Myers

General Introductory References

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.
Oxidation States of Organic Functional Groups

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 2electron 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:
Alcohol

RCH2SiR3'

Alcohol R-CH2OH (R-CH2X )

alkyl halide X = halide

alkane sulfonate X = OSO2R'

alkyl azide X = N3

alkylamine X = NR'2

alkylthio ether X = SR'

alkyl ether X = OR'

Aldehyde (Ketone) R-CHO (RCOR')

hemiketal (hemiacetal)

Oppenauer Oxidation
Chromium (VI) Oxidants
Sodium Hypochlorite
N-Bromosuccinimide (NBS)
Bromine
Cerium (IV) Oxidants

Pyridinium Dichromate (PDC)

R'

RCX2R'

geminal dihalide

dithiane

R'

R'

Carboxylic Acid R-CO2H

ester

Bromine

Ester

R'

R''O NR2'''

aminal

R'
N

imine

R''
R'

RCO2R'

amide

N
R''

thioester

SR'

trihalomethyl

R'
N
OH

orthoester

ketene

RCX3

O
hydroxamic acid

R'''

nitrile

R'

R C N

O
R

O
O

CH3 (OBO ester shown)

Acid

O2/Pt

Jones Oxidation

Carbonic Acid Ester ROH + CO2 (ROCO2H)

MoOPH

Rubottom Oxidation

Lactone

isocyanate

O2/Pt

-Hydroxy Ketone

Davis Oxaziridine

Fetizon's Reagent

oxime

OR''

R''O

carbamate
Diol

R'

enol ether (enamine)

Ester

Ruthenium Tetroxide
Ketone

R'

R''O OR'''

ketal (acetal)

Baeyer-Villiger Oxidation
Alcohol

N NR''2

hydrazone

Corey-Gilman-Ganem Oxidation
Ketone

organosilanes

organometallics in general RCH2M (M = Li, MgX, ZnX...)

Acid

Sodium Chlorite
Silver Oxide
Potassium Permanganate
Aldehyde

organoboranes RCH2BR2'

R''O OH

Aldehyde or Ketone

Dimethylsulfoxide-Mediated Oxidations
Dess-Martin Periodinane (DMP)
o-Iodoxybenzoic Acid (IBX)
tetra-n-Propylammonium Perruthenate (TPAP)
N-Oxoammonium-Mediated Oxidation
Manganese Dioxide
Barium Manganate
Aldehyde

Chem 215

Oxidation

N-Oxoammonium-Mediated Oxidation

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'''

Mark G. Charest

Alcohol

Pummerer Rearrangement

Aldehyde or Ketone

HO CH3 OH
H3C
H
Dimethylsulfoxide-Mediated Oxidations

H3C

Reviews

(CF3CO)2O, Ac2O
2,6-lutidine

Tidwell, T. T. Organic Reactions 1990, 39, 297-557.

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
N-chlorosuccinimide.
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.
+

H H

BH+

RCO2

O
HO CH3 OH
H3C
H

Tidwell, T. T. Synthesis 1990, 857-870.

H3C

S Ph

Lee, T. V. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 7, p. 291-303.

(CH3)2S O

HO CH3 OH
H 3C
H

OAc

>60%

H3C

Ph

O
R

HO CH3 OH
H 3C
H

+S

AcO

O
H

S Ph

S Ph
+

Schreiber, S. L.; Satake, K. J. Am. Chem. Soc. 1984, 106, 4186-4188.

Swern Procedure
Typically, 2 equivalents of DMSO are activated with oxalyl chloride in dichloromethane at or
below 60 C.
Subsequent addition of the alcohol substrate and triethylamine leads to carbonyl formation.
The mild reaction conditions have been exploited to prepare many sensitive aldehydes.
Careful optimization of the reaction temperature is often necessary.

(CH3)2S

H H CH3
+
+
S
CH3
R
O

Huang, S. L.; Mancuso, A. J.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482.
RCH2OH

(CH3)2S

X
HO

H
R

+
O

(CH3)2S

TBSO

2. 10% Pd/C, AcOH, EtOAc

O

3. (COCl)2, DMSO; Et3N

78 50 C

OBn

alkoxysulfonium ylide

TBSO

1. TBSCl, Im, DMAP, CH2Cl2

HO

CH2
+
S
CH3
O

H H
R

H+

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.

