Inorganic nanoparticles promoted synthesis of oxygen-containing heterocycles

2.2.1 Two-component reactions

CuO NPs catalyzed the synthesis of poly-substituted furans 5 via oxidative C–H/C–H functionalization was developed in 2016 [17]. In this reaction, CuO NPs were used as reusable catalysts in direct functionalization of α,β-unsaturated carbonyl compounds 3 through conjugate addition in aqueous ethanol. Through the oxidative reaction of 1,3-diphenyl-prop-2-ene-1-one 3 and acetylacetone 4 in aqueous ethanol, Payra et al. explored a 3,4-dicabonyl-substituted furan derivative 5 using CuO NPs as a catalyst and tertiary butyl hydroperoxide (TBHP) as an oxidizing agent. This method afforded the products in greater isolated yields (70–91%) with faster reaction time. Moreover, the recyclability and homogenous nature of CuO NP catalyst and use of aqueous ethanol as a green solvent made the protocol environment benign (Scheme 2).

Scheme 2

CuO NPs catalyzed the synthesis of poly-substituted furans. a) Method overview; (b) representative examples.

Ji et al. reported a highly efficient protocol for the synthesis of benzofurans 8 via one-pot two-component reaction of o-iodophenols 6 with phenylacetylene 7. The reaction occurs in the presence of palladium NPs supported on N,O-dual-doped hierarchical porous carbon through Sonogashira cross-coupling followed by cyclization of o-halogenated phenols 6 with terminal alkynes 7 under copper- and ligand-free conditions (Scheme 3). The catalyst has great stability and is simple to recover for further usage. The approach is an environmentally friendly way to create biologically useful heterocyclic compounds [18].

Scheme 3

Synthesis of benzofurans employing Pd@N,O-carbon. (a) Method overview; (b) representative examples.

2.2.2 Three-component reactions

A one-pot three-component reaction between isocyanides 11, secondary amines 9, and an electron-poor 2-hydroxybenzaldehyde derivative 10 for the synthesis of benzo[b]furan derivatives 12 using silica NPs from rice husk ash as a green catalyst at ambient temperature was reported in 2014 [19]. Due to greater electrophilicity of the carbonyl groups of electron-withdrawing 2-hydroxybenzaldehyde derivatives relative to carbonyl groups of electron-releasing 2-hydroxybenzaldehyde derivatives, the electron-withdrawing 2-hydroxybenzaldehyde derivatives have more preference as a suitable starting material over electron-releasing derivatives (Scheme 4).

Scheme 4

Three-component synthesis of benzo[b]furan derivatives using silica NPs. (a) Method overview; (b) representative examples.

According to the possible mechanism of this reaction (Scheme 5), the intermediate A would be produced by the condensation of 2-hydroxybenzaldehyde derivative 10 and secondary amine 9, which would then react with the alkyl isocyanide 11 to produce intermediate B. The cyclization of the ionic intermediate B would produce benzofuran, followed by tautomerization of intermediate C afforded the desired product, benzo[b]furan derivatives 12.

Scheme 5

Mechanism for the formation of benzo[b]furan derivatives using silica NPs.

In 2018, a facile synthesis of trans-dihydroindeno[1,2-b]furans 16 was developed via one-pot three-component reaction between N-[2-(aryl)-2-oxoethyl)]pyridinium bromide 13 with 1,3-indandione 14 and an aryl glyoxal 15 in the presence of nano-γ-Fe₂O₃-quinuclidine based as a catalyst in an aqueous medium [20]. The advantages of this approach include fast setup, avoidance of toxic catalysts and organic solvents, reusability of the catalyst, little catalyst loading, quick reaction times, and simple product separation (Scheme 6).

Scheme 6

Synthesis of trans-dihydroindeno[1,2-b]furans with γ-Fe₂O₃-quinuclidine NPs. (a) Method overview; (b) representative examples.

Shirzaei et al. reported a green approach for the synthesis of furan derivatives using thiocarbohydrazide doped iron nanoparticles as catalyst. This three components reaction of dialkyl acetylenedicarboxylate 18 with aromatic aldehydes 10 and aromatic amines 17 in the presence of the catalyst was carried out in EtOH giving high yields of the product (Scheme 7). The general route for the preparation of nanocatalyst, Fe₃O₄@SiO₂@ionic liquid (IL) as a heterogeneous acidic catalyst, is shown in Scheme 8. The catalyst’s capacity to be reused up to five times without experiencing any desired decrease in efficacy is by far its most notable attribute. As a result, this catalyst offers several advantages over additional non-magnetic catalysts [1].

