Abstract
Pyrazole and its derivatives are an important class of heterocyclic compounds, present in several biologically and medicinally active compounds. Compounds containing 2,4-dihydro-3H-pyrazol-3-one structural motif, including 4,4′-(arylmethylene)-bis-(1H-pyrazol-5-ols), have attracted interest because they exhibit a wide range of biological activities and as the chelating and extracting reagents for different metal ions. There are two main strategies to the synthesis of bis(pyrazolyl)methane derivatives. The first involves the one-pot pseudo three-component reactions of 3-methyl-5-pyrazolone derivatives and aldehydes, and the second approach is the one-pot pseudo five-component reactions of β-keto esters, hydrazins and aldehydes. This review includes the recent investigation in the multi-component synthesis and their applications of bis(pyrazolyl)methanes and describes the literature reports for the period of 2014 to early 2021.
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Introduction
Heterocyclic compounds are widely distributed in nature and are essential to life. Pyrazole derivatives are an important class of heterocyclic compounds having a 5-membered ring structure with three carbon atoms and two neighbor nitrogen atoms. There are several applications of pyrazole core-based organic molecules in various areas including pharmacy and agro-chemical industries. 2,4-Dihydro-3H-pyrazol-3-one derivatives including 4,4′-(arylmethylene)-bis-(1H-pyrazol-5-ols), have attracted interest because they exhibit a wide range of biological activities such as anti-malarial [1], anti-inflammatory [2, 3], anti-nociceptive [4], antipyretic [5], antifungal [6], anti-virals [7], antidepressant [8], antibacterial [9, 10], antitumor [11], antioxidant [12] and anti-filarial agents [13]. In addition, these derivatives are applied as fungicides [14], analgesic [15], pesticides [16], insecticides [17], and as the chelating and extracting reagents for different metal ions [18,19,20]. There are two main strategies to the synthesis of bis(pyrazolyl)methane derivatives. The first involves the one-pot pseudo three-component reactions of two equivalents of 3-methyl-5-pyrazolone derivatives and one equivalent of aldehydes, and the second approach is the one-pot pseudo five-component reactions of two equivalents of β-keto esters, two equivalents of hydrazins and one equivalent of aldehydes.
Prior to 2014, bis(pyrazolyl)methanes were synthesized under different conditions and using various catalysts including piperidine catalyzed the reaction of pyrazolone with p-methoxybenzaldehyde [21], reaction of arylidene anilines with pyrazolone [22], solid-state Michael addition of pyrazolone to 4-arylidene-5 pyrazolones [23], reaction of pyrazolones with phenacylpyridinium salt in refluxing glacial acetic acid containing ammonium acetate [24], treatment of 4-[2-cyano-2-ethoxycarbonyl-1-(aryl)ethyl]-3-methyl-1-phenylpyrazolin-5-ones with pyrazolone [25], ring opening of bis-pyrazolo[5,4-b]-4H-pyranes with KOH (10%) in refluxing EtOH [10], reaction of aldehydes and pyrazolones in the presence of sodium dodecyl sulfate in aqueous media [26], treatment of aryl aldehydes and 1-phenyl-3-trifluoromethylpyrazol-5-one in aqueous media without catalyst [27], electrochemically induced catalytic reaction of pyrazolone with aromatic aldehydes using NaBr as an electrolyte [28]. Also, synthesis of bis(pyrazolyl)methanes has been accomplished via one-pot three-component reaction of pyrazolones with aromatic aldehydes using various conditions and catalysts such as ceric ammonium nitrate (CAN) [7], solvent- and catalyst-free at 120–130 °C [29], silica-bonded s-sulfonic acid [30], cellulose sulfuric acid [31], piperidine under ultrasound irradiation [32], diammonium hydrogen phosphate [33], poly(ethylene glycol)-bound sulfonic acid (PEG-SO3H) [34], sulfuric acid ([3-(3-silicapropyl)sulfanyl]propyl)ester [35], catalyst-free in refluxing H2O [36], silica sulfuric acid (SSA) [37], PEG-400 and catalyst-free [38], ionic liquid [HMIM]HSO4 under ultrasonic irradiation [39], N-(3-silicapropyl)-N-methylimidazolium hydrogen sulfate ([Sipmim]HSO4) [40], 3-aminopropylated silica gel [41], 1,3,5-tris(hydrogensulfato) benzene (THSB) [42], 1,3-disulfonic acid imidazolium tetrachloroaluminate {[Dsim]AlCl4} [43], LiOH. H2O in water [44], xanthan sulfuric acid (XSA) [45], phosphomolybdic acid [46], 2-hydroxyethylammonium acetate (2-HEAA) as a task-specific ionic liquid [47], ammonium acetate [48], silica-bonded N-propyltriethylenetetramine (SBNPTT) [49], melamine trisulfunic acid [50], ionic liquid 1-sulfopyridinium chloride {[pyridine–SO3H]Cl} [51], poly(4-vinylpyridine)-supported Brønsted ionic liquid ([P4VPy-BuSO3H]HSO4) [52] and [Cu(3,4-tmtppa)](MeSO4)4 [53]. Moreover, pseudo five-component synthesis of bis(pyrazolyl)methanes has been carried out under different conditions and catalysts such as silica-bonded N-propylpiperazine sulfamic acid (SBPPSA) under solvent-free conditions [54], catalyst-free in refluxing H2O [55], pyridine trifluoroacetate [56], AcOH at room temperature [57], microwave irradiation (300 W) [12], sulfonated rice husk ash (RHA-SO3H) under solvent-free conditions [58] and catalyst-free under ultrasonic irradiation [59]. However, a review article on the synthesis of these compounds has been published by Gouda until the end of 2013 [60]. In this review, we want to cover the recent synthetic methodologies and their applications of bis(pyrazolyl)methane derivatives and describe the literature reports for the period of 2014 to early 2021.
Synthesis of bispyrazoles via one-pot pseudo three-component reactions
In 2014, Sadeghi and Ghorbani Rad synthesized a series of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) 1 in 83–96% yields via stirring of 3-methyl-1-phenyl-2-pyrazoline-5-one (2a) with various aromatic aldehydes in the presence of nano-SiO2/HClO4 as a catalyst in water under reflux within 20 min (Scheme 1) [61].
Nano-SiO2/HClO4 catalyzed synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) 1
Next, synthesis a series of bis(pyrazolyl)methanes in 85–94% yields was accomplished via a one-pot pseudo three-component condensation reaction of 2a with aromatic aldehydes using ZnO nanoparticles as a recyclable and highly efficient catalyst in EtOH-H2O under reflux conditions for 15–30 min. The reaction with aliphatic aldehydes did not take place. In the proposed mechanism, firstly, the α,β-unsaturated adduct is generated by the Knoevenagel condensation reaction between aromatic aldehyde and 2a. Then, Michael addition of 2a to the α,β-unsaturated adduct followed by 1,3-proton shift gives the desired products. In this reaction, ZnO NPs act as a Lewis acid catalyst with high surface area by activating the carbonyl group of the aldehyde [62].
After that, Zare and co-workers developed preparation of bis(pyrazolyl)methanes 3 in 74–97% yields via condensation of 2a with aryl/heteroary aldehydes catalyzed by trityl chloride (Ph3CCl) as a homogeneous organocatalyst under mild and solvent-free conditions at 60 °C for 4–22 min. In a reasonable mechanism as illustrated in Scheme 2, resonance forms 4 and 5 can first be produced from aryl aldehyde and Ph3CCl in a reversible reaction. They act as an activated aldehyde, reacting with tautomer 2b of 2a providing 6, which converts to 7 by proton transfer. Intermediate 7 can interconvert to 8 by loss of Ph3COH. 8 and Ph3COH then react to yield benzylidene intermediaite 9, Ph3CCl, and H2O. Then, 9 react with another molecule of 2b to generate 10. In the last step, tautomerization of 10 affords the desired products 3 [63].
Ph3CCl catalyzed synthesis of bis(pyrazolyl)methanes 3
Later, two efficient and green methods for the synthesis of bispyrazoles in 90–96% yields in the absence of any catalyst or solvent were developed by heating (at 120 °C) for 10 min or microwave irradiation at 60 °C (300 W) for 3 min of intimate mixtures of 2a and aldehydes in 2:1 mol ratio [64].
