Oxidations at Carbon
General references
March, Advanced Org Chem, 1992, 1158-1238
Trost, Comp. Org. Syn. 1991, vol 7
Carey and Sundberg, Advanced Org Chem, part B, 615-664
Smith, Org Syn, Chap 3
O
OH
CH3
H
C(-IV)
C(-II)
isonitrile R
C(+II)
C
N
O
RCH2X X=halide
RCH2NR2
RCH2SR
RCH2PR2
COR
R
C(+III)
Acetal: RCH(OR)2
RHC NR
Masked form:
CH
OR
R
H2
C
OH
O
CH
R
C(-II)
R
R
C(0)
C
R
C(II)
Ketal: R2C(OR)2
aminal: R2C(OR)(NR2)
dithiane: R2C(SR)2
Imine: R2C NR
R
O
O
CH
R
C(+I)
C(-1)
alkane
RCH2M
RCH2SiR3
O
C(+IV)
H
C(0)
CH2
R
C
COH
H
OH
CH3
R
C(-III)
O
CH
CH2
H
O
COR
RO
C(+IV)
ester
amide
thioester
nitrile
RCX3
Ortho ester: RC(OR)3
Masked form:
O
OR
C
OR
Ketene Ketene acetal
O
carbamate
RO S NR2
xanthate
RO O SR
urea
H2N
carbodiimide
RN
NH2
C
isocyanate
RN
C
O
NR
Chromium-based Oxidations
Very powerful oxidants
Many variations on the theme
Reactivity modulated by ligands on Cr (Org. Rxn., 1998, 53, 1-122)
Likely pretty toxic
H2CrO4
Jones reagent
As solution with H2SO4 in acetone/water
Very strong and not very selective
Mechanism has been studied extensively
Predominant mechanism likely to be Cr(VI) --> Cr(IV), taken as prototype for other Cr-based reagents
Mechanism: See Westheimer J. Phys. Chem. 1959, 538; Chem Rev. 1949, 419
Involving radical intermediates: Wieberg, JACS, 1974, 1884
Involving Cr(IV) --> Cr(II) Espenson, JACS, 1992, 4205
O
HO Cr
Consensus mechanism:
O
OH + HO Cr O
-
O
(H2CrO4 pKa = -1)
O
H
O
+
OH+
HO Cr
O
k1
O
O
+
Cr
HO
k2
O
H
Evidence: kH/kD = 6
rate = d[Cr(VI)]/dt = (k1[H+] + k2[H+]2)[HCrO4][ROH]
O
O
'instantaneous'
O Cr O
pyridine
O
k1/k2 = 0.04
OH
Jones Reagent: Reactivity
Jones reagent can promote acid-catalyzed reactions (desilylation, Friedel-Crafts type, olefin migrations, epoxide
openings) and diol cleavage, as in the examples below.
C8H17
85%
AcO
AcO
OH
O
AcO
OH
O
CO2H
AcO
O
TL, 1988, 6403
O
OTBS
BnO
Jones Reagent
88-97%
O
CO2CH3
CO2H
BnO
O
CO2CH3
P. A. Evans, ACIEE, 1999, 3175
Cr-amine reagents
review: Org. React. 1998, 1-122
added amine helps moderate reactivity of Cr and buffers reaction mixture
Three common reagents:
CrO3Py2 (Collins Reagent): hydroscopic, often requires excess, if dry will stop at aldehyde
[ClCrO3][PyH] (pyridinium chlorochromate, PCC, Corey's reagent): often oxidant of choice for first
attempt, used in cunjuction with mol sieves (to keep dry and prevent clumping) or Celite (usually 1:1
mass ratio for both); Air stable, not too hydroscopic; will stop at aldehyde
(PyH+)2Cr2O7 (pyridinium dichromate, PDC): in CH2Cl2, alcohol to aldehyde; more often used in DMF
for alcohol to acid
Examples
CrO3Py2
OH 6 equiv
OH
O
84%
O
PCC
O
JOC, 1971, 2035
AcO
81%
O
O
AcO
JOC, 1992, 3789
CrO3Py2
96%
OH
O
PCC
98%
Tet, 1974, 2027
HO
OH
O
BzO
O
O
CH3
CrO3Py2
CH3
67%
BzO
TL, 1985, 3731
O
O
O
CH3
O
CH3
Cr-amine reagents
examples, cont.
