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. 2022 Aug 4;7(32):28471–28480. doi: 10.1021/acsomega.2c03187

Synthesis of a Zirconium Complex of an N,O-type p-tert-Butylcalix[4]arene and Its Application in Some Multicomponent Reactions

Varun Rawat †,‡,*, Arkadi Vigalok ‡, Anshu Kumar Sinha †, Garima Sachdeva †, Chandra Mohan Srivastava †, Gyandshwar K Rao †,*, Arun Kumar §, Mandeep Singh ∥, Komal Rathi ⊥, Ved Prakash Verma ⊥,*, Bhupender Yadav #, Amit Kumar Pandey #, Monika Vats †,*
PMCID: PMC9386809  PMID: 35990458

Abstract

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The synthesis and characterization of a new octahedral Zr(IV) complex of oxygen-depleted N,O-type calixarene ligand comprising two distal-functionalized pyrazole rings have been reported. The cone shape and structure of the prepared complex were confirmed univocally by single-crystal X-ray diffraction and NMR studies. The Zr metal lies at 2.091 Å from the plane of the calixarene ring. This complex has been utilized as an efficient catalyst for the synthesis of Biginelli adducts, bis(indolyl)methanes, and coumarins. This complex (Cl2Zr–calixarene) showed superior activity for these multicomponent reactions in comparison to the corresponding Ti(IV) and Zn(II) analogues. Ferrocene-appended bis(indolyl)methane, prepared using this catalyst, was also evaluated for its anticancer activity against the A-172 cell line.

Introduction

Calix[n]arenes (n = 4, 5, 6, 8), due to their shape and host–guest binding capabilities, have found numerous applications in molecular recognition, self-assembly, drug delivery, and catalysis.1−8 It is well known that calix[4]arenes (calixarene) allow easy functionalization, expediently affording hundreds of grams in simple one-pot reactions.9−11 Another interesting aspect of the three-dimensional calixarene platform is its ability to encapsulate donors to a definitive binding pocket, making it more appealing than other ubiquitous ligands such as salens or porphyrins.12 A drawback of using calixarene scaffolds in metal catalysis is the presence of only oxygen hard-donors, which limits their coordination and catalytic ability.13−16 The introduction of soft donors along with the presence of hard donors might be useful in tuning the stereoelectronic environment around the metal center. Thus, we were interested in exploiting the calixarene coordination properties by introducing soft donors, such as nitrogen, directly in place of one or more hard oxygen donors in its lower rim. Consequently, we reported a modified Ullmann coupling reaction for the synthesis of oxygen-depleted distal-functionalized bis(pyrazole)calixarene (BPC) ligand 1.16 The BPC ligand 1 is particularly interesting since its structure mimics the His2-Tyr2 coordination sphere of enzymes such as galactose oxidase.17 Recently biomimetic and coordination studies of this ligand 1 with some transition and noble metals have been reported.12,18,19

Group 4 metal complexes have gained significant attention due to their low cost, high catalytic activity, easy availability, and low toxicity.20−24 Zr(IV) complexes are known to show higher coordination numbers and are more milder Lewis acids than Ti(IV) complexes, and thus often show better selectivity.8,25,26 Several Zr(IV) compounds are employed as Lewis acid catalysts that activate carboxyl and imino groups effectively.27−29 To the best of our knowledge, very few examples of Zr complexes of calixarene are known in the literature.30−34 As part of our research interest in developing new transition metal–calix[4]arene complexes for various organic transformation, we turned our attention toward the synthesis and application of a zirconium complex of our BPC ligand 1.

Results and Discussion

Synthesis and Characterization of [Cl2Zr{κ4-(bis(pyrazole))-p-tert-butylcalix[4]arene}], Cl2Zr–BPC (2)

Previously, we have reported a metathetical reaction of TiCl4 with BPC ligand 1, which leads to the formation of a Cl2Ti–bis(pyrazole)calix[4]arene complex (Cl2Ti-1) with rapid elimination of HCl.16 Unfortunately, using a similar protocol with ZrCl4, we could not obtain the anticipated Cl2Zr–BPC complex 2. Thus, a systematic study of reaction conditions was essential to obtain the desired complex 2. The results of such studies are presented in the Supporting Information (Table S1).35 After several experiments, when metathesis was carried out with ZrCl4(THF)2 in toluene at 110 °C, complex 2 could be afforded in a 76% yield (Scheme 1).

Scheme 1. Synthesis of Cl2Zr–bis(pyrazole)calix[4]arene (Cl2Zr–BPC) Complex 2; [tert-Butyl = tBu].

Scheme 1

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The structure of complex 2 was established using 1H, 13C, 15N NMR spectroscopy, HRMS, and single-crystal X-ray diffraction. The 1H NMR spectra of complex 2 showed a singlet at δ 1.00 and 1.33 ppm corresponding to the 18 hydrogens of t-butyl groups. A pair of doublets at δ 2.76 and 3.45 ppm due to the methylene bridge confirms the cone conformation of complex 2. This is also elaborated by its 13C NMR spectra, which showed a signal at 33.6 ppm.35−37 The pyrazole ring coordination mode was verified by preparing 15N-labelled Zr–Calix complex 2-N and comparing its 15N NMR with a ligand. The 15N spectra of 2-N display two doublets at δ 271.7 and 208.2 ppm (JNN = 9.2 Hz). The substantial change in the position of the nitrogen signal of the 15N labelled free ligand 1-N strongly suggests that this atom is coordinated to the Zr-metal center (Figure 1). Final evidence for such coordination and cone conformation came from the single-crystal structure of 2.

Figure 1.

Figure 1

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15N NMR spectra of bis(pyrazole)calix[4]arene ligand (BPC) 1-N and Cl2Zr–BPC 2-N.

Yellow colored crystals were obtained from the saturated solution of the complex in benzene/CDCl3 (1:1). Cl2Zr–BPC 2 crystallizes in the triclinic space group, with two molecules along with three molecules of benzene in the unit cell as a solvent. X-ray diffraction studies revealed a cone conformation, where the Zr atom is coordinated with the pyrazole nitrogen unambiguously [CCDC number 2022513]. Complex 2 is monomeric, and the coordination polyhedron is formed by the chelation of two nitrogen atoms of the dianionic BPC ligand 1.

The geometry can be best described as pseudo-octahedral, in which pyrazole Ns occupy the trans-position, and both Cl and O are present at cis to each other (Figure 2a). The angle between N–Zr–O, Cl–Zr–N, and O–Zr–O is 94.9, 83.8, and 94.6°, respectively. The Zr metal lies at 2.091 Å from the plane of the calixarene ring (Figure 2b). The Zr–N distance [2.274 Å] is slightly longer than the Ti–N distance [2.160 Å] due to the larger ionic radius of the Zr(IV) ion.15

Figure 2.

