Green Chemistry in Organic Synthesis: Recent Update on Green Catalytic Approaches in Synthesis of 1,2,4-Thiadiazoles

: Green (sustainable) chemistry provides a framework for chemists, pharmacists, medicinal chemists and chemical engineers to design processes, protocols and synthetic methodologies to make their contribution to the broad spectrum of global sustainability. Green synthetic conditions, especially catalysis, are the pillar of green chemistry. Green chemistry principles help synthetic chemists overcome the problems of conventional synthesis, such as slow reaction rates, unhealthy solvents and catalysts and the long duration of reaction completion time, and envision solutions by developing environmentally benign catalysts, green solvents, use of microwave and ultrasonic radiations, solvent-free, grinding and chemo-mechanical approaches. 1,2,4-thiadiazole is a privileged structural motif that belongs to the class of nitrogen–sulfur-containing heterocycles with diverse medicinal and pharmaceutical applications. This comprehensive review systemizes types of green solvents, green catalysts, ideal green organic synthesis characteristics and the green synthetic approaches, such as microwave irradiation, ultrasound, ionic liquids, solvent-free, metal-free conditions, green solvents and heterogeneous catalysis to construct different 1,2,4-thiadiazoles scaffolds.


Introduction
In 1991, the term "green chemistry" was first coined by Anatas, and the Environmental Protection Agency defined green chemistry or sustainable chemistry as "the designed chemical processes and products that eliminate or reduce the generation or use of hazardous substance" [1][2][3][4].In the 1990s, green chemistry came into existence due to the prominent work of Warner, Trost, Anastas, Sheldon, Clarke and others [5][6][7][8][9].Green chemistry is a new concept, introduced in the 20th century to develop new synthetic procedures, methodologies and chemical processes in the field of chemistry and chemical technology to accommodate the conventional existing procedures and strategies to make them environmentally benign and economical.This can be achieved by utilizing various approaches and strategies, such as ultrasound-assisted protocols, green solvents, solvent-free drugs synthesis, ionic liquids, microwave-assisted approaches, green reduction procedures, oxidation catalysts, solid acid-base catalysts and heterogeneous metal catalysis, etc. [10][11][12].Anastas and Warner introduced the key criteria for green chemistry in a set of 12 principals that laid down the fundamentals of green chemistry [1][2][3][4]13], as illustrated in Figure 1 [14,15].

Green Approaches in Organic Synthesis
The concept of green chemistry introduced the environmentally benign synthetic protocols for the synthesis of heterocycles that has had a significant impact in many fields, such as the use of green solvents, solvent-free synthesis, sustainable catalytic materials, reduced energy consumption, improved atom economy, optimized reaction yields, the use of alternative energy sources, the introduction of multicomponent reactions (MCRs), ionic liquids and the design of high-efficiency and time-saving reactions that work at ambient temperatures [16][17][18][19][20][21][22][23][24][25].Pollution and an increase in energy demands prompted the design of novel synthetic protocols to fulfill the requirements of green and sustainable chemistry to promote the synthesis of organic products in an ecofriendly environment [26,27].The new green and sustainable synthetic approaches are listed below and have advantages over conventional synthetic approaches, as depicted in Figure 2 [28][29][30][31][32][33][34][35]: 1. Solvent-free approach; 2. Grinding approach; 3. Ball milling approach; 4. Solid-wet approach; 5. Ultrasonic-assisted approach; 6. Microwave-assisted approach; 7. MOF green synthesis approach; 8. Electrochemical green catalytic synthetic approach.
In organic synthesis, avoiding the use of harmful and toxic solvents, as well as catalysts, was quite a difficult and highly challenging objective achieved by modern synthetic chemists.In green and sustainable organic synthesis, the ideal synthesis consists in following rational design fetchers to comprehensively implement the green chemistry principles, as displayed in Figure 3 [36][37][38][39][40][41].

Green Approaches in Organic Synthesis
The concept of green chemistry introduced the environmentally benign synthetic protocols for the synthesis of heterocycles that has had a significant impact in many fields, such as the use of green solvents, solvent-free synthesis, sustainable catalytic materials, reduced energy consumption, improved atom economy, optimized reaction yields, the use of alternative energy sources, the introduction of multicomponent reactions (MCRs), ionic liquids and the design of high-efficiency and time-saving reactions that work at ambient temperatures [16][17][18][19][20][21][22][23][24][25].Pollution and an increase in energy demands prompted the design of novel synthetic protocols to fulfill the requirements of green and sustainable chemistry to promote the synthesis of organic products in an ecofriendly environment [26,27].The new green and sustainable synthetic approaches are listed below and have advantages over conventional synthetic approaches, as depicted in Figure 2 [28][29][30][31][32][33][34][35]: 1.
Electrochemical green catalytic synthetic approach.In organic synthesis, avoiding the use of harmful and toxic solvents, as well as catalysts, was quite a difficult and highly challenging objective achieved by modern synthetic chemists.In green and sustainable organic synthesis, the ideal synthesis consists in following rational design fetchers to comprehensively implement the green chemistry principles, as displayed in Figure 3 [36][37][38][39][40][41].

