A system for the KI-Oxon-catalyzed, ultrasound-based synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs)

Abstract

A system (100) for KI-Oxone catalyzed ultrasound-based synthesis of imidazo [1,2-a]pyridine-3-carboxylates (IPCs), consisting of: a) a reaction vessel (102) configured to contain a reaction mixture comprising β-ketoesters, 2-aminopyridines, and a KI-oxone catalyst system in an ethanol-water solvent; b) an ultrasonic irradiation unit (104) configured to supply ultrasonic energy to the reaction mixture at room temperature; c) a catalyst feed system (106) configured to introduce a KI-Oxone catalyst system to generate in situ I+ OH species for the α-halogenation of β-ketoester; d) a reaction monitoring unit (108) configured to monitor reaction completion by thin layer chromatography; e) a solvent removal unit (110) configured to evaporate solvent under reduced pressure; f) an extraction system (112) configured to dissolve the resulting solid in a saturated sodium bicarbonate solution and extract it with chloroform; and g) a purification unit (114) configured to purify crude products using silica gel column chromatography with hexane / ethyl acetate eluent.

Description

FIELD OF THE INVENTION

[0001] The present disclosure relates to a system for KI-Oxone catalyzed ultrasound-based synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs). BACKGROUND OF THE INVENTION

[0002] Fused N-heterocyclic structures, particularly imidazo[1,2-a]pyridines (IPY), are essential building blocks for bioactive natural products and pharmaceuticals due to their significant biological functions, including antibacterial, antifungal, antiviral, anti-inflammatory, and antiulcerative effects. The development of hybrid molecules that combine multiple bioactive heterocyclic scaffolds into single units with enhanced or combined biological activity represents a significant advance in pharmaceutical synthesis.

[0003] Existing synthetic techniques for functionalized IPY derivatives include cyclocondensations of 2-aminopyridines with α-halocarbonyl compounds, tandem imine formation-oxidative cyclization processes, and multicomponent coupling strategies. However, most conventional approaches are based on transition-metal-catalyzed coupling reactions, which have ecological and economic disadvantages. Transition-metal-free approaches, while preferred due to their environmentally friendly synthetic methodology, often have limitations in terms of efficiency and scope.

[0004] Current hypervalent iodine(III) reagent systems such as (diacetoxyiodo)benzene (DIB), phenyliodine diacetate (PIDA), and phenyliodine bis(trifluoroacetate) (PIFA) are used for the α-functionalization of carbonyl groups and the subsequent synthesis of imidazo[1,2-a]pyridine-3-carboxylates via α-halogenated β-ketoester intermediates. However, these hypervalent iodine catalysts suffer from significant drawbacks, including low solubility and stability, explosive nature, high cost, and low weight, which limit their practical application.

[0005] Therefore, there is a need for an improved system that enables the efficient synthesis of imidazo[1,2-a]pyridine-3-carboxylates using a transition-metal-free approach while overcoming the limitations of existing hypervalent iodine catalyst systems. The present invention addresses this need by providing a KI-Oxone-catalyzed, ultrasound-promoted synthesis system that enables the efficient, safe, and economical production of functionally diverse IPCs with improved biological activity. Summary of the invention

[0006] The present disclosure relates to a system for KI-Oxone-catalyzed ultrasound-assisted synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs). The present invention relates to a comprehensive system for the KI-Oxone-catalyzed, ultrasound-assisted synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs). The system integrates ultrasonic irradiation, catalyst delivery, reaction monitoring, extraction, purification, and characterization, thus enabling the efficient synthesis of functionally diverse IPCs with antituberculous activity through a transition-metal-free one-pot approach.

[0007] The present disclosure further relates to a system for providing KI-Oxone catalyzed, ultrasonically promoted synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs).The system comprises: a) a reaction vessel containing a reaction mixture of β-keto ester, 2-aminopyridines, and the KI-Oxone catalyst system in an ethanol-water solvent; b) an ultrasonic irradiation unit that supplies ultrasonic energy to the reaction mixture at room temperature; c) a catalyst delivery system that introduces the KI-Oxone catalyst system to generate in situ I+ OH species for the α-halogenation of β-keto ester; d) a reaction monitoring unit that monitors reaction completion by thin-layer chromatography; e) a solvent removal unit that evaporates the solvent under reduced pressure; f) an extraction system that dissolves the obtained solid in a saturated sodium bicarbonate solution and extracts it with chloroform; and g) a purification unit that purifies the crude products by silica gel column chromatography using hexane / ethyl acetate as eluent.

