Acessibilidade / Reportar erro

Imidazo[1,2-a]pyridine A3-Coupling Catalyzed by a Cu/SiO2 Material

Abstract

In this work, we report the preparation of a copper-silica material (Cu/SiO2) by a sol-gel methodology and its characterization concerning composition and textural properties. The Cu/SiO2 material was successfully applied as a Lewis acid heterogeneous catalyst for the A3-coupling from 2-aminopyridine, aldehydes and alkynes to imidazo[1,2-a]pyridines (45-82%), which are relevant pharmacological scaffolds. The synthesis shows a number of advantages, such as easy separation from the reaction media and the minimal formation of metal aqueous wastes. Investigation of the mechanism supports the involvement of the formation of reaction intermediates inside the pores of the mesoporous material prior to 5-exo-dig cyclization.

Keywords:
imidazo[1,2-a]pyridines; heterogeneous catalyst; A3-coupling reaction


Introduction

Imidazo[1,2-a]pyridine derivatives are known for their wide range of applications in pharmaceutics as a result of their biological properties, including antiviral, antibacterial, antifungal, antiprotozoal and anti-inflammatory activities.11 Devi, N.; Singh, D.; Rawal, R. K.; Bariwal, J.; Singh, V.; Curr. Top. Med. Chem. 2016, 16, 2963.

2 Guieffier, C.-E.; Guieffier, A.; Mini-Rev. Med. Chem. 2007, 7, 888.

3 Gudmundsson, K. S.; Williams, J. D.; Drach, J. C.; Townsend, L. B.; J. Med. Chem. 2003, 46, 1449.
-44 Puerstinger, G.; Paeshuyse, J.; Declercq, E.; Neyts, J.; Bioorg. Med. Chem. Lett. 2007, 17, 390. These heterocycles are also known as gamma-aminobutyric acid (GABA) and benzodiazepine receptor agonists.55 Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.; Hallett, D.; Marchant, K. J.; Thomas, S. R.; Bioorg. Med. Chem. Lett. 2006, 16, 1518.,66 Fookes, C. J. R.; Pham, T. Q.; Mattner, F.; Greguric, I.; Loch, C.; Liu, X.; Berghofer, P.; Shepherd, R.; Gregoire, M.-C.; Katsifis, A.; J. Med. Chem. 2008, 51, 3700. Some of them are well-known commercialized drugs with sedative, anti-hypnotic and anti-psychotic effects, such as Alpidem, Zolpidem and Olprinone.77 Deep, A.; Bhatia, R. K.; Kaur, R.; Kumar, S.; Jain, U. K.; Singh, H.; Batra, S.; Kaushik, D.; Deb, P. K.; Curr. Top. Med. Chem. 2017, 17, 238. Recent investigations showed that imidazo[1,2-a]pyridines are promising drug candidates in cancer treatment.88 Goel, R.; Luxami, V.; Paul, K.; Curr. Top. Med. Chem. 2016, 16, 3590.,99 Liu, T.-C.; Peng, X.; Ma, Y.-C.; Ji, Y.-C.; Chen, D.-Q.; Zheng, M.-Y.; Zhao, D.-M.; Cheng, M. S.; Geng, M.-Y.; Shen, J.-K.; Ai, J.; Xiong, B.; Acta Pharmacol. Sin. 2016, 5, 698. The photophysical properties of these heterocyclic scaffolds have also been investigated1010 Velázquez-Olvera, S.; Salgado-Zamora, H.; Velázquez-Ponce, M.; Campos-Aldrete, E.; Reyes-Arellano, A.; Pérez-González, C.; Chem. Cent. J. 2012, 6, DOI: 10.1186/1752-153X-6-83.
https://doi.org/10.1186/1752-153X-6-83...

11 Firmansyah, D.; Ciuciu, A. L.; Hugues, V.; Blanchard-Desce, M.; Flamigni, L.; Gryko, D. T.; Chem. - Asian J. 2013, 8, 1279.
-1212 Pordel, M.; Chegini, H.; Ramezani, S.; Daee, M.; J. Mol. Struct. 2017, 1129, 105. and their potential as fluorescent probes1313 Leopoldo, M.; Lacivita, E.; Passafiume, E.; Contino, M.; Colabufo, N. A.; Berardi, F.; Perrone, R.; J. Med. Chem. 2007, 50, 5043. and fluorescent metal sensors has been explored.1414 Xiao, S.; Liu, Z.; Zhao, J.; Pei, M.; Zhang, G.; He, W.; RSC Adv. 2016, 6, 27119.

Alternatively, different copper species have received considerable attention as catalysts for different kinds of organic transformations involving alkynes, such as homocoupling (Glaser-Hay coupling),1515 Jia, X.; Yin, K.; Li, C.; Li, J.; Bian, H.; Green Chem. 2011, 13, 2175.

16 van Gelderen, L.; Rothenberg, G.; Roberto, C. V.; Wilson, K.; Raveendran, S. N.; Appl. Organomet. Chem. 2013, 27, 23.

17 Kuhn, P.; Alix, A.; Kumarraja, M.; Louis, B.; Pale, P.; Sommer, J.; Eur. J. Org. Chem. 2009, 423.
-1818 Alonso, F.; Melkonian, T.; Moglie, Y.; Yus, M.; Eur. J. Org. Chem. 2011, 2524. Huisgen 1,3-dipolar CuI-catalyzed alkyne-azide cycloaddition,1919 Yamaguchi, K.; Oishi, T.; Katayama, T.; Mizuno, N.; Chem. - Eur. J. 2009, 15, 10464.

20 Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V.; J. Am. Chem. Soc. 2005, 127, 210.

