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Chem 115
Oxidation
Alkane R-CH3
March, J. In Advanced Organic Chemistry, John Wiley and Sons: New York, 1992, p. 1158!
1238.
Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry Part B, Plenum Press: New York,
1990, p. 615!664.
Carruthers, W. In Some Modern Methods of Organic Synthesis 3rd Ed., Cambridge University
Press: Cambridge, UK, 1987, p. 344!410.
organoboranes RCH2BR2'
organosilanes
The notion of oxidation state is useful in categorizing many organic transformations. This is
illustrated by the progression of a methyl group to a carboxylic acid in a series of 2-electron
oxidations, as shown at right. Included are several functional group equivalents considered to be
at the same oxidation state.
Summary of Reagents for Oxidative Functional Group Interconversions:
O
O
OH
R
R'(H)
alcohol
R'
or
ketone
alkyl azide X = N3
alkylamine X = NR'2
RCH2SiR3'
hemiketal (hemiacetal)
N NR''2
R''O OH
R
aldehyde
hydrazone
R'
R''O OR'''
Dimethylsulfoxide-Mediated Oxidations
Oppenauer Oxidation
Sodium Hypochlorite
N-Bromosuccinimide (NBS)
N-Oxoammonium-Mediated Oxidation
Bromine
Manganese Dioxide
ketal (acetal)
aldehyde
OH
acid
aldehyde
OR'
dithiane
ester
O
R'
R
aminal
imine
R'
R'
R''O NR2'''
R
R''O
R'
RCX2R'
R'
O
H
R'
Barium Manganate
O
geminal dihalide
ketone
ester
ester
Sodium Chlorite
Silver Oxide
Bromine
amide
thioester
SR'
trihalomethyl
R'
N
OH
orthoester
Potassium Permanganate
R'''
R''
R'
ketene
RCX3
O
hydroxamic acid
O
N
R''
OR'
R'
RCO2R'
OR''
oxime
nitrile
R'
R C N
O
R
O
O
O
R
OH
alcohol
OH
acid
OH
O
R'
ketone
R'
OH
"-hydroxy
ketone
HO
O
diol
Ruthenium Tetroxide
Fetizon's Reagent
O2/Pt
O2/Pt
Jones Oxidation
N-Oxoammonium-
carbamate
lactone
Mediated Oxidation
isocyanate
RO
N
R'
R''
R N C O
alkyl haloformate
RO
S
X
xanthate
RO
SR'
O
carbodiimide
R N C N R'
urea
N
R''
R'
N
R'''
Myers
Chem 115
Oxidation
O
OH
R'
R
ketone
R
R'(H)
alcohol
Pummerer Rearrangement
or
HO CH3 OH
H3C
H
H
R
aldehyde
H3C
Dimethylsulfoxide-Mediated Oxidations
HO CH3 OH
H3C
H
CF3CO2Ac, Ac2O
2,6-lutidine
Reviews
H3C
General Mechanism
Dimethylsulfoxide (DMSO) can be activated by reaction with a variety of electrophilic reagents,
including oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide, acetic anhydride, and Nchlorosuccinimide.
The mechanism can be considered generally as shown, where the initial step involves
electrophilic (E+) attack on the sulfoxide oxygen atom.
Subsequent nucleophilic attack of an alcohol substrate on the activated sulfoxonium intermediate
leads to alkoxysulfonium salt formation. This intermediate breaks down under basic conditions to
furnish the carbonyl compound and dimethyl sulfide.
+
(CH3)2S O
(CH3)2S X
+S
Ph
HO CH3 OH
H3C
H
OAc
>60%
H3C
AcO
S Ph
S Ph
+
H H
R
HO CH3 OH
H3C
H
BH+
RCO2
S Ph
O
Lee, T. V. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 7, p. 291!303.
H3C
Huang, S. L.; Mancuso, A. J.; Swern, D. J. Org. Chem. 1978, 43, 2480!2482.
+
RCH2OH +
(CH3)2S X
H H CH3
+
S+
R
CH3
O
CH2
S+
O
CH3
H H
R
H+
H
R
HO
(CH3)2S
78 " 50 C
OBn
alkoxysulfonium ylide
66%
Methylthiomethyl (MTM) ether formation can occur as a side reaction, by nucleophilic attack of
an alcohol on methyl(methylene)sulfonium cations generated from the dissociation of sulfonium
ylide intermediates present in the reaction mixture. This type of transformation is related to the
Pummerer Rearrangement.
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2354!2359.
RO
H+
CH3
CH3
OH
N
Cl
CH3
(COCl)2, DMSO;
O
+
ROH + H2C S CH3
TBSO
TBSO
HO
Et3N, 78 C
99%
100-g scale
CHO
N
Cl
Fang, F. G.; Bankston, D. D.; Huie, E. M.; Johnson, M. R.; Kang, K.-C.; LeHoullier, C. S.; Lewis, G.
C.; Lovelace, T. C.; Lowery, M. W.; McDougald, D. L.; Meetholz, C. A.; Partridge, J. J.; Sharp, M. J.;
Xie, S. Tetrahedron 1997, 53, 10953!10970.
Mark G. Charest, Jonathan William Medley
Myers
CH3O
CH3O
CH3
HO
OR1
CH3O
Chem 115
Oxidation
CH3
CH3O
OH
O
(COCl)2, DMSO;
CH3
R1O
CH3
OCH3
H
CH3
CH3
OCH3
R1O
OR
BzO
94%
OCH3
FK506
H
OR
TFA, pyr
CH3
OTBDPS
DMSO, EDC
HO
BzO
80%
CH3
CH3
OTBDPS
O
OR1
Et3N, 78 C
H
OR
CH3
OCH3
OR
Parikh-Doering Procedure
R = TIPS, R1 = TBS
Jones, T. K.; Reamer, R. A.; Desmond, R.; Mills, S. G. J. Am. Chem. Soc. 1990, 112, 2998!3017.
Ease of workup and at-or-near ambient reaction temperatures make the method attractive for largescale reactions.
Pfitzner-Moffatt Procedure
Parihk, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-5507.
Examples
Ph
Ot-Bu
DMSO, DCC
Cl
TFA, pyr
OH
8 " 23 C
Bn2N
H
99.9% ee
>95%
99.9% ee
Alternative carbodiimides that yield water-soluble by-products (e.g., 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC)) can simplify workup procedures.
Cl
OH
Bn2N
Ph
190-kg scale
Liu, C.; Ng, J. S.; Behling, J. R.; Yen, C. H.; Campbell, A. L.; Fuzail, K. S.; Yonan, E. E.; Mehrotra, D.
V. Org. Process Res. Dev. 1997, 1, 45!54.
Ot-Bu
O
87%
SO3pyr, Et3N,
H
H
HO
Corey, E. J.; Kim, C. U.; Misco, P. F. Org. Synth. Coll. Vol. VI 1988, 220!222.
Br
DMSO, CH2Cl2
H
H
0 " 23 C
OHC
Br
99%
H
H
DMSO, DCC
OH
CO2CH3 TFA, pyr
O
CH3
9 : 1 #,$ : %,#
S
H3C
CH3
CHO
CO2CH3
CH3
CH3
CHO
H
CO2CH3
O
CH3
S
H3C
CH3
H3C
Semmelhack, M. F.; Yamashita, A.; Tomesch, J. C.; Hirotsu, K. J. Am. Chem. Soc. 1978, 100,
5565!5576.
Br
CH3
H
H
Et
Br
()-kumausallene
Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. Engl. 1999,
38, 3175!3177.
Mark G. Charest, Jonathan William Medley
Myers
Chem 115
Oxidation
Examples
DMP has found wide utility in the preparation of sensitive, highly functionalized molecules.