Figure 2

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(a) Molecular structure of the Zr(IV) complex 2. (b) Structure representing the cone conformation and the location of the Zr atom from the plane of the calixarene ring [CCDC number 2022513]. The tBu group and hydrogen atoms are omitted for clarity.

Catalytic Application of Cl2Zr–BPC (2)

As the structure of Cl2Zr–BPC complex 2 was similar to that of the Cl2Ti-complex of BPC ligand 1 (1-Ti), it was interesting to directly compare their catalytic activity in model organic reactions. Also, the cone conformation in 2 provides an open face for the reactions to occur, while the coordinating nitrogens help stabilize the metal center. It is also expected that the calixarene cavity, cone angle, and the surrounding pyrazoles (coordinating with Zr–metal center) would cause some inhibition in the approach of the substrate, thereby providing selectivity. Among many other applications of 2, the synthesis of pharmaceutically active heterocyclic compounds seemed attractive to us. Thus, the catalytic activity of 2 has been explored in the synthesis of 3,4-dihydropyrimidin-2(1H)-ones (Biginelli adducts).38 As a prototypical substrate, the multicomponent Biginelli reaction of p-hydroxybenzaldehyde with ethyl acetoacetate and urea has been carried out in the presence of 5 mol % Cl2Zr–BPC complex 2 in CH2Cl2 at room temperature for 4 h. However, no product formation was observed (Table 1, entry 1). Refluxing the reaction mixture resulted in an 11% yield of the corresponding Biginelli adduct 3a (Table 1, entry 2). Thus, changing the reaction condition by altering the solvent, reaction time, temperature, and catalyst was necessary for obtaining the title compound 3a in a high yield. When the reaction was carried out in EtOH, a substantial increase in the yield (66%) of compound 3a was noticed (Table 1, entry 6). After trying several other reactions condition, the best yield (91% of 3a) could be obtained when 1 mol % of catalyst 2 was used under solvent-free conditions (Table 1, entry 11). The corresponding titanium and zinc complex (Cl2Ti-1 and Zn-1) under similar reaction conditions gave a poor yield of Biginelli adduct 3a (35 and 11%, respectively) (Table 1, entry 14 and 15). Besides, for the metal–calixarene complexes, a subpar Biginelli reaction was also carried out with precursor Zr-salts (ZrCl4(THF)2 and ZrCl4; Table 1, entry 17–18) and ZrO2 (Table 1, entry 19). To the best of our knowledge, the finest yield (81%) for Biginelli adduct 3a is reported with SnCl4·5H2O and sulfonated calixarene, which require either a large catalyst loading (40 mol % SnCl4·5H2O)39 or a longer reaction time (8 h with sulfonated calixarene).40

Table 1. Optimization of the Biginelli Reactiona.

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entry catalyst mol (%) solvent time (h) temperature (°C) yield (%)b
1 2 5 CH2Cl2 4 room temperature no reaction
2 2 5 CH2Cl2 4 reflux 11
3 2 5 THF 4 reflux 24
4 2 5 CH3CN 4 reflux 53
5 2 5 CH3Cl 4 reflux 22
6 2 5 EtOH 4 reflux 66
7 2 5 DMF 4 reflux 47
8 2 5 neat 2 80 84
9 2 1 neat 2 80 88
10 2 1 neat 3 80 88
11 2 1 neat 1 80 91
12 2 1 neat 1 100 85
13 2 0.5 neat 2 80 83
14 Cl2Ti-1 1 neat 2 80 35
15 Zn-1 1 neat 2 80 11
16 1 1 neat 2 80 no reaction
17 ZrCl4(THF)2 1 neat 2 80 31
18 ZrCl4 1 neat 2 80 29
19 ZrO2 1 neat 2 80 10
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a

Reaction condition: 4-hydroxybenzaldehyde (1 mmol), urea (1.1 mmol), ethyl acetoacetate (2 mmol), catalyst, dry solvent (2 mL).

b

Isolated yield after chromatographic purification.

The scope of our catalyst system was briefly investigated by subjecting several aromatic aldehydes under the optimized reaction conditions. Indeed, the protocol gave excellent yields of the respective Biginelli adduct (3a–g). The method has shown a high tolerance for sensitive functional groups, such as the chloro, hydroxyl, cyano, and nitro groups, present in the aromatic nucleus. However, the reaction failed in the case of o-substituted aromatic aldehydes, which was a limitation of this protocol (Table 2, entry h and i). The inertness of the o-substituted substrates may be attributed to the inhibition in the activation of the carbonyl function by the Zr–metal center, which is marginally present in a pocket. These restrictions, owing to the shape of the ligand, are helpful in preventing any exogenic binding leading to the selectivity of the reaction.

Table 2. Substrate Scope for the Biginelli Reactiona.

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entry R yield (%)b
a 4-OH 91
b 4-NO2 95
c H 86
d 4-CN 94
e 4-Cl 89
f 4-Me 90
g 4-OMe 93
h 2-NO2 no reaction
i 2-Me no reaction
j 2-Cl no reaction
k 2-OH no reaction
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a

Reaction condition: benzaldehyde (1 mmol), urea (1.1 mmol), ethyl acetoacetate (2 mmol), catalyst 2 (1 mol %), 80 °C, 1 h.

b

Isolated yield after chromatographic purification.

At this point, we reasoned thate Cl2Zr–BPC complex 2 could be a valuable catalyst in the synthesis of medicinally useful bis(indolyl)methanes.41 As a model substrate, the condensation of p-chlorobenzaldehyde with indole was first carried out with limited success in the presence of 1 mol % of catalyst 2 under the solvent-free condition (Table 3, entry 1). In order to determine the optimum reaction conditions, we examined the influence of the temperature, solvent, reaction time, and the amounts of catalyst 2 on a model reaction between p-chlorobenzaldehyde (1 mmol) and indole (2 mmol). The highest yield could be attained with 1 mol % of catalyst 2, when the reaction was carried out in CH3CN at 60 °C (Table 3, entry 10). To our surprise, increasing the temperature or the amount of catalyst lowered the yield (Table 3, entry 9). Several other solvents such as DMF were also screened, and only a moderate yield was obtained (Table 3, entry 13). As opposed to catalyst 2, the corresponding Ti- and Zn-analogues gave a moderate to poor yield of the title compound under similar reaction conditions (Table 3, entry 14 and 15).

Table 3. Optimization of the Bis(indolyl)methane Synthesisa.