Green Synthetic
Approaches

Green Catalysts in Organic Synthetic Approaches
The present study is a brief description of the role of catalysis in green synthetic transformations and green synthesis of drugs, chemical reagents, polymeric materials, nanomaterials and others organic materials for a sustainable future.Environmentally benign synthetic strategies are mainly possible due to the vital role of catalysts in lowering the activation energy, due to which reactions are possible at low heat energy or at room temperature and products are achieved in good-to-excellent yields by generating fever coproducts, by-products and other waste substances.Catalysis is the pillar of green chemistry, and catalysts used in the green organic synthesis must be safe, easy to handle, reusable, biodegradable and cost-effective, recyclable, recovered efficiently and display a high reaction rate to afford products in maximum yields with shorter time duration and different types of green catalysts is depicted in Table 1 [42][43][44][45][46].

Green Catalysts in Organic Synthetic Approaches
The present study is a brief description of the role of catalysis in green synthetic transformations and green synthesis of drugs, chemical reagents, polymeric materials, nanomaterials and others organic materials for a sustainable future.Environmentally benign synthetic strategies are mainly possible due to the vital role of catalysts in lowering the activation energy, due to which reactions are possible at low heat energy or at room temperature and products are achieved in good-to-excellent yields by generating fever co-products, by-products and other waste substances.Catalysis is the pillar of green chemistry, and catalysts used in the green organic synthesis must be safe, easy to handle, reusable, biodegradable and cost-effective, recyclable, recovered efficiently and display a high reaction rate to afford products in maximum yields with shorter time duration and different types of green catalysts is depicted in Table 1 [42][43][44][45][46].

Green Solvents in Organic Synthetic Approaches
The major focus of green chemistry is the elimination of solvents from chemical processes and organic synthesis or replacement of hazardous solvents with ecofriendly solvents.The attention under the remit of green chemistry is ascribed to the large volume of solvents used in the manufacture of drugs, paints, textiles, polymers, solvent extractions and purification in final formulations and other industrial products that drastically damage the environment and living organism and that must be reduced, replaced and eliminated from processes and switched to greener processes and green solvents [147][148][149][150][151][152][153][154].The green solvents that are mostly used in organic synthesis are mentioned in Table 2.
1,2,4-thiadiazole is a privileged pharmacophore that exhibits a diverse and broad spectrum of biological activities, such as human leukemia cell, antibacterial, anti-inflammatory, insecticidal, herbicidal and fungicidal agents, anticonvulsant, cardiovascular, cathepsin B inhibitors, dual 5-lipoxygenase and cyclooxygenase inhibitors, antidiabetic, antiulcerative and allosteric modulators [244][245][246][247][248][249][250][251][252].Synthetic chemists and pharmacists are attracted to the 1,2,4-thiadiazole moiety due to its versatile biological and pharmacological profile, and R&D scientists are interested in developing new synthetic approaches and methodologies to afford 1,2,4-thiadiazole scaffolds.This review article covers green and ecofriendly synthetic routes to produce 1,2,4-thiadiazole hybrids and their medicinal significance from 2000 to 2022.The plethora of research about green approaches and medicinal importance cited in this review article will be helpful for researchers in future for drug discovery and the development of novel bioactive 1,2,4-thiadiazole drug candidates.
The following are different ecofriendly green synthetic strategies to produce 1,2,4thiadiazole structural hybrids by utilizing various synthetic conditions to achieve products in high yields within a short period of time.The following are different ecofriendly green synthetic strategies to produce 1,2,4thiadiazole structural hybrids by utilizing various synthetic conditions to achieve products in high yields within a short period of time.

PIFA Catalyst for Formation of N-S Bond via Intramolecular Cyclization
Mariappan et al. developed a synthetic green and broad substrate scope protocol for S-N bond formation via intramolecular cyclization to afford substituted 5-amino-based 1,2,4-thiadiazole derivatives in the presence of hypervalent iodine (III) as an inexpensive catalyst (Scheme 1).The merit of this synthetic approach is that it is metal-free and has a short reaction time and good-to-excellent yield of products at ambient temperature.A

