Ultrasound-assisted synthesis of imidazo[1,2-a ]pyridines an d sequential one-pot preparation of 3-selanyl-imidazo[1,2-a ]pyridine derivatives

A simple and rapid method to synthesize imidazo[1,2-a ]pyridines starting from 2-aminopyridine and 2-bromoacetophenone derivatives under ultrasonic irradiation was developed. This protocol tolerates a wide range of 2-bromoacetophenone derivatives to produce a variety of imidazo[1,2-a ]pyridines in good to excellent yields. Additionally, the one-pot preparation of 3-(organylselanyl)imidazo[1,2-a ]pyridines via a sequential method is presented. In this case, different diorganyl diselenides were used as starting materials to afford the corresponding coupling products in excellent yields and short reaction times under sonication. The reactions were conducted in PEG-400, a cheap and nontoxic solvent, compatible with the ultrasound conditions in an environmentally benign process


Introduction
N-Heterocycles are structures found in natural and synthetic organic compounds relevant in many chemical and biological aspects. 1 Among them, the imidazo [1,2-a]pyridines are one of the most studied class of heterocycles, due to their therapeutic use as antiviral, 2 antituberculotic, 3 antibacterial, 4 antipsychotic 5 and antitumor agents. 6,7In this way, the imidazo [1,2-a]pyridine scaffold is present in several established leading drugs, such as Alpidem, Necopidem, Olprinone, Saripidem, Zolimidine and Zolpidem.
Selenium-containing heterocycles are relevant in biochemical and pharmacological processes since several organoselenium compounds are known to exhibit interesting biological properties. 25,26Moreover, many organoselenium compounds have been used in a wide spectrum of organic reactions as precursors in the construction of functional materials. 27,284][35][36][37] Reactions promoted by ultrasound are faster due to the turbulent flow of the liquid phase caused by the cavitation, which enhances the mass transfer in heterogeneous systems. 38,39In this sense, due to our interest in the development of green procedures for the synthesis of biologically active organochalcogen-containing N-heterocycles, 18,29,31,32,40,41 we describe here the ultrasound-promoted syntheses of imidazo[1,2-a]pyridines and 3-selanyl-imidazo [1,2-a]pyridines via a sequential one-pot reaction.

