Catalyst-and Solvent-free Synthesis of Imidazo [ 1 , 2-a ] pyridines

It has long been known that imidazo[1,2-a]pyridine derivatives exhibit diverse biological activities and were used as antiviral, antiulcer, antibacterial, antifungal, antiprotozoal, antiherpes, anti-inflammatory. Recently, Leopoldo et al. reported synthetic approaches leading to 4-[ω-[4-arylpiperazin-1-yl]alkoxy]phenyl) imidazo[1,2-a] pyridine derivatives (Figure 1, I), which were described as fluorescent high-affinity dopamine D 3 receptor ligands as potential probes for receptor visualization, and the fluorescent moiety compound 2-(4-methoxyphenyl) imidazo[1,2-a]pyridine (Figure 1, II), which is characterized by the 2-phenylimidazo[1,2-a]pyridine moiety, presented an oxygen that can be easily functionalized to afford potential D 3 receptor ligands structurally related to the D 3 receptor ligands. The majority of reported imidazo[1,2-a]pyridines syntheses proceeded from the condensation reaction of the α-bromocarbonyl compounds with 2-aminopyridine derivative under neutral or weak basic conditions. A mechanism for the reaction has been proposed, which includes the nucleophilic substitution of the bromide by the pyridine-nitrogen in the 2-aminopyridine derivative. Imidazo[1,2-a]pyridine derivatives were also synthesized by solid support and using catalyst such as Al 2 O 3 15 and TiCl 4 . Other methodologies included treating 2-aminopyridines with α-tosyloxyketones, a polymer supported [hydroxy(sulfonyloxy)iodo]benzene with ketones or alcohols, alkynyl(phenyl)iodonium salts, α-diazoketones, and propargyl bromide. Although these methods are suitable for certain synthetic conditions sometimes, however, some of these procedures are associated with one or more disadvantages such as hazardous organic solvents, high cost, long reaction time, low yield, use of stoichiometric and even excess amounts of reagents or catalysts, special apparatus and drastic reaction conditions, which leaves scope for further development of new environmentally clean syntheses.


Introduction
It has long been known that imidazo [1,2-a]pyridine derivatives exhibit diverse biological activities 1 and were used as antiviral, 2 antiulcer, 3 antibacterial, 4 antifungal, 5 antiprotozoal, 6 antiherpes, 7 anti-inflammatory. 8Recently, Leopoldo et al. 9 reported synthetic approaches leading to 4-[ω-[4-arylpiperazin-1-yl]alkoxy]phenyl) imidazo [1,2-a]  pyridine derivatives (Figure 1, I), which were described as fluorescent high-affinity dopamine D 3 receptor ligands as potential probes for receptor visualization, and the fluorescent moiety compound 2-(4-methoxyphenyl) imidazo[1,2-a]pyridine (Figure 1, II), which is characterized by the 2-phenylimidazo[1,2-a]pyridine moiety, presented an oxygen that can be easily functionalized to afford potential D 3 receptor ligands structurally related to the D 3 receptor ligands. 10The majority of reported imidazo [1,2-a]pyridines syntheses proceeded from the condensation reaction of the α-bromocarbonyl compounds with 2-aminopyridine derivative under neutral 11 or weak basic conditions. 12 mechanism for the reaction has been proposed, 13 which includes the nucleophilic substitution of the bromide by the pyridine-nitrogen in the 2-aminopyridine derivative.Imidazo [1,2-a]pyridine derivatives were also synthesized by solid support 14 and using catalyst such as Al 2 O 3 15 and TiCl 4 . 16Other methodologies included treating 2-aminopyridines with α-tosyloxyketones, 17 a polymer supported [hydroxy(sulfonyloxy)iodo]benzene with ketones or alcohols, 18 alkynyl(phenyl)iodonium salts, 19 α-diazoketones, 20 and propargyl bromide. 21lthough these methods are suitable for certain synthetic conditions sometimes, however, some of these procedures are associated with one or more disadvantages such as hazardous organic solvents, high cost, long reaction time, low yield, use of stoichiometric and even excess amounts of reagents or catalysts, special apparatus and drastic reaction conditions, which leaves scope for further development of new environmentally clean syntheses.
As the increase in environmental consciousness chemical research and industry, 22 the challenge for a sustainable environment calls for clean procedures that can avoid using harmful organic solvents, or even better, do not need solvent at all.In continuation of our interest in green chemistry, 23 we herein wish to report the neat reaction of 2-aminopyridine with α-haloketones under catalyst-and solvent-free conditions, affording imidazo[1,2-a]pyridine derivatives in good to excellent yields.

