New composition of N-methylpyridinium methylsulfate as a reaction medium for the synthesis of derivatives of 3,3'-(phenylmethylene)bis(1H-indole)

Abstract

An ionic liquid composition comprising N-methylpyridinium methylsulfate, formulated and characterized as a green, acidic and thermally stable reaction medium, in particular for enabling the synthesis of derivatives of 3,3'-(phenylmethylene)bis(1H-indole) by means of electrophilic substitution reactions between aromatic aldehydes and indole derivatives, wherein said ionic liquid performs the dual role of solvent and Brønsted acid catalyst and is substantially free of conventional mineral or Lewis acid catalysts.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to the field of organic and heterocyclic synthesis, in particular to the field of green chemistry and environmentally friendly reaction media. Specifically, the invention relates to a novel ionic liquid composition comprising N-methylpyridinium methylsulfate, which is effectively used as a reaction medium and as a catalytic system to facilitate the synthesis of substituted derivatives of 3,3'-(phenylmethylene)bis(1H-indole) through electrophilic substitution reactions involving indoles and aromatic aldehydes. BACKGROUND OF THE INVENTION

[0002] The background description contains information that may be useful for a better understanding of the present disclosure. It is not admitted that any information contained herein is prior art or relevant to the disclosure claimed herein, nor is any particular or impliedly referenced publication to be considered prior art.

[0003] The scope of the present invention encompasses the domain of organic synthesis and green reaction media, particularly the use of ionic liquids in the formation of heterocyclic compounds. More specifically, the invention relates to a novel composition of N-methylpyridinium methylsulfate that functions as a dual-purpose reaction medium and catalyst in the synthesis of 3,3'-(phenylmethylene)bis(1H-indole) and its derivatives. These indole derivatives have received substantial attention in recent years due to their broad spectrum of biological activities, including anticancer, anti-inflammatory, antimicrobial, and enzyme-inhibiting properties. The development of environmentally friendly and high-yield synthesis protocols for such pharmacologically active scaffold compounds is therefore of immense importance in medicinal chemistry and process development.

[0004] The conventional synthesis of bis(indolyl)methanes typically involves acid-catalyzed electrophilic substitution reactions, in which indole acts as a nucleophile and attacks aldehydes or ketones under acidic conditions. While these reactions provide good results in terms of yield, they typically rely on the use of strong protic or Lewis acids, organic solvents, high temperatures, and prolonged reaction times. Such methods often pose problems such as toxicity, environmental pollution, lack of medium reusability, and lack of atom economy. Therefore, there is a growing need to develop sustainable, green, and recyclable alternatives to replace traditional acidic and organic solvent systems while ensuring high selectivity and yield.

[0005] Numerous prior art publications attempt to overcome these limitations by introducing alternative catalytic systems. For example, US Patent No. 6,303,590 discloses the synthesis of bis(indolyl)methanes using Lewis acids such as FeCl3 and InCl3 in organic solvents such as dichloromethane or ethanol. Likewise, WO2004061833A1 teaches a process for the preparation of bis(indolyl)methanes using p-toluenesulfonic acid (PTSA) as a catalyst in the presence of polar organic solvents. Another reference, US20050277608A1, describes the use of acidic ionic liquids based on imidazolium salts to catalyze such transformations under microwave conditions. These techniques, although reasonably efficient, continue to suffer from drawbacks regarding reagent costs, reaction toxicity, complexity of product separation, and solvent disposal.

[0006] Furthermore, the traditional reaction media and catalysts presented in these publications suffer from several significant drawbacks, such as the use of toxic or volatile organic solvents (e.g., chloroform, dichloromethane), non-recyclable acidic catalysts, and high temperature conditions that can lead to thermal decomposition of sensitive substrates. Many catalytic systems require anhydrous conditions or inert atmospheres, limiting their industrial scalability and environmental compatibility. The use of metal-based catalysts also raises concerns about potential trace metal contamination in the final product, particularly in pharmaceutical applications, requiring additional purification steps that increase costs and processing time.In addition, these methods often exhibit low selectivity when applied to substrates with electron-withdrawing or electron-donating groups, which limits their versatility.

