Module I
Oxidation Reactions
Lecture 2
2.1 Manganese Oxidants
Keywords: Oxidation, Alcohol, Alkene, Sulfide, Catalyst, Maganese, Terminal
Oxidant
2.1.1 Introduction
Manganese (Mn) is the 12th most abundant element (0.1%) on earth’s crust with atomic number
25. Though manganese exists with the oxidation states from –3 to +7, the common oxidation
states are +2, +3, +4, +6 and +7. The +2 oxidation state, which has a pale pink color due to spin
forbidden d-d transition is found in living organisms for essential functions. The manganese in
the oxidation state +7 is deep purple in colour and a strong oxidizing agent (Mn+7 + 5e- →
Mn+2).
2.1.2 Manganese(III) Reagents and Catalysts
2.1.2.1 Selective Oxidation of Benzylic and Allylic Alcohols
A combination of Mn(OAc)3 and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) has been
used for the selective oxidation of benzylic and allylic alcohols. The reaction works under mild
conditions (Scheme 1).
OH
Mn(OAc)3 (6 equiv)
O
20 mol% DDQ
CH2Cl2, rt
O
OH
Mn(OAc)3 (6 equiv)
Ph
20 mol% DDQ
CH2Cl2, rt
Scheme 1
2.1.2.3 Oxidation of Sulfides to Sulfoxides
1
Ph
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Oxidation Reactions
Oxidation of sulfides to sulfoxides is one of the important transformations in organic synthesis.
Sulfides could be selectively oxidized to sulfoxides in good yields with hydrogen peroxide in the
presence of a manganese(III) Schiff-base complex 1 under ambient conditions (Scheme 2).
S
Me
O
S
Catalyst 1
+
N
N
Mn
Me
ClO4-
O
O
H2O2, AcOH
Catalyst 1
Scheme 2
2.1.2.4 Asymmetric Epoxidation of Alkenes
Jacobsen and Katsuki groups have explored asymmetric expoxidation of unfunctionalized
alkenes using chiral Mn(III)-salen complexes in the presence of terminal oxidants such as PhIO
and NaOCl (Scheme 3-4). The most interesting feature of the reaction is that simple alkenes are
oxidized with high asymmetric induction. This process has now been extensively used in
pharmaceutical industries.
N
Me
Jacobsen catalyst (2)
NaOCl, DCM, 4 °C
N
Mn
O Cl O
Me
O
84%
ee 92%
Jacobsen catalyst (2)
Examples for Applications
Jacobsen
asymmetric
epoxidation
MeCN
O
O oleum
N
H2O
tartaric acid
Me
OH
NH2
overall 50% yield
>99% ee
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Oxidation Reactions
Jacobsen
asymmetric
epoxidation
O
C2F5
O
O
2-piperidone
t
C2F5
O
BuOK
C2F5
N
OH
O
BRL-55834
Potassium channel activator
Scheme 3
O2N
O
Me
Me Katsuki catalyst (3)
AcHN
PhIO
O2N
O
AcHN
78%
ee 96%
Me
Me
N
N
Mn
O
O
Me
H
PF6-
O
Me
Ph
Me Ph H
Me
Katsuki catalyst (3)
Scheme 4
Mechanism
The mechanism of this reaction is not fully understood but it has been proposed that the oxidant
oxidizes Mn(III)-salen to Mn(IV)-salen, which oxidizes the alkene (Scheme 5). There are three
possible reaction pathways such as concerted, metallo oxetane and radical pathway but the most
accepted one is the concerted pathway.
N
Mn
O Cl O
NO N
Mn
O Cl O
N
NaOCl
Active catalyst
3
N O N
Mn
O Cl O
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Oxidation Reactions
Me
Ph
N O N
Mn
O Cl O
Me
Ph
N
Me
Ph
N
Mn
O Cl O
+
O
Concerted
N O N
Mn
O Cl O
Ph
Me
Metallo Oxetane
Radical
•
Me
Ph
N
Me
Mn
O Cl O
Me
Ph
N
+
O
e
ps
lla
o
C
Me
Ph
Ph
Mn
O
N O N
Mn
O Cl O
N
Me
N
Mn
+
O Cl O
Ph O
Rotation
then
Collapse
Scheme 5
2.1.2. 5 Asymmetric Sulfoxidation
The above described Katsuki catalytic system is also effective for the asymmetric oxidation of
sulfides to sulfoxides (Scheme 6). The oxidation of aryl alkyl sulfides has been extensively
studied with moderate to high enantioselectivity.
