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Advanced organic reactions 2000 warren

SELECTIVITY
SELECTIVITY
Science 1983, 219, 245
Chemoselectivity
preferential reactivity of one functional group (FG) over another
- Chemoselective reduction of C=C over C=O:
H2,
Pd/C

O

O

- Chemoselective reduction of C=O over C=C:
O

OH

NaBH4

O


O

+

NaBH4, CeCl3

OH
only

- Epoxidation:
MCPBA

+
OH

OH

O

O
(2 : 1)

VO(acac)2,
tBuOOH
OH

OH

O

exclusively

Regioselectivity
- Hydration of C=C:
1) B2H6
2) H2O2, NaOH

OH


R

R

OH
R
1) Hg(OAc)2, H2O
2) NaBH4

- Friedel-Crafts Reaction:
O
RCOCl,
AlCl3

R

+

R
O

O
SiMe3

RCOCl,
AlCl3

R

OH

1


SELECTIVITY
- Diels-Alder Reaction:
R

R

O

O

R

+

+
O
major
O

R

minor
O

R

+

+

R

O
minor

major
O

O

+
O

H

OAc

O

O

H

OAc

O

O

OAc

O

O

OAc

OAc

Raney Ni, H2

+
O

H

SPh

O

O

H

O

O

SPh

H

O

Change in mechanism:
SPh
PhSH, H+
R

R

R

SPh

PhSH, (PhCO2)2

Stereochemistry:
Relative stereochemistry: Stereochemical relationship between two or more stereogenic centers
within a molecule

H

H

HO
cholesterol

H
enantiomers
same relative stereochemistry

H
OH

syn: on the same side ( cis)
anti: on the opposite side (trans)
- differences in relative stereochemistry lead to diastereomers.
Diastereomers= stereoisomers which are not mirror images; usually have different physical
properties

2


SELECTIVITY
Absolute Stereochemistry: Absolute stereochemical assignment of each stereocenter (R vs S)
Cahn-Ingold-Prelog Convention (sequence rules)
- differences in absolute stereochemistry (of all stereocenters within the molecule) leads to
enantiomers.
- Reactions can "create" stereocenters
O
Ph

MeMgBr

HO

H

Ph

MeMgBr

CH3
H

H 3C

OH

Ph

H

O

enantiomers
(racemic product)

Ph
H
HO

CH3

Ph

H

MeMgBr

Diastereomeric transition states- not necessarily equal in energy
Me

Me

Me

N

O

Ph

Zn

O

CH3 CH3
Zn

Me
N

O

O
CH3 CH3

H

Zn

H 3C

H

Zn
Ph

H 3C

HO
Ph

CH3

HO

CH3

H

H

Ph

Diastereoselectivity
CH3MgBr
Ph

CH3

Ph

CHO

HO

+

CH3

Ph

H

H OH
anti

syn

Diastereomers

Cram Model (Cram's Rule): empirical
O
O
M
S

R

O

S

M

H 3C
Nu

H

CH3MgBr

CH3MgBr

L
R

L

favored

H
Ph

3


SELECTIVITY

4

Felkin-Ahn Model
S O

O M
L

R

L

Nu

Nu

M R

S

disfavored

favored

Chelation Control Mode
M
OR
O

O
R
S

M

HO

OR

CH3MgBr

CH3MgBr

M

S

favored

Nu

M

R

S

OR

R

HO
TBSO

O

TBSO

MgBr

relative stereochemical control

H O

H O

OBn

OBn

Stereospecific
Stereochemictry of the product is related to the reactant in a mechanistically defined manner; no
other stereochemical outcome is mechanistically possible.
i.e.; SN2 reaction- inversion of configuration is required
Br2

H

H 3C

Br

Br2

H

meso

H
CH3

Br

CH3 Br

+

H
CH3

Br

CH3
H

Br
H

CH3 Br

enantiomers (racemic)

Stereoselective
When more than one stereochemical outcome is possible, but one is formed in excess (even if that
excess is 100:0).
CH3

H2, Pd/C

H
H
α-pinene
O

only isomer
O

O

H

H

O

H

+

CH3
H
not observed
O

O

LDA, CH3I
N

O
S

N

O

+

S

N

O
S

(96 : 4)
Diasteromers

Diastereoselective
Enantiospecific


OXIDATIONS
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
R2CH-OH

HCrO4

-

R
R

H+

Cr

C O

O-

R

O-

O

R

+ HCrO3- +

H+

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
R2CH-OH

Jones
reagent

R

acetone

R

O

- saturated 1° alcohols are oxidized to carboxylic acids.
Jones
reagent
RCH2-OH

acetone

O
R

hydration
H

HO OH

Jones
reagent

R

acetone

H

O
R

OH

- Acidic media!! Not a good method for H+ sensitive groups and compounds

5


OXIDATIONS
1) Jones,
acetone

SePh
OH

6

SePh
CO 2CH 3

2) CH2N2

Me 3Si

Me 3Si
JACS 1982, 104, 5558

H17C 8

H17C 8

O

O

O

OH
Jones
acetone

O

O

O

JACS 1975, 97, 2870

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
OH
ArO

H

CH 2Cl 2

O

O
ArO

O

JACS 1969, 91, 44318.

