OXIDATIONS 5

Oxidations
Carey & Sundberg: Chapter 12 problems: 1a,c,e,g,n,o,q; 2a,b,c,f,g,j,k; 5; 9 a,c,d,e,f,l,m,n; 13
Smith: Chapter 3 March: Chapter 19

I. Metal Based Reagents

1. Chromium Reagents
2. Manganese Rgts.
3. Silver
4. Ruthenium
5. other metals
II Non-Metal Based Reagents
1. Activated DMSO
2. Peroxides and Peracids
3. Oxygen/ ozone
4. others
III. Epoxidations

Metal Based Reagents

Chromium Reagents
- Cr(VI) based
- exact stucture depends on solvent and pH
- Mechanism: formation of chromate ester intermediate
Westheimer et al. Chem Rev. 1949, 45, 419 JACS 1951, 73, 65.
HO
HCrO4 - O- R
R Cr
R2CH-OH C O O-
O + HCrO3- + H+
H+ R R
H
+ H2O

Jones Reagent (H 2CrO4, H2Cr2O7, K2Cr2O7)

J. Chem. Soc. 1946 39
Org. Syn. Col. Vol. V, 1973, 310.
- CrO3 + H2O → H2CrO4 (aqueous solution)
K2Cr2O7 + K2SO4
- Cr(VI) → Cr(III)
(black) (green)

- 2°- alcohols are oxidized to ketones

Jones
reagent R
R2CH-OH O
acetone R

- saturated 1° alcohols are oxidized to carboxylic acids.

Jones Jones
reagent O HO OH O
hydration reagent
RCH2-OH
acetone R H R H acetone R OH

- Acidic media!! Not a good method for H+ sensitive groups and compounds
 OXIDATIONS 6
1) Jones, SePh
SePh acetone
CO 2CH 3
OH 2) CH2N2
Me 3Si Me 3Si
JACS 1982, 104, 5558
H17C 8 H17C 8
O O
OH O
Jones

O acetone O
JACS 1975, 97, 2870
O O

Collins Oxidation (CrO3•2pyridine)

TL 1969, 3363
- CrO3 (anhydrous) + pyridine (anhydrous) → CrO 3•2pyridine↓
- 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH 2Cl2)
without over-oxidation
- Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent
often leads to improved yields.
- Useful for the oxidation of H+ sensitive cmpds.
- not particularly basic or acidic
- must use a large excess of the rgt.

CrO3•(C 5H5N)2 H
OH CH 2Cl 2 JACS 1969, 91, 44318.
O
ArO O
ArO O
O
O

CrO3 catalyzed (1-2 mol % oxidation with NaIO6 (2.5 equiv) as the reozidant in wet aceteonitrile.
oxidized primary alcohols to carboxylic acids.
Tetrahedron Lett. 1998, 39, 5323.

Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation)

TL 1975 2647
Synthesis 1982, 245 (review)
CrO3 + 6M HCl + pyridine → pyH+CrO3 Cl- ↓
- Reagent can be used in close to stoichiometric amounts w/ substrate
- PCC is slighly acidic but can be buffered w/ NaOAc

PCC, CH 2Cl 2

OHC
HO JACS 1977, 99, 3864.

O
O
PCC, CH 2Cl 2
CHO
O
O OH TL, 1975, 2647
 OXIDATIONS 7
- Oxidative Rearrangements
Me OH
Me
PCC, CH 2Cl 2
JOC 1977, 42, 682
O
Me
Me

PCC, CH 2Cl 2
JOC 1976, 41, 380
OH O

- Oxidation of Active Methylene Groups

PCC, CH 2Cl 2

O O O
JOC 1984, 49, 1647

PCC, CH 2Cl 2
O O

- PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole

JOC 1984, 49, 550.

