34
Oxidation of Alcohols R H OH H R H O R OH O R H OH H R R O R H OH H No Reaction 1° alcohol: 2° alcohol: 3° alcohol:
Oxidation of Alcohols
R H
OHH
R H
O
R OH
O
R H
OHH
R R
O
R H
OHHNo Reaction
1° alcohol:
2° alcohol:
3° alcohol:
A. Chromium Based Reagents
General Mechanism: ! ! !
- 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)
R OH
HHO CrLn
R O
HH
CrO
Ln-1 R H
O+ slow
H3OR OH
O
R OH
OHH
:B
A. Chromium Based Reagents
1. CrO3/H2SO4 (aq): Jones Oxidation ! ! !
- 1° alcohol CO2H - rapid reaction - strongly acidic; not useful for acid sensitive substrates - reaction can effectively be run as a titration
• preparation
• reactivity
- reagent is shelf stable
CrO3 + H2O + H2SO4
H2OCr O CrHO OHO O
OOHO Cr OH
O
O2
(concentrated) (dilute)
O OH
CrO3, H2SO4acetone O OH
O
85%Yamamoto Tetrahedron
1990, 46, 4595.
A. Chromium Based Reagents
• mechanism
- stoichiometry: 3 R2CHOH + 2 CrO3 + 6 H+ 3 R2C=O + 2 Cr3+ + 6 H2O
R' O
HR
CrO
OH R R'
OslowR' OH
HR H2CrO4acetone
CrVI (red) O
+ H2CrO3 HOCrO
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) Cr(III) + Cr(V)
R2CH-OH + Cr(V) R2C=O + Cr(III) + 2 H+
A. Chromium Based Reagents
2. CrO3•pyridine: Collins reagent ! ! !
- 1° alcohol CHO - neutral to slighlty basic; good for acid sensititve substrates - requires large excess of reagent; anhydrous conditions
• preparation
• reactivity
CrO3 + 2 pyridineNCrN
OOO
hygroscopic red crystalline
solid
H2O (Cr2O7)2-(pyrH+)2
(yellow)
- important: add CrO3 to pyridine (reverse results in strong exotherm!) - Sarett: in situ generation in pyridine - Collins: isolated solid; reaction in CH2Cl2 - Radcliff: in situ generation in CH2Cl2
CrO3, pyrCH2Cl2
OH
H
O
H Ratcliffe JOC 1970, 35, 4000.95%
A. Chromium Based Reagents
3. Pyridinium Chlorochromate (PCC): Corey-Suggs Oxidation ! !
- 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
• reactivity
- stable; commercially available
- chloride facilitates formation of chromate ester
CrO3 + HCl + pyridineNH
CrO
orange solidO
ClO
O OH
O PCC4Å MS, CH2Cl2
94%
O O
O
Nicolaou J. Am. Chem. Soc.1988, 110, 4672
A. Chromium Based Reagents
4. Pyridinium Dichromate (PDC): Corey-Schmidt Oxidation ! !
- product of reaction depends on solvent used CH2Cl2: 1° alcohol CHO DMF: 1° alcohol CO2H (allylic alcohols give CHO)
- oxidizes more slowly than other Cr-based reagents - mild conditions; less acidic than PCC
• preparation
• reactivity
- stable; commercially available
CrO3 + pyridine + H2O NH
orange solid
2 Cr2O72-
PDCDMF
PDCCH2Cl2 OH CO2HO Corey Tetrahedron Lett.
1970, 20, 399.
B. Manganese Based Reagents
1. Manganese Dioxide (MnO2) !
- selective oxidation of allylic and benzylic alcohols; significant rate difference! - 1° alcohol CHO - slow reaction, requires large excess of reagent - H bonding solvents show strong deactivating effect; non-polar solvents best - mild; no isomerization of double bonds upon oxidiation of allylic alcohols
• reagent
• reactivity
- dark brown or black solid
- structure/activity depends on preparation - non-stoichiometric material containes Mn(II) and Mn(III) oxides and hydrated species