PCC
70%
O
OH
OEt
O
O
OEt
De Brabander, OL, 2002, 481
OTBS
H H
OH PDC
DMF
O
O
OPv
PDC
OPv
OH
O
O
O
OH
91%
NH
O
NH
O
Tet, 1988, 2149
JOC, 1986, 2717
O
OTBS
H H
O
O
O
PDC
AcO
BnO
DMF
>78%
AcO
OH
BnO
JOC, 1985, 2095
O
Cr-amine reagents
alternative reaction manifolds
PCC
O
OH
OH
O
O
PDC
PCC, NaOAc
40%
H3CO
H3CO
CO2CH3
CO2CH3
JACS, 1987, 3991
HO
Tet, 1980, 3091
[2+2]
OH
McDonald, JACS, 1994, 7921
similar reactivity with Mn: JOC, 2004,
3386; with Re JACS 1997, 6022
O Cr O
HO
O
repeat
O Cr O
HO
O
or
repeat
O Cr O
HO
O
O
O
H
9%
H
OH
CHO
Cr-mediate synthesis of β,β-disubstituted enones
Dauben, JOC, 1977, 682
overall transformation:
R
O
R-M
PCC
O
mechanism
O
R
R-M
R
R
OH
O
[3,3]
Cr
O
O
OH
H
OCrO3H
O
no H to eliminate
examples
O
O
MeLi;
PCC
90%
MeLi; O
PCC
90%
O
CHO
O
MgB r
62%
Activated DMSO oxidations
General mechanism
X
O+
S+
X Y
activating agent
O
S+
H
S+
O
R
HO
R3N
O
R
H
R
R
O
-
S+
R
R
HO
R
Cl
S+
O
S
+
O
CO2 + CO + Cl- +
R
+
S
(so please keep
everything in the
hood!)
R
an added step with (COCl)2 as activating agent:
O
R
S+
O
R
Cl
ClMany activating agents are available. Some of the more common:
DCC (Pfitzner-Moffatt oxidation) JACS, 1963, 3027
Ac2O JACS, 1967, 2416
SO3-Pyridine (Perikh-Doering oxidation) JACS, 1967, 5505
Cl2 TL, 1973, 919
SOCl2 Tet, 1978, 1651
(COCl)2 (Swern oxidation) JOC, 1978, 2480
R
as above
Activated DMSO oxidations
Applications
positives
Very mild conditions
Reactions are very fast and reliable
Never go to acid
Inexpensive and nontoxic reagents
negatives
Carbodiimide-derived urea hard to remove in Moffatt
(use of EDCI partially addresses this problem)
Opperationally more involved that some other methods
(but still pretty easy)
Pummerer rearrangement can interfere (see below)
DMS angers the biologists
Examples
O
O
O
O
OH
[O]
80-90%
N
H3C
i-Pr
O
O
O
O
N
+
i-Pr
CH3
O
O
N
H3 C
i-Pr
[O]
Ratio
CrO3, Py, rt
Jones
PCC
PDC, Py, TFA
SO3-Py, DMSO, Et3N, 0 oC
73:27
79:21
92:8
97:3
99:1
Evans, JACS, 1984, 1154
O
Activated DMSO oxidations
Applications
O
OH
Br
O
O
(ClCO)2, DMSO; Et3N
86%
Br
H
O
OTBDPS
OBn
H
HO
HO
(COCl)2, DMSO; O
Et3N;
NH3
O
H
OTBDPS
Falck, OL, 2002, 969
OBn
OBn
H
H
O
N
not isolated
Heathcock JACS, 1988, 8734
OTES OMe
HO
OTES OMe
SO3-Py, DMSO, Et3N
90%
O
OMOM
OMOM
De Brabander, ACIEE, 2003, 1648
Limitations and Extensions of DMSO-based oxidations: the Pummerer Reaction
review: Org. React. 1991, 157
What:
R
R'
S
R'
O
H
How:
R
R'
S
O
O
activation
R'
S
+
OCOR
R
S+
R'
usually use Ac2O or TFAA
R
O
R
R'
OX
S
R'
Why:
install protecting group
O
O
DMSO
Ac2O/AcOH
O
TBSO
O
H3C
O
introduce aldehyde (or equivalent):
O
O
O
H
H
N
H3C
Ts
O
CH3
Methyl thiomethyl ether
removed with Hg(II)
O
TBSO
OMTM
TL, 2003, 3175
O
O
O
1. PhSLi
2. mCPBA
=
S
TBSO
OH
O
O
Ph
S
O
H
H
OH
N
H3 C
Ts
1.TFAA
2. Hg(II), MeOH
MeO
CH3 MsOH
(78%)
OMe
O
O
H
H
OH
N
H3 C
Ts
Rapoport, JOC, 1985, 325
CH3
Limitations and Extensions of DMSO-based oxidations: the Pummerer Reaction, cont.