DMP oxidations are characterized by short reaction times, use of a single equivalent of oxidant,
and can be moderated with regard to acidity by the incorporation of additives such as pyridine.
DMP and its precurser o-iodoxybenzoic acid (IBX) are potentially heat and shock sensitive and
should be handled with appropriate care.
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1983, 48, 4155!4156.
H3C
H3C
H3C H
TBSO
H
I
KBrO3
65 C, 2.5 h
CO2H
then 23 C, ~24 h
74% overall
+ Ac2O + AcOH
DMP
R1R2CHOH
AcOH
Ac O
O
I
DMP
Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Tetrahedron
Lett. 2000, 41, 1359!1362.
Use of other oxidants in the following example led to conjugation of the ",#-unsaturated ketone,
which did not occur when DMP was used.
CH3
H
OAc
slow
OAc
+ R1R2C=O + AcOH
O
O
R1R2CHOH
AcOH
R1
R2
Ac O
O
I
II
OCHR1R2
fast
OCHR1R2
O
O
Se
R2
For the synthesis of sensitive $-amino aldehydes from the corresponding alcohols, the use of
DMP suppresses epimerization.
Ph
DMP
Ph
O
OH
FmocHN
wet CH2Cl2
FmocHN
H
23 C
99% ee
99% ee
>95%
IBX
Addition of one equivalent of water has been found to accelerate the alcohol oxidation reaction
with DMP, perhaps due to the formation of an intermediate analogous to II. It is proposed that
the decomposition of II is more rapid than the initially formed intermediate I:
R1
DMP
~100%
Ac OAc
O
I
OAc
O
85 C
()-7-deacetoxyalcyonin acetate
Se
O
O
H
O
OH
H3C
H
H3C
HO AcOO
I
O
HO
H3C
H
H3C
TBSO
89% overall
2.0 M H2SO4
1. DIBAL
2. DMP
CH3
CH3
PivO
Boeckman, R. K.; Shao, P.; Mulins, J. J. Org. Synth. 1999, 77, 141!152.
H3C
H3C
CH3
+ R1R2C=O + AcOH
H3C
DEIPSO
O
OTES
O O
1. DDQ, CH2Cl2, H2O
CH3
CH3 CH3
CH3 H
2. DMP, CH2Cl2, pyr
H
O
TBSO
TESO
93% overall
O Si(t-Bu)2
OPMB
OCH3
O
CH3
O
CH3
CH3
OTES
TESO
H
O
H3C
O
H
DEIPSO
O O
H
CH3 CH3
CH3 H
H
()-cytovaricin
TBSO
TESO
H
OTES
CH3
O
O Si(t-Bu)2
OCH3
O
CH3
O
CH3
OTES
TESO
Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001!
7031.
Mark G. Charest, Jonathan William Medley
Myers
Chem 115
Oxidation
DMP oxidation in the presence of phosphorous ylides allows for the trapping of sensitive
aldehydes.
IBX is used as a mild reagent for the oxidation of 1,2-diols without C-C bond cleavage.
H3C O
HO
H3C
OH
PhCO2H
CO2CH3
AcO
HO
H3C
IBX, DMSO
CH3O2C
Ph3P=CHCO2CH3
H3C O
AcO
85%
HO
OH
Pyridines are not oxidized at a rate competitive with the oxidation of a primary alcohol.
O
HO
NHFmoc
DMP
NHFmoc
OH
N
>90%
SCH3
Myers, A. G.; Zhong, B.; Kung, D. W.; Movassaghi, M.; Lanman, B. A.; Kwon, S. Org. Lett. 2000, 2,
DMP has been used to oxidize secondary acyclic and macrocyclic amides to the corresponding
imides in moist DMSO/fluorobenzene at elevated temperature.
Me
N
H
H
N
OtBu
99%
SCH3
3337!3340.
CHO
IBX, DMSO
Me
H
N
N
H
OtBu
4.0 equiv IBX
86%
OH
toluene, DMSO
Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005, 44, 5992!5997.
H
84%
The DMP precursor IBX is gaining use as a mild reagent for the oxidation of alcohols.
A simpler preparation of IBX has been reported.
I
CO2H
oxone, H2O
70 C
79-81%
TIPS
TIPS
toluene, DMSO
H
87%
OH
OH
O
O
toluene, DMSO
IBX
OH
Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537!4538.
O
52%
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596!7597.
Mark G. Charest, Jonathan William Medley
Myers
Chem 115
Oxidation
CH3
CH3
Reviews
H3C
HO
Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639!666.
Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13!19.
CH3
OR'
O
O
H3C
CH
OR 3
CH3
H3C
59%
H3C
27-g scale
However, perruthenate salts with large organic counterions prove to be mild and selective
oxidants in a variety of organic solvents.
CH3
OR'
CH2Cl2, 23 C
H3C
Ruthenium tetroxide (RuO4, Ru(VIII)) and, to a lesser extent, the perruthenate ion (RuO4,
Ru(VII)) are powerful and rather nonselective oxidants.
H3C
O
TPAP, NMO
CH
OR 3
CH3
O
O
CH3O
CH3O
The following oxidation state changes have been proposed to occur during the reaction:
OH
TBSO
78%
H3C CH3
H CH3O
OTBS
H
H
O
O
O
TBSO
Julia-Lythgoe
Olefination
OH
TPAP, CH2Cl2
N
TEOC
23 C
H
Bu4
N
TEOC
N+F,
OCH3 H OTBS O
O
O
CH3
CH3
TESO
29%
84%
CH3O
CH3O
O CH
3
CH3
CH3
CH3
CH3
()-indolizomycin
CH3O2C
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30!39.
HO
CH3
CH3
87%
CH3
TESO
OCH3 H OTBS O
O
O
O
OH
CH3
CH3
CH3
OH
H3C
H3C
CH3
4 MS, 23 C
O
H3C
H3C CH3
H CH3O
OTBS
H
H
O
O
OH
THF
0 C
H3C CH3
H CH3O
OTBS
H
H
O
O
CH3O
CH3O
Examples
O
H3C CH3
H HO
OAc
H
H
O
O
O
CH3
OH H OH
O
CH3
CH3
70%
Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992, 48, 1145!1174.
O CH
3
n-Pr
O
bryostatin 3
O
OH
Myers
Chem 115
Oxidation
N-Oxoammonium-Mediated Oxidation
Examples
TEMPO, NaOCl
Reviews
OBn
BocHN
OH
C6H11
N-Oxoammonium salts are mild and selective oxidants for the conversion of primary and
secondary alcohols to the corresponding carbonyl compounds. These oxidants are unstable and
are invariably generated in situ in a catalytic cycle using a stable, stoichiometric oxidant.
NaBr, NaHCO3
77%
OBn
BocHN
H
C6H11
>95% de
Leanna, R. M.; Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992, 33, 5029!5032.
See also: Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gryza, H.; Prokopoxicz, P. Tetrahedron 1998, 54,
R
X
R1
N
O
H OH
R2
HX
R3
R2
R3
R
N 1
OH
6051!6064.
OH
N-oxoammonium salt
O
OTBDPS
R1
HO
O
H
R2
R1
R1
R1
O
H
R2
H3C CH3
R1
H3C CH3
O
O
B
H
R2
R1
O
O
R1
+H+
H+
kuehneromycin A
R
N 1
OH
R
+
N
O
R1
PhS
Golubev, V. A.; Sen', V. D.; Kulyk, I. V.; Aleksandrov, A. L. Bull. Acad. Sci. USSR, Div. Chem.
Sci. 1975, 2119!2126.