Results and Discussion
The initial experiments to optimize the reaction conditions were performed using 2-aminopyridine 1 and 2-bromoacetophenone 2a as model substrates to establish the best reaction conditions to prepare 2-phenylimidazo[1,2-a]pyridine 3a under ultrasound irradiation.In this study we have evaluated the influence of different bases and solvents, as well as the reaction time, as described in Table 1.
Aiming to check the necessity of base, a base-free reaction was performed, but in this case, only 39% yield of the expected product 3a was obtained after 30 min (Table 1, entry 5).From this point, a screening through different bases was conducted (Table 1, entries 6-12), which revealed that K2CO3 was superior under the ultrasound conditions (entry 7).An improvement in the reaction yield was achieved when the amount of K2CO3 was raised from 1.0 to 1.5 equiv, giving 3a in 92% yield (Table 1, entry 14).To our delight, when the reaction was sonicated for only 15 min, a similar yield of 3a was obtained (94%), proving that the efficient energy-transfer by the ultrasonic irradiation can promote a fast reaction.Next, with the best reaction conditions found, the substrate scope was evaluated with respect to differently substituted 2-bromoacetotophenones 2a-h.These reactions led to the corresponding imidazo[1,2a]pyridines 3a-h (Table 2).
An inspection in the results of Table 2 shows that the expected imidazo[1,2-a]pyridines 3a-h were obtained in good to excellent yields at reaction times no longer than 30 min.It can also be observed that the presence of electron-withdrawing or electron-releasing groups directly attached to the aryl moiety of the acetophenone does not affect significantly the reactivity of the carbonyl group.However, electron-poor starting acetophenones seems to be less reactive compared to the electron-rich ones (Table 2, entries 2-8).a Reactions were performed using 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1.5 equiv, 0.75 mmol) in PEG-400 (1 mL) under ultrasonic irradiation (60% of amplitude).b Number in parenthesis refers to the reaction using 2 equiv of 1 (1.0 mmol).
For example, the presence of fluorine or nitro groups in the phenyl ring of the 2-bromoacetophenones 2c (R = 4-F) and 2e (R = 4-NO2), negatively influenced the reaction, and the respective products 3c and 3e were obtained in 70% and 55% yields (Table 2, entries 3 and 5).A similar decrease in reactivity was observed starting from the electron-rich 2-bromo-4'-methoxyacetophenone (2g, R = 4-OMe), and the expected product 3g was isolated in 67% yield using the optimal conditions.Fortunately, better yields were obtained from these recalcitrant ketones when an excess of 2-aminopyridine 1 (2 equiv) was used, raising the yields of 3c, 3e and 3g to 88%, 80% and 90%, respectively, while reducing the reaction time to 15 min in the case of 3c (Table 2, values in parenthesis).Notably, these reactions do not suffer from steric effects of the substituents at 2bromoacetophenone counterpart 2. For instance, the reactions using the sterically constrained 2-bromo-1-(2chlorophenyl)ethan-1-one 2d and 2-bromo-1-(2-methoxyphenyl)ethan-1-one 2h, afforded the corresponding products 3d and 3h in 79% and 98% yields, which are close to those obtained starting from the unsubstituted 2-bromoacetophenone 2a (Table 2, entries 4 and 8).The possibility of obtaining chloro-substituted imidazo-[1,2-a]pyridines 3b and 3d is noteworthy, once it allows the possibility of future reactions like TM-catalyzed couplings.
0][31][32] In this line, the development of alternative, green methods based in ultrasound synthesis of organochalcogen-containing Nheterocycles under non-conventional reaction media is an interesting field of research, in consideration of economic, environmental and health issues. 42Still, the growing interest in these compounds as promising new drugs, functional materials, catalysts and synthetic intermediates collaborate to reinforce the importance of this class of compounds. 25,26Thus, to extend the application of our US-assisted protocol, we decided to study the possibility of performing an one-pot sequential direct selanylation reaction of the pre-formed imidazo[1,2a]pyridines 3, aiming to prepare selanylimidazopyridines 5 (Table 3).We started our investigations using the reaction to form imidazo[1,2-a]pyridine 3a (Table 2, entry 1), with diphenyl diselenide 4a as the selenylating species.After the preformation of 3a (15 min under sonication), diphenyl diselenide 4a (0.6 equiv) and the catalyst were added in the same vessel, without isolation of 3a, and the sonication was continued for additional 2 h (Table 3).Reactions were performed using initially 1 (0.5 mmol), 2a (0.5 mmol), K2CO3 (0.75 mmol, 1.5 equiv.) in PEG-400 (1.0 mL) under ultrasonic irradiation (60% of amplitude) for 15 min.After that, in the same vessel, 4a (0.3 mmol) and the additive were added.The ultrasonic irradiation was continued for additional 2 h.b Yield is given for isolated product after the sequential two step one-pot procedure.c An additional 1 equiv (0.5 mmol) of K2CO3 was added with the diselenide 4a.d At the end of the reaction, 3a and 4a were recovered.NR = no reaction.