OTBS
(COCl)2, DMSO;

ROH + H2C S CH3

OTBS

RO

H+

CH3

HO

OCH3

Et3N, 78 C
90%

Fenselau, A. H.; Moffatt, J. G. J. Am. Chem. Soc. 1966, 88, 1762-1765.

OCH3
H

Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738-3753.

Mark G. Charest

Chromium (VI) Oxidants

Collins Reagent: CrO3 pyr2

Reviews
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.
Luzzio, F. A. Organic Reactions 1998, 53, 1-122.
The mechanism of chromic acid-mediated oxidation has been extensively studied and is
commonly used as a model for other chromium-mediated oxidations.

CrO3 pyr2 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.
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.
Collins, J. C.; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 30, 3363-3366.

R 2CHOH +

HCrO4

R2 C O CrO3H
H

+ H

R2CHOCrO3H + H2O
R2C O

Collins, J. C.; Hess, W. W.; Org. Synth. 1972, 52, 5-9.

+ HCrO3 + BH+

In situ preparation of the reagent circumvents the difficulty and danger of preparing the pure
complex.
OH
O
H3 C
H3 C

CrO3, pyr, CH2Cl2

Holloway, F.; Cohen, M.; Westheimer, F. H. J. Am. Chem. Soc. 1951, 73, 65-68.
H

H3 C

A competing pathway involving free-radical intermediates has been identified.

95%

CH3

R2CHOH

Cr(IV)

R2COH

Cr(III)

H+

Ratcliffe, R.; Rodehorst, R. J. Org. Chem. 1970, 35, 4000-4003.

R2COH

Cr(VI)

R2C=O

Cr(V)

H+

Examples

R2CHOH

Cr(V)

R2C=O

Cr(III)

2H +

HO
H3 C
O

Wiberg, K. B.; Mukherjee, S. K. J. Am. Chem. Soc. 1973, 96, 1884-1888.

Fragmentation has been observed with substrates that can form stabilized radicals.

PhCHO

(CH3)3C

OH
Cr O
O

OCrO3H

OTBS

1. n-Bu4 N+F, THF

2. Collins Reagent
O

CH3
CH3

CH 2Cl2
81% overall

CH3

CH3
()-periplanone B

Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493-2495.

O

1. H2, 10% Pd-C

OCH3
H

CH3O2C

O
CH3 CH3

83%

Doyle, M.; Swedo, R. J.; Rocek, J. J. Am. Chem. Soc. 1973, 95, 8352-8357.
Tertiary allylic alcohols are known to undergo oxidative transposition.

CH 3

Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422-428.
O

Cr(III)

89%

Wiberg, K. B.; Szeimies, G. J. Am. Chem. Soc. 1973, 96, 1889-1892.

H
Ph C O Cr(IV)
(CH 3)3C

O
H3 C

CrO3, pyr

H3 C

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.
Mark G. Charest

Pyridinium Chlorochromate (PCC, Corey's Reagent)

Sodium Hypochlorite: NaOCl

Sodium hypochlorite in acetic acid solution selectively oxidizes secondary alcohols to

+N

ketones in the presence of primary alcohols.

ClCrO3

A modified procedure employs calcium hypochlorite, a stable and easily handled solid

PCC

hypochlorite oxidant.
Examples

PCC is an air-stable yellow solid which is not very hygroscopic.

OH

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.

CH3

NaOCl, AcOH

The slightly acidic character of the reagent can be moderated by buffering the reaction mixture
with powdered sodium acetate.

H3 C

OH

Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 26, 2647-2650.

Addition of molecular sieves can accelerate the rate of reaction.

HO

CH3
O

H
Cl

OTIPS
O

NC

PCC, 25 C

4 MS

CH3
OH

O
H
Cl

H3 C

OTIPS
O

CH3
N

2. MOMCl, DIEA

O
H3 C

OMOM

Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431-7432.