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entry catalyst mol (%) solvent time (h) temperature (°C) yield (%)b
1 2 1 neat 2 80 23
2 2 1 EtOH 2 reflux 35
3 2 1 THF 2 reflux 11
4 2 1 toluene 2 reflux 21
5 2 1 CH3CN 2 reflux 78
6 2 1 CH3CN 1 reflux 88
7 2 1 CH3CN 0.5 reflux 76
8 2 0.5 CH3CN 1 reflux 70
9 2 5 CH3CN 1 reflux 68
10 2 1 CH3CN 1 60 93
11 2 1 CH3CN 1 50 72
12 2 1 CH3CN 1 70 90
13 2 1 DMF 2 60 58
14 Cl2Ti-1 1 CH3CN 2 60 57
15 Zn-1 1 CH3CN 2 60 28
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a

Reaction condition: p-chlorobenzaldehyde (1 mmol), indole (2 mmol), dry solvent (2 mL), catalyst.

b

Isolated yield after column chromatography.

To investigate the applicability of Cl2Zr–BPC complex 2 in the synthesis of a variety of bis(indolyl)methanes, the protocol was extended to other substrates including ferrocene carboxaldehyde. Substantial disparities in the yield were not observed by the presence of electron-withdrawing or electron-donating groups on the benzaldehyde ring (Table 4).

Table 4. Substrate Scope for Bis(indolyl)methanesa.

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entry R-CHO yield (%)b
a 4-chlorobenzaldehyde 93
b 4-hydroxybenzaldehyde 92
c 4-methylbenzaldehyde 95
d 4-nitrobenzaldehyde 96
e cyclohexanone 89
f 4-methoxybenzaldehyde 93
g ferrocenecarboxaldehyde 86
h 2-nitrobenzaldehyde no reaction
i 2-methylbenzaldehyde no reaction
j 2-chlorobenzaldehyde no reaction
K 2-hydroxybenzaldehyde no reaction
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a

Reaction condition: aldehyde (1 mmol), indole (2 mmol), dry CH3CN (2 mL), catalyst 2 (1 mol %), 60 °C, 1 h.

b

Isolated yield after column chromatography.

Encouraged by these results, we decided to study the Pechmann condensation of phenols and ethyl acetoacetate. Indeed, our complex 2 was found to be active in catalyzing the condensation between α-naphthol and ethyl acetoacetate under the solvent-free condition (80 °C, 2 h, 89% isolated yield) (Scheme 2).35 More such applications of the new Cl2Zr–BPC complex 2 and other main group metal complexes are currently under investigation and will be reported in due course.

Scheme 2. Pechmann Condensation with Cl2Zr–bis(pyrazole)calix[4]arene (Cl2Zr–BPC) Complex 2.

Scheme 2

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Proposed Reaction Mechanism for the Biginelli Reaction

A plausible reaction mechanism for the Biginelli adduct formation is given in Figure 3. The Lewis acid Zr center in catalyst 2 is thought to accelerate the imine formation and ensuing addition/cyclization reactions. We assume the activation of aldehyde by 2 facilitates the condensation with urea. The coordination of imine with the Zr center present in catalyst 2 drives the reaction further through enolate addition. The final step involves the cyclization stage, which again is aided by the Lewis acid activation by calixarene 2. Similar activation by catalyst 2 is proposed for bis(indolyl)methane and coumarin synthesis.

Figure 3.

Figure 3

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Role of complex-2 in catalyzing Biginelli reaction.

Biological Evaluation of Ferrocene-appended Bis(indolyl)methane (4g)

Cancer is the world’s most dangerous disease, and it is the leading cause of death for humans. Among different types of cancer, brain cancer is counted as one of the fatal types of cancer. Glioblastoma is the most aggressive stage of brain cancer, which needs to be addressed well on time before brain cancer becomes the most common type. This leads to the continuous search for potent anticancer drugs for brain cancer with low toxicity and high potency. Iron-based organometallic compounds, such as ferrocene derivatives, have shown remarkable properties such as a low preparation cost, high stability, reduction–oxidation reversibility, catalytic activity, and ligand exchange capability. These amazing properties and diverse structure of ferrocene derivatives present them as potential candidates as anticancer agents against brain cancer cell lines (A-172).42

There are many probable mechanisms suggested in the literature for cancer cell death due to ferrocene-based anticancer agents. The potency may be due to the interruption of the redox homeostasis in cancer cells resulting in apoptosis,42 DNA intercalation or fragmentation,43 cell cycle arrest44 or ROS generation in cell.45

The cancerous A-172 cell line is a glioblastoma cell line, which is related to the most aggressive stage of brain cancer. The anticancerous activity of the synthesized compound 4g against the A-172 cell line was assessed via the MTT assay and compared with control Dulbecco’s modified Eagle medium (DMEM). The compound 4g was found to inhibit the cancer growth against the A-172 cell line in comparison to the control. The inhibition was started at 10 μM of the sample solution, as observed from Figure 4.35 Thus, the results of anticancer screening suggest that the synthesized compound is an anticancer agent. In the light of the available literature, the anticancer activity of this complex may be attributed to reversible redox properties of the compound, resulting in generation of radicals and leading to oxidative degradation of DNA and ROS production.46

Figure 4.

Figure 4

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Anticancer activity of ferrocene-appended bis(indolyl)methane (4g, inset figure) in comparison to control at different time intervals and at various concentrations (1, 5, 10, 15, and 10 μM) of the sample against the A-172 cell line.

The MTT assay results suggest that the synthesized complex can be a potential candidate for cancer therapy. However, further experimentation work is needed to establish the precise mechanism responsible for the anticancer activity of the synthesized complex.

Conclusions

In conclusion, we have described the complexation study of the Zr metal with 1,3-bis(pyrazole)-p-tert-butylcalix[4]arene ligand (BPC) 1. Also, the resulting complex Cl2Zr–BPC 2 has been used as a catalyst for the synthesis of medicinally important heterocyclic compounds, such as 3,4-dihydropyrimidin-2(1H)-ones, bis(indolyl)methanes and coumarins. This complex showed tolerance toward a wide range of functional groups and gave a high yield of the respective compounds. This complex showed better catalytic activity than the related titanium (Cl2Ti-1) and zinc (Zn-1) complex under similar reaction conditions in terms of yield. The aforementioned results are indicative of the efficiency of our catalyst system and provide an important supplemental method for the synthesis of important heterocyclic compounds. Mechanistic studies, other catalytic applications of the complex 2, as well as biological evaluation of some of synthesized compounds are currently underway.

Experimental Section

The synthetic manipulations involving air-sensitive compounds were performed in a nitrogen-filled Innovative Technology glovebox. All solvents were degassed and stored under high-purity nitrogen and activated 4 Å molecular sieves. All deuterated solvents were stored under high-purity nitrogen on 3 Å molecular sieves. Commercially available reagents (Aldrich, Spectrochem, and CDH) were used as received. The NMR spectra were recorded on a Bruker AVANCE 400 MHz spectrometer. All measurements were performed at 22 °C in CDCl3/C6D6/DMSO-d6 unless stated otherwise. Tetramethylsilane (δ 0.00 ppm) served as an internal standard in 1H NMR and CDCl3 (δ 77.23 ppm) in 13C NMR. Chemical shifts are reported in parts per million. Splitting patterns are described as singlet (s), doublet (d), triplet (t), multiplet (m), and broad singlet (br s). Mass spectra were recorded on a VG-Autopec M-250 instrument. The cancerous A-172 cell line (glioblastoma) was procured from NCS, Pune. The Roche assay kit has been used for performing MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay.