Scheme 7

Synthesis of furan derivatives catalyzed by Fe₃O₄@SiO₂@IL. (a) Method overview; (b) representative examples.

Scheme 8

General route for the synthesis of Fe₃O₄@SiO₂@IL.

According to the plausible mechanism of the reaction, MNP catalyst promotes the condensation of the carbonyl group between intermediates A and B to produce the intermediate C. The catalyst further activates the carbonyl group of intermediate C, followed by nucleophilic attack through Michael addition, producing intermediate D. Finally, the removal of H⁺ terminated the reaction, generating the desired product 19 (Scheme 9). In another study, 4-carboxybenzyl sulfamic acid-functionalized Fe₃O₄ NPs were also used as a novel catalyst in this reaction [2].

Scheme 9

Proposed mechanism for the synthesis of furans catalyzed by {Fe₃O₄@SiO₂@IL}.

Feng and his co-workers, in 2021, slightly modified the previous work in Scheme 7 for the synthesis of furan derivatives [21]. In this work, they used sulfamic acid 2-aminobenzothiazole-6-carboxylic acid (SA-ABTCA)-functionalized Fe₃O₄ as nanocatalyst for the synthesis of novel 3,4,5-trisubstituted furan-2(5H)-ones derivatives 21 via one-pot reaction of aryl aldehydes 10, 4-amino pyridine 20, and dimethylacetylenedicarboxylate 18. The average particle diameter determined by the Scherrer equation afforded the crystalline size for SA-ABTCA Fe₃O₄ NPs to be about 21 nm. Moreover, some compounds also exhibited good antibacterial activity and can be further promoted as powerful antibacterial agents. The antibacterial active compounds have higher effectiveness against Bacillus subtilis but exert moderate activity against both gram-positive and gram-negative bacteria. This green nanocatalytic protocol for the synthesis of the desired compound offers clean production in a brief amount of time and has strong reversibility, making the strategy more feasible and affordable for researchers (Scheme 10).

Scheme 10

SA-ABTCA-Fe₃O₄ catalyzed synthesis of novel 3,4,5-trisubstituted furans. (a) Method overview; (b) representative examples.

Wang et al. developed an effective carbonylation of cinnamyl chloride 22 and phenylacetylene 11 with CO₂ 23 to afford 4-dihydronaphtho[2,3-c]furan-1(3H)-one 24 using α-cyclodextrin (α-CD) doping dendritic fibrous nano-silica (DFNS)-supported gold NPs as a catalyst [22]. It was discovered that the DFNS/α-CD/Au nanostructures could be nominated because of their efficient and distinctive catalytic behavior during the synthesis of the desired compound (Scheme 11).

Scheme 11

Synthesis of 4-dihydronaphtho[2,3-c]furan-1(3H)-ones in the presence of DFNS/α-CD/Au NPs. (a) Method overview; (b) representative examples.

2.3.1 Two-component reactions

A high atom economy and efficient approach to synthesize a xanthone 25 skeleton via highly efficient copper-based magnetically recoverable nanocatalyzed coupling of 2-substituted benzaldehydes 10 with phenol derivatives 6 was developed by Cintia and his co-workers [23]. The catalyst is easily recovered by means of an external magnet and reused again as a catalyst for further reaction without significant loss of catalytic activity. Moreover, the technology offers an interesting protocol for the production of a small library of xanthones 25 in very good yield and is compatible with a number of functional groups. Better yields of the cyclization products were obtained with regard to the electronic characteristics of the substituents when electron-donating groups were present on the aromatic ring of the phenols (Scheme 12).

Scheme 12

Synthesis of xanthone skeleton using Cu nanoparticle (CuNP) catalyst. (a) Method overview; (b) representative examples.

Anshu and his co-workers reported a highly efficient, chemoselective synthesis of pyrano[2,3-c:6,5-c′]dipyrazol]-2-ones 28 in water via one-pot reaction of carbonyl compounds 26 with 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 27 (1:2 ratio) in the presence of Ag NPs decked graphene oxide (GO) composite as a catalyst (Scheme 13). This technique demonstrates the high selectivity of pyranodipyrazolones 28 over arylmethylene bispyrazolols and arylmethylenepyrazolones. Due to the loss of two water molecules, the method has a high atom economy and is environmentally friendly. Furthermore, the catalyst was easily recoverable and could be recycled at least seven times without suffering a significant reduction in catalytic activity [24].

Scheme 13

The chemo-selective synthesis of pyrano[2,3-c:6,5-c′]dipyrazol]-2-ones. (a) Method overview; (b) representative examples.

