes, building unit [DhaTph (LAG)] and COFs with chemically labile Schiff
which was subsequently recovered and reused for five more runs base centers such as [LZU-1] by utilizing a variety of aromatic
with no drop in the catalytic activity [75]. These methods are amine/hydrazide and aldehydes under LAG method [82]. This
environmentally benign than the corresponding solution-based protocol delivered highly pure products in good yields with mod-
protocols. For instance, the grindstone synthesis of zolimidine erate crystallinity and porosity and at a faster rate as compared to
carried out by Das et al. using LAG with EtOH was found to have an the conventional solvothermal methodology. With regard to co-
E-factor of 1.77 [34], while an analogous method by Bagdi et al. crystal synthesis, Solaimalai and coworkers employed the grind-
employing solution-phase synthesis, with 1,2-dichlorobenzene as stone technique to investigate the suitability of a mixture of
solvent generated an E-factor of 14.22 [76], although both garnered menthol and camphor as a green eutectic solvent in the synthesis of
similar yields. cocrystals, for the enhancement of biopharmaceutical properties of
Grindstone reactions occasionally display exceptional control poorly water-soluble drugs [83]. Piroxicam-benzoic acid (PRX-BA)
over chemo-, regio- and stereo-selectivity during the course of cocrystals were synthesized by grinding equimolar quantities of
product formation by manual grinding. The high concentration of PRX and BA in a mortar-pestle with dropwise addition of the green
reacting species under neat or solventless conditions offers eutectic solvent. This simple, economical method is well scalable
different selectivities than analogous solution-based reactions [26]. and eliminates the disadvantages posed by conventional methods
For example, Tanaka et al. carried out Reformatsky and Luche re- of synthesis. In another experiment, the cocrystallization behavior
actions more efficiently in the absence of solvent [77]. Satasia et al. of antiprotozoal tinidazole (TNZ) was investigated in order to
demonstrated N-formylation of amines by employing a novel ionic identify the possibility of preparing new solid forms as an attempt
liquid (HIL-[Ch-OSO3H]3W12PO40) as the catalyst, in which only the to enhance its solubility and physical stability [84]. Fandin ~ o et al.
N-formylated products were chemoselectively furnished [78]. employed LAG for the synthesis of three cocrystals of TNZ with p-
Bhutia et al. developed an efficient hand-grinding procedure for the aminobenzoic acid (PABA), citric acid (CA), and salicylic acid (SA),
stereoselective synthesis of cis-fused chromano[4,3-c]isoxazoles and two eutectics with nicotinamide (NA) and succinic acid (SA).
via an intramolecular 1,3-dipolar nitrone cycloaddition affording Although the prepared cocrystals and eutectics did not significantly
high diastereoselectivity as observed in solution phase methods enhance the aqueous solubility of this API, the cocrystals, however,
[65,79]. improved the solid-state photostability of TNZ.
Along with its ability to aid known reactions, grindstone
1.3. Grinding vs. ball-milling chemistry is also instrumental in accessing the reactions that are
not easily attainable through conventional methods. A series of API-
Mechanochemical force can be employed by two prominent ILs incorporating lidocaine and medium chain dicarboxylic acids as
techniques, either by grinding in a mortar and pestle, termed as counter ions were synthesized using grindstone chemistry by
grindstone chemistry or by milling in mixer mill or a planetary mill Zotova et al., aimed towards their discovery and development for
by the grinding balls which is referred as ball-milling [17]. Although pharmaceutical applications [85]. Simple neat grinding afforded
milling, with much higher grinding force, several instrumental the ILs lidocainium hemiadipate solid salt and lidocainium hemi-
advantages, variation in milling parameters is by far a superior glutarate, lidocainium hemipimelate, lidocainium hemsuberate in
technique, grindstone chemistry with simple instrumentation, easy higher yields, with shorter reaction times and in the absence of
experimental set-up, no or less energy consumption is a frequently solvents in contrary to conventional solution-based synthesis,
used technique for a plethora of applications. If the grinding is which requires large volumes of solvents and purification steps. Lee
conducted at a speed of 50e200 rpm, the milling is conducted at a and group developed a simple approach for the synthesis of a
frequency of 5e60 Hz or 600e850 rpm. The power of high-energy fullerene-nanodiamond composite by hand-grinding dry C60
ball milling (HEBM) is even higher. Therefore, energy-intensive powder with nanodiamond (ND) in a mortar and pestle [86]. This
organic reactions, such as CeH bond activation can be efficiently novel protocol does not require organic solvents and is highly
carried out in a ball-mill [18], but hand-grinding is hardly employed scalable. The furnished C60-ND composites were found to be easily
for similar transformations. The recent advancements in milling dispersible in water and displayed enhanced activity for the
techniques include cryo-milling, continuous mode milling (twin- removal of water contaminants and for the induction of cancer cell
screw extrusion, TSE), photo-mechanochemistry, which offer the apoptosis. Prusti et al. reported the design of two positional
employment of mechanochemistry in a wide variety of reactions. isomeric AIEgens TMBpCBZ and CBZpTMB [p ¼ anthracene-linked
However, grindstone chemistry is mostly limited to room temper- vinyl] by interchanging the two electron-rich CBZ and TMB cores
ature reactions. Often, the sheer power of a ball-mill speed-up the [87]. These compounds were easily synthesized in high yields
reactions, which are otherwise sluggish by simple grindstone (~80%) at room temperature by grinding phosphonates and
4
aldehydes, thereby avoiding the need for expensive metal/ligand enormous industrial implications [88]. In the last century, Toda's
combinations for their synthesis. Although both isomers are strong group explored various traditional CeC bond formation reactions
solid-state emitters, it was interestingly found that after grinding in employing grindstone chemistry that include aldol condensation
a mortar and pestle, TMBpCBZ displayed reversible spectacular [28], Dieckmann condensation [89], Reformatsky reaction [77],
piezo-fluorochromic features with a 62 nm redshift, whereas, Luche reaction [77], Grignard reaction [25], etc. which are reflected
CBZpTMB remained unchanged. This protocol was found to be in their excellent review article on solvent-free reactions [22]. In
easily scalable, making real-world access to these materials more this section, a few more recent and important contributions on CeC
feasible [87]. The literature is vast in this direction and the above bond forming reactions are included demonstrating the scope of
section is a glimpse of the scope of grindstone chemistry in con- grindstone technique.
ducting transformations other than organic reactions. Grindstone chemistry was successfully used towards aldol
condensation/Claisen-Schmidt condensation by grinding in
2. Grindstone derived organic transformations: A brief mortar-pestle [90,91]. Recently, Li et al. synthesized novel
account quinoline-based a-arylidene cycloketones, i.e., (Z)-3-arylidene/fer-
rocenylmethylene-5-methyl/phenyl-1H-pyrano[3,4-b]quinolin-
Over the years, grindstone chemistry has established itself as 4(3H)-ones (3) involving solvent-free aldol condensation reaction
being a simple and greener technology for various chemical between pyrano[3,4-b]quinoline-4(3H)-ones (1) and various aro-
transformations from traditional CeC bond formation to different matic aldehydes (2) by grinding in a mortar and pestle using KOH as
name reactions to various multicomponent transformations. In this the base at room temperature (Fig. 2a) [90]. They first synthesized
section, we intend to give a brief overview of the use of grindstone 1, the cyclic ketones with active methylene moiety, and performed
chemistry for these classical organic transformations with selected aldol condensation with various aromatic and heteroaromatic al-
recent examples. dehydes to get a-arylidene cycloketones (3) with quinoline ring in
high to excellent yields. Out of the various acids and bases
employed as catalysts for the aldol condensation, KOH (1 equiv)
2.1. Traditional CeC bond formation
was found to give the best results under solvent-free grinding at
room temperature. Notably, the condensation product of 1 and
Carbon-carbon bond formation reactions are crucial for syn-
benzaldehyde afforded only 61% yield after refluxing in ethanolic
thetic chemists for years in building up molecules and have
Fig. 2. Different condensation reactions carried out using grindstone technique.
5
solution for 5 h as compared to 89% yield in just 1 h by grinding, study of Michael addition between b-nitroalkenes (12) and 1,3-
indicating hand-grinding a facile approach than solvent-based dicarbonyl compounds (13) or other active methylene compounds
methods. Some of the compounds displayed anti-tumor activity (14) revealed that quartz sand (0.75 g per 0.1 mmol of substrates)
when screened for the same. Kumar et al. demonstrated the works better as the grinding auxiliary furnishing good to excellent
Claisen-Schmidt condensation between acetophenones (4) and aryl yields of the desired products (15 or 16). In another interesting
aldehydes (5), and synthesized some interesting chalcones (6), study, Luo and Shan synthesized highly substituted cyclohexanols
useful intermediates of flavonoids, using anhydrous barium hy- (18), one of the Kostanecki ketones, by a tandem aldol condensa-
droxide (C-200) as solid support in a mortar-pestle in good to tion, Michael reaction and cyclization of acetophenone with various
excellent yields within a short reaction time at room temperature aromatic aldehydes (17) in 2:3 ratio (Fig. 2f) [101]. The two-
(Fig. 2b) [91]. This method selectively furnished 6 without the component tandem cyclization was catalyzed by a mixture of
formation of any cyclized products. In a different approach towards NaOH and K2CO3 (2:1 M ratio) in mortar-pestle for 5e20 min at
ClaiseneSchmidt condensation, Rateb and Zohdi prepared several room temperature and the product formation was indicated by the
chalcones by grinding a mixture of appropriate methyl ketones disappearance of the liquid component and the insoluble solid
with aldehydes in the presence of NaOH (solid) under solvent-free product was collected after water-wash of inorganic bases making
conditions [92]. The desired products were purified by simple the protocol an efficient one for the synthesis of 1,2,3,4,5-
filtration involving washing the product residue with cold water pentasubstituted cyclohexanols. The products (18) showed iden-
followed by recrystallization. Similar to aldol reaction, the first tical stereochemistry with the adjacent groups bearing a trans
solid-state Lewis base-catalyzed Henry reaction for the synthesis of relationship (Fig. 2f).
2-nitroalkanols (9) by grinding technique was reported by Phukan Among other important CeC bond formation reactions, Agarwal
et al. by employing cheap and readily available imidazole as the et al. demonstrated a rapid mechanochemical Diels-Alder reaction
catalyst (Fig. 2c) [93]. In general, the grinding of aldehydes (7) with to access bi-, tri-, and tetra-cyclic systems (23e26) via LAG with
nitroalkanes (8) gave the desired products (9) generally in high EtOAc in mortar and pestle (Fig. 3a) [102]. Optimization studies
yields. Furthermore, it was observed that the addition of sand (used revealed that the dienes (1,3-diphenyl-2-benzofuran, 19 and
as friction-enhancing solid) tremendously accelerated the reaction cyclopentadiene, 20) and diverse electron-deficient dienophiles (21
rate for solid/liquid and liquid/liquid substrates. The absence of side and 22) under neat grinding afforded the product in only 75% yield
products and catalyst recyclability without much loss in the prod- after rigorous grinding for 15 min, whereas, the LAG protocol using
uct formation are few important advantages of this method. EtOAc (2e3 drops) resulted in complete conversion of the reactants
Knoevenagel condensation is one of the most widely applied in just 5 min, giving the products in quantitative yields. Various
reactions and studied well using grindstone chemistry. Various dienes and diverse electron-deficient dienophiles were ground
catalytic conditions have been successfully investigated for car- together under catalyst-free and solvent-free conditions in a
rying out this reaction with various aldehydes and active methy- mortar-pestle to afford the corresponding Diels-Alder adducts in
lene compounds as reactants using mechanochemical grinding quantitative yields. The high yields ensured no formal purification
[94e99]. To briefly illustrate them, a green and economic approach is required.
for the Knoevenagel condensation of substituted aromatic and A Wittig reaction was explored by Leung and coworkers
heteroaromatic aldehydes (10) with malononitrile catalyzed by adopting hand-grinding protocol in synthesizing (E)- and (Z)-1-(4-
water extract of banana (WEB), a natural base, was described by bromophenyl)-2-phenylethene (28) by grinding a mixture of ben-
Kantharaju et al. (Fig. 2d) [94]. The solvent-free procedure fur- zyltriphenylphosphonium chloride (27) and 4-bromobenzaldehyde
nished the desired products (11) within just 10 min of grinding and in the presence of potassium phosphate under the solvent-free
sufficiently pure products were obtained by simple filtration. In condition at room temperature in just 20 min (Scheme 3b) [30]
another study, Ren et al. demonstrated an “improved” Knoevenagel The reaction produced both (E) and (Z) isomers of 28 in about 70%
condensation reaction by grinding aldehydes and malononitrile in yield, but only the E isomer could be isolated by crystallization. A
glass mortar-pestle in the absence of solvents and catalysts [95]. Horner-Wadsworth-Emmons reaction was demonstrated by Mar-
Surprisingly no products were obtained when the same reaction roquín and coworkers for the synthesis of piperlotines A, C, and
conditions were employed using porcelain mortar and pestle. Pasha derivatives (31) via mechanochemical activation of different alde-
and coworkers used Na2CO3 to catalyze the Knoevenagel conden- hydes (29) and b-amidophosphonate (30) in the presence of K2CO3
sation of aromatic aldehydes with active methylene compounds to (1.2 equiv) in mortar-pestle (Fig. 3c) [31]. The gentle grinding of the
afford arylmethylidene products under grindstone chemistry [96]. substrates in open-air afforded thermodynamically controlled E-
Thirupathi and coworkers used L-tyrosine, an organocatalyst, in the isomers as the sole products in moderate to good yields. This
Knoevenagel condensation between arylaldehydes with Meldrum's method tolerated both the presence of EDGs, EWGs and unsatu-
acid in a mortar-pestle at room temperature to produce substituted ration in the aldehydes (29).
5-benzylidene-2,2-dimethyl- [1,3]dioxane-4,6-diones [97]. Met- In another study, a solid-state Corey-Chaykovsky reaction was
wally and coworkers synthesized 5-arylidene-4-thiazolidinones demonstrated by Yin et al. for the cyclopropanation of 4-
from various aromatic aldehydes and 4-thiazolidinones by ferrocenylacetophenones (32) via grinding of the substrates in
grinding in a mortar and pestle in the presence of anhydrous mortar-pestle followed by microwave irradiation (Fig. 3d) [103].
ammonium acetate [98]. Recently, in another interesting approach, Few novel (4-ferrocenyl)benzoylcyclopropanes (34) were prepared
Madan employed ZnO nanoparticles towards the synthesis of by grinding 32 with substituted aldehydes (33) using NaOH and
Knoevenagel condensation products of indole-3-carbaldehydes Al2O3 as the grinding matrix followed by microwave irradiation of
and 3-methyl-1-phenyl-5-pyrazolone with an active methylene the reaction mixture. This was followed by the addition of another
group employing the same solvent-free grindstone protocol [99]. ground mixture of trimethylsulfoxonium iodide, NaOH, and Al2O3
A Michael addition reaction was demonstrated by Xie et al. for to the previous mixture and the resultant mixture was further kept
the synthesis of various nitro diketone derivatives (15 and 16) under microwave irradiation. The final cyclopropyl ketone de-
employing grindstone chemistry (Fig. 2e) [100]. The optimization rivatives (34) were obtained in 85e99% yields.
6
Fig. 3. Selected name reactions involving CeC bond formation by grindstone technique.
2.2. Formation of Schiff base and related derivatives case. Notably, N-acylhydrazone (NAH) moiety is a privileged
structural scaffold in medicinal chemistry. They validated the
Schiff bases are organic compounds with a broad spectrum of method with aromatic, heteroaromatic, aliphatic aldehydes and
biological activities, including anti-inflammatory [104], antimicro- ketones as well as sugars (Fig. 4b). On the other hand, hydrazides
bial [105], antitubercular [106], anticancer [107], etc. and several of derived from several benzoic acids, heteroaromatic acids or even
them are used in the medicinal and pharmaceutical fields. In ferrocene carboxylic acid participated equally well in the conden-
addition, Schiff bases are useful intermediates in the synthesis of sation reaction to prepare a library of 51 compounds. In most of the
dyes, pigments, as polymer stabilizers, and so on [108]. cases, the essentially pure hydrazones were obtained avoiding
Grindstone chemistry has been vastly employed for Schiff base workup and purification steps. However, the same method failed to
formation reactions. In the past, solid-state condensation reactions afford hydrazones (or imines) from N-Boc-amine or a sulfinamide
afforded Schiff bases upon grinding a mixture of carbonyl com- (-SONH2) or sulfonamide (-SO2NH2) derivatives. In another study,
pounds and amine derivatives in mortar and pestle under neat or Barbaza n et al. reported grindstone mediated hydrazone synthesis
solvent-less conditions, such as using water as an LAG agent by condensation of ferrocene carboxaldehyde and benzoyl hydra-
[109e111]. For example, Sachdeva and co-workers demonstrated a zide [113]. Yang et al. developed another grindstone method to
protocol for the synthesis of racemic mixture of Schiff bases (37), as prepare N-arylsulfonylhydrazones by condensation of benzensul-
potential antimicrobial agents, by the condensation of substituted fonyl hydrazides with various arylaldehydes/ketones using L-tyro-
aromatic or heteroaromatic aldehydes (35) with DL-alanine (36) sine as the organocatalyst [114]. On the other hand, Aakero € y et al.
(Fig. 4a) [109]. Some of these Schiff bases derived from aromatic reported the synthesis of ketoximes (44) via a mechanochemical
aldehydes with trimethoxy, dimethoxy, hydroxyl, nitro, and chloro synthetic pathway involving the grinding of different ketones (43)
groups or furfural showed good antibacterial and antifungal ac- with hydroxylamine hydrochloride and NaOH in the presence of
tivities. The hydrazone formation by hand-grinding was explored methanol (0.1e0.2 mL) as LAG agent in a porcelain mortar-pestle
by Filho and coworkers (Fig. 4b) [112]. The grinding of various (Fig. 4c) [115]. Aromatic ketones with both EDG and EWG, hetero-
carbonyl compounds 38 (including cyclic ketones, 39) with N-acyl aryl ketones as well as aliphatic ketones participated in the reaction
hydrazides (40) in the presence of catalytic amount of AcOH and a and several of them afforded stoichiometric yields of the corre-
few drops of water as LAG agent only for a few minutes afforded a sponding ketoximes. In a similar approach, Saikia et al. prepared a
large number of N-acylhydrazones (41) in over 90% yields in each series of aldo/ketoximes by solid-phase grinding of a mixture of
7
Fig. 4. Formation of Schiff bases and related reactions employing the grindstone technique.
carbonyl compounds (aliphatic, heterocyclic, and aromatic) and aromatic substrates (51) with NaNO2 (20 mol%), KHSO4 (10 mol%)
hydroxylamine hydrochloride in the presence of cheap Lewis acid, and peroxides (10 mol%) was smoothly carried out in a mortar-
Bi2O3 as the catalyst [116]. Venkateswarlu and coworkers synthe- pestle and the products (52) were obtained in 65e85% yields. A
sized N-(tert-butylsulfinyl)imines (47) from chiral tert-butylsulfi- total of five different peroxides (H2O2, TBHP, PDS, PMS or SPB) were
namides (46) employing grindstone chemistry involving a solid tested and all gave similar results. The comparison between the
acid, perchloric acid-silica (HClO4,SiO2) catalyzed reaction of conventional method and grindstone technique revealed that the
various aldehydes (45) with N-tert-butylsulfinamides (46) (Fig. 4d) reaction time can be shortened from hours to a few min by simple
[117]. The use of simple silica gel or other solid acid catalysts (e.g. grinding in a mortar-pestle. They examined in situ generation of
H2SO4,SiO2, p-TSA.SiO2) offered lower yields and took longer time. active nitronium ion as the nitrating species. Thus, the group
The grinding of substrates in an Agate mortar with a catalyst load of commented that the method does not produce any radical species
80 mg/mol in the absence of solvent furnished the desired products which are usually produced in situ when a peroxy species is used
in short reaction times, restoring the chirality of initial tert-butyl- for several other reactions.
sulfinamide derivatives. This method was validated by using both Karade and coworkers carried out halogenation of various are-
electron-withdrawing groups (EWGs) and electron-donating nes (53) by mortar pestle grinding with NaCl, NaBr or I2 by using
groups (EDGs) in the aromatic aldehydes. No significant substitu- (diacetoxyiodo)benzene as an oxidant (Fig. 5b) [121]. As expected,
ent effect was observed in terms of yield or reaction time. In the reaction offered high regioselectivity with p-position being
another study, the acidic nature of aqueous citrus juices was more favoured. For example, halogenation of anisole, N,N-dime-
explored in utilizing them as natural and green catalysts for the thylaniline and acetanilide exclusively furnished para-products.
synthesis of b-enaminone derivatives (50) via enamination of 1,3- The yields of bromination and iodination products (54) were
dicarbonyls (48) with various aromatic/aliphatic primary amines found to be relatively higher compared to the yields of chlorination.
(49) in a mortar-pestle by Marvi et al. (Fig. 4e) [118]. Citrus juices of The alternative route of halogenation from diazonium salts, i.e.
four different fruits i.e. lime, lemon, orange and grapefruit along Sandmeyer reaction was also carried out by simple hand-grinding
with SiO2 as a solid matrix were screened and the former delivered by Bamoniri et al. to synthesize various aryl iodides (56) in good
the best results. The catalytic system of lime/SiO2 (5 drops/1 g) to excellent yields via diazotization of electron-rich and electron-
furnished about 15 derivatives of 50 in good to excellent yields deficient aromatic amines (55) with NaNO2 in the presence of a
under ambient conditions. reusable solid-acid catalyst, nano silica periodic acid (nano
SiO2eHIO4) followed by iodination with KI (Fig. 5c) [122]. The
amount of catalyst used was fixed as 50 mg/mmol of the substrate
2.3. Aromatic substitution reactions which gave yields above 90%, whereas, with a decrease in the
amount of catalyst, the yields reduced below 50%. The nanocatalyst
Aromatic substitution often ends up with the products which was prepared by the group and its reusability study showed that it
serve as the intermediates or precursors of important organic could be used up to 5 cycles without much decrease in its catalytic
compounds, polymers, dyes, pharmaceuticals, agrochemicals, etc. activity (83% effective). In another study, Vibhute and coworkers
[119]. In this direction, Suresh et al. used a grindstone protocol for developed a hand-grinding protocol for the iodination of phenols
the nitration of aromatic and heteroaromatic compounds (51) by a with aldehyde and ketone functionalities by a combination of
combination of NaNO2/KHSO4 under mild conditions avoiding the iodine and iodic acid [123].
use of any mineral acid (Fig. 5a) [120]. The mono-nitration of
8
Fig. 5. Grindstone mediated aromatic substitution reactions.
The mechanochemical Vilsmeier-Haack reaction was reported supported metal nitrates under acid-free conditions (Fig. 6b) [128].
by Mohammed et al. for formylation and acylation of various ani- The method involves the use of inexpensive and readily available
soles (57) and pyridines (58) by grinding them vigorously with 3d block nitrates of Fe(III) and Mn(II) which had been screened
Vilsmeier-Haack reagent, 59 to give the desired products (60 and along with different PEGs such as PEG-200, 300, 400, 600, 3000 and
61) using a mortar and pestle (Fig. 5d) [124]. The protocol was 6000 as additives. The use of PEG-400 with the two nitrates was
found to be more advantageous over solution-phase reaction both found to be the best among PEGs for cinnamic acid which resulted
in terms of reaction rate and environment friendliness. The method in better conversion within 30 min. The cinnamic acid derivatives
was validated using different EWGs and EDGs derivatives and it was with EDGs reacted faster (30 min) than those with EWGs (60 min).
found that the yields are almost comparable in both cases and not The aliphatic acid (such as crotonic acid) took more time for
much substituent effect is observed. Balali et al. reported a regio- completion affording nitroalkenes in relatively lower yields.
selective o-formylation of phenols by grinding various phenols with The rearrangement reaction is also possible by simple grinding.
paraformaldehyde and Mg(OMe)2 [125]. This grinding protocol Sharma et al. successfully demonstrated Baker-Venkataraman rear-
using mortar pestle gave exclusively the ortho-substituted prod- rangement of 2-cinnamoyloxyacetophenones (67) by solid-phase
ucts. A high yielding mechanochemical method for the synthesis of grinding with potassium hydroxide in a porcelain mortar-pestle
fluorescein-phenylalaninol (FPA) receptor was reported by Rathod (Fig. 6c) [129]. The desired products 2-hydroxybenzoylcinna
et al., exploiting the Reimer-Tiemann reaction under the grindstone moylmethanes (68), which are the key intermediates in the syn-
chemistry [126]. The manual grinding of fluorescein and solid thesis of flavones and 2-styrylchromones, were formed by Baker-
NaOH in a mortar-pestle under LAG (few drops of MeOH) produced Venkataraman rearrangement within just 3e5 min. A short library
the desired fluorescein monoaldehyde in good yields. The synthe- of 2-hydroxydibenzoylmethanes were prepared from 2-aryloxyaceto
sized fluorescein Schiff base was utilized as the colorimetric and phenones by this rearrangement reaction. The reaction mixtures
fluorimetric sensor for the simultaneous detection and removal of were filtered after acidification and pure products were obtained by
toxic mercury ions in the aqueous solution. recrystallization from aqueous ethanol in good to excellent yields.
The hand-grinding tool can be used for regio-/chemo-selective
synthesis. Bharate and coworkers performed a regioselective O-
2.4. Miscellaneous other reactions
benzylation or benzoylation on rohitukine (69), an alkaloid with
anticancer activity, in mortar-pestle in the presence of catalytic
The versatility of grindstone chemistry was demonstrated by
amount of potassium fluoride impregnated alumina (Fig. 6d) [130].
several other name reactions as well. In this regard, Rahman and
Rohitukine (69) has two phenolic eOH groups at C5 and C7 and one
coworkers established a non-hazardous hand-grinding protocol for
is alcoholic eOH (at C20 ). As C5eOH is H-bonded with 4-carbonyl
Cannizzaro reaction in which they ground various aryl aldehydes
oxygen, regioselective benzylation (or benzoylation) was possible
(62) with solid sodium hydroxide to get corresponding Cannizzaro
at phenolic-OH group of C7. As no strong base was used in the re-
products (63 and 64) in 94e99% yields in just 10 min of grinding
action media, the method showed chemoselectivity towards
(Fig. 6a) [127]. The reactions proceeded exothermically wherein the
phenolic eOH over an alcoholic functionality. Grinding of rohitu-
rise in temperature was recorded ranging between 25 and 100 C.
kine (69) with different benzyl and benzoyl halides (70, X ¼ Cl or
The purification was done by acidifying the reaction mixture, which
Br) in the presence of 5 mol% of KF-alumina afforded the desired
leads to precipitation of the acid (63) and upon filtration pure al-
products (71) in high yields. The alkylation was found sluggish in
cohols (64) were obtained in the filtrate, thereby, avoiding the
the solution phase (e.g. acetone or DMF) or neat grinding in model
tedious purification steps. In another study, the Hunsdiecker-like
reactions with 4-methoxy benzyl bromide. The solid catalyst could
conversion of a,b-unsaturated acids (65) to nitroalkenes (66) was
be recycled for several cycles without a loss in reactivity.
accomplished by Ramesh et al. by grinding them along with PEG
9
Fig. 6. Application of grindstone chemistry for miscellaneous other reactions.
Asymmetric transformation is recognized as one of the most heterocyclic amines were successfully protected with Boc-group by
important chemical transformations, particularly for the synthesis grinding with (Boc)2O in the presence of CuI NPs (20 mg/mmol) in a
of chiral drugs. The hand-grinding method is occasionally mortar and pestle delivering 14 compounds (76). This method
employed for asymmetric catalysis [131]. Chauhan et al. developed afforded the products in high yields (82e92%) within shorter re-
a mechanochemical route for a highly stereoselective Michael action times (5e15 min). The CuI catalyst was recycled after
addition of trisubstituted b-ketoesters (or 1,3-diketones, 72) and centrifugation with EtOAc and water, and was used for three cycles
nitroalkene derivatives (73) via simple grinding with pestle and with a slight drop in catalytic activity in the third cycle.
mortar (Fig. 6e) [132]. Grinding an equimolar quantity of 1,3-
diketone (72) and nitroalkene (73), in the presence of cupreine 2.5. Multicomponent reactions
derived organocatalyst (BnCPN, 5 mol%) delivered the Michael
adducts (74) with vicinal tertiary and quaternary stereocenters in Over the years, multicomponent reactions (MCRs) gained
high yields with excellent stereoselectivity (up to 99% ee and up to immense importance as useful tools for the synthesis of value-
99:1 d.r). The grinding-assisted organocatalysis protocol proceeded added molecules in the fields like medicinal chemistry, drug dis-
at a much faster rate in comparison to the reactions performed covery research, agrochemistry and so on. Mortar-pestle grinding is
under traditional stirring in toluene or under neat conditions. The used in several types of MCRs leading to heterocycles, which will be
grinding enabled the appropriate mixing of the catalyst and sub- discussed in the next section. In this section, we intend to discuss
strates and frictional force pushed the reaction to the forward di- selected examples of MCRs leading to acyclic compounds. In this
rection. The presence of EWGs in the substrate, 73 expedites the direction, Mani et al. synthesized several Mannich bases (79)
product formation with better yields as compared to EDGs. involving the reactions of dopamine (77), vanillin and substituted
Although protection-deprotection chemistry is highly useful in ketones (78), utilizing the grindstone technique (Fig. 7a) [134]. A
synthetic organic chemistry, only limited attempts are made in this total of 12 compounds were prepared using the protocol under
direction employing grindstone technique. Recently, Kantharaju catalyst-free conditions with 87e96% of yields. These dopamine-
et al. described a mechanochemical protocol for the Boc-protection derived Mannich bases (79) displayed significant antioxidant and
of primary amines (75) employing copper iodide nanoparticles as anti-tyrosinase activities. In a similar approach, Mohan et al.
the catalyst (Fig. 6f) [133]. Various aliphatic, aromatic, and developed a grindstone protocol for Betti reaction between aryl
10
Fig. 7. Multicomponent name reactions aided by mortar-pestle grinding.
aldehydes (80), 2-naphthol, and aromatic amines (Fig. 7b) [135]. reaction based on the grinding of different solids involved the
The grinding of these three components in a mortar-pestle in the formation of a liquid phase with a uniformly distributed eutectic
presence of catalytic amount of MeSO3H gave 1-aminoalkyl-2- melt that brings the reacting components in close proximity to
naphthol derivatives (81) in good to excellent yields. A syrupy re- react efficiently. The scope of the method was explored with 16
action mixture was washed with water and once the acid was examples.
removed, the desired products (81) were obtained as solids making Among various other multicomponent reactions, Chimni and
product separation easy. However, a couple of attempts with coworkers reported decarboxylative reactions of isatin derivatives
aliphatic aldehydes resulted in very poor yields of Betti products. (86), malononitrile and b-ketoacids (87), carried out in a mortar
The scope of the method was demonstrated by the synthesis of 1- and pestle with DBU as the catalyst to afford 3,3-disubstituted-2-
aminoalkyl-2-naphthols (81) in large-scale (0.25 M batches). For indolinone derivatives (88) (Scheme 1a) [137]. Different organo-
these reactions, various components and the catalyst were taken in catalysts, such as DMAP, DABCO, DBU, pyridine, pyrrolidine, were
a large porcelain bowl and ground with the help of a hand-held tested during the optimization studies and the best results were
electric food mixer with stainless steel rotors. The large-scale re- obtained with 10 mol% DBU. The protocol smoothly gave oxindole
actions were also completed within 5 min and the desired products derivatives (88) in up to 98% yields in a short time. Water wash of
were obtained in 83e95% yield. the resultant reaction mixture and simple filtration offered column
A Passerini reaction was exploited by Sato et al. for the synthesis chromatography free purification of the products. They also
of 3-N-acylamino azulenes (85) via manual grinding of a mixture of demonstrated the reductive cyclization of suitable 2-indolinone
3-isocyano-7-isopropyl-1,4-dimethylazulene (82), benzaldehydes derivatives to biologically important spirooxindoles (89) in high
(83), and various carboxylic acids (84) in an Agate mortar-pestle yield (89%) employing the grindstone technique (Scheme 1a). In
(Fig. 7c) [136]. The grindstone protocol was found superior than another recent study, a one-pot, base-catalyzed tandem reaction
the solution phase Passerini reaction. They demonstrated with involving sequential aldol condensation and Michael addition was
model substrates, isonitrile (82, 1.0 equiv), p-chlorobenzaldehyde developed by Hu et al. for the synthesis of 3,4,5-trisubstituted
(2.0 equiv) and decanoic acid (2.0 equiv) that the reaction proceeds isoxazoles (94) by hand grinding (Scheme 1b) [138]. The grinding
smoothly to completion within 20 min to furnish the correspond- of aromatic aldehydes (90) and 3,5-dimethyl-4-nitroisoxazole (91)
ing Passerini product in 81% yield, while the same reaction in THF in the presence of pyrrolidine provided 5-styryl-3-methyl-4-
afforded 45% yield after 18 h, or in CTAB derived micellar media in nitroisoxazoles (92) via aldol condensation within just 3e10 min.
72% yield even after 24 h. They postulated that the solvent-free The Michael addition between the aldol product (92) and active
11
Scheme 1. Other multicomponent reactions aided by grindstone chemistry.
Scheme 2. Regio- and stereo-selective synthesis of dihydroindeno[1,2-b]pyrrole derivatives (98) by hand-grinding [142].
methylene compounds (93) in the presence of Et3N furnished (94) multicomponent cyclocondensation reactions. The vast literature in
in up to 93% yields by grinding for another 3e5 min in the same this direction is presented below based on their core structures. The
mortar. It was observed that the protocol works only for malono- subsections are made based on the ring size and the number of
nitrile derivatives or nitroacetates but failed to give any product heteroatoms present.
with ethyl acetoacetate or acetylacetone even after prolonged
grinding. 3.1. Five-membered heterocycles with a single heteroatom
3. Heterocycle synthesis by grindstone chemistry 3.1.1. Pyrroles

