Oxidation of Unsaturated Systems
2 general reactivity patterns:
2 electron oxidation
Yn+2
-H+
X
X H
Yn+2
X
X+ +
Yn +
A-
simple example
OH
Me2SCl+
O +
O
S+
1 electron oxidation
or
X
-1 e-
or
X
we will focus on oxidation of aromatic rings and enol/enolate systems
Reduction potentials of oxidants we will look at (bigger number = stronger [O]):
Couple
Eo
0.16
Cu(II) + eCu(I)
0.77
Fe(III) + eFe(II)
V(V) + e1.00
V(IV)
Tl(III) + 2 eTh(I)
1.25
Mn(III) + eMn(II)
1.56
Ce(IV) + eCe(III)
1.6
Pb(IV) + 2 ePb(II)
1.6-1.7
S
+
Cl-
Oxidation of electron rich aromatic rings
Oxidation of phenols
2 e- processes
I(III) reagents
OAc
2 possible mechanisms
I
OH
O
Ph
R
R
review: Pelter, Tet, 2001, 273
2 major reagents:
R
OAc
R
OAc
I
I
OAc
O
phenyl iodonium diacetate (PIDA)
AKA (diacetoxy) iodobenzene (DIB)
AKA iodobenzene diacetate
Ph
O
R
R
Nu
OTFA
I
Nu
R
OTFA
R
O
O
Nu
phenyl iodonium bis(trifluoroacetate) (PIFA)
aka bis(trifluoroacetoxy) iodobenzene (BTIB)
aka Iodobenzene bis(trifluoroacetate)
Note: PhI 8x105 times better
leaving group than OTf
R
R
+ PhI + 2AcOH
or
R
R
Nu
Simplest case: hydroquinone to quinone
OH
O
O
PhI(OAc)2
OH
O
OH
PhI(OAc)2
+
-H
O
catechol
OH
hydroquinone
O
OH
Solvent addition
OH
O
O
OH
PhI(OAc)2
PhI(OAc)2
MeOH
MeOH
68%
H3CO
OCH3
more e- rich than s.m.
H3CO
H3CO
O
H3CO
O
O
PhI(OAc)2
H2O/MeOH
91%
H3CO
O
HO
no rxn here
OH
O
OCH3
Addition of aromatic ring
O
OH
OCH3
HO2C
OCH3
N
CF3CH2OH
HO2C
polar, non-nucleophilic solvent
F3C
O
OCH3
PhI(O2CCF3)2
OCH3
N
64%
F3C
O
non-nucleophilic amide
Kita, JOC, 1996, 5857
Addition of olefin
OH
O
O
PhI(OAc)2
OCH3
MeOH
H3CO
H3CO
OCH3
H3CO
OCH3
92% OCH3
JOC, 1996, 1267
Addition of indole
H3C
O
ArO2SHN
CH3
a
N
N
H
CO2CH3
O
H3 C
O
ArO2SHN
PhI(OAc)2
LiOAc
CH3
N
N
H
CO2CH3
O
HO
O
N
H
b
N
H
Br
Br
H3 C
CH3
H3 C
N
N
ArO2SHN
a
ArO2SHN
O
+
1:1
b
N
HN
CO2CH3
O
CH3
CO2CH3
O
O
Diazonamide A
Br
H
N
H
O ~15%
O
Br
NH
~30%; 3:1 mix of cis-5,5 diastereomers
Harran, ACIEE, 2003, 4961
Oxidations involving Nitrogen
OTMS
Br
O
OTMS
Br
Br
Br
Br
N
N
CF3CH2OH
N
H
N
H
N
O
Unprotecte phenol gave lower yields;
Competing reaction at OH and NH
I
Ph
N
H
H3CO
O
N
H3CO
HN
N
PhI(O2CCF3)2
CF3CH2OH
H3CO
N
H
O
Discorhabdin C
Kita, JACS, 1992, 2175
O
O2CCF3
O
H3CO
N
-H+
-TMS
42%
PhI(O2CCF3)2
N
H
Br
H3CO
O
N
O
H3CO
O
H3CO
H3CO
N
N
H3CO
70%
JOC, 2005, 2256
H
O
Indole oxidation
Cl
AcO
Ph
O
H3CO
I
CH3
S N
H3CO
Ar
HN S
N
CH3
H3C
HOAc
OAc
PhI(OAc)2
or
30%
H3C
O
N
N
H3C I
Ph
N
OAc
Cl
H3CO
H3CO
Cl
OH OH
O
N
N
H3C
H
S
S
N
O
CH3
Sporidesmin A
