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 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: Alcohol
organosilanes
organometallics in general RCH2M (M = Li, MgX, ZnX...)
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)
N NR''2
Oppenauer Oxidation Chromium (VI) Oxidants Sodium Hypochlorite N-Bromosuccinimide (NBS) Bromine Cerium (IV) Oxidants
R
hydrazone
R'
R
R
R'
dithiane R
Pyridinium Dichromate (PDC)
ester
Bromine
thioester
Ester
R''O NR2'''
aminal
R
R
R'
R' N
imine R
R'' R'
O
O
R
hydroxamic acid
amide
R
N R''
SR'
trihalomethyl
R
R' N OH
orthoester
R'''
ketene R
RCX3
nitrile
R'
R C N
O R
O O
CH3 (OBO ester shown)
Acid
O2/Pt
Jones Oxidation
Carbonic Acid Ester ROH + CO2 (ROCO2H)
Davis Oxaziridine
MoOPH
Rubottom Oxidation
Lactone
isocyanate
O2/Pt
O
O
α-Hydroxy Ketone carbamate
Fetizon's Reagent
S
R'
RCO2R'
Ester
Ruthenium Tetroxide
Diol
S
Carboxylic Acid R-CO2H
Bayer-Villiger Oxidation
Ketone
R'
R''O enol ether (enamine)
O
Alcohol
R
RCX2R'
geminal dihalide
O
Corey-Gilman-Ganem Oxidation Ketone
R'
R''O OR''' ketal (acetal)
OR''
N oxime
Acid
Silver Oxide Sodium Chlorite 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 115
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
R
N R''
R' N R'''
Mark G. Charest
Alcohol
• Pummerer Rearrangement
Aldehyde or Ketone
HO CH3 OH H3C H Dimethylsulfoxide-Mediated Oxidations
H3C
(CF3CO)2O, Ac2O 2,6-lutidine
O
O H
• Reviews
Tidwell, T. T. Organic Reactions 1990, 39, 297-557.
• 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. +
–
Ph
O
HO CH3 OH H 3C H
O
O
OAc
H
>60%
O
O
H3C
–
AcO
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.
+
+
+
+S
O R
H3C
General Mechanism
H H
H
–BH+ – –RCO2
O HO CH3 OH H3C H
Tidwell, T. T. Synthesis 1990, 857-870.
B
O
O
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
E
(CH3)2S
X
X
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
+
(CH3)2S
TBSO
2. 10% Pd/C, AcOH, EtOAc O
O
3. (COCl)2, DMSO; Et3N
O
–78 → –50 °C
OBn
alkoxysulfonium ylide
TBSO
1. TBSCl, Im, DMAP, CH2Cl2
HO
CH2 + S CH3 O
H H R
–H+
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 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
OTBS (COCl)2, DMSO;
+
ROH + H2C S CH3
RO
–H+
S
CH3
HO
OCH3
Et3N, –78 °C 90%
Fenselau, A. H.; Moffatt, J. G. J. Am. Chem. Soc. 1966, 88, 1762-1765.
O
OCH3 H
Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738-3753. Mark G. Charest
CH3O
CH3O
CH3 HO OR1
CH3O CH3
CH3O
OH O
(COCl)2, DMSO;
N
CH3
H
R1 O CH3
OCH3
CH3
OR
R = TIPS, R1 = TBS
Hanessian, S.; Lavallee, P. Can. J. Chem. 1981, 59, 870-877. Parikh-Doering Procedure • 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. Pfitzner-Moffatt Procedure
• Ease of workup and at-or-near ambient reaction temperatures make the method attractive for large-scale reactions. 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
• Typically, oxidations are carried out with an excess of DCC at or near 23 °C.
OH
DMSO, DCC
Cl
O
87%
H
O
CH3
9 : 1 β,γ : α,β
S H3 C
CH3
H
CHO CO2CH3
O
CH 3
CH3
O
O
O
SO3•pyr, Et3N,
H
O
H
Br
H
DMSO, CH2Cl2
O
H
0 → 23 °C
OHC
H
O
Br
H
99%
+
CO2CH3 O
CH 3
H S
CH3
H
CHO
S H3 C
CH3
N
95%
H HO H
DMSO, DCC OH CO2CH3 TFA, pyr
Bn
CH2Cl2, –15 °C
O
H
Corey, E. J.; Kim, C. U.; Misco, P. F. Org. Synth. Coll. Vol. VI 1988, 220-222.
H
O
Evans, D. A.; Ripin, D. H.; Halstead, D. P.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 6816-6826.
Ot-Bu O
TFA, pyr
SO3•pyr, DIEA, DMSO CH3
N
• Alternative carbodiimides that yield water-soluble by-products (e.g., 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC)) can simplify workup procedures.
