A Convenient Method for the Synthesis of Imidazo[1,2-a]pyridines with a New Approach

Dedicated to Prof. Gebhard Haberhauer on the occasion of his birthday

Abstract

A new approach for the efficient synthesis of imidazo[1,2-a]pyridines is described. The synthesis was carried out via the reaction of functionalized 2-aminopyridine that were formed through a three-component reaction and phenacyl bromide derivatives.

Key words

functionalized imidazo[1,2-a]pyridines - 2-aminopyridines - cyclocondensation reaction

• References and Notes

• 1a Langtry HD. Benfield P. Drugs 1990; 40: 291
• 1b Mizushige K. Ueda T. Yukiiri K. Suzuki H. Cardiol. Drug Rev. 2002; 20: 163
• 1c Kang CB. Sen Y. Del Valle JR. Org. Lett. 2012; 14: 6162
• 1d Kim YB. Kang CW. Ranatunga S. Yang H. Sebti SM. Del Valle JR. Bioorg. Med. Chem. Lett. 2014; 24: 4650
• 2a Bottai T. Cartault F. Pouget R. Blayac JP. Petit P. Clin. Neuropharmacol. 1995; 18: 79
• 2b Herath A. Dahl R. Cosford ND. P. Org. Lett. 2010; 12: 412
• 3 Biftu T. Feng D. Fisher M. Liang G. Qian X. Scribner A. Dennis R. Lee S. Liberator PA. Brown C. Gurnett A. Leavitt PS. Thompson D. Mathew J. Misura A. Samaras S. Tamas T. Sina JF. McNulty KA. McKnight CG. Schmatz DM. Wyvratt M. Bioorg. Med. Chem. Lett. 2006; 16: 2479
• 4 Palmer AM. Grobbel B. Jecke C. Brehm C. Zimmermann PJ. Buhr W. Feth MP. Simon WA. Kromer W. J. Med. Chem. 2007; 50: 6240
• 5a Sumalatha Y. Reddy TR. Reddy PP. Satyanarayana B. Arkivoc 2009; (ii): 315
• 5b Holm KJ. Goa KL. Drugs 2000; 59: 865
• 6 Durand A. Thenot JP. Bianchetti G. Morselli PL. Drug Metab. Rev. 1992; 24: 239
• 7a Nair DK. Mobin SM. Namboothiri IN. N. Org.Lett. 2012; 14: 4580
• 7b Chernyak N. Gevorgyan V. Angew. Chem. Int. Ed. 2010; 49: 2743
• 8a Lee H. Kim SJ. Jung KH. Son MK. Yan HH. Hong S. Hong S. Oncol. Rep. 2013; 30: 863
• 8b Kamal A. Kumar GB. Nayaka VL. Reddya VS. Basha A. Rajender S. Reddy MK. Med. Chem. Commun. 2015; 6: 606
• 8c Kamal A. Reddy JS. Ramaiah MJ. Dastagiri D. Bharathi EV. Sagar MV. P. Pushpavalli SN. C. V. L. Ray P. Pal-Bhadra M. Med. Chem. Commun. 2010; 1: 355
• 8d Mohan DC. Donthiri RR. Rao SN. Adimurthy S. Adv. Synth. Catal. 2013; 355: 2217
• 8e Al-Tel TH. Al-Qawasmeh RA. Eur. J. Med. Chem. 2010; 45: 5848
• 9a Kim O. Jeong Y. Lee H. Hong S. Hong S. J. Med. Chem. 2011; 54: 2455
• 9b Cai L. Cuevas J. Temme S. Herman MM. Dagostin C. Widdowson DA. Innis RB. Pike VW. J. Med. Chem. 2007; 50: 4746
• 9c Starr JT. Sciotti RJ. Hanna DL. Huband MD. Mullins LM. Cai H. Gage JW. Lockard M. Rauckhorst MR. Owen RM. Lall MS. Tomilo M. Chen H. McCurdy SP. Barbachyn MR. Bioorg. Med. Chem. Lett. 2009; 19: 5302
• 9d Al-Tel TH. Al-Qawasmeh RA. Zaarour R. Eur. J. Med. Chem. 2011; 46: 1874
• 10 Shono H. Ohkawa T. Tomoda H. Mutai T. Araki KC. ACS Appl. Mater. Interfaces 2011; 3: 654
• 11a Wang Y. Frett B. Li H. Org. Lett. 2014; 16: 3016
• 11b Stasyuk V. Banasiewicz V. Cyraneski V. Gryko V. J. Org. Chem. 2012; 77: 5552
• 12 Yadav JS. Reddy BV. S. Rao YG. Srinivas M. Narsaiah AV. Tetrahedron Lett. 2007; 48: 7717