Synthesis of [Cl2Zr{κ4-(bis(pyrazole))-p-tert-butylcalix[4]arene}], Cl2Zr–BPC (2)

To the bis(pyrazole)calixarene ligand (BPC) 1 (20 mg, 0.026 mmol) dissolved in 4 mL of dry toluene, 11.3 mg of a ZrCl4(THF)2 (0.030 mmol) in dry toluene (1 mL) was added. The resulting mixture was heated at 110 °C for 12 h. The reaction mixture was cooled to room temperature, and dry diisopropylethylamine (7 mg, 0.0546 mmol dissolved in 1 mL of dry toluene) was added. The reaction was further stirred for 1 h, followed by filtration and solvent evaporation, giving the crude product 2, which was crystalized in a mixture of toluene and pentane (0.5 mL toluene: 2 mL pentane), which furnished a yellowish solid compound 2.

Complex (2): 18 mg (76% yield); yellowish solid; 1H NMR (400 MHz, C6D6): δ 1.00 (s, 18 H, t-Bu), 1.33 (s, 18H, t-Bu), 2.96 (d, 4H, J = 13.8 Hz, −CH2), 3.45 (d, 4H, J = 13.8 Hz, −CH2), 5.80 (t, 2H, J = 2.4 Hz, Ar), 6.34 (d, 2H, J = 2.2 Hz, Ar), 6.74 (s, 4H, Ar), 7.00 (s, 4H, Ar) and 9.10 (d, 4H, J = 2.4 Hz, Ar); 13C NMR (100 MHz, C6D6): δ 30.8 (t-Bu), 31.6 (t-Bu), 33.6 (CH2), 33.8 (C), 34.2 (C), (all aromatics): 107.0, 124.1, 126.4, 128.4, 129.1, 130.7, 133.8, 135.2, 139.5, 139.8, 141.1, 147.1, 152.4 and 158.2; HRMS (ESI) calcd for C50H58Cl2N4O2Zr [M]+, 906.2984; found, 906.2980.

General Experimental Procedure for the Biginelli Reaction

A round-bottom flask fitted with a reflux condenser was charged with benzaldehyde (1 mmol), ethyl acetoacetate (2 mmol), urea (1.1 mmol), and 1 mol % catalyst [0.01 mmol, ≈8 mg of Cl2Ti–BPC complex, ≈8 mg of Zn–BPC complex and ≈9 mg of Cl2Zr–BPC complex 2]. The mixture was stirred for 1 h at 80 °C under nitrogen. After the completion of the reaction, the reaction mixture was removed from heating, and 2 mL of EtOH was added. The reaction mixture was again stirred for an additional 15 min and then poured over ice to precipitate as the crude product. The Crude product was filtered and purified by column chromatography using hexane/EtOAc (7:3 v/v) to afford the compounds 3a–g (Table 2). Physical and spectral data of known compounds are in good agreement with those reported in the literature.47,48

Ethyl 4-(4-Hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a)

251 mg (91% yield with Cl2Zr–BPC complex 2); 97 mg (35% yield with Cl2Ti–BPC complex); 30 mg (11% yield with Zn–BPC complex); yellowish solid, mp 225–227 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.07 (t, 3H, J = 7.1 Hz, CH3), 2.22 (s, 3H, CH3), 3.94 (q, 2H, J = 7.1 Hz, CH2), 5.03 (d, 1H, J = 3.0 Hz, CH), 6.67 (d, 2H, J = 8.2 Hz, Ar), 7.01 (d, 2H, J = 8.5 Hz, Ar), 7.62 (br s, 1H, NH), 9.12 (br s, 1H, OH), 9.33 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ 14.7 (CH3), 18.3 (CH3), 54.0 (CH), 59.7 (CH2), (all olefins and aromatics): 100.3, 115.6, 128.0, 136.0, 148.3, 152.8, 157.1, 166.0.

Ethyl 6-Methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3b)

290 mg (95% yield); yellow solid, mp 206–208 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.09 (t, 3H, J = 7.0 Hz, CH3), 2.27 (s, 3H, CH3), 3.98 (q, 2H, J = 7.1 Hz, CH2), 5.27 (s, 1H, CH), 7.52 (d, 2H, J = 8.6 Hz, Ar), 7.93 (br s, 1H, NH), 8.23 (d, 2H, J = 8.6 Hz, Ar), 9.39 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ 14.5 (CH3), 18.3 (CH3), 54.1 (CH), 59.9 (CH2), (all olefins and aromatics): 98.6, 124.3, 128.1, 147.2, 149.9, 152.1, 152.2, 152.4, 165.5.

Ethyl 6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3c)

224 mg (86% yield); white solid mp 202–204 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.11 (t, 3H, J = 7.12 Hz, CH3), 2.27 (s, 3H, CH3), 4.00 (q, 2H, J = 7.0 Hz, CH2), 5.17 (d, 1H, J = 3.3 Hz, CH), 7.23–7.35 (m, 5H, Ar), 7.75 (br s, 1H, NH), 9.22 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 14.6 (CH3), 18.3 (CH3), 54.5 (CH), 59.7 (CH2), (all olefins and aromatics): 99.8, 126.8, 127.8, 128.9, 145.4, 148.9, 152.7, 165.9.

Ethyl 4-(4-Cyanophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3d)

268 mg (94% yield); yellow solid mp 179–181 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.09 (t, 3H, J = 7.1 Hz, CH3), 2.26 (s, 3H, CH3), 3.96–4.01 (m, 2H, CH2), 5.22 (d, 1H, J = 3.0 Hz, CH), 7.43 (d, 2H, J = 8.3 Hz, Ar), 7.83 (d, 2H, J = 8.4 Hz, Ar), 7.86 (br s, 1H, NH), 9.33 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ 14.5 (CH3), 18.3 (CH3), 54.3 (CH), 59.8 (CH2), (all olefins and aromatics): 98.7, 110.6, 119.2, 127.8, 133.0, 149.8, 150.5, 152.3, 165.6.

Ethyl 4-(4-Chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3e)

262 mg (89% yield); yellow solid mp 213–215 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.09 (t, 3H, J = 7.1 Hz, CH3), 2.25 (s, 3H, CH3), 3.99 (q, 2H, J = 7.1 Hz, CH2), 5.14 (d, 1H, J = 3.3 Hz, CH), 7.26 (d, 2H, J = 8.6 Hz, Ar), 7.41 (d, 2H, J = 8.6 Hz, Ar), 7.80 (d, 1H, J = 2.9 Hz, NH), 9.28 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ 14.5 (CH3), 18.3 (CH3), 53.8 (CH), 59.7 (CH2), (all olefins and aromatics): 99.2, 128.7, 128.9, 132.2, 144.2, 149.2, 152.4, 165.7.