In addition, ammonium acetate is employed as a catalyst for the condensation reaction of 1-aryl-3-alkyl-1H-pyrazol-5-ol (alkyl = CF3, CH3) with aromatic or aliphatic aldehydes. This condensation reaction was performed by grinding at room temperature for 5–10 min giving 4,4′-aryl or alkyl methylene-bis(1H-pyrazol-5-ols) in 80–95% yields. In the proposed mechanism, the reaction proceeds via Knoevenagel-type condensation of aldehyde with pyrazole using NH4OAc to afford benzylidene intermediaite, followed by Michael addition of another molecule of pyrazole to yield the desired products. These compounds were tested in vitro antibacterial activity against S. aureus, X. protophormiae, P. aeruginosa and B. licheniformis. Among them, CF3 group-containing compounds show excellent antibacterial activity and CH3 group containing compounds were not active [48].
Further, bispyrazole derivatives were synthesized in 83–93% yields in the presence of aqueous extract of fruit (biosurfactant) as a biobased green acidic catalyst from the reaction between aryl aldehydes and 2a at 60 °C. At first, Knoevenagel condensation proceeded rapidly for 2 min to give orange coloured arylidenepyrazolones which were converted to the target products within 15–60 min via Michael step [65].
In 2015, Eskandari et al. described synthesis of bispyrazoles in 85–92% yields via condensation of 2a with aromatic aldehydes catalyzed by Mohr’s salt in EtOH:H2O (1:1) under reflux conditions for 20–30 min. In addition, the reaction with aliphatic aldehydes did not take place [66].
Moreover, 2-carbamoylhydrazine-1-sulfonic acid and carbamoylsulfamic acid as nano-structure organocatalysts were applied for the solvent-free synthesis of bis(pyrazolyl)methanes in 83–98% yields by the reaction of several aromatic aldehydes with 2a at 60 °C for 10–210 min. The probable mechanism includes the creation of benzylidene intermediaite via the nucleophilic addition of 2a to aryl aldehyde, followed through dehydration. Next, the second molecule of 2a adds in the Michael addition approach to yield the corresponding products [67].
After that, a rapid and environmentally friendly method was developed for the preparation of bis(pyrazolyl)methanes in 86–97% yields by condensing 2a with various aldehydes catalyzed by CsF in de-ionized water at ambient temperature for 5–10 min. In the reasonable mechanism, CsF probably plays two important roles, first it increases the electrophilicity of the carbonyl carbon of the aldehyde, and secondly the fluoride counter ion works as a base generating the enolate of pyrazolone [68].
Later, 12-tungstophosphoric acid (H3PW12O40) is employed as a catalyst for the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) 11 in 91–98% yields by the reaction of two equivalents of 3-methyl-1H-pyrazol-5(4H)-one (12a) with aromatic aldehydes in refluxing EtOH for 10–60 min. Considering the Brønsted acidic nature of H3PW12O40 = HA, a plausible mechanism is depicted in Scheme 3. It is believed that 12b (first equivalent of enolic form of 12a) reacts initially with aryl aldehyde to give the intermediate 13, which then reacts with second equivalent of 12b to afford the desired products 11 [69].
H3PW12O40 catalyzed synthesis of bis(pyrazolyl)methanes 11
Nanomagnetite-Fe3O4 is applied as a recyclable nanomagnetite catalyst for the preparation of bis(pyrazolyl)methane derivatives in 74–95% yields via the condensation reaction of 2a with aryl aldehydes at 70 °C under solvent-free conditions for 3–9 min. In the suggested mechanism, at first, 2a converts to the other tautomer 2b in the presence of nonamagnetite-Fe3O4. Nucleophilic addition of 2b on activated of carbonyl group of aldehyde affords benzylidene intermediaite. Additions of another molecule of 2b to benzylidene adduct followed by tautomerization and aromatization gives the target products [70].
Elinson and co-workers reported preparation of bis(pyrazolyl)methanes in 93–99% yields by the reaction of aromatic aldehydes and 2a in refluxing EtOH under catalyst-free conditions for 5 min. The plausible mechanism involves ionization of 2a leads to the formation of pyrazole anion. This process can be thermally activated. Then, Knoevenagel condensation reaction of pyrazole anion with aryl aldehyde affords benzylidene intermediate. Subsequently, benzylidene intermediate and another equivalent of 2a undergo Michael addition yields bispyrazole anion, which then undergoes intramolecular tautomeric transformation results the desired products [71].
Further, synthesis of bispyrazoles in 84–95% yields was accomplished by the condensation of 2a with aromatic aldehydes catalyzed by SbCl5/SiO2 NPs as a recyclable catalyst in refluxing water within 20 min [72].
Karami and co-workers noted that treatment of various aromatic aldehydes with 2a catalyzed by ZnO NWs as a recyclable catalyst in EtOH:H2O (1:1) under reflux conditions for 15–30 min gave bis(pyrazolyl)methane derivatives in 84–90% yields. The reaction with aliphatic aldehydes was unsuccessful. It seems that the problem in the case of aliphatic ones is likely to be enolyzed. In the plausible mechanism, α,β-unsaturated adduct is obtained via reaction of 2a with aldehyde. Then, 1,4-addition of 2b on α,β-unsaturated adduct followed by [1, 3]-sigmatropic proton shift affords the corresponding products [73].
In 2016, Cu-isatin Schiff base supported on γ-Fe2O3 is prepared and employed as a recyclable catalyst for the synthesis of bis-derivative 14 in 85–97% yields by the reaction of aromatic and aliphatic aldehydes with 2a in H2O at room temperature for 30–50 min. A possible mechanism for the formation of 14 is depicted in Scheme 4. Firstly, compound 2b reacts with aldehyde followed by dehydration to give benzylidene intermediaite, which is then react with the second molecule of 2b through Michael addition to afford bispyrazoles 14 [74].
Cu-isatin Schiff base-γ-Fe2O3 catalyzed synthesis of bispyrazoles 14
Next, nano-magnetic Fe3O4-based vanadic acid [MNPs@VO(OH)2] was used as a solid acid catalyst for the synthesis of bispyrazole derivatives 15 in 72–96% yields via the reaction 2a with of aromatic and heteroaromatic aldehydes in 4–5 drops ethanol at 40 °C for 5–45 min. A proposed mechanism for the preparation of 15 is illustrated in Scheme 5. Initially, the reaction between 2b and aldehyde affords intermediate 16. Then, intermediate 16 and the second molecule of 2b undergo Michael addition to give the desired products 15 [75].
[MNPs@VO(OH)2] catalyzed synthesis of bis-derivatives 15
Pawar and co-workers described catalyst-free green synthesis of bispyrazoles in 80–91% yields by the reaction of aromatic aldehydes with 2a in ethylene glycol at 90 °C for 1–2 h. In this method, all the reactions proceeded smoothly and the corresponding products were purified by simple recrystallization without further purification [76].
Furthermore, alum (KAl(SO4)2 12H2O) as a reusable catalyst was applied to synthesize bis(pyrazolyl)methanes in 81–95% yields via the reaction of 2a with carbonyl compounds (aromatic/heteroaromatic aldehydes or N-alkyl substituted isatin derivatives) at 60 °C under solvent-free conditions for 15–300 min [77].
The [Amb]L-prolinate was prepared from the immobilization of L-prolinate anion onto amberlite IRA900OH and used as an organocatalyst for the synthesis of bispyrazoles 17 by the condensation reaction of 2a with aromatic aldehydes. The reaction was performed in EtOH under reflux conditions for 5–18 min giving the corresponding products 17 in 82–98% yields. A reasonable mechanism for the synthesis of 17 is depicted in Scheme 6. Initially, an iminium carboxylate 18 is obtained via reaction of aldehyde with L-prolinate anion of catalyst. Next, L-prolinate anion abstracts a proton from 2a to form the enolate intermediate 19. Subsequent Michael addition of enolate 19 to the iminium carboxylate 18 affords intermediate 20. Finally, Michael addition of the second molecule of 19 to 20 leads to the formation of the corresponding products 17 [78].
Synthesis of bis(pyrazolyl)methanes 17 catalyzed by [Amb]L-prolinate
Moreover, a Knoevenagel condensation reaction of 1-(2,3,4,6-tetra-O-acetyl-1-β-D-glucopyranose)-2-(4-formylphenyl)-ethane (21) with 2a in EtOH under reflux conditions for 10 h gave bispyrazole derivative 22 in 73% yield instead of a benzylidene-pyrazolinone derivative (Scheme 7) [79].