PIFA Catalyst for Formation of N-S Bond via Intramolecular Cyclization
Mariappan et al. developed a synthetic green and broad substrate scope protocol for S-N bond formation via intramolecular cyclization to afford substituted 5-amino-based 1,2,4-thiadiazole derivatives in the presence of hypervalent iodine (III) as an inexpensive catalyst (Scheme 1).The merit of this synthetic approach is that it is metal-free and has a short reaction time and good-to-excellent yield of products at ambient temperature.A mixture of N-(phenyl carbamothioyl) benzimidamide 2 was treated with phenyliodine (III) bis(trifluoroacetate) (PIFA) in 1,2-dichloroethane (DCE) to achieve the corresponding 1,2,4thiadiazole derivatives 3, as depicted in Scheme 1.The plausible mechanism suggested that the PIFA was reacted with midoyl thiourea to generate an intermediate in which the NH nucleophilic group attacks the sulfur atom to afford the corresponding product with the removal of trifluoro acetic acid and iodobenzene.The advantage of this synthetic protocol is that the product yield is good: either substrate has electron-donating or electronwithdrawing groups, or both [253].
Catalysts 2022, 12, x FOR PEER REVIEW 7 of 24 which the NH nucleophilic group attacks the sulfur atom to afford the corresponding product with the removal of trifluoro acetic acid and iodobenzene.The advantage of this synthetic protocol is that the product yield is good: either substrate has electron-donating or electron-withdrawing groups, or both [253].

Molecular I2 Catalysis and Oxidative N-S Bond Formation
Wang et al. reported an efficient synthetic approach for the construction of 5-aminoand 3,5-diamino-substituted 1,2,4-thiadiazoles via oxidative N-S Bond formation in scalable fashion by utilizing molecular iodine as the sole oxidant as displayed in Scheme 2. This transition, metal-free, short reaction time and mild reaction conditions strategy transformed imidoyl and guanyl thiourea 4 into 1,2,4-thiadiazole 5 in the presence of K2CO3, acetonitrile and molecular iodine as a catalyst at room temperature.The products of gramscale synthesis were afforded in excellent yields, 96-99%, as shown in Scheme 2. The diverse electron-donating, such as methyl (Me), and electron-withdrawing, such as Cl, Br, NO2 and CF3, substituents on the aryl group of aromatic thioamides were well-tolerated and afforded maximum yields of the respective products.As the aromatic thioamides were weaker in nucleophilicity, which resulted in relatively lower yields with strong electron-withdrawing groups [254].

Molecular I2 Catalysis for Regio-Specific and Expeditious Synthetic Approach
Mangarao et al. reported an expeditious approach to achieve the novel N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole hybrid structures (8,10) by treating substituted isothiocyanate 7 with 2-aminopyridine/amidine (6,9), which underwent intramolecular cyclization to form N-S bonds in the presence of an inexpensive I2 catalyst and acetonitrile as a solvent at ambient temperature as shown in Scheme 3. The merits of this facile and highly efficient regio-specific synthetic approach are insensitivity to moisture and air, being metal-free, highly efficient in product yield, gram-scale synthesis and wide substrate spectrum [255].

Molecular I 2 Catalysis and Oxidative N-S Bond Formation
Wang et al. reported an efficient synthetic approach for the construction of 5-aminoand 3,5-diamino-substituted 1,2,4-thiadiazoles via oxidative N-S Bond formation in scalable fashion by utilizing molecular iodine as the sole oxidant as displayed in Scheme 2. This transition, metal-free, short reaction time and mild reaction conditions strategy transformed imidoyl and guanyl thiourea 4 into 1,2,4-thiadiazole 5 in the presence of K 2 CO 3 , acetonitrile and molecular iodine as a catalyst at room temperature.The products of gram-scale synthesis were afforded in excellent yields, 96-99%, as shown in Scheme 2. The diverse electron-donating, such as methyl (Me), and electron-withdrawing, such as Cl, Br, NO 2 and CF 3 , substituents on the aryl group of aromatic thioamides were well-tolerated and afforded maximum yields of the respective products.As the aromatic thioamides were weaker in nucleophilicity, which resulted in relatively lower yields with strong electron-withdrawing groups [254].
Catalysts 2022, 12, x FOR PEER REVIEW 7 of 24 which the NH nucleophilic group attacks the sulfur atom to afford the corresponding product with the removal of trifluoro acetic acid and iodobenzene.The advantage of this synthetic protocol is that the product yield is good: either substrate has electron-donating or electron-withdrawing groups, or both [253].

Molecular I2 Catalysis and Oxidative N-S Bond Formation
Wang et al. reported an efficient synthetic approach for the construction of 5-aminoand 3,5-diamino-substituted 1,2,4-thiadiazoles via oxidative N-S Bond formation in scalable fashion by utilizing molecular iodine as the sole oxidant as displayed in Scheme 2. This transition, metal-free, short reaction time and mild reaction conditions strategy transformed imidoyl and guanyl thiourea 4 into 1,2,4-thiadiazole 5 in the presence of K2CO3, acetonitrile and molecular iodine as a catalyst at room temperature.The products of gramscale synthesis were afforded in excellent yields, 96-99%, as shown in Scheme 2. The diverse electron-donating, such as methyl (Me), and electron-withdrawing, such as Cl, Br, NO2 and CF3, substituents on the aryl group of aromatic thioamides were well-tolerated and afforded maximum yields of the respective products.As the aromatic thioamides were weaker in nucleophilicity, which resulted in relatively lower yields with strong electron-withdrawing groups [254].

