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Allylic Oxidations and
Oxidation of Ketones to Enones
Jeff Cannon!Chemistry Topics!
May 3, 2011!
OH
[O] O O[O]
Common Allylic Oxidation Techniques Selenium dioxide:
Transition Metal C–H Insertion:
OAcPd(II), ox.
SeO2
tBuOOHOAc OAc
OH
CuCl
t-BuOOH, AcOH
OAc
Palladium:
Copper:
Mechanism of Selenium-Mediated Allylic Oxidation Se HO
O SeOHO
Se OHO
OSeOH
Ene
reaction
[2,3]
H
OSeO
δ+
SeOHO
δ–
RR
Me SeO2 RR
Me
OH
RSeO2
R
OH
R R
R
R R
R
OHSeO2
Displays good selectivity trends for substituted olefins:
Examples of Selenium Dioxide Allylic Oxidation in Synthesis
MeCO2Me
OSEMSEMO
cat. SeO2t-BuOOH
CH2Cl2, rt(61%)
MeCO2Me
OSEMSEMO
OH
MeCO2Me
OSEMSEMO
O
cristatic acid
Fürstner Org. Lett. 2000, 2, 2467:
Stork J. Am. Chem. Soc. 2009, 131, 11402:
O
NMeO
O
OMe
O
NMeO
O
OMe
OHHH
SeO2, t-BuOOH
CH2Cl2, H2O(61%)
Common Allylic Oxidation Techniques Selenium dioxide:
Transition Metal C–H Insertion:
OAcPd(II), ox.
SeO2
tBuOOHOAc OAc
OH
CuCl
t-BuOOH, AcOH
OAc
Palladium:
Copper:
Mechanism of Transition Metal-Catalyzed Allylic Oxidation
PdOAc
Pd(OAc)2
R(AcO)2Pd
R
Pd(0)
R
HOAc
R
OAc
Oxidant
Oxidant•H2
ArCO3t-Bu [Cu] OCOAr
[Cu]OCOAr
OCOAr
Copper:
Palladium:
Examples of Transition Metal-Catalyzed Allylic Oxidation White:
Stahl:
Andrus:
N
O
CuN
OEtEt
Ph PhPF6O
OO
O2NCH3CN, –20, 8 d(41%, 99% ee)
+O
NO2
O
HN O
OBenzoquinone
AcOH(64%)
Pd(OAc)2
SPh
O
HN O
O
OAc
N N
O
Pd(OAc)2
AcOH, O2 (atm)60 °C(76%)
OAc
Summary of Allylic Oxidation Reactions Selenium dioxide mediated allylic oxidations: • Proceed through a double-pericyclic (ene, [2,3]) mechanism • Are often highly selective • Can have multiple byproducts:
• Selenoxide elimination • Pummerer-type reactions • Selenium dioxide readily oxidizes ketones to 1,2-diketones • Overoxidation products can be problematic
Transition metal-catalyzed allylic oxidations: • Palladium-catalyzed reactions currently only effective on terminal olefins • Palladium regioselectivity can be tuned by ligand selection • Copper reacts with internal olefins, but regioselectivity is poor • Enantioselectivity is possible, but not general yet
Common Ketone to Enone Techniques
Saegusa Oxidation:
Pd(II)
Ox.
O Me
TBSO
LDA
TMSCl
OTMSMe
TBSO
O Me
TBSO
Selenoxide Elimination:
O O OSePh
LDA
PhSeCl CH2Cl2, Py
H2O2
IBX Oxidation: O
H
TIPS
O
H
TIPSIBX
Mechanism of Selenoxide Elimination
R
OSePh [O]
R
OSe
H
O
Phsyn elimination
R
O
• Syn elimination produces selectively the trans olefin in acyclic systems!
• Endocyclic double-bonds formed selectively unless no syn hydrogen is available!
• Conjugated products formed selectively!
Examples of Selenoxide Elimination Tadano, J. Am. Chem. Soc. 2003, 125, 14722:!
Smith, J. Am. Chem. Soc. 2009, 131, 2348:!
