Development of Novel Green Approaches to Synthesize Indole Derivatives

Abstract

Green chemistry approaches involve the utilization of non-toxic raw materials and the reduction of harmful chemical byproducts during the synthesis. In recent years, there has been an increasing emphasis on the field of green chemistry which includes the chemical production process, strategic synthetic planning, assessment of manufacturing costs, and effective management of waste generated during the synthesis. In this perspective, various green approaches have been developed in the recent years to synthesize indole derivatives. Indole, a class of heterocyclic compounds containing nitrogen, finds considerable applications in the synthesis of various organic molecules. The agricultural and pharmaceutical industries require innovative and efficient synthetic approaches for indole derivatives due to their wide range of applications. Furthermore, these scaffolds provide notable advantages in the realm of pharmaceutical research owing to their extensive array of applications like antiviral, antifungal, anticancer, anti-inflammatory, antimalarial, and antioxidant activities. Previously, numerous endeavours have been undertaken to synthesise indole derivatives. However, the use of Lewis acids or bases, along with transition-metal catalysts, does not align with the concepts and objectives of green chemistry. However, in the last decades, there has been a notable emphasis towards the development of novel eco-friendly approaches to the synthesis of indole derivatives. Consequently, our research focused on the development of environmentally friendly methodologies for synthesizing indole derivatives. Initially we focused on the design and implementation of a highly effective and environmentally friendly method for the electrophilic substitution of indoles with aromatic aldehydes to synthesise bis-indole derivatives using the α-amylase enzyme as a catalyst in an aqueous medium. Furthermore, bis(indolyl)methanes (BIMs) have garnered significant interest owing to their capacity to function as inhibitors for colon tumours and the proliferation of cancer cell lines. As a result of a wide array of clinical applications, a protocol has been devised that offers several benefits, including environmentally friendly reaction conditions, utilisation of biodegradable catalysts, and enhanced conversion rates. Furthermore, the versatility of the protocol was demonstrated through the use of several substitutions on indole and benzaldehyde, resulting in the synthesis of the respective products with high yields ranging from 63% to 89%. Moreover, we have demonstrated the practicality of this transformation by successfully producing four distinct bioactive compounds on a gram scale. Furthermore, the green metrics were calculated for the scale-up reaction, which demonstrated the environmental sustainability of this methodology and establishes it as a highly advantageous approach for application in organic synthesis. Subsequently, we continued to expand our research and develop sustainable and efficient methodologies for the synthesis of both symmetrical and unsymmetrical 3,3',3''–trisindoles in a highly selective way. Trisindoles have garnered significant attention owing to their diverse array of biological functions. Several methods have previously been documented in the literature for the synthesis of 3,3',3''–trisindoles in the present context. Nevertheless, the majority of the techniques are limited to generating exclusively symmetrical 3,3',3''–trisindoles. Thus, we developed a protocol which involves the utilisation of α-amylase enzyme as a catalyst, enabling a highly selective reaction. Moreover, a range of isatin and indole derivatives with different substituents were employed to demonstrate the applicability of the methodology. As a result, symmetrical or unsymmetrical 3,3',3''–trisindoles were produced with isolated yields ranging from 43% to 97%. Subsequently, a plausible mechanism is suggested and explored through the application of molecular dynamics (MD) study in order to get further understanding regarding the involvement of residues present in the active site of the α-amylase enzyme. The results demonstrated the significance of Glu230, Lys209, and Asp206 residues located within the active region of α-amylase in facilitating the catalytic process. Additionally, the utilisation of Density Functional Theory (DFT) investigation indicated the emergence of bisindole and alkylideneindolenine intermediates in the course of the transformation. We successfully synthesized four distinct 3,3',3''–trisindoles of significant biological relevance on a gram scale, thereby demonstrating the reliability and scalability of this methodology. In continuation of our research we also demonstrate α-amylase catalysed nucleophilic addition of diazo acetate to an imine that is formed in-situ through the interaction of 2-amino pyridines and benzaldehydes. The nucleophilic addition of diazo compounds to imines has been a well-established reaction for a considerable period. Although several bases, organocatalysts, and other substances have been employed to catalyse this process, no enzyme has been investigated so far. In this study, we provide a biocatalytic nucleophilic addition of diazo compounds with in-situ produced imines. This reaction involves the reaction between 2-amino pyridine and benzaldehyde, utilising an α-amylase enzyme, and is conducted under sustainable reaction conditions. In order to establish the universality of this transformation, various substituted 2-amino pyridines, benzaldehydes and ethyl diazoacetate were also tested and the resulting compounds were obtained with moderate to good yields. Furthermore, control studies have been conducted to investigate if the process is catalysed inside the native active site of the α-amylase enzyme.Finally, we have also developed a novel biocatalyst i.e. myoglobin (Mb) for the chemoselective carbene insertion into the N-H bond of amino phenols, over the O-H bond, by using diazo acetates as the carbene precursor. The myoglobin derived from sperm whale, was found to be highly chemo selective for the N-H insertion reaction involving amino phenols and ethyl diazo acetate. However, the overall conversion rate of this reaction was very low. In this context, a library of Mb-variants was developed by the implementation of a site-directed mutagenesis approach and the results revealed that the Mb-variant with a twofold mutation (H64V, V68A) exhibited high reactivity and demonstrated a high degree of selectivity as a biocatalyst for N-H insertion. Furthermore, the broad applicability and practicality of Mb(H64V,V68A)-catalyzed chemoselective N-H insertion were shown through the scaled-up reactions involving variously substituted aminophenols and diazo compounds. These reactions yielded N-H insertion products with isolated yields ranging from 61% to 86%, along with excellent chemoselectivities. Next, we have successfully developed a biocatalytic Groebke-Blackburn-Bienayme (GBB) multicomponent reaction that is environmentally sustainable for the synthesis of indole-based imidazo[1,2-a]pyridine derivatives, using α-amylase enzyme as the catalyst. The imidazo[1,2-a]pyridine framework has garnered considerable interest owing to its use as a foundational structure in various medications that are currently accessible in the market, such as zolimidine, zolpidem, Olprinone, Soraprazan, and others. Moreover, there has been significant interest in indole-based imidazo[1,2-a]pyridine derivatives owing to their demonstrated anticancer and antibacterial properties. Nevertheless, there is a scarcity of documented techniques for the production of indole-based imidazo[1,2-a]pyridines. Therefore, we have conducted a study that demonstrates the effective development of a biocatalytic methodology for the synthesis of indole-based imidazo[1,2-a]pyridine derivatives which involves the reaction of 2-aminopyridine, indole-3-carboxaldehyde, and isocyanide in the presence of EtOH solvent and enzyme catalyst. The methodology demonstrated a high level of generality and resilience by the successful synthesis of indole-based imidazo[1,2-a]pyridines with various substituents, resulting in favourable isolated yields. Moreover, to enhance the reusability of α-amylase as a catalyst for the GBB multicomponent reaction, it was immobilised onto magnetic metal-organic framework (MOF) materials known as Fe3O4@MIL-100(Fe). The immobilised α-amylase demonstrated the ability to be reused for up to four consecutive catalytic cycles without seeing a substantial decline in its catalytic activity.