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
O

PCC, CH 2Cl 2
OH

O

CHO
TL, 1975, 2647


OXIDATIONS
- 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
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

3,5-dimethyl
pyrazole

H

HO

H
O

H
(87%)

Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation)
TL 1979, 399
- Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓
PDC

PDC
CHO

CH 2Cl 2

OH

DMF

1° alcohol

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

CO 2H

7


OXIDATIONS
- 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
cross-link
N

CH 2 CH

R2CH-OH

R2C=O

CH 2 CH

CrO3, HCl
N

N
Cr(III)

N
Cr(VI)O3 •HCl

8

partially
spent
reagent

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

Synthesis 1979, 815

O

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
JACS 1972 94, 4024.

(purple benzene)

O
O

O
K+

O

MnO 4O

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

J. Chem. Soc. 1953, 2189
JACS 1955, 77, 4145.

(62%)
O

HO

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

MnO2,
ROH, NaCN
CO 2R

OH

CO 2Me

JACS1968, 90, 5616. 5618

MnO 2, Hexanes
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
Ph

OH
O

H

O
JOC 1981, 46, 3936

RuO4, NaIO4

OH
CH 3

CO 2H

Ph

CCl 4, H2O, CH3CN

OH
Ph

RuO4, NaIO4

10

Ph

CCl 4, H2O, CH3CN

CO 2H

H

96% ee

CH 3

94%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

OSiMe 2tBu

O
N+
-O Me

TL 1989, 30, 433

(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
- oxidation of only the most reactive hydroxyl
O
OH

Synthesis 1979, 401
O

Ag 2CO 3

O

OH

OH
O

O

OH

O

OH

Ag 2CO 3, C 6H6

O
O
O

JACS 1981, 103, 1864.
mechanism: TL 1972, 4445.


OXIDATIONS
- Oxidation of 2° alcohol over a 1° alcohol
OH

OH

Ag2CO3, Celite

OH

JCS,CC 1969, 1102

(80%)

O

Silver Oxide (AgO2)
- mild oxidation of aldehyde to carboxylic acids
AgO 2, NaOH
RCHO

CHO

RCO 2H
CO 2H

AgO 2

JACS 1982, 104, 5557
Ph
Ph

Prevost Reaction Ag(PhCO2)2, I2
Ag(PhCO 2)2, I2

AcO

OAc

AcOH

AcO

Ag(PhCO 2)2, I2

OH

AcOH, H 2O

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

OH

Os
O O

OH

O

OsO 4, NMO

osmate ester
intermediate

cis stereochemistry

- use of R 3N-O as a reoxidant
TL 1976, 1973.
OsO 4, NMO

O
O

O

OH

O

OH

OH
OH

TL 1983, 24, 2943, 3947
Stereoselectivity:

OsO 4
R3

R2
RO

H

R4

OsO 4, NMO

HO H
R2
HO
R3
RO
H R4

11


OXIDATIONS
- new mechanism: reaction is accelerated in the presences of an 3° amine
R1

R1

O

O O

R2

Os
O

O

[2+2]

R3N

R1
R2

O Os

O

12

O

Os O

O

O

R2

O
NR3

[O]
[3+2]

OsO2

R1
O
O

R2

O

[O]
hydrolysis

R1

Os O

R2

+

O

HO

OH

OsO4

- Oxidative cleavage of olefins to carboxylic acids.
JOC 1956, 21, 478.
- Oxidative cleavage of olefins to ketones & aldehydes.
OH
CHO
CHO

OH
OsO 4, NMO

O

O

NaIO4

OH

O

H2O

O
O

O

O

O

O

OAc

O

OAc

OAc

JACS 1984, 105, 6755.