Kishi, JACS, 1973, 6493
OAc OAc
H3CO
CH3
H3CO
O
N
N
H3C
H
O
S
S
N CH3
Ar
CH3
Trapping the dieneone from I(III) oxidations
intramolecular cation trapping; intermolecular diene trapping:
CH3
H3C
O
O
O
OH
PhI(O2CCF3)2
O
O
CH3
CH3
O
69%
Wood, OL, 2002, 493
E
O
intermolecular cation trapping; intramolecular diene trapping
H3CO2C
OH
O
H3C
H3C
OH
O
PhI(OAc)2
E
O
HO
H3CO2C
O
O
O
Wood, OL, 2001, 2435
intramolecular cation trapping; intramolecular diene trapping
OH
O
CH3
H
H3CO
HO
H3C
OTs
PhI(OAc)2
66%
CH3
H3CO
O
TsO
Danishefsky, TL, 2005, 843
?
BzO
O
OH
O
Tashironin
Trapping the dieneone from I(III) oxidations: Michael addition
O
HO
O
O
PhI(OAc)2
Br
Pri
Br
O
i
Pr
i
O
O
N
i
Pr
Si
Pr
Si
PS
NAlloc
O
Alloc
PS
PS = polystyrene resin
Pd(PPh3)4
morpholine
O
O
O
SR2 Pri
Br
O
R 1O
NH
i
O
HSR2
Pr
Pri
Br
Si
O
PS
HO
Shair, JACS, 2001, 6740
NH
i
Pr
Si
PS
Oxidation of electron rich aromatic rings
Oxidation of phenols
2 e- processes
Special case of o-(hydroxymethyl)-phenols
IVII
OH
OH
O
OH
O
O
NaIO4
-I
V
nucleophilic
addition
cycloadditions
conjugate addition
examples
OH
OH
O
O
HO
NaIO4
H3CO
TMSO
Calicheamicin
Danishefsky
ACIEE, 1994, 858
O
H3CO
O
OH Danishefsky
JACS, 1988, 6890
OH
OH
O
O
OH
O
OH
O
O 1, 2
NaIO4
O
H
O
O
O
H
O
1. H2O2
2. (NO2)2C6H3CO3H
O
O
H triptonide
van Tamelen,
JACS, 1980, 5424
Oxidation of electron rich aromatic rings
Oxidation of phenols and phenolic ethers
1 e- processes
V reagents
Review: Hirao, Chem. Rev. 1997, 2707
Chem Rev. 1994, 519
V can be V(-3) to V(+5)
Usually changes oxidation state in 1e- steps
OH
OH
O
V
F
OH
F
F
HO
OH
OH
OH
8
V
:
:
4
1
V
VV
O
O
VIV
+
-H
-V
IV
VV
O
-H+
OH
'inner sphere'
PhOH
OH
VV
S.E.T
-VIV
-H+
BDE for PhO-H = 85 kcal
'outer sphere'
OH
O
1st choice: P,P coupling:
OH
VOCl3
75%
HO
HO
2nd choice, P,O
H3CO
H3CO
OCH3
VOF3
OH
NCH3
HO
NCH3
HO
68%
O
OCH3
If no OH, slower, and must be outer sphere
EtO2C
CO2Et
O
CO2Et
O
CO2Et
VOF3
O
JOC, 1978, 2521
O
45%
H3CO
H3CO
OCH3
OCH3
Kende,
JACS, 1976, 267 H CO
3
OCH3
Oxidation of electron rich aromatic rings
Oxidation of phenols and phenolic ethers
1 e- processes
Other metals
for 1e- oxidations of aromatic rings using Tl(O2CCF3), see Taylor and McKillop, JACS, 1981, 6856
1 e- oxidations with Fe(III): review: Chem Rev 1994, 519
OCH3
OCH3
OCH3
CH
3
OCH3
FeCl3
Outer sphere
oxidation
95%
CH3
H3CO
CH3
OCH3
OCH3
EtO
OCH3
FeCl3
EtO
CH3
OCH3
-2e-, -H+
H3CO
OCH3
H3CO
OCH3
OCH3
OCH3
OCH3
EtO
O
CH3
+Cl-, -CH3Cl
98%
Miller, JOC, 1980, 749
EtO
H3CO
CH3
Oxidation with Fe(III), cont.
