Green Catalysts and/or Green Solvents for Sustainable Multi-Component Reactions

Abstract

Here, we describe some well-known multicomponent reactions and the progress made over the past decade to make these processes even more environmentally friendly. We focus on the Mannich, Hantzsch, Biginelli, Ugi, Passerini, Petasis, and Groebke–Blackburn–Bienaymé reactions. After describing the origin of the reactions and their mechanisms, we summarize some advances in terms of the eco-compatibility of these different MCRs. These are followed by examples of some reactions, considered as variants, which are less well documented but which are promising in terms of structures generated or synthetic routes.

1. Introduction

Multi-component reactions, sometimes confused with tandem or domino reactions, are very important in green chemistry, given the diversity of products they can generate.

The multicomponent reaction itself is sustainable, since most of atoms present in the starting substrates are found in the final product [1], but it can also be improved by using green catalysts and/or green solvents. Indeed, this kind of reaction is quite old, dating back to the previous century, but the emergence of combinatorial chemistry in industry during the 1990’s brought it back onto the stage.

The aim of combinatorial chemistry and its various methods is to minimize the time needed to synthesize products of interest in a given core structure, in order to maximize patent exploitation time for pharmaceutical companies for economic purposes. Industries have all turned to these new processes that use mixtures in solution or supported synthesis. This impetus was based on Bruce Merrifield’s work in 1963 about synthesis of supported polypeptides [2]. This type of synthesis is widely used in this field at the industrial level. These reactions have thus emerged as the methodology of choice for making large numbers of compounds with great diversity in a minimum of time, especially as these reactions involve amino, carbonyl (aldehyde, ketone, carboxylic acid) and other commercially available substrates with a wide variety of structures.

The limiting factor at the outset was the small number of isonitriles often involved in these reactions. The availability of isonitriles is no longer an issue, and work on these reactions has moved towards the use of green reagents or solvents to improve durability.

The positive effects of catalysis in terms of improving processes to meet certain principles of green chemistry, as well as action on the solvents used, can speed up the transition to eco-compatible chemistry. Indeed, solvents are the most important constituents in terms of quantity in a chemical reaction, and they account for a large proportion of environmental performance. This is why, in addition to reducing catalyst quantities, the use of less toxic or even recyclable and/or biomass-derived alternatives as reaction solvents can have a significant impact. For this reason, here, we have chosen examples using mainly solvents possibly derived from biomass and not from petroleum.

In this review, we discuss the different criteria that can characterize a multi-component reaction, and we focus on improvements made in recent years in terms of eco-compatibility and increased diversity. A domino reaction involves chemical transformations with the formation of bonds and new functionalities that enable subsequent reactions. The differences between so-called cascade or tandem reactions are not obvious, and it is common to see approximations in naming, although this depends on how the reaction is initiated or how the reactions propagate. However, definitions often vary. Here, the processed reactions are domino-type reactions involving at least three substrates and often more. Moreover, most of the substrates’ atoms are found in the final product [3,4,5].

2. Multi-Component Reactions (MCRs)

Multi-component reactions are processes that approximate to what nature is capable of creating from various compounds in the same pot. They are efficient and selective reactions that can generate complex structures from standard but multifunctional compounds. The mechanisms can be reversible or irreversible and involve both intermolecular and intramolecular reactions. It is noteworthy that intramolecular reactions often generate a degree of stereoselectivity. The most well-known MCRs are the three or four-component Mannich [6,7], Hantzsch [8,9], Biginelli [10,11], Ugi [12,13], Passerini [14,15], Petasis [16], Groebke–Blackburn–Bienaymé [17] reactions. Transition metal catalysts are sometimes used in multicomponent processes to increase reactivity and selectivity, which may be limited in some reactions. In fact, the problems with multi-component reactions are the potential by-products generated if the reaction is not complete. Increasing reactivity therefore guarantees fewer purification problems. Although the use of catalysts does not always guarantee a long-lasting reaction, it is necessary to weigh up the benefit-risk balance, as with drugs. Is it not better to use a few percent of metal catalysts, even those recognized as non-green, than to carry out solvent-intensive purification? Similarly, is it not better to limit the impact of the reaction solvent rather than the catalyst? The main improvement associated with these MCR reactions concerns the atomic savings they provide, both in terms of the reaction itself to obtain elaborated products and the enormous atomic gain due to the absence of intermediate purifications required in conventional multi-step processes previously used to synthesize these target compounds.