Molecular I2 Catalysis for Regio-Specific and Expeditious Synthetic Approach
Mangarao et al. reported an expeditious approach to achieve the novel N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole hybrid structures (8,10) by treating substituted isothiocyanate 7 with 2-aminopyridine/amidine (6,9), which underwent intramolecular cyclization to form N-S bonds in the presence of an inexpensive I2 catalyst and acetonitrile as a solvent at ambient temperature as shown in Scheme 3. The merits of this facile and highly efficient regio-specific synthetic approach are insensitivity to moisture and air, being metal-free, highly efficient in product yield, gram-scale synthesis and wide substrate spectrum [255].

Molecular I 2 Catalysis for Regio-Specific and Expeditious Synthetic Approach
Mangarao et al. reported an expeditious approach to achieve the novel N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole hybrid structures (8,10) by treating substituted isothiocyanate 7 with 2-aminopyridine/amidine (6,9), which underwent intramolecular cyclization to form N-S bonds in the presence of an inexpensive I 2 catalyst and acetonitrile as a solvent at ambient temperature as shown in Scheme 3. The merits of this facile and highly efficient regio-specific synthetic approach are insensitivity to moisture and air, being metal-free, highly efficient in product yield, gram-scale synthesis and wide substrate spectrum [255].

Ultrasonic-Assisted Synthesis in Water
Chauhan et al. reported the conversion of thiobenzamide 11 with chloranil 14, under ultrasound irradiation in an aqueous medium at ambient temperature, to the corresponding 1,2,4-thiadiazole 15 with a metal-free, catalyst-free, convenient and environmentally benign one-pot protocol.The sequential intermolecular combination of thiomide 11 with chloranil 14 (oxidant) through intramolecular oxidative coupling of N-H and S-H bonds afforded 3,5-disubstituted 1,2,4-thiadiazoles in good-to-excellent yields as displayed in Scheme 5 [257].

Ultrasonic-Assisted Synthesis in Water
Chauhan et al. reported the conversion of thiobenzamide 11 with chloranil 14, under ultrasound irradiation in an aqueous medium at ambient temperature, to the corresponding 1,2,4-thiadiazole 15 with a metal-free, catalyst-free, convenient and environmentally benign one-pot protocol.The sequential intermolecular combination of thiomide 11 with chloranil 14 (oxidant) through intramolecular oxidative coupling of N-H and S-H bonds afforded 3,5-disubstituted 1,2,4-thiadiazoles in good-to-excellent yields as displayed in Scheme 5 [257].

HTACas PTC for Green Synthesis Using Molecular Oxygen as an Oxidant
Zhao et al. developed an efficient green methodology in which molecular oxygen is used as a terminal oxidant to furnish 1,2,4-thiadizoles as depicted in Scheme 6.The oxi-Scheme 5. Ultrasonic-assisted synthesis of 1,2,4-thiadiazoles 15.

HTACas PTC for Green Synthesis Using Molecular Oxygen as an Oxidant
Zhao et al. developed an efficient green methodology in which molecular oxygen is used as a terminal oxidant to furnish 1,2,4-thiadizoles as depicted in Scheme 6.The oxidative dimerization of alkyl and aryl thioamides 16 was achieved in the presence of I 2 as a catalyst, hexadecyltrimethyl ammonium chloride (HTAC) as a phase transfer catalyst (PTC) and con.H 2 SO 4 as a regenerative agent.The substituted thiomide underwent transformation into the substituted 1,2,4-thiadiazoles 17 in excellent yields via intramolecular oxidative coupling of N-H and N-S bonds.The lowest 35% yield indicated that the electron-withdrawing substituent on the benzene ring of benzothioamide failed to undergo the dimerization reaction compared with the electrodonating substituents [258].

HTACas PTC for Green Synthesis Using Molecular Oxygen as an Oxidant
Zhao et al. developed an efficient green methodology in which molecular oxygen is used as a terminal oxidant to furnish 1,2,4-thiadizoles as depicted in Scheme 6.The oxidative dimerization of alkyl and aryl thioamides 16 was achieved in the presence of I2 as a catalyst, hexadecyltrimethyl ammonium chloride (HTAC) as a phase transfer catalyst (PTC) and con.H2SO4 as a regenerative agent.The substituted thiomide underwent transformation into the substituted 1,2,4-thiadiazoles 17 in excellent yields via intramolecular oxidative coupling of N-H and N-S bonds.The lowest 35% yield indicated that the electron-withdrawing substituent on the benzene ring of benzothioamide failed to undergo the dimerization reaction compared with the electrodonating substituents [258].

