Oxidations at CarbonGeneral referencesMarch, Advanced Org Chem, 1992, 1158-1238Trost, Comp. Org. Syn. 1991, vol 7Carey and Sundberg, Advanced Org Chem, part B, 615-664Smith, Org Syn, Chap 3
HCH3
C(-IV)
RCH3
C(-III)R
CH2
OH
C(-1)
RCH
OH
RR
H2C
R
C(-II)
RC
O
RC(0)
RCH
O
C(+I)
HCH2
OH
C(-II)H
CH
O
C(0)
C(II)
RCOR
O
C(+III)
HCOH
O
C(+II)
O
C
OC(+IV)
ROCOR
O
C(+IV)
alkaneRCH2MRCH2SiR3
RCH2X X=halideRCH2NR2RCH2SRRCH2PR2
Acetal: RCH(OR)2
CHOR
Masked form:RHC NR
esteramidethioesternitrileRCX3Ortho ester: RC(OR)3Masked form:O
COR
OR
Ketene Ketene acetal
carbamate
O
NR2ROxanthate
S
SRRO
ureaO
NH2H2N
carbodiimideRN C NR
isocyanate
RN C O
isonitrile R N C
Ketal: R2C(OR)2aminal: R2C(OR)(NR2)dithiane: R2C(SR)2Imine: R2C 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
H2CrO4Jones reagentAs solution with H2SO4 in acetone/waterVery strong and not very selectiveMechanism has been studied extensivelyPredominant 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
Consensus mechanism:
OH
O
Cr
O
O-HO
(H2CrO4 pKa = -1)
+
O
Cr
O
OHO
OH+
Cr
O
OHO
+
H
H O
CrOHHO
+O
Evidence: kH/kD = 6 rate = d[Cr(VI)]/dt = (k1[H+] + k2[H+]2)[HCrO4][ROH] k1/k2 = 0.04
O
Cr
O
OO'instantaneous'
pyridine
O
k1
k2
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
AcOO
Jones Reagent
85%
AcOOH
OH
AcOO
O
AcO O CO2HTL, 1988, 6403
BnOOTBS
OCO2CH3
BnO CO2H
OCO2CH3
88-97%
P. A. Evans, ACIEE, 1999, 3175
Cr-amine reagentsreview: Org. React. 1998, 1-122
added amine helps moderate reactivity of Cr and buffers reaction mixtureThree 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
OHCrO3Py26 equiv O
JOC, 1971, 2035
84%
OH O
CrO3Py2
96%
Tet, 1974, 2027
O
OBzO
HO
CH3
CH3
CrO3Py2
67%
O
OBzO
O
CH3
CH3TL, 1985, 3731
OO
AcO
OH
PCC
OO
AcO
O
81%
JOC, 1992, 3789
OH
O
PCC98%
Examples
Cr-amine reagentsexamples, cont.
O
OH
O
O
PCC70%
De Brabander, OL, 2002, 481
O
OH
OEt
OPvPDC
O
O
OEt
OPv
JOC, 1986, 2717
AcO
OO O
BnOAcO
OO O
BnOOH
PDC
DMF>78%
JOC, 1985, 2095
NH
OH
OTBSH H
ONH
OH
OTBSH H
OO
PDCDMF91%
Tet, 1988, 2149
Cr-amine reagentsalternative reaction manifolds
OH
PCCO OH O
H3COCO2CH3
H3COCO2CH3
PDC
O
40%
JACS, 1987, 3991HO
PCC, NaOAc
CHOTet, 1980, 3091
OH O Cr OHO O
O Cr OHO O
or
O Cr OHO O
O OOHH H
repeat
repeat
[2+2]
McDonald, JACS, 1994, 7921similar reactivity with Mn: JOC, 2004, 3386; with Re JACS 1997, 6022
9%
Cr-mediate synthesis of β,β-disubstituted enonesDauben, JOC, 1977, 682
overall transformation:
OR-MPCC
R
O
mechanismO
OH
R
R-M O
R
CrOO
OHno H to eliminate
[3,3]
OCrO3HH
R
O
examples
O
MeLi;PCC
O90%
O
MeLi;PCC90%
O
O
MgB r
CHO
62%
Activated DMSO oxidations
DCC (Pfitzner-Moffatt oxidation) JACS, 1963, 3027Ac2O JACS, 1967, 2416SO3-Pyridine (Perikh-Doering oxidation) JACS, 1967, 5505Cl2 TL, 1973, 919SOCl2 Tet, 1978, 1651(COCl)2 (Swern oxidation) JOC, 1978, 2480
Many activating agents are available. Some of the more common:
General mechanism
O-
S+ + X Yactivating agent
O
S+
X
HO R
S+
O
R
R3NS+
O
R
H-
H R
O R
R
R
R
+
S(so please keep everything in the hood!)