Pyrrole or pyrrolidine is a common structural scaffold of several
Heterocyclic scaffolds are widely abundant among a variety of natural products and is one of the most explored heterocycles in
natural products including alkaloids, natural dyes, drugs, proteins, drug discovery research [139,140]. Their profound bioactivities
enzymes, etc. A large variety of heterocycles were prepared by have motivated the development of various strategies for their
simple grinding in a mortar-pestle by various two-component and synthesis [140,141]. Perumal and coworkers synthesized highly
12
functionalized indenone-fused dihydropyrroles (98) in a regio- and ninhydrin (97) leading to the formation of intermediate A, which
stereo-selective manner using a hand-grinding protocol (Scheme 2) undergoes intramolecular cyclization to afford the title compound,
[142]. The grinding of equimolar amounts of (E)-3-(dimethyla- 98. No significant substituent effect was seen in terms of yield or
mino)-1-arylprop-2-en-1-ones (95) with anilines (96) and ninhy- reaction time. After completion, the reaction mixture was triturated
drin (97) in the presence of a few drops of acetic acid for a period of with crushed ice, the resulting solid filtered off to afford sufficiently
5e8 min led to the construction of 3-aroyl-3a,8b-dihydroxy-1-aryl- pure 3-aroyl-3a,8b-dihydroxy-1-aryl-1,8b-dihydroindeno[1,2-b]
1,8b-dihydroindeno[1,2-b]pyrrol-4(3aH)-ones (98) with cis-ring pyrrol-4(3aH)-ones (98) offering a simple way of product isolation
junction stereochemistry. A model reaction to prepare dihy- without column chromatography. The low E-factor (0.44) makes
droindeno[1,2-b]pyrroles, 98a in the solution phase (DMF, TFA or the protocol an efficient one for the synthesis of dihydroindeno[1,2-
water) afforded poor yields of the desired product even after b]pyrroles.
employing a variety of catalysts such as CAN, p-TSA, InCl3, or AcOH,
and high temperature. Whereas, the reaction afforded 96% yield of
3.1.2. Furans
98a in just 6 min of grinding the substrates with 0.1 mL of acetic
Furan, an oxygen-containing five-membered heterocycle, fea-
acid per mmol of 95 (h ¼ 0.2 mL/mg of solid substrates). Thus,
tures in several pharmaceutically important molecules [143,144].
liquid-assisted grinding expedited the reaction by several folds. As
This instigates the development of environmentally benign syn-
it can be seen in the selected examples, the protocol could be
thetic methods for a variety of compounds containing this het-
successfully extended to several aromatic, aliphatic (viz. n-propyl,
erocyclic scaffold [145]. Among available grinding protocols,
n-butyl, cyclopropyl), or benzylamines in 96 and a variety of aryl
Chuang and Chen developed a one-pot three-component route for
and heteroaryl in enaminoketones (95) to generate a broad library
the synthesis of highly functionalized 2,3-dihydrofurans (102) from
of 22 dihydropyrrole heterocycles (98) in 84e94% of yields. The
1,3-dicarbonyl compounds (99), aromatic aldehydes (100), and N-
domino transformation follows an initial Michael addition of ani-
phenacylpyridinium bromides (101) in a diastereoselective manner
line (96) to enaminoketones (95) followed byelimination of dime-
(Scheme 3) [146]. Initially, they developed a solution-phase method
thylamine and attack of the corresponding enaminoketones to
by heating the reaction mixture in acetonitrile at 60 C for 14 h to
Scheme 3. The diastereoselective synthesis of 2,3-dihydrofurans (102) via a one-pot three-component route [146].
13
afford 2,3-dihydrofurans (102) in high yields, however, the reaction route using solvent-drop grinding for the synthesis of highly
time was shortened to just 1 h when the substrates (99e101) were regioselective naphtho[2,3-b]thiophenes (105) [149], a class of
manually ground in a mortar-pestle. The presence of a Lewis base compounds which is known for significant cytotoxicity against
was required to catalyze the reaction and a short screening several human solid tumors [150]. The thiophene fused naph-
revealed that 2.5 equiv of piperidine gave the best results among thoquinone derivatives (105) were synthesized by grinding 1,4-
the options tried (e.g. DABCO, DBU, etc.). The authors proposed that naphthoquinone (103) with a-enolicdithioesters and b-oxothioa-
benzylidene-1,3-dicarbonyl compounds (B) were generated in situ mides (104) via a [3 þ 2] oxidative heteroannulation process
by grinding 99 and 100, which is followed by a Michael addition of (Scheme 4) [149]. Notably, no additional co-catalyst or activator
pyridinium ylide, formed by the action of piperidine on 101, to form was necessary for the reaction. On screening with various bases
Michael adduct C and its subsequent intramolecular cyclization of including DABCO, TEA, TBU, pyridine, it was observed that 1 equiv
afforded 2,3-dihydrofurans (102) with trans-stereoselectivity. The DMAP afforded better yields. The reaction mechanism was pro-
method worked equally well with both EDGs and EWGs in the ar- posed to proceed through the formation of Michael adduct D. The
omatic aldehydes and different 1,3-dicarbonyl compounds deliv- intermediate D upon in-situ oxidation forms E that undergoes
ering the products in moderate to good yields (Scheme 3). The E- regioselective [3 þ 2] S-cyclization to exclusively furnish the
factor of this protocol was 3.74. desired 2,3-disubstituted naphtho[2,3-b]thiophene-4,9-diones
(105). It was observed that a-enolicdithioesters (104) bearing
3.1.3. Thiophenes electron-donating groups reacted faster and furnished the desired
Thiophene moiety is common in many therapeutically active products (105b,c, 105e,f) in better yields than those (105a,105d)
agents and fused thiophenes are an important class of heterocycles derived from 104 with electron-withdrawing groups. Even
due to the broad spectrum of biological activities [147,148]. Singh electron-rich heteroaromatic a-enolicdithioesters were tolerated
and coworkers developed the DMAP promoted mechanochemical well, offering similar yields of the corresponding products (105g,h).
Scheme 4. DMAP promoted regioselective mechanochemical synthesis of 2,3-disubstituted naphtho[2,3-b]thiophene-4,9-diones (105) in mortar-pestle [149].
14
3.2. Six-membered heterocycles with a single heteroatom 111d). However, the percent yield of the product dropped signifi-
cantly for aliphatic aldehydes (entry 110d).
3.2.1. Pyridines Kumar and Sharma developed a grindstone method for the
Pyridines and their derivatives are among the most prevalent synthesis of another series of highly functionalized 1,4-
heterocyclic scaffolds found in natural products, pharmaceuticals dihydropyridines (116), a class of compounds which show cardio-
and specific functional materials and are known to possess signif- vascular and antihypertensive activity [156]. The reaction proceeds
icant biological activities such as antimicrobial, anticonvulsant, via a domino multicomponent reaction involving the grinding of
antiviral, antiHIV, anticancer, anti-inflammatory activities [151]. amines (112), diethyl acetylenedicarboxylate (113), active methy-
There are several methods for the synthesis of this important lene compounds (114) and aldehydes (115) in an Agate mortar-
scaffold in conventional media violating several greener aspects pestle for just 5e20 min in the absence of any catalyst (Scheme
[152e154]. In 2008, a mechanochemical version of Hantzsch syn- 6). A variety of aromatic amines (112) and aromatic aldehydes
thesis of dihydropyrans was reported by Kapoor and coworkers (115) were ground with 113 and 114 to afford 27 examples of the
(Scheme 5) [155]. The synthesis of 18 examples of hexahy- desired products (116) in 79e99% yields. However, isatin or
droquinolines derivatives (110) involved the grinding of four aliphatic aldehydes did not afford any product. The reaction is
components of aldehydes (106), b-ketoesters (107), dimedone proposed to proceed via an aza-Michael addition between 112 and
(109), and ammonium acetate together in an Agate mortar-pestle 113 to form intermediate F, and a Knoevenagel condensation of 114
for 10e20 min. The group reported that the optimization studies with 115 to form intermediate G. Another Michael type addition
resulted in mediocre yield (55%) of product 110a from benzalde- between donor F and acceptor G resulted in the formation of the
hyde when the reaction was carried out in refluxing ethanol for 4 h, adduct H, which on subsequent cyclization and tautomerization
however, the solvent-free grindstone protocol furnished the same afforded the products (116).
compound (110a) in 95% yield in 15 min. In a similar manner, 14 One of the earlier reports on the cyclocondensation of chalcone,
examples of 2-amino-hexahydroquinoline derivatives (111) were malononitrile and NH4OAc to pyridine derivatives using grindstone
synthesized by taking a malononitrile/cyanoesters derivative (108) technique was reported by Gupta et al., in 2010 [157]. In recent
instead of b-ketoesters (107) in up to 88% yields. The versatility of times, Nikpassand and coworkers demonstrated a one-pot, cata-
the method was demonstrated with both electron-rich and lyst-free grinding procedure for the synthesis of [6-amino-3-
electron-deficient aromatic aldehydes (selected entries 110a,b and methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (119)
111a-c) as well as heteroaromatic aldehydes (selected entries 110c, having potential antiherpetic, antimicrobial and antitumor activ-
Scheme 5. One-pot, four-component synthesis of polyhydroquinolines (110 or 111) [155].
15
Scheme 6. Synthesis of highly functionalized 1,4-dihydropyridines (116) via a domino multicomponent synthesis [156].
got completed within 25 min with 86% yield of 123a upon the
addition of water as an additive. Notably, the reaction in refluxing
ethanol could afford 40% yield of 123a and the addition of p-TSA
(10 mol%) as the catalyst could not show much improvement (45%
yield after 1.5 h). It was considered that the reactions proceed via an
initial Knoevenagel condensation between 120 and 121 followed by
Michael addition of 1,3-disubstituted-5-amino-pyrazole (122),
cyclization and subsequent aerial oxidation to produce pyrazolo
[3,4-b]quinolone derivatives (123). Different cinnamaldehyde de-
Scheme 7. Synthesis of 6-amino-3-methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5- rivatives (120) as well as a variety of 5-amino-pyrazoles with aro-
carbonitrile (119) [158]. matic and aliphatic ssubstituents at 1- and 3-positions (122)
participated equally to afford yields of corresponding products
(123) in a range of 75e90% and so, no significant substituent effect
ities (Scheme 7) [158]. The cyclo-condensation of substituted
was observed (Scheme 8).
benzaldehydes (117), 3-amino-5-methylpyrazole (118), and malo-
nonitrile afforded the pyridine derivatives (119) in excess of 90%
yields in most of the cases. The optimization studies on model 3.2.2. Pyrans
substrates employing Lewis acids (e.g. ZnCl2, K10, and nano-Fe3O4) The pyran ring is the core part of various classes of biologically
or Lewis bases (L-proline) as catalyst in refluxing EtOH hardly and pharmaceutically important heterocycles like benzopyrans,
affected complete conversion to the desired product. Even the use chromones, coumarins, flavonoids, xanthones, and naph-
of other green media, the ionic liquids (e.g. [bmim]BF4) at elevated thoquinones [160,161]. Recently, a one-pot multicomponent reac-
temperature (80 C) could offer products in much lower yields. The tion was reported by Awasthi and coworkers for the synthesis of 2-
protocol was validated with various substituents in the aromatic amino-4H-benzo[b]pyrans (125), a class of heterocycle with a range
ring of the aldehydes (117) and no substituent effect was observed of bioactivities including anticoagulant, antitumor, anticancer,
both in terms of yields or the rate of the reaction. antiallergic, diuretic, antibacterial activities [162]. A mixture of ar-
Yadav and Parvin reported a protocol for the construction of omatic aldehydes (124), dimedone (109) and malononitrile were
pyrazole-fused pyridine ring by liquid assisted grinding of a,b-un- ground in a mortar-pestle for just 2e10 min to afford 2-amino-4H-
saturated aldehydes (120), 2-hydroxy-1,4-naphthoquinone (121) benzo[b]pyran derivatives (125) in high to excellent yields (Scheme
and 5-aminopyrazoles (122) in the presence of water as LAG agent 9) [162]. The reactions were catalyzed by a specially designed
(h ¼ 0.25 mL/mg of substrate) (Scheme 8) [159]. This three- amine functionalized magnetic nano-particle, NH2@SiO2@Fe3O4, as
component reaction yielded styryl-linked benzo[h]pyrazolo[3,4-b] the heterogenous catalytic system. An amount of 10 mg of catalyst
quinoline-5,6(10H)-diones (123) by grinding the reactants in a per mmol of 124 was found optimum for faster reactions and better
porcelain mortar for 20e30 min in the presence of 0.25 mL of H2O yields. The amine functionality in NH2@SiO2@Fe3O4 has a definite
per mg of substrate. The optimization studies revealed that the role to play in catalyzing Knoevenagel condensation followed by
reaction under neat conditions was sluggish producing 123a in 68% Michael addition steps as a Lewis and subsequent intramolecular
yield after 80 min of rigorous grinding, whereas, the same reaction cyclization, protonation leads to tetrahydrobenzo[b]pyrans (125).
As seen in Scheme 9, aromatic aldehydes containing electron-
16
Scheme 8. Liquid assisted synthesis of styryl linked benzo[h]pyrazolo[3,4-b]quinoline-5,6(10H)-diones (123) [159].
withdrawing groups provided the expected products (125a,b) in complete conversion. As compared to mechanochemical grinding,
relatively higher yields than those with electron-donating groups thermal heating and direct crystallization yielded the desired
(see entries 125c-e). They demonstrated that the catalyst product (127) in lower yields (<50%) in an equimolar ratio of the
(NH2@SiO2@Fe3O4) could be recycled up to eight times with a substrates. The generality of the protocol was established by
nominal drop in %conversion. The estimated E-factor was as low as reacting various salicylaldehyde derivatives (126) with malononi-
0.08 and a high atom economy (95.4%) ensured the grinding pro- trile to prepare a short library of 11 examples of 127. The strategy
tocol a more viable alternative than several other existing methods was further extended towards the synthesis of quinoline de-
for tetrahydrobenzo[b]pyrans [162]. In an earlier work, Thanga- rivatives via grinding of malononitrile with o-aminobenzaldehydes
mani employed the grindstone technique to synthesize biologically under neat conditions.
active 2-amino-4H-benzo[b]pyran derivatives by grinding various In a similar line, Raval and coworkers described a grindstone
substituted aromatic aldehydes, dimedone, and malononitrile in assisted multicomponent synthetic route to 3,4-dihydropyrano[c]
the presence of solid sodium ethoxide (10 mol%) as catalyst [163]. chromene derivatives [130] by ionic liquid assisted grinding of a
Chromene or 1-benzopyran are ubiquitous among several nat- mixture of 4-hydroxycoumarin (128), aromatic aldehydes (129) and
ural products and display a spectrum of biological activities [164]. malononitrile at ambient temperature (Scheme 11) [75]. The re-
Trivedi and coworkers investigated the condensation of malono- action was catalyzed by the ionic liquid, [DBU][Ac], which was
nitrile with salicylaldehyde (126) towards the synthesis of (2- separately prepared from DBU and acetic acid by ultrasound irra-
amino-3-cyano-4H-chromene-4-yl)malononitriles (127) using diation [166]. The model reaction, carried out by them, did not
three different strategies i.e. mechanochemical grinding, thermal proceed in the absence of the ionic liquid but smoothly resulted the
heating and direct crystallization (Scheme 10) [165]. The strategy product (130a) in the presence of just 3.03 mol% of [DBU][Ac] in
involving catalyst-free grinding delivered the best results affording 5 min. They prepared 11 examples of 130 taking both EDGs or EWGs
the products (127) in up to 98% yields when the ratio of 126 and in the aldehyde (129) with >90% yields in most of the cases. The
malononitrile was kept as 1:2. After grinding was complete, reac- catalyst, [DBU][Ac], could be successfully recycled up to 5 cycles
tion mixtures were kept at room temperature for 0.5e1 h for without much depreciation in the yields.
17
Scheme 9. Synthesis of 2-amino-4H-benzo[b]pyran derivatives (125) by amine functionalized nano-catalyst, NH2@ SiO2@Fe3O4 [162].
In order to use a green catalyst in a green protocol, Kantharaju