Ot-Bu
H 3C
OH
Bn
• Separation of the by-product dicyclohexylurea and MTM ether formation can limit usefulness.
Cl
OCH3
EDC = (CH3)2N (CH 2)3 N C N CH2CH3 • HCl H
CH3
BzO 94%
O
O
R1O
OR
OCH3
FK506
H OR
O
TFA, pyr
N
CH3
OCH3
HO
O
DMSO, EDC
O BzO
O
80%
O
O
CH3
CH3
OTBDPS
OTBDPS
O
O OR1
Et3N, –78 °C
H OR
CH3
H3 C
CH3
Semmelhack, M. F.; Yamashita, A.; Tomesch, J. C.; Hirotsu, K. J. Am. Chem. Soc. 1978, 100, 5565-5576.
Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 3175-3177.
O
H H
Et Br
H
O
Br
H
(–)-kumausallene
Mark G. Charest
Dess-Martin Periodinane (DMP)
• 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 H H3 C TBSO
H
1. DIBAL 2. DMP
O I
CH3
CH3 H3C H H3C TBSO
H3C H H3C HO AcOO
H O
H
I
89% overall
PivO
Boeckman, R. K.; Shao, P.; Mulins, J. J. Org. Synth. 1999, 77, 141-152.
H3C
H3C CH3
O
(–)-7-deacetoxyalcyonin acetate
H
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 –
I +
O OH + I
2.0 M H2SO4
KBrO3
65 °C, 2.5 h
CO2 H
~100%
IBX
Polson, G.; Dittmer, D. C. J. Org. Chem. 1988, 53, 791-794.
O
74% overall
O CH3O
DMP
OH
• Addition of one equivalent of water has been found to accelerate the reaction, 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.
DMP
R1R2CHOH –AcOH
O
I
OAc I + R1R2C=O + AcOH
slow
O O
O
R1R2CHOH –AcOH R1 R2 Ac O O I O
II O
H
OCHR1R2 I + R1R2C=O + AcOH
fast
OCHR1R 2
O O
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
CHO
• 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.
H
OAc
70%
O CH3O
CH3
R1 R2 H
DMP
Danishefsky, S. J.; Mantlo, N. B.; Yamashita, D. S.; Schulte, G. K. J. Am. Chem. Soc. 1988, 110, 6890-6891.
Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
Ac O O I
O
O
Ac OAc O I OAc O
85 °C
Se
Se + Ac2O + AcOH
O O
then 23 °C, ~24 h
O
DMP
H3C DEIPSO
O
O OTES O O 1. DDQ, CH2Cl2, H2O H 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 OTES H DEIPSO O O H CH 3 CH3 CH3 CH3 H H (–)-cytovaricin O TBSO TESO O Si(t-Bu)2 O OCH3 O CH3 O CH3 OTES TESO H
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 aldehydes.
• Pyridines are not oxidized at a rate competitive with the oxidation of a primary alcohol.
HO
OH OH
DMP, CH2Cl2, DMSO
+
CH 3O2C
N
PhCO2H
CHO
IBX, DMSO N
99%
CO2CH 3
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 saturated alcohol or carbonyl compound.
O NHFmoc
HO
DMP
NHFmoc
H
O
OH
>90%
SCH3
2.3 equiv IBX
SCH3
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
N
• A simpler preparation of IBX has recently been reported.
H O OH + I
oxone, H2O
CO2H
O
N
84%
–
I
toluene, DMSO
70 °C
O O
79-81%
O
O
H
IBX
TIPS
Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.
H
2.0 equiv IBX
TIPS
toluene, DMSO H
H
87% • IBX is used as a mild reagent for the oxidation of 1,2-diols without C-C bond cleavage. H3 C H3 C
AcO
HO
O
H3 C
85%
6.0 equiv IBX
H3 C
IBX, DMSO AcO
OH
Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022.
toluene, DMSO OH
HO
O
OH
O
O
52%
O 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
• Reviews
F
OH
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.
TPAP, NMO, CH2Cl2
N
H3C
CHO
H 3C
4 Å MS, 23 °C
– • Ruthenium tetroxide (RuO4, Ru(VIII)) and, to a lesser extent, the perruthenate ion (RuO4 , Ru(VII)) are powerful and rather nonselective oxidants.
N
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. • To achieve high catalytic turnovers, the addition of powdered molecular sieves (to remove both the water of crystallization of NMO and the water formed during the reaction) is essential.