Substrate directed hydroxylations:
-by hydroxyl groups

Chem. Rev. 1993, 93, 1307
HO

OsO4,
pyridine

O

HO

HO
O

HO

+

O

HO
HO

HO
3:1
HO

OsO4,
pyridine

O

HO
O

TMSO
TMSO

HO

CH3

HO

CH3 OH

OsO4, Et2O

HO
OH

CH3

CH3

+

OH
CH3

(86 : 14)

- by amides
AcO

AcO
OH

MeS

OsO4

MeS
OH

HN

O
OAc

CH3 OH

HN

O
OAc


OXIDATIONS
- by sulfoxides
••

••

OMe

O

OsO4

S

OMe OH

O
S

OH
1) OsO4
2) Ac2O

S
HN

OAc

(2 : 1)

••

••

O

13

O
S

O

AcO

O

HN

(20 : 1)

- by sulfoximines
O
Ph S

O
Ph S

OH

MeN

MeN

OsO4, R3NO

O

OH


OH

OH
OH

OH
CH3
Raney nickel
H 3C

OH
OH
OH
CH3

- By nitro groups
PhO2S

PhO2S

1) OsO4

N
NHR

N

+

2) acetone, H

N
NHR

N
O2N

O2N

N
N

N

O

N

O
N

N
HO

HO

NHR

N

NHR

N

N
N

N

O

N

O

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

OH
OH

X

+
OH
OH

X= OH
= OMe
= OAc
= NHSO2R

- Ligand effect:

80 : 20
98 : 2
99 : 1
60 : 40

OsO4
OH

K3Fe(CN)6, K2CO3
MeSO2NH2, tBuOH/H2O

OH
OH

OsO4 (no ligand)
Quinuclidine
DHQD-PHAL

X

4:1
9:1
> 49 : 1

+

X

(directing effect ?)
(directing effect ?)

OH
OH

OH


OXIDATIONS
Chem. Rev. 1994, 94, 2483.

Sharpless Asymmetric Dihydroxylation (AD)
- Ligand pair are really diastereomers!!

14

dihydroquinidine ester

N
"HO

Ar

OH"

H

H
R3

OR'

R2

R3 OH

0.2-0.4% OsO4

R2

R1

acetone, H 2O, MNO

80-95 % yield
20-80 % ee

OH

R1
H OR'
"HO

Ar

OH"

MeO
Ar =

N

dihydroquinine ester

N
R'= p-chlorobenzoyl

Mechanism of AD:
L
HO

OH

O
O
H 2O

O

O

Os

O

O
O
O

First Cycle
(high enantioselectivity)

O

Os

O
O

Second Cycle
(low enantioselectivity)

[O]

[O]

O
O

Os

O

O

L

Os
O

L

O
O

O
O

Os

O

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
O

H

Et

N

N N

N
N

O

H

O

H

OMe

MeO

O

H

MeO
N

OMe

N
N

N
(DHQ)2-PHAL

(DHQD)2-PHAL
JOC 1992, 57, 2768.

Et

N N


OXIDATIONS

15

- Other second generation ligands
N

Et
Et
O

H
MeO

Et
N

Ph
O

N

N

H

N

OMe

Ph

N

N
O

H

O

OMe

N

N

PYR

IND

Proposed catalyst structure:
O

H

O
O

Os

N

MeO

N

Os

"Bystander
quinoline
(side wall)

Asymmetric
Binding
Cleft

O

N
H

H

N

N

O

N

N

N

O

Phthalazine
Floor

OMe

OMe

OMe
O

Corey Model: JACS 1996, 118, 319
Enzyme like binding pocket;
[3+2] addition of OsO4 to olefin.

N

O
O

Os O
N O

O

N

H

N N
O

O

N

DHQL

Rs

RM

RL

H

DHQ

RL large and flat,
i.e Aromatics work particularly well


OXIDATIONS
Olefin

Preferred Ligand

ee's

PYR, PHAL

30 - 97 %

PHAL

70 - 97 %

IND

20 - 80 %

PHAL

90 - 99.8 %

PHAL

90 - 99 %

PHAL, PYR
+ MeSO2NH2

20 - 97 %

R1
R2
R1

R1
R2

R2

R1

R2
R3

R1
H
R2

R3

R1
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
N

OMe

OMe
AD
(DHQD)2PYR

O

N

N

O

94 % ee

O
O

OH
OH

OH

- Kinetic resolution (not as good as Sharpless asymmetric epoxidation)
H
Ph
tBu

Ph
H
tBu

H
Ph

H
Ph

AD mix α
30% conversion

Ph
H

OH
OH
tBu

tBu

olefins with axial
dissymmetry

H

Ph

+

OH
OH

+

tBu
(4 : 1)

tBu
enriched

16


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
Ph

O

N
Na

CO2Me

Ph

O

OH

Cl
Ph

O

NH

+
CO2Me

Ph

K2OsO6H4 (cat)
Ligand

CO2Me

Ph
N

OH

O

Ph

O

Ligand= PHAL
AQN

4:1
1:4

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

OR'

R

O

+

Mo
O
L

R

O

H
R

R

Pd(OAc) 2,
CH 3CN, 80° C

HO

H
R

O

H
R

- CO 2

O

O Pd

-

TL 1984, 25, 2791
Tetrahedron 1987, 43, 3903

O

OH

2

HO

CO

H
OH
JACS 1989, 111, 8039.

