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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.
C
R
R
H
O
Cr
HO
O-
O-
O
R
R
+ H 2 O
H+
HCrO 4 - R 2 CH-OH
Jones Reagent (H 2 CrO 4 , H 2 Cr 2 O 7 , K 2 Cr 2 O 7 )
J. Chem. Soc. 1946 39
Org. Syn. Col. Vol. V , 1973 , 310.
- CrO 3 + H 2 O → H 2 CrO 4 (aqueous solution)
K 2 Cr 2 O 7 + K 2 SO 4
- Cr(VI) → Cr(III)
(black) (green)
- 2°- alcohols are oxidized to ketones
O
R
acetone R
Jones reagent R 2 CH-OH
- saturated 1° alcohols are oxidized to carboxylic acids.
R H
O
R H
HO OH
R OH
O
acetone
Jones hydration reagent RCH 2 -OH
Jones reagent
acetone
- Acidic media!! Not a good method for H+^ sensitive groups and compounds
Me 3 Si
OH
SePh CO 2 CH 3
Me 3 Si
SePh
O
O
H 17 C 8
OH
O
O
O
H 17 C 8
O
O
2) CH 2 N 2
acetone
- Jones, acetone
JACS 1982 , 104 , 5558
Jones
JACS 1975 , 97 , 2870
Collins Oxidation (CrO 3 •2pyridine)
TL 1969 , 3363
- CrO 3 (anhydrous) + pyridine (anhydrous) → CrO 3 •2pyridine↓
- 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH 2 Cl 2 )
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.
OH
O
O
ArO
CrO 3 •(C 5 H 5 N) 2
CH 2 Cl (^2) O JACS^^1969 ,^^91 , 44318.
O
O
ArO
H
CrO 3 catalyzed (1-2 mol % oxidation with NaIO 6 (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+CrO 3 Cl-^ ↓
- Reagent can be used in close to stoichiometric amounts w/ substrate
- PCC is slighly acidic but can be buffered w/ NaOAc
HO
OHC
OH
O
O
CHO
O
O
TL , 1975 , 2647
PCC, CH 2 Cl 2
JACS 1977 , 99 , 3864.
PCC, CH 2 Cl 2
- 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.
N N
CH 2 CH
N
CH 2 CH
N
CH 2 CH
cross-link (^) CrO 3 , HCl
Cr(VI)O 3 •HCl
R 2 CH-OH R 2 C=O
Cr(III)
partially spent reagent
to remove Cr(III)
- HCl wash
- KOH wash
- H2O wash
CrO 3 /Et 2 O/CH 2 Cl 2 /Celite
Synthesis 1979 , 815.
- CrO 3 in non-aqueous media does not oxidized alcohols
- CrO 3 in 1:3 Et 2 O/CH 2 Cl 2 /celite will oxidized alcohols to ketone and aldehydes
HO
C 8 H 17
O
C 8 H 17
Synthesis 1979 , 815
CrO 3 Et 2 O/CH 2 Cl 2 /celite
H 2 CrO 7 on Silica
- 10% CrO 3 to SiO 2
- 2-3g H 2 CrO 3 /SiO 2 to mole of R-OH
- ether is the solvent of choice
Manganese Reagents
Potassium Permanganate KMnO 4 /18-Crown-6 (purple benzene)
JACS 1972 94 , 4024.
O
O O
O
O
O
K MnO 4 -
- 1° alcohols and aldehydes are oxidized to carboxylic acids
- 1:1 dicyclohexyl-18-C-6 and KMnO 4 in benzene at 25°C gives a clear purple solution as high
as 0.06M in KMnO 4.
O
CO 2 H
CHO
CHO
Synthesis 1984 , 43 CL 1979, 443
JACS 1972 , 94 , 4024
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 (BaMnO 4 )
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 MnO 2
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 MnO 2 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
HO
HO
OH
O
HO
J. Chem. Soc. 1953 , 2189 JACS 1955 , 77 , 4145.
MnO 2 , CHCl 3
- oxidation of 1° allylic alcohols to α,β-unsaturated esters
OH CO
2 Me
OH
CO 2 R
JACS 1968 , 90 , 5616. 5618
MnO 2 , ROH, NaCN
MnO 2 , Hexanes MeOH, NaCN
Manganese (III) Acetate α-hydroxylation of enones
Synthesis 1990 , 1119 TL 1984 25 , 5839
O
Mn(OAc) 3 , AcOH
O
AcO
Ruthenium Reagents
Ruthenium Tetroxide
- effective for the conversion of 1° alcohols to RCO 2 H and 2° alcohols to ketones
- oxidizes multiple bonds and 1,2-diols.
