Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

Microwave-assisted (MWA) multicomponent reactions (MCRs) have successfully emerged as one of the useful tools in the synthesis of biologically relevant heterocycles. These reactions are strategically employed for the generation of a variety of heterocycles along with multiple point diversifications. Over the last few decades classical MCRs such as Ugi, Biginelli, etc. have witnessed enhanced yield and efficiency with microwave assistance. The highlights of MWA-MCRs are high yields, reduced reaction time, selectivity, atom economy and simpler purification techniques, such an approach can accelerate the drug discovery process. The present review focuses on the recent advances in MWA-MCRs and their mechanistic insights over the past decade and shed light on its advantage over the conventional approach.


Introduction
Recently, organic chemists are focussed to develop environment friendly sustainable technologies and procedures using atom-efficient reactions from suitable starting materials to meet the demands of present as well as future generations [1][2][3]. The need arises as the traditional method of synthesis has become unsustainable both from an environmental and economic perspective due to increased amounts of waste generation, toxic solvents, and no real-time control of pollution generated, etc. [4]. Therefore, in this connection, the multicomponent reaction (MCR) is one such approach where three or more reactants combine to form a single product retaining the majority of the atoms of the starting materials. The ability of forming multiple bonds in one-pot via a multicomponent reaction provides a novel and sustainable method in drug discovery [4]. In the recent years, these reactions have emerged as a promising strategy following green chemistry principles such as reduction in waste generation, step-economy, minimum use of solvents, along with atom and bond-forming economy. In addition, MCRs are eco-friendly with simple purification procedures, faster reactions favoring chemo-and regioselectivity in some cases [5][6][7]. The multicomponent strategy has provided an easy access to the synthesis of complex bioactive molecules with multiple point diversity incorporating up to eight components in one-pot [8]. The pharmaceutical industry has witnessed a considerable surge in drug synthesis via multicomponent strategies [9][10][11], including the synthesis of atorvastatin, a potent HMG-CoA reductase inhibitor. Dömling and co-workers efficiently demonstrated an Ugi-based MCR approach towards the synthesis of atorvastatin in four steps ruling out the lengthy seven step protocol, and paving a rapid entry to the drug discovery market [12].
Alternatively, microwave-assisted (MWA) organic synthesis marked its presence on the scientific map in 1986 with two reports of organic syntheses in the kitchen microwave [13,14]. This paved a new direction in synthetic chemistry wherein technology was incorporated to achieve the desired results adroitly. The golden decade of MWA organic synthesis (2000-10), witnessed microwaves with optic fibre or IR pyrometers for temperature detection along with specific glass reaction vessels that can withstand pressure and temperature in the reaction generated especially by low boiling solvents. Microwaveassisted heating reduces reaction time from hours to minutes and seconds. It provides efficient and uniform heating proving to be a rapid method over the conventional ones. Reactants are directly heated when microwave heating is employed while with the conventional methods, the reaction vessel is first heated and the heat is transferred through convection to the participating reactants [15][16][17][18][19]. Over the years, microwave reactors have undergone considerable changes making it adaptable at various levels of organic synthesis. Primarily, there are three types of microwave reactors namely monomode microwave reactors, multimode microwave reactors for parallel synthesis and multimode microwave reactors for single-batch scale-up. The reactors vary in capacity and the distribution mode of the electromagnetic wave in the reactor vessel. The introduction of the Si-C (silicon-carbon) vials enables high temperature resistance and selective heating of the heterogeneous catalyst [20][21][22][23].
Even though the MWA technology is advantageous, a major challenge posed is the scale-up at the industry level where protocol efficiency at kilogram scale is mandatory. With rapid heat generation, and litres of solvents often safety seems to be compromised imposing restrictions on using microwaves at a scale-up level. However, the batch process and continuous flow process seem to provide an entry into scale-up standards with safety. The microwave reactors serving the purpose of batch and parallel approach are designed in various capacity and modes to achieve the uphill task easily [19].
The contemporary organic chemistry procedure involving microwave heating has paved way for the molecular diversity that helps in reducing the time required for the drug discovery process. As multicomponent reactions and microwave reactions hold their respective advantage over other synthetic protocols, merging strategy with technology proves to be an asset in organic synthesis. In view of the same, chemists worldwide have experimented with the combination which has proved to be highly efficient and sustainable. Over the past decade, researchers have focused on developing greener synthetic strategies for the construction of various pharmacophores which can prove to be vital in a drug discovery process [24][25][26][27][28]. These efforts have not gone unnoticed and have been shaped into reviews in 2010, 2011 by Jiang and Orru respectively [29,30], focusing on the synthetic aspect of five, six, seven and dicyclic structures. Later in 2013, Gupta et al. compiled reports of microwave-assisted cross-coupling, MCR with few cycloaddition reactions [31]. During the course of writing this review, we realized the very presence of two reviews by K. Kamanna and G. Anilkumar highlighting the progressive efforts in MWA-MCRs [32,33]. Recently, Dolzhenko centered a book chapter around named MCR assisted by microwave irradiations [34]. Similarly, in the recent past our research group [35] focussed on unveiling microwave reactions for non-fused single nitrogencontaining heterocycles. A mechanistic understanding of a reaction progression promotes better conceptualization of strategies effectively. This review aims at bridging the hiatus of the previous reviews with mechanistic insights into the MWA-MCRs employed for the synthesis of organic and medicinally significant molecules. The review has been classified on the basis of the pharmacophores constructed by adopting the MWA-MCRs strategy.