Initially, the reaction was tested just by adding PhSeSePh 4a and an additional amount of base (K2CO3; 0.5 mmol) in the reaction vessel containing the preformed imidazo[1,2-a]pyridine 3a.Unfortunately, none of the expected product 5a was obtained after 2 h of sonication and the imidazo[1,2-a]pyridine 3a and diselenide 4a were recovered (Table 3, entry 1).Then, we decided to investigate the influence of different well-known reagents able to produce in situ electrophilic selenium species such as NBS, FeCl3, I2, KI and copper salts (Table 3, entries 2-7).Analysis of the preliminary reactions showed that moderate to excellent yields of the expected product 5a were obtained under US in PEG-400.Remarkably, when the reaction was carried out using a mixture of KI/CuSO4 (2/2 equiv), the expected 5a was obtained in 95% yield after 2 h (Table 3, entry 7).In order to evaluate the optimal amount of KI/CuSO4, a reaction was conducted using 1 equiv of this mixture of salts.However, the yield of 5a was dramatically reduced to 41% (Table 3, entry 8).When the reaction was performed using only KI, consumption of the starting materials was not observed (Table 3, entry 9), while using CuSO4 alone produced only 38% yield of product 5a (Table 3, entry 10).Thus, the best conditions in the one-pot reaction to prepare 3-phenylselanyl-imidazo[1,2-a]pyridine 5a requires sonication of a mixture of the preformed imidazo[1,2-a]pyridine 3a in PEG-400 with diphenyl diselenide 4a (0.6 equiv) in the presence of KI/CuSO4 (2 equiv) for 2 h (Table 3, entry 7).
We evaluated the scope of the reaction regarding to a range of imidazo[1,2-a]pyridines 3, prepared in situ from different 2-bromoacetophenone derivatives 2. It was observed that the reaction is very sensitive to steric effects due to substituents in the 2-bromoacetophenone counterpart 2. This low reactivity was not observed in the synthesis of the respective imidazo[1,2-a]pyridines 3d (R = 2-Cl) and 3h (R = 2-OMe); therefore it cannot be attributed to this step of the one-pot synthesis.For instance, the ortho-chloro-substituted acetophenone 2d gave only 5% yield of the expected product 5k, while the reaction using ortho-methoxy derivative 2h failed completely (Table 4, entries 11 and 15).The presence of electron-withdrawing group at the para-position in the phenyl ring of the 2-bromoacetophenone negatively affects the reaction, and products 5i (R = 4-Cl), 5j (R = 4-F) and 5l (R = 4-NO2) were obtained in 54%, 57% and 49% yields, respectively (Table 4, entries 9, 10 and 12).These yields are slightly lower than those observed for 2-bromoacetophenone derivatives 2f (R = 4-CH3) and 2g (R = 4-OMe), which afforded the respective selenylated products 5m and 5n in 72% and 70% yields (Table 4, entries 13 and 14).Besides the diorganyl diselenides 4, some reactions were also conducted using diphenyl disulfide 6 and diphenyl ditelluride 7 as chalcogen sources.Diphenyl disulfide 6 led to the formation of 3phenylsulfanyl-imidazo[1,2-a]pyridine 5p in 54% yield.The ditelluride analogue 7, however, did not react under the optimal reaction conditions (Table 4, entries 16 and 17).Interesting, the reactions to obtain products 5c and 5n were interrupted after 1 h of sonication, once it was observed decomposition of the products after a longer reaction time (Table 4, entries 3 and 14).
To investigate the possible mechanism involved in this reaction, some control experiments were performed, as depicted in Scheme 2. In order to rule out the hypothesis that the reaction could proceed through a radical mechanism, we performed the reaction under the standard conditions but in the presence of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (Scheme 2-A).After 2 h of reaction, the product 5a was obtained in 92% yield, hinting that a radical pathway is not involved in the reaction.In addition, and according to the conditions described by Brotherton and coworkers, 43 KI is believed to react with CuSO4 to generate K2SO4 and CuI2.Copper(II) iodide is very unstable and disproportionates to CuI and I2 (Scheme 2-B).We believe that these transformations could be happening in a similar way under the sonication process.Plausibly, both iodine and copper(I) iodide could be responsible for generate electrophilic species of selenium, as demonstrated by the results from Table 3, entries 4 and 6.Following, two additional control reactions were performed to investigate the possible formation of R 2 Se-X (X = halogen) in the reaction medium and the influence of the generated copper salts in the reactivity (Scheme 2-C).Firstly, the commercially available phenylselanyl bromide 8 was used instead of PhSeSePh/CuSO4/KI under the standard US conditions, giving the product 5a in 82% yield.Then, to investigate the possible participation of the copper salts present in the reaction media, CuBr was joined to the reagents.After 2 h of sonication, the reaction exhibited virtually the same efficiency, indicating that the halogenated species of selenium (Scheme 3, intermediate B) is the main active selenium species in the present protocol.