21 Worell, B. T.; Malik, J. A.; Fokin, V. V.; Science 2013, 340, 457.

22 Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.; Angew. Chem., Int. Ed. 2002, 41, 2596.
-2323 Buckley, B. R.; Figueres, M. M. P.; Khan, A. N.; Heaney, H.; Synlett 2016, 27, 51. Diels-Alder cycloadditions2424 Reymond, S.; Cossy, J.; Chem. Rev. 2008, 108, 5359.,2525 . Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P.; J. Am. Chem. Soc. 1999, 121, 7559. and Sonogashira cross coupling.2626 Thomas, A. M.; Sujatha, A.; Anilkumar, G.; RSC Adv. 2014, 4, 21688.

27 Gallop, C. W. D.; Chen, M.-T.; Navarro, O.; Org. Lett. 2014, 16, 3724.

28 Yan, H.; Wang, Y.; Pan, C.; Zhang, H.; Yang, S.; Ren, X.; Li, J.; Huang, G.; Eur. J. Org. Chem. 2014, 2754.
-2929 Santra, S.; Mitra, S.; Bagdi, A. K.; Majee, A.; Hajra, A.; Tetrahedron Lett. 2014, 55, 5151. CuI salts were successfully applied as catalysts in the synthesis of imidazopyridines from aminopyridine and nitroolefines.3030 Yan, R. L.; Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M.; J. Org. Chem. 2012, 77, 2024. Other cyclization methods from aminopyridines involve the combination of CuI and PdII salts, as well as CuI and InIII under aerobic conditions.3131 Zhang, Y.; Chen, Z.; Wu, W.; Zhang, Y.; Su, W.; J. Org. Chem. 2013, 78, 12494. Some methods explore the use of CuI and ligands, such as bipyridine.3232 Cao, H.; Liu, X.; Liaou, J.; Huang, J.; Qiu, H.; Chen, Q.; Chen, Y.; J. Org. Chem. 2014, 79, 11209.

Among the several methods for the synthesis of imidazo[1,2-a]pyridines,3333 Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A.; Chem. Commun. 2015, 51, 1555. the multicomponent reaction between 2-aminopyridine, aldehyde and alkyne (A3-coupling) has received considerable attention as a straight route to products with a wide scope of substituents, with the advantages of atom economy, lower toxic waste generation and an environmental friendly method. In this context, a very mild methodology using a single catalyst as the active specie was published using iodine in water while the use of indium bromide as Lewis acid catalyst requires the presence of triethylamine as additive and molecular sieves yielding a series of substituted imidazo[1,2-a]pyridines.3434 Siddiqui, I. R.; Rahila, P. R.; Srivastava, A.; Shamin, S.; Tetrahedron Lett. 2014, 55, 1159.,3535 Reddy, B. V. S.; Reddy, P. S.; Reddy, Y. J.; Yadav, J. S.; Tetrahedron Lett. 2011, 52, 5789. One report shows a very clean solvent and catalyst-free synthesis of imidazo[1,2-a]pyridines from 2-aminopyridine and a-bromoacetophenone.3636 Zhu, D.-J.; Chen, J.-X.; Liu, M.-C.; Ding, J.-C.; Wu, H.-Y.; J. Braz. Chem. Soc. 2009, 20, 482. Copper(II) salts were also proven useful on intramolecular oxidative cyclization from haloalkynes and 2-aminopyridines.3737 Gao, Y.; Yin, M.; Wu, W.; Huang, H.; Jiang, H.; Adv. Synth. Catal. 2013, 355, 2263.

Catalysis of copper sulfate in the presence of p-toluenesulfonic acid (10 mol%) leads to moderate to good yields in three and two-component approaches and similar results were observed using a mixture of copper iodide and copper triflate.3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.,3939 Palano, T.; Park, K.; Kumar, M. R.; Jung, H. M.; Lee, S.; Eur. J. Org. Chem. 2012, 5038. Cherniak and Gevorgyan4040 Cherniak, N.; Gevorgyan, V.; Angew. Chem., Int. Ed. 2010, 49, 2743. described the use of binary CuI and CuII catalysts in toluene at high temperature. A mixture of CuI-CuII generated in situ from CuSO4 and glucose was shown to be a useful method for the 5-exo-dig cycloisomerization.4141 Guchhait, S. K.; Chandgude, A. L.; Priyadarshani, G.; J. Org. Chem. 2012, 77, 4438. Also, glucose was found an applicable additive for reactions catalyzed by copper oxide/alumina in heterogeneous strategies.4242 Balijapalli, U.; Iyer, S. K.; Dyes Pigm. 2015, 121, 88.

It is noteworthy that Mishra and Ghosh4343 Mishra, S.; Ghosh, R.; Synthesis 2011, 21, 3463. reported the use of CuI and NaHSO4.SiO2 as binary catalysts, a semi-heterogeneous approach.They have also proved the necessity of both Lewis and Brϕnsted acids in the reaction media to efficiently perform cycloisomerization. Another report by Corma and co-workers4444 Luz, I.; Xamena, F. X. L.; Corma, A.; J. Catal. 2012, 285, 285. shows the ability of CuII-MOF (MOF: metal-organic framework) on catalyzing the same reaction by a combination of the adsorbed Lewis acid on a microporous and flexible framework. The use of other copper-MOF has shown efficiency on catalyzing imidazo[1,2-a]pyridines synthesis although the preparation of the catalysts usually involves harsh conditions.4545 Gupta, A. K.; De, D.; Katoch, R.; Garg, A.; Bharadwaj, P. K.; Inorg. Chem. 2017, 56, 4697. Recently, copper and porphyrin-MOF derivatives were successfully applied on the synthesis of imidazo[1,2-a]pyridines, however a copper solution must be periodically replaced for zinc exchange on catalyst preparation.4646 Dutta, G.; Jana, A. K.; Natarajan. S.; Chem. - Asian J. 2018, 13, 66. In this context the use of small amounts of copper nanoparticles where also successful, but they suffer of several steps for preparation or low stability for storage.4747 Hussain, N.; Gogoi, P.; Das, M. R.; Sengupta, P.; Fedorov, V. E.; Asanov, I. P.; Kozlova, M. N.; Artemkina, S. B.; Appl. Catal., A 2017, 542, 368.,4848 Zong, C.; Zeng, R.; Zou, J.; Chem. Res. Chin. Univ. 2014, 30, 632. Superparamagnetic iron-copper nanoparticles leads to higher yields of imidazo[1,2-a]pyridines (75-95%), but the catalyst preparation involves the use of very high range of temperature (500-900 ºC) and they also require the use of euthetic mixture citric acid-dimethyl urea which favors the imine intermediate formation.4949 Lu, J.; Li, X.-T.; Ma, E.-Q.; Mo, L.-P.; Zhang, Z.-H.; ChemCatChem 2014, 6, 2854. In addition to copper, other publications5050 Maleki, A.; Helv. Chim. Acta 2014, 97, 587.

