Allylic Oxidations and Oxidation of Ketones to...
Transcript of Allylic Oxidations and Oxidation of Ketones to...
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.