H3C CH3 HCH3O CH3O OTBS TPAP, NMO, CH Cl 2 2 CH3O H H O O 4 Å MS, 23 °C
CH 3O CH3O
The following oxidation state changes have been proposed to occur during the reaction:
O
•
OH –
Ru(VII) + 2e → Ru(V)
TBSO
78%
H3C CH3 HCH3O OTBS H H O O O
O
H
O
TBSO
2Ru(V) → Ru(VI) + Ru(IV)
Julia-Lythgoe Olefination
Ru(VI) + 2e– → Ru(IV) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625-1627. • Examples O
OH
O
O
O
N TEOC
23 °C H
N TEOC
0 °C H
OCH3 H OTBS O O O
CH3
N
CH3 TESO
H
O CH 3
O
TPAP, NMO, CH2 Cl2 4 Å MS, 23 °C CH3 CH3
O H3C
CH3 87%
CH3 TESO
O OCH3 H OTBS O O O OH O CH3
CH3 CH3
OH
H 3C
H 3C CH3
H3C CH3 HCH3O OTBS H H O O
CH3 O CH3O O
OH
29%
84%
H3C CH3 HCH3O OTBS H H O O
CH3O CH3O
Bu4N+F–, THF
TPAP, CH2Cl2
O
CH3
CH3
(±)-indolizomycin CH3O2C Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30-39.
H3 C CH 3 H HO OAc H H O O O
HO
CH3
TPAP, NMO, CH2 Cl2 4 Å MS, 23 °C
CH3
O
OH H OH O
CH3
H
CH3
70% Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992, 48, 1145-1174.
O CH3 n-Pr
O bryostatin 3
O
Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew. Chem., Int. Ed. Engl. 2000, 39, 2290-2294.
OH
O Mark G. Charest
N-Oxoammonium-Mediated Oxidation • Reviews
• Examples
de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153-1174.
H3 C
Bobbitt, J. M.; Flores, C. L. Heterocycles 1988, 24, 509-533.
O
Rozantsev, E. G.; Sholle, V. D. Synthesis 1971, 401-414.
CH3 N
Boc OH
TEMPO, NaOCl, NaBr EtOAc : toluene : H2O
CH3
H3 C O
N
H
(1 : 1 : 0.15)
• 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.
Boc
O
90% Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gryza, H.; Prokopoxicz, P. Tetrahedron 1998, 54, 6051-6064.
X–
R
+
N O
R1
H OH + R2
O
–HX
R
+ R2
R3
R3
R1
N OH
OH
N-oxoammonium salt
O OTBDPS
• Three possible transition states have been proposed:
R
+
N
–O
R
R1 O
H
+
N
HO R2 R1
R
N
OTBDPS
H3C CH3
R1
H3C CH3 98%
O O
B
H R2
R1
H
23 °C
R1 O
TEMPO, BAIB, CH2Cl2
H
R2 R1
O O
Ganem, B. J. Org. Chem. 1975, 40, 1998-2000.
O
OH H
CHO
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 2
N O
+H+
R1
–H
R
+
R N 1 OH
R +
N O
R1
PhS
TEMPO, BAIB, CH2Cl2 CH2OH
PhS
23 °C
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. • 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 m-chloroperoxybenzoic acid (m-CPBA), sodium hypochlorite (NaOCl), [bis(acetoxy)-iodo]benzene (BAIB), sodium bromite (NaBrO2 ), and Oxone (2KHSO5•KHSO4•K2SO4 ).
H3 C H3 C
CH3 N O
CH3
TEMPO
H3 C
CH2 OH SePh
TEMPO, BAIB, CH2Cl2 23 °C
H 3C
CHO SePh
55% De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974-6977. Mark G. Charest
Manganese Dioxide: MnO2
TBSO
H
TBSO
H
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
H
O
H
H
OAc
H
SAr
MnO2, acetone 76%
HO
O HO
OAc
H
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. • The structure and reactivity of active manganese dioxide depends on the method of preparation. • 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. • 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.
H3C CH3
CH3
H CH 3
CH3 CH3
HO
MnO2
OH
acetone
CH3 75%
CH3 OH H CH 3
CH3
CH3
H3C CH3
O
• Examples CH3 H 3C CH3
CH3
CH3
H 3C CH3 OH
CH3
CH3 H
MnO2
CH3 OH
O
pet. ether
CH3
HO
CH3
• Vinyl stannanes are tolerated.
Ball, S.; Goodwin, T. W.; Morton, R. A. Biochem. J. 1948, 42, 516-523.
CH3 CH2OH
Bu3Sn
CHO
CH 2OH
61%
CO2Et
OHC
CHO
74%
CHO
• Syn or anti vicinal diols are cleaved by MnO2 . HO
2. MnO2, CH2Cl2 CH3
CH2 Cl2
CH3 Bu3Sn
Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659-5662.
1. DIBAL, C6H6
H3 C
MnO2
89%
Crombie, L.; Crossley, J. J. Chem. Soc. 1963, 4983-4984.
EtO2C
paracentrone
Haugan, J. A. Tetrahedron Lett. 1996, 37, 3887-3890.
