Myers Oxidation Chem 215

General Introductory References Alkane R-CH3

March, J. In Advanced Organic Chemistry, John Wiley and Sons: New York, 1992, p. 1158-1238. organoboranes RCH2BR2' organometallics in general RCH2M (M = Li, MgX, ZnX...)
organosilanes RCH2SiR3'
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. Alcohol R-CH2OH (R-CH2X )

Oxidation States of Organic Functional Groups alkyl halide X = halide alkane sulfonate X = OSO2R' alkyl azide X = N3

The notion of oxidation state is useful in categorizing many organic transformations. alkylamine X = NR'2 alkylthio ether X = SR' alkyl ether X = OR'
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.
Aldehyde (Ketone) R-CHO (RCOR')
Summary of Reagents for Oxidative Functional Group Interconversions:
OR''
R''O OH N NR''2 N
Alcohol Aldehyde or Ketone hemiketal (hemiacetal) hydrazone oxime
R R' R R' R R'
Dimethylsulfoxide-Mediated Oxidations Oppenauer Oxidation
Dess-Martin Periodinane (DMP) Chromium (VI) Oxidants R''O OR''' R''O NR2'''
o-Iodoxybenzoic Acid (IBX) Sodium Hypochlorite ketal (acetal) geminal dihalide RCX2R' aminal
R R' R R'
tetra-n-Propylammonium Perruthenate (TPAP) N-Bromosuccinimide (NBS)
N-Oxoammonium-Mediated Oxidation Bromine R''O R''
N
Manganese Dioxide Cerium (IV) Oxidants enol ether (enamine) dithiane S S imine
R R'
Barium Manganate R R' R R'

Aldehyde Acid
Carboxylic Acid R-CO2H O
Sodium Chlorite Silver Oxide Pyridinium Dichromate (PDC) O
ester RCO2R' R''' ketene
Potassium Permanganate amide R N
O R'' R R'
Aldehyde Ester
thioester R SR' trihalomethyl RCX3 nitrile R C N
Corey-Gilman-Ganem Oxidation Bromine
O
Ketone Ester O
R'
hydroxamic acid R N orthoester R O CH3 (OBO ester shown)
Baeyer-Villiger Oxidation OH O
Alcohol Acid

Ruthenium Tetroxide O2/Pt Jones Oxidation Carbonic Acid Ester ROH + CO2 (ROCO2H)

Ketone α-Hydroxy Ketone O O S

carbamate R'' alkyl haloformate xanthate
Davis Oxaziridine RO N RO X RO SR'
MoOPH Rubottom Oxidation
R'
O
Diol Lactone
isocyanate R N C O carbodiimide R N C N R' urea R R'
N N
Fetizon's Reagent O2/Pt N-Oxoammonium-Mediated Oxidation
R'' R'''

Mark G. Charest
 • Pummerer Rearrangement
Alcohol Aldehyde or Ketone
HO CH3 OH HO CH3 OH
H3C H H 3C H
(CF3CO)2O, Ac2O B
Dimethylsulfoxide-Mediated Oxidations H3C O O 2,6-lutidine H3C O O H H
H H
• Reviews
S Ph –BH+ O +S Ph
Lee, T. V. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon O –
O
Press: New York, 1991, Vol. 7, p. 291-303.
–RCO2
R
Tidwell, T. T. Synthesis 1990, 857-870. HO CH3 OH HO CH3 OH
H3C H H 3C H –
Tidwell, T. T. Organic Reactions 1990, 39, 297-557. AcO
H3C O O OAc >60% H3C O O
General Mechanism H H
S Ph S Ph
• Dimethylsulfoxide (DMSO) can be activated by reaction with a variety of electrophilic reagents, +
including oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide, acetic anhydride, and
N-chlorosuccinimide. Schreiber, S. L.; Satake, K. J. Am. Chem. Soc. 1984, 106, 4186-4188.

• The mechanism can be considered generally as shown, where the initial step involves Swern Procedure
+
electrophilic (E ) attack on the sulfoxide oxygen atom.
• Typically, 2 equivalents of DMSO are activated with oxalyl chloride in dichloromethane at or
• Subsequent nucleophilic attack of an alcohol substrate on the activated sulfoxonium intermediate below –60 °C.
leads to alkoxysulfonium salt formation. This intermediate breaks down under basic conditions to
furnish the carbonyl compound and dimethyl sulfide. • Subsequent addition of the alcohol substrate and triethylamine leads to carbonyl formation.

+ – + + • The mild reaction conditions have been exploited to prepare many sensitive aldehydes.
(CH3)2S O + E (CH3)2S X Careful optimization of the reaction temperature is often necessary.

Huang, S. L.; Mancuso, A. J.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482.
+ H H CH3
RCH2OH + (CH3)2S X S
+ + X–
–H+ R O CH3 HO TBSO
1. TBSCl, Im, DMAP, CH2Cl2
–
HO TBSO
H H CH2 H 2. 10% Pd/C, AcOH, EtOAc
+ + (CH3)2S O O
S 3. (COCl)2, DMSO; Et3N
R O CH3 R O
–78 → –50 °C
alkoxysulfonium ylide OBn O 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 Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew.
ylide intermediates present in the reaction mixture. This type of transformation is related to the Chem., Int. Ed. Engl. 1998, 37, 2354-2359.
Pummerer Rearrangement.
OTBS OTBS

(COCl)2, DMSO;
+ RO S
ROH + H2C S CH3 HO Et3N, –78 °C O
CH3 OCH3 OCH3
–H+
H
90%

Fenselau, A. H.; Moffatt, J. G. J. Am. Chem. Soc. 1966, 88, 1762-1765. Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738-3753.

Mark G. Charest
 CH3O CH3 CH3O CH3 OTBDPS OTBDPS
DMSO, EDC O
HO O O
CH3O HO CH3O O
OH O TFA, pyr
OR1 OR1
CH3 CH3 BzO OCH3 BzO OCH3
(COCl)2, DMSO; O
O N N FK506 94%
CH3 Et3N, –78 °C CH3
H H
EDC = (CH3)2N (CH 2)3 N C N CH2CH3 • HCl
O 80% O
OR O OR O
H H
OCH3 OCH3 Hanessian, S.; Lavallee, P. Can. J. Chem. 1981, 59, 870-877.
R1 O R1O
CH3 CH3 CH3 CH3 Parikh-Doering Procedure
OR OR
R = TIPS, R1 = TBS • Sulfur trioxide-pyridine is used to activate DMSO.

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
large-scale reactions.

Pfitzner-Moffatt Procedure Parihk, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-5507.

• The first reported DMSO-based oxidation procedure. • Examples

• Dicyclohexylcarbodiimide (DCC) functions as the electrophilic activating agent in conjunction with
a Brønsted acid promoter. H3 C H 3C
OH O
• Typically, oxidations are carried out with an excess of DCC at or near 23 °C.
Bn SO3•pyr, DIEA, DMSO Bn
• Separation of the by-product dicyclohexylurea and MTM ether formation can limit usefulness. CH3 CH2Cl2, –15 °C CH3
N N
• Alternative carbodiimides that yield water-soluble by-products (e.g., 1-(3-dimethylaminopropyl)-3- O O
ethylcarbodiimide hydrochloride (EDC)) can simplify workup procedures. O 95% O

Cl Ot-Bu DMSO, DCC Cl Ot-Bu Evans, D. A.; Ripin, D. H.; Halstead, D. P.; Campos, K. R. J. Am. Chem. Soc. 1999, 121,
6816-6826.
OH TFA, pyr O

87% H SO3•pyr, Et3N, H

H H
O O
H DMSO, CH2Cl2 H
Corey, E. J.; Kim, C. U.; Misco, P. F. Org. Synth. Coll. Vol. VI 1988, 220-222. HO 0 → 23 °C OHC
O Br O Br
H H H H
CH3
H H H 99%
CHO CHO
OH DMSO, DCC
+
CO2CH3 TFA, pyr CO2CH3 CO2CH3
O CH3 O CH 3 O CH 3
H H
S 9 : 1 β,γ : α,β S S O
H
Evans, P. A.; Murthy, V. S.; Roseman, J. D.;
H3 C CH3 H3 C CH3 H3 C CH3 Rheingold, A. L. Angew. Chem., Int. Ed. Engl. Et O Br
1999, 38, 3175-3177. H H
Br

Semmelhack, M. F.; Yamashita, A.; Tomesch, J. C.; Hirotsu, K. J. Am. Chem. Soc. 1978, 100, (–)-kumausallene
5565-5576.