NH NH
N N

- selective oxidation of allylic alcohols

OH
OH

PCC, CH 2Cl 2

H H 3,5-dimethyl
pyrazole H H
HO
O
(87%)

Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation)

TL 1979, 399
- Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓

PDC PDC
CHO CH 2Cl 2 DMF CO 2H
OH

1° alcohol

-allylic alcohols are oxidized to α,β-unsaturated aldehydes

 OXIDATIONS 8
- Supported Reagents Comprehensive Organic Synthesis 1991, 7, 839.
PCC on alumina : Synthesis 1980, 223.
- improved yields due to simplified work-up.
PCC on polyvinylpyridine : JOC, 1978, 43, 2618.
CH 2 CH CH 2 CH R2CH-OH R2C=O CH 2 CH
cross-link CrO3, HCl partially
spent
N N N N reagent
Cr(VI)O3 •HCl Cr(III)

to remove Cr(III)
1) HCl wash
2) KOH wash
3) H2O wash

CrO3/Et2O/CH2Cl2/Celite
Synthesis 1979, 815.
- CrO3 in non-aqueous media does not oxidized alcohols
- CrO3 in 1:3 Et2O/CH2Cl2/celite will oxidized alcohols to ketone and aldehydes

C 8H17 C 8H17
CrO3
Et2O/CH 2Cl 2/celite

(69%)

HO O Synthesis 1979, 815

H2CrO7 on Silica
- 10% CrO3 to SiO2
- 2-3g H2CrO3/SiO2 to mole of R-OH
- ether is the solvent of choice

Manganese Reagents
Potassium Permanganate KMnO4/18-Crown-6 (purple benzene)
JACS 1972 94, 4024.
O
O O
K+ MnO 4-
O O
O

- 1° alcohols and aldehydes are oxidized to carboxylic acids

- 1:1 dicyclohexyl-18-C-6 and KMnO4 in benzene at 25°C gives a clear purple solution as high
as 0.06M in KMnO4.
O

JACS 1972, 94, 4024

CO 2H

CHO
Synthesis 1984, 43
CL 1979, 443

CHO
 OXIDATIONS 9
Sodium Permanganate
TL 1981, 1655
- heterogeneous reaction in benzene
- 1° alcohols are oxidized to acids
- 2° alcohols are oxidized to ketones
- multiple bonds are not oxidized
Barium Permanganate (BaMnO4)
TL 1978, 839.
- Oxidation if 1° and 2° alcohols to aldehydes and ketones- No over oxidation
- Multiple bonds are not oxidized
- similar in reactivity to MnO2
Barium Manganate
BCSJ 1983, 56, 914

Manganese Dioxide
Review: Synthesis 1976, 65, 133
- Selective oxidation of α,β-unsatutrated (allylic, benzylic, acetylenic) alcohols.
- Activity of MnO2 depends on method of preparation and choice of solvent
- cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double
bond.
OH OH
HO HO
MnO 2, CHCl3

(62%) J. Chem. Soc. 1953, 2189

JACS 1955, 77, 4145.
HO O

- oxidation of 1° allylic alcohols to α,β-unsaturated esters

MnO2,
OH ROH, NaCN
CO 2R

OH CO 2Me
MnO 2, Hexanes JACS1968, 90, 5616. 5618
MeOH, NaCN

Manganese (III) Acetate α-hydroxylation of enones

Synthesis 1990, 1119 TL 1984 25, 5839
O O
Mn(OAc)3, AcOH AcO

Ruthenium Reagents
Ruthenium Tetroxide
- effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones
- oxidizes multiple bonds and 1,2-diols.
 OXIDATIONS 10
RuO4, NaIO4 CO 2H
Ph OH Ph
O CCl 4, H2O, CH3CN O
JOC 1981, 46, 3936
OH
RuO4, NaIO4
Ph OH Ph CO 2H
CCl 4, H2O, CH3CN
H CH 3 H CH 3 94%ee
96% ee

HO
RuO2, NaIO4 O
TL 1970, 4003
CCl 4, H2O
O O
O O

Tetra-n-propylammonium Perruthenate (TPAP, nPr4N+ RuO4-)

Aldrichimica Acta 1990, 23, 13.
Synthesis 1994, 639
- mild oxidation of alcohols to ketones and aldehydes without over oxidation

OH O
TPAP
MeO 2C MeO 2C
OSiMe 2tBu O OSiMe 2tBu

N+ TL 1989, 30, 433

-O Me

(Ph3P)4RuO2Cl3 RuO2(bipy)Cl2
- oxidizes a wide range of 1°- and 2°-alcohols to aldehydes and ketones without oxidation of
multiple bonds.
OH
CHO
CHO
OH JCS P1 1984, 681.