Synthesis of bispyrazole derivative 22
In 2017, Mosaddegh et al. reported synthesis of bispyrazoles in 81–98% yields via the reaction of 2a with aromatic aldehydes using Ce(SO4)2.4H2O as a reusable catalyst in H2O:EtOH (1:1) solution at reflux for 5–25 min. The plausible mechanism for this reaction involves formation of benzylidene intermediate of nucleophilic addition of 2b to aromatic aldehyde followed by elimination of one molecule of water. Subsequently, Michael addition of the second molecule of 2b to benzylidene adducts to afford the desired products [80].
4-Sulfophthalic acid (4-H3SPA) solution 50 wt% in H2O is employed as a catalyst for the preparation of bis(pyrazolyl)methanes in 88–97% yields by condensing 2a with aryl and heteroaryl aldehydes under aqueous conditions at room temperature within 10–20 min [81].
After that, Saghanezhad and co-workers succeeded in preparation of bis(pyrazolyl)methanes in 80–92% yields via the reaction of aromatic aldehydes and 2a using caffeine-H3PO4 (7.5 mol%) as an efficient recyclable catalyst at 80 °C under solvent-free conditions within 55–75 min [82].
Moreover, N1,N1,N2,N2-tetramethyl-N1,N2-bis(sulfo)ethane-1,2-diaminium chloride ([TMBSED][Cl]2) as an acidic ionic liquid catalyst was applied for the synthesis of bis(pyrazolyl)methanes 23 in 88–95% yields by the condensation reaction of 2a with aromatic aldehydes in EtOH at 60 °C within 15–45 min. The plausible mechanism for the preparation of 23 is illustrated in Scheme 8 [83].
The production of bis(pyrazolyl)methanes 23 promoted by [TMBSED][Cl]2
Bispyrazoles 24 were synthesized in 87–98% yields by using {Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl} as a recyclable solid acid catalyst from the reaction between 2a and aromatic aldehydes at 90 °C under solvent-free conditions within 10–45 min. A possible mechanism for the formation of 24 is outlined in Scheme 9. At first, 2a converts to its enol form (2b) through interaction with the nanomagnetic catalyst and attacks the activated aldehyde to give intermediate 25 via dehydration. Then, treatment of the second molecule of 2b with 25 to give the intermediate 26, which undergo tautomerization and aromatization leads to the corresponding products 24 [84].
{Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl} catalyzed synthesis of bis(pyrazolyl)methanes 24
Furthermore, an efficient and eco-friendly protocol was introduced for the synthesis of bispyrazoles in 87–97% yields by the condensation reaction of 2a with aryl aldehydes using boehmite nanoparticles (BNPs) (an aluminum oxide hydroxide (γ-AlOOH) mineral) as a recyclable catalyst at 80 °C under solvent-free conditions for 8–35 min. In the suggested mechanism, BNPs formulate electrophilic activation of the aldehyde to increase the rate of formation of the benzylidine intermediate. Subsequently, it accelerates the rate of the Michael addition of a second equivalent of 2b on the benzylidine adducts for the formation of the desired products [85].
Also, 1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazol-5(4H)-one (27) in 85% yield was prepared using ethylacetoacetate (28) and 2,4-dinitrophenylhydrazine (29) in HOAc under reflux conditions for 4 h. Then, Knoevenagel condensation reaction of 27 with p-hydroxybenzaldehyde in refluxing EtOH using piperidine for 5 h afforded the pyrazolone derivative 30 in 78% yield. Pyrazolone 30 reacted with pyrazolone 27 in the presence of sodium ethoxide in ethanol at 100 °C for 1 h to give 4,4′-((4-hydroxyphenyl)methylene)bis(1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazol-5-ol) (31) in 80% yield (Scheme 10) [86].
Preparation of bis(pyrazolyl)methane 31
In 2018, Mohammed Khan and co-workers reported that preparation of bis(pyrazolyl)methane derivatives in good to excellent yields by condensing 2a with different aldehydes catalyzed by CsF as catalyst in ethanol at ambient temperature for 2–3 h. In this reaction, CsF plays two important roles. Firstly, it increases the positive charge on the carbonyl carbon of the aldehyde, and secondly the fluoride ion works as a base producing the enolate of pyrazolone. As a result, the formation of carbon–carbon double bond by condensation with the aldehydes forms an intermediate 1,4-Michael type substrate serving for a 1,4-attack by the second fluoride-generated enolate of the pyrazolone resulting in the formation of the corresponding bis-pyrazoles. These compounds demonstrated diverse in vitro DPPH radical scavenging activities with IC50 values ranging between 55.2 ± 1.2–149.6 ± 1.7 µM, as compared to standard BHT (butylated hydroxytoluene) (IC50 = 128.8 ± 2.1 µM). Further chemical modifications and research work on these molecules may result in clinically useful antioxidants [87].
Later, silica vanadic acid with Lewis and Bronsted acid sites is employed as a recyclable catalyst for the Knoevenagel–Michael reaction of 2a with aromatic aldehydes. This reaction was performed in 4–5 drops ethanol at room temperature within 30–80 min resulting bispyrazoles 32 in 72–95% yields. A reasonable mechanism for the formation of 32 is shown in Scheme 11. The catalyst activates the aldehyde group for nucleophilic attack by 2b to yield 33, which is then treated with the second molecule of 2b to produce the target products 32 [88].
Silica vanadic acid catalyzed synthesis of bis(pyrazolyl)methanes 32
Graphene oxide/Fe3O4/L-proline nano-hybrid is synthesized and used as a catalyst for the preparation of bis(pyrazolyl)methanes in 87–98% yields by the reaction of 2a with aryl aldehydes in refluxing EtOH for 5–15 min. GO/Fe3O4/L-proline catalyst was separated simply by using an external magnet and employed in six runs for the synthesis of the desired products [89].
Bis(pyrazolyl)methanes 34 are obtained in 56–89% yields by the reaction of 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-ol (35) with aryl aldehydes in the absence of catalyst in EtOH:H2O (1:3) under reflux conditions for 24 h. In the proposed mechanism as indicated in Scheme 12, nucleophilic carbon of pyrazolone in enol form attacks the electrophilic carbonyl carbon of benzaldehyde thus resulting in the formation of an intermediate 36. Successful removal of water molecule from intermediate 36 formed the another α,β-unsaturated intermediate 37. This intermediate 37 still has an electrophilic center at β-position, thus another attack of the second molecule of pyrazolone at β-position leads to the formation of 34. Synthetic bis-pyrazolones 34 were evaluated for their oxidative burst inhibitory effect of zymosan stimulated whole blood phagocytes by using luminol enhanced chemilluminescence technique. All molecules demonstrated the potent ROS inhibition activity in the range of IC50 = 1.2 ± 0.1–48.8 ± 3.9 M as compared to the standard ibuprofen (IC50 = 54.2 ± 9.2 M) [90].
Green synthesis of bis(pyrazolyl)methanes 34
In 2019, Ghorbani-Choghamarani and his group reported that preparation of bis(pyrazolyl)methanes in good yields (75–92%) was accomplished by the treatment of 2a with aromatic aldehydes using Ni-guanidine@MCM-41NPs as a recyclable catalyst in CH3CN at 80 °C for 15–60 min [91].
In 2020, Rostami and Kordrostami developed a strategy for the preparation of bispyrazole derivatives 38 in 90–99% yields by the condensation reaction of 2a with aromatic aldehydes using graphene oxide functionalized pyridine-methanesulfonate (GO@PyH-CH3SO3) as a recyclable nano-catalyst at 70 °C under solvent-free conditions for 8–30 min. The possible mechanism for the synthesis of 38 is illustrated in Scheme 13. According to the mechanism, at first, aldehyde was activated by acidic proton, while 2b was activated by methane sulfonate group. Nucleophilic addition of 2b to aldehyde followed by water elimination resulted benzylidene intermediate 39. Then, Michael addition of second molecule of 2b to the activated intermediate 39 explored the intermediate 40; by eliminating the second water molecule, the products were obtained [92].
GO@PyH-CH3SO3 catalyzed synthesis of bis(pyrazolyl)methanes 38
Furthermore, More and co-workers have shown the reaction of 2a with aromatic and heteroaromatic aldehydes using chitosan-SO3H (CTSA) as a biodegradable polymeric catalyst at 70 °C under solvent-free conditions for 15–70 min afforded bis(pyrazolyl)methanes in 79–96% yields. For the formation of the products, chitosan sulfonic acid increases the electrophilic character of aldehyde via proton donor. Firstly, 2a converts to its enol form (2b) and attacks the activated aldehyde with catalyst to yield benzylidene intermediate via dehydration. Then, the intermediate and second equivalents of 2b undergo Michael addition to yield the desired products [93].
