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. 2023 Jan 16;8(4):4146–4155. doi: 10.1021/acsomega.2c07129

Synthesis, Characterization, Pharmacogenomics, and Molecular Simulation of Pyridinium Type of Ionic Liquids and Their Applications

Ramalingam Tamilarasan †,‡, Kilivelu Ganesan †,*, Annadurai Subramani §, Liyakath Benazir Ali ∥, Mohammed Mujahid Alam ⊥, Amanullah Mohammed #
PMCID: PMC9893258  PMID: 36743060

Abstract

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Substituted pyridinium bromides are prepared by conventional and solvent-free greener methods. The solvent-free solid-phase (greener) method is superior to the conventional method because of its nontoxic nature, simple reaction setup procedure, and twenty times less time consumption. Column chromatography and toxic organic solvents are avoided. Substituted pyridinium salts 1–2(a–c) show excellent catalytic response in the preparation of β-amino carbonyl derivatives using the conventional approach. Pharmacokinetics is very important in target validation and in shifting a lead compound into a drug. The physicochemical properties discussed here can be used effectively in the drug designing candidate, which is a cumbersome process in clinical research. In addition, molecular simulations are demonstrated, and compounds 1–2(a–c) possess the most potent VEGFR-2 kinase protein inhibitory activities, and most interestingly, compound 2a strongly binds and regulates the VEGFR-2 kinase activity in therapeutic approaches and cancer prevention.

1. Introduction

Ionic liquids (ILs) have earned themselves a reputation as excellent reaction media. Earlier applications of ILs were mainly as electrolytes, solvents, and extractants. The scope of their application is now broader and covers their use as reaction media, fuel cells, optical fluids, solar cells, energetic materials, heat transfer fluids, and lubricants, to name only a few.1 The properties of imidazolium/pyridinium salt are varied with different counter anions, which can enhance or suppress the catalytic activities.2−5 Pyrazole and its derivatives have emerged as important compounds among the other heterocyclic compounds due to their medicinal properties like anti-inflammatory,6,7 analgesic,8,9 antimicrobial,10 anticancer,11 antiviral,12 antipyretic,13 and antianxiety activities,14 and some of the reports proved that adding other materials like nitrogen-containing phosphane15,16 and ligands17,18 to pyrazolium/pyridinium19,20 and imidazolium21−24 can give more stability to the compound, which are recyclable catalytic moieties. The drug discovery and evolution process aims at finding a compound, possessing good pharmacodynamic and pharmacokinetic properties. It is eminent that drugs designed can be more productive if physicochemical properties are carefully analyzed and applied in a defined way during development. The early prediction of ADME properties in the drug-designing phase considerably diminishes the fraction of pharmacokinetics-related failures in clinical trials.25 The proposed set of compounds is optimized by virtual ADME screening by the tool SwissADME.

Synthesized protic ILs in the form of 1-alkyl- and 1-alkoxymethylimidazolium lactates found that antimicrobial activities of the protic ILs are strongly related to the length of the substituent and the type of anion. Anthracene-linked trimeric imidazolium bromide is prepared by the conventional approach.26 Trimeric imidazolium salt formed an excellent selective sensor for picric acid.27 Dimeric, trimeric, and tetrameric pyridinium cations with a bromide counter anion played a crucial role in detecting various anions in an aqueous environment.28 Host–guest interaction is involved between β-cyclodextrin and alkyl/aryl-substituted dimeric imidazolium salt in a kneading approach.29

In the present work, we have synthesized quaternary ammonium-based pyridinium salts under conventional/solvent-free silica-supported conditions as well as their catalytic properties, which are described here. Using the conventional/solid-phase approach, we investigated one-spot preparation of β-amino carbonyl derivatives with the optimal concentration of our synthesized pyridinium salts. The preparation of β-amino carbonyl derivatives with our catalyst is substantially more effective, to the best of our knowledge, based on the literature. Furthermore, we explored the molecular modeling and binding affinities of quaternary ammonium-based pyridinium type of ionic liquids as pharmacological molecules against various macromolecular receptors, such as H-bonding, π–π stacking, salt bridge, and hydrophobic contacts.