H H

Ba[Ru(OH)2O3]
-oxidizes only the most reactive alcohols (benzylic and allylic)
(Ph3P)3RuCl2 + Me3SiO-OSiMe3
- oxidation of benzylic and allylic alcohols TL 1983, 24, 2185.

Silver Reagents
Ag2CO3 ( Fetizon Oxidation) also Ag2CO3/celite Synthesis 1979, 401
- oxidation of only the most reactive hydroxyl

O O
OH Ag 2CO 3 O

OH OH JACS 1981, 103, 1864.

mechanism: TL 1972, 4445.
O
O OH Ag 2CO 3, C 6H6 O
OH O
O O
 OXIDATIONS 11
- Oxidation of 2° alcohol over a 1° alcohol
OH Ag2CO3, Celite OH
JCS,CC 1969, 1102
OH (80%) O
Silver Oxide (AgO2)
- mild oxidation of aldehyde to carboxylic acids
AgO 2, NaOH RCO 2H
RCHO

CO 2H
CHO AgO 2

JACS 1982, 104, 5557

Ph
Ph

Prevost Reaction Ag(PhCO2)2, I2

Ag(PhCO 2)2, I2 AcO OAc

AcOH

Ag(PhCO 2)2, I2 AcO OH

AcOH, H 2O

Other Metal Based Oxidations

Osmium Tetroxide OsO 4
review: Chem. Rev. 1980, 80, 187.
-cis hydroxylation of olefins
old mechanism:

OsO 4, NMO O O OH
Os
O O OH

osmate ester
intermediate cis stereochemistry

- use of R 3N-O as a reoxidant

TL 1976, 1973.

OsO 4, NMO O OH
O
O OH
O OH
OH
TL 1983, 24, 2943, 3947
Stereoselectivity: OsO 4

R2 R3 HO H
OsO 4, NMO R2 HO
R4 R3
RO H RO H R4
 OXIDATIONS 12
- new mechanism: reaction is accelerated in the presences of an 3° amine
R1 R1
O
O O R1 R3N R2
R2 O
Os R2 O
O Os Os O
O O [2+2] O
O O NR3
[O]

[3+2] R1 OsO2
[O]
R2
O hydrolysis R1 R2
O
Os O
O + OsO4
O HO OH
- Oxidative cleavage of olefins to carboxylic acids.
JOC 1956, 21, 478.
- Oxidative cleavage of olefins to ketones & aldehydes.
OH

CHO
OH O
OsO 4, NMO NaIO4 CHO H2O
O OH O O
O O
O O
O O
OAc OAc
OAc
JACS 1984, 105, 6755.

Substrate directed hydroxylations: Chem. Rev. 1993, 93, 1307

-by hydroxyl groups
HO HO
OsO4,
O HO HO
pyridine
O + O
HO
HO HO
3:1

HO
OsO4, HO
O pyridine O
TMSO
TMSO

HO CH3 HO CH3 OH HO CH3 OH

OsO4, Et2O
OH + OH

CH3 CH3 (86 : 14) CH3

- by amides
AcO AcO
OH
MeS MeS
OsO4
OH
HN HN
O O

OAc OAc
 OXIDATIONS 13
- by sulfoxides
•• O OMe •• O OMe OH
S OsO4 S

OH
(2 : 1)

••
O OAc

••
1) OsO4 O
S 2) Ac2O S

HN O AcO HN O

(20 : 1)
- by sulfoximines
O O
Ph S Ph S O
OH OH
MeN OsO4, R3NO MeN ∆ OH
OH
OH OH
CH3
Raney nickel

H 3C OH
OH
OH
CH3
- By nitro groups
PhO2S N
PhO2S N 1) OsO4 NHR
+ N
N NHR 2) acetone, H O2N
O2N N N
N N O O

N
N HO N NHR
HO N NHR
N N
N N O O

- OsO4 bis-hydroxylation favors electon rich C=C.