Review 1 Acridine
Acridine is a polycyclic heteroarene with structural basis as anthracene in which one of the central carbon atoms is replaced by a nitrogen atom. Tacrine (1) is an acridine derivative used in the treatment of Alzheimer's disease. A plethora of acridine derivatives have been synthesized and clinically proved with various biological activities such as ethacridine (antibacterial drug; 2), acranil (antiviral drug; 3) and quinacrine (antimalarial agent; 4, Figure 1) [36,37].
The relevance of acridine in drug discovery galvanized Singh and co-workers [38] to develop a water-promoted three-component reaction involving aldehydes 5, cyclic 1,3-diketone 6 and ammonium acetate powered by microwave irradiation resulting in 4-arylacridinediones 7 in moderate to good yields under catalyst-free conditions (Scheme 1). A rationale of mechanism proposed the transformation via a Knoevenagel condensation between aldehyde and a molecule of 6 affording A. The concurrent condensation of ammonium acetate with another molecule Scheme 2: Proposed mechanism for acridinedione synthesis. of 6 led to the formation of an enaminone B. Later, the successive Michael addition of A and enaminone B followed by an intramolecular cycloaddition with concomitant dehydration delivered the final product 7 (Scheme 2).
In 2018, our research group [39] contemplated and developed an expeditious process for the synthesis of phenanthrene-fused tetrahydrodibenzoacridinones 9 using phenanthren-9-amine 8, aldehydes 5, and cyclic 1,3-diketones 6 as structural units in ethanol under microwave irradiation to result in the targeted products in excellent yields. A conventional heating used for the same protocol delivered the desired products in longer reaction time (3 h) with lower yields (60%) as compared to microwave (20 min with 91% yield). The library of molecules synthesized was found to be active against SKOV-3 cancer cells with 9a emerging as a promising molecule with IC 50 = 0.24 ± 0.05 μM (Scheme 3). The protocol surfaces the efficiency of MWA-MCR in the construction of fused polycycles with functional diversity for the generation of a library of pharmacologically active molecules.
A plausible mechanism as shown in Scheme 5 suggested the involvement of an elementary formation of Knoevenagel adduct A from the reaction between the aldehyde and 11. This adduct undergoes an intermolecular Michael addition to naphthylamine resulting in the formation of B. A subsequent intramolecular nucleophilic cyclization leads C followed by dehydration forms D and finally 12. The synthesized naphthoacridines 12 with 2,3-diaminonaphthalene produces 14 via dehydration and dehydrogenation.

Azepines
Azepines are represented by unsaturated seven atom heterocyles with nitrogen replacing a carbon atom. The benzene-fused azepines known as benzoazepines have marked their impor-tance in the treatment of various disorders, such as in hypertension (15) and in congestive cardiac failure (16). They are also known for their use as neuroprotective (17) and antitubercular agents (18, Figure 2) [42][43][44].  In 2011, Van der Eycken and co-workers [45] tailored a microwave-assisted multicomponent reaction for fast and efficient generation of diastereoselective dibenzo[c,e]azepinones. The protocol utilized substituted 2'-formylbiphenyl-2-carboxylic acid 19, benzylamines 20, and isocyanides 21 in TFE and Na 2 SO 4 as drying agent for the construction of azepinone 22 and exemplified a modified Ugi reaction (four-component reaction). The aldehyde and acid component of the Ugi reaction was functionalized on the same biaryl ring employing a Suzuki-Miyaura coupling. The authors advocated the use of microwave as it consistently increased the yield from 49% to 82% along with drastic reduction in side product formation and reaction time from 24 h to 50 min when compared to the conventional method. The method proved to be efficient even with chiral amino acids resulting in separable diastereomeric mixtures. The synthesized molecules manifested potent antiproliferative activity against tumor cell lines leading to the discovery of new lead compounds (Scheme 6).
A tentative mechanism in Scheme 7 depicts the formation of iminium ion A from the reaction between 19 and 20 after the intramolecular protonation by carboxylic acid. The A conformer stabilized by electrostatic interaction between carboxylate and iminium moieties undergoes a nucleophilic attack by isocyanide to generate nitrilium ion B. The intramolecular acylation of B forms C followed by Mumm rearrangement results in the formation of the desired products 22. Simultaneously, Li and co-workers [46] reported a three-component reaction for the synthesis of benzo[f]azulen-1-ones 24 using substituted phenylenediamine 23, aldehydes 5 and cyclic 1,3-diketone such as tetronic acid 6c under microwave irradiation in aqueous conditions delivering the product in good yields (70-89%). The use of a non-polar solvent resulted in the formation of side products like benzimidazole, indicating the importance of water as solvent in this protocol along with its high   efficiency as absorber for microwave irradiation providing environmentally benign reaction conditions. The authors further extended the acid-catalyzed protocol for the synthesis of penta-cyclic isoindole-fused furo [1,4]diazepines 26 using substituted 2-formylbenzoic acids 25, phenylenediamine and tetronic acid with water as solvent (Scheme 8).
The mechanism leading to the formation of the final product 24 and 26 involves an initial condensation between tetronic acid and benzene-1,2-diamine to give enaminone A. An intermediate B generated by the addition of aldehyde to enaminone A on intramolecular cyclization furnishes the final product 24 via C. Cyclic isoindole-fused furo [1,4]diazepines 26 were obtained by dehydration of the carbonyl group on the aromatic ring on treatment with an amino group. The authors attributed the high nucleophilicity of the amino group in the substrate 23 to control the regioselectivity of the reaction (Scheme 9).
In 2017, Lin and co-workers [49] designed a TFA-catalyzed three-component reaction for the regioselective synthesis of 3-functionalized indoles 34 by employing amines 32, arylglyoxal monohydrate 33 and cyclic 1,3-diketones 6 under microwave irradiation in the greener solvent system EtOH/H 2 O (Scheme 10). A plausible mechanism (Scheme 11) suggests a TFA-catalyzed Knoevenagel condensation between 4-hydroxy-6-methyl-2H-pyran-2-one and arylglyoxal to form intermediate A. Michael addition of amine to intermediate A gives B which further undergoes an intramolecular nucleophilic addition reaction to yield C which on cyclization and with subsequent loss of water from D produce the desired products 34.
Meshram and co-workers [50] demonstrated an aqueous phase, diastereoselective, multicomponent reaction involving substituted isatins 35, β-nitrostyrene 36 and benzylamine (20) or α-amino acids 37 using microwave irradiation to afford a library of spirooxindoles 38 in good yields under catalyst-free conditions. Observations revealed that the conventional refluxing method produced only 10% of the desired product and brought microwave assistance to light. The synthesized molecules showed good antimicrobial activity against Escherichia coli, Candida tropicalis, Staphylococcus aureus and Pseudomonas aeruginosa (Scheme 12).
Similarly, the same group extended the work by illustrating [51] a three and four-component microwave-assisted base and catalyst-free reaction for the synthesis of substituted spirooxindoles 40. The three-component reaction involved the reaction between substituted isatin 35, but-2-ynedioates 39 and amino acids 37. Likewise, the four-component reaction comprised of isatin 35, but-2-ynedioates 39, amino acids 37 and phenacyl bromides 41 to yield the N-acylated spirooxindoles 42 in good yields (Scheme 13). The reaction effectively explored the 1,3 dipolar compound generated with isatin and amino acids subjecting them to the potential dipolarophile but-2-ynedionates to deliver the target molecules. Both the reactions proceeded well in water aiding in greener synthesis of biologically active molecules. The synthesized molecules exhibited significant activity against human lung cancer cell line A549.
A plausible mechanism shown in Scheme 14 explains the formation of azomethine ylide B by condensation of isatin with amino acid followed by release of a molecule of CO 2 via A. The imine B undergoes 1,3-dipolar cycloaddition with the dipolarophiles 39. The cyclization yields the desired product 40 of the three-component reaction whereas a further reaction with phenacyl bromide 41 results the product of the four-component reaction 42.
Recently, our group [52] efficiently employed the synergistic approach of MWA-MCR to deliver pyrrolidinyl spirooxindole 44. The isatin 35, primary amino acids 37 and 3-alkenyloxindole 43 were considered to be the building blocks united in ethanol as solvent (Scheme 15). The notable highlights of the described methodology are diastereoselective C-C and C-N bond formation, high yields, non-toxic product, and cost-effectiveness along with a greener approach.
The synthetic strategy introduces primary amines for 1,3dipolar cycloaddition which is less explored due to the probability of competitive Strecker degradation over decarboxylation of  azomethine ylides. The protocol reveals the efficiency of MW assisted reaction with reduced reaction time from 18 h to 12 min and enhanced the yield from 69% to 84% over the conventional protocol as observed during the study. The explored mechanism in Scheme 16 indicates an in situ anti-azomethine ylide (A) generation (between isatin and primary amine) favored due to steric hindrance in syn-ylide. The crucial step determines the route via ylide formation over the expected Strecker degradation. The azomethine ylide trapped by 3-alkenylindole undergoes 1,3-dipolar cycloaddition and led to the cycloadducts 44.