Mark G. Charest
Dess-Martin Periodinane (DMP) • Examples

• DMP has found wide utility in the preparation of sensitive, highly functionalized molecules. H3C H3C H3C
CH3 CH3 CH3
• DMP oxidations are characterized by short reaction times, use of a single equivalent of oxidant, H3C 1. DIBAL H3C H3C
and can be moderated with regard to acidity by the incorporation of additives such as pyridine. H H H H H H
H3 C H3C H3C
2. DMP
• DMP and its precurser o-iodoxybenzoic acid (IBX) are potentially heat and shock sensitive and TBSO O TBSO O HO AcOO
should be handled with appropriate care. I I
89% overall
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1983, 48, 4155-4156. (–)-7-deacetoxy-
PivO O H
alcyonin acetate
Boeckman, R. K.; Shao, P.; Mulins, J. J. Org. Synth. 1999, 77, 141-152.
Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683-2686.
Plumb, J. B.; Harper, D. J. Chem. Eng. News 1990, July 16, 3.
HO O
DMP
–
I
2.0 M H2SO4 O OH+ Se Se
+ KBrO3 I + Ac2O + AcOH ~100%
65 °C, 2.5 h
CO2 H O
Polson, G.; Dittmer, D. C. J. Org. Chem. 1988, 53, 791-794.
O IBX
Ac OAc O O
85 °C O
I O DMP O
then 23 °C, ~24 h OAc
O CH3O CHO
CH3O
O DMP OH 70%
74% overall
Danishefsky, S. J.; Mantlo, N. B.; Yamashita, D. S.; Schulte, G. K. J. Am. Chem. Soc. 1988, 110,
• Addition of one equivalent of water has been found to accelerate the reaction, perhaps due to the 6890-6891.
formation of an intermediate analogous to II. It is proposed that the decomposition of II is more
rapid than the initially formed intermediate I. • Use of other oxidants in the following example led to conjugation of the β,γ-unsaturated ketone,
which did not occur when DMP was used.
Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552. CH3
H
R1 R2 H3C O
O
Ac O OAc DEIPSO H O O OTES
O H H 1. DDQ, CH2Cl2, H2O
R1R2CHOH slow CH3
DMP I I + R1R2C=O + AcOH CH3 H CH3 CH3
–AcOH H 2. DMP, CH2Cl2, pyr
OAc O O
O TBSO TESO 93% overall
I O O OPMB O Si(t-Bu)2
OCH3
O O CH3
CH3 CH3
R1R2CHOH TESO OTES
–AcOH H
H3C O
O
R1 R2 DEIPSO H O O OTES
H CH 3
Ac O H OCHR1R2 CH3 H CH3 CH3
O fast H
I I + R1R2C=O + AcOH (–)-cytovaricin TBSO O
TESO
OCHR1R 2
O O O O Si(t-Bu)2
OCH3
II O O O O CH3
CH3
TESO OTES

Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287. 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
 • DMP oxidation in the presence of phosphorous ylides allows for the trapping of sensitive • Pyridines are not oxidized at a rate competitive with the oxidation of a primary alcohol.
aldehydes.

HO CHO
OH IBX, DMSO
OH DMP, CH2Cl2, DMSO CH 3O2C
+ N N
PhCO2H CO2CH 3 99%
Ph3P=CHCO2CH3
94% (2.2 : 1 E,E : E,Z)
Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022.

Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M. J. Org. Chem. 1997, 62, 9376-9378.
• IBX has been shown to form α,β-unsaturated carbonyl compounds from the corresponding
O saturated alcohol or carbonyl compound.
NHFmoc NHFmoc
HO DMP H

OH O
SCH3 >90% SCH3 2.3 equiv IBX
toluene, DMSO

Myers, A. G.; Zhong, B.; Kung, D. W.; Movassaghi, M.; Lanman, B. A.; Kwon, S. Org. Lett., in press. 88%

o-Iodoxybenzoic Acid (IBX)

4.0 equiv IBX
• The DMP precursor IBX is gaining use as a mild reagent for the oxidation of alcohols.
OH toluene, DMSO O
N N
• A simpler preparation of IBX has recently been reported.
H
– 84%
I O OH
oxone, H2O +
I
CO2H 70 °C
O O H O H
79-81% O IBX 2.0 equiv IBX
TIPS TIPS
toluene, DMSO
Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538. H H
87%
• IBX is used as a mild reagent for the oxidation of 1,2-diols without C-C bond cleavage.

O O OH O
H3 C H3 C
6.0 equiv IBX
H3 C IBX, DMSO H3 C
toluene, DMSO

OH O
AcO 85% AcO 52%
HO HO
OH O

Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596-7597.

Mark G. Charest
tetra-n-Propylammonium Perruthenate (TPAP): Pr4N+RuO4 –
F OH F
• Reviews CHO
Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639-666.
TPAP, NMO, CH2Cl2
Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13-19. N N
H3C 4 Å MS, 23 °C H 3C
–
• Ruthenium tetroxide (RuO4, Ru(VIII)) and, to a lesser extent, the perruthenate ion (RuO4 ,
Ru(VII)) are powerful and rather nonselective oxidants. 79%

• However, perruthenate salts with large organic counterions prove to be mild and selective
oxidants in a variety of organic solvents. Robol, J. A.; Duncan, L. A.; Pluscec, J.; Karanewsky, D. S.; Gordon, E. M.; Ciosek, C. P.; Rich, L. C.;
Dehmel, V. C.; Slusarchyk, D. A.; Harrity, T. W.; Obrien, K. A. J. Med. Chem. 1991, 34, 2804-2815.
• In conjunction with a stoichiometric oxidant such as N-methylmorpholine-N-oxide (NMO), TPAP
oxidations are catalytic in ruthenium, and operate at room temperature. The reagents are
relatively non-toxic and non-hazardous. H3C CH3 H3C CH3
CH 3O HCH3O CH3O HCH3O
OTBS TPAP, NMO, CH Cl OTBS
• To achieve high catalytic turnovers, the addition of powdered molecular sieves (to remove both CH3O 2 2 CH3O
the water of crystallization of NMO and the water formed during the reaction) is essential. H H H H
O O 4 Å MS, 23 °C O O
•
The following oxidation state changes have been proposed to occur during the reaction: O O
78%
OH O H
–
Ru(VII) + 2e → Ru(V) TBSO O TBSO O
2Ru(V) → Ru(VI) + Ru(IV)
Julia-Lythgoe
Ru(VI) + 2e– → Ru(IV) Olefination

Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, H3C CH3 H3C CH3
1625-1627. CH3O HCH3O CH3 O HCH3O
OTBS OTBS
CH3O CH3O
• Examples H H H H
O O O O

OH O O TPAP, NMO, CH2 Cl2 O

O O O OH
OCH3 H OTBS O 4 Å MS, 23 °C OCH3 H OTBS O
TPAP, CH2Cl2 Bu4N+F–, THF
CH3 O O CH3 O O
N N 0 °C N CH3 CH3
23 °C CH3 87% CH3
H CH3 CH3
TEOC H TEOC H O OH O
TESO O CH TESO
84% 29% 3 CH3

O
OH
H3C H 3C H 3C
CH3 CH3 CH3
H3 C CH 3
(±)-indolizomycin H HO
OAc
CH3O2C
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30-39. H H
O O

O
HO CH3 TPAP, NMO, CH2 Cl2 O CH3 Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.;
OH H OH Nishiyama, S.; Yamamura, S. Angew. Chem., Int. Ed.
4 Å MS, 23 °C CH3 O O
H Engl. 2000, 39, 2290-2294.
CH3
70% OH
O CH3

Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992, 48, 1145-1174. n-Pr O
O
bryostatin 3
Mark G. Charest
N-Oxoammonium-Mediated Oxidation
• Reviews • Examples
de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153-1174. CH3 CH3
H3 C Boc H3 C Boc
Bobbitt, J. M.; Flores, C. L. Heterocycles 1988, 24, 509-533. N TEMPO, NaOCl, NaBr N
O O
Rozantsev, E. G.; Sholle, V. D. Synthesis 1971, 401-414. OH EtOAc : toluene : H2O H
(1 : 1 : 0.15) O
• 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 90%
are invariably generated in situ in a catalytic cycle using a stable, stoichiometric oxidant.
Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gryza, H.; Prokopoxicz, P. Tetrahedron 1998, 54, 6051-6064.
R + R1 H OH –HX O R R1
N + + N
X–
O R2 R3 R2 R3 OH
OH O
N-oxoammonium salt
OTBDPS TEMPO, BAIB, CH2Cl2 H OTBDPS
• Three possible transition states have been proposed: 23 °C
H3C CH3 H3C CH3
R R1
R + R1 R + R1 N 98%
N N O
–O O HO O
B O
R2 H
H R1 R2
R1 R2 H O OH
R1 O
O
H
CHO
Ganem, B. J. Org. Chem. 1975, 40, 1998-2000.
Jauch, J. Angew. Chem., Int. Ed. Engl. 2000, 39, 2764-2765.
Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A. Tetrahedron Lett. 1986, 27, 1119-1122. H
H3C CH3
Bobbitt, J. M.; Ma, Z. J. Org. Chem. 1991, 56, 6110-6114.
kuehneromycin A
• N-Oxoammonium salts may be formed in situ by the acid-promoted disproportionation of nitroxyl
radicals. Alternatively, oxidation of a nitroxyl radical or hydroxyl amine can generate the
corresponding N-oxoammonium salt. • Selective oxidation of allylic alcohols in the presence of sulfur and selenium has been
demonstrated.
disproportionation
R R1 +H+ R R R R1
N N 1 N PhS TEMPO, BAIB, CH2Cl2 PhS
2 +
O +
–H OH O 23 °C
CH2OH CHO
nitroxyl radical
70%
Golubev, V. A.; Sen', V. D.; Kulyk, I. V.; Aleksandrov, A. L. Bull. Acad. Sci. USSR, Div. Chem. Sci.
1975, 2119-2126.
H3 C CH2 OH TEMPO, BAIB, CH2Cl2 H 3C CHO
• 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 23 °C
m-chloroperoxybenzoic acid (m-CPBA), sodium hypochlorite (NaOCl), [bis(acetoxy)-iodo]benzene SePh SePh
(BAIB), sodium bromite (NaBrO2 ), and Oxone (2KHSO5•KHSO4•K2SO4 ). 55%

H3 C CH3 De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62,
TEMPO 6974-6977.
H3 C N CH3
O Mark G. Charest
Manganese Dioxide: MnO2 TBSO TBSO
H H H H
• Reviews SAr SAr
MnO2, acetone
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. OAc OAc
H H 76% H
231-236. HO HO O HO O HO

Fatiadi, A. J. Synthesis 1976, 65-104.