OH

CH3

CH3
N

PCC, CH2Cl2
S

H
H3C

71%

PCC, 25 C
4 MS
100%

OH

86%

H
H3 C

OH

Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777-12782.

Browne, E. J. Aust. J. Chem. 1985, 38, 756-776.

OH

CH3
OH

NaOCl, AcOH

NaOAc

N
CH2Ph

1. NaOCl, AcOH

93%

Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871-8872.

OH

NC
100%

H3 C

Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982, 23, 35-38.

Examples

91%

Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.; Albizati, K. F. Tetrahedron Lett. 1982,
23, 4647-4650.

Antonakis, K.; Egron, M. J.; Herscovici, J. J. Chem. Soc., Perkin Trans. I 1982, 1967-1973.

PhCH2

CH3

PhCH 2
O

N
N
CH2Ph

Knapp, S.; Hale, J. J.; Bastos, M.; Gibson, F. S. Tetrahedron Lett. 1990, 31, 2109-2112.

n-C9H19 CH2OH
OH
CH3

n-C9H19 CH2OH

NaOCl, AcOH
71%

O
CH3

Winter, E.; Hoppe, D. Tetrahedron 1998, 54, 10329-10338.

Mark G. Charest

Potassium Permanganate: KMnO4

In the following example, a number of other oxidants (including Jones reagent, NaOCl, and
RuO2) failed.

Review
Fatiadi, A. J. Synthesis 1987, 85-127.

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.
Oxidation occurs through a coordinated permanganate intermediate by hydrogen atom-abstraction
or hydride transfer.

t-BuOH, H2 O, 0 C

TsN

N
Ts
H

H
O

TsN

N
Ts
CH3O

2. (CH3)3SiCHN 2

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

H3C

O
CH3

O
H3C

OTBS

Silver Oxide: Ag2O

t-BuOH, H2O

CHO

CH3

()-yohimbane

KMnO4, NaH2PO4

A classic method used to oxidize aldehydes to carboxylic acids.

85%

Cis/trans isomerization can be a problem with unsaturated systems under the strongly basic
reaction conditions employed.

OTBS
OTBS

OCH3

BnO
Abiko, A.; Roberts, J. C.; Takemasa, T.;
Masamune, S. Tetrahedron Lett. 1986,
27, 4537-4540.

O
H3C

O
CH3

O
H3 C

OTBS

Examples
CHO

CO2 H

CH3

HO

2. HCl

CHO
N
Boc

t-BuOH, H2O, 5 C
93.5%

CN

KMnO4, NaH2 PO4

OCH3
90-97%

H3 C
CH3
CH3
CHO

O
N
O

Ag2O, CH3OH
0 C

CH3
CH3
CO2H

72%

O
Heffner, R. J.; Jiang, J.; Joulli, M. M. J. Am. Chem. Soc.
1992, 114, 10181-10189.
(CH3)2N

vanillic acid

Pearl, I. A. Org. Synth. IV 1963, 972-978.

H3C

CO2H
N
Boc

HO

OCH3

Examples
CN

CO2H
1. Ag2O, NaOH

OTBS

H
H

OTBS

N
HH

Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64,

3237-3243.

NH

N
H
H3C

()-nummularine F

Sonawane, H. R.; Sudrik, S. G.; Jakkam, M. M.; Ramani, A.; Chanda, B. Synlett. 1996, 175-176.

CH3

Mark G. Charest

 Additional Examples

In the following example, all chromium-based oxidants failed to give the desired acid.
O
S

O
OCH3

CHO

OTBDPS
H

CH3O

CO2H

1. Ag2O, NaOH
2. HCl

OMEM

OMEM

OTBDPS

PDC, DMF

OH

CH3O
O

100%

Mazur, P.; Nakanishi, K. J. Org. Chem. 1992, 57, 1047-1051.

81%

CO2H

PDC can oxidize aldehydes to the corresponding methyl esters in the presence of methanol. It
appears that in certain cases, the oxidation of methanol by PDC is slow in comparison to the
oxidation of the methyl hemiacetal.