[0007] The present invention overcomes these disadvantages by introducing a novel and recyclable ionic liquid-based composition, namely N-methylpyridinium methylsulfate, which serves not only as a solvent but also as a protonic acid catalyst for facilitating the electrophilic substitution of indoles with aromatic aldehydes under ambient conditions. Unlike previously reported systems, the present composition is non-volatile, thermally stable, biodegradable, and operationally safe, making it particularly suitable for green chemistry protocols. It eliminates the need for additional catalysts, reduces reaction time, and ensures high regioselectivity and high yield across a broad substrate range. SUMMARY OF THE INVENTION

[0008] This section is intended to introduce, in simplified form, certain objects and aspects of the present disclosure, which are further elaborated upon in the Detailed Description below. This summary is not intended to identify the key elements or scope of the claimed subject matter.

[0009] The present invention provides a novel and industrially useful composition comprising N-methylpyridinium methylsulfate—an ionic liquid designed as an environmentally friendly, non-volatile, and recyclable reaction medium, specifically for the synthesis of derivatives of 3,3'-(phenylmethylene)bis(1H-indole). The composition exhibits dual functionality by serving as both a polar solvent and a Brønsted acid catalyst, eliminating the need for conventional hazardous mineral acids, metallic catalysts, or toxic organic solvents. The ionic liquid promotes efficient Friedel-Crafts-like electrophilic substitution between indole nucleophiles and aromatic aldehydes through in situ activation under mild to ambient temperatures, resulting in the formation of the bis(indolyl)methane framework.The physicochemical properties of the composition—including thermal stability, low vapor pressure, high ionic conductivity, and selective solvation capacity—improve substrate compatibility and reaction kinetics, resulting in better atom economy and superior yield profiles.

[0010] Furthermore, the invention leverages the recyclable and water-compatible nature of the N-methylpyridinium methylsulfate composition to promote more environmentally friendly chemical processes, in line with the goals of sustainable development and the principles of green chemistry. Said composition can be reused over multiple reaction cycles without significant loss of catalyst efficiency, reducing operating costs and environmental impact in industrial syntheses. Thus, the invention provides an optimized, scalable, and environmentally friendly reaction medium that enables high-yield one-pot syntheses of bioactive indole derivatives under pure reaction conditions, making it suitable for pharmaceutical, agrochemical, and fine chemical applications.The invention represents a significant advance over conventional reaction media in terms of operational simplicity, reduced toxicity, increased selectivity, and compatibility with a wide range of aromatic aldehyde and indole substrates. DETAILED DESCRIPTION OF THE INVENTION

[0011] A detailed description of embodiments of the disclosure is given below.

[0012] In the following description, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present invention. It will be apparent to those skilled in the art that the embodiments of the present invention may be practiced without some of these specific details.

[0013] The present invention relates to a novel and industrially significant composition comprising N-methylpyridinium methylsulfate (hereinafter referred to as [mPyrMeSO4]) used as a green, non-volatile, thermally stable ionic liquid reaction medium for the efficient and selective synthesis of a broad class of derivatives of 3,3'-(phenylmethylene)bis(1H-indole). The invention represents a profound methodological advance in synthetic organic chemistry, replacing conventional volatile organic solvents with a specially adapted ionic liquid that not only improves reaction yield and selectivity but also complies with the principles of sustainable and environmentally friendly chemical processes.

[0014] The enormous research focus on ionic liquids over the past two decades has led to a revolution in synthetic and materials chemistry. The field has experienced unprecedented expansion due to the unique physicochemical properties of ionic liquids, such as negligible vapor pressure, high thermal stability, tunable polarity, and remarkable solvation ability. Among the various classes of ionic liquids, pyridinium-based ionic liquids have emerged as promising candidates due to their ease of synthesis, economic viability, and compatibility with a wide range of organic transformations.The present invention therefore arises at the interface between green chemistry and heterocyclic synthesis, with a specially developed ionic liquid - N-methylpyridinium methylsulfate - acting as an excellent solvent system for condensation reactions between indoles and aldehydes / ketones.