Ethyl 6-Methyl-2-oxo-4-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3f)

247 mg (90% yield); white solid mp 166–168 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.10 (t, 3H, J = 7.0 Hz, CH3), 2.23 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.98 (q, 2H, J = 7.1 Hz, CH2), 5.10 (d, 1H, J = 3.3 Hz, CH), 7.11 (s, 4H, Ar), 7.71 (t, 1H, J = 2.9 Hz, NH), 9.18 (d, 1H, J = 1.3 Hz, NH); 13C NMR (100 MHz, DMSO-d6): δ 14.6 (CH3), 18.2 (CH3), 21.1 (CH3), 54.1 (CH), 59.6 (CH2), (all olefins and aromatics): 99.8, 126.6, 129.4, 136.8, 142.4, 148.6, 152.7, 165.8.

Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3g)

270 mg (93% yield); white solid mp 199–201 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.10 (t, 3H, J = 7.1 Hz, CH3), 2.23 (s, 3H, CH3), 3.72 (s, 3H, CH3), 3.98 (q, 2H, J = 7.1 Hz, CH2), 5.08 (d, 1H, J = 3.2 Hz, CH), 6.86 (d, 2H, J = 8.8 Hz, Ar), 7.15 (d, 2H, J = 8.7 Hz, Ar), 7.69 (d, 1H, J = 2.3 Hz, NH), 9.18 (d, 1H, J = 1.4 Hz, NH); 13C NMR (100 MHz, DMSO-d6): δ 14.6 (CH3), 18.23 (CH3), 53.8 (CH3), 55.5 (CH), 59.6 (CH2), (all olefins and aromatics): 99.9, 114.2, 127.9, 137.5, 148.5, 152.6, 158.9, 165.8.

General Experimental Procedure for Bis(indolyl)methane Formation

To a solution of aldehyde (1 mmol) and indole (2 mmol) dissolved in CH3CN (2 mL), 1 mol % catalyst [0.01 mmol, ≈8 mg of Cl2Ti–BPC complex, ≈8 mg of Zn–BPC complex, and ≈9 mg of Cl2Zr–BPC complex 2] was added. The reaction mixture was stirred under nitrogen at 60 °C for 1 h. After completion of the reaction, the reaction mixture was poured into water and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum. The crude compound was purified by column chromatography using hexane/EtOAc (8:2 v/v) to afford the compounds 4a–g (Table 4). Physical and spectral data of known compounds are in good agreement with those reported in the literature.49,50

3,3′-((4-Chlorophenyl)methylene)bis(1H-indole) (4a)

332 mg (93% yield); white solid mp 75–77 °C; 1H NMR (400 MHz, CDCl3): δ 1.34 (br s, 2H, NH), 5.88 (s, 1H, CH), 6.56 (s, 2H, CH=C), 7.06 (t, 2H, J = 7.6 Hz, Ar), 7.22 (m, 4H, Ar), 7.34 (d, 2H, J = 8.6 Hz, Ar), 7.39 (d, 2H, J = 8.6 Hz, Ar), 7.77 (s, 2H, NH); 13C NMR (100 MHz, CDCl3): δ 39.7, 111.4, 119.2, 119.5, 119.9, 122.2, 123.8, 127.0, 128.5, 130.3, 131.9, 136.8, 142.7.

4-(Di(1H-indol-3-yl)methyl)phenol (4b)

311 mg (92% yield); white solid mp 123–125 °C; 1H NMR (400 MHz, DMSO-d6): δ 5.71 (s, 1H, CH), 6.66 (d, 2H, J = 8.4 Hz, CH=C), 6.79 (s, 2H), 6.86 (d, 2H, J = 7.7 Hz, Ar), 7.03 (t, 2H, J = 8.0 Hz, Ar), 7.15 (d, 2H, J = 8.0 Hz, Ar), 7.28 (d, 2H, J = 8.4 Hz, Ar), 7.35 (d, 2H, J = 8.4 Hz, Ar), 9.17 (s, 1H, OH), 10.79 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δ 111.8, 115.2, 118.5, 119.1, 119.6, 121.2, 123.7, 123.8, 127.1, 129.6, 135.6, 137.0, 155.7.

3,3′-(p-Tolylmethylene)bis(1H-indole) (4c)

320 mg (95% yield); yellow solid mp 95–97 °C; 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H, CH3), 5.78 (s, 1H, CH), 6.81–7.36 (m, 14H, Ar and CH=C), 8.34 (s, 1H, NH), 10.82 (d, 1H, J = 1.8 Hz NH); 13C NMR (100 MHz, DMSO-d6): δ 21.1, 79.7, 111.8, 111.9, 118.5, 118.6, 118.7, 119.6, 121.3, 123.8, 123.9, 127.1, 128.7, 129.1, 135.0, 136.9, 137.0, 142.4.

3,3′-((4-Nitrophenyl)methylene)bis(1H-indole) (4d)

352 mg (96% yield); yellow solid mp 220–222 °C; 1H NMR (400 MHz, DMSO-d6): δ 6.03 (s, 1H, CH), 6.87–7.38 (m, 10H, Ar and CH=C), 7.60 (d, 2H, J = 8.7 Hz, Ar), 8.17 (d, 2H, J = 8.8 Hz, Ar), 10.96 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ 101.4, 111.8, 112.0, 112.1, 117.0, 117.1, 118.9, 119.2, 119.3, 120.4, 121.3, 121.6, 123.9, 124.2, 124.3, 125.7, 126.7, 126.8, 129.9, 136.9, 137.0, 146.2, 153.6.

3,3′-(Cyclohexane-1,1-diyl)bis(1H-indole) (4e)

280 mg (89% yield); white solid mp 117–119 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.52–1.59 (m, 6H, CH2), 2.4 (m, 4H, CH2), 6.68–6.69 (m, 2H, CH=C), 6.69–6.87 (m, 2H, Ar), 6.88–7.37 (m, 6H, Ar), 10.75 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δ 23.1, 26.9, 37.1, 38.9, 111.7, 117.8, 120.5, 121.0, 122.4, 122.5, 126.3, 137.4.

3,3′-((4-Methoxyphenyl)methylene)bis(1H-indole) (4f)

327 mg (93% yield); white solid mp 189–191 °C; 1H NMR (400 MHz, DMSO-d6): δ 3.71 (s, 3H, OCH3), 5.78 (s, 1H, CH), 6.81–6.89 (m, 6H, Ar and CH=C), 7.02–7.04 (m, 2H, Ar), 7.05–7.37 (m, 6H, Ar), 10.81 (d, 1H, J = 1.76 Hz NH); 13C NMR (100 MHz, DMSO-d6): δ 55.4, 111.9, 113.8, 118.6, 118.9, 119.6, 121.3, 123.9, 127.1, 129.7, 137.1, 137.4, 157.7.

