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