One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction

A novel three-component reaction has been developed to assemble biologically and pharmaceutically important tetracyclic fused imidazo[1,2-a]pyridines in a one-pot fashion utilizing readily available 2-aminopyridines, isatins and isocyanides. The three-component coupling proceeds through the Groebke–Blackburn–Bienaymé reaction followed by a retro-aza-ene reaction and subsequent nucleophilic reaction of the in-situ generated imidazo[1,2-a]pyridines bearing an isocyanate functional group.


Introduction
Multicomponent reactions (MCRs) have attracted considerable attention in organic and medicinal chemistry due to their high efficiency, simple operability, atom economy and unmatched versatility [1][2][3][4][5][6]. Especially, these reactions serve as an ideal synthetic tool for the assembly of structurally diverse and biologically relevant heterocycles, and thus have been extensively investigated by organic and medicinal chemists to explore lead compounds in drug discovery efforts [7][8][9][10].
In view of the significance of the GBB reaction and the imidazo[1,2-a]pyridine core structure, the further development of new GBB-based methods for the efficient synthesis of novel polycyclic fused imidazo[1,2-a]pyridines is highly desirable. In an earlier study, we have developed a GBB/lactamization MCR strategy, which provided the rapid access to isoquinolinonefused imidazo[1,2-a]pyridines with potent and selective CDK2 inhibition properties [34,35]. As a continuing effort, we report herein our recent efforts in the development of a GBB-based MCR method for the one-pot synthesis of diverse quinazolin-2one fused imidazo[1,2-a]pyridines (Scheme 1). Parts of the work have been disclosed in a previous patent [36].

Results and Discussion
It is noteworthy that there was no report on a ketone-involving GBB reaction, and several attempts to explore the GBB reaction utilizing ketones as carbonyl reactant failed [27,37]. These difficulties could be partially explained in terms of the electronic and steric effect of the ketone involved. More importantly, when a ketone is used in the reaction the formed unstable [4 + 1] cycloaddition adduct could not undergo a [1,3]-alkyl shift. On the other hand the reaction with an aldehyde allows further conversion through a [1,3]-hydride shift to form a stable and aromatic imidazole. Therefore, we envisioned that a ketoneinvolved reaction could proceed, if the [4 + 1] cycloaddition adduct can further rearrange to form an aromatic imidazole. With this idea in mind, we started to study an isatin-involved GBB reaction [38,39], because the resulting [4 + 1] cycloaddition adduct could further proceed with a retro-aza-ene reaction via a concerted [1,5]-hydride shift.
We first explored the reaction of 2-aminopyridine (2a), isatin (3a) and tert-butyl isocyanide (4a). Under the classical reaction conditions (entry 1, Table 1), the product 1a was isolated only in 4% yield. Performing the reaction under reflux conditions slightly improved the yield to 11%. We next examined solvent effects in this MCR reaction and various solvents were screened, as summarized in Table 1. We observed that protic solvents with medium polarity can facilitate the reaction by product precipitation from the reaction mixture and n-BuOH proved to be the most suitable solvent in the reaction. Performing the reaction in refluxing n-BuOH in the presence of one equivalent of HClO 4 for 8 h, compound 1a was obtained in 30% isolated yield. Other acids including p-toluenesulfonic acid (PTSA), HCl, and HOAc were also screened, and the results indicated that the use of PTSA led to a slightly decreased yield, and weaker acids failed to promote this process. It is worth noting that the reaction proceeded incompletely and significant amounts of isatin (3a) were recovered. When increased amounts (1.35 equiv) of 2-aminopyridine (2a) and tert-butyl isocyanide (4a) were used, the yield of 1a could be further improved to 42%.
Under the optimized reaction conditions, we started to investigate the reaction scope. The MCR of various 2-aminopyridines, isatins and isocyanides proceeded well under the optimized conditions and the combinational synthesis delivered structurally diverse quinazolin-2-one-fused imidazo[1,2-a]pyridines ( Figure 1). It was found that the electronic properties of the  substituents attached to the isatin and 2-aminopyridine had no obvious effect on the reactivity. When tert-butyl isocyanide (4a) was used, the reaction proceeded equally well with electron-withdrawing or electron-donating substituted isatins and 2-aminopyridines, delivering the desired products 1b-m in 35-55% yield. Similar results were obtained from the reaction with cyclohexyl isocyanide (4b) to give 1n-y. All products were characterized by 1 H NMR, 13 C NMR, HRMS spectra and the structure of 1o was further confirmed by X-ray diffraction analysis (see Supporting Information File 1 for details).
A possible mechanism for the MCR is proposed in Figure 2.
The MCR proceeds through the formation of a protonated imine species from 2-aminopyridine and isatin which then undergoes a formal [4 + 1]

Conclusion
In conclusion we have developed a GBB-based multicomponent reaction of isatins, 2-animopyridines and isocyanides, which provides a direct and rapid access to diverse tetracylic fused imidazo[1,2-a]pyridines with moderate yields. To the best of our knowledge, the described chemistry represents the first example of the GBB reaction involving ketones, transforming the simple starting materials into complex heterocycles of pharmaceutical relevance in a highly efficient fashion. The developed MCR proceeds through a domino GBB/retro-aza-ene/ nucleophilic cyclization process under mild reaction conditions, and its high efficiency and simple operation will make it have potential applications in the compound library synthesis.

Experimental
Typical procedure for multicomponent reaction. To a solution of isatin (3, 1.0 mmol), 2-aminopyridine (2, 1.35 mmol) and isocyanide (4, 1.35 mmol) in 4 mL of n-butyl alcohol was added HClO 4 (1.0 mmol), and the reaction mixture was stirred under refluxing temperature for 8 h. When the reaction mixture had cooled to room temperature, the formed precipitate was collected by filtration, rinsed with ethanol and dried to afford the target compounds 1.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization and spectral data for synthesized compounds and X-ray data for compound 1o.