Red-Light Methylene Blue/Iodide Photocatalysis for the Aerobic Construction of Imidazo[1,2-a]pyridines: Statistical Optimisation, Mechanistic Profiling and Continuous-Flow Scale-Up
Keywords:
organophotocatalysis, methylene blue, imidazo[1,2-a]pyridine, quantum yield, continuous flow, design of experiments, aerobic oxidationAbstract
Imidazo[1,2-a]pyridines sit in many marketed drugs, yet most routes to them still rely on stoichiometric halogenating agents, copper salts or heat. We report a metal-free alternative in which methylene blue (MB) and potassium iodide (KI) assemble 2-arylimidazo[1,2-a]pyridines from 2-aminopyridines and aryl methyl ketones under 660 nm light, in ethanol, with air as the terminal oxidant. A matched-photon-flux screen of seven organic photocatalysts placed MB first (82.0 ± 1.0% qNMR yield), ahead of rose bengal (73.0%) and eosin Y (68.0%). A resolution-V fractional factorial design (16 combinations, 48 responses; R2 = 0.9941) reduced five factors to three, and a central composite design located a provisional optimum at 2.20 mol% MB, 23.5 mol% KI and 8.5 h (predicted 87.87%; validated 88.22%). Under rounded practical conditions the model product 2-phenylimidazo[1,2-a]pyridine (IP01) formed in 88.00 ± 0.61% qNMR and 85.0 ± 0.8% isolated yield. Thirty substrates gave products in 48–88% isolated yield (mean 73.9%), and eight failures are reported with their causes. Low-conversion competition experiments gave a Hammett ρ of −0.653 (R2 = 0.9991). Light on/off cycling, an initial quantum yield of 0.0983 ± 0.0027, Stern–Volmer quenching led by iodide (KSV = 220 M−1), a parallel kinetic isotope effect of 1.41 and an 81% dark yield from a preformed α-iodoketone together point to light-driven ketone iodination followed by thermal ring closure. A 10 mL gas–liquid PFA coil reactor delivered 5.07 g of IP01 over 30 h at 87% isolated yield (space–time yield 16.9 g L−1 h−1), lowering process mass intensity from 94 in batch to 61 in flow.
References
Bagdi, A. K., Santra, S., Monir, K., & Hajra, A. (2015). Synthesis of imidazo[1,2-a]pyridines: A decade update. Chemical Communications, 51(9), 1555–1575. https://doi.org/10.1039/C4CC08495K
Buettner, G. R. (1987). Spin trapping: ESR parameters of spin adducts. Free Radical Biology and Medicine, 3(4), 259–303. https://doi.org/10.1016/S0891-5849(87)80033-3
Cambié, D., Bottecchia, C., Straathof, N. J. W., Hessel, V., & Noël, T. (2016). Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chemical Reviews, 116(17), 10276–10341. https://doi.org/10.1021/acs.chemrev.5b00707
Crisenza, G. E. M., Mazzarella, D., & Melchiorre, P. (2020). Synthetic methods driven by the photoactivity of electron donor–acceptor complexes. Journal of the American Chemical Society, 142(12), 5461–5476. https://doi.org/10.1021/jacs.0c01416
Elgrishi, N., Rountree, K. J., McCarthy, B. D., Rountree, E. S., Eisenhart, T. T., & Dempsey, J. L. (2018). A practical beginner's guide to cyclic voltammetry. Journal of Chemical Education, 95(2), 197–206. https://doi.org/10.1021/acs.jchemed.7b00361
Fukuzumi, S., & Ohkubo, K. (2014). Organic synthetic transformations using organic dyes as photoredox catalysts. Organic & Biomolecular Chemistry, 12(32), 6059–6071. https://doi.org/10.1039/C4OB00843J
Hansch, C., Leo, A., & Taft, R. W. (1991). A survey of Hammett substituent constants and resonance and field parameters. Chemical Reviews, 91(2), 165–195. https://doi.org/10.1021/cr00002a004
Kuhn, H. J., Braslavsky, S. E., & Schmidt, R. (2004). Chemical actinometry (IUPAC Technical Report). Pure and Applied Chemistry, 76(12), 2105–2146. https://doi.org/10.1351/pac200476122105
Lakowicz, J. R. (2006). Principles of fluorescence spectroscopy (3rd ed.). Springer. https://doi.org/10.1007/978-0-387-46312-4
Marzo, L., Pagire, S. K., Reiser, O., & König, B. (2018). Visible-light photocatalysis: Does it make a difference in organic synthesis? Angewandte Chemie International Edition, 57(32), 10034–10072. https://doi.org/10.1002/anie.201709766
Montgomery, D. C. (2017). Design and analysis of experiments (9th ed.). Wiley.
Pitre, S. P., McTiernan, C. D., Vine, W., DiPucchio, R., Grenier, M., & Scaiano, J. C. (2015). Visible-light actinometry and intermittent illumination as convenient tools to study Ru(bpy)3Cl2 mediated photoredox transformations. Scientific Reports, 5, 16397. https://doi.org/10.1038/srep16397
Prier, C. K., Rankic, D. A., & MacMillan, D. W. C. (2013). Visible light photoredox catalysis with transition metal complexes: Applications in organic synthesis. Chemical Reviews, 113(7), 5322–5363. https://doi.org/10.1021/cr300503r
Reichardt, C. (1994). Solvatochromic dyes as solvent polarity indicators. Chemical Reviews, 94(8), 2319–2358. https://doi.org/10.1021/cr00032a005
Romero, N. A., & Nicewicz, D. A. (2016). Organic photoredox catalysis. Chemical Reviews, 116(17), 10075–10166. https://doi.org/10.1021/acs.chemrev.6b00057
Sambiagio, C., & Noël, T. (2020). Flow photochemistry: Shine some light on those tubes! Trends in Chemistry, 2(2), 92–106. https://doi.org/10.1016/j.trechm.2019.09.003
Sheldon, R. A. (2017). The E factor 25 years on: The rise of green chemistry and sustainability. Green Chemistry, 19(1), 18–43. https://doi.org/10.1039/C6GC02157C
Simmons, E. M., & Hartwig, J. F. (2012). On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angewandte Chemie International Edition, 51(13), 3066–3072. https://doi.org/10.1002/anie.201107334
Vitaku, E., Smith, D. T., & Njardarson, J. T. (2014). Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. Journal of Medicinal Chemistry, 57(24), 10257–10274. https://doi.org/10.1021/jm501100b
Downloads
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