OsO4
X + X
X OH OH
OH OH

X= OH 80 : 20 (directing effect ?)
= OMe 98 : 2
= OAc 99 : 1
= NHSO2R 60 : 40 (directing effect ?)
- Ligand effect:
OsO4
X + OH
OH K3Fe(CN)6, K2CO3 OH OH
MeSO2NH2, tBuOH/H2O OH OH

OsO4 (no ligand) 4:1

Quinuclidine 9:1
DHQD-PHAL > 49 : 1
 OXIDATIONS 14
Sharpless Asymmetric Dihydroxylation (AD) Chem. Rev. 1994, 94, 2483.
- Ligand pair are really diastereomers!!
dihydroquinidine ester

N
"HO OH" Ar
H
H OR'
R3 R3 OH
R2 0.2-0.4% OsO4
R2 80-95 % yield
R1 20-80 % ee
acetone, H 2O, MNO
R1 OH
H OR'

"HO OH" Ar
MeO
N Ar =
dihydroquinine ester
N
R'= p-chlorobenzoyl
Mechanism of AD:
L
HO OH

O
O O
H 2O Os
O O

O
O O
Os
O O
First Cycle Second Cycle
(high enantioselectivity) [O] (low enantioselectivity) [O]
O
O
O Os
O O
O
L Os
O O
L

O
O O
Os
O O
O

R 3N HO OH

H 2O, L
- K3Fe(CN)6 as a reoxidant gives higher ee's- eliminates second cycle
TL 1990, 31, 2999.
- Sulfonamide effect: addition of MeSO2NH2 enhances hydrolysis of Os(VI) glycolate
(accelerates reaction)
- New phthalazine (PHAL) ligand's give higher ee's
N Et
Et N
Et N Et
N N
N N N
O O
H H O O
OMe H H
MeO
MeO OMe

N N
N N
(DHQD)2-PHAL (DHQ)2-PHAL
JOC 1992, 57, 2768.
 OXIDATIONS 15
- Other second generation ligands
N Et Et
Et Ph N N
O O N O
H H H
MeO N N OMe O OMe

Ph
N N N
PYR IND

Proposed catalyst structure:

"Bystander
quinoline
O Os Asymmetric
O H N (side wall)
MeO N Binding
O Os Cleft
O
N
H
H N
N N
O N
O

Phthalazine
OMe Floor
N

OMe
OMe

Corey Model: JACS 1996, 118, 319 O N

Enzyme like binding pocket; O
O
[3+2] addition of OsO4 to olefin. Os O N H
N O N N
O O N

DHQL

Rs RM RL large and flat,

i.e Aromatics work particularly well
RL H

DHQ
 OXIDATIONS 16
Olefin Preferred Ligand ee's

R1 PYR, PHAL 30 - 97 %

R2

R1 PHAL 70 - 97 %

R1
IND 20 - 80 %
R2

R2
R1 PHAL 90 - 99.8 %

R2
R3
R1 PHAL 90 - 99 %
H

R2
R3 PHAL, PYR 20 - 97 %
R1
+ MeSO2NH2
R4

"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant

AD-mix α (DHQ)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C)
AD-mix β (DHQD)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4

O
HO
O
Campthothecin
N
N
O

OMe OMe OMe

AD
N O (DHQD)2PYR N O N O

94 % ee OH O
OH OH

- Kinetic resolution (not as good as Sharpless asymmetric epoxidation)

H Ph
Ph H olefins with axial
dissymmetry
tBu tBu

H H
Ph Ph
AD mix α Ph OH
OH
30% conversion
OH H
+ +
Ph OH
tBu H tBu
tBu (4 : 1) tBu

enriched
 OXIDATIONS 17
Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813,
preparation of α-aminoalcohols from olefin. Syn addition as with the dihydroxylation
regiochemistry can be a problem

O O
Cl OH
Ph O N CO2Me
Na Ph O NH Ph
CO2Me +
Ph CO2Me N O Ph
K2OsO6H4 (cat) Ph
Ligand OH O
Ligand= PHAL 4:1
AQN 1:4

Molybdenum Reagents
MoOPH [MoO5•pyridine (HMPA)]
JOC 1978, 43, 188.
- α-hydroxylation of ketone, ester and lactone enolates.

O O
O- O O THF, -78°C
+ Mo R'
R' O R
R O
L L OH

Palladium Reagents
Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates (Tsuji Oxidation)
Tetrahedron 1986, 42, 4361
O
R O 2 CO R R R
OH Pd(0)
H O O O Pd O
H - CO 2 H
R Pd(OAc) 2, R - R
R
CH 3CN, 80° C TL 1984, 25, 2791
Tetrahedron 1987, 43, 3903

HO
H HO
OH O CO H
2 OH

Pd2(DBA) 3•CHCl 3, JACS 1989, 111, 8039.