Pyrans
Pyran is a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom with two double bonds. Numerous natural compounds containing pyrans and benzopyrans (fused pyrans) are identified. Epicalyxin (45) is used as an anticancer agent against human HT-1080 fibrosar-   coma and murine 26-L5 carcinoma. Laninamivir (46) is a pyran-based drug used as a neuraminidase inhibitor and zanamivir (47) for prevention of influenza A and B. β-Lapachone (48) shows diverse biological activities like anticancer, antibacterial and anti-inflammatory activities [53]. Benzopyrans and naphthopyrans represent a class of fused pyrans that has been studied for antimicrobial effects (49 and 50, Figure 4) [54]. Therefore, researchers have quested upon generation of pyrans and benzopyrans employing MCR powered by microwave assistance.
For instance, Tu and co-workers [55] reported a one-pot twostep tandem procedure subjecting phenylenediamine 23, 2-hydroxynaphthalene-1,4-diones (11), aldehyde 5 with malononitrile (51) in presence of acetic acid under microwave irradiation for the synthesis of highly functionalized benzopyrans 52. The method was successfully employed for the construction of chromene and phenazine motifs exhibiting the applicability of the protocol to engender diverse chemical entities (Scheme 17). The harsh reaction conditions with longer reaction time and limited substrate scope highlights the importance of the above mentioned strategy to obtain such fused molecules [56].
A detailed mechanism was proposed, with the initial formation of benzo[a]phenazin-5-ol A through condensation of diamine 23 and 2-hydroxynaphthalene-1,4-dione (11). A simultaneous The synthesis of indoline-spiro fused pyran derivatives 53 was reported by Jiang and co-workers [57] employing a multicomponent reaction between substituted isatins 35, cyclic 1,3-diketones 6 and malononitrile (51) in an aqueous medium without any catalyst. Reaction diversity was examined by using different 1,3-diketones and isatins (Scheme 19). Products obtained from non-chromatographic techniques such as filtration proved the versatility of the strategy.
A rationale mechanism for the synthesis of 53 was described in Scheme 20. Incipiently, a fast Knoevenagel condensation between isatin and malononitrile produced isatylidene malononi-trile derivative A. This intermediate A undergoes Michael addition with tetronic acid to afford an intermediate B. Ultimately, the cycloaddition of the hydroxy group to the cyano group afforded the desired product 53 via C.
Meanwhile, Nepali and co-workers [58] reported the potential of naphthopyrans as non-purine xanthine oxidase inhibitors. They explored a silicated fluoroboric acid-catalyzed three-component cycloaddition involving acyclic 1,3-diketones 54, β-naphthol (55) and aldehyde 5 for the synthesis of substituted naphthopyrans 56 under microwave irradiation under solventfree conditions. The library of compounds proved to be active as xanthine oxidase inhibitors with the most potent molecule showcasing IC 50 = 4 μM (Scheme 21).

