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Synlett 2018; 29(01): 89-93
DOI: 10.1055/s-0036-1590906
letter
© Georg Thieme Verlag Stuttgart · New York

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

Saeed Balalaie*
a   Peptide Chemistry Research Center, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
b   Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
,
Fatemeh Derakhshan-Panah
a   Peptide Chemistry Research Center, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
c   Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran   Email: zolfi@basu.ac.ir   Email: mzolfigol@yahoo.com
,
Mohammad Ali Zolfigol*
c   Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran   Email: zolfi@basu.ac.ir   Email: mzolfigol@yahoo.com
,
Frank Rominger
d   Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
› Author AffiliationsWe are grateful to the Iran National Science Foundation (INSF, Grant No. 96003234) for financial support.
Further Information

Publication History

Received: 05 July 2017

Accepted after revision: 19 August 2017

Publication Date:
05 September 2017 (online)

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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

Supporting Information

    Figures, Tables, and CIF files giving 1H NMR, 13C NMR, IR, and HRMS spectra for compounds 6a–h and X-ray crystal data for compounds 6g. Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1590906.
  • Supporting Information
 

  • References and Notes

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  • 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): νmax = 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): νmax = 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) Å3, 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 SADABS26a based on the Laue symmetry of the reciprocal space, μ = 2.38 mm–1, Tmin = 0.90, Tmax = 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