The mechanism of this reaction involves electrophilic activation of benzaldehyde 26 by coordinating with the Lewis acid sites of Ag NPs/GO (Ag NPs/GO) composite. Then, Knoevenagel condensation of activated benzaldehyde A with pyrazolone 27 formed Knoevenagel adduct B. Furthermore, activation of adduct B by the catalyst through coordination with oxygen facilitates the Michael addition of a second pyrazolone 27 unit forming hydroxyl derivate C. Finally, successive cyclization afforded the desired product 28 with the loss of water molecule and released the catalyst for the next cycle (Scheme 14).

Scheme 14

Plausible mechanism for synthesis of pyrano[2,3-c:6,5-c’]dipyrazol]-2-ones.

A highly efficient and recyclable CoNP@SBA-15 (Co nanoparticles@santa barbara amorphous-15) nanocatalyst supported an aqueous and environmentally friendly approach for the synthesis of 1,8-dioxo-octahydroxanthenes 30 through the reaction of dimedone 29 with aromatic aldehydes 10 (2:1 ratio) was developed by Rajabi et al. [25]. In this protocol, high yields, minimal catalyst loading, quick reaction times, and simple workup offered the benefits of employing this heterogeneous catalytic system. Additionally, the catalyst was successfully reused 10 times in a row without significantly losing any catalytic activity. The catalyst with a pore size of 3.6 nm had a surface area of 448 m² g⁻¹ and 0.77 mL g⁻¹ mesoporous pore volume (Scheme 15).

Scheme 15

Synthesis of 1,8-dioxo-octahydroxanthenes in the presence of CoNP@SBA-15. (a) Method overview; (b) representative examples.

An efficient, selective, rapid, and eco-friendly microwave-assisted direct synthesis of xanthones 32 via intermolecular catalytic coupling of salicylaldehydes 10 and 1,2-dihaloarenes 31 using green nanopalladium-supported catalyst (PdNPs) was developed in 2019 (Scheme 16). The reaction proceeds with high regioselectivity and excellent yields, and the catalyst can be recycled up to four times without significant loss of its catalytic activity [26].

Scheme 16

Microwave-assisted synthesis of xanthones using a green nanopalladium-supported catalyst. (a) Method overview; (b) representative examples.

Mechanistically, the oxidative addition of 1,2-dihaloarene 31 with palladium (O) catalyst formed aryl-palladium(ii) intermediate A. Then, salicylate 10, generated under basic conditions by displacing the halide, reacts with intermediate A to form aryl(aryloxy) palladium(ii) intermediate B. Consequently, intermediate B undergoes a C–H activation through the C–H bond of the aldehyde to afford cyclic palladium intermediate C. Finally, the desired xanthone 32 is formed by the β-elimination of C and an intramolecular nucleophilic substitution (Scheme 17).

Scheme 17

Proposed catalytic cycle for the PdNP-catalyzed direct synthesis of xanthones.

2.3.2 Three-component reactions

Nezhad et al. [27] explored a silica-coated Fe₃O₄@SiO₂ MNP-catalyzed synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives 35 under mild, green, and heterogeneous conditions through one-pot three-component coupling reaction between indole derivatives 33, salicylaldehyde 10, and malononitrile 34 (Scheme 18). The synthesis of MNPs supported l-cysteine (LCMNP) is shown in Scheme 19.

Scheme 18

Synthesis of 2-amino-4H-chromene-3-carbonitriles using LCMNP. (a) Method overview; (b) representative examples.

Scheme 19

Synthesis of MNPs supported l-cysteine.

The designed technique allowed for the reuse of this magnetic recyclable organ catalyst system seven times without the need for any modifications to its catalytic activity. These NPs have an average size of 10 nm according to dynamic light scattering analysis, with a spherical shape displayed in TEM images of the NPs.

A facile one-pot ultrasound-assisted efficient synthesis of benzo[g]chromenes 37 using Fe₃O₄/polyethylene glycol (PEG) core/shell NP was developed in 2016 [28]. The reaction proceeds through one-pot three-component condensation of aldehyde 10 (1 mmol), malononitrile 34 (1.5 mmol), and 2-hydroxy-1,4-naphthoquinone 36 (1 mmol) in ethanol with 12 mg of nano-Fe₃O₄/PEG. The significant benefits of this protocol include simple setup, rapid reaction times, easy workup, catalyst recycling, little catalyst loading, and the effective and efficient use of ultrasonic irradiation (Scheme 20). After completion of the reaction, the catalyst was separated by an external magnetic field and can be reused five times with a slight reduction in the product yields on each reuse (run 1, 95%; run 2, 95%; run 3, 94%; run 4, 94%; run 5, 93%).

