Oxidation of Alcohols O O H OH 1 alcohol: R H R H R OH O - - PowerPoint PPT Presentation

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Oxidation of Alcohols O O H OH 1 alcohol: R H R H R OH O - - PowerPoint PPT Presentation

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Oxidation of Alcohols O O H OH 1 alcohol: R H R H R OH O H OH 2 alcohol: R H R R H OH 3 alcohol: No Reaction R H A. Chromium Based Reagents General Mechanism: :B O H H H H slow O + O CrL n R OH

slide-1
SLIDE 1

Oxidation of Alcohols

R H OH H R H O R OH O R H OH H R R O R H OH H No Reaction 1° alcohol: 2° alcohol: 3° alcohol:

slide-2
SLIDE 2
  • A. Chromium Based Reagents

General Mechanism:

  • 1° alcohols: under anhydrous conditions (Collins, PCC, PDC) will stop at aldehyde
  • in presence of aqueous acid (Jones), see further (rapid) oxidation to carboxylic acid
  • oxidation of 2° alcohols give ketones
  • these processes generate chromium waste (toxic)

R OH H H O CrLn R O H H Cr O Ln-1 R H O + slow H3O R OH O R OH OH H :B

slide-3
SLIDE 3
  • A. Chromium Based Reagents
  • 1. CrO3/H2SO4 (aq): Jones Oxidation
  • 1° alcohol  CO2H
  • rapid reaction
  • strongly acidic; not useful for acid sensitive substrates
  • reaction can effectively be run as a titration
  • preparation
  • reactivity
  • reagent is shelf stable

CrO3 + H2O + H2SO4 H2O Cr O Cr HO OH O O O O HO Cr OH O O 2 (concentrated) (dilute) O OH CrO3, H2SO4 acetone O OH O 85%

Yamamoto Tetrahedron 1990, 46, 4595.

slide-4
SLIDE 4
  • A. Chromium Based Reagents
  • mechanism
  • stoichiometry: 3 R2CHOH + 2 CrO3 + 6 H+  3 R2C=O + 2 Cr3+ + 6 H2O

R' O H R Cr O OH R R' O slow R' OH H R H2CrO4 acetone CrVI (red) O + H2CrO3 HOCrO CrIII (green) R2CH-OH + Cr(VI) R2C=O + Cr(IV) + 2 H+ R2CH-OH + Cr(IV) R2C=O + Cr(II) + 2 H+ Cr(II) + Cr(VI) Cr(III) + Cr(V) R2CH-OH + Cr(V) R2C=O + Cr(III) + 2 H+

slide-5
SLIDE 5
  • A. Chromium Based Reagents
  • 2. CrO3•pyridine: Collins reagent
  • 1° alcohol  CHO
  • neutral to slighlty basic; good for acid sensititve substrates
  • requires large excess of reagent; anhydrous conditions
  • preparation
  • reactivity

CrO3 + 2 pyridine N Cr N O O O hygroscopic red crystalline solid H2O (Cr2O7)2-(pyrH+)2 (yellow)

  • important: add CrO3 to pyridine (reverse results in strong exotherm!)
  • Sarett: in situ generation in pyridine
  • Collins: isolated solid; reaction in CH2Cl2
  • Radcliff: in situ generation in CH2Cl2

CrO3, pyr CH2Cl2 OH H O H

Ratcliffe JOC 1970, 35, 4000.

95%

slide-6
SLIDE 6
  • A. Chromium Based Reagents
  • 3. Pyridinium Chlorochromate (PCC): Corey-Suggs Oxidation
  • 1° alcohol  CHO
  • can use in near stoichiometric amounts (ca. 1.5 equiv)
  • mild conditions; slightly acidic  can buffer with NaOAc
  • add powd MS or Celite to facilitate product isolation
  • addition of MS can accelerate rxn rate
  • can promote allylic rearrangements
  • preparation
  • reactivity
  • stable; commercially available
  • chloride facilitates formation of chromate ester