Pd2(DBA) 3•CHCl 3,
CH 3CN, 80° C

OH

O

R

R

Pd(0)
O

H

H

(Tsuji Oxidation)

O

O 2 CO

OH

R'
OH

L

Palladium Reagents
Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates
Tetrahedron 1986, 42, 4361
R

O

THF, -78°C

O

H

O

O

Oxidation of silylenol ethers and enol carbonates to enones
O

OTMS

Pd(OAc) 2,
CH 3CN

O

O
O

OTIPS
Ph

O

Pd(OAc) 2,
CH 3CN

(NH 4)2Ce(NO 3)6
DMF, 0°C

O

O
Ph

TL 1995, 36, 3985

R


Oppenauer Oxidation

OXIDATIONS
Organic reactions 1951, 6, 207

Synthesis 1994, 1007
OiPr
+O Al

R1R2CHOH
(CH3)2C=O

OiPr

OiPr
+O Al
O OiPr

H
R1

R2

O
R1

18

+ Al(OiPr)3
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.
Me

Me
S+

S+

+ E

O-

Me

E

O

Organic Reactions 1990, 39, 297

Nu:

Nu

S

Me

Me

+

+ E-O
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

(COCl) 2

S + O-

CH 2Cl 2, -78°C

Me

R2CH-OH Me
Me

Me

-CO, -CO 2

Cl -

Me
S + Cl
Me

O

R
R

S+ O

Cl

S+ O

Et3N:

Me

R

S

+

O

Me

R

H
B:

O
Cl

O

DMSO, (COCl) 2
OH

Moffatt Oxidation (DMSO/DCC)

O

JACS 1965, 87, 5661, 5670.

Me

C 6H11

S + O-

CF 3CO 2H,
Pyridine

Me
+
C 6H11 N C

TL 1988, 29, 49.

CH 2Cl 2, Et3N

N C 6H11

OH
CO 2Me
O

Me

NH
S

+

O C

R2CH-OH

Me

R
O

H

R
B:

C 6H11
CHO
DCC/ DMSO
CO 2Me

CF 3CO 2H,
Pyridine

JACS 1978, 100, 5565

O

S

SO3/Pyridine

S+ O

N

Me

R
R

Me

S

JACS 1967, 89, 5505.
CO 2Me
HO

H

CONH 2
H

HO

OH

OH

CO 2Me
H

SO 3, pyridine,
DMSO, CH 2Cl 2

CONH 2
H
HO

O

JACS 1989, 111, 8039.


OXIDATIONS
Corey-Kim Oxidation

(DMS/NCS)

19

JACS 1972, 94, 7586.
O

Me

Me
S:

+

S + Cl

N Cl

Me

Me
O
N-Chlorosuccinimide
(NCS)

Acc. Chem. Res. 1980, 13, 419

••

••

••

O O

singlet

"ene" reaction

H
O

Tetrahedron 1981, 37, 1825



•• ••
•O O •
•• ••
triplet

••

Oxygen & Ozone
Singlet Oxygen

Ph3P:

H

O

O

O

OH
Tetrahedron 1981, 1825

1) O2, hν, Ph2CO
2) reduction

Ozone

HO

Comprehensive Organic Synthesis 1991, 7, 541
O

O 3, CH 2Cl 2

O

O

-78°C

O

Ph3P:

O O

NaBH 4

+

O

O

H
Jones

OH

RCOOH

Other Oxidations
Mukaiyama Oxidation

BCSJ 1977, 50, 2773
O
R

PrMgBr
CH OH

R

N

R

N

N

N
R

O

CH O MgBr

O

R

THF

R

OH
Cl
MeO

CH 3

O

O

NH

O
O
SEt
SEt
MeO

N

Cl

O
N N

N

O

MeO

CH 3

OHC
O

NH

OEt

O
tBuMgBr, THF
(70%)

SEt
SEt
MeO
JACS 1979, 101, 7104

OEt


OXIDATIONS

20

O

OH

tBuMgBr, THF
O
N

N

N

N
O

O

O

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

JACS 1992, 113, 7277.

