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Augusto Hernandez

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

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Augusto Hernandez

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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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