O
CO2Me
4
OCOPh
OCOPh
BzCl
CO2Me
+
4
SOPh
-
4
(Evans-Mislow
rearrangement)
S+
O
CO2Me
[2,3]
Ph
Li
O
S
Ph
retro E.-M.
OCOPh
O
CO2Me
4
Corey, TL, 1982, 3463
O
Nitrogen Nucleophile:
Carbon Nucleophiles
S
Ph
NH2
O
1. Ac2O, TFAA,
AcONa, 2,6-lut.
2. HgCl2, CaCO3
65%
O
OCOPh
S
CO2Me
Ph
4
SPh
TMSOTf
i-Pr2NEt
O
NH Kaneko, JACS, 1985, 5490
d.r = 2.7:1
41%
SMe
S
O
N
O
O
OX
S+
OMe
OMe
TsOH
Δ
MeO
N
MeO
Perkin 1, 1985, 605
O
H
adjacent carbonyl
increases acidity and
promotes elimination
Hypervalent Iodine-based reagents
the Dess-Martin reagent
KBrO3/H2SO4
I
(D.&M. JACS 1991, 7277)
HO
Ac2O,
AcOH
I
O
or
CO2H Oxone (KHSO5 + sulfate salts)
(JOC, 1999, 4537)
AcO
O
RCH2OH
OAc -AcOH
O
OAc
O
H
H
O
O
O
I
O
O
(added acid
doesn't help)
O
O
AcO
H
I+
path b
-OAc
O
O
Dess-Martin periodinane
(DMP)
Commercially available
(added base doesn't help)
path a
AcO
I
O
O
O
path a B
H
AcO
or
OI+
O
O
tight ion pair
O
OAc
O
IBX
low solubility in most organic
solvents (but, see below)
explosive on impact or >200oC
Advantages of DMP:
Reliable with complex molecules
Often need ~1 equiv
Effective for 1o or 2o ROH; never go to acid
Easy to use (nearly idiot-proof)
Mechanism:
AcO
AcO
I
AcO
AcO
I
O
O
O
path c
R
Hypervalent Iodine-based reagents
one equivalent of water was found to accelerate the reaction: Schreiber, JOC, 1994, 7549
AcO
More e- donating
than OAc...