80%
MnO2
CH3
CH3 OH
O H3 C
CH 3 H3 C
Cresp, T. M.; Sondheimer, F. J. Am. Chem. Soc. 1975, 97, 4412-4413.
CH3
CH3
O
MnO2
100%
CH3 CH 3
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 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. •
Effectively the reverse of the Meerwein-Pondorff-Verley Reduction.
• Examples
R
• 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.
R CH2 OH
BaMnO4, CH2Cl2
R1 L R3 M R2 O L H O R4
CHO
40 °C CH 2OH
CHO 66%
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
H 3C
H3 C OH
• Examples OH
BaMnO4
CH2OH
CHO pivaldehyde, toluene
92%
H3C CH3
H3 C CH3
2 mol % F5
H3 C Howell, S. C.; Ley, S. V.; Mahon, M. J. Chem. Soc., Chem. Commun. 1981, 507-508.
(S)-perillyl alcohol
F5 B OH
H3 C
99% CH3 H3 C H SEMO
O
CH2OH
CH 3 BaMnO4, CH2Cl2
H3 C
H
H 98%
O
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 cat. Zr(O-t-Bu)4 , Cl3CHO, CH2Cl2 OH
Burke, S. D.; Piscopio, A. D.; Kort, M. E.; Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; Shankaran, K. J. Org. Chem. 1994, 59, 332-347. H3 C
CH3
3 Å MS 86%
O 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 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
B
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.
+
OTBS
OH Cr O O
OCrO3H
1. n-Bu4 N+F–, THF CH3
CH3
O
O
CH 2Cl2 81% overall
O
CH3
CH3 (±)-periplanone B
Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493-2495. O
1. H2, 10% Pd-C
OCH3 H
2. Collins Reagent
CH3O2C
O CH3 CH3
83%
O
H
2. Collins Reagent O
Doyle, M.; Swedo, R. J.; Rocek, J. J. Am. Chem. Soc. 1973, 95, 8352-8357.
O
H
O
(CH3)3C•
–Cr(III)
• 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
PhCHO
O
89%
O
Wiberg, K. B.; Szeimies, G. J. Am. Chem. Soc. 1973, 96, 1889-1892.
H Ph C O Cr(IV) (CH 3)3C
O
H
O H3 C
CrO3, pyr
H
H
H3 C
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
ketones in the presence of primary alcohols.
ClCrO3– +N
• A modified procedure employs calcium hypochlorite, a stable and easily handled solid
H
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
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
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
O
CH3 O
H Cl
OTIPS O
PCC, 25 °C 4 Å MS
CH3 OH
O H Cl
H3 C
OTIPS
100%
H
CH3 N
OH
Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431-7432. CH3
CH3 N
PCC, CH2Cl2
N CH2Ph
PCC, 25 °C 4 Å MS 100%
O
NaOCl, AcOH S H H3C
O
71%
OH
CH3 OH
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.
O
OMOM
93%
H
NaOAc
S
N
O H3 C
2. MOMCl, DIEA
O
Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871-8872.
N
1. NaOCl, AcOH
NC
NC
PhCH2
OH
PhCH 2 O
N
O
N N CH2Ph
Knapp, S.; Hale, J. J.; Bastos, M.; Gibson, F. S. Tetrahedron Lett. 1990, 31, 2109-2112.
H
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
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 primary alcohols.
• Cerium (IV) complexes catalyze the selective oxidation of secondary alcohols in the presence of 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
HO
OH
CH3
HO NBS, DME, H2O
CH3
CH3 H3C
• 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
>98%
H3C
CH3
CH3
O
O
NPh OH CH2OH
Corey, E. J.; Ishiguro, M. Tetrahedron Lett. 1979, 20, 2745-2748.
Ce(SO4)2 •2H2SO4, KBrO3
O
O
HO H
O O
H3C HO O
O
H t-Bu
O
Br2, AcOH
O
HO H HO H
HO O
H >51%
O
O O CH3
48%
(±)-palasonin
Rydberg, D. B.; Meinwald, J. Tetrahedron Lett. 1996, 37, 1129-1132.
O O
• TEMPO catalyzes the selective oxidation of primary alcohols to aldehydes in a biphasic mixture of dichloromethane and aqueous buffer (pH = 8.6) in the presence of N-chlorosuccinimide (NCS) as a stoichiometric oxidant and tetrabutylammonium chloride (Bu4 N+Cl–).
H t-Bu
O
H3C
NaOAc
O
O
NPh O CH2OH
7 : 3 CH3CN, H2O, 80 °C
• Bromine has been employed for the selective oxidation of activated alcohols. In the following example, a lactol is oxidized selectively in the presence of two secondary alcohols.
O
O
O
H OH
(±)-ginkgolide B
TEMPO, NCS, +
OH
O
–
Bu4N Cl 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.
OH
+
CH2Cl2, H2O,
OH
CHO
pH 8.6 77%
• Stannylene acetals are oxidized in preference to alcohols in the presence of bromine.
