Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis of Bioactive Heterocycles

*Biplob Borah and L. Raju Chowhan*

#### **Abstract**

Considering the great prevalence of heterocyclic compounds in the core structure of numerous natural products, synthetic drug candidates, active pharmaceutical ingredients, and also in optoelectronic materials; tremendous efforts have been dedicated toward their synthesis and functionalization. But, the exploitation of hazardous, volatile organic solvents and toxic reagents caused disadvantageous effects on the atom economy and eco-friendly nature of the chemical transformation. Therefore, developing chemical processes providing easy access to complex target molecules by avoiding the utilization of hazardous solvents and reagents for making our environment toxic-free is of increasing significance for chemists in both academia and industry. The synergic combination of the features of mechanochemical activation as alternative energy input with the efficiency associated with small organic molecules that can catalyze chemical reactions is predominantly relevant to fulfill the goal of green and sustainable chemistry. This chapter is dedicated to providing a critical overview on the application of mechanochemical techniques for the synthesis of five- and six-membered heterocycles, as well as complex-fused heterocycles and spiro-heterocycles under organocatalytic conditions.

**Keywords:** mechanochemistry, bioactive heterocycles, organocatalysis, ball-milling, grinding method

#### **1. Introduction**

Heterocyclic compounds comprise a broad range of structural motifs ubiquitously found in the architecture of numerous natural products and active pharmaceutical ingredients [1–3]. They are frequently existed in the markedly available drug candidates, fine chemicals and play a fundamental role in medicinal chemistry as a consequence of their outstanding biological activities, such as anticancer, antibacterial, anti-HIV, antidiabetic, antimalarial [4–8]. Furthermore, they are considered as significant fragments in many optoelectronic materials, such as laser dyes, fluorescent whiteners, organic light-emitting diodes (OLEDs), polymers, optical recording,

organic solar cells, organic semiconductors, fluorescent probes, fluorescent activity, and sensitizers for dye-sensitized solar cells [9–12].

Owing to these above-mentioned properties and broad chemical landscape, the construction and functionalization of molecules featuring heterocyclic framework as the key ingredients have attracted much more attention in synthetic organic chemistry [13–17]. However, the utilization of volatile organic solvents in a chemical process often results in the formation of chemical waste on both laboratory and industrial scales. This chemical waste was supposed to be one of the main sources of environmental pollution. Therefore, the design and development of a synthetic chemical route that leads to the expedient and rapid synthesis of diverse and highly functionalized heterocyclic scaffolds by avoiding or reducing the utilization of volatile organic solvents, toxic reagents, and hazardous chemicals to make our environment green and sustainable is highly desired and has emerged as a key challenge of modern synthetic organic chemistry. Furthermore, exploitation of energy in a chemical process either for heating or for cooling leads to an undesirable effect on the living environment.

To address many of these problems, mechanochemical methods, including ballmilling and grinding *via* a mortar and pestle have recently received a considerable and steadily increasing interest that has proved to be an excellent alternative and highly feasible environmentally benign energy inputs for organic synthesis. Concurrent to ultrasonic sonochemistry, solar light- and microwave-assisted chemistry, the introduction of mechanochemistry as an attractive and eco-friendly activation method has made rapid strides to be considered as the method of choice for organic synthesis, as it avoids the use of hazardous solvents and is less energy-consuming. The mechanical energy produced by grinding or milling of two solids or a solid and a liquid material breaks the order of the crystalline structure and makes close contact between the starting materials on a molecular scale, thereby producing the desired products. Mechanochemistry allows chemical transformation to be carried out in solvent-free conditions and makes them energy efficient by reducing high-temperature conditions to ambient temperature. Similar to ultrasound- and microwave-assisted organic synthesis, as well as solar light-induced organic synthesis which are associated with not only the enhancements of the reaction rates but also, involves in reducing the reaction times; the avoidance of toxic organic solvents, reduced reaction time, improved safety, less energy consumption, simple workup, and improved yields make mechanochemical method incredibly advantageous economically and ecologically favorable procedure in green chemistry [18–23].