and Khatavi used water extract of banana (WEB) to catalyze the
synthesis of 2-amino-4H-chromene derivatives (132e134) from
several benzaldehydes (131), malononitrile and a/b-naphthol (or
resorcinol) in a mortar-pestle (Scheme 12) [167]. WEB from the
agro-waste of banana-peels ash has a basic character and the
extract also provides a media for liquid-assisted grinding of the
substrates.
They observed that 3 mL per mmol of the substrate was the ideal
Scheme 10. Mechanochemical synthesis of (2-amino-3-cyano-4H-chromene-4-yl) volume of WEB required for the above conversion. The employ-
malononitrile (127) [165]. ment of resorcinol, a-naphthol and b-naphthol furnished the cor-
responding products (132) in 68e79% (7 examples), 133 in 74e79%
(4 examples) and 134 in 72e76% (5 examples), respectively. The
bioassay of some of these chromene derivatives showed good
antimicrobial activities.
In another solvent-free approach to chromene synthesis, Eli-
nson et al. demonstrated the condensation of salicylaldehydes
(135), malononitrile and 3-methyl-2-pyrazolin-5-one (136) in a
porcelain mortar-pestle [168]. The three-component reactions
were catalyzed by sodium acetate in the presence of small quan-
tities of water as a LAG agent to furnish 2-amino-4-(1H-pyrazol-4-
Scheme 11. Synthetic route to access 3,4-dihydropyrano[c]chromene derivatives (130)
yl)-4H-chromenes (137) in excellent yields (Scheme 13) [168]. In
using grindstone chemistry [75].
Scheme 12. Use of water extract of banana (WEB) for the synthesis of 2-amino-4H-chromene derivatives (132e134) [167].
18
Scheme 13. Multicomponent synthesis of substituted 2-amino-4-(1H-pyrazol-4-yl)-4H-chromenes (137) by LAG with water [168].
model reactions it was observed that 10 mol% of NaOAc and 0.5 mL