In this study, we summarize the currently available literature about the multicomponent reactions we consider the most sustainable. In addition to the best-known MCR reactions, a large number of anonymous MCRs have been developed and reported over the past two or three decades and can be considered variants of the classical MCRs listed above. It is also interesting to note that enantioselective syntheses under environmentally friendly conditions have been developed. Where possible, we mention one such example at the end of each section.

2.1. Mannich 3-MCR

The Mannich reaction, which involves the reaction of an aldehyde derivative, an amine, and a compound with at least one acidic hydrogen, has been used to generate a variety of pharmaceutical products. This three-component reaction takes place under acid catalysis and can produce a wide variety of compounds [7]. The mechanism begins with the condensation of an amine with an enolizable carbonyl compound to form an iminium ion, which represents the electrophilic compound. The iminium reacts with a nucleophile represented by an enolizable ion, leading to the so-called Mannich base (Scheme 1). Lewis acids generally catalyze this reaction, and the search for sustainable processes involves the use of green catalysts. Green catalysts are non-toxic and/or recyclable and/or abundant catalysts that do not exploit or overexploit planetary resources. Similarly, solvents may include water or ionic liquids, with the use of microwave irradiation or ultrasonic irradiation, as well as any solvent that is biodegradable and/or reusable, or the process may even be solvent- and catalyst-free.

An example of this catalyst- and solvent-free methodology is the synthesis of 7-azagramine analogues by the Mannich reaction involving 7-azaindole derivatives in the presence of aromatic aldehydes and heteroaromatic amines [18]. The researchers tested different solvent and catalysts conditions using Lewis or Brönsted acids (p-TSA, FeCl₃, ZnCl₂, HCl and others) for the synthesis of these indole derivatives. Under the different reaction conditions tested, the nature of the catalyst was found to have no significant influence on the expected product yield. Even in the absence of catalyst and solvent, this M3CR afforded 7-azagramine analogues in excellent yields (71–87%) after heating within 3–4 h at 80–85 °C. This represents an interesting process given the therapeutic appeal of indole and azaindole derivatives (Scheme 2). Other Mannich reactions were carried out without a catalyst, implying that the ketone in the reaction mechanism was sometimes sufficiently reactive to undergo nucleophilic attack by the amine without a catalyst being required to increase its electrophilicity [19,20,21,22].

Lewis acid catalysts used to increase the electrophilicity of the carbonyl and to promote enolization of the ketone to generate a good nucleophilic partner include Zinc [23], with solvent-free (Scheme 3a) or ZnO nanoparticles enabling the catalyst to be reused, thus making it greener (Scheme 3b) [24]. Both aqueous and alcoholic media involve the use of InCl₃ (20 mol%). This reaction can take place in water, but is more easily performed with methanol, and possibly ethanol, so the reaction can be carried out overnight with excellent results and can even be diastereoselective, starting from a chiral amine (Scheme 3c) [25,26].

Similarly, other simple catalysts such as iron derivatives (Scheme 4) [27,28,29,30] have been used to increase electrophilicity or promote nucleophilicity of compounds. Here, we focus on the abundant metal iron; in this example, Fe³⁺ acts as a catalyst for imine formation. It also increases carbon’s electrophilicity by complexing the aldehyde and then, the imine. Finally, it catalyzes the ketone enolization step. The results are very interesting, enabling solvent-free products to be obtained with very good yields and optimized reaction times ranging from 10 min to 2 h depending on the reagents used. Other iron (III) salts have also been used.