But, again the occurrence of transition-metal-catalyst(s) in chemical processes even at the lowest level communicates the unfavorable effects on the atom economy and sustainability of the transformation. Notwithstanding, transition metal catalyst(s) has been successfully employed in the synthesis of valuable structural building blocks [24–26]; their occurrences in the chemical process caused serious effects because of their highly toxic nature, and the requirements of high cost for the preparation of catalytic system. Apart from these, the removal of transition-metalcatalyst(s) from the chemical transformation which is predominately needed in the pharmaceutical industry is not so easy and as a consequence, there will be high chances for contamination of the final compounds. Interestingly, the development of a synthetic chemical route for the construction of structural scaffolds with high atomand step-economy which utilized alternative materials that are not only environmentally benign but also found to be in large scale in anywhere with minimum cost by reducing or circumventing the exploitation of transition metal catalyst(s), additives, supportive ligands, and toxic reagents to make a pollution-free environment are highly

#### *Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

desired. For this purpose, the application of small organic molecules described as organocatalysts, in organic transformations have provided a new alternative route for the efficient synthesis of complex molecular structure in terms of synthetic efficiency and from the green chemistry viewpoint. The unique ability to accomplish chemical transformation through different activation modes, avoidance of expensive catalysts and metal catalyst(s), high stability, ready availability and easy recoverability, lower activation energy, high efficiency, as well as with an immediate reduction in the toxicity and reaction costs makes organocatalysis a highly advantageous and considerable approach in synthetic organic chemistry [13, 27–30]. These advantages of organocatalysis can contribute to many of the requirements of green and sustainable chemistry.

Considering the versatile applicability of mechanochemical activation in organic synthesis and the significant contribution of organocatalysis in organic transformation, here we provide a critical overview on the organocatalytic expedient synthesis of different types of highly functionalized five- and six-membered heterocycles as well as complex-fused heterocycles and spiro-heterocycles by using mechanochemical techniques, including ball-milling and grinding with mortar and pestle. The mechanochemical activation in organic reactions is well-reviewed by many researchers [19–23, 31–35] and we hope, the present chapter would be helpful for researchers working in these fields.

#### **2. Mechanochemical organocatalytic reactions for the synthesis of five-membered heterocycles**

#### **2.1 Synthesis of five-membered heterocycles containing one-heteroatom**

#### *2.1.1 Synthesis of pyrroles*

The five-membered nitrogen-containing heterocycle, pyrroles and its derivatives are well-established building blocks of many naturally occurring and synthetic drug molecules [13]. The most commonly applied method for the synthesis of pyrroles realizes the Paal-Knorr method that involves the reaction of 1,4-dicarbonyl compounds and primary amines or ammonia.

In 2016, Akelis et al. [36] developed a simple, facile, and highly efficient mechanochemical method for the synthesis of a variety of substituted pyrroles **3** from the reaction of 1,4-dicarbonyl compound **1** and amines **2** utilizing 1 mol% of citric acid as the organocatalyst under ball-milling condition for 15–30 minutes in the absence of solvent (**Figure 1**). This reaction offers the corresponding pyrroles **3** in 08–84% yields and the products were obtained in a very short reaction time. Encouraged by this result, they further extended their methodology for the desymmetrization of amines or to access bis(pyrroles) **6** by using several aryl or aliphatic diamines **4** and 1,4-dicarbonyl compound **1** as the reactants under the same reaction condition. The formation of mono-pyrroles **5** *that is* desymmetrization of amines and bis(pyrroles) **6** depends on the reactant diketones **1** and diamines **4**.

Another ball-milling approach for the synthesis of 3,4-disubstituted pyrroles has been accomplished by Bolm et al. [37] in 2021 (**Figure 2**). Under the influences of organic base DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene), the desired products **9** derived from the reaction of enones **8** with TosMIC (toluenesulfonylmethyl isocyanide) **7** at milling frequency of 35 Hz for 1 hour in solvent-free condition has been obtained in moderate to good yield (34–92% yield). A vast array of

**Figure 1.**

*Synthesis of pyrroles assisted by ball-mill under the organocatalytic condition.*

#### **Figure 2.**

*DBU catalyzed van Leusen pyrrole synthesis under mechanochemical activation.*

electron-withdrawing and electron-donating groups was found to be well worked under this standard condition. The tolerability of a broad functional group, simple operational procedure, short reaction time, is some of the key features of this strategy. *Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