Scheme 2. Control experiments.
In this way, according to the results obtained and with the support of the literature, we can propose the following mechanism for the formation of the selenylated product 5 by the one-pot reaction (Scheme 3).Initially, 2-aminopyridine 1 nucleophilicaly attacks 2-bromoacetophenone 2 to generate the pyridinium intermediate A. Then, intermediate A undergoes an intramolecular attack of the NH2 to produce imidazo[1,2a]pyridine 3, with water release.In the next step, molecular iodine, formed in the medium, 43,44

Conclusions
In conclusion, a series of imidazo[1,2-a]pyridines were synthesized via ultrasound-mediated reaction of 2aminopyridine with 2-bromoacetophenone derivatives.This strategy was efficiently extended to the one-pot synthesis of 3-selanylimidazo[1,2-a]pyridines, by the reaction of imidazo[1,2-a]pyridines formed in situ with diorganyl diselenide in the presence of copper(II) sulfate/potassium iodide under sonication.The advantages in using ultrasound include short reaction times, mild reaction conditions and ease of operation.All the reactions were conducted in air atmosphere using PEG-400 as a non-toxic and environmentally benign solvent.

Experimental Section
General.Reactions were monitored by TLC which was carried out on Merck silica gel (60 F254) by using UV light as visualizing agent and 5% vanillin in 10% H2SO4 and heat as developing agents.Column chromatography was performed using silica gel (70-230 mesh).Proton nuclear magnetic resonance spectra ( 1 H NMR) were obtained at 400 MHz on Bruker DPX 400 spectrometer.Spectra were recorded in CDCl3 and CDCl3/DMSO-d6 solutions.Chemical shifts are reported in ppm, referenced to tetramethylsilane (TMS) as the external reference.Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), double doublet (dd), double triplet (dt) and multiplet (m).Coupling constants (J) are reported in Hertz.Carbon-13 nuclear magnetic resonance spectra ( 13 C NMR) were obtained at 100 MHz on a Bruker DPX 400 spectrometer.Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl3.Low-resolution mass spectra (MS) were obtained with a Shimadzu GC-MS-QP2010P mass spectrometer.GC analysis were conducted on a RESTEC RTX-5MS capillary column (30 m, 0.25 mm id, 0.25 µm film thickness) using the products dissolved in ethyl acetate with the following conditions: Injected sample volume was 1.0 µL; He constant flow, 54.1 mL/min; initial inlet temperature, 40 °C ramped to 72 °C at 10 °C/min followed by a 5 °C/min ramp to 100 °C (held for 10 min) and 10 °C/min to 280 °C and held for 20 min (total run time: 56.8 min).The ultrasound-promoted reactions were performed using a Cole Parmer-ultrasonic processor Model CPX 130, with a maximum power of 130 W, operating at amplitude of 60% and a frequency of 20 kHz.The temperature of the reaction under US was monitored using an Incoterm digital infrared thermometer Model Infraterm (Brazil).High-resolution mass spectra (HRMS) were obtained for all compounds on a LTQ Orbitrap Discovery mass spectrometer (Thermo Fisher Scientific).This hybrid system meets the LTQ XL linear ion trap mass spectrometer and an Orbitrap mass analyzer.The experiments were performed via direct infusion of sample (flow: 10 μL/min) in the positive-ion mode using electrospray ionization.Elemental composition calculations for comparison were executed using the specific tool included in the Qual Browser module of Xcalibur (Thermo Fisher Scientific, release 2.0.7)software.Melting point (mp) values were measured in a Marte PFD III instrument with a 0.1 o C precision.
General procedure for the synthesis 2-arylimidazo[1,2-a]pyridines 3a-h.To a 10 mL vial was added a mixture of 2-aminopyridine 1 (0.5 mmol), 2-bromoacetophenone derivative 2 (0.5 mmol) and K2CO3 (0.103 g, 0.75 mmol) in PEG-400 (1 mL).Then, the ultrasonic probe was introduced in the flask and the mixture was sonicated at 20 kHz and 60% of amplitude.The progress of the reaction was monitored by TLC and after the time indicated in Table 2, the reaction mixture was received in water (10 mL), extracted with ethyl acetate (3 x 5 mL), dried over MgSO4 and concentrated under vacuum.The residue was purified by column chromatography using silica gel and a mixture of ethyl acetate/hexanes as the eluent.

Table 1 .
Optimization of the reaction conditions to prepare imidazo[1,2-a]pyridine 3a a b Reaction performed for 15 min.NR = No Reaction