2. Results and Discussion

Synthesis of benzyl/4-nitrobenzyl-substituted pyridinium bromide 1a/2a from N,N-dimethyl pyridine-4-amine (1.853 × 10–3 mmol; 1.0 equiv) is treated with benzyl/4-nitrobenzyl bromide (1.65 × 10–2 mmol; 2.05 equiv) in the presence of 20 mL of dry CH3CN under refluxing conditions for 30–45 min to give benzyl/4-nitrobenzylated pyridinium bromide 1a/2a in quantitative yield. To reduce the toxicity of the N-alkylation reaction, it is tried using a solvent-free silica-supported approach under muffle furnace conditions, which is completed in lesser reaction time with higher yield (Scheme 1).

Scheme 1. Synthesis of Benzyl/4-Nitrobenzyl-Substituted Quaternary Ammonium-Based Pyridinium Bromide Using Multiple Approaches.

Scheme 1

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Reagent and conditions: Conventional approach (CA): CH3CN, ref, 30–45 min, 82–85%; Solid-supported approach (SSA): Muffule furnace, 100 °C, 10–15 min, 96–98%.

N-alkylation reaction by the solvent-free silica-supported approach is much superior to the conventional approach because of its nontoxicity, shorter reaction time with higher yield, and easy work up. 4-Nitrobenzyl bromide reacts much faster than benzyl bromide due to the weaker C-Br bond in 4-nitrobenzyl bromide.

An anion exchange reaction is carried out with substituted quaternary ammonium-based pyridinium bromide 1a/2a in the presence of different counter anions containing inorganic salts, such as K4PF6, NaBF4, and LiCF3SO3, in the presence of 20 mL of deionized water at room temperature with stirring for 2 h to give anion exchange products of compounds 1–2(b-d) in 94–98% yield (Scheme 2).

Scheme 2. Preparation of Different Counteranions Containing Quaternary Ammonium-Based Pyridinium Salts.

Scheme 2

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3. Catalytic Activity

We have tried the Mannich reaction using a catalytic amount of benzyl/4-nitrobenzyl-substituted pyridinium salts with and without solvent. 4-Nitrobenzyl-substituted pyridinium bromide 2a showed excellent catalytic activity than the others. To optimize the catalytic concentration of substituted quaternary ammonium-based pyridinium salts, the reaction is carried out with various concentrations, such as 3.608 × 10–5, 7.217 × 10–5, and 1.082 × 10–4 mmol. Among these concentrations, 1.082 × 10–4 mmol showed excellent catalytic response than the others. While increasing the concentration, there is no appreciable change in the reaction. So, 1.082 × 10–4 mmol concentration is the optimum concentration to prepare β-amino carbonyl compounds.

Various β-amino carbonyl derivatives are prepared by conventional and solvent-free silica-supported approaches, which are catalyzed by benzyl/4-nitrobenzyl quaternary ammonium-based pyridinium salts. The results are summarized in Tables 1 and 2 and compared the catalytic efficiency with available literature reports.30 Senapak and co-workers prepared β-amino carbonyl derivatives31 in the presence of an acidic ionic polymer bearing imidazolium type of catalyst required nearly 24 h for completion of the reaction. When comparing the catalytic response between compounds 1a and 2a, compound 2a showed excellent catalytic response even in very low concentrations. After examining the literature reports, compound 2a is superior to the available reports due to its shorter reaction period, solvent-free, nontoxicity, higher yield, and environmentally friendly nature (Scheme 3).

Table 1. Preparation of β-Amino Carbonyl Derivative Catalyst by Benzyl-Substituted Quaternary Ammonium-Based Pyridinium Salts 1(a–d).