of water per mmol of the substrate was ideal for LAG to achieve 95%
yield of the desired product after 10 min of grinding while the re-
action was sluggish in the absence or lower mol% of the catalyst.
According to the proposed mechanism, sodium acetate catalyzes a
Knoevenagel condensation between 135 and malononitrile and the
corresponding adduct I reacts with 136 via a Michael addition to
form J, which subsequently cyclizes to K and tautomerizes to form
137. The easy product separation by water wash of the catalyst is a
Scheme 15. Synthesis of 3-carboxycoumarin derivatives (142) by water-assisted
merit of this grindstone protocol. grinding [174].
Coumarins are ubiquitous among many natural products and
are important intermediates in industries like pharmaceuticals,
perfumes, cosmetics, etc. [169]. This has fascinated chemists to- tetrahydropyridones compounds [174]. Grinding of various 2-
wards developing various methods for their synthesis [170]. One of hydroxybenzaldehydes (140) with Meldrum's acid (141) in a
the common routes for coumarin synthesis is Pechmann conden- catalyst-free condition gave high to excellent yields of 3-
sation [171], which was adopted by Narwal et al. employing a hand- carboxycoumarin derivatives (142) (Scheme 15). The reaction
grinding technique to synthesize various coumarin derivatives mixture was moistened with a few drops of water to assist grinding
(139) from activated phenols (138) and ethyl acetoacetate in the of mostly a solid mass of substrates at room temperature. After
solid phase (Scheme 14) [172]. Both phenols (138) and ethyl- 20 min of grinding, the reaction mixture was left at room tem-
acetoacetate were ground in the presence of P2O5 in a porcelain perature for another 40 min for complete conversion (yield:
mortar-pestle to furnish a small library of coumarin derivatives 85e92%). The grinding protocol offers a facile synthetic route to
within a short period of time in excellent yields. Employment of these biologically important coumarin derivatives in a non-
two equivalents of anhydrous P2O5 produced the maximum yield of hazardous way devoid of organic solvents and costly catalysts,
the products. In a similar study, Jain et al. demonstrated a two- which are usually required for their synthesis in the conventional
component approach to access coumarins via Pechmann conden- ways [175].
sation involving substituted phenols and a-keto esters in the
presence of catalytic amount of p-TSA [173].
Kumar et al. developed a grindstone protocol for the synthesis of 3.3. Five-membered with two heteroatoms
3-carboxycoumarins, which are key synthetic intermediates of
cephalosporins, penicillins, isoureas and oxygen-bridged 3.3.1. Pyrazoles
Pyrazoles and their derivatives display a plethora of biological
activities such as antimicrobial, anticancer, antidepressant, etc.
[176,177]. There are several reports on the synthesis of these
compounds in conventional media having drawbacks like the use of
organic solvents, strong base and long reaction times [178]. In 2010,
Martins and coworkers described a solvent-free mechanochemical
protocol for the synthesis of pyrazoles (144) by condensation of b-
dimethylaminovinylketones (143) and hydrazine (as H2SO4 salt) in
the presence of p-TSA (20 mol%) as catalyst (Scheme 16) [179]. The
optimization studies revealed that the reaction does not proceed in
Scheme 14. Grindstone assisted Pechmann condensation for the synthesis of neat conditions, however, the use of 50% p-TSA as catalyst resulted
coumarin derivatives (139) [172]. in the formation of the desired product, 144a, with a decent yield of
19
Scheme 16. Mechanochemical protocol for the synthesis of substituted pyrazoles (144) [179].
64% after 6 min. Upon reduction of the catalyst concentration to about the cyclization of indolylchalcone (149) with phenyl-
20%, the yield of 144a improved to 90%. The screening of catalysts hydrazine (150) to afford 4,5-dihydro-3-(2-arylindol-3-yl)-5-(4-
and grinding matrices such as SiO2, KHSO4, and NaHSO4 could not chlorophenyl)-N1-phenylpyrazoles (151) (Scheme 18) [181]. The
afford a better yield. Notably, under classical reaction conditions, synthesis of 149 by grinding 3-acetyl-2-aryl-1H-indoles (147) with
heating in ethanol in the presence of p-TSA afforded 79% of 144a p-chlorobenzaldehyde (148) in a mortar-pestle was previously re-
only after 2 h. Thus, the grinding condition was a much facile ported by the same group [182]. The reaction progressed well in the
approach for the synthesis of pyrazoles (144). It was proposed that presence of a few drops of acetic acid as the catalyst as well as the
the grinding generates heat leading to melting of the substrates in LAG agent and complete conversion was observed after grinding
the reaction mixture to provide a uniformly distributed liquid the substrates for 20e40 min in the mortar to afford the products
phase with a high density of reactants in close contacts to propel (151) in 78e91% yield. In contrast, the same reaction under con-
the reaction to completion in just a few minutes. The validation ventional conditions by refluxing in ethanol gave lower yields of
study with different b-enaminones derivatives (143) including 151 (yield of 71e79% after 6 h of reflux). The E-factor of the grinding
heteroaromatic substrates, afforded the respective products (144) method was much lower (0.152) than the solution-phase synthesis
with yield in the range of 60e91%. It was observed that the prod- of 151 using EtOH (E-factor 103.93). The newly synthesized phe-
ucts bearing electron-donating groups (144b,c) formed at a faster nylpyrazoles (151) showed good antibacterial activities against
rate, whereas, the presence of strong electron-withdrawing groups E. coli and S. aureus, and also found potent antifungal agents against
in the substrates slows down the product formation (e.g. 144d took C. albicans and A. niger.
12 min). This protocol was successfully employed towards the On the other hand, Rashdan et al. reported a one-pot three-
large-scale synthesis of pyrazoles following the same reaction ki- component condensation reaction for the synthesis of novel pyr-
netics with no drop in the yield (e.g. 144a was obtained in 90 and azolo[1,2-b]phthalazinedione derivatives (155) by employing
92% yields for 25 mmol and 50 mmol batches, respectively in grindstone chemistry (Scheme 19) [183]. The method involved the
6 min). solvent-free grinding of 1,2,3-triazolyl-pyrazolecarbaldehydes
In a similar approach, Vibhute and coworkers developed a (152), active methylene compounds (such as malononitriles or
grindstone strategy towards the synthesis of 2-pyrazolines (146) by ethyl cyanoacetate) (153) and 6-nitrophthalhydrazide (154) in the
reacting different substituted 20 -hydroxychalcones (145) with hy- presence of sodium hydroxide at room temperature for 20e30 min
drazine hydrate under LAG conditions (Scheme 17) [180]. The group to afford products in 73e92% yields. The group first synthesized a
synthesized 8 pyrazoline compounds (146) using acetic acid series of hydrazones containing the 1,2,3-triazole moiety by
(10 mol%) (h ¼ 0.19 mL/mg of substrates) as the catalyst to afford the grinding acetyl triazole derivatives with phenylhydrazine in the
products with a yield of 78e94% within a short span of 5e12 min of presence of a drop of glacial acetic acid, which were then subjected
grinding. AcOH played the dual role of a catalyst and an LAG agent. to Vilsmeier reaction conditions to deliver the 1,2,3-triazolyl-pyr-
Pathak and coworkers adopted the grinding technique to bring azole-carbaldehyde (152) derivatives. The group reported that the
Scheme 17. Solvent-free synthesis of 2-pyrazolines (146) using grinding technique [180].
20
Scheme 18. Synthesis of 4,5-dihydro-3-(2-arylindol-3-yl)-5-(4-chlorophenyl)-N1-phenylpyrazoles (151) using grindstone technique [181].
Scheme 19. Synthesis of novel pyrazolo[1,2-b]phthalazinedione derivatives (155) by employing grindstone chemistry [183].
formation of 155a took 2 h time in refluxing ethanol, indicating the