Organic synthesis using microwave irradiation is now well documented. In addition, ultrasound-assisted organic synthesis to decrease reaction time is beginning to gain a strong following among chemists involved in green processes [31]. Regarding the Mannich MCR reaction, Pelit and Turgut [32] reported that, in solvent-free conditions and in presence of camphorsulfonic acid, naphthoxazines were obtained in good yields (Scheme 5). The various reagents played the role of reagents and solvents for the liquids and allow mobility and interactions of the molecules, whether under microwave irradiation or ultrasound. These reactions can also take place in green solvents.

The first study of the catalytic and enantioselective Mannich reaction performed in aqueous medium, an ideal solvent due to its environmentally friendly nature, was carried out and described by Lu et al. in 2007 [33,34]. The use of a threonine-derived organocatalyst proved effective (Scheme 6). This method was applied to aliphatic as well as aromatic aldehydes and enabled them to obtain β-amino-a-hydroxy-ketones in good yields. However, enantioselectivities varied from moderate to high (68–97% ees). In 2008, Wu et al. described an asymmetric Mannich MCR, again in aqueous media, with a hydrophobic organocatalyst O-silyl-serine. Results obtained with various aldehydes and aromatic amines in the presence of various carbonyl donors led to the expected Mannich products with good enantioselectivities (up to 92% ee) [35].

2.2. Hantzsch MCRs

The Hantzsch reaction [8,9] to generate substituted pyridines takes place between an aldehyde with two β-ketoester equivalents and a reagent bearing the future pyridine nitrogen. This compound can be either ammonia or ammonium acetate for the most common reactions. This reaction yields dihydropyridine, which is oxidizable into pyridine with various oxidants. This MCR allows the use of green solvents such as water or ethanol. It therefore features three substrates, but only one reacts twice during the process; so, it is comparable to a four-component reaction. The mechanism (Scheme 7) begins with an aldolization reaction between the aldehyde and the ketoester, followed by a conjugated Michael addition to the enone. The next step involves addition of the amino derivative to the ketone function, followed by cyclization of this imine or enamine, as appropriate, onto the other ketone. Yields are generally good and the environmental impact is reduced, but here, we can choose another oxidant to be even greener. FeCl₃ is often used to oxidize dihydropyridine to pyridine.

Variants of the Hantzsch MCR

Variations of this reaction using malonitrile instead of the ketoester provide oxidant-free access to pyridines via Knoevenagel condensation, followed by dehydration. An example of this reaction was carried out in a green solvent from biomass and was produced by our team in 2021 [36]. To achieve the synthesis of highly functionalized pyridines, the reaction was performed in eucalyptol [37] with the stoichiometry already reported in the literature [38]. In this case, it turns out that the addition of a catalyst did not improve the yield. Finally, some derivatives were synthesized using benzaldehyde (1 equiv.), pyrrolidine or another amine (2 equiv.), and malonitrile (2 equiv.). The yields were comparable to those described in conventional solvents (Scheme 8) [36].

Another variant was developed in 2017 to synthesize 2,6-diamino-pyran-3,5-dicarbonitriles, via heterogeneous catalysis using benzaldehyde, various malonitriles, and cyanoacetamide (Scheme 9) [39]. In this example, chitosan, an abundant natural polysaccharide, was used in combination with calcium hydroxyapatite to enhance the reactivity [40]. Here, the expected products were obtained in good yields after 30 min of stirring at room temperature. The same authors carried out other studies using less green mixed Cu/ZrO₂, Sm/ZrO₂, or Mn/ZrO₂ catalysts, but chitosan was found to be more efficient, making it an excellent option for easy separation and recyclability.

Due to their low vapor pressure and great resistance to oxidation and reduction, ionic liquids are considered as green solvents. Srivastava et al. [41] used this type of medium for the synthesis of 3,4-dihydropyrano[c]chromene and tetrahydrobenzo[b]pyrans, heterocyclic scaffolds found in many natural products with high therapeutic potential. Here again, multicomponent methods have been reported, including the use of an aldehyde, a malonitrile, and a 1,3-dicarbonyl compound to synthesize pyran derivatives (Scheme 10).