Results and Discussion
To optimize the reaction conditions, initial studies were concentrated on reactions of the α-bromoacetophenone with 2-aminopyridine as a model reaction.After careful screening, to our delight, the reaction occurred for 20 min affording 2-phenylimidazo[1,2-a]pyridine (3a) in 91% yield at 60 o C in the absence of catalyst and solvent (Table 1, entry 11).It was observed that the mixture was initially in a solid state, and then turned to liquid state during the process of stirring, finally solidified to a light yellow solid mass.
Encouraged by this result, we further carried out comparative reactions to optimize the reaction conditions.The results are summarized in Table 1.When the reaction was carried out at room temperature in the absence of catalyst and solvent, only 65% yield was obtained, even when the reaction time was prolonged to 24 h (  1, entries 7-10).It is remarkable that the reaction carried out at 60 o C in the absence of catalyst and solvent afforded 3a in excellent yield (91%), which is significantly higher than those obtained for the nonpolar or polar solvents.The structure of 3a was characterized by 1 H NMR, 13 C NMR, IR and by comparison with authentic samples prepared by literature procedure.The 1 H NMR spectra of 3a shows a characteristic peak at d 7.87 ppm corresponding to the hydrogen of imidazole ring, whereas in the 13 C NMR spectrum, the peak appearing of d 108.1, 145.7 and 145.8 ppm corresponds to C-3, C-2 and C-9, respectively, of the imidazole ring.And in the IR spectrum, the structure of 3a showed C=N stretching peak at 1625 cm -1 .
With the optimized conditions in hand, the reactions of different 2-aminopyridines with various α-haloketones were examined to explore the scope and generality of this present protocol for the synthesis of various imidazo[1,2-a] pyridines (Table 2).As expected, the reaction proceeded smoothly with yields ranging from good to excellent and tolerated various functional groups such as chloro, methyl and methoxy groups.
As shown in Table 2, the α-bromoacetophenone with electron-rich functionality as well as electron-poor functionality undergoes condensation reaction with 2-aminopyridine or substituted 2-aminopyridine equally well to afford the corresponding products in good to excellent yields.Even when employing the hindered α-methylphenacyl bromide and 2-aminopyridine or 2-amino-5-methylpyridine, good yields (Table 2, entries 10-11, 70% and 64%, respectively) were also obtained after slightly prolonging the reaction time to 60 min.Nevertheless, 2-aminopyridine with electron-withdrawing substituted group chloro is less nucleophilic and more slowly than electron-neutral or donating analogues.
Encouraged by our success, we screened a few reactions of the commercially available and deactivated α-chloroketone with 2-aminopyridine or 2-amino-5-methylpyridine.To our delight, when employing α-chloroacetophenone and 2-aminopyridine or 2-amino-5-methylpyridine, excellent yields (Table 2, entries 12-13, 83% and 88%, respectively) were obtained after slightly prolonging the reaction time to 80 min and 40 min, respectively.Furthermore, the para-and ortho-substituted 2,2',4'-trichloroacetophenone with 2-aminopyridine or 2-amino-5-methylpyridine also can afford the corresponding products 3l and 3m in 75% and 65% yields, respectively (Table 2, entries 14-15).In summary, we have described a simple, highly efficient, and facile procedure for the synthesis of imidazo[1,2-a] pyridine derivatives from the readily available starting materials.To the best of our knowledge, this is the first report catalyst-free synthesis of imidazo[1,2-a]pyridines in the absence of solvent under mild conditions.The procedure offers simple experimental procedure, short reaction time, catalyst-free, solvent free, low cost, efficient yield and mild reaction conditions, which makes this method a useful and attractive strategy in view of economic and environmental advantages.Currently, studies on the extension of this protocol are ongoing in our laboratory.

Experimental
All reagents were commercial available and used without any purification.Melting points were recorded on Digital Melting Point Apparatus WRS-1B and are uncorrected.IR spectra were recorded on a Bruker-EQUINOX55 spectrometer.Mass spectra (EI, 70 ev) were measured with SHIMADZU GCMS-QP2010 Plus. 1 H NMR and 13 C NMR spectra were recorded on a Brucker AC 300 instrument using CDCl 3 as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature.Chemical shifts were given in d relative to TMS, the coupling constants J are given in Hz.Elemental analysis was determined on a Carlo-Erba 1108 instrument.All reactions were conducted using standard Schlenk techniques.Column chromatography was performed using EM Silica gel 60 (300-400 mesh).

General procedure for the preparation of pyrazoles
A mixture of α-haloketone 2 (1.0 mmol), 2-aminopyridine or substituted 2-aminopyridine 1 (1.0 mmol) was stirred at 60 o C under vigorous magnetic stirring for the specified time as mentioned in Table 2.The progress of the reaction was monitored by TLC.After completion of the reaction, the product was washed with dehydrated alcohol or ethyl acetate (3 × 10 mL).The combined organic solvent was removed under vacuum to obtain the crude solid product.The crude product was further purified by silica gel column chromatography using ethyl acetate-petroleum ether (1:3) as eluent to afford the pure product 3.
The spectral and analytical data of all compounds are given below.

Table 1 .
The condensation of 2-aminopyridine with α-bromoacetophenone under different reaction conditions a b Isolated yield.cThe reaction was carried out at room temperature for 24 h.