Pyrroles
Pyrroles are five-membered heterocycles consisting of four carbon atoms and a nitrogen atom. The pyrrole ring is found to be Scheme 20: Proposed mechanism for indoline-spiro-fused pyran.
The diverse pharmacological activities of pyrroles enlivened Kumar and co-workers [61] to report a facile and eco-friendly microwave-assisted four-component reaction involving chromene-aldehyde (61), amines 32, acyclic 1,3-diketones 54 and nitromethane using silica-gel-supported polyphoshoric acid as catalyst under neat conditions for the synthesis of tetrasubstituted pyrroles 62. A comparative study of the protocol employing the conventional and microwave approach proved the microwave strategy to be advantageous with enhanced yield from 87-95% in reduced time (3 h to 46 min). The parameters were successful in overcoming the drawbacks such as functional group compatibility, regiospecifity, multi-step procedure etc. suffered by traditional methods [62,63]. The catalyst offered recovery and reusability up to five successive runs with excellent yields (86% to 95%). The approach paved a new way to solid-support-mediated MWA-MCR using a heterocatalyst (Scheme 22).
A possible mechanism suggested by authors proceeded via a Michael addition between nitrostyrene adducts A and β-keto enamine B generated in situ consequently undergoes cyclization C and dehydration D to afford the desired product 62. PPA-SiO 2 accelerates the reaction by enhancing the electrophilicity of the 1,3-diketones and the aldehydes by increasing the rate of generation of the β-enaminocarbonyl and nitrostyrene intermediates. Activation of Michael addition followed cyclization was catalyzed by silica-supported PPA-SiO 2 (Scheme 23).
Fused pyrroles have also been constructed by exploring the utility of a multicomponent reaction coupled with microwave irradiation. One such demonstration was reported by Padmini and co-workers [64] wherein a four-component reaction between substituted aldehydes 5, phenanthroline (63) in ethanol as a solvent with excellent yields. The conventional approach delivered the desired product in 62% yield after 6 h which reveals the efficiency of microwaves in increasing the yield and reducing the reaction time. The studies for the anticancer activity of the synthesized molecules revealed them to be more potent than the standard doxorubicin against AGS cancer cell lines along with good antimicrobial activity (Scheme 24).
The proposed mechanism (Scheme 25) involved a Knoevenagel condensation between aldehyde 5 and malononitrile (51) to form arylidene intermediate A. Then A reacts with isocyanide 21 to produce intermediate B which coordinates with 1,10-phenanthrolines and affords intermediate C. A subsequent cyclization D and aromatization E with loss of HCN yield the desired products 64. The lower yields in case of aliphatic isocyanides were reasoned with its low nucleophilicity losing the competition with aryledenemalononitrile A in the reaction with phenanthroline.
The Biginelli reaction is one of the frequently employed MCRs for the synthesis of dihydropyrimidinones. The classical Biginelli reaction suffers from drawbacks such as harsh reac- tion conditions, longer reaction time and low yields [70]. Several attempts have been made to improve the reaction conditions using various catalyst/reagents, ionic liquids etc. [71,72].
Contributing to this need, dos Anjos et al. [73] reported a basecatalyzed three-component reaction between aromatic aldehydes 5, ethyl cyanoacetate (73) (active methylene group) and benzamidine (74) in aqueous media for the construction of substituted pyrimidinones 75 under microwave irradiation (Scheme 26). The study of the protocol on a conventional system directed a reduced yield of mere 18% in 16 h. A slight variation to the protocol with malononitrile (51) as the active methylene compound affords a series of substituted 4-aminopyrimidines 76 in moderate yields. The efficacy of the synthesized dihydropyrimidinones as antinociceptive was also established. The authors proposed two different mechanisms in which the first mechanism involved two subsequent reactions. The first one being a Knoevenagel condensation between aromatic aldehyde and ethyl cyanoacetate to yield a Knoevenagel intermediate A which upon subsequent reaction with benzamidine, forms Michael adduct B. A consecutive ring closure yields the desired product 75 aided by the attack of nitrogen lone pair in Michael's adduct C via a sequential ethanol elimination (E) from D followed by aerial oxidation of intermediate F. Another proposed mechanism follows the formation of imine derivative G produced by the reaction between aldehyde and amidine. The imine G thereby reacts with ethyl cyanoacetate to result in intermediate I, which on intramolecular cyclization leads to D. The remaining pathway pursues same mechanism as the first one (Scheme 27).
Later in 2016, Gopalakrishnan and co-workers [74] demonstrated the construction of dihydropyrimidinones 78 utilizing a three-component reaction of acyclic 1,3-diketones 54, urea/thiourea (77) and aldehyde 5 exploring La 2 O 3 as catalyst under microwave irradiation under solvent-free conditions with good functional group tolerance and excellent yields (Scheme 28). The reaction failed to produce the desired product at room temperature even after extended period of time. A comparative analysis of the strategy with different catalyst under refluxing conditions surfaced the efficiency of microwave in reducing the time from hours to seconds and increasing the yield considerably.
The postulated mechanism indicates the formation of acylimine A from the lanthanum oxide-catalyzed reaction of aldehyde and

77.
Further, addition of acyclic 1,3-diketone ester enolate to acylamine A form B which upon subsequent cyclization and dehydration resulted in the formation of desired products 78 (Scheme 29).

