Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

Using an aerobic oxidative coupling, different new imidazo[1,2-a]-N-heterocycles with gem-difluroroalkyl side chains have been prepared in fair yields by the reaction of gem-difluoroenones with aminopyridines, -pyrimidines and -pyridazines. Condensed heterocycles of this type play an important role as key core structures of various bioactive compounds. Further, starting with a chloroimidazopyridazine derivative, Pd-catalyzed coupling reactions as well as nucleophilic substitutions have been performed successfully in order to increase the molecular diversity.

On the other hand, the incorporation of fluorine or fluorinated groups into organic molecules has been widely recognized as a general strategy toward drug development in pharmaceutical research. This is connected to fluorine's electronegativity, size, and lipophilicity [15,16], which can strongly improve the biological properties of molecules through, for instance, increase of metabolic stability and bioavailability for many drugs and pharmacological tools. So, the preparation of fluorinated molecules is a very attractive research area for organic and medicinal chemists [17][18][19][20].
Our research program aims to synthesize new fluorinated molecules based on the easy access and the versatility of fluorinated propargylic derivatives [21]. Thus, taking into account the known biological properties of the imidazo-fused N-heterocycles, we became interested in the preparation of new derivatives of this type possessing gem-difluorinated side chains as indicated in Figure 1. Such new fluorinated heterocycles could be of interest for bioorganic and medicinal chemistry studies.
Several synthetic approaches for imidazopyridines are available, but only a few examples have been reported to date for the construction of this scaffold with introduction of fluorine [22], trifluoromethyl [23] or trifluoroethyl groups [24]. Herein, we report the synthesis of imidazo[1,2-a]pyridines, imidazo[1,2a]pyrimidines, and imidazopyridazines with fluorinated side chains following an efficient strategy developed by Hajra et al. [25]. This methodology, developed for the synthesis of 3-aroylimidazopyridines, involves a copper(II) acetate-catalyzed aerobic oxidative amination and it proceeds through a tandem Michael addition followed by an intramolecular oxidative amination. Therefore, our target molecules A could be synthesized by the oxidative coupling of 2-aminopyridines with α,β-unsaturated ketones B, themselves easily accessible from gem-difluoropropargylic alcohols C through a base-mediated isomerization process (Scheme 1) [26,27].

Results and Discussion
The required propargylic alcohols 5a-e (type C, Scheme 1) were obtained in 27-73% yields by reaction of the lithium salt of the easily accessible gem-difluoro propargylic derivatives 4 [28] with aromatic aldehydes. Then, the DBU-mediated isomerization afforded the desired enones 6a-e in 21-66% yields (Scheme 2 and Table 1).
Scheme 3: Synthesis of 7a.  were well tolerated under the optimized conditions affording the tandem products 7 in fair to moderate yields, although lower yields were obtained in the cases of 7j and 7g (32% and 36%, respectively). Moreover, two other important heterocyclic frameworks, imidazo[1,2-a]pyrimidines 7d and imidazo[1,2-b]pyridazines 7e, have been synthesized by the same method albeit in slightly decreased yields ( Table 2, entries 4 and 5).
The structures of molecules 7 are in full agreement with their spectroscopical (NMR) and analytical data (HRMS). For the imidazopyridines, the structure of 7a was confirmed by X-ray analysis ( Figure 2) [30] and the other derivatives were proposed by analogy. In the same way as for the imidazopyridazines, the structure of 7e was established by X-ray analysis [30] and this was extended to the other derivatives. These results unambiguously demonstrate the regiochemistry of the reaction. These cascade reactions proceed first through a Michael addition of the primary amine on the enone, followed by an intramolecular cyclization by the pyridine/pyrimidine nucleus. Unfortunately, no crystal structure could be obtained for the imidazopyrimidines and therefore the corresponding structures 7d and 7g were proposed by analogy.
These oxidative coupling conditions appeared compatible with the first isomerization step, therefore, the possibility of a "onepot" reaction was considered. Indeed, by heating alcohol 5a (Table 1, entry 1) with 2-aminopyridine and DBU (1,8-diazabicycloundec-7-ene) under the same conditions as mentioned above, the desired imidazopyridine derivative 7a was isolated in 33% yield (Scheme 4). This one-pot process gives an overall yield very close to the two-step reaction (38%).
Further, the halogen-substituted substrate 7e appeared as an attractive precursor to increase the molecular diversity around this scaffold. In order to explore this possibility, we performed two Suzuki-Miyaura reactions, as representative examples of Pd-catalyzed coupling processes (Table 3). They gave the target molecules 8 and 9 in 46% and 53% yields, respectively. On the other hand, two nucleophilic substitution reactions using phenol and morpholine gave the expected heterocycles 10 and 11 in 73% and 23% yields, respectively.

Conclusion
In summary, we developed a short and completely regioselective method for the synthesis of imidazo[1,2-a]-N-heterocycles with gem-fluorinated side chains starting from easily accessible propargylic fluorides. Although the yields are only moderate to fair, this short (1-2 steps) method offers significant flexibility to prepare focused libraries of molecules with this core structure. Such new fluorine-containing heteroaromatic frameworks would be of much interest for biological studies in different areas of life sciences.

Experimental
Representative procedure for the synthesis of imidazopyridine 7a The syntheses of propargylic fluorides 5 and enones 6 were performed in a similar way as described before [26].
Thus the mixture was cooled to room temperature, filtered, washed and extracted with dichloromethane. The organic phase was concentrated and the crude product was purified by column chromatography on silica gel, using petroleum ether/ethyl acetate as eluent. Imidazopyridine 7a was isolated in 33% yield.

Supporting Information
Supporting Information File 1 Experimental details and characterization data of new compounds with copies of 1 H, 13 C and 19 F NMR spectra.