0.50%
TEMPO, NCS, Cbz
CH3 OH N
H3C O O
OH O O
O Sn
Bu
CH3 N Cbz
Cbz Br2
Bu3SnOCH3 70%
CH3 OH N
H3 C O O
OH O O
OH
OH
CH3 N Cbz H2 Pd/C 90%
Bu
H3 C
OH H
H N
HO H3C
N
O
H
O
O H HO O H
(+)-spectinomycin
CH3
Bu4N+Cl–
8
OH
CH2Cl2, H2O, pH 8.6
OH
O CHO
8 82%
+ 8
OH
52% O
CO2CH3
Nicolaou, K. C.; Ohshima, T.; Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. J. Chem. Soc., Chem. Commun. 1999, 809-810.
OH
>95%
OMOM HO H3 C O
CO2H
HO CH3
H CH3
(±)-antheridic acid
NaClO2, NaH2PO4,
OMOM
90%
O O H 3C H H 3C
H
O
H H
OMOM
O
Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004-1015.
CH3 O
OCH3
OSEM
1. DMP, CH2Cl2, pyr 2. NaClO2, NaH2PO4 2-methyl-2-butene, t-BuOH, H2O 3. CH2N2 98%
OMOM
OH
acetone, H2O
O
O
H3C
OCH3 OTf
2-methyl-2-butene H
H3C
H3C CH3O
O
OCH3 OTf
OH
OH
2,6-lutidine
Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574-5576.
O
H3 C O
THF, t-BuOH, H2O
2-methyl-2-butene TBSO H3C CHO CO CH 2 3
CH3
O
2-methyl-2-butene,
1. NaClO2, NaH2PO4, t-BuOH, H2O
n-Bu3Sn
1. TPAP, NMO, CH2Cl2 2. NaClO2, NaH2PO 4
O
H3C
O
CH3
O
(+)-monensin A
H3 C CH3O CH3 O2C H CH3 CH3
O
O O H 3C H H3C
H3 C
H
H3C O
H H
CH3 O
OCH3
Ireland, R. E.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7166-7172.
OSEM
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
H
TsN
N Ts CH3O
2. (CH3)3SiCHN 2
H O
80%
H
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
H H
OTBS
O
N
N HH
Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237-3243.
O
O
OTBS
(–)-yohimbane
KMnO4, NaH2PO4 Silver Oxide: Ag2O
t-BuOH, H2O
CHO
CH3
• 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
OTBS
• Examples CHO
Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S. Tetrahedron Lett. 1986, 27, 4537-4540.
O H3C
O CH3
O H3 C
O
O
CO2 H
CH3
CO2H 1. Ag2O, NaOH
HO
2. HCl
HO
OCH3
OTBS
OCH3 90-97%
vanillic acid
• Examples O
CN
CN
O
Pearl, I. A. Org. Synth. IV 1963, 972-978.
KMnO4, NaH2 PO4 CHO N Boc
t-BuOH, H2O, 5 °C 93.5%
H3C
CO2H N Boc
H3 C CH3 CH3 CHO
O
O NH
N O
0 °C
CH3 CH3 CO2H
72%
O Heffner, R. J.; Jiang, J.; Joullié, M. M. J. Am. Chem. Soc. 1992, 114, 10181-10189. (CH3)2N
Ag2O, CH3OH
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 S
OCH3 CHO
O
OTBDPS H
CH3O
CO2H
1. Ag2O, NaOH 2. HCl
OMEM
O
OTBDPS
PDC, DMF
OH
CH3O O 100%
OMEM Mazur, P.; Nakanishi, K. J. Org. Chem. 1992, 57, 1047-1051.
81%
O
CO2H
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 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.
O
H O
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.
SEt
BnO
CH3O BnO BnO
PDC, DMF 6 equiv CH 3OH
O
SEt
BnO
>71% • 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.
O'Connor, B.; Just, G. Tetrahedron Lett. 1987, 28, 3235-3236. 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.
O
O
O
1. PDC, DMF
CHO
AcO BnO CH3 CH3 CH3
H H
CH3
H3 C
H3C CH3
H3C CH3
TBSO
TBSO OH
H H
PDC, DMF H3 C
CO2H
NH
O
O
CH3
NH 91%
O
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
O
AcO OH BnO CH3 CH3 CH3
aldehyde.
H3C CH3 [O]
O
Ph S O
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.
S
Ph S O
PDC, CH2Cl2
CH2OH 68%
S
CHO
Terpstra, J. W.; van Leusen, A. M. J. Org. Chem. 1986, 51, 230-238.
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 esters.
• Bromine in alcoholic solvents is a convenient and inexpensive method for the direct conversion of aldehydes into ester derivatives.