[0015] The synthesis of the ionic liquid used in this invention is based on the methylation of pyridine using dimethyl sulfate in a toluene medium under controlled conditions. The reaction is highly exothermic, requiring careful temperature control and the use of an inert nitrogen atmosphere. The methylation process leads to the formation of a biphasic mixture in which the dense, hydrophilic phase of [mPyrMeSO4] separates from the lighter toluene phase. The ionic liquid is then subjected to several toluene washes to remove organic impurities, followed by drying under reduced pressure at elevated temperature (approximately 75°C) to obtain a highly pure, colorless, and hygroscopic liquid in a remarkable yield of 91%.

[0016] The resulting [mPyrMeSO4] is characterized by its dual ionic nature and excellent solvation capabilities, making it an ideal medium for proton-donating reactions, particularly electrophilic substitution reactions involving indoles. Surprisingly, this special ionic liquid was found to promote the reaction between indole and various carbonyl-containing substances (aromatic aldehydes, ketones, benzoin, and benzil) with exceptional regio- and chemo-selective control under ambient conditions, without the need for external catalysts or aggressive reagents. This offers significant advantages in terms of operational simplicity, atom economy, and safety.

[0017] The general synthetic route for preparing derivatives of 3,3'-(phenylmethylene)bis(1H-indole) involves the addition of indole and a suitable aldehyde or ketone to [mPyrMeSO4] in a round-bottom flask, followed by the addition of quenched methanol to generate a homogeneous reaction mixture. The role of quenched methanol (prepared by gently mixing sulfuric acid with methanol) is critical in catalyzing the condensation process while ensuring uniform solvation of the reactants. The reaction proceeds rapidly at room temperature and is completed within 20 minutes, as verified by thin-layer chromatography (TLC) using a hexane:ethyl acetate mobile phase ratio.

[0018] The crystalline product is isolated by pouring the reaction mixture into crushed ice, which leads to precipitation. The resulting solid is subjected to solvent extraction using dichloromethane-water systems to isolate the pure product. Several aqueous washes (10 × 5 mL distilled water) followed by drying over anhydrous sodium sulfate ensure the removal of polar impurities and residual acid. The final product is then collected by evaporation of the dichloromethane and dried in an oven to obtain pure bis(indolyl)methane in high yield and purity.

[0019] In a comprehensive optimization study, a series of ionic liquids—including, but not limited to, [emimBr], [bmimBr], [prmimBr], [hmimBr], [omimBr], [emimBF4], [bmimBF4], [hmimBF4], [bPyrBr], [bPyrBF4], and [mmimMeSO4]—were investigated under identical conditions for their performance in promoting the above-mentioned condensation reaction. However, among all tested solvents, only [mPyrMeSO4] showed a significant catalytic effect, providing up to 90% yield at room temperature (27°C), while all other ionic liquids showed negligible or no conversion under the same conditions.

[0020] Further experiments were conducted to evaluate the influence of reaction temperature on yield. Interestingly, increasing the temperature from 27°C to 40°C and 50°C did not significantly increase the yield beyond 90%, implying that the reaction using [mPyrMeSO4] already proceeds optimally at ambient temperature. This feature underscores the efficiency and sustainability of the developed protocol, as no energy-intensive heat input is required.

[0021] An equally crucial component of the optimization study was the investigation of the effect of varying ionic liquid concentrations. When the reaction was carried out with different volumes of [mPyrMeSO4] (between 1 mL and 5 mL), it was shown that, despite small fluctuations in yield, the reaction remained highly efficient even with minimal solvent volume. This demonstrates the high solvation and catalytic efficiency of [mPyrMeSO4], which operates effectively even under stoichiometrically constrained conditions.

[0022] To further demonstrate the general applicability of the protocol, a wide range of aldehydes and ketones bearing either electron-donating or electron-withdrawing groups were reacted with indole under the specified conditions. These included aromatic aldehydes bearing -OH, -OMe, -NO2, -Cl, and -Br substituents, all of which provided the corresponding bis(indolyl)methane derivatives in excellent yields of 85% to 92%. The tolerance to various electronic substituents highlights the robust and non-discriminatory reaction window of the process.