      Concentration of benzyl quaternary ammonium-based pyrazolium salts
      4.308 × 10–5 mmol 8.616 × 10–5 mmol 1.292 × 10–4 mmol
      CA SSA CA SSA CA SSA
s. no catalyst β-amino carbonyl derivatives time (h:m) yield % time (h:m) yield % time (h:m) yield % time (h:m) yield % time (h:m) yield % time (h:m) yield %
1 1a 3a 1.50 76 0.55 78 1.25 81 0.45 84 1.00 86 0.35 91
3b 1.00 80 0.30 83 0.35 85 0.20 88 0.15 90 0.10 95
3c 1.20 79 0.40 81 0.55 84 0.30 86 0.30 89 0.20 94
3d 1.40 77 0.50 79 1.15 82 0.40 84 0.50 88 0.30 92
3e 2.15 74 1.05 76 1.50 79 0.55 83 1.25 87 0.45 91
2 1b 3a 2.00 73 1.05 76 1.35 78 0.55 82 1.10 83 0.45 88
3b 1.10 77 0.40 80 0.45 83 0.30 86 0.20 88 0.20 95
3c 1.30 75 0.50 78 1.05 81 0.40 83 0.40 86 0.30 92
3d 1.50 71 1.00 74 1.25 76 0.50 79 1.00 82 0.40 87
3e 2.25 69 1.15 72 2.00 76 1.05 77 1.35 81 0.55 86
3 1c 3a 2.10 71 1.20 74 1.45 78 1.05 79 1.20 84 0.55 89
3b 1.20 74 0.50 77 0.55 79 0.40 82 0.30 86 0.30 91
3c 1.40 72 1.00 75 1.15 77 0.50 80 0.50 82 0.40 87
3d 2.00 70 1.10 73 1.35 75 1.00 78 1.10 80 0.50 85
3e 2.35 67 1.25 70 2.10 72 1.15 75 1.45 78 1.05 87
4 1d 3a 2.15 68 1.25 71 1.50 73 1.10 77 1.25 78 1.00 89
3b 1.25 70 0.55 73 1.00 75 0.45 78 0.35 80 0.35 85
3c 1.45 67 1.05 70 1.20 72 0.55 74 0.55 79 0.45 88
3d 2.05 63 1.15 66 1.40 68 1.05 73 1.15 78 0.55 84
3e 2.45 61 1.30 64 2.15 70 1.20 69 1.50 81 1.10 87
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Table 2. Preparation of β-Amino Carbonyl Derivative Catalyst by 4-Nitrobenzyl-Substituted Quaternary Ammonium-Based Pyridinium Salts 2(a–d).

      Concentration of 4-nitrobenzyl quaternary ammonium-based pyrazolium salts
      3.608 × 10–5 mmol 7.217 × 10–5 mmol 1.082 × 10–4 mmol
      CA SSA CA SSA CA SSA
S. No Catalyst β-amino carbonyl derivatives time (h:m) yield % time (h:m) yield % time (h:m) yield % time (h:m) yield % time (h:m) yield % time (h:m) yield %
1 2a 3a 1.20 81 0.40 87 1.00 90 0.20 93 0.30 93 0.10 95
3b 0.30 88 0.20 84 0.20 89 0.10 90 0.10 91 0.05 94
3c 0.50 79 0.25 86 0.30 90 0.13 92 0.15 94 0.07 95
3d 1.10 81 0.35 90 0.50 93 0.17 95 0.25 94 0.10 97
3e 1.45 79 0.55 89 1.25 92 0.27 96 0.43 93 0.27 98
2 2b 3a 1.30 85 0.45 85 1.10 89 0.25 91 0.40 92 0.15 96
3b 0.40 75 0.25 82 0.20 88 0.15 91 0.10 90 0.10 97
3c 1.00 80 0.30 83 0.40 91 0.18 90 0.25 93 0.12 93
3d 1.20 73 0.40 89 1.00 91 0.22 93 0.35 93 0.15 96
3e 1.55 81 1.00 86 1.35 91 0.32 94 0.53 92 0.32 97
3 2c 3a 1.40 73 0.50 82 1.10 86 0.30 90 0.50 91 0.20 94
3b 0.50 75 0.30 80 0.30 93 0.20 89 0.15 91 0.15 96
3c 1.00 73 0.35 84 0.50 89 0.23 88 0.35 90 0.17 92
3d 1.20 80 0.45 88 1.10 89 0.27 92 0.45 91 0.20 93
3e 1.55 71 1.05 82 1.45 90 0.37 94 1.03 91 0.37 95
4 2d 3a 1.45 73 0.55 80 1.15 84 0.35 89 0.55 90 0.25 90
3b 0.55 81 0.35 79 0.35 85 0.25 88 0.20 89 0.25 93
3c 1.05 88 0.40 80 0.55 87 0.28 89 0.45 91 0.22 91
3d 1.25 79 0.50 86 1.15 88 0.32 91 0.50 90 0.25 92
3e 2.00 81 1.10 81 1.50 89 0.42 90 1.05 89 0.42 94
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Scheme 3. Synthesis of Substituted Amino Carbonyl Derivatives Using Multiple Methods.