[0008] An object of the present disclosure is to provide a system for KI-Oxone catalyzed, ultrasound-promoted synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs).

[0009] Another object of the present disclosure is to provide a transition metal-free synthesis system that eliminates the need for toxic metal catalysts while maintaining high efficiency in the preparation of imidazo[1,2-a]pyridine-3-carboxylates by KI-oxone-mediated oxidative CN bond formation.

[0010] Another object of the present disclosure is to combine ultrasonic irradiation with catalyst delivery and monitoring systems to achieve rapid synthesis (22-30 minutes) under mild reaction conditions at room temperature.

[0011] Another objective of the present disclosure is to characterize the prepared IPCs by characterizing IR, NMR and mass spectra and confirming the structure of the synthesized IPCs by X-ray crystallographic analysis.

[0012] To further clarify the advantages and features of the present disclosure, the invention will be explained in more detail with reference to specific embodiments illustrated in the accompanying drawings. These drawings illustrate only typical embodiments of the invention and are therefore not to be considered as limiting its scope. The invention will be described and explained in more detail with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE CHARACTERS

[0013] These and other features, aspects, and advantages of the present disclosure will become better understood when the following detailed description is read with reference to the accompanying drawings, in which like characters represent like parts throughout. Fig. 1 shows a block diagram of the system for KI-Oxone catalyzed ultrasound-based synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs) according to an embodiment of the present disclosure; and Fig. 2 illustrates a diagram showing the synthesis mechanism used by the system according to an embodiment of the present disclosure.

[0014] Those skilled in the art will also appreciate that the elements in the drawings are shown for convenience and are not necessarily to scale. For example, the flowcharts illustrate the method by key steps to enhance understanding of aspects of the present disclosure. Furthermore, with respect to device construction, one or more components of the device may be represented in the drawings by conventional symbols. The drawings may show only the specific details relevant to understanding embodiments of the present disclosure in order not to clutter the drawings with details that would be readily apparent to those skilled in the art from the present description. DETAILED DESCRIPTION:

[0015] To facilitate understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the drawings and will be clearly described. However, the scope of the invention is not limited thereby. Changes and further modifications to the illustrated system, as well as further applications of the principles of the invention, are possible, as would normally occur to one skilled in the art to which the invention pertains.

[0016] It will be understood by those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not intended to be limiting thereof.

[0017] References in this specification to "one aspect," "another aspect," or similar language mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Therefore, the language "in one embodiment," "in another embodiment," and similar language throughout this specification may or may not refer to the same embodiment.

[0018] The terms "comprises," "comprising," or other variations thereof are intended to cover non-exclusive inclusion, such that a process or method comprising a list of steps may include not only those steps, but also additional steps not expressly listed or inherent in that process or method. Likewise, the statement "comprises" for one or more devices, subsystems, elements, structures, or components does not exclude, without further limitation, the existence of other devices, subsystems, elements, structures, components, or additional devices, subsystems, elements, structures, or components.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. The systems, methods, and examples provided herein are for illustrative purposes only and should not be considered limiting.

[0020] Embodiments of the present disclosure will be described in detail below with reference to the accompanying drawings.

[0021] Fig. 1 shows a block diagram of the system for KI-Oxone catalyzed ultrasound-based synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs) according to an embodiment of the present disclosure.

