department of organic chemistrydiposit.ub.edu/dspace/bitstream/2445/61063/28/8. organic...department...
TRANSCRIPT
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Rouen CathedralClaude Monet, 1892-94
2014-2015 Autumn
8. Oxidations
Dr. Pere Romea Department of Organic Chemistry
Organic Synthesis
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Oxidations
+ O– H
+ O– HOH
R1 HH
O
R1
O
R1H OH
OH
R1 R2H
O
R1
O
R1R2 OR2
1ary Alcohol
2ary Alcohol
Aldehyde
Ketone
Carboxylic Acid
Ester
+ O
+ H2O + 2 O
+ 2 O
C CC CH OH
C CO
C CHO OH
C COO
AlkeneAlcohol
Epoxide
1,2-Diol
Carbonyls
2Pere Romea, 2014
-
Oxidations
+ O– H
+ O– H
1ary Alcohol
2ary Alcohol
Aldehyde
Ketone
Carboxylic Acid
OH
R1 HH
O
R1
O
R1H OH
OH
R1 R2H
O
R1
O
R1R2 OR2
Ester
Cr(VI) Reagents
DMSO/E+ Mixtures
Other oxidizing agents
3 Pere Romea, 2014
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Carbonyls from Alcohols
Cr(VI) Reagents
Cr(IV)
H
OH
RH R H
O
H
O
RH
Cr
O
OHO
OCrO
O
HOCrOH
O
H
O
RHO
Cr
O
OHO
H
OH
RHO R OH
OOCrO
O
+
HOCrOH
O
+
Cr(IV)
Cr(VI)
Cr(VI)
HOCrOH
O
Cr(III)Cr(IV) – Overoxidation is a problem– Aqueous media facilitate the oxidation of the resultant aldehyde
– Chromium wastes are harmful
4Pere Romea, 2014
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Carbonyls from Alcohols
– CrO3/H3O+: Jones reagent
H
OH
RH R OH
O
R2
OH
R1H R1 R2
O
Aqueous media facilitate the oxidation of the resultant aldehyde
5
– CrO3/2py: Collins reagent
H
OH
RH R H
O
R2
OH
R1H R1 R2
O
Kinetics are rather slow and high loadings are usually required
N Cr N
O
O O
These reagents are hygroscopic and can easily catch fire and burn during their preparation,so other commercially available reagents are usually employed
Pere Romea, 2014
-
Carbonyls from Alcohols
OTBSO
O
O
O
O
1) TBAF, THF
2) CrO3 2py, CH2Cl281%
OH
H
O
H
CrO3 2py
CH2Cl295%
O OO
OO
O
CO2t-Bu
OHH
O OO
OO
O
CO2H
OH
1) Jones
2) HCOOH
96%
6
BnOOTBS
OCO2Me
BnO CO2HO
CO2Me
Jones
–10 °C to rt
90%
Pere Romea, 2014
-
Carbonyls from Alcohols
H
OH
RH R H
O
R2
OH
R1H R1 R2
O
– [pyH]+[CrO3Cl]–: pyridinium chlorochromate, PCC
N H
O
CrO Cl
O
More reactive than the Collins reagent
Somehow Lewis acid character
– 2[pyH]+[Cr2O7]2–: pyridinium dichromate, PDC
N H2 [Cr2O7]2–
H
OH
RH R H
O
R2
OH
R1H R1 R2
O
CH2Cl2R OH
ODMF
7 Pere Romea, 2014
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Carbonyls from Alcohols
OH H
OPDC
CH2Cl292%
MeO2C OH MeO2C H
OPCC
CH2Cl285%
NH
OH
O
HTBSO
H
NHCO2H
O
HTBSO
HPDC
DMF
91%
8
O
HO
OTIPSHClNC
O
H
OOTIPSH
ClNC
O
H
O
PCC
CH2Cl2, 4 Å MS, rt
100%
Pere Romea, 2014
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Carbonyls from Alcohols
DMSO/Electrophile mixtures
– The activation of DMSO with an electrophile gives an alkoxysulfonium salt
– This proceeds through a acid/base and an ene reaction
– There is a variety of electrophiles: DCC, (COCl)2, py-SO3,...
