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Oxidations
Oxidations
Oxidations
1 alcohol:
2 alcohol:
H OH
R
O
H
H OH
R
3 alcohol:
H OH
No Reaction
OH
!
:B
H H
R
OH
H H
O CrLn
H3O
OH
H OH
R
slow
O
Cr Ln-1
OH
- 1 alcohols: under anhydrous conditions (Collins, PCC, PDC) will stop at aldehyde
- in presence of aqueous acid (Jones), see further (rapid) oxidation to carboxylic acid
- oxidation of 2 alcohols give ketones
- these processes generate chromium waste (toxic)
preparation
O
O
HO Cr O Cr OH
O
O
H2O
O
HO Cr OH
O
(dilute)
(concentrated)
CrO3, H2SO4
O
OH
acetone
85%
OH
- 1 alcohol CO2H
- rapid reaction
- strongly acidic; not useful for acid sensitive substrates
- reaction can effectively be run as a titration
Yamamoto Tetrahedron
1990, 46, 4595.
OH
R H
H2CrO4
acetone
CrVI (red)
R'
O
Cr
slow
OH
+
R
R'
H2CrO3
CrIII (green)
R2CH-OH + Cr(VI)
R2C=O + Cr(IV) + 2 H+
R2CH-OH + Cr(IV)
R2C=O + Cr(II) + 2 H+
Cr(II) + Cr(VI)
R2CH-OH + Cr(V)
HOCrO
Cr(III) + Cr(V)
R2C=O + Cr(III) + 2 H+
preparation
N O
O Cr
O
N
CrO3 + 2 pyridine
hygroscopic
red crystalline
solid
H2O
(Cr2O7)2-(pyrH+)2
(yellow)
O
CrO3, pyr
CH2Cl2
95%
- 1 alcohol CHO
- neutral to slighlty basic; good for acid sensititve substrates
- requires large excess of reagent; anhydrous conditions
preparation
N
H
O
Cr
O
Cl
O
orange solid
OH
PCC
4 MS, CH2Cl2
O
O
94%
- 1 alcohol CHO
- can use in near stoichiometric amounts (ca. 1.5 equiv)
- mild conditions; slightly acidic can buffer with NaOAc
- add powd MS or Celite to facilitate product isolation
- addition of MS can accelerate rxn rate
- can promote allylic rearrangements
preparation
orange solid
N
H
Cr2O72-
reactivity
PDC
O
CH2Cl2
PDC
OH
DMF
CO2H
Corey Tetrahedron Lett.
1970, 20, 399.
reagent
- dark brown or black solid
O
OH
MeO
MnO2
acetone
MeO
OH
MeO
reactivity
MnO2, NaCN
MeOH, AcOH
O
OH
CO2Me
CN
CN
KMnO4, NaH2PO4
CHO
N
Boc
tBuOH, H2O
94%
CO2H
N
Boc
O
RuCl3-NaIO4
MeCN, CCl4, H2O
OBz
60%
HO
OBz
HO O
- 1 alcohol CO2H
- powerful, non-selective oxidant; will also attack multiple bonds,1,2-diols,
ethers, aromatic rings, etc.
N
HO
CBz
TPAP, NMO
4 MS, CH2Cl2
N
O
CBz
- 1 alcohol CHO
- mild oxidant; no over oxidation, does not react with multiple bonds
- use of MS required to remove water and achieve high catalyst turnover
- modified conditions allow for oxidation of 1 alcohol to carboxylic acid
(Stark Org. Lett. 2011, 13, 4164)
http://www.synarchive.com/named-reactions/Ley-Griffith_Oxidation
OH
E
S O
S O
H
R
B
E
CH2
O S
Me
H
CH2
O S
Me
Me
S
Me
activation:
Cl
O
S O
Cl
Cl
O
S
Me
Cl S
Me
Cl
O
+ CO2 + CO + Cl-
O
DMSO, (COCl)2
CH2Cl2; then Et3N
OH
CHO
- 1 alcohol CHO
- most common of DMSO based reagents
- very mild run at low temp (-78 to -60C)
- low sensitivity to steric factors
- preparation of -alkoxy carbonyl derivatives may be problematic use Et2NiPr
S O
N C N
N C N
reactivity
OBz
OBz
OH
MeO
OBPS
DMSO, EDC
TFA, pyr
94%
O
MeO
OBPS
- 1 alcohol CHO
- first reported DMSO based oxidant; less commonly used
- separation of by-pyroduct (dicyclohexylurea) can be difficult use EDC
HClMe2N
N C N
activation
S O
O
S
O
S O S O
O
reactivity
H
HO
O
H
H
SO3pyr, DMSO
Br
CH2Cl2; Et3N
O
O
H
H
- 1 alcohol CHO
- easy workup; well suited to large scale reactions
Br
reactivity
MeO
MeO
Ag2CO3
toluene, 110
NMe
84%
HO
NMe
Rappoport - codeine
- 1 alcohol CHO
- original oxidant modified by Fetizon adsorb on celite to increase surface area
- neutral conditions; very sensitive to steric factors
- $$$, must use large excess small scale reactions
- reaction does not proceed through cationic intermediate (no rearrangements, etc.)