#### *2.1.2 Synthesis of furans*

A simple but highly attractive one-pot procedure for the synthesis of *trans*-2,3-disubstituted 2,3-dihydrofurans in a diastereoselective manner by employing mechanochemical techniques as a powerful green energy source under solvent-free conditions was developed by Chuang and Chen (**Figure 3**) [38]. With the help of piperidine as the organocatalyst, the desired products **13** were accomplished *via* grinding of several 1,3-dicarbonyl compounds **10**, aldehydes **11,** and *N*-phenacyl pyridinium bromides **12** in a mortar and pestle for 1–1.5 hours at room temperature have been achieved in 51–79% yield. This reaction was also possible to carry out in conventional solution conditions, however, the mechanochemical method was found to be very superior in terms of green chemistry point of view and synthetic efficiency. The reaction condition was found to be tolerable to a variety of 1,3-dicarbonyl compounds and also aryl aldehydes comprising different electron-withdrawing and electron-donating substituents.

#### *2.1.3 Synthesis of thiophenes*

The Gewald method which involves the reaction of ketones, α-methylene carbonyl compounds, activated nitriles, and elemental sulfur is a well-established approach for the synthesis of 2-amino thiophenes. In this regard, Mack et al. [39] reported a Gewald reaction of acetophenone **14**, ethyl cyanoacetate **15**, and sulfur **16** under the ball-milling conditions with a stainless-steel ball (1/8th inch) at 18 Hz for the synthesis of thiophenes **17** by using morpholine as the organocatalyst in solvent-free condition at 130°C. By applying this method, a total of six compounds were synthesized in a 14–53% yield. Although solvent-free, as well as metal-free, waste-free short reaction time, makes the advantages of this protocol, however, the low-substrate scopes mark a limitation of this procedure and call for further developments otherwise outstanding developments (**Figure 4**).

#### **2.2 Synthesis of five-membered heterocycles containing two-heteroatoms**

#### *2.2.1 Synthesis of pyrazoles*

As nitrogen-containing heterocycle, pyrazole and their derivatives have a significant role in the field of medicinal chemistry and material sciences. As a consequence, substantial efforts have been dedicated to their synthesis [16]. In line with this, a highly efficient one-pot mechanochemical method for the synthesis of a series of

#### **Figure 3.**

*Secondary amine catalyzed grinding assisted one-pot three-component diastereoselective synthesis of dihydrofurans.*

**Figure 4.**

*Organocatalytic mechanochemical one-pot synthesis of thiophene derivatives.*

sulfur-containing pyrazole derivatives **21** under solvent-free conditions has been developed by Saeed and Channar (**Figure 5**) [40]. With the help of a mortar and pestle, the authors manually ground the readily available 3-chloro-2,4-pentanedione **18**, hydrazine **19**, and thiophenol **20** by using piperidine as the base organocatalyst at room temperature for 10–17 minutes. This three-component reaction afforded the corresponding products **21** in 72–88% yields. Broad functionality, short reaction time, mild reaction condition, metal-free, operational simplicity are some of the salient features of this protocol.

#### *2.2.2 Synthesis of thiazoles*

Edrees, Gomha et al. [41] demonstrated the successful application of mechanochemical techniques in the synthesis of a library of highly functionalized thiazole derivatives bearing pyrazole core in their structure (**Figure 6)**. By using DABCO (1,4-Diazabicyclo[2.2.2]octane) as the catalyst, the treatment of pyrazole-1 carbothioamide **22** with α-haloketones **23** or **26** under grinding with mortar and

*Piperidine catalyzed one-pot three-component grinding assisted synthesis of pyrazoles.*

*Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

#### **Figure 6.**

*Grinding assisted one-pot synthesis of diverse thiazole derivatives bearing pyrazole moiety.*

pestle at room temperature was found to proceed in solvent-free condition to form the desired products **25** and **28** in moderate to good yields, respectively. In both cases, the reaction was completed through the initial formation of intermediate **24** and **27** which undergo cyclization and dehydration to afford the final products. A wide variety of electron-withdrawing and electron-donating substituents present on the aryl ring of the α-haloketones **23** or **26** were found to be well worked under this reaction condition.