MeO
MeO
OH
OHMnO2acetone
MeO
MeO
OH
O
B. Manganese Based Reagents
2. Manganese Dioxide, ROH, NaCN: Corey-Gilman-Ganem Oxidation !!
- direct oxidation of 1° allylic/benzylic alcohols to esters - more commonly used for the conversion of conjugated aldehydes to esters
• reagent
• reactivity
- modified MnO2 oxidation
OOH
MnO2, NaCNMeOH, AcOH O CO2Me
B. Manganese Based Reagents
3. Potassium Permanganate (KMnO4)
• reactivity
- 1° alcohol CO2H; also useful for the oxidation of aldehydes - powerful oxidant; over oxidation/side reactions may be a problem also oxidizes alkenes, 1,2-diols, etc. - insoluble in organic solvents - may be successful when other oxidants fail (Jones, AgO, NaOCl). - R4NMnO4 shows similar reactivity and is soluble in organics
N
O
CHOBoc
CNKMnO4, NaH2PO4
tBuOH, H2O94%
N
O
CO2HBoc
CN
Joullié J. Am. Chem. Soc.1992, 114, 10181.
C. Ruthenium Based Reagents
1. Ruthenium Tetraoxide (RuO4)
- 1° alcohol CO2H - powerful, non-selective oxidant; will also attack multiple bonds,1,2-diols, ethers, aromatic rings, etc.
• reagent
• reactivity
- toxic - catalytic procedures use 1-5% Ru metal with a stoichiometric oxidant
O
OBzH
HO
RuCl3-NaIO4MeCN, CCl4, H2O
60%
O
OBzH
HO O Overman J. Am. Chem. Soc. 1997, 119, 12031.
C. Ruthenium Based Reagents
2. Tetra-n-propylammonium Perruthenate (Pr4N+RuO4-): TPAP
- 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)
• reagent
• reactivity
- developed by Steve Ley (Imperial College Cambridge) - catalytic; used in conjunction with a stoichiometric oxidant (NMO) - perruthate salts with a large counterion are mild and selective oxidants
N
HO
CBzTPAP, NMO
4Å MS, CH2Cl2
N
O
CBz
Jacobsen J. Am. Chem. Soc. 2004, 126, 706.
C. Ruthenium Based Reagents
2. Tetra-n-propylammonium Perruthenate (Pr4N+RuO4-): TPAP
• mechanism
http://www.synarchive.com/named-reactions/Ley-Griffith_Oxidation
D. DMSO Based Reagents
General Mechanism: ! ! !
- mild class of reagents - don’t have environmental issues associated with use of Cr based reagents - no over oxidation oxidation of 1° alcohols give aldehydes - oxidation of 2° alcohols give ketones
S O S O E
R OH
R O SMe
CH2H
R O SMe
CH2H
R O SMe
Me
EB
+
D. DMSO Based Reagents
1. DMSO, (COCl)2; Et3N: Swern Oxidation ! !
- 1° alcohol CHO - most common of DMSO based reagents - very mild run at low temp (-78 to -60°C) - low sensitivity to steric factors - preparation of β-alkoxy carbonyl derivatives may be problematic use Et2NiPr
• activation:
• reactivity
- also TFAA, Ac2O, SOCl2, Cl2, P2O5
O
OH
DMSO, (COCl)2CH2Cl2; then Et3N
O
CHOFunk J. Org. Chem.1987, 52, 3173.
S O Cl ClO
O
+ O ClO
O
SCl
SMe
MeCl
+ CO2 + CO + Cl-
D. DMSO Based Reagents
2. DMSO, DCC, TFA, pyridine: Moffatt Oxidation ! !
- 1° alcohol CHO - first reported DMSO based oxidant; less commonly used - separation of by-pyroduct (dicyclohexylurea) can be difficult use EDC - may result in formation of MTM ethers (side reaction)
• activation: DMSO + DCC
• reactivity
N C NS O + N C NO
S
N C NHCl•Me2N
OMeO
OHOBz
OBPSDMSO, EDC
TFA, pyr94%
OMeO
OOBz
OBPS Hannessian Can. J. Chem.1981, 59, 870.
