Introduction

Heterocyclic rings, especially nitrogen-containing heterocycles, play a vital fulfil in organic and bioorganic chemistry by virtue of their application in pharmaceutical research, drug design, sensor and medicinal chemistry [1,2,3,4,5]. Twelve small molecule medications containing heterocyclic moieties, which often include nitrogen and account for more than 50 billion USD annually in sales, were among the top 25 best-selling pharmaceuticals in 2014 [6]. Based on FDA databases, drugs containing nitrogen-based heterocycles are approximately 59% of unique small-molecule drugs [7] as anti-cancer [8], antiviral [9], anti-convulsant [10], antibacterial and among others [11]. In the nitrogen-containing heterocycles area, imidazopyridine as constituents of an assortment of biologically active molecules, natural products and also several imperative marketed drugs namely zolpidem, saripidem, alpidem and necopidem have recently garnered widespread attention from organic and medicinal chemists [12] (Fig. 1). In this line, the direct C-3 functionalization of imidazo[1,2-a]pyridines could be considered a critical synthetic pathway; thus, several reports for example amination, sulfenylation, thiocyanation, arylation, halogenation have been published in recent years [13,14,15,16,17]. Nevertheless, there are some dilemmas namely using precious and detrimental metal catalysts such as Cobalt(II) phthalocyanine tetrasodium sulfonate, vanadyl (acetylacetonate), Ir(ppy)2(dtbbpy)PF6, Pd(OAc)2, NiBr2, applying strong oxidant and base such as K2S2O8, Ag2CO3, H2O2, Cs2CO3 or deploying alternative energy input systems namely microwave radiation, ultrasound irradiation or electrochemical equipment [18].

Fig. 1
figure 1

Imidazo[1,2-a]pyridines and coumarin in pharmacologically active substances

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Apart from imidazopyridine, coumarins meanwhile are known as a privileged structure of an extensive range of drugs and biologically active molecules and natural products [19]. Coumarin compounds are found in nature in a substantial number of plants, especially in high concentration in the tonka bean, sweet woodruff and sweet grass [20]. Coumarin scaffolds moreover have been extensively deployed as antimicrobial, antifungal, anti-tumor, anti-HIV, anti-arrhythmia, antioxidant, and anti-inflammatory agents [21,22,23,24] (Fig. 1). To be more precise, Warfarin, a significant coumarin-based oral anticoagulant, has been utilized in clinics for the prevention of thrombotic events [21]. Besides that, coumarin-based small-molecule demonstrate beneficial applications as optical brighteners, fluorescence sensors, and molecular photonic devices [25].

In light of the importance of imidazopyridine along with coumarin in drug discovery, designing a facile synthetic strategy to direct access to the scaffold containing both of these two structures is tremendously critical. Hybridization of two or more pharmacophores into a single structure is highly desirable, on account of the fact that these hybrids enjoy multiple biological activities, enhanced selectivity profiles, dual action modes and/or minimize side effects [26]. Take imidazopyridine-coumarin conjugated molecules with promising anti-hepatitis C virus activity along with protease activator as perfect examples [27, 28]. Consequently, the exploration of novel and expeditious methods for synthesizing imidazopyridine linked coumarins are essential and crucial. In continuation of our research interests on heterocyclic compounds [29,30,31], we represent a facile and diversity-oriented synthetic route to construct 2-aryl-imidazo[1,2-α]pyridine linked coumarins via tandem sp2 C-H functionalization/decarboxylation process in sustainable medium like ethyl acetate in the absence of catalyst, metal, base, oxidant.

Results and Discussion

After preparation of a broad spectrum of imidazopyridines and coumarin 3-carboxylic acid in green media such as deep eutectic solvent (DES) and water with excellent yield, our investigation focused on exploring the optimal conditions by selecting 1a and 2a as the model substrates and testing various media namely DMSO, DES (Choline chloride and urea), water, ethanol, PEG-400, CH3CN, dioxane, ethyl acetate. The ensured product 3a was achieved with appropriate yield without using any catalyst in ethyl acetate at 120 °C in a sealed tube. The lower temperature like reflux conditions produced inferior results, and there was no reaction when the temperature was lowered to 60 °C and ambient temperature. Using a sealed tube and high temperature leads to an increase in reaction pressure. When it comes to volume alterations and entropy-decreasing transformation, high pressure chemistry has been demonstrated to be a key synthetic technique in organic synthesis among physical activation modalities [32]. Depending on the nature of the transition state and the individual solvent-pressure interactions, pressure may additionally have a significant impact on reaction speeds. This happens whenever the volume of the medium changes during the development of the transition state [33]. Aspect dioxane, the reaction in other solvents was not associated with good yield. Considering the energy-related costs for the environment, ethyl acetate is not totally ideal; however, it depicts a considerable enhancement over acetonitrile, toluene, dimethylacetamide and chlorobenzene. According to health and safety related issues, this solvent is one of the best non-harmful organic media which is a pivotal augmentation towards pharmaceutical compliance/compatibility, in addition to the lower burden for the environment [34]. Adding basic and acidic catalyst including NaHCO3, K2CO3, KtBuO, Et3N, DABCO, and PTSA did not lead to more efficiency. ZnCl2 as Lewis acids catalyst also examined but no desired product was achieved (Table 1). Regarding the reaction time, the reaction in 48 h is associated with excellent efficiency. In shorter times such as 24 h and 8 h, the reaction is associated with a dramatic decrease in yield. Consequently, carrying out under catalyst-free condition is an advantage of this synthetic route on consideration of the fact that organic syntheses without using any catalysts are totally according to the philosophy of green chemistry by alleviating of the pollutant production and omitting of harmful and detrimental chemicals, reduced cost and operational simplicity. Further, catalyst-free reactions normally could enhance E-factor and mass intensity as two critical green chemistry metrics [35].