Scheme 20

Fe₃O₄/PEG core/shell catalyzed synthesis of benzo[g]chromenes. (a) Method overview; (b) representative examples.

Davood and Masoumeh developed an efficient, green, and reusable thiourea dioxide‐grafted γ‐Fe₂O₃/hydroxyapatite (HAp) MNP for the synthesis of pyranopyridine derivatives 39 in high yields. The reaction proceeds through one‐pot three‐component reactions between aldehydes 10, malononitrile 34, and 3‐cyano‐6‐hydroxy‐4‐methyl‐pyridin‐2(1H)‐one 38 under mild and solvent‐free conditions (Scheme 21). The catalyst is easily recyclable in a magnetic field and can be used five times in a row without noticeably losing any substantial catalytic activity. From the study of field‐emission (FE‐SEM) and TEM, the NPs display a regularly spherical morphology with an average diameter of about 80 nm [29].

Scheme 21

Thiourea dioxide‐grafted γ‐Fe₂O₃/HAp catalyzed synthesis of pyranopyridine derivatives. (a) Method overview; (b) representative examples.

Green and magnetic recyclable formamidine sulfonic acid-functionalized Fe₃O₄@SiO₂ as an efficient and hydrogen bonding catalyst for the synthesis of pyrano[2,3-d] pyrimidinone derivatives 41 via one-pot three-component condensation reaction of benzaldehyde 10 (1 mmol), malononitrile 34 (1.2 mmol), and barbituric acid 40 (1 mmol) in water at room temperature was employed by Ghandi et al. [30]. The catalyst could be employed repeatedly without a noticeable decrease in its activity, and Fourier transform infrared (FT-IR) observations show no substantial changes in the structure of the catalyst before and after the reaction. This reaction protocol has a short reaction time, high yield, simplicity of product isolation, clean reaction profile, and environmental benignity (Scheme 22).

Scheme 22

One-pot three-component synthesis of pyrano[2,3-d] pyrimidinone derivatives. (a) Method overview; (b) representative examples.

A practical three-component reaction between 4-hydroxycoumarin 43, malononitrile 34/ethylcyanoacetate 42 and arylaldehydes 10 for the synthesis of 4-aryl-substituted pyranofuzed coumarins 44 using recyclable molybdenum oxide nanocatalyst (MoO₃ NPs) was described by Yaghoub and his co-workers (Scheme 23). The SEM image analysis of MoO₃ NPs shows a diameter of about 40 nm of the nanocatalyst without any amorphous or other kinds of crystallized phase particles. The catalyst can be recovered and reused over six successive runs in comparable yields with that obtained from freshly prepared catalysts. The TEM and XRD patterns of the reused catalyst clearly displayed that no notable agglomeration or changes in the crystalline phase had taken place through each run [31].

Scheme 23

MoO₃ NPs catalyzed the synthesis of 4-aryl-substituted pyranofuzed coumarins. (a) Method overview; (b) representative examples.

Sadjadi et al. [32] reported a heterogeneous nanocatalyst Ag@cyclodextrin nanosponge (CDNS)-santa barbara amorphous‐15 (SBA‐15) promoted three‐component reaction of benzaldehydes 10, 4‐hydroxycoumarin 43, and urea 44 or thiourea 45 under ultrasonic irradiation to afford benzopyranopyrimidines 46. The catalyst can be recovered after the reaction and reused for up to four reaction runs with slight Ag (0) leaching and loss of catalytic activity (Scheme 24).

Scheme 24

Ag@CDNS-SBA‐15 promoted the synthesis of benzopyranopyrimidines. (a) Method overview; (b) representative examples.

According to the proposed mechanism (Scheme 25), activation of aldehyde 10 by the catalyst (compound A) followed by Knoevenagel condensation reaction with urea 45/thiourea 46 formed intermediate B. Then, the reaction of intermediate B with 4-hydroxycumarin 43 afforded intermediate C. Finally, the cyclization of intermediate C with the loss of a water molecule formed the desired final product 47/48.

Scheme 25

Plausible mechanism for synthesis of benzopyranopyrimidines.

Highly efficient and magnetically retrievable amine-functionalized SiO₂@Fe₃O₄ NP-catalyzed green and mechanochemical one-pot multicomponent synthesis of bioactive 2‑amino‑4H‑benzo[b]pyrans 49 was explored in 2020 (Scheme 26). The reaction is an environmentally benign reaction achieved by simply grinding substituted aromatic aldehydes 10, dimedone 29, and malononitrile 34 at room temperature under solvent and waste-free conditions with good yields, high purity, milder reaction conditions, and short reaction time.