A very simple and straightforward grinding-assisted method to access benzofused thiazole derivatives under organocatalytic conditions was disclosed by Agarwal and Gandhi (**Figure 7**) [42]. In this context, they manually grind the readily available 2-aminobenzenethiol **29** and several aldehydes **11** by using urea nitrate as the organocatalyst in solvent-free conditions at room temperature. By applying this operationally simple methodology, a total of six benzo-fused thiazole products **30** were synthesized in excellent yield within a very short reaction time.

#### **Figure 7.** *Grinding-assisted construction of benzo-fused thiazoles under organocatalysis.*

#### *2.2.3 Synthesis of imidazoles*

Rajitha et al. [43] disclosed the utilization of grinding techniques for the condensation reaction of benzo[*c*][1,2,5]thiadiazole-4,5-diamine **31** with different substituted aldehydes **32** under the influences of cellulose sulfuric acid as the organocatalyst in solvent-free condition at room temperature to access a variety of benzo-fused imidazoles **33** in moderate to excellent yield. The reaction was found to be well tolerated for both aryls and heteroaryl-substituted aldehydes. The mild reaction condition, short reaction time, use of recyclable and reusable catalyst, environmentally as well as eco-friendly benign, simple work-up procedure, wide substrate scopes are some of the advantages of this protocol (**Figure 8**).

#### **2.3 Synthesis of five-membered heterocycles containing three-heteroatoms**

#### *2.3.1 Synthesis of oxadiazoles*

Kategaonkar [44] developed an environmentally benign procedure for the construction of oxadiazole derivatives **36** from the condensation reaction of 1*H-*indazole-3-carboxylic acid hydrazide **34** and aromatic acids **35** by applying the high catalytic activity of the cellulose sulfuric acid as the organocatalyst under grinding condition by using a simple mortar and pestle in solvent-free condition at room temperature. The reaction was completed within only 5–10 minutes to afford the desired products **36** in good to excellent yield. To broaden the substrate scopes, a variety of aromatic acids bearing electron-rich and electron-poor substituents on the aryl ring were subjected to 1*H-*indazole-3-carboxylic acid hydrazide under the optimized reaction condition and all are found to be efficiently worked by this mechanochemical reaction (**Figure 9**).

#### *2.3.2 Synthesis of thiadiazoles*

Thiadiazoles are well-established five-membered heterocyclic compounds with three heteroatoms including two nitrogen atoms and one sulfur in their structure. They are known to be an important skeleton in medicinal and synthetic chemistry due to their wide prolific pharmacological profile. Considering their importance, Aziem et al. [45] introduced the grinding process as an eco-friendly and environmentally friendly chemical technology for the organocatalytic synthesis of various 1,3,4-thiadiazole derivatives **39** comprising benzofuran moiety in their structure. With the help of a mortar and pestle, the author's manually ground benzofuran-bearing hydrazinecarbodithioate **37** and hydrazonoyl halides **38** in presence of TEA (triethylamine) as the catalyst under the solvent-free condition at room temperature which eventually

#### **Figure 8.** *Organocatalytic mechanochemical synthesis of benzo-fused imidazoles.*

*Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

**Figure 9.**

*CSA catalyzed rapid access to oxadiazoles 36 by means of mechanochemical activation.*

**Figure 10.**

*Tertiary amine catalyzed grinding assisted synthesis of thiadiazoles comprising benzofuran moiety.*

leads to the formation of the desired products **39** in moderate to excellent yield within a very short reaction time (**Figure 10a**). Enlightened by this result, they extended their protocol to synthesize another type of thiadiazole derivatives containing chromone moiety in their structure. The same reaction condition was found to be tolerable to hydrazine-carbodithioate of type **40** and hydrazonoyl halides **38** to deliver the corresponding 1,3,4-thiadiazole derivatives **41** in good yields (**Figure 10b**).