- controlled overoxidation possible with some substrates (selective lactol oxidation)
HO
MeO
OH
MOMO
MeO
OBn
Ag2CO3/celite
benzene, 80C
MOMO
OBn
O
O
reactivity
CHO
HO
Ag2O
EtOH (aq)
CO2H
HO
80%
- mild method for the conversion of CHO CO2H (in presence of free OH)
- unsaturated aldehydes are problematic (isomerization)
- weak oxidant
F. Other Oxidants
1. Dess-Martin Periodinane
preparation
O
O
CO2H
KBrO3
H2SO4
Ac2O
O
I
O
HO
(IBX) shock
sensitive
O
I OAc
AcO OAc
white
solid
pTsOH, 100C
O
O
MeO
Dess-Martin
CH2Cl2
OH
O
MeO
CHO
- 1 alcohol CHO
- mild reagent; nearly neutral conditions gives off AcOH, but can buffer
- will not oxidize N or S
F. Other Oxidants
mechanism
AcO O
AcO I
AcO
O
- AcOH
AcO O
AcO I
O
OH
H
O
H
AcO I
O
+
2 AcOH
F. Other Oxidants
2. o-Iodoxybenzoic acid (IBX)
preparation
O
CO2H
I
oxone
H2O, 70C
O
I
O
HO
O
IBX (2.3 equiv)
toluene, DMSO
88%
"SIBX"
IBX
F. Other Oxidants
2. o-Iodoxybenzoic acid (IBX)
49%
CO2H
22%
preparation
HO2C
O
CO2H
I
oxone
H2O, 70C
O
I
O
HO
CO2H
O
IBX (2.3 equiv)
toluene, DMSO
88%
29%
F. Other Oxidants
mechanism
O
O O
I
HO
- H2O
H
H
OH
H
I
H
O
O
O
O
O I
HO
O
I
O HO
HO
HO I
F. Other Oxidants
3. Al(OiPr)3, acetone: Oppenauer Oxidation
reactivity
OH
Al(OiPr)3
acetone
MeO
MeO
Me
Me
Al(OiPr)3
OiPr
O Al OiPr
H O
H OiPr
O Al OiPr
OiPr
H+ transfer
- HOiPr
OiPr
O Al
OiPr
OiPr
Al OiPr
O
H
F. Other Oxidants
4. Sodium Chlorite (NaClO2): Pinnick Oxidation
reactivity
CHO
NaClO2
OH
tBuOH, H2O
CHO
CO2H
NaClO2
tBuOH, H2O
OH
CO2H
- useful method for oxidation of sensitive CHO CO2H, esp. ,-unsaturated CHO
- use hampered by formation of chlorine dioxide
- suppressed by addition of chlorine scavenger (alkene)
5. Sodium Hypochlorite (NaOCl): Stevens Oxidation
reactivity
OH
OH
NaOCl
AcOH
86%
OH
F. Other Oxidants
6. TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy):
reactivity
Boc
N
O
OH
Boc
N
O
90%
- 1 alcohol CHO
- used in presence of stoichimetric oxidant (mCPBA, NaOCl, PhI(OAc)3, oxone, etc.
- works best in simple systems
- selective oxidation of alcohols in presence of S or Se
mechanism
[O]
[O]
N
O
N
O
N
OH
RCH2OH + B
RCHO
N
O O
H
BH
R
Oxidation of Ketones
O
O
O
OH
Ketone Enone
1. IBX
!
reactivity
O
!
O
H
TIPS
H
IBX (2 equiv)
tol/DMSO
TIPS
H
87%
2. Saegusa Oxidation!
reactivity
OTMS
Pd(OAc)2
MeCN, rt
O
Ketone Enone
2. Saegusa Oxidation!
mechanism
Ketone Enone
3. Selenoxide Elimination
reactivity
O
O
LDA;
PhSeBr
O
SePh
H2O2
Ketones Esters/Lactones
1. Baeyer Villager Oxidation
reactivity
mCPBA
Me
O
mCPBA
Me
H
Alpha Hydroxylation
1. Rubottom Oxidation
reactivity
OTMS
O
OR
mCPBA
CH2Cl2
R = H, TMS
reactivity
O
O
LDA;
MoOPh
OH
OO
O Mo O
(Me2N)3P O N O
MoOPh
- MoOPh = MoO5pryHMPA
- attack of enolate at peroxyl oxygen atom leads to O-O bond cleavage
Alpha Hydroxylation
3. Davis Oxaziridine !
preparation
Ph
N
PhSO2
!
mCPBA or
oxone
O Ph
N
PhSO2
OTBS
HO
KHMDS;
Davis oxaziridine
O
O
H
OTMS
O
Ph
Me
68%
1. NaHMDS
2.
Ph
Cl
N
O S
O
O
O
OTMS
Me
OH
Cl
61%, 95% ee