Module I
Oxidation Reactions
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,
187
Os,
188
Os,
189
Os,
190
Os, 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:
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 OsO
4
-catalzyed reactions are more valuable (Scheme 1).
OsO
4
vapours are poisonous and result in damage to the respiratory tract and temporary damage to the eyes. Use OsO
4
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
OsO
4
Na
2
SO
3
Et
2
O, 24 h
OsO
4
Na
2
SO
3
Et
2
O, 24 h
Scheme 1
OH
OH
OH
1

Module I Oxidation Reactions
The use of tertiary amine such as triethyl amine or pyridine enhances the rate of reaction
(Scheme 2).
OH
OsO
4
, Pyridine
K
2
CO
3
, KOH
Et
2
O, 30 min
OH
Scheme 2
Catalytic amount of OsO
4
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 -methylmorpholineN -oxide, molecular oxygen, sodium periodate and sodium hypochlorite, have been found to be effective
(Scheme 3-7).
O
Me
HO
2
C
Me
CO
2
H
OsO
4
, H
2
O
2 tert-BuOH, 12 h, rt
Me
C
8
H
17
OsO
4
, H
2
O
2 tert-BuOH, 24 h, rt
HO
HO
2
C
Me
OH
CO
2
H
Me
C
8
H
17
O
HO
OH
Scheme 3
Me
Ph
Me
OsO
4
, t-BuOOH t-BuOH, Et
4
NOH
OsO
4
, t-BuOOH t-BuOH, Et
4
NOH
Me
Me
Ph OH OH
OH
OH
Me
Scheme 4
2

Module I Oxidation Reactions
Me
O
OH
OsO
4
, NaClO
3
H
2
O, 50 °C
OsO
4
, AgClO
3
H
2
O, 0 °C
HO
OH
OH
OH
CO
CO
2
2
Me
H
H
OAc
OsO
4
, Ba(ClO
3
)
2
H
2
O, 5 h
H
Me
CO
2
Me
Me
OH
HO
HO
H
CO
2
H
OAc
O
H
CO
2
Me
Me
CO
2
Me
Me
CO
2
H
CO
2
H
OsO
4
, KClO
3
H
2
O, 50 °C
HO
HO
Me
CO
2
H
CO
2
H
Scheme 5
O
MeO
2
C
Me
CO
2
H
CO
2
H
AcO
Me
Me
OsO
4
, NMO aqueous acetone
t-BuOH
OsO
4
, NMO aqueous acetone
t-BuOH
MeO
2
C
HO
HO
Me
Me
CO
2
H
CO
2
H
AcO
Me
OH
OH
O
Scheme 6
3

Module I Oxidation Reactions
O O
OsO
4
, NaIO
4 aqueous acetone
AcO AcO
Me
O
Me
Me
Me
O
O
Me
H
O
Me
OsO
4
, NaIO
4 dioxane-water
Me
Me
O
O
Me
H
O
Me
Scheme 7
O
In the latter case, the resultant diols undergo oxidative cleavage to give aldehydes or ketones.
This reaction is known as Lemieux-Johnson Oxidation . NaIO
4
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 NaIO
4
to give the dicarbonyl compounds (Scheme 9).
OsO
4
+
OsO
4 addition to double bond
O
O
Os
O
O osmate ester
NaIO
4 oxidative cleavage
OHC
CHO
Scheme 9
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.
4

Module I
O
O
Os
O
O
+ R
O
Os
O
O
O
+ L*
Oxidation Reactions
O
Os
O
O
L*
O
R
O
O
Os
O
O
R
R
O
O
Os
O
L*
O
R
OH
OH
Unligated Pathway
Racemic Product
R
OH
OH
Ligand Accelerated Pathway
Optically Active Product
Scheme 10
Et
N
MeO
H
O
N
Dihydroquinoline
DHQ
R
Et
N
R O
H
OMe
R = acyl, aryl
N
Dihydroquinidine
DHQD
DHQD

Attack
R s
R
L

Attack
DHQ
R
M
OsO
4 t-BuOH:H
2
O, oxidant
DHQD
DHQ
R s
R
L
OHOH
R
M
R s
R
L
R
OHOH
M
R
L
= larger substituent
R s
= smaller substituent
R
M
= 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).
5

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 O
AD-mix
 t-BuOH-H
2
O HO
O O
Me
OH
Me
Me
H
Me
AD-mix
 t-BuOH-H
2
O
Me
H
Me
OH
OH
Me Me
Me
H
Me
AD-mix
 t-BuOH-H
2
O
Me
H
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
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 OsO
4
. In this process, alkene reacts with chloroamine in the presence of OsO
4
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.
6