#### **3. Mechanochemical organocatalytic reactions for the synthesis of six-membered heterocycles**

#### **3.1 Synthesis of six-membered heterocycles containing one-heteroatom**

#### *3.1.1 Synthesis of pyridines*

Synthesis of a vast array of 1,4-dihydropyridine derivatives under mechanochemical activation has been achieved by Sarada et al. [46]. With the help of a

mortar and pestle, grinding of readily available aldehydes **11**, 2 equivalent of ethyl acetoacetate **42**, and ammonium acetate **43** in presence of 20 mol% of chlorosulfonic acid (CSA) as the organocatalyst under the solvent-free condition at room temperature results in the formation of the corresponding products **44** in moderate to good yields within a very short reaction time. A wide variety of aliphatic and substituted aryl aldehydes were found to be well tolerated by this methodology (**Figure 11a**). Similar to this, the application of ball-milling techniques as an alternative energy input for the one-pot synthesis of 1,4-dihydropyridines was demonstrated by Ghafuri et al. [47]. By using imidazole dicarboxylic acid (IDCA) as the organocatalyst, the desired products **46**, derived from several substituted aldehydes **11**, β-ketoesters **45**, and ammonium acetate **43** were obtained in good to excellent yield under solvent-free conditions. Short reaction time, energy efficiency, mild reaction conditions are some of the advantages of this protocol (**Figure 11b**).

#### *3.1.2 Synthesis of quinolines*

A highly efficient and environmentally benign approach for the synthesis of polysubstituted quinolines *via* Friedländer reaction under ball-milling conditions was developed by Javanshir et al. [48]. For this purpose, authors performed a solvent-free two-component reaction of 2-aminoaryl ketones **47** and a variety of active methylene compounds **48** under the influences of 30 mol% of *p*-TSA (*p*-toluene sulfonic acid). Initial optimization for the reaction condition of this reaction in presence of different catalytic systems, such as chitosan, cyanuric chloride, *p*-TSA, MCM-41 suggested the utilization of *p*-TSA as the best catalytic system under solvent-free conditions. A total of twelve quinoline products **49** were synthesized in poor to excellent yield by this method within a very few minutes (**Figure 12**).

#### **Figure 11.**

*One-pot mechanochemical synthesis of 1,4-dihydropyridines under organocatalysis.*

*Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

**Figure 12.** *Organocatalytic mechanochemical assisted synthesis of quinolines.*

#### *3.1.3 Synthesis of pyrans*

The synthesis of 4*H*-Pyran core and their derivatives have attracted tremendous attention over the last decades due to their great prevalence in natural product chemistry, and medicinal chemistry [49]. To develop a rapid, facile, and simple method inconsistent with the green chemistry principle, the group of Naimi-Jamal [50] introduced ball-milling techniques in combination with the organocatalytic system as a perfect chemical process for the synthesis of a vast array of 2-amino-4*H*-pyrans. The synthesis involves the one-pot three-component reaction of aldehydes **50**, malononitrile **51**, and ethyl acetoacetate **42** in presence of piperazine as the organocatalyst under the ball-milling condition at frequency 20 Hz–25 Hz for 20–90 minutes. Noticeably, the reaction was carried out at room temperature in absence of solvent, and the corresponding products **52** were achieved in good to excellent yields (**Figure 13a**). Subsequent to this report, Dekamin and Eslami [51] disclosed the utilization of potassium phthalimide (POPI) as the metal-free organocatalyst for the mechanochemical one-pot three-component synthesis of 2-amino-4*H*-pyrans from the reaction of aldehydes **50**, malononitrile **51**, and ethyl acetoacetate **42** under the solvent-free condition at ambient temperature. The reaction required only 5 mol% of catalyst to efficiently form the desired products **52** in 90–98% yields (**Figure 13b**).

#### **3.2 Synthesis of six-membered heterocycles containing two-heteroatoms**

#### *3.2.1 Synthesis of quinoxalines*

Cellulose sulfuric acid was applied as an efficient metal-free organocatalytic system for the solid-state construction of highly functionalized quinoxaline derivatives by Rajitha et al. (**Figure 14**) [52]. By using a mortar and pestle, grinding of substituted 3-bromoacetyl coumarins **53** and thiadiazole-substituted diamine **31** under the

**Figure 13.**

*Organocatalytic three-component synthesis of 4H-pyrans under ball-milling condition.*

**Figure 14.** *Cellulose sulfuric acid-catalyzed mechanochemical synthesis of quinoxalines.*

solvent-free condition at room temperature for 20–30 minutes results in the formation of coumarin-substituted quinoxaline derivatives **54** in good to excellent yields. Different substitutions by electron-rich and electron-poor groups on the coumarin ring smoothly underwent the reaction and had no detrimental effect on the product yields. Similarly, other types of substituted coumarins **55** were found to be well worked under the same reaction condition to provide the desired product **56** in quantitative yield. Environmentally benign conditions, inexpensive, good yield of the products, exploitation of recyclable and reusable catalysts are some key features of this protocol.

*Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

#### *3.2.2 Synthesis of pyrimidines*

Barman et al. [53] disclosed a metal-free highly convenient one-pot approach under mechanochemistry for the synthesis of 3,4-dihydropyrimidines. With the help of a mortar and pestle, the author's grind substituted 1,3-diketones **10**, aldehydes **11**, and urea or thiourea **57** under the influences of L-tyrosine as the organocatalyst in solvent-free condition at room temperature which eventually led to the desired products **58** in 81–91% yields. Initially, the reaction was performed in presence of different catalytic systems, such as L-proline, glycine, L-serine, L-tyrosine, camphorsulphonic acid, and different reaction mediums, such as ethanol, microwave, solvent-free; among them, the solvent-free grinding method using L-tyrosine as the catalyst was found to be the best condition for this reaction. Not only the aryl aldehydes possessing different electron-poor and electron-rich groups but also heteroaryl aldehydes were efficiently underwent the reaction under this condition (**Figure 15**).

#### *3.2.3 Synthesis of quinazolinones*

Quinazolinones and their derivatives are well-established heterocycles commonly encountered in many natural products and synthetic drug candidates. To realize their importance, a rapid mechanochemical assisted one-pot methodology for the synthesis of diverse quinazolinone derivatives has been developed by Shingare et al. (**Figure 16**) [54]. By introducing 10 mol% of vitamin B1, also known as thiamine hydrochloride as the organocatalyst, the solid-state treatment of anthranilic acid **59**, triethyl orthoformate **60**, and various amines **61** under the grinding condition at room temperature afforded the corresponding quinazolinone products **62** in good to excellent yields. A wide variety of aryl amines bearing electron-withdrawing as well as electron-donating substituents smoothly worked well by this environmentally benign protocol. The effectiveness of the methodology was demonstrated by recycling and reusing the catalyst up to five consecutive reactions without affecting the significant outcome of the protocol.

Another achievement for the synthesis of different types of quinazolinones **64** and **66** has been accomplished by Saha et al. [55] by employing ball-milling techniques as an environmentally benign energy source (**Figure 17**). With the help of 10 mol% of *p*-TSA (*p*-toluene sulfonic acid) as the Brønsted acid catalyst, the solvent-free reaction of anthranilamide **63** and aldehydes **11** under mechanochemical grinding conditions delivers the corresponding quinazolinone products **64** in moderate to excellent yield within 3–15 minutes. While the reaction of anthranilamide **63** with

#### **Figure 15.**

*L-tyrosine catalyzed three-component synthesis of 3,4-dihydropyrimidine.*

#### **Figure 16.**

*Thiamine hydrochloride catalyzed three-component synthesis of 4-(3H)-quinazolinone by grindstone technique.*

#### **Figure 17.**

*p-TSA catalyzed grinding assisted synthesis of diverse quinazolinone derivatives.*

different carbonyl compounds **65** under the same reaction condition afforded the quinazolinone products of type **66** in moderate to excellent yield in only 5 minutes. Broad functional group tolerances, mild reaction conditions, solvent-free, waste-free, metal-free are some of the key advantages of this protocol. The practicality of the protocol was established by performing gram scale synthesis in quantitative yield.

#### **4. Mechanochemical organocatalytic reactions for the synthesis of complex-fused poly-heterocycles**

#### **4.1 Synthesis of indazolo[2,1-b]phthalazine**

An efficient eco- and environmentally friendly approach for the synthesis of complex-fused heterocycle, namely indazolo[2,1-*b*]phthalazine under mechanochemical

*Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

method was developed by Wang et al. (**Figure 18**) [56]. By using 3 mol% of *p*-TSA (*p*-toluene sulfonic acid) as the catalyst, the three-component grinding-assisted reaction between phthalhydrazide **67**, dimedone **68**, and aldehydes **50** was found to proceed under the solvent-free condition at room temperature to deliver the desired products **69** in 83–92% yields. The utilization of grinding as a green energy source, metal-free, simple work-up procedure, mild reaction condition, low catalyst loading, broad functionality is some of the salient features of this protocol.

