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