A review on synthetic investigation for quinoline- recent green approaches

ABSTRACT Quinolines are a prominent heterocyclic motif and crucial building blocks in creating physiologically active compounds. Due to the fast development of novel medicines with a quinoline nucleus, numerous research papers have been published in a short amount of time. Therefore, to comprehend the present state of the quinoline nucleus in medicinal chemistry science, it is necessary to combine new information with older data. So far, several traditional synthesis techniques have been reported in the literature to synthesize this scaffold. Pfitzinger, Gould–Jacob, Friedlander, Skraup, Doebner–von Miller, and Conrad–Limpach are examples of old synthetic methods. However, they need expensive and demanding conditions, such as high temperature, the use of non-biodegradable chemical compounds degrade the ecosystem, create irritation or harm as pollutants, and represent a threat to the environment. However, traditional synthesis processes need a difficult and time-consuming apparatus set-up, resulting in high costs and pollutants. As a result, scientists are presently developing new and innovative techniques to decrease the use of chemicals, solvents, and catalysts, which are detrimental to both humans and the environment. Therefore, we have attempted to shed light in this current review on various reactions to produce quinolines and their derivatives using various green synthetic methods. GRAPHICAL ABSTRACT


Introduction
Heterocyclic compounds have been extensively used in medicinal chemistry. Their uses are escalating by the day since they are being analyzed in multifold architectures of the bioactive compound. Quinoline and derivatives belong to the N-containing heterocycles family that has lately attracted the interest of researchers due to their wide variety of applications, such as the diverse spectrum of activities and their numerous uses in industrial and synthetic organic chemistry (1)(2)(3)(4)(5). Quinoline is a weak tertiary base that can react with acids to produce salts and is widely recognized as 1-aza-naphthalene or benzo[b]pyridine ( Figure 1). Its reaction is analogous to pyridine, and benzones may participate in electrophilic and nucleophilic substitution processes (6).
In 1834, Friedlieb Runge discovered quinoline as a colorless hygroscopic liquid by distillation of coal tar. Nevertheless, its basic heterocyclic core structure was first revealed in 1871 when Dewar noticed the chemical similarities between quinoline and pyridine (7). Since it was first uncovered, coal tar has remained the primary source of commercial quinoline, despite the development of numerous processes for its synthesis (8,9). Moreover, several derivatives with noteworthy biological activity have been isolated and/or synthesized from plants (10,11). Due to their rapid tautomerism to 2hydroxyquinolines and 4-hydroxyquinolines, the synthetic pathway for synthesis of quinoline-2(1H)-one and quinoline-4(1H)-one derivatives is reported in organic chemistry ( Figure 2) (12).

Conventional synthetic approach for quinolines and derivatives
Quinolines have been synthesized using a range of methodologies. The most widespread is the Skraup synthesis technique (29), which includes heating anilines with glycerol in the presence of sulphuric acid, ferrous sulphate, and N-nitrobenzene (this is the most common and widely used method due to the wide range of available substituents). Moreover, Doebnervon Miller (30), Conrad-Limpach-Knorr (31), and Combes (32) synthesis are alternative ways to synthesize quinoline derivatives, whereas Friedlander (33), Pfitzinger (34), and Niementowski synthesis employ ortho-substituted quinoline derivatives ( Figure 4). However, even though many of these techniques are quite successful, they are not environment-conscious since they create large amounts of detritus that must be disposed of and require a high level of operational complexity to isolate the output (35).
Furthermore, many of these techniques produce significant quantities of unwanted side products, whose removal is time-consuming, invariably wasteful, and insufficient to isolate the yield, as the procedure is simple. As a result, it is evolved into critical to adopt a protocol that might be regarded as superior and more environmentally friendly feasible 'green synthetic' methods. This method can solve environmental pollution as global warming with reduction of chemical consumption and reaction time. This review highlights all the green synthetic methods devised to synthesize quinoline scaffolds that would help researchers in the future in organic and medicinal chemistry.

Green synthetic approach for the synthesis of quinolines and its derivatives
It is crucial to adapt and incorporate new green chemistry methodologies into our routine procedures to improve yield, selectivity, productivity, energy, life, and time (36). The use of organocatalysts, pollution reduction, safer chemicals, less hazardous synthesis, waste prevention substances, and goods that are biodegradable was among the twelve principles of 'Green Chemistry' formulated in the 1990s to fulfill the current generation demands without jeopardizing the future generation needs (37,38).