#### **4.2 Synthesis of naphtho[2,3-b]thiophenes**

A domino one-pot mechanochemical route toward the synthesis of naphtho-fused thiophene heterocycle was developed by the research group of Singh (**Figure 19**) [57]. By utilizing DMAP (4-Dimethylaminopyridine) as the metal-free catalyst, the oxidative [3 + 2] heteroannulation of 1,4-naphthoquinone **70** and α-enolicdithioesters/βoxothioamides **71** under mechanochemical grinding with a mortar and pestle in solvent-free condition at room temperature afforded the corresponding naphtho[2,3-*b*] thiophene products **72** in moderate to excellent yield within a very short reaction time. It is interesting to note that, this reaction does not require any co-catalyst and an activator which marks the advantages of this protocol. To broaden the substrate scopes, a variety

**Figure 18.**

*Brønsted acid-catalyzed three-component one-pot synthesis of indazolo[2,1-b]phthalazine by grinding method.*

#### **Figure 19.**

*DMAP catalyzed grinding assisted domino thienannulation to access naphtho[2,3-b]thiophenes.*

of aryl, as well as heteroaryl-substituted α-enolicdithioesters/β-oxothioamides, was subjected to the reaction under the optimized condition and all are found to be efficiently compatible by this method.

#### **4.3 Synthesis of pyrano[4,3-b]pyrans**

Khaligh et al. [58] demonstrated the successful application of ball-milling techniques in the multicomponent reaction of substituted aldehydes **50**, malononitrile **51**, and 4-hydroxy-6-methyl-2-pyrone **73** in presence of 10 mol% of 1,4-piperazinediethanesulfonic acid (PIPES) as the organocatalyst under solvent-free condition (**Figure 20**). This reaction offers a library of pyrano[4,3-*b*]pyran derivatives **74** in good to excellent yield after 30 minutes. The electronic effects of the substitution by different electronwithdrawing as well as electron-donating substituents on the aryl ring of aldehydes were examined and all are found to be well tolerated by these reaction conditions.

#### **4.4 Synthesis of pyrano[2,3-c]pyrazoles**

A grinding assisted one-pot multicomponent approach for the rapid construction of pyrano[2,3-*c*]pyrazoles from the four-component reaction of aldehydes **50**, malononitrile **51**, acetylene dicarboxylate **75**, and hydrazine hydrate **76** in presence of L-proline as the organocatalyst in solvent-free condition was developed by Padmini et al. (**Figure 21**) [59]. Noticeably, only 10 mol% of L-proline was found to be effective for catalyzing this reaction and a total of 13 compounds were synthesized in moderate to good yield. Not only the aryl aldehydes possessing various electronic groups on different positions but also heteroaryl aldehydes smoothly undergo this reaction. The operational simplicity, mild, green reaction medium, short reaction time, and wide-substrate scopes are some key features of this approach.

#### **4.5 Synthesis of triazolo[1,5-a]pyrimidine**

Khaligh and Mihankhah [60] reported the exploitation of ball-milling techniques as a powerful alternative energy source in the three-component reaction of amino-substituted triazoles **78**, aldehydes **50**, and ethyl cyanoacetate **15** by using poly-melamine-formaldehyde (mPMF) as the nitrogen-rich porous organocatalyst under the solvent-free condition at room temperature. This solid-state reaction provides a library of triazolo[1,5-*a*]pyrimidines **79** in moderate to excellent yield after

*Mechanochemical one-pot three-component organocatalytic synthesis of pyrano[4,3-b]pyrans.*

*Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

**Figure 21.**

*L-proline catalyzed grinding assisted multicomponent synthesis of pyrano[2,3-c]pyrazoles.*

*Poly-melamine-formaldehyde catalyzed three-component mechanochemical synthesis of triazolo[1,5-a] pyrimidine.*

90 minutes (**Figure 22**). The catalyst was found to be very effective for this reaction that could be easily recycled and reused for the next consecutive reaction without altering the reactivity and selectivity of the product. The easy work-up procedure, green reaction condition, low cost, wide abundance of the substrate scope are some advantages of this mechanochemical process.