2,2,6,6-Tetramethyl-1-piperidinyloxyl (TEMPO) catalyzes the oxidation of alcohols to aldehydes
and ketones in the presence of a variety of stoichiometric oxidants, including mchloroperoxybenzoic acid (m-CPBA), sodium hypochlorite (NaOCl), [bis(acetoxy)-iodo]benzene
(BAIB), sodium bromite (NaBrO2), and Oxone (2KHSO5KHSO4K2SO4).
H3C
CH3
N
O
CH3
CHO
H
H3C CH3
nitroxyl radical
H3C
OH
H
Selective oxidation of allylic alcohols in the presence of sulfur and selenium has been
demonstrated.
disproportionation
N
O
OTBDPS
98%
23 C
TEMPO
PhS
23 C
CHO
70%
H3C
CH2OH
SePh
H3C
CHO
SePh
55%
De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974!
6977.
Mark G. Charest, Jonathan William Medley
Myers
Chem 115
Oxidation
TBSO
TBSO
SAr
Reviews
Cahiez, G.; Alami, M. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing
Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. 231!
236.
HO HO
OAc
SAr
MnO2, acetone
76%
O HO
HO
OAc
H3C CH3
H CH3
CH3
CH3
CH3
Active manganese oxides are nonstoichiometric materials (in general MnOx, 1.93 < x < 2)
consisting of Mn (II) and Mn (III) oxides and hydroxides, as well as hydrated MnO2.
HO
Hydrogen-bond donor solvents and, to a lesser extent, polar solvents have been shown to
exhibit a strong deactivating effect, perhaps due to competition with the substrate for the active
MnO2 surface.
MnO2
OH
acetone
CH3
75%
CH3
OH
H3C CH3
H CH3
CH3
CH3
Examples
CH3
CH3
H3C CH3
MnO2
H3C CH3
CH3
OH
HO
CH3
OH
CH3
CH3
>95%
1-kg scale
CH3
OEt
MnO2
H3C CH3
CH3
OEt
CH2Cl2, 0 C
OH
Bu3Sn
CH2OH
MnO2
CH2Cl2
CH3
Bu3Sn
CHO
OEt
OEt
CH3
paracentrone
Salman, M.; Babu, S. J.; Kaul, V. K.; Ray, P. C.; Kumar, N. Org. Process Res. Dev. 2005, 9,
302!305.
H3C CH3
CH3
CH3
76%
89%
O
Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659!5662.
van Amsterdam, L. J. P.; Lugtenburg, J. J. Chem. Soc., Chem. Commun. 1982, 946!947.
EtO2C
CO2Et
OHC
CHO
1. DIBAL, C6H6
CH3
74%
HO CH3
OH
CH3
H3C
MnO2
H3C
CH3
2. MnO2, CH2Cl2
H3C
100%
CH3
CH3
CH3
Ohloff, G.; Giersch, W. Angew. Chem., Int. Ed. Engl. 1973, 12, 401!402.
Myers
Chem 115
Oxidation
Oppenauer Oxidation
Review
de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007!1017.
Barium manganate and potassium manganate are deep green salts that can be used without
prior activation for the oxidation of primary and secondary allylic and benzylic alcohols.
A classic oxidation method achieved by heating the alcohol to be oxidized with a metal alkoxide in
the presence of a carbonyl compound as a hydride acceptor.
Examples
Ph
Ph
OH
BaMnO4, CH2Cl2
OH
23 C
Ph
S
Ph
85%
The reaction is an equilibrium process and is believed to proceed through a cyclic transition state.
The use of easily reduced carbonyl compounds, such as quinone, helps drive the reaction in the
desired direction.
L
R1
R3
M
R2
O
L
H
O
R4
O
H
H3C
H3C
OH
Examples
OH
BaMnO4
CH2OH
CHO
pivaldehyde, toluene
92%
H3C CH3
H3C CH3
2 mol %
F5
H3C
Howell, S. C.; Ley, S. V.; Mahon, M. J. Chem. Soc., Chem. Commun. 1981, 507!508.
(S)-perillyl alcohol
B
OH
F5
H3C
99%
CH3
H3C
H
SEMO
CH2OH
CH3
BaMnO4, CH2Cl2
H3C
H
98%
CHO
H
Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 5664!5665.
Highly reactive zirconium alkoxide catalysts undergo rapid ligand exchange and can be used in
substoichiometric quantities.
SEMO
CH3
CH3
OH
H3C
CH3
3 MS
86%
O
H3C
CH3
menthol
Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A. K.; Hayakawa, M. Synthesis 1996, 1341!
1344.
Mark G. Charest, Jonathan William Medley
Myers
Chem 115
Oxidation
Ley, S. V.; Madin, A. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol. 7, p. 251!289.
CrO3pyr2 is a hygroscopic red solid which is easily hydrolyzed to the yellow dipyridinium
dichromate ([Cr2O7]2(pyrH+)2).
Typically, 6 equiv of oxidant in a chlorinated solvent leads to rapid and clean oxidation of
alcohols.
The mechanism of chromic acid-mediated oxidation has been extensively studied and is
commonly used as a model for other chromium-mediated oxidations.
Caution: Collins reagent should be prepared by the portionwise addition of solid CrO3 to
pyridine. Addition of pyridine to solid CrO3 can lead to a violent reaction.
R2CHOH + HCrO4 + H+
R2C O CrO3H
Collins, J. C.; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 30, 3363!3366.
R2CHOCrO3H + H2O
R2C O
+ HCrO3 + BH+
H
B
Holloway, F.; Cohen, M.; Westheimer, F. H. J. Am. Chem. Soc. 1951, 73, 65!68.
H3C
CH3
95%
R2CHOH
Cr(IV)
R2COH
Cr(III)
H+
R2COH
Cr(VI)
R2C=O
Cr(V)
H+
Examples
R2CHOH
Cr(V)
R2C=O
Cr(III)
2H+
H3C
CH3 NHBoc
OH
PhCHO
OTBS
(CH3)3
OCrO3H
2. Collins Reagent
O
CH3
CH3
CH2Cl2
81% overall
CH3
CH3
()-periplanone B
O
H
CH3O2C
CH3 CH3
83%
H
>99.5% ee
1. n-Bu4N+F, THF
Doyle, M.; Swedo, R. J.; Rocek, J. J. Am. Chem. Soc. 1973, 95, 8352!8357.
CH3 NHBoc
O
Rittle, K. E.; Homnick, C. F.; Ponticello, G. S.; Evans, B. E. J. Org. Chem. 1982, 47, 3016!3018.
O
Cr(III)
CH3
50-g scale
Fragmentation has been observed with substrates that can form stabilized radicals.
H
Ph C O Cr(IV)
(CH3)3C
H3C
67%
>99.5% ee
H3C
2. Collins Reagent
CH2Cl2
CH3O2C
OCH3
CHO
CH3 CH3
90% overall
(+)-monensin
Collum, D. B.; McDonald, J. H.; Still, W. C. J. Am. Chem. Soc. 1980, 102, 2117!2120.
10
Myers
Chem 115
Oxidation
ClCrO3
+N
A modified procedure employs calcium hypochlorite, a stable and easily handled solid
hypochlorite oxidant.
PCC
Examples:
PCC is an air-stable yellow solid which is not very hygroscopic.
OH
Typically, alcohols are oxidized rapidly and cleanly by 1.5 equivalents of PCC as a solution in
N,N-dimethylformamide (DMF) or a suspension in chlorinated solvents.
OH
CH3
CH3
NaOCl, AcOH
The slightly acidic character of the reagent can be moderated by buffering the reaction mixture
with powdered sodium acetate.
