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Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac. - PDF document

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Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac. - PPT Presentation

1 OXIDATION AND REDUCTION R R R R OH R R O R OR O R O O R R R OH Nuc R R Cl R R R R R R O R R N R R R O E Introduction ID: 132769

1 OXIDATION AND REDUCTION R R' R R' OH R R' O R OR" O R O O R' R R' OH Nuc R R' Cl R R' R" R"' R R" O R R' N R" R R" O E Introduction

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Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 1 OXIDATION AND REDUCTION R R' R R' OH R R' O R OR" O R O O R' R R' OH Nuc R R' Cl R R' R" R"' R R" O R R' N R" R R" O E Introduction ¥ Fundamental backbone of organic chemistry is the ability to alter oxidation states¥ Hydroxyl and carbonyl moiety provide an invaluable means for transforming molecules so Course Outline Oxidations¥ alcohol to carbonylReductions¥ carbonyl group ¥ This is not an all inclusive lecture course¥ To list every reagent would be boring, so I have tried to be selective with the criteria being Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 2 ALCOHOL OXIDATION ¥ Alcohols can readily be oxidised to the carbonyl moiety¥ This is an incredibly important reaction - you should realise that the carbonyl group is one of the cornerstones of CÐC bond formation (organometallics, neutral nucleophiles, aldol, Julia, Peterson & Wittig reactions) R R1 OH R R1 O R OH O R1 = H ¥ Primary (R1 = H) alcohols Ð normally more reactive than seconary alcohols on steric grounds¥ Need to be able to control oxidation of primary alcohols so only obtain aldehyde or acid¥ Large number of reagents Ð all have their advantages and disadvantages¥ Look at some of the more common... Chromium (VI) Oxidants General Mechanism R HO H O Cr O O OH2 R O Cr O H HO O H O Cr O O O Cr HO OH O R ÐH2O proton transfer Cr(VI) Cr(IV) ¥ This fragmentation mechanism is common to most oxidations regardless of the nature of the reagent "Overoxidation" formation of carboxylic acids¥ Invariably achieved in the prescence of H2O and proceeds via the hydrate R H O OH OH R H O Cr O O O OH R H Cr O O OH R OH O H2O Jones OxidationH2SO4, CrO3, acetone R H OH R OH O R R1 OH R R1 O ¥ Harsh, acidic conditions limit use of this method E [O] H HO R H O R [O] E O R [R] EH General Fragmentation Mechanism Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 3 Pyridinium Chlorochromate (PCC) Cl Cr O O O NH R H OH R H O R R1 OH R R1 O must avoid water ¥ Less acidic than Jones reagent (although still acidic) Pyridinium Dichromate (PDC) O Cr O O O Cr O O O NH 2 ¥ Even milder than PCC and has useful selectivity R H O PDCDMF PDCDCM R H OH R OH O Other OxidantsManganese DioxideMnO2 ¥ Mild reagent¥ Very selective Ð only oxidises allylic, benzylic or propargylic alcohols HO OH HO O MnO2 only oxidises activated alcohol Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 4 ALCOHOL OXIDATION Activated DMSO Reagent:DMSO, activator (X) and baseTransformation:CÐOH ® C=O (primary or secondary alcohols) General Mechanism S O + X S O X HO R + R O S H base R O S R H O S + H H H H ¥ intermediate common to all activated DMSO reactions ¥ 18O labelling has determined mechanism¥ alternative activation of hydroxyl followed by displacement not occurring Common Side-ReactionsPummerer Reaction R O S R O + S R O S Displacement Reactions ¥ The cationic intermediate formed is an excellent leaving group Intramolecular H CH2OH CH2OH DMSO / (COCl)2 93% H OH O S H O Intermolecular CH2OH OBn DMSO / (COCl)2 95% CH2Cl OBn Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 5 Enolisation ¥ Generation of a carbonyl compound in the presence of an amine base is asking for trouble¥ a-chiral centre can be racemised¥ Overcome by: keeping temperature low, remove base with cold acid buffer, use Pyr.SO3 system Eliminations ¥ Problem due to mild acidity of earlier steps ¥ or if suitable leaving group present when base added O O TBSO OMe OP SO2Ph OH 1. DMSO / (COCl)2 2. Et3N O O TBSO OMe OP O O TBSO OMe OP SO2Ph O + O 67 % 28% OH HO 1. DMSO / (COCl)2 2. Et3N72% O ActivatorsPfitzner-Moffatt (DMSO / DCC then base) N C N ¥ The originalPros: mild conditions, normally rtCons: DCC urea by-product hard to remove frequently generates Pummerer side-product mildly acidic conditions lead to eliminations O O OH OH DMSO / DCCTFA / Pyr88 % O O O Swern (DMSO / (COCl)2) ¥ Most popular, as mild and easyPros: low temperature reduces enolisation very little Pummerer reactionCons: Chlorination S Cl Parikh-Doering (DMSO / PyrÐSO3) Pros: very mild conditions, very little enolisation very little Pummerer Reaction TBSO O O TBSO Ph CH 2OH TBSO O O TBSO Ph CHO DMSO / PyrÐSO3Et3N 94% ¥ active intermediate of Swern reaction Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 6 Activated DMSO Oxidations in Synthesis O O OTIPS HO 1. DMSO / (COCl)2 2. Et3N92 % O O OTIPS O ¥ 1,2-diols are not cleaved HO HO 1. DMSO / (CF3CO)2O2. Et3N90 % O O ¥ sequential reactions possible due to the high yields and purity of productsespecially useful when aldehyde readily forms hydrate Me3Si OH Me3Si O H Me3Si CO2Et 1. DMSO / (COCl)2 2. Et3N Ph3P=CMeCO2Et54% overall ¥ tertiary alcohols often do not need to be protected OMe OMe OMe OH OH H OH 1. DMSO / (COCl)2 2. Et3N81% OMe OMe OMe O O H OH ¥ selective oxidations Ð primary alcohols oxidised much faster¥ but use of iPr2S and NCS as activator (proceeds via same intermediate as Swern) oxidises primary alcohols at 0ûC but secondary at -78ûC¥ do not understand this reaction AND it was only a communication 84CC762 that has never been followed up ¥ oxidation in the presence of allylic or benzylic alcohols NMe H MeO O O OH OH DMSO / (CF3CO)2O NMe H MeO O O O O S S NMe H MeO O O OCOCF3 O S NMe H MeO O OH O O Et3N OCOCF3 (±)-tazettine61 % ¥ the activity of allylic and benzylic alcohols means they undergo rapid displacement and hence a form of protection Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 7 ¥ lactol or lactone formation can be surpressed¥ most oxidising agents oxidise primary alcohols faster than secondary and this can lead to problems OH OH [O] OH O O OH O O [O] ¥ activated DMSO does not have this problem as aldehyde only formed on addition of base OH OH DMSO / (COCl)2 O O S S O O Et3N ¥ selective oxidation of primary silyl ethers¥ Mildly acidic nature and the nucleophilic chloride ion generated allows selective deprotection and concomitant oxidation of primary TES & TMS ethers O OTES O OTES 1. DMSO / (COCl)22. Et3N62 % O O O OTES Limitations¥ activated DMSO systems will not oxidise propargylic alcohols OH OH What have we learnt?¥ Activated DMSO reactions are generally mild Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 8 Dess-Martin Periodinane (DMP) (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) Reagent:Transformation:CÐOH ® C=O (primary or secondary alcohols) O I O OAc AcO OAc General mechanism O I O OAc AcO OAc R OH H H O I O O O H O AcO R H O I O OAc R H O 2 x AcOH ¥ ligand exchange ¥ could be intra or intermolecular ¥ since introduction in 1983 become one of the most popular oxidants¥ mild reagent operating at nearly neutral conditions (buffer with NaHCO3 if worried about AcOH)¥ many very sensitive molecules can be oxidised O O H H DEIPSO TBSO H O O O O O OTES OTES TESO O O OTES H MeO Si tBu tBu H 93 % Preparation I CO2H + KBrO3 0.73 M H2SO465ûC O I O OH O O I O OAc AcO OAc AcOH ¥ mild and extremely reactive oxidant¥ Insoluble in most organic solvents and impact sensitive Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 9 Use in SynthesisSelectivity ¥ first step is ligand exchange so an inherent steric selectivity exists¥ primary alcohols oxidised faster than secondary HO O O OTBS TBSO OTBS HO OTBS OMe O O O OTBS TBSO OTBS HO OTBS OMe DMP, pyr, DCM, 88% ¥ Allylic and benzylic alcohols react ³~5 faster than saturated alcohols O O H HO OH DMP, pyr, DCM, rt 2hrs �75% O O H HO O Advantages:¥ no over oxidation is ever observedDisadvantages:¥ Behaves like periodate and cleaves 1,2-diols. BUT not always, no consistancy What have we learnt?