S
Me
NO2
Katsuki catalyst (4)
PhIO, MeCN, -20 °C
O
S
N
N
Mn
Me
O
MeO
OMe PF6-
O
NO2
Me
H
Ph
Me Ph H
Me
Me
Katsuki catalyst (4)
Scheme 6
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Oxidation Reactions
2.1.3 Mn(IV) Reagents as an Oxidant
MnO2 is a useful selective oxidizing reagent in organic synthesis. It is commercially available,
and it can also be prepared by the reaction of MnSO4∙4H2O with KMnO4 in aqueous NaOH.
G. Cahiez, M. Alami, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons,
Inc., L. A. Paquette Ed., New York, 1995, 5, 3229.
2.1.3.1 Oxidation of Alcohols
MnO2 can selectively oxidize allylic and benzylic alcohols to the corresponding carbonyl
compounds (Scheme 7). The advantage of this method is that the reaction takes place under mild
and neutral conditions, also carbon-carbon double and triple bonds are unaffected.
CHO
MnO2
OH
solvent free, rt
OSiEt3
OSiEt3
HO
I
Me
Me
Me
MnO2
CH2Cl2
Me
Me
OHC
I
Me
Me
Me
Me
Me
MnO2
benzene
HO
HO
OH
CH2OH
MnO2
Me
OH
CHO
CH2OH
CHCl3
Me
CH2OH
CHO
MnO2
Pentane, R.T.
Retinal
Vitamin A (Retinol)
Scheme 7
5
O
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Oxidation Reactions
Furthermore, at elevated temperature, saturated secondary alcohols can be oxidized to ketones
(Scheme 8).
OH
O
MnO2
Scheme 8
2.1.3.2 Oxidation of Aldehydes to Esters (Corey-Gilman-Ganem Oxidation)
The aldehydes can be selectively oxidized to esters in presence of MnO2 and hydrogen cyanide in
methanol at ambient temperature (Scheme 9). The aldehyde undergoes reaction with HCN to
give cyanohydrins, which proceeds further oxidation to acyl cyanide. The latter on alcoholysis
leads to corresponding -unsaturated carboxylic ester.
CHO
CO2Me
MnO2, NaCN
MeOH, AcOH
Me
Me
Me Me
Me Me
CHO
O
HO
CO2Me
MnO2, NaCN
MeOH, AcOH
Me
O
HO
Me
Mechanism
AcOH
+ NaCN
OH
CHO
HCN
CN
O
MnO2
CN
ROH
CO2R
+ HCN
Scheme 9
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Oxidation Reactions
2.1.3.3 Oxidation of Amines
The oxidation of amines can lead to various products depending on the nature of the starting
compound. This section describes the oxidation of amines to imines and amides (Scheme 10).
Ph-CH2-NH-Ph
MnO2/C6H6
81 oC
Ph-CH=N-Ph
Me
NMe2
N
CHO
MnO2/CHCl3
18 h/RT
Scheme 10
2.1.3.3 Oxidation of Hydrazo Compounds
Hydrazobenzene can be oxidized to azobenzene with high yield (Scheme 11).
MnO2/C6H6
Ph-NH-NH-Ph
24 h/ 81 oC
Ph-N=N-Ph
97% yield
Scheme 11
2.1.3.4 Oxidative Cleavage of 1,2-Diols
1,2-Diol undergoes oxidative cleavage to afford aldehydes or ketones (Scheme 12).
OH
OH
MnO2/CH2Cl2
CHO
CHO
4 h, R. T
Scheme 12
2.1.3.5 Aromatization
MnO2 has been widely used for the dehydrogenation and aromatization reactions (Scheme 13).
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Oxidation Reactions
MnO2/C6H6
reflux
Scheme 13
2.1.3.6. Conversion of Nitriles to Amides
Nitriles are readily converted into amides in the presence of MnO2 under reflux conditions
(Scheme 14).