H3C
OH
91%
H3C
Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.; Albizati, K. F. Tetrahedron Lett. 1982,
23, 4647!4650.
Examples
O
H
Cl
CH3
CH3
HO
PCC, 25 C
OTIPS
H
Cl
4 MS
OH
OTIPS
H3C
OH
NC
NC
100%
CH3
N
CH3
OMOM
CH3
OH
NaOAc
OH
2. MOMCl, DIEA
Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431!7432.
PCC, CH2Cl2
H3C
93%
Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871!8872.
CH3
N
1. NaOCl, AcOH
71%
NaOCl, AcOH
S
H
H3C
OH
H
H3C
86%
OH
H3C CH3
H3C CH3
H3C CH3
H3C CH3
PCC, CH2Cl2
CH
OH 3
Cr
O2
CH3
O
CrO3
CH3
CH3
n-C9H19 CH2OH
n-C9H19 CH2OH
OH
23 C
94%
CH3
NaOCl, AcOH
O
CH3
71%
11
Myers
Chem 115
Oxidation
Examples:
Tomioka, H.; Oshima, K.; Noxaki, H. Tetrahedron Lett. 1982, 23, 539!542.
CH3
HO
OH
CH3
H3C
CH3
HO
In the following example, catalytic tetrahydrogen cerium (IV) tetrakissulfate and stoichiometric
potassium bromate in aqueous acetonitrile was found to selectively oxidize the secondary
alcohol in the substrate whereas NaOCl with acetic acid and NBS failed to give the desired
imide.
O
O
O
O
O
O
O
CH3
>98%
H3C
CH3
CH3
NPh
OH
CH2OH
O
O
HO H
O
O
H3C
HO
O
Br2, AcOH
H
t-Bu
HO H
HO H
HO
O
>51%
NPh
O
CH2OH
7 : 3 CH3CN, H2O, 80 C
48%
O
O
CH3
()-palasonin
O
O
H 3C
NaOAc
Ce(SO4)22H2SO4, KBrO3
OH
H
t-Bu
OH
TEMPO, NCS,
Bu4
OH
O H
N+Cl
CH2Cl2, H2O,
OH
CHO
pH 8.6
77%
()-ginkgolide B
0.50%
Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem. 1996, 61, 7452!7454.
Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.; Thomas, J. B.; Watterson, S.
H.; Wagman, A. S. J. Am. Chem. Soc. 2000, 122, 8453!8463.
Molybdenum catalysts and H2O2 have been used to oxidize secondary alcohols in the presence
of primary alcohols:
(NH4)6Mo7O244H2O
H2O2,nBu4NCl
OH
Cbz
CH3 OH
N
H3C O
OH
O O
O
O
Sn
Bu
CH3
N
Cbz
Cbz
Br2
Bu3SnOCH3
70%
CH3 OH
N
H3C O
O
OH
OH
88%
CH3
N
Cbz
OH
O O
THF, 23 C
OH
H2
Pd/C
90%
Bu
H 3C
H
N
OH
H
HO
O
N H HO O
H
H3C
(+)-spectinomycin
CH3
Schreiner's thiourea has been shown to catalyze the selective oxidation of secondary alcohols by
NBS:
HO
CF3
CF3
CH3
OH
F3C
N
N
H
H
(0.1 equiv)
NBS, CH2Cl2
CF3
!30 C
CH3
OH
80%
12
Myers
Chem 115
Oxidation
O
O
H
Aldehyde
1. (CF3CO2)2IPh,
Cl
OH
OH
Cl
CH3CN, H2O, 0 C
OH
2. NaClO2, NaH2PO4
Acid
2-methyl-2-butene,
OTBDPS
t-BuOH, H2O
Sodium chlorite is a mild, inexpensive, and selective reagent for the oxidation of aldehydes to
the corresponding carboxylic acids under ambient reaction conditions.
CO2H
OTBDPS
82%
Br
H3C
Examples
H
H3C
NaClO2, NaH2PO4,
2-methyl-2-butene
CHO
TBSO
H3C
(+)-obtusenyne
O
t-BuOH, H2O
CO2H
TBSO
CH3
CH3
Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A. J. Org. Chem.
1999, 64, 2616!2617.
The two-step oxidation of an alcohol to the corresponding carboxylic acid is most common.
80%
n-Bu3Sn
1. NaClO2, NaH2PO4,
2-methyl-2-butene
t-BuOH, H2O
TBSO
H3C CHO CO CH
2
3
2. CF3CH2OH,
CH3
TBSO
H3C
OH
O
OH
>95%
Nicolaou, K. C.; Ohshima, T.; Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. J. Chem. Soc.,
Chem. Commun. 1999, 809!810.
OMOM
O
Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574!
5576.
HO
H3C
()-antheridic acid
OCH3
OTf
H
OMOM
NaClO2, NaH2PO4,
2-methyl-2-butene
90%
HO
CH3
H
CH3
O
O
H3C H
H3C
H3 C
O
H H
Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004-1015.
OCH3
OSEM
98%
OMOM
OH
OMOM
CH3
3. CH2N2
OCH3
OTf
acetone, H2O
H3C
H3C
CH3O
CO2H
OH
>52%
CO2CH3
2,6-lutidine
H3C
O
2-methyl-2-butene,
CH3
2. NaClO2, NaH2PO4
H3C
n-Bu3Sn
(+)-monensin A
H3C
CH3O
CH3O2C
H
CH3 CH3
O
O
H3C H
H3C
H3C
H3 C
O
H H
CH3
O
OCH3
OSEM
Ireland, R. E.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7166!7172.
Mark G. Charest
13
Myers
Chem 115
Oxidation
In the following example, a number of other oxidants (including Jones reagent, NaOCl, and RuO2)
failed:
1. KMnO4, NaH2PO4,
Potassium permanganate is a mild reagent for the oxidation of aldehydes to the corresponding
carboxylic acids over a relatively large pH range. Alcohols, alkenes, and other functional groups
are also oxidized by potassium permanganate.
TsN
N
Ts
H
Oxidation occurs through a coordinated permanganate intermediate by hydrogen atomabstraction or hydride transfer.
t-BuOH, H2O, 0 C
H
TsN
N
Ts
CH3O
2. (CH3)3SiCHN2
H
O
80%
Freeman, F.; Lin, D. K.; Moore, G. R. J. Org. Chem. 1982, 47, 56!59.
Rankin, K. N.; Liu, Q.; Henrdy, J.; Yee, H.; Noureldin, N. A.; Lee, D. G. Tetrahedron Lett. 1998, 39,
1095!1098.
Potassium permanganate in the presence of tert-butyl alcohol and aqueous NaH2PO4 was shown
to effectively oxidize the aldehyde in the following polyoxygenated substrate to the corresponding
carboxylic acid whereas Jones reagent, RuCl3(H2O)n-NaIO4, and silver oxide failed.
OCH3
BnO
O
H3C CH3
()-yohimbane
OTBS
KMnO4, NaH2PO4
t-BuOH, H2O
CHO
H3C CH3
85%
OTBS
OTBS
OCH3
BnO
O
H3C CH3
OTBS
Cis/trans isomerization can be a problem with unsaturated systems under the strongly basic
reaction conditions employed.
CO2H
Examples:
H3C CH3
CHO
OTBS
CO2H
1. Ag2O, NaOH
HO
Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S. Tetrahedron Lett. 1986, 27, 4537!4540.
HO
2. HCl
OCH3
Examples:
OCH3
vanillic acid
90-97%
O
CHO
N
Boc
H
H
OTBS
N
H H
CN
KMnO4, NaH2PO4
t-BuOH, H2O, 5 C
93.5%
CN
CO2H
N
Boc
CHO
HO
O
N
(CH3)2N
()-nummularine F
N
H
H3C
Heffner, R. J.; Jiang, J.; Joulli, M. M. J. Am. Chem. Soc. 1992, 114, 10181!10189.