H
O
O
HO
I
O
I
vs
O
H
O
O
O
O
O
O
in practice, often easiest to use CH2Cl2 out of he bottle (not distilled)
Ph
Ph
DMP
O
OH
conditions
Dry CH2Cl2
1.1 equiv H2O
Other examples:
results
97%, 14h
97% 0.5h
SciFinder search yielded 104,000 hits for DMP
O
O
DMP
70%
O
OH
H3CO
O
O
H3CO
Danishefsky, JACS, 1988, 6890
...so acetate is more basic
Hypervalent Iodine-based reagents: examples
OH
OMe
O
O
OMe
OMOM
O
O
DMP
95%
OMOM
O
CH3
CH3
De Brabander, JACS, 2002, 3245
OTMS
CO2Bn
BnO2C
CHO
DMP
93%
OH
O
OTMS
CO2Bn
BnO2C
O
O
O
O
O
O
O
Nicolaou, ACIEE, 1994, 2184
O
t-Bu
Si
O
O
Si
t-Bu
O
DMP
>95%
O
OH
OMe
t-Bu
PMBO
PMBO
N
t-Bu
O
N
OMe
O
Evans, JACS, 1990, 7001
IBX
HO
O
I
O
Insoluble in most organic solvents, but somewhat soluble in DMSO. For alcohol to
carbonyl, see TL, 1984, 8019 (why did it take 10 years for someone to try DMSO??)
O
diol to lactone:
TIPS
IBX, DMSO, rt
TIPS
H
IBX, DMSO, rt
OH
82%
82%
OH
O
MeO
MeO
OH HO
OH
(how did they make this?)
H
O
OH
Corey, TL, 1995, 3485
alcohol to carbonyl to enone:
HO
O
I
OH
O
O
2.3 equiv IBX
65 oC, DMSO
O
O
OH
Nicolaou, JACS, 2000,
7596
88%
O
H
other examples
O
H
TIPS
O
N
84%
H
87%
H
O
H
72%
TPAP
reviews: Ley, Synthesis, 1994, 639
Ru(VII) is a strong oxidant
reacts rather indescriminately as basic, aq solution
Tetra-alkyl amonium counterion modulates reactivity
most successful recipe:
TPAP (5mol%)
NMO
4AMS, CH2Cl2
OH
TPAP = [n-Pr4N][RuO4] = TetraPropylAmmonium Perruthenate
NMO = N-Methyl Morpholine N-Oxide
O
O
N+
Advantages:
Homogeneous solutions
Easy setup/workup
Suitable for complex molecules
H3C
O-
Mechanism: Problem is how to use a 3e- oxidant for a 2e- oxidation?
3RCHO + 2Ru(IV)
3RCH2OH + 2Ru(VII)
2R
O
OH
3 Morpholine
radical conditions
2Ru(VII)
OH
2 R
O
3 NMO
O
2 Ru(IV)
TPAP
O
R
Ru(IV)
+
Ru(VI)
2e- processes dominate
R
2 Ru(V)
OH
single e- transfer
(set)
TPAP: examples
N
HN
HN
HN
NH
O
ZHN
O
O
O OH
NH
O
ZHN
O
TPAP (5mol%)
NMO (150 mol%)
MS4A
78%
HN
N
O
O
O
OO
Br
Br
C6H4(o-NO2)
C6H4(o-NO2)
Ph
Ph
OTBDPS
O
Harran, ACIEE, 2001, 4766
O
H
O
O
O
OTBDPS
TPAP: 70%
Swern: 38%
MnO2: 0%
TPAP: 70%
Swern: 35%
O
TPAP: 91%
OBn
N-oxoammonium mediated oxidations
reviews: Synthesis, 1996, 1153; Heterocycles, 1988, 509
overall transformation:
O
OH
X+
N+
N-oxoammonium
O
OH
N
+
HX
+
H
Mechanism:
3 proposals in the literature
-
N+
N+
O
O
H
similar to Cope elimination
HO
N
O
H
O
H
O
B
similar to Hofmann elimination
Ganem, JOC, 1975, 1998-2000; Semmelhack, TL, 1986, 1119; Bobbitt, JOC, 1991, 6110
N-oxoammonium salts are too unstable to store; always prepared in situ using catalytic nitroxyl radical and
stoichiometric oxidant.
TEMPO is most successful. Catalyzes oxidation of 1o and 2o alcohols to aldehydes and ketones.