- Oxidation of 2° alcohol over a 1° alcohol
OH
OH (^) Ag 2 CO 3 , Celite
(80%) O
OH
JCS,CC 1969 , 1102
Silver Oxide (AgO 2 )
- mild oxidation of aldehyde to carboxylic acids
RCHO
AgO 2 , NaOH RCO
2 H
Ph
CHO
Ph
CO 2 H
AgO 2
JACS 1982 , 104 , 5557
Prevost Reaction Ag(PhCO 2 ) 2 , I 2
AcO OAc
Ag(PhCO AcO OH 2 ) 2 , I 2
AcOH, H 2 O
AcOH
Ag(PhCO 2 ) 2 , I 2
Other Metal Based Oxidations
Osmium Tetroxide OsO 4
review: Chem. Rev. 1980 , 80 , 187.
-cis hydroxylation of olefins
old mechanism:
O
Os
O O
O OH
OH
cis stereochemistry
osmate ester intermediate
OsO 4 , NMO
- use of R 3 N-O as a reoxidant
TL 1976 , 1973.
OH
O
O OH
O
O
OH
OH
R 3
R 4
R 2
RO H
HO
R 4
R 2
RO H
R 3
HO H
Stereoselectivity: (^) OsO 4
OsO 4 , NMO
TL 1983 , 24 , 2943, 3947
OsO 4 , NMO
- new mechanism: reaction is accelerated in the presences of an 3° amine
Os
O
O
O
O
O
Os
O
O
O R^2
R 1 R^3 N^ O
Os O
R 1
R 2
NR 3
O
O
OsO 2
OsO 4
[O]
HO
R 2
OH
R 1
[O]
O
Os O
R 1
R 2
O
O
O
hydrolysis
R 1
R 2
[2+2]
[3+2]
- Oxidative cleavage of olefins to carboxylic acids.
JOC 1956 , 21 , 478.
- Oxidative cleavage of olefins to ketones & aldehydes.
O
O
OAc
O
O
OAc
OH
OH
CHO
CHO
O
O
OAc
O
O
O
O
OH
JACS 1984 , 105 , 6755.
OsO 4 , NMO NaIO 4 H 2 O
Substrate directed hydroxylations: Chem. Rev. 1993 , 93 , 1307
-by hydroxyl groups
O
HO
OsO 4 , pyridine O
HO
HO
HO
O
HO
HO
HO
O
TMSO
OsO 4 , pyridine (^) O
TMSO
HO
HO
CH 3
HO^ CH 3
CH 3
HO CH^3 OH
OH +
CH 3
HO CH^3 OH
OH
OsO 4 , Et 2 O
- by amides
AcO
HN
MeS
O
OAc
AcO
HN
MeS
O
OAc
OH
OH
OsO 4
Sharpless Asymmetric Dihydroxylation (AD) Chem. Rev. 1994 , 94 , 2483.
- Ligand pair are really diastereomers!!
R 1
N
R 2
R 3
Ar H H OR'
N
Ar
H OR'
R 1
R 2
R 3 OH
OH
N
MeO
acetone, H 2 O, MNO
0.2-0.4% OsO 4
"HO OH"
"HO OH"
80-95 % yield 20-80 % ee
R'= p-chlorobenzoyl
dihydroquinidine ester
dihydroquinine ester
Ar =
Mechanism of AD:
Second Cycle (low enantioselectivity)
First Cycle (high enantioselectivity)
H 2 O
L
[O]
H 2 O, L
Os
O
L
O
O O
O
O Os
O
O L
O
O Os
O O O
O
O Os
O
O O
O
HO
OH
OH
HO
R 3 N
Os O
O O
O O
[O]
- K 3 Fe(CN) 6 as a reoxidant gives higher ee's- eliminates second cycle
TL 1990 , 31 , 2999.
- Sulfonamide effect: addition of MeSO 2 NH 2 enhances hydrolysis of Os(VI) glycolate
(accelerates reaction)
- New phthalazine (PHAL) ligand's give higher ee's
N
O
H
Et
N
MeO
N
Et
OMe
H
N
N N
O
N
O
H
Et
N
OMe
N
Et
MeO
H
N
N N
O
JOC 1992 , 57 , 2768.
(DHQD) 2 -PHAL (DHQ) 2 -PHAL
- Other second generation ligands
N
H
Et
N
MeO
N
Et
OMe
H
N
N N
O O
Ph
Ph
PYR
N
Et
OMe
H
N
N O
O
IND
Proposed catalyst structure:
N N
O
H
N
N
Os
H
N
N
OMe
O
MeO
O
H
O
O
O
N
Os
N
Phthalazine Floor
"Bystander quinoline Asymmetric (side wall) Binding Cleft
N N
O O
N
N
OMe
Os
O
O
O
O N
OMe
N
H
O
O
Corey Model: JACS 1996 , 118 , 319
Enzyme like binding pocket;
[3+2] addition of OsO 4 to olefin.