Microwave-assisted quinoline synthesis
Many chemical and pharmaceutical industries are currently grappling with environmental issues such as large amounts of solvent waste, loss of solvents/ reagents, the presence of a catalyst in the product, and so on. Green synthesis is the most efficient and preferred approach for synthesis that involves a microwaveassisted reaction to overcome these issues. Microwave transfers energy directly to the reactive species known as molecular heating by two mechanisms, (i) dipole rotation and (ii) ionic conduction. The use of microwave irradiation as an energy source, on the other hand, reduces the need for solvents in processes (refer Table 1).
Saggadi et al. have developed a 'one-pot eleven steps' reaction by microwave-assisted regioselective modified Skraup reaction and Bamberger rearrangement reacting with glycerol, nitrobenzene, and p-amino/p-nitrophenol in water as a green solvent for synthesizing 6-hydroxyquinoline in 15-20 min (Scheme 1). The % yield of the target compound obtained through p-aminophenol and p-nitrophenol are respectively 27% and 55%, while nitrobenzene gave 77% (39).
Yu et al. have developed one-pot synthetic protocol using a three-component reaction of aldehydes and 1aryl ethylidene malononitriles in ethane-1,2-dione at 100°C in the presence of sodium hydroxide as a base catalyst to synthesize novel poly-functionalized  dihydroquinoline derivatives with good yields (75-86%) (Scheme 2). This protocol has the following features: Mild condition, a cheaper catalyst, fast reaction timeframes of 8-20 min, and good regioselectivity (40).
Li et al. have developed an eco-friendly synthetic approach for the synthesis of polyfunctionalized tetracyclicindolo [2,3-b]quinoline derivatives by cycloaddition reaction of 3-arylidene-2-oxindoles with enaminones using sodium ethoxide in a polar protic solvent like ethanol at 110°C for 12 min under microwave irradiation with excellent yields (73-86%) (Scheme 3). This tactic has the following features: optimum process efficiency, quick reaction, operational simplicity but irksome work-up, and intermediate separation (41). Saggadi et al.have developed an effective one-pot, green Skraup reaction in water using affordable, plentiful, and ecological-friendly glycerol with substituted anilines at 200°C in presence of catalytic H 2 SO 4 under the influence of microwave irradiation for 15-20 min (Scheme 4). The % yield of the target compound obtained through p-aminophenol is 10-66%, whereas nitroaniline is 15-52% (42).
Chidurala et al. have designed a simple, catalyst-free, greener, one-pot multi-component condensation reaction of benzene-1,3-diol, aldehyde, ammonium acetate, and acetoacetanilide in ethanol for the production of quinoline derivatives with an excellent yield of 88-96% under microwave for 8-10 min as compared to the classical method in which % yield was found to be 72-90% in 4-6 h reaction time (Scheme 5) (43).
Zangh et al. have developed a one-pot catalyst-free method for the synthesis of fused-quinoline and quinoline dicarboxylates using the best efficient microwave-assisted process involving a cascade of denitrogenationazide, benzisoxazole formation, aza-Diels-Alder cycloaddition, and dehydrative aromatization with a high yield between 75-93% (Scheme 6). This method has following features: catalyst-free synthesis and efficient methodology (44).
Fedoseev et al. have developed a metal-free and Bronsted acid-promoted method for the production of 3,4-cyclopentane-quinoline-3-ones from indolylone in the presence of trifluoroacetic acid [TFA] in chloroform under microwave irradiation at 100°C for 30 min with a medium to excellent yields (68-99%) (Scheme 7) (45).
Ma et al. have reported a neat and efficient method for the synthesis of quinoline derivatives by reaction of ferrocene carboxaldehyde with dimedone and ketone catalyzed by ammonium acetate using water as a green reaction media via microwave (100°C) for 10-15 min. Moreover, the % yield obtained using water was 75-93%, while, with glycol, it was 32% (Scheme 8). The advantages of this reaction are economical, potential, and covers a short reaction period (46). Malvacio et al. have reported a method for the synthesis of 3-carboethoxy-quinoline-4-one from substituted aniline and diethyl malonates via Gould-Jacobs (G-J) cyclization using the flash vacuum pyrolysis protocol at 330°C for 1 h under a nitrogen atmosphere, yielding a moderate yield of 40-45% (Scheme 9). The tactic of this feature includes a short period of time, but the disadvantage of this method is its non-applicability for industrial use and its cost (47).
Libertoet al. have developed a suitable and simple one-pot microwave synthesis of 2,4-disubstituted quinolines from a series of substituted anilines, benzaldehyde derivatives, and styrene under solvent-free conditions in the presence of p-sulfonic acid calix [4]arene [CX 4 SO 3 H] as a catalyst, yielding a good yield (38-78%) over 20min. Recycling catalysts, tolerance to a wide range of functional groups, and solvent-free are all tactic features of these approaches (Scheme 10) (48).
Ojer et al. have reported an alluring and impactful metal-free Friedlander synthesis of trisubstituted quinolines by the reaction of substituted 2-amino benzaldehyde and ethyl acetoacetate using nano-carbon aerogels as a catalyst via microwave method for 4 h, resulting in a moderate yield (60-65%) (Scheme 11) (49).
Cravotto and coworkers have developed a solventfree microwave-assisted method for the synthesis of polysubstituted quinoline derivatives from o-amino benzophenone derivatives and carbonyl compounds using functionalized propylsulfonic acid [SiO 2 -Pr-SO 3 H] as a recyclable and reusable catalyst with a low to high yield (22-93%) for 30-210 min at 80°C (Scheme 12) (50).
Anvar and his team have developed one-pot, threecomponent, solvent-free rapid synthesis of quinolines and bis-quinolines usingmicrowavebyreaction between aromatic amines, aromatic aldehydes, and phenylacetylene in the presence of potassium dodecatungstocobaltate trihydrate [K 5 CoW 12 O 40 ·3H 2 O] as a recyclable catalyst that can be used five to six times without significant loss of catalytic activity, resulting in an excellent yield of 87-98% in 10 min (Scheme 13) (51).
Jiang et al. have synthesized a highly diastereoselective three-component reaction of 4-hydroxy pyran-2ones, aromatic aldehydes, and N-aryl enaminones to afford bicyclic hexahydro quinoline-2,5-diones via the Knoevenagel condensation reaction under microwave irradiation at 100°C for 20 min, resulting in a yield varying between 65-67% (Scheme 14). This outlined method has the advantage of lenient conditions,  pliability of structural modification, reliability, and scalability (52).
Kulkarni and Torokhave developed a three-component reaction of anilines, aldehydes, and 4-substituted phenyl acetylenes to produce substituted quinolines quickly and efficiently using a powerful and ecologically friendly solid acid catalyst like montmorillonite K-10 using microwave technique to produce a yield with nearly 72-96% in 10 min (Scheme 15) (53).
Peng et al. have synthesized a sequence of furo [3,4b]indeno[2,1-f ]quinolin-1-one derivatives by the condensation of an aromatic aldehyde, tetronic acid, and 9H-fluoren-2-amine in the presence of a weak acid as glacial acetic acid via microwave irradiation, forming a high product yield (79-88%) in 15 min (Scheme 17) while, with other solvents systems such as water and glycol gave minimal yield (12-35%). The advantages of this method are: functional simplicity, neat reaction, and increased safety for small-scale fast synthesis (55).
Albert-Soriano et al.have used a heterogeneous catalyst based on alkali earth metals like barium and calcium to manufacture quinoline derivatives by combining 2amino aryl aldehydes or 2-amino aryl ketones via microwave technique at 80°C without using solvent, resulting in a high yield of 67-99% (Scheme 18) (56).
Yun Li et al. have reported a microwave protocol for the production of a fused quinoline by reacting orthoheteroaryl anilines and carbon disulfide[CS 2 ] in the presence of green solvents like water through 6π-electrocyclization at 140°C for 30 min (Scheme 19) (57).