¥ DMP is a mild reagent Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 10 O Tetrapropylammonium Perruthenate TPAP Reagent:Pr4N+RuO4Ð Stoichiometric or catalytic with NMOTransformation:CÐOH ® C=O (primary or secondary alcohols)CÐOH ® CO2H (if H2O present) General mechanism ¥ not entirely clear¥ it is thought that TPAP is a 3eÐ oxidant but each step is a 2eÐ process and that radicals / S.E.T. is not involved¥ due to steric selectivity it is thought that TPAP is a bulky reagent & oxidation occurs primarily through the intermediacy of a ruthenate ester O Ru O O O R OH H H R O H H Ru O O HO O R H O O Ru O O H OH2 O Ru O O N O O N O O Ru O O O O Ru O O O O N Use in Synthesis ¥ Introduced in 1987¥ its mildness and practically have made it popular (coupled to its none explosive nature)¥ should be used dry with 4ms or get over-oxidation and cleavage of alkenes¥ mechanism changes in presence of H2O advantages:¥ good functional group tolerancea-chiral centres or double bond isomerisation¥ no competative b-elimination OH O O O O OPMB TPAP / NMO, DCM, 4ms 96% O O O O O O OPMB H2O Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 11 OH ¥ selectivity for primary hydroxyl group allows lactone preparation O OH OH TPAP / NMO, DCM / MeCN, 4ms 91% O OH O O O O TPAP ¥ secondary alcohols oxidise far slower but they do oxidise N O TMS TPAP / NMO, DCM, 4ms, 73% N O TMS OH O Swern Oxidation = 0%PCC = 0% ¥ depending on sterics can get selectivity for least hindered hydroxyl group O O HO O OH H O O OH O O HO O O H O O OH TPAP / NMO, DCM, 4ms 61% O O O AcO MeO2C H OH O OH CO2Me O O OH O ¥ lactols can be oxidised selectively (again sterics) TPAP / NMO, MeCN, 4ms 75% OH O O O AcO MeO2C H OH O OH CO2Me O O O O ¥ TPAP oxidises sulfur but not other heteroatoms SMe O O TPAP / NMO, MeCN, 4ms 80% SO2Me O O ¥ again we see how mild TPAP is Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 12 ¥ Sequential reactions Ð due to ease of w/u and anhydrous conditions, TPAP is well suited to sequential reactions OH CO2Me O CO2Me CO2Me CO2tBu TPAP / NMO, DCM, 4ms Ph3P=CMeCO2tBu 72% overall ¥ Disadvantages: TPAP can cleave 1,2-diols like other metal oxidants O O HO OH O O TPAP, NaOCl 93% O O O ¥ Disadvantages: can cause retro-aldol reaction TPAP / NMO, DCM, 4ms O O H O OH O O H O O O O ¥ retro-aldol results in cleavage of b-hydroxyketones What have we learnt?¥ TPAP is a mild oxidant Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 13 Modified Chromium (VI) OxidantsPyridinium Chlorochromate PCC Reagent:Transformation:CÐOH ® C=O (primary or secondary alcohols) NH ClCrO3 General Mechanism O R H H H O Cr O O Cl O R H H Cr O OH O R H O HO Cr OH O º CrO2 + H2O Use in Synthesis ¥ Must be dry, water hampers reaction and can result in the formation of acids (over-oxidation) OH OH H PCC, 4ms, DCM 93% O OH H ¥ Disadvantages: reagent is acidic Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 14 Pyridinium Dichromate PDC Reagent:Transformation:CÐOH ® C=O (primary or secondary alcohols) NH Cr2O7 2Ð Use in Synthesis ¥ Neutral variant of PCC¥ Addition of SiO2 to reaction aids work up and addition of pyridinium trifluroracetate increases rate¥ DCM normal solvent¥ DMF gives carboxylic acids O OH PDC, DCM 92% O O OH PDC, DMF 83% CO2Me Oxidation to the Acid R O H R O OH ¥ Many variants involving chromium or manganate which proceed via the hydrated aldehyde¥ But invariably require strongly acidic conditions so not useful in organic synthesis¥ You can find them yourselves in March or Smith¥ A mild alternative is: R O H R OH H NaClO2, NaH2PO4 ClO2 R H HO O Cl O R O OH HOCl ¥ HOCl is very unpleasnt so alkene added as a scavenger What have we learnt?¥ Chromium reagents can be used to oxidise to either aldehyde or carboxylic acid¥ They are toxic Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 15 Ru NTs Ru N Ph Ph R Kinetic Resolution by Selective Oxidation ¥ Noyori has developed a method for resolving racemic alcohols via selective oxidation¥ Uses hydrogen transfer (analgous to Oppenauer oxidation or Meerwein-Ponndorf-Verley reduction) Un R OH + Un R OH + O NH Ru TsN Ph Ph + Un R O + Un R OH + OH Yield = 43-51 %�e.e. = 90 % Un = unsaturated group ¥ note you can not get better than 50% with kinetic resolution Un R O H H O H N H NTs Ph Ph H Un R NTs Ru N Ph Ph H O Un R NTs Ru N Ph Ph H O H H H H Ru O H N H NTs Ph Ph H O O Un R OH Mechanism ¥ More appealing is the desymmetrisation of meso-diols¥ Theoretical maximum yield is 100 % OH OH H H 70 % 96 % e.e. OH O H H What have we learnt?¥ Stereoselective oxidations are now possible