H O OH
CH 3CN, 80° C H O O

Oxidation of silylenol ethers and enol carbonates to enones

O OTMS Pd(OAc) 2, O
CH 3CN

O O Pd(OAc) 2, O
CH 3CN

OTIPS O
(NH 4)2Ce(NO 3)6
DMF, 0°C
Ph Ph TL 1995, 36, 3985
 OXIDATIONS 18
Oppenauer Oxidation Synthesis 1994, 1007 Organic reactions 1951, 6, 207
OiPr R1R2CHOH OiPr O
+O Al H +O Al + Al(OiPr)3
OiPr (CH3)2C=O R1 R2
R1 O OiPr
R2
Nickel Peroxide
Chem Rev. 1975, 75, 491
Thallium Nitrate (TNN, Tl(NO 3)3•3H2O
Pure Appl. Chem. 1875, 43, 463.
Lead Tetraacetrate Pb(OAc)4 Oxidations in Organic Chemistry (D), 1982, pp 1-145.

Non-Metal Based Reagents

Activated DMSO Review: Synthesis 1981, 165; 1990, 857. Organic Reactions 1990, 39, 297
Me Me
Me E Nu: +
S+ O- + E S+ O Nu S + E-O
Me Me Me
E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F 3CSO2H,
PO5, H3PO4, Br2
Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, enols
Swern Oxidation
- trifluoroacetic anhydride can be used as the activating agent for DMSO
O
Me Me Me
(COCl) 2 Cl -CO, -CO 2
S + O- S+ O Cl - S + Cl
CH 2Cl 2, -78°C Me
Me Me O

R Me
R2CH-OH Me R Et3N: R
S+ O O + S
Me R Me
H
B:
O O
Cl
DMSO, (COCl) 2
TL 1988, 29, 49.
CH 2Cl 2, Et3N
OH O
Moffatt Oxidation (DMSO/DCC) JACS 1965, 87, 5661, 5670.
Me C 6H11 Me R
S + O- CF 3CO 2H, R R
Me NH S+ O
Pyridine R2CH-OH O
Me S +
O C Me
H
+ N R
Me
C 6H11 N C N C 6H11 C 6H11 B:

CHO
OH DCC/ DMSO
JACS 1978, 100, 5565
CO 2Me CO 2Me
CF 3CO 2H,
O Pyridine O
S S

SO3/Pyridine JACS 1967, 89, 5505.

CO 2Me CO 2Me
HO OH HO H
H
SO 3, pyridine,
DMSO, CH 2Cl 2 CONH 2
CONH 2
JACS 1989, 111, 8039.
O
H OH H
HO
 OXIDATIONS 19
Corey-Kim Oxidation (DMS/NCS) JACS 1972, 94, 7586.
O
Me Me
S: + N Cl S + Cl
Me Me
O
N-Chlorosuccinimide
(NCS)
Oxygen & Ozone
Singlet Oxygen Acc. Chem. Res. 1980, 13, 419 Tetrahedron 1981, 37, 1825
•• •• hν

••

••
•O O • O O
•• ••

••
••
triplet singlet

H "ene" reaction H Ph3P:

O
O O OH
O
Tetrahedron 1981, 1825

1) O2, hν, Ph2CO HO

2) reduction

Ozone Comprehensive Organic Synthesis 1991, 7, 541

O O
O 3, CH 2Cl 2 O O Ph3P: O + O
-78°C O O NaBH 4

H
Jones OH

RCOOH

Other Oxidations
Mukaiyama Oxidation BCSJ 1977, 50, 2773
O
N N
N N
R PrMgBr R R
O
CH OH CH O MgBr O
R THF R
R

OH
OHC
Cl CH 3 O Cl CH 3 O
O O
MeO NH MeO NH
O N N N N O
OEt OEt
O O
tBuMgBr, THF
SEt (70%) SEt
SEt SEt
MeO MeO

JACS 1979, 101, 7104

 OXIDATIONS 20
OH O
tBuMgBr, THF

O
N N
N N
O O O

Dess-Martin Periodinane JOC 1983, 48, 4155. JACS 1992, 113, 7277.
- oxidation conducted in CHCl3, CH3CN or CH2Cl2
- excellent reagent for hindered alcohols
- very mild
AcO OAc OAc

