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Visible Light-Mediated Radical Reactions of Alkyl, Alkenyl, and Aryl Iodides

This study explores a new method for engaging unactivated alkyl, alkenyl, and aryl iodides in visible-light mediated free radical reactions. Traditional reduction methods face limitations such as lack of functional group tolerance and undesired side reactions. The proposed approach leverages mild conditions, broad functional group tolerance, and high product yields, using cost-effective metal-based photocatalysts to generate radical intermediates. This research opens pathways for efficient deiodination protocols and could significantly impact total synthesis methodologies.

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Visible Light-Mediated Radical Reactions of Alkyl, Alkenyl, and Aryl Iodides

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  1. Engaging unactivated alkyl, alkenyl and aryl iodides in visible-light mediated free radical reactions. Augusto Hernandez October 23th, 2012. Nguyen, J. D.; D‘Amato, E. R.; Nayaranam, J. M. R.; Stephenson, C. R. J. Nature Chem..2012, 4, 854-859.

  2. RADICAL REDUCTION DEHALOGENATION. • Alkyl, alkenyl and aryl iodides conventional reduction methods1: • 1- Metal-halogen exchange • 2-Hydride source • Not functional group tolerant • Undesired side reactions possible • 3-Radical reductive dehalogenation • Common system: • Organotin (nBu3SnH with AIBN) • Samarium(II) iodide • Trialkylborane (Et3B and air) • Use in the total synthesis of (±)-hirsutene2: (1)Alonso, F., Beletskaya, I. P.; Yus, M. Chem. Rev.2002, 102, 4009–4091. (2) Curran, D. P. & Rakiewicz, D. M. J. Am. Chem. Soc.1985, 107, 1448–1449.

  3. RADICAL REDUCTION DEHALOGENATION. • Radical reductive dehalogenation • Common system: • Organotin (nBu3SnH with AIBN) • Samarium(II) iodide • Trialkylborane (Et3B and air) • Advantages: • Most used method • Mild conditions (pH neutral) • Short reaction time • High product yield • Disadvantages: • toxic3 • unstable to air4 • pyrophoric5 (3) Neumann, W. P. Synthesis1987, 665–683. (4) Krief, A.; Laval, A-M. Chem. Rev.1999, 99, 745–777. (5) Medeiros, M. R., Schacherer, L. N., Spiegel, D. A. & Wood, J. L. Org. Lett.2007, 9, 4427–4429.

  4. NEW SYSTEMS. • Ground-state neutral electron donors (tetraazaalkene)6,7: • Aryl and alkyl iodides: • Cobalt-catalyzed Heck-type cyclization8: • Alkyl and stannyl-cobaloxime catalyst: • Alkyl iodides only Yield: 70-90% (6) Murphy, J. A., Khan, T. A., Zhou, S. Z., Thomson, D. W.; Mahesh, M. Angew. Chem. Int. Ed.2005, 44, 1356–1360. (7) Murphy, J. A. et al. Angew. Chem. Int. Ed.2012, 51, 3673–3676. (8) Weiss, M. E., Kreis, L. M., Lauber, A.; Carreira E. M. Angew. Chem. Int. Ed.2011, 50, 11125–11128.

  5. GOAL. • Develop a new mild and efficient radical reductive deiodination protocol • Broad functional group tolerance • Easy-to-handle catalyst • Inexpensive and readily available hydrogen atom donor • Metal-based photocatalyst (Ru or Ir) : Generates radical intermediates from activated carbon-halogen bond Bromomalonates9 Polyhalomethanes10,11 Electron-deficient benzyl bromides12 -halo carbonyl13 Glycosyl bromides14 (9) Nguyen, J. D., Tucker, J. W., Konieczynska, M. D.; Stephenson, C. R. J. J. Am. Chem. Soc.2011, 133, 4160–4163. (10) agib, D. A., Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc.2009, 131, 10875–10877. (11) Dai, C., Narayanam, J. M. R.; Stephenson, C. R. J. Nature Chem.2011, 3, 140–145. (12) Shih, H. W., Vander Wal, M. N., Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc.2011, 132, 13600–13603. (13) Tucker, J. W.; Stephenson, C. R. J. Org. Lett.2011, 13, 5468–5471. (14) Andrews, R. S., Becker, J. J.; Gagné, M. R. Angew. Chem. Int. Ed.2010, 9, 7274–7276.

  6. PREVIOUS WORK. • Tin-free alternative using of [Ru(II)(bpy)3]Cl2 photocatalyst: • Use of iPr2NEt with HCOOH or Hantzsch ester15 • Tin-free radical cyclization reactions using of [Ru(II)(bpy)3]Cl2 photocatalyst16 • Use of Et3N (15)Narayanam, J. M. R., Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc.2009, 131, 8756–8757. (16) Tucker, J. W., Nguyen, J. D., Narayanam, J. M. R., Krabbe, S. W.; Stephenson, C. R. J. Chem. Commun.2010, 46, 4985–4987.

  7. PHOTOCATALYST TUNING. • Reduction of unactivated carbon-iodide bonds is difficult due to high reduction potential • Photocatalyst tuning to stronger reduction potential: change of ligand • (bipyridyl to phenylpyridyl)

  8. OPTIMIZATION. • Best reductant: tributylamine • Acetonotrile gives better • conversion • Argon sparging increase • conversion than freeze-pump-thaw • degassing

  9. SCOPE - REDUCTION OF ALKYL IODIDES AND ARYL IODIDES. • Excellent functional group tolerance. • Bu3N and HCO2H give acceptable reaction times (52h vs 24h). • Aryl bromide and chloride are not reduced. • Bu3N and HCO2H are not suitable for alkyl iodide (low yields).

  10. SCOPE - REDUCTION OF ALKENYL IODIDES. • Increase of Bu3N and HCO2H to achieve acceptable reaction times. • Procedure is effective • for intramolecular cyclization1 • No substitution or elimination product observed • Scope of products • -tetrahydrofuran • -indoline • -indole • -dihydrobenzofuran • -carbocycle

  11. GRAM SCALE REACTION / FLOW REACTION. • Gram scale reaction • 7,5 times more substrate • 20 times less photocatalyst • Flow reaction • Increase of conversion rate Flow reaction: 0,900 mol/h Batch reaction: 0,020 mol/h (17) Tucker, J. W., Zhang, Y., Jamison, T. F.; Stephenson, C. R. J. Angew. Chem. Int. Ed.2012, 51, 4144–4147.

  12. MECHANISM. • Radical based mechanism • Visible light and photocatalyst necessary • HCO2H/trialkylamine or • Hantzsch ester/trialkylamine are • electron donor/hydrogen atom donor • Acetonitrile is not an hydrogen atom donor • Photocatalyst acts only as an initiator • No catalyst turnover without electron donor • Propagation chains are short-lived 0% deuterium incorporation

  13. MECHANISM. • Reductive cleavage gives Ir(ppy)3+ and carbon radical • Hydrogen abstraction from Bu3N, Hantzsch ester or formic acid • Bu3N is oxidize to regenerate Ir(ppy) (17) Tucker, J. W., Zhang, Y., Jamison, T. F.; Stephenson, C. R. J. Angew. Chem. Int. Ed.2012, 51, 4144–4147.

  14. CONCLUSION. • Visible light photoredox-mediated reductive deiodination protocol • Can undergo intramolecularcyclization • Mild conditions • Low catalyst loading with high yields • Electron and hydrogen donors are inexpensive and readily available • High functional group tolerance • Easy to scale-up • Short reaction time with flow reaction

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