After that, guanine-La complex supported onto SBA-15 is employed as a recoverable nanocatalyst for the formation of bispyrazoles 41 in 87–98% yields by the reaction of 2a with aryl aldehydes in refluxing EtOH within 25–90 min. The suggested reaction mechanism for the synthesis of 41 is outlined in Scheme 14. At first, the intermediate 42 is generated by the Knoevenagel condensation of aldehyde and 2b using La-guanine@SBA-15 nanocatalyst. Then, Michael addition of the second mol of 2b to 42 affords intermediate 43, which undergo tautomerization to give the desired products 41 [94].
La-guanine@SBA-15 catalyzed preparation of bis(pyrazolyl)methanes 41
Moreover, MCM-41-supported nanoscale guanine bonded with Zr (IV) was synthesized and used as an efficient, chemoselectivity and recyclable catalyst system for the preparation of bis(pyrazolyl)methanes in 88–98% yields by using aromatic aldehydes and 2a in ethanol under refluxing within 10–45 min. The suggested reaction mechanism is similar to the proposed mechanism in Scheme 14. Initially, benzylidene intermediate is generated from the Knoevenagel condensation of aldehyde with 2b and dehydration using Zr-guanine-MCM-41 nanocatalyst. In the next step, bispyrazole derivatives are obtained via Michael addition of the second molecule of 2b to the benzylidene intermediate followed by tautomerization [95].
Eskandari and Karami reported a practical synthesis of bispyrazole derivatives 44 in 86–90% yields via the reaction of 2a with arylglyoxal derivatives 45 using the environmentally benign catalyst, Mohr’s salt in EtOH:H2O (2:1) under reflux conditions. A suggested mechanism for the synthesis of 44 is illustrated in Scheme 15. At first, 2a is tautomerized to 2b in the presence of Mohr’s salt. Then, nucleophilic addition of 2b to the arylglyoxal led to the formation of intermediate 46 via elimination of one molecule of water. Treatment of the second mole of 2b with 46 yielded intermediate 47 via loss of one molecule of water. Finally, 47 experiences an enol-keto tautomerization gave compounds 44 [96].
Mohr’s salt catalyzed synthesis of bispyrazoles 44
Recently, Heredia-Moya and co-workers reported synthesis of bispyrazoles in 60–99% yields by a three-component reaction of 2a with aryl aldehydes catalyzed by NaOAc in 70% EtOH at ambient temperature for 10–480 min. All synthesized compounds were evaluated for antioxidant activity by the N,N-diphenyl-N′-picrylhydrazyl (DPPH) assay. Several derivatives proved to be cytotoxic in the RKO cell line. In particular, bispyrazole containing two hydroxyl groups in the positions of 3, 4 on aromatic ring proved to be a very potent scavenger with an IC50 of 6.2 ± 0.6 µM and exhibited an IC50 of 9.9 ± 1.1 μM against RKO cell [97].
Synthesis of bispyrazoles via one-pot pseudo five-component reactions
In 2014, one-pot pseudo five-component synthetic method for the 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s 48 and 49 in 77–96% yields was developed by the reaction of aryl aldehydes, ethyl acetoacetate (28) and phenylhydrazine (50a) or hydrazine hydrate (50b) using 2-hydroxy ethylammonium propionate as catalyst at 90 °C under solvent-free conditions within 10–80 min. In the suggested mechanism, the first step involves the generation of pyrazolones 2a and 12a by the condensation of 50 with 28. Subsequently, reaction of aldehyde with two equivalents of pyrazolone to afford bis(pyrazolyl)methanes 48 and 49 via tandem Knoevenagel–Michael reaction as depicted in Scheme 16 [98].
Synthesis of bis(pyrazolyl)methanes 48 and 49 using 2-hydroxy ethylammonium propionate
After that, Safaei-Ghomi and his group reported that preparation of bis(pyrazolyl)methanes in 80–92% yields using ZnAl2O4 nanoparticles by pseudo five-component reaction of 50b, 28 and aromatic aldehydes in water at 60 °C within 14–28 min [99].
Next, N,2-dibromo-6-chloro-3,4-dihydro-2Hbenzo[e][1,2,4]thiadiazine-7-sulfonamide-1,1-dioxide (DCDBTSD) is employed as a homogeneous catalyst for the condensation reaction of 28 or methyl acetoacetate (51) with 50a and aromatic aldehydes. This reaction is performed at 80 °C under solvent-free conditions for 35–105 min, resulting bispyrazoles 52 in 71–85% yields. In the proposed mechanism, β-keto ester and the catalyst generate intermediates 53 and 54 (Scheme 17). Then, intermediate 2a is obtained by nucleophilic addition of 50a to 53 and 54 via elimination of one molecule of alcohol, which is tautomerize to 2b. Intermediate 55 is produced via condensation of 2b with 53 or 54. Subsequently, Michael addition of another intermediate 2b to 55 leads to intermediate 56, which undergoes tautomerization to afford the desired products 52 [100].
DCDBTSD catalyzed synthesis of bispyrazoles 52
In 2015, Hassankhani described an efficient method for the one-pot synthesis of bis(pyrazolyl)methanes 57 in 81–98% yields by condensation of aromatic aldehydes, 28 and 50a in the presence of Ce(SO4)2.4H2O as a recoverable catalyst under solvent-free conditions at 125 °C for 5–12 min. A reasonable mechanism is shown in Scheme 18. Initially, the reaction between 28 and 50a affords phenylhydrazone 58, which then cyclizes to give the intermediate 59. Nucleophilic addition of 1-phenyl-3-methyl-5-pyrazolone to aldehyde leads to benzylidene 60 via elimination of one mole of H2O. Finally, Michael addition of the second molecule of 1-phenyl-3-methyl-5-pyrazolone to intermediate 60 affords the corresponding products 57 [101].
Ce(SO4)2 4H2O catalyzed preparation of bis(pyrazolyl)methanes 57
Sulfonated nanohydroxyapatite functionalized with 2-aminoethyl dihydrogen phosphate (HAP@AEPH2-SO3H) was used as a reusable solid acid catalyst for the solvent-free synthesis of bispyrazoles 61 in 80–98% yields by the one-pot reaction of 28, 50a,b and aromatic/heteroaromatic aldehydes at 80 °C within 2–10 min. A possible mechanism for the formation of 61 is outlined in Scheme 19. The reaction involves the initial formation of pyrazolones 2a and 12a (which are in equilibrium with theirs other tautomeric forms 2b and 12b) by the reaction between the protonated form of 28 and 50a or 50b. Then, in acidic media, condensation of the intermediates 2b and 12b with aldehyde to give adduct 62 and subsequent dehydration, leads to the formation of 63. Michael addition of 63 to 2b/12b produces two tautomeric forms 64 and 61 followed by release of the acidic catalyst [102].
Preparation of bis(pyrazolyl)methanes 61 using HAP@AEPH2-SO3H
Safaei-Ghomi et al. noted that a solution of 28 with 50b by using CuCr2O4 as a recyclable nano-catalyst in water at ambient temperature was stirred for 15 min, then aromatic aldehydes was added and the mixture was stirred at 50 °C for 10 min to give the desired products in 84–95% yields. Also, the catalyst can be reused at least five times without any obvious change in its catalytic activity. Presumably, the reaction mechanism includes formation of pyrazolone 12b from 50b and 28, which is then reacts with aldehyde to give arylidene intermediate. Treatment of arylidene intermediate with another molecule of 12b leads to the target products [103].
After that, Na+-MMT-[pmim]HSO4 is synthesized and used as a recyclable Brönsted acidic ionic liquid catalyst for the solvent-free synthesis of bis(pyrazolyl)methanes in 87–93% yields by the one-pot condensation of 28, 50a and aryl aldehydes at 100 °C for 10–45 min. The results showed that the reaction proceed via the in situ generation of 2a, which in reaction with aldehydes produce the target products [104].
Furthermore, solvent-free one-pot three-component condensation of aromatic aldehydes, 28 and 50 was performed at 90 °C within 20–45 min using [Et3NH][HSO4] as a reusable catalyst, giving bis(pyrazolyl)methanes in 79–97% yields. The proposed mechanism involves [Et3NH][HSO4] catalyzed synthesis of 2a and 12a by the condensation of 28 with 50a,b. Next, the activated carbonyl is attacked by the nucleophilic pyrazolones to produce the Knoevenagel adducts. The subsequent addition of these fragments to pyrazolones gives the desired products [105].