For a list of stoichiometric oxidants, see JOC, 1997, 6974
O
O
N
N+
mCPBA, NaOCl, oxone, PhI(OAc)2, etc
2,2,6,6 tetramethylpiperidinyloxyl radical
(TEMPO)
N-oxoammonium mediated oxidations: examples
Boc
N
O
Boc
TEMPO, NaOCl, NaBr
EtOAc/Toluene/Water
N
O
90%
OH
O
Tetrahedron, 1998, 6051
BnO
BnO
O
O
OH
BnO
TEMPO, PhI(OAc)2
O
BnO
OBn
PhS
TEMPO, PhI(OAc)2
OBn
PhS
O
JOC, 1997, 6974
OH
HCl
H
N
mCPBA
OH
O
O
JOC, 1977, 2077
OH
TEMPO (10 mol%) TBACl (10mol%)
NCS (1.5 equiv)
8
OH
OH
O
8
JOC, 1996, 7452
MnO2
Metal oxide used for selective oxidation of allylic and benzylic alcohols; other pathways available
'MnO2' only an approximation, really MnOx where 1.93<x<2
Old batches can go bad; for preparation recipes, see Encycopedia of Reagents for Organic Synthesis
Et2O or hydrocarbon solvents most common
Alcoholic solvents slow reaction, so can be used to enhance selectivity
Usually use excess (5:1 by wt good starting point)
MnO2
Hexanes
Corey, JACS, 1968, 5616
O
OH
HO
OH
7
MnO2
O
OH
75%
7
NEt2
OH
OEt
MnO2, Et2NH
OH
O
EtOH
other reactions:
CO2Me
CO2Me
O
MnO2
92%
CO2Me
CO2Me
diol cleavage can be a problem
BocHN
MnO2
Py
O
BocHN
N
HN
CO2Me
CO2Me
Sodium Chlorite (NaClO2)
Reagent of choice for aldehyde --> acid
Often see 2 step (e.g. Swern + NaClO2) rather than Jones Oxidation
Usually include 2-Methyl-2-butene to trap reactive Cl2
OH
OH
mechanism:
Cl
ClO2H2O
O
O
OH
OH
-
+
OH
OH
O
H
Cl
examples:
O
O
H
H
NaClO2, NaH2PO4
2-Me-2-Butene
tBuOH/H2O
JOC, 1980, 4825
CO2H
CHO
TBSO
TBSO
OMe
BnO
NaOCl
O
TesO
OMOM
MeO
OMe
BnO
O
MeO
Bu3Sn
CH3
O
O
HO
NaClO2, NaH2PO4
2-Me-2-Butene
tBuOH/H2O
>80%
De Brabander,
ACIEE, 2003, 1648
OMOM
O
TesO
MeO
MeO
Bu3Sn
1.TPAP, NMO
2. NaClO2, NaH2PO4,
2-Me-2-Butene, tBuOH/H2O
>52%
CH3
O
O
HO2C
CO2H
Nicolaou, Chem Com.
1999, 809
NaClO2/TEMPO
A one pot method for alcohol --> acid has been developed by Merck Process
JOC, 1999, 2564
TEMPO (7 mol%)
NaOCl (2 mol%)
OH
NaClO2 (2 equiv)
O
pH 6.7, CH3CN/H2O
OH
O
O
N
N
NaOCl
OH
NaCl
O
NaOCl
NaClO2
OH
N
O
O
OH
Examples
O
HO2C
N
CO2H
Ph
CO2H
Ph
NHCbz
O
95%
85%
Ph
95%
Oppenauer Oxidation
Review: Syn 1994, 1007
MeerweinPonndorfVerlely (MPV)
reduction
M
+
R
O
Oppenauer
Oxidation
O
OH
O
O
+
H
R
OH
R
R
M is usually hard Lewis acid
Al, Zr, Ti, La most common
-Lewis acid activation of carbonyl
-Alkoxide formation
-Preorganization
Oppenauer and MPV infrequently used
Mild conditions, never go to acid
Thermodynamic control
Can see product inhibition (requires high [catalyst]):
i.e.
M
O
M
slow
O
R
R
H
substrate
H
examples
OH
O
Al(OtBu)3
O
O
90%
SePh
SePh
OH
O
Al2O3
Cl3CCHO
TL, 1977, 3227
JACS, 1960, 1240