Module I
Oxidation Reactions
Lecture 1
1.1 Osmium Oxidants
Keywords: Oxidation, Catalyst, Osmium, Terminal Oxidant, Dihydroxylation
1.1.1 Introduction
Osmium is the densest (density 22.59 gcm-3) transition metal naturally available. It has seven
naturally occurring isotopes, six of which are stable:
184
Os, 187Os,
188
Os,
189
Os, 190Os, and
192
Os.
It forms compounds with oxidation states ranging from -2 to +8, among them, the most common
oxidation states are +2, +3, +4 and +8. Some important osmium catalyzed organic oxidation
reactions follow:
1.1.2 Dihydroxylation of Alkenes
Cis-1,2-dihydroxylation of alkenes is a versatile process, because cis-1,2-diols are present in
many important natural products and biologically active molecules. There are several methods
available for cis-1,2-dihydroxylation of alkenes, among them, the OsO4-catalzyed reactions are
more valuable (Scheme 1).
OsO4 vapours are poisonous and result in damage to the respiratory tract and temporary
damage to the eyes. Use OsO4 powder only in a well-ventilated hood with extreme caution.
Y. Gao, Encylcopedia of Reagents for Organic Synthesis, John Wiley and Sons, Inc., L. A.
Paquette, New York, 1995, 6, 380.
OH
OsO4
Na2SO3
Et2O, 24 h
OH
OH
OsO4
Na2SO3
Et2O, 24 h
Scheme 1
1
OH
Module I
Oxidation Reactions
The use of tertiary amine such as triethyl amine or pyridine enhances the rate of reaction
(Scheme 2).
OH
OsO4, Pyridine
K2CO3, KOH
Et2O, 30 min
OH
Scheme 2
Catalytic amount of OsO4 can be used along with an oxidizing agent, which oxidizes the reduced
osmium(VI) into osmium(VIII) to regenerate the catalyst. A variety of oxidizing agents, such as
hydrogen peroxide, metal chlorates, tert-butyl hydroperoxide, N-methylmorpholine-N-oxide,
molecular oxygen, sodium periodate and sodium hypochlorite, have been found to be effective
(Scheme 3-7).
HO
OH
OsO4, H2O2
HO2C
CO2H
tert-BuOH, 12 h, rt
HO2C
CO2H
Me C8H17
Me C8H17
OsO4, H2O2
Me
Me
tert-BuOH, 24 h, rt
O
O
HO
OH
Scheme 3
OsO4, t-BuOOH
Me
Me
OH
Me
t-BuOH, Et4NOH
Me
OsO4, t-BuOOH
Ph
t-BuOH, Et4NOH
Scheme 4
2
Me
OH
Me
Ph OH OH
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Oxidation Reactions
OH
OH
OsO4, NaClO3
HO
OH
H2O, 50 °C
OH
OsO4, AgClO3
Me
CO2H
H
CO2H
Me
OH
HO
H
O
H2O, 0 °C
OAc
Me
CO2Me
HO
OsO4, Ba(ClO3)2
H2O, 5 h
O
H
CO2Me
Me
CO2H
CO2H
H
OAc
Me
CO2Me
CO2Me
OsO4, KClO3
H2O, 50 °C
Me
HO
HO
CO2H
CO2H
Scheme 5
MeO2C
MeO2C
Me
CO2H
CO2H
HO
HO
OsO4, NMO
aqueous acetone
t-BuOH
CO2H
CO2H
AcO
AcO
Me
Me
Me
Me
OsO4, NMO
aqueous acetone
t-BuOH
O
Me
O
Scheme 6
3
OH
OH
Module I
Oxidation Reactions
O
O
OsO4, NaIO4
aqueous acetone
AcO
Me
Me
O
Me
O
Me
O
Me
O
AcO
H
Me
Me
OsO4, NaIO4
O
O
Me
dioxane-water
O
Me
O
Me
H
Scheme 7
In the latter case, the resultant diols undergo oxidative cleavage to give aldehydes or ketones.
This reaction is known as Lemieux-Johnson Oxidation. NaIO4 oxidizes the reduced osmium(VI)
to osmium(VIII) along with the oxidative cleavage of the diols.
Mechanism
The reaction involves the formation of cyclic osmate ester, which undergoes oxidative cleavage
with NaIO4 to give the dicarbonyl compounds (Scheme 9).
OsO4
+
OsO4
addition to
double bond
O
O
Os
O
O
NaIO4
oxidative
cleavage
OHC
CHO
osmate ester
Scheme 9
1.1.3 Sharpless Asymmetric Dihydroxylation
Although osmylation of alkenes is an attractive process for the conversion of alkenes to 1,2diols, the reaction produces racemic products. Sharpless group attempted to solve this problem
by adding chiral substrate to the osmylation reagents, with the goal of producing a chiral osmate
intermediate (Scheme 10). The most effective chiral additives were found to be the cinchona
alkaloids, especially esters of dihydorquinidines such as DHQ and DHQD. The % ee of the diol
product is good to excellent with a wide range of alkenes.
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Module I
O
O
Os O +
O
Oxidation Reactions
O
O Os O
O
R
OH
R
R
O O
O Os L*
O
O
R
O
Os O
O
L*
O
O
Os O + L*
O
Unligated Pathway
Racemic Product
OH
OH
Ligand Accelerated Pathway
OH
R
Optically Active Product
R
Scheme 10
Et
Et
N
N
O R
H
R O
H
OMe
MeO
R = acyl, aryl
N
N
Dihydroquinoline
DHQ
Dihydroquinidine
DHQD
DHQD
Attack
Rs
RL
Attack
DHQ
RM
DHQD
OHOH
Rs
RL
OsO4
t-BuOH:H2O, oxidant
DHQ
RM
Rs
RL
RM
OHOH
RL = larger substituent
Rs = smaller substituent
RM = medium substituent
Scheme 11
If the alkene is oriented as shown in Scheme 11, the natural dihydroquinidine (DHQD) ester
forces delivery of the hydroxyls from the top face (-attack). Conversely, dihydorquinine (DHQ)
esters deliver hydroxyls from the bottom face (-attack).
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Module I
Oxidation Reactions
The reactions are generally carried out in a mixture of tert-butyl alcohol and water at ambient
temperature (Scheme 12).
O
AD-mix 
O
t-BuOH-H2O
O
O
HO
OH
Me
Me
AD-mix 
H
Me
H
t-BuOH-H2O
Me
Me
Me
Me
OH
OH
Me
AD-mix 
H
Me
H
t-BuOH-H2O
Me
Me
Me
OH
OH
Scheme 12
Features:

The reaction is stereospecific leading to 1,2-cis-addition of two OH groups to the alkenes

It typically proceeds with high chemoselectivity and enantioselectivity

The reaction conditions are simple and the reaction can be easily scaled up

The product is always a diol derived from cis-addition.

It generally exhibits a high catalytic turnover number

It has broad substrate scope without affecting the functional groups
1.1.4 Aminohydroxylation
Similar to cis-1,2-dihydroxylation, cis-1,2-aminohydroxylation of alkenes has been developed by
reaction with chloroamine in the presence of catalytic amount of OsO4. In this process, alkene
reacts with chloroamine in the presence of OsO4 to give sulfonamides that is readily converted
into the cis-1,2-hydroxyamines by cleavage with sodium in liquid ammonia (Scheme 13). This
process provides a direct cis-aminohydroxylation of alkenes, but the major problem is the poor
regioselectivity for unsymmetrical alkenes.
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Module I
Oxidation Reactions
TsHN
K2OsO2(OH)4
R
R'
R'
R
Ts-N(Na)Cl, H2O-t-BuOH
Na/liq. NH3
OH
Ts-N(Na)Cl, H2O-t-BuOH
R'
R
OH
OH
Na/liq. NH3
OH
K2OsO2(OH)4
H2N
NH2
NHTs
Scheme 13
Mechanism
The catalytically active species in the reaction most likely is an imidotrioxo osmium(VIII)
complexes, which is formed in situ from the osmium reagent and the stoichiometric nitrogen
source, i.e. chloroamine (Scheme 14). Experiments under stoichiometric conditions have been
shown that imidotrioxo osmium(VIII) complexes transfer the nitrogen atom and one of the
oxygen atoms into the substrate. The major regioisomer normally has the nitrogen placed distal
to the most electron withdrawing group of the substrate.
O
Os O +
O
NX R
R
O
O Os
O N
X
R
R
O
O Os NX
O
R
R
R H2O
R
HO
XHN
Scheme 14
1.1.5 Asymmetric Aminohydroxylation
The asymmetric cis-1,2-aminohydroxylation of alkenes with chloroamine has been explored
using the chiral osmium catalyst derived from OsO4 and cinchona alkaloids, dihydroquinidine
ligands (DHQD)2-PHAL and dihydroquinine ligands (DHQ)2-PHAL.
Et
Et
N
N
O R
H
N N
R O
H
R=
*Ak-O
O-Ak*
OMe
MeO
N
Dihydroquinoline
DHQ
N
Dihydroquinidine
DHQD
7
Phtholazine (PHAL)
Module I
Oxidation Reactions
The face selectivity for the aminohydroxylation can too be reliably predicted (Scheme 15).
(DHQD)2-PHAL
Top () Attacl
Rs
(DHQD)2-PHAL
N-Source: XNClNa
RM
OH NHX
HNX OH
R
Rs
RM
RM + s
RL
RL
O-source: H2O
Catalyst: OsO4
RL
RL
(DHQ)2-PHAL
Bottom () Attack
RL = larger substituent
Rs = smaller substituent
RM = medium substituent
(DHQ)2-PHAL
Rs
RM
+
RL
Rs
RM
OH NHX
HNX OH
X = SO2R, ROCO
Scheme 15
An alkene with these constraints receives the OH and NHX groups from above, i.e. from the face, in the case of DHQD derived ligand and from the bottom, i.e. from the -face, in the case
of DHQ derivative. For example, the asymmetric aminohydroxylation of methyl cinnamate gives
the following face selectivity based on the chiral ligand (Scheme 16).
NHX O
