Current Literature 24th July 20041

Palladium-Catalyzed Oxygenation of Unactivated sp3 C-H Bonds

Desai, L. P.; Hull, K. L.; Sanford*, M. S. University of Michigan

J. Am. Chem. Soc. 2004, 126, ASAP (Web Release 16th July 2004)

NMeO

Pd(OAc)2 5 mol%HN

MeO PdO

O

2PhI(OAc)2 1.1 eq.

NMeO

OAc

David Amantini @ Wipf Group 1 7/29/04

Current Literature 24th July 20042

Oxidation of Unactivated sp3 C-H Bonds: A Challenge in Organic Synthesis…

- REACTIVITY ( C-H bond dissociation energy in methane 104 kcal mol-1)

- SELECTIVITY ( C-H bond dissociation energy in methanol: 93 kcal mol-1)

…. while in Nature…

O

OHMycobacterium phlei

O

OH

Stearic acid Oleic acid

O

O

O

O

Rhizopus nigricansHO

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Current Literature 24th July 20043

Chemical Routes for the Intramolecular Oxidative Functionalization ofUnactivated sp3 C-H Bond

a) Reactions based on heteroatom centered radicals

b) Reactions based on Rhodium-mediated carbene and nitrene sp3 C-H bond insertions

c) Reactions based on transition metal-mediated sp3 C-H bond activation

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Current Literature 24th July 20044

Reactions Based on Heteroatom-Centered Radicals

Hoffmann-Loeffler-Freytag Reaction

Hoffmann, A. W. Ber. 1883, 16, 558.Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1958, 80, 2903.

Arigoni, D. and coworkers J.Am. Chem. Soc. 1958, 80, 2905.

Barton`s Nitrite Photolysis

Barton, D. H. R. and coworkers J.Am. Chem. Soc. 1960, 82, 2640

Breslow`s Remote Oxidation

Breslow, R. and coworkers J. Am. Chem. 1973, 95, 3251 Jung, M. E.: Johnson, T. W. J. Am. Chem. Soc. 1997, 119, 12412

R1NCl

R2

1. H, Δ

2. OH R1 NR2

O

OO

OAc

NO

hν

O

HOO

OAc

NHO

hνO

O

OHO

O

O

David Amantini @ Wipf Group 4 7/29/04

Current Literature 24th July 20045

Reactions Based on Rhodium-Mediated Carbene and Nitrene sp3 C-H BondInsertions

Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598.

For a Review on the Use of Rh-Mediated Intramolecular C-H Insertion in Natural Products Syntheses see:Taber, D. F.; Stiriba, S.-E. Chem. Eur. J. 1998, 4, 990 and references therein.

O

O

OH

OTBSO

ON2

Rh2(HNCOCPh3)4 1.5 mol%

O

O

OOTBSO

O

(-)-Tetrodotoxin

OHOH

OHOHO

OHO

HOHNH2N

NH

O

O

OO

O

OO

ONH2

ClH

Rh2(HNCOCF3)4 10 mol%PhI(OAc)2, MgO

A B C

O

O

OO

O

OO

O

NH

Cl

D

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Current Literature 24th July 20046

Reactions Based on Transition Metal-Mediated sp3 C-H Bond Activation:the Shilov Reaction

Shilov, A. E.; Shul`pin, G. B. Chem. Rev. 1997, 97, 2879. Stahl, S. S. and coworkers Angew. Chem., Int. Ed. 1998, 37, 2180.

Sen, A. and coworkers J. Am. Chem. Soc. 2001, 123, 1000.

R H + Pt (II)Oxidant

R-Y

Y = OH, Cl, ..

Pt(II)

R-H + PtR

(II)+ H

Oxidant

Reduced Oxidant

PtR

(IV)Y

R Y

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Current Literature 24th July 20047

Unactivated sp3 C-H Bond Oxidative Functionalization by Group 10 Metals

PROBLEMS:a) Harsh reaction conditions: no applications to complex organic molecules

b) Low TON

c) Low functional group tolerance

d) Low level of regioselectivity

THE KEY:The use of substrates containing coordinating functional groups that can bindthe metal catalyst and direct the oxidation process to a specific sp3 C-H bondwithin the molecule.

David Amantini @ Wipf Group 7 7/29/04

Current Literature 24th July 20048

Unactivated sp3 C-H Bond Oxidative Functionalization by Group 10 Metals:Stoichiometric Version

Sames, D. and coworkers J. Am. Chem. Soc. 2002, 124, 6900.

For other Stoichiometric Examples see: Sames, D. and coworkers J. Am. Chem. Soc. 2002, 124, 11856. Gribble, G. W. and coworkers J. Org. Chem. 2000, 65, 6278.

N

NO2

Br

DMF 100 oC

90%

NNO2

Br

Ag2CO3

Toluene

NO2N

70%

NH2N

O

1. CCl3COCl2. NaOMe, MeOH

3. H2, Pd/C

88%

O

NcHex

O

Ph

TsOH, Toluene

1.