Compound (4g)

382 mg (86% yield); brown solid mp 204–206 °C; 1H NMR (400 MHz, DMSO-d6): δ 3.95 (s, 5H, CH), 4.10 (t, 2H, J = 1.6 Hz, CH), 4.23 (t, 2H, J = 1.5 Hz, CH), 5.63 (s, 1H, CH), 6.84 (t, 2H, J = 7.7 Hz, Ar), 6.98 (t, 2H, J = 7.7 Hz, Ar), 7.18 (s, 2H, CH=C), 7.29 (d, 2H, J = 7.9 Hz, Ar), 7.43 (d, 2H, J = 7.9 Hz, Ar), 10.79 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δ 34.4, 67.1, 68.8, 94.0, 111.8, 118.3, 119.6, 119.8, 120.9, 123.2, 127.2, 136.7.

General Experimental Procedure for Pechmann Condensation

A round-bottom flask fitted with a reflux condenser was charged with α-naphthol (1 mmol), ethyl acetoacetate (2 mmol), and 1 mol % catalyst [≈9 mg of Cl2Zr–BPC complex 2]. The mixture was stirred under nitrogen for 2 h at 80 °C. After the completion of the reaction, the reaction mixture was removed from heating, and 2 mL of EtOH was added. The reaction is again stirred for an additional 15 min and then poured over ice to precipitate the product. The precipitate was filtered and recrystallized from hot ethanol to obtain the pure product. Physical and spectral data of known compounds are in good agreement with those reported in the literature.51

4-Methyl-2H-benzo[h]chromen-2-one (5a)

187 mg (89% yield); brown solid; mp 156–158 °C. 1H NMR (400 MHz, DMSO-d6): δ 2.52 (d, 3H, J = 1.2 Hz, CH3), 6.50 (d, 1H, J = 1.2 Hz, CH=C), 7.69–7.87 (m, 4H, Ar), 8.03–8.05 (m, 1H, Ar), 8.34–8.35 (m, 1H, Ar); 13C NMR (100 MHz, DMSO-d6): 19.2, (all olefins and aromatics): 114.3, 115.6, 121.7, 122.1, 122.6, 124.4, 127.9, 128.4, 129.1, 134.8, 150.1, 154.7, 160.1.

7-Hydroxy-4-methyl-2H-chromen-2-one (5b)

160 mg (91% yield) white solid mp 186–188 °C; 1H NMR (400 MHz, DMSO-d6): δ 2.36 (s, 3H, CH3), 6.14 (s, 1H, CH=C), 6.70 (d, 1H, J = 1.9 Hz, Ar), 6.80 (dd, 1H, J = 8.6 and 2.2 Hz, Ar), 7.60 (d, 1H, J = 8.6 Hz, Ar), 10.56 (br s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): 18.6, (all olefins and aromatics): 102.6, 110.7 112.4, 113.3, 127.1, 154.0, 155.2, 160.7, 161.6.

Experimental Procedure for Biological Evaluation

The anticancer potency of the complex was evaluated via MTT assay against the cancerous A-172 cell line (glioblastoma). The experiment was performed in triplicate with the help of the MTT assay kit. The synthesized complex solution was prepared in different concentrations viz., 1, 5, 10, 15, and 20 μM in DMSO in sterile conditions. For the MTT assay, DMEM + 10% FBS (fetal bovine serum) was used as a medium for the cell line. Cells were seeded in a 96 well plate, 10,000 cells in each well, and incubated overnight at 37 °C in a CO2 incubator. In the next step, media was removed, and FBS-free media (serum-free media) was added. Thereafter, the cells were treated with 100 μl of 1, 5, 10, 15, and 20 μm concentrations in respective wells for different time intervals (0–24 h). After the completion of the incubation period, 10 μL of 0.5 mg/mL of the MTT stopping reagent was added to each well. Then, the microplates were incubated for 4 h at 37 °C in a CO2 incubator. Then, 100 μL of the solubilizing buffer was added to each well. The plates were allowed to stand overnight at 37 °C in a CO2 incubator. The spectrophotometrical absorbance of the samples was recorded at 595 nm with the help of an ELISA reader.

Acknowledgments

V.P.V. thanks the Department of Science and Technology, New Delhi, India, for their research grant. This research work was financially supported by DST-SERB file number: EEQ/2019/000078.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c03187.

  • Spectral data for all synthesized compounds35 (PDF)

Author Contributions

The manuscript was written through the contributions of all authors.

The authors declare no competing financial interest.

Supplementary Material

ao2c03187_si_001.pdf (1.6MB, pdf)