[0023] In a significant advance, structurally diverse carbonyl-containing reagents such as benzil and benzoin were employed to explore the scope of extended carbon frameworks in the condensation product. Reaction of these diketones and α-hydroxyketones with indole under the same conditions provided the corresponding derivatives in yields of 85% and 75%, respectively. These results demonstrate the regioselective nature of the method, in which exclusively the terminal carbonyl group undergoes condensation, while internal functionalities remain unaffected.

[0024] A critical evaluation of the chemoselective properties of the reaction was performed using ethyl acetoacetate as a dual carbonyl-containing compound. Remarkably, the developed procedure led to the selective activation of the aldehydic center, resulting in the formation of a monocondensation product in 60% yield. This underscores the precision and functional group tolerance of the process.

[0025] To confirm the role of the ionic liquid in mediating the condensation process, a control experiment was conducted in which the reaction was attempted under otherwise identical conditions in the presence of carbon disulfide (CS2). No product was formed, confirming the essential role of [mPyrMeSO4] in stabilizing reaction intermediates and enabling the necessary transition state for successful product formation.

[0026] The present invention thus successfully establishes a highly efficient, environmentally friendly, and scalable synthetic protocol for the formation of pharmacologically relevant derivatives of 3,3'-(phenylmethylene)bis(1H-indole). These derivatives are of great pharmaceutical interest as they are believed to possess anti-inflammatory, antimicrobial, anticancer, and enzyme-inhibiting properties, making this methodology extremely valuable for medicinal chemists and synthetic organic chemists alike.

[0027] In terms of sustainability and economic viability, the ionic liquid [mPyrMeSO4] demonstrates recyclability and reusability over multiple reaction cycles. After the reaction is complete, the ionic liquid can be regenerated by simply evaporating the water and removing organic contaminants via low-pressure distillation, enabling a closed reaction system and minimizing waste generation.

[0028] The exceptional compatibility of this reaction medium with a wide range of substrates, its mild operating parameters, and its straightforward purification procedures make it ideal for industrial scale-up and use in high-throughput syntheses. Furthermore, the non-volatile and non-flammable nature of [mPyrMeSO4] increases safety in chemical manufacturing processes.

[0029] Further analytical validation of the synthesized derivatives was performed using a range of characterization techniques, including Fourier transform infrared spectroscopy (FT-IR), proton and carbon-13 nuclear magnetic resonance spectroscopy (1H and 1C NMR), and mass spectrometry (MS). The spectral data for each synthesized molecule confirmed successful condensation at the C-3 position of the indole rings, with the linking methylene groups or substituted alkylidenes exhibiting characteristic chemical shifts in the range of δ 4.5–6.0 ppm in the 1H NMR spectra. The carbon resonances of the central sp 3 - or sp 2 -hybridized carbon atoms connecting the two indole rings appeared clearly in the range of δ 35-55 ppm in the ^13C NMR spectrum, verifying the formation of the desired bis(indolyl)methane framework.

[0030] The mass spectra of the compounds further confirmed their molecular weights, with the molecular ion peaks appearing in good agreement with the calculated masses of the synthesized structures. The presence of isotopic peaks corresponding to halogen-containing substituents such as Cl and Br served as additional confirmation for the halogenated derivatives. These analytical results overall authenticate the structural integrity of the synthesized compounds and support the claim that the present method provides clean and selective access to functionalized bis(indole) derivatives without side-product formation.

[0031] Another advantageous aspect of the present invention is the moisture stability of [mPyrMeSO4], a common problem associated with many other ionic liquids, such as those based on imidazolium or phosphonium salts. The synthesized N-methylpyridinium methylsulfate exhibits remarkable stability under normal atmospheric conditions, retaining its physicochemical properties and reactivity even after prolonged exposure to air. This eliminates the need for stringent storage conditions and drying protocols, thus increasing the practicality of its application in routine synthesis processes.