In 2016, Gouda et al. succeeded in preparation of bispyrazoles 65 in 74–83% yields via the one-pot pseudo five-component reaction of 28, 50a and aryl aldehydes in acetic acid at 90 °C for 6–7 h. The suggested mechanism for the synthesis of 65 is shown in Scheme 20. Protonation of 28 by acetic acid produces the enol 66. Electrophilic attraction of 50a to the enol 66 gives the ammonium salt 67; hydronium ion transfer takes place to yield the oxonium ion 68. Cyclization of 68 gives the pyrazolium ion 69 which loss proton to convert into pyrazole 2a. Protonation of 2a by AcOH generates the enol 2b which reacts with the aldehydic carbonyl to give six-membered cyclic transition state 70 and increases the electrophilicity of the aldehyde carbonyl group and makes it more susceptible to nucleophilic attack in an intramolecular fashion to afford the intermediate 71. Subsequently, intermediate 71 abstracts the proton from AcOH and produces the enolate aldol cation 72 which interacts with 2a to generate the enol form 2b to complete the catalytic cycle. The aldol 73 on dehydration results in the formation of 4‐arylidene‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one 74 which is reacted with AcOH to generate the cation 75, condensation with 2b to afford bis‐enolate cation 76, which subsequently loss proton and form the corresponding products 65. Moreover, some of the synthesized compounds were screened for their antioxidant activity using 2,2′‐azino‐bis(3‐ethyl benzothiazoline‐6‐sulfonic acid (ABTS) method; all the investigated compounds showed similar and higher antioxidant activity than ascorbic acid and exhibited high protection against DNA damage induced by the bleomycin iron complex [106].
Synthesis of bispyrazoles 65 in AcOH
Moreover, N-methylimidazolium perchlorate ([MIm]ClO4) was prepared and used as recyclable catalyst for the preparation of bis(pyrazolyl)methanes in 77–94% yields via the condensation reaction of 28, 50a,b and aromatic/heteroaromatic aldehydes at 50 °C under solvent-free conditions for 20–60 min. In the proposed mechanism, pyrazolone would be anticipated from the very fast condensation between 50a and 50b with 28 catalyzed by [MIm]ClO4. The activated carbonyl group of the aldehyde again by the catalyst condenses with two equivalents of pyrazolone through a pyrazolenone intermediate via a tandem Knoevenagel–Michael reaction resulting in the formation of the corresponding products [107].
Microwave irradiation of 3-substituted isoxazole-5-carbaldehydes and 4-chlorophenyl hydrazine or 50b over solid support SiO2 at 70 °C under solvent-free conditions within 8–12 min gave 4-substituted pyrazolones in 78–97% yields. The mechanism of formation of bispyrazoles involves generating of intermediate hydrazone via nucleophilic addition of hydrazine to β-keto ester. Subsequently, intramolecular nucleophilic attack of amino group to carbonyl by removing of a molecular ethanol followed by cyclization to yield 12a and 35. Then, intermediates 12a and 35 interconverted the stable intermediates (enol forms). Afterwards, arylidene intermediates are formed by the nucleophilic addition of enol forms of intermediates 12b and 35 to 3-substituted isoxazole-5-carbaldehydes followed by dehydration. Michael addition of the second molecule of enol forms of intermediates 12b and 35 to arylidene intermediate, which is then tautomerize to the desired products [108].
After that, CeO2 nanoparticles are employed as a recyclable catalyst for the formation of C-tethered bis(pyrazolyl)methanes 77 in 83–90% yields by pseudo five-component condensation reaction of 50a, dimethyl acetylenedicarboxylate (78) and aryl aldehydes in water at 70 °C within 18–25 min. The mechanism of these domino reactions is proposed in Scheme 21. Firstly, the condensation reaction of 78 and 50a led to the formation of 1,3-dipole intermediate 79, which subsequently underwent proton transfer and aminolysis of the ester group, resulting the pyrazolones 80 in situ. The pyrazolone derivative was treated with aryl aldehydes, leading to arylidene pyrazolones 81. Then, the arylidene pyrazolones were further reacted with pyrazolones produced in situ to yield the final bis(pyrazolyl)methanes [109].
Synthesis of C-tethered bis(pyrazolyl)methanes 77 using CeO2 NPs
Acetic acid functionalized pyridinium salt (1-(carboxymethyl)pyridinium chloride {[cmpy]Cl}) is employed as a reusable catalyst for the condensation reaction of 50a, 28, and aryl aldehydes. This reaction was performed at 110 °C under solvent-free conditions for 3–20 min, resulting bis(pyrazolyl)methanes 82 in 73–92% yields. In a possible mechanism, compound 28 is activated by the catalyst (Scheme 22). Then, intermediate 83 is obtained by the reaction of 50a with 28 followed by removing of H2O. By intramolecular attack in intermediate 83 and removing of EtOH, compound 2a is obtained. Afterwards, 2a converts to 2b after tautomerization. Intermediate 84 is formed via the condensation of 2b with an activated aldehyde by the catalyst, which is then converted to 85 by removing of H2O. 85 as Michael acceptor is reacted with another intermediate 2b to give 86, which is tautomerize to the target products 82 [110].
Solvent-free synthesis of bispyrazoles 82 using [cmpy]Cl
Moreover, 4-(succinimido)-1-butane sulfonic acid (SBSA) as a reusable Brönsted acid catalyst catalyzes the condensation of 28, 50a,b and aryl aldehydes under solvent-free conditions at 60 °C for 20–55 min, affording bis(pyrazolyl)methanes in 82–92% yields. In the suggested mechanism for the formation of the products, pyrazolone would be anticipated from the very fast condensation between 50 and 28 in the presence of SBSA. Then, the activated carbonyl group of the aldehyde condensed with two equivalents of pyrazolone, resulting bis(pyrazolyl)methanes [111].
In 2017, Hazeri and his group reported that preparation of bispyrazoles in 75–93% yields were accomplished by the condensation reaction of 28, 50b and aryl/heteroaryl aldehydes in the presence of Ag/TiO2 nano-thin films as a recyclable catalyst in EtOH:H2O (2:1) at 70 °C for 25–55 min. In this reaction, treatment of aryl aldehyde with the acidic sites of Ag-TiO2 gives the activated carbonyl group which is followed by nucleophilic attack of 12a to afford arylidene intermediate. Michael addition of another pyrazolone to arylidene intermediate leads to the target products [112].
A convenient approach for the preparation of bispyrazoles in 56–93% yields by an efficient one-pot condensation reaction of aromatic/aliphatic aldehydes, 50a and β-ketoesters (28 and ethyl benzoylacetate) by using K2CO3 in CH3CN at ambient temperature for 1–4.5 h is described. It was found that aromatic aldehydes with electron withdrawing substituent afforded the corresponding products in high yield and in short reaction times. When the reaction was carried out with aromatic aldehydes containing moderately strong electron donating groups, the target products obtained with lower yield. Moreover, aliphatic aldehydes reacted with 50a and β-keto ester under similar condition to yield the target compounds in good to moderate yields [113].
An environmentally friendly method has been developed for the synthesis of bis(pyrazolyl)methanes in good yields (76–93%) by condensation reaction of aromatic/heteroaromatic aldehydes, 50b and 28 using aspirin as a green catalyst in EtOH/H2O at 60 °C for 20–55 min. The proposed mechanism for this reaction involves formation of pyrazolone 12a of 28 and 50b. Then, Knoevenagel condensation of the activated carbonyl group of the aldehyde with pyrazolone to give the arylidene pyrazolone, which undergoes Michael addition with another pyrazolone to afford the desired products [114].
L-proline as an organocatalyst has been employed for the preparation of bis(pyrazolyl)methanes 87 in 84–95% yields via the reaction of aromatic/heteroaromatic aldehydes, 50a and 28 in refluxing EtOH for 55–80 min. A suggested mechanism for the formation of 87 is shown in Scheme 23. Initially, nucleophilic reaction of L-proline on the 28 followed by dehydration affords intermediate 88, which is treated with 50a followed by removing L-proline to produce 2b. In the next step, nucleophilic addition of 2b to intermediate 89 to afford arylidene 90, which undergo Michael addition with the second molecule of 2b to give the desired products 87. Bispyrazole containing thiophene-2-yl ring, emerged as the most interesting compound in this series exhibiting excellent DPPH radical scavenging activity and found to be more potent than the standard drug BHT used [115].