superiority of the grindstone technique over the solution-phase
method. The reaction proceeds via Knoevenagel condensation to
form heterylidenenitrile intermediate, L which upon Michael
addition of the NH group of 154 to the olefinic bond of L, followed
by cyclization affords the corresponding products in a facile way.
Some of these pyrazolo[1,2-b]phthalazinedione derivatives (155)
showed good antiproliferative activity toward hepatic cancer cells
in in-vitro studies with IC50 values as low as 3.01 ± 0.21 mg/mL. Scheme 20. AcOH catalyzed synthesis of 7-benzylidene-substituted phenyl-
Very recently, Raut et al. explored the use of grindstone tech- 3,3a,4,5,6,7-hexahydro-2H-indazoles (158) [184].
nique for the synthesis of 7-benzylidene-substituted phenyl-
3,3a,4,5,6,7-hexahydro-2H-indazoles (158) involving the reaction
between differently substituted hydrazines (156) and various 2,6- coworkers described a mechanochemical protocol for the synthesis
bis-(substituted-benzylidene)-cyclohexanones (157) in the pres- of 2-imidazoline derivatives [186]. This strategy involved solid-
ence of acetic acid (Scheme 20) [184]. The method was validated by state co-grinding of N-tosylaziridines (159) and aromatic nitriles
synthesizing 17 examples in good to excellent yields. (160) in the presence of perchloric acid as the catalyst to deliver 2-
imidazolines (161) in moderate to excellent yields (Scheme 21)
3.3.2. Imidazolines [186]. The optimization studies carried out with different acid
2-Imidazolines are prevalent in natural products and are valu- catalysts such as AcOH, TsOH, TFA, H3PO3 did not show any product
able intermediates for designing molecules with pharmacological formation (161a), whereas, HCl and H2SO4 resulted in poor yields of
activities and also applied in asymmetric catalysis [185]. Majee and 161a. Perchloric acid was found the most efficient catalyst for this
21
Scheme 21. HClO4 catalyzed mechanochemical synthesis of 2-imidazoline derivatives (161) [186].
transformation affording 95% yield of 161a within 5 min. As many by manually grinding of aromatic aldehydes (162), thio-
as 26 substituted 2-imidazoline derivatives (161) were prepared by semicarbazide (163) and a-bromoketones (164) under catalyst-free
Majee's protocol. The method did not show strong substituent ef- conditions in a glass mortar-pestle (Scheme 22) [188]. Interestingly,
fects, however, in some cases with EWG in aromatic nitriles (160), a the optimization study revealed that the liquid-assisted grinding of
significant drop in the yield of the corresponding product was seen a-bromoacetophenone, benzaldehyde and thiosemicarbazide in
(entry 161f, yield: 55%). water and EtOH afforded the product, 165a in 38% and 46% yields,
respectively, whereas, the neat-grinding gave 90% yield of the same
product within 5 min. The authors, based on the mechanistic
3.3.3. Thiazoles studies, proposed that the condensation of 162 with 163 takes place
Thiazoles and their benzo-fused derivatives are important and at first, leading to the formation of 2-benzylidenehydrazine
find growing applications as APIs [187]. Chen and coworkers carbothioamide (M). The nucleophilic attack of N-atom of the
described a grindstone-mediated one-pot multicomponent proto- thiourea unit to the a-carbon of a-bromoketones (164) followed by
col for the synthesis of 2,4-disubstituted thiazole derivatives (165)
Scheme 22. Synthesis of 2,4-disubstituted thiazole derivatives (165) under catalyst- and solvent-free grinding conditions [188].
22
Scheme 23. Synthesis of novel diphenyl-1,3-thiazole linked barbituric acid hybrids (169) by liquid-assisted grinding [189].
cyclo-condensation leads to the desired products (165). Various condensation of various aromatic aldehydes (170) with 2-
derivatives of 162 and 164 containing electron-withdrawing or aminophenol (171) catalyzed by Zn(OAc)2.2H2O (50 mol%) in a
electron-donating groups underwent smooth transformations to mortar-pestle (Scheme 24). The optimization study using ani-
give the corresponding products (165a-c) in 88e93% yields. Like- saldehyde as the model substrate, indicated no product (172a)
wise, the reactions of aliphatic aldehydes too progressed smoothly formation in the absence of Zn(OAc)2.2H2O. However, a loading of
delivering the desired products in similar yields (entry 165e). 50 mol% of Zn(OAc)2.2H2O was sufficient to form the benzoxazole
In another approach, developed by Choudhury and coworkers, derivatives (172) in 84e95% yields within just 3e5 min. The pro-
novel diphenyl-1,3-thiazole linked barbituric acid hybrids (169) posed mechanism involves an initial imine formation by conden-
were obtained by liquid assisted grinding of arylglyoxal (166), sation of 170 and 171, and cyclization by the nucleophilic attack of
barbituric acid (167) and aryl thioamides (168) in the presence of a the phenolic eOH group to the imine bond of the intermediate to
small amount of water (Scheme 23) [189]. They checked that the form 2-substituted-2,3-dihydro-benzoxazole, which upon aerial
neat grinding of the substrates (166e168) delivers the product oxidation produce benzoxazoles. The protocol was successfully
(169) only in moderate yield (55%) after 45 min. Interestingly, employed to aldehydes containing both EDGs and EWGs with equal
however, LAG in the presence of 2e3 drops of water afforded the ease and hardly any substituent effect was observed in terms of
same product in 83% at a shorter time (25 min). Notably, the same reaction times and yields, although the number of examples was
reaction by stirring in different solvents at room temperature took rather limited.
12e24 h for completion. The method was validated by synthesizing Banerjee and coworkers developed a versatile mechanochem-
19 derivatives of 169. Some of these thiazole derivatives showed ical route to access 2-aryl benzothiazoles (176) as well as 1,2-
blue emissions with good quantum yields in DMSO medium. disubstituted benzimidazole derivatives (178) (Scheme 25) [66].
The 1,3-benzazole synthesis was achieved in the absence of any
catalyst by grinding a mixture of o-aminothiophenol/o-phenyl-
3.3.4. 1,3-Benzazoles: Benzimidazoles, benzoxazoles, benzothiazoles
enediamine (173/174) and the corresponding aldehydes (175) in an
1,3-Benzazoles, namely benzimidazoles, benzoxazoles and
Agate mortar-pestle. The optimization studies involving the syn-
benzothiazoles display a wide range of bioactivities and form the
thesis of 176a pointed out that grinding under neat condition is not
core units of various marketed drugs [190e192]. Pasha and co-
suitable as intermediate imines get trapped inside the unreacted
workers reported a simple grindstone strategy towards the syn-
solid substrates. However, the addition of a small amount of sol-
thesis of 2-substituted benzoxazoles (172), a scaffold of many
vents like CHCl3, EtOAc, ACN, MeOH, EtOH or H2O as LAG agents
biologically active compounds [193]. The synthesis involved the
Scheme 24. The synthesis of 2-substituted benzoxazoles (172) catalyzed by Zn(OAc)2.2H2O [193].
23
Scheme 25. Mechanochemical synthesis of 2-aryl benzothiazoles (176) and both 2-substituted (177) and 1,2-disubstituted benzimidazole (178) derivatives [66].
could afford higher yields of 176a. Among them, EtOH was found yields). Thus, a single method could afford benzothiazoles (176), 2-
the best LAG agent affording 176a in 90% yields within 15 min. arylbenzimidazoles (177) and 1,2-disubstituted benzimidazoles
Banerjee's group also proposed that the reaction proceeded by the (178) within short reaction times, avoiding a tedious work-up step.
formation of a Schiff's base by condensation of 173 with 174 fol- Afterward, Majumdar and coworkers developed a similar
lowed by intramolecular cyclization by the attack of thiol group to grinding protocol for the synthesis of benzimidazoles derivatives
the imine bond to form dihydro-benzothiazole, N which undergoes (181, 182) using imidazolium trifluoroacetate protic ionic liquid
a spontaneous aerial oxidation delivering the corresponding (PIL) as the catalyst (Scheme 26) [194]. Out of three PILs tested for
products (176). Notably, the addition of oxidants such as H2O2, catalysis, PIL II (1-butyl-2-methyl imidazolium tri-fluoroacetate)
iodine or (NH4)2S2O8 did not offer much changes in the yield of provided better results for both 1,2-disubstituted (181) and 2-
176a indicating there is no role of any oxidant in the conversion of N substituted benzimidazoles (182). The grinding of o-phenylenedi-
to the final product, 176. A series of aromatic aldehydes with EDG amine with 2.2 equiv of benzaldehyde with different PILs revealed
(entry 176c) and EWGs (entry 176b) as well as heteroaromatic al- that the use of 5 mol% of PIL II afforded 181a in 87% yield after 2 h,
dehydes with 2-aminothiophenols (entry 176d) underwent smooth whereas, 10 mol% of PIL I and III afforded 181a with 83% and 80%
transformations delivering the desired products in good to high yields, respectively. Out of the limited numbers of substrates used
yields. The rates of the reactions were affected as aldehydes with to validate the method, 70e90% yields were observed for 181 and
strong electron-donating groups reacted (entry 176c) slowly than 65e80% yields for 182. However, the grinding of long 6 h were
that with EWGs (entry 176b). However, the method showed limi- required in some cases (entries 182c,d). As such, the studies sug-
tations when aliphatic aldehydes were used for the formation of gested that the ionic liquid assisted method of Majumdar's group
benzothiazole (entry 176e,f). When o-phenylenediamine (174) was was inferior to the catalyst-free grindstone protocol of Banerjee's
used in place of aminothiophenol (173), both 2-aryl benzimidazoles group.
(177) and 1,2-disubstituted benzimidazoles (178) can be obtained In an interesting approach, Almansour et al. demonstrated a
using the simple mortar-pestle grinding by taking appropriate highly selective construction of 2-aryl substituted benz-/naphth-
amount of o-phenylenediamine (174) in the reaction media. The imidazoles (186 or 187) involving the reaction of aromatic 1,2-
condensation of equimolar mixture of aldehydes and o-phenyl- diamines (183 or 184) with a series of substituted arylthiopro-
enediamine (174) resulted the corresponding 2-arylbenzimidazoles lines (185) in the presence of 3e5 drops of water as the LAG agent
in relatively lower yields (54e66%); also, a small amount of 1,2- (Scheme 27) [195]. The cyclocondensation of 1,2-diamines (183 or
disubstituted benzimidazoles were formed. However, the forma- 184) with arylthioprolines (185) was expected to furnish the thia-
tion of 1,2-disubstituted benzimidazole derivatives (178) were zole grafted benzimidazole (188) instead benz-/naphtha-imidaz-
rather facile when 2.2 equiv of 174 was used (entry 178a-d, 76e86% oles (186 or 187) were formed by the removal of cysteine residue
24
Scheme 26. Synthesis of substituted benzimidazoles (181, 182) by ionic liquid assisted grinding [194].
Scheme 27. Selective construction of 2-aryl substituted benz-/naphtha-imidazoles (186, 187) [195].
from 183. As per their suggested mechanistic pathway, perhaps the undergoes aerial oxidation to furnish 2-aryl benzimidazoles (186).
arylthioprolines could be in the zwitterionic form, which could The products were obtained by simple filtration, avoiding typical
react with 1,2-diamine giving the intermediate O, which upon work-up and chromatographic purification steps.
cyclization affords the dihyrobenzimidazole (P). Intermediate P The vast bioactivities led to the development of several other
25
Scheme 28. Urea nitrate and Morpholinium bisulfate [morH][HSO3] catalyzed synthesis of 2-arylbenzothiazole derivatives [196e200].
grinding protocols for 1,3-benzazoles by changing the type of cat- Due to these enthralling biological properties, various strategies
alysts in the subsequent years [196e200]. Agarwal and coworkers have been established for the construction of indoloindolpyr-
used urea nitrate as the catalyst for the synthesis of a series of 2- imidine derivatives [203,204]. In an attempt to get a viable alter-
arylbenzothiazole derivatives (191) by grinding aromatic alde- native route, Maury et al. reported a catalyst-free mechanochemical
hydes (189) and o-aminothiophenol derivatives (190) (Scheme 28) protocol for the synthesis of indoloindolpyrimidines (200) utilizing
[196]. The reactions proceeded at an unusually faster rate in the the mortar and pestle grinding method (Scheme 29) [205]. Liquid
presence of 15 mol% of urea nitrate and complete conversion was assisted grinding of a variety of isatin derivatives (197) with 1,3-
seen within just 30 s of grinding. A short library of 6 arylbenzo- diketones (198) and enaminones (199) with few drops of EtOH at
thiazole derivatives (191) were prepared in 95e98% yields (Scheme room temperature over a period of 2 h delivered indoloindolpyr-
28). However, they have not investigated the mechanistic back- imidine derivatives (200) in excellent yields (86e93%). In a model
ground to explain the extraordinarily fast reaction kinetics. Sub- reaction using barbituric acid as the 1,3-diketones it was observed
sequently, they employed the same protocol for the synthesis of 5- that the reaction does not proceed in neat condition even after 6 h.
chloro substituted benzothiazoles [197]. The reusability of the However, in the presence of catalytic amount of a Lewis acid (e.g. p-
catalyst was performed up to four cycles with no significant loss in TSA, sulfamic acid) or Lewis base (e.g. Et3N), the progress was
its catalytic activity. At a similar time, the same group separately satisfactory affording 200a in 78e82% of yields after 3e4 h of
reported the synthesis of 1,2-disubstituted benzimidazoles (193) in grinding. Interestingly, just the addition of a few drops of EtOH as
excellent yields by a urea nitrate catalyzed grinding of aromatic the LAG agent in the reaction mixture, in the absence of any cata-
aldehydes (189) and o-phenylenediamine (192) under solvent-free lyst, could take the reaction to completion within 2 h to give 200a
conditions (Scheme 28) [198]. The catalyst load was this time in 93% yield. Notably, aprotic solvents like DMF, DMSO, toluene was
optimized as 15 mol% as lower loading of urea nitrate afforded found ineffective as LAG agent. According to the mechanistic con-
lower yields of benzimidazoles at a slower rate (5% and 10% urea siderations, initially, a Knoevenagel adduct is formed by the reac-
nitrate yielded 50% and 72% of 193 in 5 min and 1 min, respec- tion of 1,3-diketones and isatin, followed by a Michael-type
tively). Once again, the 1,2-disubstituted benzimidazole derivatives addition that takes place via enamine and gives an open-chain
(193) were obtained in 92e99% yields by grinding the reaction intermediate. This intermediate undergoes imine-enamine tauto-
mixture for a few seconds. At a similar time, Kathing et al. reported merization and N-cyclization via the attack to the carbonyl group of
the use of p-TSA for the synthesis of 1,2-disubstituted benzimid- amidic isatin, delivering the desired compounds. They extended the
azoles (195) via the same cyclo-condensation reaction [199]. Just a scope of their methodology by investigating a wide range of isatins,
few milligrams of p-TSA (3.8 mg, 2 mol%) per mmol of o-phenyl- 1,3-diketones and enaminones under optimal conditions and found
enediamine (194) was enough to catalyze the reactions with a se- no significant substituent effect in terms of yields of 200.
ries of aromatic aldehyde (2 equiv with respect to 194) to afford the
corresponding products (195) in excess of 90% yields within
5e10 min of grinding. In another study, Shaikh and Chaudhar re- 3.4. Six-membered with two heteroatoms
ported the use of a cheap and reusable ionic liquid, morpholinium
bisulfate[morH][HSO3] as the catalyst for the synthesis of 2- 3.4.1. Pyrimidines and pyrimidones
arylbenzothiazoles (196). 10 mol% of morpholinium bisulfate Pyrimidines, pyrimidones and dihydropyrimidones (DHPM) are
[morH][HSO3] was required to successfully convert 2- of immense interest to researchers due to the wide range of bio-
aminothiophenol (173) and aromatic aldehydes (189) to 2- activities and use in material science [206e208]. Several bio-
arylbenzothiazoles (196) within 5e8 min of grinding in 88e95% molecules (e.g. ribonucleotides) possess pyrimidine substructures
of yields (Scheme 28) [200]. and many marine alkaloids comprise of a dihydropyrimidone
(DHPM) framework. Dihydropyrimidones are effortlessly synthe-
sized by Biginelli reaction [209], which was adopted by Bose et al.
3.3.5. Indoloindoles for the synthesis of this important heterocycle by grindstone
Indoles exhibit therapeutic properties over a wide range of technique [210]. The strategy involved the grinding of different
targets including antiviral, antitumor, anticonvulsant, antiin- benzaldehyde derivatives (201), ethyl acetoacetate and urea/thio-
flammatory, antibacterial, cardiovascular activities, etc. [201,202]. urea (202) in the presence of acid catalyst p-TSA (5 mol%) to afford
26
Scheme 29. Synthesis of indoloindolpyrimidine derivatives (200) using grindstone technique [205].
Scheme 30. Biginelli reaction in mortar-pestle for the synthesis of dihydropyrimidines (203) [210,211].
the corresponding dihydropyrimidines (203) in good to excellent similar manner, Pathak and coworkers exploited Biginelli reaction
yields (71e96%) (Scheme 30) [210]. They demonstrated a large- with similar substrates but CuCl2$2H2O as the Lewis acid catalyst to
scale synthesis of dihydropyrimidines by taking benzaldehyde, furnish dihydropyrimidinones (203) under solvent-free conditions
ethylacetoacetate and urea as the model substrates and carried out (Scheme 30) [211]. The aromatic aldehydes (201), ethyl acetoace-
the reaction at 0.5 M scale, placing the substrates and reagents in a tate and urea/thiourea (202) were ground in the presence of 0.5
large porcelain bowl and grinding conducted with the help of a equiv of CuCl2$2H2O and a few drops of conc. HCl for 2e5 min to
hand-held electric food mixer with stainless steel rotors. The re- afford 203 in up to 95% yield.
action was completed in less than 15 min with a yield of 94%. In a In another study, the synthesis of 3,4-dihydropyrimidin-2-(1H)-
27
Scheme 31. L-tyrosine catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones (206) [212].
ones (206) by hand-grinding was reported by Khaskel et al. In an interesting approach, Safari et al. reported a grinding
(Scheme 31) [212]. They used L-tyrosine as the organocatalyst for protocol towards a one-pot three-component synthesis of 4,6-
Biginelli reaction of various aldehydes (204), urea/thiourea (202) diaryl-3,4-dihydropyrimidine-2(1H)-ones (208) by Biginelli-like
and 1,3-diketones (205). The catalyst screening revealed that reaction employing carbon nanotubes (CNTs) derived magnetic
several amino acids like glycine, L-serine, L-proline, L-tyrosine and nanoparticles as reusable heterogeneous catalyst (Scheme 32)
Brønsted acids like camphorsulphonic acid, oxalic acid, HClO4 can [214]. The synthesis involved the condensation reaction between
catalyze the reaction but 10 mol% of L-tyrosine is ideal for faster various benzaldehyde derivatives (207), urea and acetophenone in
conversion and higher yields. It was proposed that L-tyrosine form a the presence of the heterogeneous catalyst, Fe3O4eCNTs, which
three-prone H-bonded network (Q) with an aldehyde (204) and was developed by them. The amount of Fe3O4eCNTs was optimized
urea derivative (202) and subsequently form intermediate R, which as 50 mg/mmol for better conversion. The protocol afforded dihy-
undergoes intramolecular cyclization to S followed by dehydration dropyrimidine-2(1H)-ones (208) in high to excellent yields in the
to furnish 3,4-dihydropyrimidin-2-(1H)-ones (206). The aromatic range of 85e98% within a short span of grinding (12e30 min). The
aldehydes, irrespective of the presence of EDGs or EWGs, resulted recyclability of Fe3O4eCNTs showed no loss in catalytic activity up
in 3,4-dihydropyrimidones, 206 in high yields (entries 206a-c). The to 5th cycle; for a model reaction yield dropped to 93% from 98% on
aliphatic (entry 206e) as well as heteroaromatic aldehydes (entry the 5th cycle. Similarly, Ramachandran et al. demonstrated the
206f) participated equally efficiently in the reaction. There are synthesis of dihydropyrimidinones (DHPM) using grindstone
other reports on Lewis acid-catalyzed Biginelli reaction as well chemistry involving the grinding of aromatic aldehydes, N-phe-
[213]. nylacetoacetamide and urea/thiourea in the presence of CuCl2$H2O
Scheme 32. Fe3O4eCNTs catalyzed synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-ones (208) [214].
28
Scheme 33. Grindstone assisted tandem Knoevenagel, aza-Michael and retro-Diels-Alder for the synthesis of 5,6-dihydropyrimidin-4(3H)-one scaffold (212) [216].
(1 equiv) and a few drops of conc. HCl in a mortar and pestle under spectroscopic studies revealed that the reaction mechanism fol-
solvent-free conditions at room temperature to obtain good to lowed a three-step tandem process involving Knoevenagel, aza-
excellent yields [215]. Michael and retro-Diels-Alder reactions. Initially, aldehyde and
Bugarcic and coworkers introduced a grindstone method for the Meldrum's acid furnish benzylidene adduct T via Knoevenagel
synthesis of structurally interesting 5,6-dihydropyrimidin-4(3H)- condensation, which is then attacked by isothiourea via the aza-
one scaffold (212) (Scheme 33) [216]. 5,6-dihydropyrimidin-4(3H)- Michael step to furnish another intermediate U. This intermediate
one is the precursor of dihydrouracil and is a difficult target for one- (U) undergoes a retro-Diels-Alder step to generate carboxyketene,
pot synthesis. They showed that simple grinding can initiate a V which in the presence of water undergoes decarboxylation to
tandem Knoevenagel, aza-Michael and retro-Diels-Alder reactions generate intermediate W followed by cyclization to give the
to produce 212 in one-pot by condensation of Meldrum's acid product, 212. The protocol was validated with a vast library of forty
(209), aldehydes (210) and isothioureas (211). During optimization 5,6-dihydropyrimidin-4(3H)-one derivatives with the yields
of the reaction condition, they observed that the use of weak bases ranging from 64 to 95%.
such as NaHCO3, Na2CO3 in excess (5 equiv) at 50 C could not
afford the desired product (212a) even after a long time of grinding.
3.4.2. Quinazolines
On the other hand, the use of ionic liquid [Bmim][HCO3] (20 mol%)
Quinazolines and their derivatives have been long studied as
as a soft base at 50 C was effective in initiating the reaction with
they exhibit therapeutic properties over a wide range of targets
24% yield of 212a, which eventually increased to 42% with 1 equiv
[217,218]. Quinazoline and quinazolinone rings are a part of many
of the ionic liquid at 100 C. However, the tautomeric purity be-
marketed drugs, for example, prazosin (used for blood pressure),
tween 3H/1H was low (79:21) (condition table, Scheme 33). Inter-
gefitinib (anti-cancer drug) and albaconazole (antifungal agent)
estingly, grinding of the same reaction in the presence of
[219]. The available synthetic protocols require the use of metal
CH3COONa (20 mol%) as the catalyst and 0.5 mL of water as the LAG
catalysts (e.g. Sc(OTf)3, SmI2) [220e222]. As a catalyst-free, greener
agent (h ¼ 0.26 mL/mg with respect to solid substrates) for 3 h could
alternative, Rong and coworkers reported a grindstone protocol for
afford the desired products (212a) in excellent yields with high
synthesizing 3-benzylquinazolin-4(1H)-one derivatives involving a
tautomeric purity of 99.9:0.1 (condition table, Scheme 33). The
one-pot three-component reaction of isatoic anhydride, benzyl-
grinding of the same reaction mixture at elevated temperature
amine and aromatic aldehydes [223]. In another recent approach,
(100 C) marginally lowered the yield and the tautomeric purity of
Kuntikana et al. developed a method for the synthesis of 3-
212a (85%, 3H/1H:99.4:0.6) (condition table, Scheme 33). Different
arylideneaminoquinazolin- 4(1H)-ones (216) via a cascade
29
Scheme 34. Synthesis of 3-arylideneaminoquinazolin-4(1H)-one derivatives (216) using grindstone chemistry [80].
condensation-cyclization reaction at ambient temperature, a syn- the synthesis of octahydroquinazolinones by employing solvent-
thetic scaffold which were inaccessible by conventional methods and catalyst-free grindstone technique [224].
(Scheme 34) [80]. This two-component synthesis involving ‘liquid- Very recently, Saha and coworkers utilized the grindstone
assisted grinding’ reactions of aldehydes/ketones (214) and o- technique to efficiently synthesize the structurally interesting 2,3-
aminobenzhydrazide (215) by DMSO afforded quinazolin-4(1H)- dihydroquinazolin-4(1H)-one (220 or 221) by simple grinding in
ones (216) in high yields, whereas, a similar solution-phase reac- a mortar-pestle (Scheme 35) [225]. The synthesis involved the
tion only led to the Schiff base formation [80]. Although in a few grinding of anthranilamide derivatives (217) with ketones (218) or
cases, neat grinding was sufficient for complete conversion using benzaldehyde derivatives (219) in the presence of p-TSA (10 mol%)
liquid aldehyde (e.g. 216a), in several other cases, the reactions did as the catalyst to afford the products in moderate to excellent
not proceed unless 2e3 drops of DMSO were added as LAG agent yields. During catalyst screening, it was observed that Lewis acids
(h ~ 0.15 mL/mg of substrates) to the reaction mixture (e.g. 216b). such as InCl3, FeCl3 and I2 could furnish the product (220a) of
Notably, the reactions were completed very fast within 2e5 min via benzaldehyde and anthranilamide only in moderate yields, but
liquid-assisted grinding. They proposed an imine formation be- swapping the catalyst from Lewis acids to Brønsted acids such as p-
tween carbonyl and the benzhydrazide group of 215 to form TSA or TFA afforded the product, 220a in excess of 90% yield. The
hydrazone (X), which interacts with another carbonyl group of 214 catalyst loading of 10 mol% of p-TSA was found optimum for com-
to form the intermediate Y. This undergoes intramolecular cycli- plete conversion of 220a within 3 min in 95% yield. The broad
zation (Z) and subsequent water removal to form the desired qui- applicability of the process was tested with various aromatic and
noxalinones (216). The E-factor of this method is low (0.53), which aliphatic aldehydes as well as ketones and a total of 15 differently
is several folds lower than Su's method (12.85) [220]. Some selected substituted derivatives of 220 were obtained in moderate to
products were screened for their antioxidant activity using 2- excellent yields. Notably, the yields of the products drop in case of
diphenyl-1-picrylhydrazyl (DPPH) radical scavenging technique aldehydes with EDG (entry 220c). A scale-up reaction produced
and compounds which displayed considerable antioxidant activity 220b in 90% yield within 10 min validating the workability of the
were later tested for their protective capacity against deoxy- process in bulk-scale. The low E-factor (0.243) makes the protocol
ribonucleic acid (DNA) impairment. Among other similar methods, an efficient one for the synthesis of 2,3-dihydroquinazolin-4(1H)-
Pramanik et al. demonstrated a three-component cyclo-conden- one.
sation reaction of dimedone, thiourea and aromatic aldehydes for
30
Scheme 35. Synthesis of 2,3- dihydroquinazolin-4(1H)-one (220 or 221) in the presence of p-TSA [225].
3.4.3. Quinoxalines compounds and diamine compounds with an overall yield of