• 13 Ueno V. Togo H. Synthesis 2004; 2673
• 14a Nair DK. Mobin SM. Namboothiri IN. N. Org. Lett. 2012; 14: 4580
• 14b Santra S. Bagdi AK. Majee A. Hajra A. Adv. Synth. Catal. 2013; 355: 1065
• 15a Yan H. Wang Y. Pan C. Zhang H. Yang S. Ren X. Li J. Huang G. Eur. J. Org. Chem. 2014; 2754
• 15b Ramesha AB. Raghavendra GM. Nandeesh KN. Rangappa KS. Mantelingu K. Tetrahedron Lett. 2013; 54: 95
• 16 Liu P. Deng C.-L. Lei X. Lin G.-Q. Eur. J. Org. Chem. 2011; 7308
• 17 Wang H. Wang Y. Liang D. Liu L. Zhang J. Zhu Q. Angew. Chem. Int. Ed. 2011; 50: 5678
• 18 Wang H. Wang Y. Peng C. Zhang J. Zhu Q. J. Am. Chem. Soc. 2010; 132: 13217
• 19a Donohoe TJ. Kabeshov MA. Rathi AH. Smith IE. D. Org. Biomol. Chem. 2012; 10: 1093
• 19b Gao Y. Yin M. Wu W. Huang H. Jiang H. Adv. Synth. Catal. 2013; 355: 2263
• 20 Bagdi AK. Santra S. Monir K. Hajra A. Chem. Commun. 2015; 51: 1555
• 21a Haas G. Stanton JL. von Sprecher A. Wenk P. J. Heterocycl. Chem. 1981; 18: 607
• 21b Gašparová R. Lácová M. Molecules 2005; 10: 937
• 21c Plaskon AS. Ryabukhin SV. Volochnyuk DM. Gavrilenko KS. Shivanyuk AN. Tolmachev AA. J. Org. Chem. 2008; 73: 6010
• 21d Sanchez LM. Sathicq ÁG. Jios JL. Baronetti GT. Thomas HJ. Romanelli GP. Tetrahedron Lett. 2011; 52: 4412
• 21e Balalaie S. Bijanzadeh HR. Mehrparvar S. Rominger S. Synlett 2016; 27: 782
• 21f Bijanzadeh HR. Mehrparvar S. Balalaie S. J. Iran. Chem. Soc. 2015; 12: 1859
• 21g Mehrparvar S. Balalaie S. Rabbanizadeh M. Rominger F. Ghabraie E. Org. Biomol. Chem. 2014; 12: 5757
• 21h Mehrparvar S. Balalaie S. Rabbanizadeh M. Ghabraie E. Rominger F. Mol. Diversity 2014; 18: 535
• 22a Ghabraie E. Balalaie S. Mehrparvar S. Rominger F. J. Org. Chem. 2014; 79: 7926
• 22b Maghari S. Ramezanpour S. Balalaie S. Darvish F. Rominger F. Bijanzadeh HR. J. Org. Chem. 2013; 78: 6450
• 22c Bararjanian M. Balalaie S. Rominger F. Movassagh B. Bijanzadeh HR. Mol. Diversity 2011; 15: 583
• 23a Khadem S. Marles RJ. Molecoules 2011; 17: 191
• 23b Gasper A. Matos MJ. Garido J. Uriarte E. Borges F. Chem. Rev. 2014; 114: 4960
• 24 Balalaie, S.; Esmaeilabadi, H.; Mehrparvar, S.; Rominger, F.; Hamdan, F.; Bijanzadeh, H. R.; submitted for publication.
• 25 Procedure for the Synthesis of 2-Amino-5-(2-Hydroxybenzoyl)nicotinonitrile (4a) A mixture of 3-formylchromone (1 mmol, 174 mg), malononitrile (1.2 mmol, 79 mg), and diammonium hydrogen phosphate (20% mol, 27 mg) was stirred in water (6 mL) at r.t. for 30 min. The mixture was then added to diammonium hydrogen phosphate (1 mmol, 27 mg), and the reaction mixture was stirred at 50 °C for 3 h. The obtained precipitate was filtered and washed with aq EtOH. Procedure for the Synthesis of 6-(2-Hydroxybenzoyl)-2-phenylimidazo[1, 2-a]pyridine-8-carbonitrile (6a) A mixture of 2-amino-5-(2-hydroxybenzoyl)nicotinonitrile (1 mmol, 239 mg) and phenacyl bromide (1 mmol, 199 mg) was stirred in DMF (2 mL) for 4 h under reflux. After completion of the reaction, the mixture was allowed to cool, water was added, and the reaction mixture was extracted with CH₂Cl₂. The organic phase was dried using Na₂SO₄. Further purification was carried out using column chromatography (eluent; n-hexane–CH₂Cl₂ = 1:1). 