Trost, B. M.; Caldwell, C. G.; Murayama, E.; Heissler, D. J. Org. Chem. 1983, 48, 3252-3265.
Fatiadi, A. J. Synthesis 1976, 133-167.

• A heterogenous suspension of active manganese dioxide in a neutral medium can selectively

oxidize allylic, benzylic and other activated alcohols to the corresponding aldehyde or ketone.
H CH 3 CH3 CH3
MnO2
• The structure and reactivity of active manganese dioxide depends on the method of preparation. H3C CH3
OH acetone
• Active manganese oxides are nonstoichiometric materials (in general MnOx, 1.93 < x < 2) CH3 CH3
consisting of Mn (II) and Mn (III) oxides and hydroxides, as well as hydrated MnO2. CH3 75%
HO
OH
• 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. H CH 3 CH3 CH3
H3C CH3
• Examples O
CH3 CH3
H 3C CH3 CH3 CH3 H 3C CH3 CH3 CH3 H HO CH3
MnO2 OH
OH O paracentrone
pet. ether
CH3 CH3
80% Haugan, J. A. Tetrahedron Lett. 1996, 37, 3887-3890.

• Vinyl stannanes are tolerated.

Ball, S.; Goodwin, T. W.; Morton, R. A. Biochem. J. 1948, 42, 516-523.

CH3 CH3
MnO2
MnO2 Bu3Sn Bu3Sn
CH2OH CHO CH 2OH CH2 Cl2 CHO

61% 89%

Crombie, L.; Crossley, J. J. Chem. Soc. 1963, 4983-4984. Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659-5662.

• Syn or anti vicinal diols are cleaved by MnO2 .

EtO2C CO2Et OHC CHO

HO CH3
1. DIBAL, C6H6 O O
OH MnO2
2. MnO2, CH2Cl2 H3 C CH3
CH 3
CH 3
H3 C CH3 H3 C CH3 CH3 100%
74%

Cresp, T. M.; Sondheimer, F. J. Am. Chem. Soc. 1975, 97, 4412-4413. Ohloff, G.; Giersch, W. Angew. Chem., Int. Ed. Engl. 1973, 12, 401-402.

Mark G. Charest
Barium Manganate: BaMnO4 Oppenauer Oxidation

• Review • Review

Fatiadi, A. J. Synthesis 1987, 85-127. 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 • A classic oxidation method achieved by heating the alcohol to be oxidized with a metal alkoxide in
prior activation for the oxidation of primary and secondary allylic and benzylic alcohols. the presence of a carbonyl compound as a hydride acceptor.

Effectively the reverse of the Meerwein-Pondorff-Verley Reduction.

•
• Examples
• 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
R R desired direction.
BaMnO4, CH2Cl2 R1 L
CH2 OH CHO
40 °C R3
R2 O M
L
CH 2OH CHO H O
66% R4
R = CH3
Proposed Transition State

Gilchrist, T. L.; Tuddenham, D. J. Chem. Soc., Chem. Commun. 1981, 657-658. Djerassi, C. Org. React. 1951, 6, 207.

Oppenauer, R. V. Rec. Trav. Chim. Pays-Bas 1937, 56, 137-144.

OH O • Examples
H 3C
H3 C OH
BaMnO4 CH2OH CHO
OH
pivaldehyde, toluene

92% H3 C CH3 2 mol %

H3C CH3
F5 F5
H3 C H3 C
B
Howell, S. C.; Ley, S. V.; Mahon, M. J. Chem. Soc., Chem. Commun. 1981, 507-508. (S)-perillyl alcohol OH

99%

Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 5664-5665.
CH3 CH 3
BaMnO4, CH2Cl2 • Highly reactive zirconium alkoxide catalysts undergo rapid ligand exchange and can be used in
H3 C CH2OH H3 C CHO
O O substoichiometric quantities.
H H H H
SEMO 98% SEMO
CH3 CH3

cat. Zr(O-t-Bu)4 , Cl3CHO, CH2Cl2

Burke, S. D.; Piscopio, A. D.; Kort, M. E.; Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; OH 3 Å MS O
Shankaran, K. J. Org. Chem. 1994, 59, 332-347.
H3 C CH3 86% H3 C CH3
menthol

Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A. K.; Hayakawa, M. Synthesis 1996,
1341-1344.

Mark G. Charest
Chromium (VI) Oxidants Collins Reagent: CrO3 •pyr2
• Reviews • CrO3 •pyr2 is a hygroscopic red solid which is easily hydrolyzed to the yellow dipyridinium
dichromate ([Cr2O7]–2 (pyrH+)2).
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. • Typically, 6 equiv of oxidant in a chlorinated solvent leads to rapid and clean oxidation of
alcohols.
Luzzio, F. A. Organic Reactions 1998, 53, 1-122.
• Caution: Collins reagent should be prepared by the portionwise addition of solid CrO3 to pyridine.
• The mechanism of chromic acid-mediated oxidation has been extensively studied and is Addition of pyridine to solid CrO3 can lead to a violent reaction.
commonly used as a model for other chromium-mediated oxidations.
Collins, J. C.; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 30, 3363-3366.
R 2CHOH + HCrO4– + H +
R2CHOCrO3H + H2O
Collins, J. C.; Hess, W. W.; Org. Synth. 1972, 52, 5-9.

R2 C O CrO3H R2C O + HCrO3– + BH+ • In situ preparation of the reagent circumvents the difficulty and danger of preparing the pure
complex.
H OH O
B H3 C H3 C
CrO3, pyr, CH2Cl2
Holloway, F.; Cohen, M.; Westheimer, F. H. J. Am. Chem. Soc. 1951, 73, 65-68.
H H
• A competing pathway involving free-radical intermediates has been identified. H3 C CH3 95% H3 C CH 3

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

HO O
+ Cr(III) + 2H + CrO3, pyr
R2CHOH + Cr(V) R2C=O H3 C H H3 C H
O O
O H O H
Wiberg, K. B.; Mukherjee, S. K. J. Am. Chem. Soc. 1973, 96, 1884-1888. 89%
O O
Wiberg, K. B.; Szeimies, G. J. Am. Chem. Soc. 1973, 96, 1889-1892.
Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422-428.
• Fragmentation has been observed with substrates that can form stabilized radicals.
OTBS O
H O 1. n-Bu4 N+F–, THF O
Ph C O Cr(IV) PhCHO + (CH3)3C• 2. Collins Reagent
(CH 3)3C –Cr(III) O
CH3 CH 2Cl2 O
CH3

CH3 CH3
Doyle, M.; Swedo, R. J.; Rocek, J. J. Am. Chem. Soc. 1973, 95, 8352-8357. 81% overall
(±)-periplanone B

• Tertiary allylic alcohols are known to undergo oxidative transposition. Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493-2495.

OH 1. H2, 10% Pd-C

O OCrO3H O OCH3 OCH3
Cr O CH3O2C 2. Collins Reagent CH3O2C CHO
O H O
CH2Cl2
CH3 CH3 CH3 CH3
83%
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

ClCrO3– ketones in the presence of primary alcohols.
+N
H • 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 CH3 CH3
N,N-dimethylformamide (DMF) or a suspension in chlorinated solvents.
NaOCl, AcOH
• The slightly acidic character of the reagent can be moderated by buffering the reaction mixture
with powdered sodium acetate.
H3 C OH 91% H3 C O
Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 26, 2647-2650.

• Addition of molecular sieves can accelerate the rate of reaction. 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.
Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982, 23, 35-38.
• Examples
HO CH3 O CH3

OH O
O PCC, 25 °C O 1. NaOCl, AcOH
H OTIPS H OTIPS H3 C OH H3 C OMOM
Cl 4 Å MS Cl 2. MOMCl, DIEA
O O
NC NC
100% H 93%
H

Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871-8872. Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431-7432.