Another privileged class of nitrogen-containing heterocycle is 80e98%, indicating the substituent effect in this reaction is insig-
quinoxaline and its derivatives due to their wide range of biological nificant. The crude products were recrystallized from EtOH to get
activities including antiviral, antibacterial, antiinflammatory and pure 224. The E-factor of this method is 1.57, which is lower than
anticancer activities [226,227]. In an earlier approach, Wu and co- Wu's method [72]. Moreover, they estimated the cost of Wu's
workers synthesized quinoxaline derivatives (224) by solid-phase method with their method and found the LAG method is about 33
grindstone chemistry using alumina as the grinding auxiliary folds cheaper than solid-phase grinding involving column chro-
(Scheme 36) [72]. The condensation of various 1,2-diketones (222) matography for product purification. Banerjee and coworkers also
and 1,2-diamines (223) were carried out in basic alumina (500 mg/ examined the microbial activities of these quinoxaline derivatives
mmol). They reported that the reaction of o-phenylenediamine and compounds like pyrido[2,3-b]pyrazines (224i) showed effec-
with benzil in neat condition afforded the desired product (224a) in tive antibacterial properties against M. smegmatis. In the same line,
only 32% yield, insisting the need for a grinding auxiliary. The use of Khalafy et al. demonstrated the use of clay as a catalyst to syn-
SiO2, acidic Al2O3, neutral Al2O3 enhanced the product formation, thesize a series of arylquinoxalines from various aromatic 1,2-
but the best result was obtained with basic Al2O3 to get 224a in 98% diamines with arylglyoxals in solvent-free grindstone chemistry
within 10 min of grinding. However, one clear drawback associated [229].
with this protocol is the product isolation from the solid support by
using organic solvent (EtOAc). Otherwise, the E-factor of the reac-
tion is low (2.15). Subsequently, Banerjee and coworkers adopted a 3.4.4. Phthalazine
liquid-assisted grinding route for quinoxalines (224) in another Phthalazine derivatives display important biological and phar-
catalyst-free approach (Scheme 36) [228]. The optimization studies maceutical activities [230]. Selvaraj et al. explored the synthesis of
revealed that the neat reaction of benzil with o-phenylenediamine naphtho[2,3-g]phthalazine derivatives (227) via grindstone chem-
as model reaction took 2 h for complete conversion with a yield of istry employing heterogeneous catalyst, Tel-Cu-NPs (telmisartan-
92% of 224a, whereas, the presence of a small amount of solvent copper nanoparticles) (1 mg/mmol) (Scheme 37) [37]. Telmisartan
such as ethanol, methanol, chloroform (0.5 mL per mmol of the is a benzimidazole-based drug used to treat high blood pressure
substrate) accelerated the reaction to more than 10 folds and the and heart failure. The heteroaromatic-N can legate to Cu(II). The
reaction was completed within 10e20 min. The best LAG agent was catalyst was synthesized by grinding CuCl2$2H2O with telmisartan
ethanol (h ¼ 1.5 mL/mg of solid substrates). They suggested water as in ethanol and then treating this mixture with NaOH. Subsequently,
not a viable solvent for LAG as partial hydrolysis of intermediate the catalyst was used in the Mannich reaction of 1,4-
imine bond is possible. However, the condensation of aqueous dihydroxyanthraquinone (225) and substituted aldehydes (226)
glyoxal with diamine went to completion without the addition of in the presence of hydrazine hydrate and Tel-Cu-NPs in EtOH
EtOH and even if water was present in the system because of the (1.5 mL/mmol) at room temperature yielding naphtho[2,3-g]
high reactivity of glyoxal, which is able to suppress hydrolytic phthalazine derivatives (227) in high yields. Furthermore, an in-
decomposition of intermediate imine. A total of 30 different de- flask extraction permitted for the recycling of the catalyst, which
rivatives of 224 were synthesized by taking different 1,3-carbonyl even after additional 10 cycles showed almost no loss in catalytic
activity. They subsequently carried out molecular docking and
31
Scheme 36. Grindstone aided synthesis of quinoxaline derivatives (224) using alumina [72], or LAG using EtOH [228].
tyrosinase inhibitory activity studies with their synthesized com- within short reaction times. Their validation studies indicated that
pounds and a few of naphtho[2,3-g]phthalazines showed promises the electronic effects of aldehydes did not influence the yields of
as potential antityrosinase agents. the products, but the steric effect did impact the yields as the
Wang and coworkers reported a solvent-free route for the three- products of ortho-substituted aldehydes (entries 234b,c) were
component synthesis of 2H-indazolo[2,1-b]phthalazine-triones obtained in lower yields as compared to the corresponding para-
(231) in the presence of a catalytic amount of p-TSA by hand- substituted ones (entries 234d,e). The reaction proceeded well
grinding (Scheme 38) [231]. The reaction involves the grinding of with heterocyclic aldehydes (thiophene-2-carboxaldehyde and
phthalhydrazide (228), aldehyde derivatives (229), and dimedone pyridine-2-carboxaldehyde) to furnish the corresponding products
derivatives (230) in the presence of p-TSA (3 mol%) to afford the (entries 234f,g) and also with aliphatic aldehydes to form the
desired products with high yields in short times. The optimization products (234h,i) in high yields. However, this protocol did not
studies with a model reaction of phthalhydrazide, benzaldehyde work in the case of ketones which was attributed to the less elec-
and dimedone revealed that the reaction progress is very slow in trophilic nature of the carbonyl carbon as well as its steric hin-
the absence of any catalyst with a yield of only 25% after grinding drance and resulted in lower yields of the corresponding products
for 30 min. However, the use of 3 mol% of p-TSA increased the yield (234j). At similar times, Agarwal and coworkers adopted an anal-
of the reaction significantly to 91% within 2 min (yield is 63% and ogous strategy for the synthesis of perimidine derivatives (234)
76% in the presence of 1 mol% and 2 mol% of p-TSA after 10 min of using a recyclable solid-acid catalyst under metal-free conditions
grinding). Furthermore, they also presented a comparative study (Scheme 39) [36]. Different substituted aldehydes (232) demon-
with the earlier reports, which clearly showed the superiority of strated cyclo-condensation reaction with 1,8-diaminonaphthalene
this protocol over the conventional methods. The scope of the (233) in the presence of carbon sulfonic acid (CeSO3H, 15 mol%)
method was validated by synthesizing 12 derivatives of 231 in as the catalyst and EtOH as LAG agent under ambient reaction
excellent yields. conditions to deliver the desired products (234) in excellent yields
(95e99%) with very fast kinetics of few seconds to a minute only.
The optimization studies revealed that the reaction is sluggish in
3.4.5. Perimidines the absence of a solvent or catalyst. The reaction progress was slow,
Perimidines are fused nitrogen-containing heterocyclic naph- and only 60% of 234k was obtained after 5 min of grinding, as
thalenes that possess significant biological properties [232]. observed by Anilkumar's group. However, when the reaction was
Employing the grinding method, Anilkumar and coworkers very carried in the presence of 15 mol % of CeSO3H and EtOH as LAG
recently described the synthesis of perimidines (234) by grinding agent, the reaction showed complete conversion within 1 min
various aldehydes/ketones (232) with 1,8-diaminonaphthalene yielding 98% of 234k. The scope of the reaction was examined with
(233) (Scheme 39) [233]. Mortar-pestle grinding for 5 min under various aldehydes to afford the products with electron-donating
solvent-free and catalyst-free conditions afforded the desired 2,3- (234k) or electron-withdrawing groups (234b,d,e) as well as
dihydro-1H-perimidines (234) in moderate to excellent yields
32
Scheme 37. Synthesis of naphtho[2,3-g]phthalazine derivatives (227) via grindstone chemistry [37].
Scheme 38. Grindstone mediated three-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones (231) [231].
heteroaromatic aldehydes (234f,g). The authors proposed that [235]. Several reported methods use multi-step sequences [236] or
carbon sulfonic acid quickly activates the carbonyl group of 232 and expensive catalysts [237] for their synthesis. A few green protocols
the eOH functionality present in Ce SO3H activates the amine for 1,6-naphthyridine derivatives are also available [238]. In 2015,
groups of 233. This facilitates the Schiff base formation and the Hameed demonstrated a grinding protocol towards a one-pot,
subsequent attack of the other amine group of 1,8- catalyst-free, pseudo-five-component synthesis of 1,2-dihydro
diaminonaphthalene (233) to form the perimidine derivative [1,6]naphthyridines (237) involving substituted ketones (235) (2
(234) by cyclocondensation. Reusability studies of the solid catalyst equiv), malononitrile (2 equiv) and amines (236) (1 equiv) using a
revealed that it could be used up to 5 runs without any copious loss mortar-pestle at room temperature (Scheme 40) [239]. The reac-
in its activity. The protocol worked well in gram-scale, giving the tion followed a fast reaction kinetics and the products were ob-
desired product in the same yield (234e was obtained in 98% yield). tained in just about 5e7 min with 90e97% yields. Notably, the
The estimated green matrices, E-factor 0.075, atom-economy 93.9% green protocol by Mukhopadhyay et al. requires refluxing the
and reaction mass efficiency 93.04% indicate the efficiency of the substrates in aqueous media for hours to achieve good yields of 237
protocol. [238]. The method was employed on different aliphatic primary
amines and cyclic secondary amines to afford the desired products
(237g,h) and (237a-f), respectively in excellent yields. The products
3.4.6. Naphthyridines were easily purified by filtering the resulting precipitate, then
1,6-Naphthyridines are explored as antitumor agents for cancer washing with EtOH and recrystallizing from absolute EtOH.
chemotherapy [234] and show antibacterial properties as well
33
Scheme 39. Synthesis of perimidine derivatives (234) using a recyclable solid acid catalyst, carbon-SO3H [36,233].
3.5. Heterocycles with three or more heteroatoms unsymmetrical 2,5-disubstituted 1,3,4-oxadiazole derivatives (240)
using grindstone chemistry (Scheme 41) [242]. The solvent-free
3.5.1. Oxadiazoles grinding of aryl aldehydes (238) with aromatic hydrazides (239)
1,3,4-Oxadiazoles are known for anticancer, antiviral and antiin the presence of a catalytic amount of molecular iodine (20 mol%)
fungal properties [240,241]. Makrandi and coworkers developed a in a mortar-pestle afforded the desired 2,5-disubstituted oxadia-
mechanochemical protocol for the synthesis of symmetrical and zoles (240) in excellent yields within 5e7 min. The reaction
34
Scheme 40. Pseudo-five-component synthesis of 1,2-dihydro [1,6]naphthyridines (237) [239].
Scheme 41. I2 catalyzed synthesis of 2,5-disubstitutedoxadiazoles (240) using grindstone chemistry [242].
proceeds via the formation of acyl hydrazone followed by oxidative afford any better results for grinding at room temperature. As the
cyclization in the presence of aerial oxygen to give the desired 2,5- intramolecular cycloaddition was sluggish at room temperature,
disubstituted 1,3,4-oxadiazoles (240). A short library of 9 oxadia- the reaction mass was heated at 60 C for 1.5 h for complete con-
zoles was prepared in 88e92% yields. version (yield of 243a was 84%). The protocol worked well with
aliphatic as well as aromatic hydroxylamines and was applied to
different O-allyl salicylaldehydes with the same effectiveness. It
3.5.2. Chromano[4,3-c]isoxazoles
was noticed that nitrones derived from N-phenylhydroxylamine
Chromanoisoxazoles are known to possess biomedical proper-
afforded the intramolecular cycloaddition product (entries 243a-g)
ties such as antidepressant, antipsychotic and antianxiolytic ac-
at a faster rate compared to N-methylhydroxylamine nitrones
tivities [243]. Banerjee and coworkers used the hand-grinding
desired products (entries 243h-j). As the phenyl group is an elec-
technique to access cis-fused chromano[4,3-c]isoxazoles (243) in a
tron pulling unit, the corresponding nitrones are more reactive,
catalyst and solvent-free manner (Scheme 42) [65]. Grinding of O-
whereas the electron donation ability of the methyl group makes
allyl salicylaldehydes (241) and alkyl/aryl hydroxylamines (242) in
the 1,3-dipolarophile less reactive.
an Agate mortar-pestle afforded the corresponding nitrone and the
reaction mass was heated at 60 C for 4 h to afford the desired
products (243) in good to excellent yields via intramolecular 1,3- 3.5.3. Dihydropyrano[2,3-c]pyrazoles
dipolar nitrone cycloaddition. The model reaction of O-allyl sali- Ambethkar et al. synthesized an array of dihydropyrano[2,3-c]
cylaldehyde and hydroxylamine under neat grinding resulted in a pyrazole derivatives (246) through a one-pot four-component re-
pasty mass containing the nitrone (AD) within 15 min. Further action by grinding acetylene ester (244), hydrazine hydrate, aryl
grinding the reaction mixture to form chromanoisooxazole (243a) aldehydes (245) and malononitrile in the presence of L-proline as
was slow and only 20% product was obtained after grinding for 2 h. catalyst (Scheme 43) [74]. The model reaction by grinding 4-
Interestingly, for this reaction, LAG with EtOH, ACN or CHCl3 did not fluorobenzaldehyde, diethylacetylene dicarboxylate, hydrazine
35
Scheme 42. Synthesis of cis-fused chromano[4,3-c]isoxazoles (243) via intramolecular 1,3-dipolar nitrone cycloaddition reaction involving hand-grinding in mortar-pestle [65].
Scheme 43. L-proline catalyzed one-pot protocol for the synthesis of dihydropyrano[2,3-c]pyrazole derivatives (246) by hand-grinding under solvent-free conditions [74].
hydrate and malononitrile in neat conditions afforded only 40% yields of 246a are low (84% and 58%, respectively), L-proline was
yield of the desired product (246a) after 10 min. However, with the found to be the most efficient. The products derived from aldehydes
addition of 10 mol% L-proline the reaction proceeded to completion bearing EWGs (entries 246a,b; yields >90%) gave better yields than
within 10 min providing 246a in 93% yield. The Brønsted acid, p- those with EDGs (entries 246c,d; yields ~70%). The authors sug-
TSA or Lewis acid, SnCl2 can act as catalysts but the corresponding gested the following probable mechanistic pathway involving the
36
formation of a cyclic intermediate AE from the interaction of both electron-withdrawing and electron-donating substituents
diethylacetylenedicorboxylate (244) and hydrazine hydrate, and a were well tolerated in the cyclocondensation. The yields of the final
Knoevenagel adduct of aldehyde (245) and malononitrile. These products derived from acetophenones with electron-withdrawing
intermediates undergo Michael addition followed by intra- groups (entries 250b,c) were found to be a little higher than
molecular cyclization and tautomerization to furnish the desired electron-rich derivatives (entries 250d,e). The successful trans-
products (246). They also tested the antimicrobial activities of these formation with acetyl heteroaromatic compounds further added to
compounds and some of them exhibited activity against Staphylo- the broad substrate scope of this mechanochemical protocol (entry
coccus albus, Streptococcus pyogenes, Klebsiella pneumonia, Pseudo- 251a). They demonstrated a gram scale synthesis of zolimidine
monas aeruginosa and Candida albicans fungal strains. showcasing the utility of the grinding protocol. The E-factor (1.77)
and cost of this method was found to be significantly lower than the
3.6. Fused heterocycles with N-atom at the ring junction reported conventional methods for zolimidine synthesis [76].
In a different strategy, the solvent-free and catalyst-free
3.6.1. Imidazo[1,2-a]pyridines grinding of 2-aminopyridines (252) and a wide variety of u-bro-
The imidazo[1,2-a]pyridines, predominantly with substituents momethylketones (253), described by Nallagondu and coworkers,
at 2- and 3-positions, are of significant pharmaceutical interest as gave imidazo[1,2-a]pyridine derivatives (254) in excellent yields
they exhibit a huge spectrum of pharmacological activities (Scheme 45) [247]. Interestingly, the model reaction of 2-
[244,245]. Several imidazo[1,2-a]pyridines are marketed drugs, for aminopyridine and u-bromoacetophenone under neat conditions
example, the alpidem is anxiolytic agent, zolpidem is used for afforded the product (254a) in 99% yield within 3 min, in contrast,
insomnia, zolimidine for peptic ulcer, and many more [62,245,246]. LAG with different solvents like EtOH, water, IPA, PEG, glycerol gave
Most of the available two-component and multi-component stra- poor results yielding 254a in a range of 60e85% only after 7e10 min
tegies for their synthesis involve metal catalysts and hazardous of grinding in Agate mortar-pestle. As seen in Scheme 45, the
organic solvents [62,245,246]. As a greener alternative, Banerjee desired products (254a-h) from structurally varied
and coworkers demonstrated a grindstone procedure for the iodine uebromomethylketones and 2-aminopyridines were obtained in
promoted synthesis of 2-arylimidazo[1,2-a]pyridines (250 or 251). 99% yields within just 3e5 min, making it a very efficient protocol
They used an indigenous electrical grinder for the cyclo- for C2-substituted imidazo[1,2-a]pyridines. Furthermore, they
condensation reactions of aryl methyl ketones (247 or 248) and 2- conducted the grinding reaction in the multi gram-scale without
aminopyridines (249) (Scheme 44) [34]. The automated grinding any drop in the yield of the corresponding product.
was found better over manual grinding and neat heating. The
grinding speed of the electrical grinder was also varied and it was 3.6.2. Benzo[d]imidazo[2,1-b]thiazole
found that 100 rpm was the best. A model reaction of acetophenone Benzo[d]imidazo[2,1-b]thiazole is an important sulfur-
and 2-aminopyridine by grinding for 6 h in the absence of any containing heterobicycle having N-atom at the ring junction that
catalyst did not afford any product, 250a. The addition of I2 as the are the core structure of some natural alkaloids, agrochemicals, and
catalyst could take the reaction to the forward direction and 30 mol pharmacologically active molecules [248]. Khurana and coworkers
% of I2 was found as the optimum concentration for a better yield of developed a simple one-pot synthetic protocol to access benzo[d]
250a (72% in 3 h). The reactions were conducted under neat- imidazo[2,1-b]thiazole derivatives (258) by grinding phenylglyoxal
grinding conditions if one of the substrates was liquid and LAG (255), cyclic enolizable carbonyl compounds (256), and 2-
(0.2 mL per mmol of the substrate, h ¼ 1.08 mL/mg) when both were aminobenzothiazole (257) in glycerol as the LAG agent
solids to deliver an array of the desired products (250 or 251) in (h ¼ 1.13 mL/mg of solid substrates) at room temperature (Scheme
good to high yields at ambient temperature. Different acetophe- 46) [249]. The model reaction between phenylglyoxal, 2-
none derivatives (247 or 248) and 2-aminopyridines (249) with aminobenzothiazole and 5,5-dimethylcyclohexane-1,3-dione
Scheme 44. I2 promoted synthesis of 2-arylimidazo[1,2-a]pyridines (250, 251) implementing automated grindstone chemistry [34].
37
Scheme 45. Synthesis of imidazo[1,2-a]pyridine derivatives (254) under solvent-free and catalyst-free grinding conditions [247].
Scheme 46. Regioselective synthesis of benzo[d]imidazo[2,1-b]thiazole (258) derivatives by grinding [249].
resulted in 86% yield within 15 min when ground using glycerol as for completion. The amount of glycerol is optimized as 0.5 mL/
the LAG agent, whereas, the same reaction required heating of 24 h mmol of the substrates. They proposed that mechanistic pathway
in various solvents to afford 258a in moderate yields in the solution involves Knoevenagel condensation of phenylglyoxal with 1,3-
phase. Other than glycerol, ethylene glycol, ethanol and PEG-400 dicarbonyl compounds (256) to form an intermediate, AH. It then
were screened as LAG agents but the reactions took a longer time undergoes Michael type addition with 2-aminobenzothiazole
38
Scheme 47. Three-component synthesis of 3,6-disubstituted-bis-1,2,4-triazolo-[4,3-b:30 ,40 - f]pyridazines (261) employing grindstone chemistry [252].
producing another intermediate, AI, which subsequently un- aminotetrazole and 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-
dergoes intramolecular cyclization (AJ) followed by dehydration to amine (265) under solvent-free conditions resulted in the forma-
deliver the desired products (258). A library of 20 benzo[d]imidazo tion of respective products (266e268) in a period of 10e20 min
[2,1-b]thiazoles was prepared at room temperature in 87e90% with high yields. Using the reaction conditions, a total of 17 de-
yields by 10e30 min of grinding (entries 258a-h). rivatives were synthesized by the group. They also conducted
antimicrobial activity assay of the title compounds and a couple of
3.6.3. Triazolopyridazines them displayed comparable antibacterial activity as the marketed
1,2,4-triazolo[4,3-b]pyridazine derivatives, another fused het- drug penicillin G and streptomycin.
erocycle with N-atom at the ring junction, exhibit extensive phar-
macological activities [250,251]. Aggarwal and coworkers reported 3.7. Spirocycles
a three-component reaction between 3,6-dihydrazinopyridazine
(259), an aromatic or heteroaromatic aldehyde (260) and iodo- Spirocycles with hetero-atoms such as spirooxindoles,
benzene diacetate (IBD) to synthesize sterically hindered 3,6- spiroindole-thiazolidinones are the core units of a number of
disubstituted-bis-1,2,4-triazolo-[4,3-b:30 ,40 -f]pyridazines (261) pharmaceuticals and natural products [256,257]. Grindstone
employing grindstone chemistry (Scheme 47) [252]. It was chemistry was successfully employed for the facile synthesis of
considered that both hydrazine functionalities of 259 react with 2 various spirocycles [27,35,258e260]. In an interesting approach,
equiv of aldehydes (260) resulting in the intermediate AK, which Ahmed and coworkers demonstrated a grinding protocol towards
was subsequently oxidatively cyclized by the addition of 2.2 equiv the synthesis of photochromic tetrahydroindolizines (THIs) (272)
of hypervalent iodine, IBD to furnish the desired products (261) in and also studied the substituent effect on their photochromic
moderate to good yields in 1 h. The solvent-free grinding approach properties (Scheme 49) [258]. Grinding a mixture of spi-
afforded the desired compounds in 54e68% yields in one-pot, rocyclopropenes (269), 1-substituted aryl-3,4-dihydroisoquino
which is a significant enhancement as compared to the reported lines (270) in the presence of silica gel (2 g) as the grinding auxil-
solution-phase multistep procedure (20e29%) for 261 [253]. iary in a mortar-pestle delivered five THIs (272). A 40 min of
grinding followed by 2 h rest period, further 40 min grinding and
3.6.4. Azolopyrimidines standing for 8 h delivered the desired products, dialkyl-50 ,60 -dihy-
Both pyrimidine and pyrazole are significant pharmacophores dro-100 b-substituted-10 H-spiro[fluorine-9,10 -pyrrolo[2,1-a]iso-
and their fused systems (e.g. pyrazolyl-pyrimidines) are the scaf- quinoline-20 ,30 -dicarboxylate (272) in 64e87% yields. The
folds of medicinal interests [254]. Gomha and coworkers efficiently photochromic THIs were formed via electrophilic attack of 269 to
exploited the grindstone technique to prepare an array of pyr- the N-heterocycle dihydroisoquinoline derivatives (270) and
azolylbenzo [4,5]imidazo[1,2-a]pyrimidines (266), pyrazolyl-tri- consequently opened via a cyclopropyl-allyl intermediate (AL) to
azolo[1,5-a]pyrimidines or pyrazolyl-tetrazolo[1,5-a]pyrimidines give the colored betaines (271), which is thermally closed to give
(267), and bis-azolopyrimidines (268) (Scheme 48) [255]. The 272 via 1,5-electrocyclization pathway. The newly synthesized THIs
acetic acid catalyzed grinding reaction of pyrazolylchalcones or its offered diverse photochromic behaviors.
bis-pyrazolyl-chalcones (262) with the appropriate heterocyclic In another study, Bazgir and coworkers reported a one-pot,
amines such as 2-aminobenzimidazole (263), aminotriazole (264), pseudo four-component mechanochemical protocol to furnish
Scheme 48. Usefulness of pyrazolylchalcone synthons towards the synthesis of pyazolopyrimidines (266e268) by hand-grinding [255].
39
Scheme 49. Grindstone mediated synthesis of photochromic tetrahydroindolizines (THIs) (272) [258].
spiro[diindenopyridine-indoline]triones (277) or spiro 87e95% yields. However, reactants like 1-methyl isatin, 2-
[acenaphthylene-diindenopyridine]triones (278) (Scheme 50) cyanoacetamide and acyclic 1, 3-dicarbonyl compounds such as
[259]. The protocol involves the grinding of 1,3-indandione (273), ethylacetoacetate gave trace amounts of the products (entries
aromatic amines (274), with isatins (275) or acenaphthylene-1,2- 282g,h) due to the electronic effects. The authors proposed that the
dione (276) in the presence of p-TSA as the catalyst to furnish the reaction proceeds by the formation of Knoevenagel condensation
products (277 or 278) in high yields. The pilot experiment carried product AM, which undergoes subsequent Michael addition (AN),
out by grinding isatin, aniline, and 1,3-indanedione in the presence intramolecular cyclization (AO) and tautomerization to furnish the
of 30 mol% of p-TSA for 3e4 min afforded the corresponding desired products, 282. The products were obtained in sufficiently
product (277a) in 85% yield, while without p-TSA, the yields of pure form by simple filtration avoiding tedious workups or column
products were low (<40%) even after 30 min of grinding. This chromatographic purification steps. The feasibility of the protocol
method was validated using substitutions in isatin and anilines was further demonstrated by the gram scale (5 mmol) production
with both EDGs and EWGs delivering 20 examples of the title of (282a) in 92% yield. The green metrics of this protocol are E-
compounds, spiro[diindenopyridine-indoline]triones (277a-f) in factor 0.054, atom economy 85% other than simple experimental
high to excellent yields (80e91%). Also, a small library of 5 de- set-up establishing the usefulness of the grindstone method in the
rivatives of spiro[acenaphthylene-diindenopyridine]triones effortless synthesis of these heterocycles in a short time.
(278a,b) was prepared in a similar manner in high yields Recently Gobinath et al. reported another spirocycle synthesis in
(82e89%). The method was tested in a gram scale (0.1 mol, 60 g of one-pot with the aid of mortar-pestle grinding [35]. The syntheses
reaction mass) with the synthesis of 277a in a glass bowl using a of 10-phenyl-3,4,6,7-tetrahydro-1H-spiro [acridine-9,20-indoline]-
mechanical stirrer to obtain 85% yield in just 5 min. 1,3,8-trione derivatives (286) were achieved via a pseudo-four-
Sharma and coworkers recently developed a catalyst-free hand component reaction by grinding of isatins (1 equiv) (283), 1,3-
grinding strategy towards a domino multicomponent reaction to cyclohexanedione (2 equiv) (284) and substituted anilines (1
afford 2-amino-2-oxospiro[indoline-3,40 -pyran]-30 -carbonitriles equiv) (285) under solvent-free conditions for 10 min grinding
(282) in excellent yields (Scheme 51) [260]. The reaction involves catalyzed by p-TSA (Scheme 52) [35]. The method gave excellent
the grinding of isatin or acetanaphthelenequinone (279), malono- yields of the spirocycles, 286 (78e95%) derived from aromatic
nitrile or ethylcyanoacetate (280) and enolizable 1,3-dicarbonyl amines with both EWG and EDG delivering a short library of 10
compounds (281) to afford the desired spirocycle (282) in excel- compounds. On cytotoxic screening of the products, the derivative
lent yields. During the optimization studies with isatin, malono- of p-methoxyaniline was found to be highly active against MCF-7
nitrile and dimedone, they observed multiple unidentifiable cancer cell lines.
products when all the substrates were ground together without any
catalyst. Therefore, a stepwise domino reaction strategy was
adopted by grinding isatin and malononitrile for 10 min followed 3.8. Diversity oriented heterocycle synthesis
by the addition of the third component, dimedone to the reaction
mixture and grinding it for another 15 min to afford the desired A few grinding protocols are available for the synthesis of more
product (282a) in 94% yield. LAG using different solvents such as than one heterocycles using the same methodology by a simple
water, glycerol and PEG-400 did not affect any improvement in the change of one of the key substrates. In one such approach, an
product yield, and thus, the neat condition was adopted for other interesting chemodivergent multi-component synthesis of pyrroles
derivatives. By varying substrates 19 derivatives of 2-oxospiro (289) and tetrahydropyridines (290) were developed by Dhina-
[indoline-3, 40 -pyran]-30 -carbonitriles (282) were prepared in karan et al. via mortar-pestle grinding [261]. The catalyst-free
grinding of ethyl (E)-3-(aryl/alkyl amino)acrylates (287), 2,2-
40
Scheme 50. Synthesis of spiro[diindenopyridine-indoline]triones (277) and spiro[acenaphthylene-diindenopyridine]triones (278) using grindstone technique [259].
dihydroxy-1-arylethan-1-ones (288) and malononitrile afforded product, which further undergoes Michael addition with enamine
either the expected tetrasubstituted pyrroles, 289 or unexpected 287, resulting in the formation of the intermediate, AQ. If a phenyl
tetrahydropyridines, 290 as the major product under the same re- with EWG is present in N-aryl ring in AQ, the cyclization involving
action condition by the electronic effect in (E)-3-(aryl/alkyl amino) the secondary amine group and the carbonyl is favoured and re-
acrylates (287) (Scheme 53) [261]. The representative reaction action proceeds via path (a), leading to the formation of poly-
involving 2,2- dihydroxy-1-phenylethan-1-one, malononitrile and substituted pyrrole 289 (Scheme 53). On the other hand, the
ethyl (E)-3-((4-bromophenyl)amino)acrylate showed the superi- presence of EDG in the N-aryl ring of the intermediate AQ favours
ority of hand-grinding (yield of 289a is 85% after 10 min of the attack of the secondary amine group to one of the nitrile
grinding) over solvent-phase reactions using solvents like EtOH, functionalities leading to the six-membered cyclic product 290 via
CHCl3, H2O etc. under refluxing conditions (yields of 289a is 80% in path (b) (Scheme 53). The method was validated by changing the N-
EtOH after 30 min; 40% in H2O after 6 h; 50% in CHCl3, after 6 h). substituents in enamine and 10 examples of pyrrole, 289 as the
Interestingly, under optimized grinding conditions, they observed major product and 12 examples of tetrahydropyridines, 290 as the
unexpected chemoselectivity governed by the substitutions in the major products were prepared in 70e85% yields.
N-aryl ring of enamine 287. In the cases of N-phenyl, N-heterocycle Fahmi et al. developed a grindstone technique for the synthesis
and N-phenyl ring with electron-withdrawing substituents in of a variety of nitrogen-based heterocycles with promising bio-
enamine 287, the cyclization involving the secondary amine group logical activities by the condensation of a,b-epoxyketones (291)
and the carbonyl is favoured leading to the formation of poly- with various amine derivatives involving imine formation followed
substituted pyrroles (289). On the other hand, N-phenyl rings with by cyclization via the opening of epoxy ring (Scheme 54) [262].
electron-donating substituents favor cyclization involving the sec- Firstly, grinding 291 with hydrazine or phenylhydrazine for
ondary amine group and the nitrile functionality to afford tetra- 5e7 min under solvent-free conditions in a porcelain mortar-pestle
hydropyridines (290). As per the plausible mechanism, initially, the at room temperature afforded the stable pyrazoline-4-ol de-
pseudo-aldehyde, 288 and malononitrile furnish 2-(2-oxo-2- rivatives (292) with a yield of 80e93%. The same reaction in the
arylethylidene)malononitrile (AP), the Knoevenagel condensation conventional approach by refluxing in ethanol takes 7e14 h
41
Scheme 51. A hand grinding mediated domino multicomponent synthesis of 2- amino-2-oxospiro[indoline-3,40 -pyran]-30 -carbonitriles (282) [260].
Abdel-Aziem and coworkers synthesized a library of new pyr-