RL
Rs RM
H
DHQL
DHQ
RL large and flat,
i.e Aromatics work particularly well
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
Ph
CO 2 Me
Ph O N
Cl
O
Na
K 2 OsO 6 H 4 (cat) Ligand
Ph
CO 2 Me
OH
NH
O
Ph O Ph CO^2 Me
N
OH
O
O
Ph
Ligand= PHAL 4: AQN 1:
Molybdenum Reagents
MoOPH [MoO 5 •pyridine (HMPA)]
JOC 1978 , 43 , 188.
- α-hydroxylation of ketone, ester and lactone enolates.
R
R'
O-
Mo
O
O
O
O
O
L L
R
R'
O
OH
THF, -78°C
Palladium Reagents
Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates (Tsuji Oxidation)
Tetrahedron 1986 , 42 , 4361
OH
R
R
H
O CO
O
R
R
H O
O
O
R
R
H Pd^
O
R
R
O
OH
HO
OH
H
H
O CO
O
OH
HO
O
H
H
JACS 1989 , 111 , 8039.
TL 1984 , 25 , 2791
Tetrahedron 1987 , 43 , 3903
2
Pd 2 (DBA) 3 •CHCl 3 , CH 3 CN, 80° C
- CO 2 -
Pd(0)
Pd(OAc) 2 , CH 3 CN, 80° C
2
Oxidation of silylenol ethers and enol carbonates to enones
O (^) OTMS (^) Pd(OAc) O 2 , CH 3 CN
O Pd(OAc) 2 , O CH 3 CN
O
O
Ph
OTIPS
Ph
O
(NH 4 ) 2 Ce(NO 3 ) 6 DMF, 0°C TL 1995 , 36 , 3985
Oppenauer Oxidation Synthesis 1994 , 1007 Organic reactions 1951 , 6 , 207
O Al
OiPr
OiPr
O
OiPr
OiPr
O
R 2
R 1
H
O
R 1 R 2
R 1 R 2 CHOH
(CH 3 ) 2 C=O
+ Al(OiPr) 3
Nickel Peroxide
Chem Rev. 1975 , 75 , 491
Thallium Nitrate (TNN, Tl(NO 3 ) 3 •3H 2 O
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
S+
Me
Me
S+
Me
O-^ O^
E
Me
S+
Me
Nu + E-O
Nu:
E= (CF 3 CO) 2 O, SOCl 2 , (COCl) 2 , Cl 2 , (CH 3 CO) 2 O, TsCl, MeCl, SO 3 /pyridine, F 3 CSO 2 H,
PO 5 , H 3 PO 4 , Br 2
Nu:= R-OH, Ph-OH, R-NH 2 , RC=NOH, enols
Swern Oxidation
- trifluoroacetic anhydride can be used as the activating agent for DMSO
Me
S+
Me O- Me
S+
Me O
Cl
O
O Me
S+
Me Cl
R
R
O
Me
S+
Me O
R
R
H
Me
S
Me
Et 3 N:
B:
R 2 CH-OH
CH 2 Cl 2 , -78°C
-CO, -CO 2
Cl-
(COCl) 2
O
OH
O
O
Cl
TL 1988 , 29 , 49. CH 2 Cl 2 , Et 3 N
DMSO, (COCl) 2
Moffatt Oxidation (DMSO/DCC) JACS 1965 , 87 , 5661, 5670.
Me
S+
Me O-
Me
S+
Me O C
NH
C 6 H 11
N
C 6 H 11
Me
S+
Me O
R
R
O
C 6 H 11 N C N C 6 H 11
R
R
+ H
CF 3 CO 2 H,
Pyridine
B:
R 2 CH-OH
O
OH
CO 2 Me
S
O
CHO
CO 2 Me
S
JACS 1978 , 100 , 5565
DCC/ DMSO
CF 3 CO 2 H,
Pyridine
SO 3 /Pyridine JACS 1967 , 89 , 5505.
OH
CONH 2
OH
CO 2 Me HO (^) H
H
O
HO
CONH 2
CO 2 Me HO (^) H
H
SO 3 , pyridine, DMSO, CH 2 Cl 2 JACS 1989 , 111 , 8039.
