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)2O

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.