References

  1. Kumar R.; Sharma A.; Singh H.; Suating P.; Kim H. S.; Sunwoo K.; Shim I.; Gibb B. C.; Kim J. S. Revisiting fluorescent calixarenes: from molecular sensors to smart materials. Chem. Rev. 2019, 119, 9657–9721. 10.1021/acs.chemrev.8b00605. [DOI] [PubMed] [Google Scholar]
  2. Mokhtari B.; Pourabdollah K.; Dalali N. Applications of nano-baskets of calixarenes in chromatography. Chromatographia 2011, 73, 829–847. 10.1007/s10337-011-1954-1. [DOI] [Google Scholar]
  3. Nimse S. B.; Kim T. Biological applications of functionalized calixarenes. Chem. Soc. Rev. 2013, 42, 366–386. 10.1039/c2cs35233h. [DOI] [PubMed] [Google Scholar]
  4. Ovsyannikov A.; Solovieva S.; Antipin I.; Ferlay S. Coordination polymers based on calixarene derivatives: Structures and properties. Coord. Chem. Rev. 2017, 352, 151–186. 10.1016/j.ccr.2017.09.004. [DOI] [Google Scholar]
  5. Sémeril D.; Matt D. Synthesis and catalytic relevance of P(III) and P(V)-functionalised calixarenes and resorcinarenes. Coord. Chem. Rev. 2014, 279, 58–95. 10.1016/j.ccr.2014.06.019. [DOI] [Google Scholar]
  6. Homden D. M.; Redshaw C. The use of calixarenes in metal-based catalysis. Chem. Rev. 2008, 108, 5086–5130. 10.1021/cr8002196. [DOI] [PubMed] [Google Scholar]
  7. Santoro O.; Redshaw C. Use of Titanium Complexes Bearing Diphenolate or Calix[n]arene Ligands in α-Olefin Polymerization and the ROP of Cyclic Esters. Catalysts 2020, 10, 210–239. 10.3390/catal10020210. [DOI] [Google Scholar]
  8. Santoro O.; Redshaw C. Metallocalix[n]arenes in catalysis: A 13-year update. Coord. Chem. Rev. 2021, 448, 214173–214210. 10.1016/j.ccr.2021.214173. [DOI] [Google Scholar]
  9. Agrawal Y. K.; Pancholi J. P.; Vyas J. M. Design and synthesis of calixarene. J. Sci. Ind. Res. 2009, 68, 745–768. [Google Scholar]
  10. Sliwa W.; Deska M. Functionalization reactions of calixarenes. Arkivoc 2011, 2011, 496–551. 10.3998/ark.5550190.0012.110. [DOI] [Google Scholar]
  11. Wieser C.; Dieleman C. B.; Matt D. Calixarene and resorcinarene ligands in transition metal chemistry. Coord. Chem. Rev. 1997, 165, 93–161. 10.1016/s0010-8545(97)90153-3. [DOI] [Google Scholar]
  12. Keck M.; Hoof S.; Herwig C.; Vigalok A.; Limberg C. Oxygen-Depleted Calixarenes as Ligands for Molecular Models of Galactose Oxidase. Chem.—Eur. J. 2019, 25, 13285–13289. 10.1002/chem.201903820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Redshaw C.; Walton M. J.; Lee D. S.; Jiang C.; Elsegood M. R.; Michiue K. Vanadium(V) Oxo and Imido Calix[8]arene Complexes: Synthesis, Structural Studies, and Ethylene Homo/Copolymerisation Capability. Chem.—Eur. J. 2015, 21, 5199–5210. 10.1002/chem.201406084. [DOI] [PubMed] [Google Scholar]
  14. Ladipo F. T.; Sarveswaran V.; Kingston J. V.; Huyck R. A.; Bylikin S. Y.; Carr S. D.; Watts R.; Parkin S. Synthesis, characterization, and alkyne cyclotrimerization chemistry of titanium complexes supported by calixarene-derived bis(aryloxide) ligation. J. Organomet. Chem. 2004, 689, 502–514. 10.1016/j.jorganchem.2003.10.039. [DOI] [Google Scholar]
  15. Soriente A.; De Rosa M.; Fruilo M.; Lepore L.; Gaeta C.; Neri P. Study on an aldol reaction catalyzed by Ti(IV)/calix[n]arene complexes. Adv. Synth. Catal. 2005, 347, 816–824. 10.1002/adsc.200505023. [DOI] [Google Scholar]
  16. Rawat V.; Press K.; Goldberg I.; Vigalok A. Straightforward synthesis and catalytic applications of rigid N,O-type calixarene ligands. Org. Biomol. Chem. 2015, 13, 11189–11193. 10.1039/c5ob01987g. [DOI] [PubMed] [Google Scholar]
  17. Ito N.; Phillips S. E.; Stevens C.; Ogel Z. B.; McPherson M. J.; Keen J. N.; Yadav K. D.; Knowles P. F. Novel thioether bond revealed by a 1.7 Å crystal structure of galactose oxidase. Nature 1991, 350, 87–90. 10.1038/350087a0. [DOI] [PubMed] [Google Scholar]
  18. Sinha A. K.; Vigalok A.; Rawat V. Catalytic application of zinc complex of oxygen depleted 1,3-bis(pyrazole)-p-tert-butylcalix[4]arene. Tetrahedron Lett. 2019, 60, 796–799. 10.1016/j.tetlet.2019.02.017. [DOI] [Google Scholar]
  19. Keck M.; Hoof S.; Rawat V.; Vigalok A.; Limberg C. The Coordination Behavior of Oxygen-depleted Calixarenes towards d 10 Noble Metal Ions. Z. Anorg. Allg. Chem. 2020, 646, 904–908. 10.1002/zaac.202000138. [DOI] [Google Scholar]
  20. Nakata N.; Toda T.; Ishii A. Recent advances in the chemistry of Group 4 metal complexes incorporating [OSSO]-type bis(phenolato) ligands as post-metallocene catalysts. Polym. Chem. 2011, 2, 1597–1610. 10.1039/c1py00058f. [DOI] [Google Scholar]
  21. Bochmann M. The chemistry of catalyst activation: The case of group 4 polymerization catalysts. Organometallics 2010, 29, 4711–4740. 10.1021/om1004447. [DOI] [Google Scholar]
  22. Collins R. A.; Russell A. F.; Mountford P. Group 4 metal complexes for homogeneous olefin polymerisation: a short tutorial review. Appl. Petrochem. Res. 2015, 5, 153–171. 10.1007/s13203-015-0105-2. [DOI] [Google Scholar]
  23. Sun Z.; Zhao Y.; Santoro O.; Elsegood M. R. J.; Bedwell E. V.; Zahra K.; Walton A.; Redshaw C. Use of titanocalix[4]arenes in the ring opening polymerization of cyclic esters. Catal. Sci. Technol. 2020, 10, 1619–1639. 10.1039/c9cy02571e. [DOI] [Google Scholar]
  24. Hofmeister G. E.; Alvarado E.; Leary J. A.; Yoon D. I.; Pedersen S. F. Synthesis and characterization of dimetallacalix[8]arene complexes. J. Am. Chem. Soc. 1990, 112, 8843–8851. 10.1021/ja00180a028. [DOI] [Google Scholar]
  25. Bradley D.; Mehrotra R. C.; Rothwell I.; Singh A.. Alkoxo and Aryloxo Derivatives of Metals; Elsevier Science, 2001. [Google Scholar]
  26. Sauer A.; Kapelski A.; Fliedel C.; Dagorne S.; Kol M.; Okuda J. Structurally well-defined group 4 metal complexes as initiators for the ring-opening polymerization of lactide monomers. J. Chem. Soc., Dalton Trans. 2013, 42, 9007–9023. 10.1039/c3dt00010a. [DOI] [PubMed] [Google Scholar]
  27. Zhang Z. H.; Li T. S. Applications of zirconium (IV) compounds in organic synthesis. Curr. Org. Chem. 2009, 13, 1–30. 10.2174/138527209787193783. [DOI] [Google Scholar]