Transition-Metal-Free Green Protocol Using Air as Oxidant
A novel and green approach was developed by Yang et al. with a broad substrate scope, mild reaction conditions, good functional group tolerance and high regioselectivity to construct the S-N bond of a 1,2,4-thiadiazole core via oxidative coupling.In this metalfree and gram-scale synthetic strategy, substituted amidines 18 and substituted isothiocyanates 19 were treated for the construction of the S-N bond via I2 mediated oxidative coupling to produce 5-amino-1,2,4-thiadiazole derivatives 20 in the presence of TMEDA (N,N,N′,N′-tetramethyl ethylene diamine), air (oxidant) and acetonitrile as the solvent.In this synthetic pathway, 1,2,4-thiadiazoles were afforded in moderate-to-excellent yields (Scheme 7) [259].Scheme 6. Synthesis of 1,2,4-thiadiazoles 17 using molecular oxygen as oxidant.

Transition-Metal-Free Green Protocol Using Air as Oxidant
A novel and green approach was developed by Yang et al. with a broad substrate scope, mild reaction conditions, good functional group tolerance and high regioselectivity to construct the S-N bond of a 1,2,4-thiadiazole core via oxidative coupling.In this metal-free and gram-scale synthetic strategy, substituted amidines 18 and substituted isothiocyanates 19 were treated for the construction of the S-N bond via I 2 mediated oxidative coupling to produce 5-amino-1,2,4-thiadiazole derivatives 20 in the presence of TMEDA (N,N,N ,Ntetramethyl ethylene diamine), air (oxidant) and acetonitrile as the solvent.In this synthetic pathway, 1,2,4-thiadiazoles were afforded in moderate-to-excellent yields (Scheme 7) [259].

HTACas PTC for Green Synthesis Using Molecular Oxygen as an Oxidant
Zhao et al. developed an efficient green methodology in which molecular oxygen is used as a terminal oxidant to furnish 1,2,4-thiadizoles as depicted in Scheme 6.The oxidative dimerization of alkyl and aryl thioamides 16 was achieved in the presence of I2 as a catalyst, hexadecyltrimethyl ammonium chloride (HTAC) as a phase transfer catalyst (PTC) and con.H2SO4 as a regenerative agent.The substituted thiomide underwent transformation into the substituted 1,2,4-thiadiazoles 17 in excellent yields via intramolecular oxidative coupling of N-H and N-S bonds.The lowest 35% yield indicated that the electron-withdrawing substituent on the benzene ring of benzothioamide failed to undergo the dimerization reaction compared with the electrodonating substituents [258].

Transition-Metal-Free Green Protocol Using Air as Oxidant
A novel and green approach was developed by Yang et al. with a broad substrate scope, mild reaction conditions, good functional group tolerance and high regioselectivity to construct the S-N bond of a 1,2,4-thiadiazole core via oxidative coupling.In this metalfree and gram-scale synthetic strategy, substituted amidines 18 and substituted isothiocyanates 19 were treated for the construction of the S-N bond via I2 mediated oxidative coupling to produce 5-amino-1,2,4-thiadiazole derivatives 20 in the presence of TMEDA (N,N,N′,N′-tetramethyl ethylene diamine), air (oxidant) and acetonitrile as the solvent.In this synthetic pathway, 1,2,4-thiadiazoles were afforded in moderate-to-excellent yields (Scheme 7) [259].

Solid-Solid Oxidative Coupling
Hassan Zali Boeini reported a novel, rapid, simple and efficient protocol for the conversion of the equimolar amount, pulverized thiobenzamide 21 and N-bezyl-DABCOtribromide in wet solid-solid conditions to produce 1,2,4-thiadiazoles 22 in excellent yields compared with conventional methods (Scheme 8).In this green method, intramolecular oxidative coupling and efficient cyclization constructed the aryl-substituted 1,2,4-thiadiazoles.This short-term, ambient temperature and high yield are the key features of this environmentally benign approach compared with the conventional synthetic approach of 1,2,4-thiadiazoles [260].
version of the equimolar amount, pulverized thiobenzamide 21 and N-bezyl-DABCO-tribromide in wet solid-solid conditions to produce 1,2,4-thiadiazoles 22 in excellent yields compared with conventional methods (Scheme 8).In this green method, intramolecular oxidative coupling and efficient cyclization constructed the aryl-substituted 1,2,4-thiadiazoles.This short-term, ambient temperature and high yield are the key features of this environmentally benign approach compared with the conventional synthetic approach of 1,2,4-thiadiazoles [260].
bromide in wet solid-solid conditions to produce 1,2,4-thiadiazoles 22 in excellent yields compared with conventional methods (Scheme 8).In this green method, intramolecular oxidative coupling and efficient cyclization constructed the aryl-substituted 1,2,4-thiadiazoles.This short-term, ambient temperature and high yield are the key features of this environmentally benign approach compared with the conventional synthetic approach of 1,2,4-thiadiazoles [260].