CH3 CH3 CH3 CH3

N N OH O
PCC, CH2Cl2
NaOCl, AcOH
NaOAc
S S
H H
OH O OH 86% OH
71% H3C H3 C

Browne, E. J. Aust. J. Chem. 1985, 38, 756-776. Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777-12782.

PhCH2 OH PhCH 2 O n-C9H19 CH2OH n-C9H19 CH2OH

N N PCC, 25 °C N N
H OH NaOCl, AcOH O
O N 4 Å MS O N
CH2Ph CH2Ph CH3 CH3
100% 71%

Knapp, S.; Hale, J. J.; Bastos, M.; Gibson, F. S. Tetrahedron Lett. 1990, 31, 2109-2112. Winter, E.; Hoppe, D. Tetrahedron 1998, 54, 10329-10338.

Mark G. Charest
Selective Oxidations Using N-Bromosuccinimide (NBS) or Bromine Selective Oxidations using Other Methods

• NBS in aqueous dimethoxyethane selectively oxidizes secondary alcohols in the presence of • Cerium (IV) complexes catalyze the selective oxidation of secondary alcohols in the presence of
primary alcohols. primary alcohols and a stoichiometric oxidant such as sodium bromate (NaBrO3).

• Examples Tomioka, H.; Oshima, K.; Noxaki, H. Tetrahedron Lett. 1982, 23, 539-542.

CH3 CH3 • In the following example, catalytic tetrahydrogen cerium (IV) tetrakissulfate and stoichiometric
HO OH HO O potassium bromate in aqueous acetonitrile was found to selectively oxidize the secondary
NBS, DME, H2O alcohol in the substrate whereas NaOCl with acetic acid and NBS failed to give the desired
imide.
CH3 CH3
H3C >98% H3C
CH3 CH3 O O O O O O
Ce(SO4)2 •2H2SO4, KBrO3
NPh NPh O
Corey, E. J.; Ishiguro, M. Tetrahedron Lett. 1979, 20, 2745-2748. OH 7 : 3 CH3CN, H2O, 80 °C O O
CH2OH CH2OH CH3
• Bromine has been employed for the selective oxidation of activated alcohols. In the following 48% (±)-palasonin
example, a lactol is oxidized selectively in the presence of two secondary alcohols.

O Rydberg, D. B.; Meinwald, J. Tetrahedron Lett. 1996, 37, 1129-1132.

O HO H
HO H O HO H O
O O O O • TEMPO catalyzes the selective oxidation of primary alcohols to aldehydes in a biphasic mixture
H Br2, AcOH H of dichloromethane and aqueous buffer (pH = 8.6) in the presence of N-chlorosuccinimide (NCS)
t-Bu t-Bu
H3C O NaOAc H3C O as a stoichiometric oxidant and tetrabutylammonium chloride (Bu4 N+Cl–).
HO H HO H
O O
O >51% O
OH TEMPO, NCS, OH O
(±)-ginkgolide B
+ –
Bu4N Cl +
Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.; Thomas, J. B.; Watterson, S. H.; OH CH2Cl2, H2O, OH
Wagman, A. S. J. Am. Chem. Soc. 2000, 122, 8453-8463. CHO
pH 8.6

• Stannylene acetals are oxidized in preference to alcohols in the presence of bromine. 77% 0.50%

TEMPO, NCS,
CH3 OH CH3 CH3 OH CH3 OH OH O
Bu4N+Cl–
N N N N H OH CHO +
Cbz Cbz Cbz Cbz H H OH CH2Cl2, H2O, OH
N O O CH3 8 8 8
H3 C pH 8.6
OH Br2 OH H2
H3C O H3 C O
O O Bu3SnOCH3 O O Pd/C HO O 82% <0.1%
H HO
N O
O O OH H3C H
O 70% 90%
Sn
(+)-spectinomycin Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem. 1996, 61, 7452-7454.
Bu
Bu

Hanessian, S.; Roy, R. J. Am. Chem. Soc. 1979, 101, 5839-5841.

Mark G. Charest
 Aldehyde Acid
1. (CF3CO2)2IPh,
Cl Cl
CH3 CN, H2 O, 0 °C
OH OH
Sodium Chlorite: NaClO 2 2. NaClO2, NaH2PO4
2-methyl-2-butene,
• Sodium chlorite is a mild, inexpensive, and selective reagent for the oxidation of aldehydes to
the corresponding carboxylic acids under ambient reaction conditions. OTBDPS t-BuOH, H2O CO2H OTBDPS
S S
• 2-methyl-2-butene is often incorporated as an additive and has been proposed to function as a
scavenger of any electrophilic chlorine species generated in the reaction. 82%
Lindgren, B. O.; Nilsson, T. Acta. Chem. Scand. 1973, 27, 888-890.

Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825-4830.

• Examples Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Br Cl

Honma, T.; Murai, A. J. Org. Chem. 1999, 64, 2616-2617. H3C O
H NaClO2 , NaH2PO4, H
H3 C O H3C O
2-methyl-2-butene (+)-obtusenyne
CHO t-BuOH, H2O CO2H
TBSO CH3 TBSO CH3 • The two-step oxidation of an alcohol to the corresponding carboxylic acid is most common.
80%

n-Bu3Sn O CH3 n-Bu3Sn O CH3

Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825-4830. 1. TPAP, NMO, CH2Cl2
O 2. NaClO2, NaH2PO 4 O
H3C H3 C
O O 2-methyl-2-butene,
1. NaClO2, NaH2PO4, O
CF3OCO
THF, t-BuOH, H2O
2-methyl-2-butene O OH OH
t-BuOH, H2O TBSO >52%
TBSO
H3C CHO CO CH H3C CO2CH3
2. CF3 CH2OH, O
2 3 Nicolaou, K. C.; Ohshima, T.; Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. J. Chem. Soc.,
2,6-lutidine Chem. Commun. 1999, 809-810.

>95% OH
OMOM
H3C 1. DMP, CH2Cl2, pyr
H3C H3C CH3
O CH3O 2. NaClO2, NaH2PO4
HO
Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, H3 C HO O O O OSEM 2-methyl-2-butene,
CO2H O O
5574-5576. O H H 3C H H H H OCH3
CH3 CH3 t-BuOH, H2O
H 3C
(±)-antheridic acid 3. CH2N2

OCH3 OCH3 98%

NaClO2, NaH2PO4,
OTf OTf OMOM
2-methyl-2-butene H3 C H3 C
H3C CH3
H OH CH3O
acetone, H2O
(+)-monensin A CH3 O2C
O O O O O O O OSEM
OMOM OMOM H H 3C H H H H OCH3
90% CH3 CH3 H3C

Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004-1015. Ireland, R. E.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7166-7172.
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 TsN t-BuOH, H2 O, 0 °C TsN
N N
are also oxidized by potassium permanganate. Ts 2. (CH3)3SiCHN 2 Ts
H H
H CH3O
• Oxidation occurs through a coordinated permanganate intermediate by hydrogen atom-abstraction
or hydride transfer. H H
O 80% O

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 N
to effectively oxidize the aldehyde in the following polyoxygenated substrate to the corresponding N
Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, HH H
carboxylic acid whereas Jones reagent, RuCl3 (H2O)n-NaIO4, and silver oxide failed. 3237-3243.
H
OTBS
OCH3
BnO OTBS (–)-yohimbane
KMnO4, NaH2PO4
O O O O O Silver Oxide: Ag2O
t-BuOH, H2O
CHO
H3C CH3 H3C CH3 • A classic method used to oxidize aldehydes to carboxylic acids.
85%
OTBS • Cis/trans isomerization can be a problem with unsaturated systems under the strongly basic
reaction conditions employed.
OTBS
OCH3 • Examples
BnO OTBS
Abiko, A.; Roberts, J. C.; Takemasa, T.; CHO CO2H
Masamune, S. Tetrahedron Lett. 1986, O O O O O 1. Ag2O, NaOH
CO2 H
27, 4537-4540. H3C CH3 H3 C CH3 HO 2. HCl HO
OCH3 OCH3
OTBS
90-97% vanillic acid
• Examples
Pearl, I. A. Org. Synth. IV 1963, 972-978.
O CN O CN
KMnO4, NaH2 PO4
CHO t-BuOH, H2O, 5 °C CO2H H3C H3 C
N N
Boc Boc CH3 Ag2O, CH3OH CH3
93.5%
CH3 0 °C CH3
CHO CO2H
O 72%
O O
Heffner, R. J.; Jiang, J.; Joullié, M. M. J. Am. Chem. Soc. NH Sonawane, H. R.; Sudrik, S. G.; Jakkam, M. M.; Ramani, A.; Chanda, B. Synlett. 1996, 175-176.
1992, 114, 10181-10189. N
N
(CH3)2N H CH3
O
H3C
(–)-nummularine F
Mark G. Charest
 • In the following example, all chromium-based oxidants failed to give the desired acid. • Additional Examples

O O OTBDPS O OTBDPS
CO2H PDC, DMF OH
S OCH3 S H CH3O
CH3O
CHO 1. Ag2O, NaOH CO2H O O
100%
OMEM 2. HCl OMEM
Mazur, P.; Nakanishi, K. J. Org. Chem. 1992, 57, 1047-1051.
O 81% O
N N
• 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
Ovaska, T. V.; Voynov, G. H.; McNeil, N.; Hokkanen, J. A. Chem. Lett. 1997, 15-16. oxidation of the methyl hemiacetal.