[0022] Referring to Fig. 1, the system (100) comprises: a) a reaction vessel (102) containing a reaction mixture of β-ketoester, 2-aminopyridines, and the catalyst system KI-Oxone in an ethanol-water solvent; b) an ultrasonic irradiation unit (104) which applies ultrasonic energy to the reaction mixture at room temperature; c) a catalyst feed system (106) which introduces the catalyst system KI-Oxone to generate in situ I+ OH species for the α-halogenation of the β-ketoester; d) a reaction monitoring unit (108) which monitors the completion of the reaction by means of thin-layer chromatography; e) a solvent removal unit (110) which evaporates the solvent under reduced pressure; f) an extraction system (112) which dissolves the resulting solid in a saturated sodium bicarbonate solution and extracts it with chloroform; and g) a purification unit (114) which purifies the crude products by silica gel column chromatography with hexane / ethyl acetate as eluent.

[0023] In one embodiment, the ultrasonic irradiation unit (104) is configured to maintain the ultrasonic irradiation for a duration of 22-30 minutes.

[0024] In one embodiment, the catalyst delivery system (106) is configured to introduce the KI-Oxone catalyst system in a 1.0 equivalent ratio relative to the β-ketoester.

[0025] In one embodiment, the reaction vessel (102) is configured to maintain β-ketoesters and 2-aminopyridines in a 1:1 molar ratio.

[0026] In one embodiment, the reaction vessel (102) is configured to contain an ethanol-water solvent system with a total volume of 3 ml.

[0027] In one embodiment, the reaction monitoring unit (108) is configured to use a solvent system of ethyl acetate and ether (25:75) for thin layer chromatography analysis.

[0028] In one embodiment, the extraction system (112) is configured to perform a triple extraction with chloroform, followed by washing with water and drying over anhydrous Na2 SO4.

[0029] In one embodiment, the purification unit (114) is configured to use 60-120 mesh silica gel and hexane / ethyl acetate (9:1 v / v) as eluent for column chromatography.

[0030] In one embodiment, the system (100) further comprises a characterization unit (116) configured to characterize synthesized imidazo[1,2-a]pyridine-3-carboxylates by IR spectroscopy, NMR spectroscopy, and mass spectrometry.

[0031] In one embodiment, the system (100) further comprises: an antituberculous activity evaluation unit (118) configured to evaluate the antituberculous activity of synthesized imidazo[1,2-a]pyridine-3-carboxylates.

[0032] The present invention provides a sophisticated system for the synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs) using a KI-Oxone-catalyzed, ultrasound-assisted approach. The system represents a significant advance in heterocyclic synthesis technology by integrating multiple specialized units that work synergistically to produce pharmaceutically relevant compounds with antituberculous properties.

[0033] The core of the system consists of a reaction vessel containing the reaction mixture of β-ketoester, 2-aminopyridines, and the KI-Oxone catalyst system in an ethanol-water solvent environment. The KI-Oxone catalyst system generates I+ OH species in situ, which facilitate the α-halogenation of the β-ketoester and lead to subsequent oxidative C–N bond formation with 2-aminopyridines. This approach eliminates the need for transition metals and makes the synthesis environmentally friendly and cost-effective.

[0034] The ultrasonic irradiation unit is specially designed to apply ultrasonic energy to the reaction mixture at room temperature for 22-30 minutes in a controlled manner. This ultrasonic irradiation significantly increases the reaction rate and yield while maintaining mild reaction conditions. The system ensures precise stoichiometric control with β-ketoester and 2-aminopyridines in a 1:1 molar ratio and KI-Oxone catalyst in a 1:1 equivalent ratio.

[0035] Real-time reaction monitoring is performed via an integrated thin-layer chromatography system using an ethyl acetate-ether solvent (25:75), allowing precise determination of reaction completion. The system is equipped with dedicated extraction and purification units. The solvent removal unit concentrates the reaction mixture under reduced pressure, followed by an extraction system that dissolves the resulting solid in a saturated sodium bicarbonate solution and performs a triple extraction with chloroform.

[0036] The purification unit uses silica gel column chromatography (60-120 mesh) with a hexane / ethyl acetate eluent system (9:1 v / v) to obtain pure IPCs. Advanced characterization capabilities are provided by integrated IR spectroscopy, NMR spectroscopy, and mass spectrometry units, ensuring complete structural confirmation of the synthesized products.

