Ox Id at Ions

8/2/2019 Ox Id at Ions

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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)

RCH2

OH

C(-1)

RCH

OH

RR

H2C

R

C(-II)

RC

O

R

C(0)

RCH

O

C(+I)

HCH2

OH

C(-II)

HCH

O

C(0)

C(II)

RCOR

O

C(+III)

HCOH

O

C(+II)

O

C

O

C(+IV)

ROCOR

O

C(+IV)alkaneRCH2MRCH2SiR3

RCH2X X=halideRCH2NR2RCH2SRRCH2PR2

Acetal: RCH(OR)2

CH

OR

Masked form:

RHC NResteramidethioesternitrileRCX3

Ortho ester: RC(OR)3Masked form:

O

C

OR

OR

Ketene Ketene acetal

carbamateO

NR2RO

xanthateS

SRRO

urea

O

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


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Chromium-based Oxidations Very powerful oxidants

Many variations on the themeReactivity 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 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, 419Involving radical intermediates: Wieberg, JACS, 1974, 1884Involving Cr(IV) --> Cr(II) Espenson, JACS, 1992, 4205

Consensus mechanism:

OH

O

Cr

O

O-HO

(H2CrO4 pKa = -1)

+

O

CrO

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

CrO

OO

'instantaneous'

pyridine

O

k1

k2


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Jones Reagent: Reactivity

Jones reagent can promote acid-catalyzed reactions (desilylation, Friedel-Crafts type, olefin migrations, epoxideopenings) and diol cleavage, as in the examples below.

C8H17

AcOO

Jones Reagent

85%

AcOOH

OH

AcOO

O

AcO O CO2H

TL, 1988, 6403

BnOOTBS

OCO2CH3

BnO CO2H

OCO2CH3

88-97%

P. A. Evans, ACIEE, 1999, 3175


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Cr-amine reagentsreview: 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

OH

CrO3Py26 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

O

O

AcO

OH

PCC

O

O

AcO

O

81%

JOC, 1992, 3789

OH

O

PCC

98%

Examples


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Cr-amine reagentsexamples, cont.

O

OH

O

O

PCC70%

De Brabander, OL, 2002, 481

O

OH

OEt

OPv PDC

O

O

OEt

OPv

JOC, 1986, 2717

AcO

OO O

BnO

AcO

OO O

BnO

OH

PDC

DMF>78%

JOC, 1985, 2095

NH

OH

OTBSH H

ONH

OH

OTBSH H

O

O

PDCDMF

91%

Tet, 1988, 2149


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Cr-amine reagentsalternative reaction manifolds

OH

PCC

O OH O

H3CO

CO2CH3

H3CO

CO2CH3

PDC

O

40%

JACS, 1987, 3991HO

PCC, NaOAc

CHOTet, 1980, 3091

OHO

Cr OHO

O

OCr O

HOO

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%


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Cr-mediate synthesis of ,-disubstituted enonesDauben, JOC, 1977, 682

overall transformation:

OR-MPCC

R

O

mechanism

O

OH

R

R-M O

R

CrOO

OH

no H to eliminate

[3,3]

OCrO3HH

R

O

examplesO

MeLi;PCC

O

90%

O

MeLi;PCC

90%

O

O

MgB r

CHO

62%


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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 Y

activating agent

O

S+

X

HO R

S+

O

R

R3NS+

O

R

H-

H R

O R

R

R

R

+

S

(so please keepeverything in thehood!)

an added step with (COCl)2 as activating agent:

O

S+

O

O

Cl

Cl-

S+

Cl

CO2 + CO + Cl- +

HO

R

R

S+

O

R

Ras above


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Activated DMSO oxidationsApplications

Very mild conditionsReactions are very fast and reliableNever go to acidInexpensive and nontoxic reagents

positives 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 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, rt

Jones

PCC

PDC, Py, TFA

SO3-Py, DMSO, Et3N, 0oC

73:27

79:21

92:8

97:3

99:1

Evans, JACS, 1984, 1154


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Activated DMSO oxidationsApplications