• 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 O
Ley, S. V.; Madin, A. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., H
Pergamon Press: New York, 1991, Vol. 7, p. 251-289. PDC, DMF CH3O
BnO O O
SEt BnO SEt
BnO 6 equiv CH 3OH BnO
• PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume of water, BnO BnO
adding pyridine and collecting the precipitated product.
>71%
• Non-conjugated aldehydes are readily oxidized to the corresponding carboxylic acids in good
yields in DMF as solvent.
O'Connor, B.; Just, G. Tetrahedron Lett. 1987, 28, 3235-3236.
• Primary alcohols are oxidized to the corresponding carboxylic acids in good yields.
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.
• PDC has also been used to oxidize alcohols to the corresponding carboxylic acids.
• In the following example, PDC was found to be effective while many other reagents led to
oxidative C-C bond cleavage. TBSO CH3 TBSO CH3
H H PDC, DMF H H
OH
H3C CH3 H3C CH3 H3 C H3 C CO2H
NH NH
O O O O O 91% O
1. PDC, DMF
CHO CO2CH 3
AcO 2. CH 2N2 AcO
BnO CH3 CH3 CH3 BnO CH3 CH3 CH3 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 H3C CH3 H3C CH3 aldehyde.
oxidants Ph Ph
O O O O S
[O] S
CH3 O PDC, CH2Cl2
AcO OH AcO O
BnO CH3 CH3 CH3 BnO CH3 CH3 O CH2OH CHO
S S
68%

Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem. 1985, 50, Terpstra, J. W.; van Leusen, A. M. J. Org. Chem. 1986, 51, 230-238.
2095-2105.

Mark G. Charest
 Aldehyde Ester
Bromine

• Review

Corey-Gilman-Ganem Oxidation Palou, J. Chem. Soc. Rev. 1994, 357-361.

• A convenient method to convert unsaturated aldehydes directly to the corresponding methyl • Bromine in alcoholic solvents is a convenient and inexpensive method for the direct conversion of
esters. aldehydes into ester derivatives.

• Cis/trans isomerization, a problem when other reagents such as basic silver oxide are employed, • Under the reaction conditions employed, secondary alcohols are not oxidized to the
is avoided. corresponding ketones.

• The aldehyde substrate is initially transformed into a cyanohydrin intermediate. Subsequent • Oxidation of a hemiacetal intermediate is proposed.
oxidation of the cyanohydrin furnishes an acyl cyanide which is then trapped with methanol to
give the desired methyl ester. • Olefins, benzylidine acetals and thioketals are incompatiable with the reaction conditions.
• Conjugate addition of cyanide ion can be problematic. • A variety of esters can be prepared.
• Examples • Examples
OH OH
O CH3 O CH3 H OH H OH
O MnO2, CH3CN O H3C O Br2, H2O, alcohol H3C O
O CH3 O CH3 CHO CO2R
AcOH, CH3OH NaHCO3
O H3C O O H3C O O
O CHO NOBn O NOBn H H
81% OCH3 R = Me, 94%
R = Et, 91%
R = i-Pr, 80%
OH
OH
O Ph O Ph
Br2, H2O, CH3 OH
O OH
Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. O CHO O CO2CH3
NaHCO3
1999, 121, 5176-5190. O NH H3C O H3C O
CH3 CH3
O 89%
(–)-lycoricidine
Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W. Tetrahedron Lett. 1988, 29,
• In the following example, stepwise addition of reagents proved to be essential to achieve high 5087-5090.
yields.
Lichtenthaler, F. W.; Jargils, P.; Lorenz, K. Synthesis 1988, 790-792.

H3C CH3 CH3 1. CH 3CN, AcOH, H3C CH3 CH3

CH3 OH, 1 h TBSO TBSO
O Br2 , H2O, CH3OH O
O O
CHO 2. MnO2 CO2CH3
HO CH3 HO CH3 N H NaHCO3 N OCH3
CO2CH3 CO2CH3
97% (2Z, 4E)-xanthoxin
78%

Yamamoto, H.; Oritani, T. Tetrahedron Lett. 1995, 36, 5797-5800. Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenländer, F. Tetrahedron 1996, 52, 6409-6420.

Mark G. Charest
 Ketone Ester
• Examples

Bayer-Villiger Oxidation HO H
CH3O CH3 O
• Reviews m-CPBA, NaHCO3 CO2H
Krow, G. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon O CH3
CH2Cl2
Press: New York, 1991, Vol. 7, p. 671-688. O H
O HO HO H
95% (±)-PGF2α
Krow, G. R. In Organic Reactions, Paquette, L. A., Ed., John Wiley and Sons: New York, 1993,
Vol. 43, p. 251-296.
Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675-5677.
• A classic method for the oxidative conversion of ketones into the corresponding esters or
lactones by oxygen insertion into an acyl C-C bond. Ph Ph
OCH3
• The migratory preference of alkyl groups has been suggested to reflect their electron-releasing OCH3 m-CPBA, Li2CO3 n-C16H33 N O
n-C16 H33 N O
ability and steric bulk. CH2Cl2 O
O O
• Typically, the order of migratory preference is tertiary > secondary > allyl > primary > methyl. O 99% O
• The reactivity order of Bayer-Villiger oxidants parallels the acidity of the corresponding carboxylic
acid (or alcohol): CF3CO3 H > p-nitroperbenzoic acid > m-CPBA = HCO3H > CH3 CO3H > HOOH Miller, M.; Hegedus, L. S. J. Org. Chem. 1993, 58, 6779-6785.
> t-BuOOH.
COR'
• Selective Bayer-Villiger oxidation in the presence of unsaturated ketones and isolated olefins has
O been achieved.
O R'CO3H O –R'CO2H O
R CH3 CH3
RL R RL RL O R H2O2 (anhydrous),
O BOMO BOMO
H O Ti(Oi-C3H7)4 , ether O
H H
RL = Large Group Criegee Intermediate DIEA, –30 °C H3 C
H3 C O
H O H
• Primary and secondary stereoelectronic effects in the Bayer-Villiger reaction have been
demonstrated. >55% O
COR
primary
O
effect O CH3
H
O AcO
• Primary effect: antiperiplanar alignment of RL and σO-O O
RL R
Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am.
• Secondary effect: antiperiplanar alignment of Olp and σ∗C-RL secondary H3 C O OH
effect Chem. Soc. 1983, 105, 625-627. H
O OH
Proposed TS O
eucannabinolide
Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. Engl. 2000, 39, 2852-2855. • Carbamates have been prepared in some cases.

• The Bayer-Villiger reaction occurs with retention of stereochemistry at the migrating center. CH3
CH3
O O O
N N
H D CF3CO3 H H O D H O D
+
D T Na2HPO4 m-CPBA, CH3OH O
D T D T O
N
N O
CH3 70%
Turner, R. B. J. Am. Chem. Soc. 1950, 72, 878-882. CH3

Gallagher, T. F.; Kritchevsky, T. H. J. Am. Chem. Soc. 1950, 72, 882-885. Azizian, J.; Mehrdad, M.; Jadid, K.; Sarrafi, Y. Tetrahedron Lett. 2000, 41, 5265-5268.
 Alcohol Acid OMOM OMOM
AcHN RuO2 (H2O)2, NaIO4 AcHN

Ruthenium Tetroxide: RuO4 OH CH3CN, CCl4, H2O OH

N N
• RuO4 is used to oxidize alcohols to the corresponding carboxylic acid. It is a powerful oxidant Boc Boc O
98%
that also attacks aromatic rings, olefins, diols, ethers, and many other functional groups.

• Catalytic procedures employ 1-5% of ruthenium metal and a stoichiometric oxidant, such as Clinch, K.; Vasella, A.; Schauer, R. Tetrahedron Lett. 1987, 28, 6425-6428.
sodium periodate (NaIO4 ).
• 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 is further oxidized to the corresponding carboxylic acid by RuO4. The amine is
proposed to avoid the formation of insoluble Ru-carboxylate complexes and return the metal to protonated and thereby protected from oxidation.
the catalytic cycle.

Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838-3840. HO H 1. RuCl3 -NaIO4, O OCH3
OH
Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936-3938. CH3N CH3 CN, CCl4 , H2O CH3N
OBz OBz
•HF 2. (CH3)3SiCHN2
• Examples

CO 2H (S)-(+)-cocaine
RuCl3 , NaOCl 78% overall

CCl4, H2O Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773-4775.
CO 2H

70% Molecular Oxygen

Sptzer, U. A.; Lee, D. G. J. Org. Chem. 1974, 39, 2468-2469. • 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
RuO2 , NaIO4 O
Bn O2/Pt Bn
CCl4, H2O HO2C CO2H OH OH
O
NH NH
Boc Boc
68% 65%

Smith, A. B., III; Scarborough, R. M., Jr. Synth. Commun. 1980, 10, 205-211. Mehmandoust, M.; Petit, Y.; Larcheveque, M. Tetrahedron Lett. 1992, 33, 4313-4316.