Ovaska, T. V.; Voynov, G. H.; McNeil, N.; Hokkanen, J. A. Chem. Lett. 1997, 15-16.

Attempts to form the ethyl and isopropyl esters were less successful.

Pyridinium Dichromate: (pyrH+)2Cr2O7

Note that in the following example sulfide oxidation did not occur.

Review
O

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.

BnO
BnO

PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume of water,
adding pyridine and collecting the precipitated product.
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.

1. PDC, DMF

CHO

AcO
BnO CH3 CH3 CH3

BnO

6 equiv CH 3OH

SEt

BnO

O'Connor, B.; Just, G. Tetrahedron Lett. 1987, 28, 3235-3236.

PDC has also been used to oxidize alcohols to the corresponding carboxylic acids.
TBSO

H H

CH3

H3 C

H3C CH3

SEt

>71%

In the following example, PDC was found to be effective while many other reagents led to
oxidative C-C bond cleavage.

CH3O
BnO
BnO

PDC, DMF

Garegg, P. J.; Olsson, L.; Oscarson, S. J. Org. Chem. 1995, 60, 2200-2204.

Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399-402.

H3C CH3

TBSO
OH

PDC, DMF

NH
91%

H H

CH3

H3 C

CO2H
O

NH

CO2CH 3

AcO
BnO CH3 CH3 CH3

2. CH 2N2

Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetrahedron 1988, 44, 2149-2165.

78%
However, a suspension of PDC in dichloromethane oxidizes alcohols to the corresponding
other
oxidants

H3C CH3
O

AcO
OH
BnO CH3 CH3 CH3

aldehyde.

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

Terpstra, J. W.; van Leusen, A. M. J. Org. Chem. 1986, 51, 230-238.

Mark G. Charest

Jones Oxidation

N-Oxoammonium-Mediated Oxidation of Alcohols to Carboxylic Acids

A general method for the preparation of nucleoside 5'-carboxylates:

Jones reagent is a standard solution of chromic acid in aqueous sulfuric acid.

Acetone is often benefical as a solvent and may function by reacting with any excess
oxidant.

HO

Isolated olefins usually do not react, but some olefin isomerization may occur with
unsaturated carbonyl compounds.

1,2-diols and -hydroxy ketones are susceptible to cleavage under the reaction conditions.

CH3CN, H2O

O
H3C

CH3

O
H3C

B = A (90%)

Examples

HO2C

TEMPO, PhI(OAc)2

CH3

B = U (76%)
O

O
CH3

CH3

Jones reagent

B = C (72%, NaHCO3 added)

CH3

CH3

B = G (75%, Na salt, NaHCO3 added)

0 C
CH3

Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293-295.

CH3

85%

CO2H

A brief follow-up treatment with sodium chlorite was necessary to obtain complete oxidation to
the bis-carboxylic acid in the following example.

OH
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.
Silyl ethers can be cleaved under the acidic conditions of the Jones oxidation.

OBn
O

CF3CONH

PivO
OTBS

BnO
O

CO2CH3

CO2H

BnO

Jones reagent

10 23 C

Ph

CO2CH3

H
N
O

1. H2, 20% Pd(OH)2-C,

OBn

NH

CH3CN, NaHCO3, H2O

N

O
O

H
H

O
O

CH3

O
1. Jones reagent

CH3 2. HCO2H

3
O

CO2t-Bu

CH3

NaH2PO4, isopentene
49% overall

H2N

NH

CF3CONH

OH

PivO
NH3, CH3OH

O
N

O
NH

CH3

CO2H

CH2OBn

HO2C
O CO H
2
O

O
3

96% overall

H2N

HO

3. NaClO2, t-BuOH, H2O

HO2C

O
N

Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. Engl. 1999,
38, 3175-3177.

OH

2. PhI(OAc)2, TEMPO

88-97%

Ketones have been prepared efficiently by oxidation of the corresponding secondary alcohol.

EtOAc, EtOH

OPiv

55 C
65%

O CO H
2
O

H
N

Ph
O

NH

OPiv

O
N

O
NH

4-desamino-4-oxo-ezomycin A2

()-CP-263,114
Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825-7826.