Synthesis of bis(pyrazolyl)methanes 87 using L-proline
Furthermore, immobilized lanthanum (III) triflate on graphene oxide (La(OTf)2-grafted-GO) as a reusable catalyst is synthesized and used for the one-pot five-component synthesis of bispyrazoles in 70–98% yields by the reaction of 50a, 28 and aryl/heteroaryl aromatic at 100 °C under solvent-free conditions for 10–45 min. In this reaction, the carbonyl groups in 28 are activated by the acidic functional groups of the catalyst to react with 50a to give pyrazolone. Next, the activated aldehydes by the catalyst undergo a tandem reaction with the activated pyrazolones by basic sites to generate the corresponding products [116].
Lalitha and co-workers succeeded in the preparation of bispyrazoles 91 in 85–94% yields via the reaction of 50b, 28 and aromatic aldehydes in glycerol at 80 °C for 1–13 min. A possible mechanism for the formation of 91 is presented in Scheme 24. Firstly, intermediate 12a is obtained by the condensation of 28 with 50b, which is converted into 12b by tautomerisation. Aromatic aldehyde is activated by the glycerol through the hydrogen bonding followed by nucleophilic attack of 12b at the carbonyl group to give intermediate 92. Intermediate 92 is converted to the Knoevenagel adduct 93 by dehydration. Adduct 93 as a Michael acceptor is activated by glycerol. Then, 93 undergo Michael addition with another molecule of 12b to yield intermediate 94, which is converted into the target products 91 by tautomerization [117].
Glycerol assisted synthesis of bis(pyrazolyl)methanes 91
Sulfonated honeycomb coral (HC-SO3H) as a green, high stability and reusability of the catalyst was used for the solvent-free synthesis of bispyrazoles 95 in 82–98% yields by the reaction of 50a,b, aryl aldehydes and 28 at 70 °C within 1–18 min. In this reaction, allylic aldehydes such as cinnamaldehyde and heteroaromatic aldehydes such as pyridine carboxaldehydes led to the expected products. A possible mechanism for the formation of 95 is outlined in Scheme 25. According to this mechanism, treatment of 50 and protonated form of 28, eventually leads to the formation of pyrazolones 2a and 12a, which are in equilibrium with their tautomeric forms 2b and 12b. In the next step, the condensation reaction between intermediates 2b or 12b and aldehyde in the acidic condition, followed by dehydration, gives intermediate 96. Michael addition reaction between 2b or 12b and 96 leads to the product 97, which is converted into the corresponding products 95 by tautomerization [118].
Preparation of bispyrazoles 95 catalyzed by HC-SO3H
Microwave irradiation of 50a with dimethyl acetylenedicarboxylate (78) and aromatic aldehydes in the presence of bis(1(3-methoxysilylpropyl)-3-methyl-imidazolium) copper tetrachloride tethered to colloidal silica nanoparticles as a recyclable catalyst in H2O at 50 °C for 10–15 min gave bispyrazoles in 82–96% yields [119].
In addition, Mn-[4-chlorophenyl-salicylaldimine-methylpyranopyrazole]Cl2 ([Mn-4CSMP]Cl2) as nano-Schiff base complex catalyst is synthesized and used for the preparation of bis(pyrazolyl)methanes in 59–95% yields by the condensation reaction of 50a, 28 and various aryl aldehydes at 100 °C under solvent-free conditions for 20–80 min [120].
A green, simple and efficient approach for the synthesis of bis(pyrazolyl)methanes 98 and 99 in 81–98% yields is described via condensation of hydrazines with dialkyl acetylenedicarboxylats/β-keto esters 100 and aromatic aldehydes in the presence of Dabco-base ionic liquid as a recyclable catalyst in H2O at 80 °C for 10–180 min. A suggested mechanism for the preparation of the products is proposed in Scheme 26. The formation of products can be rationalized by the initial formation of intermediates 101 or 102 via condensation of hydrazines with dialkyl acetylenedicarboxylates or β-keto esters. Knoevenagel condensation of 101 or 102 with aldehyde and subsequent dehydration, led to the formation of 103. Then, Michael addition of another intermediates 101 or 102 to 103 generated adducts 104 followed by tautomerization afforded the corresponding products 98 and 99 [121].
[Dabco-C4]Cl catalyzed synthesis of bispyrazoles 98 and 99
In 2018, Abed and co-workers obtained bis(pyrazolyl)methane derivatives in 85–96% yields from the condensation reaction of 50a with 28 and different aryl/heteroaryl aldehydes using morpholinium glycolate as the homogeneous reusable catalyst under solvent-free conditions at 80 °C for 5–12 min. At the beginning of reaction, morpholinium glycolate activates 28, and then 50a attacks the carbonyl groups of 28 to give pyrazolone 2a, which is further rearranged into tautomer 2b. In a next step, Knoevenagel type of reaction takes place between activated aldehydes and 2b followed by removing of H2O to give arylidene intermediate. Then, Michael addition reaction between arylidene pyrazolone and 2b, followed by tautomerization and aromatization affords the target products [122].
After that, an efficient synthesis of 4,4′-(phenylmethylene)bis(1H-pyrazol-5-ol)-3-carboxylates in 80–94% yields was achieved by the reaction of 50a, dimethyl acetylenedicarboxylate (78) and aromatic aldehydes using nano-NiZr4(PO4)6 as reusable catalyst in water at 60 °C within 15–28 min [123].
Zare and Abshirini noted that treatment of 50a, 28 and aromatic aldehydes using N,N,N′,N′-tetramethylethylenediaminium-N,N′-disulfonic acid hydrogen sulfate ([TMEDSA][HSO4]2) as a Brønsted-acidic ionic liquid catalyst in EtOH at 70 °C for 20–50 min afforded bis(pyrazolyl)methanes in 81–93% yields [124].
Potassium arylmethylene-4-(1H-pyrazol-5-ol)-4′-(1H-pyrazol-5-olate) derivatives have been synthesized in 68–88% yields by the condensation reaction of dimethyl acetylenedicarboxylate or diethyl acetylenedicarboxylate, 50a, aryl aldehydes and K2CO3 without any catalyst in EtOH under refluxing for 5 h [125].
Moreover, ionic liquid 1,3-disulfonic acid imidazolium trifluoroacetate ([Dsim][TFA]) is employed as a highly efficient catalyst for the condensation reaction between 50a, 28 and aryl aldehydes in refluxing EtOH. In this reaction, bis(pyrazolyl)methanes 105 have been synthesized in 75–93% yields within 15–150 min. A suggested mechanism is illustrated in Scheme 27. Firstly, trifluoroacetate anion of the catalyst assists 50a for nucleophilic addition to the activated carbonyl group of 28 (by acidic hydrogen of [Dsim][TFA]) to give 106, which is converted into 107 by dehydration. Intermediate 107 undergoes intramolecular cyclization to yield 2a. 2a is converted to its tautomer 2b, and this tautomer is added to the carbonyl group of aldehyde to give intermediate 108, which is then afforded Michael acceptor 109 by dehydration. Afterwards, Michael addition reaction of another molecule 2b to 109 provides 110. Tautomerization of 110 leads to the desired products 105. The high catalytic effectuality of [Dsim][TFA] can be attributed to helping both acidic and basic moieties of it (cation and anion) for progressing all steps of the reaction; i.e. dual-functionality [126].
Synthesis of bispyrazoles 105 using [Dsim][TFA]
Silica bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydrogen sulfate ((SB-DABCO)HSO4) is synthesized as a dual-catalyst and used for the preparation of bispyrazoles in 81–89% yields by the condensation reaction of hydrazine derivatives (RNHNH2: R = C6H5, 4–Me–C6H4, 4–OMe–C6H4), β-keto esters (R′COCH2CO2Et: R′ = Me, Pr, Ph) and aryl and heteroaryl aldehydes in refluxing EtOH for 35–480 min. The proposed mechanism for this reaction involves formation of pyrazolone intermediate of hydrazines and β-keto esters. After this, the tandem Knoevenagel–Michael reaction of pyrazolone intermediate with aldehydes leads to the formation of the target products. They suggested that ((SB-DABCO)HSO4) serves two catalytic functions: first, to electrophilically activate the aldehydes and carbonyl group of β-keto esters through the interaction between positively charged hydrogen of HSO4− and the carbonyl oxygen, and second, to enhance the nucleophilicity of the hydrazines and β-keto esters through the interaction between Cα–H with nitrogen of DABCO-like part of the catalyst [127].