CH3 CH3
• Primary alcohols are oxidized selectively in the presence of secondary alcohols.
O O
R H RuCl3-NaIO4 R H
OH O O OH O O
R CH3 CN, CCl4 , H2 O R HO 1. O2/Pt CH3O
OCH3 OCH3
2. CH3I
H H O NHPf O O NHPf
OBz 60% OBz
HO HO O CH3 CH3
CH3 85% CH3
R = CH3 (±)-scopadulcic acid B
Pf = 9-phenylfluorenyl

Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1997, 119, 12031-12040. Park, K. H.; Rapoport, H. J. Org. Chem. 1994, 59, 394-399.
Jones Oxidation N-Oxoammonium-Mediated Oxidation of Alcohols to Carboxylic Acids

• Jones reagent is a standard solution of chromic acid in aqueous sulfuric acid. • A general method for the preparation of nucleoside 5'-carboxylates:

• Acetone is often benefical as a solvent and may function by reacting with any excess
oxidant. B B
O HO2C O
HO TEMPO, PhI(OAc)2
• Isolated olefins usually do not react, but some olefin isomerization may occur with
unsaturated carbonyl compounds. CH3CN, H2O
O O O O
• 1,2-diols and α-hydroxy ketones are susceptible to cleavage under the reaction conditions.
H3C CH3 B = A (90%) H3C CH3
• Examples B = U (76%)
O O B = C (72%, NaHCO3 added)
CH3 CH3 CH3 CH3 B = G (75%, Na salt, NaHCO3 added)
Jones reagent
0 °C
CH3 CH3 Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293-295.
85%
CO2H
• A brief follow-up treatment with sodium chlorite was necessary to obtain complete oxidation to
OH
the bis-carboxylic acid in the following example.
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. OBn
1. H2, 20% Pd(OH)2-C,
O OBn
• Silyl ethers can be cleaved under the acidic conditions of the Jones oxidation. CF3CONH O EtOAc, EtOH
PivO OPiv
O 2. PhI(OAc)2, TEMPO
OTBS H
BnO Jones reagent BnO CO2H O CH3CN, NaHCO3, H2O
Ph N NH
O –10 → 23 °C O N O 3. NaClO2, t-BuOH, H2O
CO2CH3 CO2CH3
O O
N NaH2PO4, isopentene
88-97% CH2OBn
O 49% overall
Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. Engl. 1999,
38, 3175-3177.
HO2C HO2C
• Ketones have been prepared efficiently by oxidation of the corresponding secondary alcohol. O O
H2N O CO H CF3CONH O CO H
2 OH 2 OPiv
HO O PivO O
OH O
H H NH3, CH3OH H
O O O O
CH3 CH3 H2N NH 55 °C Ph N NH
O H O H N O N O
1. Jones reagent
O H O H O O O
O CH3 2. HCO2H O CH3 NH 65% NH
O O
3 3 O O
O CO2t-Bu
96% overall O CO2H 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
 Ketone α-Hydroxy Ketone • Enantioselective hydroxylation of prochiral ketones has been demonstrated.

O O
Davis Oxaziridine 1. NaHMDS
CH3 CH3
Ph 2. H3C CH3 Ph
• Reviews Cl OH
Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919-934. Cl
O S N
Jones, A. B. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
OO
Press: New York, 1991, Vol. 7, p. 151-191.
61% (95% ee)
• N-Sulfonyloxaziridines are prepared by the biphasic oxidation of the corresponding sulfonimine
with m-CPBA or Oxone.
Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919-934.

m-CPBA or Oxone O R'

RSO2N=CHR' O O O
N 1. KHMDS, HMPA, OH O
RSO2
THF, –10 °C
H O CH3 H O CH3
Davis oxaziridine: R = R' = Ph O 2. –78 °C O
TBDPSO OTBS TBDPSO OTBS
H H3C CH3 H
S S
• Nucleophilic attack by enolates on the electrophilic oxaziridine oxygen furnishes α-hydroxy
ketones.
O S N
• Potassium enolates are generally the most successful. OO OH
OH O
• Examples 73% H O CH3
O OH
CH3 CH3 OH HO H
KHMDS, Davis Smith, A. B., III; Empfield, J. R.; Rivero, R. A.; Vaccaro, H. A.;
S
O O Duan, J. J.-W.; Sulikowski, M. M. J. Am. Chem. Soc. 1992,
oxaziridine, THF 114, 9419-9434. (±)-breynolide
taxol
CH3 –78 → –20 °C CH3
HO HO
CO2 Et CO2Et O O
97% at OH
OCH3 1. NaHMDS OCH3
57% conversion
2. H3C CH3
CH3O O OCH3 Cl CH3O O OCH3
Wender, P. A.; et al. J. Am. Chem. Soc. 1997, 119, 2757-2758.
Cl
O S N
OO OCH3
OTBS KHMDS, Davis OTBS CH3O
H3C H3C 50% (94% ee)
HO
oxaziridine, THF
taxol
O –78 → –20 °C O
O O H
H H
OTMS OTMS
68% OH
CH3 O O

Grandi, M. J. D.; Coburn, C. A.; Isaacs, R. C. A.; Danishefsky, S. J. J. Org. Chem. 1993, 58 Davis, F. A.; Chen, B. J. Org. Chem. 1993, 58, 1751-1753. (+)-O-trimethylbrazilin
7728-7731.

Mark G. Charest
Molybdenum peroxy compounds: MoO5•pyr•HMPA Rubottom Oxidation

O O
O Mo • Epoxidation of a silyl enol ether and subsequent silyl migration furnishes α-hydroxylated ketones.
O
O
((CH3)2N)3P O N • Silyl migration via an oxacarbenium ion has been postulated.

SiR3 SiR3 SiR3 O

O O O –
O + OSiR3
• Oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) is commonly used to O
R1 R1 R1 R1
oxidize enolates to the corresponding hydroxylated compound.
R2 R2 R2 R2
• It is proposed that nucleophilic attack of the enolate occurs at a peroxyl oxygen atom, leading to
O-O bond cleavage.
Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 4319-4322.
• β-Dicarbonyl compounds are not hydroxylated.
Brook, A. G.; Macrae, D. M. J. Organomet. Chem. 1974, 77, C19-C21.
• Examples Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40, 3427-3429.

CHO O OHC OH O
H3C H3C
O 1. LDA, THF, –78 °C O CH3 CH3
TBDPSO O TBDPSO O
2. MoOPH CH3 CH3
O O
H3C CH3 91% H3C CH3
m-CPBA, NaHCO3
Et3SiO O
H3 O+ H EtOAc H
CH3 HO CH3

70% H3C
OHC OH H 3C
H3 C
CHO
Jansen, B. J. M.; Sengers, H.; Bos, H.; de Goot, A. J. Org.
Chem. 1988, 53, 855-859.
H3 C CH3 Clive, D. L. J.; Zhang, C. J. Org. Chem. 1995, 60, 1413-1427.

(±)-warburganal

OTBS O
PMBO PMBO OTBS
H3C H C dimethyldioxirane
O CH3 O R1 3 CH3
R2
H3C H3C camphorsulfonic acid
BOMO OTBS BOMO OTBS
H 1. LDA, THF, –78 °C H OTBS OTBS
2. MoOPH, –40 °C 79%
CH3 CH3
CH3 CH3
O S R1 = H, R2 = OH 45% O S O CH3
R1 = OH, R2 = H 25% dimethyldioxirane =
CH3S CH3S O CH3

Kato, N.; Okamoto, H.; Arita, H.; Imaoka, T.; Miyagawa, H.; Takeshita, H. Synlett. 1994, 337-339. Reddy, K. K.; Saady, M.; Falck, J. R. J. Org. Chem. 1995, 60, 3385-3390.

Mark G. Charest
 Diol Lactone
• Lactols are oxidized selectively.

HO OH HO O
• Review
O O
Procter, G. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon O O
Press: New York, 1991, Vol. 7, p. 312-318. Ag2CO3 on
H3 C O H3C O
H Celite, toluene H
Fetizon's Reagent H3C CH3 H 3C CH3
75-85 °C
• Silver carbonate absorbed on Celite has been found to selectively oxidize primary diols to H3C H 3C
lactones. 77%
(+)-mevinolin
Fetizon, M.; Golfier, M.; Louis, J.-M. J. Chem. Soc., Chem. Commun. 1969, 1102-1118.
Clive, D. L. J.; et al. J. Am. Chem. Soc. 1990, 112, 3018-3028.
Fetizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 13, 4445-4448.
Other Methods
Kakis, F. J.; Fetizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T. J. Org. Chem.
1974, 39, 523-533. • Platinum and oxygen have been used for the selective oxidation of primary alcohols to lactones.