Scheme 26

SiO₂@Fe₃O₄ catalyzed synthesis of 2‑amino‑4H‑benzo[b]pyrans. (a) Method overview; (b) representative examples.

Furthermore, the proposed catalyst has a number of significant properties, including broad functional group tolerance, enhanced yield, and recyclability [33]. A schematic illustration for the formation of NH₂@SiO₂@Fe₃O₄ MNPs is shown in Scheme 27.

Scheme 27

Synthesis of NH₂@SiO₂@Fe₃O₄ MNPs.

The mechanism of the reaction is driven specifically by the basic amino sites of the catalyst. Initially, Knoevenagel condensation between malononitrile 34 and aromatic aldehyde 10 formed the arylidiene malononitrile A, followed by Michael’s addition of dimedone 29 to arylidiene malononitrile A to form the intermediate B. Finally, intramolecular cyclization and protonation to the intermediate B results in the formation of the desired products 49, and the catalyst is regenerated in the reaction mixture (Scheme 28). In another study, a magnetic nanocatalyst Fe₃O₄@SiO₂-imidazole (imid)-H₃PMo₁₂O₄ NPs (PMA ⁿ ) was used for this reaction under ultrasonic irradiation or reflux conditions by Preeti and his co-workers [34].

Scheme 28

Mechanism of synthesis of 2‑amino‑4H‑benzo[b]pyrans.

An eco-friendly novel Schiff base complex of copper coated on epoxy-modified Fe₃O₄@SiO₂ MNPs nanocatalyst for the synthesis of chromene-annulated heterocycles via one-pot three-component reaction of aromatic aldehydes 10, various phenols (2-hydroxynaphthalene-1,4-dione 36/resorcinol 51/β-naphthol 50), and malononitrile 34 in ethanol under reflux conditions was explored in 2021. This method represents a novel and significant advancement in the synthesis of several chromene-annulated heterocycles with no usage of column chromatography, simple techniques, good yields, and magnetic recoverability of the catalyst (Scheme 29). The higher activity of this nanocatalyst due to its small size between 26 and 45 nm leads to the dispersion and diffusion of the nanocatalyst in the reaction mixture and can be rapidly taken out from the mixture with an external magnet. Furthermore, it can be reused directly in seven sequential runs without any loss in activity after washing with ethanol and drying it (Scheme 29) [35].

Scheme 29

Fe₃O₄@SiO₂ MNPs catalyzed the synthesis of chromene-annulated heterocycles. (a) Method overview; (b) representative examples.

According to the plausible mechanism of this reaction, Knoevenagel condensation reaction between aldehydes 10 and malononitrile 34 in the presence of the Schiff base complex of copper coated on epoxy modified Fe₃O₄@SiO₂ MNPs nanocatalyst as a Lewis acid formed Knoevenagel product C. Then, the intermediate E is produced through Michael’s addition of 2-hydroxynaphthalene-1,4-dionein D with Knoevenagel product C. Finally, intramolecular nucleophilic cyclization of intermediate F, formed by enolization of intermediate E afforded the 2-amino-4H-chromene derivatives 37/52/53. Then, the nanocatalyst was removed by a magnetic field from the reaction mixture for further use (Scheme 30).

Scheme 30

Plausible mechanism for the synthesis of chromene-annulated heterocycles.

2.3.3 Four-component reactions

Zahra and Mohammad explored a facile one-pot, four-component condensation reaction of ethyl-3-oxobutanoate 4, hydrazine hydrate 54, aromatic aldehydes 10, and barbituric acid 40 employing an efficient Cu-immobilized mesoporous silica NP, [Cu²⁺ @MSNs-(CO₂ ⁻)₂] as a catalyst for the synthesis of pyrazolopyranopyrimidines 55 in water. The catalyst was characterized by using nitrogen adsorption–desorption analysis, SEM, small angle powder XRD, thermal analyses (TGA and DTA), FT-IR studies, SEM, TEM, and EDX. The catalyst can be easily recovered from the reaction mixture at the end and reused numerous times without any loss in its catalytic activity (Scheme 31). The present protocol offered a relatively short reaction time, ease of product isolation, efficiency, generality, and high yield of products [36].

Scheme 31

Cu-immobilized mesoporous silica NP synthesis of pyrazolopyranopyrimidines. (a) Method overview; (b) representative examples.