NH
CH3
HO
H3C
CHO
O
COOH
Ag2O, NaOH
HO
23 C
H3C
CHO
O
HO
H
()-K-76
H
()-K-76 monocarboxylic acid
14
Myers
Chem 115
Oxidation
Additional Examples
In the following example, all chromium-based oxidants failed to give the desired acid.
H3C
CO2H
1. Ag2O, NaOH
2. HCl
OMEM
H3C O
CO2H
OCH3
CHO
OMEM
81%
OH
H3C
H
H
97%
H
H
50-g scale
O
N
H3C O
PDC
Ovaska, T. V.; Voynov, G. H.; McNeil, N.; Hokkanen, J. A. Chem. Lett. 1997, 15!16.
Pyridinium Dichromate: (pyrH+)2Cr2O7
Attempts to form the ethyl and isopropyl esters were less successful.
Review
Ley, S. V.; Madin, A. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol. 7, p. 251!289.
PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume of water,
adding pyridine and collecting the precipitated product.
Note that in the following example sulfide oxidation did not occur.
O
H
BnO
BnO
O
O
SEt
BnO
Non-conjugated aldehydes are readily oxidized to the corresponding carboxylic acids in good
yields in DMF as solvent.
Primary alcohols are oxidized to the corresponding carboxylic acids in good yields.
In the following example, PDC was found to be effective while many other reagents led to
oxidative C-C bond cleavage.
H3C CH3
1. PDC, DMF
CHO
AcO
BnO CH3 CH3 CH3
SEt
BnO
PDC has also been used to oxidize alcohols to the corresponding carboxylic acids.
H H
CH3
H3C
TBSO
OH
PDC, DMF
H H
CH3
H3C
CO2H
NH
CO2CH3
AcO
BnO CH3 CH3 CH3
2. CH2N2
>71%
TBSO
6 equiv CH3OH
CH3O
BnO
BnO
H3C CH3
PDC, DMF
NH
91%
Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetrahedron 1988, 44, 2149!2165.
78%
other
oxidants
H3C CH3
O
AcO
OH
BnO CH3 CH3 CH3
H3C CH3
[O]
Ph
S
O
AcO
BnO CH3 CH3 O
CH3
Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem. 1985, 50,
2095!2105.
Ph
S
O
PDC, CH2Cl2
CH2OH
68%
CHO
15
Myers
Chem 115
Oxidation
O
O
H
Aldehyde
Bromine
OR'
Review
Ester
Manganese Dioxide!NaCN!CH3OH
Bromine in alcoholic solvents is a convenient and inexpensive method for the direct conversion
of aldehydes into ester derivatives.
Under the reaction conditions employed, secondary alcohols are not oxidized to the
corresponding ketones.
Cis/trans isomerization, a problem when other reagents such as basic silver oxide are
employed, is avoided.
The aldehyde substrate is initially transformed into a cyanohydrin intermediate. Subsequent
oxidation of the cyanohydrin furnishes an acyl cyanide which is then trapped with methanol to
give the desired methyl ester.
Examples
Examples
OH
O
O
CH3
CH3
MnO2, NaCN
AcOH, CH3OH
CHO NOBn
81%
CH3
CH3
H
NH
OH
Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176!5190.
In the following example, stepwise addition of reagents proved to be essential to achieve high
yields.
HO
H3C
1. NaCN, AcOH,
2. MnO2, CH3OH
CHO
H
NaHCO3
H3C
R = Me, 94%
R = Et, 91%
R = i-Pr, 80%
TBSO
CH3
HO
97%
Yamamoto, H.; Oritani, T. Tetrahedron Lett. 1995, 36, 5797!5800.
O
CH3
N
CO2CH3
CO2R
N
CO2CH3
NaHCO3
O
OCH3
78%
Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenlnder, F. Tetrahedron 1996, 52, 6409!6420.
A variation of this reaction using NBS as oxidant has been employed in tandem with the catalytic
enantioselective Michael addition of nitromethane to an enal:
CHO
CH3
CO2CH3
TBSO
COOMe
F3C
CH3OH, 1 h
CHO
H3C
()-lycoricidine
O
CH3
H3C
Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W. Tetrahedron Lett. 1988, 29,
5087!5090.
CH3
NOBn
OH
CH3
H3C
OCH3
OH
H3C
H OH
H OH
OH
N
H
Ph
Ph
OTMS
(0.1 equiv)
CH3NO2, CH3OH;
F3C
NO2
NBS
69%, 93% ee
(2Z, 4E)-xanthoxin
Jensen, K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jrgensen, K. A. Org. Lett. 2012,
14, 1516!1519.
Mark G. Charest, Jonathan William Medley
16
Myers
Chem 115
Oxidation
O
R
Examples
O
R'
Ketone
OR'
HO
CH3O
CH3O
Ester
m-CPBA, NaHCO3
Reviews
Krow, G. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 7, p. 671-688.
The reactivity order of Bayer-Villiger oxidants parallels the acidity of the corresponding
carboxylic acid (or alcohol): CF3CO3H > p-nitroperbenzoic acid > m-CPBA = HCO3H >
CH3CO3H > HOOH > t-BuOOH.
COR'
O
O
O
R'CO3H
O
R'CO2H
R
R
RL
RLO
RL
R
O
H
RL = Large Group
Criegee Intermediate
Primary and secondary stereoelectronic effects in the Bayer-Villiger reaction have been
demonstrated.
COR
primary
O
effect
O
H
O
Primary effect: antiperiplanar alignment of RL and "O-O
RL
R
Secondary effect: antiperiplanar alignment of Olp and "#C-RL
secondary
effect
n-C16H33
OCH3
D
T
CF3CO3H
Na2HPO4
D
T
H
D
99%
H2O2 (anhydrous),
BOMO
O
H3C
Ti(Oi-C3H7)4, ether
DIEA, 30 C
O
CH3
BOMO
H3C
>55%
CH3
AcO
Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am.
Chem. Soc. 1983, 105, 625-627.
H3C
OH
OH
eucannabinolide
Carbamates have been prepared in some cases.
CH3
CH3
N
O
O
n-C16H33
m-CPBA, Li2CO3
CH2Cl2
The Bayer-Villiger reaction occurs with retention of stereochemistry at the migrating center.
H
D
()-PGF2!
Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. Engl. 2000, 39, 2852-2855.
Ph
OCH3
N
Ph
Proposed TS
HO H
Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675-5677.
The migratory preference of alkyl groups has been suggested to reflect their electron-releasing
ability and steric bulk.
Typically, the order of migratory preference is tertiary > secondary > allyl > primary > methyl.
HO
95%
Krow, G. R. In Organic Reactions, Paquette, L. A., Ed., John Wiley and Sons: New York, 1993,
Vol. 43, p. 251-296.
A classic method for the oxidative conversion of ketones into the corresponding esters or
lactones by oxygen insertion into an acyl C-C bond.
CO2H
CH3
CH2Cl2
Bayer-Villiger Oxidation
D
T
N
O
N
CH3
m-CPBA, CH3OH
70%
N
O
CH3
Azizian, J.; Mehrdad, M.; Jadid, K.; Sarrafi, Y. Tetrahedron Lett. 2000, 41, 5265-5268.
Mark G. Charest
17
Myers
Chem 115
Oxidation
R
OMOM
OMOM
O
AcHN
OH
Alcohol
RuO2(H2O)2, NaIO4
OH
Acid
OH
N
Boc
AcHN
N
Boc O
98%
OH
Clinch, K.; Vasella, A.; Schauer, R. Tetrahedron Lett. 1987, 28, 6425!6428.