CrO3 + HCl + pyridine N H Cr O

  • range solid

O Cl O O OH O PCC 4Å MS, CH2Cl2 94% O O O

Nicolaou J. Am. Chem. Soc. 1988, 110, 4672

slide-7
SLIDE 7
  • A. Chromium Based Reagents
  • 4. Pyridinium Dichromate (PDC): Corey-Schmidt Oxidation
  • product of reaction depends on solvent used

CH2Cl2: 1° alcohol  CHO DMF: 1° alcohol  CO2H (allylic alcohols give CHO)

  • oxidizes more slowly than other Cr-based reagents
  • mild conditions; less acidic than PCC
  • preparation
  • reactivity
  • stable; commercially available

CrO3 + pyridine + H2O N H

  • range solid

2 Cr2O72-

PDC DMF PDC CH2Cl2 OH CO2H O

Corey Tetrahedron Lett. 1970, 20, 399.

slide-8
SLIDE 8
  • B. Manganese Based Reagents
  • 1. Manganese Dioxide (MnO2)
  • selective oxidation of allylic and benzylic alcohols; significant rate difference!
  • 1° alcohol  CHO
  • slow reaction, requires large excess of reagent
  • H bonding solvents show strong deactivating effect; non-polar solvents best
  • mild; no isomerization of double bonds upon oxidiation of allylic alcohols
  • reagent
  • reactivity
  • dark brown or black solid
  • structure/activity depends on preparation
  • non-stoichiometric material containes Mn(II) and Mn(III) oxides and hydrated

species

MeO MeO OH OH MnO2 acetone MeO MeO OH O

slide-9
SLIDE 9
  • B. Manganese Based Reagents
  • 2. Manganese Dioxide, ROH, NaCN: Corey-Gilman-Ganem Oxidation
  • direct oxidation of 1° allylic/benzylic alcohols to esters
  • more commonly used for the conversion of conjugated aldehydes to esters
  • reagent
  • reactivity
  • modified MnO2 oxidation

O OH MnO2, NaCN MeOH, AcOH O CO2Me

slide-10
SLIDE 10
  • B. Manganese Based Reagents
  • 3. Potassium Permanganate (KMnO4)
  • reactivity
  • 1° alcohol  CO2H; also useful for the oxidation of aldehydes
  • powerful oxidant; over oxidation/side reactions may be a problem

 also oxidizes alkenes, 1,2-diols, etc.

  • insoluble in organic solvents
  • may be successful when other oxidants fail (Jones, AgO, NaOCl).
  • R4NMnO4 shows similar reactivity and is soluble in organics

N O CHO Boc CN KMnO4, NaH2PO4 tBuOH, H2O 94% N O CO2H Boc CN

Joullié J. Am. Chem. Soc. 1992, 114, 10181.

slide-11
SLIDE 11
  • C. Ruthenium Based Reagents
  • 1. Ruthenium Tetraoxide (RuO4)
  • 1° alcohol  CO2H
  • powerful, non-selective oxidant; will also attack multiple bonds,1,2-diols,

ethers, aromatic rings, etc.

  • reagent
  • reactivity
  • toxic
  • catalytic procedures use 1-5% Ru metal with a stoichiometric oxidant

O OBz H HO RuCl3-NaIO4 MeCN, CCl4, H2O 60% O OBz H HO O

Overman J. Am. Chem. Soc. 1997, 119, 12031.

slide-12
SLIDE 12
  • C. Ruthenium Based Reagents
  • 2. Tetra-n-propylammonium Perruthenate (Pr4N+RuO4
  • ): TPAP
  • 1° alcohol  CHO
  • mild oxidant; no over oxidation, does not react with multiple bonds
  • use of MS required to remove water and achieve high catalyst turnover
  • modified conditions allow for oxidation of 1° alcohol to carboxylic acid

(Stark Org. Lett. 2011, 13, 4164)

  • reagent
  • reactivity
  • developed by Steve Ley (Imperial College  Cambridge)
  • catalytic; used in conjunction with a stoichiometric oxidant (NMO)
  • perruthate salts with a large counterion are mild and selective oxidants