O
OH
N N
O
N N
O O
O
tBuMgBr, THF
Dess-Martin Periodinane JOC 1983 , 48 , 4155. JACS 1992 , 113 , 7277.
- oxidation conducted in CHCl 3 , CH 3 CN or CH 2 Cl 2
- excellent reagent for hindered alcohols
- very mild
O
I
O
AcO OAc
OAc
R
O
R
O
I
O
OAc
HO
RO
O
RO
(99%)^ JOC^^1991 ,^^56 , 6264
Dess-Martin
R 2 CH-OH
Chlorite Ion
-oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids.
Tetrahedron 1981 , 37 , 2091
OBn
CHO
OBn OBn
CO 2 H
OH
H
tBuOH, H 2 O
NaClO 2 , NaH 2 PO 4
Selenium Dioxide
- Similar to singlet oxygen (allylic oxidation)
OAc
OAc
OH
- SeO 2
- NaBH 4
Phenyl Selenium Chloride
OLi O SePh
O
Se
H
O-
Ph (^) O
H 2 O 2 - PhSeOH
THF
PhSeCl
- PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a
selenoxide elinimation.
Peroxides & Peracids
- R 3 N: → R 3 N-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.
m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide
Cl
O
O
O
H H
NO 2
O
O
O 2 N O
R 1 R 2
O
HO O Ar
O
R 1 C
O
H
R 2
O
O
R 1 O
O
R 2 +^ ArCO 2 H
O Ar
- 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
O
O
O
mCPBA (^) O
O
O O HO
HO
CO 2 H
CHO
HO
O
CO 2 H
OH
PGE 1
JACS 1971 , 93 , 1491
O
CH 3
CH 3
mCPBA
(80 %)
O
O
CH 3
CH 3
Tetrahedron Lett. 1977 , 2173 Tetrahedron Lett. 1978 , 1385
Oxone (postassium peroxymonosulfate) Tetrahedron 1997 , 54, 401
RCHO
oxone
acetone (aq)
RCOOH
Oxaziridines
reviews: Tetrahedron 1989 , 45 , 5703; Chem. Rev. 1992 , 92 , 919
N C
O
R R 2
R 3
- hydroxylation of enolates
N
O
PhSO 2
Ph
R'
R
O
_
R'
R
O
O
Ph
NSO 2 Ph
_
R'
R
O
HO
+ PhSO 2 N=CHPh
R'
R
O
_
+ PhSO 2 N=CHPh
R'
R
O
Ph NHSO 2 Ph
By-product supresed by using bulkier oxaziradine such as camphor oxaziradine
R'
R
O (^) Base
O
O
H
CO 2 Me
O
O
H
OCO 2 Me
mCPBA, NaHPO 3 TL 1988 , 23 , 2793
Henbest Epoxidation- epoxidation directed by a polar group
OH
mCPBA
OH OH
O + O
10:1 diastereoselection OAc
mCPBA
OAc OH
O + O
1:4 diastereoselection
NH
mCPBA
O
Ph NH
O
Ph
O
"highly selective"
H
O
H
O
O
Ar
H
O
proposed transition state: -OH directs the epoxidation
- for acyclic systems, the Henbest epoxidation is often less selective
Rubottom Oxidation: JOC 1978 , 43 , 1588
O
LDA, TMSCl
OTMS
mCPBA
TMSO
O H^2 O^
O
OH
Sharpless Epoxidation tBuOOH w/ VO(acac) 2 , Mo(CO) 6 or Ti(OR) 4
Reviews: Comprehensive Organic Synthesis 1991 , vol 7, 389-
Asymmetric Synthesis 1985 , vol. 15 , 247-
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.
- Catalysts: VO(acac) 2 ; Mo(CO) 6 ; Ti(OiPr) 4
- Oxidant: tBuOOH; PhC(CH 3 ) 2 OOH
OH
VO(acac) 2 tBuOOH OH O
(CH 2 )n
OH
(CH 2 )n
OH
O
ring size VO(acac) 2 MoO 2 (acac) 2 mCPBA
Acyclic Systems:
Rc
Rt
R 3
R 1
R 2
O
L M
O
O
L
tBu
A1,3-strain
A1,2-strain
1,3-interaction
Rc
R 3 Rt
R 1
R 2
O
M
O
O
L L
Major influences:
A1,2-Strain between Rg and R 1 (Rg and R 2 )
A1,3-strain between R 2 and Rc (R 1 and Rc)
1,3-interactions between L and R 1 (L and R 2 )
OH
VO(acac) 2 , tBuOOH
OH OH
O O
O
H
H
H
H 3 C
O
M
O
tBu L
O L
H
H
O
M
O
tBu
L
L
CH 3
H