Despite the efforts already made in this field, the search for new methods to synthesize these derivatives from non-toxic products remains necessary. The authors report the use of an ionic liquid as a catalyst due to its low toxicity. In fact, the saccharin-based ionic liquid [Bmim]sac is involved in 3,4-dihydropyrano[c]chromene and tetrahydrobenzo[b]pyran synthesis. After 10 min of stirring at 80 °C, the desired product was obtained with yields ranging from 70 to 95%. In addition, the reusability of the ionic liquid [Bmim]sac was also investigated, and it could be reused 5 times. Indeed, the purity was preserved even if a slight drop in yield was observed. Consequently, this ionic liquid remains a promising tool for large-scale applications.

An example of highly diastereoselective synthesis of optically active 1,4-dihydropyridines DHPs via the multicomponent Hantzsch reaction using chiral C-glycosyl aldehyde was reported by Dondoni et al. [42] (Scheme 11). That study was carried out in view of the presence of a chiral hydroxylated tetrahydrofuran moiety in biologically active natural compounds [43], with methanol as solvent, which could be advantageously replaced by ethanol or even an ethanol/water mixture. The reason why we detail it here is that we believe it to be of great interest. Various furanosyl derivatives were brought into the presence of acetylacetone and enamine ester in this diastereoselective Hantzsch reaction. When it was carried out with (S)- or (R)-proline (10 mol%) as catalyst, C-glyco-DHPs were obtained with excellent diastereoisomeric excess (>95%), although yields were low (47–50%). The results obtained with either proline suggested that the chiral furanosyl reagent and not only the proline catalyst determined the stereochemical selectivity.

2.3. Biginelli MCR

Pietro Biginelli developed the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by condensation reaction between an aromatic aldehyde, urea, and ethyl acetoacetate. The reaction is similar to all long-lasting MCRs and generally takes place in ethanol [44,45]. This provides access to various pyridines and pyrimidines. Therefore, this reaction can give access to numerous potential therapeutic applications. Here again, the initial synthesis conditions were modified in order to improve yields. As a matter of fact, catalyst recyclability and milder conditions have been studied in the literature [46,47]; consequently, Biginelli synthesis has been carried out without solvent [48] and under microwave or ultrasound activation [49,50]. Brønsted or Lewis catalysts have also been studied, notably rare earths. It now seems established that despite the various possible mechanisms considered, the Biginelli reaction is an MCR catalyzed by urea via the formation of iminium (Scheme 12).

Chitra et al. efficiently synthesized antibacterial compounds via a Biginelli MCR in the presence of isopropyl acetoacetate aldehydes and urea or thiourea in ethanol, catalyzed by strontium chloride hexahydrate. Unfortunately, strontium is not very abundant (Scheme 13) [51].

Many examples of Biginelli reactions were mentioned by M. Marinescu [52], including reactions carried out in an alcoholic solvent, using sustainable heating (microwaves or ultrasound) and non-toxic catalysts. M. Marinescu was thus able to demonstrate the varieties of compounds that could be synthesized in an environmentally friendly way.

Rai et al. have developed a diastereoselective Biginelli reaction using a novel methylene substrate and unprotected aldoses. Synthesis can be carried out in a few minutes under microwave irradiation and does not require additional protection and deprotection steps (Scheme 14) [53].

The reaction takes place, solvent-free, in the presence of urea or thiourea and Montmorillonite K-10 nanoclay. The use of deprotected aldoses as aldehydes, in addition to the structure of the scaffold generated, enabled them to increase the water solubility of the synthesized compound. Rai et al. obtained dihydropyrimidines in good yields (76–89%), with a diastereomeric excess of over 92% [53].

2.4. Ugi MCR

The Ugi-4CR reaction, which dates back to 1959, is one of the best-known MCRs. This reaction has been used in the pharmaceutical industry to easily generate a diversified library of compounds for high-throughput bioassays and detection of positive results [1,12,13,54,55,56,57]. In this reaction, an amine, a carbonyl derivative (aldehyde or ketone), a carboxylic acid, and finally, an isocyanide react together to synthesize an α-acetoamidocarboxamide, according to the mechanism described in Scheme 15.