N HO CBz TPAP, NMO 4Å MS, CH2Cl2 N O CBz

Jacobsen J. Am. Chem. Soc. 2004, 126, 706.

slide-13
SLIDE 13
  • C. Ruthenium Based Reagents
  • 2. Tetra-n-propylammonium Perruthenate (Pr4N+RuO4
  • ): TPAP
  • mechanism

http://www.synarchive.com/named-reactions/Ley-Griffith_Oxidation

slide-14
SLIDE 14
  • D. DMSO Based Reagents

General Mechanism:

  • mild class of reagents
  • don’t have environmental issues associated with use of Cr based reagents
  • no over oxidation  oxidation of 1° alcohols give aldehydes
  • oxidation of 2° alcohols give ketones

S O S O E R OH R O S Me CH2 H R O S Me CH2 H R O S Me Me E B +

slide-15
SLIDE 15
  • D. DMSO Based Reagents
  • 1. DMSO, (COCl)2; Et3N: Swern Oxidation
  • 1° alcohol  CHO
  • most common of DMSO based reagents
  • very mild  run at low temp (-78 to -60°C)
  • low sensitivity to steric factors
  • preparation of β-alkoxy carbonyl derivatives may be problematic  use Et2NiPr
  • activation:
  • reactivity
  • also TFAA, Ac2O, SOCl2, Cl2, P2O5

O OH DMSO, (COCl)2 CH2Cl2; then Et3N O CHO

Funk J. Org. Chem. 1987, 52, 3173.

S O Cl Cl O O + O Cl O O S Cl S Me Me Cl + CO2 + CO + Cl-

slide-16
SLIDE 16
  • D. DMSO Based Reagents
  • 2. DMSO, DCC, TFA, pyridine: Moffatt Oxidation
  • 1° alcohol  CHO
  • first reported DMSO based oxidant; less commonly used
  • separation of by-pyroduct (dicyclohexylurea) can be difficult  use EDC
  • may result in formation of MTM ethers (side reaction)
  • activation: DMSO + DCC
  • reactivity

N C N S O + N C N O S

N C N HCl•Me2N

O MeO OH OBz OBPS DMSO, EDC TFA, pyr 94% O MeO O OBz OBPS

Hannessian Can. J. Chem. 1981, 59, 870.

slide-17
SLIDE 17
  • D. DMSO Based Reagents
  • 3. SO3•pyridine, DMS; Et3N: Parikh-Doehring
  • 1° alcohol  CHO
  • easy workup; well suited to large scale reactions
  • activation
  • reactivity

S O O S O O + S O O S O O O O Br H H H H HO SO3•pyr, DMSO CH2Cl2; Et3N O O Br H H H H O

Evans ACIEE 1999, 38, 3175

slide-18
SLIDE 18
  • E. Silver Based Oxidants
  • 1. Ag2CO3/celite: Fetizon’s reagent
  • 1° alcohol  CHO
  • original oxidant modified by Fetizon  adsorb on celite to increase surface area
  • neutral conditions; very sensitive to steric factors
  • $$$, must use large excess  small scale reactions
  • reaction does not proceed through cationic intermediate (no rearrangements, etc.)
  • controlled overoxidation possible with some substrates (selective lactol oxidation)
  • reactivity

HO MeO OH MOMO OBn Ag2CO3/celite benzene, 80°C MeO MOMO OBn O O

Kallmerten Tetrahedron Lett. 1990, 31, 4305.

O NMe HO MeO Ag2CO3 toluene, 110° O NMe O MeO 84%

Rappoport - codeine

slide-19
SLIDE 19
  • E. Silver Based Oxidants
  • 2. Silver (I) Oxide (Ag2O)
  • mild method for the conversion of CHO  CO2H (in presence of free OH)
  • unsaturated aldehydes are problematic (isomerization)
  • weak oxidant
  • reactivity

HO CHO Ag2O EtOH (aq) HO CO2H 80%

Kitching JCSP1 1995, 1309.

slide-20
SLIDE 20
  • F. Other Oxidants
  • 1. Dess-Martin Periodinane
  • can determine quality of reagent by solublity in CH2Cl2
  • preparation
  • 1° alcohol  CHO
  • mild reagent; nearly neutral conditions  gives off AcOH, but can buffer
  • will not oxidize N or S
  • reactivity

O MeO OH O Dess-Martin CH2Cl2 O MeO CHO O

Danishefsky J. Am. Chem. Soc. 1991, 113, 3850.