I R I
••
R2CH-OH
OAc O + O + 2 AcOH
O
R
O O

Dess-Martin O
HO JOC 1991, 56, 6264
(99%)
RO
RO
Chlorite Ion
-oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids.
Tetrahedron 1981, 37, 2091

NaClO 2, - HClO2
NaH2PO 4
tBuOH, H 2O OBn OBn
OBn
OH
CHO H CO 2H
-O-Cl-O

Selenium Dioxide
- Similar to singlet oxygen (allylic oxidation)
1) SeO2
2) NaBH 4
OAc
OAc

OH
Phenyl Selenium Chloride
O O Ph O
OLi
SePh Se
PhSeCl H2O 2 - PhSeOH
O-
THF
H
- PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a
selenoxide elinimation.

Peroxides & Peracids

- R3N: → R3N-O
- sulfides → sulfoxides → sulfones
-Baeyer-Villiger Oxidation- oxidation of ketones to esters and lactones via oxygen insertion
Organic Reactions 1993, 43, 251 Comprehensive Organic Synthesis 1991, vol 7, 671.
 OXIDATIONS 21
m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide
O H O H
O O 2N O
O O

Cl NO 2
H
O O
O
R1 C R2
R1 R2 R2 + ArCO2H
O R1 O
O
O Ar
HO O Ar
O
- Concerted R-migration and O-O bond breaking. No loss of stereochemistry
- Migratory aptitude roughly follows the ability of the group to stabilize positive charge:
3° > 2° > benzyl = phenyl > 1° >> methyl
JACS 1971, 93, 1491

O O
HO
O
O mCPBA O CO2H
CHO

O O HO CO2H
O HO OH
PGE1
O
O
CH3 mCPBA O Tetrahedron Lett. 1977, 2173
Tetrahedron Lett. 1978, 1385
(80 %) CH3
CH3
CH3

Oxone (postassium peroxymonosulfate) Tetrahedron 1997, 54, 401

oxone
RCHO RCOOH
acetone (aq)

Oxaziridines
reviews: Tetrahedron 1989, 45, 5703; Chem. Rev. 1992, 92, 919
O
R3
N C
R R2
- hydroxylation of enolates
O
_
O O R O
Base R'
R R _ R + PhSO2N=CHPh
R' R' R'
O NSO2Ph
O Ph HO
Ph
N
PhSO2
O By-product
_ supresed by using
O R
R' bulkier oxaziradine
R + PhSO2N=CHPh such as camphor
R' oxaziradine
Ph NHSO2Ph
 OXIDATIONS 22
Asymmetric hydroxylations
O
O
MeO 2C NaN(SiMe3)2, THF HO

MeO 2C Tetrahedron 1991, 47, 173

OMe
OMe
N (67% ee)
Ar SO 2 O
MeO O MeO O O OH O
KN(SiMe3)2 OH
CO2Me CO2Me OH
OH

MeO N MeO MeO O OH OH

SO2 O
(>95% ee)

- hydroxylation of organometallics
R-Li or R-Mg → R-OH JACS 1979, 101, 1044

- Asymmetric oxidation of sulfides to chiral sulfoxides.

JACS 1987, 109, 3370.
Synlett, 1990, 643.

Remote Oxidation (functionalization) Comprehensive Organic Synthesis 1991, 7, 39.

Barton Reaction

NOCl, CH2Cl2
pyridine hν
- NO
OH O • O
NO • OH
H •

•NO JACS 1975, 97, 430

OH OH
NO N N

HO perhydrohistricotoxin
ketone C5H11
oxidation state

Epoxidations
Peroxides & Peracids
- olefins → epoxides Tetrahedron 1976, 32, 2855
- α,β-unsaturated ketones, aldehydes and ester → α,β-epoxy- ketones, aldehydes and esters
(under basic conditions).
O O
tBuOOH
triton B, C6H6
O JACS 1958, 80, 3845
(CH 2)n (CH 2)n
 OXIDATIONS 23
CO 2Me O CO 2Me