cheap, non-toxic
OH
OH
H3CO
H3CO
K3Fe(CN)6
-2e-, -2H+
NH
NH
H3CO
H3CO
OH
OH
O
-2e-, -2H+
H3CO
HO
N
H3CO
NH
35%
HCO
O
Chem Comm
1966, 142
H3CO
O
2 examples for the price of 1:
RO
H3CO
Tl(OAc)3
BF3 Et2O
H3CO
OCH3
OR
RO
OR
55%
RO
OR
TMSI
R = CH3
R=H
FeCl3
85%
O
O
HO
K2CO3
79%
O
HO
O
OH
Anderson,
OL, 2005, 123
OH
O
O
HO
O
Oxidation of electron rich aromatic rings
Oxidation of arenes
n x 2 e- processes
Ru(VIII) and oxidative cleavage
RuO4 is very strong oxidizing agent, very expensive.
Usually use catalytic RuO2 or RuCl3 with stoichiometric cheap [O] e.g. NaIO4, NaOCl
Review: Encylcopedia Reagents for Organic Synthesis
OH
O
O
OH
cat. RuCl3
NaOCl
O
OH
O
O
O
O
RuCl3/H5IO6
CCl4/CH3CN
e- poor
e- rich
O
HO2C
O
O
JOC, 1990, 1928
O
O
H
O
H
RuCl3/NaIO4
H2O/CH3CN/EtOAc
>64%
O
OH
70%
JOC, 1974, 2468
N
BOC
Ph
O
H
O
H
N
BOC
Clayden, JACS, 2005, 2412
CO2H
Oxidation of electron rich aromatic rings
Oxidation of arenes
n x 2 e- processes
Ru(VIII) and oxidative cleavage
heteroaromatics
O
RuCl3/NaIO4
CCl4/CH3CN
1min
H3CO
O
OBz
OBz then CH2N2
>90%
TBSO
H
OBz
H3CO
CO2CH3
OBz
O
OBz
TBSO
H Jacs, 1988, 3929
OBz
simple olefins work, too
H
H
H
H
H
RuO2/NaIO4
CCl4/CH3CN
92%
H
H
H
O
O
Chem. Comm. 1986, 1319
Oxidation of enols
Introduction
Three general pathways for oxidation of enols and enolates:
Mn+1
X = H, Li
Mn+1
O
O
OX
Mn+1
or
n
-M
1 e- oxidation
M = VV, CuII, I2 (s.e.t.)
CeIV, FeIII, PbIV,
O
OX
Nucleophile
O
X = H, Li
Mn+2
M = TlIII, PbIV,IIII
Mn+2
2 e- oxidation
X = SiR3, CH3
Mn+1
M = VV, CuII, CeIV
-M
n
OX
Mn+1
-Mn
electrophile
O
electrophile
OX
1 e- oxidation
electrophile
Oxidation of enols
2e- processes
IIII and TlIII
IIII and TlIII react with enols to give α-metallo carbonyl intermediates
(recall IV reagents convert enols to enones - see carbonyl oxidation class)
OH
O
O
M
OH
PhI(OAc)2
~
electrophile
Nucleophile
O
O
OCH3
O
H3CO
I(Ph)(OAc)
O
examples
O
CH3OH
Ph
H3CO
PhI(OAc)2
N
OCH3
Ph
N
KOH/CH3OH
65%
S
OH
O
no Ox at S!