Green solvent-based approach for quinoline synthesis.
Toxic solvents are used in large quantities during chemical synthesis for cleaning and degreasing. However, the use and discharge of chlorinated solvents are hazardous to human health and the environment. A contrario green solvents are non-toxic and environmentally friendly solvents. These solvents are biodegradable and easily generated from natural renewable resources. Therefore, for the synthesis of quinoline and its derivatives, water, ethanol, isopropanol, ionic liquids, deep   Table 2).
Teimouri et al. have designed a highly multifaceted, rapid, and straightforward synthetic route for poly-substituted quinolines via Friedlander condensation of 2-Scheme 11. Microwave-assisted Friedlander synthesis for quinoline using aerogel as nano-catalyst.
Scheme 12. Friedlander synthesis of polysubstituted quinoline using propylsulfonic acid as recyclable catalyst.    [KOtBu] and water-ethyl acetate (1:1) medium at ambient temperature for 2 h with a yield varying between 73-93% (Scheme 43). The benefit of this method is that it does not need the use of chromatographic methods for purification (81). Shahabi  Esfandiary et al. have developed a highly potent, onepot reaction for substituted quinoline synthesis by reacting 2-bromobenzoic acid, piperidine, and phenylacetylene derivatives using γ-Fe 2 O 3 @Cu-LDH@Cysteine-Pd as a nano-catalyst and choline azide as a green solvent at 80°C for 4 h, to obtain moderate to high yields (76-93%) (Scheme 45) (83).