In the following example, sodium periodate cleaves the 1,2-diol to an aldehyde, which
Sharpless has introduced the use of acetonitrile as solvent to improve catalyst turnover. It is
proposed to avoid the formation of insoluble Ru-carboxylate complexes and return the metal to
the catalytic cycle.
HO H
CH3N
HF
Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936!3938.
1. RuCl3-NaIO4,
OH
OBz
OCH3
CH3N
OBz
2. (CH3)3SiCHN2
Examples
(S)-(+)-cocaine
78% overall
CO2H
RuCl3, NaOCl
Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773!4775.
CCl4, H2O
CO2H
Molecular Oxygen
70%
Molecular oxygen in the presence of a platinum catalyst is a classic method for the oxidation of
primary alcohols to the corresponding carboxylic acids.
Examples
O
RuO2, NaIO4
CCl4, H2O
HO2C
Bn
CO2H
Boc
68%
Smith, A. B., III; Scarborough, R. M., Jr. Synth. Commun. 1980, 10, 205!211.
O
H
R
H
HO
RuCl3-NaIO4
CH3CN, CCl4, H2O
OBz
R = CH3
60%
NH
OH
Boc
65%
NH
HO
Bn
Mehmandoust, M.; Petit, Y.; Larcheveque, M. Tetrahedron Lett. 1992, 33, 4313!4316.
CH3
CH3
R
OH
O2/Pt
OH O
H
OBz
O
()-scopadulcic acid B
OH O
HO
OCH3
O
NHPf
CH3
CH3
1. O2/Pt
CH3O
2. CH3I
85%
OCH3
O
NHPf
CH3
CH3
Pf = 9-phenylfluorenyl
Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1997, 119, 12031!12040.
18
Myers
Chem 115
Oxidation
Jones Oxidation
HO
O
CH3
CH3CN, H2O
CH3
Jones reagent
85%
CH3
CH3
Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293!295.
Corey, E. J.; Trybulski, E. J.; Melvin, L. S.; Nicolaou, K. C.; Secrist, J. A.; Lett, R.; Sheldrake, P.
W.; Flack, J. R.; Brunelle, D. J.; Haslanger, M. F.; Kim, S.; Yoo, S. J. Am. Chem. Soc. 1978,
100, 4618!4620.
A brief follow-up treatment with sodium chlorite was necessary to obtain complete oxidation to
the bis-carboxylic acid in the following example.
OBn
Silyl ethers can be cleaved under the acidic conditions of the Jones oxidation.
CO2CH3
CF3CONH
Jones reagent
BnO
CO2H
O
10 # 23 C
CO2CH3
H
N
Ph
O
NH
Jones reagent
NCBz
H2N
O
HO
Thottahil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M. K. Y.; Kissick, T. P. J. Org. Chem. 1986,
51, 3140!3143.
OH
CH2OBn
NaH2PO4, isopentene
49% overall
HO2C
O CO H
2
O
NH
H2N
CF3CONH
OH
PivO
NH3, CH3OH
O
N
O
NH
55 C
65%
O CO H
2
O
H
N
Ph
O
NH
OPiv
O
N
O
NH
4-desamino-4-oxo-ezomycin A2
O
Ph
Ph
2. PhI(OAc)2, TEMPO
CH3CN, NaHCO3, H2O
HO2C
5 C
NCBz
EtOAc, EtOH
OPiv
Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. Engl. 1999,
38, 3175!3177.
HO
OBn
PivO
88-97%
OH
CH3
OH
OTBS
CO2H
BnO
H3C
B = U (76%)
CH3
0 C
CH3
B = A (90%)
O
CH3
HO2C
TEMPO, PhI(OAc)2
O
O
H3C
Examples:
OH
90%
Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
Tetrahedron Lett. 1998, 39, 5323!5326.
19
Myers
Chem 115
Oxidation
O
O
R'
R'
H3C
OH
"-Hydroxy Ketone
Ketone
CH3
Davis Oxaziridine
Reviews
n-Bu
CH3
NBn
Li
Ph
Ph
CH3
n-Bu
Ot-Bu
O
N
m-CPBA or Oxone
RSO2N=CHR'
RSO2
R'
THF, 10 C
O
H
HO
CH3
CO2Et
OTBS
CH3
CO2Et
57% conversion
Ph
CH3
CH3
Cl
Ph
CH3
OH
CH3
CH3
OH
Smith, A. B., III; Empfield, J. R.; Rivero, R. A.; Vaccaro, H. A.; Duan, J. J.-W.; Sulikowski, M. M. J.
Am. Chem. Soc. 1992, 114, 9419!9434.
CH3O
OCH3
2. H3C
CH3
Cl
CH3O
OH
OCH3
Cl
O S N
OO
OCH3
OCH3
CH3O
Cl
O S N
OO
H
OH
CH3O
Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919!934.
OTBS
OCH3 1. NaHMDS
1. NaHMDS
2. H3C
H
HO
OH O
OH
()-breynolide
73%
taxol
97% at
TBDPSO
O S N
OO
O
HO
Ot-Bu
OH
OH O
CH3 2. 78 C
H3C
CH3
CH3 OH
78 # 20 C
1. KHMDS, HMPA,
H
TBDPSO
S
oxaziridine, THF
n-Bu
Ot-Bu
27-kg scale
Examples
KHMDS, Davis
NBn O
Traverse, J.; Leong, W. W.; Miller, S. P.; Albaneze-Walker, J.; Hunter, T. J.; Wang, L.; Liao, H.;
Arasappan, A.; Trzaska, S. T.; Smith, R. M.; Lekhal, A.; Bogen, S. L.; Kong, J.; Bennett, F.; Njoroge,
F. G.; Poirier, M.; Kuo, S.-C.; Chen, Y.; Matthews, K. S.; Demonchaux, P.; Ferreira, A. Patent: WO
2011014494.
CH3
Ph
O S N
OO
NBn OLi
Jones, A. B. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press:
New York, 1991, Vol. 7, p. 151!191.
N-Sulfonyloxaziridines are prepared by the biphasic oxidation of the corresponding sulfonimine
with m-CPBA or Oxone.
CH3
(+)-O-trimethylbrazilin
Mark G. Charest, Jonathan William Medley
20
Myers
Chem 115
Oxidation
Rubottom Oxidation
O O
Mo
((CH3)2N)3P O N
Epoxidation of a silyl enol ether and subsequent silyl migration furnishes "-hydroxylated ketones.
O
Oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) is commonly used to
oxidize enolates to the corresponding hydroxylated compound.
It is proposed that nucleophilic attack of the enolate occurs at a peroxyl oxygen atom, leading
to O-O bond cleavage.
SiR3
O
R1
R1
SiR3
O
R1
R2
R2
OSiR3
R1
R2
R2
Examples
Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40, 3427-3429.
H3C
OHC OH O
H3C
CHO O
1. LDA, THF, 78 C
TBDPSO
2. MoOPH
H3C CH3
91%
CH3
O
CH3
H3C CH3
Et3SiO
H3O+
OHC OH
H3C
CH3
EtOAc
HO
70%
H3C
CH3
O
m-CPBA, NaHCO3
H
TBDPSO
CH3
CH3
H3C
CHO
H3C CH3
()-warburganal
Jansen, B. J. M.; Sengers, H.; Bos, H.; de Goot, A. J. Org. Chem. 1988, 53, 855-859.