S
TL, 1984, 4745
O
H3CO
H3CO
N
H3CO
OCH3
OH
PhIO
KOH/CH3OH H3CO
80%
H
N
TL, 1986, 2023
H
regio, chemo- & stereoselective! HO
O
H3CO
OCH3
Oxidation of enols
2e- processes
IIII and TlIII
WIth TlIII, often see ring contraction
O
CH3
O
Tl(NO3)2
Tl(NO3)3
CH3OH
O
HO
Tl(NO3)3
1,2 aryl
shift
O
H3CO
McKillop, Taylor, JACS, 1973, 3340
O
OH
Tl(NO3)2
NaHCO3
(via epoxide)
heat
(ring contraction)
OH
84%
CO2H
84%
McKillop, Taylor, JACS, 1973, 3381
O
Tl(NO3)3
AcOH
CO2H
95%
Tet, 1974, 1423
Oxidation of enols
2e- processes (except when it's 1e-)
Pb(OAc)4
Pb(OAc)4 (aka LTA) is versitile, strong oxidant. Also used to oxidize aromatic rings [not usually as clean as PhI(O2CR)]. Can cleave diols to
dicarbonyl compounds (even trans diols!!)
O
Overall transformation:
O
Pb(OAc)4
OAc
1e- and 2e- processes compete:
O
OH
O
PbIV(OAc)3
O
O
PbIVO
OAc
+ PbII(OAc)2
+ AcOH
O
bond
homolysis
O
2 e- process
O
II
+ Pb (OAc)2 +
O
radical recombination
chain propagation
PbIV(OAc)4
PbII(OAc)2 +
O
O
Pb(OAc)4 examples
O
O
CH3
O
Pb(OAc)4, BF3-Et2O
CH3
CH3
O
OAc
CH3
86%
JCS, 1965, 6
AcO
AcO
H
O
H
H
CO2CH3
O
CO2CH3
OAc
Pb(OAc)4, AcOH
75%
O
O
OAc
H
H
OAc
Phenols are similar to enols:
O
O
OAc O
Ac2O,
H+
O
1. Pb(OAc)4
AcOH
OH
C3H7
H
C3H7
OAc
OAc
CH3
TL, 1986, 5071
OAc
OH
O
HOOAc
C3H7
OAc
OH
C3H7
Pattenden, Perin 1, 1988, 1677
Oxidation of enols
1e- processes
Oxidation of dicarbonyl compounds
Mn(OAc)3
Review: Snider, Chem Rev. 1996, 339
Mn(III) salts convert β-dicarbonyl compounds to electron-poor radicals:
Mn(III)
O
O
O
O
O
R'
slow
R
R
R
R
R
R'
R
R'
O
usual application is cyclization onto tethered olefin
Mn(III)
O
O
Mn(OAc)3
Mn(II)
O
O
O
O
O
outer sphere?
OH
O
O
HO
HO
64%
O
H
Corey, JACS, 1984, 5384
O
H
O
O
Oxidation of enols
1e- processes
Oxidation of dicarbonyl compounds
Mn(OAc)3
O
Cu as co-oxidant
O
O
O
OCH3
O
O
OCH3
no Cu
H abstraction
OCH3
Mn(OAc)3
CuII(OAc)2
O
O
OCH3
--Cu(II) oxidizes radical 350 X faster
than Mn(III) oxidizes radical
--With CuX2 (X = halide, SCN)
get alkyl-X
CuIII
O
O
-Cu(I), -H+
OCH3
Or, electron transfer could
lead to cation, then olefin
71%
Oxidation of enols
1e- processes
Oxidation of dicarbonyl compounds
Mn(OAc)3
Examples
Tandem, with addition to aromatic ring
O
O
O
CO2Et
Mn(OAc)3
HOAc
CO2Et
CO2Et
H
Snider, TL, 1987, 845
H
O
CO2R
O
Mn(OAc)3
Cu(OAc)2
6-endo preferred over
5 exo b/c sterics
CO2R O
CO2R
CO2R O
86%
O
CO2R
O
Mn(OAc)3
Cu(OAc)2
CO2R
H
???