Solvent-free reaction for quinolines synthesis.
The importance of solvent systems in conventional synthetic protocols is well defined and critical for driving a reaction. However, the most commonly used solvents such as methylene chloride (DCM), chloroform, acetonitrile, dimethylformamide (DMF), N,N-dimethylsulfoxide (DMSO), and toluene are hazardous and toxic too. Chemical synthesis without a reaction medium (solvents) is an imaginary thought because the solvent is indispensable in a reaction system. Several neat protocols for synthesizing quinolines with or without catalyst are discussed below (refer Table 3        Moreover, this protocol has easy recovery and reusability of catalyst, broad substrate scopes, and cost-effective. In addition to that, quinoline was also developed through a catalyst-free approach by Patil et al. via a one-pot four-component green synthesis of hexahydroquinoline through enaminone intermediate by the reaction of dimedone, ammonium acetate (acting as reagent as well as a catalyst), aryl aldehydes, and malononitrile in a green solvent like water for 1-1.5 h without using an external catalyst, resulting in yields varying between 57-85% (Scheme 65). The tactic has features like rapid reaction, excellent atom economy, quick set-up, and purification of products by the non-chromatographic method (103).

Biocatalyst and photo-catalyst based green approach for quinolines synthesis.
Green chemistry's primary goals are to improve process selectivity, maximize the use of starting materials, and replace toxic and stoichiometric reagents with environmentally friendly catalysts to make it easier to separate final reaction blends with catalyst recovery. Biodegradable, non toxic by-products from numerous industries utilized green catalysts in diverse processes. For example, enzymes are biological catalysts that lower the activation energy of a reaction when used in organic synthesis, allowing it to proceed at room temperature or moderate temperatures. The biocatalysts are substrate-specific and environmentally beneficial, as well as biodegradable (refer Table 4). Tufail et al. have developed a novel Friedlander method for synthesis of several multisubstituted quinolines using organo-promotor malic acid by the reaction of substituted 2-amino benzophenone or o-acyl anilines and carbonyl compounds with an active methylene group at 55-80 0 C for 3.5-7 h, resulting ingoodyields (72-95%) (Scheme 66). The tactical's features include broad substrate scope, solvent-free reaction at room temperature, fast reaction, easily operated, affordable, high atom economy, excellent yield (104). Fei et al. have developed a novel, efficient one-pot copper-catalyzed sequential approach for the synthesis of functionalized quinolines through substituted enamino esters and ortho-halogen aromatic carbonyl derivatives catalyzed by Copper iodide [CuI] and Lproline at 120°C for 18 h to obtain yields varying between 45-86% (Scheme 68) (106).

Nano-catalyst based green approach for quinolines synthesis.
Nanoparticles have gained much attention from researchers because of their high catalytic activity, reusability, and benign nature in green chemistry. Below are several promising nanocatalyst-based approaches for quinolines synthesis (refer Table 5).
Xie et al. have synthesized functionalized quinolines by reductive annulation of 2-nitro aryl carbonyls with alkynoates and alkynones using newly nitrogen-doped Zirconium Dioxide [ZrO 2 @C] supported cobalt [Co/ N-ZrO 2 @C] nano-catalyst in the presence of formic acid at 110°C for 18 h to produce 83% yield(Scheme 73). This protocol has the following advantages: a broad substrate range, strong functional compatibility, excellent transfer hydrogenation selectivity, repeatable earthabundant metal catalyst, and easy operation (111).
Apart from nano-catalysts, Reddy et al. have discovered an effective, easy, fast reaction strategy towards the access of pyrimido [4, 5-b]quinoline-diones by the condensation of aldehydes, anilines, and barbituric acid mediated by a supramolecular green catalyzed

Miscellaneous green synthetic approaches for quinolines synthesis.
Many other green approaches for synthesizing quinoline have been reported, such as mechanochemistry, which deals with the chemical behavior of mechanically stressed solids and eliminates the use of solvents. Moreover, the ultrasound-assisted method also enhances the rate of the chemical reactions for quinoline and its derivatives (refer Table 6).    the Friedlander heteroannulation reaction of substituted 2-aminoaryl ketones and α-methylene ketones using L-(+)-tartaric acid-DMU (30:70) as a catalytical reaction medium at 70°C to obtain yields varying between 70-95% (Scheme 96) (134).

Conclusion
Quinoline and its derivatives possess a wide range of pharmacological activities and are also utilized as ligands in numerous biologically-modelled transition metal complexes. In this review, we have compiled and discussed all commonly used green methods, such as ultrasound-assisted, microwave-irradiation, heterogeneous acid-catalyzed methods, photo-catalyzed, solvent-free conditions with a critical presentation of data in a tabulated form so that the researcher can create a new environmentally sustainable, efficient, and cost-effective technique.
In addition, numerous quinoline derivatives play a significant role in the progress of organic synthesis and applications to medicinal chemistry. However, in the creation of novel techniques, it was possible to find that using Friedlander or multicomponent reactions (MCR) results in increased atom economy and using solventfree conditions, ionic liquids assisted, and ultrasound irradiation synthetic methodologies meet the requirements of 'green chemistry. ' In a nutshell, this type of recent review is necessary from today's point of view as we need an environmentally clean protocol for the large-scale production of such an essential biological moiety (135,136), which may be used further in many reactions to develop a potent pharmacophore for the future.