Pyrrolo[2,3-d]pyrimidines:
Bhuyan and co-workers [80] reported an efficient MWA three-component reaction between N,N-disubstituted-6-aminouracil 86, arylglyoxal monohydrate 33, and amines 32 in AcOH resulting in the synthesis of 5-arylaminopyrrolo[2,3-d]pyrimidines 87 in good to excellent  yields (Scheme 30). The dual-use of acetic acid as a catalyst and solvent along with simple filtration and a recrystallization procedure to obtain pure products adds advantage over the other reported protocols [81,82].  nagel condensation between arylglyoxal and malononitrile. This is followed by the Michael addition of aminouracil to intermediate C to give D. Finally, desired product 90 is formed by intramolecular cyclization of intermediate D and subsequent rearrangement of E. Abonia and co-workers [85] established a catalyst-free construction of quinoline-based pyridopyridines 97 by employing a microwave-assisted three-component reaction of 3-formyl-2oxoquinoline derivatives 95, 2,4,6-triaminopyrimidine (96) and a cyclic 1,3-diketone such as dimedone (6a) in DMF. The resulting products were obtained in moderate to good yields. The authors observed the formation of pyrazolopyridine under conventional heating in lower yield (38%) with extended reaction time (20 h). Interestingly, the replacement of triaminopy-rimidine with substituted aminopyrazoles 98 resulted in functionalized dihydro-1H-pyrazolo [3,4-b]pyridines 99 under the same conditions. Moreover, the reaction preceded well even with other 1,3-diketones along with primary heterocyclic amines (Scheme 36). The modest yields of 99 compared to 97 were reasoned with the decomposition of the amines. Suprisingly, the adaptation of conventional strategy delivered the aromatized product in better yields (62-75%). The increased yield was attributed to the lower decomposition observed for the starting material amines. The authors proposed that the final aromatized product was derived from the initial formation of the dihydro derivative 99, followed by aromatization under the described conditions. The preliminary in vitro antitumor studies of the compounds displayed low to moderate activity. A plausible mechanism suggests the formation of 2,6-dibenzylidene heterocyclic ketones A by the condensation of aromatic aldehydes and heterocyclic ketones followed by a [3 + 3] cycloaddition between A and amidine giving off the intermediate B, which undergoes 1,5-hydrogen transfer followed by 1,3-hydrogen transfer to give the final products (101, Scheme 39).  (1,2-a)pyrimidine: The generation of imidazoheterocycles has been a daunting challenge for the chemist due to the harsh condition requirements, such as multi-step protocol, high temperature and longer reaction time [87][88][89]. Overcoming these synthetic barriers, Patel and co-workers [90] developed an efficient microwave-assisted protocol for the construction of imidazopyrimidine clubbed pyrazoles 105. The onepot one step/two step approach by the authors employed a KOH-mediated reaction of 4-carbaldehyde pyrazoles 102, acetophenones 103 and 2-aminobenzimidazole (104) in a greener solvent mixture of ethanol/water (1:1) under microwave irradiation at 340 W (Scheme 40). The conventional approach delivered the desired products in a two-step procedure with prolonged reaction time (28 h) advocating the efficiency of microwave technology. The protocol was used to design densely diversified imidazopyrimidines, which were further studied for their antimicrobial, antituberculosis and antimalarial effects.

Imidazo
Scheme 41 demonstrates the mechanism involving a direct Claisen-Schmidt condensation to intermediate A followed by a sequential [3 + 3] cycloaddition with 104 yields B. Finally, dehydration and hydrogen removal from B furnished the desired products 105 in good to moderate yields.