OH H3C H3C CH3

H
O Pt/O2
Ag2CO3 on
OH O acetone, water
Celite, C6H6
CH3 CH3 HO H3C OH HO H3C O H3C O
N reflux N HO O O
96%
>74% O damsin O
(±)-bukittinggine
Kretchmer, R. A.; Thompson, W. J. J. Am. Chem. Soc. 1976, 98, 3379-3380.

Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem. 1992, 57, 2575-2585. • TEMPO derivatives have been employed in the preparation of lactones.
O
• Epimerizable lactones have been prepared.
NaBrO2, CH2Cl2
O
HO OH NaHCO3 (aq)
OH CH3 O MOMO OBn Ag2CO3 on CH3O MOMO OBn
OBz
Celite, C6 H6 H3C
80 °C H3C CH3
CH3 OH CH3 CH3 CH3 O H CH3 CH3 CH3 N
O H3 C CH3
75% O
94%

O Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990, 55, 462-466.

O • Ru complexes have also been employed.

CH3O
N RuH2(PPh3)4, O
Coutts, S. J.; Kallmerten, J. Tetrahedron Lett. 1990, O H CH3 H3C
31, 4305-4308. H 3C OCH3 H C O OH PhCH=CHCOCH3 O
3 H3 C
OH toluene H3C
O NH2
CH3O CH3
CH3 CH3 100%

(±)-macbecin I Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S. J. Org. Chem. 1986, 51, 2034-2039.
 Oxidative Cleavage of Diols
TBS TBS TBS
PhS PhS PhS
O O O
Sodium periodate (NaIO4) O O O O O
HO Pb(OAc)4
O
• Reviews: O OH O O O
toluene, 0 °C
HO HO 20–45 min
Wee, A. G.; Slobodian, J. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing H
Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. 420–423. 90%
(CH2)6OBn (CH2)6OBn (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, 4509–4511.

HO O
OH PMBO H
PMBO • α-Hydroxyketones can be cleaved as well:
O NaIO4, NaOH, EtOH O

O O C8H15
C8H15 0 → 25 °C, 2 h H3C
H3C H O O OCH3
O >95% H3C
O H3C CH3 OH
H3C O H3C
O Pb(OAc)4 H3C
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.; Jung, J.; Choi, H.-S.; Yoon, W. H. J. Am. Chem. Soc. O
CH3 CH3
2002, 124, 2202–2211. CH3OH–PhH (1:2)
0 °C, 30 min H3C CH
3
H3C CH3 CO2CH3 CO2CH3
82%
Lead Tetraacetate (Pb(OAc)4)

Corey, E. J.; Hong, B. J. Am. Chem. Soc. 1994, 116, 3149–3150.

• 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, • Oxidative cyclizations sometimes occur. This process likely proceeds by a free-radical
p. 190–195. mechanism involving homolytic cleavage of an RO–Pb bond.
Butler, R. N. In Synthetic Reagents, Pizey, J. S., Ed., 1977, Vol 3, p. 277–419.

Rubottom, G. M. In Oxidation in Organic Chemistry, Trahanovsky, W. S., Ed.; Organic Chemistry, H3C OAc H3C OAc
A Series of Monographs, Vol 5, 1982, Part D, p. 1–145. H Pb(OAc)4 H
H3C
• A common reagent for the cleavage of diols. However, Pb(OAc)4 is a strong oxidant and can PhH, 80 °C, 18 h
react with a variety of functional groups. H O H
AcO 68% AcO
• Examples: H H
HO CH3 CH3

HO O
OTBDPS 1. Pb(OAc)4, PhH
HO OH Bowers, A.; Denot, E.; Ibáñez, L. C.; Cabezas, M. A.; Ringold, H. J. J. Org. Chem. 1962, 27,
O
1862–1867.
HO CH3 2. NaBH4, CH3OH OTBDPS
H3C
Mihailovic, M. L.; Cekovic, Z. Synthesis 1970, 5, 209–224.
84% (two steps)
• In addition, Pb(OAc)4 can oxygenate alkenes, oxidize allylic or benzylic C–H bonds, and has
been used to introduce an acetate group α to a ketone.
Takao, K.; Watanabe, G.; Yasui, H.; Tadano, K. Org. Lett. 2002, 4, 2941–2943.

Landy Blasdel
 • Examples
Oxidative Cleavage of Alkenes
CH3 O CH3
OH OH
Ozone 1. O3, CH2Cl2–CH3OH
H3C OBn H3C OBn
(15:1), –78 °C
• Reviews: H H H
H
Berglund, R. A. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing O 2. thiourea, –78 °C O
Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, H3C H3C
p. 270–275. OTMS 65%
OTBS OTMS
O OTBS
Ph
Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol 7, p. 543–558, 574–578. Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am.
Chem. Soc. 1997, 119, 12976–12977.
Murray, R. W. In Techniques and Methods of Organic and Organometallic Chemistry ,
Denny, D. B., Ed., Marcel Dekker: New York, 1969, Vol 1, p. 1–32. • Forming the primary ozonide with sterically hindered olefins is difficult, and epoxides can be
formed instead:
Murray, R. W. Acc. Chem. Res. 1968, 1, 313–320.
CH3 CH3
• Ozone is the most common reagent for the oxidative cleavage of olefins. 1. O3, (ClH2C)2, 0 °C
H3C H3C
• The reaction is carried out in two steps: H3C 2. Zn, HOAc, 75 °C H3C O
H3C CH3 CH3
H3C
(1) a stream of O3 in air or O2 is passed through the reaction solution at low temperature 71%
(0 °C to –78 °C) until excess O3 in solution is evident from its blue color. Hochstetler, A. R. J. Org. Chem. 1975, 40, 1536–1541.
(2) reductive or oxidative work-up.
• Alkenes are ozonized more readily than alkynes:
• Mechanism:
R1 R3 O R4
O O O H3CO H H3CO H
+ R3 1. O3, CH2Cl2, CH3OH
O +
O O R2 R4 R1 R3 R1 R2 O O 2. S(CH3)2 O
R2 R4 O N N
Ph OH
molozonide 3. NaBH4
R3 R4
OTBS 92% OTBS
O O reductant
+ O O
R1 R2 R3 R4 O • When a TMS-protected alkyne was used in the example above, the authors observed
R1
products arising from ozonolysis of the alkyne as well.
R2
ozonide Banfi, L.; Guanti, G. Tetrahedron Lett. 2000, 41, 6523–6526.
• Considered to be a concerted 3 + 2 cycloaddition of O3 onto the alkene.
• Ozonolysis of silyl enol ethers can afford carboxylic acids as products:
• Because ozonides are known to be explosive, they are rarely isolated and typically are transformed
directly to the desired carbonyl compounds.
OTMS 1. O3, CH3OH–CH2Cl2
• Dimethyl sulfide is the most commonly used reducing agent. Others include I2, phosphine,
(3:1), –78 °C CH3
thiourea, catalytic hydrogenation, tetracyanoethylene, Zn–HOAc, LiAlH4, and NaBH4. The latter O OCH3
two reductants afford alcohols as products. 2. S(CH3)2, O
H3C OCH3 –78 °C → 23 °C HO
• Oxidative workup provides either ketone or carboxylic acid products. The most common oxidants H
are H2O2, AgO2, CrO3, KMnO4, or O2. 92%

• Alkenes with electron-donating substituents are cleaved more readily than those with electron- Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan, S. M. J. Org. Chem. 1997, 62, 78–87.
withdrawing substituents, see: Pryor, W. A.; Giamalva, D.; Church, D. F. J. Am. Chem. Soc. 1985,
107, 2793–2797.
Landy Blasdel
 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,
NTs NTs O
1999, p. 423–426. H3CO H3CO
OBn OBn H
Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol. 7, p.564.

VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973. OsO4 (cat.), NaIO4, THF–H2O (3:1)...................................77%

1. OsO4 (cat.), NMO, acetone–H2O–t-BuOH (4:2:1);

2. NaIO4, THF–H2O (3:1)...................................................89%
• A two-step procedure involving initial dihydroxylation with OsO4 to form 1,2-diols, followed by
cleavage with periodate.

• This procedure offers an alternative to ozonolysis, where it can be difficult to achieve • Frequently the two-step protocol is found to be superior to the one-pot procedure. In the example
selectivity for one olefin over another due to difficulties in adding precise quantities of ozone. shown, over-oxidation of the aldehyde was observed in the one-pot reaction.

• Sharpless dihydroxylation conditions (AD-Mix α/β) can lead to enhanced selectivities.

Bianchi, D. A.; Kaufman, T. S. Can. J. Chem. 2000, 78, 1165–1169.