BOMO
O
H3C
H3C
H
1. LDA, THF, 78 C
CH3
O
CH3S
CH3
CH3
H3C
H
R1H3C
R2
2. MoOPH, 40 C
R1 = H, R2 = OH 45%
R1 = OH, R2 = H 25%
CH3
CH3
O
OTBS
PMBO
PMBO
OTBS
BOMO
OTBS
OTBS
dimethyldioxirane
OTBS
OTBS
camphorsulfonic acid
79%
dimethyldioxirane =
O
O
CH3
CH3
CH3
CH3S
Reddy, K. K.; Saady, M.; Falck, J. R. J. Org. Chem. 1995, 60, 3385-3390.
Kato, N.; Okamoto, H.; Arita, H.; Imaoka, T.; Miyagawa, H.; Takeshita, H. Synlett. 1994, 337-339.
Mark G. Charest
21
Myers
Chem 115
Oxidation
OH
HO
HO
O
diol
OH
O
lactone
H3C
Review
O
H3C
Procter, G. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 7, p. 312!318.
HO
H3C
Celite, toluene
CH3
H3C
75-85 C
H3C
Fetizon's Reagent
O
Ag2CO3 on
CH3
H3C
77%
(+)-mevinolin
Silver carbonate absorbed on Celite has been found to selectively oxidize primary diols to
lactones.
Fetizon, M.; Golfier, M.; Louis, J.-M. J. Chem. Soc., Chem. Commun. 1969, 1102!1118.
Other Methods
Fetizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 13, 4445!4448.
Platinum and oxygen have been used for the selective oxidation of primary alcohols to lactones.
Kakis, F. J.; Fetizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T. J. Org. Chem.
1974, 39, 523!533.
OH
H3C
CH3
H
H3C
Pt/O2
acetone, water
OH
CH3
Celite, C6H6
N
Ag2CO3 on
reflux
HO H3C
HO
CH3
HO H3C
OH
96%
O H3C
O
O
damsin
()-bukittinggine
TEMPO has been employed as a catalyst for the preparation of lactones.
Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem. 1992, 57, 2575!2585.
OH
CH3O
MOMO
OBn
Ag2CO3 on
Celite, C6H6
CH3 OH
>74%
OH
CH3O
MOMO
OBn
H3C
80 C
O
H3C
H3C
H3C
Boc
N
O
OH
CH3
H3C
TEMPO, (AcO)2IPh
OH OH
CH3
CH2Cl2, 23 C
95%
H3C
H3C
Boc
N
CH3
O
CH3
75%
Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron
Lett., 2003, 44, 57!59.
O
O
CH3O
N
H
O
CH3
OCH3 H C
3
H3C
CH3O
O
O
H3C
NH2
H3C
OH
OH
PhCH=CHCOCH3
toluene
CH3 CH3
()-macbecin I
RuH2(PPh3)4,
100%
O
H3C
CH3
Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S. J. Org. Chem. 1986, 51, 2034!2039.
Coutts, S. J.; Kallmerten, J. Tetrahedron Lett. 1990, 31, 4305!4308.
22
TBS
O
TBS
PhS
HO
Reviews:
Wee, A. G.; Slobodian, J. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing
Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. 420423.
TBS
PhS
O
HO
(CH2)6OBn
toluene, 0 C
2045 min
O
H
90%
(CH2)6OBn
Pb(OAc)4
O
OH
HO
PhS
(CH2)6OBn
OH
NaIO4, NaOH, EtOH
O
H3C
C8H15
O
H3C
PMBO H
O
0 " 25 C, 2 h
>95%
O
!-Hydroxyketones can be cleaved as well:
O
H3C
C8H15
H3C CH3 OH
H3C
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.; Jung, J.; Choi, H.-S.; Yoon, W. H. J. Am. Chem. Soc.
2002, 124, 22022211.
H
O
Pb(OAc)4
O
CH3
H3C CH3
CO2CH3
OCH3
H3C
H3C
O
CH3OHPhH (1:2)
0 C, 30 min
H3C CH
3
CH3
CO2CH3
82%
H3C
A common reagent for the cleavage of diols. However, Pb(OAc)4 is a strong oxidant and can
react with a variety of functional groups.
HO
O
HO
OTBDPS
CH3
1. Pb(OAc)4, PhH
2. NaBH4, CH3OH
Pb(OAc)4
H
AcO
Examples:
H3C OAc
HO CH3
PhH, 80 C, 18 h
68%
O
AcO
CH3
O
HO
H3C
OH
OTBDPS
Bowers, A.; Denot, E.; Ibez, L. C.; Cabezas, M. A.; Ringold, H. J. J. Org. Chem. 1962, 27,
18621867.
Mihailovic, M. L.; Cekovic, Z. Synthesis 1970, 5, 209224.
In addition, Pb(OAc)4 can oxygenate alkenes, oxidize allylic or benzylic CH bonds, and has
been used to introduce an acetate group ! to a ketone.
Takao, K.; Watanabe, G.; Yasui, H.; Tadano, K. Org. Lett. 2002, 4, 29412943.
Landy Blasdel
23
Examples
CH3
CH3
OH
Ozone
H3C
H
Reviews:
Berglund, R. A. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing
Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999,
p. 270275.
H3C
OBn
H
O
2. thiourea, 78 C
OTMS
65%
Ph
Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol 7, p. 543558, 574578.
OTBS
OH
1. O3, CH2Cl2CH3OH
(15:1), 78 C
H3C
H
OBn
H
O
H3C
O
OTMS
OTBS
Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am.
Chem. Soc. 1997, 119, 1297612977.
Forming the primary ozonide with sterically hindered olefins is difficult, and epoxides can be
formed instead:
CH3
CH3
1. O3, (ClH2C)2, 0 C
Ozone is the most common reagent for the oxidative cleavage of olefins.
H3C
H3C
2. Zn, HOAc, 75 C
H3C CH3
H3C
H3C
71%
O
CH3
H3C
Mechanism:
R1
O
R3
+
O
R2
R1
R4
R2
R4
R3
R4
R1
R2
R3
H3CO
O
O
R3 R4
O
+
R1
R2
R3
R4
H
N
OH
3. NaBH4
reductant
Ph
molozonide
O
H3CO
R1
O
O
R2
ozonide
92%
OTBS
OTBS
When a TMS-protected alkyne was used in the example above, the authors observed
products arising from ozonolysis of the alkyne as well.
Banfi, L.; Guanti, G. Tetrahedron Lett. 2000, 41, 65236526.
Dimethyl sulfide is the most commonly used reducing agent. Others include I2, phosphine,
thiourea, catalytic hydrogenation, tetracyanoethylene, ZnHOAc, LiAlH4, and NaBH4. The latter
two reductants afford alcohols as products.
Oxidative workup provides either ketone or carboxylic acid products. The most common oxidants
are H2O2, AgO2, CrO3, KMnO4, or O2.
Alkenes with electron-donating substituents are cleaved more readily than those with electronwithdrawing substituents, see: Pryor, W. A.; Giamalva, D.; Church, D. F. J. Am. Chem. Soc. 1985,
107, 27932797.
H3C
1. O3, CH3OHCH2Cl2
(3:1), 78 C
OCH3
2. S(CH3)2,
78 C ! 23 C
92%
CH3
OCH3
O
HO
H
Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan, S. M. J. Org. Chem. 1997, 62, 7887.
Landy Blasdel
24
OsO4, NaIO4
OCH3
OCH3
1 or 2 steps
Wee, A. G.; Liu, B. In Handbook of Reagents for Organic Synthesis: Oxidizing and
Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York,
1999, p. 423426.
A two-step procedure involving initial dihydroxylation with OsO4 to form 1,2-diols, followed by
cleavage with periodate.