51 Tajbakhsh, M.; Farhang, M.; Hosseinzadeh, R.; Sarrafi, Y.; RSC Adv. 2014, 5, 23116.
-5252 Guntreddi, T.; Allam, B. K.; Singh, K. N.; Synlett 2012, 23, 2635. have reported the use of heterogeneous magnetic nanoparticles of Fe3O4, which are easily recovered and recycled from the reaction media. More recently, a synthesis at mild conditions, involving CuCl2/nano-TiO2 as the catalyst in the reaction between 2-aminopyridines and unactivated ketones, was also described.5353 Meng, X.; Wang, Y.; Yu, C.; Zhao, P.; RSC Adv. 2014, 4, 27301.

Metal/silica materials were employed as catalysts in the synthesis of other types of heterocycles in multicomponent reactions and they have shown advantages such as easy preparation, easy handling and the possibility of recovery. These materials are often prepared by a sol-gel method from an organosilyl precursor in the presence of metal salts.5454 Hench, L. L.; West, J. K.; Chem. Rev. 1990, 90, 33.,5555 Benvenutti, E. V.; Moro, C. C.; Costa, T. M. H.; Quim. Nova 2009, 32, 1926. In/SiO2 was applied as a heterogeneous catalyst in a Hantzsch 1,4-dihydropyridine multicomponent synthesis.5656 Affeldt, R. F.; Benvenutti, E. V.; Russowsky, D.; New J. Chem. 2012, 36, 1502. Later, the same material was employed and successfully recycled in A3-coupling, leading to propargylamines.5757 da Silva, T. L.; Rambo, R. S.; Rampon, D. S.; Radatz, C. S.; Benvenutti, E. V.; Russowsky, D.; Schneider, P. H.; J. Mol. Catal. A: Chem. 2015, 399, 71. Alternatively, a cheaper Cu/SiO2 material was described and employed in a Biginelli 3,4-dihydropyrimidinone multicomponent synthesis by Russowsky et al.5858 Russowsky, D.; Benvenutti, E. V.; Roxo, G. S.; Grasel, F.; Lett. Org. Chem. 2007, 4, 39.,5959 Radatz, C. S.; Soares, L. A.; Vieira, E. R.; Alves, D.; Russowsky, D.; Schneider, P. H.; New J. Chem. 2014, 38, 1410. and more recently, in a 1,2,3-triazole synthesis by click chemistry. In this work, we prepared and characterized a Cu/SiO2 material with different conditions by sol-gel method and investigated their application as heterogeneous catalysts in the A3-coupling reaction to produce different substituted imidazo[1,2-a]pyridines, without using additives.

Experimental

General experimental methods

1H and 13C nuclear magnetic resonance (NMR) spectra in CDCl3 were recorded on Varian or Bruker 400 MHz and 100 MHz respectively, using tetramethylsilane (TMS) as internal standard. Chemical shifts (d) are expressed in parts per million referenced to the residual solvent (i.e., 1H 7.27, 13C 77.16 ppm for CDCl3). Signal multiplicity is expressed as follows: s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), dt (doublet of triplet), td (triplet of doublet). J values are given in hertz (Hz). For novel compounds, the high-resolution mass spectrometry (HRMS) measurement, Bruker Daltonics Micro-TOF instrument was used in electrospray ionization (ESI) mode. All reactions and purity of the synthesized compounds were monitored by thin-layer chromatography (TLC) using silica gel 60 F254 aluminium plates. Visualization was accomplished by UV light, exposure to iodine vapor and by treating the plates with vaniline followed by heating. Unless otherwise indicated, materials and solvents were purchased and used without further purification. The images of Cu/SiO2 materials were obtained using scanning electron microscopy (SEM) on a JEOL microscope (JSM 5800) connected to a secondary electron detector and energy dispersive X-ray spectroscopy (EDS), performed with Cu/SiO2 dispersed on a doubled-faced conducting tape on a stainless steel support and coated with gold using Bal-Tec SCD050 Sputter-Coater apparatus. The N2 adsorption-desorption isotherms of Cu/SiO2 materials were determined at liquid-nitrogen boiling point, using Tristar II Krypton 3020 Micromeritics equipment. The materials were previously degassed at 120 ºC under vacuum for 10 h. The specific surface areas were determined by the Brunauer-Emmett-Teller (BET) multipoint technique and the pore size distribution curves were obtained by using the Barrett-Joyner-Halenda (BJH) and density functional theory (DFT) methods.

General procedure for the synthesis of Cu/SiO2 material 2

In a vial flask adapted with a magnetic bar were added 5 mL of ethanol, 2 mL of deionized water and 1 drop (circa 50 mL) of hydrofluoric acid. Then, it was added CuCl2 (1.2 mmol, 0.150 g) and the solution stirred until complete homogenization. The mixture was poured onto tetraethyl orthosilicate (TEOS, 22.4 mmol, 5.0 mL), stirred until complete homogenization and after the formation of a translucid glassy material (gelation), the vial was closed and kept under heating (40 ºC) for 7 days. After this time, the vial cap was removed and kept under mild heating (30 ºC) for more 7 days for slow solvent evaporation. The solid was then removed from the vial, powdered and treated at high temperature (300 ºC) for 4 h while during this process the material color change from green to dark brown. After cooling, the green powder was washed with distilled water (3 × 20 mL) and ethanol (20 mL) and then dried at 100 ºC for 24 h.