[0032] The dielectric properties of [mPyrMeSO4], including high polarity and pronounced dipolarity / polarization parameters, contribute significantly to its ability to stabilize reaction intermediates such as carbenium ions or transition-state complexes formed during electrophilic substitution reactions. This dielectric compatibility enables improved reaction kinetics without external energy input or Lewis acid catalysis. These properties make the reaction highly efficient under thermodynamically mild conditions, expanding its applicability to heat-sensitive substrates and intermediates.

[0033] From a mechanistic perspective, the condensation reaction in the presence of [mPyrMeSO4] is proposed to proceed via activation of the carbonyl-containing compound through protonation or hydrogen bonding interactions, mediated by the protonic nature of the medium. The indole, acting as a nucleophile, attacks the activated carbonyl center, leading to a stabilized carbinolamine intermediate. This intermediate undergoes dehydration and is subsequently converted into the bis(indolyl)methane product by further nucleophilic attack by an indole molecule. The ionic nature of the medium further stabilizes charged transition states, leading to high product integrity and reduced side-product formation.

[0034] Remarkably, the described method proved to be tolerant to air and humidity, as no protective gas atmosphere or glovebox was required during synthesis. This underscores the operational simplicity of the invented protocol as well as its potential for application in academic institutions, the pharmaceutical industry, and fine chemicals, where batch consistency and procedural robustness are of utmost importance.

[0035] The invention further includes the application of this method to the synthesis of novel derivatives using substituted indoles, such as 5-bromoindole and 5-nitroindole, under similar conditions. The resulting compounds exhibit altered electronic properties and are of considerable interest for further biological activity assays. The successful synthesis of these derivatives demonstrates the broad functional group tolerance of the protocol, particularly with substrates with different electronic characteristics.

[0036] To investigate the scalability of the reaction, a Grammass synthesis was performed using 10 mmol of indole and 5 mmol of benzaldehyde in 10 mL of [mPyrMeSO4]. The product was isolated in 88% yield, reflecting the efficiency observed in small-scale experiments, without any significant loss of selectivity or purity. This result confirms the potential of the invented method for scale-up to pilot plant and production scale.

[0037] Furthermore, the method eliminates the need for post-reaction neutralization steps, which are typically required when using mineral acid catalysts such as HCl or H2SO4 in traditional protocols. This not only reduces reagent consumption but also prevents the formation of salt scum, contributing to a lower E-factor and thus a more environmentally friendly process.

[0038] The thermal behavior of the ionic liquid was investigated using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The results show decomposition onset above 220°C, with no significant weight loss observed below 180°C, confirming its high thermal stability. This robustness to thermal stress extends the operating range for reactions requiring higher temperatures, although the present condensation reactions proceed efficiently below ambient temperature.

[0039] Based on the present data, the invention offers a superior alternative to classical Lewis acid-catalyzed methods, such as those using BF3 OEt2, AlCl3, or FeCl3—reagents that are often corrosive, moisture-sensitive, and environmentally harmful. In contrast, the ionic liquid-based method eliminates the use of such reagents, thereby reducing the risk to operators and the environment.

[0040] The described process also complies with the 12 principles of Green Chemistry, particularly those emphasizing atom economy, energy efficiency, the use of safer solvents, and design for degradability. Product isolation through simple precipitation and filtration further contributes to waste minimization and process simplification.

[0041] As an extension of the present work, efforts are underway to develop structurally related pyridinium-based ionic liquids with functionalized anions, such as ethyl sulfate, tosylate, or acetate, to further expand the spectrum of supported reactions. Initial experiments indicate that tuning both the cationic and anionic components can fine-tune the polarity and hydrogen-bonding ability of the ionic liquid, thereby modulating reaction selectivity and yield.

[0042] Additionally, molecular modeling and computer simulation studies were initiated to map the reaction energy level and evaluate the stabilization of the transition state in the presence of [mPyrMeSO4]. Preliminary density functional theory (DFT) calculations show a significant reduction in the activation energy barriers for the condensation pathway, consistent with the empirical observation of increased reaction rates.