Basic Alumina Catalyst for Synthesis of Substituted 1,2,4-Thiadiazoles via Grinding Approach
Xu et al. developed a solvent-free, environmentally benign synthetic approach to synthesize 3,5-disubstituted-1,2,4-thiadiazole structural hybrids 30 in excellent yields (90-99%) through the reaction of substituted thiomide 28 with NBS 29 in the presence of basic alumina and grinding this reaction mixture for 5-15 min at room temperature as shown in Scheme 11.This synthetic protocol displayed advantages over existing strategies to access substituted 1,2,4-thiadiazoles in terms of efficiency, higher yields, short duration of reaction time and neat conditions.This facile and highly efficient methodology showed Scheme 10. Green synthesis of substituted diaryl-1,2,4-thiadiazoles 27.

Basic Alumina Catalyst for Synthesis of Substituted 1,2,4-Thiadiazoles via Grinding Approach
Xu et al. developed a solvent-free, environmentally benign synthetic approach to synthesize 3,5-disubstituted-1,2,4-thiadiazole structural hybrids 30 in excellent yields (90-99%) through the reaction of substituted thiomide 28 with NBS 29 in the presence of basic alumina and grinding this reaction mixture for 5-15 min at room temperature as shown in Scheme 11.This synthetic protocol displayed advantages over existing strategies to access substituted 1,2,4-thiadiazoles in terms of efficiency, higher yields, short duration of reaction time and neat conditions.This facile and highly efficient methodology showed compatibility with variety of functional groups such as the trifluoromethyl, methyl, methoxy, chloro, pyridyl and thienyl groups [263].

Basic Alumina Catalyst for Synthesis of Substituted 1,2,4-Thiadiazoles via Grinding Approach
Xu et al. developed a solvent-free, environmentally benign synthetic approach to synthesize 3,5-disubstituted-1,2,4-thiadiazole structural hybrids 30 in excellent yields (90-99%) through the reaction of substituted thiomide 28 with NBS 29 in the presence of basic alumina and grinding this reaction mixture for 5-15 min at room temperature as shown in Scheme 11.This synthetic protocol displayed advantages over existing strategies to access substituted 1,2,4-thiadiazoles in terms of efficiency, higher yields, short duration of reaction time and neat conditions.This facile and highly efficient methodology showed compatibility with variety of functional groups such as the trifluoromethyl, methyl, methoxy, chloro, pyridyl and thienyl groups [263].
5.12.Synthesis of 1,2,4-Thiadiazole-5-Carboxylates by Microwave-Assisted Approach Fordyce et al. generated the substituted ethyl 1,2,4-thiadiazole-5-carboxylate scaffolds 33 by the cycloaddition of 0.56 molar oxathiazolone 31 with 0.5 molar ethyl cyanoformate (ECF) 32 in the presence of p-xylene solvent under microwave-assisted heating at 160 • C for 10 min as represented in Scheme 12.The solvent and excessive ethyl cyanoformate were removed under reduced pressure, and residue was subjected to purification and spectroscopic characterizations.The merits of microwave-assisted green synthetic methodology were the shorter reaction time and easy work-up to produce ethyl-1,2,4-thiadiazole-5-carboxylate products in moderate-to-good yields [264].

Basic Alumina Catalyst for Synthesis of Substituted 1,2,4-Thiadiazoles via Grinding Approach
Xu et al. developed a solvent-free, environmentally benign synthetic approach to synthesize 3,5-disubstituted-1,2,4-thiadiazole structural hybrids 30 in excellent yields (90-99%) through the reaction of substituted thiomide 28 with NBS 29 in the presence of basic alumina and grinding this reaction mixture for 5-15 min at room temperature as shown in Scheme 11.This synthetic protocol displayed advantages over existing strategies to access substituted 1,2,4-thiadiazoles in terms of efficiency, higher yields, short duration of reaction time and neat conditions.This facile and highly efficient methodology showed compatibility with variety of functional groups such as the trifluoromethyl, methyl, methoxy, chloro, pyridyl and thienyl groups [263].

Synthesis of 1,2,4-Thiadiazole-5-Carboxylates by Microwave-Assisted Approach
Fordyce et al. generated the substituted ethyl 1,2,4-thiadiazole-5-carboxylate scaffolds 33 by the cycloaddition of 0.56 molar oxathiazolone 31 with 0.5 molar ethyl cyanoformate (ECF) 32 in the presence of p-xylene solvent under microwave-assisted heating at 160 °C for 10 min as represented in Scheme 12.The solvent and excessive ethyl cyanoformate were removed under reduced pressure, and residue was subjected to purification and spectroscopic characterizations.The merits of microwave-assisted green synthetic methodology were the shorter reaction time and easy work-up to produce ethyl-1,2,4-thiadiazole-5-carboxylate products in moderate-to-good yields [264].