Scheme 3

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Reagent and conditions: CA: CH3CN, ref, 10–165 min, 80–96%; SSA: Muffule furnace, 100 °C, 05–70 min, 84–98%.

We have tried the catalytic efficiency of 4th cycle benzyl/4-nitrobenzyl quaternary ammonium-based pyridinium salt in the preparation of β-amino carbonyl compound. Even in the 4th cycle, the product obtained was the same as observed in the fresh use shown in Figure 1.

Figure 1.

Figure 1

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Mannich reaction under recycled substituted quaternary ammonium-based pyridinium salts.

3.1. Molecular Modeling

A molecular simulation study is an attractive scaffold to understand the ionic liquid–protein interactions, which can corroborate our experimental results. The best interaction site of compounds with target protein is visualized in Figures 2 and 3, and data are summarized in tables. The observed docking score value of compounds 1–2(a–d) reveals −4.14, −6.41, −4.34, −4.15, −4.571, −5.742, −5.442, and −5.927 kcal/mol. The docking score results revealed that all compounds are well located in the hydrophobic site and strongly interact with the VEGFR-2 kinase receptor via π–π stacking and hydrophobic and hydrogen-bonding interactions.

Figure 2.

Figure 2

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Molecular simulation. 2D and 3D structures of compounds 1a, 2a, 1b, and 1c with the receptor VEGFR-2 kinase.

Figure 3.

Figure 3

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Molecular simulation. 2D and 3D structures of compounds 1a, 2b, 2c, and 2d with the receptor VEGFR-2 kinase.

All compounds also displayed many hydrophobic contacts; surprisingly, 2a showed the highest docking score, which was influenced by a hydrogen bond with residue CYS 919, π–π interaction with ARG 1027, salt bridge LYS 838, and numerous hydrophobic contacts like LEU 840, TYR 927, LEU 1035, PHE 1047, ALA 866, PHE 921, CYC 919, PHE 918, and VAL 848. The effect of noncovalent intermolecular π–π stacking interactions on all molecules is not surprising to show. From the above facts, compound 2a strongly binds and regulates the VEGFR-2 kinase activity in therapeutic strategies and cancer prevention (Table 3).

Table 3. Molecular Docking Studies of Compounds 1–2(a–d) with VEGFR-2 Kinase.

    active sites with a mode of interaction
ionic liquids docking score kcal·mol–1 H-bond π-π stacking salt bridge hydrophobic contacts (cutoff at 5 Å)
1a –4.14     LYS 838 LEU 840, TYR 927, PHE 921, CYS 919, PHE 918, ALA 866, VAL 848, LEU 1035, PHE 1047
2a –6.41 CYS 919   LYS 838 LEU 840, TYR 927, LEU 1035, PHE 1047, ALA 866, PHE 921, CYC 919, PHE 918, VAL 848
1b –4.34 ARG 1027     TYR 1054, ILE 1053, PHE 845, ALA 844, LEU 1049, TYR 1059, MET 1072, TYR 1082, PRO 1068, LEU 1067, LEU 802
1c –4.15 ARG 1027     LEU 802, LEU 1067, PRO 1068, TYR 1082, TYR 1059, LEU 1049, PHE 845, ALA 944, ILE 1053, TYR 1054
1d –5.742 ARG 1066     LEU 802, ALA 1065, LEU 1067, TYR 1082, PRO 1068, MET 1072, TYR 1059, LEU 1045, ILE 1049, ILE 1053, TYR 844, PHE 845, ALA 881
2b –4.571 CYS 919     TYR 927, PHE 921, LEU 840, CYS 919, PHE 918, ALA 866, VAL 848, PHE 1047, LEU 1035
2c –4.678 CYS 919     TYR 927, PHE 921, CYS 919, PHE 918, LEU 840, ALA 866, VAL 848, PHE 1047, LEU 1035
2d –5.927 LYS 838 ASN 923 THR 926   LYS 920 PHE 1047, VAL 848, LEU 1035, ALA 866, PHE 918, CYS 919, PHE 921, LEU 849
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3.2. Physicochemical Properties