MeS
Me
OE
MeS
Me
OE
R1
O R2H
H
R1
O R2HS
Me
H
R1 R2
O
NR3
O
H
R2R1
SMe – Me2S
Alkoxysulfonium salt
9
Activated sulfoxide
Pere Romea, 2014
-
Carbonyls from Alcohols
Electrophile
10
Activated sulfoxide Reaction name
MoffatR N C N RNHR
NR
MeSMe
O
MeSMe
O
MeSMe
OE
MeSMe
X
SwernMe
SMe
Cl
ClCl
O
O
Parikh-DoeringSO
O O MeSMe
OSO3
Pere Romea, 2014
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Carbonyls from Alcohols
– Moffatt: DCC, cat H+
MeSMe
O
R N C N R
H
NHRNR
MeSMe
O
R1
O R2H
H
R1
O R2HS
Me
H
R1 R2
O
OMeO
OTBDPS
H HOH
OMeO
OTBDPS
H HO
DMSO, DCC, H+ cat
CH2Cl280%
O
HOHCO2Me
Si-PrO
HCHO
CO2Me
Si-PrO
HCHO
CO2Me
Si-Pr
DMSO, DCC
TFA-py
80%
+
9 : 1
– It was the first– Room temperature
11
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Carbonyls from Alcohols
– Swern: (COCl)2, Et3N, –78 °C
R1
O R2HS
Me
HR1 R2
O
NR3
O
H
R2R1
SMe – Me2S
MeS
Me
O
Cl
R1
O R2H
HCl
Cl
O
O
Cl
O
OMe
SMe
O – CO2, – CO
Cl
ClS
Me
Me
– HCl
– Very mild conditions
OMeTBSO
O O
OTIPS
H
MeO
O N
OHOH
OMe
O
H
TIPS
OTBS
OMeTBSO
O O
OTIPS
H
MeO
O N
OO
OMe
O
H
TIPS
OTBS
DMSO, (COCl)2, Et3N
CH2Cl2, –78 °C
80%
DMSO, (COCl)2, Et3N
CH2Cl2, –78 °C
> 90%
HO
OMe
OTBSH
OMe
OTBS
O
12
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Carbonyls from Alcohols
– Parikh-Doering: SO3 . py, R3N
– Temperature: 0 °C, rt– Easy work-up
Mechanism?
DMSO, SO3 py, i--Pr2NEt
CH2Cl2, –15 °C
94%
O
OTBS
ON OH
OR
O
OTBS
ON O
ORR: N
OO
Bn
13
O
O•
BrHHO
H
H
H
O
O•
BrHO
H
H
H
H
DMSO, SO3 py, Et3N
CH2Cl2, rt
99%
Pere Romea, 2014
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Carbonyls from Alcohols
Iodine(V)–based reagents
– Dess-Martin Periodinane: DMP OI
O
OAcAcOOAc
I (V) I (III)
R1
O R2H
H
– AcOH R1 R2
O
O
I
O
AcO
OAc
OAc
O
I
O
AcO
OAc
R1
O R2H
O
I
O
OAc
– AcOH
– This is a very mild oxidant that can safely be used in structurally complex and sensitive substrates
– NaHCO3 or pyridine are often added to moderate the acidity of the reaction mixture
– The addition of one equivalent of water usually enhances the kinetics
14 Pere Romea, 2014
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Carbonyls from Alcohols
i-Pr
O
I
OTBS
HOH H
i-Pr
O
I
OTBS
H H
H
ODMP
CH2Cl289%
OI
O
OAcAcOOAc
DMP
O
OR3SiO
TBSOH
H
OH TESO
O
Ot-Bu2Si
OOTES
O OTESOMe
OTES
OOO
OR3SiO
TBSOH
H
O TESO
O
Ot-Bu2Si
OOTES
O OTESOMe
OTES
OO
DMP, py
CH2Cl293%
15 Pere Romea, 2014
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Carbonyls from Alcohols
Iodine(V)–based reagents
– 2-Iodoxybenzoic acid: IBX
– There are safely concerns regarding the potentially violent decomposition upon impact or at high T
– Low solubility in typical organic solvents.