O
OOO
OSePh
O
OOO
O
NaIO4, rtTHF/H2O
(90%)
O
OOO
O
HO
Pinnick
(–)-okilactomycin
O
OO OH
OMPM
O
OO OH
OMPM
i) PhSeCl, Et3N
ii) mCPBA, CH2Cl2 –50 °C (>48%) O
OO
HH
O
HH
OH
(+)-macquarimicin A
H
Common Ketone to Enone Techniques
Saegusa Oxidation:
Pd(II)
Ox.
O Me
TBSO
LDA
TMSCl
OTMSMe
TBSO
O Me
TBSO
Selenoxide Elimination:
O O OSePh
LDA
PhSeCl CH2Cl2, Py
H2O2
IBX Oxidation: O
H
TIPS
O
H
TIPSIBX
Mechanism of Saegusa Oxidation OSiR3
Pd(OAc)2OSiR3Pd(OAc)2
OPdOAc O
PdOAc
O
HPdOAci) Red. Elimination
ii) Reoxidation (BQ or O2)
• Often requires a large amount of Pd(OAc)2 (>0.5 equiv) to acquire a substantial rate!
• Fairly mild oxidation conditions!
• Enol silanes are easily formed from corresponding ketones!
Examples of Saegusa Oxidation Sasaki, J. Am. Chem. Soc. 2002, 124, 14983:
O
O
O
OTBS
O
RO
RO
Me
H
Me
H
H
H H 1) LHMDS, TMSCl
2) Pd(OAc)2
O
O
O
OTBS
O
RO
RO
Me
H
Me
H
H
H H
(>94%)
gambierol
Crimmins, J. Am. Chem. Soc. 1986, 108, 3435:
Me
O
H1) EtMe3SiOAc TBAF
2) cat. Pd(OAc)2 benzoquinone Me
O
Me
Me
silphinene
Common Ketone to Enone Techniques
Saegusa Oxidation:
Pd(II)
Ox.
O Me
TBSO
LDA
TMSCl
OTMSMe
TBSO
O Me
TBSO
Selenoxide Elimination:
O O OSePh
LDA
PhSeCl CH2Cl2, Py
H2O2
IBX Oxidation: O
H
TIPS
O
H
TIPSIBX
Mechanism of IBX Oxidation
• Will oxidize ketones, enol silanes, and alcohols directly to enones.
• More cost-effective than Saegusa conditions
• IBX will oxidize alcohols to ketones and aldehydes
O OYI
O
O
HO O OI
O
OHOY
O
OI
O
OHOY
O
OI
O
OHOY
OH
OI
O
O
HO
–YO–
Y = H
Y = H or SiR3
SET
Examples of IBX Oxidation Charette, J. Am. Chem. Soc. 2008, 130, 13873:
BzN
H
OHH
OAc
Me IBX
toluene/DMSO(75%)
BzN
H
OH
OAc
MeHN
H
HOH
Me
ent-lepadin B
Overman, J. Am. Chem. Soc. 2008, 130, 5368:
NH
N
O
MeO2CNBoc
N
O
MeO2C
1) IBX, 70 °C
2) TFA (40%)
Summary of Oxidations of Ketones to Enones Selenoxide Elimination: • Syn-elimination mechanism usually provides high stereoselectivity
• Requires use of toxic and odorous selenium reagents • Similar reactivity extends to sulfoxide elimination
Saegusa Oxidation: • β-Hydride elimination of palladium enolate mechanism
• Often requires >0.5 equiv. of Pd(OAc)2 to proceed, though truly catalytic examples exist
• Oxidation is site-selective if enol-silane can be generated selectively, including from conjugate addition reactions.
IBX oxidation: • Single-electron transfer oxidation mechanism
• Mild reaction conditions can provide enone directly from ketone or alcohol • Will react with other oxidizable alcohols in the molecule
Seminal References Selenium Allylic Oxidation:
Guillemonat, A. Annali di Chimica Applicata 1939, 11, 143–211.
Metal-catalyzed allylic oxidation: Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc.
2010, 132, 15116–15119. Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc.
2005, 127, 6970–6971. Andrus, M. B.; Lashley, J. C. Tetrahedron 2002, 58, 845–866.
Selenoxide elimination: Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 5434–5447.
Saegusa oxidation: Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
IBX oxidation: Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem.
Soc. 2002, 124, 2245–2258.
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