an added step with (COCl)2 as activating agent:
O
S+
O
O
Cl
Cl-
S+
ClCO2 + CO + Cl- +
HO
R
R
S+
O
R
Ras above
Activated DMSO oxidations Applications
Very mild conditionsReactions are very fast and reliableNever go to acidInexpensive and nontoxic reagents
positives negativesCarbodiimide-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 N
O OH
H3C
O
i-Pr
O N
O O
CH3
O
i-Pr
O N
O O
H3C
O
i-Pr
[O]+
[O] Ratio
80-90%
CrO3, Py, rtJonesPCCPDC, Py, TFASO3-Py, DMSO, Et3N, 0 oC
73:2779:2192:897:399:1
Evans, JACS, 1984, 1154
Activated DMSO oxidations Applications
O O OTBDPS
BrH
OH(ClCO)2, DMSO; Et3N 86%
O O OTBDPS
BrH
O
Falck, OL, 2002, 969
HO
HHO
OBn
O
HO
OBn
(COCl)2, DMSO;Et3N;NH3
not isolated
N
H
OBn
Heathcock JACS, 1988, 8734
HO
OTES OMe
OMOM
SO3-Py, DMSO, Et3N 90%
O
OTES OMe
OMOMDe Brabander, ACIEE, 2003, 1648
Limitations and Extensions of DMSO-based oxidations: the Pummerer Reactionreview: Org. React. 1991, 157
What:R' S
R
O
R' O
How:
R' SR
O
R' S+R
OX
H
R' S+R
R' SR
OCOR
R'
Oactivation
usually use Ac2O or TFAA
Why:install protecting group
O
O
OHTBSO
DMSOAc2O/AcOH O
O
OTBSO
SH3C
=O
O
OMTMTBSO
Methyl thiomethyl etherremoved with Hg(II)
TL, 2003, 3175
introduce aldehyde (or equivalent):
O O
O
CH3
NH3C Ts
H HO
O O
O
CH3
NH3C Ts
H HOH
SPh
O
1. PhSLi2. mCPBA
1.TFAA2. Hg(II), MeOHMsOH
O O
O
CH3
NH3C Ts
H HOH
MeO
OMe
Rapoport, JOC, 1985, 325
(78%)
Limitations and Extensions of DMSO-based oxidations: the Pummerer Reaction, cont.
CO2Me
O
4
SOPh
Li
+BzCl CO2Me
OCOPh
4
S+
Ph-O
(Evans-Mislowrearrangement)
CO2Me
OCOPh
OS
Ph
CO2Me
OCOPh
SPh
O
retro E.-M.
4
4
1. Ac2O, TFAA,AcONa, 2,6-lut.2. HgCl2, CaCO3
65%Corey, TL, 1982, 3463
Nitrogen Nucleophile:
O NH2
SO
Ph NHO
SPh
d.r = 2.7:1 41%
TMSOTfi-Pr2NEt
Kaneko, JACS, 1985, 5490Carbon Nucleophiles
N O
SO
OMe
OMe
TsOH Δ N
MeO
MeO O
SMe
Perkin 1, 1985, 605
O
S+
H
OX
adjacent carbonyl increases acidity and promotes elimination
[2,3]
CO2Me
OCOPh
4
O
Hypervalent Iodine-based reagents
the Dess-Martin reagent
I
CO2H
KBrO3/H2SO4 (D.&M. JACS 1991, 7277)
orOxone (KHSO5 + sulfate salts)(JOC, 1999, 4537)
OI
OHO
O IBXlow solubility in most organic solvents (but, see below)explosive on impact or >200oC
Ac2O,AcOH O
I
O
AcO
OAc
AcO
Dess-Martin periodinane (DMP)Commercially availableAdvantages of DMP:
Reliable with complex moleculesOften need ~1 equivEffective for 1o or 2o ROH; never go to acidEasy to use (nearly idiot-proof)
Mechanism:
O
I
O
AcO
OAc
AcO
O
I
O
O
OAc
AcORCH2OH-AcOH
Bpath a path a (added base doesn't help)
path bO
I+
O
AcO
-OAc (added acid doesn't help)
O
I
O
O
O
AcO O
O
I+
O
O
AcO O-
tight ion pair
orpath c O
R
HO H
HO
H
Hypervalent Iodine-based reagents
one equivalent of water was found to accelerate the reaction: Schreiber, JOC, 1994, 7549
O
I
O
O
O
AcO OH
vsO
I
O
O
O
HO OHMore e- donating
than OAc...