16
OI
O
OHO
– A mixture of PhCO2H, Ph(COOH)2, and IBX (22/29/49) has been developed
– DMSO is the choice or polymer-supported IBX
– Not susceptible to hydrolysis
– Remarkable chemoselectivity: exceptionally mild oxidant for the highly selective transformation of
primary and secondary alcohols into carbonyl compounds, and 1,2-diols into hydroxycarbonyls
– Catalytic amounts of IBX can be used in the presence of stoichiometric amounts of ozone
Pros and cons:
For a review, Kirsch, S. F. ACIE 2011, 50, 1524
Pere Romea, 2014
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Carbonyls from Alcohols
17
IBX
1:1 DMSO/THF
O O
OH
OOTIPS
MOMO
O O
OH
OOTIPS
MOMOO
O O
H
OOTIPS
MOMOPinnik Ox
see later
89% overall yield23 °C
O
1) TBAF
2) IBX, EtOAc, reflux
70%
OOHO
TBSO
OMe
O
Ph
O
OOHO
OMe
O
Ph
O
O
Pere Romea, 2014
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Carbonyls from Alcohols
Ruthenium–based reagents
– Tetra-n-propylammonium perruthenate: TPAP ORuO
O ONPr4
– Used as catalyst in the presence of stoichiometric amounts of a second oxidant (NMO, O2)
O
NMe O
NMO
TPAP, NMO
CH2Cl2, ta
97%
TBSOOH
O
O
TBSOH
O
O
O
CH2Cl2, 4 Å MS, ta
TPAP (10 mol%), O2OH H
O
85%
18 Pere Romea, 2014
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Carbonyls from Alcohols
Radicals as oxidizing agents
– 2,2,6,6-Tetramethylpiperidinyloxy: TEMPO NO
– TEMPO is a very mild and chemoselective
oxidant: only 1ary and 2ary alcohols are affected
– 1ary Alcohols are oxidized more easily than
2ary Alcohols : chemo- & siteselective
– TEMPO is used under catalytic premises in the
presence of stoichiometric amounts of another
oxidizing agent as ClO–, PhI(OAc)2, or Cu(I)/O2
– The mechanism depends on this second reagent
19Other mechanisms have been proposed
NO
NO
NOH
NO O
HH R
RCHO
RCH2OH + B
HB
OxidationOxidation
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Carbonyls from Alcohols
20
OHN
O
Boc
HN
O
Boc
O
NaBr (1 eq), NaHCO3 (3 eq)
EtOAc/toluè/H2O, 0 °C
90%
TEMPO (20 mol%), NaClO (1 eq)
TEMPO (10 mol%), PhI(OAc)2 (2 eq)
CH2Cl2, rt
65%
AcO i-Pr
O
HO
HO
AcO i-Pr
O
HOH
O
HO
OH
H
OHO
TEMPO (10 mol%)
CH2Cl2, rt
PhI(OAc)2 (1 eq)
HO
OHO
NaClO2, NaH2PO4
t-BuOH/H2O, rt
76% overall
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Carbonyls from Alcohols
Radicals as oxidizing agents
– 2-Azaadamantane N-oxyl radicals:
AZADO
21
N O N O N O N O
TEMPO AZADO 1-Me-AZADO 1,3-Me2-AZADO Iwabuchi, Y. JACS 2006, 128, 8412
– Four Me groups flanking the nearby catalytic center in TEMPO prevent bulky substrates forming the key intermediates
– AZADO family, a structurally less hindered class of nitroxyl radicals, may overcome this problem
5 mol% AZADO
NaClO2, pH 4.6
HOCO2H CO2Me
TMSCHN2MeOH
67% overall
Structurally hindered alcohol Sodium chlorite acts as the stoichiometric oxidant and
transforms the resulting aldehyde into a carboxylic acid. See next slide
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Carboxylic Acids from Carbonyls