Green Synthesis of 1,2,4-Thiadiazole via Ionic Liquids
Zali-Boeini et al. reported the synthesis of a new facile and efficient environmentally friendly methodology to afford 3,5-disubstituted-1,2,4-thiadiazole by using pentyl pyridinium tribromide ionic liquids as the solvents, as well as reagent to carry out the oxidative dimerization of aryl thiomide.An equimolar mixture of arythiomide and pentylpyridinium tribromide ionic liquids was mixed together and stirred for 3-7 min at ambient temperature to obtain substituted 1,2,4-thiadiazole structural motifs in excellent yields.The recyclable pentylpyridinium tribromide compound, named room-temperature ionic liquids (RTILs), can be used 4-5 times to carry out oxidative dimerization.This synthetic approach is smooth, rapid, clean and environmentally benign and achieved products in 88-97% yield (Scheme 13) [265].
tive dimerization of aryl thiomide.An equimolar mixture of arythiomide and pentylpyridinium tribromide ionic liquids was mixed together and stirred for 3-7 min at ambient temperature to obtain substituted 1,2,4-thiadiazole structural motifs in excellent yields.The recyclable pentylpyridinium tribromide compound, named room-temperature ionic liquids (RTILs), can be used 4-5 times to carry out oxidative dimerization.This synthetic approach is smooth, rapid, clean and environmentally benign and achieved products in 88-97% yield (Scheme 13) [265].
idinium tribromide ionic liquids was mixed together and stirred for 3-7 min at ambient temperature to obtain substituted 1,2,4-thiadiazole structural motifs in excellent yields.The recyclable pentylpyridinium tribromide compound, named room-temperature ionic liquids (RTILs), can be used 4-5 times to carry out oxidative dimerization.This synthetic approach is smooth, rapid, clean and environmentally benign and achieved products in 88-97% yield (Scheme 13) [265].

Oxidative Dimerization of Thioamides by Using Oxone as Safe Oxidant
Yoshimura et al. selected the ecofriendly, inexpensive, safe and readily available oxone as an oxidative dimerization agent.They developed an efficient, novel synthetic protocol to furnish 1,2,4-thiadiazole 17 structural motifs in good-to-excellent yields through the treatment of substituted thioamide 16 with oxone as oxidant in the presence of DCM at ambient temperature, as displayed in Scheme 15.In the present synthetic protocol, both the EW and ED substituents furnished 1,2,4-thiadiazoles in good yields, which is the main advantage of this green strategy [267].

Molecular I 2 as Catalyst for Synthesis of 1,2,4-Thiadiazoles via Oxidative N-S Bond Formation
Jatangi et al. reported a facile, efficient, environmentally benign and convenient synthetic approach for the synthesis of 3-substituted 5-amino-1,2,4-thiadiazole scaffolds in a scalable fashion.In this metal-free and high-substrate-tolerance methodology, the reaction of substituted isothiocynates 29 and substituted amidoximes 38 was carried out at 60 • C in the presence of I 2 , with potassium carbonate and water as green solvents, to afford substituted 1,2,4-thiadiazole derivatives 39 in good-to-high yields, as depicted in Scheme 16 [268].
Yoshimura et al. selected the ecofriendly, inexpensive, safe and readily available oxone as an oxidative dimerization agent.They developed an efficient, novel synthetic protocol to furnish 1,2,4-thiadiazole 17 structural motifs in good-to-excellent yields through the treatment of substituted thioamide 16 with oxone as oxidant in the presence of DCM at ambient temperature, as displayed in Scheme 15.In the present synthetic protocol, both the EW and ED substituents furnished 1,2,4-thiadiazoles in good yields, which is the main advantage of this green strategy [267].

Molecular I2 as Catalyst for Synthesis of 1,2,4-Thiadiazoles via Oxidative N-S Bond Formation
Jatangi et al. reported a facile, efficient, environmentally benign and convenient synthetic approach for the synthesis of 3-substituted 5-amino-1,2,4-thiadiazole scaffolds in a scalable fashion.In this metal-free and high-substrate-tolerance methodology, the reaction of substituted isothiocynates 29 and substituted amidoximes 38 was carried out at 60 °C in the presence of I2, with potassium carbonate and water as green solvents, to afford substituted 1,2,4-thiadiazole derivatives 39 in good-to-high yields, as depicted in Scheme 16 [268].

Molecular I2 as Catalyst for Synthesis of 1,2,4-Thiadiazoles via Oxidative N-S Bond Formation
Jatangi et al. reported a facile, efficient, environmentally benign and convenient synthetic approach for the synthesis of 3-substituted 5-amino-1,2,4-thiadiazole scaffolds in a scalable fashion.In this metal-free and high-substrate-tolerance methodology, the reaction of substituted isothiocynates 29 and substituted amidoximes 38 was carried out at 60 °C in the presence of I2, with potassium carbonate and water as green solvents, to afford substituted 1,2,4-thiadiazole derivatives 39 in good-to-high yields, as depicted in Scheme 16 [268].