...so acetate is more basic
in practice, often easiest to use CH2Cl2 out of he bottle (not distilled)
Ph
OH
Ph
O
DMP
conditions resultsDry CH2Cl21.1 equiv H2O
97%, 14h97% 0.5h
SciFinder search yielded 104,000 hits for DMP
Other examples:
O
O
OHH3CO
O
O
OH3CO
DMP70%
Danishefsky, JACS, 1988, 6890
Hypervalent Iodine-based reagents: examples
O
OOMe
OMOM
CH3
OH
O
OOMe
OMOM
CH3
O
DMP95%
De Brabander, JACS, 2002, 3245
O
BnO2C CO2BnOTMS
O OO
O
BnO2C CO2BnOTMS
O OO
CHOOH
DMP93%
Nicolaou, ACIEE, 1994, 2184
O
SiO
t-Bu
t-Bu
OHPMBO
N O
OMe
O
SiO
t-Bu
t-Bu
OPMBO
N O
OMe
DMP>95%
Evans, JACS, 1990, 7001
IBX
OI
OHO
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??)
diol to lactone:
OHOH
(how did they make this?)
IBX, DMSO, rt
O
OH82%
TIPS
OHMeO
HO
IBX, DMSO, rt
82%
TIPS
MeOOH
H
OHCorey, TL, 1995, 3485
alcohol to carbonyl to enone:
OH2.3 equiv IBX65 oC, DMSO
O O
H
IO
OHO
OH
O
88%
Nicolaou, JACS, 2000, 7596
other examples
NO
84%
O
H
H
TIPS87%
O
O
H H72%
TPAPreviews: Ley, Synthesis, 1994, 639
Ru(VII) is a strong oxidantreacts rather indescriminately as basic, aq solutionTetra-alkyl amonium counterion modulates reactivitymost successful recipe:
OH TPAP (5mol%)NMO4AMS, CH2Cl2
O TPAP = [n-Pr4N][RuO4] = TetraPropylAmmonium PerruthenateNMO = N-Methyl Morpholine N-Oxide
N+
O
O-H3CAdvantages: Homogeneous solutionsEasy setup/workupSuitable for complex molecules
Mechanism: Problem is how to use a 3e- oxidant for a 2e- oxidation?3RCH2OH + 2Ru(VII) 3RCHO + 2Ru(IV)
OHradical conditions
O
TPAPO
2e- processes dominate
2Ru(VII)
OHR
OR
2 Ru(V)
Ru(IV) + Ru(VI)
2 Ru(IV)
2
2
OHR
OR
3 NMO
3 Morpholine
single e- transfer (set)
TPAP: examples
ZHNO
HN
O
N
OH
O
HNNH
O
C6H4(o-NO2)
Br
ZHNO
HN
O
N
O
O
HNNH
O
C6H4(o-NO2)
Br
TPAP (5mol%)NMO (150 mol%)MS4A
78%
Harran, ACIEE, 2001, 4766OTBDPS
O
TPAP: 70%Swern: 38%MnO2: 0%
O
O
OTBDPS
TPAP: 70%Swern: 35%
O
OO
OBn
H
TPAP: 91%
O
Ph
O
Ph
N-oxoammonium mediated oxidationsreviews: Synthesis, 1996, 1153; Heterocycles, 1988, 509
overall transformation:
OH
N
OH
H
+
N-oxoammonium
X- OO
N+ + + HX
Mechanism:3 proposals in the literature
N+
O-O
H
N+
OHO
HB
NO
OH
similar to Cope elimination similar to Hofmann eliminationGanem, 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
N
O
2,2,6,6 tetramethylpiperidinyloxyl radical (TEMPO)