Purines
Purines are categorized as heterocyclic aromatic compounds, consisting of a pyrimidine ring fused to an imidazole ring. Adenine and guanine are purine nitrogenous bases found in nucleic acids. Utilizing purine analogs as isosteres are wellthought-out as an important approach in medicinal chemistry and in drug discovery domains [91,92]. Purine scaffolds, such  as allopurinol (106) used as the first choice of drug in gout therapy and temozolomide (107) used in the treatment of brain cancer are well-known examples [93,94]. Among the purine scaffolds, 5-aza-9-deazapurine and 5-azapurine have been identified as a favorable skeleton for the construction of new compounds such as 108 and 109 ( Figure 8) [95,96].
Considering this fact, Dolzhenko and co-workers [97] reported the first microwave-assisted multicomponent strategy for the regioselective construction of substituted 5-aza-adenines 113 using cyanamide (110), triethyl orthoformate (111) and 5-amino-1,2,4-triazoles 112 as structural units with methanol as solvent (Scheme 42). Simple filtration with no product isomer formation gives this protocol an edge over the other traditional methods [98,99]. The conventional method produced the target molecule in a trace amount (1.5%). Addition of TMSCl to this approach resulted in 2.5% yield of the desired product. On the contrary in the presence of microwave irradiation the regioselctive 5-aza-adenine was afforded in 65% yield within 20 min in the absence of TMSCl. This indicates the importance of microwave in the construction of such pharmacologically relevant molecules under benign conditions. Similarly, the same group [100] explored an one-pot three-component reaction involving cyanamide (110), 2-amino-4-phenylimidazole 114 and triethyl orthoformate (111) using ethyl acetate as a solvent for the exclusive synthesis of 5-aza-7deaza-adenines 115 over the other regioisomer (A) in good to excellent yields (Scheme 43). A comparative study with the conventional approach produced the desired product in 13% yield with an elongated reaction time of 24 h. A scale protocol adapted with same reaction conditions afforded the product with a better yield of 92% supporting the scale-up strategy with microwaves. The protocol provided an easy admittance to 5-aza-7-deazapurine molecules used as antiviral and cytotoxic agents [101].
The potential rearrangement explained the regioselectivity during ring closure as depicted in Scheme 44. Theoretically, two regioisomeric pairs of adenine (115, A) and isoadenine are possible (C, D) (Scheme 44). However, using the multicomponent approach one product, 4-amino-7-arylimidazo[1,2a] [1,3,5]triazines 115, could be only obtained. The regioisomer A being less stable due to steric hindrance between the amino and the aryl group rearranges to give desired product 115. The mechanism involved in the formation of intermediate B is similar to the mechanism proposed for amino-1,3,5-triazine ring rearrangement [102] in an analogous heterocyclic system. 8 Pyridines/fused pyridines 8
Shamsuzzaman and co-workers [107] demonstrated the microwave-assisted synthesis of steroidal pyridines 123 utilizing steroidal ketones 122, aldehydes 5, malononitrile (51)/methyl cyanoacetate and ammonium acetate as structural units and MgO nanoparticles as a catalyst in ethanol solvent. The reaction proceeded even in absence of a catalyst but resulted in a very low yield (Scheme 45). The authors methodically explored the surface defects of MgO such as edges, kinks and corners to advantage as they are regarded to enhance the efficiency of the catalyst by playing a crucial role in splitting the chemical bonds of the absorbed molecules [108].
The reusability of the heterogeneous catalyst is also an advantage of the stated strategy. The higher yields >82% obtained from the microwave-assisted protocol reveal its competency Scheme 46: Proposed mechanism for steroidal pyridine. over the conventional method (79%) along with the time parameter wherein the time was reduced from hours to just minutes (6 h to 20 min). The protocol adroitly represents the efficiency of microwave and multicomponent strategy in the generation of complex molecules like steroids. The mechanism follows a pathway where an imine A is generated from the reaction between steroidal ketone and ammonium acetate. Simultaneously, the aldehyde and malononitriles undergoes Knoevenagel condensation resulting in alrylidene intermediate B. This is followed by Michael addition of imine A on the activated alrylidene intermediate B and subsequent intramolecular cyclization C and aromatization D affords the target molecules 123 (Scheme 46).
N-alkylated pyridones are valuable scaffolds offering biological activity such as immunomodulators, memory-enhancers and anticancer agents [109,110]. A direct approach to achieve N-alkylated pyridones are less explored and those available present limitations such as poor selectivity and yields, expensive catalyst and poor chemoselectivityy [111,112]. Therefore, in search of a straightforward approach to such molecules.
Mekheimer and co-workers [113] developed a protocol for the synthesis of N-alkylated 2-pyridones 125 utilizing a microwaveassisted three-component reaction of aldehydes 5, malononitrile (51) and N-alkyl-2-cyanoacetamides 124 as structural units and K 2 CO 3 as base promoter using EtOH as solvent (Scheme 47). The introduction of microwave drastically improved the yield from 65-77% to 81-94% along with reduction in time from 180 min to 15 min when a comparative study with conventional approach was performed. In the same direction, Huang and co-workers [114] for the first time reported a microwave-assisted four-component domino reaction involving acyclic 1,3-diketones 54, amines 32, diethyl malonate (126) and triethyl orthoformate (111) for the synthesis of substituted pyridone derivatives 127 at 120 °C under catalyst-and solvent-free conditions. The reaction proved adaptable even for uncommon amines such as simple alkylamines in good to moderate yields (Scheme 49). The initial assessment under refluxing conditions in presence of catalyst and solvent afforded the products in low yields (20-40%) in 2-3 h. Whereas catalyst-and solvent-free conditions under microwave irradiation spiked the yield to 84% in 30 min demonstrating the effectiveness of the technological approach.

Pyrazolopyridine:
Quiroga and co-workers [123] envisioned an environmentally benign three-component microwaveassisted synthesis of pyrazolo [3,4-b]pyridine-5-spirocycloalkanedione 139 derivatives via a reaction between 5-(4-R-benzyl amino)pyrazoles 137, cyclic 1,3-diketones 6 and formaldehyde (138) in ethanol as solvent. The protocol shows good functional group tolerance with both EDG and EWG on pyrazoles resulting in moderate to good yields (Scheme 53). An interesting observation revealed that employing indanedione as the cyclic diketone directed the formation of an aromatized molecule 139a instead of the expected spiro product. The authors rationalized 139a formation through a competitive intramolecular cyclo condensation over intermolecular cyclo condensation reaction with loss of benzyl alcohol delivering a stable aromatized product. Although the yields were comparable under reflux and microwave approach, the conventional approach provided access to the desired molecule in 24 h whereas the microwave assistance exponentially reduced the reaction time to 25 min.  The synthesis of regioselectively functionalized macrocyclanefused pyrazolo [3,4-b]pyridine derivatives 142 was demonstrated by Jiang and co-workers [124] by employing aldehydes 5, 5-methyl-3-aminopyrazole (140) and cycloketones 141 as building blocks in a one-pot manner with AcOH and TFA as promoter under microwave irradiation. This method stands out with its high efficiency and shorter reaction time to produce the macrocyclane-fused pyrazolo [3,4-b]pyridine skeleton (Scheme 55). The above protocol offers regioselectively 2-arylated pyrazolopyridines which the other reported protocols failed to produce with similar starting material. The previous reports produced 4-arylpyrazolopyridines [125][126][127].

Quinolines
Quinolines are bicyclic aromatic heterocycles consisting of a fused pyridine and benzene ring. Quinoline and its derivatives are important both from synthetic as well as biological perspective owing to their plethora of pharmacological activities. They are potent anticancer (144), antimicrobial (145), and anticonvulsant agents (146, Figure 11) [129].