H2O2-Catalyzed Synthesis of 1,2,4-Thiadiazoles
Cao et al. reported the hydrogen-peroxide-mediated synthetic transformations of substituted thiourea 4 into 1,2,4-thiadiazoles 5 through the construction of the N-S Bond under metal-free synthetic conditions with ethanol as the sole solvent at ambient temperature as shown in Scheme 18.The advantages of this synthetic strategy are large-scale preparation, operationally simple, ethanol as the green solvent and clean by-products.1,2,4-thiadiazole structural hybrids were obtained in good-to-excellent yields [270].

H 2 O 2 -Catalyzed Synthesis of 1,2,4-Thiadiazoles
Cao et al. reported the hydrogen-peroxide-mediated synthetic transformations of substituted thiourea 4 into 1,2,4-thiadiazoles 5 through the construction of the N-S Bond under metal-free synthetic conditions with ethanol as the sole solvent at ambient temperature as shown in Scheme 18.The advantages of this synthetic strategy are large-scale preparation, operationally simple, ethanol as the green solvent and clean by-products.1,2,4-thiadiazole structural hybrids were obtained in good-to-excellent yields [270].

H2O2-Catalyzed Synthesis of 1,2,4-Thiadiazoles
Cao et al. reported the hydrogen-peroxide-mediated synthetic transformations of substituted thiourea 4 into 1,2,4-thiadiazoles 5 through the construction of the N-S Bond under metal-free synthetic conditions with ethanol as the sole solvent at ambient temperature as shown in Scheme 18.The advantages of this synthetic strategy are large-scale preparation, operationally simple, ethanol as the green solvent and clean by-products.1,2,4-thiadiazole structural hybrids were obtained in good-to-excellent yields [270].

Conclusions
Advances in green synthetic organic chemistry may result in a more ecofriendly future with the help of green technologies, processes and synthetic reaction conditions, such as green solvents, green catalysts, solvent-free and less energy-consuming strategies and microwave-and ultrasonic-assisted approaches that transform reactants into products with sustainability.The chemical industrial sector and academic research mostly rely on hazardous catalysis and solvents.Therefore, alternative green solvents and green catalysis are the future of our ecosystem in reducing or even eliminating these hazardous materials' effects on the environment and can lead to the optimized yield of products in a shorter period of time, in accordance with all 12 principles of green chemistry.In this plethora of research, various green catalytic approaches have been applied to furnish different 1,2,4thiadiazole structural hybrids in good-to-excellent yields by utilizing various green solvents, solvent-free procedures, ionic liquid approaches, grinding and chemo-mechanical protocols, microwave-and ultrasonic-assisted time reduction techniques.We think that the next decade will be a major mark of applying green and sustainable catalysis methodologies to promote organic transformations in academia and industry alike.

Conclusions
Advances in green synthetic organic chemistry may result in a more ecofriendly future with the help of green technologies, processes and synthetic reaction conditions, such as green solvents, green catalysts, solvent-free and less energy-consuming strategies and microwave-and ultrasonic-assisted approaches that transform reactants into products with sustainability.The chemical industrial sector and academic research mostly rely on hazardous catalysis and solvents.Therefore, alternative green solvents and green catalysis are the future of our ecosystem in reducing or even eliminating these hazardous materials' effects on the environment and can lead to the optimized yield of products in a shorter period of time, in accordance with all 12 principles of green chemistry.In this plethora of research, various green catalytic approaches have been applied to furnish different 1,2,4-thiadiazole structural hybrids in good-to-excellent yields by utilizing various green solvents, solvent-free procedures, ionic liquid approaches, grinding and chemo-mechanical protocols, microwave-and ultrasonic-assisted time reduction techniques.We think that the next decade will be a major mark of applying green and sustainable catalysis methodologies to promote organic transformations in academia and industry alike.

Figure 1 .
Figure 1.Twelve principles of green chemistry.

Figure 1 .
Figure 1.Twelve principles of green chemistry.

Figure 2 .
Figure 2. Green approaches and their advantages over conventional approaches.

Figure 2 .
Figure 2. Green approaches and their advantages over conventional approaches.

Figure 3 .
Figure 3. Characteristics of ideal green synthetic approach.

Figure 3 .
Figure 3. Characteristics of ideal green synthetic approach.

& Advantages Over Conventional Approaches Ultrasonic-assisted Approach Microwave-assisted Approach Ball Milling Approach Use of green solvents Use of green catalysts Reduction of reaction time Good to excellent yields Energy reduction MOF Green Synthesis Approach Electrochemical Green Approach Figure 2.
Green approaches and their advantages over conventional approaches.

Table 1 .
Types of catalysts used in green organic synthesis.

Table 2 .
Green solvents in organic synthesis.