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.
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.
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. Synthesis 1987, 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.
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.
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
Electron-deficient benzyl bromides12
Polyhalomethanes10,11
-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.
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.
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)
OPTIMIZATION.
•Best reductant: tributylamine
•Acetonotrile gives better
conversion
•Argon sparging increase
conversion than freeze-pump-thaw
degassing
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).
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
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.
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
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.
CONCLUSION.
Visible light photoredox-mediated reductive deiodination protocol
•Can undergo intramolecular cyclization
•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