DHQD
Ph
O
Ph
p-TolSO2NClNa
OMe
OH O
OMe +
Ph
OH
OMe
NHX
X = p-TolSO2
NHX O
OsO4, H2O
OMe +
Ph
DHQ
OH O
OH
Ph
OMe
NHX
Scheme 16
With respect to the yield, regio- and enantioselectivity, reaction depend on number of
parameters, e.g. the nature of starting material, the ligand, the solvent, the type of nitrogen source
(sulfonamides), carbamates and carboxamides as well as the size of its substituent. For some
examples (Scheme 17):
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Module I
Oxidation Reactions
K2OsO2(OH)4
O
Ph
OCH3
TsHN
Ph
TsNClNa 3H2O
t-BuOH:H2O
R.T.
K2OsO2(OH)4
O
Ph
OCH3
(DHQ)2PHAL
EtO2CNClNa
n-PrOH:H2O
R.T.
K2OsO2(OH)4
O
Ph
i
O Pr
O
(DHQ)2PHAL
OCH3
OH
69% yield
82% ee
EtO2CHN
O
Ph
OCH3
OH
78% yield
99% ee
AcHN
O
(DHQ)2PHAL
AcNHBr/LiOH
t-BuOH:H2O
4 oC
OiPr
Ph
OH
>77% yield
99% ee
Scheme 17
Mechanism
OsO4 may undergo reaction with chloroamine to give an active imido-osmium intermediate a
that could readily co-ordinate with chiral ligand ‘L’ to afford chiral imido-osmium intermediate
b (Scheme 18). The latter may react with alkene to yield c via (2+2)-cycloaddition that may
rearrange to give d that could undergo hydrolysis with water to give the target hydroxylamine
derivative.
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Module I
Oxidation Reactions
K2OsO2(OH)4 + NaNCl
X
R'
R"
HO
NH
X
L
O
O Os N R
O
a
H2O
R'
O
O Os
O N N R"
R X
O
Os N X
OL
b
O
L
L = DHQ or DHQD
R"
R'
NaNCl
X
R'
O
O Os
O L N R"
d R
R'
O
O Os
O L N R"
R
c
Scheme 18
1.1.5 Reaction with Alkynes
Alkynes react with OsO4 in the presence of tertiary amines such as pyridine to give osmium(VI)
ester complexes, which on hydrolysis with sodium sulfite yield the corresponding carbonyl
compounds (Scheme 19-20). In the case of terminal alkynes, carboxylic acids are obtained
(Scheme 21)
OsO4
R
R
Pyridine
O O
Os
Py O O
R
Py
O
O Py
Os
O
R
Scheme 19
10
O Py
Na2SO3
RCOCOR
Module I
Oxidation Reactions
O
OsO4, KClO3
Ph
Ph
Ph
Ph
aqueous acetone/t-BuOH
O
HO
Me
OsO4, KClO3
Me
OH
water-Et2O
OH O
Me
Me
O
OH
Scheme 20
H
H
O
OsO4, KClO3
O
OH
water-Et2O
Scheme 21
Examples:
O
O
AD
O
(DHQD)2-PYDZ
MeO
OH
O
MeO
OH
Yield: 99%
ee : 98%
E. J. Corey, A. Guzman-Perez, M. C. Noe, J. Am. Chem. Soc. 1995, 117, 10805.
O
O
(DHQD)2PYDZ
K2CO3, K3Fe(CN)6
OMe
TBHP
HO
Me
OMe
OH
Me
Yield: 86%
ee : 98%
A. Guzman-Perez, E. J. Corey, Tetrahedron Lett. 1997, 38. 5941.
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Oxidation Reactions
Problems
Give the major products for the following reactions:
OsO4
1.
MeO2C
NaIO4
A
B + C
OsO4, NMO
2.
MeO2C
O
H O
NCOPh
3.
H
4.
D
t-BuOH:H2O
Ph
E
H
O
Ph
OsO4, DHQD
NMO
t-BuOH:H2O
OsO4, DHQ
O
5.
OsO4
Ba(OH).8H2O
G
NMO
t-BuOH:H2O
O
K2OsO2(OH)4
O
6. Ph
F
OCH3
(DHQD)2PHAL
TsNClNa 3H2O
t-BuOH:H2O
R.T.
K2OsO2(OH)4
(DHQ)2PHAL
7.
TsNClNa 3H2O
t-BuOH:H2O
R.T.
Text Book
J. Clayden, N. Creeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University
Press, New York, 2001.
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Oxidation Reactions
13