mCPBA, NaOCl, oxone, PhI(OAc)2, etc N+
O
N-oxoammonium mediated oxidations: examples
OH
NO
Boc TEMPO, NaOCl, NaBrEtOAc/Toluene/Water
90% O
NO
Boc
Tetrahedron, 1998, 6051
O
BnO OBn
BnO
OHTEMPO, PhI(OAc)2
O
BnO OBn
BnO
O
PhS
OH
TEMPO, PhI(OAc)2PhS
OJOC, 1997, 6974
OH
HN
HCl
mCPBAO
O
JOC, 1977, 2077OH
OH8
TEMPO (10 mol%) TBACl (10mol%) NCS (1.5 equiv)
OH
O8JOC, 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<2Old batches can go bad; for preparation recipes, see Encycopedia of Reagents for Organic SynthesisEt2O or hydrocarbon solvents most commonAlcoholic solvents slow reaction, so can be used to enhance selectivityUsually use excess (5:1 by wt good starting point)
OH O
MnO2Hexanes Corey, JACS, 1968, 5616
HO OH
7
MnO2 O OH
775%
OH
OH
MnO2, Et2NHO
OEtNEt2
EtOH
other reactions:CO2Me
CO2Me
CO2Me
CO2Me
MnO2
92% HN
O
CO2Me
BocHN
MnO2 Py
N
O
CO2Me
BocHN
diol cleavage can be a problem
Sodium Chlorite (NaClO2)Reagent of choice for aldehyde --> acidOften see 2 step (e.g. Swern + NaClO2) rather than Jones OxidationUsually include 2-Methyl-2-butene to trap reactive Cl2
O
Cl
O
-O
H2O
OH
OH O
OH
ClOH
OH
H
O
OH+ NaOCl
ClO2-
H
CHO
TBSO
H
CO2H
TBSO
NaClO2, NaH2PO42-Me-2-ButenetBuOH/H2O JOC, 1980, 4825
O
MeO
TesO
OMeBnO
OMeO
OMOM
NaClO2, NaH2PO42-Me-2-ButenetBuOH/H2O
O
MeO
TesO
OMeBnO
CO2HMeO
OMOM
>80%
De Brabander, ACIEE, 2003, 1648
O
OBu3Sn
HO
CH31.TPAP, NMO2. NaClO2, NaH2PO4, 2-Me-2-Butene, tBuOH/H2O O
OBu3Sn
HO2C
CH3
>52%Nicolaou, Chem Com.1999, 809
examples:
mechanism:
NaClO2/TEMPOA one pot method for alcohol --> acid has been developed by Merck ProcessJOC, 1999, 2564
OH
TEMPO (7 mol%)NaOCl (2 mol%)NaClO2 (2 equiv)pH 6.7, CH3CN/H2O
O
OH
N
O
N
O
OH
O
N
OH
O O
OH
NaClO2
NaOCl
NaOCl
NaCl
Examples
N
O
OHO2C
Ph
95%
PhCO2H
NHCbz
85%
Ph
CO2H
95%
Oppenauer OxidationReview: Syn 1994, 1007
OH
R R+
O O
H
OM
O
R R
+OHOppenauer
Oxidation
Meerwein-Ponndorf-Verlely (MPV)reduction
M is usually hard Lewis acidAl, Zr, Ti, La most common-Lewis acid activation of carbonyl-Alkoxide formation-PreorganizationOppenauer and MPV infrequently used
Mild conditions, never go to acidThermodynamic controlCan see product inhibition (requires high [catalyst]):
i.e.O
M
H
O
R R
M
Hsubstrate
slow
examples
OH Al(OtBu)3
OO
JACS, 1960, 1240
O
90%
SePh
OH
Al2O3Cl3CCHO
SePh
O
TL, 1977, 3227