• Cis/trans isomerization, a problem when other reagents such as basic silver oxide are employed, is avoided.
• Under the reaction conditions employed, secondary alcohols are not oxidized to the corresponding ketones.
• 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.
• Oxidation of a hemiacetal intermediate is proposed.
• Conjugate addition of cyanide ion can be problematic.
• A variety of esters can be prepared.
• Examples
OH
O
O
O
• Examples
OH O
CH3 CH3
O MnO2, CH3CN
O
AcOH, CH3OH
O O
O
CHO NOBn 81%
• Olefins, benzylidine acetals and thioketals are incompatiable with the reaction conditions.
CH3 CH3
H OH H3C
CHO
H3C
NOBn
H OH
O O
O H
Br2, H2O, alcohol
H3C
O
NaHCO3
H3C
O
CO2R H
R = Me, 94% R = Et, 91% R = i-Pr, 80%
OCH3
O
OH OH O Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176-5190.
O
OH NH
O
O H3C
O
Ph
O Br2, H2O, CH3 OH
CHO
O
NaHCO3
O CH3
H3C
89%
Ph CO2CH3
O CH3
(–)-lycoricidine • In the following example, stepwise addition of reagents proved to be essential to achieve high yields. H3C
HO
CH3 O CH3
CH3
1. CH 3CN, AcOH,
H3C
2. MnO2
Lichtenthaler, F. W.; Jargils, P.; Lorenz, K. Synthesis 1988, 790-792.
CH3 TBSO
CH3 OH, 1 h CHO
CH3
Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W. Tetrahedron Lett. 1988, 29, 5087-5090.
HO
97%
Yamamoto, H.; Oritani, T. Tetrahedron Lett. 1995, 36, 5797-5800.
O CH3
CO2CH3
(2Z, 4E)-xanthoxin
TBSO
O N CO2CH3
Br2 , H2O, CH3OH H
NaHCO3
O N CO2CH3
OCH3
78% Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenländer, F. Tetrahedron 1996, 52, 6409-6420.
Mark G. Charest
Ketone
Ester • Examples
Bayer-Villiger Oxidation
Krow, G. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 7, p. 671-688.
HO
CH3 O
CH3O
• Reviews
H CO2H CH3
m-CPBA, NaHCO3 O
CH2Cl2
O
O
H
HO
HO H (±)-PGF2α
95%
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. • The migratory preference of alkyl groups has been suggested to reflect their electron-releasing ability and steric bulk.
n-C16 H33
• Typically, the order of migratory preference is tertiary > secondary > allyl > primary > methyl. • 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 > t-BuOOH. COR' O O O R'CO3H O –R'CO2H R RL R RL O RL R O H
RL = Large Group
Criegee Intermediate
effect
OCH3
N
O
n-C16H33
m-CPBA, Li2CO3 CH2Cl2
O
99%
O O
O
O
O
Miller, M.; Hegedus, L. S. J. Org. Chem. 1993, 58, 6779-6785. • Selective Bayer-Villiger oxidation in the presence of unsaturated ketones and isolated olefins has been achieved. CH3
H2O2 (anhydrous),
BOMO O H3 C
• 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 σO-O RL R secondary • Secondary effect: antiperiplanar alignment of Olp and σ∗C-RL
Ph OCH3 N
Ph
Ti(Oi-C3H7)4 , ether
H
DIEA, –30 °C H
CH3 BOMO
O
H3 C
O
H
H
O
>55%
O
CH3 AcO Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am. Chem. Soc. 1983, 105, 625-627.
Proposed TS
H3 C
O H
O
O
OH OH
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.
D
O
O
O H
D T
CF3CO3 H Na2HPO4
H D
O
D T
+
H D
Turner, R. B. J. Am. Chem. Soc. 1950, 72, 878-882. Gallagher, T. F.; Kritchevsky, T. H. J. Am. Chem. Soc. 1950, 72, 882-885.
O
CH3 CH3
D
N
T
N O
N CH3
m-CPBA, CH3OH
O
70%
N O CH3
Azizian, J.; Mehrdad, M.; Jadid, K.; Sarrafi, Y. Tetrahedron Lett. 2000, 41, 5265-5268.
Alcohol
Acid
OMOM
OMOM
AcHN
RuO2 (H2O)2, NaIO4
Ruthenium Tetroxide: RuO4 • RuO4 is used to oxidize alcohols to the corresponding carboxylic acid. It is a powerful oxidant 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 sodium periodate (NaIO4 ). • 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.
OH
N Boc
CH3CN, CCl4, H2O 98%
OH
• In the following example, sodium periodate cleaves the 1,2-diol to an aldehyde, which
is further oxidized to the corresponding carboxylic acid by RuO4. The amine is protonated and thereby protected from oxidation. HO H
Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936-3938.