I O CO2H I O HO O I O O AcO OAc OAc KBrO3 H2SO4 Ac2O pTsOH, 100°C (IBX) shock sensitive white solid

slide-21
SLIDE 21
  • F. Other Oxidants
  • addition of 1 equiv water accelerates reaction (Schreiber)
  • mechanism

O I O AcO AcO AcO H R H OH O I O AcO AcO H R H O

  • AcOH

H R O + O I O AcO + 2 AcOH

slide-22
SLIDE 22
  • F. Other Oxidants
  • 2. o-Iodoxybenzoic acid (IBX)
  • intermediate in the synthesis of Dess-Martin periodinane; simpler prep
  • preparation
  • in excess will oxidize alcohols to α,β-unsaturated aldehydes and ketones

(or saturated aldehydes/ketones to α,β-unsaturated compounds)

  • mild reagent for oxidation of 1,2-diols without oxidative cleavage
  • insoluble in most organic solvents, except DMSO or DMSO mixtures
  • reactivity

I O CO2H I O HO O

  • xone

H2O, 70°C OH IBX (2.3 equiv) toluene, DMSO 88% O

Nicolaou J. Am. Chem. Soc. 2000, 122, 7596.

slide-23
SLIDE 23
  • F. Other Oxidants
  • 2. o-Iodoxybenzoic acid (IBX)
  • intermediate in the synthesis of Dess-Martin periodinane; simpler prep
  • preparation
  • in excess will oxidize alcohols to α,β-unsaturated aldehydes and ketones

(or saturated aldehydes/ketones to α,β-unsaturated compounds)

  • mild reagent for oxidation of 1,2-diols without oxidative cleavage
  • insoluble in most organic solvents, except DMSO or DMSO mixtures
  • reactivity

I O CO2H I O HO O

  • xone

H2O, 70°C OH IBX (2.3 equiv) toluene, DMSO 88% O

Nicolaou J. Am. Chem. Soc. 2000, 122, 7596. CO2H HO2C CO2H IBX 49% 22% 29% "SIBX"

Quideau Org. Lett. 2003, 5, 2903.

slide-24
SLIDE 24
  • F. Other Oxidants
  • alcohol oxidation: mirrors Dess-Marin periodinane mechanism
  • mechanism

O I O HO H R H OH O I O O

  • H2O

H R O + O I O HO O O H R H O I O O HO O O I O O HO HO H O

slide-25
SLIDE 25
  • F. Other Oxidants
  • 3. Al(OiPr)3, acetone: Oppenauer Oxidation
  • classical method for alcohol oxidation
  • takes advantage of reversible reaction between ketones and metal alkoxides
  • mild conditions, infrequently used; does not work well with 1° alcohols
  • reactivity
  • mechanism

Me MeO OH Al(OiPr)3 acetone Me MeO O

Boger J. Org. Chem. 1984, 49, 4045.

  • use of acetone solvent drives reaction to the right

OH Al(OiPr)3 O Al OiPr OiPr OiPr H

  • HOiPr

O Al OiPr OiPr

O

O Al OiPr OiPr O H+ transfer O Al OiPr OiPr O H H O

slide-26
SLIDE 26
  • F. Other Oxidants
  • 4. Sodium Chlorite (NaClO2): Pinnick Oxidation
  • useful method for oxidation of sensitive CHO  CO2H, esp. α,β-unsaturated CHO
  • use hampered by formation of chlorine dioxide
  • suppressed by addition of chlorine scavenger (alkene)
  • reactivity