azolopyridazines (298), pyrazoles (300), and pyrimidines (302) by a
cyclocondensation reaction of 2-(3-(dimethylamino)acryloyl)-3H-
benzo[f]chromen-3-one (296) with various substituents such as
hydrazonoyl halides (297), hydrazines (299) and 2-amino-hetero-
cycles (301), respectively, via a mortar-pestle grinding (Scheme 55)
[263]. For pyrazolopyridazines (298) synthesis, a weak base, so-
dium carbonate, was used during grinding, whereas, pyrazoles
(300) could be obtained in catalyst-free conditions and synthesis of
pyrimidines (302) required catalytic amount of AcOH for successful
conversion. These compounds were also synthesized in conven-
Scheme 52. A one-pot synthesis of 10-phenyl-3,4,6,7-tetrahydro-1H-spiro[acridine- tional media by heating in ethanol. There were obvious advantages
9,20-indoline]-1,3,8-trione (286) derivatives via a pseudo-four-component cyclo-
condensation reaction [35].
for grinding technique such as operational simplicity, solvent-free
conditions, facile work-up coupled with high to excellent yields.
The anticancer activity of the synthesized compounds was checked
yielding 59e83% of 292. Next, grinding 291 with urea/thiourea in a for in vitro antiproliferative against different human tumor cell lines
porcelain mortar-pestle for 3e10 min in the presence of a few drops such as melanoma, leukemia and cancers of the brain, lung, colon,
of acetic anhydride afforded imidazoline derivatives (293) with a ovary, prostate, breast and kidney. The results displayed that pyr-
yield of 81e86%, which otherwise would take 2e3 h to complete in azolo[3,4-d]pyridazines derivatives (298), pyrazole (300) exhibited
refluxing ethanol to afford relatively lower yields (71e80%) of 293. powerful anticancer activity.
Subsequently, reacting 291 with semicarbazide in a mortar-pestle Abdullah and Rabeaa demonstrated the synthesis of some
afforded 1,2,4-oxadiazin derivative (294) and pyrazole derivative pyrazole-derived heterocycles using diversity oriented synthesis
(295) with a yield of 60% and 80%, respectively. involving condensation of a heteroaromatic amine, 303 with
42
Scheme 53. A chemodivergent multi-component synthesis of pyrroles (289) and tetrahydropyridines (290) using grindstone technique [261].
various aromatic aldehydes (304) and then treating the corre- derivatives. Schiff bases 305 upon neat grinding with sodium azide
sponding Schiff's bases (305) with sodium azide to convert to tet- in the absence of any catalyst or additive produced tetrazole de-
razoles (306) and also with various anhydrides (307) to obtain rivatives (306) in excellent yields within 12e15 min. Again, the
oxazepine derivatives (308) using a simple hand-grinding tech- conversion of 305 to oxazepine derivatives (308) were more facile
nique (Scheme 56) [264]. The Schiff base (305) of 4- and six derivatives were obtained from phthalic, maleic and suc-
aminoantipyrine (303) and aromatic aldehydes (304) are used as cinic anhydride (307) within 5e10 min of grinding in 83e93%
precursors for the synthesis of oxazepine and oxazepane yields.
43
Scheme 54. Synthesis of various nitrogen-based heterocycles by condensation of a,b-epoxyketones (291) with various amine derivatives in a mortar-pestle [262].
Scheme 55. Synthesis of new pyrazolopyridazines (298), pyrazoles (300), and condensed pyrimidines (302) via grinding of 2-(3-(dimethylamino)acryloyl)-3H-benzo[f]chromen-3-
one with different reagents [263].
4. Derivatization of heterocycles investigations revealed that bis(indolyl)methanes (311) formation

takes a longer time (30e90 min) in the solution phase using
The appropriate derivatization of preassembled heterocyclic common solvents such as ACN, MeOH, EtOH in the presence of
cores is an important tool to accomplish the synthesis of targeted catalysts such as ZrCl4, ZrOCl2, [Hmim][HSO4], Ph3CCl, whereas, a
drugs or new chemical entities for activity screening in the fields of small amount of CSA (0.1 g/mmol of aldehyde) as the catalyst under
biology, pharmaceuticals, and agrochemicals. Although there are grinding condition effectively form the title products in >90% yield
limited attempts as compared to the construction of heterocycles, within 8 min. The catalyst CSA was prepared easily by treatment of
the grindstone technique is successfully employed in the derivati- chlorosulfonic acid on cellulose in hexane under stirring conditions
zation of heteroaromatic systems as well. In this section, the and isolated by filtration. Total 11 examples of 311 were prepared in
available literature on grindstone-aided derivatization of hetero- 85e95% yields. After the reaction, CSA was filtered and reused
aromatics will be discussed. without much loss in reactivity. Earlier, Pasha and coworkers re-
Bis(indolyl)methanes are important for their immense anti- ported a similar hand-grinding method for the synthesis of
cancer activities [265e267]. 3,30 -Diindolylmethane is a novel bis(indolyl)methanes (311) by grinding indole with various alde-
mitochondrial H þ -ATP synthase inhibitor that can induce hydes (309) using a catalytic amount of p-TSA (6 mol%) in a mortar-
p21Cip1/Waf1 expression by induction of oxidative stress in human pestle for just 3e8 min (Scheme 57) [269].
breast cancer cells [265]. A standard and convenient method for the Brahmachari and Das demonstrated the mechanosynthesis of
synthesis of bis(indolyl)methanes is the FriedeleCrafts reaction gem-(b-dicarbonyl)arylmethane derivatives (315) via C-3 alkylation
between indoles and carbonyl compounds in the presence of an of indoles (314) via L-proline catalyzed MCR involving 1,3-
acid or base. A solvent-free grindstone process for the synthesis of dicarbonyl compounds (312) and aromatic aldehydes (313) as the
bis(indolyl)methanes (311) was described by Sadaphal et al. other substrates (Scheme 58) [32]. The reactions were conducted in
involving the condensation reaction of aromatic aldehydes (309) a watch glass grinding with a spatula under solvent-free conditions
and indole (310) in a 1:2 ratio in the presence of cellulose sulfuric at room temperature. Initial studies showed that the grinding of
acid (CSA) as the solid-acid catalyst (Scheme 57) [268]. The initial benzaldehyde, 4-hydroxycoumarin and indole to afford bis-indole
44
Scheme 56. Diversity oriented conversion of 4-aminoantipyrine (303) to tetrazole (306) and oxazepine (308) derivatives using grindstone technique [264].
Scheme 57. Solvent-free grindstone process for the synthesis of bis(indolyl)methanes (311) [268,269].
derivative (316) instead of the desired product (315a) when Lewis catalyst, HNO3@nano SiO2 (12 mg/mmol) in mortar-pestle (Scheme
acid (AlCl3, ZrOCl2, Bi(NO3)3) or the ionic liquid ([Hmim][HSO4]) are 59) [270]. The catalyst was prepared by stirring commercial nano
used as the catalysts, whereas, organocatalyst, L-proline could SiO2 (2.5 g) with conc. HNO3 (1 mL) in dry CHCl3 at room tem-
catalyze the formation of the title product, 315a in 75% yield within perature for 3 h. The requirement of catalyst is confirmed by con-
1 h. This atom-economic grinding procedure afforded moderate to ducting a model reaction which showed the formation of only 21%
high yields of non-racemic products (315), which displayed varying of the title compound in the absence of any catalyst even after
optical rotations. However, they did not report the enantiomeric 100 min under the neat condition as compared to 94% yield of the
excess (ee) of the reactions in their article. The scope and generality product within 5 min if HNO3@nano SiO2 (12 mg/mmol) is used as a
of the protocol was explored by reacting a variety of aromatic al- catalyst in the mixture. A library of 16 derivatives of di(indolyl)
dehydes containing electron-donating or electron-withdrawing indoline-2-ones (319) was prepared in 70e95% yields within
substituents in the aromatic ring with 4-hydroxycoumarin (or 2e15 min of grinding. Notably, the reaction could also be per-
other carbonyl compounds, 312) and substituted indoles (314) and formed with the same ease in the solution phase (such as ACN,
the corresponding products (entries 315a-g) were obtained in MeOH and EtOH) resulting in excellent yields of 319 (90e95%)
moderate to high yields (53e93%). Aliphatic aldehydes like butyr- within 40e60 min. A remarkable decrease in reaction times for
aldehyde also took part in the reaction with a low yield (44%) of the grinding method is attributed to local heat generation during pul-
desired product (entry 315h). The Michael addition from the indole verization by a pestle than the simple collision of two substrates in
moiety to the Knoevenagel adduct of 312 and 313 furnishes the the solution phase, indicating the superiority of the grinding pro-
desired products. tocol over the conventional method.
In another recent work on C-3 activation of indoles, Nikoofar Halogenation of heteroaromatic ring is a useful tool for further
and coworkers presented a solvent-free procedure for the synthesis functionalization, such as cross-coupling reactions. In one such
of both symmetrical and unsymmetrical di(indolyl)indoline-2-ones approach, Banerjee and group demonstrated a late-stage haloge-
(319) by grinding isatin (317) with indoles (318) with a solid acid nation at C3-position of 2-arylimidazo[1,2-a]pyridine (250a) as an
45
Scheme 58. L-Proline catalyzed mechanochemical C-3 alkylation of indole to form gem-(b-dicarbonyl)arylmethane derivatives (315) by mortar-pestle grinding [32].
Scheme 59. Synthesis of symmetrical and unsymmetrical di(indolyl)indoline-2-ones (319) by grinding isatins and indoles or pyrrole with HNO3@nano SiO2 [270].
bioactivities [271]. The development of mild and metal-free