Farooqui et al. succeeded in the formation of bispyrazoles 111 in 90–93% yields by the condensation of 50a, 28 and aromatic aldehydes using lemon juice as an efficient and eco-friendly catalyst in EtOH/H2O at 80 °C for 30–40 min. In a reasonable mechanism that is outlined in Scheme 28, at first, 2a convert to 2b after tautomerisation. Next, 2b attacks to the carbonyl group of aldehyde that is activated by the lemon juice via hydrogen bonds and results to intermediate 112 as a Michael acceptor after dehydration. Then, another molecule of 2b attacks to 112 to afford Intermediate 113, which is converted into the target products 111 after tautomerisation and aromatization. All the synthesized compounds showed good to moderate antibacterial, antifungal and antioxidant activities [128].
Lemon juice catalyzed synthesis of bispyrazole derivatives 111
In 2019, Olyaei and co-workers developed the preparation of 2,2′-bis(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-1-phenylethanone 114a in 85% yield through the condensation of 28, 50b and phenylglyoxal monohydrate using heteroarylamines containing electron-withdrawing group in water under reflux conditions within 55 min. Also, condensation of 28 and 50a by using guanidine hydrochloride (10 mol%) as catalyst in H2O under refluxing after 90 min gave 3-methyl-1-phenyl-1H-pyrazol-5-ol. Then, by the addition of phenylglyoxal monohydrate and heteroarylamines containing electron-withdrawing group to the reaction mixture under reflux conditions afforded 2,2-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenylethanone (114b) in 81% after 60 min. In these reactions, bis-pyrazolylmethanes were obtained as only products instead of the expected 1H-furo[2,3-c]pyrazole-4-amine derivatives 115. As a proposed mechanism depicted in Scheme 29, the reaction occurred via initial formation of intermediate 116 from the reaction of 2a or 12a and phenylglyoxal monohydrate followed by Michael addition of pyrazols instead of amines to 116 resulted products 114a,b because of the higher nucleophilicity of pyrazol than amines bearing strong electron-withdrawing group [129].
Synthesis of bispyrazoles 114a,b
Later, cage like CuFe2O4 hollow nanostructure is synthesized and used as a reusable catalyst for the preparation of bis(pyrazolyl)methanes in 89–98% yields by the one pot condensation reactions of hydrazines 50a,b, 28 and different aromatic aldehydes at 80 °C within 2–25 min under the solvent-free condition. The high activity of the catalyst could be described by the presence of open cavities in this structure. It allows the reaction to be carried out into the interior spaces of catalyst structure due to the ability of the reactants for diffusion [130].
Alpha-Casein as a recyclable and non-toxic catalyst was applied for the preparation of bis(pyrazolyl)methanes in 79–94% yields via the condensation reaction of 28, 50b and aromatic aldehyde in EtOH:H2O (2:1) at 60 °C for 15–40 min. In the proposed mechanism, 12a is formed from the reaction between 28 and 50b. Then, arylidene intermediate is produced via Knoevenagel condensation of 12a with the activated carbonyl group of the aromatic aldehyde. Finally, desirable products are obtained by Michael addition of another 12a to arylidene intermediate [131].
Guanidine hydrochloride as an organocatalyst was applied for the synthesis of bispyrazoles in 82–92% yields by the reaction of 50, 28 and various aromatic aldehydes in water under reflux conditions within 30–60 min. It should be noted that synthesis of 2a was carried out via the reaction of 50a with 28 by using catalyst in refluxing water for 90 min. In this reaction, the condensation reaction of 50 with 28 catalyzed by guanidinium chloride afford adducts 2a and 12a, which are tautomerize to 2b and 12b, respectively. Then, arylidene intermediate is likely formed by the condensation of aromatic aldehyde with 2b and 12b. Subsequently, Michael addition of another intermediate 2b and 12b to arylidene intermediates, followed by tautomerization give the corresponding products [132].
In 2020, Ghaffari Khaligh and co-workers obtained bis(pyrazolyl)methane derivatives 117 in 74–86% yields by the reaction of phenylhydrazine or 4-chlorophenylhydrazine with 28 and aromatic aldehydes using etraethylammonium L-prolinate as reusable catalyst in refluxing EtOH for 50–65 min. A possible reaction mechanism is presented in Scheme 30. The L-prolinate can act simultaneously as a hydrogen bond donor and a Lewis base through the secondary amine and carboxylate groups, respectively, to activate the phenylhydrazines and 28. Intermediate 118 is formed by nucleophilic attack of phenylhydrazine to the activated 28 followed by dehydration. Intramolecular cyclization of 118 affords adduct 2a, which is tautomerize to 2b. Nucleophilic addition of 2b to the activated carbonyl group of aldehyde followed by dehydration gives intermediate 119. Finally, the second molecule of 2b is added to 119 to yield bispyrazoles 117 [133].
Tetraethylammonium L-prolinate catalyzed synthesis of bis(pyrazolyl)methanes 117
4,4'-Trimethylenedipiperidine) TMDP) was as an organocatalyst employed for the synthesis of bis(pyrazolyl)methanes 120 in 73–86% yields by condensation of phenylhydrazines with 28 and aryl/heteroaryl aldehydes. The reaction was performed by conventional and nonconventional processes: (a) in EtOH under refluxing in the presence of catalyst (b) at ambient temperature using organocatalyst in a planetary ball mill (rotational frequency (10 Hz)) under solvent-free conditions. Also, the organocatalyst could be recycled and reused for ten runs. A probable reaction mechanism is illustrated in Scheme 31. The TMDP can act simultaneously as a hydrogen bond donor and a Lewis base through the nitrogen atom of second piperidine moiety to promote the condensation reaction of phenylhydrazine with 28 which affords 3-methyl-l-phenyl-5-pyrazolone. The catalyst also activates the carbonyl group of aldehyde for the Knoevenagel condensation, which gives the intermediate 121. Finally, Michael addition of the second molecule of 3-methyl-l-phenyl-5-pyrazolone to 121 affords bispyrazoles 120 [134].
TMDP catalyzed synthesis of bispyrazoles 120
Ansari et al. described green synthesis of 4,4′-((4-methoxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) and 4,4′-((4-nitrophenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) by the condensation reaction of 50a, 28 and 4-methoxybenzaldehyde or 4-nitrobenzaldehyde under ultrasonic irradiation in EtOH/H2O for 15–20 min and its potential application was investigated for N80 steel corrosion mitigation in 15% HCl. The results indicated that the good inhibitive action of bis(pyrazol-5-ols) in the acidic solution, which is due to the formation of inhibitor film [135].
After that, a highly efficient and environmentally benign method designed for the solvent-free preparation of bispyrazole derivatives from the condensation of substituted aromatic aldehyde, 50a and 28. Ionic liquid (NMPYT) was used as an ecofriendly catalyst under microwave irradiation for 13–20 min and resulted the corresponding products in 85–94% yields [136].
Furthermore, Tamoradi and co-workers noted that treatment of 50a with 28 and aromatic aldehydes using Ni complex supported on CoFe2O4 NPs as a recyclable catalyst in DMSO at 80 °C for 30–60 min afforded bis(pyrazolyl)methane derivatives 122 in 89–98% yields. Proposed mechanism for the preparation of bispyrazoles 122 in the presence of CoFe2O4@IDA-Ni MNPs is outlined in Scheme 32 [137].
CoFe2O4@IDA-Ni MNPs catalyzed synthesis of bispyrazoles 122
Jonnalagadda et al. have demonstrated an efficient method for the preparation of bis(pyrazolyl)methane derivatives in 92–99% yields under ultrasound irradiation using 28, 50a and aromatic aldehydes as reactants in EtOH:H2O at ambient temperature for 5–8 min. Treatment of 50a with 28 produces the pyrazolone intermediate 2a, which then tautomerizes to give the intermediate 2b. Next, condensation of aryl aldehyde with 2b affords Knoevenagel arylidene intermediate. In the next step, Michael addition of 2b to arylidene intermediate, followed by tautomerization leading to the formation of the target products [138].