CN
CONH2
MnO2/SiO2
C6H6/ 4 h/reflux
100%
Scheme 14
Examples:
HO
O
CH3
CH3
MnO2
1.
CH2OH
CH2OH
K. M. Brummond, P. C. Still, H. Chen, Org. Lett. 2004, 6, 149.
CH2OH
CH2OH
MnO2
2.
CH3
OH
CH3
O
P. C. Mukharji, A. N. Ganguly, Tetrahedron 1969, 25, 5281.
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Oxidation Reactions
2.1.4 Mn(VII) Reagents as an Oxidant
Potassium permanganate (KMnO4) is a strong oxidizing agent, and its reactivity depends on
whether it is used in acid, neutral or basic conditions. In acid solution, Mn(VII) is reduced to
Mn(II), while in basic and neutral conditions, MnO2 is usually formed.
2.1.4.1 Oxidation of Aromatic Side Chains
Alkyl side chain present in aromatic ring is readily oxidized to carboxylic acids (Scheme 15).
O
Me
Alkaline KMnO4
OH CTMACl = CH3(CH2)215N+(CH3)3ClPhase transfer catalyst
4 h, reflux
CTMACl
80%
Scheme 15
Application in the synthesis of Saccharin
O
S
NH2
O
Me
O
S
NH2
O
OH
KMnO4
O
S O
NH
-H2O
O
Saccharin
O
2.1.4.2 Oxidation of Aromatic Rings
Benzene ring can be cleaved if it is fused to heterocyclic ring system. Thus, quinonline and
isoquinoline can be oxidized to dicarboxylic acids in the presence of alkaline KMnO4 (Scheme
16).
CO2H
KMnO4
N
reflux
Scheme 16
9
N
CO2H
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Oxidation Reactions
2.1.4.3 Oxidation of Alcohols
Alkaline KMnO4 and barium permanganate selectively oxidize alcohols to aldehydes and
ketones (Scheme 17).
OH
OEt
Me
KMnO4
aq. NaH2PO4
O
OEt
Me
pet ether
O
OH
TBSO
Ba(MnO4)2
CH2Cl2
O
CHO
TBSO
Scheme 17
2.1.4.4 Oxidation of Aldehydes
Aldehydes are oxidized to carboxylic acids with good yield at ambient temperature (Scheme 18).
O
Me
KMnO4
H
O
Me
OH
H2SO4, H2O
O
Me
O
H
Me
OAc
KMnO4
Me
CO2, acetone
H
Me Me
OH
Me
OAc
H
Me Me
Scheme 18
2.1.4.5 1,2-Dihydroxylation
The alkaline KMnO4 is most commonly used for selective cis-dihydroxylation from the less
hindered side of the double bond (Scheme 19).
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Oxidation Reactions
alkaline
KMnO4
OH
H2O
OH
cis-diol
Scheme 19
The permanganate ion adds to the double bond to form a cyclic ester, which after alkaline
hydrolysis gives the desired cis-1,2-diol (Scheme 20).
addition to
double bond
KMnO4 +
O
O
Mn
O
O
cyclic ester
intermediate
alkaline
hydrolysis
OH
OH
cis -1,2-diol
Scheme 20
Lemieux-von Rudloff Reagent
Mixtures of sodium periodate (NaIO4) and potassium permanganate (KMnO4) in aqueous
organic solvent used for oxidative cleavage of a double bond.
Me
Me
NaIO4, KMnO4
OH
Me
acetone, H2O
Me
11
HO2C
OH
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Oxidation Reactions
Problems
1. Provide the major product for the following reactions:
KMnO4
1.
NaOH
MnO2
H
4.
HCN, MeOH
O
N
KMnO4
2.
reflux
N
MnO2
5.
NH
OH
OH
OH
MnO2
3.
6.
CHCl3, RT
HO
CH2Cl2, RT
MnO2
acetone, RT
2. Give suitable reagent and reaction conditions for the following transformations.
CH2OH
A
CHO
OH
B
3.
1.
OH
CHO
CHO
O
2.
4.
Text Book
M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed., John Wiley and Sons, Inc., New
York, 2001.
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