Pinnik oxidation: sodium chlorite, NaClO2:
– Sodium chlorite is a cheap, mild, and chemoselective oxidizing reagent: only aldehydes are affected
– 2-Methyl-2-butene is usually added to remove the resultant sodium hypochlorite
RCHO + ClO2– RCO2H + ClO
–
22
O
TBSOCO2MeCHO
OF3C
OO
TBSOCO2Me
O
O
1) NaClO2, NaH2PO4, 2-methyl-2-butenet-BuOH, H2O
95%
2) CF3CH2OH, 2,6-lutidine
O
CHO
H
TBSO
O
CO2H
H
TBSO
NaClO2, NaH2PO4, 2-methyl-2-butene
t-BuOH, H2O
80%
Pere Romea, 2014
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Carboxylic Acids from Carbonyls
– Pinnik oxidation is often the second step of an oxidizing sequence
leading from primary alcohols to carboxylic acids
23
O
PGO OMe OH
O
O
O
OOPG
OMe
CO2Me
O
PGO OMe
O
O
O
OOPG
OMe
2) NaClO2, NaH2PO4, 2-methyl-2-butenet-BuOH, H2O
95%
3) CH2N2
1) DMP, py, CH2Cl2
O O
Bu3Sn
HOH O O
Bu3Sn
CO2HH1) TPA, NMO, CH2Cl2
55%
2) NaClO2, NaH2PO4, 2-methyl-2-buteneTHF, t-BuOH, H2O
Pere Romea, 2014
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Esters from Ketones
Baeyer-Villiger oxidation: Peracids, RCO3H:
R1 R2
O
R1 R2
OO O
RO
HRCO3H
– RCO2H R1 OR2
O
(H) > tertiary > secondary > benzyl ≈ phenyl > vinyl > primary > Me
– Although steric factors can come in to play, the propensity to migrate is enhanced by EDG groups
– Migration of R2 proceeds with retention of the configuration
– The oxidation is catalyzed by acids
– Electronically poor peracids and electronrich ketones give faster oxidations
– Peracids react with olefines very easily
24 Pere Romea, 2014
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Esters from Ketones
25
m-CPBA
95%
CH2Cl2
MeO
OO
MeO
O
OAcO
I
MeO
OO
AcO
MeO
O2) I2, KI1) NaOH
3) Ac2O, py
n-Bu3SnH
99%
benzene,rt
EtO
OTBDPS
OH
O
O
Et
OTBDPSOH
CO2Me
OTBDPS
TESOTMSO Et
1) MeOH, K2CO3
74% overall
2) TESCl, base, TMSCl
m-CPBA
AcOH
– A variety of peracids can be used …
O
O
O
CH3CO3H
85%
NCO2Me
Boc
O
NCO2Me
Boc
OH
1) CF3CO3H, CH2Cl2
58%
2) Na2HPO4, H2O
… but mCPBA is the most common one
Pere Romea, 2014
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1
Oxidations
+ O– H
+ O– H
+ O
+ H2O + 2 O
+ 2 O
OH
R1 HH
O
R1
O
R1H OH
OH
R1 R2H
O
R1
O
R1R2 OR2
1ary Alcohol
2ary Alcohol
Aldehyde
Ketone
Carboxylic Acid
Ester
C CC CH OH
C CO
C CHO OH
C COO
AlkeneAlcohol
Epoxide
1,2-Diol
Carbonyls
Pere Romea, 2014
-
Oxidations
+ O
+ H2O + 2 O
+ 2 O
C CC CH OH
C CO
C CHO OH
C COO
AlkeneAlcohol
Epoxide
1,2-Diol
Carbonyls
Epoxidation of alkenes
Dihydroxylation of alkenes
Other oxidations
2 Pere Romea, 2014
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Epoxidation of Alkenes
With peracids
– The third oxygen of peracids has a remarkable electrophilic character and the carboxylate is a good leaving group …
– Since alkenes have a nucleophilic character (remember electrophilic additions to C=C), they react with peracids and an oxygen is transferred in a syn concerted step.