D. DMSO Based Reagents
3. SO3•pyridine, DMS; Et3N: Parikh-Doehring ! !
- 1° alcohol CHO - easy workup; well suited to large scale reactions
• activation
• reactivity
S OO S O
O+ S
OOS
OO
O
O
BrH
HH
HHO
SO3•pyr, DMSOCH2Cl2; Et3N
O
O
BrH
HH
HO
Evans ACIEE 1999, 38, 3175
E. Silver Based Oxidants
1. Ag2CO3/celite: Fetizon’s reagent ! !
- 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)
• reactivity
HO MeO
OH
MOMO OBnAg2CO3/celitebenzene, 80°C
MeO MOMO OBn
OO
Kallmerten Tetrahedron Lett. 1990, 31, 4305.
O
NMeHO
MeO
Ag2CO3toluene, 110° O
NMeO
MeO
84%Rappoport - codeine
E. Silver Based Oxidants
2. Silver (I) Oxide (Ag2O) ! !
- mild method for the conversion of CHO CO2H (in presence of free OH) - unsaturated aldehydes are problematic (isomerization) - weak oxidant
• reactivity
HO
CHO Ag2OEtOH (aq) HO
CO2H
80% Kitching JCSP1 1995, 1309.
F. Other Oxidants
1. Dess-Martin Periodinane ! !
- can determine quality of reagent by solublity in CH2Cl2
• preparation
- 1° alcohol CHO - mild reagent; nearly neutral conditions gives off AcOH, but can buffer - will not oxidize N or S
• reactivity
O
MeOOH
O Dess-MartinCH2Cl2
O
MeO CHO
O
Danishefsky J. Am. Chem. Soc. 1991, 113, 3850.
IO
CO2H
I
O
HO OIO
O
AcOOAc
OAc
KBrO3H2SO4
Ac2OpTsOH, 100°C
(IBX) shocksensitive
whitesolid
F. Other Oxidants
- addition of 1 equiv water accelerates reaction (Schreiber)
• mechanism
OI
OAcO
AcOAcO
H RH
OH
OI
OAcO
AcO
H RH
O
- AcOH
H R
O+
OI
O
AcO + 2 AcOH
F. Other Oxidants
2. o-Iodoxybenzoic acid (IBX) ! !
- intermediate in the synthesis of Dess-Martin periodinane; simpler prep
• preparation
- in excess will oxidize alcohols to α,β-unsaturated aldehydes and ketones (or saturated aldehydes/ketones to α,β-unsaturated compounds) - mild reagent for oxidation of 1,2-diols without oxidative cleavage - insoluble in most organic solvents, except DMSO or DMSO mixtures
• reactivity
IO
CO2H
I
O
HO O
oxoneH2O, 70°C
OH
IBX (2.3 equiv)toluene, DMSO
88%
O
Nicolaou J. Am. Chem. Soc. 2000, 122, 7596.
F. Other Oxidants
2. o-Iodoxybenzoic acid (IBX) ! !
- intermediate in the synthesis of Dess-Martin periodinane; simpler prep
• preparation
- in excess will oxidize alcohols to α,β-unsaturated aldehydes and ketones (or saturated aldehydes/ketones to α,β-unsaturated compounds) - mild reagent for oxidation of 1,2-diols without oxidative cleavage - insoluble in most organic solvents, except DMSO or DMSO mixtures
• reactivity
IO
CO2H
I
O
HO O
oxoneH2O, 70°C
OH
IBX (2.3 equiv)toluene, DMSO
88%
O
Nicolaou J. Am. Chem. Soc. 2000, 122, 7596.
CO2HHO2C
CO2H
IBX 49%
22%
29%
"SIBX"
Quideau Org. Lett. 2003, 5, 2903.
F. Other Oxidants
- alcohol oxidation: mirrors Dess-Marin periodinane mechanism
• mechanism
OI
O
HO
H RH
OH
OI
O
O
- H2O
H R
O+
OI
O
HOOO
H
RH
O IO
O
HOO O
IO
O
HO
HO
H
O
F. Other Oxidants
3. Al(OiPr)3, acetone: Oppenauer Oxidation
- classical method for alcohol oxidation - takes advantage of reversible reaction between ketones and metal alkoxides - mild conditions, infrequently used; does not work well with 1° alcohols
• reactivity
• mechanism
MeMeO
OHAl(OiPr)3acetone
MeMeO
O
Boger J. Org. Chem. 1984, 49, 4045.