5,6-Dihydroquinazolinones
Menéndez and co-workers [138] described an efficient microwave-assisted sequential four-component reaction of chalcones 157, acyclic 1,3-diketone 54, butylamine (158) and ammonium formate (159) using CAN as a catalyst and ethanol as solvent. This is followed by sequential addition of formamide (160) under microwave irradiation to yield polysubstituted 5,6-dihydroquinazolinones 161 in good to moderate yields (Scheme 64). The protocol exemplifies the use of MW-assisted MCR for the construction of the aromatic ring from a simple aliphatic chain. Non-chromatographic techniques for purification of the products further added to the list of advantages to the method. The authors also succeeded in developing a metal free N-bromosuccinimide-mediated MW-assisted halogenation elimination sequence resulting in aromatization of dihydroquinazolinones 161a reducing the use of traditional highly polluting dehydrating agents [139]. agent under microwave conditions. A sequential addition of adenine 164 in the presence of a K 2 CO 3 yields regioisomers of substituted purine quinazolinone 165 in an 80:20 ratio (Scheme 66). The authors observed a variation in the ratio of regioisomer formation with a slight deviation in reaction conditions such as microwave power, reaction time or temperature. The set protocol was successfully employed for the synthesis of structural analogues of IC87114 (166), first isoform-selective PI3K-δ inhibitor used as an anticancer agent [141].

Fused quinazolinones
The fused substituted benzothiazolo/benzimidazoloquinazolinones 167 was achieved by Singh and co-workers [142] from aldehyde 5, cyclic 1,3-diketones 6a,b and 2-aminobenzoazoles 104 as the structural fragments with Sc(OTf) 3 as catalyst under microwave irradiation in solvent-free conditions (Scheme 67). The catalytic activity of the catalyst was evident to remain intact even with three successive runs and provided with an environmentally benign and cost effective approach towards the construction of fused quinazolinones.
Based on the literature [143,144], the authors deduced a plausible mechanism as described in Scheme 68. Initial activation of oxygen on the carbonyl group of cyclic 1,3-diketone B and aldehyde A by Sc(OTf) 3 is followed by Knoevenagel condensation between these activated groups C. Sc(OTf) 3 enhances the electrophilic character of oxygen by coordinating with carbonyl oxygen. This facilitated an easy attack on the carbonyl carbon D Scheme 68: Proposed mechanism for fused benzothiazolo/benzoimidazoloquinazolinones.