Brønsted acidic dicationic ionic liquid immobilized on Fe3O4@SiO2NPs as a magnetically separable catalyst was applied for the preparation of bis(pyrazolyl)methanes 123 in 88–98% yields by condensation of 50a,b with 28 and aromatic aldehydes at 80 °C under solvent-free conditions for 3–25 min. A plausible mechanism is represented in Scheme 33. Initially, nucleophilic addition of 50 to the activated carbonyl group 28 affords 124, which undergoes intramolecular cyclization, followed by removal of EtOH leading to the formation of pyrazolone 125. In the next step, pyrazolones 125 rearranged into tautomers 2b and 12b and underwent Knoevenagel condensation to activated aldehydes to give intermediate 126. Michael acceptor 127 is formed by dehydration of 126 and treated with second molecule of pyrazolone to yield intermediate 128, which undergo tautomerization and aromatization to yield the target products 123 [139].
Synthesis of bispyrazoles 123 using Fe3O4@SiO2-NDIS
A rapid, green and efficient procedure for the preparation of bispyrazole derivatives 129 in 84–98% yields is reported via condensation of 50a with 28 and aromatic aldehydes using Pd(0)-guanidine@MCM-41 as a recyclable catalyst at 80 °C under solvent-free conditions for 14–30 min. The reasonable mechanism for synthesis of 129 is illustrated in Scheme 34. In the first step, palladium nanocatalyst activates carbonyl groups in the ethyl acetoacetate, and then 50a attacks the carbonyl groups to give pyrazolone 130, which is further rearranged into tautomer 2b. Next, a Knoevenagel-type of reaction takes place between activated aldehyde and 2b followed by dehydration to yield adduct 131. Subsequently, Michael addition reaction between 131 and 2b is facilitated to generate intermediate 132, which undergoes tautomerization and aromatization leads to the formation of the desired products 129 [140].
MCM-41@guanidine-Pd(0) catalyzed synthesis of bis(pyrazolyl)methanes 129
A rapid and very efficient approach for the preparation of bispyrazoles 133 in 82–96% yields has been reported using nickel-guanidine complex immobilized on MCM-41 (MCM-41@Gu@Ni) as a recyclable nanocatalyst (5 times) by the reaction of aromatic aldehydes, 50a and 28 in EtOH at 60 °C for 25–50 min. The plausible mechanism for the synthesis of 133 is represented in Scheme 35. Firstly, the carbonyl group 28 is activated by the nanocatalyst nickel for attack of lone pair of nitrogen form 50a to yield pyrazolone 134. Subsequently, the activated aromatic aldehyde undergoes a tandem reaction with intermediate 2b (which is the tautomer of intermediate 134) leads to intermediate 135 after dehydration. The next step is a Michael addition of another intermediate 2b to 135 to afford intermediate 136, which is then tautomerize to the expected products 133 [141].
MCM-41@Gu@Ni catalyzed synthesis of bispyrazoles 133
In 2021, a tetradentate acidic catalyst based on pentaerythritol tetrabromide and methylimidazole is synthesized and used for the solvent-free synthesis of bispyrazoles 137 in 88–97% yields from 50a, 28 and aryl aldehydes. The reaction proceeds at 100 °C within 4–14 min. The reasonable mechanism for the formation of 137 is depicted in Scheme 36. Initially, condensation reaction between 50 and 28 affords intermediate 138, which is converted into the product 139 by dehydration. In the next step, pyrazolone 2a is produced by cyclization of product 139 and removal of EtOH, which is in equilibrium with its tautomeric form 2b. Subsequently, intermediate 140 is obtained via condensation of 2b with the activated carbonyl group of aromatic aldehyde. Then, Michael addition reaction between 140 and another intermediate 2b affords the adduct 141. In the last step, after tautomerization and aromatization, the corresponding products 137 are formed [142].
[Tmim] [HSO4]4 catalyzed synthesis of bis(pyrazolyl)methanes 137
After that, an efficient strategy for the synthesis of (Fe3O4@THAM-Pd) as a recoverable organometallic nanocatalyst has been designed and used for the preparation of bispyrazoles 142 in 60–92% yields by coupling of 28, 50b and aromatic aldehydes at 70 °C for 35–60 min in EtOH:H2O (1:1). A possible mechanistic pathway is illustrated in Scheme 37. Firstly, pyrazolone produced from the reaction between 28 and 50b. Then, the addition of pyrazolone to the carbonyl group of the aldehydes activated by the catalyst affords Knoevenagel adduct 143. Finally, Michael addition of another pyrazolone to 143 leads to the desirable products 142 [143].
Fe3O4@THAM-Pd MNPs catalyzed synthesis of bispyrazoles 142
Recently, Patil and co-workers synthesized a series of bispyrazoles 144 in 84–94% yields by the condensation reaction of 28, 50b and aromatic aldehydes using a naturally sourced bio-surfactant, chickpea leaf exudates (CLE), as a recyclable Brønsted acid-type catalyst in iso-PrOH at 60 °C within 15–30 min (Scheme 38). Also, iso-PrOH provides dual performance (co-surfactant and co-solvent) in this reaction [144].
Synthesis of bispyrazoles 144 by using chickpea leaf exudates (CLE)
Conclusions
Pyrazole and its derivatives such as 4,4′-(arylmethylene)-bis-(1H-pyrazol-5-ols) have attracted interest because they exhibit a wide range of biological activities such as antibacterial, antioxidant, antifungal, anti-malarial, anti-inflammatory, anti-nociceptive, antipyretic, antivirals, antidepressant, antitumor, anti-filarial agents and as the chelating and extracting reagents for different metal ions. The present work contributes the different classical strategies for the synthesis of bispyrazole derivatives via one-pot pseudo three-component reactions and one-pot pseudo five-component reactions and reporting their applications for the period of 2014 to early 2021 in the presence of various homogeneous and heterogeneous catalysts such as nano-SiO2/HClO4, ZnO NPs, Ph3CCl, NH4(OAc), biosurfactant, Mohr’s salt, 2-carbamoylhydrazine-1-sulfonic acid, CsF, H3PW12O40, nanomagnetite-Fe3O4, SbCl5/SiO2 NPs, Cu-isatin Schiff base supported on γ-Fe2O3, MNPs@VO(OH)2, alum, [Amb]L-prolinate, Ce(SO4)2.4H2O, 4-H3SPA, caffeine-H3PO4, TMBSED][Cl]2, {Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl}, γ-AlOOH, silica vanadic acid, GO/Fe3O4/L-proline, Ni-guanidine@MCM-41NPs, GO@PyH-CH3SO3, chitosan-SO3H, La-guanine@SBA-15, Zr-guanine-MCM-41, 2-hydroxy ethylammonium propionate, ZnAl2O4 nanoparticles, Ce(SO4)2.4H2O, HAP@AEPH2-SO3H, CuCr2O4, Na+-MMT-[pmim]HSO4, [Et3NH][HSO4], ([MIm]ClO4, CeO2 NPs, 1-(carboxymethyl)pyridinium chloride {[cmpy]Cl}, 4-(succinimido)-1-butane sulfonic acid, Ag/TiO2, aspirin, L-proline, La(OTf)2-grafted-GO, sulfonated honeycomb coral, [Mn-4CSMP]Cl2, Dabco-base, morpholinium glycolate, nano-NiZr4(PO4)6, [TMEDSA][HSO4]2, [Dsim][TFA], (SB-DABCO)HSO4, lemon juice, CuFe2O4, alpha-Casein, guanidine hydrochloride, etraethylammonium L-prolinate, 4,4'-trimethylenedipiperidine, CoFe2O4@IDA-Ni MNPs, Fe3O4@SiO2NPs, Pd(0)-guanidine@MCM-41, MCM-41@Gu@Ni, [Tmim] [HSO4]4, Fe3O4@THAM-Pd, chickpea leaf exudates, Bronsted acids or catalyst-free conditions under green approach, ultrasound and microwave-mediated and solvent-free conditions. The advantages of the above methodologies include: environmentally friendly and operational simplicity, green conditions, extremely short times, high efficiency, simple work-up procedures, easily recyclable, reusable and excellent activity of the catalysts, the use of a nontoxic, biocompatible, biodegradable and metal-free ionic liquids and high to excellent yields of the some new products. In addition, this review article will help not only to the synthetic chemists but also to the medicinal and pharmaceutical chemists to update information on recent developments in this field.
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The authors thank the Research Council of Islamic Azad University of Takestan and Payame Noor University for financial supports.
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Sadeghpour, M., Olyaei, A. Recent advances in the synthesis of bis(pyrazolyl)methanes and their applications. Res Chem Intermed 47, 4399–4441 (2021). https://doi.org/10.1007/s11164-021-04592-7
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DOI: https://doi.org/10.1007/s11164-021-04592-7