A molecular sketcher based on Chem Axon’s Marvin JS (http://www.chemaxon.com) was used to draw the 2D structure of the molecules to be analyzed. The 2D structures of the designed chemical library have been converted to canonical SMILES format and used to compute the ADME properties in the SwissADME tool.32 The results observed from Table 4 show that the molecular weights of compounds 1–2(a–d) lie below 500 Daltons and thus obey one of the criteria of the Lipinski rule of five. The compounds possess less than 10 rotatable bonds; hence, they satisfy the criterion for oral bioavailability. The PSA is calculated using the fragmental technique called topological polar surface area (TPSA), considering sulfur and phosphorus as polar atoms.33 This has proved to be a useful descriptor in many models and rules to quickly estimate some ADME properties, especially with regard to biological barrier crossing, such as absorption and brain access.34 It is evident from Table 4 that the TPSA values range from 3.88 to 95.52 Å2, whereas the compounds 2a and 1a are found to be more polar with TPSA 95.52 Å2 and the compounds 1(a–d) have the lowest TPSA value of 3.88 Å2.

Table 4. Physicochemical Properties.

monomers MW TPSA #rotatable bonds ESOL class
M1 464.24 3.88 5 poorly soluble
M2 554.23 95.52 7 poorly soluble
M4 479.05 3.88 5 poorly soluble
M7 569.04 95.52 7 poorly soluble
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3.3. Pharmacokinetic Properties

Compounds 2a and 1a were observed to have high intestinal absorption except for compounds 1a and 1d, which have low GI absorption and high TPSA, and the compounds with high GI absorption could permeate quite easily across the intestinal lining of the cell membrane. Distribution of drugs into the central nervous system (CNS) plays an important role in drug discovery as the CNS lies behind the blood–brain barrier (BBB). Drugs need to pass over the blood–brain barrier (BBB) to reach their target. It is observed from Table 5 that compounds 2a and 1a have no BBB penetration and hence do not affect the CNS. P-glycoprotein (P-gp) plays a key role in keeping nonessential molecules out of the brain and thus has partial permeability.35,36Table 5 shows that all six compounds are substrates of P-gp and all compounds are metabolized by CYP2C19 and CYP1A2. From the log Kp values, it is seen that compound 1d has the least negative value, and thus, it is more skin permeant. Compound 2a has more negative log Kp values and the least is the skin permeant.

Table 5. Pharmacokinetic Properties.

monomers GI absorption BBB permeant P-gp substrate log Kp (cm/s) CYP2C19 inhibitor CYP1A2 inhibitor
M1 low Yes No –4.92 No No
M2 high No No –5.71 Yes No
M4 low Yes No –3.24 No No
M7 high No No –4.03 No No
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3.4. Skin Permeable Model

The total polar surface area (TPSA) values are dependent on skin permeation detection. The more polar the molecule is the less skin permeant. Hence, from Table 6, compounds 2a and 1a have TPSA of 95.52 Å2, which is found to be less skin permeant, and 2a and 1a with TPSA of 3.88 Å2 are considered as more skin permeant.

Table 6. Skin Permeable Model.

molecule TPSA log Kp (cm/s)
1 3.88 –4.92
2 95.52 –5.71
4 3.88 –3.24
7 95.52 –4.03
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3.5. Boiled Egg Representation

Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) is the representation of curcumin and Schiff base diol monomers (Figure 4). The BOILED-Egg is the instinctive method to assess passive gastrointestinal absorption (HIA) and brain penetration (BBB) with respect to WLOGP-versus-TPSA.34 The white yolk of the egg is of high probability of passive absorption by the gastrointestinal tract, and the yellow region (yolk) is of high probability of brain penetration. Compounds 2a and 1a lie in the white region. The compounds that are nonsubstrates of P-gp are indicated by red dots.

Figure 4.

Figure 4

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Boiled egg representation.