[0043] A comparative life cycle analysis (LCA) and hazard assessment of the proposed process compared to conventional acid-catalyzed syntheses highlight the superior safety, lower environmental impact, and reduced carbon footprint of the ionic liquid protocol. These results further support the industrial feasibility and compliance of the developed system with modern sustainable manufacturing guidelines.

[0044] The invention may also find applications beyond indole condensation reactions. Initial experiments suggest that [mPyrMeSO4] could also be useful for catalyzing multicomponent reactions such as Biginelli-, Hantzsch-, and Mannich-type reactions, in which a similar electrophilic activation of carbonyl compounds represents a central mechanistic step.

[0045] Importantly, the ionic liquid [mPyrMeSO4] can be synthesized using industrially available raw materials such as pyridine and dimethyl sulfate, making it cost-effective and readily available. Its synthesis route avoids halogenated precursors, thereby preventing the formation of persistent organic pollutants and reducing regulatory concerns.

[0046] In summary, the present invention discloses a novel and highly efficient composition and process for the synthesis of bis(indolyl)methane derivatives using N-methylpyridinium methylsulfate as a green ionic liquid reaction medium. The invention represents a significant advance in sustainable heterocyclic chemistry by providing high yields, a broad substrate scope, environmental safety, and operational simplicity.

[0047] The scope of the invention encompasses not only the specific composition of the ionic liquid and the described synthetic process, but also includes all variants that operate within the underlying conceptual framework of green chemistry and ionic liquid-assisted condensation reactions. Such variants may include structurally similar pyridinium compounds or alternative protic ionic liquids with comparable physicochemical properties and reactivity profiles.

[0048] Another aspect of the invention concerns the demonstration of chemoselectivity and regioselectivity in the synthesis of unsymmetrical bis(indolyl)methane derivatives. For this purpose, experiments were conducted with mixtures of differently substituted indoles (e.g., 5-bromoindole and 5-methoxyindole) in equimolar ratios. The resulting product distribution, monitored by high-performance liquid chromatography (HPLC) and confirmed by 1H NMR, showed a strong preference for hetero-bis substitution, which predominantly leads to the unsymmetrical product. This suggests that the ionic liquid medium exerts a subtle templating or directing influence on the nucleophilic attack pathway, possibly through differential stabilization of the intermediate (iminium ion or carbocation) due to steric or electronic compatibility with the ionic environment of the solvent.

[0049] The invention is further illustrated by the development of a miniaturized, microwave-assisted reaction protocol, where the exclusive use of [mPyrMeSO4] as the reaction medium enables rapid synthesis under irradiation at 80–100 °C within less than 3 minutes. Comparable or even superior yields compared to conventional thermal methods were achieved under microwave conditions, without measurable decomposition of the ionic liquid or the formation of byproducts. This microwave-activated approach highlights the thermally robust and dielectrically compatible nature of the ionic liquid and opens avenues for high-throughput synthesis in academic and industrial research laboratories.

[0050] A significant environmental and economic advantage of the present invention lies in the easy recycling and reusability of [mPyrMeSO4] over multiple reaction cycles. After completion of the reaction, the bis(indolyl)methane product is simply precipitated by adding a minimal amount of cold water or ethyl acetate, followed by filtration. The remaining ionic liquid is recovered by rotary evaporation of the aqueous filtrate and can be directly reused without further purification. Experimental data show that the recycled [mPyrMeSO4] maintains its catalytic and solvation efficiency for at least six consecutive reaction cycles with negligible loss in product yield or selectivity, demonstrating excellent process sustainability.

[0051] The present invention further provides for the formulation of binary or ternary solvent systems in which [mPyrMeSO4] is combined with environmentally friendly co-solvents such as glycerol, ethanol, or polyethylene glycol (PEG-400) to modulate viscosity and optimize reaction kinetics. These mixed solvent systems maintain the green profile of the process while providing improved mass transfer and reducing stirring effort, which is particularly advantageous in large-volume reactor setups. The resulting formulations also exhibit tunable solubility behavior, enabling tailored application of the process for less soluble or structurally bulky substrates.

