Microwave-Assisted Synthesis of Bis-Heterocycles Containing the Imidazo[1,2-a]Pyridine by Groebke-Blackburn-Bienaymé Reaction

: A series of six fused bis -heterocycles having imidazo[1,2-a]pyridine bound with quinoline were synthesized by microwave-assisted Groebke-Blackburn-Bienaymé reaction (GBBR) under green catalysis. The GBB products are privileged scaffolds and their synthesis is of great interest in synthetic and medicinal chemistry.

Among them, bis-heterocycles have attracted much attention due to their numerous applications in many fields, such as organic synthesis, optics, materials, and polymer sciences, agrochemistry, and mainly in medicinal chemistry [14]. The research towards finding novel applications is supported on the basic principle, a union makes force [15]. Two heterocycles can be suitably placed to construct complex products having potential new or enhanced known properties.
Imidazo [1,2-a]pyridine core is present in a lot of drugs, useful in various treatments of brain diseases and CNS-related disorders. For example, zolpidem is the most prescribed drug for insomnia [15]. The GBBR is one of the highest important classes of isocyanide-based multicomponent reactions (I-MCRs) and the most efficient methods for the synthesis of fused imidazole analogs. GBBR usually requires a solvent and catalyst. In this context, GBBR methodologies using various green catalysts, such as Lewis acids, Bronsted acids, solid-supported organic bases and inorganic salts have been reported [16]. It is highlighted that the reported methodologies have some drawbacks such as high temperature, low yields, expensive catalyst and non-greener solvents.
Microwave irradiation (MW) plays a central role in synthetic organic chemistry mainly to decrease reaction times. Herein the goal is to develop an efficient protocol for the synthesis of new heterocyclic scaffolds containing imidazole and quinoline cores under ecofriendly conditions. MW offers several benefits over conventional methods including short reaction time and yield enhancements.
Foroumadi and co-workers reported in 2015 the synthesis of imidazo[1,2-a]pyridine in moderate yields (82-93%) via a GBBR using NH4Cl in stoichiometric quantities and hard conditions (Scheme 1) [17]. Our methodology has some advantages, for example, the synthetic process worked well under green catalyst. Besides short reaction times and MW energy source. The principal objective in our research group during the last years has been to develop versatile and efficient I-MCR-based methodologies to synthesize a series of novel unsymmetrical bisheterocycles containing privileged nucleus in medicinal chemistry [10][11][12]18].
As a part of our research program in the development of green or eco-friendly IMCR strategies herein, we describe the one-pot synthesis of new unsymmetrical bis-heterocycles via the GBBR under mild conditions. The target molecules containing two different complex heterocycles such as imidazo[1,2-a]pyridine bound with quinoline moiety.

Results and Discussion
Following our interests in the efficient synthesis of bis-heterocycles containing frameworks of interest in medicinal chemistry, our work consists of the synthesis of six new analogs of 2chloroquinoline imidazo[1,2-a]pyridine which were synthesized in moderate to good yields (54-67%) via GBBR under mild green conditions (Scheme 2). In order to find the optimum conditions for the GBBR involved in the synthetic strategy toward unsymmetrical bound-type bis-heterocycles 6a, 2-chloro-3-formylquinoline (1) was reacted sequentially with one equivalent of methyl-2-aminopyridine-4-carboxylate (5a), tertbutyl isocyanide (2a) which were selected as the model reaction (Table 1). According to our main line of research, green solvents, moderate temperatures, and green catalysts were studied to optimize the reaction conditions. Firstly, we performed the GBBR at room temperature in water (Table 1, entry 1) but the starting materials remained completely unconsumed. When the reaction was carried out in ethanol without catalyst at r.t (Table 1, entry 3), the product 6a was obtained in 13% yield. Due to the low yields obtained, we decided to use a catalyst and we decided to try a reaction using NH4Cl in 10% mol which is a green, inexpensive and easily available catalyst. In the literature, there are many reports of the use of NH4Cl in GBBR in stoichiometric amounts and longer reaction times were required. In 2018, we reported for the first time of NH4Cl in GBBR in a catalytic amount [18]. The TLC of the reaction with NH4Cl revelated that the product yield was increased. Under MW at 60 °C in EtOH and NH4Cl, the yield was better than USI 54 and 42% of 6a respectively. The course of the reaction was monitored by TLC and characterized by 1 H y 13 C NMR.
Using optimized conditions, a series of six new 2-chloroquinoline imidazo[1,2-a]pyridine were synthesized (shown in Scheme 3). The versatility of the developed methodology was examined using different isocyanides such as aryl and alkyl (2a-c) and two different aminoazines with withdrawing groups. The respective products 6a-f were obtained in moderate to good yields (54-67%).

Experimental Section
General Information: 1 H and 13 C NMR spectra were acquired on a 500 MHz spectrometer. The solvent for NMR samples was CDCl3. Chemical shifts are reported in parts per million (δ/ppm). Internal reference for NMR spectra is tetramethylsilane at 0.00 ppm. Coupling constants are reported in Hertz (J/Hz). Multiplicities of the signals are reported using the standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). NMR spectra were analyzed using the MestreNova software version 10.0.1-14719 (Mestrelab Research, S.L., Santiago de Compostela, Spain). The reaction progress was monitored by TLC and the spots were visualized under UV light (254 or 365 nm). Flash column chromatography was performed using silica gel (230-400 mesh) and mixtures in different proportions of hexanes with ethyl acetate as mobile phase. Chemical names and drawings were obtained using the ChemBioDraw Ultra 13.0.2.3020 software package (PerkinElmer Inc., Waltham, MA, USA).

Conclusions
In conclusions, herein we described GBBR protocol under green catalyst for the synthesis of bisheterocycles containing privileged nucleus in medicinal chemistry.
Additionally, this strategy has advantages in comparison with previous works due to the strategy herein described takes place under mild and green conditions. Author Contributions: All authors contributed equally to this work.