OPMB PMBO OH PMBO O

cat. OsO4, NMO NaIO4
H3C H3C OH H3C
H
THF, acetone, THF, H2O • An improved one-pot procedure uses 2,6-lutidine as a buffering agent:
CH3 CH3 CH3 CH3 CH3 CH3
H2O, 23 °C 23 °C

93% (two steps)

Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.; Sheidt, K. A. J. Org. Chem. OsO4, NaIO4,
CH3 OPMB CH3 OPMB CH3 OPMB
2002, 67, 4275–4283. 2,6-lutidine
H +
CH3 CH3 HO CH3
dioxane–H2O (3:1)
OTBS O OTBS O OTBS
• The procedure is most often performed in two steps, but the transformation is sometimes
accomplished in one: 90% 6%

H3CO H3CO H3CO

• Ozonolysis of this substrate resulted in PMB removal.

O OsO4, NaIO4 O CH3MgI O
• The authors found that without base, the α-hydroxyketone was formed in ~30% yield.
N N N Using pyridine as base, epimerization of the aldehyde product was observed.
H THF, H2O, 23 °C H THF H
H3CO H3CO H3CO
62% conversion 47% (two steps)
H O H3C OH
Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–3219.
• Notice that in the example above, the less-hindered olefin was cleaved selectively.

Maurer, P. J.; Rapoport, H. J. Med. Chem. 1987, 30, 2016–2026.

Landy Blasdel
 Oxidative Cleavage of Alkenes Ketone α,β-Unsaturated Ketone

RuO4
See also: o-Iodobenzoic Acid
• References: (IBX) earlier in handout
General Reference:
Martín, V. S.; Palazón, J. M.; Rodríguez, C. M. In Handbook of Reagents for Organic Synthesis:
Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
New York, 1999, p. 346–353. Pergamon Press: New York, 1991, Vol. 7, p. 119–149.

Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.,
Pergamon Press: New York, 1991, Vol 7, p.564–571, 587. Saegusa Oxidation
Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838–3840.
• A two-step procedure involving silyl enol ether formation, followed by treatment with Pd(II).
• RuO4 is a powerful oxidant that is nevertheless useful in many synthetic transformations.
• The reaction can be performed with stoichiometric Pd(II), or can be rendered catalytic if a
• RuO4 has been used to cleave alkenes where other oxidation methods (e.g., O3, OsO4/NaIO4) terminal oxidant, such as O2 or p-benzoquinone, is used.
have failed.
• Mechanism:
• Reaction conditions are relatively mild and usual involving generation of RuO4 in situ from
RuO2•2H2O or RuCl3•H2O and an oxidant, such as NaIO4.
O OTMS Pd(OAc)2 PdII OTMS
• Solvent mixtures of CCl4, H2O and CH3CN have been determined to be optimal. CH3CN is TMS-Cl
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, 3936–3938.

• RuO4 will also oxidize alcohols (to ketones), ethers (to lactones or to two carboxylic acids), diols TMS-OAc
(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. O O PdII
β-elim O
PdII

Pd(0)
CH3 CH3 H

CH3 RuO2, NaIO4 CH3 Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
H3C H H
CH3 CCl4–CH3CN–H2O O CH3 Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem. Int. Ed. 1999, 38,
(1:1:1.5), 23 °C, 1 h 2015–2016
CH3 CH3
68% H3C
O LiTMP, TMS-Cl
H H
Myers, A. G.; Condroski, K. R. J. Am. Chem. Soc. 1995, 117, 3057–3083. O OTIPS THF, –78 °C TMSO OTIPS
PMBO PMBO

Pd(dba)2•CHCl3 (5 mol%),
O diallyl carbonate, CH3CN
H H
H3C
H RuO2, NaIO4 CH3 O OTIPS 90% (two steps)
CH3 PMBO
CCl4–CH3CN–H2O CH3
H CH3 H
82% O CH
3 • In this case, diallyl carbonate is used as a terminal oxidant.

Mehta, G.; Krishnamurthy, N. J. Chem. Soc., Chem. Commun. 1986, 1319–1321. Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc.
2002, 124, 14546–14547.

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 Ketone α,β-Unsaturated Ketone
• Examples:

O 1. LDA, THF O O
Selenation/Oxidation/Elimination –78 °C H2O2, pyridine
SePh
Ph 2. PhSeBr Ph CH2Cl2–H2O, Ph
Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., 25 °C, 30 min
Pergamon Press: New York, 1991, Vol. 7, p. 128–135. 66%
Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 14, 1979–1982. • Generating the enolate under kinetic conditions can allow for formation of the less-substituted
double bond.
Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem. Soc. 1973, 95, 6137–6139.

Reich, H. J.; Reich, I. L.; Renga, J. M. J. Am. Chem. Soc. 1973, 95, 5813–5815. Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 5434–5447.

Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 5434–5447.
O O
1. LDA; PhSeCl
• PhSeBr and PhSeCl can be used to selenate enolates of ketones, esters, lactones and lactams. H3C H3C
CH3 2. H2O2 CH3
• PhSeSePh can be used as well, but ketone enolates are unreactive H3C H3C

• Aldehydes can be selenated via: 64%

– enol ethers: Nicolaou, K. C.; Magolda, R. L.; Sipio, W. J. Synthesis 1979, 982–984. Annis, G. D.; Paquette, L. A. J. Am. Chem. Soc. 1982, 104, 4504–4506.

– enamines: Williams, D. R.; Nishitani, K. Tetrahedron Lett. 1980, 21, 4417–4420.

H H
O O
– one-step procedure with PhSeSePh, SeO2, and a catalytic amount of H2SO4: Miyoshi, N.;
1. LDA, THF, O O 1. LDA, THF,
Yamamoto, T.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett. 1982, 23, 4813–4816.
HMPA, –78 °C HMPA, –78 °C
2. PhSeSePh H CH H CH 2. PhSeSePh
• Mechanism: 3 3
88% cis-fused trans-fused 85%
O
O base O PhSeBr
H H
O O
SePh O O

H SePh H SePh
[O] CH3 CH3

H2O2, THF, H2O, H2O2, THF, H2O,

O AcOH, 0 °C AcOH, 0 °C
Se O
+ H ~ 100% 96%
Ph OH
Se
Ph O H H H
O O O
O + O O
• Common oxidants include H2O2, O3, and NaIO4.
H CH3 H
• Elimination is syn-specific, see: Jones, D. N.; Mundy, D.; Whitehouse, R. D. J. Chem. Soc., 10 : 90
Chem. Commun. 1970, 86–87.
• The example above illustrates how the stereospecificity (syn) of the elimination can be used to
• Electron withdrawing groups on the phenyl ring facilitate the elimination step, which can be achieve selectivity in olefin formation.
difficult with primary or β- or γ-branched selenoxides: Sharpless, K. B.; Young, M. W. J. Org.
Chem. 1975, 40, 947–948.
Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120–122.
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 Alkene Allylic alcohol
• Examples:
CH3 CH3
SeO2 OH

• References O CH3 SeO2, t-BuOOH O CH3

O OH O OH
Bulman Page, P. C.; McCarthy, T. J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., dioxane, 23 °C
CH3 O CH3 O
Eds.; Pergamon Press: New York, 1991, Vol. 7, p. 84–91, 108–110. O O
H3C 95% H3C
CH3 CH3
Rabjohn, N. In Organic Reactions, 1976,Vol 24, p. 261–415.

Xia, W. J.; Li, D. R.; Shi, L.; Tu, Y. Q. Tetrahedron Lett. 2002, 43, 627–630.
• General method for oxidizing alkenes to allylic alcohols.

• Although the reaction can be performed with stoichiometric SeO2, catalytic methods employing a
stoichiometric oxidant (e.g., t-BuOOH) are more frequently used. H3C H3C
H3C SeO2, t-BuOOH H3C
• Mechanism:
O OH H3C CH2Cl2 0 °C H3C OH
Se
CH3 O Se O H H 99% H H
H3C H3C
TBSO TBSO
CH3 ene reaction CH3

[2,3]-sigmatropic
rearrangement Yu, W.; Jin, Z. J. Am. Chem. Soc. 2001, 123, 3369–3370.

Se
OH HO O
Br
O
H3C H3C
CH3 CH3
H

H
Singleton, D. A.; Hang, C. J. Org. Chem. 2000, 65, 7554–7560. CbzN CH3

SeO2, t-BuOOH
CH2Cl2, 0 °C → 23 °C
Selectivity:

(a) oxidation typically occurs at the more highly substituted terminus of the alkene O
Br Br Br
(b) the order of reactivity of C–H bonds is CH2 > CH3 > CH O O H O
[rule (a) takes precedence over rule (b)]
+ +
HO O
(c) when the double bond is within a ring, oxidation occurs within the ring H H H

(4) gem-dimethyl trisubstituted alkenes form (E)-α-hydroxy alkenes stereoselectively H H H

CbzN CH3 CbzN CH3 CbzN CH3

14% 77% trace

Hoekstra, W. 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. 358–359.

Bhalerao, U. T.; Rapoport, H. J. Am. Chem. Soc. 1971, 93, 4835–4840. Muratake, H.; Natsume, M. Angew. Chem. Int. Ed., Eng. 2004, 43, 4646–4649.
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