1. RuCl3 -NaIO4, OH
CH3N •HF
• Examples
O
CH3 CN, CCl4 , H2O
OBz
OCH3
CH3N
OBz
2. (CH3)3SiCHN2
CO 2H
CCl4, H2O
N Boc O
Clinch, K.; Vasella, A.; Schauer, R. Tetrahedron Lett. 1987, 28, 6425-6428.
Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838-3840.
RuCl3 , NaOCl
AcHN
(S)-(+)-cocaine
78% overall
Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773-4775.
CO 2H
70%
Molecular Oxygen • Molecular oxygen in the presence of a platinum catalyst is a classic method for the oxidation of primary alcohols to the corresponding carboxylic acids.
Sptzer, U. A.; Lee, D. G. J. Org. Chem. 1974, 39, 2468-2469.
• Examples O
RuO2 , NaIO4 CCl4, H2O
O
HO2C
Bn
CO2H
Boc
68% Smith, A. B., III; Scarborough, R. M., Jr. Synth. Commun. 1980, 10, 205-211.
O
O H
R OBz
R = CH3
60%
HO
NH
OH Boc
65%
NH
• Primary alcohols are oxidized selectively in the presence of secondary alcohols.
H
R
CH3 CN, CCl4 , H2 O H
HO
R
RuCl3-NaIO4
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
O
HO
OCH3 O
NHPf CH3 CH3
1. O2/Pt 2. CH3I 85%
Pf = 9-phenylfluorenyl Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1997, 119, 12031-12040.
O
CH3O
Park, K. H.; Rapoport, H. J. Org. Chem. 1994, 59, 394-399.
OCH3 O
O
NHPf CH3 CH3
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.
O
HO
• Isolated olefins usually do not react, but some olefin isomerization may occur with unsaturated carbonyl compounds.
B
• 1,2-diols and α-hydroxy ketones are susceptible to cleavage under the reaction conditions.
CH3CN, H2O
O
O H3C
CH3
O
O H3C
B = A (90%)
• Examples
B
O
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
O
PivO OTBS
BnO O
CO2CH3
CO2H
BnO
Jones reagent
O
–10 → 23 °C
O
H N
Ph
1. H2, 20% Pd(OH)2-C,
OBn
NH
O
2. PhI(OAc)2, TEMPO CH3CN, NaHCO3, H2O
O N
CO2CH3
EtOAc, EtOH
OPiv
O
O N
88-97%
3. NaClO2, t-BuOH, H2O
CH2OBn
NaH2PO4, isopentene
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 • Ketones have been prepared efficiently by oxidation of the corresponding secondary alcohol. OH O O
H
O O
O
O
CH3
O 1. Jones reagent
H
CH3 2. HCO2H
O
O
3 O
CO2t-Bu
CH3
O
H2N
NH
H
PivO NH3, CH3OH
O N
O NH
CH3
CO2H
O
CF3CONH
OH
O 3
96% overall
HO2C O CO H 2 O
H H
O
O HO
O
H
H2N
55 °C
O CO H 2 O
H N
Ph O
NH
OPiv
O N
NH
65%
O
O
O O
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
α-Hydroxy Ketone
Ketone
• Enantioselective hydroxylation of prochiral ketones has been demonstrated. O
Davis Oxaziridine Ph
• Reviews
O
1. NaHMDS
CH3
2. H3C
Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919-934.
OH
Cl N
O S OO
Jones, A. B. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 7, p. 151-191.
CH3
Ph
CH3 Cl
61% (95% ee) • N-Sulfonyloxaziridines are prepared by the biphasic oxidation of the corresponding sulfonimine with m-CPBA or Oxone.
m-CPBA or Oxone
RSO2N=CHR'
RSO2
O N
Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919-934.
R'
O
O
THF, –10 °C
O
H
Davis oxaziridine: R = R' = Ph
O
TBDPSO S
H
O
1. KHMDS, HMPA, CH3 OTBS
• Nucleophilic attack by enolates on the electrophilic oxaziridine oxygen furnishes α-hydroxy ketones.
2. –78 °C CH3 H3C
• Examples
O
HO
CH3 CO2 Et
CH3 OH
KHMDS, Davis
O
oxaziridine, THF
taxol
–78 → –20 °C HO 97% at
O
H
O O
HO
H
S
O OCH3 1. NaHMDS
CH3O
O
OCH3
2. H3C
CH3 Cl
CH3 OH
(±)-breynolide
O
57% conversion
CH3 OTBS
OH OH O
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.
CH3 CO2Et
H
S
73% CH3
O
H TBDPSO
O S N OO
• Potassium enolates are generally the most successful.
OH O
CH3O
OH
OCH3
O
OCH3
Wender, P. A.; et al. J. Am. Chem. Soc. 1997, 119, 2757-2758.