CHO OH NaClO2 tBuOH, H2O CO2H OH CHO NaClO2 tBuOH, H2O CO2H

  • 5. Sodium Hypochlorite (NaOCl): Stevens Oxidation
  • selective oxidation of 2° alcohols
  • modified procedure uses calcium hypochlorite – a stable solid
  • reactivity

NaOCl AcOH OH OH O OH 86%

Corey J. Am. Chem. Soc. 1998, 120, 12777.

slide-27
SLIDE 27
  • F. Other Oxidants
  • 6. TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy):
  • 1° alcohol  CHO
  • used in presence of stoichimetric oxidant (mCPBA, NaOCl, PhI(OAc)3, oxone, etc.
  • works best in simple systems
  • selective oxidation of alcohols in presence of S or Se
  • reactivity
  • mechanism

OH N O Boc TEMPO, NaOCl, NaBr EtOAc:toluene:H2O (1:1:0.15) O N O Boc 90% N O N O N OH N O O H R H RCH2OH + B RCHO [O] BH [O]

slide-28
SLIDE 28

Oxidation of Ketones

O O O O O OH

slide-29
SLIDE 29

Ketone  Enone

  • 1. IBX
  • Nicolaou J. Am. Chem. Soc. 2002, 124, 2245.
  • reactivity

H H TIPS O H H TIPS O IBX (2 equiv) tol/DMSO 87%

  • 2. Saegusa Oxidation
  • Saegusa J. Org. Chem. Soc. 1978, 43, 1011.
  • most often stoichimetric in Pd, but use of cat Pd in presence of stoichimetric
  • xidant is known (see, for example: Lebel JOC 2013, 78, 776)
  • reactivity

OTMS O Pd(OAc)2 MeCN, rt O O

Danishefsky J. Am. Chem. Soc. 2008, 130, 13765.

slide-30
SLIDE 30

Ketone  Enone

  • 2. Saegusa Oxidation
  • mechanism
slide-31
SLIDE 31

Ketone  Enone

  • 3. Selenoxide Elimination
  • reactivity

O LDA; PhSeBr O O SePh H2O2

  • other oxidants include NaIO4, O3, mCPBA, etc.
slide-32
SLIDE 32

Ketones  Esters/Lactones

  • 1. Baeyer Villager Oxidation
  • reaction of ketone with peracids (mCPBA, trifluoroperacetic acid, peracetic acid)
  • migration occurs at more highly substituted (more electron rich) position:
  • migratory aptitude: 3° > 2° > benzyl > Ph > 1° > cyclopropyl > Me > H
  • stereochemistry is retained
  • note peracids react with other functionality (alkenes, amines, sulfides, etc.)
  • reactivity

O mCPBA O O O H Me mCPBA O O H Me

slide-33
SLIDE 33

Alpha Hydroxylation

  • 1. Rubottom Oxidation
  • Rubottom Tetrahedron Lett. 1974, 15, 4319.
  • epoxidation of silyl enol ether, followed by silyl migration
  • dimethydioxirane (DMDO) can also be used for epoxidation
  • reactivity

OTMS mCPBA CH2Cl2 O OR R = H, TMS

  • 2. MoOPh Oxidation
  • MoOPh = MoO5•pry•HMPA
  • attack of enolate at peroxyl oxygen atom leads to O-O bond cleavage
  • reactivity

O LDA; MoOPh O OH Mo O O O O O O N (Me2N)3P MoOPh

slide-34
SLIDE 34

Alpha Hydroxylation

  • 3. Davis Oxaziridine
  • N-sulfonyloxaziridines prepared by oxidation of corresponding sulfonimine
  • chiral reagents are known
  • preparation
  • reactivity

N Ph PhSO2 mCPBA or

  • xone

N Ph PhSO2 O

  • nucleophilic attack of enolate on electrophilic oxaziridine oxygen
  • potassium enolates tend to work best

OTBS H OTMS O O KHMDS; Davis oxaziridine 68% OTBS H OTMS O O HO Ph Me O

  • 1. NaHMDS

2.

Cl Cl N O S O O

Ph Me O OH 61%, 95% ee