3.6. Bioavailability Radar

The drug-likeness of a molecule can be rapidly assessed from the bioavailability radar (Figure 5). The pink-colored zone is the suitable physiochemical space for oral bioavailability, and the radar plot of the molecule has to fall entirely in the zone to be considered drug-like.37 The pink area represents the optimal range of each property: LIPO (lipophilicity): −0.7 < XLOGP 3 < +5.0; SIZE: 150 g/mol < MW < 500 g/mol; POLAR (polarity): 20 Å2 < TPSA < 130 Å2; INSOLU (insolubility): 0 < Log S (ESOL) < 6; INSATU (insaturation): 0.25 < fraction of Csp3 < 1; FLEX (flexibility): 0 < No. of rotatable bonds < 9. From the SwissADME prediction output, it is evident that all compounds were in the optimal range of all of the five properties, except for solubility, enabling them to be considered to possess proficient chemotherapeutic potentials.

Figure 5.

Figure 5

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Bioavailability radar.

4. Conclusions

Benzyl/4-nitrobenzyl quaternary ammonium-based pyridinium salts are prepared under conventional/solvent-free silica-supported Muffle furnace conditions. The Muffle furnace method is nearly ten times faster than the conventional method. Catalytic studies of benzyl/4-nitrobenzyl pyridinium salts are carried out with different concentrations for the preparation of β-amino carbonyl compound, and it is observed that 4-nitrobenzyl pyridinium salts showed higher catalytic activity than benzyl-substituted pyridinium salts because of their better Lewis character. Even in very low concentrations, it showed potential catalytic activity. Br–, PF6–, CF3SO3–, and BF4– counter anions containing substituted quaternary ammonium-based pyridinium salts are also tried in the preparation of β-amino carbonyl compound. Among these, the bromide counter anion containing salts showed higher catalytic activity than the other counteranions. Interestingly, candidate 1c has much more interaction and higher binding affinity with the model protein active site of the VEGFR-2 kinase receptor. Pharmacokinetic studies have taken our compound of interest to the various PBPK models and helped our research to identify the best lead compound. The predicted gastrointestinal absorption of the compounds, bromide counterion-containing compounds, was displayed high and could assess the absence of toxicity at the CNS level due to nonpermeation across the blood–brain barrier. The log Kp values were found to be optimal and hence are predicted to have good permeability and oral absorption, and the oral bioavailability is found to be universal. This study employed pharmacokinetic research and molecular simulations to find an intriguing structure to be used as a future drug candidate for human health.

5. Experimental Section

5.1. General Procedure for N-Alkylation Reaction by the Conventional Approach

N,N-dimethyl pyridine-4-amine (1.853 × 10–3 mmol; 1.0 equiv) is treated with benzyl/4-nitrobenzyl bromide (1.65 × 10–2 mmol; 2.05 equiv) in the presence of 20 mL of dry acetonitrile under refluxing conditions for 30–45 min. to give N-alkylated product of compound 1a/2a.

5.2. General Procedure for N-Alkylation Reaction by the Solvent-Free Silica-Supported Approach

Benzyl/4-nitrobenzyl bromide (1.65 × 10–2 mmol; 1.05 equiv) is mixed with required equivalent of N,N-dimethyl pyridine-4-amine, followed by fine grinding with 5 g of silica gel (60–120 mesh) and kept in a Muffle furnace at 100 °C (optimized temperature) for 10–15 min to afford desired products of compound 1a/2a in quantitative yield.

5.2.1. 1-Benzyl-4-[benzyl (dimethyl) azaniumyl]pyridine-1-ium Bromide (1a)

Yield: 1.0 g (86%), Liquid 1H NMR: (400 MHz, DMSO-d6) δ: 3.75 (s, 6H), 4.78 (s, 2H), 5.65 (s, 2H), 7.56–7.72 (m, 10H), 8.17–8.25 (d, 4H).13C NMR: (100 MHz, DMSO-d6) δ: 32.4, 58.6, 62.4, 123.5, 124.1, 130.9, 143.3, 145.9 and 146.7.MS (FAB): m/z 464.24 [M]+; Anal. Calcd. for C21H24Br2N2: C: 54.33; H: 5.21; N: 6.03; Found: C: 54.28; H: 5.16; N: 5.98.