General procedure for the A3-coupling to substituted imidazo[1,2-a]pyridines

In a Schlenk tube under inert atmosphere were added 2-aminopyridine (1.1 mmol, 0.112 g), aldehyde (1.0 mmol), Cu/SiO2 (10 mol%), terminal alkyne (1.5 mmol) and toluene (0.5 mL). The mixture was heated to 120 ºC and stirred for 48 h. The mixture was then filtered and the solvent removed under vacuum and the crude product was purified by column chromatography with hexanes, ethyl acetate and triethylamine (84:10:4) as eluent.

3-Benzyl-2-phenylimidazo[1,2-a]pyridine (4a)3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.

Yield 68% (193.3 mg); 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J 7.4 Hz, 2H), 7.67 (d, J 8.7 Hz, 2H), 7.42 (t, J 7.5 Hz, 2H), 7.36-7.20 (m, 4H), 7.18-7.10 (m, 3H), 6.67 (t, J 6.9 Hz, 1H), 4.48 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 144.8, 144.1, 136.7, 134.5, 128.9, 128.5, 128.1, 127.6, 126.8, 124.0, 123.3, 117.6, 117.5, 112.1, 29.8.

3-Benzyl-2-(2-methoxyphenyl)imidazo[1,2-a]pyridine (4b)3535 Reddy, B. V. S.; Reddy, P. S.; Reddy, Y. J.; Yadav, J. S.; Tetrahedron Lett. 2011, 52, 5789.

Yield 64% (201.2 mg); 1H NMR (400 MHz, CDCl3) δ 7.67-7.61 (m, 3H), 7.35 (td, J 8.3, 1.8 Hz, 1H), 7.26-7.17 (m, 3H), 7.15-7.10 (m, 3H), 7.05 (td, J 7.5, 0.8 Hz, 1H), 6.95 (d, J 8.2 Hz, 1H), 6.65 (td, J 6.8, 1.0 Hz, 1H), 4.28 (s, 2H), 3.61 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 157.1, 144.9, 141.6, 137.4, 132.3, 129.5, 128.7, 128.1, 126.5, 123.8, 123.6, 120.8, 119.7, 117.7, 111.9, 110.9, 55.2, 30.3.

3-Benzyl-2-(3-methoxyphenyl)imidazo[1,2-a]pyridine (4c)4949 Lu, J.; Li, X.-T.; Ma, E.-Q.; Mo, L.-P.; Zhang, Z.-H.; ChemCatChem 2014, 6, 2854.

Yield 81% (254.7 mg); 1H NMR (400 MHz, CDCl3) δ 7.71-7.65 (m, 2H), 7.38-7.19 (m, 6H), 7.18-7.10 (m, 3H), 6.93-6.87 (m, 1H), 6.68 (t, J 6.8 Hz, 1H), 4.48 (s, 2H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) d159.9, 144.9, 143.9, 136.0, 129.5, 129.0, 127.7, 127.0, 124.2, 123.4, 120.6, 117.9, 117.6, 114.1, 113.3, 112.3, 55.3, 29.9.

3-Benzyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (4d)3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.

Yield 72% (226.4 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J 8.7 Hz, 2H), 7.67-7.60 (m, 2H), 7.35-7.20 (m, 3H), 7.18-7.07 (m, 2H), 6.96 (d, J 8.7 Hz, 2H), 6.66 (td, J 6.8, 2.2 Hz, 1H), 4.45 (s, 2H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) d159.3, 144.8, 144.0, 136.9, 129.3, 129.0, 127.7, 127.1, 126.8, 123.9, 123.2, 117.3, 117.0, 114.1, 112.0, 55.3, 29.9.

3-Benzyl-2-(2-fluorophenyl)imidazo[1,2-a]pyridine (4e)4848 Zong, C.; Zeng, R.; Zou, J.; Chem. Res. Chin. Univ. 2014, 30, 632.

Yield 78% (236.0 mg); 1H NMR (400 MHz, CDCl3) d7.73 (td, J 7.5, 1.8 Hz, 1H), 7.69-7.62 (m, 2H), 7.34 (m, 1H), 7.28-7.05 (m, 8H), 6.65 (dt, J 6.6, 3.3 Hz, 1H), 4.34 (s, 2H); 13C NMR (100 MHz, CDCl3) d161.3, 158.8, 145.2, 139.1, 136.8, 132.2, 129.9, 129.8, 128.9, 128.0, 126.8, 124.5, 124.4, 124.2, 123.8, 122.7, 122.5, 119.8, 117.8, 116.1, 115.9, 112.2, 30.1.

3-Benzyl-2-(3-fluorophenyl)imidazo[1,2-a]pyridine (4f)

Yield 71% (214.5 mg); 1H NMR (400 MHz, CDCl3) δ 7.71-7.64 (m, 2H), 7.54 (d, J 7.5 Hz, 2H), 7.36 (dd, J 14.2, 7.5 Hz, 1H), 7.32-7.21 (m, 3H), 7.21-7.14 (m, 1H), 7.12 (d, J 7.4 Hz, 2H), 7.06-6.99 (m, 1H), 6.73-6.66 (m, 1H), 4.48 (s, 2H); 13C NMR (100 MHz, CDCl3) d164.4, 161.9, 145.0, 143.0, 137.0, 136.9, 136.6, 130.2, 130.1, 129.2, 127.7, 126.1, 124.5, 123.8, 123.8, 123.5, 118.2, 117.8, 115.3, 115.1, 114.7, 114.5, 112.5, 29.9; HRMS (ESI) m/z, calcd. for C20H15N2F [M + H]+: 303.1298, found: 303.1293.