Recently, W. Zhang et al. [58] have documented different variants leading to a very large diversity of molecules. Indeed, different types of acids, carbonyl compounds, and amino derivatives (ranging from amines, hydrazines, and azides to isocyanides) have been used. For this reason, we will not dwell on the most detailed reactions described in the literature. Ugi MCRs are generally carried out in conventional solvents, using conventional catalysts. To our knowledge, no biomass-derived solvents have yet been used. However, many reactions can be carried out in aqueous or alcoholic media with the help of microwave or ultrasonic activation.

While the enantioselective UGI reaction requires the use of chiral catalysts and generally conventional solvent conditions, this is not the case for diastereoselective Ugi reactions, which can be carried out in alcoholic solvents. For diastereoselective U-4CR, the most promising results have been obtained using chiral amines [59,60,61]. Dyker et al. described the synthesis of chiral isoindoles and dihydroisoquinolines [62]. The 5-center, 4-component Ugi reaction (U-5C-4CR) using a chiral amino acid, an alkyne, and an isocyanate afforded the desired Ugi compounds in moderate yields (68–71%) and diastereoselectivities (66–82% des) (Scheme 16). The reaction was carried out in methanol, a solvent that could be advantageously replaced by ethanol or even a more environmentally friendly solvent. The derivative obtained by subsequent reaction with the alkyne moiety led to dihydroisoquinolines by 6-endo-dig cyclization or to isoindoles by 5-exo-dig cyclization under suitable conditions.

2.5. Passerini MCR

The Passerini mechanism is comparable to the one involved in Ugi’s reaction, even though there are only three components, with the same catalysis conditions (Scheme 17). However, variants involving derivatives with carboxylic acid characters are possible; the isocyanide and the carbonyl derivative are identical to those reported by W. Zhang et al. [58]. This MCR reaction, which like the UGI reaction is one of the best-known MCRs, has not, to our knowledge, been carried out in biomass-based solvents. So, we do not describe it further and focus instead on less common MCRs. However, we believe it would be interesting to work in this direction in future research.

Some enantioselective catalytic Passerini-3CR reactions have been carried out, but these require the use of asymmetric catalysts and generally take place in solvents such as dichloromethane, toluene, etc., which does not allow the desired sustainability [63,64,65].

2.6. Petasis MCR

The Petasis MCR, also known as the Petasis Borono–Mannich reaction, involves a carbonyl derivative, an amine, and a boronic acid to lead to substituted amines with good yields, whether catalyzed or not. The reaction is stereoselective and proceeds easily under mild conditions. Moreover, no protection or deprotection step is required. Finally, Lewis acids or metals may also be added to catalyze this reaction [66,67,68]. It is noteworthy that this MCR was more recently developed than those previously described. Some variations have been described in the literature, involving different substrates [69]. The generally accepted mechanism is described in Scheme 18, as follows.

Reddy et al. [70] described the reaction catalyzed by rare earth triflates, notably lanthanum (La(OTf)₃) under microwave irradiation, leading to the desired products in good yields (80–98%). However, the reaction is always carried out in dioxane. Other catalysts, such as indium bromide, have also been used effectively, but always in a conventional solvent [71]. Mojzych et al. [72] have recently listed the operating conditions that can be used in order to synthetize various products via this MCR; although various catalysts considered green are listed, little effort has been made to use accessible solvents, with the exception of Yadav et al. [73], who have worked on the use of [Bmim]BF₄ ionic liquids. Their use as a solvent increases the reactivity of boronic acids and therefore give much better results in terms of yield. In addition, the ease of separation and recycling of the ionic liquid makes it a green solvent and an environmentally friendly catalyst (Scheme 19).