- use of acetone solvent drives reaction to the right
OH Al(OiPr)3 O AlOiPr
OiPrOiPr
H- HOiPr O Al
OiPr
OiPr
O
O AlOiPr
OiPrO
H+ transfer O AlOiPr
OiPrO
H
HO
F. Other Oxidants
4. Sodium Chlorite (NaClO2): Pinnick Oxidation
- useful method for oxidation of sensitive CHO CO2H, esp. α,β-unsaturated CHO - use hampered by formation of chlorine dioxide - suppressed by addition of chlorine scavenger (alkene)
• reactivity
CHO
OH
NaClO2tBuOH, H2O
CO2H
OH
CHONaClO2
tBuOH, H2O
CO2H
5. Sodium Hypochlorite (NaOCl): Stevens Oxidation
- selective oxidation of 2° alcohols - modified procedure uses calcium hypochlorite – a stable solid
• reactivity
NaOClAcOH
OHOH
OOH
86% Corey J. Am. Chem. Soc. 1998, 120, 12777.
F. Other Oxidants
6. TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy):
- 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
• reactivity
• mechanism
OHN
O
Boc TEMPO, NaOCl, NaBrEtOAc:toluene:H2O (1:1:0.15) O
NO
Boc
90%
NO
NO
NOH
NO O
H RH
RCH2OH + B
RCHO
[O]
BH
[O]
Oxidation of Ketones
OO O
O
OOH
Ketone Enone 1. IBX ! !
- Nicolaou J. Am. Chem. Soc. 2002, 124, 2245.
• reactivity
H
H
TIPS
O H
H
TIPS
OIBX (2 equiv)
tol/DMSO
87%
2. Saegusa Oxidation! !
- Saegusa J. Org. Chem. Soc. 1978, 43, 1011. - most often stoichimetric in Pd, but use of cat Pd in presence of stoichimetric oxidant is known (see, for example: Lebel JOC 2013, 78, 776)
• reactivity
OTMS
O
Pd(OAc)2MeCN, rt
O
ODanishefsky J. Am. Chem. Soc.
2008, 130, 13765.
Ketone Enone 2. Saegusa Oxidation! ! !
• mechanism
Ketone Enone
3. Selenoxide Elimination ! • reactivity
OLDA;PhSeBr
O OSePh H2O2
- other oxidants include NaIO4, O3, mCPBA, etc.
Ketones Esters/Lactones
1. Baeyer Villager Oxidation ! !
- reaction of ketone with peracids (mCPBA, trifluoroperacetic acid, peracetic acid) - migration occurs at more highly substituted (more electron rich) position: - migratory aptitude: 3° > 2° > benzyl > Ph > 1° > cyclopropyl > Me > H - stereochemistry is retained - note peracids react with other functionality (alkenes, amines, sulfides, etc.)
• reactivity
O mCPBA
O
O O
HMe mCPBA O
O
HMe
Alpha Hydroxylation
1. Rubottom Oxidation ! !
- Rubottom Tetrahedron Lett. 1974, 15, 4319. - epoxidation of silyl enol ether, followed by silyl migration - dimethydioxirane (DMDO) can also be used for epoxidation
• reactivity
OTMS
mCPBACH2Cl2
OOR
R = H, TMS
2. MoOPh Oxidation ! !
- MoOPh = MoO5•pry•HMPA - attack of enolate at peroxyl oxygen atom leads to O-O bond cleavage
• reactivity
O
LDA;MoOPh
OOH
MoO OOO
OO N(Me2N)3P
MoOPh
Alpha Hydroxylation
3. Davis Oxaziridine ! !
- N-sulfonyloxaziridines prepared by oxidation of corresponding sulfonimine - chiral reagents are known
• preparation
• reactivity
NPh
PhSO2
mCPBA oroxone
NPh
PhSO2
O
- nucleophilic attack of enolate on electrophilic oxaziridine oxygen - potassium enolates tend to work best
OTBS
H OTMSOO
KHMDS;Davis oxaziridine
68%
OTBS
H OTMSOO
HO
Ph MeO 1. NaHMDS
2.
ClCl
NO
SOO
Ph MeO
OH
61%, 95% ee