3-Benzyl-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (4g)3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.

Yield 82% (248.0 mg); 1H NMR (400 MHz, CDCl3) δ 7.77-7.71 (m, 2H), 7.71-7.64 (m, 2H), 7.34-7.24 (m, 3H), 7.21-7.15 (m, 1H), 7.14-7.08 (m, 4H), 6.71 (td, J 6.8, 1.0 Hz, 1H), 4.46 (s, 2H); 13C NMR (100 MHz, CDCl3) d163.9, 161.5, 145.0, 143.4, 136.8, 130.8, 130.0, 129.9, 129.2, 127.8, 127.1, 124.3, 123.5, 117.7, 115.8, 115.6, 112.4, 29.9.

3-Benzyl-2-(pyridin-3-yl)imidazo[1,2-a]pyridine (4h)

Yield 80% (228.4 mg); 1H NMR (400 MHz, CDCl3) d9.00 (s, 1H), 8.61-8.54 (m, 1H), 8.14-8.09 (m, 1H), 7.78-7.63 (m, 2H), 7.40-7.04 (m, 8H), 6.72 (m, 1H), 4.47 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 148.9, 148.7, 145.2, 140.9, 136.2, 135.5, 130.6, 129.1, 127.6, 127.1, 124.7, 123.6, 123.5, 118.5, 117.6, 112.6, 29.7; HRMS (ESI) m/z, calcd. for C19H15N3 [M + H]+: 286.1344, found: 286.1363.

3-Benzyl-2-cyclohexylimidazo[1,2-a]pyridine (4j)3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.

Yield 60% (174.1 mg); 1H NMR (400 MHz, CDCl3)d 7.63-7.56 (m, 3H), 7.30-7.17 (m, 3H), 7.12-7.02 (m, 3H), 6.60 (td, J 6.8, 0.9 Hz, 1H), 4.28 (s, 2H), 2.89-2.76 (m, 1H), 1.95-1.76 (m, 6H), 1.46-1.30 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 150.0, 144.5, 137.1, 128.8, 127.8, 126.7, 123.2, 123.1, 117.1, 116.3, 111.6, 36.9, 33.3, 29.0, 26.9, 26.0.

3-(3,5-Bis(trifluoromethyl)benzyl)-2-phenylimidazo [1,2-a]pyridine (4k)4545 Gupta, A. K.; De, D.; Katoch, R.; Garg, A.; Bharadwaj, P. K.; Inorg. Chem. 2017, 56, 4697.

Yield 75% (315.8 mg); 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.72 (t, J 7.8 Hz, 3H), 7.64 (d, J 6.9 Hz, 1H), 7.57 (s, 2H), 7.44 (t, J 7.5 Hz, 2H), 7.37 (t, J 7.3 Hz, 1H), 7.27-7.21 (m, 1H), 6.79 (t, J 6.8 Hz, 1H), 4.60 (s, 2H); 13C attached proton test (APT) NMR (100 MHz, CDCl3)d145.4, 145.3, 140.0, 134.2, 131.0 (q, 2J C-F 33.4 Hz), 128.9, 128.3, 128.2, 127.9, 127.3, 124.6, 123.8 (q, 1J C-F 245.2 Hz), 122.8, 121.3, (q, 3JC-F 3.6 Hz), 118.1, 115.5, 112.9, 29.8.

3-(4-Methylbenzyl)-2-phenylimidazo[1,2-a]pyridine (4l)3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.

Yield 57% (170.0 mg); 1H NMR (400 MHz, CDCl3) d7.82-7.77 (m, 2H), 7.68 (m, 2H), 7.42 (m, 2H), 7.33 (m, 1H), 7.18-7.12 (m, 1H), 7.10 (d, J 7.9 Hz, 2H), 7.02 (d, J 7.9 Hz, 2H), 6.67 (t, J 6.7 Hz, 1H), 4.44 (s, 2H), 2.31 (s, 3H); 1313 Leopoldo, M.; Lacivita, E.; Passafiume, E.; Contino, M.; Colabufo, N. A.; Berardi, F.; Perrone, R.; J. Med. Chem. 2007, 50, 5043.C NMR (100 MHz, CDCl3) d144.7, 143.9, 136.4, 134.4, 133.5, 129.6, 128.6, 128.1, 127.6, 127.5, 124.1, 123.4, 117.9, 117.4, 112.1, 29.3, 21.0.

3-(4-Methoxybenzyl)-2-phenylimidazo[1,2-a]pyridine (4m)3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.

Yield 35% (110.0 mg); 1H NMR (400 MHz, CDCl3) δ 7.84-7.79 (m, 2H), 7.72-7.67 (m, 2H), 7.44 (t, J 7.6 Hz, 2H), 7.36 (t, J 7.3 Hz, 1H), 7.19-7.13 (m, 1H), 7.05 (d, J 8.2 Hz, 1H), 6.84 (d, J 8.6 Hz, 2H), 6.71-6.65 (m, 1H), 4.42 (s, 2H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 144.8, 143.9, 134.5, 128.7, 128.6, 128.6, 128.2, 127.7, 124.2, 123.5, 118.1, 117.5, 114.4, 112.2, 55.3, 29.0.

4-((2-Phenylimidazo[1,2-a]pyridin-3-yl)methyl)benzonitrile (4n)

Yield 14% (43.33mg); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J 4.4 Hz, 1H), 7.76-7.68 (m, 3H), 7.66-7.58 (m, 3H), 7.48-7.35 (m, 4H), 7.29-7.20 (m, 3H), 6.77 (t, J 6.8 Hz, 1H), 6.66-6.61 (m, 1H), 6.50 (d, J 8.3 Hz, 1H), 4.56 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 148.1, 145.2, 144.8, 142.7, 137.8, 134.2, 133.0, 128.9, 128.6, 128.2, 128.1, 124.6, 123.0, 118.7, 117.9, 116.1, 114.0, 112.7, 111. 1, 108.7, 30.1; HRMS (ESI) m/z, calcd. for C21H15N3 [M + H]+: 310.134, found: 310.1381.