Module I
R R'
K
2
OsO
2
(OH)
4
Ts-N(Na)Cl, H
2
O-t-BuOH
TsHN
R
K
2
OsO
2
(OH)
4
Ts-N(Na)Cl, H
2
O-t-BuOH
Scheme 13
Oxidation Reactions
R'
OH
Na/liq. NH
3
OH Na/liq. NH
3
H
2
N
R
R'
OH
OH
NHTs
NH
2
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
O
Os
O
NX
+
R
R O
R
O Os
O
N
X
R
Scheme 14
R
O
O Os
O
NX
R H
2
O
R
HO
XHN
R
The asymmetric cis -1,2-aminohydroxylation of alkenes with chloroamine has been explored using the chiral osmium catalyst derived from OsO
4
and cinchona alkaloids, dihydroquinidine ligands (DHQD)
2
-PHAL and dihydroquinine ligands (DHQ)
2
-PHAL.
Et
N
O R
H
MeO
N
Dihydroquinoline
DHQ
Et
R O
N
H
OMe
R =
*Ak-O
N N
O-Ak*
N
Dihydroquinidine
DHQD
Phtholazine (PHAL)
7

Module I Oxidation Reactions
The face selectivity for the aminohydroxylation can too be reliably predicted (Scheme 15).
(DHQD)
2
-PHAL
Top (

) Attacl
(DHQD)
2
-PHAL
HNX OH
R s
R
L
R
M
+ R s
R
L
OH NHX
R
M
R s
R
L
R
M
Bottom (

) Attack
(DHQ)
2
-PHAL
N-Source: XNClNa
O-source: H
2
O
Catalyst:
OsO
4
R
L
R s R
M
+
(DHQ)
2
-PHAL
R
L
= larger substituent
R s
= smaller substituent
R
M
= medium substituent
X = SO
2
HNX OH
R, ROCO
R
L
R s
R
M
OH NHX
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).
Ph
O
OMe p-TolSO
2
NClNa
OsO
4
, H
2
O
NHX O OH O
DHQD
Ph
OH
OMe
+ Ph
NHX
OMe
X = p -TolSO
2
DHQ
Ph
NHX O
OH
OMe +
Ph
OH O
NHX
OMe
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):
8

Module I
Ph
Ph
Ph
Oxidation Reactions
O
OCH
3
K
2
OsO
2
(OH)
4
(DHQ)
2
PHAL
TsNClNa 3H
2
O t-BuOH:H
2
O
R.T.
TsHN O
Ph
OH
69% yield
82% ee
OCH
3
O
OCH
3
K
2
OsO
2
(OH)
4
EtO
2
CHN
(DHQ)
2
PHAL
Ph
EtO
2
CNClNa n-PrOH:H
2
O
R.T.
OH
O
78% yield
99% ee
OCH
3
O
O i
Pr
K
2
OsO
2
(OH)
4
(DHQ)
2
PHAL
AcNHBr/LiOH t-BuOH:H
2
O
4
o
C
AcHN O
Ph
OH
>77% yield
99% ee
O i
Pr
Scheme 17
Mechanism
OsO
4
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.
9

Module I Oxidation Reactions
K
2
OsO
2
(OH)
4
+ NaNCl
X
R'
HO
H
2
O
R"
NH
X
O
O Os
O a
N R
L
R'
O
O
Os
O
N N
R
X
R"
L
O
O
O
Os
L b
N X
L = DHQ or DHQD
R"
R'
NaNCl
X
R'
O
O
Os
O
L
N d
R
R"
O
O
O
Os
L
R'
N R"
R c
Scheme 18
Alkynes react with OsO
4
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)
R R
OsO
4
Pyridine
O
Py
Os
O
R
Py O O
R
O
O
O
Os
O
Py
Py
Na
2
SO
3
RCOCOR
Scheme 19
10

Module I
Ph
HO
Me
H
Oxidation Reactions
OsO
4
, KClO
3
Ph aqueous acetone/t-BuOH
Me
OH
OsO
4
, KClO
3 water-Et
2
O
Ph
O
Ph
O
Me
OH O
O OH
Me
Scheme 20
O
H
OsO
4
, KClO
3 water-Et
2
O
O
OH
Scheme 21
O O
O
AD
O
OH
MeO
(DHQD)2-PYDZ MeO OH
Yield: 99% ee : 98%
E. J. Corey, A. Guzman-Perez, M. C. Noe, J. Am. Chem. Soc. 1995, 117, 10805.
Me
O
O
OMe
(DHQD)
2
PYDZ
K
2
CO
3
, K
3
Fe(CN)
6
HO
TBHP
Me OH
Yield: 86% ee : 98%
OMe
A.
Guzman-Perez, E. J. Corey, Tetrahedron Lett. 1997, 38. 5941.
11

Module I
Give the major products for the following reactions:
1.
OsO
4
A
NaIO
4
B + C
Oxidation Reactions
4.
2.
3.
MeO
2
C
OsO
4
, NMO
MeO
2
C
H
O
NCOPh
OsO
4 t-BuOH:H
2
O
H
O
OsO
4
, DHQD
Ph
Ph
NMO t-BuOH:H
2
O
D
O
H
E
5.
6.
Ph
7.
O
O
OsO
4
, DHQ
NMO t-BuOH:H
2
O
F
Ba(OH) 8H
2
O
G
O
OCH
3
K
2
OsO
2
(OH)
4
(DHQD)
2
PHAL
TsNClNa 3H
2
O t-BuOH:H
2
O
R.T.
K
2
OsO
2
(OH)
4
(DHQ)
2
PHAL
TsNClNa 3H
2
O t-BuOH:H
2
O
R.T.
J.
Clayden, N. Creeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University
Press, New York, 2001.
12

Module I Oxidation Reactions
13