5.2.2. 1-Nitrobenzyl-4-[nitrobenzyl (dimethyl) azaniumyl]pyridine-1-ium Bromide (2a)

Yield: 1.0 g (86%); Liquid; 1H NMR: (400 MHz, DMSO-d6) δ: 3.85 (s, 6H), 4.47 (s, 2H), 5.60 (s, 2H), 6.91–7.41 (m, 8H), 8.61–8.63 (d, 4H); 13C NMR: (100 MHz, DMSO-d6) δ: 33.6, 40.5, 60.7, 108.4, 128.7, 129.2, 134.2, 137.7 and 142.6; MS (FAB): m/z 554.23 [M]+; Anal. Calcd. for C21H22Br2N4O4: C: 45.51: H: 4.00: N: 10.11. Found: C: 45.46: H: 3.96: N: 7.57.

5.3. General Procedure for Anion Exchange Reaction

Simple/substituted pyridinium bromide 1a/2a (1.705 × 10–3 mmol; 1.0 equiv) is treated with various counteranions containing inorganic salts, such as NaBF4, K4PF6, and LiCF3SO3 (3.496 × 10–3 mmol; 2.05 equiv), in 20 mL of deionized water at room temperature with stirring for 2 h to give an anion exchange product of compounds 1–2(b–d) in 90–97% yield. Both metallic bromide and pyridinium salts are soluble in water. So, separation is not easier under these circumstances, and Soxhlet extraction is used for separation with dry THF for 2 h reflux. An anion exchange reaction is confirmed by an aqueous AgNO3 solution.

5.3.1. 1-Benzyl-4-[benzyl (dimethyl) azaniumyl]pyridine-1-ium Hexafluorophosphate (1a)

Yield: 0.5 g (84%); Liquid; 1H NMR: (400 MHz, DMSO-d6) δ: 3.73 (s, 6H), 4.76 (s, 2H), 5.63 (s, 2H), 7.54–7.70 (m, 10H), 8.15–8.23 (d, 4H); 13C NMR: (100 MHz, DMSO-d6) δ: 32.2, 58.4, 62.2, 123.3, 123.9, 130.7, 143.1, 145.7 and 146.5; MS (FAB): m/z 594.36[M]+; Anal. Calcd. for C21H24F12N2P2: C: 42.44: H: 4.07: N: 4.71; Found: C: 42.39; H: 4.03; N: 4.69.

5.3.2. 1-Benzyl-4-[benzyl (dimethyl) azaniumyl]pyridine-1-ium Tetrafluoroborate (1b)

Yield: 0.5 g (94%); Liquid; 1H NMR: (400 MHz, DMSO-d6) δ: 3.72 (s, 6H), 4.75 (s, 2H), 5.62 (s, 2H), 7.53–7.69 (m, 10H), 8.14–8.22 (d, 4H); 13C NMR: (100 MHz, DMSO-d6) δ: 32.1, 58.3, 62.1, 123.2, 123.8, 130.1, 143.0, 145.6, and 146.4; MS (FAB): m/z 478.04 [M] +; Anal. Calcd. for C21H24B2F8N2: C: 52.76; H: 5.06; N: 5.86; Found: C: 52.71; H: 5.02; N:5.85.

5.3.3. 1-Benzyl-4-[benzyl (dimethyl) azaniumyl]pyridine-1-ium Trifluoromethanesulfonate (1c)

Yield: 0.3 g (95%); Liquid; 1H NMR: (400 MHz, DMSO-d6) δ: 3.71 (s, 6H), 4.74 (s, 2H), 5.61 (s, 2H), 7.52–7.68 (m, 10H), 8.13–8.21 (d, 4H); 13C NMR: (100 MHz, DMSO-d6) δ: 32.0, 58.2, 62.0, 123.1, 123.7, 130.0, 142.9, 145.5 and 146.3; MS (FAB): m/z 602.57 [M]+; Anal. Calcd. for C23H24F6N2O6S2: C: 45.84; H: 4.01; N: 4.65; Found: C: 45.80; H: 3.98; N: 4.64.