Results and Discussion

Herein, we propose the preparation and use of Cu/SiO2 as a unique heterogeneous catalyst for the A3-coupling of 2-aminopyridines, aldehydes and alkynes to obtain different imidazo[1,2-a]pyridine derivatives. Firstly, by employing CuCl2 and tetraethylorthosilicate as precursors in the presence of acid (HCl) or nucleophilic (HF) catalyst for the sol-gel process, Cu/SiO2 materials 1 and 2 were obtained, respectively. The glassy-like materials achieved after complete gelation at room temperature were powdered and dried to yield pale green solids. These materials were characterized with regards to composition and textural properties.

The scanning electron microscopy with energy dispersive spectroscopy (SEM/EDS) confirm the presence of copper in the materials and showed the irregular surface of both materials (Figure 1).

Figure 1
SEM micrograph and EDS graph for material 2.

The choice of catalyst had a less pronounced effect on the material surface area achieved by BET analysis, leading to 490 and 370 m2 g-1 for the HCl- and HF-catalyzed materials, respectively materials 1 and 2 (Figure 2). However, as shown in Figure 2, material 1 has a typical microporous profile, while material 2 is predominantly mesoporous. The results of BJH and DFT calculations showed that a mesoporous material was obtained using nucleophilic catalysis (pore size of 5.0 nm), while acid catalyst resulted in a microporous material (pore size of 0.9 nm, Figure 3). Similar catalyst effects were reported previously.6060 Brinker, C. J.; Scherer, G. W.; Sol-Gel Science: The Physics and Chemistry of Sol-Gel Processing; Academic Press, Inc: London, UK, 1990.

Figure 2
Surface area isotherms of materials 1 and 2.
Figure 3
Pore size distribution of materials 1 and 2.

The total amount of copper in the material was determined by flame atomic absorption spectrometry (FAAS) after acidic digestion of the samples, since SEM-EDS furnished a Cu:Si atom ratio on the surface only and not inside the pores of the material. In the case of material 1, more milligrams of copper were achieved per gram of sample. The data concerning pore size, surface area and copper amount for materials 1 and 2 are summarized in Table 1.

Table 1
Chemical and textural analyses overview

Materials 1 and 2 were then applied as catalysts in the three-component reaction between 2-aminopyridine 1, benzaldehyde 2a and phenylacetylene 3a, as depicted in Scheme 1.

Scheme 1
Multicomponent A3-coupling synthesis of 3-benzyl-2-phenylimidazo[1,2-a]pyridine.

Table 2 summarizes the yields of product 4a when comparing the same amount of materials 1 and 2 with pure SiO2 and the reactions in the absence of a catalyst. Non-optimized reaction conditions showed that the higher pore diameter material 2 prepared by HF catalysis resulted in a better product yield without the need for molecular sieves in refluxing toluene after 48 h (Table 2, entry 2). It is worth to mention that the use of free CuCl2 as catalyst leads to similar yields (Table 2, entry 5) but the work-up produces more wastes and requires more steps in comparison to simple filtration of the catalyst in our procedure.

Table 2
Influence of the catalyst on the imidazo[1,2-a]pyridine synthesis

After choosing material 2 as the catalyst for the A3-coupling reaction between 2-aminopyridine, benzaldehyde and phenylacetylene, a screening of the solvent and temperature was performed (Table 3). Interestingly, only toluene was found to be suitable for the cyclization reaction, although low conversion was achieved in neat conditions at 120 ºC (Table 3, entries 9 and 10). In addition, investigation of the catalyst load was made by varying the amount of catalyst from 2.5-20.0 mol% based on the total amount of copper of the material, as determined by FAAS in Table 4. It is worth to mention that the use of 10 mol% of several homogeneous copper species in the absence of Brϕnsted acid additives does not lead to considerable yield of imidazo[1,2-a]pyridines under the same conditions, as described by Liu et al.3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.

Table 3
Screening of solvents on the imidazo[1,2-a]pyridine synthesis
Table 4
Influence of catalyst load on the imidazo[1,2-a]pyridine synthesis

With these results in hand, we then studied the scope of the reaction (Scheme 2). This protocol was found suitable for a range of aldehydes bearing electron donating or electron withdrawing groups, giving the respective imidazo[1,2-a]pyridines with good yields (64-82%, Table 5, entries 1-6). It is worth mentioning that no conversion to product was achieved when using 4-nitrobenzaldehyde (entry 7).

Table 5
Scope of the reaction for different substituted imidazo [1,2-a]pyridines

Scheme 2
Multicomponent A3-coupling synthesis of different substituted imidazo[1,2-a]pyridines.

Conversely, heteroaromatic and aliphatic aldehydes also worked well in this protocol, except for 2-pyridinecarboxaldehyde (entries 8-10). Substituted aromatic alkynes gave slightly lower yields (entries 11-14) when compared to phenylacetylene. Substituents with an inductive effect, such as 3,5-bis-trifluoromethyl and methyl groups, showed better results than with mesomeric (donating or withdrawing) effect groups in achieving the corresponding imidazo[1,2-a]pyridines.

Concerning the mechanism of the reaction, we believe that the major role of the catalyst is in the approximation of the pre-formed imine (I) from 2-aminopiridine and benzaldehyde and the π-complex of Cu-phenylacetylene (II) (Scheme 3). This step may occur on the surface but mainly inside pores of the catalyst, since it was verified that the pore size distribution of 0.9 nm for material 2 gave slightly better yields when compared to material 1 with a higher surface area and a higher amount of copper per gram of material. The formation of intermediate III is crucial for 5-exo-dig cyclization, which is also aided by catalyst complexation. Intermediate I was readily detected by gas chromatography coupled to mass spectrometry when analyzing crude reaction mixtures, while intermediate III was not detected. This result agrees with the mechanistic proposal made by other authors,3535 Reddy, B. V. S.; Reddy, P. S.; Reddy, Y. J.; Yadav, J. S.; Tetrahedron Lett. 2011, 52, 5789.,3838 Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.,4343 Mishra, S.; Ghosh, R.; Synthesis 2011, 21, 3463. with imine formation from aldehyde and amine as a faster step than the propargyl alcohol formed between aldehyde and alkyne which was not observed.