Frequently the two-step protocol is found to be superior to the one-pot procedure. In the example
shown, over-oxidation of the aldehyde was observed in the one-pot reaction.
CH3 CH3
PMBO
H3C
OH
OH
PMBO
H3C
NaIO4
THF, H2O
23 C
CH3 CH3
OBn
OPMB
NTs
H3CO
OBn
Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol. 7, p.564.
H3C
NTs
H3CO
O
H
CH3 CH3
CH3 OPMB
CH3
OTBS
The procedure is most often performed in two steps, but the transformation is sometimes
accomplished in one:
dioxaneH2O (3:1)
CH3 OPMB
H
O
CH3
OTBS
CH3 OPMB
+
HO
O
90%
CH3
OTBS
6%
H3CO
H3CO
H3CO
OsO4, NaIO4,
2,6-lutidine
O
H
H3CO
THF, H2O, 23 C
62% conversion
H
H3CO
THF
47% (two steps)
CH3MgI
The authors found that without base, the !-hydroxyketone was formed in ~30% yield.
Using pyridine as base, epimerization of the aldehyde product was observed.
H3CO
H3C
OH
Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 32173219.
Notice that in the example above, the less-hindered olefin was cleaved selectively.
Maurer, P. J.; Rapoport, H. J. Med. Chem. 1987, 30, 20162026.
Landy Blasdel
25
Ketone
!,"-Unsaturated Ketone
RuO4
See also: o-Iodobenzoic Acid
(IBX) earlier in handout
References:
Martn, V. S.; Palazn, J. M.; Rodrguez, C. M. In Handbook of Reagents for Organic Synthesis:
Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons:
New York, 1999, p. 346353.
Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol 7, p.564571, 587.
Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 10111013.
A two-step procedure involving silyl enol ether formation, followed by treatment with Pd(II).
Solvent mixtures of CCl4, H2O and CH3CN have been determined to be optimal. CH3CN is
a good ligand for low valent Ru, and it prevents formation of stable Ru(II/III)carboxylate
complexes which remove Ru from the catalytic cycle. See: Carlsen, P. H. J.; Katsuki, T.;
Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 39363938.
RuO4 will also oxidize alcohols (to ketones), ethers (to lactones or to two carboxylic acids), diols
(to two carboxylic acids), alkynes (to 1,2-diketones), and aryl rings (to carboxylic acid products).
It will also remove aryl and alkyne groups, leaving carboxylic acids.
CH3
CH3
CH3
CH3
RuO2, NaIO4
CCl4CH3CNH2O
(1:1:1.5), 23 C, 1 h
68%
CH3
CH3
"-elim
Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem. Int. Ed. 1999, 38,
20152016
O
PMBO
OTIPS
THF, 78 C
CCl4CH3CNH2O
CH3
O CH
3
H
TMSO
PMBO
O
PMBO
OTIPS
Pd(dba)2CHCl3 (5 mol%),
diallyl carbonate, CH3CN
H
CH3
LiTMP, TMS-Cl
RuO2, NaIO4
82%
PdII
Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 10111013.
H
CH3
O
PdII
CH3
H3C
H3C
PdII OTMS
Pd(OAc)2
TMS-OAc
Pd(0)
OTMS
TMS-Cl
CH3
H CH3
The reaction can be performed with stoichiometric Pd(II), or can be rendered catalytic if a
terminal oxidant, such as O2 or p-benzoquinone, is used.
Mechanism:
Reaction conditions are relatively mild and usual involving generation of RuO4 in situ from
RuO22H2O or RuCl3H2O and an oxidant, such as NaIO4.
Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol. 7, p. 119149.
Saegusa Oxidation
H3C
General Reference:
OTIPS
26
Ketone
!,"-Unsaturated Ketone
Examples:
1. LDA, THF
78 C
Selenation/Oxidation/Elimination
Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol. 7, p. 128135.
Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 14, 19791982.
Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem. Soc. 1973, 95, 61376139.
Ph
O
SePh
Ph
2. PhSeBr
H2O2, pyridine
Ph
CH2Cl2H2O,
25 C, 30 min
66%
Generating the enolate under kinetic conditions can allow for formation of the less-substituted
double bond.
Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 54345447.
Reich, H. J.; Reich, I. L.; Renga, J. M. J. Am. Chem. Soc. 1973, 95, 58135815.
Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 54345447.
O
1. LDA; PhSeCl
PhSeBr and PhSeCl can be used to selenate enolates of ketones, esters, lactones and lactams.
H3C
H3C
H3C
H3C
2. H2O2
CH3
CH3
64%
one-step procedure with PhSeSePh, SeO2, and a catalytic amount of H2SO4: Miyoshi, N.;
Yamamoto, T.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett. 1982, 23, 48134816.
Mechanism:
base
PhSeBr
H CH
3
cis-fused
H
O
OH
1. LDA, THF,
HMPA, 78 C
2. PhSeSePh
H CH
3
trans-fused
85%
O
Ph
Elimination is syn-specific, see: Jones, D. N.; Mundy, D.; Whitehouse, R. D. J. Chem. Soc.,
Chem. Commun. 1970, 8687.
~ 100%
96%
Electron withdrawing groups on the phenyl ring facilitate the elimination step, which can be
difficult with primary or "- or #-branched selenoxides: Sharpless, K. B.; Young, M. W. J. Org.
Chem. 1975, 40, 947948.
SePh
CH3
H2O2, THF, H2O,
AcOH, 0 C
O
O
H
10
O
O
O
O
SePh
CH3
H
Se
O
O
[O]
Se
SePh
Ph
1. LDA, THF,
HMPA, 78 C
2. PhSeSePh
88%
90
CH3
O
O
The example above illustrates how the stereospecificity (syn) of the elimination can be used to
achieve selectivity in olefin formation.
Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120122.
Landy Blasdel
27
Alkene
Allylic alcohol
Examples:
CH3
CH3
OH
SeO2
O
References
CH3
O
Bulman Page, P. C.; McCarthy, T. J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds.; Pergamon Press: New York, 1991, Vol. 7, p. 8491, 108110.
OH
CH3 O
H3C
Although the reaction can be performed with stoichiometric SeO2, catalytic methods employing a
stoichiometric oxidant (e.g., t-BuOOH) are more frequently used.
CH3
O Se O
OH
Se
OH
CH3 O
H3C
O
CH3
H3C
OH
H
99%
TBSO
CH3
HO
H3C
H3C
SeO2, t-BuOOH
CH2Cl2 0 C
[2,3]-sigmatropic
rearrangement
H3C
95%
H3C
H3C
ene reaction
OH
CH3
O
dioxane, 23 C
O
CH3
H3C
H3C
Mechanism:
CH3
SeO2, t-BuOOH
Xia, W. J.; Li, D. R.; Shi, L.; Tu, Y. Q. Tetrahedron Lett. 2002, 43, 627630.
H3C
TBSO
Se
O
CH3
Br
H3C
CH3
H
CbzN
CH3
SeO2, t-BuOOH
CH2Cl2, 0 C " 23 C
Selectivity:
(a) oxidation typically occurs at the more highly substituted terminus of the alkene
(b) the order of reactivity of CH bonds is CH2 > CH3 > CH
[rule (a) takes precedence over rule (b)]
(c) when the double bond is within a ring, oxidation occurs within the ring
(4) gem-dimethyl trisubstituted alkenes form (E)-!-hydroxy alkenes stereoselectively
Br
O
HO
O
+
H
CbzN
14%
CH3
Br
Br
H
+
H
CbzN
H
H
77%
CH3
CbzN
CH3
trace
Muratake, H.; Natsume, M. Angew. Chem. Int. Ed., Eng. 2004, 43, 46464649.
Landy Blasdel
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