HO
O
O R
R1R2
R1R2 R
1 R2O
+ RCO2HR O
OH
O
syn Addition
mCPBA
CF3 OOH
O
Me OOH
O
Cl
O
OOH
H
OO
O
RNu NuOH + O
O
R
electrophilic oxygen good leaving group
3 Pere Romea, 2014
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Epoxidation of Alkenes
– This epoxidation is sensitive to electronic effects. It proceeds faster with electronically poor peracids (CF3CO3H > mCPBA > CH3CO3H)
and electronically rich alkenes
Me
Me
Me
Me
Me
H
Me
Me
H
H
Me
Me
H
Me
Me
H
H
H
Me
H
> >> >�
4
CO2Me CO2MeOCH2Cl2, Δ
84%
CF3CO3H
O
CHCl3,rt
72%
mCPBA
OCHCl3,rt
86%
mCPBA
Pere Romea, 2014
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Epoxidation of Alkenes
5
– This epoxidation is also sensitive to steric effects. The peracids generally approach from the less hindered side of the olefin …
… unless other functional groups near the olefin can direct the orientation of the incoming reagent
CO2HH
HHO
O CO2HH
HHO
O
OmCPBA
benzene/dioxane, 24 h, rt
80%
O
RR RR
O
RR
mCPBA+
R : HR : Me
20 min, rt24 h, rt
99< 10
1> 90
Pere Romea, 2014
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Epoxidation of Alkenes
– This happens in allylic and homoallylic alcohols: hydroxyl group can direct the approach of the peracids overcoming the steric hindrance of the system
t-Bu
OR
t-Bu
OAc
O
t-Bu
OH
O
RCO3H
R: Ac
O
H
t-BuO
HO
O H
R
RCO3H
R: H
OAc
OH
OAc
OHO
mCPBA
CH2Cl2
78%
6
OH
R3
R2
R1
R1R2 R3 O
H
OR
OOH
OH
R3
R2
R1O
RCO3H
this hydrogen bond determinesthe stereochemical outcome of the epoxidation
Pere Romea, 2014
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Epoxidation of Alkenes
With peroxides and bases: ROOH / OH–
TBHP
HOOHMe O
OH
Me
Me
– The geometry of the alkene does not control de configuration of the resulting epoxide because it is a stepwise process
H
R2
R1
R1R2
H
R3
O
R3
OO
R3R2
O
HR1
O
R
O OR
O OR
7
– Is it possible to transfer any nucleophilic oxygen?
O
R2
nucleophilic oxygen
R1O
OH + B R1
OO + HB
R1O
O
R2
O
R1O
O R2
O
R1O
O R2
O
OR1
O +
Pere Romea, 2014
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Epoxidation of Alkenes
O OO
H2O2, NaOH
85%
O
OCbzHN
N OMe
O
O
OCbzHN
N OMe
O
OTBHP, BnNMe3OH
95%
THF, –20 °C
8 Pere Romea, 2014
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Epoxidation of Alkenes
With peroxides in a neutral medium: dioxiranes
Shi
O
O CF3
CH3
O
O CH3
CH3O
OO
OO
OO
DMDO
TFDO
– Dioxiranes are three membered–rings peroxides
– They can be prepared by oxidation with Oxone.
They can be isolated in solution or prepared in situ
CH3
CH3OO
O CH3
CH3KHSO5, KHSO4, K2SO4
NaHCO3, H2O
Oxone
– Dioxiranes show an strong electrophilic character: electronrich alekenes are easily oxidized
– They are no compatible with amines or sulfur-derived compounds
– The epoxidations are carried out under very mild conditions
– The reduced system is a carbonylic compound: acetone in the case of DMDO!