5.3.4. 1-Nitrobenzyl-4-[nitrobenzyl (dimethyl) azaniumyl]pyridine-1-ium Hexafluorophosphate (2a)

Yield: 0.3 g (93%); Liquid; 1H NMR: (400 MHz, DMSO-d6) δ: 3.83 (s, 6H), 4.45 (s, 2H), 5.58 (s, 2H), 6.89–7.38 (m, 8H), 8.59–8.62 (d, 4H); 13C NMR: (100 MHz, DMSO-d6) δ: 33.4, 40.3, 60.5, 108.2, 128.5, 129.0, 134.0, 137.5, 142.4; MS (FAB): m/z 684.35 [M]+; Anal. Calcd. for C21H22F12N4O4P2; C: 36.86; H: 3.24; N: 8.19; Found: C: 36.82; H: 3.21; N: 8.18.

5.3.5. 1-Nitrobenzyl-4-[nitrobenzyl (dimethyl) azaniumyl]pyridine-1-ium Tetrafluoroborate (2b)

Yield: 0.3 g (96%); Liquid; 1H NMR: (400 MHz, DMSO-d6) δ: 3.82 (s, 6H), 4.44 (s, 2H), 5.57 (s, 2H), 6.88–7.37 (m, 8H), 8.58–8.61 (d, 4H); 13C NMR: (100 MHz, DMSO-d6) δ: 33.3, 40.2, 60.4, 108.1, 128.4, 128.9, 133.9, 137.4, 142.3; MS (FAB): m/z 568.03 [M]+; Anal. Calcd. for C21H22B2F8N4O4; C: 54.33; H: 5.21; N: 6.03; Found: C: 54.28; H: 5.16; N: 5.98.

5.3.6. 1-Nitrobenzyl-4-[nitrobenzyl (dimethyl) azaniumyl]pyridine-1-ium Trifluoromethanesulfonate (2c)

Yield: 0.3 g (97%); Liquid; 1H NMR: (400 MHz, DMSO-d6) δ: 3.81 (s, 6H), 4.43 (s, 2H), 5.56 (s, 2H), 6.87–7.36 (m, 8H), 8.57–8.60 (d, 4H); 13C NMR: (100 MHz, DMSO-d6) δ: 33.2, 40.1, 60.3, 108.0, 128.3, 128.8, 133.8, 137.3, 142.2; MS (FAB): m/z 692.56 [M]+; Anal. Calcd. for C23H22F6N4O10S2; C: 39.89; H: 3.20; N: 8.09; Found: C: 39.85; H: 3.17; N: 8.08.

5.4. General Procedure for the Synthesis of β-Amino Carbonyl Derivatives

Equal molar concentration of substituted aryl aldehyde (3.28 × 10–3 mmol; 1.0 equiv) is mixed with aniline (3.45 × 10–3 mmol; 1.05 equiv) and cyclohexanone (3.45 × 10–3 mmol; 1.05 equiv), and optimized concentration of catalyst benzylated pyridinium bromide 2a (5.44 × 10–5 mmol) is added in the presence of CH3CN under reflux for 10–165 min to give quinoline derivative of compounds 3(a–e) in 67–96%.

5.4.1. 2-(Phenyl (phenylamino) methyl) cyclohexanone (3a)

Yield: 0.5 g (91%); mp: 104–106 0C; 1H NMR: (400 MHz, DMSO-d6) δ: 1.63–1.73 (m, 2H), 1.80–1.96 (m, 4H), 2.29–2.48 (m, 2H), 2.75–2.85 (m, 1H), 4.61 (d, 1H), 6.56 (dd, 2H), 6.65 (t, 1H), 7.04–7.10 (m, 2H), 7.17–7.24 (m, 1H), 7.27–7.33 (m, 2H), 7.33–7.41 (m, 2H); 13C NMR: (100 MHz, DMSO-d6) δ: 31.2, 41.7, 42.3, 57.2, 58.0, 113.6, 114.0, 117.5, 126.9, 127.2, 128.3, 129.0, 141.5, 147.4 and 212.8. MS (FAB): m/z 279.3 [M] +; Anal. Calcd for C19H21NO; C: 81.68; H: 7.58; N: 5.01; Found: C: 81.65; H: 7.49; N: 4.98.

Acknowledgments

M.M.A. and M.A. thank the Deanship of Research, King Khalid University, Saudi Arabia for Small Research Group under the grant number R.G.P. 1/339/1443.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c07129.

  • Characterization data for 1a and 2a (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao2c07129_si_001.pdf (315.8KB, pdf)

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Supplementary Materials

ao2c07129_si_001.pdf (315.8KB, pdf)

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