2. [Me2Pt(µ-SMe2)]2

30%

NPh

NO

cHex

PtMe

Me

NO

TfOH

DCM

NO

N

ON

cHex

Pt Me

CF3CH2OH

70 oC

NO

N

ON

cHex

Pt

- CH4

KCN

42% 3 stepsdr 4.4 / 1

NO

N

ON

cHex

NH2OH

quantitative

NO

NH2

Pd/C, HCOOH, CO1.

2. NaOH, MeOH then HCl

NO

NOH45 %

(-)-Rhazinilam

(HPLC separation)

TfO TfO

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Current Literature 24th July 20049

Unactivated sp3 C-H Bond Oxidative Functionalization by Group 10 Metals:Catalytic Version

Sames, D. and coworkers J. Am. Chem. Soc. 2001, 123, 8149.For an another Catalytic example see: Sames, D. and coworkers J. Am. Chem. Soc. 2002, 124, 13372.

α-aminoacid

K2PtCl4 5 mol%CuCl2 7 eq.

H2O160 oC 10h

product1. Boc2O

2. AcOH oxidized α−aminoacid

Entry Substrate Products Distribution Yield (%)γ / δ

NH2

CO2HL-Valine

NHBoc

OO

NHBoc

OO

3 1

271

NH2

CO2HL-Norvaline2

NHBoc

OO

NHBoc

OO

2 1

NBoC

CO2H

1

21

NH2

CO2HL-Leucine3

NHBoc

OO

22

NBoC

CO2H

4

NBoC

CO2H

1

3

4.5 15

L-ProlineNH

CO2HNO REACTION

4

David Amantini @ Wipf Group 9 7/29/04

Current Literature 24th July 200410

Authors Precedent Paper: A Highly Selective Catalytic Method for theOxidative Functionalization of C-H Bonds

Sanford, M. S. and coworkers J. Am. Chem. Soc. 2004, 126, 2300.

Pd(OAc)2 1-6 mol%PhI(OAc)2 1.1-1.6 eq.

AcOH or CH3CN100 oC 12-20 h

Product

Entry Product Yield (%)

1

2

3

4

Substrate

NAcO

N

AcO

OAc

N N Ph

NN

AcO

OAcN

H

Ph

OAc

N

NAcO

EntryYield (%)

N OAc

Product

86 5 54

88 6 72

80 7 52

62 478

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Current Literature 24th July 200411

(I) Palladium-Catalyzed Oxygenation of Unactivated sp3 C-H Bonds

Sanford, M. S. and coworkers J. Am. Chem. Soc. 2004, 126,ASAP.

Pd(OAc)2 5 mol%PhI(OAc)2 1.1 eq.

AcOH -Ac2O 1-1100 oC 1.5-3.5 h

Entry Substrate Yield (%)

1

2

3

4

Product

74

78

39

NMeO

R`R

NMeO

R`R

OAc

NMeO NMeO OAc

NMeO NMeO OAc

NMeO NMeO OAc

NMeONO REACTION

5NMeO

NO REACTION

David Amantini @ Wipf Group 11 7/29/04

Current Literature 24th July 200412

(II) Palladium-Catalyzed Oxygenation of Unactivated sp3 C-H Bonds

Sanford, M. S. and coworkers J. Am. Chem. Soc. 2004, 126,ASAP.

Pd(OAc)2 5 mol%PhI(OAc)2 1.1 -3.2 eq.

AcOH -Ac2O 1-180-100 oC 5 min- 12h

Substrate Product

Entry Product Yield (%)

1

2

3

4

EntryYield (%) Product

61 5 42

75 6 66

81 7 44

86 818

Substrate

NMeO

NMeO

OAc

N OMe N OMe

OAc

NOMe

NOMe

OAc

NOMe

NOMe

OAc

Substrate

N N

OAc

N O N O OAc

N O N O

OAc

NMeOH

H

NMeOH

H

OAc

David Amantini @ Wipf Group 12 7/29/04

Current Literature 24th July 200413

(III) Palladium-Catalyzed Oxygenation of Unactivated sp3 C-H Bonds

Hypothesized Mechanism

Pd(II)

Pd-H

Oxidant

Reduced Oxidant

Y

L C H L C(II)

PdL C

YY(IV)

L C Y

David Amantini @ Wipf Group 13 7/29/04

Current Literature 24th July 200414

Summary

- An efficient and highly β selective sp3 C-H bond oxidative functionalization forO-methyl oximes and pyridines have been described.

- The level of regioselectivity displayed by the described methodology isunprecedented.

- The mild reaction conditions used along with the selectivity displayed, make themethodology a significant potential synthetic tool.

- Future work aimed to elucidate the scope and the mechanism of the transformationdescribed would be of particular interest for the synthetic community.

David Amantini @ Wipf Group 14 7/29/04