[0052] Embodiments of the invention further encompass the application of this synthetic process to the preparation of bis(indolyl)methane derivatives functionalized for specific pharmacological evaluations, such as 3,3'bis(5-nitroindol-3-yl)phenylmethane and its analogues, which have shown promising activity in initial antimicrobial and anticancer assays. This application underscores the value of the present invention, which serves not only as a synthetic tool but also as a platform for drug chemistry research and drug discovery, where reaction purity, product purity, and structural adaptability are critical parameters.

[0053] In a particularly preferred embodiment, the ionic liquid [mPyrMeSO4] was immobilized on a silica gel support to produce a heterogeneous catalyst material capable of promoting the condensation reaction in a flow reactor setup. Immobilization was achieved by wet impregnation followed by thermal treatment to obtain a stable, supported liquid phase. The resulting heterogeneous system enabled continuous synthesis of bis(indole) derivatives with minimal pressure drop and constant product yields over several hours of operation, confirming the utility of the invention for continuous flow synthesis and process intensification.

[0054] It is important to note that the present invention does not require external Lewis or Brønsted acid catalysts and does not use metal-containing reagents at any stage of the process, making the process particularly suitable for the production of metal-free products. This feature is of particular relevance in pharmaceutical synthesis, where trace metal impurities can lead to batch rejections or require costly purification steps.

[0055] The invention is also applicable to solid-phase synthesis methods employing polymer-supported aldehydes or indoles. The ionic liquid medium not only facilitates the reaction under mild conditions but also simplifies the release of the product from the solid support through gentle elution procedures, thereby increasing synthetic efficiency in combination chemistry workflows.

[0056] In a broader context, the invention establishes a new paradigm in the use of task-specific ionic liquids (TSILs) for catalytic applications. The dual functionality of [mPyrMeSO4] as both a reaction medium and an activator makes it superior to conventional solvents and catalysts by eliminating the need for multicomponent reaction systems and minimizing energy and material expenditure.

[0057] The present invention is therefore not limited to the examples and embodiments described herein. Various modifications and adaptations may be made by those skilled in the art without departing from the scope and spirit of the invention. All such embodiments and equivalents are included within the scope of the invention claimed in the appended claims. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] US 6,303,590

[0005] WO 2004061833A1

[0005] US 20050277608A1

[0005]

Claims

[1] An ionic liquid composition comprising N-methylpyridinium methylsulfate, formulated and characterized as a green, acidic and thermally stable reaction medium, in particular for enabling the synthesis of derivatives of 3,3'-(phenylmethylene)bis(1H-indole) by means of electrophilic substitution reactions between aromatic aldehydes and indole derivatives, said ionic liquid performing the dual role of solvent and Brønsted acid catalyst and being substantially free of conventional mineral or Lewis acid catalysts. [2] The composition described in claim 1, wherein the ionic liquid N-methylpyridinium methylsulfate is present in pure form without dilution or co-solution, thus providing a polar, protic environment that favors selective activation of the aldehyde-involved substrates and stabilization of carbocationic intermediates during the synthesis of bis(indolyl)methanes. [3] The composition described in claim 1, wherein the N-methylpyridinium methylsulfate is synthesized by a stoichiometric reaction between N-methylpyridinium and dimethylsulfate, thereby obtaining a non-volatile, non-flammable and water-soluble ionic liquid having a melting point below 100°C. [4] The composition described in claim 1, wherein the ionic liquid has a viscosity range of 50-200 cP at 25 °C and a pH in the range of 2 to 3, which contributes to its efficiency as a Brønsted acid reaction medium and is suitable for environmentally friendly and metal-free synthesis routes. [5] The composition described in claim 1, wherein the N-methylpyridinium methylsulfate is recyclable and retains its reaction-promoting properties over at least five synthesis cycles with negligible deterioration or change in physicochemical properties. [6] The composition described in claim 1, wherein the ionic liquid medium enables the synthesis of both symmetric and unsymmetric 3,3'-(phenylmethylene)bis(1H-indole) derivatives at ambient or moderately elevated temperatures (25-80 °C) under solvent-free or catalyst-free conditions without the need for external heating or microwave activation.