[0037] A unique feature of the system is the integrated antituberculous activity assessment unit. It evaluates the biological activity of synthesized IPCs, thus providing a comprehensive platform for drug discovery. The system enables the synthesis of highly functional IPCs with unusual antituberculous activity and offers a direct path from synthesis to therapeutic evaluation.

[0038] The system design emphasizes sustainability and efficiency through its transition-metal-free protocol, one-pot synthesis approach, use of nontoxic reagents, gentle reaction conditions, high yields, and short reaction times. This comprehensive integration of synthesis, purification, characterization, and evaluation functions makes the system particularly valuable for applications in pharmaceutical research and development.

[0039] Fig. 2 illustrates a diagram showing the synthesis mechanism used by the system according to an embodiment of the present disclosure.

[0040] According to Fig. 2, the synthesis is carried out by ultrasound-assisted KI-oxone-mediated oxidative CN bond formation from a reaction of β-ketoester and 2-aminopyridines, which facilitates the synthesis of functional imidazo[1,2-a]pridine-3-carboxylates (IPCs) (10 derivatives). The α-halogenation of the β-ketoester was easily achieved by in situ formed I + OH - -species from the KI-Oxone system.

[0041] The plausible mechanism of the reaction that the system uses to synthesize the IPCs is as follows: The halide (I - ) is initially released from the iodide source and can be reoxidized by oxone, leading to the in situ generation of halogenated species. (I + OH -). The α-iodination of the tautomeric enol form of the β-ketoester, stabilized by intramolecular hydrogen bonds, provides the 3-iodo-β-ketoester. Nucleophilic addition of 2-aminopyridine under oxidative tandem annulation with the intermediate leads to the formation of the intermediate with release of the halide (I-), which can be reoxidized by oxone to give the electrophile (I +) Subsequent intramolecular nucleophilic addition of the provided intermediate. Finally, proton transfer, followed by subsequent dehydration and dehydrogenation, produced the final product IPCs.

[0042] KI-Oxone (1.0 equiv.) was slowly added through the catalyst delivery system to a well-stirred solution of β-ketoester (1 mmol) and 2-aminopyridines (1 mmol) in ethanol:H2O (3 mL) in a reaction vessel. The ultrasonic irradiation unit exposed the reaction mixture to ultrasonic irradiation for 22–30 minutes at room temperature. The reaction monitoring unit indicated the completion of the reaction by TLC (ethyl acetate:ether, 25:75), and after completion of the reaction, the solvent was subjected to a solvent removal unit configured to evaporate the solvent under reduced pressure. The extraction system was configured to dissolve the solid obtained after evaporation in a saturated sodium bicarbonate solution and extract three times with chloroform.The purification unit is configured to wash the combined organic extracts with water, dry them over anhydrous Na2SO4, and concentrate them under vacuum to obtain the products. The crude products were purified by silica gel column chromatography (60-120 mesh; 5.5 g) using hexane / ethyl acetate (9:1 v / v) as the eluent.

[0043] The prepared IPCs were subjected to characterization, with all derivatives being characterized by IR, NMR, and mass spectra. The structure of the synthesized IPCs was confirmed by X-ray crystallography.