#### **5. Mechanochemical organocatalytic reactions for the synthesis of complex spiro-heterocycles**

In the last few decades, the field of synthetic organic chemistry has witnessed outstanding developments in the synthesis of spiro-heterocycles especially spirooxindoles due to their outstanding reactivity and prolific pharmacological activity as well as their utilization as important building blocks for the synthesis of natural products types molecules as well as medicinally privileged heterocycles [61, 62].

Considering their importance in accordance with the significant application of mechanochemistry in synthetic organic chemistry, the research group of Bazgir [63] synthesized a series of spiro[diindenopyridine-indoline]triones **82** from the threecomponent reaction of various amines **61**, 2 equivalent of 1,3-indandione **80** and substituted isatins **81** by using *p*-TSA (*p*-toluene sulfonic acid) as the Brønsted acid catalyst under grinding and solvent-free condition (**Figure 23**). A total of 20 compounds were synthesized in 80–91% yield within 3–4 minutes at room temperature. Similarly, treating amines **61** and 1,3-indandione **80** with acenaphthylene-1,2-dione **83** by replacing isatins was found to proceed under the same reaction condition to

**Figure 23.** *Brønsted acid-catalyzed multicomponent synthesis of diverse spiro-heterocycles by means of grindstone technique.*

afford the desired spiro[acenaphthylene-diindenopyridine]trione products **84** in 82–89% yields.

#### **6. Conclusion**

The frequent occurrence of heterocyclic compounds in natural, pharmaceutical, and synthetic optoelectronic materials, demands efficient methodology for their construction and selective functionalization by using them as key building blocks. But, the involvement of toxic solvents which are associated with chemical pollution often results in environmental safety concerns. Therefore, developing an alternative method to carry out organic synthesis by avoiding or minimizing the utilization of volatile organic solvents and toxic reagents by introducing environmentally benign conditions with the main focus to reduce the cost-effectiveness of the chemical transformation is highly desired. From the above observation, it is clear to conclude that the utilization of mechanochemical techniques allows all the reactions to be carried out in absence of volatile organic solvents, hazardous reagents and make them environmentally as well as eco-friendly benign. The mechanochemical techniques are found to be very efficient as compared to traditional stirring conditions from the perspective of synthetic as well as green chemistry points of view. The attractive benefits associated with mechanochemistry as a powerful alternative green energy source lead to a new frontier in the synthesis of diverse heterocyclic compounds as well as asymmetric synthesis and hope to consider as a method of choice both at the laboratory as well as in industrial level in near future.

Besides these, the development of organocatalytic reactions under mechanochemistry is set to lead the field of synthetic organic chemistry to a new height. The ability to accomplish reaction under the metal-free organocatalytic condition in the absence

*Mechanochemistry in Organocatalysis: A Green and Sustainable Route toward the Synthesis… DOI: http://dx.doi.org/10.5772/intechopen.102772*

of solvent *via* simple grinding with mortar and pestle or milling can contribute to some of the goals of green and sustainable chemistry and are considered as highly promising routes in the synthesis of diverse and densely functionalized five-membered and sixmembered heterocycles as well as complex-fused heterocycles and spiro-heterocycles.

On the other hand, some serious attention needs to be paid to broadening the substrate scopes, reducing the amount of catalyst, and developing a scalable protocol based on the industrial level.

#### **Acknowledgements**

The author thanks the Central University of Gujarat, Gandhinagar, India, and Prof. Rama Shanker Dubey, Vice-Chancellor, the Central University of Gujarat for the encouragement and continuous support. BB thanks UGC-India for the Non-NET fellowship.

#### **Conflict of interest**

"There are no conflicts to declare."

### **Author details**

Biplob Borah and L. Raju Chowhan\* School of Applied Material Sciences, Centre for Applied Chemistry, Sector-30, Central University of Gujarat, Gandhinagar, India

\*Address all correspondence to: rchowhan@cug.ac.in

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 5**