  28. Bhagat S.; Chakraborti A. K. Zirconium(IV) Compounds As Efficient Catalysts for Synthesis of α-Aminophosphonates. J. Org. Chem. 2008, 73, 6029–6032. 10.1021/jo8009006. [DOI] [PubMed] [Google Scholar]
  29. Jafarpour M.; Rezaeifard A.; Gazkar S.; Danehchin M. Catalytic activity of a zirconium(IV) Schiff base complex in facile and highly efficient synthesis of indole derivatives. Transition Met. Chem. 2011, 36, 685–690. 10.1007/s11243-011-9519-6. [DOI] [Google Scholar]
  30. Lapenta R.; De Simone N. A.; Buonerba A.; Talotta C.; Gaeta C.; Neri P.; Grassi A.; Milione S. Dinuclear zirconium complex bearing a 1,5-bridged-calix[8]arene ligand as an effective catalyst for the synthesis of macrolactones. Catal. Sci. Technol. 2018, 8, 2716–2727. 10.1039/c7cy02537h. [DOI] [Google Scholar]
  31. Giannini L.; Solari E.; Zanotti-Gerosa A.; Floriani C.; Chiesi-Villa A.; Rizzoli C. The Organometallic Chemistry of Zirconium on an Oxo Surface Provided byp-tert-Butylcalix[4]arene. Angew. Chem., Int. Ed. Engl. 1996, 35, 85–87. 10.1002/anie.199600851. [DOI] [Google Scholar]
  32. Hofmeister G. E.; Hahn F. E.; Pedersen S. F. Chiral recognition in the synthesis of dimetalla-4-tert-butylcalix[8]arene complexes. The incorporation of a metal-alkoxide ligand into a molecular cavity. J. Am. Chem. Soc. 1989, 111, 2318–2319. 10.1021/ja00188a064. [DOI] [Google Scholar]
  33. Czakler M.; Artner C.; Maurer C.; Schubert U. Calix[4]arene Derivatives of Titanium and Zirconium Alkoxides. Z. Naturforsch. 2014, 69, 1253–1259. 10.5560/znb.2014-4121. [DOI] [Google Scholar]
  34. Redshaw C. Coordination chemistry of the larger calixarenes. Coord. Chem. Rev. 2003, 244, 45–70. 10.1016/s0010-8545(03)00099-7. [DOI] [Google Scholar]
  35. See Supporting Information.
  36. Shinkai S.; Fujimoto K.; Otsuka T.; Ammon H. L. Syntheses and ion selectivity of conformational isomers derived from calix[4]arene. J. Org. Chem. 1992, 57, 1516–1523. 10.1021/jo00031a034. [DOI] [Google Scholar]
  37. Jaime C.; De Mendoza J.; Prados P.; Nieto P. M.; Sanchez C. Carbon-13 NMR chemical shifts. A single rule to determine the conformation of calix[4]arenes. J. Org. Chem. 1991, 56, 3372–3376. 10.1021/jo00010a036. [DOI] [Google Scholar]
  38. de Fátima Â.; Braga T. C.; Neto L. D. S.; Terra B. S.; Oliveira B. G.; da Silva D. L.; Modolo L. V. A mini-review on Biginelli adducts with notable pharmacological properties. J. Adv. Res. 2015, 6, 363. 10.1016/j.jare.2014.10.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rameshwar N.; Parthasarathy T.; RamReddy A. Tin(lV) catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones under solvent-free conditions. J. Chem. 2008, 47, 1871–1875. [Google Scholar]
  40. da Silva D. L.; Fernandes S. A.; Sabino A. A.; de Fátima Â. p-Sulfonic acid calixarenes as efficient and reusable organocatalysts for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones. Tetrahedron Lett. 2011, 52, 6328–6330. [Google Scholar]
  41. Singh A.; Kaur G.; Banerjee B. Recent Developments on the Synthesis of Biologically Significant bis/tris(indolyl)methanes under Various Reaction Conditions: A Review. Curr. Org. Chem. 2020, 24, 583–621. 10.2174/1385272824666200228092752. [DOI] [Google Scholar]
  42. Chaudhary A.; Poonia K. The redox mechanism of ferrocene and its phytochemical and biochemical compounds in anticancer therapy: A mini review. Inorg. Chem. Commun. 2021, 134, 109044–109053. 10.1016/j.inoche.2021.109044. [DOI] [Google Scholar]
  43. Maity B.; Gadadhar S.; Goswami T. K.; Karande A. A.; Chakravarty A. R. Impact of metal on the DNA photocleavage activity and cytotoxicity of ferrocenyl terpyridine 3d metal complexes. Dalton Trans. 2011, 40, 11904–11913. 10.1039/c1dt11102g. [DOI] [PubMed] [Google Scholar]
  44. Wu C.; Ye H.; Bai W.; Li Q.; Guo D.; Lv G.; Yan H.; Wang X. New potential anticancer agent of carborane derivatives: selective cellular interaction and activity of ferrocene-substituted dithio-o-carborane conjugates. Bioconjugate Chem. 2011, 22, 16–25. 10.1021/bc100158b. [DOI] [PubMed] [Google Scholar]
  45. Huang R.; Wallqvist A.; Covell D. G. Anticancer metal compounds in NCI’s tumor-screening database: putative mode of action. Biochem. Pharmacol. 2005, 69, 1009–1039. 10.1016/j.bcp.2005.01.001. [DOI] [PubMed] [Google Scholar]
  46. Mooney A.; Tiedt R.; Maghoub T.; O’Donovan N.; Crown J.; White B.; Kenny P. T. M. Structure-Activity Relationship and Mode of Action of N-(6-Ferrocenyl-2-naphthoyl) Dipeptide Ethyl Esters: Novel Organometallic Anticancer Compounds. J. Med. Chem. 2012, 55, 5455–5466. 10.1021/jm3004027. [DOI] [PubMed] [Google Scholar]
  47. Davanagere P. M.; Maiti B. 1,3-Bis(carboxymethyl)imidazolium chloride as a sustainable, recyclable, and metal-free ionic catalyst for the biginelli multicomponent reaction in neat condition. ACS Omega 2021, 6, 26035–26047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Jadhav C. K.; Nipate A. S.; Chate A. V.; Songire V. D.; Patil A. P.; Gill C. H. Efficient rapid access to biginelli for the multicomponent synthesis of 1,2,3,4-tetrahydropyrimidines in room-temperature diisopropyl ethyl ammonium acetate. ACS Omega 2019, 4, 22313–22324. 10.1021/acsomega.9b02286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Kalla R. M. N.; Hong S. C.; Kim I. Synthesis of bis(indolyl)methanes using hyper-cross-linked polyaromatic spheres decorated with bromomethyl groups as efficient and recyclable catalysts. ACS Omega 2018, 3, 2242–2253. 10.1021/acsomega.7b01925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Chavan K. A.; Shukla M.; Chauhan A. N. S.; Maji S.; Mali G.; Bhattacharyya S.; Erande R. D. Effective synthesis and biological evaluation of natural and designed bis(indolyl)methanes via taurine-catalyzed green approach. ACS Omega 2022, 7, 10438–10446. 10.1021/acsomega.1c07258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Jadhav N. H.; Sakate S. S.; Rasal N. K.; Shinde D. R.; Pawar R. A. Heterogeneously catalyzed pechmann condensation employing the tailored zn0.925ti0.075o nps: synthesis of coumarin. ACS Omega 2019, 4, 8522–8527. 10.1021/acsomega.9b00257. [DOI] [PMC free article] [PubMed] [Google Scholar]

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