Knapp, S. K.; Gore, V. K. Org. Lett. 2000, 2, 1391-1393.

Mark G. Charest

Oxidative Cleavage of Diols

TBS
O

Sodium periodate (NaIO4)

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

One of the most common reagents for cleaving 1,2-diols.

Tan, Q.; Danishefsky, S. J. Angew. Chem. Int. Ed., Eng. 2000, 39, 45094511.
HO
PMBO
O

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%

Lead Tetraacetate (Pb(OAc)4)

Corey, E. J.; Hong, B. J. Am. Chem. Soc. 1994, 116, 31493150.
Reviews:
Mihailovic, M. L.; Cekovic, Z. 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. 190195.

Oxidative cyclizations sometimes occur. This process likely proceeds by a free-radical

mechanism involving homolytic cleavage of an ROPb bond.

Butler, R. N. In Synthetic Reagents, Pizey, J. S., Ed., 1977, Vol 3, p. 277419.

H3C OAc

Rubottom, G. M. In Oxidation in Organic Chemistry, Trahanovsky, W. S., Ed.; Organic Chemistry,

A Series of Monographs, Vol 5, 1982, Part D, p. 1145.

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

84% (two steps)

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

 Examples

Oxidative Cleavage of Alkenes

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.

Murray, R. W. In Techniques and Methods of Organic and Organometallic Chemistry ,

Denny, D. B., Ed., Marcel Dekker: New York, 1969, Vol 1, p. 132.

Forming the primary ozonide with sterically hindered olefins is difficult, and epoxides can be
formed instead:

Murray, R. W. Acc. Chem. Res. 1968, 1, 313320.

CH3

CH3
1. O3, (ClH2C)2, 0 C

Ozone is the most common reagent for the oxidative cleavage of olefins.
H3C
H3C

The reaction is carried out in two steps:

(1) a stream of O3 in air or O2 is passed through the reaction solution at low temperature
(0 C to 78 C) until excess O3 in solution is evident from its blue color.

2. Zn, HOAc, 75 C
H3C CH3

H3C
H3C

71%

O
CH3
H3C

Hochstetler, A. R. J. Org. Chem. 1975, 40, 15361541.

(2) reductive or oxidative work-up.

Alkenes are ozonized more readily than alkynes:

Mechanism:

R1
O

R3

+
O

R2

R1

R4

R2

R4

R3
R4

R1

R2

R3

H3CO

O
O

1. O3, CH2Cl2, CH3OH

2. S(CH3)2

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.

Considered to be a concerted 3 + 2 cycloaddition of O3 onto the alkene.

Because ozonides are known to be explosive, they are rarely isolated and typically are transformed
directly to the desired carbonyl compounds.

Ozonolysis of silyl enol ethers can afford carboxylic acids as products:

OTMS

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.
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Oxidative Cleavage of Alkenes

OCH3
OCH3

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.

1. OsO4 (cat.), NMO, acetoneH2Ot-BuOH (4:2:1);

2. NaIO4, THFH2O (3:1)...................................................89%

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.

This procedure offers an alternative to ozonolysis, where it can be difficult to achieve

selectivity for one olefin over another due to difficulties in adding precise quantities of ozone.
Sharpless dihydroxylation conditions (AD-Mix /) can lead to enhanced selectivities.

cat. OsO4, NMO

THF, acetone,
H2O, 23 C

CH3 CH3

PMBO
H3C

OH
OH

Bianchi, D. A.; Kaufman, T. S. Can. J. Chem. 2000, 78, 11651169.

PMBO
H3C

NaIO4
THF, H2O
23 C

CH3 CH3

OBn

OsO4 (cat.), NaIO4, THFH2O (3:1)...................................77%

VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973.

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

An improved one-pot procedure uses 2,6-lutidine as a buffering agent:

93% (two steps)

Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.; Sheidt, K. A. J. Org. Chem.
2002, 67, 42754283.

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

Ozonolysis of this substrate resulted in PMB removal.

OsO4, NaIO4

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