[0044] In one implementation, the system (100) for KI-Oxone The catalyzed, ultrasound-promoted synthesis of imidazo[1,2-a]pyridine-3-carboxylates (IPCs) is developed through a detailed evaluation of the reaction parameters using ethyl acetoacetate (1a) and 2-aminopyridine (2a) as model substrates. The reaction was initially attempted without solvent to determine its necessity, and it was observed that no products were formed in the absence of a solvent, indicating the essential role of a suitable solvent for the operation of the system. When acetonitrile was used as the solvent, the system facilitated the formation of the desired IPCs, albeit only in a modest yield of 45%, demonstrating limited efficiency.The use of other aprotic solvents such as acetone, THF, DMF, and 1,4-dioxane under heating to 50 °C did not result in product formation, highlighting their incompatibility within the system configuration. Even when protic solvents such as water, ethanol, and methanol were used individually, yields were remarkably low. This suggests that neither polar aprotic nor simple protic solvents alone are optimal for catalysis. A significant improvement in the system's performance was achieved by using a mixed solvent system of ethanol and water in a 1:1 ratio. Under this condition, the system achieved an 80% yield of the desired product within 30 minutes of sonication. This indicates that the ethanol-water solvent system enabled efficient catalyst activation and reaction progression.Further operation of the system at room temperature with the ethanol-water solvent resulted in excellent yields within 22 minutes. This demonstrates the ability of the ultrasonic irradiation unit to promote rapid reactions under ambient conditions. Using the optimized configuration, namely KI-Oxone in a 1:1 ethanol-water solvent under ultrasonic irradiation at room temperature, the general applicability of the system was further investigated by varying the substituents on the β-ketoester and 2-aminopyridine components. The reaction of ethyl acetoacetate with 2-aminopyridine and 3-methyl-2-aminopyridine afforded IPCs in excellent yield within a short reaction time, thus confirming the efficiency of the system with simple substrates.The system also proved compatible with aromatic β-ketoesters, as demonstrated by the reaction of methyl benzoyl acetate with 2-aminopyridine and 3-methyl-2-aminopyridine, which afforded yields of 92% and 91%, respectively. Furthermore, the system was capable of processing sterically hindered substrates. For example, tert-butyl-substituted β-ketoesters reacted smoothly with 2-aminopyridine derivatives and afforded high yields, demonstrating the system's tolerance toward bulky groups. Likewise, heterocyclic-substituted β-ketoesters afforded 90–92% of the desired IPC products, indicating excellent compatibility with heteroaromatic functionalities. The cyclopropyl-functionalized β-ketoesters were converted into the IPC framework with high efficiency in the presence of both simple and alkyl-substituted 2-aminopyridines.The system demonstrated a broad substrate scope and high efficiency with consistent performance across a broad range of β-ketoesters and 2-aminopyridine derivatives. The integration of the ultrasonic irradiation unit, the precise catalyst delivery mechanism, the optimized solvent environment, and the reaction conditions together enabled a rapid and high-yielding synthesis of imidazo[1,2-a]pyridine-3-carboxylates.

[0045] In one embodiment, the system is configured to synthesize imidazo[1,2-a]pridine-3-carboxylate using an ultrasound-assisted KI-Oxone catalysis system. The synthesized IPCs are compared with other known catalysis systems using different oxidants. The KI-Oxone system is shown to be a remarkable catalyst and delivers a higher yield compared to existing systems.

[0046] In one embodiment, the prepared IPCs are subjected to X-ray crystallography. The data are acquired at 100 K, and the thermal ellipsoid is plotted with a 50% probability. To perform X-ray crystallography, the system is configured to dissolve the purified compound in a solvent mixture of dichloromethane and hexane, and the mixture is evaporated, yielding colorless crystals. The crystallographic data confirm the structure of the synthesized product. No crystallographic data for the present molecule are available in the literature.

[0047] In one embodiment, the antituberculous activity of IPC derivatives was investigated. Imidazo[1,2-a]pyridine-3-carboxylates were found to exhibit remarkable antituberculous activity. The synthesized IPCs (1-10) were tested in an antituberculous bioassay. The results confirmed that all compounds are effective at various concentrations. Among the derivatives, derivatives 1-6 and 9-10 exhibit effective activity at 1.6 µg / ml against Mycobacterium tuberculosis H37RV strain. The investigation of the antituberculous activity revealed that electron-donating substituents at the 2-position of the IPY ring are important for good activity. However, the electron-withdrawing groups at the 2-position of substituted analogues produced moderate inhibitory activity against MTB Mycobacterium tuberculosis.

[0048] The system for the synthesis of IPCs from 2-aminopyridine and β-ketoester utilizes a highly efficient KI-Oxone catalysis system. The reaction is preceded by an oxidative tandem annulation strategy, in which highly functional IPCs are synthesized under ultrasonic irradiation with high yield and a short reaction time. Crystallographic data confirm the formation of IPCs (entry 5), and comparison with the existing literature reveals the lack of crystallographic data for the synthesized derivative. Important features of the proposed system are its metal-free, nontoxic, and mild reaction conditions. The synthesized IPCs were tested for antituberculous properties, demonstrating the biological activity of several derivatives.

