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
David Amantini @ Wipf Group 2 7/29/04
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
David Amantini @ Wipf Group 3 7/29/04
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
David Amantini @ Wipf Group 5 7/29/04
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
David Amantini @ Wipf Group 6 7/29/04
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
David Amantini @ Wipf Group 8 7/29/04
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
David Amantini @ Wipf Group 10 7/29/04
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