Azizi et al. suggested an alternative to conventional solvents by using deep eutectic solvents, due to their ability to be recycled, giving them the characteristic of green solvents [74]. Similarly, several Petasis reaction procedures have been carried out solvent-free and under microwave irradiation conditions, resulting in reasonable yields of the expected products [75,76].

With regard to Petasis MCR, diastereoselective reactions have been described but are often carried out in dichloromethane or toluene as solvent. However, Schreiber et al. used a combination of L-phenylalanine with an enantiopure aldehyde in lactol form [77]. They observed an opposite enantiopreference (S) or (R) depending on the lactol used and they hypothesized that the secondary hydroxyl group, adjacent to the imine intermediate, was the factor directing the stereochemistry of this reaction. The expected stereochemical diversity of products could thus be achieved specifically by choosing the right combination of lactols and amino acids (Scheme 20).

2.7. Groebke-Blackburn-Bienaymé: GBB-3-CR

The Groebke–Blackburn–Bienaymé is a three-component reaction generally referred as GBB-3CR [4,17]. This reaction involves an aldehyde, an isocyanide, and a variable amino derivative, which can lead to a variety of therapeutically important amino heterocycles. Among these is the imidazo[1,2-a]pyridine family, widely used in central nervous system drugs. In general, this reaction is catalyzed in acidic media and implemented in conventional solvents such as ethyl acetate (EtOAc), dichloromethane (CH₂Cl₂), and alcoholic solvents (usually ethanol or methanol) (Scheme 21).

Most of the time, this reaction is catalyzed by Lewis acids. Longo Jr et al. [78] used microwave irradiation at 150 °C in methanol or ethanol in order to evaluate a number of rare earth triflates. Sc(OTf)₃ was used for the synthesis of imidazo[1,2-a]pyridines and study was carried out on other available metal triflates—M(OTf)₃, with M = Sc, Y, La, Eu, Gd, and Yb. In(OTf)₃ and Bi(OTf)₃ were also added to the study as Lewis acids in the presence of 2-aminopyridine, benzaldehyde, and tert-butyl isocyanide; yields ranged from 60 to 95%. It should be noted that Sc(OTf)₃ proved more efficient than Y(OTf)₃. Other, less expensive rare earth triflates such as La(OTf)₃ and Gd(OTf)₃ had the same catalytic activity as Sc(OTF)₃. This is not always the case in other processes, where scandium generally performs better (Scheme 22). Rare earth derivatives, which are not all that rare, have been widely mined since the 1950s, and demand continues to grow. However, the extraction of these metals requires rather polluting methods. Here again, the benefit–risk ratio has yet to be taken into consideration to determine the ecological interest of this type of catalyst.

We are currently working on optimizing the reaction conditions for this MCR-GBB in bio-based green solvents.

2.8. Others Examples of Undefined MCR

The review by Jonnalagadda et al. in 2021 showed the extent of available recyclable catalysts applied to the organic synthesis of pyranopyrazoles via the use of multicomponent reactions that respect many green chemistry principles [79]. That review showed the value of easily recyclable heterogeneous metal-based catalysts, enabling multiple reaction cycles to be carried out without loss of performance. The reactions reported were often carried out in green solvents, or even better, solvent-free. Two years later, in 2023, Punder et al. [80] referred to the same examples in a review of pyrazole synthesis methods, focusing on reactions in aqueous solvents. The reactions mentioned by these two groups concern variants of multicomponent 3-component or 4-component MCR reactions, often involving hydrazine or arylhydrazines. Here, we describe just a few of the most significant examples.

Bansal et al. [81] reported in 2021 the synthesis of tetra-substituted pyrazoles via a multicomponent reaction in an aqueous medium, an environmentally friendly protocol, as shown in Scheme 23. Arylaldehydes, ethyl acetoacetate, and PhNHNH₂ or NH₂NH₂ in the presence of cetyltrimethylammonium bromide (CTAB) were used for this green protocol, leading to interesting compounds for therapeutic applications.