[0049] The drawings and the foregoing description illustrate examples of embodiments. Those skilled in the art will recognize that one or more of the described elements may well be combined into a single functional element. Alternatively, certain elements may be separated into multiple functional elements. Elements of one embodiment may be added to another embodiment. For example, the order of the processes described herein may be changed and is not limited to the manner described herein. Furthermore, the actions of a flowchart need not be performed in the order shown; nor do all actions need to be performed. Also, actions that are not dependent on other actions may be performed in parallel with the other actions. The scope of the embodiments is in no way limited by these specific examples.Numerous variations, whether explicitly stated in the specification or not, such as differences in structure, dimensions, and use of materials, are possible. The scope of the embodiments is at least as broad as indicated in the following claims.

[0050] Advantages, further benefits, and solutions to problems have been described above with reference to specific embodiments. However, the advantages, advantages, solutions to problems, and any components that may result in or enhance an advantage, advantage, or solution are not to be construed as critical, required, or essential features or components of any or all of the claims. REFERENCES 100 The system (Includes: A) A reaction vessel. 102 reaction vessel 104 Ultrasound irradiation unit 106 Catalyst feed system 108 Reaction Monitoring Unit 110 Solvent removal unit 112 Extraction system 114 Cleaning unit 116 Characterization Unit 118 Unit for the Evaluation of Antituberculous Activity

Claims

[1] A system (100) for KI-Oxone catalyzed ultrasound-based synthesis of imidazo [1,2-a]pyridine-3-carboxylates (IPCs), consisting of: a) a reaction vessel (102) configured to contain a reaction mixture comprising β-ketoesters, 2-aminopyridines, and a KI-oxone catalyst system in an ethanol-water solvent; b) an ultrasonic irradiation unit (104) configured to supply ultrasonic energy to the reaction mixture at room temperature; c) a catalyst feed system (106) configured to introduce a KI-Oxone catalyst system to generate in situ I+ OH species for the α-halogenation of β-ketoester; d) a reaction monitoring unit (108) configured to monitor reaction completion by thin layer chromatography; e) a solvent removal unit (110) configured to evaporate solvent under reduced pressure; f) an extraction system (112) configured to dissolve the resulting solid in a saturated sodium bicarbonate solution and extract it with chloroform; and g) a purification unit (114) configured to purify crude products using silica gel column chromatography with hexane / ethyl acetate eluent. [2] The system (100) of claim 1, wherein the ultrasonic irradiation unit (104) is configured to maintain the ultrasonic irradiation for a duration of 22-30 minutes. [3] The system (100) of claim 1, wherein the catalyst delivery system (106) is configured to introduce the KI-Oxone catalyst system in a 1.0 equivalent ratio relative to the β-ketoester. [4] The system (100) of claim 1, wherein the reaction vessel (102) is configured to hold β-ketoesters and 2-aminopyridines in a 1:1 molar ratio. [5] The system (100) of claim 1, wherein the reaction vessel (102) is configured to contain an ethanol-water solvent system having a total volume of 3 ml. [6] The system (100) of claim 1, wherein the reaction monitoring unit (108) is configured to use an ethyl acetate and ether (25:75) solvent system for thin layer chromatography analysis. [7] The system (100) of claim 1, wherein the extraction system (112) is configured to perform a triple extraction with chloroform, followed by washing with water and drying over anhydrous Na2SO4. [8] The system (100) of claim 1, wherein the purification unit (114) is configured to use 60-120 mesh silica gel and hexane / ethyl acetate (9:1 v / v) as eluent for column chromatography. [9] The system (100) of claim 1, further comprising a characterization unit (116) configured to characterize synthesized imidazo[1,2-a]pyridine-3-carboxylates by IR spectroscopy, NMR spectroscopy, and mass spectrometry. [10] The system (100) of claim 1, further comprising an antituberculous activity evaluation unit (118) configured to evaluate the antituberculous activity of synthesized imidazo[1,2-a]pyridine-3-carboxylates.

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