Scheme 69:
On-water reaction for synthesis of thiazoloquinazolinone.
by the lone pair of nitrogen from 2-aminobenzazoles which stemmed the desired products 167 by dehydration (E) followed by intramolecular cyclization (F).
The traditional methods for thiadiazoloquinazolinone synthesis possessed certain limitations, such as reduced yields, multi-step procedures and expensive starting materials [145,146]. On water chemistry has been in the scientific community for a while but has received little attention [147]. Focussing their efforts towards MWA-MCR on water, Sharma and co-workers [148] established a crafty construction of thiadiazolo [2,3b]quinazolinones 169. The on water reaction involved substituted 1,3,4-thiadiazol-2-amine 168, aldehydes 5 and cyclic 1,3-diketones 6a,b in an aqueous acidic medium of p-TSA (Scheme 69). A comparative study of conventional and microwave-assisted reactions clearly resulted in an exponential increase in yield from 78% to 96% and reduced reaction time from 6 h to 5 min with the microwave approach. Good functional group tolerance was demonstrated with all three reaction components.
A catalytic OH site present among one of the four water molecules at the interface of water and the organic layer is reasoned as the reaction center. Scheme 70 explains the initiation of the reaction with Knoevenagel condensation between aldehyde and cyclic diketone to form intermediate A. The water and p-TSA Scheme 70: Proposed mechanism for the thiazoloquinazolinone synthesis.  In 2013, Pal and co-workers [149] reported a β-cyclodextrinmediated synthesis of 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones 171 in an aqueous medium. The strategy employed isatoic anhydride 170, amines 32 and 2-formylbenzoic acid (26) as the building blocks under microwave irradiation (Scheme 71). The high selectivity of cyclodextrin is attributed to the hydrophobic cavities that facilitate the specific substrate binding and reactivity. The conventional method of reaction resulted in prolonged reaction time (14-16 h) and reduced yield whereas microwave assistance aided reduced time (10 min) with increased yield (up to 95%). The protocol provides a greener and faster approach towards such biologically effective motif's which under classical protocols are tedious to synthesize.
The plausible mechanism in Scheme 72 reveals the catalyst aided activation of anhydride carbonyl, followed by nucleophilic attack of amine results in a benzamide intermediate A generated in situ. A subsequent reaction of intermediate A with formylbenzoic acid directs imine intermediate B formation followed by a concurrent intramolecular cyclization involving the acid and amide groups generates the desired products 171.
Guedes da Silva and co-workers [153] successfully developed a protocol for the efficient synthesis of hydrosoluble, air stable Cu(I) DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane, 176) and further employed it as a catalyst in the Huisgen cycloaddition reaction for the synthesis of disubstituted 1,2,3-triazoles 178 using alkyne 147, organic halide 177 and sodium azide in aqueous medium under microwave irradiation (Scheme 73). The reaction involves in situ-generated azide from organic halide which reacts with copper(I) acetylide to provide the corresponding 1,4-disubstituted 1,2,3-triazole. The cage-like DAPTA is a water soluble phosphine that can stabi-Scheme 75: Synthesis of β-hydroxy-1,2,3-triazole. lize low oxidation state metals like copper hence used as ligands with copper to form complexes that catalyze the reaction. The catalyst can be recycled and showed good reactivity up to two cycles with good yields. The conventional heating technique successfully generated the desired molecules in 14 h whereas the microwave-assisted method considerably reduced the time to 15 min with similar yields.
The possible mechanism of the reaction employing copper as catalyst proceeded with the formation of Cu acetylide complex A through the coordination of alkyne to Cu(I) which further reacts with benzyl azide B (formed from 177 and azide) leads to the formation of an intermediate C. This triazolide intermediate undergoes protonation to afford the final product, i.e., 1,4disubstituted 1,2,3-triazoles 178, thereby completing the catalytic cycle (Scheme 74). Naeimi and co-workers [154] introduced a copper-imprinted periodic mesoporous organosilica nanocomposite (Cu@PMO NC), a catalyst employed for the synthesis of β-hydroxy-1,2,3triazoles 181 in an aqueous medium. The strategy engaged epoxides 179 and sodium azide for the in situ generation of organo azides entrapped by the catalyst for further reaction with acetylide 180 under microwave irradiation. Under similar conditions, epoxides with a good leaving group direct the formation of bistriazoles 182 (Scheme 75). The method proposes a number of advantages, such as environmentally benign conditions like a solvent (water), energy consumption (microwave), reduced time (6-7 min), good to excellent yields (74-95%) and recyclability and reusability of the catalyst. The observation suggested the efficiency of the catalyst remains intact even after six cycles.
A plausible mechanism explained in Scheme 76 depicts the catalyst-mediated epoxide ring-opening by azide forms azidoaryl ethanol intermediate A. Cu(II) acetylide complex B undergoes the classical 1,3-dipolar cycloaddition product Cu(II) β-hydroxytriazolide (C). The protonlysis of the complex C directs the formation of the final desired product of β-hydroxytriazolide 181.
1,2,4-Triazoles have carved a niche as potent antifungal agents with fluconazole (173) as the representative drug of this category. The bistriazoles inspired skeletons constructed by Kamble and co-workers [155] demonstrated the efficient synergistic application of microwave and multicomponent reactions. Two strategies were studied to optimize the reaction yield. The onepot reaction involving 1,3,4-oxadiazol-2(3H)-one 183, formamide (160) and dibromoalkanes 184 in presence of K 2 CO 3 under solvent-free conditions aided the target bistriazoles 185 in moderate yield (Scheme 77).
An alternative approach suggested the sequential addition of 1,3,4-oxadiazol-2(3H)-one 183 and formamide (160) followed by dibromoalkanes 184 under similar conditions resulted in higher yields (72-93%) than the one-pot approach. The authors also observed that the multicomponent strategy under the conventional method at 200 °C failed to produce the desired molecule whereas the sequential addition under the traditional refluxing method resulted in the product in moderate yield. Such an observation clearly establishes the dominance of MWA-MCR in the generation of valuable pharmacophores. The synthesized molecules studied for antifungal activities showed moderate to excellent activity against A. niger, A. flavus, T. atroviridae, P. chrysogenum, and C. albicans. Scheme 78 depicts the ring insertion of nitrogen into 1,3,4-oxadiazol-2(3H)-one directed by formamide followed by demethylation at C-5. Two consecutive nucleophilic substitutions with dibromoalkanes yields bistriazoles 185, the target molecule.
Recently, Vedula and co-workers [158] designed a facile and efficient base-catalyzed microwave-assisted three-component reaction between thiosemicarbazide (191), substituted chalcones 157 with substituted phenacyl bromides 41 in EtOH for the construction of pyrazolothiazoles 192. A comparative study of the conventional refluxing method with the microwaveassisted protocol depicted the efficiency of microwave technology in increasing the yield from 82% to 95% in reduced time from 4 h to 5 min. The library of molecules so generated was found to be active against different cancer cell lines which make this protocol useful for the generation of molecules that can act as lead for pharmacologically active moieties (Scheme 80). The reaction is believed to proceed via the synthesis of a Hantzsch thiazole followed by condensation with substituted chalcones.
Striving towards chromene-based molecules, Safari and co-worker [160] established a three-component reaction involving substituted phenols 196-198, malononitrile (51) and aldehyde 5 using CNT-Fe 3 O 4 -IL as a magnetic nanocatalyst under microwave irradiation in an aqueous medium for the generation of various substituted 2-aminochromenes 199-201 (Scheme 81). Ionic liquids can absorb microwave energy and their ability to translate it into homogeneous heat was efficiently demonstrated in this protocol for the generation of the desired molecules. The reusability of the heterocatalyst provides an added advantage to the stated strategy with catalytic activity intact up to five successive runs. The catalyst was recovered using an external magnetic field. A plausible reaction mechanism postulated with an imidazolium cation of CNT-Fe 3 O 4 -IL activating the aldehyde followed by a Knoevenagel condensation with malononitrile gives α-cyanocinnamonitrile derivative A by ionic liquid anion. A Michael addition ensued between the activated phenols 196-198 and A provides B. Nucleophilic attack of the phenoxide group on the cyano group led to an intramolecular cyclization of product B which finally went through tautomerization to afford the desired products 199-201 (Scheme 82).

Conclusion
In summary, MWA-MCRs provide an easy access to biologically relevant molecules ranging from simple fused rings to complex steroidal molecules. This efficient merger stands as a classical example of technology-driven molecules. The MCR demonstrates an amalgamation of sub-reactions such as Knoevenagel reaction, Michael addition, cycloaddition reaction etc., in a one-pot manner to reassure the atom economy of the reaction for an environmentally benign approach. Whilst MW assistance reduces the time from hours to minutes and even to seconds with higher yields avoiding tedious purification process. The last decade has witnessed an accelerated interest in MWA-MCR to develop molecules and has hastened the process of drug discovery. Continuous efforts can cater towards development of novel approaches in generation of relevant phamacophores with a greener synthetic protocol. This review illustrates various strategies used to generate pharmacologically relevant heterocyclic molecules, such as pyrimidines, pyranes, purines, pyridines, acridine, etc., aided by MW-MCR along with their mechanistic approach. Undoubtedly, there is still an immense possibility for exploration in this field and a lot remains to be brought on the table in the near future. Therefore, this review may pave a direction for many researchers and propel them to investigate and develop newer chemical entities based on MWA-MCRs.