H3C
OTBS
KHMDS, Davis oxaziridine, THF
O
H
O
–78 → –20 °C
OTMS
HO
H3C
Cl O S N OO
OTBS
OCH3
CH3O
50% (94% ee) taxol
O
H
O
H
OTMS
OH
68% CH3 O Grandi, M. J. D.; Coburn, C. A.; Isaacs, R. C. A.; Danishefsky, S. J. J. Org. Chem. 1993, 58 7728-7731.
Davis, F. A.; Chen, B. J. Org. Chem. 1993, 58, 1751-1753.
O
(+)-O-trimethylbrazilin
Mark G. Charest
Rubottom Oxidation
Molybdenum peroxy compounds: MoO5•pyr•HMPA O
O O Mo
• Epoxidation of a silyl enol ether and subsequent silyl migration furnishes α-hydroxylated ketones.
O O
• Silyl migration via an oxacarbenium ion has been postulated.
((CH3)2N)3P O N
O • Oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) is commonly used to oxidize enolates to the corresponding hydroxylated compound.
SiR3
O
SiR3 O
R1
R1
SiR3
+
O
O
–
R2
OSiR3
R1
R1
R2
• It is proposed that nucleophilic attack of the enolate occurs at a peroxyl oxygen atom, leading to O-O bond cleavage.
O
R2
R2
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.
H3C
OHC OH O H3C
CHO O 1. LDA, THF, –78 °C
O
O
TBDPSO
O
CH3
2. MoOPH O H3C CH3
91%
H3C CH3 Et3SiO
H3 O+
OHC OH H3 C
O
m-CPBA, NaHCO3 H
CH3
O
EtOAc
HO
70%
H 3C
CH3
O
TBDPSO
CH3
H
CH3
CH3
H3C
CHO
Jansen, B. J. M.; Sengers, H.; Bos, H.; de Goot, A. J. Org. Chem. 1988, 53, 855-859. Clive, D. L. J.; Zhang, C. J. Org. Chem. 1995, 60, 1413-1427.
H3 C CH3 (±)-warburganal
O
OTBS O
H3C
H3C H
CH3 1. LDA, THF, –78 °C
H3C H
H C O R1 3 R2
PMBO BOMO
2. MoOPH, –40 °C CH3 O CH3S
S
CH3
CH3 R1 = H, R2 = OH 45% R1 = OH, R2 = H 25%
O
S
dimethyldioxirane
CH3 OTBS OTBS
camphorsulfonic acid
PMBO
OTBS
BOMO
OTBS OTBS
79%
CH3 dimethyldioxirane =
CH3S
Kato, N.; Okamoto, H.; Arita, H.; Imaoka, T.; Miyagawa, H.; Takeshita, H. Synlett. 1994, 337-339.
O O
CH3 CH3
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
H3 C
O H3C
Fetizon's Reagent • Silver carbonate absorbed on Celite has been found to selectively oxidize primary diols to lactones.
H
CH3
75-85 °C
reflux
• Platinum and oxygen have been used for the selective oxidation of primary alcohols to lactones. H3C
CH3 H
Pt/O2
O
acetone, water
O CH3
HO H3C HO
N
HO H3C
OH 96%
O H3C
O O
>74% (±)-bukittinggine
damsin
O NaBrO2, CH2Cl2 HO
MOMO
OBn
Ag2CO3 on Celite, C6 H6
CH3 OH
CH3 CH3 CH3
O
• TEMPO derivatives have been employed in the preparation of lactones.
• Epimerizable lactones have been prepared.
CH3 O
O
O
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.
OH
CH3
H 3C
77%
H3C
Celite, C6H6
H
Other Methods
OH
N
O H 3C
(+)-mevinolin
Kakis, F. J.; Fetizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T. J. Org. Chem. 1974, 39, 523-533.
Ag2CO3 on
H3C
Celite, toluene
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.
OH
O
O Ag2CO3 on
H3C
Fetizon, M.; Golfier, M.; Louis, J.-M. J. Chem. Soc., Chem. Commun. 1969, 1102-1118.
CH3
O
O
Procter, G. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 7, p. 312-318.
CH3O
MOMO
OH
OBn
O
NaHCO3 (aq) OBz
H3C
80 °C O
H3C
O H CH3 CH3 CH3
H3 C
75%
N O
CH3 CH3
94% Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990, 55, 462-466.
O
CH3O Coutts, S. J.; Kallmerten, J. Tetrahedron Lett. 1990, 31, 4305-4308.
O
H 3C CH3O
O
• Ru complexes have also been employed.
N H CH3 OCH3 H C 3
H3C O O
CH3 CH3 (±)-macbecin I
H3 C NH2
O
RuH2(PPh3)4, OH OH
PhCH=CHCOCH3 toluene 100%
O H3C CH3
Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S. J. Org. Chem. 1986, 51, 2034-2039.