Scheme 3
Proposed reaction mechanism of the A3-coupling to imidazo[1,2-a]pyridines.

Conclusions

In summary, we have successfully applied mesoporous Cu/SiO2 material as heterogeneous Lewis acid catalyst on the multicomponent synthesis of imidazo[1,2-a]pyridines with good yields, without any additive and co-catalyst as commonly found in the literature. This protocol allows the removal of the catalyst from the reaction media through simple filtration. The very simple sol-gel prepared mesoporous material showed slightly better yield of imidazo[1,2-a]pyridines even with lower copper load in comparison to microporous material.

Acknowledgments

This research was financially supported in part by CNPq, INCT-Cat, CAPES and FAPERGS-PRONEX.

  • Supplementary Information
    Supplementary information (1H and 13C NMR spectra) is available free of charge at http://jbcs.sbq.org.br as a PDF file.

References

  • 1
    Devi, N.; Singh, D.; Rawal, R. K.; Bariwal, J.; Singh, V.; Curr. Top. Med. Chem. 2016, 16, 2963.
  • 2
    Guieffier, C.-E.; Guieffier, A.; Mini-Rev. Med. Chem. 2007, 7, 888.
  • 3
    Gudmundsson, K. S.; Williams, J. D.; Drach, J. C.; Townsend, L. B.; J. Med. Chem. 2003, 46, 1449.
  • 4
    Puerstinger, G.; Paeshuyse, J.; Declercq, E.; Neyts, J.; Bioorg. Med. Chem. Lett. 2007, 17, 390.
  • 5
    Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.; Hallett, D.; Marchant, K. J.; Thomas, S. R.; Bioorg. Med. Chem. Lett. 2006, 16, 1518.
  • 6
    Fookes, C. J. R.; Pham, T. Q.; Mattner, F.; Greguric, I.; Loch, C.; Liu, X.; Berghofer, P.; Shepherd, R.; Gregoire, M.-C.; Katsifis, A.; J. Med. Chem. 2008, 51, 3700.
  • 7
    Deep, A.; Bhatia, R. K.; Kaur, R.; Kumar, S.; Jain, U. K.; Singh, H.; Batra, S.; Kaushik, D.; Deb, P. K.; Curr. Top. Med. Chem. 2017, 17, 238.
  • 8
    Goel, R.; Luxami, V.; Paul, K.; Curr. Top. Med. Chem. 2016, 16, 3590.
  • 9
    Liu, T.-C.; Peng, X.; Ma, Y.-C.; Ji, Y.-C.; Chen, D.-Q.; Zheng, M.-Y.; Zhao, D.-M.; Cheng, M. S.; Geng, M.-Y.; Shen, J.-K.; Ai, J.; Xiong, B.; Acta Pharmacol. Sin. 2016, 5, 698.
  • 10
    Velázquez-Olvera, S.; Salgado-Zamora, H.; Velázquez-Ponce, M.; Campos-Aldrete, E.; Reyes-Arellano, A.; Pérez-González, C.; Chem. Cent. J. 2012, 6, DOI: 10.1186/1752-153X-6-83.
    » https://doi.org/10.1186/1752-153X-6-83
  • 11
    Firmansyah, D.; Ciuciu, A. L.; Hugues, V.; Blanchard-Desce, M.; Flamigni, L.; Gryko, D. T.; Chem. - Asian J. 2013, 8, 1279.
  • 12
    Pordel, M.; Chegini, H.; Ramezani, S.; Daee, M.; J. Mol. Struct. 2017, 1129, 105.
  • 13
    Leopoldo, M.; Lacivita, E.; Passafiume, E.; Contino, M.; Colabufo, N. A.; Berardi, F.; Perrone, R.; J. Med. Chem. 2007, 50, 5043.
  • 14
    Xiao, S.; Liu, Z.; Zhao, J.; Pei, M.; Zhang, G.; He, W.; RSC Adv. 2016, 6, 27119.
  • 15
    Jia, X.; Yin, K.; Li, C.; Li, J.; Bian, H.; Green Chem. 2011, 13, 2175.
  • 16
    van Gelderen, L.; Rothenberg, G.; Roberto, C. V.; Wilson, K.; Raveendran, S. N.; Appl. Organomet. Chem. 2013, 27, 23.
  • 17
    Kuhn, P.; Alix, A.; Kumarraja, M.; Louis, B.; Pale, P.; Sommer, J.; Eur. J. Org. Chem. 2009, 423.
  • 18
    Alonso, F.; Melkonian, T.; Moglie, Y.; Yus, M.; Eur. J. Org. Chem. 2011, 2524.
  • 19
    Yamaguchi, K.; Oishi, T.; Katayama, T.; Mizuno, N.; Chem. - Eur. J. 2009, 15, 10464.
  • 20
    Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V.; J. Am. Chem. Soc. 2005, 127, 210.
  • 21
    Worell, B. T.; Malik, J. A.; Fokin, V. V.; Science 2013, 340, 457.
  • 22
    Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.; Angew. Chem., Int. Ed. 2002, 41, 2596.
  • 23
    Buckley, B. R.; Figueres, M. M. P.; Khan, A. N.; Heaney, H.; Synlett 2016, 27, 51.
  • 24
    Reymond, S.; Cossy, J.; Chem. Rev. 2008, 108, 5359.
  • 25
    Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P.; J. Am. Chem. Soc. 1999, 121, 7559.