R1R2
R1R2
O
O CH3
CH3O
O CH3
CH3
R1R2
OO
CH3
CH3+
syn Addition
9
-
Epoxidation of Alkenes
10
OSiMe3
OSiMe3O
DMDOacetone, CH2Cl2
–40 °C, 3 h100%
O
Cl
HO
O
Cl
HOO
DMDOacetone, Δ, 57 h
100%
O
O
Ph O
O
PhO
Oxone, NaHCO3
CH3CN/H2O, 0 C, 1.25 h
99%
CH3
CF3O
CO2Me CO2MeODMDO
acetone
100%
Pere Romea, 2014
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Epoxidation of Alkenes
HO
O OH
O
O
N
S
HO
O OH
O
O
N
SO
DMDO
97%
11
HOOH
HOOH
O O
O O O
OHO HO
HO
H HO H O H OH
CSA, toluene, 0 °C 31% overall
Shi, Oxone CH3CN, H2O, pH 10.5, 0 °C
Pere Romea, 2014
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Epoxidation of Alkenes
Enantioselective epoxidation of allylic alcohols: Sharpless epoxidation
12
R2 OH
R1
R3TBHP
5-10 mol% Ti(i-PrO)4
TBHP
5-10 mol% Ti(i-PrO)4
EtO2CCO2Et
OH
OH
(2R,3R) Diethyl TartrateL-(+)-DET
(2S,3S)-Diethyl TartrateD-(–)-DET
6-12 mol% 6-12 mol%
R2 OH
R1
OR3
R2 OH
R1
R3O
EtO2CCO2Et
OH
OH
MS, CH2Cl2, –20 °C MS, CH2Cl2, –20 °C
R1R2 R3
OH
(2R,3R) Diethyl TartrateL-(+)-DET
(2S,3S)-Diethyl TartrateD-(–)-DET
Pere Romea, 2014
-
Epoxidation of Alkenes
– Unless disubstituted Z alkenes, any other alkene can be submitted to Sharpless AE
OH OH
OH
OH OH
OH OH OH
Not appropriate
OH OHO
5 mol % TiL4 (+)-DIPT 0 °C 2 h 90% ee 65%
5 mol % TiL4 (+)-DIPT –20 °C 3 h > 98% ee 89%
10 mol % TiL4 (+)-DET –10 °C 24 h 86% ee 74%
5 mol % TiL4 (+)-DET –10 °C 12 h 95% ee 88%
OHO
PhOHPh
OHO
H15C7
OH
H15C7
OHO
Pr
OH
Pr
13Pere Romea, 2014
-
Epoxidation of Alkenes
- The asymmetric induction imparted by the TBHP, TiL4, tartrate system is pretty high
OHO
O OHO
O
OOH
OO
O
mCPBA
TBHP, Ti(i-PrO)4
TBHP, Ti(i-PrO)4, (–)-DIPT
TBHP, Ti(i-PrO)4, (+)-DIPT
1 : 1.4
1 : 2.3
1 : 90
22 : 1
+
OOHR
OOHR
OO
SPhR
OH
OHTi(i-PrO)4
(+)-DIPT, TBHPCH2Cl2, –20 °C
> 95% ee 92%
PhSH, NaOH
t-BuOH/H2O, Δ
71%R: CHPh2
OH OHOTi(i-PrO)4
(–)-DET, TBHP, MSCH2Cl2, –20 °C
> 98% ee 92% 14Pere Romea, 2014
-
Oxidations
+ O
+ H2O + 2 O
+ 2 O
C CC CH OH
C CO
C CHO OH
C COO
AlkeneAlcohol
Epoxide
1,2-Diol
Carbonyls
Epoxidation of alkenes
Dihydroxylation of alkenes
Other oxidations
15 Pere Romea, 2014
-
Dihydroxylation of Alkenes
syn Diols with OsO4
16
NMO
Catalytic version: OsO4 is costly and toxic, so it is advantageous to use it as catalyst with a cooxidant (NMO)
syn Addition
R1R2 R3
R4
OsO
O
O
O
R1R2 R3
R4
OOs
O
O O
R1R2 R3
R4
OHHO
Oxidation
N
O
OH2O
OsO
O
O
OOs(VIII)
Os(VI)Os(VIII)
Stoichiometric version: recall MnO4–
R1R2 R3
R4
OsO
O
O
O
R1R2 R3
R4
OOs
O
O O
R1R2 R3
R4
OHHOHydrolysis
OHOs
HO
O OOs(VI)
Os(VIII)
syn Addition
Pere Romea, 2014
-
Dihydroxylation of Alkenes
PhPh
PhPh
OH
OH
PhPh
OH
OH
OsO4 cat, NMO
t-BuOH, H2O+
Racemic mixtureIs it possible to obtain a diol stereoselectively?