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, Et3N90%

O

OTES OMe

OMOM

De Brabander, ACIEE, 2003, 1648


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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 IBX

low solubility in most organic

solvents (but, see below)explosive on impact or >200oC

Ac2O,

AcOHO

I

O

AcO

OAc

AcO

Dess-Martin periodinane(DMP)

Commercially availableAdvantages 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:

O

I

O

AcO

OAc

AcO

O

I

O

O

OAc

AcORCH2OH-AcOH

Bpath a path a (added base doesn't help)

path b

O

I+

O

AcO

-OAc (added aciddoesn't help)

O

I

O

O

O

AcOO

O

I+

O

O

AcOO-

tight ion pair

orpath c O

R

H

O H

HO

H


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Hypervalent Iodine-based reagents

one equivalent of water was found to accelerate the reaction: Schreiber, JOC, 1994, 7549

O

I

O

O

O

AcOO

H

vs

O

I

O

O

O

HOO

HMore 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 results

Dry 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


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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

O

O

O

BnO2C CO2BnOTMS

O O

O

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


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IBX

O

I

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:

OH

OH(how did they make this?)

IBX, DMSO, rt

O

OH

82%

TIPS

OH

MeOHO

IBX, DMSO, rt

82%

TIPS

MeOOH

H

OHCorey, TL, 1995, 3485

alcohol to carbonyl to enone:

OH

2.3 equiv IBX

65 oC, DMSO

O O

H

IO

OHO

OH

O

88%

Nicolaou, JACS, 2000,7596

other examples

N

O

84%

O

H

H

TIPS

87%

O

O

H H

72%


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TPAPreviews: Ley, Synthesis, 1994, 639

Ru(VII) is a strong oxidantreacts rather indescriminately as basic, aq solutionTetra-alkyl amonium counterion modulates reactivitymost successful recipe:

OHTPAP (5mol%)NMO

4AMS, CH2Cl2

O TPAP = [n-Pr4N][RuO4] = TetraPropylAmmonium PerruthenateNMO = N-Methyl Morpholine N-Oxide

N+

O

O-H3C

Advantages: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)

OH

radical conditionsO

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)


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TPAP: examples

ZHNO

HN

O

N

OH

O

HN

NH

O

C6H4(o-NO2)

Br

ZHNO

HN

O

N

O

O

HN

NH

O

C6H4(o-NO2)

Br

TPAP (5mol%)

NMO (150 mol%)MS4A78%

Harran, ACIEE, 2001, 4766

OTBDPSO

TPAP: 70%Swern: 38%MnO2: 0%

O

O

OTBDPS

TPAP: 70%Swern: 35%

O

OO

OBn

H

TPAP: 91%

O

Ph

O

Ph


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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

H

B

NO

OH

similar to Cope elimination 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

N

O

2,2,6,6 tetramethylpiperidinyloxyl radical(TEMPO)

mCPBA, NaOCl, oxone, PhI(OAc)2, etcN+

O


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N-oxoammonium mediated oxidations: examples

OH

N

O

BocTEMPO, NaOCl, NaBrEtOAc/Toluene/Water

90% O

N

O

Boc

Tetrahedron, 1998, 6051

O

BnO OBn

BnO

OH TEMPO, PhI(OAc)2

O

BnO OBn

BnO

O

PhS

OH

TEMPO, PhI(OAc)2PhS

O

JOC, 1997, 6974

OH

HN

HCl

mCPBA

OO

JOC, 1977, 2077

OH

OH8

TEMPO (10 mol%) TBACl (10mol%)NCS (1.5 equiv)

OH

O8JOC, 1996, 7452


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MnO2

Metal oxide used for selective oxidation of allylic and benzylic alcohols; other pathways available'MnO2' only an approximation, really MnOx where 1.93


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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:


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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

NO

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%


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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

Ox Id at Ions

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