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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. - PowerPoint PPT Presentation
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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.
R1 R2
I
RI
I
R I
Ir
N
N N
VISIBLELIGHT
R1 R2
H
RH
H
R
H
RADICAL REDUCTION DEHALOGENATION.
Alkyl, alkenyl and aryl iodides conventional reduction methods1:
1- Metal-halogen exchange2-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.
InBu3SnH, AIBN
H
H
H
RADICAL REDUCTION DEHALOGENATION.
Radical reductive dehalogenation
•Common system: •Organotin (nBu3SnH with AIBN)
•Samarium(II) iodide•Trialkylborane (Et3B and air)
(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.
Advantages:•Most used method
• Mild conditions (pH neutral)
•Short reaction time•High product yield
Disadvantages:toxic3
unstable to air4
pyrophoric5
initiation
RX
Bu3SnX
R
R'Bu3SnH Bu3Sn
R'H Bu3SnH
Propagation
NEW SYSTEMS.
(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.
•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
RN
N N
N
I
X R
R
MeO
O R
R
I
R = H or MeX = NMs or O
R X R
R
MeO
O R
RYield: 60-80%
Yield: 70-90%
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
(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.
RO2C CO2R
Br
F CO2R
Br
F CO2R
Br
FCF3
I
CBr3
Br
CHI2
I
CCl3
Br
BrEWG
ArBr
OAr
BrAr
NR2
O O
OR'R'O
OR'
BrR'O
Polyhalomethanes10,11
Electron-deficient benzyl bromides12
-halo carbonyl13 Glycosyl bromides14
PREVIOUS WORK.
•Tin-free alternative using of [Ru(II)(bpy)3]Cl2 photocatalyst: Use of iPr2NEt with HCOOH or Hantzsch ester15
(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.
•Tin-free radical cyclization reactions using of [Ru(II)(bpy)3]Cl2 photocatalyst16
Use of Et3N
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.
(17) Tucker, J. W., Zhang, Y., Jamison, T. F.; Stephenson, C. R. J. Angew. Chem. Int. Ed. 2012, 51, 4144–4147.
C8F17
I
HO
f ac-Ir(ppy)3 (0.005mol%)Hantzsch ester (1.1 equiv.)
Bu3N (2.0 equiv.)
MeCN, visible light10h, 92%
C8F17
H
HO
4.6mmol (3 g)
Flow reaction
Increase of conversion rate
Gram scale reaction
•7,5 times more substrate•20 times less photocatalyst
O Ph
f ac-Ir(ppy)3 (0.050mol%)HCO2H (5.0 equiv.)Bu3N (5.0 equiv.)
MeCN, flow LEDtr = 40min, 93%
OI
O Ph
OH
f ac-Ir(ppy)3 (1.0mol%)HCO2H (5.0 equiv.)Bu3N (5.0 equiv.)
MeCN, visible light30h 95%
O Ph
OI
Batch reaction: 0,020 mol/h
Flow reaction: 0,900 mol/h
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
NTs
I f ac-Ir(ppy)3 (2.5mol%)
MeCN, visible light24h
NTs
I
NTs
I
14% 75%
I
TsHN
f ac-Ir(ppy)3 (1.0mol%)HCO2H (5.0 equiv.)Bu3N (5.0 equiv.)
MeCN-d3, visible light20h, 92h
H
TsHN
0% deuterium incorporation
Ir(ppy)3
visible lightIr(ppy)3*
Ir(ppy)+
NTs
I
NTs
NTs
NTs
I
NTs
I
NTs
MECHANISM.
(17) Tucker, J. W., Zhang, Y., Jamison, T. F.; Stephenson, C. R. J. Angew. Chem. Int. Ed. 2012, 51, 4144–4147.
•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)
CONCLUSION.
R1 R2
I
RI
I
R I MeCN, visible light24h, r.t.
f ac-Ir(ppy)3
Hantzsch ester or HCO2HBu3N
R1 R2
H
RH
H
R
H
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