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VVIMP Oxidations PDF
VVIMP Oxidations PDF
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
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
- 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
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.
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
PCC, CH 2Cl 2
O O O
JOC 1984, 49, 1647
PCC, CH 2Cl 2
O O
NH NH
N N
OH
OH
PCC, CH 2Cl 2
H H 3,5-dimethyl
pyrazole H H
HO
O
(87%)
PDC PDC
CHO CH 2Cl 2 DMF CO 2H
OH
1° alcohol
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%)
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
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
OH CO 2Me
MnO 2, Hexanes JACS1968, 90, 5616. 5618
MeOH, NaCN
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
OH O
TPAP
MeO 2C MeO 2C
OSiMe 2tBu O OSiMe 2tBu
(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
CO 2H
CHO AgO 2
Ph
Ph
AcOH
AcOH, H 2O
OsO 4, NMO O O OH
Os
O O OH
osmate ester
intermediate cis stereochemistry
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.
HO
OsO4, HO
O pyridine O
TMSO
TMSO
- 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
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
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
Phthalazine
OMe Floor
N
OMe
OMe
DHQL
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
O
HO
O
Campthothecin
N
N
O
94 % ee OH O
OH OH
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
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.
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
••
••
•O O • O O
•• ••
••
••
triplet singlet
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
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.
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
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
OMe
OMe
N (67% ee)
Ar SO 2 O
MeO O MeO O O OH O
KN(SiMe3)2 OH
CO2Me CO2Me OH
OH
- hydroxylation of organometallics
R-Li or R-Mg → R-OH JACS 1979, 101, 1044
NOCl, CH2Cl2
pyridine hν
- NO
OH O • O
NO • OH
H •
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
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
OH OH
O
(CH2)n (CH2)n
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
Homoallylic Systems
L
L
V OtBu
O O O
OH OH
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
(R)-glycidol
OH water soluble
O
OH
(+)-DIPT
(S)-glycidol
O
O O
O S NO2 organic soluble
OH
O
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
(+)-DIPT, Ti(OiPr)4,
tBuOOH, 3A sieves +
(90 % ee)
O O
OH OH
OH 95 : 5
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%
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
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
H H H H
N N NaOCl N N
Mn Mn
O Cl O O O
O
(98% ee)
O
86% ee
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
1) LDA
2) Cp 2TiCl2 OH
F3C O