Table 1 Optimization of Reaction Conditions
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In order to investigate substrate scope of this transformation, an extensive range of imidazopyridines as well as various coumarin 3-carboxylic acid are examined (Fig. 2). A multitude of substituents on the phenyl ring of 2-phenylimidazo-[1,2-a]pyridine encompassing the electron donating groups (CH3, OMe) as well as electron-withdrawing groups (Cl, Br, Ph) were successfully applied. Substrates bearing substituents on the C6 position of imidazo[1,2-a]pyridines were also investigated with appropriate yield. Besides that, a diverse range of coumarin 3-carboxylic acid containing electron-donating and electron withdrawing such as OH, OMe, Br and NO2 were directly used to the reaction. In addition, a complex structure 3p containing three heterocycles for example imidazo[1,2-a]pyridines, coumarin and benzodioxole motifs was successfully synthesized. Next, the generality of our synthetic procedure for imidazo heterocycles namely benzo[d]imidazo[2,1-b]thiazole 3q were satisfactorily explored with appropriate yield. As the synthesized products were new, all of them were characterized using of FT-IR, 1HNMR, 13CNMR and DEPT method.

Fig. 2
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Structure and isolated yields of products

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To emphasize further the utility of the imidazopyridine-linked coumarins described herein, we conducted some late-stage functionalization. Considering importance of C − C cross coupling [36,37,38] such as the Suzuki–Miyaura and Sonogashira reaction in total synthesis and drug discovery, the bromo group of 3c was coupled with p-methylphenylacetylene and (3-methoxyphenyl)boronic acid to give the derivative 4a-b (Fig. 3).

Fig. 3
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Further synthetic applications

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Based on the experimental results, a mechanism was suggested that involves the electrophilic activation of the alkene of coumarin-3-carboxylic acid 1a through a synergistic effect between the carboxylic group and imidazopyridine moiety 2a. Additionally, hydrogen bond formation between the oxygen atom and the hydroxyl group further enhances the electrophilicity of the alkene and brings the 2-phenyl-imidazo[1,2-a]pyridine close to the electron-deficient double bond, allowing for conjugate addition to form intermediate A [39]. The subsequent isomerization, tautomerization, and decarboxylation would result in 3a. It was suggested that hydrogen bonding is crucial to the overall process and the accomplishment of this transition, as illustrated in Fig. 4. It is also possible that due to the increase in polarity and ionicity of the intermediates, solvents with high polarity such as water, DMSO, and acetonitrile had a weaker performance compared to solvents with low polarity such as ethyl acetate and dioxane. Control tests using 3-acetyl coumarin were conducted at the prescribed circumstances in order to clarify the reaction process. Notably, no detectable reaction occurred, and the substrate remained intact. The outcome suggests that the presence of the carboxyl group at the C-3 position of the coumarin moiety is crucial for the observed transformation.

Fig. 4
figure 4

Proposed reaction pathway to access imidazopyridine linked coumarins

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Optical Studies

As the conjugated structure of synthesized compounds accompanied by simultaneous presence of two fluorescence heterocycles on one structure which render them highly fluorescent, here we decided to evaluate their photophysical properties. The UV absorption and photoluminescence (PL) spectra of ensued products which solvated in mixture of DMSO and EtOH provide valuable structural and optical property information. Maximum absorptions occur at 225, 265 and 320 nm in the UV absorption spectra of the produced derivatives (Fig. 5a). Changing the replacement at position 6 and 8 on coumarins ring and also 4 of 2-phenyl-imidazo[1,2-a]pyridine moiety of final products to phenyl, methyl, hydroxy, or methoxy lead to a decrease and shift of the absorption peaks to a longer wavelength. Furthermore, the substitution of phenyl and methoxy at the final scaffolds site culminated in a further adsorption in the region 265. As seen in Fig. 5b, the PL spectra of the imidazopyridine linked coumarins containing an electron-donating group such OMe on the aromatic ring at the C8 position of coumarins 3n as well as phenyl 3d and benzodioxole motifs 3p on 2-phenyl-imidazo[1,2-a]pyridine demonstrate increased PL intensity, whereas the electron-withdrawing group like NO2 in the coumarins position 3i has an inductive impact and decline PL intensity. It is likely to be deduced that the nitro group as a heavy substitution arises internal conversion and declines the fluorescence pathway transition. This conclusion is likely attributable to the self-absorption phenomena that occurs in the structure of compounds. Moreover, final products exhibit a Stokes shift about 155 nm.

Fig. 5
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UV absorption (left) and PL spectra (right) of synthesized imidazopyridine-linked coumarins in DMSO/ethanol (C = 1 × 10–4 M)

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Conclusions

To recapitulate, a straightforward and sustainable synthetic route to assemble a diverse range of imidazopyridine linked coumarins was developed. These reactions were conducted through tandem C(sp2)–H functionalization/decarboxylation reaction without using any catalyst or additive like oxidant in ethyl acetate as an environmentally benign solvent. The utilities of ensured products in further organic synthesis were carried out by critical cross-coupling reactions such as Suzuki–Miyaura and Sonogashira reaction. The procedure is simple to implement and uses easily accessible substrates to yield a rich chemical library that will prove useful in organic, medicinal, and clinical diagnostics.