- OsO4 is costly, toxic, and volatile! The only interesting way to use it is under catalytic premises
OH
OH
OsO4 cat, NMO
t-BuOH, H2Osyn Addition
17
OOH
OO
OOH
OO
HOHO
OsO4 cat, NMO
t-BuOH, H2O
84%
Substrate–controlled dihydroxylation
Pere Romea, 2014
-
Dihydroxylation of Alkenes
Sharpless enantioselective dihydroxylation
– Asymmetric Sharpless dihydroxylation uses osmium(VIII) complexes containing chiral tertiary amines as ligands– Iron(III) acts as oxidant– The mechanism is complex
O
OsO O
O O OsOO
O
L
L quiral
Os(VIII)
O OsOO
O
L
OH
HO
2 H2O, 2 OH
H4OsO62
+ L +
Os(VI)
2 [Fe(CN)6]3 , 2 OH2 [Fe(CN)6]
4 , 2 H2O
Fe(III)Fe(II)
NNO O
N
N NEt
H
OMe
N
MeO
H
EtNN
O O
N
N N
H
OMe
N
MeO
H
EtEt
(DHQ)2-PHAL(DHQD)2-PHAL
Chiral tertiary amines
18
-
Dihydroxylation of Alkenes
AD-mix-α : K2[H4OsO6], (DHQ)2-PHAL, K3[Fe(CN)6], K2CO3
AD-mix-β : K2[H4OsO6], (DHQD)2-PHAL, K3[Fe(CN)6], K2CO3
– Commercially available mixtures of oxidants are ligands are commonly used
– The most suitable alkenes for the Sharpless AD are
Not appropriateNot appropriate
RLRS RM
H
AD-mix-β(DHQD)2-PHAL
AD-mix-α(DHQ)2-PHAL 19Pere Romea, 2014
-
Dihydroxylation of Alkenes
AD-mix-a (DHQ)2-PHAL
AD-mix-b (DHQD)2-PHAL
H17C8 80 (S) 84 (R)
Ph 97 (S) 97 (R)
Ph 93 (S) 94 (R)
BuBu 93 (S) 97 (R)
Bu 95 (S) 98 (R)
ee % ee %
ArCO2Et Ar
CO2EtOH
OH
AD-mix-α
t-BuOH, H2O
99% ee 72%
ArCO2Et
OH
OH
AD-mix-β
t-BuOH, H2O
98% ee 89%
20 Pere Romea, 2014
-
Dihydroxylation of Alkenes
O
O
OMe
OO
O
O
OMe
OO
O
O
OMe
OO
OH
OH
OH
OH
OsO4 – NMO AD mix α AD mix β
anti
sin
(1.9 : 1) 88% (54 : 1) 86% (1 : 35) 86%
OH
OH
OEt
O
OEt
OOH
OH
OEt
O
OEt
OOH
OH
HOOH
AD-mix-β
93% ee 78%
AD-mix-β
92% ee 78%
AD-mix-β
95% ee 93%
AD-mix-β
98% ee 70%
21Pere Romea, 2014
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22
Oxidations
+ O
+ H2O + 2 O
+ 2 O
C CC CH OH
C CO
C CHO OH
C COO
AlkeneAlcohol
Epoxide
1,2-Diol
Carbonyls
Epoxidation of alkenes
Dihydroxylation of alkenes
Other oxidations
22 Pere Romea, 2014
-
Carbonyls from Alkenes
Ozonolysis
C CO3
C C
OOO
C CO
OO O O
COC C O CO
CO
O CO
O
COH
CHO
H HRED
red
OXID
RED: NaBH4, Zn/AcOH. red: Me2S, Ph3P. OXID: H2O2
1,3-dipolar cycloadditionmolozonide
This is a mild, reliable, and minimal side products or waste producing process
23
NTBSO
O
Ph
OMeN
TBSOO
OH
OMe1) O3, MeOH/CH2Cl2, –78 °C
2) Me2S, then NaBH4
92%
OMe
OTMS
CHO
OMeHO
O1) O3, MeOH/CH2Cl2, –78 °C
2) Me2S, –78 °C to rt
92%
-
Carbonyls from Alkenes
Wacker Process
R
O
RPdCl2 cat, Cu (II) cat
O2, H2O, HClMethyl Ketone
R
Pd(II)L4
RPd(II)L3
R
OHPd(II)L3
OH Pd(II)L2H
H Pd(II)L3
Pd(0)Ln
R
H2O
β-Hydride eliminationR
OH
R
O
HL
Cu(I)
Cu(II)
O2
24
Originally developed by Wacker Chemie in the 50s and 60sThis Wacker process involves
a series of redox steps with oxygen serving as the terminal oxidant
-
Carbonyls from Alkenes
SPhO
PMBO
TBSO
SPhO
PMBO
TBSOO
15 mol% PdCl2, CuCl, O2DMF, H2O
40%Forsyth, C. J. OL 2013, 15, 1178
Occasionally, highly regioselective Wacker oxidations of internal alkenes are possible ...