methods for syntheses of organic selenocyanates is of current
research focus [272]. In this direction, Xiao et al. used an electro-
philic selenocyanating reagent N-selenocyanatophthalimide
(PhthSCN) (322) for the synthesis of 3-selenocyanato-substituted
chromones (or quinolones, 323) from 2-hydroxyphenyl enami-
nones (321) by a tandem cyclization selenation in mortar-pestle
Scheme 60. Late stage halogenation at the C3-position of 2-arylimidazo[1,2-a]pyridine (Scheme 61) [273]. The reaction condition was standardized by
(250a) using an electrical grinder [34].
using 2-hydroxyphenyl enaminone, N-selenocyanatophthalimide
(322) as model substrates which afforded 323a with yields of
extension of their work on the synthesis of imidazo[1,2-a]pyridines 44e71% after 12 h when carried out in the solution phase using
(Scheme 60) [34]. 2-Phenylimidazo[1,2-a]pyridines (250a) was different solvents such as CH2Cl2, DCE, THF, ACN, toluene, and DMF.
subjected to CeH halogenation in the heteroaromatic ring by However, the same reaction in grinding condition afforded 323a
grinding with N-iodosuccinimide (NIS) and N-bromosuccinimide with a yield of 86% within 20 min. The other selenocyanating re-
(NBS) in an electrical grinder at 100 rpm for 1 h to afford corre- agent, selenocyanobenziodoxolone also afforded the desired
sponding Br-or I-substituted imidazo[1,2-a]pyridines (320) in product (323a) but in lower yield (72%). This protocol displayed a
excellent yields (90% and 92%, respectively). broad substrate scope with regards to phenylenaminones with
Organic selenocyanates are important functionality for various various electron-donating or electron-withdrawing groups as well
selenium-containing compounds, which exhibit a range of as phenols (entries 323a-c) or N-protected anilines (entries 323d,e)
which took part in the reaction with equal ease. The generality of
46
Scheme 61. Synthesis of 3-selenocyanato-substituted chromones (or quinolones, 323) from 2-hydroxyphenyl enaminones (321) using N-selenocyanatophthalimide (PhthSeCN)
(322) by employing grindstone chemistry [273].
Scheme 62. Synthesis of alkynyl substituted 4,5,6,7-tetrahydroindoles (326,328) [274,277].
the protocol was demonstrated by a few examples of thiocyanation Table A, Scheme 62). Notably, the presence of bulky substituents
of enaminones with PhthSCN (entry 323f), which gave the corre- (like CH(Me)OBu) on C1 of pyrrole did not affect the regioselectivity
sponding thiocyanated products in good to excellent yields. The but took a longer time (12 h) for completion (entry 4, Table A,
method was validated in the gram-scale synthesis of organic Scheme 62). Later the same group developed another method for
selenocynates. the CeH butadiynylation via cross-coupling reaction of substituted
The cross-coupling reactions are scantily explored using the 4,5,6,7-tetrahydroindoles (324) with 1-halobutadiynes (327) under
grindstone technique. In one such study, Trofimov et al. demon- mild, solvent- and transition metal-free conditions (Scheme 62)
strated a transition metal-free chemo- and regio-selective ethy- [277]. Multialkynyl cross-coupling reactions have been a topic of
nylation of 4,5,6,7-tetrahydoindoles (324) with 3-halopropynoates research interest for the last few decades [278]. The starting sub-
(325) by grinding them in a china dish with solid K2CO3 to afford strates, 1-halobutadiynes (327) were prepared from brominated
ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)-2-propynoates (326) in good esters of propiolic acid via Cadiot-Chodkiewicz cross-coupling with
to excellent yields (Scheme 62) [274]. The C-2 alkynylation of indole trimethylsilylacetylene in the presence of Pd(PPh3)2Cl2/CuI. Again
usually requires a transition metal for the cross-coupling [275]. 10 times of K2CO3 against the substrate was used for solid-phase C-
However, Trofimov and group achieved this under aerobic condi- 2 selective cross-coupling reaction. A drop in the yield was
tions at room temperature by the hand-grinding approach. Notably, observed if the grinding matrix was changed to Al2O3. The influ-
2e10 folds amount of K2CO3 (by weight) with respect to tetrahy- ence of halogen in the reaction kinetics of the cross-coupling re-
doindoles (324) was used, which acts as a base and provides a action was tested with 1-halobutadiynes taking Br or I as the
grinding media for successful C-2 selective cross-coupling. Their halogen. The conversion was seen after 1 h, but Br-butadiyne
previous effort of ethynylation of 4,5,6,7-tetrahydroindole on active appeared reacting faster than I-butadiynes with tetrahydroindole.
Al2O3 surface via hand-grinding was not highly chemoselective The substrate scope was checked by varying substituents (R1) at N-
[276]. They checked that the reactions did not proceed in the so- atom of tetrahydroindole (324) and the products (328) were ob-
lution phase (diethyl ether, CHCl3) or without the addition of K2CO3, tained with moderate to high yields ranging from 43% to 80% by
and generally took 1 h for completion by hand-grinding, affording grinding reaction mixture up to 5 h (entries 1e3, Table B, Scheme
moderate to high yields (50e90%) of the products (entries 1e3, 62). Next, they studied the influence of the phenyl spacer situated
47
Scheme 63. Synthesis of long-chain hexatriynyl- and octatetraynyl-substituted tetrahydroindoles (331) [279].
between the butadiyne fragment and an ester group on the materials and intricate structures including co-crystals, composites,
coupling reaction using 1-bromobutadiyne and 1-chlorobutadiyne. dyes, MOFs, COFs, etc. were prepared by the grindstone method. It
In both cases, the reaction time was longer (24 h), delivering low is postulated that the grinding of reacting components under the
yields of the products (entries 4 and 5, Table B, Scheme 62). neat conditions or in the presence of a small volume of solvent as
To further extend the scope, Szafert, Trofimov and coworkers LAG agent allows the formation of a liquid/semi-liquid interphase
synthesized long-chain hexatriynyl- and octatetraynyl-substituted with a high density of uniformly distributed reactants in close
pyrroles (331) by grinding N-substituted pyrroles (329) with 1- contacts to propel the reaction to completion mostly in just a few
haloalkynes (330) in the presence of K2CO3 as the catalyst as well minutes. Keeping the main focus on the use of mortar-pestle
as solid support (Scheme 63) [279]. This time 5 g of K2CO3 per mmol grinding for the construction and derivatization of heterocycles,
of polyalkyne (330) was used for the smooth conversion to the title this review article captured a brief account on the other areas of
products 331 via C2eH activation of the aromatic ring of tetrahy- applications to provide the entire spectrum on the scope of
droindoles. It was observed that the reactions of 1- “grindstone chemistry” to the readers.
bromohexatriynes and N-substituted tetrahydroindoles worked As seen in section 3, a variety of heterocycles could be efficiently
well, and the products were obtained with yields up to 97% with the synthesized by simple hand-grinding that include heterocycles
reaction times ranging between 3 and 24 h (entries 331a-c). with a single heteroatom (like pyrroles, furans, thiophenes, pyri-
However, the reactions with unsubstituted tetrahydroindole gave dines, chromenes, etc.), with two heteroatoms (like 1,3-benzazole,
products with low to moderate yields (8e52%) (entries 331d,e) pyrimidines, quinoxalines, etc.), or even spirocycles, fused hetero-
after a long time of grinding (19e72 h). Again, reactions with 1- cycles etc. often with the aim of synthesizing new and important
iodotetraynes were found sluggish and took 24e48 h for comple- heterocyclic scaffolds with biological and medicinal importance.
tion. A limitation of the method is that the reactions with unsub- Although there is a limited number of attempts, the derivatizations
stituted tetrahydroindoles are slow and low-yielding. of preassembled heterocyclic cores were also accomplished by
grindstone technique that include halogenation, selective alkyl-
ation of the heteroaromatic rings, CeH activation etc. In several
5. Summary and future perspective cases, the solvent- and catalyst-free transformations were achieved
in a shorter time with higher yields ticking the check-box of several
Mechanochemistry, i.e. the chemical transformations achieved green matrices. For example, the grindstone method of Das et al.
by mechanochemical force, is a tool to conduct solvent-less re- [34] for marketed drug, zolimidine with an E-factor of 1.77 is much
actions and has been recognized by IUPAC as one of the ten world- greener and cheaper than a fancy solution-phase method by Bagdi
changing technologies. While mechanical milling is a superior and et al. [76] with an E-factor of 14.22. In several other cases, the use of
more versatile technique, a pair of mortar-pestle is the simplest tool green-solvents like EtOH, PEG, H2O or an ionic-liquid as LAG agents
for mechanochemical activation, and the technique, called “grind- offered faster reaction kinetics and higher yields. Notably, facile
stone chemistry,” has benevolent characteristics like simple aerial oxidation due to “open-air” grinding, easy separation prod-
instrumentation and operational simplicity. Since its formal intro- ucts by simple filtration, easy recovery of heterogeneous catalysts
duction by Toda et al. in the last century [22], “grindstone chem- are some of the common features of grindstone chemistry. How-
istry” has traveled a long stride forward, particularly in recent ever, manual grinding by a person is a labor-intensive process and
years, and has been employed in a myriad of organic trans- concerns like “does the reaction kinetics depend on the physical
formations. This includes but is not limited to traditional CeC bond power or the grinding speed?” or “how long the hand-grinding can
formation, Schiff base and its derivatives, various name reactions, be continued?” or “what is the scalability?” are some concerns
multicomponent reactions, and several of them led to the con- often raised on manual-grinding. The solution to these problems is
struction of heterocycles by cyclocondensation. Moreover, valuable
48
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[33] C. Duangkamol, S. Jaita, S. Wangngae, W. Phakhodee, M. Pattarawarapan, RSC
The authors declare that they have no known competing Adv. 5 (2015) 52624e52628, https://doi.org/10.1039/c5ra10127a.
financial interests or personal relationships that could have [34] D. Das, Z.T. Bhutia, P.C. Panjikar, A. Chatterjee, M. Banerjee, J. Heterocycl.
appeared to influence the work reported in this paper. Chem. 57 (2020) 4099e4107, https://doi.org/10.1002/jhet.4106.
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[36] N. Sahiba, A. Sethiya, J. Soni, S. Agarwal, ChemistrySelect 5 (2020)
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52
Padmini C. Panjikar was born on 20th April 1988 in Goa, Akhil A. Bhosle was born on 15th June 1995 in Goa, India.
India. She received her B$Sc. degree and M.Sc. degree in He has received his B$Sc. degree and M.Sc. degree in
Chemistry in 2008 and 2010 respectively from Goa Uni- Chemistry in 2016 and 2018 respectively from Goa Uni-
versity. Since June 2012 she has been working as an As- versity. Later in January 2019 he joined the Department of
sistant Professor in Chemistry at Parvatibai Chowgule Chemistry, BITS PILANI K K Birla Goa Campus, Goa, India
College, Margao Goa. In 2019 she joined the Department as a Junior Research Fellow and is now pursuing his
of Chemistry, BITS PILANI K K Birla Goa Campus, Goa, India doctoral studies under the supervision of Prof. Mainak
as a part-time Ph.D. student and is working under the su- Banerjee since August 2019.
pervision of Prof. Mainak Banerjee.
Prof. Mainak Banerjee was born in 1975 in Kolkata, India.

He obtained his Masters degree in Organic Chemistry
from University of Calcutta in 1998. He obtained his PhD
degree in 2006 from Jadavpur University, Kolkata India,
Dharmendra Das was born on August 01, 1991 in Assam, working on the total synthesis of abietane diterpenoids.
India. He has received his B$Sc. (Hons) degree in Chem- After two post-doc. stints in South Korea, he started his in-
istry in 2013 from Dibrugarh University, Assam, India. He dependent research career in 2009 as an assistant profes-
obtained his M.Sc. and M. Phil. degree in Organic Chem- sor in the Department of Chemistry at BITS Pilani K K Birla
istry in 2015 and 2017 from Sikkim Central University, Goa Campus. At present, he is a professor in the same
Tadong, Gangtok, Sikkim, India. Later in December 2017 department. His research interest includes green chemis-
he joined the Department of Chemistry, BITS PILANI K. K. try, supramolecular chemistry, mechanochemistry etc.
Birla Goa Campus, Goa, India and is now pursuing his
doctoral studies under the supervision of Prof. Mainak
Banerjee since August 2018.
Prof. Amrita Chatterjee was born in 1976 in Kolkata India.

She obtained her Masters degree in Organic Chemistry
from University of Calcutta in 2000. She obtained her PhD
degree in 2006 from Jadavpur University, Kolkata India in
the group of Late Dr. Pranab K. Bhattacharya, working on
the area of organic synthesis in aqueous media. In 2006,
she joined the group of Prof. Kyo Han Ahn's lab in POST-
ECH, and working in the area of the molecular sensor. In
Shruti Iyer was born on June 7, 1999, in Chennai, India. She 2009, she joined BITS Pilani K K Birla Goa Campus as an
received her Integrated M.Sc. degree in Chemistry in 2021 assistant professor. Currently, she is working as a profes-
from BITS PILANI K K Birla Goa Campus, Goa, India. She sor at the same university. Her research interest includes
has completed her M. Sc. dissertation under the supervi- aggregation induced emission based sensor, carbon-
sion of Prof. Mainak Banerjee in 2021. nanomaterial based sensor and green chemistry.
53

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Tetrahedron 112 (2022) 132753

Contents lists available at ScienceDirect

Tetrahedron report 1261

Grindstone chemistry: A “green” approach for the synthesis and

1. Introduction grindstone chemistry, was introduced by Toda et al. in the last

Fig. 1. Different types of grinding tools.

Fig. 2. Different condensation reactions carried out using grindstone technique.

Fig. 5. Grindstone mediated aromatic substitution reactions.

Fig. 6. Application of grindstone chemistry for miscellaneous other reactions.

Fig. 7. Multicomponent name reactions aided by mortar-pestle grinding.

Scheme 1. Other multicomponent reactions aided by grindstone chemistry.

3. Heterocycle synthesis by grindstone chemistry 3.1.1. Pyrroles

Scheme 5. One-pot, four-component synthesis of polyhydroquinolines (110 or 111) [155].

Scheme 8. Liquid assisted synthesis of styryl linked benzo[h]pyrazolo[3,4-b]quinoline-5,6(10H)-diones (123) [159].

In order to use a green catalyst in a green protocol, Kantharaju

model reactions it was observed that 10 mol% of NaOAc and 0.5 mL

Scheme 18. Synthesis of 4,5-dihydro-3-(2-arylindol-3-yl)-5-(4-chlorophenyl)-N1-phenylpyrazoles (151) using grindstone technique [181].

formation of 155a took 2 h time in reﬂuxing ethanol, indicating the

Scheme 31. L-tyrosine catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones (206) [212].

Scheme 32. Fe3O4eCNTs catalyzed synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-ones (208) [214].

3.4.3. Quinoxalines compounds and diamine compounds with an overall yield of

Scheme 38. Grindstone mediated three-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones (231) [231].

Scheme 40. Pseudo-ﬁve-component synthesis of 1,2-dihydro [1,6]naphthyridines (237) [239].

Scheme 46. Regioselective synthesis of benzo[d]imidazo[2,1-b]thiazole (258) derivatives by grinding [249].

Abdel-Aziem and coworkers synthesized a library of new pyr-

4. Derivatization of heterocycles investigations revealed that bis(indolyl)methanes (311) formation

bioactivities [271]. The development of mild and metal-free

Scheme 62. Synthesis of alkynyl substituted 4,5,6,7-tetrahydroindoles (326,328) [274,277].

doi.org/10.1016/j.ejmech.2014.12.004. (2012) 534e538, https://doi.org/10.3762/bjoc.8.61.

[216] N. Jankovi c, S. Stefanovi c, J. Petronijevi

Prof. Mainak Banerjee was born in 1975 in Kolkata, India.

Prof. Amrita Chatterjee was born in 1976 in Kolkata India.

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