mCPBA, NaHPO3
TL 1988, 23, 2793

O O
H H

O O

Henbest Epoxidation- epoxidation directed by a polar group

OH OH OH

mCPBA
O + O

10:1 diastereoselection
OAc OAc OH

mCPBA
O + O

1:4 diastereoselection
O O
Ph NH
Ph NH
mCPBA "highly selective"
O

Ar

O O
H proposed transition state:
O -OH directs the epoxidation
H
O

- for acyclic systems, the Henbest epoxidation is often less selective

Rubottom Oxidation: JOC 1978, 43, 1588

O OTMS TMSO O
O H2O
LDA, TMSCl OH
mCPBA

Sharpless Epoxidation tBuOOH w/ VO(acac)2, Mo(CO)6 or Ti(OR) 4

Reviews: Comprehensive Organic Synthesis 1991, vol 7, 389-438
Asymmetric Synthesis 1985, vol. 15, 247-308
Synthesis, 1986, 89. Org. React. 1996, 48, 1-299.
Aldrichimica Acta 1979, 12, 63
review on transition mediated epoxidations: Chem. Rev. 1989, 89, 431.
- Regioselective epoxidation of allylic and homo-allylic alcohols
- will not epoxidize isolated double bonds
- epoxidation occurs stereoselectively w/ respect to the alcohol.
 OXIDATIONS 24
- Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4
- Oxidant: tBuOOH; PhC(CH3)2OOH
VO(acac)2
tBuOOH
OH OH
O

OH OH

O
(CH2)n (CH2)n

ring size VO(acac)2 MoO2(acac)2 mCPBA

5 >99% -- 84
6 >99 98 95
7 >99 95 61
8 97 42 <1
9 91 3 <1

Acyclic Systems:
tBu
O R1
L M
L R3 Rt
1,3-interaction O
O
R3 Rc
Rt
R2 O
R1 Rc O
A1,2-strain
M
O
R2 L
A1,3-strain L

Major influences:
A1,2-Strain between Rg and R1 (Rg and R2)
A1,3 -strain between R2 and Rc (R1 and Rc)
1,3-interactions between L and R1 (L and R2)

VO(acac)2,
tBuOOH
O
+ O
OH OH OH
(4 : 1)

tBu
CH3 H L O
H M
H O O L O
M L O H
L H 3C
O H
tBu
H
 OXIDATIONS 25
VO(acac)2,
tBuOOH
O
+ O
OH OH OH
(19 : 1)

tBu H
O H 3C H
L
M H
L O H 3C O O
H 3C O H M L
H H L
O
tBu
CH3

SiMe3 SiMe3 SiMe3

VO(acac)2,
tBuOOH
O
+ O
OH OH OH
(> 99 : 1)

- Careful conformational analysis of acyclic systems is needed.

Homoallylic Systems
L
L
V OtBu
O O O
OH OH

dominent stereocontrol element

Titanium Catalyst structure:

RO2C
OR OR
RO CO2R
Ti O O
Ti
O O O OR

O OR

OR

CO2R CO2R
OR O OR O
RO CO2R RO CO2R
Ti O O O
Ti Ti Ti O
CO2R
O O O O O CO2R
O O O
O O

tBu tBu
OR OR
Disfavored Favored
 OXIDATIONS 26
Asymmetric Epoxidation
tBuOOH, Ti(OiPr), (+) or (-) Diethyl Tartrate, 3Å molecular sieves
Empirical Rule
R1
R2 (+)- DET epoxidation from the bottom
(-)- DET epoxidation from the top
R3 OH

Catalytic system: addition of molecular sieves to "soak" up any water with 3A sieves, 5-10 mol %
catalyst is used.
Preparation of Allylic Alcohols:

[(CH3)2CHCH2]2AlH Na (MeOCH2CH2O)2AlH2
CO2R'
R (DIBAL) R OH
(REDAL)
R CHO R C C CH2OH
R R
[(CH3)2CHCH2]2AlH
CO2R' H2, Lindlar's Catalyst
OH

"In situ" derivatization of water soluble epoxy-alcohol

(-)-DIPT
O
OH

(R)-glycidol
OH water soluble
O
OH
(+)-DIPT
(S)-glycidol
O
O O
O S NO2 organic soluble
OH
O

Alkoxide opening of epoxy-alcohol product

reduced by use of Ti(OtBu)4 and catalytic conditions
O- O
O OH
OH OH
R from R
Ti(OiPr)4

Stoicheometric vs Catalytic epoxidation:

(+)-DET
Ti(OiPr)4
tBuOOH
O
OH OH

stoicheometric: 85% ee
catalytic (6-7 mol %) 47% yield >95% ee
in situ deriv. with PNB 78% yield 92 % ee >98 %ee after 1 recrystallization
(+)-DET
R Ti(OiPr)4 R
tBuOOH
O
OH OH

yields: 50 - 100 %
ee: > 95%
 OXIDATIONS 27
Ring Opening of Epoxy-Alcohols
REDAL OH

R OH
O 1,3-Diol
AE
R OH R OH

R OH
DIBAL
OH
1,2-Diol

Two dimensional amplification

OH OH OH

(+)-DIPT, Ti(OiPr)4,
tBuOOH, 3A sieves +
(90 % ee)

O O
OH OH
OH 95 : 5
major minor

major minor major minor

95 : 5 95 : 5
OH OH
O O OH
O

O O
OH OH O
OH

90 % meso 0.25 %
(>99.5 % ee) 9.75%

Kinetic Resolution of Allylic Alcohols

(+)-DIPT, Ti(OiPr)4,
OH tBuOOH, 3A sieves O
OH + OH
R R R

CO2R
OR
O H
RO CO2R
Ti O
Ti O
O O O CO2R
O
O

tBu
OR
 OXIDATIONS 28
R3 R4 kinetic resolution R3 R4 R3 R4
-20 °C, 0.5 - 6 days O
R2
OH
R2
OH + R2
OH

R1 R1 R1

40 - 50 % yield 40 - 50 % yield
> 99 % ee high ee

Reiterative Approach to the Synthesis of Carbohydrate

OR OR (+)-DET, Ti(OiPr)4,
OR (MeO)2P(O)CH2CO2Me DIBAL tBuOOH, 3A sieves

CHO NaH
OH
CO2Me

OR OR OR OR
HO-
OH OH acetone, H+ O mCPBA, Ac2O
O -
O
OH PhS
HO O Pummerer
SPh SPh
PhS-
CHO
OR OR OR
HO H
O O O
DIBAL HO H

OAc O HO H
O O CHO O
HO H
SPh O CHO CH2OH

L-glucose

Jacobsen Aysmmetric Epoxidation

JACS 1990, 112, 2801; JACS 1991, 113, 7063; JOC 1991, 56, 2296.
- Reaction works best for cis C=C conjugated to an aromatic ring

H H H H
N N NaOCl N N
Mn Mn
O Cl O O O
O

tBu tBu tBu tBu

O 5 mol % Cat. ,NaOCl, O

H2O, CH2Cl2

(98% ee)
O

86% ee

Methyltrioxoruthenium (MTO) Ru(VII)

Sharpless et al. JACS 1997, 117, 7863, 11536.
0.5 mol % MTO Ru (VII),
Ph pyridine, CH2Cl2 Ph
O
1.5 eq. 30% H2O2 (aq.)
 OXIDATIONS 29
Oxaziridines
- Asymmetric epoxidation of olefins Tetrahedron 1989 45 5703
CH3
O2 O
Ph * N S N *
C6F5
Ph *

Dioxiranes (Murray's Reagent) Reviews: Chem. Rev. 1989, 89, 1187; ACR 1989, 27, 205
Org. Syn. 1996, 74, 91
KHSO 5 O
O
"oxone" O
- epoxidation of olefins
OTBS O
OTBS
O
TBSO O TBSO O JOC 1990, 55, 2411
TBSO CH 2Cl 2, acetone TBSO
(100%) O

- Asymmetric epoxidation JACS 1996, 118, 491.

- oxidation of sulfides to sulfoxides and sulfones
- oxidation of amines to amine-N-oxides
- oxidation of aldehydes to carboxylic acids
- hydroxylation of enolates

1) LDA
2) Cp 2TiCl2 OH

H JOC 1994, 59, 2358

O 3) O
O O
- bis-trifluoromethyldioxirane, much more reactive
JACS 1991, 113, 2205.
F3C O

F3C O

- oxidation of alcohols to carbonyl compounds. 1° alcohols give a mixture of aldehydes and

carboxylic acids.
- Insertion into 3° C-H bonds to give R3C-OH

DCC-H2O2 JOC 1998, 63, 2564

R O
N H O
H2O2, MeOH R
R N C N R R + H C H
H C O N N
N O
R R
R