OAc

OAc

AcO

••

I

O

OAc

R

R2CH-OH

I
O

+

+ 2 AcOH

O

R
O

O

HO

Dess-Martin

O
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,
NaH2PO 4
OBn

- HClO2
OBn

OBn
OH
H

tBuOH, H 2O

CHO

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

OLi
PhSeCl

O
SePh

H2O 2

Ph
Se
O-

THF

O
- PhSeOH

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

O

H
O

O 2N

O

O

O

H

O
R1

R2

O
O

HO

O

NO 2

Cl

R1

H

Ar

O

C R2
O

R1

O

+

R2

ArCO2H

Ar

O
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
mCPBA

O

HO

O
CO2H

O

CHO
O

HO

O

O

CO2H

HO

OH
PGE1

O
O
CH3

O

mCPBA

Tetrahedron Lett. 1977, 2173
Tetrahedron Lett. 1978, 1385

CH3

(80 %)
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
N C
R

R3
R2

- hydroxylation of enolates
O
R

O

Base

R

R'

O

_
R
R'

O
O

PhSO2
O
R

Ph

N

R

R'

+ PhSO2N=CHPh

HO
Ph
O

_
R'

O

R'
_
NSO2Ph

R

+ PhSO2N=CHPh
Ph

R'
NHSO2Ph

By-product
supresed by using
bulkier oxaziradine
such as camphor
oxaziradine


OXIDATIONS

22

Asymmetric hydroxylations
O

O
NaN(SiMe3)2, THF

MeO 2C

HO
Tetrahedron 1991, 47, 173

MeO 2C
OMe

OMe
N
Ar

MeO

O

SO 2 O
MeO

KN(SiMe3)2

CO2Me

(67% ee)
O

O

OH
CO2Me

OH

O
OH
OH

N
SO2 O

MeO

MeO

MeO

O

OH

OH

(>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)
Barton Reaction

Comprehensive Organic Synthesis 1991, 7, 39.

NOCl, CH2Cl2
pyridine
OH


O

NO

- NO


O


OH

H



•NO

JACS 1975, 97, 430
OH

OH

NO

N

N
ketone
oxidation state

HO

C5H11

perhydrohistricotoxin

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

(CH 2)n

tBuOOH
triton B, C6H6

O

O
(CH 2)n

JACS 1958, 80, 3845


OXIDATIONS
O CO 2Me

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

OAc

O

10:1 diastereoselection
OH

OAc
mCPBA

+

O

O

1:4 diastereoselection
O
Ph

O
NH

Ph

NH
"highly selective"

mCPBA
O

Ar
O
H
H

O
proposed transition state:
-OH directs the epoxidation

O

O
H

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

JOC 1978, 43, 1588

O

OTMS
LDA, TMSCl

TMSO
mCPBA

O

H2O

O
OH

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.

23


OXIDATIONS
- Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4
- Oxidant: tBuOOH; PhC(CH3)2OOH

VO(acac)2
tBuOOH

OH

OH

O

OH

OH

(CH2)n

O

(CH2)n

ring size
5
6
7
8
9

VO(acac)2
>99%
>99
>99
97
91

MoO2(acac)2
-98
95
42
3

mCPBA
84
95
61
<1
<1

Acyclic Systems:
L

M

1,3-interaction

O

R3
A1,2-strain

tBu

O
O

R1
R3

L

Rc

Rt

R1

Rt

R2

Rc

O

O
M

R2

L

A1,3-strain

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

O
L

(Rg and R2)
(R1 and Rc)
(L and R2)

VO(acac)2,
tBuOOH
O
OH

+

O

OH

OH

(4 : 1)

tBu

CH3

H

O

L
M

H
H
L

O

O

M

L
O

O

L

tBu

O

H 3C
H

H
H

24


OXIDATIONS
VO(acac)2,
tBuOOH
O
OH

+

O

OH

OH

(19 : 1)

tBu
L
H 3C
H

H

H 3C

O

H

M
L

H
O

O

O

H 3C

H

O

M

L

L

H

O

tBu

CH3
SiMe3

SiMe3

VO(acac)2,
tBuOOH

O
OH

SiMe3

+
OH

O

OH

(> 99 : 1)

- Careful conformational analysis of acyclic systems is needed.
Homoallylic Systems
L
L
O

O
OH

V

OtBu

O

OH

dominent stereocontrol element

Titanium Catalyst structure:
RO2C
OR
Ti

CO2R
O

O

O

RO

O

OR
O

Ti

OR
OR

O
OR
CO2R
O

OR
Ti

CO2R
O

O

O

RO

O

OR
O
CO2R

Ti
O

RO
Ti
O

O

CO2R
O

CO2R
O

O

tBu
OR

Disfavored

O
O

tBu
OR

Ti

O

Favored

O
CO2R

25


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