6-(2-Hydroxybenzoyl)-2-phenylimidazo[1,2-a]pyridine-8-carbonitrile (6a) Colorless powder, 176 mg, 52%, mp 198–200 °C. IR (KBr): ν_max = 3411, 2237, 1626, 1604 cm^–1. ¹HNMR (300 MHz, DMSO-d ₆): δ = 6.99 (t, 1 H, J = 8.1 Hz, H-Ar), 7.01–7.04(d, 1 H, J = 7.5 Hz, H-Ar), 7.35–7.51 (m, 5 H, H-Ar), 7.97 (d, 2 H, J = 7.5 Hz, H-Ar), 8.20 (br s, 1 H, H-2-pyridyl), 8.67 (s, 1 H, H-imidazole), 9.22 (d, 1 H, J = 1.56 Hz, H-4-pyridyl), 10.36 (s, 1 H, OH). ¹³CNMR (75 MHz, DMSO-d ₆): δ = 99.6, 112.3, 115.2, 117.0, 119.5, 122.9, 124.2, 126.0, 129.0, 129.0, 130.5, 132.1, 132.3, 133.7, 136.1, 142.6, 146.9, 156.4, 192.0. ESI-HRMS: m/z calcd for C₂₁H₁₃N₃O₂ [M + H]⁺: 340.1083; found: 340.1083. 2-(4-Bromophenyl)-6-(5-fluoro-2-hydroxybenzoyl)imidazo[1,2-a]pyridine-8-carbonitrile (6g) Yellow powder, 235 mg, 54%, mp 259–261 °C. IR: (KBr): ν_max = 3402, 2225, 1674, 1593 cm^–1.¹HNMR (300 MHz, DMSO-d ₆): δ = 6.99–7.03(m, 1 H, H-Ar), 7.26–7.37 (m, 2 H, H-Ar), 7.65 (d, 2 H, J = 8.34 Hz, H-Ar), 7.90 (d, 2 H, J = 8.35 Hz, H-Ar), 8.24 (s, 1 H, H-2-pyridyl), 8.68 (s, 1 H, H-imidazole), 9.24 (s, 1 H, H-4-pyridyl), 10.27 (s, 1 H, OH). ¹³CNMR (75 MHz, DMSO-d ₆): δ = 99.8, 112.7, 115.0, 115.8, 116.1, 118.2, 118.3 ( ³J _C–F = 7.2 Hz), 120.0, 120.3 ( ²J _C–F = 24 Hz), 122.0, 122.6, 124.9, 125.0, 127.9, 131.5, 131.9, 132.2, 136.5, 142.7, 145.8, 152.4, 153.6, 156.7 ( ¹J _C–F = 234.75 Hz), 190.5. ESI-HRMS: m/z calcd for C₂₁H₁₁BrFN₃O₂ [M + H]⁺: 436.0094; found: 436.0094. Yellow crystal (polyhedron), dimensions 0.160 × 0.130 × 0.130 mm³, crystal system monoclinic, space group P2₁/c, Z = 4, a = 8.5182(4) Å, b = 8.5756(4) Å, c = 24.0705(12) Å, α =90°, β = 94.4088(8)°, γ = 90°, V = 1753.12(15) ų, ρ = 1.653 g cm^–3, T = 200(2) K, θ _max = 28.313°, radiation Mo Kα, λ = 0.71073 Å, 0.5° Ω scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 3.92 and a completeness of 99.8% to a resolution of 0.75 Å, 17588 reflections measured, 4356 unique (R(int) = 0.0291), 3370 observed (I > 2σ(I)), intensities were corrected for Lorentz and polarization effects, an empirical scaling and absorption correction was applied using SADABS^26a based on the Laue symmetry of the reciprocal space, μ = 2.38 mm^–1, T_min = 0.90, T_max = 0.97, structure refined against F ² with a full-matrix least-squares algorithm using the SHELXL-2016/6 (Sheldrick, 2016) software, 257 parameters refined, hydrogen atoms were treated using appropriate riding models, except H32 of the hydroxy group, which was refined isotropically, goodness of fit 1.04 for observed reflections, final residual values R1(F) = 0.034, wR(F ²) = 0.082 for observed reflections, residual electron density –0.68 to 0.72 eÅ^–3. CCDC 1557527 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.^26b
• 26a Sheldrick GM. SADABS. Bruker Analytical X-ray-Division; Madison, WI: 2014
• 26b Sheldrick GM. Acta Crystallogr., Sect. C: Struct. Chem. 2015; 71: 3