  • 26
    Thomas, A. M.; Sujatha, A.; Anilkumar, G.; RSC Adv. 2014, 4, 21688.
  • 27
    Gallop, C. W. D.; Chen, M.-T.; Navarro, O.; Org. Lett. 2014, 16, 3724.
  • 28
    Yan, H.; Wang, Y.; Pan, C.; Zhang, H.; Yang, S.; Ren, X.; Li, J.; Huang, G.; Eur. J. Org. Chem. 2014, 2754.
  • 29
    Santra, S.; Mitra, S.; Bagdi, A. K.; Majee, A.; Hajra, A.; Tetrahedron Lett. 2014, 55, 5151.
  • 30
    Yan, R. L.; Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M.; J. Org. Chem. 2012, 77, 2024.
  • 31
    Zhang, Y.; Chen, Z.; Wu, W.; Zhang, Y.; Su, W.; J. Org. Chem. 2013, 78, 12494.
  • 32
    Cao, H.; Liu, X.; Liaou, J.; Huang, J.; Qiu, H.; Chen, Q.; Chen, Y.; J. Org. Chem. 2014, 79, 11209.
  • 33
    Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A.; Chem. Commun. 2015, 51, 1555.
  • 34
    Siddiqui, I. R.; Rahila, P. R.; Srivastava, A.; Shamin, S.; Tetrahedron Lett. 2014, 55, 1159.
  • 35
    Reddy, B. V. S.; Reddy, P. S.; Reddy, Y. J.; Yadav, J. S.; Tetrahedron Lett. 2011, 52, 5789.
  • 36
    Zhu, D.-J.; Chen, J.-X.; Liu, M.-C.; Ding, J.-C.; Wu, H.-Y.; J. Braz. Chem. Soc. 2009, 20, 482.
  • 37
    Gao, Y.; Yin, M.; Wu, W.; Huang, H.; Jiang, H.; Adv. Synth. Catal. 2013, 355, 2263.
  • 38
    Liu, P.; Fang, L.-S.; Lei, X.; Lin, G.-Q.; Tetrahedron Lett. 2010, 51, 4605.
  • 39
    Palano, T.; Park, K.; Kumar, M. R.; Jung, H. M.; Lee, S.; Eur. J. Org. Chem. 2012, 5038.
  • 40
    Cherniak, N.; Gevorgyan, V.; Angew. Chem., Int. Ed. 2010, 49, 2743.
  • 41
    Guchhait, S. K.; Chandgude, A. L.; Priyadarshani, G.; J. Org. Chem. 2012, 77, 4438.
  • 42
    Balijapalli, U.; Iyer, S. K.; Dyes Pigm. 2015, 121, 88.
  • 43
    Mishra, S.; Ghosh, R.; Synthesis 2011, 21, 3463.
  • 44
    Luz, I.; Xamena, F. X. L.; Corma, A.; J. Catal. 2012, 285, 285.
  • 45
    Gupta, A. K.; De, D.; Katoch, R.; Garg, A.; Bharadwaj, P. K.; Inorg. Chem. 2017, 56, 4697.
  • 46
    Dutta, G.; Jana, A. K.; Natarajan. S.; Chem. - Asian J. 2018, 13, 66.
  • 47
    Hussain, N.; Gogoi, P.; Das, M. R.; Sengupta, P.; Fedorov, V. E.; Asanov, I. P.; Kozlova, M. N.; Artemkina, S. B.; Appl. Catal., A 2017, 542, 368.
  • 48
    Zong, C.; Zeng, R.; Zou, J.; Chem. Res. Chin. Univ. 2014, 30, 632.
  • 49
    Lu, J.; Li, X.-T.; Ma, E.-Q.; Mo, L.-P.; Zhang, Z.-H.; ChemCatChem 2014, 6, 2854.
  • 50
    Maleki, A.; Helv. Chim. Acta 2014, 97, 587.
  • 51
    Tajbakhsh, M.; Farhang, M.; Hosseinzadeh, R.; Sarrafi, Y.; RSC Adv. 2014, 5, 23116.
  • 52
    Guntreddi, T.; Allam, B. K.; Singh, K. N.; Synlett 2012, 23, 2635.
  • 53
    Meng, X.; Wang, Y.; Yu, C.; Zhao, P.; RSC Adv. 2014, 4, 27301.
  • 54
    Hench, L. L.; West, J. K.; Chem. Rev. 1990, 90, 33.
  • 55
    Benvenutti, E. V.; Moro, C. C.; Costa, T. M. H.; Quim. Nova 2009, 32, 1926.
  • 56
    Affeldt, R. F.; Benvenutti, E. V.; Russowsky, D.; New J. Chem. 2012, 36, 1502.
  • 57
    da Silva, T. L.; Rambo, R. S.; Rampon, D. S.; Radatz, C. S.; Benvenutti, E. V.; Russowsky, D.; Schneider, P. H.; J. Mol. Catal. A: Chem. 2015, 399, 71.
  • 58
    Russowsky, D.; Benvenutti, E. V.; Roxo, G. S.; Grasel, F.; Lett. Org. Chem. 2007, 4, 39.
  • 59
    Radatz, C. S.; Soares, L. A.; Vieira, E. R.; Alves, D.; Russowsky, D.; Schneider, P. H.; New J. Chem. 2014, 38, 1410.
  • 60
    Brinker, C. J.; Scherer, G. W.; Sol-Gel Science: The Physics and Chemistry of Sol-Gel Processing; Academic Press, Inc: London, UK, 1990.

Data availability

Publication Dates

  • Publication in this collection
    16 Sept 2019
  • Date of issue
    Sept 2019

History

  • Received
    16 Jan 2019
  • Accepted
    14 May 2019
Sociedade Brasileira de Química Instituto de Química - UNICAMP, Caixa Postal 6154, 13083-970 Campinas SP - Brazil, Tel./FAX.: +55 19 3521-3151 - São Paulo - SP - Brazil
E-mail: office@jbcs.sbq.org.br