Purpose <p>Imidazo[1,2-<i>a</i>]pyridine is a pivotal fused heterocycle in medicinal chemistry, widely recognized as a foundational scaffold due to its diverse biological and therapeutic applications. The need for efficient, sustainable, and high-yielding synthetic methodologies for imidazo[1,2-<i>a</i>]pyridine derivatives continue to drive research interest in this domain.</p> Methods <p>The present study focuses on developing a highly efficient and sustainable synthetic strategy for imidazo[1,2-<i>a</i>]pyridine derivatives with improved yield and broad applicability. A multistep reaction pathway was employed using readily available starting materials, followed by structural confirmation of the synthesized compounds through FTIR, ¹H NMR, ¹³C NMR, and mass spectrometry analyses.</p> Results <p>The optimized reaction conditions yielded products in excellent yields ranging from 91% to 98%, demonstrating superior efficiency, enhanced purity, and high scalability compared to conventional methods. Furthermore, molecular docking studies were performed to evaluate the binding affinity of the synthesized derivatives toward the target protein, revealing significant interactions with key active-site residues that support their potential biological relevance. Drug-likeness assessment based on Lipinski’s Rule of Five confirmed that all compounds exhibited acceptable physicochemical properties, indicating good oral bioavailability and favorable pharmacokinetic profiles. In this approach, alternative coupling systems such as DMTMM and greener solvents (MeCN, 2-MeTHF) are also discussed for further improving the sustainability profile.</p> Conclusion <p>Overall, this novel synthetic approach provides a reliable, eco-efficient, and versatile route for the formation of imidazo[1,2-<i>a</i>]pyridine frameworks and holds strong potential for future applications in medicinal chemistry and pharmaceutical development.</p>