H
H
O NO CO2Me
OH
H
H
O NO CO2Me
OH
O
25 mol% PdCl2, CuCl, O210:1 DMF/H2O, rt
79%Li, A. JACS 2012, 134, 920
O O O O O10 mol% PdCl2, Cu(OAc)2, O27:1 AcNMe2/H2O
84% Smith, A. B, III. JACS 1999, 121, 10648
25For an interesting analysis, see: Grubbs, R. H. ACIE 2014, 53, 8654
-
Oxidation of Diols
Oxidative cleavage with NaIO4
C C
OI
OC O CO
OI
O
O
O
HOC C
OHHO OHO O
OI
HO
OH
O
26
– When using with OsO4, alkenes can be transformed into carbonyls
NOTE: RuO2/NaIO4 pair works in a similar manner
OTBS
PMBO
CHOOTBS
PMBO
OsO4, NaIO4, 2,6-lutidine
Dioxane/H2O, rt
90%
O
OC8H15
PMBO
OH
OH
O O
OC8H15
CHOPMBO
ONaIO4, NaOH
EtOH, rt
95%
-
Allylic Oxidation
Oxidation of allylic and benzylic alcohols with MnO2
– A heterogeneous mixture of MnO2 under neutral conditions can selectively oxidize allylic, benzylic, and other activated alcohols to the corresponding aldehydes or ketones
89%
Bu3Sn OH Bu3Sn CHOMnO2
CH2Cl2
27
•
H
OHHO
OH
•
H
OHHO
O
MnO2, acetone
75%
acetone, rt
94%
OHMeO
MeO
OH
OHMeO
MeO
O
MnO2
Pere Romea, 2014
-
Allylic Oxidation
– Allylic positions can be oxidized with stoichiometric SeO2 or cat SeO2/TBHP
Oxidation of allylic positions with SeO2
– The oxidation usually affects the most substituted part of the double bond– Reactivity ranking: CH2 > CH3 > CH– Risk: overoxidations
28
HO
SeO
SeO OH
OSe
HO OH
Ene reaction [2,3]-Sigmatropic Hydrolysis
50%
SeO2, TBHP
CH2Cl2CO2Me CO2Me
HO + Aldehyde (5%)
OO
R
O
OO
O
R
O
O
OH
95%
SeO2, TBHP
dioxane, rt
Pere Romea, 2014
-
α-Oxidation of Ketones
Oxidation with mCPBA: Rubottom oxidation
R1R2
O
R1R2
OSiR3
R1R2
OSiR3
OR1
R2OSiR3
O
R1R2
O
OSiR3
mCPBA
R1
OSiMe3
Pd(II)R1
OSiMe3
PdIIR1
OPdII
R1 H
O
PdIIR1
O
Oxidation with Pd(II): Saegusa process
29
TESOH
R OH
R
70%mCPBA, NaHCO3
EtOAc
HO
TMSO
OPMB
HOTIPS
OPMB
HOTIPS
O5 mol% Pd(dba)2 . CHCl3, diallyl carbonate
CH3CN90%
Pere Romea, 2014
Chapter 8. Oxidations Part AChapter 8. Oxidations Part B