Using L-proline as a catalyst, Jun et al. [82] demonstrated the efficient (84–93%) synthesis of spiro[indoline-3,4-pyrano[2,3-c]pyrazole] derivatives via reaction of four components. These spiro derivatives were obtained by reacting α,β-dicarbonyl derivative, malonitrile, symmetrical acetylenic diester, and phenyl hydrazine variously substituted in the para position. In addition, to ensure the viability of the four-component reaction, it was carried out in a mixture of EtOH/H₂O solvents (1:1) and under ultrasound to obtain the expected compounds in 30–60 min (Scheme 24).

Dihydropyrano[2,3-c]pyrazoles can be obtained using a variety of processes. Banerjee et al. [83] used ZrO₂ nanoparticles at room temperature, with yields ranging from 90 to 98%. In addition, these ZrO₂ nanoparticles were recyclable and reusable. In 2020, Zahoor et al., synthesized some pyrano[2,3-c]pyrazoles hydrazine with various arylaldehydes in the presence of L-cysteine (0.5 mole) as a natural catalyst by heating the aqueous medium containing 10% ethanol (9:1) to 90 °C (Scheme 25) [84].

The synthesis of numerous pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidinediones derivatives was achieved by Daraie and Heravi via the same multicomponent sustainable approach, from ethyl acetoacetate, arylaldehyde, hydrazine, and 6-amino-1,3-dimethyluracil. This reaction was performed in water with simple organocatalysts such as triethylamine or L-proline (Scheme 26). The authors were able to obtain the desired heterocycles in very good yields with both triethylamine (82–92%) and L-proline (75–90%) [85].

These MCRs can be likened to a Hantzsch variant in which the amine is replaced by a hydrazine or arylhydrazine.

The last examples of this type of reaction to be mentioned here, using arylcarbaldehyde, malonitrile, ethylacetoacetate, and hydrazine to lead to pyranopyrazoles, involve the use of unusual natural, bio-based catalysts, including citric acid from lemon juice [86], caffeine [87], and sodium ascorbate [88]. Reactions took place in water or in water with ethanol as co-solvent. Overall, this is a particularly sustainable route for the production of various pyranopyrazoles (Scheme 27).

To conclude this series of examples on this note of strong sustainability, we consider the use of another natural source: mango, to achieve the synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-dione derivatives. These heterocycles have shown activity as potential antipyretic, antifungal, and antiproliferative agents. Here again, the use of waste products from the fruit juice and compote industry, for example, can be useful for the development of biologically interesting structures. Indeed, Kamana et al. used dried mango peels to develop a catalyst for the multicomponent synthesis of various 1H-pyrazolo[1,2-b]phthalazine-5,10-diones by condensation of an aldehyde, malononitrile, and phthalhydrazide [89]. This aqueous extract of mango peel ash, known as WEMPA, was prepared as follows: the peel was dried in the sun and then, the fruit peel was burnt to produce ash, which was collected at a ratio of 10 g to 100 mL of water. After agitation and filtration, the filtrate recovered was called aqueous extract of mango peel ash (WEMPA). WEMPA has been shown to contain various metal oxides, which are likely to be responsible for its ability to catalyze this multi-component reaction. Mixing the reagents in molecular quantities solubilized in ethanol in the presence of this WEMPA solution under microwave irradiation enabled the team to obtain the desired products (12 examples) in just a few minutes (6–8 min) with very satisfactory yields (83–89%), making this method a particularly durable alternative (Scheme 28).

3. Conclusions

In this study, we set out to identify sustainable methods for building biologically interesting structures via multi-component reactions that are already very atom-efficient. We are also interested in coupling these MCRs to so-called green catalysts and solvents, to limit further our environmental impact. Of course, the list of possibilities is far from exhaustive, but we have attempted to group together the possibilities for synthesizing O,N,S heterocycles, whether stereo-controlled or not, with commercially available reagents, enabling us to easily generate libraries of compounds. We have avoided description of results with complex catalysts requiring previous synthesis. The use of catalysts derived from food, or simply from what nature provides us, also seem to us to be very interesting routes to be highlighted and explored in future research.