70%
HH
Oxidation of enols
1e- processes
Oxidation of enolates
General information
Cu(II) [usually Cu(OTf)2 or CuCl2], Fe(III) [usually FeCl3 in DMF], and I2 promote enolate dimerization
Proposed mechanistic picture pretty similar for all three:
O
Mn+1
OLi
Mn
LDA
O
O
dimerize
1/2
1 e- oxidation
O
umpolung product
Other possibilities exist for Cu(II) and Fe(III)
O
Mn+2
-M
O
1/2
n
1/2
O
M
OLi
n
O
Mn+1
OLi
O
O
Mn+1
n
1/2
M
O
Generic reaction O
Oxidation of enols
1e- processes
Oxidation of enolates
Cu(II) examples
1. LDA
2. CuCl2
O
1/2
umpolung product O
Saegusa, JACS, 1977, 1487
Examples
O
O
46%
73%
82%
O
O
O
+
:
3
1. LDA
2. CuCl2
2
2
Product ratio
40
20
H3C
O
1. LDA
2. CuCl2
CH3
O
O
1
R
O
N
O
O
O
O
O
Stereoselective Coupling
O
O
O
Cross-coupling
1
O
O
N
R
Et
N
O
Et
O
98:2 (no stereochemical model given)
Porter, TL, 1993, 4457
Generic reaction
O
Oxidation of enols
1e- processes
Oxidation of enolates
Fe(III) examples
O
1. LDA
2. FeCl3/DMF
1/2
O
umpolung product
Frazier, JOC, 1980, 5408
Sample products
O
O
O
OEt
EtO
O
69%
O
52%
60%
1. LDA
2. FeCl3/DMF
+ TolO S
2
SO2Tol
SO2Tol
TolO2S
α,γ: 16%
H3CO
H3C
N
O
N O
Boc
MeO
O
SO2Tol
γ,γ: 68%
Kochi, JACS, 1974, 3332
TL, 1985, 5923
H3CO
H3C
O
N
OLDA;
Fe(acac)3 H3C
N
O
H
N
H3C
O
Boc
O
41%
OCH3
Barran, ACIEE, 2005, 606
N
O
O
Oxidation of enols
1e- processes
Oxidation of enol ethers
OSiMe3
dimerization
OSiMe3
Ph
Ph
Ph
-e-TMS
1
OSiMe3
[O]
-1e-
Ph
Ph
1
O
O
Ph
Ph
yield (%)
55
73
45
30
[O]
Cu(OTf)2/Cu2O
Ag2O
Pb(OAc)4
VO(OEt)Cl2
ref
Kobayashi, Chem. Pharm Bull. 1980, 262
Saegusa, JACS, 1975, 649
Moriarty, TL, 1987, 873
Ohshiro, TL, 1992, 5823
cross-coupling
OSiMe3
OSiMe3
O
VO(OEt)Cl2
+
Ph
Ph
(2 equiv)
cyclization
more substituted = easier to oxidize
more substituted = poorer nucleophile
93%
OSiMe3
O
O
VO(OCH2CF3)Cl2
SiMe3
83%
Livinghouse, JACS, 1998, 2658
O
Oxidation of enols
1e- processes
Oxidation of enol ethers
data in conflict with proposed mechanism:
O
O
hν
Ph Bu3SnSnBu3
Ph
Ph
I
O
OSiMe3
Ph Cu(OTf)2/Cu2O
+
no 5-exo products
O
O
Ph
V
OSiMe3
+
Ph
O
Cl
6-endo
17%
Curran, JOC, 1989, 3104
6-endo-derived
7%
Snider, JOC, 1990, 4786
6-endo
13%
OSiMe3
I
O
Ph
Ph
Ph
+
I 5-exo
43%
radical intermediate
but
O
O
Cl
O
58% y
85%ee
Kurihara,
Chem. Lett. 2001, 1324